A theoretical framework for estimating cerebral oxygen metabolism changes using the calibrated-BOLD method: Modeling the effects of blood volume distribution, hematocrit, oxygen extraction fraction, and tissue signal properties on the BOLD signal

Calibrated blood oxygenation level dependent (BOLD) imaging, a technique used to measure changes in cerebral O2 metabolism, depends on an accurate model of how the BOLD signal is affected by the mismatch between changes in cerebral blood flow (CBF) and cerebral metabolic rate of O2 (CMRO2). However, other factors such as the cerebral blood volume (CBV) distribution at rest and with activation also affect the BOLD signal. The Davis model originally proposed for calibrated BOLD studies (Davis et al., 1998) is widely used because of its simplicity, but it assumes CBV changes are uniformly distributed across vascular compartments, neglects intravascular signal changes, and ignores blood-tissue signal exchange effects as CBV increases and supplants tissue volume. More recent studies suggest that venous CBV changes are smaller than arterial changes, and that intravascular signal changes and CBV exchange effects can bias estimated CMRO2. In this paper, recent experimental results for the relationship between deoxyhemoglobin and BOLD signal changes are integrated in order to simulate the BOLD signal in detail by expanding a previous model to include a tissue compartment and three blood compartments rather than only the venous blood compartment. The simulated data were then used to test the accuracy of the Davis model of calibrated BOLD, demonstrating that the errors in estimated CMRO2 responses across the typical CBF–CMRO2 coupling range are modest despite the simplicity of the assumptions underlying the original derivation of the model. Nevertheless, the accuracy of the model can be improved by abandoning the original physical meaning of the two parameters α and β and treating them as adjustable parameters that capture several physical effects. For a 3 Tesla field and a dominant arterial volume change with activation, the accuracy of the Davis model is improved with new values of α = 0.14 and β = 0.91.

Research highlights
► We developed a detailed BOLD fMRI model including recent experimental measurements.
► In particular, the model incorporates volume changes of three vascular compartments.
► New parameters for the Davis model improve estimates of oxygen metabolism.
► Knowledge of blood volume will have the biggest impact on future improvements.
► Accurate measurement of the scaling parameter is a confounding factor.