Biological Psychology 99 (2014) 100–114

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Biological Psychology
journal homepage: www.elsevier.com/locate/biopsycho

The error processing system in major depressive disorder: Cortical

phenotypal marker hypothesis
Poppy L.A. Schoenberg a,b,c,∗
a
Faculty of Science, Intelligent Systems, Radboud University Nijmegen, The Netherlands
b
Department of Cognitive Neuroscience, University Medical Centre Nijmegen, The Netherlands
c
Netherlands Institute for Advanced Study, Wassenaar, The Netherlands

a r t i c l e i n f o a b s t r a c t

Article history: Major depressive disorder (MDD) ensues reduced goal-directed cognition and behaviour. Cognitive and
Received 17 April 2013 emotional flexibility to disengage and adapt future responses was examined in the error processing sys-
Accepted 19 March 2014 tem (error-related negativity/ERN, error-positivity/Pe event-related potentials) of 58 depressed patients
Available online 26 March 2014
(21 current, 37 remitted) vs. 27 controls undergoing cognitive and affective Go/NoGo paradigms. ERN
was equivalent between patient and controls for the cognitive task, albeit amplitude attenuated in
Keywords:
patients during the affective task. Blunted ERN amplitudes were evident between patients and controls
Major depressive disorder
in males compared to females, plausibly underpinned by disparities in dopaminergic pathways. Patients
ERN
Pe
displayed enhanced Pe amplitudes for both cognitive and affective tasks. Abberations in cortical error
ERP processing in MDD appear specific to affective systems for the pre-attentive ERN, opposed to cognitive
Error processing system and affective processing for the consciously-integrated Pe. Heightened Pe, observed in both current and
Phenotypal marker remitted patients, advocates the possibility of the Pe waveform as a candidate intermediate phenotype
of depression.
© 2014 Elsevier B.V. All rights reserved.

1. Introduction
Major depressive disorder (MDD) is an intensely debilitating
psychiatric condition, with an estimated 75–85% risk of lifetime
recurrence, marked by severe detriments in functioning and quality
of life (Greden, 2001; Lai, 2011). Higher prevalence and greater risk
have been identified in females compared to males (Kessler, Chiu,
Demler, Merikangas, & Walters, 2005), although predominantly
psycho-social factors have explored this apparent pattern (Nolen-
Hoeksema, 2001; Piccinelli & Wilkinson, 2000). Furthermore, the
disorder appears to be moderately heritable with particular sur-
mised candidate genetic factors predisposing higher liability to
MDD (for comprehensive reviews, see Elder & Mosack, 2011;
Levinson, 2006).
Converging evidence suggests MDD reflects a complex cul-
mination of affective and cognitive deficits, characterised by
valence-specific maladaptions, such as hyperfocus and sensitivity
to negative stimuli, impaired cognitive control in processing nega-
tive stimuli (Fossati, 2008), and an inability to disengage from asso-
ciated negative emotionality and experience (Foland-Ross et al.,
∗ Correspondence to: Radboud University Nijmegen, Postbus 9010, 6500GL,
Nijmegen, The Netherlands. Tel.: +31 24 365 2632; fax: +31 24 365 2728.
E-mail addresses: schoenberg@scientist.com, P.Schoenberg@cs.ru.nl
2013). How these affective and cognitive dynamics operate mech-
anistically within MDD, and to what extent they are interrelated,
are yet to be precisely formulated within a pathophysiological
system.
Two principle neuroanatomical structures correlate to the aeti-
ology and maintenance of MDD. Namely, the prefrontal cortex (PFC:
BA 10) and the anterior cingulate cortex (ACC: BA 24, 32, 33), asso-
ciated with, particularly emotion, self-regulatory circuitries of the
brain (Maletic et al., 2007), paradox to their mediatory roles in
cognitively engaging tasks. Sub-systems of the PFC, i.e. the ventro-
medial and lateral orbital PFC, are associated with basal regulative
states related to mood, aggression, pain processing, and perser-
vatory behaviour. These regions also mediate more cognitively
demanding processes in collaboration with the dorsolateral PFC,
specifically executive functioning, working memory, and sustained
attention (Bush, Luu, & Posner, 2000; Maletic et al., 2007). Col-
lectively, ventromedial prefrontal-subcortical regions transduce
information from key cortical pathways related to an array of cog-
nitive and affective domains towards the generation of affective
meaning and subsequent goal-directed emotional response and
behaviour (Roy, Shohamy, & Wager, 2012).
The ACC is analogous to an epicentral monitoring hub of the
complex transmittal network within the brain, whose primary role
is to gauge conflicts between brain regions elicited to opposing
response options, and activate further processing via the PFC for

