Comparison of pulsed arterial spin labeling encoding schemes and absolute perfusion quantification

Arterial spin labeling (ASL) using magnetic resonance imaging (MRI) is a powerful noninvasive technique to investigate the physiological status of brain tissue by measuring cerebral blood flow (CBF). ASL assesses the inflow of magnetically labeled arterial blood into an imaging voxel. In the last 2 decades, various ASL sequences have been proposed which differ in their ease of implementation and their sensitivity to artifacts. In addition, several quantification methods have been developed to determine the absolute value of CBF from ASL magnetization difference images. In this study, we evaluated three pulsed ASL sequences and three absolute quantification schemes. It was found that FAIR-QUIPSSII implementation of ASL yields 10–20% higher signal-to-noise ratio (SNR) and 18% higher CBF as compared with PICORE-Q2TIPS (with FOCI pulses) and PICORE-QUIPSSII (with BASSI pulses). In addition, quantification schemes employed can give rise to up to a 35% difference in CBF values. We conclude that, although all quantitative ASL sequences and CBF calibration methods should in principle result in the similar CBF values and image quality, substantial differences in CBF values and SNR were found. Thus, comparing studies using different ASL sequences and analysis algorithms is likely to result in erroneous intra- and intergroup differences. Therefore, (i) the same quantification schemes should consistently be used, and (ii) quantification using local tissue proton density should yield the most accurate CBF values because, although still requiring definitive demonstration in future studies, the proton density of blood is assumed to be very similar to the value of gray matter.     

Comparison of multislice and single-slice acquisitions for pulsed arterial spin labeling measurements of cerebral perfusion

Multislice Q2TIPS is a widely used pulsed arterial spin labeling (PASL) technique for efficient and accurate quantification of cerebral blood flow (CBF). Slices are typically acquired inferior to superior from a tagging plane. Superior slices show signal loss greater than the loss expected from blood T1 decay. In order to assess the reasons for this additional signal loss, three single-slice acquisition studies were compared to multislice acquisition (six slices) in healthy volunteers. In Study 1 (n=8), the tagging plane was fixed in location, and the inversion time (TI2) was 1500 ms for each slice. For Study 2 (n=12), the tagging plane was fixed as in Study 1; however, TI2 increased as slices were acquired further from the tagging plane. In Study 3 (n=9), the tagging plane was kept adjacent to the imaging slice, and TI2 was 1500 ms for every slice. Gray matter (GM) and white matter (WM) signal-to-noise ratio (SNR) and CBF were measured per slice. GM SNR from single-slice acquisitions was significantly higher at slices 4-6 in Study 2 and at slices 2-6 in Study 3 compared to multislice acquisitions. Signal loss in distal slices of multislice acquisitions can be attributed to the destruction of tagged bolus in addition to blood T1 decay. If limited brain coverage is acceptable, perfusion images with greater SNR are achievable with limited slices and placement of the tagging region immediately adjacent to the site of interest.     

Why perfusion in neonates with congenital heart defects is negative--technical issues related to pulsed arterial spin labeling

Pulsed arterial spin labeling (PASL) perfusion MRI has unique advantages for measuring cerebral blood flow (CBF) in the pediatric population. In neonates with congenital heart defects (CHDs), however, a considerable number of negative CBF values were observed in PASL perfusion images. A set of specific physiological and biophysical conditions were proposed as plausible explanations for this phenomenon, including small body size, low blood flow, prolonged tracer life time (blood T1) and the "shunt" between pulmonary and systemic circulations in CHD. An optimized PASL scheme with a restricted label volume was proposed, and experimental data demonstrated reduced spurious negative values and lower intersubject variability of perfusion measurements in neonates with CHD as compared to standard PASL sequences.     

