Examining the role of dopamine in methylphenidate's effects on resting brain function

The amplitude of low-frequency fluctuations (ALFF) and global functional connectivity density (gFCD) are fMRI (Functional MRI) metrics widely used to assess resting brain function. However, their differential sensitivity to stimulant-induced dopamine (DA) increases, including the rate of DA rise and the relationship between them, have not been investigated. Here we used, simultaneous PET-fMRI to examine the association between dynamic changes in striatal DA and brain activity as assessed by ALFF and gFCD, following placebo, intravenous (IV), or oral methylphenidate (MP) administration, using a within-subject double-blind placebo-controlled design. In putamen, MP significantly reduced D_2/3 receptor availability and strongly reduced ALFF and increased gFCD in the brain for IV-MP (Cohen's d > 1.6) but less so for oral-MP (Cohen's d < 0.6). Enhanced gFCD was associated with both the level and the rate of striatal DA increases, whereas decreased ALFF was only associated with the level of DA increases. These findings suggest distinct representations of neurovascular activation with ALFF and gFCD by stimulant-induced DA increases with differential sensitivity to the rate and the level of DA increases. We also observed an inverse association between gFCD and ALFF that was markedly enhanced during IV-MP, which could reflect an increased contribution from MP's vasoactive properties.