Quantitative evaluation of oxygenation in venous vessels using T2‐Relaxation‐Under‐Spin‐Tagging MRI

Noninvasive measurement of cerebral venous oxygenation can serve as a tool for better understanding fMRI signals and for clinical evaluation of brain oxygen homeostasis. In this study a novel technique, T2‐Relaxation‐Under‐Spin‐Tagging (TRUST) MRI, is developed to estimate oxygenation in venous vessels. This method uses the spin labeling principle to automatically isolate pure blood signals from which T2 relaxation times are determined using flow‐insensitive T2‐preparation pulses. The blood T2 is then converted to blood oxygenation using a calibration plot. In vivo experiments gave a baseline venous oxygenation of 64.8 ± 6.3% in sagittal sinus in healthy volunteers (n = 24). Reproducibility studies demonstrated that the standard deviation across trials was 2.0 ± 1.1%. The effects of repetition time and inversion time selections were investigated. The TRUST technique was further tested using various physiologic challenges. Hypercapnia induced an increase in venous oxygenation by 13.8 ± 1.1%. On the other hand, caffeine ingestion resulted in a decrease in oxygenation by 7.0 ± 1.8%. Contrast agent infusion (Gd‐DTPA, 0.1 mmol/kg) reduced venous blood T2 by 11.2 ms. The results of this study show that TRUST MRI is a useful technique for quantitative assessment of blood oxygenation in the brain. Magn Reson Med 60:357–363, 2008. © 2008 Wiley‐Liss, Inc.     

Comparison of BOLD and direct‐MR neuronal detection (DND) in the human visual cortex at 3T

Direct‐MR neuronal detection (DND) of transient magnetic fields has recently been investigated as a novel imaging alternative to the conventional BOLD functional MRI (fMRI) technique. However, there remain controversial issues and debate surrounding this methodology, and this study attempts clarification by comparing BOLD responses in the human visual system with those of DND. BOLD relies on indirectly measuring blood oxygenation and flow changes as a result of neuronal activity, whereas the putative DND method is based on the hypothesis that the components of the in vivo neuronal magnetic fields, which lie parallel to the B₀ field, can potentially modulate the MR signal, thus providing a means of direct detection of nerve impulses. Block paradigms of checkerboard patterns were used for visual stimulation in both DND and BOLD experiments, allowing detection based on different frequency responses. This study shows colocalization of some voxels with slow BOLD responses and putative fast DND responses using General Linear Model (GLM) analysis. Frequency spectra for the activated voxel cluster are also shown for both stimulated and control data. The mean percentage signal change for the DND responses is 0.2%, corresponding to a predicted neuronal field of 0.14 nT. Magn Reson Med 60:1147–1154, 2008. © 2008 Wiley‐Liss, Inc.     

Noninvasive quantification of whole‐brain cerebral metabolic rate of oxygen (CMRO2) by MRI

Cerebral metabolic rate of oxygen (CMRO₂) is an important marker for brain function and brain health. Existing techniques for quantification of CMRO₂ with positron emission tomography (PET) or MRI involve special equipment and/or exogenous agents, and may not be suitable for routine clinical studies. In the present study, a noninvasive method is developed to estimate whole‐brain CMRO₂ in humans. This method applies phase‐contrast MRI for quantitative blood flow measurement and T₂‐relaxation‐under‐spin‐tagging (TRUST) MRI for venous oxygenation estimation, and uses the Fick principle of arteriovenous difference for the calculation of CMRO₂. Whole‐brain averaged CMRO₂ values in young, healthy subjects were 132.1 ± 20.0 μmol/100 g/min, in good agreement with literature reports using PET. Various acquisition strategies for phase‐contrast and TRUST MRI were compared, and it was found that nongated phase‐contrast and sagittal sinus (SS) TRUST MRI were able to provide the most efficient and accurate estimation of CMRO₂. In addition, blood flow and venous oxygenation were found to be positively correlated across subjects. Owing to the noninvasive nature of this method, it may be a convenient and useful approach for assessment of brain metabolism in brain disorders as well as under various physiologic conditions. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Concurrent fMRI and optical measures for the investigation of the hemodynamic response function.

