Effects of Stimulants on Brain Function in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis

Abstract

BackgroundPsychostimulant 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.MethodsThe 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.ResultsThe 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.ConclusionsPsychostimulants 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.

Lisdexamfetamine Effects on Executive Activation and Neurochemistry in Menopausal Women with Executive Function Difficulties

“…This was observed in an ROI analysis at all levels of the n-back task performed as well as in a whole-brain analysis. These results accord with a copious literature of neuroimaging studies of stimulant effects in individuals with ADHD (Rubia et al, 2014), and moreover highlight the mechanism of this drug's action in a population who exhibits similar executive deficits but who do not meet criteria for ADHD. A meta-analysis of 14 fMRI data sets found stimulants relative to placebo/off-medication most consistently increase activation in the insula/IFC (Rubia et al, 2014).…”

“…These results accord with a copious literature of neuroimaging studies of stimulant effects in individuals with ADHD (Rubia et al, 2014), and moreover highlight the mechanism of this drug's action in a population who exhibits similar executive deficits but who do not meet criteria for ADHD. A meta-analysis of 14 fMRI data sets found stimulants relative to placebo/off-medication most consistently increase activation in the insula/IFC (Rubia et al, 2014). This finding is present during tasks probing executive domains of interference inhibition (Rubia et al, 2014), time discrimination (Rubia et al, 2014), and working memory (Spencer et al, 2013).…”

“…A meta-analysis of 14 fMRI data sets found stimulants relative to placebo/off-medication most consistently increase activation in the insula/IFC (Rubia et al, 2014). This finding is present during tasks probing executive domains of interference inhibition (Rubia et al, 2014), time discrimination (Rubia et al, 2014), and working memory (Spencer et al, 2013). The insula is part of the cinglo-opercular control network critical for cognitive control, and is particularly important in the maintenance of task sets and error monitoring (Power et al, 2011).…”

“…Previous studies have shown that stimulant medications increase blood-oxygen-level-dependent (BOLD) signal in executive regions, including the insula (Rubia et al, 2014) and DLPFC (Wong and Stevens, 2012) in subjects with ADHD. In addition, stimulants also decrease glutamate levels in the PFC of children with ADHD (Wiguna et al, 2012).…”

Real‐time fMRI neurofeedback in adolescents with attention deficit hyperactivity disorder

“…The improvement of rIFG activation in the active group in the stop task concomitant with no brain activation changes in the control group is also interesting, given that rIFG activation enhancement has been shown to be the most consistent effect of stimulant medication on ADHD brain function [Rubia et al, 2014b], suggesting comparable neurofunctional effects of stimulant medication and rtfMRI‐NF of rIFG.…”