Quantification of rodent cerebral blood flow (CBF) in normal and high flow states using pulsed arterial spin labeling magnetic resonance imaging

PURPOSE: To implement a pulsed arterial spin labeling (ASL) technique in rats that accounts for cerebral blood flow (CBF) quantification errors due to arterial transit times (dt)-the time that tagged blood takes to reach the imaging slice-and outflow of the tag. MATERIALS AND METHODS: Wistar rats were subjected to air or 5% CO(2), and flow-sensitive alternating inversion-recovery (FAIR) perfusion images were acquired. For CBF calculation, we applied the double-subtraction strategy (Buxton et al., Magn Reson Med 1998;40:383-396), in which data collected at two inversion times (TIs) are combined. RESULTS: The ASL signal fell off more rapidly than expected from TI = one second onward, due to outflow effects. Inversion times for CBF calculation were therefore chosen to be larger than the longest transit times, but short enough to avoid systematic errors caused by outflow of tagged blood. Using our method, we observed a marked regional variability in CBF and dt, and a region dependent response to hypercapnia. CONCLUSION: Even when flow is accelerated, CBF can be accurately determined using pulsed ASL, as long as dt and outflow of the tag are accounted for.     

Mapping of vertebral artery perfusion territories using arterial spin labeling MRI

PURPOSE: To demonstrate the use of a noninvasive arterial spin labeling (ASL) MRI technique and evaluate vertebral artery (VA) territories in the brain. MATERIALS AND METHODS: Vessel-encoded ASL was used to determine the territories of the left and right VAs in five healthy subjects. Territory maps were analyzed quantitatively by comparing the fractional contributions of the left and right VAs in selected regions of interest within the brain. RESULTS: VA territory maps demonstrated a complicated pattern of perfusion to the posterior aspect of the brain, but were consistent with the posterior cerebral and cerebellar artery distributions. Cerebellar perfusion was predominantly ipsilateral (P<0.01). The total left and right VA contributions were unequal (P<0.01), and there was relatively little mixing in the vertebrobasilar system. CONCLUSION: Vessel-encoded ASL can reveal individual VA territories in the brain. In a small sample of healthy volunteers the VAs appeared to contribute unequally, provide predominantly ipsilateral supply to the cerebellum, and undergo minimal mixing in the basilar artery.     

Applications of arterial spin labeled MRI in the brain

Perfusion provides oxygen and nutrients to tissues and is closely tied to tissue function while disorders of perfusion are major sources of medical morbidity and mortality. It has been almost two decades since the use of arterial spin labeling (ASL) for noninvasive perfusion imaging was first reported. While initial ASL magnetic resonance imaging (MRI) studies focused primarily on technological development and validation, a number of robust ASL implementations have emerged, and ASL MRI is now also available commercially on several platforms. As a result, basic science and clinical applications of ASL MRI have begun to proliferate. Although ASL MRI can be carried out in any organ, most studies to date have focused on the brain. This review covers selected research and clinical applications of ASL MRI in the brain to illustrate its potential in both neuroscience research and clinical care.     

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.     

Test-retest reliability of arterial spin labeling with common labeling strategies

Purpose

To compare the test–retest reproducibility of three variants of arterial spin labeling (ASL): pseudo‐continuous (pCASL), pulsed (PASL) and continuous (CASL).

Materials and Methods

Twelve healthy subjects were scanned on a 3.0T scanner with PASL, CASL, and pCASL. Scans were repeated within‐session, after 1 hour, and after 1 week to assess reproducibility at different scan intervals.

Results

Comparison of within‐subject coefficients of variation (wsCV) demonstrated high within‐session reproducibility (ie, low wsCV) for CASL‐based methods (gray matter [GM] wsCV for pCASL: 3.5% ± 0.02%, CASL: 4.1% ± 0.07%) compared to PASL (wsCV: 7.5% ± 0.06%), due to the higher signal‐to‐noise ratio (SNR) associated with continuous labeling, evident in the 20% gain in temporal SNR and 58% gain in raw SNR for pCASL relative to PASL. At the 1‐week scan interval, comparable reproducibility between PASL (GM wsCV 9.2% ± 0.12%) and pCASL (GM wsCV 8.5% ± 0.14%) was observed, indicating the dominance of physiological fluctuations.

Conclusion

Although all three approaches are capable of measuring cerebral blood flow within a few minutes of scanning, the high precision and SNR of pCASL, with its insensitivity to vessel geometry, make it an appealing method for future ASL application studies. J. Magn. Reson. Imaging 2011;33:940–949. © 2011 Wiley‐Liss, Inc.     