Validation study of a pulsed arterial spin labeling technique by comparison to perfusion computed tomography

Abnormalities in cerebral blood flow (CBF) are believed to play a significant role in the development of major neonatal neuropathologies. One approach that would appear ideal for measuring CBF in this fragile age group is arterial spin labeling (ASL) since ASL techniques are noninvasive and quantitative. The purpose of this study was to assess the accuracy of a pulsed ASL method implemented on a 3-T scanner dedicated to neonatal imaging. Cerebral blood flow was measured in nine neonatal piglets, the ASL–CBF measurements were acquired at two inversion times (TI) (1200 and 1700 ms), and CBF was measured by perfusion computed tomography (pCT) for validation. Perfusion CT also provided images of cerebral blood volume, which were used to identify large blood vessels, and contrast arrival time, which were used to assess differences in arterial transit times between gray and white matter. Good agreement was found between gray matter CBF values from pCT (76±1 ml/min per 100 g) and ASL at TI=1700 ms (73±1 ml/min per 100 g). At TI=1200 ms, ASL overestimated CBF (91±2 ml/min per 100 g), which was attributed to substantial intravascular signal. No significant differences in white matter CBF from pCT and ASL were observed (average CBF=60±1 ml/min per 100 g), nor was there any difference in contrast arrival times for gray and white matter (0.95±0.04 and 0.99±0.03 s, respectively), which suggests that the arterial transit times for ASL were the same in this animal model. This study verified the accuracy of the implemented ASL technique and showed the value of using pCT to study other factors that can affect ASL–CBF measurements.     

Perfusion in rat brain at 7 T with arterial spin labeling using FAIR-TrueFISP and QUIPSS

Measurement of perfusion in longitudinal studies allows for the assessment of tissue integrity and the detection of subtle pathologies. In this work, the feasibility of measuring brain perfusion in rats with high spatial resolution using arterial spin labeling is reported. A flow-sensitive alternating recovery sequence, coupled with a balanced gradient fast imaging with steady-state precession readout section was used to minimize ghosting and geometric distortions, while achieving high signal-to-noise ratio. The quantitative imaging of perfusion using a single subtraction method was implemented to address the effects of variable transit delays between the labeling of spins and their arrival at the imaging slice. Studies in six rats at 7 T showed good perfusion contrast with minimal geometric distortion. The measured blood flow values of 152.5±6.3 ml/100 g per minute in gray matter and 72.3±14.0 ml/100 g per minute in white matter are in good agreement with previously reported values based on autoradiography, considered to be the gold standard.     

Quantitative analysis of arterial spin labeling FMRI data using a general linear model

Arterial spin labeling techniques can yield quantitative measures of perfusion by fitting a kinetic model to difference images (tagged-control). Because of the noisy nature of the difference images investigators typically average a large number of tagged versus control difference measurements over long periods of time. This averaging requires that the perfusion signal be at a steady state and not at the transitions between active and baseline states in order to quantitatively estimate activation induced perfusion. This can be an impediment for functional magnetic resonance imaging task experiments. In this work, we introduce a general linear model (GLM) that specifies Blood Oxygenation Level Dependent (BOLD) effects and arterial spin labeling modulation effects and translate them into meaningful, quantitative measures of perfusion by using standard tracer kinetic models. We show that there is a strong association between the perfusion values using our GLM method and the traditional subtraction method, but that our GLM method is more robust to noise.     

Quantification of cerebral blood flow in nonhuman primates using arterial spin labeling and a two-compartment model

Noninvasive absolute quantification of cerebral blood flow (CBF) with high spatial resolution is still a challenging task. Arterial spin labeling (ASL) is a promising magnetic resonance imaging (MRI) method for accurate perfusion quantification. However, modeling of ASL data is far from being standardized and has not been investigated in great detail. In this study, two-compartment modeling of monkey ASL data in three physiological conditions (baseline, sensory activated and globally elevated CBF) is reported. Absolute perfusion and arterial transit times were derived for gray matter (GM) and white matter (WM) separately. The uncertainties of the model's result were determined by Monte Carlo simulations. The fitted CBF values for GM were 133 ml/min/100 ml at baseline condition, 165 ml/min/100 ml during visual stimulation and 234 ml/min/100 ml for globally elevated CBF after intravenous injection of acetazolamide. The ratio of GM to WM CBF was 2.5 at baseline and was found to decrease to 1.6 after application of acetazolamide. The corresponding arterial transit times decreased from 742 to 607 ms in GM and from 985 to 875 ms in WM. Monte Carlo simulations showed that absolute CBF values can be determined with an error of 11-15%, while the arterial transit time values have a coefficient of variation of 25-31%. With an alternative acquisition scheme, the precision of the arterial transit times can be improved significantly. The CBF values in the occipital lobe of the monkey brain quantified with ASL are higher than previously reported in positron emission tomography studies.     

