Global intravascular and local hyperoxia contrast phase-based blood oxygenation measurements

AbstractThe measurement of venous cerebral blood oxygenation (Yv) has potential applications in the study of patient groups where oxygen extraction and/or metabolism are compromised. It is also useful for fMRI studies to assess the stimulus-induced changes in Yv, particularly since basal Yv partially accounts for inter-subject variation in the haemodynamic response to a stimulus. A range of MRI-based methods of measuring Yv have been developed recently. Here, we use a method based on the change in phase in the MR image arising from the field perturbation caused by deoxygenated haemoglobin in veins. We build on the existing phase based approach (Method I), where Yv is measured in a large vein (such as the superior sagittal sinus) based on the field shift inside the vein with assumptions as to the vein's shape and orientation. We demonstrate two novel modifications which address limitations of this method. The first modification (Method II), maps the actual form of the vein, rather than assume a given shape and orientation. The second modification (Method III) uses the intra and perivascular phase change in response to a known change in Yv on hyperoxia to measure normoxic Yv in smaller veins. Method III can be applied to veins whose shape, size and orientation are not accurately known, thus allowing more localised measures of venous oxygenation. Results demonstrate that the use of an overly fine spatial filter caused an overestimation in Yv for Method I, whilst the measurement of Yv using Method II was less sensitive to this bias, giving Yv=0.62±0.03. Method III was applied to mapping of Yv in local veins across the brain, yielding a distribution of values with a mode of Yv=0.661±0.008

Inhaled Oxygen as a Quantitative Intravascular MRI Contrast Agent

Increasing the fraction of inspired oxygen (FiO2) generates MR contrast by two distinct mechanisms: increased T2 from deoxyhemoglobin dilution in venous compartments (blood oxygenation level-dependent effect or BOLD) and reduced T­1 from paramagnetic molecular oxygen dissolved in blood plasma and tissues. Many research and clinical applications using hyperoxic contrast have recently emerged, including delineating ischemic stroke penumbra, oxygen delivery to tumors, and functional MRI data calibration. However, quantitative measurements using this contrast agent depend on the precise knowledge of its effects on the MR signal – of which there remain many crucial missing pieces. This thesis aims to obtain a more quantitative understanding of intravascular hyperoxic contrast in vivo, with the hope of increasing its precision and utility. Specifically, our work focuses on the following areas: (1) paramagnetic effects of molecular oxygen BOLD and arterial spin labeling (ASL) data, (2) degree and temporal characteristics of hyperoxia-induced reductions in cerebral blood flow (CBF), (3) use of oxygen in quantitative measurements of metabolism, and (4) biophysical mechanisms of hyperoxic T1 contrast. In Chapter 2, the artifactual influence of paramagnetic molecular oxygen on BOLD-modulated hyperoxic gas studies is characterized as a function of static field strength, and we show that optimum reduction in FiO2 mitigates this effect while maintaining BOLD contrast. Since ASL measurements are highly sensitive to arterial blood T­1 (T1a), the value of T1a in vivo is determined as a function of arterial oxygen partial pressure in Chapter 3. The effect of both the degree and duration of hyperoxic exposure on absolute CBF are quantified using simultaneous ASL and in vivo T1a measurements, as described in Chapter 4. In Chapter 5, hyperoxic gas calibration of BOLD/ASL data is used to measure cerebral oxygen metabolism in a hypermetabolic swine model, with our results comparing favorably to 17O2 measurements of absolute metabolism. In Chapter 6, a model to describe the relationship between CBF, oxygen consumption, and hyperoxic T1 reduction is developed, which allows for a more rigorous physiological interpretation of these data. Taken together, this work represents several important steps towards making hyperoxia a more quantitative MRI contrast agent for research and clinical applications

Dynamic Assessment of Cerebral Metabolic Rate of Oxygen (cmro2) With Magnetic Resonance Imaging

