Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis

Abstract

Background: Psychostimulant medication, most commonly the catecholamine agonist methylphenidate, is the most effective treatment for attention-deficit/hyperactivity disorder (ADHD). However, relatively little is known on the mechanisms of action. Acute effects on brain function can elucidate underlying neurocognitive effects. We tested methylphenidate effects relative to placebo in functional magnetic resonance imaging (fMRI) during three disorder-relevant tasks in medication-naïve ADHD adolescents. In addition, we conducted a systematic review and meta-analysis of the fMRI findings of acute stimulant effects on ADHD brain function.

Methods: The fMRI study compared 20 adolescents with ADHD under either placebo or methylphenidate in a randomized controlled trial while performing stop, working memory, and time discrimination tasks. The meta-analysis was conducted searching PubMed, ScienceDirect, Web of Knowledge, Google Scholar, and Scopus databases. Peak coordinates of clusters of significant effects of stimulant medication relative to placebo or off medication were extracted for each study.

Results: The fMRI analysis showed that methylphenidate significantly enhanced activation in bilateral inferior frontal cortex (IFC)/insula during inhibition and time discrimination but had no effect on working memory networks. The meta-analysis, including 14 fMRI datasets and 212 children with ADHD, showed that stimulants most consistently enhanced right IFC/insula activation, which also remained for a subgroup analysis of methylphenidate effects alone. A more lenient threshold also revealed increased putamen activation.

Conclusions: Psychostimulants most consistently increase right IFC/insula activation, which are key areas of cognitive control and also the most replicated neurocognitive dysfunction in ADHD. These neurocognitive effects may underlie their positive clinical effects.

Keywords: ADHD; fMRI; meta-analysis; methylphenidate; review; stimulants.

Figure 1

Increased (orange) and decreased (blue) activation with methylphenidate relative to placebo in adolescents with attention-deficit/hyperactivity disorder (ADHD) during a tracking stop and a time discrimination task.

Figure 2

(A) Meta-analysis results in three-dimension at p < .005 showing brain regions of increased (red/orange) and decreased (blue) activation after a single dose of stimulant medication in children and adolescents with attention-deficit/hyperactivity disorder compared with placebo/off-medication. Relative to placebo, increased activation is shown with acute stimulant medication in right inferior prefrontal cortex extending deep into the insula and bordering superior temporal lobe and decreased activation in anterior cingulate cortex and supplementary motor area. (B) Meta-analysis results in two-dimension at peak Montreal Neurological Institute coordinates: 38, 18, −4 (corresponding to Talairach coordinates: 42, 20, −12) at p < .005, showing right inferior frontal cortex reaching into insula and anterior cingulate cortex/supplementary motor area. (C) Meta-analysis results in two-dimension at peak Montreal Neurological Institute coordinates: 38, 18, −4 (corresponding to Talairach coordinates: 42, 20, −12) at a more lenient p < .05, showing in addition a cluster in right putamen and rostral anterior cingulate.