SNR and functional sensitivity of BOLD and perfusion-based fMRI using arterial spin labeling with spiral SENSE at 3 T

Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies using parallel imaging to reduce the readout window have reported a loss in temporal signal-to-noise ratio (SNR) that is less than would be expected given a purely thermal noise model. In this study, the impact of parallel imaging on the noise components and functional sensitivity of both BOLD and perfusion-based fMRI data was investigated. Dual-echo arterial spin labeling data were acquired on five subjects using sensitivity encoding (SENSE), at reduction factors (R) of 1, 2 and 3. Direct recording of cardiac and respiratory activity during data acquisition enabled the retrospective removal of physiological noise. The temporal SNR of the perfusion time series closely followed the thermal noise prediction of a √R loss in SNR as the readout window was shortened, with temporal SNR values (relative to the R=1 data) of 0.72 and 0.56 for the R=2 and R=3 data, respectively, after accounting for physiological noise. However, the BOLD temporal SNR decreased more slowly than predicted even after accounting for physiological noise, with relative temporal SNR values of 0.80 and 0.63 for the R=2 and R=3 data, respectively. Spectral analysis revealed that the BOLD trends were dominated by low-frequency fluctuations, which were not dominant in the perfusion data due to signal processing differences. The functional sensitivity, assessed using mean F values over activated regions of interest (ROIs), followed the temporal SNR trends for the BOLD data. However, results for the perfusion data were more dependent on the threshold used for ROI selection, most likely due to the inherently low SNR of functional perfusion data.     

Prospective motion correction for 3D pseudo-continuous arterial spin labeling using an external optical tracking system

Head motion is an unsolved problem in magnetic resonance imaging (MRI) studies of the brain. Real-time tracking using a camera has recently been proposed as a way to prevent head motion artifacts. As compared to navigator-based approaches that use MRI data to detect and correct motion, optical motion correction works independently of the MRI scanner, thus providing low-latency real-time motion updates without requiring any modifications to the pulse sequence. The purpose of this study was two-fold: 1) to demonstrate that prospective optical motion correction using an optical camera mitigates artifacts from head motion in three-dimensional pseudo-continuous arterial spin labeling (3D PCASL) acquisitions and 2) to assess the effect of latency differences between real-time optical motion tracking and navigator-style approaches (such as PROMO). An optical motion correction system comprising a single camera and a marker attached to the patient's forehead was used to track motion at a rate of 60 fps. In the presence of motion, continuous tracking data from the optical system was used to update the scan plane in real-time during the 3D-PCASL acquisition. Navigator-style correction was simulated by using the tracking data from the optical system and performing updates only once per repetition time. Three normal volunteers and a patient were instructed to perform continuous and discrete head motion throughout the scan. Optical motion correction yielded superior image quality compared to uncorrected images or images using navigator-style correction. The standard deviations of pixel-wise CBF differences between reference and non-corrected, navigator-style-corrected and optical-corrected data were 14.28, 14.35 and 11.09 mL/100 g/min for continuous motion, and 12.42, 12.04 and 9.60 mL/100 g/min for discrete motion. Data obtained from the patient revealed that motion can obscure pathology and that application of optical prospective correction can successfully reveal the underlying pathology in the presence of head motion.     

An automated image-processing strategy to analyze dynamic arterial spin labeling perfusion studies. Application to human skeletal muscle under stress

Arterial spin labeling (ASL) perfusion measurements allow the follow-up of muscle perfusion with high temporal resolution during a stress test. Automated image processing is proposed to estimate perfusion maps from ASL images. It is based on two successive analyses: at first, automated rejection of the image pairs between which a large displacement is detected is performed, followed by factor analysis of the dynamic data and cluster analysis to classify pixels with large signal variation characteristic of vessels. Then, after masking these "vascular" pixels, factor analysis and cluster analysis are further applied to separate the different muscles between low or high perfusion increase, yielding a functional map of the leg. Data from 10 subjects (five normal volunteers and five elite sportsmen) had been analyzed. Resulting time perfusion curves from a region of interest (ROI) in active muscles show a good accordance whether extracted with automated processing or with manual processing. This method of functional segmentation allows automated suppression of vessels and fast visualization of muscles with high, medium or low perfusion, without any a priori knowledge.     

