Streamlined quantitative BOLD for detecting visual stimulus-induced changes in oxygen extraction fraction in healthy participants: toward clinical application in human glioma.

OBJECTIVE: Monitoring brain oxygenation is critical in brain tumors, as low oxygenation influences tumor growth, pathological angiogenesis, and treatment resistance. This study examined the ability of the streamlined quantitative (sq)BOLD MRI technique to detect oxygenation changes in healthy individuals, as well as its potential application in a clinical setting. METHODS: We used the asymmetric spin echo (ASE) technique with FLAIR preparation, along with model-based Bayesian inference to quantify the reversible transverse relaxation rate (R2') and oxygen extraction fraction (OEF) across the brain at baseline and during visual stimulation in eight healthy participants at 3T; and two patients with glioma at rest only. RESULTS: Comparing sqBOLD-derived parameters between baseline and visual stimulation revealed a decrease in OEF from 0.56 ± 0.09 at baseline to 0.54 ± 0.07 at the activated state (p = 0.04, paired t test) within a functional localizer-defined volume of interest, and a decline in R2' from 6.5 ± 1.3s-1 at baseline to 6.2 ± 1.4s-1 at the activated state (p = 0.006, paired t test) in the visual cortex. CONCLUSION: The sqBOLD technique is sensitive enough to detect and quantify changes in oxygenation in the healthy brain and shows potential for integration into clinical settings to provide valuable information on oxygenation in glioma.

MRI-Based Assessment of Brain Tumor Hypoxia: Correlation with Histology.

Cerebral hypoxia significantly impacts the progression of brain tumors and their resistance to radiotherapy. This study employed streamlined quantitative blood-oxygen-level-dependent (sqBOLD) MRI to assess the oxygen extraction fraction (OEF)-a measure of how much oxygen is being extracted from vessels, with higher OEF values indicating hypoxia. Simultaneously, we utilized vessel size imaging (VSI) to evaluate microvascular dimensions and blood volume. A cohort of ten patients, divided between those with glioma and those with brain metastases, underwent a 3 Tesla MRI scan. We generated OEF, cerebral blood volume (CBV), and vessel size maps, which guided 3-4 targeted biopsies per patient. Subsequent histological analyses of these biopsies used hypoxia-inducible factor 1-alpha (HIF-1α) for hypoxia and CD31 for microvasculature assessment, followed by a correlation analysis between MRI and histological data. The results showed that while the sqBOLD model was generally applicable to brain tumors, it demonstrated discrepancies in some metastatic tumors, highlighting the need for model adjustments in these cases. The OEF, CBV, and vessel size maps provided insights into the tumor's hypoxic condition, showing intertumoral and intratumoral heterogeneity. A significant relationship between MRI-derived measurements and histological data was only evident in the vessel size measurements (r = 0.68, p < 0.001).

Ultra-high spatial resolution BOLD fMRI in humans using combined segmented-accelerated VFA-FLEET with a recursive RF pulse design.

PURPOSE: To alleviate the spatial encoding limitations of single-shot echo-planar imaging (EPI) by developing multi-shot segmented EPI for ultra-high-resolution functional MRI (fMRI) with reduced ghosting artifacts from subject motion and respiration. THEORY AND METHODS: Segmented EPI can reduce readout duration and reduce acceleration factors, however, the time elapsed between segment acquisitions (on the order of seconds) can result in intermittent ghosting, limiting its use for fMRI. Here, "FLEET" segment ordering, where segments are looped over before slices, was combined with a variable flip angle progression (VFA-FLEET) to improve inter-segment fidelity and maximize signal for fMRI. Scaling a sinc pulse's flip angle for each segment (VFA-FLEET-Sinc) produced inconsistent slice profiles and ghosting, therefore, a recursive Shinnar-Le Roux (SLR) radiofrequency (RF) pulse design was developed (VFA-FLEET-SLR) to generate unique pulses for every segment that together produce consistent slice profiles and signals. RESULTS: The temporal stability of VFA-FLEET-SLR was compared against conventional-segmented EPI and VFA-FLEET-Sinc at 3T and 7T. VFA-FLEET-SLR showed reductions in both intermittent and stable ghosting compared to conventional-segmented and VFA-FLEET-Sinc, resulting in improved image quality with a minor trade-off in temporal SNR. Combining VFA-FLEET-SLR with acceleration, we achieved a 0.6-mm isotropic acquisition at 7T, without zoomed imaging or partial Fourier, demonstrating reliable detection of blood oxygenation level-dependent (BOLD) responses to a visual stimulus. To counteract the increased repetition time from segmentation, simultaneous multi-slice VFA-FLEET-SLR was demonstrated using RF-encoded controlled aliasing. CONCLUSIONS: VFA-FLEET with a recursive RF pulse design supports acquisitions with low levels of artifact and spatial blur, enabling fMRI at previously inaccessible spatial resolutions with a "full-brain" field of view.

