Neural Evidence for Enhanced Error Detection in Major Depressive Disorder

Article (PDF Available)inAmerican Journal of Psychiatry 164(4):608-16 · April 2007with116 Reads
DOI: 10.1176/appi.ajp.164.4.608 · Source: PubMed
Abstract
Anomalies in error processing have been implicated in the etiology and maintenance of major depressive disorder. In particular, depressed individuals exhibit heightened sensitivity to error-related information and negative environmental cues, along with reduced responsivity to positive reinforcers. The authors examined the neural activation associated with error processing in individuals diagnosed with and without major depression and the sensitivity of these processes to modulation by monetary task contingencies. The error-related negativity and error-related positivity components of the event-related potential were used to characterize error monitoring in individuals with major depressive disorder and the degree to which these processes are sensitive to modulation by monetary reinforcement. Nondepressed comparison subjects (N=17) and depressed individuals (N=18) performed a flanker task under two external motivation conditions (i.e., monetary reward for correct responses and monetary loss for incorrect responses) and a nonmonetary condition. After each response, accuracy feedback was provided. The error-related negativity component assessed the degree of anomaly in initial error detection, and the error positivity component indexed recognition of errors. Across all conditions, the depressed participants exhibited greater amplitude of the error-related negativity component, relative to the comparison subjects, and equivalent error positivity amplitude. In addition, the two groups showed differential modulation by task incentives in both components. These data implicate exaggerated early error-detection processes in the etiology and maintenance of major depressive disorder. Such processes may then recruit excessive neural and cognitive resources that manifest as symptoms of depression.
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Neural Evidence for Enhanced Error Detection
in Major Depressive Disorder
Pearl H. Chiu, Ph.D.
Patricia J. Deldin, Ph.D.
Objective: Anomalies in error processing
have been implicated in the etiology and
maintenance of major depressive disorder.
In particular, depressed individuals exhibit
heightened sensitivity to error-related in-
formation and negative environmental
cues, along with reduced responsivity to
positive reinforcers. The authors examined
the neural activation associated with error
processing in individuals diagnosed with
and without major depression and the
sensitivity of these processes to modula-
tion by monetary task contingencies.
Method: The error-related negativity and
error-related positivity components of the
event-related potential were used to char-
acterize error monitoring in individuals
with major depressive disorder and the
degree to which these processes are sensi-
tive to modulation by monetary reinforce-
ment. Nondepressed comparison subjects
(N=17) and depressed individuals (N=18)
performed a flanker task under two exter-
nal motivation conditions (i.e., monetary
reward for correct responses and mone-
tary loss for incorrect responses) and a
nonmonetary condition. After each re-
sponse, accuracy feedback was provided.
The error-related negativity component
assessed the degree of anomaly in initial
error detection, and the error positivity
component indexed recognition of errors.
Results: Across all conditions, the de-
pressed participants exhibited greater
amplitude of the error-related negativity
component, relative to the comparison
subjects, and equivalent error positivity
amplitude. In addition, the two groups
showed differential modulation by task
incentives in both components.
Conclusions: These data implicate exag-
gerated early error-detection processes in
the etiology and maintenance of major
depressive disorder. Such processes may
then recruit excessive neural and cogni-
tive resources that manifest as symptoms
of depression.
(Am J Psychiatry 2007; 164:608–616)
Excessive sensitivity to negative environmental cues
has long been posited to play a significant role in the etiol-
ogy and maintenance of major depressive disorder (1, 2).
In the clinic and laboratory, depressed individuals consis-
tently magnify the significance of failure (3, 4), exhibit bias
toward negative (or against positive) self-descriptors (5),
have difficulty recovering once an error has been commit-
ted, and show detrimental sensitivity to mistakes and neg-
ative feedback (6–8). Such impairments are consistent
with cognitive theories of depression that suggest emo-
tional and behavioral manifestations of depression are
maintained by an automatic tendency to distort environ-
mental information in a negatively biased way (1, 2).
In major depression, this enhanced sensitivity to nega-
tive environmental cues appears to be coupled with de-
creased hedonic capacity as well as reduced responsivity
to pleasant stimuli and other positive reinforcers, such as
monetary incentives or favorable social cues (9–12). In ad-
dition, dysphoric participants consistently exhibit equiva-
lent behavioral responses to neutral and rewarding payoff
conditions, whereas nondepressed individuals develop re-
sponse biases toward rewarding stimuli (13, 14). Func-
tional neuroimaging investigations, pharmacologic chal-
lenge studies, and animal models of depression provide
converging evidence that reward-related neural pathways
are hyporesponsive to rewarding stimuli yet show hyper-
responsivity to dopamine agonists in depressed individu-
als (15–17).
