J Neural Transm (2017) 124:133–144

DOI 10.1007/s00702-016-1646-y

PSYCHIATRY AND PRECLINICAL PSYCHIATRIC STUDIES - ORIGINAL ARTICLE

Transcranial direct current stimulation improves clinical

symptoms in adolescents with attention deficit hyperactivity
disorder
Cornelia Soff1,2 • Anna Sotnikova1,3 • Hanna Christiansen2 • Katja Becker1 •

Michael Siniatchkin3

Received: 29 July 2016 / Accepted: 5 November 2016 / Published online: 16 November 2016
 Springer-Verlag Wien 2016

Abstract Anodal transcranial direct current stimulation
(tDCS) of the prefrontal cortex has repeatedly been shown
to improve working memory. As patients with attention
deficit hyperactivity disorder (ADHD) are characterized by
both underactivation of the prefrontal cortex and deficits in
working memory that correlate with clinical symptoms, it
is hypothesized that the modulation of prefrontal activity
with tDCS in patients with ADHD increases performance
in working memory and reduces symptoms of ADHD. To
test this hypothesis, fifteen adolescents with ADHD
(12–16 years old, three girls and 12 boys) were treated
according to the randomized, double-blinded, sham-con-
trolled, crossover design with either 1 mA anodal tDCS
over the left dorsolateral prefrontal cortex or with the sham
protocol 5 days each with a 2 weeks pause between these
conditions. Anodal tDCS caused a significant reduction in
clinical symptoms of inattention and impulsivity in ado-
lescents with ADHD compared to sham stimulation. The
clinical effects were supported by a significant reduction in
inattention and hyperactivity in a standardized working
memory test (QbTest). The described effects were more
pronounced 7 days after the end of stimulation, a fact
which emphasizes the long-lasting clinical and
& Michael Siniatchkin
siniatchkin@med-psych.uni-kiel.de
1
Department for Child and Adolescent Psychiatry,
Psychosomatics and Psychotherapy, Philipps-University,
Marburg, Germany
2 neuronal activity in the cerebral cortex (Nitsche and Paulus
Institute of Clinical Psychology, Philipps-University,
Marburg, Germany
3 the cathodal stimulation to a reduction of neuronal activity,
Institute of Medical Psychology and Medical Sociology,
Christian Albrecht University, Preußerstraße 1–9,
24105 Kiel, Germany
neuropsychological changes after tDCS. This study pro-
vides the first evidence that tDCS may reduce symptoms of
ADHD and improve neuropsychological functioning in
adolescents and points on the potential of tDCS as a form
of treatment for ADHD.
Keywords ADHD
Transcranial direct current
stimulation
Working memory
Introduction
With a prevalence of 5%, attention deficit hyperactivity
disorder (ADHD) is one of the most common neuropsy-
chiatric disorders among children and adolescents (Thomas
et al. 2015). The multimodal treatment of ADHD, con-
sisting of psychoeducation, medical treatment and behav-
ioral therapy, has been shown to be highly effective in a
majority of patients (Feldman and Reiff 2014). However,
about 30% of patients do not respond well to medication
(Childress and Sallee 2014). At best modest effects of
behavioral therapy, high withdrawal rates to stimulants due
to side effects, and critical attitude of parents to pharma-
cotherapy (Clavenna and Bonati 2014; Evans et al. 2014;
Gajria et al. 2014) emphasize the urgent need to develop
alternative treatment strategies for patients with ADHD.
Transcranial direct current stimulation (tDCS) repre-
sents an alternative approach to treat neuropsychiatric
disorders (Kuo et al. 2014). The tDCS is a noninvasive
method which can induce changes of excitability and
2000). The anodal stimulation leads to enhancement and
both of which influences neuropsychological functions
linked to the respective stimulation area (Stagg and Nitsche

