Measurement of rat brain perfusion by NMR using spin labeling of arterial water: In vivo determination of the degree of spin labeling

In vivo NMR experiments are performed to determine the degree of spin labeling for measurement of tissue perfusion by NMR using spin labeling of arterial water by adiabatic fast passage. Arterial water spins are labeled using flow in the presence of a field gradient and B₁ irradiation to fulfill the conditions for adiabatic fast passage spin inversion. It is demonstrated that the NMR-measured tissue perfusion is not affected by changing the degree of spin labeling as long as the degree of spin labeling is determined and accounted for according to the model used for calculating perfusion. By measuring the degree of spin labeling with different arterial blood flow velocities induced by different arterial pCO₂, it is also demonstrated that, when spin labeling is carried out by adiabatic fast passage, the degree of spin labeling is not affected by changes in arterial blood flow velocity over a broad range.     

Skeletal muscle perfusion measurements using adiabatic inversion of arterial water

Quantitative NMR measurements of perfusion using magnetic labeling of arterial water have been demonstrated previously in several different highly perfused organs. The success of these previous experiments suggested that arterial labeling may be of use in measuring perfusion in skeletal muscle, where resting perfusion is very low and where increased perfusion after exercise is transient. In the experiments described in this paper, adiabatic inversion of arterial water has been used to make single-voxel measurements of perfusion in the lower hind limb of rats. At rest, the NMR results were quantified to yield a perfusion rate of about 13.8 ml/100g/min. After perturbation due to ischemic exercise, large relative changes in the NMR signal were observed. The peak change of about 2.5% of the NMR signal occurred shortly after perturbation and was followed by a return to resting levels over a period of about 4 min.     

Improved accuracy of human cerebral blood perfusion measurements using arterial spin labeling: accounting for capillary water permeability.

A two-compartment exchange model for perfusion quantification using arterial spin labeling (ASL) is presented, which corrects for the assumption that the capillary wall has infinite permeability to water. The model incorporates an extravascular and a blood compartment with the permeability surface area product (PS) of the capillary wall characterizing the passage of water between the compartments. The new model predicts that labeled spins spend longer in the blood compartment before exchange. This makes an accurate blood T(1) measurement crucial for perfusion quantification; conversely, the tissue T(1) measurement is less important and may be unnecessary for pulsed ASL experiments. The model gives up to 62% reduction in perfusion estimate for human imaging at 1.5T compared to the single compartment model. For typical human perfusion rates at 1.5T it can be assumed that the venous outflow signal is negligible. This simplifies the solution, introducing only one more parameter than the single compartment model, PS/v(bw), where v(bw) is the fractional blood water volume per unit volume of tissue. The simplified model produces an improved fit to continuous ASL data collected at varying delay time. The fitting yields reasonable values for perfusion and PS/v(bw).     

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.     

Cerebral perfusion and arterial transit time changes during task activation determined with continuous arterial spin labeling.

Perfusion imaging by arterial spin labeling (ASL) can be highly sensitive to the transit time from the labeling site to the tissue. We report the results of a study designed to separate the transit time and perfusion contributions to activation in ASL images accompanying motor and visual stimulation. Fractional transit time decreases were found to be comparable to fractional perfusion increases and the transit time change was found to be the greatest contributor to ASL signal change in ASL sequences without delayed acquisition. The implications for activation imaging with ASL and the arterial control of flow are discussed.     

A two‐stage approach for measuring vascular water exchange and arterial transit time by diffusion‐weighted perfusion MRI

