| Brain dopamine (DA) plays an important role in cognitive control, and failures of cognitive control are often treated with dopaminergic drugs. However, there is large variability in dopaminergic drug effects both across and within individuals. The neurobiological basis of this variability is unclear, which poses a major problem not only for neuropsychiatry (i.e. treatment of disorders), but also for the cognitive neuroscience of cognitive control. The present project will fill this gap by adopting an innovative approach, in which methods from psychopharmacology and genetics are combined with functional neuroimaging and theory-based task-design. Elucidation of factors that mediate dopaminergic drug efficacy will, at a theoretical level, address basic questions about the neurobiological basis of cognitive control, and at a clinical level promote the development of drug research targets and individualized therapy. Cognitive control generally refers to the active maintenance of goal-relevant representations (cognitive stability). However, cognitive control also depends on the ability to flexibly update goal-relevant representations (cognitive flexibility). Our constantly changing environment requires the balance between cognitive stability and flexibility to be dynamic. How does the brain regulate this balance? What neural mechanisms cause some individuals to be generally stable and (over)focused and others to be generally flexible and unfocused? What happens when the regulation of this balance goes awry (e.g. in Parkinson?s disease and drug addiction)? And finally, who will benefit and who will suffer adverse side-effects from drug treatment? I propose that cognitive stability and flexibility are mediated by DA in the PFC and the striatum respectively, and that individual differences in stability and flexibility reflect quantitative variation in baseline DA levels in these respective brain regions. The work will elucidate (genetic) factors that mediate variability in cognitive control and dopaminergic drug efficacy, and will advance the neuroscience of cognitive control as well as treatment development in neuropsychiatry. |
