Methylphenidate enhances executive function and optimizes prefrontal function in both health and cocaine addiction

Abstract

Previous studies have suggested dopamine to be involved in error monitoring/processing, possibly through impact on reinforcement learning. The current study tested whether methylphenidate (MPH), an indirect dopamine agonist, modulates brain and behavioral responses to error, and whether such modulation is more pronounced in cocaine-addicted individuals, in whom dopamine neurotransmission is disrupted. After receiving oral MPH (20 mg) or placebo (counterbalanced), 15 healthy human volunteers and 16 cocaine-addicted individuals completed a task of executive function (the Stroop color word) during functional magnetic resonance imaging (fMRI). During MPH, despite not showing differences on percent accuracy and reaction time, all subjects committed fewer total errors and slowed down more after committing errors, suggestive of more careful responding. In parallel, during MPH all subjects showed reduced dorsal anterior cingulate cortex response to the fMRI contrast error>correct. In the cocaine subjects only, MPH also reduced error>correct activity in the dorsolateral prefrontal cortex (controls instead showed lower error>correct response in this region during placebo). Taken together, MPH modulated dopaminergically innervated prefrontal cortical areas involved in error-related processing, and such modulation was accentuated in the cocaine subjects. These results are consistent with a dopaminergic contribution to error-related processing during a cognitive control task.

Keywords: Stroop; anterior cingulate cortex; cerebellum; cocaine addiction; dopamine; dorsolateral prefrontal cortex; executive function; fMRI; methylphenidate; norepinephrine.

Figure 1.

fMRI Stroop color-word task. Subjects pressed for ink color as quickly and accurately as possible (performance was recorded throughout). fMRI response to conflict trials (all incongruent), error trials (all error), and their interaction were each compared with active baselines (all congruent trials, all correct trials, and congruent correct trials, respectively). (A) Examples of color words: the circled (blue) stimulus is congruent; all others are incongruent. (B) Individual trial, comprised of a 1300-ms color-word stimulus and 350-ms interstimulus interval. (C) Individual run, comprised 200 individual trials and a 3200-ms interval to separate runs.

Figure 2.

The impact of oral methylphenidate (20 mg) on brain and behavior during the Stroop color-word task in 15 healthy individuals and 16 individuals addicted to cocaine. Compared with placebo, and in all subjects, methylphenidate (A) decreased task-related errors, (B) increased posterror slowing, and (C) decreased right dorsal anterior cingulate cortex (dACC) response to the contrast error > correct. (D) There was also a medication × group interaction in the left DLPFC (lower error > correct DLPFC response during MPH in the cocaine subjects, but lower error > correct DLPFC response during placebo in the controls; note that the correct congruent baseline means that BOLD response below zero does not necessarily indicate deactivations as also indicated in Methods). For (C) and (D), Figure shows mean percent blood-oxygen-level-dependent (BOLD) signal change during methylphenidate and placebo, with associated means and standard errors separately for cocaine subjects and control subjects. For display purposes, Figure activations are thresholded at P < 0.005 voxel-level uncorrected. Anatomical images are presented in neurological convention (L = L).