A growing literature suggests that increased activity in
paralimbic emotion-related neural structures and aber-
rant connectivity among these regions contribute to mal-
adaptive affective reactions and sensitivity to negative
cues in major depression (18–21). That is, depressed indi-
viduals appear to exhibit an exaggerated response in the
anterior cingulate cortex that contributes to an imbalance
in corticolimbic networks that shifts influence to limbic
regions. Indeed, researchers have observed increased me-
tabolism in the rostral anterior cingulate cortex coupled
with decreased activity in prefrontal cortical areas among
nondepressed participants in whom sadness is induced
(20). Similarly, depressed individuals show increased acti-
vation of the anterior cingulate cortex and paralimbic
brain structures in response to negative stimuli (18). Met-
abolic studies further suggest that depressed individuals
Am J Psychiatry 164:4, April 2007 609
CHIU AND DELDIN
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show high baseline cerebral blood flow in rostral anterior
cingulate regions (19). Together, these data indicate that
excessive sensitivity to negative cues may be associated
with enhanced activity in regions of the anterior cingulate
cortex and anomalous corticolimbic connectivity, which
may then contribute to the disruption of emotion regula-
tion processes.
Although these neural data and concomitant behavioral
and affective symptoms are central to the clinical presen-
tation and current conceptualizations of major depressive
disorder, much remains unknown regarding the mecha-
nisms that contribute to the maladaptive responses to
negative stimuli. The temporal and functional resolution
of event-related brain potentials allows the investigation
of specific neural and cognitive processes associated with
the hypersensitivity to negative cues seen in major depres-
sion. In the present work, the error-related negativity and
error positivity components of the event-related potential
facilitated the assessment of sequential error-processing
mechanisms in depressed patients.
The error-related negativity is an event-related potential
component that manifests 50–100 msec after incorrect re-
sponses in a variety of binary choice tasks (22, 23). The
component is reliably measured at midline frontocentral
scalp sites and is considered to be a robust electrophysio-
logical measure of the initial engagement of an intact re-
sponse-monitoring system that provides resources for
early detection of an error or conflict (23, 24). Studies us-
ing source localization and functional magnetic reso-
nance imaging (fMRI) converge on regions of the anterior
cingulate cortex as probable neural generators of the er-
ror-related negativity component and related error pro-
cessing (25–27). Given the substantial evidence that indi-
viduals with depression show excessive sensitivity to
errors, failure, and negative cues along with evidence of
enhanced activity in error-related regions of the anterior
cingulate cortex (2–4, 21), a primary goal of the present
work was to test the hypothesis that depression is charac-
terized by hypersensitivity to errors in early stages of error
detection, as would be indicated by enhanced amplitude
of the error-related negativity component. To date, we
know of no published work that has examined error-re-
lated negativity in individuals in a major depressive epi-
sode relative to nonpsychiatric comparison subjects (see
reference 28 for a preliminary study on geriatric individu-
als with current and remitted depression).
An error-locked centroparietal positivity (29–31) occurs
subsequent to the error-related negativity, typically within
200–400 msec after incorrect responses. Increasing evi-
dence indicates that the error positivity component re-
flects recognition of an error, as indicated by the presence
of smaller error positivity (but unchanged error-related
negativity) in response to unperceived errors than in re-
sponse to perceived errors (30). As targeted investigations
of error positivity are scarce and have not, to our knowl-
edge, been thus far examined in major depression, the
present study did so as an exploratory aim.
As already outlined, depressed individuals exhibit
heightened sensitivity to error-related information and
negative environmental cues, along with reduced respon-
sivity to positive reinforcers. In order to clarify the neural
processes contributing to such symptoms and assess the
sensitivity of these measures to motivating task incentives,
event-related potentials associated with sequential as-
pects of error processing were measured as participants
with and without major depressive disorder performed a
common speeded response-competition task that reliably
elicits errors and their accompanying physiological pro-
cesses (22). Physiological and behavioral responses to er-
rors in this task were measured in a neutral condition and
under positive and negative task contingencies.
Method
Participants
The participants were 18 individuals with major depressive dis-
order who were experiencing a current major depressive episode
and 17 nonpsychiatric comparison subjects. All of the volunteers
were recruited from community and mental health centers
throughout the Greater Boston area through newspaper, Internet,
and poster advertisements. Following an initial telephone screen-
ing in which basic exclusion criteria were applied, qualifying par-
ticipants were invited to the laboratory for diagnostic assessment.
