Journal of Affective Disorders 210 (2017) 241–248

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Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Research paper

Cognitive control dysfunction in emotion dysregulation and MARK

psychopathology of major depression (MD): Evidence from transcranial
brain stimulation of the dorsolateral prefrontal cortex (DLPFC)
⁎
Mohammad Ali Salehinejada,b, , Elham Ghanavaic, Reza Rostamia, Vahid Nejatid
a
Department of Psychology, University of Tehran, Tehran, Iran
b
Department of Psychology, University of Kansas, Lawrence, KS, USA
c
Department of Psychology, Islamic Azad University, Science & Research Branch, Tehran, Iran
d
Institute for Cognitive & Brain Sciences, Shahid Beheshti University, Tehran, Iran

A R T I C L E I N F O A BS T RAC T

Keywords: Background: Previous studies showed that MD is associated with a variety of cognitive deficits and
Major depression (MD) executive dysfunctions which can persist even in remitted states. However, the role of cognitive impairments
Executive functions in MD psychopathology and treatment is not fully understood. This article aims to discuss how executive
Cognition functions central components (e.g., Working memory and attention) mediate MD psychopathology considering
Emotion
the role of dorsolateral prefrontal cortex (dLPFC) and present findings of a brain stimulation experiment to
tDCS
support this notion.
Dorsolateral prefrontal cortex (DLPFC)
Methods: The effect of transcranial direct current stimulation (tDCS) of the dLPFC on enhancing cognitive
control functions was investigated. Twenty-four patients with MD (Experimental group=12, Control group=12)
received 10 sessions of tDCS (2 mA for 30 min) over 10 consecutive days. The experimental group received
active stimulation and the control group received sham stimulation. Participant's performance on cognitive
functions (PAL, SRM, RVP and CRT from CANTAB) and their depression scores were assessed before and after
tDCS.
Results: Results showed that brain stimulation of the dLPFC improved executive dysfunction in patients and a
significant improvement on depression scores was also observed suggesting that cognitive control dysfunction
may be a mediator in emotional dysregulation and psychopathology of MD.
Limitations: No follow-up investigation was done in this study which does not allow to infer long-term effect of
tDCS. Low-focality of tDCS might have stimulated adjacent areas too.
Conclusion: Cognitive components, namely cognitive control dysfunction, play role in MD psychopathology as
they are involved in emotion dysregulation in MD. The amount of contribution of cognitive components in MD
psychopathology is however, an open question. tDCS can be used as an intervention to improve cognitive
dysfunction in MD.

1. Background
As one of the most incapatiating and prevalent conditions world-
wide, major depression (MD) is characterized by altered cognitive and
emotional functioning (Diener et al., 2012) marked with various
emotional and cognitive impairments (Davidson et al., 2002;
Marazziti et al., 2010; Nezhad et al., 2011). A large number of studies
show that MD is associated with cognitive deficits in several domains
including different types of memory, attention, executive functions
(EF), perception and psychomotor skills (Marazziti et al., 2010; Rock
et al., 2014; Wagner et al., 2012) and studies even suggest that
cognitive deficits might persist beyond the acute stages of illness in
MD (Bora et al., 2013). In addition to cognition, emotion is also
impaired in MD in terms of emotion dysregulation and sustained
negative affects that are suggested to be central to MD psychopathology
(Gotlib and Joormann, 2010). Although studies have shown an
interaction between cognition and emotion in MD, the way they
interact has been subject to controversy and most studies prioritized
emotional components over cognitive components in MD psycho-
pathology.
Previous studies suggest that cognitive components have substan-
tial implications in MD psychopathology. These studies suggest that

⁎
Correspondence to: Institute for Cognitive & Brain Sciences, Shahid Beheshti University, Daneshjoo Blvd, Velenjak, Tehran, Iran.
E-mail address: salehinejadmohammadali@gmail.com (M.A. Salehinejad).