Effects of indomethacin on cerebral blood flow at rest and during hypercapnia: an arterial spin tagging study in humans

PURPOSE: To investigate using an arterial spin tagging (AST) approach the effect of indomethacin on the cerebral blood flow (CBF) response to hypercapnia.MATERIALS AND METHODS: Subjects inhaled a gas mixture containing 6% CO(2) for two 5-minute periods, which were separated by a 10-minute interval, in which subjects inhaled room air. In six subjects, indomethacin (i.v., 0.2 mg/kg) was infused in the normocapnic interval between the two hypercapnic periods.RESULTS: Indomethacin reduced normocapnic gray matter CBF by 36 +/- 5% and reduced the CBF increase during hypercapnia from 43 +/- 9% to 16 +/- 5% in gray matter (P < 0.001) and from 48 +/- 11% to 35 +/- 9% in white matter (P < 0.025).CONCLUSION: The results demonstrate that an AST approach can measure the effects of indomethacin on global CBF increases during hypercapnia and suggest that an AST approach could be used to investigate pharmacological effects on focal CBF increases during functional activation.     

Multiphase pseudocontinuous arterial spin labeling (MP‐PCASL) for robust quantification of cerebral blood flow

Pseudocontinuous arterial spin labeling (PCASL) has been demonstrated to provide the sensitivity of the continuous arterial spin labeling method while overcoming many of the limitations of that method. Because the specification of the phases in the radiofrequency pulse train in PCASL defines the tag and control conditions of the flowing arterial blood, its tagging efficiency is sensitive to factors, such as off‐resonance fields, that induce phase mismatches between the radiofrequency pulses and the flowing spins. As a result, the quantitative estimation of cerebral blood flow with PCASL can exhibit a significant amount of error when these factors are not taken into account. In this paper, the sources of the tagging efficiency loss are characterized and a novel PCASL method that utilizes multiple phase offsets is proposed to reduce the tagging efficiency loss in PCASL. Simulations are performed to evaluate the feasibility and the performance of the proposed method. Quantitative estimates of cerebral blood flow obtained with multiple phase offset PCASL are compared to estimates obtained with conventional PCASL and pulsed arterial spin labeling. Our results show that multiple phase offset PCASL provides robust cerebral blood flow quantification while retaining much of the sensitivity advantage of PCASL. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

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.     

ADC characterization of region-specific response to cerebral perfusion deficit in rats by MRI at 9.4 T.

Region-specific cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) of water in the rat brain were quantified in vivo by high-field MRI (9.4 T) for 6-7 h after middle cerebral artery occlusion (MCAO). Upon occlusion, average CBF fell from about 1.5-2 ml/g/min to below 0.5 ml/g/min in cortical areas and the amygdala, and below 0.2 ml/g/min in the caudate putamen. CBF in some of the homologous contralateral areas also decreased by 20-30%. Average ADC decreased from about 8 center dot 10(-4) to 5 center dot 10(-4) mm(2)/s in the caudate putamen and parietal cortex. Corresponding changes in ADC were lower in the frontal cortex and negligible in the piriform cortex, suggesting that the perfusion threshold for ADC decrease may be different for different brain regions in the same animal. The area of decreased ADC correlated well with the infarction area revealed by 2,3,5-triphenyltetrazolium chloride (TTC) staining of brain slices in vitro. A better understanding of the mechanisms linking ADC and CBF changes to ischemic cell disorders may prove useful in characterizing the degree of tissue damage, and in developing and evaluating treatment strategies.     

Effect of magnetization transfer on the measurement of cerebral blood flow using steady-state arterial spin tagging approaches: A theoretical investigation

A simple four-compartment model for magnetization transfer was used to obtain theoretical expressions for the relationship between regional cerebral blood flow and ΔM, the change in longitudinal magnetization of brain water spins when arterial water spins are perturbed. The theoretical relationship can be written in two forms, depending on the approach used to normalize ΔM. Using the first approach, the calculation of cerebral blood flow requires a knowledge of R₁ (ω₁, Δω), the longitudinal relaxation rate observed in the presence of continuous off-resonance RF irradiation. Using the second approach, the calculation of cerebral blood flow requires a knowledge of ?₁(ω₁, Δω), where ?₁(ω₁, Δω) is given by the product of R₁(ω₁, Δω) and the fractional steady-state longitudinal water magnetization in the presence of off-resonance RF irradiation. If the off-resonance RF irradiation used for arterial tagging does not produce appreciable magnetization transfer effects, ?₁, (ω₁, Δω) can be approximated by the longitudinal relaxation rate measured in the absence of offresonance RF irradiation, R_1obs. Theoretical expressions obtained by using the four-component model for magnetization transfer are compared with equivalent expressions obtained by using two-compartment models.     