http://dx.doi.org/10.1016/j.biopsycho.2014.03.005
0301-0511/© 2014 Elsevier B.V. All rights reserved.
 P.L.A. Schoenberg / Biological Psychology 99 (2014) 100–114
subsequent performance monitoring towards goal-directed out-
comes. Sub-components of the ACC indicate diverging mechanisms,
such as the mediation of cognitive and executive functioning asso-
ciated with the dorsal ACC, contrary to the ventral ACC involved
in the processing of affective information and adaptive response
(Bush et al., 2000). Moreover, the ACC is purportedly an anatomi-
cal generator associated with the brain’s error processing system,
alongside reciprocal interplays with regions of the PFC and basal
ganglia (Falkenstein et al., 2001; Ullsperger & von Cramon, 2004).
Electroencephalographic (EEG) recordings have shown this sys-
tem can be temporally mapped from tasks designed to elicit error
responses, reflected by an early negative voltage event-related
potential (ERP), the error-related negativity (ERN), and recipro-
cal correct-related negativity (CRN), peaking around 50–150 ms.
A later evoked (200–400 ms) positive voltage ERP, the error-
positivity (Pe) and reciprocal correct-positivity (Pc), are evoked in
response to consciously detected error-making.
Remaining a point of contention, the ERN component rep-
resents a polyfactorial cortical index of error processing, such
as overall activation of the error detection system to mismatch
(Gehring, Goss, Coles, Meyer, & Donchin, 1993; Vidal, Hasbroucq,
Grapperon, & Bonnet, 2000), conflict monitoring generated by error
vs. correct response choice (Yeung, Botvinick, & Cohen, 2004), an
emotional index of error processing (Luu, Collins, & Tucker, 2000),
or the interplay between these cognitive and affective dynam-
ics (Yeung, 2004). The later neural correlate of error processing
(the Pe), is thought to reflect error awareness and affective
evaluation to error significance (Falkenstein, 2004; Nieuwenhuis,
Ridderinkhof, Blom, Band, & Kok, 2001; Overbeek, Nieuwenhuis, &
Ridderinkhof, 2005). Minimal preceding research pertains to error
processing ERPs in MDD, despite presenting a logical avenue of
inquiry based on excessive sensitivity to negative cues charac-
terised by the illness. Extant studies indicate patients suffering a
current depressive episode yield significantly higher ERN ampli-
tude compared to non-depressed controls (Chiu & Deldin, 2007),
also found in a small sample of patients with moderate depres-
sion (Holmes & Pizzagalli, 2010). The variant feedback-dependent
ERN presents blunted amplitude for post-error trials (negative
feedback-dependent) in remitted depressed patients compared to
healthy controls (Ruchsow et al., 2004, 2006). Attenuated ERN
amplitudes are also present in children and adolescents with MDD
(Ladouceur et al., 2012), suggesting neural expression is mediated
by degrees of illness severity and brain maturation. Severity of
illness, clinical co-morbidity, and maturation potentially modu-
late contradictory directions in the Pe waveform within MDD. For
example, geriatric depressed patients (Alexopoulos et al., 2007),
and patients with psychomotor retardation (Schrijvers et al., 2008)
show reduced Pe amplitude, whereas these findings have not been
replicated elsewhere (Chiu & Deldin, 2007; Holmes & Pizzagalli,
2008).
One aim of this investigation was to examine further whether
cortical aberrations in error processing in MDD have implications
for the global waveform, or are specific to early (ERN) or late (Pe)
ERP components. Based on heightened sensitivity to negative cues,
it was predicted enhancements in both components of the wave-
form would be observed in patients. A related question inquired
whether these aberrations in error processing operate relative to
cognitive or affective functioning, and to what extent dysregulation
in cognitive and affective dynamics are interrelated in MDD? Thus,
two experiments utilising similar paradigms were conducted; a
cognitive Go/No-Go task presenting letter stimuli, and an affective
Go/No-Go task comprising valenced word stimuli.
Moreover, despite the apparent female preponderance in the
prevalence, morbidity risk, and incidence related to MDD, possible
sex-related differences in the neural substrates of cognitive and
affective processing which may account for such remain relatively
101
unexamined and undefined. Non-clinical studies allude healthy
males present enhanced ERN and N2, also regulated by the ACC dur-
ing conflict monitoring, amplitudes compared to females (Clayson,
Clawson, & Larson, 2011; Larson, South, & Clayson, 2011), suggest-
ing overall males require greater ACC activation to engage similar
levels of performance monitoring as females (Li, Huang, Constable,
& Sinha, 2006). This pattern is mediated by anxiety, where ERN
amplitudes significantly increase in females scoring high in the
worry dimension (Moran, Taylor, & Moser, 2012). Thus, a sup-
plementary line of interest was to examine whether sex-related
cortical differences in performance monitoring, specific to error
processing, present in healthy populations diverge in depression,
potentially contributing towards a neural explanation for report-
edly dissimilar female/male depressive symptom prevalence and
expression.
Coupled with MDD’s genetic heritability, a final encompass-
ing aim was to explore the concept that aberrations in error
processing may represent an intermediate cortical phenotypal
marker, expressing underlying dysfunction and dysregulation in
neurophysiological and neurotransmissional systems associated
with the examined ERPs, potentially useful for wider research clas-
sifying endophenotypes.
2. Experiment I: cognitive error processing
2.1. Methods
2.1.1. Sample
Table 1 illustrates demographic and clinical measures. Overall, 85 participants;
27 HCs recruited via public advertisements, and 58 depressed patients (21 current,
37 remitted) were recruited via the Radboud University Medical Centre Nijmegen
(UMCN) psychiatric clinic and associated UMCN Mindfulness Centre. Patients were
either currently being treated at the UMCN or undergoing an intake assessment
to receive treatment, and were screened for eligibility to take part in the research
by a specialist team at the clinic. Patient inclusion criteria comprised current pri-
mary DSM-IV-TR diagnosis of major depressive disorder, diagnosed by a qualified
consultant psychiatrist, in people aged 21–65 years. Current or remitted depres-
sion was classified by the Mini-International Neuropsychiatric Interview (M.I.N.I:
Sheehan et al., 1998). Included patients (current/remitted) had suffered between 1
and 3 previous episodes. Exclusion criteria (also for HCs) were alcohol/substance
abuse/dependence within the last 6 months, current or previous co-morbid bipolar
disorder-, psychosis-, obsessive compulsive disorder-, eating disorders-, personality
disorders-, neurological disorders (e.g. ADHD, ASDs, epilepsy)-, and learning dif-
ficulties. Informed written consent to participate in an ethically approved (CMO,
Arnhem-Nijmegen) research study was obtained.
2.1.2. Cognitive Go/NoGo task
Five letters (A, F, H, Y, X): h = 2 cm, w = 1.5 cm, white on black background, were
sequentially presented in random order. Overall, 495 stimuli (393 Go, 99 NoGo = 20%
inhibition rate) were presented in 3 × 165 stimuli blocks, with rest intervals between
each block. Stimulus duration was 500 ms, with a randomised interstimulus inter-
val (ISI) between 750 and 2200 ms. Participants were instructed to press a button
as quickly and accurately as possible whenever the letters ‘A’, ‘F’, ‘H’, or ‘Y’ were
presented, and to not press whenever an ‘X’ was presented. Before recording, a 30
stimuli (24 Go) practise block ensured task comprehension.
2.1.3. Electrophysiological recording
EEG data were acquired using Brain Vision Recorder 1.03 and QuikAmps 72 hard-
ware (www.BrainProducts.com), recorded from 30 Ag/AgCl active electrode sensors
with integrated noise subtraction circuits (actiCAP: Brain Products) located in accor-
dance with the 10–10 electrode system (sites: Fp1, Fp2, AFz, F7, F3, Fz, F4, F8, FC5,
FC1, FCz, FC2, FC6, T7, C3, Cz, C4, T8, CP5, CP1, CP2, CP6, P7, P3, Pz, P4, P8, O1, Oz,
O2). Average online reference was used, and referenced to the right mastoid offline.
Ground electrode was placed on the forehead. Vertical and horizontal ocular activity
were calculated by bipolar derivations of electro-oculogram signals recorded using
Ag/AgCl cup electrodes above and below the left eye, and 1 cm to the outer can-
thi of each eye, respectively. Impedance was maintained ≤10 K. Electrical signal
was continuously sampled at a digitization rate of 500 Hz, with a band-pass filter of
0.1–100 Hz.
2.1.4. Signal processing
ERP analysis was conducted using Brain Vision Analyzer 2.0.2. Data were fil-
tered between 0.1 and 30 Hz (24-dB/octave slope), using zero-phase shift band-pass
(Infinite Impulse Response Butterworth) filters, and a 50 Hz notch. Occular arte-
facts were corrected using the regression method (Gratton, Coles, & Donchin, 1983).
102 P.L.A. Schoenberg / Biological Psychology 99 (2014) 100–114

Table 1
Demographic and clinical data.