Functional magnetic resonance imaging (fMRI) signal variations are based on a combination of changes in cerebral blood flow (CBF) and volume (CBV), and blood oxygenation. We investigated the relationship between these hemodynamic parameters in the rodent barrel cortex by performing fMRI concurrently with laser Doppler flowmetry (LDF) or optical imaging spectroscopy (OIS), following whisker stimulation and hypercapnic challenge. A difference between the positions of the maximum blood oxygenation level-dependent (BOLD) and CBV changes was observed in coronal fMRI maps, with the BOLD region being more superficial. A 6.5% baseline blood volume fraction in this superficial region dropped to 4% in deeper cortical layers (corresponding to total hemoglobin baseline volumes Hbt0 = 110 microM and 67 microM, respectively), as inferred from maps of deltaR2*. Baseline volume profiles were used to parameterize the Monte Carlo simulations (MCS) to interpret the 2D OIS. From this it was found that the optical blood volume measurements (i.e., changes in total hemoglobin) equated with CBV-MRI measurements when the MRI data were taken from superficial cortical layers. Optical measures of activation showed a good spatial overlap with fMRI measurements taken in the same plane (covering the right hemisphere surface). Changes in CBV and CBF followed the scaling relationship CBV = CBF(alpha), with mean alpha = 0.38 +/- 0.06.     

Calibration and validation of TRUST MRI for the estimation of cerebral blood oxygenation

Recently, a T₂‐Relaxation‐Under‐Spin‐Tagging (TRUST) MRI technique was developed to quantitatively estimate blood oxygen saturation fraction (Y) via the measurement of pure blood T₂. This technique has shown promise for normalization of fMRI signals, for the assessment of oxygen metabolism, and in studies of cognitive aging and multiple sclerosis. However, a human validation study has not been conducted. In addition, the calibration curve used to convert blood T₂ to Y has not accounted for the effects of hematocrit (Hct). In this study, we first conducted experiments on blood samples under physiologic conditions, and the Carr‐Purcell‐Meiboom‐Gill T₂ was determined for a range of Y and Hct values. The data were fitted to a two‐compartment exchange model to allow the characterization of a three‐dimensional plot that can serve to calibrate the in vivo data. Next, in a validation study in humans, we showed that arterial Y estimated using TRUST MRI was 0.837 ± 0.036 (N=7) during the inhalation of 14% O2, which was in excellent agreement with the gold‐standard Y values of 0.840 ± 0.036 based on Pulse‐Oximetry. These data suggest that the availability of this calibration plot should enhance the applicability of T₂‐Relaxation‐Under‐Spin‐Tagging MRI for noninvasive assessment of cerebral blood oxygenation. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.     

Functional MRI with magnetization transfer effects: Determination of BOLD and arterial blood volume changes

The primarily intravascular magnetization transfer (MT)‐independent changes in functional MRI (fMRI) can be separated from MT‐dependent changes. This intravascular component is dominated by an arterial blood volume change (ΔCBV_a) term whenever venous contributions are minimized. Stimulation‐induced ΔCBV_a can therefore be measured by a fit of signal changes to MT ratio. MT‐varied fMRI data were acquired in 13 isoflurane‐anesthetized rats during forepaw stimulation at 9.4T to simultaneously measure blood‐oxygenation‐level–dependent (BOLD) and ΔCBV_a response in somatosensory cortical regions. Transverse relaxation rate change (ΔR₂) without MT was –0.43 ± 0.15 s^?1, and MT ratio decreased during stimulation. ΔCBV_a was 0.46 ± 0.15 ml/100 g, which agrees with our previously‐presented MT‐varied arterial‐spin‐labeled data (0.42 ± 0.18 ml/100 g) in the same animals and also correlates with ΔR₂ without MT. Simulations show that ΔCBV_a quantification errors due to potential venous contributions are small for our conditions. Magn Reson Med 60:1518–1523, 2008. © 2008 Wiley‐Liss, Inc.     