Changes in the exchange rate of water across the blood‐brain barrier, denoted k_w, may indicate blood‐brain barrier dysfunction before the leakage of large‐molecule contrast agents is observable. A previously proposed approach for measuring k_w is to use diffusion‐weighted arterial spin labeling to measure the vascular and tissue fractions of labeled water, because the vascular‐to‐tissue ratio is related to k_w. However, the accuracy of diffusion‐weighted arterial spin labeling is affected by arterial blood contributions and the arterial transit time (τ_a). To address these issues, a two‐stage method is proposed that uses combinations of diffusion‐weighted gradient strengths and post‐labeling delays to measure both τ_a and k_w. The feasibility of this method was assessed by acquiring diffusion‐weighted arterial spin labeling data from seven healthy volunteers. Repeat measurements and Monte Carlo simulations were conducted to determine the precision and accuracy of the k_w estimates. Average grey and white matter k_w values were 110 ± 18 and 126 ± 18 min^?1, respectively, which compare favorably to blood‐brain barrier permeability measurements obtained with positron emission tomography. The intrasubject coefficient of variation was 26% ± 23% in grey matter and 21% ± 17% in white matter, indicating that reproducible k_w measurements can be obtained. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.     

Localized proton NMR spectroscopy of brain tumors using short-echo time STEAM sequences

Recent progress in localized proton NMR spectroscopy has been utilized to improve the spatial resolution and the metabolic specificity in a study of 19 patients with intracranial tumors. Selected examples demonstrate that short echo time stimulated echo acquisition mode sequences are able (a) to account for macroscopic tissue heterogeneity by reducing the volume of interest to 2-8 ml and (b) to facilitate a reasonable characterization of tumor metabolism by increasing the number of accessible metabolites. Proton NMR spectra were acquired within measuring times of 6.5 min on a 2.0 T whole-body system using the imaging headcoil.     

Reduction of errors in ASL cerebral perfusion and arterial transit time maps using image de‐noising

In this work, the performance of image de‐noising techniques for reducing errors in arterial spin labeling cerebral blood flow and arterial transit time estimates is investigated. Simulations were used to show that the established arterial spin labeling cerebral blood flow quantification method exhibits the bias behavior common to nonlinear model estimates, and as a result, the reduction of random errors using image de‐noising can improve accuracy. To assess the effect on precision, multiple arterial spin labeling data sets acquired from the rat brain were processed using a variety of common de‐noising methods (Wiener filter, anisotropic diffusion filter, gaussian filter, wavelet decomposition, and independent component analyses). The various de‐noising schemes were also applied to human arterial spin labeling data to assess the possible extent of structure degradation due to excessive spatial smoothing. The animal experiments and simulated data show that noise reduction methods can suppress both random and systematic errors, improving both the precision and accuracy of cerebral blood flow measurements and the precision of transit time maps. A number of these methods (and particularly independent component analysis) were shown to achieve this aim without compromising image contrast. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Volumetric measurement of perfusion and arterial transit delay using hadamard encoded continuous arterial spin labeling

Creating images of the transit delay from the labeling location to image tissue can aid the optimization and quantification of arterial spin labeling perfusion measurements and may provide diagnostic information independent of perfusion. Unfortunately, measuring transit delay requires acquiring a series of images with different labeling timing that adds to the time cost and increases the noise of the arterial spin labeling study. Here, we implement and evaluate a proposed Hadamard encoding of labeling that speeds the imaging and improves the signal‐to‐noise ratio efficiency. Volumetric images in human volunteers confirmed the theoretical advantages of Hadamard encoding over sequential acquisition of images with multiple labeling timing. Perfusion images calculated from Hadamard encoded acquisition had reduced signal‐to‐noise ratio relative to a dedicated perfusion acquisition with either assumed or separately measured transit delays, however. Magn Reson Med 69:1014–1022, 2013. © 2012 Wiley Periodicals, Inc.     

Magnetic resonance imaging of perfusion in the isolated rat heart using spin inversion of arterial water

Measurement of regional myocardial perfusion is important for the diagnosis and treatment of coronary artery disease. Currently used methods for the measurement of myocardial tissue perfusion are either invasive or not quantitative. Here, we demonstrate a technique for the measurement of myocardial perfusion using magnetic resonance imaging (MRI) with spin tagging of arterial water. In addition, it is shown that changes in perfusion can be quantitated by measuring changes in tissue T₁. Perfusion images are obtained in Lan-gondorff-perfused, isolated rat hearts for perfusion rates ranging from 5 to 22 ml/g/min. The MRI-determined perfusion rates are in excellent agreement with perfusion rates determined from measurement of bulk perfusate flow (r = 0.98). The predicted linear dependence of the measured T₁ (T_1app) on per-fusion is also demonstrated. The ability of perfusion imaging to measure regional variations in flow is demonstrated with hearts in which perfusion defects were created by ligation of a (coronary artery. These results indicate that MRI of perfusion using spin inversion of arterial water gives quantitative maps of cardiac perfusion.     