Demographic Patients Controls Between-group comparison

All (CD + RD) CD RD Patients vs. HC CD vs. RD

Age/Range 49.2 (10.3)/24–64 47.5 (9.5)/24–61 50.2 (10.7)/25–64 48.9 (7.7)/37–60 F = 0.023, p = 0.88 F = 0.902, p = 0.35
Sex: F/M (%) 37/21 [64/36] 16/5 [76/24] 21/16 [57/43] 16/11 [59/41] 2 = 2.781, p = 0.60 2 = 2.190, p = 0.14
Medicated: Y/N (%) 40/18 [69/31] 17/4 [81/19] 23/14 [62/38] – – 2 = 2.210, p = 0.14
Educationa 4.94 (1.9) 4.22 (2.0) 5.33 (1.8) 5.48 (1.6) 2 = 5.472, p = 0.60 2 = 9.183, p = 0.24
Clinical Variable
IDSb 25.9 (11.0) 33.3 (11.0) 22.0 (8.9) 7.3 (6.2) F = 64.130, p < 0.0001*** F = 13.336, p = 0.001**
STAI-Sb 39.5 (10.3) 43.0 (12.0) 37.6 (8.9) 29.4 (8.1) F = 17.710, p < 0.0001*** F = 10.912, p < 0.0001***
a
Education categories (according to education system in the Netherlands): 1 = LWOO (pre-vocational education with learning support), 2 = VMBO (12–16 yrs), 3 = HAVO
(12–17 yrs), 4 = VWO (12–18 yrs), 5 = MBO (16–20 yrs), 6 = HBO (vocational/professional training), 7 = WO (university level higher education/training).
b
IDS: Inventory of Depressive Symptomatology (Rush, Gullion, Basco, Jarrett, & Trivedi, 1996), STAI (* clinically relevant scores = >45): State-Trait Anxiety Inventory
(Spielberger, Gorsuch, Lushene, Vagg, & Jacobs, 1983).

Data were segmented into the following epochs (length = −200 to 600 ms relative 2.2.2. Event-related potentials (ERPs)
to response or stimulus onset): (1) response-locked false alarms to NoGo stimuli Four ERP datasets (1CD, 2RD, 1 HC) were dropped from the
(FA), (2) response-locked correct hits to Go stimuli (CH). Data were baseline cor-
analyses due to having too few error trials (<5) available for the
rected from −200 to −50 ms epochs. Visual inspection of individual participant
averages defined error processing ERPs within the following temporal epochs: ERN ERN/Pe ERP averaging procedure. Of the remaining statistically
(30–150 ms), Pe (200–450 ms) on false alarm (FA) trials to NoGo stimuli; and CRN viable N = 81 sample, there were no significant differences between
(30–150 ms), Pc (200–450 ms) on correctly rejected NoGo trials. Individual averages groups pertaining to the mean (SD), and range, of the number of tri-
for each valence condition were then calculated, prior to grand average calculation. als used to calculate individual averages for the ERN/Pe. As follows:
The adaptive mean value around the identified peak amplitude, specifically defined
as 3−/+ data points (12 ms) within each ERP temporal epoch, were extracted for sub-
3-level Group (CD, RD, HC) (p = 0.31: CD = X̄21.0( 13.8), range
sequent statistical analyses. Adaptive mean ERP amplitude has been suggested to 5–49; RD = 17.5 (10.3), range 5–40; HC = 15.9 (8.7), range 5–34); 2-
offset low signal-to-noise ratio more reliably whilst maintaining individual ERP vari- level Group (patients, HCs) (p = 0.28: patients = 18.6 (11.6), range
ability (Clayson, Baldwin, & Larson, 2012). It should be noted, the peak amplitude 5–49; HC = above). Topographical voltage maps for the ERN and Pe
measure was also analysed, whereby overall results concurred with the adaptive
components are presented in Fig. 1.
mean amplitude extraction, albeit due to reportage length confines are not explicitly
reported hereafter.
2.2.2.1. ERN/CRN. A significant main effect of Condition (F(1,
2.1.5. Statistical analyses 78) = 122.977, p < 0.0001), but no main effect of 3-level Group
Data from the FCz electrode were used in statistical analyses, as ERN and Pe (p = 0.38), were apparent. Examining both 2-level Group (patients
adaptive mean amplitudes were maximal at this site across groups for both compo- vs. HC) and Sex IVs, main effect of Condition (p < 0.0001) was con-
nents.
firmed. There was no main effect of Group (p = 0.10), although
Condition (Go, NoGo) × Group (CD, RD, HC) repeated-measures ANOVA (r-
ANOVA), with Greenhouse Geisser correction where appropriate, examined significant Group × Sex (F(1, 77) = 6.156, p = 0.02) and trend Condi-
ERN/CRN and Pe/Pc amplitude and latency measures separately. Posthoc contrasts tion × Group × Sex (F(1, 77) = 3.361, p = 0.07) interactions revealed
were examined using the conservative Scheffe test to avoid Type I errors. male patients had significantly lower ERN amplitudes compared
Sex was also examined as an IV via a Condition × Group × Sex r-ANOVA.
to male HCs (F(1, 30) = 7.584, p = 0.01 – (♂patients: −6.8 (5.7) ␮V
However, due to lower, and unequal, patient numbers per cell for CD and RD
when also stratified by Sex; Group was defined by 2-levels for these analyses,
vs. ♂HCs: −13.3 (7.2) ␮V), see Fig. 2). The opposite, of higher ERN
i.e. patient (CD + RD) vs. HC, so to maintain viable statistical power. Multivari- amplitude, was evident in female patients compared to female HCs,
ate GLM analysed behavioural measures, i.e. number of correct hits (CH), false albeit to non-significant levels (p = 0.53–(♀patients: −9.4 (7.8) ␮V
alarms (FA), correct NoGo (C-NoGo), error of omission (EoO), and response vs. ♀HCs: −7.9 (5.5) ␮V).
time (RT) data. Significant findings were followed up with posthoc one-way
Examining latency, main effect of Condition (F(1, 78) = 5.823,
ANOVAs.
p = 0.02), but not 3-level Group (p = 0.13), were evident. How-
ever, main effect of 2-level Group (F(1, 77) = 3.921, p = 0.05),
2.2. Results and Group × Sex (F(1, 77) = 4.957, p = 0.03) interaction, illustrated
male patients yielded overall slower latencies compared to male
2.2.1. Task measures HCs, and significantly so for CRN (F(1, 30) = 4.788, p = 0.04 –
Two behavioural log-files (1 patient) were corrupted by a tech- (♂patients: 71.9 (50.9) ms vs. ♂HCs: 37.8 (8.8) ms)). A less clear
nical failure, thus absent from the statistical analyses. Performance pattern was evident with regards to latency data between female
data are outlined in Table 2. Patients yielded slower RTs for FAs groups.
compared to HCs (Table 2).
2.2.2.2. Pe/Pc. Pe amplitudes were greater than Pc for all groups
(F(1, 78) = 126.897, p < 0.0001). Main effect of 3-level Group (F(2,
Table 2
Accuracy number (N) and reaction times (RT) for the cognitive Go/NoGo task in 78) = 4.029, p = 0.022), illustrated both CD and RD patients had
patients vs. healthy controls. higher amplitudes compared to HCs, significantly so between RD
patients and HCs (Scheffe p = 0.04 – (RD patients: 12.7 (6.1) ␮V
Patient () X̄ Control () X̄ Comparison
vs. HCs: 9.4 (3.2) ␮V)), and approaching significance between CD
FA (N) 19.4 (12.5) 15.5 (9.4) p = 0.16 patients and HCs (Scheffe p = 0.07 – (CD patients: 12.9 (6.0) ␮V)).
FA (RT) 325.3 (52.1) 307.9 (32.2) p = 0.12
CH (N) 392.8 (6.8) 395.0 (1.5) p = 0.12
Examining 2-level Group × Sex IVs: main effect of Condition
CH (RT) 398.9 (53.9) 413.8 (58.7) p = 0.26 (F(1, 77) = 97.134, p < 0.0001) was confirmed. A main effect of
C-NoGo 79.6 (12.5) 83.5 (9.4) p = 0.16 Group (F(1, 77) = 7.345, p = 0.008), and Condition × Group (F(1,
EoO (N) 3.2 (6.8) 1.0 (1.5) p = 0.12 77) = 4.420, p = 0.04) interaction was also confirmed, i.e. patients
FA, false alarms to NoGo stimuli; CH, correct hits to Go stimuli; C-NoGo, correctly yielded enhanced Pe amplitudes compared to HCs (Fig. 3).
rejected NoGo stimuli; EoO, error of omission to Go stimuli. Lack of significant main effect of Sex (p = 0.64), or Group × Sex
 P.L.A. Schoenberg / Biological Psychology 99 (2014) 100–114 103

