Breath-hold calibrated fMRI mapping of absolute cerebral metabolic rate of oxygen metabolism (CMRO2): an assessment of the accuracy and repeatability in a healthy adult population

We previously introduced a calibrated fMRI framework that utilises respiratory modulation with only a single gas (CO2) to map the grey matter (GM) cerebral metabolic rate of oxygen consumption (CMRO2). The method decouples and estimates the cerebral blood volume (CBV) and the oxygen extraction fraction (OEF) from a single measure of the maximum BOLD modulation. The method links the two parameters of interest with a model of oxygen diffusion from capillaries to mitochondria which incorporates the cerebral blood flow (CBF). Here we apply this framework to gas-free breath hold calibrated fMRI (bhc-fMRI), where simultaneous BOLD and ASL acquisitions are combined with modulation of arterial CO2 through repeated breath-holding. The accuracy and repeatability of the method is assessed in 33 healthy volunteers at rest and during continuous visual stimulation. Average GM OEF estimated from bhc-fMRI was 0.37 ± 0.04 indicating a small bias of 0.04 (with limits of agreement from -0.11 to 0.12) compared to the whole brain OEF of 0.32 ± 0.07 estimated from sagittal sinus using T2 Relaxation Under Spin Tagging (TRUST). The within session repeatability of GM estimates were moderate to good for OEF, with ICC = 0.75 (0.56-0.87) and good to excellent for CMRO2, with ICC = 0.88 (0.74-0.94). An ROI analysis in the visual cortex found an average CBF increase of 16%, a CMRO2 increase of 12%, and an OEF decrease of 3% during the visual stimulation. The bhc-fMRI measurement of CMRO2 is simple to implement, has comparable accuracy and repeatability to existing gas-based methods and is sensitive to modulations in metabolism during functional hyperaemia.


S1. Maximum BOLD Signal (M) incorporating Flow-Diffusion Model of Oxygen Transport
The maximum BOLD signal change that would be obtained with a complete removal of deoxyhemoglobin from the imaging voxel (M) 1 can be approximated as: where TE is the echo time of the sequence and the subscript 0 depicts baseline values.SVO2 is venous oxygen saturation and [Hb] is the concentration of hemoglobin in blood.CBVV is the BOLD sensitive blood volume including the venous and capillary blood volumes.A and β are constants related to field strength, vessel geometry, and water diffusion in the extravascular space.
The venous oxygen saturation (SVO2) can be expressed as a function of the oxygen extraction fraction (OEF) and arterial oxygen content as 2 : Or, rearranging the terms, as: where CaO2 is the arterial oxygen concentration in blood and φ is the oxygen binding capacity of hemoglobin (fixed at φ=1.34 mlO2/gHb).
Therefore, combining Equation S2b with Equation S1, M can be expressed as: A compartmental model describes radial diffusion of oxygen out of a straight cylindrical capillary of unit length through the following differential equation: where CcapO2 and PcapO2 are the concentration and the partial pressure of oxygen at a relative position x along and time t within the capillary, PmO2 is the oxygen at the end of the diffusion path, namely at the mitochondria, and k is the effective permeability of the path, combining both capillary endothelium and brain tissue 3, 4 : Assuming steady-state, Equation S4 becomes 5 : /1 where Tcap is the capillary transit time (CTT).
In the presence of multiple capillaries, a simplified approach neglects possible effects of CTT variability (or heterogeneity) on the net oxygen extraction of the capillary ensemble within a voxel and modifies Equation S5 by simply substituting CTT with the mean CTT (MCTT) in the capillary bed.
MCTT can be expressed as the ratio between the capillary blood volume (CBVcap) and CBF obtaining: Since PcapO2 and CcapO2 are quickly equilibrated (less than a few milliseconds), depending upon the Hb oxygen binding curve described by the Hill equation: the differential Equation S6 can be expressed as: ) where P50 (mmHg) is the oxygen partial pressure when half of Hb is saturated with oxygen (generally P50≈26 mmHg, h is the Hill constant, fixed at h=2.8).An explicit solution to derive OEF0 from Equation S8 can be obtained assuming a linear decrease of CcapO2(x) along the capillary, which makes the right term of Equation S8 constant, obtaining: where <CcapO2 (x)> represents the average value of CcapO2 (x) in the capillary.
), with SaO2 being arterial saturation, Equation S9 can be integrated and obtain, by equating the loss of oxygen from the capillary to CMRO2, the following equation: CBVcap is here assumed to be a fraction of CBVv, i.e., CBVv=ρ•CBVcap.Substituting CBVcap, from Equation S10 into Equation S3, we obtain S11, an equation for M constrained by the flow-diffusion model of oxygen exchange in the capillaries:

Figure
Figure S1: Example subject parameter maps

Table S1 :
(2)t-retest reliability of OEF for Harvard-Oxford cortical atlas regions.Values of OEF and coefficient of variation (CV) are presented as mean ± standard deviation across participants.Intraclass correlation (ICC) is presented as ICC (95% confidence intervals), two-way mixed effects with absolute agreement.Note that a visual stimulus was presented during measurement OEF(2).The lateral occipital cortex, intracalcarine cortex, lingual gyrus, occipital fusiform gyrus and occipital pole are omitted here, as they contain areas of significant CBF response to the visual stimulus at the group level.

Table S2 :
Test-retest reliability of CMRO2 for Harvard-Oxford cortical atlas regions.Values of CMRO2 and coefficient of variation (CV) are presented as mean ± standard deviation across participants.Intraclass correlation (ICC) is presented as ICC (95% confidence intervals), two-way mixed effects with absolute agreement.Note that a visual stimulus was presented during measurement (2)O2(2).The lateral occipital cortex, intracalcarine cortex, lingual gyrus, occipital fusiform gyrus and occipital pole are omitted here, as they contain areas of significant CBF response to the visual stimulus at the group level.