Functional arterial spin labeling: Optimal sequence duration for motor activation mapping in clinical practice

Purpose:

To determine the minimal optimal functional arterial spin labeling (fASL) sequence duration allowing steady and reproducible motor activation mapping.

Materials and Methods:

Three magnetic resonance imaging (MRI) sessions including fASL and blood oxygenation level‐dependent (BOLD) functional MRI (fMRI) sequences were performed on 12 healthy subjects at 3T with a 32‐channel coil. The raw 7‐minute fASL sequence was truncated to obtain six fASL sequences with durations ranging from 1–6 minutes. All the resulting fASL activations were compared between themselves and with both the 7‐minute fASL and BOLD activations. Quantitative parameters assessed activation location (activated volume, barycenter, and distance between barycenters), activation quantification (activation‐related cerebral blood flow), and intraindividual reproducibility across fMRI sessions. The statistical analysis was based on analysis of variance (ANOVA) and Tukey's multiple comparisons.

Results:

Four‐minute fASL achieved steady location and quantification of activation with the activated volume corresponding to 81% of the 7‐minute fASL volume and a barycenter located 1.2 mm from the 7‐minute fASL barycenter and 3.0 mm from the BOLD fMRI barycenter. Four‐minute fASL reproducibility was high and statistically equivalent to 7‐minute values.

Conclusion:

A 4‐minute fASL sequence is thus a reliable tool for motor activation mapping and suitable for use in clinical practice. J. Magn. Reson. Imaging 2012; 36:1435–1444. © 2012 Wiley Periodicals, Inc.     

Functional brain imaging using a blood oxygenation sensitive steady state.

Blood oxygenation level dependent (BOLD) functional MRI (fMRI) is an important method for functional neuroimaging that is sensitive to changes in blood oxygenation related to brain activation. While BOLD imaging has good spatial coverage and resolution relative to other neuroimaging methods (such as positron emission tomography (PET)), it has significant limitations relative to other MRI techniques, including poor spatial resolution, low signal levels, limited contrast, and image artifacts. These limitations derive from the coupling of BOLD functional contrast to sources of image degradation. This work presents an alternative method for fMRI that may over-come these limitations by establishing a blood oxygenation sensitive steady-state (BOSS) that inverts the signal from deoxygenated blood relative to the water signal. BOSS fMRI allows the imaging parameters to be optimized independently of the functional contrast, resulting in fewer image artifacts and higher signal-to-noise ratio (SNR). In addition, BOSS fMRI has greater functional contrast than BOLD. BOSS fMRI requires careful shimming and multiple acquisitions to obtain a precise alignment of the magnetization to the SSFP frequency response.     

Functional MRI bold signal coincides with electrical activity in the rat whisker barrels

Functional MRI (fMRI) provides a noninvasive method for mapping brain functional activity based on blood oxygenation level dependent (BOLD) image contrast that is primarily due to localized increases in perfusion. Recently, Malonek and Grinvald (Science 272:551–554, 1996) suggested that during sustained functional activation, the increases in perfusion were spread over a much larger area than the localized electrical activity. In this study, it is demonstrated that the spatial distribution of the BOLD fMRI signal during sustained stimulation of rat whiskers has the same spatial pattern and dimension as that of neuronal electrical activity in the rat whisker barrels.     

