Methylphenidate reorganizes cortical hierarchy through dopaminergic modulation

Abstract

Abstract Dopaminergic signaling shapes large-scale brain network architecture, constraining neural communication along a principal gradient that spans unimodal sensorimotor to transmodal association cortices. While more differentiated gradients are typically linked to enhanced cognition, it remains unclear whether dopamine-enhancing psychostimulants, such as methylphenidate (MP), amplify or compress this functional hierarchy to support attention. Across two double-blind, placebo-controlled studies in healthy adults (n = 38 and n = 20), we combined 60 mg oral MP with PET and fMRI to assess striatal dopamine function and cortical organization. MP consistently compressed the principal gradient, reducing segregation between sensory and association areas. The degree of compression predicted individual variation in striatal D1 and D2 receptor availability. MP-induced gradient compression in inferior parietal cortex tracked attention improvements. Critically, we validated key findings in a large, independent cohort from the Adolescent Brain Cognitive Development (ABCD) study (n = 4,958). These results highlight a dopamine-sensitive mechanism linking cortical functional reorganization with cognitive performance.