Age-related differences in cerebral blood flow and cortical thickness with an application to age prediction.

Cerebral cortex thinning and cerebral blood flow (CBF) reduction are typically observed during normal healthy aging. However, imaging-based age prediction models have primarily used morphological features of the brain. Complementary physiological CBF information might result in an improvement in age estimation. In this study, T1-weighted structural magnetic resonance imaging and arterial spin labeling CBF images were acquired in 146 healthy participants across the adult life span. Sixty-eight cerebral cortex regions were segmented, and the cortical thickness and mean CBF were computed for each region. Linear regression with age was computed for each region and data type, and laterality and correlation matrices were computed. Sixteen predictive models were trained with the cortical thickness and CBF data alone as well as a combination of both data types. The age explained more variance in the cortical thickness data (average R2 of 0.21) than in the CBF data (average R2 of 0.09). All 16 models performed significantly better when combining both measurement types and using feature selection, and thus, we conclude that the inclusion of CBF data marginally improves age estimation.

Simulations of the effect of diffusion on asymmetric spin echo based quantitative BOLD: An investigation of the origin of deoxygenated blood volume overestimation.

Quantitative BOLD (qBOLD) is a technique for mapping oxygen extraction fraction (OEF) and deoxygenated blood volume (DBV) in the human brain. Recent measurements using an asymmetric spin echo (ASE) based qBOLD approach produced estimates of DBV which were systematically higher than measurements from other techniques. In this study, we investigate two hypotheses for the origin of this DBV overestimation using simulations and consider the implications for experimental measurements. Investigations were performed by combining Monte Carlo simulations of extravascular signal with an analytical model of the intravascular signal. HYPOTHESIS 1: DBV overestimation is due to the presence of intravascular signal which is not accounted for in the analysis model. Intravascular signal was found to have a weak effect on qBOLD parameter estimates. HYPOTHESIS 2: DBV overestimation is due to the effects of diffusion which are not accounted for in the analysis model. The effect of diffusion on the extravascular signal was found to result in a vessel radius dependent variation in qBOLD parameter estimates. In particular, DBV overestimation peaks for vessels with radii from 20 to 30 µm and is OEF dependent. This results in the systematic underestimation of OEF. IMPLICATIONS: The impact on experimental qBOLD measurements was investigated by simulating a more physiologically realistic distribution of vessel sizes with a small number of discrete radii. Overestimation of DBV consistent with previous experiments was observed, which was also found to be OEF dependent. This results in the progressive underestimation of the measured OEF. Furthermore, the relationship between the measured OEF and the true OEF was found to be dependent on echo time and spin echo displacement time. The results of this study demonstrate the limitations of current ASE based qBOLD measurements and provide a foundation for the optimisation of future acquisition approaches.

Dependence of the MR signal on the magnetic susceptibility of blood studied with models based on real microvascular networks.

PURPOSE: The primary goal of this study was to estimate the value of ß , the exponent in the power law relating changes of the transverse relaxation rate and intra-extravascular local magnetic susceptibility differences as ΔR2∗∝(Δχ)ß . The secondary objective was to evaluate any differences that might exist in the value of ß obtained using a deoxyhemoglobin-weighted Δχ distribution versus a constant Δχ distribution assumed in earlier computations. The third objective was to estimate the value of ß that is relevant for methods based on susceptibility contrast agents with a concentration of Δχ higher than that used for BOLD fMRI calculations. METHODS: Our recently developed model of real microvascular anatomical networks is used to extend the original simplified Monte-Carlo simulations to compute ß from the first principles. RESULTS: Our results show that ß=1 for most BOLD fMRI measurements of real vascular networks, as opposed to earlier predictions of ß=1 .5 using uniform Δχ distributions. For perfusion or fMRI methods based on contrast agents, which generate larger values for Δχ , ß=1 for B0≤ 9.4 T, whereas at 14 T ß can drop below 1 and the variation across subjects is large, indicating that a lower concentration of contrast agent with a lower value of Δχ is desired for experiments at high B0 . CONCLUSION: These results improve our understanding of the relationship between R2* and the underlying microvascular properties. The findings will help to infer the cerebral metabolic rate of oxygen and cerebral blood volume from BOLD and perfusion MRI, respectively.

