Spatiotemporal dynamics of error processing dysfunctions in major depressive disorder.

Cognitive theories of depression have long postulated that automatically activated cognitive schemata and a predisposition to process information in a negative manner are prominent features of depression.1 Consistent with this, depression is characterized by ineffective inhibition of negative information,2 difficulty disengaging attention from negative cues,3 greater interference from negative distractors,4 amplification of the significance of failure,5 and increased likelihood of committing errors immediately after an initial mistake.6–10 Although these negative processing biases have been critically implicated in the etiology and maintenance of depression, little is known about their underlying mechanisms and neural substrates. Emerging neuroimaging evidence suggests that, in major depressive disorder (MDD), negative processing biases may result from dysfunctions in paralimbic regions implicated in affective responses such as the amygdala and the rostral anterior cingulate cortex (ACC)11–13 and/or dysfunctions in cortical regions involved in cognitive control (ie, the ability to guide action and thought in accordance with internally generated goals), such as the dorsolateral prefrontal cortex (PFC) and dorsal ACC.13–18 Moreover, patients with MDD show reduced connectivity between the dorsolateral PFC and rostral ACC regions after the presentation of personally relevant negative stimuli.13 Collectively, these findings suggest that abnormal responses to errors and negative cues in depression6–10 might be due to exaggerated paralimbic activation, a failure to recruit PFC-based cognitive control after committing an error, or a combination of these 2 factors, possibly resulting from disrupted frontocingulate connectivity. To the best of our knowledge, these hypotheses have yet to be fully investigated. The goal of this study was to address these important questions. To this end, we capitalized on the high temporal resolution of event-related potentials (ERPs) and on novel approaches to investigate spatiotemporal dynamics of brain mechanisms that underlie error processing in a sample of unmedicated patients with MDD. The ERP analyses focused on error-related negativity (ERN) and error positivity (Pe), 2 components assumed to reflect dissociable aspects of error processing and partially originating from regions within the ACC.19 The ERN, a negative voltage deflection measured over midline frontocentral regions beginning with the occurrence of an incorrect response and peaking approximately 50 to 150 milliseconds later,20,21 is hypothesized to represent a negative reinforcement learning signal conveyed through the mesencephalic dopamine system22,23; accordingly, the ERN is assumed to index the automatic initial detection of unfavorable performance outcomes, which then triggers recruitment of PFC-based cognitive control.24 The Pe, a positive voltage deflection peaking approximately 150 to 500 milliseconds after mistakes, is hypothesized to index conscious error awareness and subjective affective evaluative processes after errors.20 Fitting these conceptualizations, ERN is not contingent on the conscious experience of errors, whereas the Pe is observed when subjects are aware of having committed an error.25–27 Extending reports of abnormal error processing in depression,6–10 recent ERP studies have described enhanced ERN amplitude in clinically depressed patients,28 elderly patients with MDD who remain symptomatic after antidepressant treatment,29 and individuals with increased levels of negative affect30,31 but not in medicated patients with MDD in remission.32 Moreover, increased ERN amplitude has been found to predict poor treatment response in a small sample of patients with geriatric depression.33 Although these ERN findings highlight dysfunctional error processing in depression, at first glance, they appear paradoxical in light of theoretical considerations22 and empirical findings21,34 that link increased ERN with adaptive performance adjustments. To reconcile these data, we hypothesized that, in depression, initial exaggerated error processing (increased ERN) is not followed by successful recruitment of PFC-based cognitive control, leading to posterror impairments. Notably, decreased ERN in error trials after a prior mistake32 has been described in patients with MDD, providing indirect support for this hypothesis. Therefore, on the basis of prior findings,11,13,28,29 we hypothesized that unmedicated patients with MDD would show (1) decreased performance in trials immediately after errors, (2) increased scalp ERN and rostral ACC activation after committing errors, and/or (3) disrupted connectivity between the rostral ACC and dorsolateral PFC regions, which might explain deficits in the recruitment of cognitive control and the lack of adaptive performance after error commission. With respect to Pe, we hypothesized that patients with MDD would display higher amplitudes, reflecting increased subjective affective evaluation of errors. Because of inconsistent Pe findings in depression,28,29 we considered this latter hypothesis tentative.