Quantification of the BOLD response via blood gas modulations

This thesis is intended to contribute to a quantitative understanding of the blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal in order to increase its clinical potential. Here, the vascular, neuronal and physical processes which combine to give a resulting BOLD signal are investigated using respiratory challenges. The effect of isocapnic hyperoxia on vascular responses is investigated at 7 Tesla. No significant change was found in resting-state cerebral blood flow (CBF), resting-state cerebral blood volume (CBV) and task-evoked CBF. This challenges a previously held idea that hyperoxia is vasoconstrictive. The effect of isocapnic hyperoxia on neuronal oscillations was assessed with magnetoencephalography (MEG). Whilst a significant reduction in oscillatory power is reported in the occipital lobe, the change is significantly smaller than the global reduction previously measured with hypercapnia. These findings suggest that hyperoxia is an ideal tool for calibrated BOLD fMRI. The relationship between the change in blood oxygenation and change in transverse relaxation plays a key role in calibrated BOLD fMRI. However, previous measurements have been confounded by a change in CBV. Here, the relationship was found to be sub-linear across 1.5, 3 and 7 Tesla. Previous results which suggest a supralinear relationship at 1.5/3 Tesla and a linear relationship at 7 Tesla, are attributed to the relative contribution of intravascular/extravascular signals and their dependence on field strength, blood oxygenation and echo time. Finally, a comparison of single and multiphase ASL is made at 7 Tesla, with a modified Look-locker EPI sequence presented which allows simultaneous measurement of CBF and transit time, whilst increasing the available BOLD signal. This could have important implications for hypercapnia calibrated BOLD fMRI, where choice of ASL sequence may affect the estimated change in CMRO2. Furthermore, it provides a framework for future cerebral haemodynamic studies where simultaneous measurements are required

Quantification of the BOLD response via blood gas modulations

This thesis is intended to contribute to a quantitative understanding of the blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal in order to increase its clinical potential. Here, the vascular, neuronal and physical processes which combine to give a resulting BOLD signal are investigated using respiratory challenges. The effect of isocapnic hyperoxia on vascular responses is investigated at 7 Tesla. No significant change was found in resting-state cerebral blood flow (CBF), resting-state cerebral blood volume (CBV) and task-evoked CBF. This challenges a previously held idea that hyperoxia is vasoconstrictive. The effect of isocapnic hyperoxia on neuronal oscillations was assessed with magnetoencephalography (MEG). Whilst a significant reduction in oscillatory power is reported in the occipital lobe, the change is significantly smaller than the global reduction previously measured with hypercapnia. These findings suggest that hyperoxia is an ideal tool for calibrated BOLD fMRI. The relationship between the change in blood oxygenation and change in transverse relaxation plays a key role in calibrated BOLD fMRI. However, previous measurements have been confounded by a change in CBV. Here, the relationship was found to be sub-linear across 1.5, 3 and 7 Tesla. Previous results which suggest a supralinear relationship at 1.5/3 Tesla and a linear relationship at 7 Tesla, are attributed to the relative contribution of intravascular/extravascular signals and their dependence on field strength, blood oxygenation and echo time. Finally, a comparison of single and multiphase ASL is made at 7 Tesla, with a modified Look-locker EPI sequence presented which allows simultaneous measurement of CBF and transit time, whilst increasing the available BOLD signal. This could have important implications for hypercapnia calibrated BOLD fMRI, where choice of ASL sequence may affect the estimated change in CMRO2. Furthermore, it provides a framework for future cerebral haemodynamic studies where simultaneous measurements are required

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

The effect of isocapnic hyperoxia on neurophysiology as measured with MRI and MEG

The physiological effect of hyperoxia has been poorly characterised, with studies reporting conflicting results on the role of hyperoxia as a vasoconstrictor. It is not clear whether hyperoxia is the primary contributor to vasoconstriction or whether induced changes in CO2 that commonly accompany hyperoxia are a factor. As calibrated BOLD fMRI based on hyperoxia becomes more widely used, it is essential to understand the effects of oxygen on resting cerebral physiology. This study used a RespirActTM system to deliver a repeatable isocapnic hyperoxia stimulus to investigate the independent effect of O2 on cerebral physiology, removing any potential confounds related to altered CO2. T1-independent Phase Contrast MRI was used to demonstrate that isocapnic hyperoxia has no significant effect on carotid blood flow (normoxia 201 ± 11 ml/min, -0.3 ± 0.8 % change during hyperoxia, p = 0.8), whilst Look Locker ASL was used to demonstrate that there is no significant change in arterial cerebral blood volume (normoxia 1.3 ± 0.4 %, -0.5 ± 5 % change during hyperoxia). These are in contrast to significant changes in blood flow observed for hypercapnia (6.8 ± 1.5 %/mmHg CO2). In addition, magnetoencephalography provided a method to monitor the effect of isocapnic hyperoxia on neuronal oscillatory power. In response to hyperoxia, a significant focal decrease in oscillatory power was observed across the alpha, beta and low gamma bands in the occipital lobe, compared to a more global significant decrease on hypercapnia. This work suggests that isocapnic hyperoxia provides a more reliable stimulus than hypercapnia for calibrated BOLD, and that previous reports of vasoconstriction during hyperoxia probably reflect the effects of hyperoxia-induced changes in CO2. However, hyperoxia does induce changes in oscillatory power consistent with an increase in vigilance, but these changes are smaller than those observed under hypercapnia. The effect of this change in neural activity on calibrated BOLD using hyperoxia or combined hyperoxia and hypercapnia needs further investigation