The brain is almost entirely dependent on oxidative metabolism to meet its energy requirements. As such, the cerebral metabolic rate of oxygen (CMRO2) is a direct measure of brain energy use. CMRO2 provides insight into brain functional architecture and has demonstrated potential as a clinical tool for assessing many common neurological disorders. Recent developments in magnetic resonance imaging (MRI)-based CMRO2 quantification have shown promise in spatially resolving CMRO2 in clinically feasible scan times. However, brain energy requirements are both spatially heterogeneous and temporally dynamic, responding to rapid changes in oxygen supply and demand in response to physiologic stimuli and neuronal activation. Methods for dynamic quantification of CMRO2 are lacking, and this dissertation aims to address this gap. Given the fundamental tradeoff between spatial and temporal resolution in MRI, we focus initially on the latter. Central to each proposed method is a model-based approach for deriving venous oxygen saturation (Yv) – the critical parameter for CMRO2 quantification – from MRI signal phase using susceptometry-based oximetry (SBO). First, a three-second-temporal-resolution technique for whole-brain quantification of Yv and CMRO2 is presented. This OxFlow method is applied to measure a small but highly significant increase in CMRO2 in response to volitional apnea. Next, OxFlow is combined with a competing approach for Yv quantification based on blood T2 relaxometry (TRUST). The resulting interleaved-TRUST (iTRUST) pulse sequence greatly improves T2-based CMRO2 quantification, while allowing direct, simultaneous comparison of SBO- and T2-based Yv. iTRUST is applied to assess the CMRO2 response to hypercapnia – a topic of great interest in functional neuroimaging – demonstrating significant biases between SBO- and T2-derived Yv and CMRO2. To address the need for dynamic and spatially resolved CMRO2 quantification, we explore blood-oxygen-level-dependent (BOLD) calibration, introducing a new calibration model and hybrid pulse sequence combining OxFlow with standard BOLD/CBF measurement. Preliminary results suggest Ox-BOLD provides improved calibration “M-maps” for converting BOLD signal to CMRO2. Finally, OxFlow is applied clinically to patients with obstructive sleep apnea (OSA). A small clinical pilot study demonstrates OSA-associated reductions in CMRO2 at baseline and in response to apnea, highlighting the potential utility of dynamic CMRO2 quantification in assessing neuropathology

Calibrated BOLD using direct measurement of changes in venous oxygenation

Calibration of the BOLD signal is potentially of great value in providing a closer measure of the underlying changes in brain function related to neuronal activity than the BOLD signal alone, but current approaches rely on an assumed relationship between cerebral blood volume (CBV) and cerebral blood flow (CBF). This is poorly characterised in humans and does not reflect the predominantly venous nature of BOLD contrast, whilst this relationship may vary across brain regions and depend on the structure of the local vascular bed. This work demonstrates a new approach to BOLD calibration which does not require an assumption about the relationship between cerebral blood volume and cerebral blood flow. This method involves repeating the same stimulus both at normoxia and hyperoxia, using hyperoxic BOLD contrast to estimate the relative changes in venous blood oxygenation and venous CBV. To do this the effect of hyperoxia on venous blood oxygenation has to be calculated, which requires an estimate of basal oxygen extraction fraction, and this can be estimated from the phase as an alternative to using a literature estimate. Additional measurement of the relative change in CBF, combined with the blood oxygenation change can be used to calculate the relative change in CMRO2 due to the stimulus. CMRO2 changes of 18 ± 8% in response to a motor task were measured without requiring the assumption of a CBV/CBF coupling relationship, and are in agreement with previous approaches

Respiratory challenge MRI: practical aspects

Respiratory challenge MRI is the modification of arterial oxygen (PaO2) and/or carbon dioxide (PaCO2) concentration to induce a change in cerebral function or metabolism which is then measured by MRI. Alterations in arterial gas concentrations can lead to profound changes in cerebral haemodynamics which can be studied using a variety of MRI sequences. Whilst such experiments may provide a wealth of information, conducting them can be complex and challenging. In this paper we review the rationale for respiratory challenge MRI including the effects of oxygen and carbon dioxide on the cerebral circulation. We also discuss the planning, equipment, monitoring and techniques that have been used to undertake these experiments. We finally propose some recommendations in this evolving area for conducting these experiments to enhance data quality and comparison between techniques

Multiparametric measurement of cerebral physiology using calibrated fMRI

The ultimate goal of calibrated fMRI is the quantitative imaging of oxygen metabolism (CMRO2), and this has been the focus of numerous methods and approaches. However, one underappreciated aspect of this quest is that in the drive to measure CMRO2, many other physiological parameters of interest are often acquired along the way. This can significantly increase the value of the dataset, providing greater information that is clinically relevant, or detail that can disambiguate the cause of signal variations. This can also be somewhat of a double-edged sword: calibrated fMRI experiments combine multiple parameters into a physiological model that requires multiple steps, thereby providing more opportunity for error propagation and increasing the noise and error of the final derived values. As with all measurements, there is a trade-off between imaging time, spatial resolution, coverage, and accuracy. In this review, we provide a brief overview of the benefits and pitfalls of extracting multiparametric measurements of cerebral physiology through calibrated fMRI experiments