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.     

Detrimental effects of BOLD signal in arterial spin labeling fMRI at high field strength.

Arterial spin labeling (ASL) MRI is a useful technique for noninvasive measurement of cerebral blood flow (CBF) in humans. High field strength provides a unique advantage for ASL because of longer blood T(1) relaxation times, making this technique a promising quantitative approach for functional brain mapping. However, higher magnetic field also introduces new challenges. Here it is shown that the CBF response determined using ASL functional MRI (fMRI) at 3.0 T contains significant contamination from blood-oxygenation-level-dependent (BOLD) effects. Due to interleaved acquisitions of label and control images, difference in blood oxygenation status between these two scans can cause incomplete cancellation of the static signal upon image subtraction, resulting in a BOLD-related artifact in the estimated CBF hemodynamics. If not accounted for, such an effect can complicate the interpretation of the ASL results, e.g., causing a delayed onset and offset of the response, or inducing an artifactual poststimulus undershoot. The BOLD contribution also decreases the sensitivity of ASL-based fMRI. Correction methods are proposed to reduce the artifact, giving increased number of activated voxels (18+/-5%, P=0.006) and more accurate estimation of CBF temporal characteristics.     

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.     

Relative changes of cerebral arterial and venous blood volumes during increased cerebral blood flow: implications for BOLD fMRI.

Measurement of cerebral arterial and venous blood volumes during increased cerebral blood flow can provide important information regarding hemodynamic regulation under normal, pathological, and neuronally active conditions. In particular, the change in venous blood volume induced by neural activity is one critical component of the blood oxygenation level-dependent (BOLD) signal because BOLD contrast is dependent only on venous blood, not arterial blood. Thus, relative venous and arterial blood volume (rCBV) and cerebral blood flow (rCBF) in alpha-chlorolase-anesthetized rats under hypercapnia were measured by novel diffusion-weighted (19)F NMR following an i.v. administration of intravascular tracer, perfluorocarbons, and continuous arterial spin labeling methods, respectively. The relationship between rCBF and total rCBV during hypercapnia was rCBV(total) = rCBF(0.40), which is consistent with previous PET measurement in monkeys. This relationship can be linearized in a CBF range of 50-130 ml/100 g/min as DeltarCBV(total)/ DeltarCBF = 0.31 where DeltarCBV and DeltarCBF represent rCBV and rCBF changes. The average arterial volume fraction was 0.25 at a basal condition with CBF of approximately 60 ml/100 g/min and increased up to 0.4 during hypercapnia. The change in venous rCBV was 2-fold smaller than that of total rCBV (DeltarCBV(vein)/DeltarCBF = 0.15), while the arterial rCBV change was 2.5 times larger than that of total rCBV (DeltarCBV(artery)/DeltarCBF = 0.79). These NMR results were confirmed by vessel diameter measurements with in vivo videomicroscopy. The absolute venous blood volume change contributes up to 36% of the total blood volume change during hypercapnia. Our findings provide a quantitative physiological model of BOLD contrast.     

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.     

BOLD and CBV-weighted functional magnetic resonance imaging of the rat somatosensory system.

A multislice spin echo EPI sequence was used to obtain functional MR images of the entire rat brain with blood oxygenation level dependent (BOLD) and cerebral blood volume (CBV) contrast at 11.7 T. Maps of activation incidence were created by warping each image to the Paxinos rat brain atlas and marking the extent of the activated area. Incidence maps for BOLD and CBV were similar, but activation in draining veins was more prominent in the BOLD images than in the CBV images. Cerebellar activation was observed along the surface in BOLD images, but in deeper regions in the CBV images. Both effects may be explained by increased signal dropout and distortion in the EPI images after administration of the ferumoxtran-10 contrast agent for CBV fMRI. CBV-weighted incidence maps were also created for 10, 20, and 30 mg Fe/kg doses of ferumoxtran-10. The magnitude of the average percentage change during stimulation increased from 4.9% with the 10 mg Fe/kg dose to 8.7% with the 30-mg Fe/kg dose. Incidence of activation followed a similar trend.     

Comparison of diffusion-weighted high-resolution CBF and spin-echo BOLD fMRI at 9.4 T.

