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 b c

Faculty of Science, Intelligent Systems, Radboud University Nijmegen, The Netherlands Department of Cognitive Neuroscience, University Medical Centre Nijmegen, The Netherlands Netherlands Institute for Advanced Study, Wassenaar, The Netherlands

a r t i c l e

i n f o

Article history: Received 17 April 2013 Accepted 19 March 2014 Available online 26 March 2014 Keywords: Major depressive disorder ERN Pe ERP Error processing system Phenotypal marker

a b s t r a c t Major depressive disorder (MDD) ensues reduced goal-directed cognition and behaviour. Cognitive and emotional flexibility to disengage and adapt future responses was examined in the error processing system (error-related negativity/ERN, error-positivity/Pe event-related potentials) of 58 depressed patients (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 patients during the affective task. Blunted ERN amplitudes were evident between patients and controls in males compared to females, plausibly underpinned by disparities in dopaminergic pathways. Patients displayed enhanced Pe amplitudes for both cognitive and affective tasks. Abberations in cortical error processing in MDD appear specific to affective systems for the pre-attentive ERN, opposed to cognitive and affective processing for the consciously-integrated Pe. Heightened Pe, observed in both current and 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 (NolenHoeksema, 2001; Piccinelli & Wilkinson, 2000). Furthermore, the disorder appears to be moderately heritable with particular surmised candidate genetic factors predisposing higher liability to MDD (for comprehensive reviews, see Elder & Mosack, 2011; Levinson, 2006). Converging evidence suggests MDD reflects a complex culmination of affective and cognitive deficits, characterised by valence-specific maladaptions, such as hyperfocus and sensitivity to negative stimuli, impaired cognitive control in processing negative stimuli (Fossati, 2008), and an inability to disengage from associated 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: [email protected], [email protected] http://dx.doi.org/10.1016/j.biopsycho.2014.03.005 0301-0511/© 2014 Elsevier B.V. All rights reserved.

2013). How these affective and cognitive dynamics operate mechanistically 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 aetiology and maintenance of MDD. Namely, the prefrontal cortex (PFC: BA 10) and the anterior cingulate cortex (ACC: BA 24, 32, 33), associated 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 ventromedial and lateral orbital PFC, are associated with basal regulative states related to mood, aggression, pain processing, and perservatory 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). Collectively, ventromedial prefrontal-subcortical regions transduce information from key cortical pathways related to an array of cognitive 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

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subsequent performance monitoring towards goal-directed outcomes. Sub-components of the ACC indicate diverging mechanisms, such as the mediation of cognitive and executive functioning associated 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 anatomical 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 system 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 reciprocal correct-related negativity (CRN), peaking around 50–150 ms. A later evoked (200–400 ms) positive voltage ERP, the errorpositivity (Pe) and reciprocal correct-positivity (Pc), are evoked in response to consciously detected error-making. Remaining a point of contention, the ERN component represents 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 dynamics (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 characterised by the illness. Extant studies indicate patients suffering a current depressive episode yield significantly higher ERN amplitude compared to non-depressed controls (Chiu & Deldin, 2007), also found in a small sample of patients with moderate depression (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 modulate 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 waveform 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

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unexamined and undefined. Non-clinical studies allude healthy males present enhanced ERN and N2, also regulated by the ACC during conflict monitoring, amplitudes compared to females (Clayson, Clawson, & Larson, 2011; Larson, South, & Clayson, 2011), suggesting 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 supplementary 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 reportedly dissimilar female/male depressive symptom prevalence and expression. Coupled with MDD’s genetic heritability, a final encompassing 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 classifying 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 primary DSM-IV-TR diagnosis of major depressive disorder, diagnosed by a qualified consultant psychiatrist, in people aged 21–65 years. Current or remitted depression 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 difficulties. 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 interval (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 hardware (www.BrainProducts.com), recorded from 30 Ag/AgCl active electrode sensors with integrated noise subtraction circuits (actiCAP: Brain Products) located in accordance 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 canthi 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 filtered 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 artefacts were corrected using the regression method (Gratton, Coles, & Donchin, 1983).