Fig. 1. Topographical maps for ERN (left) and Pe (right) epochs in patients (above) compared to HCs (below) during the cognitive Go/NoGo task. (For interpretation of the
references to color in this figure legend, the reader is referred to the web version of the article.)

interaction (p = 0.70), reflected this was true for both female
and male data. Interestingly, follow-up ANOVAs revealed female
patients yielded significantly higher Pe amplitudes compared
to female HCs (F(1, 49) = 4.808, p = 0.033 – (♀patients: 12.6
(6.0) ␮V vs. ♀HCs: 9.0 (3.33) ␮V)), not found in the male data
(p = 0.15–(♂patients: 12.9 (6.1) ␮V vs. ♂HCs: 10.0 (3.1) ␮V)).
There were no significant findings pertaining to latency
measures.
3. Experiment II: affective error processing
3.1. Method
The sample and electrophysiological (online) recording protocol
was the same as Experiment I (see Sections 2.1.1 and 2.1.3). Task
presentation order was counter-balanced.

3.1.1. Affective Go/NoGo task

2.2.3. Medication effects
Although number of medicated (n = 40) vs. non-medicated
(n = 18) patients was not statistically significant, multi-variate
GLM analysis was conducted with medication status cate-
gory as fixed factor, to rule out the possibility that the
found neurophysiological differences between patients and
HCs were not due to anti-depressant pharmacology. No sig-
nificant differences for any of the ERP (amplitude/latency)
measures between medicated and non-medicated patients were
found.
The task comprised 12 × 100 stimuli blocks with rest inter-
vals between each block. Stimuli consisted of positive, negative,
and neutral Dutch words extracted from two standardised word
databases rating/categorising words by valence (refer to, 1.
Arnold et al., 2011; Fitzgerald et al., 2011; and 2. Hermans
& De Houwer, 1994). Each block consisted of two possible
“word valence types” defined as Go or NoGo stimuli within
each block (80 × Go − 20 × NoGo (20% inhibition rate)), consti-
tuting six possible “block types” (i.e.: 1. Positive (Go)-Negative
(NoGo); 2. Positive-Neutral; 3. Negative-Positive; 4. Negative-
Neutral; 5. Neutral-Positive; 6. Neutral-Negative). Each block type
104 P.L.A. Schoenberg / Biological Psychology 99 (2014) 100–114
Fig. 2. Cognitive Go/NoGo task: False Alarms to NoGo stimuli at FCz for females (green) vs. male data (black) in patients (thick) and HCs (thin) (0 ms = response onset). (For
interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
was repeated in the experimental constituting 12 overall randomly
presented blocks, where word stimuli were randomly presented
within each block. Within the overall experiment, 600 different
words were used to reduce stimuli habituation/familiarity. Stim-
ulus duration was randomly presented between 500 and 1500 ms,
with a randomised ISI between 800 and 1750 ms. Prior to each block
standardised instructions were given onscreen, verified verbally by
the experimenter, indicating which word valence to press vs. not
press for, of the two possible valence types included in the forth-
coming presented block. Instruction presentation doubled as a rest
period, the duration of which was determined by the participant.
3.1.2. Signal analysis
Evoked potentials were extracted using the same signal
processing parameters as Experiment I (Sections 2.1.3 and 2.1.4).
However, data were segmented into response-locked CH and FA
trials also categorised by valence block type, i.e. POS, NEG, and
NEU stimuli. Adaptive mean amplitudes were maximal at FCz for
the ERN component across groups, and at Pz for the Pe compo-
nent in HCs, compared to FCz for POS and NEG stimuli and Pz
for NEU stimuli in patients. As such, subsequent statistical anal-
yses included FCz electrode data for the ERN, further to FCz and Pz
electrode sites for analyses on the Pe component.
3.1.3. Statistical analysis
Condition (ERN, CRN) × Valence (POS, NEG, NEU) × 3-
level Group (CD, RD, HC), and Condition × Valence × Site
(FCz/ + Pz) × 3-level Group, r-ANOVAs analysed ERN and Pe
amplitude and latency data, respectively. The r-ANOVAs were
re-run with 2-level Group (patient vs. HCs) + Sex IVs. Posthoc
contrasts were examined using the conservative Scheffe test, and
Greenhouse Geisser correction was applied when assumptions of
sphericity had been violated. Follow up between subjects com-
parisons utilised one-way ANOVA with applied Scheffe posthoc
contrasts.
3.2. Results
Three patients (1 CD) and one HC did not participate in this task
because Dutch was not their first language.
3.2.1. Behavioural data
Behavioural log-files for five participants (1 CD, 3RD, 1HC) were
corrupted due to technical equipment failure, so could not be
included in the behavioural statistical analyses.
Main effect of Group for CH response time (RT) to NEG stimuli
(F(2, 73) = 3.092, p = 0.05), revealed CD patients yielded faster RTs
(see Table 2) compared to RD (Scheffe, p = 0.99) and HCs (Scheffe,
p = 0.09), although posthoc contrasts indicated differences were
not significant. Main effect of Group for CH rate to NEU stimuli
(F(2, 73) = 4.266, p = 0.02), showed CD yielded fewer CHs com-
pared to RD (Scheffe, p = 0.19), and significantly so compared to
HCs (Scheffe, p = 0.02). Finally, main effect of Group for EoO (erro-
neously omitted Go trials) rate for NEU stimuli (F(2, 73) = 4.291,
 P.L.A. Schoenberg / Biological Psychology 99 (2014) 100–114 105