The quantification of blood oxygenation-level dependent (BOLD) functional MRI (fMRI) signals is closely related to cerebral blood flow (CBF) change; therefore, understanding the exact relationship between BOLD and CBF changes on a pixel-by-pixel basis is fundamental. In this study, quantitative CBF changes induced by neural activity were used to quantify BOLD signal changes during somatosensory stimulation in alpha-chloralose-anesthetized rats. To examine the influence of fast-moving vascular spins in quantifying CBF, bipolar gradients were employed. Our data show no significant difference in relative CBF changes obtained with and without bipolar gradients. To compare BOLD and CBF signal changes induced by neural stimulation, a spin-echo (SE) sequence with long SE time of 40 ms at 9.4 T was used in conjunction with an arterial spin labeling technique. SE BOLD changes were quantitatively correlated to CBF changes on a pixel-by-pixel and animal-by-animal basis. Thus, SE BOLD-based fMRI at high magnetic fields allows a quantitative comparison of functional brain activities across brain regions and subjects.     

Spatial/temporal correlation of BOLD and optical intrinsic signals in humans.

Comparing the BOLD signal with electrophysiological maps and other perfusion-dependent signals, such as the optical intrinsic signal (OIS), within subjects should provide insight into the etiology of the BOLD signal. Tongue activations were compared in five human subjects using BOLD fMRI, 610-nm OIS, and the electrocortical stimulation map (ESM). Robust fMRI activations centered on the lateral inferior aspect of the central sulcus and extended into pre- and post-central gyri, adjacent to ESM tongue loci. OIS and fMRI maps colocalized, although optical responses were spatially larger (P <.001 across multiple thresholds) and contained more gyral components. The timecourses of the fMRI and OIS signals were similar, appearing within 2.5 s and peaking 6-8 s after task onset. Although many processes contribute to increased 610-nm reflectance, optical spectroscopy and fluorescent dye imaging suggest that a significant part of this signal is due to a concomitant decrease in deoxyhemoglobin and increase in oxyhemoglobin concentrations. The spatial/temporal correlation of BOLD and the positive 610-nm response within subjects suggests that the two signals may share similar etiologies. The OIS/fMRI inconsistencies may be due to cell swelling and light-scattering contributions to OIS and fMRI sensitivity. This study also demonstrates that fMRI maps do not precisely colocalize with ESM, rather they emphasize changes in adjacent venous/sulcal structures.     

BOLD signal in the motor cortex shows a correlation with the blood volume of brain tumors

PURPOSE: To investigate whether and how the blood-oxygenation-level-dependent (BOLD) functional MRI (fMRI) signal is modified by brain tumors. MATERIALS AND METHODS: The BOLD signal depends on the perfusion, which in turn may be affected in the presence of a tumor. Some studies have demonstrated a reduced BOLD signal in the tumor-bearing hemisphere. The BOLD signal variation in the motor cortex area was studied with finger tapping in a brain tumor group and a control group. An a priori volume-of-interest (VOI)-based method was applied that allows quantification of the mean BOLD signal amplitude and extent of activated volume. BOLD signal amplitude and activated volume were correlated with the extent of edema, a mass effect on the central sulcus, tumor volume, distance of tumor to somatosensory cortex, and tumor blood volume. RESULTS: In the tumor group the ipsilateral activated volume was reduced by 21% (P = 0.025) and the mean signal amplitude was reduced by 16% (P = 0.004). The mean BOLD signal amplitude shows a significant correlation with the total intratumoral blood volume (P = 0.014). CONCLUSION: We concluded that the peritumoral perfusion was reduced resulting due to a tumor aspirating perfusion (steal phenomenon).     

Quantification of perfusion fMRI using a numerical model of arterial spin labeling that accounts for dynamic transit time effects.

A new approach to modeling the signal observed in arterial spin labeling (ASL) experiments during changing perfusion conditions is presented in this article. The new model uses numerical methods to extend first-order kinetic principles to include the changes in arrival time of the arterial tag that occur during neuronal activation. Estimation of the perfusion function from the ASL signal using this model is also demonstrated. The estimation algorithm uses a roughness penalty as well as prior information. The approach is demonstrated in numerical simulations and human experiments. The approach presented here is particularly suitable for fast ASL acquisition schemes, such as turbo continuous ASL (Turbo-CASL), which allows subtraction pairs to be acquired in less than 3 s but is sensitive to arrival time changes. This modeling approach can also be extended to other acquisition schemes.     

Influence of vascular filling and perfusion on BOLD contrast during reactive hyperemia in human skeletal muscle.

Mechanisms generating BOLD contrast are complex and depend on parameters that are prone to large variations, in particular in skeletal muscle. Here, we simultaneously measured perfusion by ASL, and BOLD response in the calf muscle of 6 healthy volunteers during post-ischemic reactive hyperemia. We tested whether the relation between the two was altered for varying degrees of leg vascular replenishment induced by prior positioning of the leg at different heights relative to the heart. We found that the BOLD response depended on perfusion, but also on the degree of repletion of leg blood vessels. We conclude that simultaneous determination of perfusion by ASL is important to identify the mechanisms underlying BOLD contrast in the skeletal muscle.     