Physiological origin of low‐frequency drift in blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI)

We investigated the biophysical mechanism of low‐frequency drift in blood‐oxygen‐level‐dependent (BOLD) functional magnetic resonance imaging (fMRI) (0.00–0.01 Hz), by exploring its spatial distribution, dependence on imaging parameters, and relationship with task‐induced brain activation. Cardiac and respiratory signals were concurrently recorded during MRI scanning and subsequently removed from MRI data. It was found that the spatial distribution of low‐frequency drifts in human brain followed a tissue‐specific pattern, with greater drift magnitude in the gray matter than in white matter. In gray matter, the dependence of drift magnitudes on TE was similar to that of task‐induced BOLD signal changes, i.e., the absolute drift magnitude reached the maximum when TE approached T whereas relative drift magnitude increased linearly with TE. By systematically varying the flip angle, it was found that drift magnitudes possessed a positive dependence on image intensity. In phantom experiments, the observed drift was not only much smaller than that of human brain, but also showed different dependence on TE and flip angle. In fMRI studies with visual stimulation, a strong positive correlation between drift effects at baseline and task‐induced BOLD signal changes was observed both across subjects and across activated pixels within individual participants. We further demonstrated that intrinsic, physiological drift effects are a major component of the spontaneous fluctuations of BOLD fMRI signal within the frequency range of 0.0–0.1 Hz. Our study supports brain physiology, as opposed to scanner instabilities or cardiac/respiratory pulsations, as the main source of low‐frequency drifts in BOLD fMRI. Magn Reson Med 61, 2009. © 2009 Wiley‐Liss, Inc.     

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.     

Anesthetic effects on regional CBF,BOLD, and the coupling between task‐induced changes in CBF and BOLD: An fMRI study in normal human subjects

Functional MR imaging was performed in sixteen healthy human subjects measuring both regional cerebral blood flow (CBF) and blood oxygen level dependent (BOLD) signal when visual and auditory stimuli were presented to subjects in the presence or absence of anesthesia. During anesthesia, 0.25 mean alveolar concentration (MAC) sevoflurane was administrated. We found that low‐dose sevoflurane decreased the task‐induced changes in both BOLD and CBF. Within the visual and auditory regions of interest inspected, both baseline CBF and the task‐induced changes in CBF decreased significantly during anesthesia. Low‐dose sevoflurane significantly altered the task‐induced CBF‐BOLD coupling; for a unit change of CBF, a larger change in BOLD was observed in the anesthesia condition than in the anesthesia‐free condition. Low‐dose sevoflurane was also found to have significant impact on the spatial nonuniformity of the task‐induced coupling. The alteration of task‐induced CBF‐BOLD coupling by low‐dose sevoflurane introduces ambiguity to the direct interpretation of functional MRI (fMRI) data based on only one of the indirect measures—CBF or BOLD. Our observations also indicate that the manipulation of the brain with an anesthetic agent complicates the model‐based quantitative interpretation of fMRI data, in which the relative task‐induced changes in oxidative metabolism are calculated by means of a calibrated model given the relative changes in the indirect vascular measures, usually CBF and BOLD. Magn Reson Med 60:987–996, 2008. © 2008 Wiley‐Liss, Inc.     

Titration of the BOLD effect: separation and quantitation of blood volume and oxygenation changes in the human cerebral cortex during neuronal activation and ferumoxide infusion.

Most functional magnetic resonance imaging (fMRI) techniques are sensitive to susceptibility variations and rely on the change in blood oxygenation level in response to neuronal activation (BOLD). The BOLD effect is accompanied by a change in cerebral blood flow (rCBF) and cerebral blood volume (rCBV). Intravascular contrast agents, such as magnetite nanoparticles, can be used to measure changes in rCBV. A new measuring protocol has been developed that enables the separate quantification of changes in blood volume and oxygenation levels. A combination of alternating acoustic stimulation blocks and infusion of a superparamagnetic contrast agent offers the possibility to disentangle the competing influences of oxygenation and blood volume changes. Serial blood sampling during infusion was used to assess the actual contrast agent concentration during infusion in order to calculate absolute blood volume changes during neuronal resting and activation states. Magn Reson Med 42:829-836, 1999.     

Characterization of effects of mean arterial blood pressure induced by cocaine and cocaine methiodide on BOLD signals in rat brain.

