Quantitative BOLD: mapping of human cerebral deoxygenated blood volume and oxygen extraction fraction: default state.

Since Ogawa et al. (Proc Natl Acad Sci USA 1990;87:9868-9872) made the fundamental discovery of blood oxygenation level-dependent (BOLD) contrast in MRI, most efforts have been directed toward the study of dynamic BOLD (i.e., temporal changes in the MRI signal during changes in brain activity). However, very little progress has been made in elucidating the nature of BOLD contrast during the resting or baseline state of the brain, which is important for understanding normal human performance because it accounts for most of the enormous energy budget of the brain. It is also crucial for deciphering the consequences of baseline-state impairment by cerebral vascular diseases. The objective of this study was to develop a BOLD MR-based method that allows quantitative evaluation of tissue hemodynamic parameters, such as the blood volume, deoxyhemoglobin concentration, and oxygen extraction fraction (OEF). The proposed method, which we have termed quantitative BOLD (qBOLD), is based on an MR signal model that incorporates prior knowledge about brain tissue composition and considers signals from gray matter (GM), white matter (WM), cerebrospinal fluid (CSF), and blood. A 2D gradient-echo sampling of spin-echo (GESSE) pulse sequence is used for the acquisition of the MRI signal. The method is applied to estimate the hemodynamic parameters of the normal human brain in the baseline state.     

Optimization strategies for evaluation of brain hemodynamic parameters with qBOLD technique

Quantitative blood oxygenation level dependent technique provides an MRI‐based method to measure tissue hemodynamic parameters such as oxygen extraction fraction and deoxyhemoglobin‐containing (veins and prevenous part of capillaries) cerebral blood volume fraction. It is based on a theory of MR signal dephasing in the presence of blood vessel network and experimental method—gradient echo sampling of spin echo previously proposed and validated on phantoms and animals. In vivo human studies also demonstrated feasibility of this approach but also recognized that obtaining reliable results requires high signal‐to‐noise ratio in the data. In this paper, we analyze in detail the uncertainties of the quantitative blood oxygenation level dependent parameter estimates in the framework of the Bayesian probability theory, namely, we examine how the estimated parameters oxygen extraction fraction and deoxygenated cerebral blood volume fraction depend on their “true values,” signal‐to‐noise ratio, and data sampling strategies. On the basis of this analysis, we develop strategies for optimization of the quantitative blood oxygenation level dependent technique for deoxygenated cerebral blood volume and oxygen extraction fraction evaluation. In particular, it is demonstrated that the use of gradient echo sampling of spin echo sequence allows substantial decrease of measurement errors as the data are acquired on both sides of spin echo. We test our theory on phantom mimicking the structure of blood vessel network. A 3D gradient echo sampling of spin echo pulse sequence is used for the acquisition of the MRI signal that was subsequently analyzed by Bayesian Application Software. The experimental results demonstrated a good agreement with theoretical predictions. Magn Reson Med 69:1034–1043, 2013. © 2012 Wiley Periodicals, Inc.     

Quantitative BOLD: the effect of diffusion

Purpose:

To make the quantitative blood oxygenation level‐dependent (qBOLD) method more suitable for clinical application by accounting for proton diffusion and reducing acquisition times.

Materials and Methods:

Monte Carlo methods are used to simulate the signal from diffusing protons in the presence of a blood vessel network. A diffusive qBOLD model was then constructed using a lookup table of the results. Acquisition times are reduced by parallel imaging and by employing an integrated fieldmapping method, rather than running an additional sequence.

Results:

The addition of diffusion to the model is shown to have a significant impact on predicted signal formation. This is found to affect all fitted parameters when the model is applied to real data. Parallel imaging and integrated fieldmapping allowed the GESSE (gradient echo sampling of a spin echo) acquisition to be made in less than 10 minutes while maintaining high signal‐to‐noise ratio (SNR).

Conclusion:

By incorporating integrated field mapping and parallel imaging techniques, GESSE data were acquired within clinically acceptable acquisition times. These data fit closely to the diffusive qBOLD model, providing more realistic and robust measurements of T₂ and blood oxygenation than the static model. J. Magn. Reson. Imaging 2010;32:953–961. © 2010 Wiley‐Liss, Inc.     