Interdatabase Variability in Cortical Thickness Measurements.

The phenomenon of cortical thinning with age has been well established; however, the measured rate of change varies between studies. The source of this variation could be image acquisition techniques including hardware and vendor specific differences. Databases are often consolidated to increase the number of subjects but underlying differences between these datasets could have undesired effects. We explore differences in cerebral cortex thinning between 4 databases, totaling 1382 subjects. We investigate several aspects of these databases, including: 1) differences between databases of cortical thinning rates versus age, 2) correlation of cortical thinning rates between regions for each database, and 3) regression bootstrapping to determine the effect of the number of subjects included. We also examined the effect of different databases on age prediction modeling. Cortical thinning rates were significantly different between databases in all 68 parcellated regions (ANCOVA, P < 0.001). Subtle differences were observed in correlation matrices and bootstrapping convergence. Age prediction modeling using a leave-one-out cross-validation approach showed varying prediction performance (0.64 < R2 < 0.82) between databases. When a database was used to calibrate the model and then applied to another database, prediction performance consistently decreased. We conclude that there are indeed differences in the measured cortical thinning rates between these large-scale databases.

Modeling hyperoxia-induced BOLD signal dynamics to estimate cerebral blood flow, volume and mean transit time.

A new method is proposed for obtaining cerebral perfusion measurements whereby blood oxygen level dependent (BOLD) MRI is used to dynamically monitor hyperoxia-induced changes in the concentration of deoxygenated hemoglobin in the cerebral vasculature. The data is processed using kinetic modeling to yield perfusion metrics, namely: cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). Ten healthy human subjects were continuously imaged with BOLD sequence while a hyperoxic (70% O2) state was interspersed with baseline periods of normoxia. The BOLD time courses were fit with exponential uptake and decay curves and a biophysical model of the BOLD signal was used to estimate oxygen concentration functions. The arterial input function was derived from end-tidal oxygen measurements, and a deconvolution operation between the tissue and arterial concentration functions was used to yield CBF. The venous component of the CBV was calculated from the ratio of the integrals of the estimated tissue and arterial concentration functions. Mean gray and white matter measurements were found to be: 61.6 ±â€¯13.7 and 24.9 ±â€¯4.0 ml 100 g-1 min-1 for CBF; 1.83 ±â€¯0.32 and 1.10 ±â€¯0.19 ml 100 g-1 for venous CBV; and 2.94 ±â€¯0.52 and 3.73 ±â€¯0.60 s for MTT, respectively. We conclude that it is possible to derive CBF, CBV and MTT metrics within expected physiological ranges via analysis of dynamic BOLD fMRI acquired during a period of hyperoxia.

Gas-free calibrated fMRI with a correction for vessel-size sensitivity.

Calibrated functional magnetic resonance imaging (fMRI) is a method to independently measure the metabolic and hemodynamic contributions to the blood oxygenation level dependent (BOLD) signal. This technique typically requires the use of a respiratory challenge, such as hypercapnia or hyperoxia, to estimate the calibration constant, M. There has been a recent push to eliminate the gas challenge from the calibration procedure using asymmetric spin echo (ASE) based techniques. This study uses simulations to better understand spin echo (SE) and ASE signals, analytical modelling to characterize the signal evolution, and in vivo imaging to validate the modelling. Using simulations, it is shown how ASE imaging generally underestimates M and how this depends on several parameters of the acquisition, including echo time and ASE offset, as well as the vessel size. This underestimation is the result of imperfect SE refocusing due to diffusion of water through the extravascular environment surrounding the microvasculature. By empirically characterizing this SE attenuation as an exponential decay that increases with echo time, we have proposed a quadratic ASE biophysical signal model. This model allows for the characterization and compensation of the SE attenuation if SE and ASE signals are acquired at multiple echo times. This was tested in healthy subjects and was found to significantly increase the estimates of M across grey matter. These findings show promise for improved gas-free calibration and can be extended to other relaxation-based imaging studies of brain physiology.