Estimation of perfusion and arterial transit time in myocardium using free‐breathing myocardial arterial spin labeling with navigator‐echo

Arterial spin labeling (ASL) provides noninvasive measurement of tissue blood flow, but sensitivity to motion has limited its application to imaging of myocardial blood flow. Although different cardiac phases can be synchronized using electrocardiography triggering, breath holding is generally required to minimize effects of respiratory motion during ASL scanning, which may be challenging in clinical populations. Here a free‐breathing myocardial ASL technique with the potential for reliable clinical application is presented, by combining ASL with a navigator‐gated, electrocardiography‐triggered TrueFISP readout sequence. Dynamic myocardial perfusion signals were measured at multiple delay times that allowed simultaneous fitting of myocardial blood flow and arterial transit time. With the assist of a nonrigid motion correction program, the estimated mean myocardial blood flow was 1.00 ± 0.55 mL/g/min with a mean transit time of ∼400 msec. The intraclass correlation coefficient of repeated scans was 0.89 with a mean within subject coefficient of variation of 22%. Perfusion response during mild to moderate stress was further measured. The capability for noninvasive, free‐breathing assessment of myocardial blood flow using ASL may offer an alternative approach to first‐pass perfusion MRI for clinical evaluation of patients with coronary artery disease. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Efficient sampling of early signal arrival for estimation of perfusion and transit time in whole-brain arterial spin labeling

Arterial spin labeling can be used to measure both cerebral perfusion and arterial transit time. However, accurate estimation of these parameters requires adequate temporal sampling of the arterial spin labeling difference signal. In whole-brain multislice acquisitions, two factors reduce the accuracy of the parameter estimates: saturation of labeled blood in transit and inadequate sampling of early difference signal in superior slices. Label saturation arises when slices are acquired inferior-to-superior such that slice selection in proximal slices spoils the label for a distal slice. Inadequate sampling arises when the time spent acquiring inferior slices is too long to allow early sampling of the difference signal in superior slices. A novel approach to multislice imaging is proposed to address these two issues. In round-robin arterial spin labeling, slices are acquired in a different order after every pair of control-label acquisitions. Round-robin arterial spin labeling enables the acquisitions of all slices across the same range of postlabel delays in a descending superior-to-inferior order. This eliminates the temporal sampling problem and greatly reduces label saturation. Arterial transit time estimates obtained for the whole brain with round-robin arterial spin labeling show better agreement with a single-slice acquisition than do conventional multislice acquisitions.     

Measurement of human myocardial perfusion by double-gated flow alternating inversion recovery EPI.

This paper presents a flow-sensitive alternating inversion recovery (FAIR) method for measuring human myocardial perfusion at 1.5 T. Slice-selective/non-selective IR images were collected using a double-gated IR echoplanar imaging sequence. Myocardial perfusion was calculated after T1 fitting and extrapolation of the mean signal difference SI(Sel - SI(NSel). The accuracy of the method was tested in a porcine model using graded intravenous adenosine dose challenge. Comparison with radiolabeled microsphere measurements showed a good correlation (r = 0.84; mean error = 20%, n = 6) over the range of flows tested (0.9-7 ml/g/min). Applied in humans, this method allowed for the measurement of resting myocardial flow (1.04+/-0.37 ml/g/min, n = 11). The noise in our human measurements (SE(flow) = 0.2 ml/g/min) appears to come primarily from residual respiratory motion. Although the current signal-to-noise ratio limits our ability to measure small fluctuations in resting flow accurately, the results indicate that this noninvasive method has great promise for the quantitative assessment of myocardial flow reserve in humans.     

