Daniel Bulte

BACKGROUND AND PURPOSE The imaging technique known as Oxygen-Enhanced MRI is under development as a noninvasive technique for imaging hypoxia in tumours and pulmonary diseases. While promising results have been shown in preclinical experiments, clinical studies have mentioned experiencing difficulties with patient motion, image registration, and the limitations of single-slice images compared to 3D volumes. As clinical studies begin to assess feasibility of using OE-MRI in patients, it is important for researchers to communicate about the practical challenges experienced when using OE-MRI on patients to help the technique advance. MATERIALS AND METHODS We report on our experience with using two types of T1 mapping (MOLLI and VFA) for a recently completed OE-MRI clinical study on oropharyngeal squamous cell carcinoma. RESULTS We report: (1) the artefacts and practical difficulties encountered in this study; (2) the difference in estimated T1 from each method used - the VFA T1 estimation was higher than the MOLLI estimation by 27% on average; (3) the standard deviation within the tumour ROIs - there was no significant difference in the standard deviation seen within the tumour ROIs from the VFA versus MOLLI; and (4) the OE-MRI response collected from either method. Lastly, we collated the MRI acquisition details from over 45 relevant manuscripts as a convenient reference for researchers planning future studies. CONCLUSION We have reported our practical experience from an OE-MRI clinical study, with the aim that sharing this is helpful to researchers planning future studies. In this study, VFA was a more useful technique for using OE-MRI in tumours than MOLLI T1 mapping.

BackgroundIt is well-established that what is good for the heart is good for the brain. Vascular factors such as hypertension, diabetes, and high cholesterol, and genetic factors such as the apolipoprotein E4 allele increase the risk of developing both cardiovascular disease and dementia. However, the mechanisms underlying the heart–brain association remain unclear. Recent evidence suggests that impairments in vascular phenotypes and cerebrovascular reactivity (CVR) may play an important role in cognitive decline. The Heart and Brain Study combines state-of-the-art vascular ultrasound, cerebrovascular magnetic resonance imaging (MRI) and cognitive testing in participants of the long-running Whitehall II Imaging cohort to examine these processes together. This paper describes the study protocol, data pre-processing and overarching objectives.Methods and DesignThe 775 participants of the Whitehall II Imaging cohort, aged 65 years or older in 2019, have received clinical and vascular r...

Pancreatic disease can be spatially inhomogeneous. For this reason, quantitative imaging studies of the pancreas have often targeted the 3 main anatomical pancreatic segments, head, body, and tail, traditionally using a balanced region of interest (ROI) strategy. Existing automated analysis methods have implemented whole-organ segmentation, which provides an overall quantification, but fails to address spatial heterogeneity in disease. A method to automatically refine a whole-organ segmentation of the pancreas into head, body, and tail subregions is presented for abdominal magnetic resonance imaging (MRI). The subsegmentation method is based on diffeomorphic registration to a group average template image, where the parts are manually annotated. For a new whole-pancreas segmentation, the aligned template’s part labels are automatically propagated to the segmentation of interest. The method is validated retrospectively on the UK Biobank imaging substudy (scanned using a 2-point Dixon ...

We introduce PyPlr—a versatile, integrated system of hardware and software to support a broad spectrum of research applications concerning the human pupillary light reflex (PLR). PyPlr is a custom Python library for integrating a research-grade video-based eye-tracker system with a light source and streamlining stimulus design, optimisation and delivery, device synchronisation, and extraction, cleaning, and analysis of pupil data. We additionally describe how full-field, homogenous stimulation of the retina can be realised with a low-cost integrating sphere that serves as an alternative to a more complex Maxwellian view setup. Users can integrate their own light source, but we provide full native software support for a high-end, commercial research-grade 10-primary light engine that offers advanced control over the temporal and spectral properties of light stimuli as well as spectral calibration utilities. Here, we describe the hardware and software in detail and demonstrate its cap...

The change in longitudinal relaxation rate (R1 ) produced by oxygen has been used as a means of inferring oxygenation levels in magnetic resonance imaging in numerous applications. The relationship between oxygen partial pressure (pO2 ) and R1 is linear and reproducible, and the slope represents the relaxivity of oxygen (r1Ox ) in that material. However, there is considerable variability in the values of r1Ox reported, and they have been shown to vary by field strength and temperature. Therefore, we have compiled 28 reported empirical values of the relaxivity of oxygen as a resource for researchers. Furthermore, we provide an empirical model for estimating the relaxivity of oxygen in water, saline, plasma, and vitreous fluids, accounting for magnetic field strength and temperature. The model agrees well (R2  = 0.93) with the data gathered from the literature for fields ranging from 0.011 to 8.45 T and temperatures of 21-40 °C. This provides a useful resource for researchers seeking to quantify pO2 in simple fluids in their studies, such as water and saline phantoms, or bodily fluids such as vitreous fluids, cerebrospinal fluids, and amniotic fluids.