Fig. 3. Cognitive Go/NoGo task: NoGo (black) and Go (blue) at FCz in patients (thick) vs. healthy controls (thin) for ERN (30–150 ms) and Pe (200–450 ms) waveforms at FCz
(0 ms = response onset). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

p = 0.02), indicated CD patients yielded the most EoOs compared
to RD (Scheffe, p = 0.16), and a significant margin compared to HCs
(Scheffe, p = 0.02) (Table 2).
Two-level Group × Sex analyses, showed main effect of Group
for CH rates to NEU stimuli (F(1, 72) = 5.127, p = 0.03), where
patients yielded fewer CHs (Table 2). Main effect of Group for EoOs
for NEU stimuli (F(1, 72) = 4.837, p = 0.03) revealed patients com-
mitted more EoO. Finally, a main effect of Sex showed females had
consistently faster RTs compared to males across conditions and
significantly so for FAs to NEG stimuli (F(1, 72) = 6.649, p = 0.01 –
(♀: 478.9 (55.2) ms vs. ♂: 519.5 (70.8) ms). However, no Group × Sex
interactions were evident.
3.2.2. Event-related potentials (ERPs)
Two ERP datasets (1RD, 1HC) for POS, four (2RD, 2HC) for
NEG, and seven (2CD, 3RD, 2HC) for NEU valence conditions were
dropped from statistical analyses due to having too few error trials
(<5) available for the ERN/Pe ERP averages. There were no signif-
icant differences in mean (SD), and range of the number of trials
used to calculate ERN/Pe individual averages (Table 3). Topograph-
ical voltage maps for the ERN and Pe components are presented in
Fig. 4a and b.
Two-level Group × Sex IV analyses indicated main effects of
Condition (p < 0.0001), Valence (F(2, 136) = 3.178, p = 0.05), and
Group (F(1, 68) = 7.132, p = 0.009), highlighting a general pat-
tern of lower ERN amplitudes in patients compared to HCs
(Fig. 5). Furthermore, a significant Group × Sex (F(1, 68) = 10.584,
p = 0.002) interaction revealed male patients yielded consistently
lower ERN amplitudes compared to male HCs, for POS (p = 0.07
(♂patients = −1.4(2.7) ␮V vs. ♂HCs = −3.2(1.9) ␮V)), NEG (p = 0.005
(♂patients = −1.5(2.4) ␮V vs. ♂HCs = −4.2(2.0) ␮V)), and NEU
(p = 0.10 (♂patients = −2.4(5.5) ␮V vs. ♂HCs = −5.6(2.4) ␮V)) condi-
tions, not evident between female patients and female HCs. Within
the patient group, female patients yielded consistently higher ERN
amplitudes compared to the male patients, albeit to non-significant
margins. Within the HC group, HC males yielded consistently
higher ERN amplitudes compared to HC females (Fig. 6), signifi-
cantly so for NEG (F(1, 25) = 12.241, p = 0.002 (♀HC = −1.6(1.8) ␮V
vs. ♂HC = −4.2(2.0) ␮V)), and NEU (F(1, 23) = 17.924, p < 0.0001
(♀HC = −2.1(1.7) ␮V vs. ♀HC = −5.6(2.4) ␮V)) conditions.
Examining latency, main effect of Condition was evident for 3-
level (F(1, 69) = 40.579, p < 0.0001), and 2-level (F(1, 68) = 33.365,
p < 0.0001) Group analyses. No main effects of 3-level (p = 0.76), or
2-level (p = 0.56) Group, Sex (p = 0.56), or interactions were found.

3.2.2.1. ERN/CRN. Main effect of Condition (F(1, 69) = 107.913, 3.2.2.2. Pe/Pc. Main effect of Condition (F(1, 74) = 67.962,
p < 0.0001) indicated amplitudes were greater for ERN compared p < 0.0001) revealed amplitudes were greater for Pe than Pc
to CRN across the sample. No main effect of Group (p = 0.16) or across the sample. Significant interactions Condition × Group (F(2,
interactions were found. 74) = 3.059, p = 0.05), Valence × Site × Group (F(4, 148) = 2.453,
 106
Table 3
Accuracy number (N) and reaction times (RT) for affective Go-NoGo task in: (a) patients vs. healthy controls, and (b) current vs. remitted patients.

(a) Patient (CD + RD) (␴)X̄ Control (never-depressed) (␴)X̄ Effects/Interactions

Positive Negative Neutral Positive Negative Neutral 2-level group (patient, HC)

FA (N) 28.5 (11.7) 22.5 (12.1) 22.0 (12.9) 27.9 (7.7) 24.5 (9.2) 23.0 (9.5)
FA (RT) 500.4 (75.9) 496.9 (69.9) 507.4 (83.5) 490.9 (70.8) 487.7 (50.8) 505.0 (60.4) Sex, p = 0.01 (NEG)
CH (N) 283.6 (29.6) 284.0 (36.9) 277.1 (27.8) 288.8 (22.7) 282.7 (32.2) 290.4 (15.0) Group, p = 03 (NEU)

P.L.A. Schoenberg / Biological Psychology 99 (2014) 100–114

CH (RT) 574.33 (69.3) 584.5 (73.4) 568.8 (71.0) 586.9 (54.6) 604.3 (60.5) 574.2 (64.3)
C-NoGo 50.7 (11.9) 56.9 (73.4) 51.8 (11.4) 52.1 (7.7) 59.1 (8.1) 50.4 (11.1)
EoO 36.3 (29.6) 32.9 (31.4) 42.4 (27.9) 31.2 (22.7) 37.3 (32.2) 29.6 (15.0) Group, p = 0.03 (NEU)
No. Trials available 16.33 (10.6), range 5–54 15.2 (9.5), range 5–42 13.6 (10.33), range 5–62 15.8 (6.6), range 5–25 15.1 (7.7), range 5–38 13.1 (4.4), 5–25 POS: p = 0.09
for ERN/Pe ERP
individual
averages
NEG: p = 0.06
NEU: p = 0.17

(b) Current depressed (␴)X̄ Remitted depressed (␴)X̄ 3-level Group (CD, RD, HC)

Positive Negative Neutral Positive Negative Neutral

FA (N) 32.1 (13.9) 25.1 (14.9) 25.2 (16.0) 26.3 (9.8) 21.0 (10.0) 20.0 (10.4)
FA (RT) 481.2 (67.4) 492.3 (69.5) 504.9 (75.2) 511.7 (79.3) 499.5 (71.2) 508.9 (89.3)
CH (N) 286.2 (33.0) 282.2 (36.5) 269.1 (37.0) 282.1 (27.9) 285.1 (37.8) 281.8 (19.6) Group, p = 0.05 (NEG)
Group, p = 0.02 (NEU)
CH (RT) 555.6 (72.6) 557.7 (70.6) 556.2 (80.8) 585.5 (66.0) 600.5 (71.4) 576.2 (64.8)
C-NoGo 47.9 (13.9) 53.2 (16.1) 49.9 (14.0) 52.4 (10.5) 59.1 (9.8) 52.8 (9.6)
EoO 33.8 (33.0) 37.8 (36.5) 50.9 (37.0) 37.9 (27.8) 29.9 (28.2) 37.4 (29.7) Group, p = 0.02 (NEU)
No. Trials available 20.0 (14.0), range 6–54 19.2 (11.4), range 5–42 16.7 (14.4), range 5–62 14.2 (7.4), range 5–32 13.0 (7.6), range 5–32 11.8 (6.8), range 5–27 POS: p = 82
for ERN/Pe ERP
individual
averages
NEG: p = 0.97
NEU: p = 0.84

