Using MRI to measure drug action: caveats and new directions.

Investigating pharmacological modulation of brain activity using magnetic resonance imaging (MRI) presents an exciting opportunity to bridge the gap between preclinical and clinical studies, and holds the potential to be a useful tool in the discovery and development of novel therapeutic agents. Most functional MRI studies to date have utilized the blood oxygen level dependent (BOLD) contrast mechanism. Although this has some advantages over other techniques and is widely available, BOLD has two significant limitations for the study of drug effects; it is an indirect measurement of neuronal function, and produces only a relative (non-quantitative) measure of blood dynamics. Here we describe the various experimental manipulations that have been used to reduce the impact of these limitations, and discuss new ways of collecting and analysing imaging data that allow us to assess functional connectivity of the brain. We recommend some complementary techniques (such as arterial spin labelling and magnetoencephalography) that, if used in conjunction with BOLD functional MRI, will increase the interpretability and thus the utility of MRI for pharmacology research.