Abstract
Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans.
Highlights
Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes
State of the art arterial spin labeling (ASL) sequences allow for quantitative cerebral blood flow (CBF) evaluation and are used for evaluation of metabolism associated with neural activity[11,12,13,14,15]
We tested for direct relationships between drug-induced ∆CBF and underlying receptor density maps using correlational analysis
Summary
Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. Metabolic task-based and resting state magnetic resonance imaging (MRI) of blood oxygen level dependence and cerebral blood flow (CBF) are commonly applied for studying human brain function, disease pathology and for evaluation of pharmacodynamic (PD) effects associated with pharmacological interventions[1,2,3,4,5,6,7,8,9]. State of the art arterial spin labeling (ASL) sequences allow for quantitative CBF evaluation and are used for evaluation of metabolism associated with neural activity[11,12,13,14,15] Despite their wide-spread applications in healthy and diseased populations there is limited understanding of whether and how metabolic effects measured through these techniques reflect underlying activity in specific neurotransmitter systems[1,2,4,7,16]. Addressing those limitations is key to wide-spread application of metabolic MRI in translational medicine
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