123

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134
2011). Recent studies have confirmed that tDCS induces
significant and long-lasting neuroplastic effects, establish-
ing the potential of this technique for therapeutic purposes
(Nitsche and Paulus 2001; Liebetanz et al. 2002; Brunoni
et al. 2013). It has been demonstrated repeatedly that tDCS
may be used effectively to improve symptoms of depres-
sion, neurocognitive abilities, and motor function in
patients with stroke, reduce pain, and symptoms of tinnitus
and Parkinson’s disease (Kuo et al. 2014). The clinical
effect of tDCS in any neuropsychiatric disorder is mediated
by the effect of stimulation on the key neuropsychological
or cognitive function which is abnormal in this disorder.
There is exponentially growing evidence that tDCS can
influence a great number of neuropsychological/cognitive
functions (Elmasry et al. 2015; Kuo and Nitsche 2015).
The effect of tDCS on working memory (WM) may open a
way for application of tDCS in treatment of patients with
ADHD.
This study was motivated by the following findings
which underlie the rational of this study: (1) Children and
adolescents with ADHD show more omission errors, false
alarms, slower reaction time (RT), and higher RT vari-
ability (RTV) in n-back working memory tasks compared
with healthy age-matched control subjects (Chamberlain
et al. 2011; Feige et al. 2013; Klein et al. 2006). (2) The
lower performance of ADHD patients in n-back tasks may
be explained by diminished activation of the prefrontal
cortex, especially of the dorsolateral prefrontal cortex
(DLPFC), as evidenced by a number of fMRI and neuro-
physiological studies (Bedard et al. 2014; Cubillo et al.
2014; McCarthy et al. 2014; Siniatchkin et al. 2012a;
Valera et al. 2010). (3) Anodal tDCS over the left DLPFC
significantly improves the performance in WM tasks in
healthy subjects, as well as in patients with depression,
Parkinson’s disease, and in those recovering from stroke
(for review see Brunoni and Vanderhasselt 2014; Hill et al.
2016). (4) 1 mA anodal tDCS causes a significant and
long-lasting increase in cortical excitability in children and
adolescents which is comparable with the excitability
changes observed in adults (Moliadze et al. 2015b).
Therefore, 1 mA anodal tDCS can be applied in children
and adolescents with ADHD. (5) Recently, different studies
have demonstrated significant effects of tDCS over DLPFC
on WM in spontaneous hypertensive rats (Leffa et al. 2016)
and over the left DLPFC on executive functions and
attention in children and adolescents with ADHD (Ban-
deira et al. 2016; Munz et al. 2015; Soltaninejad et al.
2015). However, none of these studies have investigated
effects of tDCS on clinical symptoms of ADHD using
standardized clinical observation instruments.
Based on the studies listed above, it can be suggested
that an increase in activation in the left DLPFC by means
of anodal tDCS may improve WM performance and
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C. Soff et al.
influence clinical symptoms in children and adolescents
with ADHD. Here, this hypothesis was studied in an
explorative, randomized, double-blinded and sham-con-
trolled study.
Materials and methods
Participants
Patients were referred to the Department of Child and
Adolescent Psychiatry, Psychosomatics and Psychotherapy
of the Philipps-University in Marburg, Germany. The final
sample consisted of 15 adolescents (12 male, three female)
with a mean age of 14.2 years (SD 1.2, range 12–16). The
inclusion and exclusion criteria were proven and neuro-
logical examination was carried out by an experienced
neuropediatrician. The inclusion criteria were as follows:
(I) ADHD without comorbid conduct disorders, autism or
tic disorders as diagnosed according to guidelines by an
experienced child and adolescent psychiatrist; (II) no other
neuropsychiatric (Child Behavior Checklist global score
and anxiety depression scale T \ 70) or pediatric disorders;
(III) sufficient compliance of the child and his/her family.
The exclusion criteria were IQ \80, epilepsy, including
pathological EEG-patterns (e.g., increased neural
excitability), former cerebral seizure, drug abuse, increased
intracranial pressure, former craniocerebral injury accom-
panied by loss of consciousness, any metallic implantations
in the facial or skull area, cochlear implant, pacemaker,
pregnancy. All included adolescents met the criteria for the
combined or hyperactive-impulsive type according to
DSM-IV [314.01 (American Psychiatric Association
1994)] or for the hyperkinetic disorder according to ICD-10
(F90.0, International Classification of Diseases (ICD),
2010). The diagnosis of ADHD was supported by the
parents’ version of a German adaptive Diagnostic Check-
list for ADHD (FBB-ADHD) (Dopfner et al. 2004, 2008;
Döpfner and Lehmkuhl 2003). Moreover, all participants
underwent specific neurocognitive and neuropsychological
testing before inclusion in the study (see Table 1). The
performance in the WM test within QbTest (QbTech
Stockholm, Sweden) was especially abnormal in each of
the included patients as compared with Qb normative data
(Brocki et al. 2010; Reh et al. 2015). Patients receiving
stimulant treatment (n = 5, only short-acting immediate-
release methylphenidate) had to discontinue medication at
least 96 h before the first assessment and were not allowed
to use medication throughout the whole study. All subjects
had normal or corrected to normal vision as assessed by the
Snellen chart and were right-handed as determined by the
Edinburgh handedness inventory. None presented with any
neurological symptoms during neurological examination.
Transcranial direct current stimulation improves clinical symptoms in adolescents with…
Table 1 IQ and selection of clinical and neuropsychological data at
baseline
M SD
IQ 99.7
CBCL (T values)
Total problems 64.1
Internalizing problems 57.2
Externalizing problems 64.2
Attention problems 69.2
QbTest (percentiles)
Error of commission 73
Error of omission 83
RT variability 75
Time active 92
Distance 95
CBCL child behavior checklist, TAP test battery of attentional per-
formance, WM working memory, QbTest quantified behavior test
All adolescents were mentally normally developed, had
normal structural MRI and EEG, and were German native
speakers. None of them took any additional medication or
presented with any history of developmental disorders or
language problems. All adolescents and their parents were
instructed about the study, and written informed consent
according to the 1964 Declaration of Helsinki (including its
later amendments) was obtained. The study was approved
by the local Ethics Committee. All adolescents received a
movie voucher in exchange for their participation.
Procedure
This study was designed as a randomized, double-blinded,
