The effects of capillary transit time heterogeneity on the BOLD signal

Neurovascular coupling mechanisms give rise to vasodilation and functional hyperemia upon neural activation, thereby altering blood oxygenation. This blood oxygenation level dependent (BOLD) contrast allows studies of activation patterns in the working human brain by functional MRI (fMRI). The BOLD-weighted fMRI signal shows characteristic transients in relation to functional activation, such as the so-called initial dip, overshoot, and post-stimulus undershoot. These transients are modulated by other physiological stimuli and in disease, but the underlying physiological mechanisms remain incompletely understood. Capillary transit time heterogeneity (CTH) has been shown to affect oxygen extraction, and hence blood oxygenation. Here, we examine how recently reported redistributions of capillary blood flow during functional activation would be expected to affect BOLD signal transients. We developed a three-compartment (hemoglobin, plasma, and tissue) model to predict the BOLD signal, incorporating the effects of dynamic changes in CTH. Our model predicts that the BOLD signal represents the superposition of a positive component resulting from increases in cerebral blood flow (CBF), and a negative component, resulting from elevated tissue metabolism and homogenization of capillary flows (reduced CTH). The model reproduces salient features of BOLD signal dynamics under conditions such as hypercapnia, hyperoxia, and caffeine intake, where both brain physiology and BOLD characteristics are altered. Neuroglial signaling and metabolism could affect CBF and capillary flow patterns differently. Further studies of neurovascular and neuro-capillary coupling mechanisms may help us relate BOLD signals to the firing of certain neuronal populations based on their respective BOLD "fingerprints."