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Table 1 Demographic and clinical data. Demographic

Patients

Age/Range Sex: F/M (%) Medicated: Y/N (%) Educationa Clinical Variable IDSb STAI-Sb

Controls

Between-group comparison

All (CD + RD)

CD

RD

Patients vs. HC

CD vs. RD

49.2 (10.3)/24–64 37/21 [64/36] 40/18 [69/31] 4.94 (1.9)

47.5 (9.5)/24–61 16/5 [76/24] 17/4 [81/19] 4.22 (2.0)

50.2 (10.7)/25–64 21/16 [57/43] 23/14 [62/38] 5.33 (1.8)

48.9 (7.7)/37–60 16/11 [59/41] – 5.48 (1.6)

F = 0.023, p = 0.88 2 = 2.781, p = 0.60 – 2 = 5.472, p = 0.60

F = 0.902, p = 0.35 2 = 2.190, p = 0.14 2 = 2.210, p = 0.14 2 = 9.183, p = 0.24

25.9 (11.0) 39.5 (10.3)

33.3 (11.0) 43.0 (12.0)

22.0 (8.9) 37.6 (8.9)

7.3 (6.2) 29.4 (8.1)

F = 64.130, p < 0.0001*** F = 17.710, p < 0.0001***

F = 13.336, p = 0.001** 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 to response or stimulus onset): (1) response-locked false alarms to NoGo stimuli (FA), (2) response-locked correct hits to Go stimuli (CH). Data were baseline corrected from −200 to −50 ms epochs. Visual inspection of individual participant averages defined error processing ERPs within the following temporal epochs: ERN (30–150 ms), Pe (200–450 ms) on false alarm (FA) trials to NoGo stimuli; and CRN (30–150 ms), Pc (200–450 ms) on correctly rejected NoGo trials. Individual averages for each valence condition were then calculated, prior to grand average calculation. 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 subsequent statistical analyses. Adaptive mean ERP amplitude has been suggested to offset low signal-to-noise ratio more reliably whilst maintaining individual ERP variability (Clayson, Baldwin, & Larson, 2012). It should be noted, the peak amplitude measure was also analysed, whereby overall results concurred with the adaptive mean amplitude extraction, albeit due to reportage length confines are not explicitly reported hereafter. 2.1.5. Statistical analyses Data from the FCz electrode were used in statistical analyses, as ERN and Pe adaptive mean amplitudes were maximal at this site across groups for both components. Condition (Go, NoGo) × Group (CD, RD, HC) repeated-measures ANOVA (rANOVA), with Greenhouse Geisser correction where appropriate, examined ERN/CRN and Pe/Pc amplitude and latency measures separately. Posthoc contrasts were examined using the conservative Scheffe test to avoid Type I errors. Sex was also examined as an IV via a Condition × Group × Sex r-ANOVA. 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, i.e. patient (CD + RD) vs. HC, so to maintain viable statistical power. Multivariate GLM analysed behavioural measures, i.e. number of correct hits (CH), false alarms (FA), correct NoGo (C-NoGo), error of omission (EoO), and response time (RT) data. Significant findings were followed up with posthoc one-way ANOVAs.

2.2. Results 2.2.1. Task measures Two behavioural log-files (1 patient) were corrupted by a technical failure, thus absent from the statistical analyses. Performance data are outlined in Table 2. Patients yielded slower RTs for FAs compared to HCs (Table 2).

Table 2 Accuracy number (N) and reaction times (RT) for the cognitive Go/NoGo task in patients vs. healthy controls.

FA (N) FA (RT) CH (N) CH (RT) C-NoGo EoO (N)

Patient () X¯

Control () X¯

Comparison

19.4 (12.5) 325.3 (52.1) 392.8 (6.8) 398.9 (53.9) 79.6 (12.5) 3.2 (6.8)

15.5 (9.4) 307.9 (32.2) 395.0 (1.5) 413.8 (58.7) 83.5 (9.4) 1.0 (1.5)

p = 0.16 p = 0.12 p = 0.12 p = 0.26 p = 0.16 p = 0.12

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.