sham-controlled crossover study to investigate effects of
anodal tDCS over the left DLPC on the clinical course of
ADHD. All adolescents received both anodal tDCS as well
as sham stimulation on five consecutive days (Monday to
Friday, d1–d5). To ensure the absence of carryover effects,
a washout period of 2 weeks was established between the
two treatment periods. The baseline (d0) included a detailed
IQ assessment, clinical ADHD ratings, and assessment of
neuropsychological parameters. The randomization to one
of the two study arms was carried out by an independent
researcher. The protocols (tDCS or sham stimulation) for
every patient and every session were preprogrammed in the
stimulation device, so that both patient and investigators
were blind to stimulation conditions. The investigator
entered only a number of patients into the device and the
device differentiated which setting of stimulation has to be
applied.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
135
Patients in group 1 received the anodal tDCS from d1 to
d5 for 20 min each day. Stimulation at d1 took place in the
MR scanner. For details on the procedure and results of the
fMRI study see Sotnikova et al. (2016). Briefly, to inves-
12.5
tigate influence of 1 mA anodal tDCS over the left DLPFC
on neuronal networks of WM in patients with ADHD, the
5.8 same n-back WM paradigm as in the QbTest (and in the
7.1 following four sessions without MRI) was carried out
6.4 during fMRI recordings in 3 T scanner simultaneously with
5.8 20 min tDCS or sham stimulation. From d2 to d5, the
patients performed the neuropsychological assessment
33 (QbTest) during each stimulation (online). In addition,
20 assessment of ADHD symptoms was carried out after
32 stimulation on d5. Group 2 first received the sham stimu-
12 lation (same procedure as group 1). Seven days after the
9 end of stimulation (d12), all patients in each group under-
went neuropsychological assessment and assessment of
clinical symptoms. Between d22 and d26, patients in group
1 received sham stimulation; those in group 2, anodal
tDCS. The procedure on d22–d33 was analogous to that on
d1–d12 (Fig. 1).
Measures
Since the main aim of the study was to provide evidence
for lasting clinical effects of tDCS on ADHD symptoms,
the primary outcome measure was defined as changes of
the parents’ version of a German adaptive ADHD Diag-
nostic Checklist, FBB-ADHD from baseline (d0) to 7 days
after the end of stimulation (d12). Seven days after the end
of stimulation was chosen because tDCS performed during
a number of consecutive days may cause long-lasting
behavioral and neurocognitive changes (Brunoni et al.
2013). The FBB-ADHD is a part of the German Diagnostic
System for Mental disorders in Children and Adolescents
(DISYPS-II, see Döpfner et al. 2008; Döpfner and Lehm-
kuhl 2003). The number of items in this questionnaire is
equal to the number of DSM-IV items. Moreover, the
questionnaire also provides a severity score for each
ADHD symptom (from 0 = not at all to 3 = very much).
With a Cronbach’s a from 0.78 to 0.90, internal consistence
was satisfactory to very good in different studies (Dopfner
et al. 2006; Erhart et al. 2008). FBB-ADHD is a stan-
dardized instrument to diagnose ADHD in Germany and
has been used repeatedly to document the clinical course of
the disorder in relation with behavioral and drug treatment
in a great number of randomized placebo-controlled trials
(Dopfner et al. 2015; Hautmann et al. 2013). FBB-ADHD
is characterized by psychometric properties that allow
detection of changes even in the very brief window of time
such as only 1 week (Dopfner et al. 2011; Schulz et al.
2010).
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136
Fig. 1 a Crossover design tDCS study according to Wellek and
Blettner (2012). d0: baseline assessment: WISC-IV, QbTest, FBB-
ADHD, d1: working memory paradigm in the scanner, d2–d4 QbTest,
d5 QbTest, FBB-ADHD, d12: QbTest, FBB-ADHD, d22: working
memory paradigm in the scanner, d23–d25: QbTest, d26: QbTest, FBB-
ADHD, d33: QbTest, FBB-ADHD. Pt. patient, Rand. randomization,
tDCS transcranial direct current stimulation, fMRI functional
The secondary outcome measures were defined as
changes of performance in the WM test as part of Quan-
tified Behavior Test or QbTest (Qb-Tech Stockholm,
Sweden; Reh et al. 2015; Vogt and Shameli 2011). QbTest
is a commercial neuropsychological test that combines the
n-back WM paradigm with apparative measurement of
motor activity (using an infrared camera) and aims at
assessing all three core ADHD symptoms (i.e., inattention,
hyperactivity and impulsivity). Because the validity of
neuropsychological tests for diagnosis of ADHD and
diagnostic utility of tests remains controversial (McGee
et al. 2000; Merkt et al. 2016), n-back test alone appear to
have an insufficient ability to discriminate between ADHD
and other clinical conditions. In QbTest, additional use of
motor assessment enhances test validity because of
hyperactivity measures as demonstrated in large samples of
normative data (n = 576; Ulberstad 2012) and patients’
data (n = 828; Reh et al. 2015). A great advantage of
QbTest is that this measure is very sensitive to changes in
ADHD symptoms and may be applied successfully to study
effects of any kind of treatment (Bijlenga et al. 2015;
Wehmeier et al. 2012). Every time QbTest produces par-
allel versions by randomly generating sequences of stimuli,
and in such a way, is suitable for repeated measures. In this
study, QbTest was performed during the whole time of
stimulation (20 min). In QbTest, a combination of the n-
back task with the no-go component is used: as in the
classical n-back task, subjects were asked to press a button
as soon as possible, if a figure (circle or square) corre-
sponded with a previous figure (1-back) in terms of both
shape and color (target stimulus). The subjects had to keep
track of the two features and refrain from responding, if
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C. Soff et al.
magnetic resonance imaging, WISC-IV Wechsler intelligence scale
for children—fourth edition, FBB-ADHD parents’ version of German
adaptive ADHD diagnostic checklist, d0–d33 day 0 (baseline) until
day 33 after the beginning of the study, d12, d33 seven days after the
end of stimulation. b Electrode montage with anode over the left
DLPFC (F3) and cathode over the vertext (Cz)
only one feature matched. All stimuli were presented in a
random order for 200 ms with a 2-s interstimulus interval.
In total, 600 stimuli were shown at a 25% target ratio.
Participants’ activities during the test were recorded by
reading the coordinates (X and Y) of the headband marker.
Since QbTest consists of eleven primary and six subsidiary
test parameters, we reduced the risk of type one error by