http://dx.doi.org/10.1016/j.jad.2016.12.036
Received 1 July 2016; Received in revised form 8 November 2016; Accepted 17 December 2016
Available online 31 December 2016
0165-0327/ © 2016 Elsevier B.V. All rights reserved.
M.A. Salehinejad et al.
biased cognitive processing is related to emotion dysregulation in MD
(Gotlib and Joormann, 2010; Nitschke et al., 2004) which is aligned
with cognitive theories of depression (e.g., Beck et al., 1987; Ellis and
Grieger, 1986). However, empirical studies about the biased cognitive
functions in MD yielded mixed results (Gotlib and Joormann, 2010).
In this study, we first discuss how cognition and emotion are
interrelated with a particular focus on role of the prefrontal cortex
(PFC). We will also argue how cognitive impairments, specifically the
PFC-related executive dysfunction, are related to emotion dysregula-
tion and psychopathology of MD and how they interact with emotional
components. We then present findings of a brain stimulation experi-
ment to support the above notion.
1.1. PFC, cognitive functions and emotion
The PFC is a collection of cortical regions that have interconnec-
tions with almost all cortical and subcortical structures, involved in
affect and cognition (Miller and Cohen, 2001). According to Miller and
Cohen (2001), cognitive control or goal-directed action is the primary
function of the PFC. To fulfil a goal-directed action we need to keep
task-relevant information active and inhibit task-irrelevant informa-
tion. Working memory (WM) and attentional control are necessary for
keeping task-relevant information active as well as manipulating that
information to accomplish behavioural goals (Gazzaniga et al., 2014).
Lateral regions of the PFC especially the left dorsolateral PFC (l-
dLPFC) are suggested to be responsible for these PFC-related cognitive
functions (Miller and Cohen, 2001; Ochsner and Gross, 2005).
The PFC is not only important for cognitive control functions but
also for affective states and emotional processing (Davidson, 2002).
The critical role of the PFC in goal-directed behaviours explains why it
is important for regulation of mood and emotion. In situations where
mood and emotion are involved, the arousal of emotion is usually
inconsistent with other goals that have already been expressed
(Davidson et al., 2002) and the PFC is required to signal to other
brain regions to produce an appropriate response. For example in
experience of loss, the availability of continuous sadness may not be
adaptive to a person's goals. In such case the PFC is required to
produce adaptive emotion-based decision making in service of the
goals.
Cognitive regulation of emotions is one of the cognitive mechan-
isms through which the PFC is involved in emotional processing.
Cognitive regulation of emotions is a major emotion regulatory strategy
that regulates emotional responsivity through cognitive control
(Ochsner and Gross, 2005). In contrast to behavioural regulation,
cognitive regulation moderates unpleasant experience, neutralizes
negative experience and might decrease physiological arousal (Gross,
2002; Salehinejad et al., 2017). Attentional control, a PFC-related
function, is a major type of cognitive regulation and is often referred to
“selective aspect of information processing”, enabling us to focus on
goal-relevant information and ignore goal-irrelevant ones (Ochsner
and Gross, 2005). It facilitates cognitive appraisal of emotions by
assessing the significance of stimuli to current goals (Scherer et al.,
2001) and then channelling appropriate emotional response (Kalisch
et al., 2006). In sum, studies indicate that the lateral PFC regions are
related to control processes over cognitive functions as well as
emotions.
1.2. PFC and cognitive-emotional abnormalities in MD
MD is marked with structural and functional abnormalities in the
brain especially in the PFC regions (Price and Drevets, 2012; Ye et al.,
2012) which are related to cognitive and emotional impairments
(Davidson et al., 2002; Diener et al., 2012; Drevets and Furey, 2009).
Neuroimaging studies suggest that the lateral PFC regions are more
implicated in cognitive dysfunction whereas the medial PFC regions are
more associated with control of emotions and affects (Koenigs and
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Journal of Affective Disorders 210 (2017) 241–248
Grafman, 2009; Long et al., 2015; Ochsner and Gross, 2005; Roiser
and Sahakian, 2013). Studies showed that depressed individuals have
poor WM (Rock et al., 2014; Rose and Ebmeier, 2006; Wang et al.,
2015) and impaired attentional processing (Clark et al., 2005; Maalouf
et al., 2010) leading to a biased processing of information.
It has been shown that there is an imbalance of function between
the right and left dLPFC in depression known as the “imbalance
hypothesis of MD” (Grimm et al., 2008; Nitsche et al., 2009a; Plewnia
et al., 2015). According to this notion there is a relative hypoactivity
and hyperactivity in the left and right dLPFC respectively in MD
(Grimm et al., 2008; Nitschke et al., 2004). This imbalance of function
in the dLPFC is associated with impaired WM (Fregni et al., 2005;
Nitschke et al., 2004) and attention (Sánchez-Navarro et al., 2014;
Schafer and Moore, 2011) in MD leading to affective and attentional
biases toward negative information, which in turn, reinforces depres-
sive symptoms (Plewnia et al., 2015).
This imbalance of function influences emotional processing in some
ways one of which is the inability to initiate and maintain attention