Hepatic vein transit time of an ultrasound contrast agent: simplified procedure using pulse inversion imaging

The aim of this study was to ascertain whether a new ultrasound technique, namely pulse inversion imaging, could assess the arrival of a contrast agent in the hepatic veins, and to describe possible advantages of this procedure in determining transit time over a previously described method based upon spectral Doppler quantification. 15 subjects were scanned using pulse inversion imaging. A bolus injection of 2.5 g Levovist (Schering AG, Berlin, Germany) 300 mg x ml(-1) was given into an antecubital vein. Median transit times of 16 s (range 14-20 s) were found in patients with liver cirrhosis (n=4), 22 s (range 16-27 s) in patients with focal liver lesions (n=8) and 31 s (range 30-32 s) in control subjects (n=3). The maximum interobserver variation was 2 s and the maximum intraobserver variation was 3 s (n=10). Transit time was assessed by both pulse inversion imaging and spectral Doppler quantification in six patients. Comparison of the two methods showed transit times within 2 s apart in five patients and within 5 s apart in one patient. In conclusion, it is possible to assess transit time using pulse inversion imaging. This method is simpler than a previously described method requiring computer analysis. Moreover, several liver veins can be assessed simultaneously. Different transit times were observed in different liver veins in two patients with liver tumours. A short transit time (<27 s) appears to be found only in patients with liver disease. After transit time assessment, it is possible to use the injected contrast agent for late phase imaging of the liver parenchyma.     

Multislice perfusion imaging in human brain using the C-FOCI inversion pulse: comparison with hyperbolic secant.

Perfusion studies based on pulsed arterial spin labeling have primarily applied hyperbolic secant (HS) pulses for spin inversion. To optimize perfusion sensitivity, it is highly desirable to implement the HS pulse with the same slice width as the width of the imaging pulse. Unfortunately, this approach causes interactions between the slice profiles and manifests as residual signal from static tissue in the resultant perfusion image. This problem is currently overcome by increasing the selective HS width relative to the imaging slice width. However, this solution increases the time for the labeled blood to reach the imaging slice (transit time), causing loss of perfusion sensitivity as a result of T(1) relaxation effects. In this study, we demonstrate that the preceding problems can be largely overcome by use of the C-shaped frequency offset corrected inversion (FOCI) pulse [Ordidge et al., Magn Reson Med 1996;36:562]. The implementation of this pulse for multislice perfusion imaging on the cerebrum is presented, showing substantial improvement in slice definition in vivo compared with the HS pulse. The sharper FOCI profile is shown to reduce the physical gap (or "safety margin") between the inversion and imaging slabs, resulting in a significant increase in perfusion signal without residual contamination from static tissue. The mean +/- SE (n = 6) gray matter perfusion-weighted signal (DeltaM/M(o)) without the application of vascular signal suppression gradients were 1.19 +/- 0. 10% (HS-flow-sensitive alternating inversion recovery [FAIR]), and 1. 51 +/- 0.11% for the FOCI-FAIR sequence. The corresponding values with vascular signal suppression were 0.64 +/- 0.14%, and 0.91 +/- 0. 08% using the HS- and FOCI-FAIR sequences, respectively. Compared with the HS-based data, the FOCI-FAIR results correspond to an average increase in perfusion signal of up to between 26%-30%. Magn Reson Med 42:1098-1105, 1999.     

Localized 15N NMR spectroscopy of rat brain by ISIS.

Three-dimensional image-selected in vivo spectroscopy (ISIS), combined with proton-decoupled nuclear-Overhauser-enhanced 15N nuclear magnetic resonance (NMR), was used to localize [15N]metabolites, observed by a head coil, to the brain in rats. In spontaneously breathing anesthetized rats given intravenous [15N]ammonium acetate infusion, brain [5-15N]glutamine was observed in the localized spectrum with a v1/2 of 5 Hz in 19-28 min at 4.7 T, while the signal from blood [15N]urea was eliminated by the localization process. In rats given [15N]leucine infusion, the peak representing predominantly (89%) brain [15N]glutamate was observed, with elimination of the signal from muscle [15N]alanine. In vivo peak areas of the brain [15N]metabolites in the localized spectra were proportional to their concentrations. The advantages and limitations of localization by ISIS using a volume coil with a homogeneous B1 field are compared with those of localization by a surface coil for in vivo 15N NMR study of neurotransmitters in the brain.     