Validation of quantitative estimation of tissue oxygen extraction fraction and deoxygenated blood volume fraction in phantom and in vivo experiments by using MRI

The blood oxygenation level dependent signal of cerebral tissue can be theoretically derived using a network model formed by randomly oriented infinitely long cylinders. The validation of this model by phantom and in vivo experiments is still an object of research. A network phantom was constructed of solid polypropylene strings immersed in silicone oil, which essentially eliminated the effect of spin diffusion. The volume fraction and magnetic property of the string network was predetermined by independent methods. Ten healthy volunteers were measured for in vivo demonstration. The gradient echo sampled spin echo signal was evaluated with the cylinder network model. We found a strong interdependency between the two network characterizing parameters deoxygenated blood volume and oxygen extraction fraction. Here, different sets of deoxygenated blood volume/oxygen extraction fraction values were able to describe the measured signal equally well. However, by setting one parameter constant to a predetermined value, reasonable estimates of the other parameter were obtained. The same behavior was found for the in vivo demonstration. The signal theory of the cylinder network was validated by a well‐characterized phantom. However, the found interdependency that was found between deoxygenated blood volume and oxygen extraction fraction requires an independent estimation of one variable to determine reliable values of the other parameter. Magn Reson Med 63:910–921, 2010. © 2010 Wiley‐Liss, Inc.     

Experimental measurement of extravascular parenchymal BOLD effects and tissue oxygen extraction fractions using multi‐echo VASO fMRI at 1.5 and 3.0 T

Quantitative interpretation of BOLD fMRI signal changes has predominantly employed empirical models for the whole parenchyma and a calibration step is usually needed to determine the physiological parameters during activation. Although analytical expressions are available for the extravascular and intravascular components of the BOLD effects, it is difficult to experimentally separate tissue from blood signal contributions at the low magnetic fields in which most fMRI studies are performed. Even if this can be achieved, an additional problem that remains is the separation of two types of extravascular BOLD effects, namely those around microvasculature (in the parenchyma close to the site of activation) and those around draining macrovasculature (e.g., in tissue and CSF more remote from the site of activation). In the recently developed vascular space occupancy technique, blood signals are nulled and the activations are localized predominantly in gray matter, allowing experimental measurement of parenchymal extravascular R₂* and its changes accompanying activation. When comparing such data with total parenchymal R₂* changes in BOLD fMRI, the extravascular fractions were found to be 47 ± 7% (mean ± SEM, n = 4) and 67 ± 6% at 1.5 and 3.0 T, respectively, in line with expectations that intravascular BOLD contributions are reduced at higher field. The present approach provides a noninvasive means to determine parenchymal oxygen extraction fraction (OEF) in situ. During visual stimulation, OEF values measured at 1.5 and 3.0 T were in good agreement, giving 0.23 ± 0.01 and 0.21 ± 0.01, respectively. Magn Reson Med 53:808–816, 2005. © 2005 Wiley‐Liss, Inc.     

Improvement of hyperemic myocardial oxygen extraction fraction estimation by a diffusion‐prepared sequence

Myocardial oxygen extraction fraction (OEF) during hyperemia can be estimated using a double‐inversion‐recovery‐prepared T₂‐weighted black‐blood sequence. Severe irregular electrocardiogram (ECG) triggering due to elevated heart rate and/or arrhythmias may render it difficult to adequately suppress the flowing left ventricle blood signal and thus potentially cause errors in the estimates of myocardial OEF. Thus, the goal of this study was to evaluate another black‐blood technique, a diffusion‐weighted‐prepared turbo spin echo sequence for its ability to determine regional myocardial OEF during hyperemia. Control dogs and dogs with acute coronary artery stenosis were imaged with both the double‐inversion‐recovery‐ and diffusion‐weighted‐prepared turbo spin echo sequences at rest and during either dipyridamole or dobutamine hyperemia. Validation of MRI OEF estimates was performed using blood sampling from the artery and coronary sinus in control dogs. The two methods showed comparable correlations with blood sampling results (R² = 0.9). Similar OEF estimations for all dogs were observed, except for the group of dogs with severe coronary stenosis during dobutamine stress. In these dogs, the diffusion‐weighted method provided more physiologically reasonable OEF (hyperemic OEF = 0.75 ± 0.08 versus resting OEF of 0.6) than the double‐inversion‐recovery method (hyperemic OEF = 0.56 ± 0.10). Diffusion‐weighted preparation may be a valuable alternative for more accurate oxygenation measurements during irregular ECG‐triggering. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Influence of residual oxygen-15-labeled carbon monoxide radioactivity on cerebral blood flow and oxygen extraction fraction in a dual-tracer autoradiographic method

