Neural Correlates of Error Monitoring Modulated by Atomoxetine in Healthy Volunteers

Background: Atomoxetine is a selective norepinephrine reuptake inhibitor clinically used for treatment of attention-deficit/hyperactivity disorder. In healthy control subjects, doses of 40 mg or 60 mg improved inhibitory control in combination with modulation of prefrontal cortex functioning. We investigated the effects of atomoxetine (80 mg) on error monitoring as a second key component of cognitive control. Methods: Twelve healthy, male volunteers were included in a randomized double-blind, placebo-controlled, within-subjects design to examine the effects of a single dose of atomoxetine on neural activities during a combined Eriksen flanker-Go/NoGo task as measured by functional magnetic resonance imaging. Results: Behaviorally, atomoxetine led to a significant increase in failed inhibition. Functionally, interaction analysis revealed a significant increase of the error signal (incorrect minus correct NoGo trials) under atomoxetine in bilateral inferior frontal cortex and presupplementary motor area. Drug-dependent increases in error signaling did not correlate with increased error rates. Analysis of neuropsychological data indexed a significant increase in phasic alertness. Conclusions: Results support that atomoxetine increases neural sensitivity for errors in healthy control subjects, possibly due to an accentuated representation of the task set. However, this gain was accompanied by deterioration in inhibitory control, possibly reflecting a shift beyond the optimal working range of the norepinephrine system.