FA, false alarms to NoGo stimuli; CH, correct hits to Go stimuli; C-NoGo, correctly rejected NoGo stimuli; EoO, error of omission to Go stimuli.
 P.L.A. Schoenberg / Biological Psychology 99 (2014) 100–114 107

p = 0.05), and an overall main effect of 3-level Group (F(2,
74) = 4.534, p = 0.01), indicated HCs yielded consistently lower
amplitudes across valence conditions compared to CD (Scheffe,
p = 0.02), and RD (Scheffe, p = 0.08). A marked pattern highlighted
CD patients had significantly higher Pe amplitudes for NEG
stimuli (Fig. 5) at FCz (CD > HC: Scheffe, p = 0.02 (CD = 8.8(7.3) ␮V;
RD = 7.0(4.0) ␮V; HC = 4.9(2.2) ␮V)), and Pz (CD > HC: Scheffe,
p = 0.01 (CD = 8.9(5.2) ␮V; RD = 6.2(4.6) ␮V; HC = 5.0(2.3) ␮V)). A
further pattern showed RD patients yielded significantly higher
Pe amplitudes for NEU stimuli (Fig. 7), compared to HC at FCz
(RD > HC: Scheffe, p = 0.01(CD = 6.7 (4.7) ␮V; RD = 8.7 (8.2) ␮V;
HC = 4.0(1.9) ␮V)), and Pz (RD > HC: Scheffe, p = 0.05 (CD = 8.1
(3.8) ␮V; RD = 8.1 (7.0) ␮V; HC = 4.8(2.2) ␮V)).
Analyses with 2-level Group × Sex IVs confirmed main effects of
Group (p = 0.01), Condition (p < 0.0001), and Valence × Site × Group
(p = 0.02), in addition to a Condition × Group (F(1, 73) = 5.868,
p = 0.02) interaction. Overall, the patient group showed consis-
tently higher Pe and Pc amplitudes compared to HCs (Fig. 5),
significantly so at FCz and Pz for NEG (FCz: F(1, 80) = 6.005, p = 0.02
(patients = 7.7(5.5) ␮V; HC = 4.9(2.2) ␮V); Pz: F(1, 80) = 4.875,
p = 0.03 (patients = 7.3(4.9) ␮V; HC = 5.0(2.3) ␮V)), and NEU (FCz:
F(1, 78) = 7.845, p = 0.006 (patients = 8.0(7.2) ␮V; HC = 4.0(1.9) ␮V);
Pz (F(1, 78) = 7.534, p = 0.008 (patients = 8.1(6.0) ␮V;
HCs = 4.8(2.2) ␮V))) conditions. There was no main effect of
Sex (p = 0.96), or Group × Sex (p = 0.79) interaction.
Examining latency, main effect of Condition was found for 3-
level (F(1, 74) = 6.946, p = 0.01) and 2-level (F(1, 73) = 4.091, p = 0.05)
Group, indicating generally longer latencies for Pe compared to Pc.
No main effects of 3-level Group (p = 0.15), 2-level Group (p = 0.58),
or Sex (p = 0.28), were evident.
3.2.3. Medication effects
Significant differences exclusively pertained to ERN latency data
for the POS (F(1, 53) = 4.642, p = 0.04 (medicated = 57.6(27.1) ms vs.
non-medicated = 42.5(14.6) ms)), and NEU (F(1, 49) = 6.863, p = 0.01
(medicated = 57.4(27.5) ms vs. non-medicated = 82.9(40.4) ms)),
conditions. No medication effects pertained to amplitude variables.
4. Discussion
The encompassing and intertwining aims of the present
research pertained to examine the cortical error processing system

