Emerging evidence indicates that depression is characterized by impairments in executive control required for adaptive responding15,55
and particularly by deficits in adjusting behavior after errors or negative feedback.7,8,15,56
In this study, patients with MDD had significantly lower accuracy in Stroop trials immediately after a mistake but were unimpaired in trials after a correct response. Replicating recent findings, this study indicated that patients with depression showed significantly larger ERN at frontocentral sites28,29,33
but unaffected Pe.28
The lack of group differences in Pe is not surprising given prior inconsistent findings in the literature.28,29
When interpreted within the framework of prior ERP studies,22,23
the present findings indicate that depression is characterized by hypersensitivity to errors during early stages of the information-processing flow but unimpaired conscious experience and recognition of errors. Thus, larger ERN might reflect dysfunctions in the automatic detection of an unfavorable performance outcome, which could convey a signal that errors are large and salient. Interestingly, the only finding of abnormal Pe in depression was observed in geriatric patients with depression who remained symptomatic after an 8-week treatment with escitalopram oxalate.30
In light of the present and prior28,29
Pe null findings, it is possible that disruption in later stages of error processing might emerge only in samples of treatment-resistant patients and/or geriatric patients with depression. Future studies will be needed to test this hypothesis.
Although the behavioral and scalp ERP analyses replicated prior reports of abnormal reactions to error in depression, the present study provided novel insights about the spatiotemporal dynamics of brain mechanisms that underlie these abnormalities. Specifically, through an integration of a distributed source localization technique and functional connectivity analyses, we showed that depression is associated with (1) increased activation within midline regions that encompass the rostral ACC and the medial PFC 80 milliseconds after committing an error and (2) disrupted connectivity between the rostral ACC and the left dorsolateral PFC.
Increased posterror activation in the rostral ACC and medial PFC is intriguing when considering the functional roles of these regions. In prior studies, rostral ACC activation has been reported during (1) processing of negatively valenced stimuli in emotional Stroop tasks,57–59
and errors associated with monetary loss61
; (2) increased physiological reactions to behavioral stressors during a challenging Stroop task62
; and (3) induction of sad mood.63
Collectively, these findings underscore the role of the rostral ACC in affective responses to errors and in processing the subjective and/or emotional significance of events.19,61,64,65
The medial PFC (BA 10), on the other hand, has been strongly implicated in self-reflective judgments66–70
and cognitive aspects of self-evaluation,71
raising the possibility that this region plays a key role in automatic self evaluations.72
On the basis of these findings, we speculate that heightened rostral ACC and medial PFC activation after committing errors might reflect exaggerated affective appraisal of a perceived failure and potentiated self-relevant negative processing bias. Future studies are warranted to test this hypothesis and evaluate whether abnormalities within frontomedial regions may foster the emergence and maintenance of automatically activated cognitive schemata that might confer increased vulnerability to depression.1
The functional connectivity analyses revealed that, for the comparison group, activity within the rostral ACC and medial PFC region at the point of maximal ERN (80 milliseconds after committing an error) was positively correlated with subsequent left dorsolateral PFC activity (472 milliseconds after committing an error). Accordingly, healthy subjects who most strongly activated the rostral ACC 80 milliseconds after committing an error were also the ones recruiting most strongly the left dorsolateral PFC 472 milliseconds after committing an error. This pattern mirrors recent fMRI findings that show that dorsal ACC activation elicited by the Stroop interference predicted greater dorsolateral PFC recruitment, which in turn decreased the incongruency effect on the next trial.54
The present findings provide strong support for the theory that in healthy participants the ACC and ERN signal that an outcome is worse than expected, facilitating the subsequent recruitment of cognitive control.22–24
According to these conceptualizations, activity within the ACC and PFC regions should be positively correlated during the generation of adaptive behavioral adjustments. In prior research, the limited temporal resolution of fMRI has made it difficult to investigate the temporal unfolding of ACC and dorsolateral PFC interactions. To our knowledge, the present study is the first demonstration that activity within the rostral ACC and medial PFC at the point of the ERN predicts subsequent dorsolateral PFC activity and provides direct empirical evidence that supports the role of the ERN in the recruitment of executive control processes necessary for adaptive behavioral adjustments after mistakes.
Notably, among patients with MDD, those with the highest left dorsolateral PFC activation 472 milliseconds after committing errors showed more adaptive posterror behavioral adjustments (ie, higher accuracy and longer RTs after committing errors) compared with patients with MDD who failed to recruit the left dorsolateral PFC after mistakes. Interestingly, the behavioral differences emerged despite virtually identical depression severity (mean [SD] Beck Depression Inventory scores: 22.22 [9.46] vs 22.11 [9.45]). These findings are intriguing, particularly when considering the role of dorsolateral PFC regions in cognitive control24
and emotional regulation,73,74
as well as data indicating that relatively increased left PFC activity during resting states predict better physiological recovery after negative pictures.75
Overall, these findings suggest that, in a subgroup of patients with MDD, dorsolateral PFC–based compensatory processes might protect against performance deterioration despite hyperresponsiveness to errors and rostral ACC and medial PFC hyperactivation during early stages of the information processing flow. Since in healthy samples increased ERN amplitude has often, albeit not consistently, been associated with adaptive behavioral adjustments,21,34,76
failure to recruit dorsolateral PFC–based cognitive control might explain the apparent contradictory finding of larger ERN but worse posterror behavioral adjustments in MDD. In summary, our findings support the claim that patients with depression may not be able to effectively recruit their dorsolateral PFC to account for changes in affective state or task difficulty13
and thus help reconcile prior behavioral and ERP findings of abnormal error processing in depression.
Several limitations of the present study should be emphasized. First, although the source localization used in the present study has received considerable empirical support from more traditional tomographic methods (eg, fMRI,44
positron emission tomography,45
and intracranial recordings46
), its relatively low spatial resolution is one of the primary limitations of this study. Second, although the ERN findings occurred well before the onset of the feedback cues, we cannot fully exclude the possibility that the reported results were partially affected by group differences in feedback processing (eg, failure on the part of the patients to disengage from negative feedback). Although future studies will be required to resolve this issue, the present findings replicate prior reports of increased ERN in paradigms with28
feedback. Thus, when seen within the framework of prior literature, it is parsimonious to interpret our findings as reflecting dysfunctional error processing in depression. Third, it is unclear how the present findings relate to recent evidence that decreased resting (ie, task-free) ventral ACC activity predicted impaired posterror behavioral adjustments in a nonclinical sample characterized by elevated depressive symptoms.9
Future studies will be required to directly test the relationship between resting and task-related ACC activation in conjunction with abnormal error processing along a continuum of depression severity. These limitations notwithstanding, the present study sheds new light into the spatiotemporal dynamics of brain mechanisms underlying the dysregulated action-monitoring system in depression and suggests that rostral ACC and medial PFC hyperresponsiveness to internal representations of errors and failures to recruit cognitive control have the potential to explain abnormal responses to errors in MDD, as well as the emergence and maintenance of negative processing biases in depression.