The basic exclusion criteria included left-handedness, history of
seizures or stroke, head injuries resulting in more than 10 min-
utes of unconsciousness or with neurological sequelae, hormone
disorder, history of ECT or chemotherapy for cancer, current
pregnancy or menopause, and history of substance abuse or de-
pendence. In addition, the exclusion criteria for the comparison
subjects included any current or past axis I diagnosis.
Psychiatric inclusion and exclusion criteria were assessed with
the Structured Clinical Interview for DSM-IV-TR Axis I Disorders,
Research Version, Patient Edition (SCID-I/P). All diagnoses were
based on the consensus of two independent trained doctorate-
level raters (P.C. and another rater). Written informed consent
was obtained during the first laboratory visit, after a complete de-
scription of the study and procedures to the participants.
Among the depressed individuals, the average length of the cur-
rent depressive episode was 22 months, and the average number of
prior episodes was 2.5. Five depressed participants also received
comorbid diagnoses of the following anxiety disorders: social pho-
bia (N=1), panic disorder (N=1), panic disorder and social phobia
(N=2), and posttraumatic stress disorder (N=1). Six individuals
were taking antidepressant medication at the time of the study; five
of these six were concurrently undergoing psychotherapy. Analyses
of the physiological measures did not yield statistically significant
differences between individuals with and without treatment; thus,
all individuals were included in the reported analyses. (It should be
noted, however, that the low numbers of subjects—six medicated
and 12 unmedicated depressed participants—may not yield suffi-
cient statistical power to detect true between-group differences.
Thus, the possibility that antidepressant medications affect the
amplitude of error-related negativity or error positivity remains to
be examined in future investigations.)
The depressed and comparison groups did not differ signifi-
cantly in age (comparison: mean=37.9 years, SD=13.1; depressed:
mean=33.7 years, SD=12.5) or years of education (comparison:
mean=16.1 years, SD=2.0; depressed: mean=15.7 years, SD=2.2)
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(two-tailed t tests, p>0.30 for both). The two groups also had sim-
ilar proportions of Caucasian participants (comparison: N=14;
depressed: N=15) and men (comparison: N=10; depressed: N=6)
(chi-square analyses, p>0.10 for both).
Self-Report Measures
Prior to physiological recording, the participants completed
the Beck Depression Inventory (BDI), the Beck Hopelessness
Scale (32), and the Mood and Anxiety Symptom Questionnaire
(33). These were chosen to measure the current severity of de-
pression symptoms, hopelessness, and the presence of depres-
sion relative to anxiety symptoms, respectively. The two groups
differed predictably on all measures, and the scores are presented
in Table 1.
Task
The primary task was a modified flanker task in which a target
arrow is flanked on the top and bottom by congruent, incongru-
ent, or neutral distractors (34). Participants were given a two-but-
ton response box and instructed to respond in the direction of the
target arrow. Accuracy feedback, varying by incentive condition,
was presented for 250 msec at 1300 msec following the response
in each trial. A variable intertrial interval (range=1500–2500
msec), measured from feedback offset to onset of the subsequent
flanker stimulus, was used. See Figure 1 for a schematic represen-
tation of the procedure.
The participants performed 360 trials in each of three condi-
tions, presented in a block design. Each physiology recording ses-
sion began with the “neutral” condition, followed by two counter-
balanced “incentive” conditions. In each incentive condition, the
participants were informed that they could earn up to an extra
five dollars. Specifically, in the “reward” block, the participants
were told they would receive “an extra five cents for each correct
response, and nothing for incorrect responses.” In the “punish-
ment” block, the participants were informed they would begin
with the full amount and would “lose five cents for each incorrect
response.” Accuracy and speed were equally emphasized, and in
order to maintain orientation to the task, a feedback message of
“late” was presented regardless of accuracy when a participant’s
reaction time exceeded a timeout criterion, which was calculated
as 85% of the individual’s mean reaction time (23) during a prac-
tice block preceding the physiology recording. The practice con-
sisted of 60 trials, during which the flanker task was performed
without visual feedback; the participants were informed that this
was a practice block and were simply instructed to respond as
quickly and accurately as possible. The comparison and de-
pressed groups did not differ in reaction time or accuracy in the
practice block.
