Use of magnetic resonance imaging in pharmacogenomics

Abstract

Because of the large variation in the response to psychoactive medication, many studies have attempted to uncover genetic factors that determine response. While considerable knowledge exists on the large effects of genetic polymorphisms on pharmacokinetics and plasma concentrations of drugs, effects of the concentration at the target site and pharmacodynamic effects on brain functions in disease are much less known. This article reviews the role of magnetic resonance imaging (MRI) to visualize response to medication in brain behaviour circuits in vivo in humans and assess the influence of pharmacogenetic factors. Two types of studies have been used to characterize effects of medication and genetic variation. In task-related activation studies the focus is on changes in the activity of a neural circuit associated with a specific psychological process. The second type of study investigates resting state perfusion. These studies provide an assessment of vascular changes associated with bioavailability of drugs in the brain, but may also assess changes in neural activity after binding of centrally active agents. Task-related pharmacogenetic studies of cognitive function have characterized the effects in the prefrontal cortex of genetic polymorphisms of dopamine receptors (DRD2), metabolic enzymes (COMT) and in the post-synaptic signalling cascade under the administration of dopamine agonists and antagonists. In contrast, pharmacogenetic imaging with resting state perfusion is still in its infancy. However, the quantitative nature of perfusion imaging, its non-invasive character and its repeatability might be crucial assets in visualizing the effects of medication in vivo in man during therapy.

Keywords: neuroleptics; perfusion imaging; pharmacogenetic imaging.

Figure 1

Intermediate phenotypes provided by imaging techniques are biological markers of brain function that may clarify the association between therapy, individual factors, including the genetic makeup, and response. In this article we review mainly the role of task-activated and resting perfusion phenotypes. A third emerging phenotype, connectivity, has just begun to be applied to pharmacological imaging studies in man

Figure 2

(A) Schematic illustration of the ASL technique. An inversion pulse inverts the spins of the water molecules in the blood in the neck, disrupting the signal from these molecules when they are sampled after reaching the brain. The cerebral blood flow (CBF) is estimated from the difference between two images, one taken with and one taken without the inversion pulse. (B) Regional CBF maps created from the ASL signal, averaged from about 300 hundred individuals. The maps represent transversal slices taken at the level of the midbrain, the thalamus and basal ganglia, and the cerebral hemispheres immediately above the corpus callosum (the coordinates are in Montreal Neurological Institute space). The figure shows that cortical and subcortical grey matter and regions rich in vessels are brighter than white matter and ventricular spaces, reflecting higher regional perfusion values