A total of 45 male Sprague-Dawley rats were employed to determine whether cocaine or cocaine methiodide (CM) administration can induce a significant increase in mean arterial blood pressure (MABP) in rats, and whether such an increase in MABP can produce a global increase in blood oxygenation level-dependent (BOLD) contrast in the rat brain detectable by functional magnetic resonance imaging (fMRI). Cocaine methiodide is a quaternary derivative of cocaine that shares the same cardiovascular effects of cocaine, but does not penetrate the blood-brain barrier (BBB). Experimental results demonstrated that both CM (with doses of 2.5 and 7.5 mg/kg) and cocaine (with doses of 1.25 and 5.0 mg/kg) can induce a significant MABP change (30-80%). It was found that CM can only produce scattered, weak, and transient BOLD signals in a few voxels of the rat brain, and that these MABP-induced BOLD signals are not dose-dependent. In contrast, the administration of cocaine induced dose-dependent biphasic BOLD signals that were consistent with pharmacologically-induced cerebral vascular constriction and neuronal activity in the mesolimbic systems of the rat brain. The potential confounding factor of the MABP changes had little effect on the interpretation of drug-induced BOLD signal changes. These results confirm that the BOLD-weighted fMRI method can be extended to map drug-induced neuronal activity.     

CBF, BOLD, CBV, and CMRO(2) fMRI signal temporal dynamics at 500-msec resolution

PURPOSE: To investigate the temporal dynamics of blood oxygenation level-dependent (BOLD), cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate of oxygen (CMRO(2)) changes due to forepaw stimulation with 500-msec resolution in a single setting. MATERIALS AND METHODS: Forepaw stimulation and hypercapnic challenge on rats were studied. CBF and BOLD functional MRI (fMRI) were measured using the pseudo-continuous arterial spin-labeling technique at 500-msec resolution. CBV fMRI was measured using monocrystalline iron-oxide particles following CBF and BOLD measurements in the same animals. CMRO(2) change was estimated via the biophysical BOLD model with hypercapnic calibration. Percent changes and onset times were analyzed for the entire forepaw somatosensory cortices and three operationally defined cortical segments, denoted Layers I-III, IV-V, and VI. RESULTS: BOLD change was largest in Layers I-III, whereas CBF, CBV, and CMRO(2) changes were largest in Layers IV-V. Among all fMRI signals in all layers, only the BOLD signal in Layers I-III showed a poststimulus undershoot. CBF and CBV dynamics were similar. Closer inspection showed that CBV increased slightly first (P < 0.05), but was slow to peak. CBF increased second, but peaked first. BOLD significantly lagged both CBF and CBV (P < 0.05). CONCLUSION: This study provides important temporal dynamics of multiple fMRI signals at high temporal resolution in a single setting.     

Validation of oxygen extraction fraction measurement by qBOLD technique

Measurement of brain tissue oxygen extraction fraction (OEF) in both baseline and functionally activated states can provide important information on brain functioning in health and disease. The recently proposed quantitative BOLD (qBOLD) technique is MRI‐based and provides a regional in vivo OEF measurement (He and Yablonskiy, MRM 2007, 57:115–126). It is based on a previously developed analytical BOLD model and incorporates prior knowledge about the brain tissue composition including the contributions from grey matter, white matter, cerebrospinal fluid, interstitial fluid and intravascular blood. The qBOLD model also allows for the separation of contributions to the BOLD signal from OEF and the deoxyhemoglobin containing blood volume (DBV). The objective of this study is to validate OEF measurements provided by the qBOLD approach. To this end we use a rat model and compare qBOLD OEF measurements against direct measurements of the blood oxygenation level obtained from venous blood drawn directly from the superior sagittal sinus. The cerebral venous oxygenation level of the rat was manipulated by utilizing different anestheisa methods. The study demonstrates a very good agreement between qBOLD approach and direct measurements. Magn Reson Med 60:882–888, 2008. © 2008 Wiley‐Liss, Inc.     

Quantifying the blood oxygenation level dependent effect in cerebral blood volume-weighted functional MRI at 9.4T.

