The Link to Oxidative Metabolism Varies across rs-fMRI Metrics: A Whole-Brain Assessment Using Macrovascular Correction

One of the major obstacles to the clinical application of resting-state functional magnetic resonance imaging (rs-fMRI) is the complex nature of its measurements, which limits interpretability. An approach to enhance the interpretability of the rs-fMRI metrics is to link them to more fundamental brain physiology, especially cerebral metabolism. Previous studies have established associations between glucose metabolism (CMRglu) and rs-fMRI measurements. In spite of this, oxidative metabolism (CMRO2) is more closely related to cerebral blood flow (CBF) and thus the BOLD signal, and its relationship with CMRglu is complex. Additionally, most currently published rs-fMRI metrics are uncorrected for macrovascular contribution, which may obscure the neuronal contributions. In this study, we measured resting CMRO2 (along with the oxygen extraction fraction, OEF and cerebral blood flow, CBF) using gas-free calibrated fMRI. We used linear mixed-effects (LME) models to examine associations between CMRO2 and various rs-fMRI metrics before and after macrovascular correction. We found that: 1) significant associations exist between CMRO2 and multiple rs-fMRI metrics, with the strongest association found for the global functional density (gFCD) and the weakest for seed-based functional connectivity (FC); 2) associations with rs-fMRI metrics also varied for OEF and CBF; 3) significant sex differences were observed in the above associations; 4) the use of macrovascular correction substantially strengthened the goodness fit of all LME models examined. This latter improvement further validates the use of macrovascular correction in rs-fMRI. These results provide a framework for linking rs-fMRI metrics to fundamental brain physiology, thus improving interpretability of rs-fMRI measurements. This is the first study to formally link whole-brain MRI-based baseline CMRO2 and rs-fMRI metrics, and helps to push the envelope for rs-fMRI in future clinical applications.