Quantification of the impact of a confounding variable on functional connectivity confirms anti-correlated networks in the resting-state

The effect of regressing out the global average signal (GAS) in resting state fMRI data has become a concern for interpreting functional connectivity analyses. It is not clear whether the reported anti-correlations between the Default Mode and the Dorsal Attention Networks are intrinsic to the brain, or are artificially created by regressing out the GAS. Here we introduce a concept, Impact of the Global Average on Functional Connectivity (IGAFC), for quantifying the sensitivity of seed-based correlation analyses to the regression of the GAS. This voxel-wise IGAFC index is defined as the product of two correlation coefficients: the correlation between the GAS and the fMRI time course of a voxel, times the correlation between the GAS and the seed time course. This definition enables the calculation of a threshold at which the impact of regressing-out the GAS would be large enough to introduce spurious negative correlations. It also yields a post-hoc impact correction procedure via thresholding, which eliminates spurious correlations introduced by regressing out the GAS. In addition, we introduce an Artificial Negative Correlation Index (ANCI), defined as the absolute difference between the IGAFC index and the impact threshold. The ANCI allows a graded confidence scale for ranking voxels according to their likelihood of showing artificial correlations. By applying this method, we observed regions in the Default Mode and Dorsal Attention Networks that were anti-correlated. These findings confirm that the previously reported negative correlations between the Dorsal Attention and Default Mode Networks are intrinsic to the brain and not the result of statistical manipulations. Our proposed quantification of the impact that a confound may have on functional connectivity can be generalized to global effect estimators other than the GAS. It can be readily applied to other confounds, such as systemic physiological or head movement interferences, in order to quantify their impact on functional connectivity in the resting state.