building the three factors (Reh et al. 2015): Qb_Inattention
(omission errors, reaction time and reaction time variabil-
ity), Qb_Hyperactivity (time of activity, distance traveled
by the reflective headband marker, area of activity as the
surface covered by the headband reflector during the test,
number of microevents as small movements of the reflec-
tive marker, motor simplicity as a measure of complexity
of the motion) and Qb_Impulsivity (commission errors,
multiresponse with more than one button press per stimu-
lus, anticipatory score for too fast responses). In general,
the three QbTest factors show adequate construct and
discriminant validity (Reh et al. 2015). However, the
approach also offers the practical advantage that the factors
are easier to understand by patients, and the results remain
clearer for clinicians.
After every session, any adverse effects were evaluated
via a semi-structured interview based on previously pub-
lished interviews (Poreisz et al. 2007).
Transcranial direct current stimulation
During every session, tDCS was applied by an experienced
neuropediatrician. Electrical current was generated by a
CE-certified stimulator (NeuroConn Co., Illmenau, Ger-
many) and applied via a pair of rubber electrodes (round
Transcranial direct current stimulation improves clinical symptoms in adolescents with…
anode with a surface area of 314 mm2 and a current density
of 2.9 A/m2 and a rectangular cathode with a surface area
of 1250 mm2 and a current density of 0.80 A/m2) with a
current strength of 1 mA for 20 min. For sham stimulation,
we used identical electrodes and stimulation sites. During
sham stimulation, the current was ramped up for 8 s, fol-
lowed by 5 s of 1 mA stimulation and then ramped down
for 8 s. The impedance was controlled by the device
throughout each tDCS session, kept at \10 kX and limited
by the voltage. Exceeding these limits (e.g., increase of
impedance due to dried up or shifting electrodes) would
have resulted in automatic termination of the stimulation
(see instruction manual of the NeuroConn stimulator). Both
subject and experimenter were blind to the type of
stimulation.
In contract to other studies demonstrating effects of
tDCS on n-back WM (Brunoni and Vanderhasselt 2014;
Hill et al. 2016), a new electrode montage with the anode
over the left DLPFC and cathode over the vertex was used
(the distance between electrodes was enough to avoid shunt
effects). The choice of this montage was justified by the
following aspects: (1) one of the most a frequent and
reliable neuropsychological abnormality in ADHD is the
high RT variability in cognitive tasks (Klein et al. 2006;
Uebel et al. 2010; Chamberlain et al. 2011). In patients
with ADHD, the RT variability has been associated with
the activity in the premotor cortex (Suskauer et al. 2008).
Because modeling the electrical current distribution
revealed the greatest stimulation current densities between
the primary stimulating and return electrodes with the
global maxima at the edges of electrodes (Salvador et al.
2015; Opitz et al. 2015), it could be suggested that using
the described montage we would effectively stimulate not
only the left DLPFC but also the left premotor cortex and
could expect not only effects of tDCS on errors in a WM
task but also on motor function, especially on the RT
variability.
Statistical analyses
First, the three established Qb-factors Inattention, Hyper-
activity, and Impulsivity (Reh et al. 2015) were z-trans-
formed for further analyses. Then, these z-transformed
variables were used to compare the differences between
anodal and sham tDCS at each assessment. Self and
observer ratings were performed at baseline, d5, d12, d26,
and d33.
At the first step, statistics with the consideration of our
crossover design was carried out. Due to the crossover
design of the study, several measurements of the outcome
parameters existing for each patient were included. Thus,
the assumption of independent observations is not met.
Therefore, the differences between anodal and sham tDCS
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
137
were analyzed with mixed linear models. These models
allowed testing for the effects of period, carryover, and
treatment on the outcome measures in the framework of
repeated measurements. Dependent variables were Inat-
tention, Hyperactivity and Impulsivity (parent-rating
FBB_Inattention, FBB_Hyperactivity, FBB_Impulsivity as
well as QbTest Qb_Inattention, Qb_Hyperactivity,
Qb_Impulsivity). Important times of measurement for
these analyses were d5 and d26, which were entered into the
model and analyzed as a fixed effect of day (effect of
period). To test for any carryover effects, the order of
treatment was included as a fixed effect of group. Anodal
and sham stimulation were entered as a fixed effect of
treatment. Baseline values were included in the model as
covariates, because both groups differed in some of the
baseline data despite randomization (although nonsignifi-
cantly). Because of significant effects of period and car-
ryover in Hyperactivity [fixed effect of day: F(1,
13) = 0.001; p = 0.03; fixed effect group: F(1,
13) = 5.33; p = 0.04], the results concerning the treatment
effect of the mixed linear models are limited in interpre-
tation. Therefore, further statistical analyses, evaluating
only the first period until washout, had exploratory
character.
Since the data were normally distributed (p [ 0.8 in the
Kolmogorov–Smirnov test) and characterized by homoge-
neous variances (F test), parametric tests were applied. To
analyze differences in the pre-post data (d0–d5 and d0–d12)
of the tDCS sessions (anodal/sham), ANOVA with a
within-subjects factor TIME (d0 vs. d5 vs. d12) and STI-
MULATION (tDCS vs. sham), as well as post hoc, inde-
pendent, two-tailed t tests were used. Test statistics with
p B 0.05 indicate significant results. It means if the p value
is less or equal to the alpha of 5%, then we reject the null
hypothesis, and say the result is statistically significant. No
correction of the error levels for multiple testing was per-
formed because of the explorative character of the phase II
proof of concept study. All analyses were performed with
IBM SPSS Statistics version 20.0 (SPSS Co., Chicago,
USA). Since return of teacher questionnaires was poor
(n = 6), only parent-ratings were used for analyses.
Results
Effect of tDCS on clinical course of ADHD (primary
outcome)
All patients demonstrated a very good compliance, were
highly motivated and did not miss any sessions. The blinding
seemed to succeed because 46% of subjects reported tingling
and itching sensations under electrode during sham stimu-
lation (see ‘‘Results’’) and 40% of subjects were unable to
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138 C. Soff et al.