Objective  Cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO₂), oxygen extraction fraction (OEF), and cerebral blood volume (CBV) are quantitatively measured with PET with ¹⁵O gases. Kudomi et al. developed a dual tracer autoradiographic (DARG) protocol that enables the duration of a PET study to be shortened by sequentially administrating ¹⁵O₂ and C¹⁵O₂ gases. In this protocol, before the sequential PET scan with ¹⁵O₂ and C¹⁵O₂ gases (¹⁵O₂–C¹⁵O₂ PET scan), a PET scan with C¹⁵O should be preceded to obtain CBV image. C¹⁵O has a high affinity for red blood cells and a very slow washout rate, and residual radioactivity from C¹⁵O might exist during a ¹⁵O₂–C¹⁵O₂ PET scan. As the current DARG method assumes no residual C¹⁵O radioactivity before scanning, we performed computer simulations to evaluate the influence of the residual C¹⁵O radioactivity on the accuracy of measured CBF and OEF values with DARG method and also proposed a subtraction technique to minimize the error due to the residual C¹⁵O radioactivity. Methods  In the simulation, normal and ischemic conditions were considered. The ¹⁵O₂ and C¹⁵O₂ PET count curves with the residual C¹⁵O PET counts were generated by the arterial input function with the residual C¹⁵O radioactivity. The amounts of residual C¹⁵O radioactivity were varied by changing the interval between the C¹⁵O PET scan and ¹⁵O₂–C¹⁵O₂ PET scan, and the absolute inhaled radioactivity of the C¹⁵O gas. Using the simulated input functions and the PET counts, the CBF and OEF were computed by the DARG method. Furthermore, we evaluated a subtraction method that subtracts the influence of the C¹⁵O gas in the input function and PET counts. Results  Our simulations revealed that the CBF and OEF values were underestimated by the residual C¹⁵O radioactivity. The magnitude of this underestimation depended on the amount of C¹⁵O radioactivity and the physiological conditions. This underestimation was corrected by the subtraction method. Conclusions  This study showed the influence of C¹⁵O radioactivity in DARG protocol, and the magnitude of the influence was affected by several factors, such as the radioactivity of C¹⁵O, and the physiological condition.     

Application of sensitivity-encoded echo-planar imaging for blood oxygen level-dependent functional brain imaging.

The benefits of sensitivity-encoded (SENSE) echo-planar imaging (EPI) for functional MRI (fMRI) based on blood oxygen level-dependent (BOLD) contrast were quantitatively investigated at 1.5 T. For experiments with 3.4 x 3.4 x 4.0 mm(3) resolution, SENSE allowed the single-shot EPI image acquisition duration to be shortened from 24.1 to 12.4 ms, resulting in a reduced sensitivity to geometric distortions and T(*)(2) blurring. Finger-tapping fMRI experiments, performed on eight normal volunteers, showed an overall 18% loss in t-score in the activated area, which was substantially smaller than expected based on the image signal-to-noise ratio (SNR) and g-factor, but similar to the loss predicted by a model that takes physiologic noise into account.     

Cerebral oxygen extraction fraction and cerebral venous blood volume measurements using MRI: effects of magnetic field variation.

The presence of magnetic background field inhomogeneity (DeltaB) may confound quantitative measures of cerebral venous blood volume (vCBV) and cerebral oxygen extraction fraction (MR_OEF) with T2*-based methods. The goal of this study was to correct its effect and obtain more accurate estimates of vCBV and MR_OEF. A 3D high-resolution gradient echo sequence was employed to obtain DeltaB maps by two algorithms. The DeltaB maps were then used to recover the signal loss in images acquired by a 2D multiecho gradient echo / spin echo sequence. Finally, both quantitative estimates of MR_OEF and vCBV were obtained from the DeltaB- corrected 2D multiecho gradient echo / spin echo images. A total of 12 normal subjects were studied. An overestimated vCBV was observed in the brain (4.29 +/- 0.78%) prior to DeltaB correction, while the measured vCBV was substantially reduced after DeltaB correction. Whole brain vCBV of 2.97 +/- 0.44% and 2.68 +/- 0.47% were obtained by the two different DeltaB correction methods, in excellent agreement with the reported results in the literature. Furthermore, when MR_OEF was compared with and without DeltaB correction, no significant differences (P = 0.467) were observed. The ability to simultaneously obtain vCBV and MR_OEF noninvasively may have profound clinical implications for the studies of cerebrovascular disease.     

