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Global effects in functional MRI are temporal modulations in signal intensity resulting from various scanner and subject phenomena. These effects contribute to the overall variance, reducing the effect size associated with an experimental paradigm. Statistical estimations that include an approximation for concurrent global effects will reduce the residual error within the model and so improve statistical power of the study. Conventionally, estimates of global effects are derived from mean intracerebral signal intensities, but these may be prone to contributions from localised experimentally evoked signal changes. In such cases, inaccurate estimates of global effects may result in erroneous inferences of neural modulations based on statistical artefact. A novel, computationally simple, method of estimating global effects is proposed using muscle tissue acquired within the same acquisition volume. Quantitative improvements in sensitivity are reported for a somatosensory stimulation paradigm using global muscle signal intensities as a covariate of no-interest. The method is independent of local neurogenic signal changes and, under particular experimental conditions, may be more representative of true global effects. The utility of this strategy to applications in small-animal functional MRI that evoke systemic physiological changes as a result of the experimental manipulation is critically discussed. Copyright © 2007 John Wiley & Sons, Ltd.

Several neuroimaging techniques now exist that provide ways of studying functional activity in the living brain. Having been widely used in the fields of cognitive and sensory neuroscience, functional neuroimaging has more recently been applied to investigating the way in which psychoactive agents affect brain activity. The non-invasive nature of functional magnetic resonance imaging (fMRI), coupled with its excellent spatial and temporal resolution and proven ability for investigating sensory, motor and cognitive functions in a non-invasive and repeatable way, have made it a particularly attractive technique for drug research, providing an insight into the functional effects of receptor activation in vivo in far greater detail than previously possible. This application of fMRI techniques to neuropharmacology, termed pharmacological MRI or phMRI [1], has been used to successfully demonstrate those regions of the brain that respond to a range of different psychoactive compounds. In addition to providing information concerning the regional specificity of drug action, the time course over which drugs act can also be established, as can the results of interactions between different compounds, and their central effects on cognition can be ascertained. By imaging activity throughout the entire brain, phMRI can determine the duration of druginduced brain activity in all regions of interest with a temporal resolution down to several seconds, without the need for selective regional sampling. Despite its infancy, the use of phMRI has greatly expanded in recent years, having being used to examine the effects of CNS penetrating drugs in both humans and animals. Initial demonstrations that functional neuroimaging was able to detect druginduced changes in brain activity in both humans [2–5] and animals [6–10], highlighted the enormous potential of such techniques for investigating drug action within the CNS. PhMRI is of particular interest to the pharmaceutical industry, with it being seen as having the potential to establish novel surrogate markers in animal disease models and provide early evidence of proof-of-concept for novel compounds, as well as helping characterize brain penetrability, pharmacokinetics, and the regionally specific actions of new drugs. By comparing existing “gold-standard” compounds with the patterns of neuronal activity induced by novel pharmaceutical agents, phMRI may help to establish potential efficacy, side effects, and therapeutic targets early in development. As phMRI is non-invasive and does not involve exposure to ionizing radiation, it can also be incorporated into longitudinal investigations of the neuroadaptive changes that occur during chronic treatment schedules that underlie the actions of many therapeutic agents.