Table 2 Changes in inattention, hyperactivity and impulsivity tDCS group compared to sham stimulation, especially seven
induced by tDCS from baseline to day 12 as assessed by FBB-ADHD days after tDCS [T(12) = -2.12; p = 0.05].
(parent-rating)
Baseline d5 d12 Effect of tDCS on neuropsychological measures
(secondary outcome)
FBB_Inattention
tDCS 2.10 (0.47) 1.79 (0.46) 1.65 (0.40)*
Table 3 and Fig. 3 show the differences in the pre-post data
Sham 1.41 (0.70) 1.46 (0.57) 1.56 (0.24)
(d0–d12) of the tDCS sessions (anodal/sham) with significant
FBB_Hyperactivity
results from independent t tests (exploratory analyses) for
tDCS 1.04 (0.50) 1.00 (0.48) 0.71 (0.45)
QbTest. ANOVA generally revealed no significant main
Sham 0.84 (0.64) 0.78 (0.63) 0.71 (0.48)
effects and only a significant interaction TIME 9 -
FBB_Impulsivity
STIMULATION for Hyperactivity [F(2, 24) = 4.156;
tDCS 1.80 (0.69) 1.46 (0.60) 1.07 (0.55)
p = 0.028]. At the end of stimulation (d5), there was a signif-
Sham 1.05 (0.81) 1.04 (0.85) 1.11 (0.78)
icant reduction of Hyperactivity in the tDCS condition com-
Data are given as means (and SD) pared with sham stimulation [T(13) = -2.16; p = 0.05]. This
tDCS transcranial direct current stimulation, FBB-ADHD German effect was more pronounced 7 days after the end of stimulation
observer-rating for ADHD, d5 fifth day of stimulation, d12 12th day of [d12: T(12) = -2.51; p = 0.02]. Moreover, the effect of tDCS
the study, seven days after stimulation
on Inattention compared with sham stimulation also became
* Significant vs. sham at p B 0.05
significant 7 days after the stimulation [T(12) = -2.14;
p = 0.05]. There were no effects of tDCS on impulsivity.