Monitoring of extra-axial brain tumor response to radiotherapy using pseudo-continuous arterial spin labeling images: Preliminary results

IntroductionTechnological developments have increased the ease of performing perfusion MRI by arterial spin labeling (ASL) in clinical settings. The objective of this study was to evaluate the effects of radiotherapy on extra-axial brain tumors by using MR perfusion images obtained using the pseudo-continuous arterial spin labeling (pcASL) method.Materials and MethodsSix consecutive patients (nine lesions) with extra-axial brain tumors treated only with radiotherapy were enrolled in this study. MR examinations, including pcASL imaging, were performed before and after radiotherapy. Cerebral blood flow, maximum tumor blood flow (mTBF), tumor volume and the ratio of signal enhancement by contrast material (enhancement ratio) were evaluated in serial examinations during the course of radiotherapy. Both the percentage change in mTBF (mTBF ratio) and the percentage change in volume (volume ratio) were calculated using values obtained before and after radiotherapy. The correlation between the volume ratio and the mTBF ratio was assessed using linear regression analysis and Spearman’s rank correlation coefficient (r_s).ResultsA strong correlation was demonstrated between the tumor volume ratio and the mTBF ratio before and after radiotherapy (r_s= 0.93, P< .01). However, no significant correlation was identified between changes in enhancement and volume ratio (r_s= 0.20) or between changes in enhancement and mTBF ratio (r_s= 0.30) before and after radiotherapy.ConclusionThe mTBF measured using pcASL may serve as an additive index for tumor volume when determining tumor response to radiotherapy even in the absence of contrast material.     

Arterial spin labeling MRI for assessment of perfusion in native and transplanted kidneys

Purpose

To apply a magnetic resonance arterial spin labeling (ASL) technique to evaluate kidney perfusion in native and transplanted kidneys.

Materials and Methods

This study was compliant with the Health Insurance Portability and Accountability Act and approved by the institutional review board. Informed consent was obtained from all subjects. Renal perfusion exams were performed at 1.5 T in a total of 25 subjects: 10 with native and 15 with transplanted kidneys. A flow-sensitive alternating inversion recovery (FAIR) ASL sequence was performed with respiratory triggering in all subjects and under free-breathing conditions in five transplant subjects. Thirty-two control/tag pairs were acquired and processed using a single-compartment model. Perfusion in native and transplanted kidneys was compared above and below an estimated glomerular filtration rate (eGFR) threshold of 60 ml/min per 1.73 m² and correlations with eGFR were determined.

Results

In many of the transplanted kidneys, major feeding vessels in the coronal plane required a slice orientation sagittal to the kidney. Renal motion during the examination was observed in native and transplant subjects and was corrected with registration. Cortical perfusion correlated with eGFR in native (r=0.85, P=.002) and transplant subjects (r=0.61, P=.02). For subjects with eGFR >60 ml/min per 1.73 m², native kidneys demonstrated greater cortical (P=.01) and medullary (P=.04) perfusion than transplanted kidneys. For subjects with eGFR <60 ml/min per 1.73 m², native kidneys demonstrated greater medullary perfusion (P=.04) compared to transplanted kidneys. Free-breathing acquisitions provided renal perfusion measurements that were slightly lower compared to the coached/triggered technique, although no statistical differences were observed.

Conclusion

In conclusion, FAIR-ASL was able to measure renal perfusion in subjects with native and transplanted kidneys, potentially providing a clinically viable technique for monitoring kidney function.     

