Elsevier

NeuroImage

Volume 104, 1 January 2015, Pages 146-155
NeuroImage

Regional quantification of cerebral venous oxygenation from MRI susceptibility during hypercapnia

https://doi.org/10.1016/j.neuroimage.2014.09.068Get rights and content

Highlights

  • There is an unmet clinical need for noninvasive oxygenation imaging in the brain.

  • We tested a new quantitative susceptibility MRI method to measure regional cerebral oxygenation.

  • We measured reduced oxygen extraction fraction during hypercapnic challenge in cerebral veins.

  • Oxygenation changes correlated with changes in end-tidal CO2 in subjects.

  • Oxygenation changes related with predicted changes made from separate perfusion MRI measures.

Abstract

There is an unmet medical need for noninvasive imaging of regional brain oxygenation to manage stroke, tumor, and neurodegenerative diseases. Oxygenation imaging from magnetic susceptibility in MRI is a promising new technique to measure local venous oxygen extraction fraction (OEF) along the cerebral venous vasculature. However, this approach has not been tested in vivo at different levels of oxygenation. The primary goal of this study was to test whether susceptibility imaging of oxygenation can detect OEF changes induced by hypercapnia, via CO2 inhalation, within selected a priori brain regions.

Ten healthy subjects were scanned at 3 T with a 32-channel head coil. The end-tidal CO2 (ETCO2) was monitored continuously and inspired gases were adjusted to achieve steady-state conditions of eucapnia (41 ± 3 mm Hg) and hypercapnia (50 ± 4 mm Hg). Gradient echo phase images and pseudo-continuous arterial spin labeling (pcASL) images were acquired to measure regional OEF and CBF respectively during eucapnia and hypercapnia. By assuming constant cerebral oxygen consumption throughout both gas states, regional CBF values were computed to predict the local change in OEF in each brain region.

Hypercapnia induced a relative decrease in OEF of − 42.3% in the straight sinus, − 39.9% in the internal cerebral veins, and approximately − 50% in pial vessels draining each of the occipital, parietal, and frontal cortical areas. Across volunteers, regional changes in OEF correlated with changes in ETCO2. The reductions in regional OEF (via phase images) were significantly correlated (P < 0.05) with predicted reductions in OEF derived from CBF data (via pcASL images). These findings suggest that susceptibility imaging is a promising technique for OEF measurements, and may serve as a clinical biomarker for brain conditions with aberrant regional oxygenation.

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

References (76)

  • E. Rostrup et al.

    Regional differences in the CBF and BOLD responses to hypercapnia: a combined PET and fMRI study

    NeuroImage

    (2000)
  • F. Schweser et al.

    Quantitative imaging of intrinsic magnetic tissue properties using MRI signal phase: an approach to in vivo brain iron metabolism?

    NeuroImage

    (2011)
  • J. Sedlacik et al.

    Investigation of the influence of carbon dioxide concentrations on cerebral physiology by susceptibility-weighted magnetic resonance imaging (SWI)

    NeuroImage

    (2008)
  • K.M. Sicard et al.

    Effects of hypoxia, hyperoxia, and hypercapnia on baseline and stimulus-evoked BOLD, CBF, and CMRO2 in spontaneously breathing animals

    NeuroImage

    (2005)
  • A.J. van der Kouwe et al.

    Brain morphometry with multiecho MPRAGE

    NeuroImage

    (2008)
  • M. Villien et al.

    Changes in cerebral blood flow and vasoreactivity to CO2 measured by arterial spin labeling after 6 days at 4350 m

    NeuroImage

    (2013)
  • B. Wu et al.

    Fast and tissue-optimized mapping of magnetic susceptibility and T2* with multi-echo and multi-shot spirals

    NeuroImage

    (2012)
  • S. Aslan et al.

    Estimation of labeling efficiency in pseudocontinuous arterial spin labeling

    Magn. Reson. Med.

    (2010)
  • R.B. Banzett et al.

    Simple contrivance “clamps” end-tidal PCO(2) and PO(2) despite rapid changes in ventilation

    J. Appl. Physiol.

    (2000)
  • B. Bilgic et al.

    Fast quantitative susceptibility mapping with L1-regularization and automatic parameter selection

    Magn. Reson. Med.

    (2013)
  • M.G. Bright et al.