differentiate between anodal tDCS and sham (they were
wrong in guessing whether past sessions included real or
sham stimulation). Table 2 and Fig. 2 show the differences
in the pre-post data (d0–d12) of the tDCS sessions (anodal/
sham) with significant results from independent t tests (ex-
ploratory analyses) for clinical measures. ANOVA revealed
no significant main effects for any of the clinical parameters
but did show significant interaction TIME 9 -
STIMULATION for inattention [F(2, 22) = 4.136;
p = 0.03]. Inattention demonstrated a clear reduction in the
Adverse effects of tDCS
The whole study protocol was received well among the ado-
lescents. All of them tolerated both tDCS and sham stimula-
tion without any problem. None of the participants interrupted
the study. A mild tingling and itching sensation under the
electrodes was the most commonly reported adverse effect.
This sensation was reported by 46% of the subjects during
anodal tDCS and by 46% during sham stimulation. None of
the subjects reported fatigue, burning, pain, or other

Fig. 2 Changes in clinical symptoms on day 5 of stimulation and transcranial direct current stimulation, FBB-ADHD German obser-
seven days after stimulation. Plots show differences in the pre-post ver-rating for ADHD. Asterisk significant vs. sham at p \ 0.05; tilt
data (d0–d12) of the tDCS sessions (anodal/sham) with significant symbol significant vs. sham at p \ 0.1. Error bars represent standard
results from independent t test for clinical measures. tDCS error

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Transcranial direct current stimulation improves clinical symptoms in adolescents with… 139

Table 3 Changes in inattention, hyperactivity and impulsivity induced by tDCS from baseline to day 12 assessed with QbTest
Baseline d2 d3 d4 d5 d12

Qb_Inattention
tDCS 0.15 (1.10) -0.002 (1.16) -0.07 (1.20)* -0.08 (1.18) 0.05 (1.20) -0.10 (1.16)*
Sham -0.17 (0.71) 0.002 (0.76) 0.08 (0.59) 0.09 (0.40) -0.06 (0.43) 0.13 (0.53)
Qb_Hyperactivity
tDCS 0.15 (1.13) -0.06 (1.12)* -0.16 (1.02)* -0.34 (1.10)* -0.17 (1.20)* -0.23 (1.13)*
Sham -0.17 (0.48) 0.07 (0.51) 0.18 (0.88) 0.39 (0.54) 0.19 (0.59) 0.30 (0.39)
Qb_Impulsivity
tDCS 0.34 (1.24) -0.75 (1.05) -0.09 (0.72) -0.23 (0.81) 0.15 (1.21) 0.19 (1.16)
Sham -0.39 (0.44) 0.06 (1.02) 0.11 (1.30) 0.26 (1.19) -0.18 (0.74) -0.26 (0.77)
Data are given as z values with means (and SD)
tDCS transcranial direct current stimulation, QbTest quantified behavior test, Qb_Inattention, Qb_Hyperactivity, Qb_Impulsivity are the three
QbTest factors; d2, d3, d4, d5 second to fifth day of stimulation, d12 12th day of the study, seven days after stimulation
* Significant vs. sham at p B 0.05

Fig. 3 Changes in QbTest factors on day 5 of stimulation and seven
days after stimulation. Plots show differences in the pre-post data (left
d0–d5 and right d0–d12) of the tDCS sessions (anodal/sham) with
significant results from independent t tests for QbTest. The scores
presented are z-scores (see the Y-axis), the lower the score, the more is
the reduction of a measure related to baseline and vice versa. tDCS
transcranial direct current stimulation, QbTest quantified behavior
test, inattention, hyperactivity, impulsivity are the three QbTest
factors. Asterisk significant vs. sham at p \ 0.05; error bars represent
standard error

uncomfortable sensations during tDCS or sham stimulation.
Furthermore, none found the stimulation procedure to be
unpleasant nor were any difficulties reported in concentrating
during neuropsychological assessment. Headache after ano-
dal stimulation was reported only by one subject. None of the
participants reported changes in visual perception or were
more hyperactive during or after the stimulation.
Discussion
Tolerability of tDCS in adolescents with ADHD
In this study, mild tingling and itching sensations under
the electrodes was the most common adverse effect and
only reported by a minority of subjects. None of the
participants found the stimulation procedure unpleasant.
Our experience with tDCS tolerability is in line with
previous reports (Krishnan et al. 2015). Moreover, we
recently investigated the side effects of tDCS systemati-
cally in different age groups and demonstrated that 1 mA
direct current polarization is safe and tolerated well by
young healthy subjects. No pathological oscillations, in
particular, no markers of epileptiform activity were
detected in EEG traces after tDCS stimulation (Moliadze
et al. 2015a). In addition, tDCS does not cause serious
adverse effects in adolescent clinical populations, even
when applied daily over a number of consecutive days
(Bandeira et al. 2016; Mattai et al. 2011; Siniatchkin et al.
2012b). Therefore, it seems likely that 1 mA anodal tDCS