toward emotional materials specifically toward neutral and positive
materials (Sánchez-Navarro et al., 2014). Depressed individuals with
hypoactivity in the l-dLPFC have difficulties in affect-guided planning
and stopping automatic responses that preserve negative affects and
attitudes (Davidson et al., 2002). In addition, they are less sensitive to
rewards and positive affects but more responsive to punishment and
negative affects as a result of cognitive control dysfunction (Must et al.,
2006). Biased self-referential processing (Lemogne et al., 2010) and
impaired strategy utilization (Hertel, 2000) are other cognitive com-
ponents in MD associated with the decreased dLPFC activity. There is
also a hyperactivity in the right PFC specially the r-dLPFC that is
associated with negative memory bias (Grimm et al., 2008; Nitschke
et al., 2004). These findings support the notion that impaired proces-
sing of emotional information in MD which is related to abnormalities
in the PFC, especially dLPFC, leads to failure in appropriate goal-
directed responses to emotional stimuli.
In sum, neuroimaging studies indicate an imbalanced cortical
activity in the dLPFC regions that are associated with cognitive
impairment and emotional difficulties in MD indicating that cognition
and emotion interact in MD psychopathology. Indeed, negative affects
and attitudes and emotional dysregulation may occur because the PFC
fails to guide appropriate response in emotional situations to serve the
person's goal. This implies that emotional dysregulation, which is
suggested to be central in MD psychopathology (Davidson et al., 2002),
might be dependent on impaired cognitive control of the PFC which
may suggest that cognitive impairment rather than emotional impair-
ment is primary in MD psychopathology. This also suggests that by
improving cognitive control functions in MD, we can expect an overall
improvement in negative emotions and affects of depressed indivi-
duals.
1.3. Brain stimulation studies
Recent studies highlighted the importance of noninvasive brain
stimulation as a mean of modulating cortical excitability (Bestmann
et al., 2015; Parkin et al., 2015). Transcranial direct current stimula-
tion (tDCS) is a neuromodulation technique in which a weak direct
current, applied on the scalp, reaches the brain and induces shifts in
membrane resting potentials and modulates cortical excitability
(Nitsche et al., 2009a). Anodal stimulation increases cortical excit-
ability, whereas cathodal stimulation has a reverse effect (Utz et al.,
2010). Neuromodulation studies have shown that anodal tDCS over the
l-dLPFC improves WM, attention and emotional functioning in MD
(Ferrucci et al., 2009; Loo et al., 2012; Salehinejad et al., 2015).
Moreover, the neuropsychological characterization of the l-dLPFC
hypoactivity and r-dLPFC hyperactivity and its association with MD
psychopathology is poorly understood (Grimm et al., 2008).
Based on the findings suggesting an asymmetry of function in the
M.A. Salehinejad et al.
left and right dLPFC, we ran a tDCS experiment with a specific montage
to see whether modulating cortical activity in the dLPFC would
improve cognitive control functions, namely the WM and attentional
control in MD; and whether such improvement in cognitive control
leads to an improvement in negative emotions and affect presumably
through increased cognitive control over emotion and emotional
regulation. The l-dLPFC was selected as the main site of anodal
stimulation, which is hypothesized to increase cortical activity in l-
dLPFC; and the r-dLPFC was selected as the main site of cathodal
stimulation, which is suggested to decrease cortical activity in r-dLPFC.
We applied this specific tDCS montage based on the imbalance
hypothesis in MD (Grimm et al., 2008), that takes into account both
the left and right dLFPC which is also the suggested montage for
studying cognitive effects of tDCS in MD (Brunoni et al., 2016).
2. Methods
2.1. Participants
We enrolled twenty four patients aged from 18 to 41 years
diagnosed with unipolar, non-psychotic MD according to DSM-IV
criteria confirmed by the participant's scores on the Beck Depression
Inventory (BDI) (Beck et al., 1961) and the Hamilton Depression
Rating Scale (HDRS) (Hamilton, 1960). Demographic data are shown
in Table 1. The patients were recruited from the local university Atieh
Mental Health Clinic. Inclusion criteria were: (1) not to be on
antidepressant or other psychotropic medications during the study
(2) moderate to severe depression score based on BDI (scores close to
29 and higher); (3) HDRS score of at least 20 (scored by an experienced
psychiatrist); (4) MD diagnosis based on a clinical interview by an
experienced psychiatrist according to the DSM-IV criteria. Exclusion
criteria were other axis I and any axis II (personality and develop-
mental) disorders. The study was conducted according to the
Declaration of Helsinki ethical standards and approved by the local
Institutional Review Board and the Ethical Committee. Patients gave
their informed consent before participation and were free to withdraw
from study at any phase.
2.2. Materials and procedure
Participants were randomly assigned in two groups of experimental
(N=12) and control (N=12). The experimental group received 20-min
active stimulation per day for 10 consecutive days and the control
group received 20-min sham stimulation. During sham condition,
electrical current was ramped up for 30 s to generate the same
sensation as active condition for the participant in the sham group
and then turned off (Palm et al., 2013). A side-effect survey was done