Ultrafast 2D NMR spectroscopy using sinusoidal gradients: principles and ex vivo brain investigations.

A new methodology capable of delivering complete 2D NMR spectra within a single scan was recently introduced. The resulting potential gain in time resolution could open new opportunities for in vivo spectroscopy, provided that the technical demands of the methodology are satisfied by the corresponding hardware. Foremost among these demands are the relatively short switching times expected from the applied gradient-echo trains. These rapid transitions may be particularly difficult to accomplish on imaging systems. As a step toward solving this problem, we assessed the possibility of replacing the square-wave gradient train currently used during the course of the acquisition by a shaped sinusoidal gradient. Examples of the implementation of this protocol are given, and successful ultrafast acquisitions of 2D NMR spectra with suitable spectral widths on a microimaging probe (for both phantom solutions and ex vivo mouse brains) are demonstrated.     

Modeling and optimization of Look-Locker spin labeling for measuring perfusion and transit time changes in activation studies taking into account arterial blood volume.

This work describes a new compartmental model with step-wise temporal analysis for a Look-Locker (LL)-flow-sensitive alternating inversion-recovery (FAIR) sequence, which combines the FAIR arterial spin labeling (ASL) scheme with a LL echo planar imaging (EPI) measurement, using a multireadout EPI sequence for simultaneous perfusion and T*(2) measurements. The new model highlights the importance of accounting for the transit time of blood through the arteriolar compartment, delta, in the quantification of perfusion. The signal expected is calculated in a step-wise manner to avoid discontinuities between different compartments. The optimal LL-FAIR pulse sequence timings for the measurement of perfusion with high signal-to-noise ratio (SNR), and high temporal resolution at 1.5, 3, and 7T are presented. LL-FAIR is shown to provide better SNR per unit time compared to standard FAIR. The sequence has been used experimentally for simultaneous monitoring of perfusion, transit time, and T*(2) changes in response to a visual stimulus in four subjects. It was found that perfusion increased by 83 +/- 4% on brain activation from a resting state value of 94 +/- 13 ml/100 g/min, while T*(2) increased by 3.5 +/- 0.5%.     

In vivo 1H NMR spectroscopy of rat brain at 1 ms echo time.

Using optimized, asymmetric radiofrequency (RF) pulses for slice selection, the authors demonstrate that stimulated echo acquisition mode (STEAM) localization with ultra-short echo time (1 ms) is possible. Water suppression was designed to minimize sensitivity to B1 inhomogeneity using a combination of 7 variable power RF pulses with optimized relaxation delays (VAPOR). Residual water signal was well below the level of most observable metabolites. Contamination by the signals arising from outside the volume of interest was minimized by outer volume saturation using a series of hyperbolic secant RF pulses, resulting in a sharp volume definition. In conjunction with FASTMAP shimming (Gruetter Magn Reson Med 1993;29: 804-811), the short echo time of 1 msec resulted in highly resolved in vivo 1H nuclear magnetic resonance spectra. In rat brain the water linewidths of 11-13 Hz and metabolite singlet linewidths of 8-10 Hz were measured in 65 microl volumes. Very broad intense signals (delta v(1/2) > 1 kHz), as expected from membranes, for example, were not observed, suggesting that their proton T2 are well below 1 msec. The entire chemical shift range of 1H spectrum was observable, including resolved resonances from alanine, aspartate, choline group, creatine, GABA, glucose, glutamate, glutamine, myo-inositol, lactate, N-acetylaspartate, N-acetylaspartylglutamate, phosphocreatine, and taurine. At 9.4 T, peaks close to the water were observed, including the H-1 of alpha-D-glucose at 5.23 ppm and a tentative H-1 resonance of glycogen at 5.35 ppm.