Quantitative imaging biomarkers derived from magnetic resonance imaging of the pancreas could reveal changes in pancreas organ volume and shape manifest in chronic disease. Recent developments in machine learning facilitate pancreas segmentation and volume extraction. Machine learning methods could also help in designing a data-driven approach to pancreas shape characterization. We present an automated pipeline for pancreas volume and shape characterization. We start off with deep learning-based segmentation; we show the impact of choice of loss function in pancreas segmentation by comparing a 3D U-Net model trained using soft Dice over cross-entropy loss. Then, a diffeomorphic algorithm for group-wise registration as well as manifold learning are used to extract prominent shape features from the segmentation masks. The technique shows potential in a subset (N = 3,909) of the UK Biobank imaging sub-study for (1) automated quality control, e.g. suboptimal pancreas coverage acquisitions; and (2) determining abnormal pancreas morphology, that might reflect different patterns of fat infiltration. To our knowledge, this work is the first to attempt learning pancreas shape features.

Purpose: Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non–small cell lung cancer (NSCLC). Patients and Methods: Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed. Results: Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change −28% [95% confidence interval (CI), −58.2 to −4.4]. In contrast, media...

Blood-oxygen-level-dependent (BOLD) imaging was a concept introduced in 1990 for evaluating brain activation. The method relies on magnetic resonance imaging (MRI) contrast resulting from changes in the microvascular ratio of oxyhaemoglobin (oxyHb) to deoxyhaemoglobin (deoxyHb). OxyHb is diamagnetic, whereas deoxyHb is paramagnetic, which produces a local bulk magnetic susceptibility effect and subsequent MRI signal change. The changes are typically observed in T(2)*-weighted functional MRI scans. However, there has recently been interest in BOLD as a way to evaluate microcirculation of any normal or diseased tissue. This review focuses on the application of BOLD imaging in the understanding of normal and diseased skeletal muscle. In addition we present new findings showing the possible application of BOLD imaging with hyperoxia for evaluating skeletal muscle physiology.

PurposeIntravoxel incoherent motion (IVIM) has been proposed as a means of non-invasive MRI measurement of perfusion parameters such as blood flow and blood volume. Its main competitor in the brain is arterial spin labelling (ASL). In theory, IVIM should not suffer from some of the same limitations as ASL such as poor signal in white matter, and assumptions about arterial arrival times that may be violated in the presence of pathology.MethodsIn this study we aimed to test IVIM as a viable alternative to ASL for quantitative imaging of perfusion parameters in the brain. First, a direct comparison was performed between IVIM and multi-post label delay pseudo-continuous ASL; second, IVIM images were acquired with and without nulling cerebrospinal fluid; and finally, ultra-high resolution IVIM was performed to minimise partial voluming.ResultsIn all three tests, IVIM failed to disprove the null hypothesis, strongly suggesting that, at least within the brain, the technique does not measur...

Cerebrovascular reactivity (CVR), the ability of cerebral vessels to dilate or constrict, has been shown to provide valuable information in the diagnosis and treatment evaluation of patients with various cerebrovascular conditions. CVR mapping is typically performed using hypercapnic gas inhalation as a vasoactive challenge while collecting BOLD images, but the inherent need of gas inhalation and the associated apparatus setup present a practical obstacle in applying it in routine clinical use. Therefore, we aimed to develop a new method to map CVR using resting-state BOLD data without the need of gas inhalation. This approach exploits the natural variation in respiration and measures its influence on BOLD MRI signal. In this work, we first identified a surrogate of the arterial CO2 fluctuation during spontaneous breathing from the global BOLD signal. Second, we tested the feasibility and reproducibility of the proposed approach to use the above-mentioned surrogate as a regressor to...