Physiological Recording and Data Reduction
EEG was recorded from 25 scalp sites by using a custom 37/64
channel bioelectric amplifier (S.A. Instrumentation, Encinitas,
Calif.) and a stretchable cap of spandex-type fabric (Electro-Cap
International, Eaton, Ohio) with Ag/AgCl electrodes positioned
according to the International 10–20 system. The data were digi-
tally sampled at 1000 Hz and analog filtered between 0.01 and 100
Hz. Electrode impedances were kept below 5 k. Electro-oculo-
gram (EOG) data were recorded from electrodes placed lateral to
the outer canthi and at the left supraorbital and suborbital posi-
tions. EEG was referenced to the left mastoid (M1) and algebra-
ically re-referenced to average mastoids off-line ([M1+M2]/2).
EOG artifact was corrected by using the regression method of
Gratton et al. (35) implemented by BrainVision Analyzer software
(Brain Products, Gilching, Germany). Individual trials exceeding
± 80 µV were automatically rejected; remaining EOG and elec-
tromyography artifacts were manually identified and rejected
from further analyses.
TABLE 1. Scores on Self-Report Symptom Measures for Comparison and Depressed Participants
a
Score
Comparison Group (N=17) Depressed Group (N=18)
Symptom Measure Mean SD Mean SD
Beck Depression Inventory 2.07 2.28 25.24 9.13
Beck Hopelessness Scale 3.08 2.69 13.29 4.78
Mood and Anxiety Symptom Questionnaire
General distress 24.60 8.07 50.88 10.72
General distress: anxiety 16.00 4.72 28.25 6.64
General distress: depression 17.54 4.35 43.69 8.78
Anxious arousal 20.77 5.15 29.67 10.01
Anhedonic depression 46.90 12.33 86.38 8.48
a
Significant differences between the comparison and depressed groups for all measures (two-tailed t test, p<0.01).
FIGURE 1. Schematic Representation of the Arrow Flanker
Task and Feedback to Comparison and Depressed Partici-
pants During Measurement of Event-Related Brain Potentials
a
a
The free response period was quantified individually as determined
in a practice block. Event-related brain potentials, the error-related
negativity and error positivity, were quantified for trials time-locked
to incorrect responses. All participants underwent the neutral feed-
back condition first. After the neutral block, the order of the reward
and punishment conditions was counterbalanced. Performance
feedback was provided for each trial in each condition.
150 msec 250 msec
Free response
Feedback
or
Incorrect
(error-related negativity/
error positivity)
L
R
Neutral
Feedback
Correct Incorrect Correct Incorrect
OOO XXX No change No change
+$$ === +5¢ No change
=== –$$ No change –5¢
Payoff
Reward
Punishment
A
B
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Statistical Analyses
The response-locked individual event-related potentials were
averaged for each error trial in the neutral and incentive (reward,
punishment) conditions. Error-related negativity was calculated
as the most negative peak in a window –30 to 150 msec around
the response, relative to a –100 msec baseline, and error positivity
was quantified as the most positive peak following the error-re-
lated negativity in a window 100–400 msec from response onset.
An initial 5×5×2 multivariate analysis of variance (MANOVA)
with Wilkss lambda correction was performed for the peak am-
plitudes for error-related negativity and error positivity in the
neutral condition in order to identify regions of maximal activa-
tion and between-group differences in component amplitudes.
The three variables included in the MANOVA were caudality
(frontal, frontocentral, central, centroparietal, parietal), laterality
(electrode sites 7, 3, z, 4, 8), and group (comparison, depressed).
The additional factor of incentive (reward, punishment) was in-
cluded in this omnibus MANOVA in analyses of the incentive con-
ditions. Subsequent incentive-by-group MANOVAs were imple-
mented at regions of maximal activation, with the factors of
caudality and/or laterality included as indicated from the larger
MANOVA. Interactions were required to be significant at each
stage before further decomposition, and significant main effects
were followed with pairwise comparisons as appropriate. All sta-
tistically significant effects from these analyses are reported in the
Results section.
In order to assess within- and between-group behavioral dif-
ferences, univariate repeated-measures analyses of variance
(ANOVAs) assessing the interaction of group (comparison, de-
pressed) and accuracy (correct, incorrect) were performed for re-
sponse latency, response accuracy, post-error latency, and post-
error accuracy in the neutral feedback condition. In addition,
group-by-accuracy-by-incentive ANOVAs were performed for
each of these measures in the incentive conditions. Finally, Pear-
son correlations were used to examine the relationship of the
symptom and behavioral variables to the amplitudes of error-re-
lated negativity and error positivity at regions of maximal activa-
tion in the neutral condition.