次声对大鼠心率与血压影响的实验观察

目的:观察大鼠暴露于8Hz,130dB及90dB次声不同时间后血压及心率的变化。方法:将90只雄性大鼠随机为对照组、90dB暴露组及130dB组各5组(n=6),在1,7,14,21和28d暴露期间施以次声,2h/d,采用颈动脉插管法记录大鼠血压与心率。结果:与对照组比较,90dB1d组及130dB1d组大鼠心率均加快(P<0.01),7,14,21,28d组无显著变化(P>0.05);130dB1d组心率快于90dB1d组(P<0.05)。90dB及130dB的1,14,21,28d组左室收缩压增加(P<0.01),90dB7d组无显著变化,而130dB7d组较90dB7d组增加(P<0.05)。90dB及130dB的1,7,14d组大鼠左室舒张压无显著变化(P>0.05),而21,28d组增加(90dB组P<0.05;130dB组P<0.01),130dB组增加较90dB组快。结论:次声对大鼠血压及心率有一定影响,与次声作用时间和声压级水平有关。     

Quantification of cerebral arterial blood volume and cerebral blood flow using MRI with modulation of tissue and vessel (MOTIVE) signals.

Regional cerebral arterial blood volume (CBVa) and blood flow (CBF) can be quantitatively measured by modulation of tissue and vessel (MOTIVE) signals, enabling separation of tissue signal from blood. Tissue signal is selectively modulated using magnetization transfer (MT) effects. Blood signal is changed either by injection of a contrast agent or by arterial spin labeling (ASL). The measured blood volume represents CBVa because the contribution from venous blood was insignificant in our measurements. Both CBVa and CBF were quantified in isoflurane-anesthetized rats at 9.4T. CBVa obtained using a contrast agent was 1.1 +/- 0.5 and 1.3 +/- 0.6 ml/100 g tissue (N = 10) in the cortex and caudate putamen, respectively. The CBVa values determined from ASL data were 1.0 +/- 0.3 ml/100 g (N = 10) in both the cortex and the caudate putamen. The match between CBVa values determined by both methods validates the MOTIVE approach. In ASL measurements, the overestimation in calculated CBF values increased with MT saturation levels due to the decreasing contribution from tissue signals, which was confirmed by the elimination of blood with a contrast agent. Using the MOTIVE approach, accurate CBF values can also be obtained.     

Separation and quantification of perfusion and BOLD effects by simultaneous acquisition of functional I(0)- and T2(*)-parameter maps.

The nature of the coupling between neuronal activity and the hemodynamic response is the subject of intensive research. As a means to simultaneously measure parametric changes of T2(*), initial intensity (I(0)) and perfusion with high temporal resolution, a multi-image EPI technique with slice-selective inversion recovery (ssIR) for arterial spin labeling was developed and implemented. Comparative measurements with and without the preceding slice-selective inversion pulse were performed. I(0) and R2(*) changes induced by primary visual stimulation were separated. For ssIR-multi-image EPI the average change of I(0) over all 12 subjects was 3.4%, corresponding to a perfusion change of 40 ml/min/100 g, whereas only minor I(0) changes were observed without inversion. On average, the R2(*) of the activated pixels changed by -0.62 sec(-1) without inversion, while a significantly reduced average R2(*) change of -0.46 sec(-1) was calculated for ssIR-multi-image EPI due to a decreased BOLD effect contribution of the intravascular compartment.     

Spatial correlations of laminar BOLD and CBV responses to rat whisker stimulation with neuronal activity localized by Fos expression.

The spatial relationship between a measured fMRI signal and its underlying neuronal activity remains unclear. One obstacle is the localization of neuronal activity; another is the spatial resolution of fMRI. In the present study, high-resolution BOLD and CBV fMRI experiments (voxel size: 156 x 156 x 2000 microm3) were conducted in the rat whisker barrel cortex at 3 T; neuronal activity across cortical layers was mapped using the Fos expression technique. Results show that BOLD response is weighted by blood volume and that pixels with high BOLD response can be located at the cortical surface or in deep layers, depending on local vasculature. In contrast to BOLD response, the pixels with high CBV response were consistently clustered in the deep cortical layers. Percentage-CBV change in cortical layers IV-V was 7.3 +/- 1.5%, which was significantly higher than in layers I-III (4.1 +/- 0.9%) and VI (4.3 +/- 0.7%) (mean +/- SEM). The laminar distribution of CBV response correlates well with neuronal activity localized by Fos expression. We conclude that neuronal activity can be inferred from CBV fMRI data with high spatial accuracy. The data indicate that both intracolumn functional connectivity and neurovascular coupling can be studied using CBV fMRI.     