Transverse signal decay under the weak field approximation: Theory and validation.

PURPOSE: To derive an expression for the transverse signal time course from systems in the motional narrowing regime, such as water diffusing in blood. This was validated in silico and experimentally with ex vivo blood samples. METHODS: A closed-form solution (CFS) for transverse signal decay under any train of refocusing pulses was derived using the weak field approximation. The CFS was validated via simulations of water molecules diffusing in the presence of spherical perturbers, with a range of sizes and under various pulse sequences. The CFS was compared with more conventional fits assuming monoexponential decay, including chemical exchange, using ex vivo blood Carr-Purcell-Meiboom-Gill data. RESULTS: From simulations, the CFS was shown to be valid in the motional narrowing regime and partially into the intermediate dephasing regime, with increased accuracy with increasing Carr-Purcell-Meiboom-Gill refocusing rate. In theoretical calculations of the CFS, fitting for the transverse relaxation rate (R2 ) gave excellent agreement with the weak field approximation expression for R2 for Carr-Purcell-Meiboom-Gill sequences, but diverged for free induction decay. These same results were confirmed in the ex vivo analysis. CONCLUSION: Transverse signal decay in the motional narrowing regime can be accurately described analytically. This theory has applications in areas such as tissue iron imaging, relaxometry of blood, and contrast agent imaging. Magn Reson Med 80:341-350, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

The effect of dissolved oxygen on the relaxation rates of blood plasma: Implications for hyperoxia calibrated BOLD.

PURPOSE: To determine the contribution of paramagnetic dissolved oxygen in blood plasma to blood-oxygenation-level-dependent (BOLD) signal changes in hyperoxic calibrated BOLD studies. METHODS: Bovine blood plasma samples were prepared with partial pressures of oxygen (pO2 ) ranging from 110 to 600 mmHg. R1 , R2 , and R2* of the plasma with dissolved oxygen were measured using quantitative MRI sequences at 3 Tesla. Simulations were performed to predict the relative effects of dissolved oxygen and deoxyhemoglobin changes in hyperoxia calibrated BOLD. RESULTS: The relaxivities of dissolved oxygen in plasma were found to be r1,O2 =1.97 ± 0.09 ×10-4 s-1 mmHg-1 , r2,O2 =2.3 ± 0.7 ×10-4 s-1 mmHg-1 , and r2,O2* = 2.3 ± 0.7 ×10-4 s-1 mmHg-1 . Simulations predict that neither the transverse nor longitudinal relaxation rates of dissolved oxygen contribute significantly to the BOLD signal during hyperoxia. CONCLUSION: During hyperoxia, the increases in R2 and R2* of blood from dissolved oxygen in plasma are considerably less than the decreases in R2 and R2* from venous deoxyhemoglobin. R1 effects due to dissolved oxygen are also predicted to be negligible. As a result, dissolved oxygen in arteries should not contribute significantly to the hyperoxic calibrated BOLD signal. Magn Reson Med 76:1905-1911, 2016. © 2015 International Society for Magnetic Resonance in Medicine.

The effect of dissolved oxygen on the susceptibility of blood.

PURPOSE: It has been predicted that, during hyperoxia, excess O2 dissolved in arterial blood will significantly alter the blood's magnetic susceptibility. This would confound the interpretation of the hyperoxia-induced blood oxygenation level-dependent signal as arising solely from changes in deoxyhemoglobin. This study, therefore, aimed to determine how dissolved O2 affects the susceptibility of blood. THEORY AND METHODS: We present a comprehensive model for the effect of dissolved O2 on the susceptibility of blood and compare it with another recently published model, referred to here as the ideal gas model (IGM). For validation, distilled water and samples of bovine plasma were oxygenated over a range of hyperoxic O2 concentrations and their susceptibilities were determined using multiecho gradient echo phase imaging. RESULTS: In distilled water and plasma, the measured changes in susceptibility were very linear, with identical slopes of 0.062 ppb/mm Hg of O2. This change was dramatically less than previously predicted using the IGM and was close to that predicted by our model. The primary source of error in the IGM is the overestimation of the volume fraction occupied by dissolved O2. CONCLUSION: Under most physiological conditions, the susceptibility of dissolved O2 can be disregarded in MRI studies employing hyperoxia.