Oxygen plays a fundamental role in functional magnetic resonance imaging (FMRI). Blood oxygenation level-dependent (BOLD) imaging is the foundation stone of all FMRI and is still the essential workhorse of the vast majority of FMRI procedures. Hemoglobin may provide the magnetic properties that allow the technique to work, but it is oxygen that allows the contrast to effectively be switched on or off, and it is oxygen that we are interested in tracking in order to observe the oxygen metabolism changes. In general the changes in venous oxygen saturation are observed in order to infer changes in the correlated mechanisms, which can include changes in cerebral blood flow, metabolism, and the fraction of inspired oxygen. By independently manipulating the fraction of inspired oxygen it is possible to alter the amount of dissolved oxygen in the plasma, the venous saturation, or even the blood flow. The effects that these changes have on the observed MRI signal can be either a help or a hindrance depending on how well the changes induced are understood. The administration of supplemental inspired oxygen is in a unique position to provide a flexible, noninvasive, inexpensive, patient-friendly addition to the MRI toolkit to enable investigations to look beyond statistics and regions of interest, and actually produce calibrated, targeted measurements of blood flow, metabolism or pathology.

The calculation of the calibration parameter M, which represents the maximum theoretically possible blood oxygen level dependent (BOLD) signal increase, is an essential intermediate step in any calibrated fMRI experiment. To better compare M values obtained across different studies, it is common to scale M values from their original BOLD echo time (TE) to a different echo time according to the theory that M is directly proportional to TE. To the best of our knowledge, this relationship has never been directly tested. A pseudocontinuous arterial spin labeling sequence with five readouts (TE ranging from 20 to 78 ms) was implemented to test the relationship between M and TE, both with and without the application of flow crushing gradients. Both M and the BOLD signal were found to be linear functions of TE, but with a nonzero intercept. This intercept was reduced when crusher gradients were added, suggesting that the deviation from theory is a result of nonnegligible intravascular sign...

Introduction Imaging biomarkers are increasingly being used to evaluate novel therapeutics and targets in oncology. One such biomarker that shows promising results is MRI measurement of vessel size. A number of pre-clinical studies have shown a strong correlation with histological measurements and response to treatment. In recent years, a variant of vessel size imaging (VSI) that uses an evoked BOLD response (using gas challenges) has been demonstrated in the human brain. This new technique offers a completely non-invasive method of evaluating disease and treatment in a clinical setting. Here we investigate the possibility of acquiring BOLD-VSI data in the brainstem, which is the location of 10% of childhood brain tumors. As with standard fMRI studies, data from the brainstem is highly influenced by cardiogenic noise. Two different data acquisition methodologies: dual-echo EPI (gradient/spin) and multi-echo single-shot-sampling of spin-echo refocusing (MESSER), are compared with and without cardiac gating. The initial results demonstrate an increase in performance for both gated acquisitions (against their respective continuous acquisitions), each demonstrating a significant reduction in chi-square fitting residuals. While the dual-echo readout demonstrably outperforms the MESSER acquisition both with and without cardiac gating. Theory VSI is based on the vessel size dependence of T2 and T2*-weighted acquisitions. Changes in susceptibility during breathing challenges result in differential changes in T2 and T2*-weighted signals, from which estimates of mean vessel radius can be made using appropriate biophysical models. During data acquisition the brainstem is subject to cardiac noise due to the basilar artery and natural elongation and contraction of the whole brainstem. Gated acquisitions have been shown to significantly reduce this noise, but result in temporal fluctuations in signal due to the changing repetition time (TR). Fitting to multi-echo acquisitions can overcome these fluctuations, creating purely T2 or T2*-weighted images. In this study a MESSER acquisition is used with 3 EPI readouts either side of a refocusing pulse. The first three echoes (free-induction decay) are used to calculate R2*, while the second set of echoes (spin-echo re-phasing) are used to calculate as per Jochimsen et al, where . Alternatively, single echo data can be corrected for the temporal signal changes with a T1 map. Here we estimate T1 from the GE readout according to the method outlined by Guimaraes et al, minimising the function S(n,i)[1-exp(-TRi/T1n)] during signal plateau periods (where S(n,i) is the measured signal and TRi is the repetition time for each readout). Methods Two healthy volunteers were scanned on a 3 Tesla Siemens Verio with a 32-channel head coil. For each subject a diffusion weighted scan (3 orthogonal directions with two b values (0 and 1000mm/s)) and four VSI scans were acquired. The VSI data was acquired using a dual GE-SE EPI readout (TR=2s, TE=30/90ms) and a MESSER EPI readout (TR=2s, TE=13,31,49,78,95,113ms Spin Echo time=125ms). A GRAPPA factor of 2 was used for both readouts. Thirteen axial slices (3.1x3.1x4mm voxels, 1.0mm interslice gap) were acquired with and without cardiac gating. Each VSI imaging paradigm consisted of one 18minute session, comprised of 3x3minute hyperoxic periods interleaved with 3x3minute periods of normal air. During periods of hyperoxia, 100% oxygen was delivered to the volunteers via a non-rebreathing mask. All individual echoes were motion corrected and spatially smoothed (8mm FWHM) with FSL. A 2 order time domain filter was then used to further reduce noise (this was applied to the MESSER data after relaxation rate calculation to maintain any baseline drift and T1 dependence between echoes). Dual-echo data was high-pass filtered to remove baseline changes. The MESSER data was fit with a linear regression to produce ΔR2 and ΔR2* data. Relaxation rate changes for the dual echo data were calculated as ΔR2*=−log(SGE(t)/S0,GE)/TEGE and ΔR2=−log(SSE(t)/S0,SE)/TESE. The plateau periods from the triggered GE data (with TR times calculated from DICOM headers) were used to estimate T1 maps, and correct for variations in TR. A weighted total least squares regression was used to calculate q, the ratio of ΔR2* and ΔR2. q values were masked, limited to a range of 1 to 25 and converted to mean vessel radii via a polynomial fit to Monte-Carlo model data (using the group mean ADC value of 0.753μm/ms and an assumed susceptibility change of 0.2ppm). Results The figure shows example vessel size maps calculated with each acquisition method. The group averaged brainstem values and fitting residuals are given in the table below. The dual-echo gated sequence appears to provide the most accurate estimates of vessel size, producing the smallest chi-square fitting residuals (mean chi-square/DOF<0.5). The figure clearly illustrates the superiority of the gated MESSER acquisition compared…

