Review article
BOLD functional MRI in disease and pharmacological studies: room for improvement?

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Abstract

In the past decade the use of blood oxygen level-dependent (BOLD) fMRI to investigate the effect of diseases and pharmacological agents on brain activity has increased greatly. BOLD fMRI does not measure neural activity directly, but relies on a cascade of physiological events linking neural activity to the generation of MRI signal. However, most of the disease and pharmacological studies performed so far have interpreted changes in BOLD fMRI as “brain activation,” ignoring the potential confounds that can arise through drug- or disease-induced modulation of events downstream of the neural activity. This issue is especially serious in diseases (like multiple sclerosis, brain tumours and stroke) and drugs (like anaesthetics or those with a vascular action) that are known to influence these physiological events.

Here we provide evidence that, to extract meaningful information on brain activity in patient and pharmacological BOLD fMRI studies, it is important to identify, characterise and possibly correct these influences that potentially confound the results. We suggest a series of experimental measures to improve the interpretability of BOLD fMRI studies. We have ranked these according to their potential information and current practical feasibility.

First-line, necessary improvements consist of (1) the inclusion of one or more control tasks, and (2) the recording of physiological parameters during scanning and subsequent correction of possible between-group differences. Second-line, highly recommended importants aim to make the results of a patient or drug BOLD study more interpretable and include the assessment of (1) baseline brain perfusion, (2) vascular reactivity, (3) the inclusion of stimulus-related perfusion fMRI and (4) the recording of electrophysiological responses to the stimulus of interest. Finally, third-line, desirable improvements consist of the inclusion of (1) simultaneous EEG–fMRI, (2) cerebral blood volume and (3) rate of metabolic oxygen consumption measurements and, when relevant, (4) animal studies investigating signalling between neural cells and blood vessels.

Section snippets

The trouble with stand-alone BOLD fMRI studies

Blood oxygen level-dependent (BOLD) signal is the most widely used image contrast in functional magnetic resonance imaging (fMRI) of the human brain [1], [2]. BOLD-based fMRI has been used extensively in the past 15 years to investigate diseases in the brain [3]. Results from those studies have been often used to suggest pathophysiological mechanisms of disease. More recently, BOLD fMRI has been also used to investigate the pharmacological modulation of brain activity [4], aimed at elucidating

Suggestions for improving BOLD fMRI studies

The strategy for improving BOLD fMRI studies should aim to assess the contribution of all the physiological events that relate the BOLD response to the neural activity, as discussed above. It is currently not possible to quantify completely all of these contributions in humans. Here we suggest a series of practical experimental approaches that are promising to characterise and sometimes correct possible confounds, and that we hope will undergo improvement, refinement and replacement with more

Recommendation

In this final section, we aim to give a practical “guide” to make the results of patient and drug BOLD studies more reliable and interpretable. We have considered the balance between the importance of the information yield by the additional experiments and the current practical feasibility of implementing them. These recommendations are summarised in Fig. 3 and divided into three broad categories: necessary, strongly recommended and desirable.

The first line of improvements that we consider

Acknowledgments

RGW acknowledges the generous support of the MRC (Career Development Award). GDI is University Research Fellow of the Royal Society.

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