Characterizing the modulation of resting-state fMRI metrics by baseline physiology

The blood-oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal is commonly used to assess functional connectivity across brain regions, particularly in the resting state (rs-fMRI). However, the BOLD fMRI signal is not merely a representation of neural activity, but a combination of neural activity and vascular response. These aspects of the BOLD signal are easily influenced by systemic physiology, potentially biasing BOLD-based functional connectivity measurements. In this work, we focus on the following physiological modulators of the BOLD signal: cerebral blood flow (CBF), venous blood oxygenation, and cerebrovascular reactivity (CVR). We use simulations and experiments to examine the relationship between the physiological parameters and rs-fMRI functional connectivity measurements in three resting-state networks: default mode network, somatosensory network and visual network. By using the general linear model, we demonstrate that physiological modulators significantly impact functional connectivity measurements in these regions, but in a manner that depends on the interplay between signal- and noise-driven correlations. Moreover, we find that the physiological effects vary by brain region and depend on the range of physiological conditions probed; the associations are more complex than previously reported. The results confirm that it is important to account for the effect of physiological modulators when comparing resting-state fMRI metrics. We note that such modulatory effects may be amplified by disease conditions, which will warrant future investigations.