Measurement of cerebrovascular reactivity (CVR) can give valuable information about existing pathology and the risk of adverse events, such as stroke. A common method of obtaining regional CVR values is by measuring the blood flow response to carbon dioxide (CO2)-enriched air using arterial spin labeling (ASL) or blood oxygen level-dependent (BOLD) imaging. Recently, several studies have used carbogen gas (containing only CO2 and oxygen) as an alternative stimulus. A direct comparison was performed between CVR values acquired by ASL and BOLD imaging using stimuli of (1) 5% CO2 in air and (2) 5% CO2 in oxygen (carbogen-5). Although BOLD and ASL CVR values are shown to be correlated for CO2 in air (mean response 0.11 ± 0.03% BOLD, 4.46 ± 1.80% ASL, n = 16 hemispheres), this correlation disappears during a carbogen stimulus (0.36 ± 0.06% BOLD, 4.97 ± 1.30% ASL). It is concluded that BOLD imaging should generally not be used in conjunction with a carbogen stimulus when measuring CVR, an...

Vessel size imaging (VSI) is a magnetic resonance imaging (MRI) technique that aims to provide quantitative measurements of tissue microvasculature. An emerging variation of this technique uses the blood oxygenation level-dependent (BOLD) effect as the source of the imaging contrast. Gas challenges have the advantage over contrast injection techniques in that they are noninvasive and easily repeatable because of the fast washout of the contrast. However, initial results from BOLD-VSI studies are somewhat contradictory, with substantially different estimates of the mean vessel radius. Owing to BOLD-VSI being an emerging technique, there is not yet a standard processing methodology, and different techniques have been used to calculate the mean vessel radius and reject uncertain estimates. In addition, the acquisition methodology and signal modeling vary from group to group. Owing to these differences, it is difficult to determine the source of this variation. Here we use computer mode...

This paper describes a new method of measuring some magnetic properties of steel under applied biaxial stresses in the x-y plane when the steel is magnetized in the z direction (called "z magnetization"). Results are compared with two other sets of experimental data. The conclusions are that z magnetization is prone to several sources of error of significant amounts, whichever

ABSTRACT We present a direct comparison of the normal and initial methods of obtaining an induction curve. It has long been held that ideally the data sets obtained by each method are equivalent; however, acceptable agreement was not experimentally realizable. We propose that, by careful application of contemporary techniques of measuring flux density and field strength, normal and initial induction curves may be obtained that are equivalent within experimental error (approximately 1%). This realization is of great benefit, for although the normal induction curve is the accepted standard for presenting a ferromagnetic profile, data for an initial induction curve are simpler and considerably quicker to obtain by software-controlled data acquisition