Fig. 4. (a) Topographical maps for the ERN (left) and Pe (right) epochs in patients (above) compared to HCs (below) for positive NoGo conditions. (b) Topographical maps
for the ERN (left) and Pe (right) epochs in patients (above) compared to HCs (below) for negative NoGo conditions. (For interpretation of the references to color in this figure
legend, the reader is referred to the web version of the article.)
108 P.L.A. Schoenberg / Biological Psychology 99 (2014) 100–114
Fig. 4. (Continued ).
in MDD, specifically; (1) whether aberrations are linked to cogni-
tive and/or affective processing, during early or later mechanistic
neural stages; (2) to explore any sex-related differences in error-
related functionality; (3) to question and contribute towards the
idea that cortical disparities in error processing reflect a possible
intermediate phenotype of depression.
4.1. Early error detection/conflict monitoring
It was hypothesised that non-feedback dependent ERN would
be enhanced in depressed patients due to heightened sensitivity
to error-related information and negative stimuli, ergo, generating
greater activation of a pre-conscious conflict monitoring mecha-
nism in response to errors. This conjecture was not supported by
data from the cognitive task as no significant findings pertained
to ERN/CRN waveforms between patients and healthy controls,
further evidenced by group equivalence in behavioural task perfor-
mance. Moreover, the hypothesis was refuted based on the findings
from the affective Go/NoGo task, whereby an opposite pattern
emerged. That is, globally, patients showed significantly reduced
ERN amplitudes compared to HCs.
Flanker task findings examining the effects of negative feed-
back upon error processing in exclusively remitted patients also
report no comparable differences in error rates, reaction times,
or neurophysiology of the ERN (Ruchsow et al., 2004). However,
within the patient group blunted ERN amplitudes for error trials
preceded by an error were present, but no difference in ERN for
error trials preceded by a correct response. Results were replicated
using an adapted Go/NoGo task (Ruchsow et al., 2006), suggesting
a detrimental perception towards failure and negative feedback
attenuates neurophysiological indexes of error processing within
the disorder, plausibly attributed to hypoactivity of underlying cen-
tral reward pathways associated with the left prefrontal cortex
(Ruchsow et al., 2004). Furthermore, depressed patients presenting
severe symptomatology including anhedonia, apathy, and psy-
chomotor retardation, also show reduced ERN (Schrijvers et al.,
2008).
Increased ERN has been recorded in remitted patients (Holmes
& Pizzagalli, 2008), further to ERN magnitude and symptom sever-
ity positively correlating (Chiu & Deldin, 2007). However, findings
appeared to be mitigated by co-morbid anxiety, suggesting the
neurobiological mechanisms underlying anxiety plausibly have
 P.L.A. Schoenberg / Biological Psychology 99 (2014) 100–114
Fig. 5. Affective Go/NoGo task: False Alarms to NoGo at FCz in for Positive (green), Negative (black), and Neutral (blue) conditions in patients (thick) vs. HCs (thin)
(0 ms = response onset). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
activating effects upon cortical error processing, supported by the
presence of enhanced ERN in anxiety disorders (Endrass, Klawohn,
Schuster, & Kathmann, 2008; Hajcak, McDonald, & Simons, 2003).
In accord with the present study findings, blunted ERN amplitudes
were present in a depressed patient sample with no co-morbidity
anxiety disorders or clinically relevant levels of anxiety at the
time of testing as measured by the STAI. Overall, early phase
error processing in MDD appears dependent upon affective mate-
rial linked to subsequent dysregulation in emotion processing,
rather than exclusive cognitive-based impairment, and viably has
a complex intrinsic relationship with degree of negative affect.
For example, when delaying the feedback signal in a Flanker task,
greater medial frontal negativity waveforms for all feedback types
characterise depressed patients compared to non-depressed con-
trols. However, enhanced neurophysiological response is evident
in moderately depressed, compared to blunted response in the
more severely depressed (Tucker, Luu, Frishkoff, Quiring, & Poulsen,
2003).
Collectively, it could be surmised that attenuated ERN is associ-
ated with greater negative affect and symptom severity, whereas
enhanced ERN activation characterises mild to moderate depres-
sion, plausibly representing a ‘maintenance mechanism’. That is, a
core composite of error processing involves an automatic template
upgrading mechanism to mismatch and related conflict detec-
tion. Thus if heightened, potentially renders vulnerability towards
misinterpreting and perceptually inflating negative environmen-
tal cues, a risk factor for maintaining negatively-biased cognition
109
and mood. During the remissive phase of MDD enhanced activation
in this early juncture of error processing increases vulnerability to
relapse, maintaining the cyclical nature of the disorder. Whereas,
blunted ERN characterises severe symptomatology and covert
cognitive dysfunction specific to emotion processing, adjunct to
emotional and behavioural ‘shut down’, i.e. anhedonia, apathy,
fatigue; clinical hallmarks of full manifestation of the illness.
4.2. Error awareness and evaluative significance
In line with MDD reflecting propensity for greater motiva-
tional salience and evaluation of performance errors (Ridderinkhof,
Ramautar, & Wijnen, 2009), in turn, sensitivity to error aware-
ness (Hughes & Yeung, 2011); globally, higher Pe amplitudes were
apparent in patients compared to controls. Moreover, disentangling
current from remitted depression showed Pe amplitudes were gen-
erally higher in the currently depressed patients, where discernable
heightened neurophysiological response pertained to errors for
negative stimuli. Curiously, higher Pe amplitudes for errors to neu-
tral stimuli were present in the remitted depressed group. The
cognitive task also showed patients to have heightened Pe ampli-
tudes compared to non-depressed controls, although no distinction
between current and remitted depression. These findings suggest
Pe aberrations in MDD are emotion-specific, and also present in
the absence of a current depressive episode, whereby degree of
illness and negative affect appear to have mediating effects upon
the conscious stage of error evaluation.
110 P.L.A. Schoenberg / Biological Psychology 99 (2014) 100–114
Fig. 6. Affective Go/NoGo task: False Alarms to NoGo stimuli at FCz in Female (green)
and Male (black) data for Positive (above), Negative (middle) and Neutral (below)
conditions in patients (thick) vs. HCs (thin) (0 ms = response onset). (For interpreta-
tion of the references to color in this figure legend, the reader is referred to the web
version of the article.)
Extant enquiry into the Pe in MDD remains equivocal. Reduced
Pe has been found in depressed patients with psychomotor slow-
ing (Schrijvers et al., 2008), geriatric MDD patients (Alexopoulos
et al., 2007), and higher anxiety severity in MDD patients (Olvet,
Klein, & Hajcak, 2010). Studies incorporating reward trials in error
eliciting task designs report null results in moderately depressed
patients for non-reward (neutral) and incentive conditions (Chiu &
Deldin, 2007). Further observations cite equivalent Pe waveforms
in moderately depressed patients vs. controls on no-incentive tri-
als, contrary to attenuated Pe amplitude in patients for reward
conditions (Holmes & Pizzagalli, 2010). Blunted Pe observations in
depression may lie with task paradigm rather than symptom sever-
ity, as a study investigating the impact of symptom reduction on
action monitoring ERPs in severely depressed patients found no
correlation between changes in symptom severity after a 7-week
intervention and blunted Pe amplitude. However, one patient was
also diagnosed with post-traumatic stress disorder (PTSD), and a
further two with chronic fatigue syndrome, possibly contaminating
the overall patient sample (n = 15) (Schrijvers et al., 2009).
Enhanced Pe amplitude found here in a larger sample of exclu-
sively MDD patients, supports a concept of ‘error fixation’ in
depression and increased evaluative significance towards errors
made for negatively valenced material. These results corrobo-
rate with neuroimaging studies mapping attentional biases to
negative material in MDD, reporting increased activation in the
rostral anterior cingulate cortex (rACC) and precuneus (Elliott,
Rubenstein, Sahakian, & Dolan, 2000; Mitterschiffthaler et al.,
2008; Vuilleumier, Armony, Driver, & Dolan, 2001), indicating
aberrations in top-down cognitive control of attention to emo-
tional, particularly negatively valenced, stimuli. Moreover, the
fact remitted patients exhibited inflated Pe amplitudes to neu-
tral stimuli is plausibly connected to the inherent vulnerability in
MDD, particularly when acute symptoms have subsided, to inter-
pret ambiguous material as negative (Gur, Erwin, Gur, & Zwil, 1992;
Keeley, Davidson, Crane, Matthews, & Pace, 2007), in turn, sustain-
ing a disposition to experience negative mood states, and potential
vulnerability to relapse.
4.3. Sex differences in error processing in MDD
Neurophysiological differences between female and male
patients were exclusive to the ERN. Overall, male patients showed
consistently lower ERN amplitudes compared to female patients,
for both the cognitive and affective tasks. Reduced monitoring
at this early stage of error processing suggests impaired ACC
regulation. For example, it is proposed that disinhibition of the
ACC is facilitated by dopaminergic neurotransmission (Holroyd
& Coles, 2002); a neuromodulator predominantly involved in
the central cortical reward pathway (Arias-Carrión, Stamelou,
Murillo-Rodríguez, Menéndez-González, & Pöppel, 2010; Munro
et al., 2006), impacting self-regulatory processes and related goal-
directed outputs. Moreover, dopamine is closely linked to the
ERN as the key neurotransmissional modulator for the waveform
(Holroyd & Coles, 2002; Meyer et al., 2012). As such, attenuated
ERN amplitudes in male patients relative to female patients may
have been linked to reduced underlying dopaminergic activity.
In this vein, sex differences in dopaminergic neurotransmis-
sion have found to be primarily dependent upon gonadal steroids,
reflected by enhanced straital dopamine activity, specifically medi-
ated by connection between oestrogen receptors and the basal
ganglia (Di Paolo, 1994), accounting for the general trend for higher
dopamine levels in healthy females compared to healthy males.
Supporting evidence includes Positron Emission Tomography (PET)
studies investigating sex differences in d-amphetamine-induced
dopamine catabolism (Riccardi et al., 2006, 2011), where females
reveal considerably heightened dopamine release in subcortical
 P.L.A. Schoenberg / Biological Psychology 99 (2014) 100–114 111