123

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140
is a safe and well tolerable method for treatment of
adolescents with ADHD.
Effects of tDCS on clinical symptoms and cognitive
function
Because patients with ADHD are characterized by poorer
performance in n-back tasks, a fact which correlates with
clinical symptoms (Chamberlain et al. 2011; Klein et al.
2006), it can be suggested that application of tDCS over the
left DLPFC for a number of consecutive days may result in
long-term improvement in both neuropsychological func-
tion and clinical course. This hypothesis was supported in
this study. Both clinical rating scale and the n-back task
integrated in QbTest revealed improvement in INAT-
TENTION. Inattention as a factor of QbTest includes the
variables as RT, RT variability, and error of omission
(Döpfner and Lehmkuhl 2003). Improvement in these
parameters corresponds well with previous studies which
applied the anodal tDCS over the left DLPFC during a
single session (Berryhill and Jones 2012; Boggio et al.
2006; Fregni et al. 2005; Jo et al. 2009; Keeser et al. 2011;
Martin et al. 2014; Mulquiney et al. 2011; Mylius et al.
2012; Oliveira et al. 2013; Teo et al. 2011). Note that the
effects of 5 days of stimulation lasted for at least additional
7 days and became even stronger in the long-term
perspective.
The potential of tDCS for the treatment of ADHD has
been discussed previously (Rubio et al. 2016) and sup-
ported by other authors as well. Leffa et al. (2016) stimu-
lated spontaneous hypertensive rats (an animal model of
ADHD) over eight consecutive days using tDCS over the
prefrontal cortex and caused a significant improvement of
WM (Leffa et al. 2016). Soltaninejad et al. (2015) and
Bandeira et al. (2016) applied anodal tDCS over the left
DLPFC in children and adolescents with ADHD and
demonstrated an increase in correct responses during a task
for sustained attention, improved signal detection, ability to
switch between an ongoing activity and a new one, and
more efficient processing speed (Bandeira et al. 2016;
Soltaninejad et al. 2015). Munz et al. (2015) applied
oscillating (0.75 Hz) anodal tDCS bilaterally over DLPFC
in children with ADHD during non-REM sleep and showed
a significant decrease in RT and RT variability in a Go-
NoGo task performed in a day after nocturnal stimulation
(Munz et al. 2015). There were no effects on alertness and
finger sequence tapping. And finally, Cosmo et al. (2015)
demonstrated that anodal tDCS over the left DLPFC in
adults with ADHD has no influence on behavioral perfor-
mance in a Go-NoGo task (Cosmo et al. 2015). It is dif-
ficult to find correspondence between results of our and
previous studies because of methodological differences.
With the exception of Bandeira et al. (2016), all cited
123
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C. Soff et al.
studies applied tDCS only during one session and investi-
gated the influence of tDCS only on neuropsychological
functions. There is no study which investigated the effects
of tDCS on the clinical course of ADHD using standard-
ized clinical instruments. Therefore, our study is the first
which provides a direct evidence for clinical effects tDCS,
especially on inattention. Bandeira et al. (2016) applied
anodal tDCS on five consecutive days (as in our study,
however, without sham control) and performed a great
number of neuropsychological tests (Bandeira et al. 2016).
The authors did not find significant changes in WM. This
discrepancy may be attributed to another montage (cathode
on the right supraorbital area), higher stimulation intensity
(2 mA, increase in intensity may cause paradoxical effects
of Tdcs; see Batsikadze et al. 2013), or measures of out-
come which were carried out immediately after the end of
stimulation (not seven days after the end of tDCS as in our
study). Especially, the aspect whether tDCS was applied
before or during any task, is important and may explain
some negative results (Bandeira et al. 2016), for example,
in the study of Cosmo et al. (2015) which applied tDCS
offline. It seems likely that online stimulation of DLPFC is
better for clinical and neuropsychological changes that
offline tDCS.
Interestingly, also hyperactivity was reduced in QbTest
immediately at the end and seven days after the end of
stimulation. The effect on hyperactivity is shown first as all
previous studies investigated only neuropsychological
parameters. None of the studies has measured activity pat-
tern in such a way as in QbTest is possible because this test
uses an infrared camera which register activity time, dis-
tance and area. Some arguments would support the effect on
(hyper) activity. In this study, we used a special electrode
montage with anode over the left DLPFC and cathode over
the vertex. Because modeling the electrical current distri-
bution revealed the greatest stimulation current densities
between the primary stimulating and return electrodes with
the global maxima at the edges of electrodes (Salvador et al.
2015; Opitz et al. 2015), it could be suggested that using the
described montage we would effectively stimulate not only
the left prefrontal cortex but also the left premotor cortex
and could expect effects of tDCS on motor performance as
well. This argument was supported by our fMRI analysis.
Applied inside the scanner, tDCS not only causes an
increase in activation in the left DLPFC but also in brain
areas of the motor network, such as supplementary motor
area and premotor cortex (Sotnikova et al. 2016). It has been
shown previously that symptoms of hyperactivity in patients
with ADHD may result from increased excitability and
reduced inhibition in the motor network (Buchmann et al.
2007; Gilbert et al. 2011; Moll et al. 2000). Since activity in