In cerebral blood volume (CBV)-weighted functional MRI (fMRI) employing superparamagnetic contrast agent, iron dose and blood oxygenation level dependent (BOLD) contamination are two important issues for experimental design and CBV quantification. Both BOLD and CBV-weighted fMRI are based upon the susceptibility effect, to which spin-echo and gradient-echo sequences have different sensitivities. In the present study, CBV-weighted fMRI was conducted using spin-echo and gradient-echo sequences at 9.4T by systematically changing the doses of contrast agent. Results suggest that BOLD contamination is a significant component in CBV-weighted fMRI at high field, particularly when relatively low dose of contrast agent is administered. A mathematical model was developed to quantify the extravascular (EV) BOLD effect. With a TE of 35 ms, the EV BOLD effect was estimated to account for 76+/-12% of the observed spin-echo fMRI signal at 9.4T. These data suggest that correcting BOLD effect may be necessary for accurately quantifying activation-induced CBV changes at high field.     

Differences in the BOLD fMRI response to direct and indirect cortical stimulation in the rat.

Functional MRI (fMRI) exploits a relationship between neuronal activity, metabolism, and cerebral blood flow to functionally map the brain. We have developed a model of direct cortical stimulation in the rat that can be combined with fMRI and used to compare the hemodynamic responses to direct and indirect cortical stimulation. Unilateral electrical stimulation of the rat hindpaw motor cortex, via stereotaxically positioned carbon-fiber electrodes, yielded blood oxygenation level-dependent (BOLD) fMRI signal changes in both the stimulated and homotypic contralateral motor cortices. The maximal signal intensity change in both cortices was similar (stimulated = 3.7 +/- 1.7%; contralateral = 3.2 +/- 1.0%), although the response duration in the directly stimulated cortex was significantly longer (48.1 +/- 5.7 sec vs. 19.0 +/- 5.3 sec). Activation of the contralateral cortex is likely to occur via stimulation of corticocortical pathways, as distinct from direct electrical stimulation, and the response profile is similar to that observed in remote (e.g., forepaw) stimulation fMRI studies. Differences in the neuronal pool activated, or neurovascular mediators released, may account for the more prolonged BOLD response observed in the directly stimulated cortex. This work demonstrates the combination of direct cortical stimulation in the rat with fMRI and thus extends the scope of rodent fMRI into brain regions inaccessible to peripheral stimulation techniques.     

Pitfalls in fMRI

Several different techniques allow a functional assessment of neuronal activations by magnetic resonance imaging (fMRI). The by far most influential fMRI technique is based on a local T2*-sensitive hemodynamic response to neuronal activation, also known as the blood oxygenation level dependent or BOLD effect. Consequently, the term ‘fMRI’ is often used synonymously with BOLD imaging. Because interpretations of fMRI brain activation maps often appear intuitive and compelling, the reader might be tempted not to critically question the fundamental processes and assumptions. We review some essential processes and assumptions of BOLD fMRI and discuss related confounds and pitfalls in fMRI – from the underlying physiological effect, to data acquisition, data analysis and the interpretation of the results including clinical fMRI. A background framework is provided for the systematic and critical interpretation of fMRI results.     

Simultaneous acquisition of gradient echo/spin echo BOLD and perfusion with a separate labeling coil

Arterial spin labeling‐based cerebral blood flow imaging complements blood oxygenation level dependent (BOLD) imaging with a measure that is more quantitative and has better specificity to neuronal activation. Relative to gradient echo BOLD, spin echo BOLD has better spatial specificity because it is less biased to large draining veins. Although there have been many studies comparing simultaneously acquired cerebral blood flow data with gradient echo BOLD data in fMRI, there have been few studies comparing cerebral blood flow with SE BOLD and no study comparing all three. We present a pulse sequence that simultaneously acquires cerebral blood flow data with a separate labeling coil, gradient echo BOLD, and spin echo BOLD images. Simultaneous acquisition avoids interscan variability, allowing more direct assessment and comparison of each contrast's relative specificity and reproducibility. Furthermore, it facilitates studies that may benefit from multiple complementary measures. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.