after tDCS sessions; all participants tolerated the tDCS treatment well
and no adverse effects were reported. Participants completed the
measures (CANTAB tests for measuring WM and attention and BDI
and HDRS for measuring mood and depressive scores) once before
Table 1
Demographic variables of participants.
Sample size (n)
Age – Mean (SD)
Gender – Male (female)
Marital Status – Single (married)
Antidepressant use during last 6 months (n)
Education Diploma
BA
MA or higher
M=Mean; SD=Standard Deviation; BA=Bachelor of Arts; MA=Master of Arts.
243
Journal of Affective Disorders 210 (2017) 241–248
Fig. 1. Experiment procedure in experimental (red) and control (blue) groups.
tDCS=transcranial direct current stimulation; PAL=Paired Associates Learning;
SRM=Spatial Recognition Memory; RVP=Rapid Visual Information Processing;
CRT=Choice Reaction Time. (For interpretation of the references to color in this figure
legend, the reader is referred to the web version of this article.)
beginning of tDCS sessions as baseline and once right after 10th tDCS
session. All patients were blind to the type of tDCS delivered in each
session. Participants in the control group were assigned to other
therapeutic protocols by end of the study (See Fig. 1).
2.3. tDCS protocol
The tDCS device in use was “ActivaDose Iontophoresis” manufac-
tured by Activa Tek, battery-driven with a 9-volt battery as its source.
Electrical direct current of 2 mA generated by the stimulator was
applied through a pair of saline-soaked sponge electrodes with size of
35 cm2 (7×5) for 20 min (with 15 s ramp up and 15 s ramp down).
Anode electrode was positioned over area F3 (l-dLPFC) and cathode
electrode was positioned over F4 (r-dLPFC) according to the 10–20
EEG International System. This specific montage is the suggested
montage for studying cognitive effects of the tDCS in depression (e.g.,
Brunoni et al., 2016).
2.3.1. Cognitive measurement
WM and attention, as components of cognitive control, were
assessed using the Cambridge Neuropsychological Test Automated
Battery (CANTAB) (Robbins et al., 1994). CANTAB is designed with
a significant focus on neuropsychological functions subserved by the
frontal lobe regions that mediate motor, cognitive and behavioural
functions (Fray et al., 1996). It's been widely used in studies investigat-
ing cognitive functions in neuropsychological diseases including MD
(Clark et al., 2009; Egerhazi et al., 2013; Owen et al., 1995; Sahakian
et al., 1990). One reason to use CANTAB for cognitive measurement
was its sensitivity to cognitive functions especially in studies involving
passage of electrical current on the frontal and temporal regions
(Falconer et al., 2010). Moreover, brain stimulation studies showed
that tDCS interventions are task specific especially during anodal
stimulation of the l-dLPFC (Pope et al., 2015). It is suggested that
Experimentalgroup Controlgroup
12 12
26.8 (7.1) 25.5 (4.6)
5 (7) 4 (8)
8 (4) 7 (5)
10 11
7 6
3 3
2 3
M.A. Salehinejad et al.
anodal tDCS over the l-dLPFC would affect performance when a
cognitive task is attentionally demanding and especially difficult to
perform, and perhaps when it engages specific WM operations (Pope
et al., 2015). The battery used in the present study was cognitively
demanding and specific to frontal functions.
A four-test CANTAB battery (30–32 min duration) selected from
CANTAB memory tests, attention tests and depression battery was
used in this study. Paired Associates Learning (PAL) and Spatial
Recognition Memory (SRM) were selected as measures of WM and
Rapid Visual Information Processing (RVP) and Choice Reaction Time
(CRT) were selected as attention measures. It is of note that we only
included tests of WM and attention, as two major components of
cognitive control, in this battery since we are primarily interested in
studying cognitive control functions in MD.
The PAL test assesses visual WM by displaying boxes on the screen
that one or more of them will contain a pattern. The patterns are then
displayed in the middle of the screen, one at a time, and the participant
must touch the box where the pattern was originally located. This test
lasts around 10 min and performance on it is assessed in terms of the
latency and memory scores. The SRM is a test of visual spatial
recognition memory in a 2-choice forced discrimination paradigm.
Participants are presented with a white square, which appears in
sequence at five different locations on the screen. In the recognition
phase, participants see a series of five pairs of squares, one of which is
in a place previously seen in the presentation phase. The other square
is in a location not seen in the presentation phase. It takes about 5 min
to complete and the performance is assessed in terms of latency and
accuracy. The RVP is a sensitive measure of sustained visual attention
(Robbins et al., 1994) and presents participants a white box in the
center of the computer screen, inside which digits from 2 to 9 appear in
a pseudo-random order at the rate of 100 digits per minute.
Participants are asked to detect target sequences of digits and register
responses using the press pad. It takes about 10 min to complete and
the output measure include latency which is a good indicator of
sustained attentional function. Finally, the CRT is a 2-choice reaction
time test during which participants should press the left hand button if
the stimulus is displayed on the left hand side of the screen, and the
right hand button if the stimulus is displayed on the right hand side of
