Methylphenidate normalizes fronto-striatal underactivation during interference inhibition in medication-naïve boys with attention-deficit hyperactivity disorder

Abstract

Youth with attention deficit hyperactivity disorder (ADHD) have deficits in interference inhibition, which can be improved with the indirect catecholamine agonist methylphenidate (MPH). Functional magnetic resonance imaging was used to investigate the effects of a single dose of MPH on brain activation during interference inhibition in medication-naïve ADHD boys. Medication-naïve boys with ADHD were scanned twice, in a randomized, double-blind design, under either a single clinical dose of MPH or placebo, while performing a Simon task that measures interference inhibition and controls for the oddball effect of low-frequency appearance of incongruent trials. Brain activation was compared within patients under either drug condition. To test for potential normalization effects of MPH, brain activation in ADHD patients under either drug condition was compared with that of healthy age-matched comparison boys. During incongruent trials compared with congruent-oddball trials, boys with ADHD under placebo relative to controls showed reduced brain activation in typical areas of interference inhibition, including right inferior prefrontal cortex, left striatum and thalamus, mid-cingulate/supplementary motor area, and left superior temporal lobe. MPH relative to placebo upregulated brain activation in right inferior prefrontal and premotor cortices. Under the MPH condition, patients relative to controls no longer showed the reduced activation in right inferior prefrontal and striato-thalamic regions. Effect size comparison, furthermore, showed that these normalization effects were significant. MPH significantly normalized the fronto-striatal underfunctioning in ADHD patients relative to controls during interference inhibition, but did not affect medial frontal or temporal dysfunction. MPH therefore appears to have a region-specific upregulation effect on fronto-striatal activation.

Figure 1

Increased brain activation with the single dose of methylphenidate compared with placebo in boys with attention deficit hyperactivity disorder (ADHD) during interference inhibition. Axial slices for within-group analysis of variance (ANOVA) results comparing methylphenidate and placebo for the contrast of incongruent–oddball trials at family-wise error-corrected cluster-level contrast of p<0.01. Methylphenidate compared with placebo enhanced activation in right inferior/premotor cortex and in a cluster comprising left cerebellum and middle and inferior temporal lobes. No brain regions were enhanced under placebo compared with methylphenidate. Talairach z-coordinates are indicated for slice distance (in mm) from the intercommissural line. The right side of the figure corresponds to the right side of the brain. The color bars indicate p-values with lighter colors reflecting more significant p-values.

Figure 2

(a) Axial slices showing significantly reduced activation in boys with attention deficit hyperactivity disorder (ADHD) under placebo compared with healthy comparison boys at family-wise error-corrected cluster-level contrast (analysis of covariance (ANCOVA)) of p<0.01 for the contrast of incongruent–oddball trials in the Simon task. No increased activation was observed in ADHD patients compared with healthy controls. (b) Under the methylphenidate condition, brain activation differences between groups were no longer observed in the clusters in right inferior/dorsolateral prefrontal cortex (DLPFC) and the left caudate/thalamus/ventromedial frontal lobe. Talairach z-coordinates are indicated for slice distance (in mm) from the intercommissural line. The right side of the figure corresponds to the right side of the brain. The color bars indicate p-values with lighter colors reflecting more significant p-values.

Figure 3

Standardized BOLD (Blood Oxygen Level Dependent) responses in areas of analysis of covariance (ANCOVA) group differences for (a) comparison between healthy control boys and attention deficit hyperactivity disorder (ADHD) boys under the placebo condition and (b) comparison between healthy control boys and ADHD boys under the methylphenidate condition. The color bars indicate p-values with lighter colors reflecting higher p-values.