Validating molecular target-enriched fMRI for disentangling drug effects on dopamine

The psychostimulant methylphenidate may exert its effects on cognition and associated brain signals via action on the dopamine or noradrenaline transporter (DAT/NET). A recently developed and increasingly popular dual-regression approach (REACT; Dipasquale et al. (2019)) hones in on the molecular mechanisms underlying (drug-induced) changes in fMRI signal by enriching the analysis with information about the spatial distribution of molecular targets of interest. This method has great potential, but hitherto lacked validation of its molecular specificity and functional relevance. Here, we leverage a unique pharmaco-fMRI dataset with established dopamine-dependent methylphenidate effects on neural reward prediction error signaling, one of the key functional signatures of dopamine. Using REACT we found that methylphenidate significantly modulated both DAT and NET-related functional connectivity networks, but only the effect on the DAT network varied with interindividual differences in striatal dopamine synthesis capacity, as measured with [¹⁸F]FDOPA PET imaging. Furthermore, methylphenidate affected DAT-related connectivity in the prefrontal cortex in the same location where it affected neural reward prediction error signaling. Together, these findings firmly establish the validity of REACT as a tool for isolating the role of dopamine from that of noradrenaline in methylphenidate's effects on brain function.