UC San Diego

The interpretation of functional MRI (fMRI) signals is complicated by the indirect relation of the signals to neural activity. Prior work has shown that significant variability in fMRI signals may be due to non-neural factors. Normalization methods that reduce fMRI signal variability due to non-neural factors and yield measures more closely related to neural activity are desirable to the fMRI community. In this work, we measured cerebral blood flow (CBF) using arterial spin labeling fMRI, the blood oxygenation level dependent (BOLD) signal using BOLD fMRI, and venous oxygenation (%O₂,v) using T2-Relaxation- Under-Spin-Tagging MRI. We used these measurements to assess the effect of non-neural factors on fMRI signals and to evaluate existing normalization methods. In the first study, we used a caffeine dose (200 mg) to decrease baseline CBF (CBF₀) and found significant (p<0.05) reductions in both the CBF activation extent and contrast- to-noise ratio (CNR) but no significant changes in the BOLD activation extent and CNR. The decreases in the CBF activation extent and CNR were consistent with a significant caffeine-induced decrease in the absolute CBF change accompanied by no significant change in the residual noise. In the second study, we found that the functional and hypercapnic BOLD and CBF responses all exhibited a significant inverse dependence on CBF₀. Hypercapnic normalization increased inter-subject variability in the normalized responses as compared to the original responses, reflecting the presence of a systematic bias term that was inversely dependent on the hypercapnic BOLD response. In contrast, normalized responses obtained by using the hypercapnic BOLD response as a covariate were unaffected by the systematic bias and exhibited reduced inter-subject variability. In the third study, we found that both %O₂,v and baseline CBF had a significant inverse dependence on the BOLD response in brain regions with both BOLD and CBF activation. Furthermore, %O₂,v was significantly correlated to CBF₀. However, CBF₀ measures were uncorrelated to %O₂,v or the BOLD response in brain regions with only BOLD activation. In these regions, localization of CBF0 measures to capillaries produced significant correlations between the CBF₀ and both %O₂,v and the BOLD response