Comparison of the dependence of blood R2 and R2* on oxygen saturation at 1.5 and 4.7 Tesla.

Gradient-echo (GRE) blood oxygen level-dependent (BOLD) effects have both intra- and extravascular contributions. To better understand the intravascular contribution in quantitative terms, the spin-echo (SE) and GRE transverse relaxation rates, R(2) and R(2)(*), of isolated blood were measured as a function of oxygenation in a perfusion system. Over the normal oxygenation saturation range of blood between veins, capillaries, and arteries, the difference between these rates, R'(2) = R(2)(*) - R(2), ranged from 1.5 to 2.1 Hz at 1.5 T and from 26 to 36 Hz at 4.7 T. The blood data were used to calculate the expected intravascular BOLD effects for physiological oxygenation changes that are typical during visual activation. This modeling showed that intravascular DeltaR(2)(*) is caused mainly by R(2) relaxation changes, namely 85% and 78% at 1.5T and 4.7T, respectively. The simulations also show that at longer TEs (>70 ms), the intravascular contribution to the percentual BOLD change is smaller at high field than at low field, especially for GRE experiments. At shorter TE values, the opposite is the case. For pure parenchyma, the intravascular BOLD signal changes originate predominantly from venules for all TEs at low field and for short TEs at high field. At longer TEs at high field, the capillary contribution dominates. The possible influence of partial volume contributions with large vessels was also simulated, showing large (two- to threefold) increases in the total intravascular BOLD effect for both GRE and SE.     

Cerebral blood oxygenation in rat brain during hypoxic hypoxia. Quantitative MRI of effective transverse relaxation rates

Oxygenation-sensitive MRI of respiratory challenges in the brain of experimental animals will considerably benefit from a quantitative relationship between cerebral blood oxygenation and MRI parameters. Here, a multi-echo gradient-echo MRI technique was used to determine effective transverse relaxation rates R = 1/T of rat brain in vivo during short periods of hypoxia and interleaved normoxic phases. The differential contribution ΔR observed during hypoxia was found to increase linearly with arterial blood deoxygenation for mild to moderate conditions. Severe deoxygenation resulted in a plateau most likely due to enhanced cerebral blood flow.     

Tracking the effects of crusher gradients on gradient‐echo BOLD signal in space and time during rat sensory stimulation

A unique method to map the effect of crusher gradients in space and time on the gradient echo blood oxygen level dependent (BOLD) signal is introduced. Using the Radial Correlation Contrast (RCC) analysis method, amplitude‐RCC maps at different time segments and different gradient strengths were obtained. The ratio of amplitude‐RCC cluster volumes, with and without crusher gradients, showed a temporal dependency with stronger volume reduction for stimulation‐onset versus stimulation‐decline. Aside from signal‐to‐noise ratio reduction in diffusion weighted images, the average temporal patterns were equal. Comparison of the data with and without crushers showed a stronger reduction in local coherence for stimulation‐onset times. We hypothesize that the stimulation decline was weighted by extravascular effects originating in expanded veins due to their larger volume and long range susceptibility which couples neighboring voxels. The ratio of amplitude‐RCC with and without crushers calculated for each voxel at each time segment yielded a spatial–temporal mapping of the crusher effect. These maps suggest that early stimulation‐onset (～9 s) is weighted by flow; later a dynamic steady‐state between intra‐ and extravascular effects is obtained. Stimulation‐decline was dominated by extravascular effects, and at late stimulation decline as well as at early stimulation onset, clusters were small and localized to expected site of neuronal activity. Magn Reson Med 60:548–554, 2008. © 2008 Wiley‐Liss, Inc.     

Xenon-129 MR imaging and spectroscopy of rat brain using arterial delivery of hyperpolarized xenon in a lipid emulsion.

Hyperpolarized (129)Xe dissolved in a lipid emulsion constitutes an NMR tracer that can be injected into the blood stream, enabling blood-flow measurement and perfusion imaging. A small volume (0.15 ml) of this tracer was injected in 1.5 s in rat carotid and (129)Xe MR spectra and images were acquired at 2.35 T to evaluate the potential of this approach for cerebral studies. Xenon spectra consistently showed two resonances, at 194.5 ppm and 199.0 ppm relative to the gas peak. The signal-to-noise ratio (SNR) obtained for the two peaks was sufficient (ranging from 12 to 90) to follow their time courses. 2D transverse-projection xenon images were obtained with an in-plane resolution of 900 microm per pixel (SNR range 8-15). Histological analysis revealed no brain damage except in two rats that had received three injections.