the screen. It takes about 6 min to complete and output measures
include latency, accuracy and number errors.
2.4. Emotional and mood assessment
To assess emotional functioning and mood we used two well-known
depression inventories that measure depressive symptoms and mood:
the BDI and HDRS. The BDI is a self-reported twenty-one questions
inventory about how the subject has been feeling in the last week and
each question has four answers ranging in intensity. The HDRS is a
multiple items questionnaire designed for measuring adult depression
and is administrated by health care professional which is currently the
most common depression measure used worldwide (Marijnissen et al.,
2002). Both measures are designed to indicate presence of depressive
symptoms in a past number of days.
2.5. Statistical analysis
The data was analyzed using PASW Statistics-SPSS 21.0. To
examine effects of tDCS on cognitive functions we employed a 2×2
Mixed ANOVA with tDCS condition (pre-stimulation/post-stimulation)
as within-subject factor, group (active/sham) as between-subject factor
and scores on CANTAB as dependent variables. A similar 2×2 Mixed
ANOVA was used for measuring effects of tDCS on mood. Our analyses
of variance (ANOVA) met linear assumptions and Leven's test was used
to examine homogeneity of variances. A significance level of P < 0.05
was used for all statistical comparisons.
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Journal of Affective Disorders 210 (2017) 241–248
3. Results
Overview of data showed different performance on the tasks in both
groups (Table 2). Results showed that anodal l-dLPFC / cathodal r-
dLPFC tDCS had significant effects on impaired WM and attention
performance of patients. First of all, the effect of tDCS on PAL test was
investigated. ANOVA results for memory score indicated a significant
main effect of tDCS (F=44.83, p < 0.1) and group (F=5.60, p < 0.2) but
no significant interaction effect was observed (F=2.47, p=0.13).
ANOVA results of error scores also indicated a significant main effect
of tDCS (F=39.93, p < 0.01), a significant main effect of group (F=6.20,
p < 0.02) and a significant interaction between the two factors
(F=10.74, p < 0.01). These results show that tDCS significantly im-
proved visual WM of patients compared to their baseline performance
and effect of tDCS on memory performance depends on group factor.
ANOVA results of the SRM also showed a significant main effect of
tDCS (F=58.87, p < 0.01) and group (F=5.04, p < 0.03) on memory
scores. A significant interaction was also found (F=10.58, p < 0.01)
indicating that patients who received active tDCS performed signifi-
cantly better than the ones who received sham stimulation. The same
pattern was also observed for latency scores of participants on SRM
(Table 3) ( Fig. 2).
We also evaluated whether tDCS could improve performance on
attentional functions as a major component of cognitive control.
ANOVA results of the RVP test showed a significant interaction effect
(F=7.31, p < 0.01) indicating that patients who received active tDCS
performed significantly better on the attention task than the ones
received sham stimulation. The main effects of tDCS (F=69.91, p <
0.01) and group (F=5.52, p < 0.03) in RVP scores were also significant.
Attentional performance was also measured using the CRT which
requires less attentional loading compared to the RVP. Results showed
significant main effect of tDCS for all output measures including
latency time (F=14.41, p < 0.01), percentage of correct (F=122.96, p
< 0.01) and number of errors (F=34.77, p < 0.01). However, no
significant interaction or significant main effect of group was observed
except for the main effect of group in correct responses (F=16.62, p <
0.01) (Table 4). The differed difficulty level of RVP and CRT tests could
possibly be one reason why tDCS had more robust effect on RVP
performance as studies showed that tDCS is more effective in tasks that
require more cognitive loading (Brunoni et al., 2016) (Fig. 3).
In addition to cognitive control functions, participant's scores on
the BDI and HDRS were significantly improved implying that cognitive
control improvement was a mediator of changes in emotional dysre-
gulation and negative mood of participants although a causal relation-
ship cannot be drawn here (Fig. 4). ANOVA results showed a significant
interaction effect (F=21.81, p < 0.01), a significant main effect of tDCS
(F=162.61, p < 0.01) but non-significant main effect of group (F=0.25,
p=0.61) on BDI scores. ANOVA result of HDRS also show the same
pattern with significant interaction effect (F=18.79, p < 0.01), a sig-
nificant main effect of tDCS (F=157.01, p < 0.01) but a non-significant
main effect of group (F=1.56, p=0.22). This shows that tDCS signifi-
cantly reduced depressive symptoms in patients who received active
stimulation.
4. Discussion
We discussed MD psychopathology from a cognitive neuroscience
point of view focusing on the role of the dLPFC in cognitive and
emotional impairments. Cognitive and emotional functions are two
major areas that are severely impaired in MD but the way they interact
has been subject of controversy. Previous neuroimaging studies
suggested the dLPFC and the vMPFC as regions involved in cognitive
and emotional processing in MD respectively (Diener et al., 2012;
Koenigs and Grafman, 2009; Long et al., 2015; Roiser and Sahakian,
2013). Brain stimulation studies also showed cognitive and emotional
improvements in MD after modulating cortical activity in the PFC
M.A. Salehinejad et al. Journal of Affective Disorders 210 (2017) 241–248