Results
Behavioral Outcomes
Neutral condition. In the neutral condition, the com-
parison and depressed groups performed equally accu-
rately (main effect of group: F=2.1, df=1, 33, p>0.10). The
effects of post-error accuracy adjustments were intact such
that all participants were more accurate after incorrect tri-
als than after correct trials (main effect of accuracy: F=23.2,
df=1, 33, p<0.001). Moreover, the depressed group showed
greater post-error increases in accuracy than did the com-
parison group (group effect: F=4.2, df=1, 33, p<0.05).
The comparison and depressed participants exhibited
equivalent reaction times. The response latencies for in-
correct trials were shorter than those for correct trials (ac-
curacy effect: F=199.5, df=1, 33, p<0.001). No effects of the
post-error adjustment on response latency were observed
(accuracy-by-group interaction: F=0.0, df=1, 33, n.s.).
Incentive conditions. The depressed and comparison
groups were equally accurate across the punishment and
reward conditions (group effect: F=2.8, df=1, 33, p>0.10).
Post-error accuracy adjustment (greater accuracy after in-
correct trials than after correct trials) was intact under
both incentive conditions across groups (accuracy effect:
F=39.4, df=1, 33, p<0.001). No interactions or main effects
involving the group factor were observed for accuracy in
the incentive conditions.
Across incentive conditions, response latencies for in-
correct trials were again shorter than those for correct trials
(accuracy effect: F=6.2, df=1, 33, p<0.05). Moreover, re-
sponse latencies in the reward condition were significantly
shorter than in the punishment condition for all partici-
pants (main effect of incentive: F=440.1, df=1, 33, p<0.001).
The effect of the post-error adjustment on response la-
tency was intact such that all participants were slower after
error trials than after correct trials (accuracy effect: F=
394.2, df=1, 33, p<0.001). No interactions or main effects
involving the group factor were observed for response la-
tencies in the incentive conditions.
The mean response times, error rates, and number of
trials comprising each condition are presented in Table 2.
Error-Related Negativity
Neutral condition. Figure 2 depicts grand average wave-
forms at midline and lateral sites for both groups. The am-
plitudes of error-related negativity for error trials showed
significant main effects of both caudality and laterality (cau-
dality effect: F=17.1, df=4, 27, p<0.001; laterality effect: F=
19.3, df=4, 27, p<0.001). Subsequent pairwise comparisons
TABLE 2. Performance on the Arrow Flanker Task Under Neutral and Incentive Conditions for 17 Comparison and 18
Depressed Participants
Reaction Time (msec)
Proportion of Trials With
Incorrect Responses
a
Number of Trials With
Incorrect Responses
Test Condition and Subject Group Mean SD Mean SD Mean SD
Neutral condition
Comparison group 201 42 0.13 0.06 30.9 18.6
Depressed group 203 38 0.12 0.08 26.3 20.7
Conditions with monetary incentives
Reward
Comparison group 187 24 0.15 0.07 34.1 17.5
Depressed group 194 31 0.13 0.07 30.0 18.9
Punishment
Comparison group 188 21 0.12 0.06 30.4 18.6
Depressed group 203 39 0.14 0.07 31.2 19.6
a
Proportion incorrect = (number of incorrect responses) / (number of correct responses + number of incorrect responses).
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revealed that for all participants, error-related negativity was
greatest at the frontal and frontocentral midline sites; the
difference between the frontal and frontocentral midline
sites was not significant (p>0.10), but all other pairwise com-
parisons of caudality were significant (p<0.001). All of the
pairwise comparisons of the midline sites with all other lat-
erality sites were also significant (p<0.001). Moreover, the
depressed group showed higher amplitudes of error-related
negativity than the comparison subjects (group effect: F=
4.6, df=1, 33, p<0.05).
Incentive conditions. Figure 3 depicts waveforms for
each condition at a representative site, FCz. In the incentive
conditions, the amplitude of error-related negativity was
also greatest at the frontal and frontocentral sites (all pair-
wise comparisons of caudality and laterality, p<0.01). In ad-
dition, the depressed group exhibited greater error-related
negativity than the comparison group (group effect: F=6.3,
df=1, 33, p<0.05). Moreover, the comparison and depressed
subjects showed different patterns of error-related negativ-
ity after errors in the incentive conditions (incentive-by-
group interaction: F=4.6, df=1, 33, p<0.05). Parsing of this
interaction revealed that the depressed individuals showed
greater error-related negativity than the comparison sub-
jects, particularly in the punishment condition (F=7.6, df=1,
33, p<0.01). In the reward condition, the depressed partici-
pants showed a pattern suggesting greater error-related
negativity than in the comparison subjects (group effect: F=
2.1, df=1, 33, p=0.16). Within the comparison subjects, er-
ror-related negativity in the reward condition was nearly
significantly greater than in the punishment condition (in-
centive effect: F=3.8, df=1, 16, p<0.07).