Modulation of cerebral blood oxygenation by indomethacin: MRI at rest and functional brain activation

The modulation of blood oxygenation level-dependent (BOLD) cerebral MRI contrast by the vasoconstrictive drug indomethacin (i.v. 0.2 mg/kg b.w.) was investigated in 10 healthy young adults without and with functional challenge (repetitive and sustained visual activation). For comparison, isotonic saline (placebo, 20 mL) and acetylsalicylate (i.v. 500 mg) were investigated as well, each in separate sessions using identical protocols. After indomethacin, dynamic T2*-weighted echo-planar MRI at 2.0 T revealed a rapid decrease in MRI signal intensity by 2.1%-2.6% in different gray matter regions (P < or = 0.001 compared to placebo), which was not observed for acetylsalicylate and the placebo condition. Regional signal differences were not significant within gray matter, but all gray matter regions differed significantly from the signal decrease of only 1.2% +/- 0.7% observed in white matter (P = 0.001). For the experimental parameters used, a 1% MRI signal decrease in response to indomethacin was estimated to correlate with a decrease of the cerebral blood flow by about 12 ml/100 g/minute, and an increase of the oxygen extraction fraction by about 15%. Responses to visual activation were not affected by saline or acetylsalicylate, and yielded 5.0%-5.5% BOLD MRI signal increases both before and after drug application. In contrast, indomethacin reduced the initial response strength to 82%-85% of that obtained without the drug. The steady-state response during sustained activation reached only 47% of the corresponding pre-drug level (P < 0.01). During repetitive activation the BOLD contrast was reduced to 66% of that observed for control conditions (P < 0.001). In conclusion, indomethacin attenuates the vasodilatory force at functional brain activation, indicating different mechanisms governing neurovascular coupling.     

Correction for vascular artifacts in cerebral blood flow values measured by using arterial spin tagging techniques

?Vascular”? artifacts can have substantial effects on human cerebral blood flow values calculated by using arterial spin tagging approaches. One vascular artifact arises from the contribution of ?tagged”? arterial water spins to the observed change in brain water MR signal. This artifact can be reduced if large bipolar gradients are used to ?crush”? the MR signal from moving arterial water spins. A second vascular artifact arises from relaxation of ?tagged”? arterial blood during transit from the tagging plane to the capillary exchange site in the imaging slice. This artifact can be corrected if the arterial transit times are measured by using ?dynamic”? spin tagging approaches. The mean transit time from the tagging plane to capillary exchange sites in a gray matter region of interest was calculated to be ～0.94 s. Cerebral blood flow values calculated for seven normal volunteers agree reasonably well with values calculated by using radioactive tracer approaches.     

Arterial spin labeling of cerebral perfusion territories using a separate labeling coil

PURPOSE: To obtain cerebral perfusion territories of the left, the right, and the posterior circulation in humans with high signal-to-noise ratio (SNR) and robust delineation. MATERIALS AND METHODS: Continuous arterial spin labeling (CASL) was implemented using a dedicated radio frequency (RF) coil, positioned over the neck, to label the major cerebral feeding arteries in humans. Selective labeling was achieved by flow-driven adiabatic fast passage and by tilting the longitudinal labeling gradient about the Y-axis by theta = +/- 60 degrees . RESULTS: Mean cerebral blood flow (CBF) values in gray matter (GM) and white matter (WM) were 74 +/- 13 mL . 100 g(-1) . minute(-1) and 14 +/- 13 mL . 100 g(-1) . minute(-1), respectively (N = 14). There were no signal differences between left and right hemispheres when theta = 0 degrees (P > 0.19), indicating efficient labeling of both hemispheres. When theta = +60 degrees , the signal in GM on the left hemisphere, 0.07 +/- 0.06%, was 92% lower than on the right hemisphere, 0.85 +/- 0.30% (P < 1 x 10(-9)), while for theta = -60 degrees , the signal in the right hemisphere, 0.16 +/- 0.13%, was 82% lower than on the contralateral side, 0.89 +/- 0.22% (P < 1 x 10(-10)). Similar attenuations were obtained in WM. CONCLUSION: Clear delineation of the left and right cerebral perfusion territories was obtained, allowing discrimination of the anterior and posterior circulation in each hemisphere.     

Estimation of intersubject variability of cerebral blood flow measurements using MRI and positron emission tomography

Purpose:

To investigate the within and between subject variability of quantitative cerebral blood flow (CBF) measurements in normal subjects using various MRI techniques and positron emission tomography (PET).

Materials and Methods:

Repeated CBF measurements were performed in 17 healthy, young subjects using three different MRI techniques: arterial spin labeling (ASL), dynamic contrast enhanced T1 weighted perfusion MRI (DCE) and phase contrast mapping (PCM). All MRI measurements were performed within the same session. In 10 of the subjects repeated CBF measurements by ¹⁵O labeled water PET had recently been performed. A mixed linear model was used to estimate between subject (CV_betw) and within subject (CV_with) coefficients of variation.

