Measurement of OEF and absolute CMRO2: MRI-based methods using interleaved and combined hypercapnia and hyperoxia
Introduction
Blood oxygenation level dependent (BOLD) fMRI is commonly used to map changes in brain activity levels but is normally performed without quantification of the underlying cerebral metabolism. fMRI is widely used as a tool in basic neuroscientific and clinical research as well as being applied clinically in a qualitative manner for pre-surgical functional mapping. Advancing methods that are able to quantify cerebrovascular and cerebral metabolic function would render fMRI considerably more useful in clinical research and clinical application across a wide range of diseases. This process has begun with the improvement in recent years of arterial spin labelling (ASL) methods for measuring cerebral blood flow (CBF). However, until recently, radiotracer techniques such as 15O PET have offered the only means of quantifying absolute cerebral oxygen metabolism. The requirement for radiotracers limits the application of such measurements longitudinally and in healthy volunteers, hampering studies of disease evolution, brain development and ageing.
The predominantly aerobic production of ATP in the healthy brain means that the local cerebral rate of metabolic oxygen consumption (CMRO2) closely parallels neural energy consumption. Therefore, it potentially offers a stable and robust marker of the (patho)physiological state of brain tissue for assessing longitudinal changes in regional brain function with plasticity and learning, neurological and psychiatric diseases, and treatment interventions. An MRI based method for examining relative changes in CMRO2 was introduced in 1998 (Davis et al., 1998). This method, employing a (presumed-isometabolic) hypercapnic vasodilatory stimulus, is restricted to estimating fractional changes in CMRO2 relative to a within-session baseline and over a timescale restricted by the sensitivity to BOLD signal changes, typically a few seconds to a few minutes. A similar method was proposed for oxygen-based calibration of the BOLD signal by Chiarelli et al. (2007), with the limitation of needing to assume the fraction of oxygen extracted from arterial blood on its passage to the veins (oxygen extraction fraction, OEF). Interpretation of the biological significance of relative changes in CMRO2 is problematic where the baseline CMRO2 may be altered in disease or drug studies (Iannetti and Wise, 2007).
MR methods have begun to emerge for estimating absolute rather than relative CMRO2. Methods yielding bulk or whole brain CMRO2 are based on measurement of CBF and venous oxygen saturation via the T2 of venous blood (Lu and Ge, 2008, Xu et al., 2009) or the pattern of magnetic field distortions around major veins (Fan et al., 2012). However, the spatial resolution of such methods is restricted to the volume of brain tissue being drained by the vein of interest. Velocity selective methods have also been used to isolate the T2 of venous blood and estimate its oxygenation based on a T2-oxygenation calibration curve (Bolar et al., 2011, Guo and Wong, 2012). A quantitative or qBOLD approach has also been demonstrated in which R2′ is sensitive to venous cerebral blood volume (CBV) and deoxyhaemoglobin concentration (He and Yablonskiy, 2007, He et al., 2008). Recently the approach of Davis et al. (1998) and Hoge et al. (1999a) has been extended to use both hypercapnia and hyperoxia induced CBF and BOLD signal changes to estimate venous deoxyhaemoglobin concentration and thus OEF and absolute CMRO2 (Bulte et al., 2012, Gauthier and Hoge, 2012). It is this approach that we develop in the current work.
The methods presented here and those of Bulte et al. (2012) and Gauthier and Hoge (2012) rely on increasing venous blood oxygenation to increase the BOLD signal by raising (i) CBF and (ii) the arterial oxygen content. Crucially, the additional oxygen carried in arterial blood both bound to haemoglobin and in solution, under isometabolic conditions, manifests as an increase in venous blood oxygenation. Similarly, increasing CBF using an isometabolic hypercapnic challenge also increases venous blood oxygenation. The present study aims to demonstrate, using interleaved hypercapnic and hyperoxic respiratory challenges similar to those of Bulte et al. (2012), the measurement of absolute CMRO2 at rest and during presentation of a continuous high contrast visual stimulus to provide an elevated absolute CMRO2 to experimentally simulate long term alteration of cerebral metabolism. This absolute measurement is compared with a more conventional evaluation of stimulus-induced relative change in CMRO2 (Davis et al., 1998).
Our computer-controlled system for administering respiratory challenges through dynamic end-tidal forcing (Wise et al., 2007) allows us to extend the interleaved approach to implement varying levels of hypercapnia simultaneously with intermittent hyperoxia. This combined respiratory challenge offers the potential to reduce the duration of the experiment. Simultaneous modulation of CBF and arterial oxygen levels would also introduce additional information with respect to an experiment in which hypercapnia and hyperoxia are induced separately. The CBF increase from hypercapnia is expected to also increase CBV to which a hyperoxia-induced BOLD signal change would be sensitive (Blockley et al., 2012a, Driver et al., 2012). We demonstrate that, using this combined approach and a model of BOLD signal incorporating the effects of increased CBF and arterial oxygen levels, we can uncover information about, the parameters in the commonly applied BOLD signal model, known as α, the exponent relating relative increases in CBF to CBV, and β, the exponent relating deoxyhaemoglobin concentration to the relaxation rate R2*, both of these model parameters being dependent on the cerebrovasculature.
Section snippets
Theory: calibration model
Our aim is to develop the form of the BOLD signal model as described by Davis et al. (1998) to yield the resting venous deoxyhaemoglobin concentration, [dHb]0, thus offering a framework for the experimental measurement of absolute CMRO2. Appendix A describes the fuller considerations behind the model summarised here. Our model description is a more general version of that expressed by Bulte et al. (2012), allowing for simultaneous modulation of CBF and arterial oxygen content (CaO2) and is
Respiratory and stimulation protocols
Eleven subjects (5 female, age: 29 ± 5.3 years) were scanned having given informed written consent. Experimental procedures were approved by the local institutional ethical review committee.
Volunteers underwent 4 scans the order of A–C being randomised but with D always occurring last within the scan session:
- A.
Interleaved hypercapnia and hyperoxia at rest (19 min) (Fig. 1)
- B.
Interleaved hypercapnia and hyperoxia with continuous visual stimulation (19 min) (Fig. 1)
- C.
Visual stimulation (90 s ON, 90 s OFF,
Results
Table 1 indicates for whole brain grey matter the CBF and fitted values, from the interleaved hypercapnia and hyperoxia design, of M and SvO2, along with the calculated absolute CMRO2. Results for different combinations of (α, β) are presented using literature values in the blue analysis pathway (Fig. 3), (0.38, 1.50), (0.2, 1.3), (0.18, 1.5) and (0.14, 0.91) and also from the orange analysis pathway (Fig. 3) (αD, 1.5), (αD, 0.91) and (αD′, βD′), where αD′ and βD′ indicate values estimated by
Discussion
We have demonstrated the measurement of absolute CMRO2 using two different respiratory manipulation protocols and the simultaneous collection of T2* weighted and ASL perfusion weighted data, by exploiting the model of Davis et al. (1998) and Hoge et al. (1999a) extended to describe T2* weighted signal changes resulting from assumed isometabolic hyperoxia and hypercapnia. Our combined approach, namely the simultaneous modulation of arterial oxygen and carbon dioxide, yields additional
Acknowledgments
RW thanks the Higher Education Funding Council for Wales and the UK Engineering and Physical Sciences Research Council (reference EP/K020404/1). AH is funded by the Banting Fellowship Program, NSERC of Canada. AS is supported by a Cardiff University President's Research Scholarship. KM is funded by a Wellcome Trust Career Development Award. The authors thank Dr. Tom Liu of the Center for fMRI at University of California San Diego with help in setting up the imaging sequences.
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