2.2.2. Event-related potentials (ERPs) Four ERP datasets (1CD, 2RD, 1 HC) were dropped from the analyses due to having too few error trials ( 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 consistently 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:

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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 3level (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.)

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Fig. 4. (Continued ).

in MDD, specifically; (1) whether aberrations are linked to cognitive and/or affective processing, during early or later mechanistic neural stages; (2) to explore any sex-related differences in errorrelated 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 mechanism 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 performance. 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 feedback 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 central reward pathways associated with the left prefrontal cortex (Ruchsow et al., 2004). Furthermore, depressed patients presenting severe symptomatology including anhedonia, apathy, and psychomotor 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 severity positively correlating (Chiu & Deldin, 2007). However, findings appeared to be mitigated by co-morbid anxiety, suggesting the neurobiological mechanisms underlying anxiety plausibly have

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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 material 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 controls. 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 associated with greater negative affect and symptom severity, whereas enhanced ERN activation characterises mild to moderate depression, plausibly representing a ‘maintenance mechanism’. That is, a core composite of error processing involves an automatic template upgrading mechanism to mismatch and related conflict detection. Thus if heightened, potentially renders vulnerability towards misinterpreting and perceptually inflating negative environmental cues, a risk factor for maintaining negatively-biased cognition

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 motivational salience and evaluation of performance errors (Ridderinkhof, Ramautar, & Wijnen, 2009), in turn, sensitivity to error awareness (Hughes & Yeung, 2011); globally, higher Pe amplitudes were apparent in patients compared to controls. Moreover, disentangling current from remitted depression showed Pe amplitudes were generally higher in the currently depressed patients, where discernable heightened neurophysiological response pertained to errors for negative stimuli. Curiously, higher Pe amplitudes for errors to neutral stimuli were present in the remitted depressed group. The cognitive task also showed patients to have heightened Pe amplitudes 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.

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Extant enquiry into the Pe in MDD remains equivocal. Reduced Pe has been found in depressed patients with psychomotor slowing (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 trials, 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 severity, 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 exclusively MDD patients, supports a concept of ‘error fixation’ in depression and increased evaluative significance towards errors made for negatively valenced material. These results corroborate 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 emotional, particularly negatively valenced, stimuli. Moreover, the fact remitted patients exhibited inflated Pe amplitudes to neutral stimuli is plausibly connected to the inherent vulnerability in MDD, particularly when acute symptoms have subsided, to interpret ambiguous material as negative (Gur, Erwin, Gur, & Zwil, 1992; Keeley, Davidson, Crane, Matthews, & Pace, 2007), in turn, sustaining a disposition to experience negative mood states, and potential vulnerability to relapse. 4.3. Sex differences in error processing in MDD

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 interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

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 goaldirected 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 neurotransmission have found to be primarily dependent upon gonadal steroids, reflected by enhanced straital dopamine activity, specifically mediated 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

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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.)

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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 globally 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 substantia nigra, a key cortical structure connected to the central reward pathway and regulation of striatal and limbic functioning, 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 monitoring (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 neurotransmissional 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 yielding blunted ERN associated with reduced dopaminergic release involved in the reward system and processing of motivationallysalient stimuli. In this vein, males show greater vulnerability to externalising disorders (Kessler et al., 2005) attributed to dysregulation 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 optimal success in female patients, whereas those that target and

increase pertinent excitatory neurotransmitter pathways may be more effective with male patients. Rigorous empirical investigations are required to explore these theorisations further. 4.4. Limitations There are several limitations of this research. Adhoc analyses 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 medication flush-out preceding EEG recording. Larger participant samples systematically examining sex-related differences in ERP parameters 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 incorporates 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 disorder. Moreover, incorporating a feedback-dependent element to the design towards error elicitation would aid more substantive theorisations 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 controls, 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 interconnection 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 internalising disorders (Hajcak, Franklin, Foa, & Simons, 2008), whereby the empirical findings indicate heightened ERN amplitudes define anxiety (Hajcak, 2012; Weinberg, Olvet, & Hajcak, 2010 – also finding no differences in the Pe component between GAD patients and controls), particularly aspects related to worry and apprehension (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 significant 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. Alternatively, 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 preattentive ERN appear specific to emotion systems in depression, expressed as blunted amplitude. Modulatory effects in the