Pulsed arterial spin labeling perfusion imaging at 3 T: estimating the number of subjects required in common designs of clinical trials

Pulsed arterial spin labeling (PASL) is an increasingly common technique for noninvasively measuring cerebral blood flow (CBF) and has previously been shown to have good repeatability. It is likely to find a place in clinical trials and in particular the investigation of pharmaceutical agents active in the central nervous system. We aimed to estimate the sample sizes necessary to detect regional changes in CBF in common types of clinical trial design including (a) between groups, (b) a two-period crossover and (3) within-session single dosing. Whole brain CBF data were acquired at 3 T in two independent groups of healthy volunteers at rest; one of the groups underwent a repeat scan. Using these data, we were able to estimate between-groups, between-session and within-session variability along with regional mean estimates of CBF. We assessed the number of PASL tag-control image pairs that was needed to provide stable regional estimates of CBF and variability of regional CBF across groups. Forty tag-control image pairs, which take approximately 3 min to acquire using a single inversion label delay time, were adequate for providing stable CBF estimates at the group level. Power calculations based on the variance estimates of regional CBF measurements suggest that comparatively small cohorts are adequate. For example, detecting a 15% change in CBF, depending on the region of interest, requires from 7-15 subjects per group in a crossover design, 6-10 subjects in a within-session design and 20-41 subjects in a between-groups design. Such sample sizes make feasible the use of such CBF measurements in clinical trials of drugs.     

Two analytical solutions for a model of pulsed arterial spin labeling with randomized blood arrival times

A fairly general theoretical model for pulsed arterial spin labeling perfusion methods has been available for some time but analytical solutions were derived for only a small number of arterial blood input functions. These mostly assumed a sudden and simultaneous arrival of the tagged blood into the imaged region. More general cases had to be handled numerically. We present analytical solutions for two more realistic arterial input functions. They both allow the arrival times of the molecules of tagged arterial blood to be statistically distributed. We consider cases of (1) a uniform distribution on a finite time interval and (2) a normal distribution characterized by its mean and standard deviation. These models are physiologically meaningful because the statistical nature of the arrival times reflects the distribution of velocities and path lengths that the blood water molecules undertake from the tagging region to the imaged region. The model parameters can be estimated from the measured dependency of the perfusion signal on the tag inversion time.     

Nonlinear magnetic field gradients can reduce SAR in flow-driven arterial spin labeling measurements

This work describes how custom-built gradient coils, designed to generate magnetic fields with amplitudes that vary nonlinearly with position, can be used to reduce the potential for unsafe tissue heating during flow-driven arterial spin labeling processes. A model was developed to allow detailed analysis of the adiabatic excitation process used for flow-driven arterial water stimulation with elimination of tissue signal (FAWSETS) an arterial spin labeling method developed specifically for use in skeletal muscle. The model predicted that, by adjusting the amplitude of the gradient field, the specific absorption rate could be reduced by more than a factor of 6 while still achieving effective labeling. Flow phantom measurements and in vivo measurements from exercising rat hind limb confirmed the accuracy of the model's predictions. The modeling tools were also applied to the more widely used continuous arterial spin labeling (CASL) method and predicted that specially shaped gradients could allow similar reductions in SAR.     

Abnormalities of cerebral blood flow in multiple sclerosis: A pseudocontinuous arterial spin labeling MRI study

Arterial spin labeling (ASL) is a noninvasive technique that can measure cerebral blood flow (CBF). To our knowledge, there is no study that examined regional CBF of multiple sclerosis (MS) patients by using this technique. The present study assessed the relationship between clinical presentations and functional imaging data in MS using pseudocontinuous arterial spin labeling (pCASL). Twenty-seven patients with MS and 24 healthy volunteers underwent magnetic resonance imaging and pCASL to assess CBF. Differences in CBF between the two groups and the relationships of CBF values with the T2-hyperintense volume were evaluated. Compared to the healthy volunteers, reduced CBF was found in the bilateral thalami and right frontal region of the MS patients. The volume of the T2-hyperintense lesion was negatively correlated with regional CBF in some areas, such as both thalami. Our results suggest that demyelinated lesions in MS mainly have a remote effect on the thalamus and that the measurement of CBF using ASL could be an objective marker for monitoring disease activity in MS.     

Absolute quantification of cerebral blood flow: correlation between dynamic susceptibility contrast MRI and model-free arterial spin labeling

Purpose

To compare absolute cerebral blood flow (CBF) estimates obtained by model-free arterial spin labeling (ASL) and dynamic susceptibility contrast MRI (DSC-MRI), corrected for partial volume effects (PVEs).