Theory and generalization of Monte Carlo models of the BOLD signal source

The dependency of the blood oxygenation level dependent (BOLD) signal on underlying hemodynamics is not well understood. Building a forward biophysical model of this relationship is important for the quantitative estimation of the hemodynamic changes and neural activity underlying functional magnetic resonance imaging (fMRI) signals. We have developed a general model of the BOLD signal which can model both intra- and extravascular signals for an arbitrary tissue model across a wide range of imaging parameters. The model of the BOLD signal was instantiated as a look-up-table (LuT), and was verified against concurrent fMRI and optical imaging measurements of activation induced hemodynamics.     

EPI-BOLD fMRI of human motor cortex at 1.5 T and 3.0 T: sensitivity dependence on echo time and acquisition bandwidth

PURPOSE: To investigate the sensitivity dependence of BOLD functional imaging on MRI acquisition parameters in motor stimulation experiments using a finger tapping paradigm. MATERIALS AND METHODS: Gradient-echo echo-planar fMRI experiments were performed at 1.5 T and 3.0 T with varying acquisition echo time and bandwidth, and with a 4 mm isotropic voxel size. To analyze the BOLD sensitivity, the relative contributions of BOLD signal amplitude and thermal and physiologic noise sources were evaluated, and statistical t-scores were compared in the motor area. RESULTS: At 1.5 T, the number of activated pixels and the average t-score showed a relatively broad optimum over a TE range of 60-160 msec. At 3.0 T, an optimum range was observed between TEs of 30-130 msec. Averaged over nine subjects, maxima in the number of pixels and t-score values were 59% and 18% higher at 3.0 T than at 1.5 T, respectively, an improvement that was lower than the observed 100% to 110% increase in signal-to-noise ratio at 3.0 T. CONCLUSION: The somewhat disappointing increase in t-scores at 3.0 T was attributed to the increased contribution of physiologic noise at the higher field strength under the given experimental conditions. At both field strengths, reducing the effective image acquisition bandwidth from 35 to 17 Hz per pixel did not affect or only marginally affect the BOLD sensitivity.     

Functional magnetic resonance imaging of the human brain based on signal enhancement by extravascular protons (SEEP fMRI).

Functional magnetic resonance imaging (fMRI) studies of the human brain were carried out at 3 Tesla to investigate an fMRI contrast mechanism that does not arise from the blood oxygen-level dependent (BOLD) effect. This contrast mechanism, signal enhancement by extravascular protons (SEEP), involves only proton-density changes and was recently demonstrated to contribute to fMRI signal changes in the spinal cord. In the present study it is hypothesized that SEEP fMRI can be used to identify areas of neuronal activity in the brain with as much sensitivity and precision as can be achieved with BOLD fMRI. A detailed analysis of the areas of activity, signal intensity time courses, and the contrast-to-noise ratio (CNR), is also presented and compared with the BOLD fMRI results. Experiments were carried out with subjects performing a simple finger-touching task, or observing an alternating checkerboard pattern. Data were acquired using a conventional BOLD fMRI method (gradient-echo (GE) EPI, TE = 30 ms), a conventional method with reduced BOLD sensitivity (GE-EPI, TE = 12 ms), and SEEP fMRI (spin-echo (SE) EPI, TE = 22 ms). The results of this study demonstrate that SEEP fMRI may provide better spatial localization of areas of neuronal activity, and a higher CNR than conventional BOLD fMRI, and has the added benefit of lower sensitivity to field inhomogeneities.     

Bayesian technique for investigating linearity in event-related BOLD fMRI.

Event-related BOLD fMRI data is modeled as a linear time-invariant system. Together with Bayesian inference techniques, a statistical test is developed for rigorously detecting linearity/nonlinearity in the BOLD response system. The test is applied to data collected from eight subjects using an event-related paradigm with a switching checkerboard as the visual stimulus. Analyzed as a group, the results clearly find the response to be nonlinear. When each subject is analyzed individually, however, the results are predominantly nonlinear, but there is some evidence to suggest that there may be a crossover from a linear to a nonlinear regime and vice versa. This could be important when estimating physiological parameters for individuals. Additionally, estimates of the hemodynamic response function and corresponding response were obtained, but there was no consistent appearance of a poststimulus undershoot in the event-related BOLD response.