Methylphenidate promotes a frontoparietal-dominant brain state improving cognitive performance: a randomized trial.

Abstract

Methylphenidate (MP) is a widely used stimulant medication for the treatment of attention deficit hyperactivity disorder that enhances brain dopamine signaling and improves attention. However, how dopamine stimulation alters brain state dynamics to support improved attention during task performance is still unclear. To address this, we employed a multimodal neuroimaging approach combining positron emission tomography, functional magnetic resonance imaging, and behavioral tasks, to discover associations between dopamine signaling, brain dynamics, and cognition. Multimodal images were collected from 37 healthy adults under a single-blind, counterbalanced, placebo-controlled crossover study. Dynamic functional analysis was used to compare the alterations in dynamic features of brain states before and after MP. Subsequently, we analyzed the correlation between these brain state changes and baseline striatal D1 and D2 dopamine receptor (D1R, D2R) availability. We also examined alterations in dynamic brain states and their effects on visuospatial tasks. The results showed that MP primarily affected frontoparietal-dominant activated (FPN+), somatomotor-dominant activated (SOM+), and visual-dominant suppressed (VIS-) brain states. Specifically, the dwell time and fractional occupancy exhibited significant increases within the FPN+ and VIS- and an opposite trend within the SOM+. Furthermore, the increase of dwell time in FPN+, which was positively correlated with baseline striatal D1R availability, was also associated with quicker response in the 2-ball-track task, but not significantly for the 3-ball-track task. The findings suggest that MP's enhancement of brain states with FPN+ and VIS- while decreasing SOM+, in part through D1R signaling might underlie MP's improvement of attention for low demanding tasks in healthy populations.Significance statement Methylphenidate (MP) is primarily prescribed for Attention-Deficit/Hyperactivity Disorder (ADHD), but it is also misused as a cognitive enhancer by individuals seeking to improve cognitive performance. Using advanced brain imaging and behavioral tasks, this study investigates how MP affects dopamine signaling, brain activity and cognitive performance. Our results demonstrate that MP promoted a frontoparietal-dominant brain state which linked to improved task performance and D1 receptor availability. This research also introduces a multi-level neuroimaging approach to studying drug effects, offering a foundation for tailoring interventions by predicting individual variations in responses to medicine.