Neural basis for individual differences in the attention-enhancing effects of methylphenidate

Stimulant drugs that boost dopamine, like methylphenidate (MP), enhance attention and are effective treatments for attention-deficit hyperactivity disorder (ADHD). Yet there is large individual variation in attentional capacity and response to MP. It is unclear whether this variation is driven by individual differences in relative density of dopamine receptor subtypes, magnitude of dopamine increases induced by MP, or both. Here, we extensively characterized the brain dopamine system with positron emission tomography (PET) imaging (including striatal dopamine D1 and D2/3 receptor availability and MP-induced dopamine increases) and measured attention task-evoked fMRI brain activity in two separate sessions (placebo and 60 mg oral MP; single-blind, counterbalanced) in 37 healthy adults. A network of lateral frontoparietal and visual cortices was sensitive to increasing attentional (and working memory) load, whose activity positively correlated with performance across individuals (partial r = 0.474, <i>P</i> = 0.008; controlling for age). MP-induced change in activity within this network correlated with MP-induced change in performance (partial r = 0.686, <i>P</i> < 0.001). The ratio of D1-to-D2/3 receptors in dorsomedial caudate positively correlated with baseline attentional network activity and negatively correlated with MP-induced changes in activity (all pFWE < 0.02). MP-induced changes in attentional load network activity mediated the association between D1-to-D2/3 ratio and MP-induced improvements in performance (mediation estimate = 23.20 [95%CI: -153.67 -81.79], <i>P</i> = 0.004). MP attention-boosting effects were not linked to the magnitude of striatal dopamine increases, but rather showed dependence on an individual's baseline receptor density. Individuals with lower D1-to-D2/3 ratios tended to have lower frontoparietal activity during sustained attention and experienced greater improvement in brain function and task performance with MP.