Graded Hypercapnia-Calibrated BOLD: Beyond the Iso-metabolic Hypercapnic Assumption

Abstract

Calibrated BOLD is a promising technique that overcomes the sensitivity of conventional fMRI to the cerebrovascular state; measuring either the basal level, or the task-induced response of cerebral metabolic rate of oxygen consumption (CMRO₂). The calibrated BOLD method is susceptible to errors in the measurement of the calibration parameter M, the theoretical BOLD signal change that would occur if all deoxygenated hemoglobin were removed. The original and most popular method for measuring M uses hypercapnia (an increase in arterial CO₂), making the assumption that it does not affect CMRO₂. This assumption has since been challenged and recent studies have used a corrective term, based on literature values of a reduction in basal CMRO₂ with hypercapnia. This is not ideal, as this value may vary across subjects and regions of the brain, and will depend on the level of hypercapnia achieved. Here we propose a new approach, using a graded hypercapnia design and the assumption that CMRO₂ changes linearly with hypercapnia level, such that we can measure M without assuming prior knowledge of the scale of CMRO₂ change. Through use of a graded hypercapnia gas challenge, we are able to remove the bias caused by a reduction in basal CMRO₂ during hypercapnia, whilst simultaneously calculating the dose-wise CMRO₂ change with hypercapnia. When compared with assuming no change in CMRO₂, this approach resulted in significantly lower M-values in both visual and motor cortices, arising from significant dose-dependent hypercapnia reductions in basal CMRO₂ of 1.5 ± 0.6%/mmHg (visual) and 1.8 ± 0.7%/mmHg (motor), where mmHg is the unit change in end-tidal CO₂ level. Variability in the basal CMRO₂ response to hypercapnia, due to experimental differences and inter-subject variability, is accounted for in this approach, unlike previous correction approaches, which use literature values. By incorporating measurement of, and correction for, the reduction in basal CMRO₂ during hypercapnia in the measurement of M-values, application of our approach will correct for an overestimation in both CMRO₂ task-response values and absolute CMRO₂.

Keywords: CMRO2; arterial spin labeling; calibrated BOLD; fMRI; hypercapnia.

Figure 1

Group-average maps of BOLD and CBF responses to the +4 and +8 mmHg ΔP_ETCO₂ hypercapnia conditions. The three slices shown are at the level of MNI coordinate Z = +12, +28, and +42 mm, respectively.

Figure 2

Comparison of M (mean ± SEM) calculated using the empirically derived α/β pairing (0.14/0.91) from the two-parameter (ΔCMRO₂ varies linearly with ΔP_ETCO₂) and one-parameter (iso-metabolic) models for subjects that did not reach the boundary conditions for both fits (visual cortex N = 9; motor cortex N = 13; remaining GM N = 14). *p < 0.05.

Figure 3

Plot of κ across subjects for each α/β pairing, for visual cortex, motor cortex, and the remaining GM. Diamonds show mean κ across subjects. The values presented at the top are mean ± SEM across subjects for κ, with bold text and ^*indicating p(κ ≠0) < 0.05 (Wilcoxon sign rank test). The numbers of subjects included after discarding those that reached the boundary conditions are presented in the form (N = #/15) at the bottom of each plot.

Figure 4

Plots of M (mean ± SEM) for each α/β pairing, comparing M calculated from the two-parameter (ΔCMRO₂ varies linearly with ΔP_ETCO₂) and one-parameter (iso-metabolic) models for subjects that did not reach the boundary conditions for both fits. The values presented at the top of each plot are Wilcoxon sign rank p-values, testing whether M differs between two- and one-parameter fits (^*p < 0.05).