    The effect of basal vasodilation on hypercapnic and hypocapnic reactivity measured using magnetic resonance imaging

    J. Cereb. Blood Flow Metab.

    (2011)
  • D.P. Bulte et al.

    Cerebral perfusion response to hyperoxia

    J. Cereb. Blood Flow Metab.

    (2007)
  • D.P. Bulte et al.

    Comparison of hypercapnia-based calibration techniques for measurement of cerebral oxygen metabolism with MRI

    Magn. Reson. Med.

    (2009)
  • R.B. Buxton et al.

    A general kinetic model for quantitative perfusion imaging with arterial spin labeling

    Magn. Reson. Med.

    (1998)
  • J.J. Chen et al.

    Global cerebral oxidative metabolism during hypercapnia and hypocapnia in humans: implications for BOLD fMRI

    J. Cereb. Blood Flow Metab.

    (2010)
  • Y. Chen et al.

    Test-retest reliability of arterial spin labeling with common labeling strategies

    J. Magn. Reson. Imaging

    (2011)
  • W. Dai et al.

    Continuous flow-driven inversion for arterial spin labeling using pulsed radio frequency and gradient fields

    Magn. Reson. Med.

    (2008)
  • T.L. Davis et al.

    Calibrated functional MRI: mapping the dynamics of oxidative metabolism

    Proc. Natl. Acad. Sci. U. S. A.

    (1998)
  • M.J. de Boorder et al.

    Phase-contrast magnetic resonance imaging measurements of cerebral autoregulation with a breath-hold challenge: a feasibility study

    Stroke

    (2004)
  • A. Deistung et al.

    ToF-SWI: simultaneous time of flight and fully flow compensated susceptibility weighted imaging

    J. Magn. Reson. Imaging

    (2009)
  • M. Elas et al.

    Quantitative tumor oxymetric images from 4D electron paramagnetic resonance imaging (EPRI): methodology and comparison with blood oxygen level-dependent (BOLD) MRI

    Magn. Reson. Med.

    (2003)
  • A.P. Fan et al.

    Phase-based regional oxygen metabolism (PROM) using MRI

    Magn. Reson. Med.

    (2012)
  • A.P. Fan et al.

    Quantitative oxygenation venography from MRI phase

    Magn. Reson. Med.

    (2013)
  • K.J. Friston et al.

    Statistical Parametric Mapping: The Analysis of Functional Brain Images

    (2007)
  • D. Gallagher et al.

    Organ-tissue mass measurement allows modeling of REE and metabolically active tissue mass

    Am. J. Physiol.

    (1998)
  • Y. Ge et al.

    Characterizing brain oxygen metabolism in patients with multiple sclerosis with T2-relaxation-under-spin-tagging MRI

    J. Cereb. Blood Flow Metab.

    (2012)
  • B.S. Geisler et al.

    Blood-oxygen-level-dependent MRI allows metabolic description of tissue at risk in acute stroke patients

    Stroke

    (2006)
  • M.A. Griswold et al.

    Generalized autocalibrating partially parallel acquisitions (GRAPPA)

    Magn. Reson. Med.

    (2002)
  • Cited by (42)

    • Quantitative susceptibility mapping (QSM) and R<inf>2</inf><sup>*</sup> in the human brain at 3 T: Evaluation of intra-scanner repeatability

      2018, Zeitschrift fur Medizinische Physik
      Citation Excerpt :

      Quantitative susceptibility mapping (QSM) [1–6] is a recently developed MRI post-processing technique to non-invasively quantify the bulk magnetic susceptibility of tissue by exploiting the phase of the MR signal from T2*-weighted gradient echo (GRE) sequences. To date, QSM has already been widely applied to assess magnetic susceptibility sources in brain tissue, including iron [7], myelin [8] and calcifications [9–11], metabolic oxygen consumption [12,13] and task-related blood oxygenation level variations [14,15] in normal subjects as well as in patients with intracranial hemorrhages [16,17], various neuro-degenerative diseases, such as multiple sclerosis [18], Parkinson's disease [19,20], Huntington's disease [21] and Alzheimer's disease [22]. Since multi-echo GRE pulse sequences are commonly employed for QSM data acquisition, the effective transverse relaxation rate, R2*, can additionally be deduced from the magnitude data as a valuable by-product of [23].

    View all citing articles on Scopus
    View full text