Correcting brain-wide correlation differences in resting-state FMRI.

Brain function in "resting" state has been extensively studied with functional magnetic resonance imaging (FMRI). However, drawing valid inferences, particularly for group comparisons, is fraught with pitfalls. Differing levels of brain-wide correlations can confound group comparisons. Global signal regression (GSReg) attempts to reduce this confound and is commonly used, even though it differentially biases correlations over brain regions, potentially leading to false group differences. We propose to use average brain-wide correlations as a measure of global correlation (GCOR), and examine the circumstances under which it can be used to identify or correct for differences in global fluctuations. In the process, we show the bias induced by GSReg to be a function only of the data's covariance matrix, and use simulations to compare corrections with GCOR as covariate to GSReg under various scenarios. We find that unlike GSReg, GCOR is a conservative approach that can reduce global variations, while avoiding the introduction of false significant differences, as GSReg can. However, as with GSReg, one cannot escape the interaction effect between the grouping variable and GCOR covariate on effect size. While GCOR is a complementary measure for resting state-FMRI applicable to legacy data, it is a lesser substitute for proper level-I denoising. We also assess the applicability of GCOR to empirical data with motion-based subject grouping and compare group differences to those using GSReg. We find that, while GCOR reduced correlation differences between high and low movers, it is doubtful that motion was the sole driver behind the differences in the first place.