Fig. 7. Affective Go/NoGo task: False Alarms to NoGo at FCz for Negative condition (sbove) and Neutral condition (below), in CD (black), RD (green), and HCs (blue)
(0 ms = response onset). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
112 P.L.A. Schoenberg / Biological Psychology 99 (2014) 100–114
regions of the globus pallidus and inferior frontal gyrus, specific
to the right hemisphere, in addition to temporal and parietal
cortical areas, thus, greater induced dopamine release glob-
ally within the brain relative to males (Riccardi et al., 2006).
Furthermore, d-amphetamine-induced dopaminergic antagonism
reveals sex-related changes in cognition and affect indexed by
the Stroop task, where increased dopamine release in the subs-
tantia nigra, a key cortical structure connected to the central
reward pathway and regulation of striatal and limbic function-
ing, correlated with positive affect in males only (Riccardi et al.,
2011). Non-clinical studies reveal healthy males demonstrate
higher ERN amplitudes compared to healthy females (Larson
et al., 2011), further to neuroimaging data suggesting males
require increased ACC cortical activity to achieve the similar
behavioural performance of females during performance monitor-
ing (Li et al., 2006). These neuroanatomical findings coupled with
the effects on positive mood in the males, point to consideration
of sex-related differences in dopamine catabolism and neuro-
transmissional release upon associated symptomatic clusters in
MDD.
A recent review found no conclusive data-driven evidence
for discrete symptomatic clinical subtypes within the disorder,
although possible sex-related subtypes were not explored (van Loo,
de Jonge, Romeijn, Kessler, & Schoevers, 2012). Female patients
show a general propensity to experience more somatic-related
problems (Lai, 2011), commonly associated with stress-based
factors (Nolen-Hoeksema, 2001). Increased dopamine release
in the accumbens nucleus within the ventral striatum, has
shown to correlate to perceived stressful environmental cues
(Mora, Segovia, del Arco, de Blas, & Garrido, 2012), indicating
greater dopaminergic system activation, which would translate
to higher ERN amplitudes. Furthermore, stress-induced dopamine
release is largely mediated by functional interaction between
the accumbens nucleus and PFC, the latter interplaying with the
ACC towards ERN generation (Ullsperger & von Cramon, 2004).
Enhanced ERN in the female patient group suggests heightened
dopaminergic activation, contrary to the male patients yield-
ing blunted ERN associated with reduced dopaminergic release
involved in the reward system and processing of motivationally-
salient stimuli. In this vein, males show greater vulnerability to
externalising disorders (Kessler et al., 2005) attributed to dysregu-
lation of the dopaminergic reward system (e.g. ADHD, addiction,
psychopathy), where such disorders also display reduced ERN
amplitudes (Franken, van Strien, Franzek, & van de Wetering,
2007; Herrmann et al., 2010; Littel et al., 2012; Munro et al.,
2007).
The possibility of blunted reward pathway activation in the
male patient group is supported by the reverse pattern observed
in the HC group; HC females had lower ERN amplitude compared
to HC males, in line with the previous findings (Larson et al.,
2011). In non-psychiatric populations, relevant cortical pathways
in males are more strongly affected by anticipated reward than
females (Munro et al., 2006; Spreckelmeyer et al., 2009), where
error-making presents a threat to the neural reward system. Ergo,
beneficial future enquiry may define possible underlying cortical
and biochemical signatures pertaining to sex-related depressive
profiles. Symptoms in females may be underlined and associated
by greater stress response bio-mechanisms, leading to heightened
help-seeking behaviours, perhaps explaining the apparent female
over-representation in this clinical group (Piccinelli & Wilkinson,
2000). Whereas, depressed males may be more vulnerable to
blunted motivational salience and mesolimbic hypoactivity related
to the anticipatory reward pathway. Such exploration could have
implications for treatment programmes, i.e. interventions aiming
to inhibit maladaptive neuromodulatory systems may have opti-
mal success in female patients, whereas those that target and
increase pertinent excitatory neurotransmitter pathways may be
more effective with male patients. Rigorous empirical investiga-
tions are required to explore these theorisations further.
4.4. Limitations
There are several limitations of this research. Adhoc anal-
yses with the (un)/medicated patient samples showed no ERP
amplitude differences attributed to medication status, although
an ideal sample would include non-medicated patients or medica-
tion flush-out preceding EEG recording. Larger participant samples
systematically examining sex-related differences in ERP param-
eters associated with MDD will provide considerable empirical
strength than the findings presented here. Previous research hints
that paradigm design may affect ERP result outcomes in MDD;
replication studies utilising Flanker or Stroop tasks, for example,
may help to consolidate the wider picture regarding the error
processing system in MDD. Furthermore, the affective Go/NoGo
task utilised valenced words for affective stimuli, which incor-
porates a high cognitive element in the semantic processing of
the word to extract emotional content. As such, affective pictorial
stimuli (e.g. IAPS) may have been more appropriate to examine
emotion system involvement in error processing within the disor-
der. Moreover, incorporating a feedback-dependent element to the
design towards error elicitation would aid more substantive theori-
sations regarding the concept of subclinical profiles in depression,
particularly to investigate the plausibility of greater hypoactivity
of the central reward system in male patients, opposed to primary
stress-based neuro-biological systems underlying female patient
aetiology and symptom expression. No explicit measures of verbal
IQ or general IQ assessments were conducted, so we cannot be sure
whether these factors were matched between patients and con-
trols, accounting for ERP anomalies. However, similar behavioural
task performances across groups and matched level of education
suggest such parameters were relatively equal.
4.5. Error processing ERPs as intermediate phenotypes of MDD
Overall, MDD can be characterised by neural abnormalities
of the error processing system. Mesocorticalimbic dysregulation
detrimentally affects dopaminergic reward pathway dynamics, in
turn mediating ERN waveform characteristics. Given the intercon-
nection between the mesolimbic system and PFC, in conjunction
with associated dopamine receptor activity, the ERN presents a
plausible intermediate phenotypal cortical marker for depression.
Albeit, an extant hypothesis (Olvet & Hajcak, 2008) suggests the
ERN waveform represents a non-specific biomarker for internal-
ising disorders (Hajcak, Franklin, Foa, & Simons, 2008), whereby
the empirical findings indicate heightened ERN amplitudes define
anxiety (Hajcak, 2012; Weinberg, Olvet, & Hajcak, 2010 – also find-
ing no differences in the Pe component between GAD patients
and controls), particularly aspects related to worry and apprehen-
sion (meta-analysis: Moran et al., 2012; Moser, Moran, Schroder,
Donnellan, & Yeung, 2013). This report found attenuated ERN
amplitudes in depressed patients, in the absence of co-morbid
anxiety disorder or state anxiety levels. Moreover, the lack of signif-
icant ERN finding here from the cognitive task, alongside equivocal
observations from existing research, weakens any argument of
consistency relating the ERN as a specific phenotype for MDD. Alter-
natively, this study indicated enhanced Pe amplitude in a relatively
‘pure’ depression sample, devoid of anxiety or other co-morbidities
present in the prevailing evidence, also during remission in the
absence of a current depressive episode.
Collectively, these findings suggest aberrations of the pre-
attentive ERN appear specific to emotion systems in depression,
expressed as blunted amplitude. Modulatory effects in the
 P.L.A. Schoenberg / Biological Psychology 99 (2014) 100–114
opposite direction of waveform enhancement may be observed in
less severe depression or co-morbid anxiety. Whereas, aberrations
of the consciously-integrated Pe component reflects heightened
error awareness and evaluation traversing both cognitive and affec-
tive systems regardless of stage of illness, presenting specificity as
a potential intermediate phenotype candidate for depression.
Financial support
This work was funded by the Netherlands Organisation for Sci-
entific Research (NWO) (SSM06011) in support of the BrainGain
SmartMix Programme for the Netherlands Ministry of Economic
Affairs and Netherlands Ministry of Education, Culture and Science;
and the Netherlands Institute for Advanced Study in the Humanities
and Social Sciences.
Conflict of interest
None.
Acknowledgements
Much appreciation and gratitude to all those who participated
in the experiments. Many thanks to Addy de Graaf for generous
assistance with research co-ordination; and to Magdalena Kowal-
czuk and Katrin Scheibe for their help with the data collection.
Thank you to the team at the Radboud University Medical Centre
for Mindfulness for helpful assistance with patient recruitment.
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