the motor network is influenced by the DLPFC (Gilbert et al.
2011; Suskauer et al. 2008), it can be suggested that the
Transcranial direct current stimulation improves clinical symptoms in adolescents with…
stimulation of the DLPFC improves the efficacy of the
networks and reduces hyperactivity. And finally, there was
only a moderate effect on impulsivity from both a clinical
and neuropsychological point of view. Although the stimu-
lation of the DLPFC may influence impulsivity as demon-
strated in a number of studies (Beeli et al. 2008; da Silva
et al. 2013; Pripfl et al. 2013), this brain region is not the
major player in the neuronal network controlling impulsivity
(Aron 2011). Other regions, such as the inferior frontal
cortex and medial prefrontal cortex, have to be investigated
as possible targets to reduce impulsivity in patients with
ADHD. Note that in the recent study Breitling et al. (2016)
demonstrated a significant effects of 1 mA anodal tDCS
applied over the right inferior frontal gyrus on interference
control and impulsivity in children with ADHD supporting
the idea of regional specificity of tDCS (Breitling et al.
2016).
Limitations of the study
First, despite a washout phase of 2 weeks, the results from
mixed linear models provided evidence for carryover
effects. Therefore, only the first treatment period in the
crossover design was taken for statistical analysis which
limited the number of patients within each condition. The
washout period of 2 weeks in this study was planned based
on results from previous studies, which also used a crossover
design and showed that a 2-week washout period was suf-
ficient to avoid carryover effects (Berryhill and Jones 2012;
Boggio et al. 2006; Fregni et al. 2005; Jo et al. 2009; Keeser
et al. 2011; Martin et al. 2014; Mulquiney et al. 2011; Mylius
et al. 2012; Oliveira et al. 2013; Teo et al. 2011). However,
all of these studies only applied tDCS once. It seems likely
that stimulation over five consecutive days may cause more
pronounced after effects which may not only last days but
even weeks. It is known that noninvasive brain stimulation
induces neuroplasticity, a more continuous modification of
cortical excitability (Lang et al. 2005; Liebetanz et al. 2002).
Previous studies have demonstrated application of anodal
tDCS over five and more consecutive days may induce
behavioral changes lasting weeks (Boggio et al.
2008, 2012). In addition, in this study the effects of anodal
tDCS lasted at least 1 week after the end of stimulation. To
avoid the influence of long-lasting after effects of tDCS, a
parallel group design (tDCS vs. sham) for clinical studies
has to be chosen in the future. Second, although a number of
comparisons became significant, a type II error cannot be
excluded. The small number of subjects may explain why
groups differed according to neuropsychological parameters
at baseline, despite of randomization. In the same way, we
cannot exclude a type I error as no Bonferroni correction
was performed, so the increased risk of multiple testing of
the a-error accumulation was not corrected.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
141
Notwithstanding, the study was of exploratory nature and
provides only a proof of principle for application of tDCS in
patients with ADHD. Third, it should be critically noted that
external assessment of the clinical symptoms solely by the
assessment of the parents may be biased by motivation of
participants. Parents might have given more positive
assessments of clinical changes under tDCS than a more
independent and objective assessment by teachers. How-
ever, the teachers’ evaluation was impossible because return
of the questionnaires was poor. Fourth, in some patients
stimulant medication was discontinued up to 96 h before the
first assessment. Although this fact might have an influence
on results, it is rather unlikely because the patients who had
medication (by the way, only short-acting immediate release
methylphenidate), were randomly distributed between the
contrasting groups. In the future, more homogeneous groups
concerning medication status, comorbidities, type of
ADHD, etc., have to be investigated. Fifth, attention,
working memory and impulsivity represent complex neu-
ropsychological constructs which are difficult to character-
ize with one test, as in this study. Additional validation of the
QbTest results presented here with concurrent neuropsy-
chological tests is necessary. Especially ecological validity
of parameters which were measured with QbTest needs a
better empirical basis to understand the relation between
changes in neuropsychological measures and clinical
symptoms of ADHD. And finally, the time point for primary
outcome measure (seven days after the end of stimulation)
was chosen voluntarily. For the future, it is better to perform
behavioral observations more frequently to find the most
optimal time point in the follow-up with the most pro-
nounced behavioral changes.
Despite these limitations, this exploratory study pro-
vides first evidence that tDCS may be effective in
enhancing cognition and reducing symptoms in adolescents
with ADHD, a fact which should encourage further studies
with larger sample sizes. Especially in patients with
insufficient response to pharmacological or behavioral
treatment, tDCS may be an alternative option.
Compliance with ethical standards
All procedures performed were in accordance with the ethical stan-
dards of the institutional research committee and with the 1964
Helsinki declaration and its later amendments. Written informed
consent was obtained from all participants.
Conflict of interest The authors declare no conflict of interest.
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