Methods

CBF was measured using DSC-MRI and model-free ASL (quantitative signal targeting with alternating radiofrequency labeling of arterial regions) at 3 T in 15 subjects with brain tumor, and the two modalities were compared with regard to CBF estimates in normal gray matter (GM) and DSC-to-ASL CBF ratios in selected tumor regions. The DSC-MRI CBF maps were calculated using a global arterial input function (AIF) from the sylvian-fissure region, but, in order to minimize PVEs, the AIF time integral was rescaled by a venous output function time integral obtained from the sagittal sinus.

Results

In GM, the average DSC-MRI CBF estimate was 150±45 ml/(min 100 g) (mean±SD) while the corresponding ASL CBF was 44±10 ml/(min 100 g). The linear correlation between GM CBF estimates obtained by DSC-MRI and ASL was r=.89, and observed DSC-to-ASL CBF ratios differed by less than 3% between GM and tumor regions.

Conclusions

A satisfactory positive linear correlation between the CBF estimates obtained by model-free ASL and DSC-MRI was observed, and DSC-to-ASL CBF ratios showed no obvious tissue dependence.     

Resolving domains of interdigitated phospholipid membranes with 95 GHz spin labeling EPR

High-field W-band (95 GHz) electron paramagnetic resonance (EPR) study of partitioning of a small nitroxide TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) in multilamellar liposomes composed from 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) is described. The high-resolution spectra with a high signal-to-noise ratio were combined with automated least-squares simulation analysis to derive accurate partitioning coefficients of TEMPO in the membrane lipid phase and to follow the membrane phase transitions. The isotropic magnetic parameters, g_iso and A_iso were used to characterize the average polarity the spin label is experiencing in the membrane. We also report an empirical correlation between g_iso and A_iso for a set of protic and aprotic solvents and use this correlation to assign domains formed by interdigitation of DPPC bilayer under a high ethanol concentration of 1.2 M.     

Azurin-Solvent interaction: an ESR spin labeling investigation

We have investigated by means of electron spin resonance (ESR) spectroscopy using two spin labels, Iodoacetamido-proxyl and 3-Maleimido-proxyl, the dynamics of two different regious around the active site of azurin, a copper containing blue protein. The ESR measurements of spin labeled azurin have been carried out in the 110–300 K temperature range on wet (H₂O, D₂O and ethanol/water mixtures) and lyophilized samples. The behaviours of the outer hyperfine splitting separation, 2A′ _zz , of the ESR spectravs temperature of the lyophilized, and fully hydrated azurin in H₂O and D₂O suggest that the two spin labels are located in regions of the protein surface with different dynamics and polarity. Moreover, all differences in the 2A′ _zz values shown by the spin labeled azurin in normal and heavy water as well as the temperature behaviour disappear when azurin is in ethanol/water mixtures. The results are discussed in terms of a close correlation between the molecular dynamics of the protein fragments to which the two spin labels are bound and the properties of the solvent used.     

Origins of intersubject variability of blood oxygenation level dependent and arterial spin labeling fMRI: implications for quantification of brain activity

Accurate localization of brain activity using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has been challenged because of the large BOLD signal within distal veins. Arterial spin labeling (ASL) techniques offer greater sensitivity to the microvasculature but possess low temporal resolution and limited brain coverage. In this study, we show that the physiological origins of BOLD and ASL depend on whether percent change or statistical significance is being considered. For BOLD and ASL fMRI data collected during a simple unilateral hand movement task, we found that in the area of the contralateral motor cortex the centre of gravity (CoG) of the intersubject coefficient of variation (CV) of BOLD fMRI was near the brain surface for percent change in signal, whereas the CoG of the intersubject CV for Z-score was in close proximity of sites of brain activity for both BOLD and ASL. These findings suggest that intersubject variability of BOLD percent change is vascular in origin, whereas the origin of inter-subject variability of Z-score is neuronal for both BOLD and ASL. For longer duration tasks (12 s or greater), however, there was a significant correlation between BOLD and ASL percent change, which was not evident for short duration tasks (6 s). These findings suggest that analyses directly comparing percent change in BOLD signal between pre-defined regions of interest using short duration stimuli, as for example in event-related designs, may be heavily weighted by large-vessel responses rather than neuronal responses.