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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 affective 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 Scientific 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 Kowalczuk 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. References Alexopoulos, G. S., Murphy, C. F., Gunning-Dixon, F. M., Kalayam, B., Katz, R., Kanellopoulos, D., et al. (2007). Event-related potentials in an emotional go/no-go task and remission of geriatric depression. Neuroreport, 18(3), 217–221. Arias-Carrión, O., Stamelou, M., Murillo-Rodríguez, E., Menéndez-González, M., & Pöppel, E. (2010). Dopaminergic reward system: A short integrative review. International Archives of Medicine, 3, 24. Arnold, J. F., Fitzgerald, D. A., Fernández, G., Rijpkema, M., Rinck, M., Eling, P. A., et al. (2011). Rose or black-coloured glasses? Altered neural processing of positive events during memory formation is a trait marker of depression. Journal of Affective Disorders, 131(1–3), 214–223. Bush, G., Luu, P., & Posner, M. I. (2000). Cognitive and emotional influences in anterior cingulate cortex. Trends in Cognitive Sciences, 4, 215–222. Chiu, P. H., & Deldin, P. J. (2007). Neural evidence for enhanced error detection in major depressive disorder. American Journal of Psychiatry, 164, 608–616. Clayson, P. E., Baldwin, S. A., & Larson, M. J. (2012). How does noise affect amplitude and latency measurement of event-related potentials (ERPs)? A methodological critique and simulation study. Psychophysiology, 50, 174–186. Clayson, P. E., Clawson, A., & Larson, M. J. (2011). Sex differences in electrophysiological indices of conflict monitoring. Biological Psychology, 87, 282–289. Di Paolo, T. (1994). Modulation of brain dopamine transmission by sex steroids. Reviews in the Neurosciences, 5, 27–42. Elder, B. L., & Mosack, V. (2011). Genetics of depression: An overview of the current science. Issues in Mental Health Nursing, 32, 192–202. Elliott, R., Rubinsztein, J. S., Sahakian, B., & Dolan, R. J. (2000). Selective attention to emotional stimuli in a verbal go/no-go task: An fMRI study. Neuroreport, 11, 1739–1744. Endrass, T., Klawohn, J., Schuster, F., & Kathmann, N. (2008). Overactive performance monitoring in obsessive-compulsive disorder: ERP evidence from correct and erroneous reactions. Neuropsychologia, 46, 1877–1887. Falkenstein, M. (2004). Errors, conflicts and the brain. Journal of Psychophysiology, 18, 153–163. Falkenstein, M., Hielscher, H., Dziobek, I., Schwarzenau, P., Hoormann, J., Sundermann, B., et al. (2001). Action monitoring, error detection, and the basal ganglia: An ERP study. Neuroreport, 12(1), 157–161. Fitzgerald, D. A., Arnold, J. F., Becker, E. S., Speckens, A. E. M., Rinck, M., Rijpkema, M., et al. (2011). How mood challenges emotional memory formation: An fMRI investigation. Neuroimage, 56(3), 1783–1790. Foland-Ross, L. C., Hamilton, P. J., Joormann, J., Berman, M. G., Jonides, J., & Gotlib, I. H. (2013). The neural basis of difficulties disengaging from negative irrelevant material in major depression. Psychological Science, 24(3), 334–344. Fossati, P. (2008). Neural signatures of cognitive and emotional biases in depression. Dialogues in Clinical Neuroscience, 10(3), 358–361. Franken, I. H. A., van Strien, J. W., Franzek, E. J., & van de Wetering, B. J. (2007). Errorprocessing deficits in patients with cocaine dependence. Biological Psychology, 75(1), 45–51.

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