Table 2
Means and SDs of cognitive tasks and depression measures.

Task Experimental pre-stimulation Experimental post-stimulation Control pre-stimulation Control post-stimulation

M (SD) M (SD) M (SD) M (SD)

PAL (memory scores) 12.67 (1.46) 15.86 (2.32) 11.78 (1.72) 13.75( (1.61)
PAL (error) 18.91 (2.83) 14.78 (2.34) 19.55 (2.05) 18.24 (1.72)
SRM (% correct) 60.65 (5.17) 67.41 (7.94) 58.38 (2.61) 61.11 (2.77)
SRM (latency)a 3233.36 (355.64) 2391.31 (691.40) 3271.46 (405.67) 3102.53 (394.27)
RVP (latency)a 468.09 (50.20) 400.60 (53.57) 492.01 (34.57) 457.50 (37.41)
CRT (latency)a 465.65 (37.54) 433.13 (46.70) 476.05 (35.86) 460.66 (34.75)
CRT (% correct) 88.91 (4.58) 95.08 (3.57) 77.66 (9.17) 82.91 (9.28)
CRT (error) 7.58 (2.84) 5.33 (2.42) 8.75 (1.13) 7.50 (2.06)
BDI 33.66 (6.45) 17.50 (4.29 28.58 (2.64) 21.08 (2.39)
HDRS 24.58 (2.57) 12.75 (3.36) 22.56 (1.92) 16.83 (2.62)

PAL=Paired Associates Learning; SRM=Spatial Recognition Memory; RVP=Rapid Visual Information Processing; CRT=Choice Reaction Time; M=Mean; SD=Standard Deviation.
a
Values marked by (a) are in ms.

Table 3 Table 4
ANOVA results of tDCS effects on CANTAB memory tests. ANOVA results of tDCS effects on CANTAB attention tests.

Cognitive functions df Mean square F Significance Eta squared Cognitive functions df Mean square F Significance Eta squared

PAL (memory RVP (latency)

scores) tDCS 1.22 31212.01 69.91 .01 0.76
tDCS 1.22 79.67 44.83 .01 0.67 Group 1.22 19594.01 5.52 .03 0.20
Group 1.22 26.85 5.60 .02 0.20 tDCS*Group 1.22 3263.70 7.31 .01 0.25
tDCS*Group 1.22 4.40 2.47 .13 0.11
CRT (latency)
PAL (error) tDCS 1.22 6888.02 14.41 .01 0.40
tDCS 1.22 88.89 39.93 .01 0.64 Group 1.22 4317.19 1.68 .21 0.71
Group 1.22 50.34 6.20 .02 0.22 tDCS*Group 1.22 880.65 1.84 .18 0.77
tDCS*Group 1.22 23.91 10.74 .01 0.32
CRT (% correct)
SRM (% correct) tDCS 1.22 391.02 122.96 .01 0.85
tDCS 1.22 292.17 58.87 .01 0.72 Group 1.22 1645.02 16.62 .01 0.43
Group 1.22 238.39 5.04 .03 0.18 tDCS*Group 1.22 2.521 0.793 .38 0.34
tDCS*Group 1.22 52.56 10.58 .01 0.32
CRT (error)
SRM (latency) tDCS 1.22 36.750 34.77 .01 0.61
tDCS 1.22 3321680.94 25.44 .01 0.53 Group 1.22 33.33 3.82 .06 0.15
Group 1.22 1824804.10 5.51 .03 0.20 tDCS*Group 1.22 3.01 2.83 .10 0.11
tDCS*Group 1.22 1472550.96 11.27 .01 0.33
RVP=Rapid Visual Information Processing; CRT=Choice Reaction Time; Transcranial
PAL=Paired Associates Learning; SRM=Spatial Recognition Memory; tDCS=Transcra- Direct Current Stimulation; Significant results are highlighted (p≤0.05) in bold.
nial Direct Current Stimulation; Significant results are highlighted (p≤0.05) in bold.

Fig. 2. Memory scores (PAL on the left, SRM on the right) after tDCS in both groups. PAL=Paired Associates Learning; SRM=Spatial Recognition Memory; MS=Memory Score;
Corr=Number of Corrects; E=Experimental Group; C=Control Group.