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

Field strength dependence of grey matter R2* on venous oxygenation

The relationship between venous blood oxygenation and change in transverse relaxation rate (ΔR2 *) plays a key role in calibrated BOLD fMRI. This relationship, defined by the parameter β, has previously been determined using theoretical simulations and experimental measures. However, these earlier studies have been confounded by the change in venous cerebral blood volume (CBV) in response to functional tasks. This study used a double-echo gradient echo EPI scheme in conjunction with a graded isocapnic hyperoxic sequence to assess quantitatively the relationship between the fractional venous blood oxygenation (1-Yv) and transverse relaxation rate of grey matter (ΔR2 * GM), without inducing a change in vCBV. The results demonstrate that the relationship between ΔR2 * and fractional venous oxygenation at all magnet field strengths studied was adequately described by a linear relationship. The gradient of this relationship did not increase monotonically with field strength, which may be attributed to the relative contributions of intravascular and extravascular signals which will vary with both field strength and blood oxygenation

Effect of Applying Leakage Correction on rCBV Measurement Derived From DSC-MRI in Enhancing and Nonenhancing Glioma

Purpose: Relative cerebral blood volume (rCBV) is the most widely used parameter derived from DSC perfusion MR imaging for predicting brain tumor aggressiveness. However, accurate rCBV estimation is challenging in enhancing glioma, because of contrast agent extravasation through a disrupted blood-brain barrier (BBB), and even for nonenhancing glioma with an intact BBB, due to an elevated steady-state contrast agent concentration in the vasculature after first passage. In this study a thorough investigation of the effects of two different leakage correction algorithms on rCBV estimation for enhancing and nonenhancing tumors was conducted. Methods: Two datasets were used retrospectively in this study: 1. A publicly available TCIA dataset (49 patients with 35 enhancing and 14 nonenhancing glioma); 2. A dataset acquired clinically at Erasmus MC (EMC, Rotterdam, NL) (47 patients with 20 enhancing and 27 nonenhancing glial brain lesions). The leakage correction algorithms investigated in this study were: a unidirectional model-based algorithm with flux of contrast agent from the intra- to the extravascular extracellular space (EES); and a bidirectional model-based algorithm additionally including flow from EES to the intravascular space. Results: In enhancing glioma, the estimated average contrast-enhanced tumor rCBV significantly (Bonferroni corrected Wilcoxon Signed Rank Test, p < 0.05) decreased across the patients when applying unidirectional and bidirectional correction: 4.00 ± 2.11 (uncorrected), 3.19 ± 1.65 (unidirectional), and 2.91 ± 1.55 (bidirectional) in TCIA dataset and 2.51 ± 1.3 (uncorrected), 1.72 ± 0.84 (unidirectional), and 1.59 ± 0.9 (bidirectional) in EMC dataset. In nonenhancing glioma, a significant but smaller difference in observed rCBV was found after application of both correction methods used in this study: 1.42 ± 0.60 (uncorrected), 1.28 ± 0.46 (unidirectional), and 1.24 ± 0.37 (bidirectional) in TCIA dataset and 0.91 ± 0.49 (uncorrected), 0.77 ± 0.37 (unidirectional), and 0.67 ± 0.34 (bidirectional) in EMC dataset. Conclusion: Both leakage correction algorithms were found to change rCBV estimation with BBB disruption in enhancing glioma, and to a lesser degree in nonenhancing glioma. Stronger effects were found for bidirectional leakage correction than for unidirectional leakage correction

Mitochondrial inhibitor atovaquone increases tumor oxygenation and inhibits hypoxic gene expression in patients with non-small cell lung cancer

Clinical trial with omics and imaging data to study response to treatment

Reproducibility of arterial spin labeling cerebral blood flow image processing: A report of the ISMRM open science initiative for perfusion imaging (OSIPI)_and the ASL MRI challenge.

Publication status: PublishedFunder: European Union; doi: http://dx.doi.org/10.13039/501100000780Funder: Netherlands Organisation for health Research and Development; doi: http://dx.doi.org/10.13039/501100001826Funder: ISMRM Perfusion Study GroupFunder: Netherlands Enterprise Agency; doi: http://dx.doi.org/10.13039/100013405Funder: EU Joint Program for Neurodegenerative Disease ResearchPURPOSE: Arterial spin labeling (ASL) is a widely used contrast-free MRI method for assessing cerebral blood flow (CBF). Despite the generally adopted ASL acquisition guidelines, there is still wide variability in ASL analysis. We explored this variability through the ISMRM-OSIPI ASL-MRI Challenge, aiming to establish best practices for more reproducible ASL analysis. METHODS: Eight teams analyzed the challenge data, which included a high-resolution T1-weighted anatomical image and 10 pseudo-continuous ASL datasets simulated using a digital reference object to generate ground-truth CBF values in normal and pathological states. We compared the accuracy of CBF quantification from each team's analysis to the ground truth across all voxels and within predefined brain regions. Reproducibility of CBF across analysis pipelines was assessed using the intra-class correlation coefficient (ICC), limits of agreement (LOA), and replicability of generating similar CBF estimates from different processing approaches. RESULTS: Absolute errors in CBF estimates compared to ground-truth synthetic data ranged from 18.36 to 48.12 mL/100 g/min. Realistic motion incorporated into three datasets produced the largest absolute error and variability between teams, with the least agreement (ICC and LOA) with ground-truth results. Fifty percent of the submissions were replicated, and one produced three times larger CBF errors (46.59 mL/100 g/min) compared to submitted results. CONCLUSIONS: Variability in CBF measurements, influenced by differences in image processing, especially to compensate for motion, highlights the significance of standardizing ASL analysis workflows. We provide a recommendation for ASL processing based on top-performing approaches as a step toward ASL standardization