Potentials and challenges for arterial spin labeling in pharmacological magnetic resonance imaging

Abstract

Pharmacological magnetic resonance imaging (phMRI) is increasingly being used in drug discovery and development to speed the translation from the laboratory to the clinic. The two primary methods in phMRI include blood-oxygen-level-dependent (BOLD) contrast and arterial spin-labeled (ASL) perfusion MRI. BOLD contrast has been widely applied in existing phMRI studies. However, because of the lack of absolute quantification and poor reproducibility over time scales longer than hours or across scanning sessions, BOLD fMRI may not be suitable to track oral and other long-term drug effects on baseline brain function. As an alternative method, ASL provides noninvasive, absolute quantification of cerebral blood flow both at rest and during task activation. ASL perfusion measurements have been shown to be highly reproducible over minutes and hours to days and weeks. These two characteristics make ASL an ideal tool for phMRI for studying both intravenous and oral drug action as well as understanding drug effects on baseline brain function and brain activation to cognitive or sensory processing. When ASL is combined with BOLD fMRI, drug-induced changes in cerebral metabolic rate of oxygen may also be inferred. Representative phMRI studies using ASL perfusion MRI on caffeine, remifentanil, and metoclopramide (dopamine antagonist) are reviewed here, with an emphasis on the methodologies used to control for potentially confounding vascular and systemic effects. Both the potentials and limitations of using ASL as an imaging marker of drug action are discussed.

Figures

Fig. 1.

A, representative whole-brain perfusion images acquired using pCASL with 3D GRASE readout. B, scatter plots showing test-retest results of pCASL perfusion measurements acquired 2 to 4 weeks apart and comparison of pCASL perfusion versus global blood flow measurements using PC-MRI in healthy children aged 7 to 17. A comparison of pCASL versus conventional PASL and pCASL can be found in Wu et al. (2007).

Fig. 2.

A, mean CBF images for the four conditions (baseline and dose levels 1–3) from a representative subject. Remifentanil doses are noted as 0.0, 0.05, 0.1, and 0.2 μg · kg−1 · min−1. B, significant dose effect was observed using absolute CBF values in global (Glo), amygdale (Amy), cingulated (Cin), hippocampus (Hip), and insula (Ins). C, ratio of regional to global CBF at each dose, thus normalizing for effects of PaCO2 shows significant dose effect in the amygdala, cingulate, and hippocampus. [Reproduced from Kofke WA, Blissitt PA, Rao H, Wang J, Addya K, and Detre J (2007) Remifentanil induced cerebral blood flow effects in normal humans: dose and ApoE genotype. Anesth Analg 105:167–175. Copyright © 2007 International Anesthesia Research Society. Used with permission.]

Fig. 3.

Mean CBF maps before and after caffeine intake (a) and ROI results of mean CBF (b), CMRGlu (c), and CMRO2/CMRGlu ratio (d). Anterior cingulate and caudate show significantly different CMRO2/CMRGlu ratio (p = 0.014), which may be associated with heightened alertness after caffeine intake. Errors bars indicate S.D.