Correlations with symptoms. In the group with major
depressive disorder (N=18), Pearson correlations between
symptoms and the magnitude of error-related negativity
in the neutral condition revealed that the magnitude in-
creased with greater severity across all measures of de-
pression (BDI: r=0.39, p<0.10; Beck Hopelessness Scale: r=
0.56, p<0.05; Mood and Anxiety Symptom Questionnaire,
depression: r=0.51, p<0.05). No relationship between er-
ror-related negativity and the Mood and Anxiety Symptom
Questionnaire ratings for anxiety or anhedonia emerged
(anxious arousal: r=–0.10; general anxiety: r=0.04; anhe-
donia: r=–0.08; all p>0.50).
FIGURE 2. Response-Locked Grand Average Waveforms for Error-Related Negativity and Error Positivity After Incorrect Re-
sponses in the Neutral Condition of the Flanker Task for Comparison and Depressed Participants
a
a
0 msec indicates the moment of the participant’s button press.
+250 µV
+250 µV
Cz
Error-related
negativity
Error positivity
FCz
Fz
Pz
CPz
C3
FC3
F3
P3
CP3
C4
FC4
F4
P4
CP4
+10 µV
500
msec
–10 µV
Comparison group
(N=17)
Depression group
(N=18)
Electro-oculogram
Vertical
Horizontal
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In the nonpsychiatric comparison group (N=17), no sta-
tistically significant correlations were observed between
error-related negativity and self-report scores (r<0.30 for
all self-report measures).
Error Positivity
Neutral condition. Figure 2 shows grand average wave-
forms at midline and lateral sites for each group. For all
participants, the amplitude of error positivity was maxi-
mal at the central and centroparietal sites. There was no
significant difference between the central and centropari-
etal sites (p>0.10), but the differences in all other pairwise
comparisons of caudality were significant (p<0.01), and
the amplitude was greater at midline sites than at lateral
sites (all laterality pairwise comparisons, p<0.05). More-
over, the comparison and depressed groups showed
equivalent amplitudes of error positivity (group effect: F=
0.03, df=1, 33, n.s.).
Incentive conditions. In the incentive conditions, the er-
ror positivity amplitudes were also greatest at sites Cz and
CPz. There was no significant difference between the cen-
tral and centroparietal sites (p>0.10), but the differences in
all other pairwise comparisons of caudality were significant
(p<0.01), and all laterality pairwise comparisons with the
midline site were significant (p<0.001). The comparison
and depressed groups did not differ in error positivity am-
plitudes (group effect: F=0.0, df=1, 33, n.s.). The incentive-
by-group analysis revealed a nearly significant difference in
the pattern of error positivity amplitude after errors in the
incentive conditions between the comparison subjects and
depressed individuals (F=3.6, df=1, 33, p<0.07). Targeted
analyses of within-group effects suggest that the depressed
group had greater error positivity in the reward condition
than in the punishment condition (p=0.09).
Correlations with symptoms. No correlations between
error positivity and scores on symptom subscales were ob-
served in the depressed or comparison participants (for
all, r<0.30).
Discussion
To our knowledge, the present study is the first to show
greater response-locked error-related negativity in individ-
uals in a current major depressive episode compared with
nonpsychiatric participants. As we will discuss, these data
inform current biological, cognitive, and clinical conceptu-
alizations of depression.
Studies implicating the anterior cingulate cortex as a
probable neural generator of error-related negativity (e.g.,
25–27, 36) also provide experimental evidence that para-
limbic regions, including the anterior cingulate cortex, re-
cruit activity in executive brain areas that modulates affec-
tive and behavioral responses when actual and intended
goal states differ (e.g., 37, 38). In the context of the current
study, enhanced error-related negativity in major depres-
sive disorder may indicate the initial recruitment of exces-
sive error-detection processes that then exaggerate the
neural and cognitive resources allocated to generating
subsequent adaptive responses. That is, an enhanced er-
ror-related negativity such as that observed in depression
may wrongly signal that errors are large or highly signifi-
cant (38, 39) and recruit excessive behavioral, cognitive,
and affective processes that manifest in the signs and
symptoms associated with the disorder (18, 21). Of clinical
relevance, the neural generators of the error-related nega-
tivity identified in source localization analyses and the
FIGURE 3. Response-Locked Grand Average Waveforms at
Site FCz for Error-Related Negativity and Error Positivity Af-
ter Incorrect Responses in Neutral and Incentive Condi-
tions of the Flanker Task for Comparison and Depressed
Participants
a
a
0 msec indicates the moment of the participants button press.
