Cerebral blood flow predicts differential neurotransmitter activity

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. Here 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 in a novel framework aimed at disentangling the observed effects to underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying activity and/or 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 validate cerebral blood flow as a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans, with widespread implications for translational medicine and drug discovery alike. Significance statementWhilst magnetic resonance imaging of cerebral blood flow is commonly applied for studying human brain disease and therapeutic interventions it remains obscure if and how such measures reflect specific underlying neurophysiological activity or disease pathology in specific neurotransmitter systems. Here we examine the effects of seven drugs with differential dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action on cerebral blood flow. We demonstrate that cerebral blood flow closely reflects specific activity changes from various underlying neurotransmitter systems. These findings and the proposed framework have widespread implications for deploying metabolic magnetic resonance imaging measures for a more informative evaluation of disease pathology and different therapeutic interventions.

Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans

“…We have previously demonstrated the sensitivity of arterial spin labelling (ASL) magnetic resonance imaging (MRI) in quantifying changes in brain's physiology after intranasal OT administration 16 , as reflected in changes in regional cerebral blood flow (rCBF) at rest, which provide a quantitative, non-invasive pharmacodynamic marker of the effects of acute doses of psychoactive drugs 27,28 , with highspatial resolution and excellent temporal reproducibility 29 . As a result of neuro-vascular coupling, changes in rCBF are likely to reflect changes in neuronal activity 30 , and they capture relevant differential neurotransmitter activity of neurochemical systems 16,31 .…”

Intrinsic Connectivity Patterns of Task-Defined Brain Networks Allow Individual Prediction of Cognitive Symptom Dimension of Schizophrenia and Are Linked to Molecular Architecture

“…For comparability, these maps, in MNI152 space, were all resampled to an isotropic 2mm spatial resolution as in our fMRI data and linearly rescaled to 0-100. Furthermore, the significantly higher expressed receptors/transporters were entered into a spatial correlation analysis (54,55) calculated as rank correlation between the node importance scores and receptor/transporter densities calculated for these nodes ( Figure 4B). The node importance score was calculated by summing the selection frequency of the connections of each node derived from the repeated 10-fold cross-validation.…”

Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans

“…Changes in rCBF provide a quantitative, noninvasive pharmacodynamic marker of the effects of acute doses of psychoactive drugs (30,31), with high spatial resolution and excellent temporal reproducibility (32). As a result of neurovascular coupling, changes in rCBF are likely to reflect changes in neuronal activity rather than vascular effects (33), and they capture relevant differential neurotransmitter activity of neurochemical systems (18,34).…”