ABSTRACT Introduction Measurement of the cerebral metabolic rate of oxygen during functional tasks is a key step towards the clinical implementation of functional MRI. The use of increased fractions of inspired oxygen as a calibration step enables the modelling of relative changes in CMRO 2 , as well as estimating the baseline cerebral blood volume. In this pilot study two subjects were imaged using a 5-slice, interleaved, gradient-echo EPI/Q2TIPS sequence while they performed a simple 2-level graded motor task followed by two short hyperoxic epochs delivered via a 2-tube nasal cannula. These data were then used to estimate the theoretical maximal BOLD signal (M) and thereby calculate the relative regional increase in CMRO 2 for each task. The hyperoxia BOLD data were then also used to produce baseline CBV maps. From the baseline CBV values and measured relative CBF changes, estimates of quantitative blood volume changes in the motor regions with activation were then calculated. Theory & Methods Analogous to the derivation of the hypercapnia-calibrated model 1 , hyperoxia calibration makes use of the expression for BOLD signal change, as well as the expression for R 2 * | dHb derived by Boxerman et al 2 . The hyperoxia calibration model described by Chiarelli et al 3 is given by: [ ] v 0 β . Additionally, CBV was calculated from the BOLD data during the hyperoxia epochs using the hyperoxia contrast method described by Bulte et al 4 . Images were acquired on a Siemens Trio 3T MRI scanner using a 12-channel head-coil. An interlaced BOLD/pulsed arterial spin-labelling (ASL) sequence was used to collect T 2 * -weighted EPI images and Q2TIPS 5 cerebral perfusion images. Changes in the blood relaxation times caused by the heightened oxygen were also taken into account 6 . The subjects were healthy normal volunteers who gave informed consent, in accordance with the ethics approval for the study. The total scan duration was 26 minutes, consisting of 6 minutes of 45 sec off/45 sec on alternating bilateral finger tapping with blocks 1 and 3 at a rate of one tap cycle per 6 seconds and blocks 2 and 4 at a rate of one cycle per 3 seconds. This was followed by two 5-minute blocks of hyperoxia separated by 4 minutes of normal air breathing. Oxygen was administered via a 2-tube nasal cannula to ensure minimal invasiveness and discomfort for the subject. Subjects were instructed to breathe both in and out through the nose to enable sampling of end-tidal gases. Oxygen was delivered at a rate of 7 litres per minute, inducing an end tidal level of ~35%, equivalent to an inspired fraction of ~50%. Analysis was performed using the FMRIB Software Library (FSL) package 7 . Results & Discussion Figs 1A and 1B shows the BOLD and perfusion changes induced in one subject for the low level motor stimulus (task 1), overlaid onto a high-resolution structural image. Next to this is the baseline cerebral blood volume map calculated from the BOLD data during the hyperoxia blocks showing absolute, quantitative values in ml of blood per 100g of tissue. The median BOLD signals and ASL changes from the motor activations at the two task levels are shown in Table 1. M in the motor areas was calculated to be 4.05% and 4.29% for subjects 1 and 2 respectively. The CBV values given here were calculated using the Grubb equation 8 (CBV/CBV 0 =(CBF/CBF 0) α , with α=0.38) and the relative changes in CMRO 2 were calculated using equation (1).

A system of new integral equations is presented. They are derived from Maxwell's equations and describe radio-frequency (RF) current densities on a two-dimensional flat plate. The equations are generalisations of Pocklington's integral equation showing phase-retardation in two dimensions. These singular equations are solved, numerically, for the case of one-dimensional geometry.…

MRI may be used to measure fractional changes in cerebral oxygen metabolism via a metabolic model. One step commonly used in this measurement is calibration with image data acquired during hypercapnia, which is a state of increased CO2 content of the blood. In this study some commonly used hypercapnia-inducing stimuli were compared to assess their suitability for the calibration step. The following stimuli were investigated: (a) inspiration of a mixture of 4% CO2, 21% O2 and balance N2; (b) 30-s breath holding; and (c) inspiration of a mixture of 4% CO2 and 96% O2 (i.e., carbogen). Measurements of BOLD and cerebral blood flow made on nine subjects during the different hypercapnia-inducing stimuli showed that each stimulus leads to a different calibration of the model. We argue that of the aforementioned stimuli, inspiration of 4% CO2, 21% O2 and balance N2 should be preferred for the calibration as the other stimuli produce responses that violate assumptions of the metabolic model.