Amplitude at FCz (µV)
–4
0
4
8
12
–8
–4
0
4
8
12
–8
Comparison
group (N=17)
Depression
group (N=18)
–4
0
4
8
12
0 250
Time (msec)
Neutral
Punishment
Reward
500
–8
Error-related
negativity
Error positivity
614 Am J Psychiatry 164:4, April 2007
ERROR DETECTION IN MAJOR DEPRESSION
ajp.psychiatryonline.org
brain regions identified in fMRI studies of error processing
overlap with brain areas implicated in treatment response
in major depressive disorder (for reviews, see references
14 and 40). The current data invite the possibility that en-
hanced error-related negativity in depression similarly re-
flects a generally heightened sensitivity to discrepancies
between affective goal states and actual states that may
serve as a promising prognostic indicator of the course of
illness and response to treatment.
The enhanced error-related negativity observed in the
depressed group also contributes to a growing literature
investigating affective influences on error-related negativ-
ity (e.g., 41, 42). Specifically, whereas enhanced error-re-
lated negativity has been observed in individuals with
high levels of negative affect (e.g., 41, 42), equivalent (28)
or diminished (43) error-related negativity has been ob-
served in individuals with remitted depression. To date,
two studies have examined a related medial frontal nega-
tivity of the event-related potential that is sensitive to neg-
ative feedback. This “feedback-related negativity” appears
to be enhanced in currently depressed individuals (3) and
diminished in those whose depression has remitted (44).
In the present study, enhanced amplitude of response-
locked error-related negativity was specifically associated
with greater severity of depression, but not anxiety symp-
toms, across a variety of scales. The current data, in con-
junction with prior reports of diminished error-related
negativity in individuals with remitted depression, thus
suggest that error-related negativity may be a viable index
of both the presence of a major depressive episode and the
severity of depression-specific symptoms.
The robustness of the enhanced error-related negativity
in major depression was evident across all conditions. In
addition, the depression and comparison groups showed
differences in the sensitivity of error-related negativity to
motivating incentives. In particular, the depressed group,
relative to the comparison group, demonstrated enhanced
error-related negativity, particularly in the punishment
condition, whereas the comparison subjects appeared to
show greater error-related negativity in the reward condi-
tion than in the punishment condition. These data indi-
cate that neural resources involved in early error detection
are susceptible to behavioral reinforcers in a manner con-
sistent with prior reports in depression. In particular, this
pattern of error-related negativity modulation is consis-
tent with the substantial evidence indicating excessive
sensitivity to loss and failure and diminished response to
hedonic cues among individuals with major depressive
disorder (e.g., 1–5, 10–14).
While group differences were observed in the magnitude
of error-related negativity, equivalent error positivity ampli-
tudes were noted in the depressed and comparison groups.
The distinct pattern in the depressed group of a normal
overt behavioral response followed by exaggerated error-re-
lated negativity and intact error positivity further impli-
cates early error detection, rather than subsequent recogni-
tion processes, in the hypersensitivity to negative cues seen
in the disorder. The depressed group also showed nonsig-
nificantly greater error positivity in the reward condition
than in the punishment condition, whereas the nonpsychi-
atric participants exhibited no differences in error positivity
amplitude between the two conditions. The patterns of er-
ror-related negativity and error positivity in the reward and
punishment conditions, coupled with the absence of group
or incentive differences in overall reaction time and accu-
racy, suggest that the neural and psychological responses
reflected in error-related negativity and error positivity rep-
resent processes serving complementary functions that are
differentially engaged to produce intact behavioral re-
sponses. In support of this conjecture, post hoc analyses re-
vealed a nearly significant negative correlation between the
amplitudes of error-related negativity and error positivity
such that greater error-related negativity was associated
with a lower amplitude of error positivity in individuals with
depression (r=0.44, N=18, p<0.10).
