Pharmacological MRI approaches to understanding mechanisms of drug action

Functional neuroimaging is a novel technique for the study of drug action in the brain. The emerging role of this method is intimately tied to the unique challenges to advancing drug development for neuropsychiatric disorders. This chapter first presents a brief overview of the important treatment needs that remain to be met, which serve as clinical targets for drug development. Important factors that hinder progress in drug development, which arise from clinical, scientific and economic issues, are acknowledged. This sets the stage for the unique advantages of functional neuroimaging modalities such as functional MRI (fMRI) as a biomarker and drug development tool, in both clinical and preclinical phases. The physiological basis of the fMRI signal is briefly outlined, and aspects of neural signaling related to this signal change, with emphasis on implications for pharmacology studies. The utility of fMRI for evaluating the full anatomic extent of central neurotransmitter systems in a dynamic manner is then described. This is a critical advantage, and particularly important for studies of how systems such as the monoamines modulate distributed neural networks during cognitive processes in both health and illness, and how these actions are modified with pharmacological intervention. Central catecholamine systems are seen as paradigmatic targets amenable to pharmacologic fMRI. fMRI is observed to occupy a unique position in the armamentarium of methods available to the pharmacologist and the drug development process, and poised to play an expanding role in basic and clinical neuroscience.