Regional quantification of cerebral venous oxygenation from MRI susceptibility during hypercapnia
Introduction
Under normal conditions, the healthy human brain receives 15% of the cardiac output and consumes 20% of total oxygen used by the body (Gallagher et al., 1998, Magistretti and Pellerin, 1996). There is an unmet clinical need for a neuroimaging method to provide repeated, non-invasive and reliable measures of regional brain oxygen utilization. Such measurements could inform pathophysiological models and target therapies in brain disorders with aberrant regional oxygenation, such as stroke (Geisler et al., 2006) and tumor (Elas et al., 2003); as well as in neurodegenerative disorders with more subtle metabolic changes such as Alzheimer's disease (Hock et al., 1997) and multiple sclerosis (Ge et al., 2012). Although there is a clinical need for robust and reliable measurements of brain oxygen utilization, previous approaches have proven to be technically challenging in vivo.
Positron emission tomography (PET) provides regional quantification of brain oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen consumption (CMRO2) through use of 15O tracers. However, the need for high-cost specialized equipment, radiation exposure, and invasive arterial sampling limit the clinical utility of 15O PET. Several magnetic resonance imaging (MRI) methods have been recently proposed to quantify cerebral oxygenation from magnetic susceptibility (Fan et al., 2012, Rodgers et al., 2013), T2 relaxation measurements in venous blood (Krishnamurthy et al., 2013, Lu and Ge, 2008), and calibrated blood-oxygen-level-dependent (BOLD) signal changes (Bulte et al., 2012, Gauthier et al., 2012). T2-relaxation-under-spin tagging (TRUST) MRI provides measures of cerebral OEF through estimates of T2 relaxation of venous blood in large veins, e.g. the superior sagittal sinus (SSS). Although TRUST has been validated against pulse oximetry (Lu et al., 2012) and optimized for reproducible, fast measurements of OEF (Liu et al., 2013), the technique is limited to global measures of oxygen extraction. Our group recently proposed a method to map absolute OEF along the cerebral venous vasculature from quantitative susceptibility mapping (QSM) reconstructions (Fan et al., 2013). This susceptibility-based approach inherently provides measures of regional cerebral OEF information within individual vessels, but remains to be tested in different oxygenation states as induced by common physiological challenges.
Carbon dioxide (CO2) is an effective vasodilator and offers an ideal cerebrovascular intervention to test the oxygenation venography method. Hypercapnia, via inhalation of 5% to 7% CO2, causes significant vascular changes to the brain. These changes include robust increases to cerebral blood flow (CBF) ranging from 35% to 50% (Kety and Schmidt, 1948, Sicard and Duong, 2005); increased cerebral blood volume (Ito et al., 2003); and higher blood concentrations of CO2 and O2. Hypercapnia has been considered a purely vascular challenge in that small or negligible changes in the cerebral metabolic rate of oxygen consumption (CMRO2), a surrogate for neural activity, have been observed in studies of hypercapnia despite dramatic cerebrovascular modulations (Chen and Pike, 2010). This effect has been demonstrated by invasive studies (Kety and Schmidt, 1948) as well as non-invasive imaging studies (van Zijl et al., 1998), and is supported by Fick's principle of arterio-venous difference that implies CMRO2 is proportional to CBF and to OEF.
