Dopaminergic Mechanisms of Cognitive Flexibility: An [18F]Fallypride PET Study

Cognitive flexibility is the ability to appropriately adapt one's thinking and behavior to changing environmental demands and is conceptualized as an aspect of executive function. The dopamine system has been implicated in cognitive flexibility; however, a direct, that is, neurochemical, link to cognitive flexibility has not been shown yet. The aim of this study was, therefore, to investigate how cognitive flexibility is mediated by dopaminergic signaling in the ventromedial prefrontal cortex (vmPFC). Methods: Eighteen participants were measured in a PET study with 174 ± 12 MBq of the D_2/3 receptor ligand [¹⁸F]fallypride in a block design with 2 parts. While participants processed 2 tasks sequentially without rule switching on a computer screen in the first part of the PET scan, they had to flexibly switch between the 2 task rules after 100 min after injection in the second part. Dopamine release (γ) was quantified using the linearized simplified reference region model contrasting the 2 task blocks (switching vs. no-switching/baseline). Results: The statistical analysis of the parametric γ-images showed that the increased cognitive demand during task switching induced a displacement of the D_2/3 receptor ligand [¹⁸F]fallypride in the vmPFC (maximum T value = 13.8; cluster size: 528 voxels; familywise error rate–corrected P < 0.001; mean γ = 0.022 ± 0.006 min⁻¹). Furthermore, a correlation between behavioral switch costs and vmPFC [¹⁸F]fallypride displacement suggested that participants showing greater dopamine release were more efficient in task switching. Conclusion: To our knowledge, this is the first experimental PET study to show direct involvement of dopamine in the vmPFC in a task-switching paradigm, confirming model assumptions about the neurochemical basis of cognitive flexibility.