BOLD-based cerebrovascular reactivity is influenced by baseline cerebral blood volume and oxygen metabolism in humans

Cerebrovascular reactivity (CVR) is a key indicator of vascular health. It is typically assessed using a vasoactive stimulus such as hypercapnia while recording perfusion changes using blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) data or measuring cerebral blood flow (CBF) directly, for example, with arterial spin labelling (ASL). Commonly used BOLD-CVR estimates, however, may be biased by differences in (baseline) cerebral blood volume (CBV). To investigate this, we acquired data from 50 participants at 3 T, obtaining BOLD-CVR, dynamic CBF-CVR, time-encoded CBF-CVR, relative CBV (rCBV) and relative oxygen extraction fraction. Additionally, dynamic simulations of BOLD signal changes were conducted. Our results showed a pronounced contrast between grey matter and white matter in BOLD-CVR, whereas CBF-CVR was similar across tissues. Both inter-subject and intra-subject analyses indicated that this grey matter/white matter contrast in BOLD-CVR primarily reflects differences in rCBV. Other potential factors, such as variations in arterial transit time or baseline CBF, did not show significant correlations. The simulations further supported these findings and, interestingly, pointed to a slow decrease of oxygen metabolism during hypercapnia. In conclusion, BOLD-CVR strongly depends on CBV, a relationship highly relevant for studies in pathologies with altered CBV, such as cerebrovascular diseases or brain tumors.