The assumption of constant CMRO2 during hypercapnia forms the basis for previous studies of: 1) cerebrovascular reserve (Bright et al., 2011, de Boorder et al., 2004), i.e. the reactivity of vessels to the gas challenge, as a measure of hemodynamic health; and 2) calibration of the BOLD signal to estimate changes in CMRO2 during a functional task (Bulte et al., 2009, Davis et al., 1998). In addition, several BOLD MRI studies have indirectly observed minimal changes in CMRO2 during hypercapnia (Rostrup et al., 2000, Sicard et al., 2003), which implies a decrease in OEF proportional to the increase in CBF during hypercapnia. Thus, hypercapnia reliably produces a predictable, global change in brain oxygenation that is detectable on MRI images with sensitivity to magnetic susceptibility. For instance, venous vessels appear dark due to the presence of paramagnetic deoxyhemoglobin (dHb) molecules on susceptibility-weighted images (SWI), and the loss of vessel contrast observed during hypercapnia is consistent with lower dHb concentration and decreased OEF (Rauscher et al., 2005, Sedlacik et al., 2008). Jain et al. went further to directly measure field shifts induced by the underlying changes in dHb concentration during hypercapnia from 2-dimensional, susceptibility-weighted phase images (Jain et al., 2011). This study quantified a 13% absolute decrease in OEF from the SSS during hypercapnia relative to baseline scans, demonstrating the utility of MRI susceptibility to noninvasively image global oxygenation state. However, Jain et al. did not examine regional OEF and the authors did not compare their observed OEF changes to expected increases in CBF during hypercapnia.
The primary aim of the present study was to test whether our approach, which measures oxygenation-dependent susceptibility shifts in cerebral veins (Fan et al., 2013), can detect the expected OEF changes that accompany the cerebrovascular responses to hypercapnia. We acquired 3-dimensional gradient echo volumes for quantitative susceptibility mapping (QSM) reconstruction of OEF along cerebral vessels during eucapnia and hypercapnia in young, healthy subjects at 3 T. Additional quantitative CBF maps were acquired using established pseudo-continuous arterial spin labeling MRI techniques (Wu et al., 2007). Assuming no change in CMRO2 during mild hypercapnia, regional changes in perfusion were used to predict local oxygenation changes for comparison with QSM-based OEF measurements in veins draining different brain regions.
Section snippets
MRI acquisitions
Imaging data were acquired in ten healthy subjects (six males and four females, aged 24 to 31 years) on a Siemens 3 Tesla Tim Trio system with a 32-channel head receive coil. No subjects had a history of neurological, cardiopulmonary, or psychiatric illness. All subjects gave written consent under the approval of the local institutional review board. Blood hematocrit (Hct), the percent of erythrocytes in blood, was measured from a fingerprick sample in each subject (HemoPoint H2 model
Physiological measurements of CBF and OEF during eucapnia and hypercapnia
The group mean of hematocrit values was 41.6 ± 4 (SD)%. Hypercapnia increased the subjects' ETCO2 from 41.3 ± 3 mm Hg to 49.9 ± 4 mm Hg and increased minute ventilation from 9.9 ± 2 L/min to 24.0 ± 6 L/min, corresponding to a hypercapnic ventilatory response of 1.6 ± 0.6 L/min per mm Hg. The breathing circuit facilitated stable levels of ETCO2 during each gas condition (Fig. 1). From the gradient echo acquisition, diminished contrast in veins, consistent with decreased susceptibility of venous blood, was observed
Discussion
The present study demonstrates the first MRI-based non-invasive approach to provide reliable measures of regional brain oxygen utilization. Susceptibility measurements from flow-compensated GE scans revealed large decreases in OEF during hypercapnia. We demonstrated robust OEF reductions in five brain areas, including three distinct cortical regions, in which the decreases in OEF significantly correlated with independent perfusion measures obtained from an established pcASL imaging technique.
Conclusions
This study demonstrates a novel, non-invasive approach to measure regional cerebral OEF from quantitative susceptibility MRI. Robust OEF changes in individual veins were observed during hypercapnia relative to eucapnia. Furthermore, the measured OEF changes in each brain region correlated with predictions of OEF changes derived from independent measures of perfusion (CBF), providing confidence in the fidelity of oxygenation measures from QSM reconstructions. Although the OEF imaging approach
Acknowledgments
Audrey Fan is supported by a training grant from the National Institute of Biomedical Imaging and Bioengineering (T32-EB001680). Dr. Karleyton Evans is supported by a grant from the National Institute of Health (K23-MH086619) and he discloses grant support from Pfizer Ltd., unrelated to the present study. Dr. Bruce Rosen would like to acknowledge the following affiliation: Department of Meridian & Acupuncture, East-West Medical Research Institute and School of Korean Medicine, Kyung Hee
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