Results:

Mean global CBF, CV_betw and CV_with using each of the four methods were for PCM 65.2 mL/100 g/min, 17.4% and 7.4%, for ASL 37.1 mL/100 g/min, 16.2% and 4.8%, for DCE 43.0 mL/100 g/min, 20.0%, 15.1% and for PET 41.9 mL/100 g/min, 16.5% and 11.9%, respectively. Only for DCE and PCM a significant positive correlation between measurements was demonstrated.

Conclusion:

These findings confirm large between subject variability in CBF measurements, but suggest also that in healthy subjects a subject‐method interaction is a possible source of between subject variability and of method differences. J. Magn. Reson. Imaging 2012;35:1290–1299. © 2012 Wiley Periodicals, Inc.     

Combined arterial spin label and dynamic susceptibility contrast measurement of cerebral blood flow

Dynamic susceptibility contrast (DSC) and arterial spin labeling (ASL) are both used to measure cerebral blood flow (CBF), but neither technique is ideal. Absolute DSC‐CBF quantitation is challenging due to many uncertainties, including partial‐ volume errors and nonlinear contrast relaxivity. ASL can measure quantitative CBF in regions with rapidly arriving flow, but CBF is underestimated in regions with delayed arrival. To address both problems, we have derived a patient‐specific correction factor, the ratio of ASL‐ and DSC‐CBF, calculated only in short‐arrival‐time regions (as determined by the DSC‐based normalized bolus arrival time [Tmax]). We have compared the combined CBF method to gold‐standard xenon CT in 20 patients with cerebrovascular disease, using a range of Tmax threshold levels. Combined ASL and DSC CBF demonstrated quantitative accuracy as good as the ASL technique but with improved correlation in voxels with long Tmax. The ratio of MRI‐based CBF to xenon CT CBF (coefficient of variation) was 90 ± 30% (33%) for combined ASL and DSC CBF, 43 ± 21% (47%) for DSC, and 91 ± 31% (34%) for ASL (Tmax threshold 3 sec). These findings suggest that combining ASL and DSC perfusion measurements improves quantitative CBF measurements in patients with cerebrovascular disease. Magn Reson Med 63:1548–1556, 2010. © 2010 Wiley‐Liss, Inc.     

Age-related cerebral perfusion changes in the parietal and temporal lobes measured by pulsed arterial spin labeling

Purpose:

To investigate age‐related regional perfusion changes focused on the medial temporal lobes and related parietal areas using a pulsed arterial spin labeling technique.

Materials and Methods:

Resting cerebral blood flow (CBF) maps were obtained from 44 healthy volunteers (18 male, 26 female; age range, 19 to 79 years) using a pulsed arterial spin labeling (PASL) MRI technique at 3 Tesla focused on the parietal and temporal lobes. Repeated measurements were performed in 20 subjects to assure the reliability and reproducibility of the applied PASL technique.

Results:

Focal age‐related CBF decreases were detected in the parietal cortex, cuneus and caudate, whereas increases were seen in the lateral and medial temporal lobe such as hippocampus, the calcarine gyrus and the thalamus. Moreover, repeated measurements demonstrated a high reliability and reproducibility of the applied PASL technique.

Conclusion:

Data provide evidence for regionally dissociated patterns of perfusion increases and decreases during ageing in the temporal and parietal lobes. J. Magn. Reson. Imaging 2011;. © 2011 Wiley Periodicals, Inc.     

Dynamics of blood flow and oxygenation changes during brain activation: The balloon model

A biomechanical model is presented for the dynamic changes in deoxyhemoglobin content during brain activation. The model incorporates the conflicting effects of dynamic changes in both blood oxygenation and blood volume. Calculations based on the model show pronounced transients in the deoxyhemoglobin content and the blood oxygenation level dependent (BOLD) signal measured with functional MRI, including initial dips and overshoots and a prolonged post-stimulus undershoot of the BOLD signal. Furthermore, these transient effects can occur in the presence of tight coupling of cerebral blood flow and oxygen metabolism throughout the activation period. An initial test of the model against experimental measurements of flow and BOLD changes during a finger-tapping task showed good agreement.     

Effect of restricted water exchange on cerebral blood flow values calculated with arterial spin tagging: a theoretical investigation.

Arterial spin tagging techniques originally used the one-compartment Kety model to describe the dynamics of tagged water in the brain. The work presented here develops a more realistic model that includes the contribution of tagged water in the capillary bed and accounts for the finite time required for water to diffuse across the blood-brain barrier. The new model was used to evaluate potential errors in cerebral blood flow values calculated using the one-compartment Kety model. The results predict that if the one-compartment Kety model is used to analyze arterial spin tagging data the observed grey matter cerebral blood flow values should be relatively insensitive to restricted diffusion of water across the capillary bed. For instance, the observed grey matter cerebral blood flow should closely approximate the true cerebral blood flow and not the product of the extraction fraction and the cerebral blood flow. This prediction is in agreement with recent experimental arterial spin tagging results.