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Spatiotemporal dynamics of error processing dysfunctions in major depressive disorder.

Holmes AJ, Pizzagalli DA

Department of Psychology, Harvard University, Cambridge, MA 02138, USA.

CONTEXT: Depression is characterized by executive dysfunctions and abnormal reactions to errors; however, little is known about the brain mechanisms that underlie these deficits. OBJECTIVE: To examine whether abnormal reactions to errors in patients with major depressive disorder (MDD) are associated with exaggerated paralimbic activation and/or a failure to recruit subsequent cognitive control to account for mistakes in performance. DESIGN: Between February 15, 2005, and January 19, 2006, we recorded 128-channel event-related potentials while study participants performed a Stroop task, modified to incorporate performance feedback. SETTING: Patients with MDD and healthy comparison subjects were recruited from the general community. PARTICIPANTS: Study participants were 20 unmedicated patients with MDD and 20 demographically matched comparison subjects. MAIN OUTCOME MEASURES: The error-related negativity and error positivity were analyzed through scalp and source localization analyses. Functional connectivity analyses were conducted to investigate group differences in the spatiotemporal dynamics of brain mechanisms that underlie error processing. RESULTS: Relative to comparison subjects, patients with MDD displayed significantly lower accuracy after incorrect responses, larger error-related negativity, and higher current density in the rostral anterior cingulate cortex (ACC) and medial prefrontal cortex (PFC) (Brodmann area 10/32) 80 milliseconds after committing an error. Functional connectivity analyses revealed that for the comparison subjects, but not the patients with MDD, rostral ACC and medial PFC activation 80 milliseconds after committing an error predicted left dorsolateral PFC (Brodmann area 8/9) activation 472 milliseconds after committing an error. CONCLUSIONS: Unmedicated patients with MDD showed reduced accuracy and potentiated error-related negativity immediately after committing errors, highlighting dysfunctions in the automatic detection of unfavorable performance outcomes. New analytic procedures allowed us to show that abnormal reaction to committing errors was accompanied by hyperactivation in rostral ACC and medial PFC regions 80 milliseconds after committing errors and a failure to recruit dorsolateral PFC-based cognitive control. Future studies are warranted to investigate whether these dysfunctions might foster the emergence and maintenance of negative processing biases and thus increase vulnerability to depression.

Published 5 February 2008 in Arch Gen Psychiatry, 65(2): 179-88.
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