245
M.A. Salehinejad et al.
Fig. 3. Attention scores after tDCS in both groups. RVP=Rapid Visual Information
Processing; CRT=Choice Reaction Time; E=Experimental Group; C=Control Group.
Fig. 4. MD scores after tDCS in both groups. BDI=Beck Depression Inventory;
HDRS=Hamilton Depression Rating Scale; E=Experimental Group; C=Control Group.
regions specifically the dLPFC (Brunoni and Vanderhasselt, 2014;
Ferrucci et al., 2009; Salehinejad et al., 2015; Shiozawa et al., 2014).
However, the role of cognitive control improvement in emotional
regulation of MD has not been studied enough.
Understanding functional mechanisms of the PFC regions allows us
to realize how cognition and emotion interact in MD. MD is character-
ized by emotional dysregulation as hallmark feature of depression
(Davidson et al., 2002). It appears that there are several cognitive
mechanisms underlying emotion dysregulation in MD. One such
mechanism is biased cognitive processing resulting from deficits in
WM and inhibitory processes (Gotlib and Joormann, 2010). In
situations with abnormalities in the PFC like MD, these cognitive
control components are impaired and negatively affect processing of
emotional information. Inability to initiate and maintain attention
toward both positive and negative emotional materials (Sánchez-
Navarro et al., 2014; Duque and Vázquez, 2015), impaired strategy
utilization in confronting emotional stimuli (Hertel, 2000), hypersen-
sitivity to negative events and affects (Gotlib and Joormann, 2010), and
negative self-referential processing (Lemogne et al., 2010) are some
emotional consequences of impaired cognitive control in MD.
The other PFC-driven mechanism involved in MD is cognitive
regulation of emotions which is suggested to modulate emotional
responsiveness (Ochsner and Gross, 2005). Cognitive regulation mod-
erates unpleasant experience, neutralizes negative experience and
might decrease physiological arousal (Gross, 2002; Salehinejad et al.,
2017) and attentional control, as a function of the PFC, is one of the
major types of cognitive regulation (Ochsner and Gross, 2005). In sum,
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Journal of Affective Disorders 210 (2017) 241–248
negative affects and emotion dysregulation in MD are associated with
impaired cognitive control that are related to functional and structural
abnormalities in the dLPFC. Therefore, by improving cognitive control
functions, such as WM and attention, it is not surprising to expect
emotion regulation and therapeutic effects in MD.
Results of the present study support the above notion. Based on the
“imbalance hypothesis of MD” (Grimm et al., 2008) and neurocognitive
model of depression characterized by dLPFC hypoactivity (Plewnia
et al., 2015), we applied a specific tDCS montage to increase and
decrease cortical activity in the left and right dLPFC respectively in
order to improve WM and attention and see how such improvement
affects depressive symptoms. Results showed a significant improve-
ment in WM and attention scores of participants after dLPFC tDCS. A
significant improvement was also observed in mood scores of patients
which we think is related to improved cognitive control deficits in MD.
An improved WM helps to better direct and guide responses to
emotional materials by maintaining all emotional information and
not just the negative one, online and available; improved attentional
control after dLPFC tDCS also enables a depressed patient to initiate
and maintain attention toward negative and positive emotional stimuli
in an unbiased way. Consequently, a functional cognitive control allows
depressed people to process emotional and neutral stimuli unbiasedly
(Plewnia et al., 2015) and enables them to utilize good-enough strategy
in emotional situations (e.g., withdrawal form negative affects). Such
improved cognitive control also modulates hypersensitivity to negative
emotions as a result of unbiased attentional processing of emotional
materials (Ochsner and Gross, 2005). This is also aligned with studies
showing that people who have more left-sided frontal activation are
better able to voluntarily suppress negative emotion (Jackson et al.,
2000). This study therefore suggests that emotional dysregulation, is
significantly associated with dysfunctional cognitive control of the PFC
and by improving cognitive control functions we can expect an
improvement in depression symptoms.
What our study found is considerable from several points: first of
all, it supported the notion that the interaction between emotion and
cognition in depression psychopathology is at least partly mediated by
cognitive components. That is, the emotional dysregulation in depres-
sion might result from impaired cognitive control functions caused by
abnormalities in the dLPFC and supports the cognitive dysfunction
treatment in MD. However, it should be noted that the present study
cannot claim a causal role of cognitive components in emotional
dysregulation observed in MD as we could not control for other
possible mediating variables. The findings rather suggest that cognitive
control components are considerably associated with emotional dysre-
gulation in MD. Although numerous studies reported therapeutic
effects in depression after modulating cortical activity (Kalu et al.,
2012; Nitsche et al., 2009b), few of them emphasized on the role of
cognitive functions in both psychopathology and treatment of depres-
sion (Hammar and Årdal, 2009).
A recent tDCS study investigated whether cognitive effects of tDCS