Limitations
The caveats regarding the current work provide impetus
for future research. First, as the primary aim of this work
was to test whether enhanced error-monitoring charac-
terizes major depressive disorder, the task implemented in
the present study was chosen explicitly to restrict task de-
mands as much as possible to processes related to error
monitoring. In comparison, prior studies have used neu-
ropsychological tasks in which the participant is likely to
be unaware of his or her accuracy until feedback is pre-
sented (6–8). Thus, while the design and simple nature of
the flanker task allowed the examination of specific error-
processing mechanisms, the differences between the de-
signs of the present study and other investigations render
direct comparisons difficult. In addition, as both error-re-
lated negativity and error positivity have previously been
observed to attenuate over time as participants’ inherent
motivation toward the task diminishes (22, 42), the block
design implemented in the current work may have re-
duced potential modulatory effects of task contingencies
on physiological measures of error processing.
Summary
The current work examined component processes of er-
ror monitoring in individuals with current major depres-
sive disorder and the effects of task incentives on these
processes. Most striking, individuals with major depres-
sion exhibited greater magnitude of error-related negativ-
ity than did nonpsychiatric comparison subjects. In addi-
tion, task incentives appeared to differentially modulate
the error-related negativity and error positivity for the two
groups. Together, these data implicate exaggerated early
error-detection processes in the etiology and maintenance
of major depressive disorder. These processes may then re-
cruit excessive neural and cognitive resources that mani-
fest as symptoms of depression.
Am J Psychiatry 164:4, April 2007 615
CHIU AND DELDIN
ajp.psychiatryonline.org
Received June 2, 2006; revision received Aug. 28, 2006; accepted
Sept. 14, 2006. From the Computational Psychiatry Unit, Depart-
ments of Neuroscience, Baylor College of Medicine; and the Depart-
ment of Psychology, University of Michigan, Ann Arbor. Address cor-
respondence and reprint requests to Dr. Chiu, Computational
Psychiatry Unit, Baylor College of Medicine, One Baylor Plaza S104,
Houston, TX 77030; pchiu@cpu.bcm.edu (e-mail).
Drs. Chiu and Deldin report no competing interests.
This work is a portion of a dissertation project conducted by Dr.
Chiu in the Department of Psychology, Harvard University, and was
supported in part by a Graduate Society Dissertation Merit Fellow-
ship from Harvard University to Dr. Chiu.
The authors thank Brooks Casas, Christen Deveney, Laura Phillips,
and Avgusta Shestyuk for assistance with participant recruitment, di-
agnostic assessment, and study implementation, and they thank
Brooks Casas, Diego Pizzagalli, and Stephen Kosslyn for comments
on early drafts of the manuscript.
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    • "Exclusion criteria included: a full-scale IQ less than 70 (n = 0), a TBI accompanied with a significant loss of consciousness (n = 4), poor behavioral performance or significant movement during data collection (n = 16), or personal history of bipolar or psychotic disorders (n = 0). Participants were also excluded for mood disorders, including major depression (n = 10), and anxiety disorders, including post-traumatic stress disorder (PTSD) (n = 3), due to the important role these disorders play for both the ERN/Ne (Chiu & Deldin, 2007; Olvet & Hajcak, 2008) and Pe (Bridwell et al., 2015) amplitude.Forth et al., 2003); Intelligence Quotient (IQ) was calculated from the Wechsler Adult Intelligence Scale–Third Version (WAIS-III) (Wechsler, 1997); Substance Use is the number of substance dependencies calculated by summing the total number of substances (alcohol and drug) for which participants met lifetime dependence diagnoses from the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) (Kaufman et al., 1997); ERN/Ne, Pe, PC1, PC2, PC3, and PC4 refer to the mean amplitude of the time-domain and principal components pertaining to ERN/Ne and Pe amplitude. "
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    • "In some studies that have identified an enhanced ERN in depression, participants' responses were followed by immediate performance feedback (Chiu & Deldin, 2007; Holmes & Pizzagalli, 2008b), which appears to influence the association between individual differences and the magnitude of the ERN (Gründler, Cavanagh, Figueroa, Frank, & Allen, 2009; Olvet & Hajcak, 2009a). Likewise, manipulations of incentive salience (e.g., associating errors with monetary gains or losses) appear to impact both the magnitude of the ERN (Hajcak, Moser, Yeung, & Simons, 2005) and the association of the ERN with depression (Chiu & Deldin, 2007; Holmes & Pizzagalli, 2008b). Future studies might examine subtypes of depression under different task conditions in order to better identify specific impairments and deficits (Weinberg, Dieterich, et al., 2015). "
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