Since its inception 20 years ago, functional magnetic resonance imaging (fMRI) of the human brain based on the blood oxygenation level dependent (BOLD) contrast phenomenon has proliferated and matured. Today it is the predominant functional brain imaging modality with the majority of applications being in basic cognitive neuroscience where it has primarily been used as a tool to localize brain activity. While the magnitude of the BOLD response is often used in these studies as a surrogate for the level of neuronal activity, the link between the two is, in fact, quite indirect. The BOLD response is dependent upon hemodynamic (blood flow and volume) and metabolic (oxygen consumption) responses as well as acquisition details. Furthermore, the relationship between neuronal activity and the hemodynamic response, termed neurovascular coupling, is itself complex and incompletely understood. Quantitative fMRI techniques have therefore been developed to measure the hemodynamic and metabolic responses to modulations in brain activity. These methods have not only helped clarify the behaviour and origins of the BOLD signal under normal physiological conditions but they have also provided a potentially valuable set of tools for exploring pathophysiological conditions. Such quantitative methods will be critical to realize the potential of fMRI in a clinical context, where simple BOLD measurements cannot be uniquely interpreted, and to enhance the power of fMRI in basic neuroscience research. In this article, recent advances in human quantitative fMRI methods are reviewed, outstanding issues discussed and future challenges and opportunities highlighted.
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