are associated with changes in depressive symptoms or not (Brunoni
et al., 2016). Although the study found robust depression improvement
but no beneficial or deleterious cognitive effects of tDCS was reported.
Results of Brunoni et al. (2016) study should be considered from
several aspects: first of all, their sample included moderately depressed
individuals with normal cognitive scores at baseline while tDCS effects
are shown to be more effective in populations with more severe
cognitive deficits (Hill et al., 2016). Secondly, neurpsychological
assessments were measured after 6 weeks of treatment and it is
possible that cognitive improvement and the emotional regulation
associated with it occurred immediately after or during the daily tDCS
phase. Finally, the tasks used in the study were not sensitive or specific
enough to detect cognitive changes (Brunoni et al., 2016) and the
authors recommended using computerized cognitive tasks that are
sensitive to the dLPFC activity and collecting both accuracy and
reaction time in future studies. In our study however, we applied a
M.A. Salehinejad et al.
computerized battery sensitive to frontal lobe functions which was
attentionaly demanding and sensitive to passage of electrical current
on the frontal lobe (Falconer et al., 2010). We also measured both
accuracy and reaction time of patients in cognitive tasks.
In addition to cognitive control dysfunction and its association with
MD psychopathology, our study suggests a tDCS montage for treating
cognitive deficits in depression. Almost all studies evaluating tDCS
effects on WM and attention in MD, applied anodal stimulation over
the l-dLPFC while applying cathodal stimulation over the right supra-
orbital area. These studies mostly emphasized on improving WM not
necessarily as a way to improve emotional regulation in MD (Fregni
et al., 2006; Loo et al., 2012). However, our study proposes that
application of anodal tDCS over the l-dLPFC concurrently with
cathodal tDCS over the r-dLPFC, modulates imbalanced cortical
activity in the dLPFC and thus improves cognitive control components,
which is supposed to improve emotional dysregulation in MD. This
specific tDCS montage is based on the “imbalance hypothesis of MD”
according to which there is a hyperactivity in the contralateral regions
of the l-dLPFC (Grimm et al., 2008). Cathodal stimulation over the r-
dLPFC would theoretically decrease the r-dLPFC activity and thus
facilitates cognitive enhancement (Brunoni et al., 2016).
It is noteworthy that the present study cannot suggest a causal
relationship between cognitive components and MD psychopathology
despite the fact that the tDCS montage used in this study was a
cognitive-enhancing montage based on the PFC-related cognitive
dysfunctions and is the suggested montage for cognitive treatment of
MD (Brunoni et al., 2016). For example, it is possible that cognitive
dysfunction is improved by reduction in depression symptoms. The
methodology and analysis used in this study cannot suggest such causal
relationship and to draw such conclusion, future studies need to
replicate the findings by controlling emotional components. The
findings of the present study would at most suggest that cognitive
components are significantly involved in psychopathology and emo-
tional dysregulation in MD which is consistent with the well-known
cognitive theories of depression and the “imbalance hypothesis” of MD
and If this is the case, then a cognitive conceptualization of MD
psychopathology may be more benefitial to MD patients and research-
ers in this field..
Future studies are recommended to consider several points our
study lacked. In term of study design it would be better to add a follow-
up investigation of tDCS effects on dependent variables to see if there is
long-term effect of tDCS on cognitive deficits and mood. Some studies
suggest that cognitive improvement would occur immediately after or
during the early tDCS phase and fade away afterwards (Brunoni et al.,
2016). Secondly, it is suggested to use more sensitive emotional
measurement in addition to the BDI and HDRS that measures
emotional functions specially the tasks involving emotional biases such
as emotional Stroop or using emotional faces in the "dot probe"
paradigm. Neuropsychological investigation of negativity bias would
also be helpful in future neuromodulation studies. Low-focality of tDCS
could also affects adjacent areas and hinder montage specificity.
Our results also provide supporting document for application of the
tDCS, as a method of cognitive enhancement (Parkin et al., 2015), in
the field of cognitive rehabilitation that attempts to apply new
techniques for improving cognitive impairments (Ponsford, 2004).
However, this study is not to suggest tDCS as the best treatment
option for MD. Instead it suggests that cognitive improvement would
be a key factor in MD treatment. Lastly, given the improving effects of
tDCS on cognitive deficits in MD, electrical stimulation of the brain
could be used as supplemental technique to maximize therapeutic
effect of psychological interventions in disorders marked with signifi-
cant cognitive deficits such as MD (D’Urso et al., 2013) which could be
an interesting future research avenue.
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Journal of Affective Disorders 210 (2017) 241–248
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Acknowledgments
We appreciate anonymous reviewers for their helpful and insightful
comments. We also thank patients for participating in the study.
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