Single-shot 3D imaging techniques improve arterial spin labeling perfusion measurements

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Single-Shot 3D Imaging Techniques Improve Arterial Spin Labeling Perfusion Measurements Matthias Gu ¨ nther,* Koichi Oshio, and David A. Feinberg Arterial spin labeling (ASL) can be used to measure perfusion without the use of contrast agents. Due to the small volume fraction of blood vessels compared to tissue in the human brain (typ. 3–5%) ASL techniques have an intrinsically low signal-to- noise ratio (SNR). In this publication, evidence is presented that the SNR can be improved by using arterial spin labeling in combination with single-shot 3D readout techniques. Specifi- cally, a single-shot 3D-GRASE sequence is presented, which yields a 2.8-fold increase in SNR compared to 2D EPI at the same nominal resolution. Up to 18 slices can be acquired in 2 min with an SNR of 10 or more for gray matter perfusion. A method is proposed to increase the reliability of perfusion quantification using QUIPSS II derivates by acquiring low-res- olution maps of the bolus arrival time, which allows differenti- ation between lack of perfusion and delayed arrival of the la- beled blood. For arterial spin labeling, single-shot 3D imaging techniques are optimal in terms of efficiency and might prove beneficial to improve reliability of perfusion quantitation in a clinical setup. Magn Reson Med 54:491– 498, 2005. © 2005 Wiley-Liss, Inc. Key words: perfusion; arterial spin labeling; GRASE; single-shot 3D; imaging technique; high signal-to-noise ratio Arterial spin labeling (ASL) can be used to measure per- fusion without the use of contrast agents (1– 4). ASL is encumbered by its intrinsically low signal-to-noise ratio (SNR), due to the small volume fraction of vessels com- pared to tissue in the human brain, typically 3–5%. None- theless, this technique is widely used in various research areas to quantify perfusion noninvasively since ASL offers the possibility of yielding quantitative perfusion values in a more direct way compared to contrast-enhanced mea- surements. However, reliable quantification is still a great challenge and currently limits the clinical usefulness. In EPI-based ASL techniques, several signal averages are used to achieve sufficient SNR in perfusion measurements. As an alternative approach to raising SNR, consideration can be given to using single-shot 3D EPI (echo volumnar imaging (5)). The intrinsically higher sensitivity in 3D imaging compared to 2D multislice single-shot imaging is due to the larger number of signals sampled in each voxel. In 2D multislice EPI, one can define M signals/image and N independently acquired images. In comparison, 3D single- shot EPI (EVI) acquires a larger number of signals per image equal to N M, with N partitioned slices obtained with the second phase encoded image axis. While the higher SNR of EVI would be highly desirable for ASL, EVI has more severe image distortions, blurring, signal loss, and artifacts than EPI. The poor image quality of EVI is due to its longer echo train in the presence of T 2 * decay, which increases sensitivity to field inhomogeneity and suscepti- bility compared to EPI. This has made EVI essentially useless as a readout sequence for most applications. The development of single-shot 3D GRASE could improve the SNR of ASL techniques similar to EVI but without the severe distortions and other image quality problems inher- ent to EVI (6). The CPMG spin echo sequence, being an integral component of the 3D GRASE sequence, would preserve signal amplitude in long echo trains far better than the rapid T 2 * decays of EPI and EVI. In addition to SNR problems, major issues in quantita- tive perfusion measurements using ASL, which might re- sult in inaccurate perfusion values, are contamination of the microvascular perfusion with macrovascular flow and different arrival times for the labeled blood in different regions (bolus arrival time, BAT). There are many publi- cations that address these issues, e.g., “crusher gradients” were suggested for suppression of intravascular blood sig- nal (7). Here, the faster flowing spins in the arteries are dephased by gradient pulses without fully refocused first moments. Nevertheless, the required strength of these gra- dients is difficult to estimate and time consuming to de- termine experimentally. Other techniques acquire the im- ages after the labeled blood has (presumably) left the ar- teries. In continuous ASL this can be done by delaying the image acquisition to longer inflow times (2), whereas in pulsed ASL the length of the bolus is limited by the ap- plication of additional saturation pulses upstream from the imaging slice a certain time before image acquisition begins (QUIPSS II (3) and Q2TIPS (4)). However, all these techniques have in common that the SNR of the resulting perfusion images, which is already intrinsically low, is decreased even further. The second problem, the variance of the BAT for differ- ent regions of the human brain, is also addressed by the above-mentioned presaturation-based techniques QUIPSS II and Q2TIPS. Since the labeled blood bolus does not reach each region of the brain at the same time, the image acquisition must be delayed to later TIs to ensure that the bolus has arrived in all areas of a particular slice at the time of acquisition. This might pose a problem in com- monly used multislice 2D EPI imaging where each slice is measured at different inflow times TI after labeling of the blood. Slices are acquired in a sequential or interleaved manner and usually assume an inflow from inferior to superior slices, which may not be true for the vascular physiology of the human brain. Advanced MRI Technologies, Sebastopol, California, U.S.A. Grant sponsor: National Center for Research Resources; Contract grant num- ber: NIH R01RR13618 – 01A1. *Correspondence to: Matthias Gu ¨ nther, Advanced MRI Technologies, 652 Petaluma Avenue, Sebastopol, CA 95472, U.S.A. E-mail: [email protected] Received 16 June 2004; revised 14 February 2005; accepted 11 March 2005. DOI 10.1002/mrm.20580 Published online in Wiley InterScience (www.interscience.wiley.com). Magnetic Resonance in Medicine 54:491– 498 (2005) © 2005 Wiley-Liss, Inc. 491

Transcript of Single-shot 3D imaging techniques improve arterial spin labeling perfusion measurements

Page 1: Single-shot 3D imaging techniques improve arterial spin labeling perfusion measurements

Single-Shot 3D Imaging Techniques Improve ArterialSpin Labeling Perfusion Measurements

Matthias Gunther,* Koichi Oshio, and David A. Feinberg

Arterial spin labeling (ASL) can be used to measure perfusionwithout the use of contrast agents. Due to the small volumefraction of blood vessels compared to tissue in the human brain(typ. 3–5%) ASL techniques have an intrinsically low signal-to-noise ratio (SNR). In this publication, evidence is presented thatthe SNR can be improved by using arterial spin labeling incombination with single-shot 3D readout techniques. Specifi-cally, a single-shot 3D-GRASE sequence is presented, whichyields a 2.8-fold increase in SNR compared to 2D EPI at thesame nominal resolution. Up to 18 slices can be acquired in2 min with an SNR of 10 or more for gray matter perfusion. Amethod is proposed to increase the reliability of perfusionquantification using QUIPSS II derivates by acquiring low-res-olution maps of the bolus arrival time, which allows differenti-ation between lack of perfusion and delayed arrival of the la-beled blood. For arterial spin labeling, single-shot 3D imagingtechniques are optimal in terms of efficiency and might provebeneficial to improve reliability of perfusion quantitation in aclinical setup. Magn Reson Med 54:491–498, 2005. © 2005Wiley-Liss, Inc.

Key words: perfusion; arterial spin labeling; GRASE; single-shot3D; imaging technique; high signal-to-noise ratio

Arterial spin labeling (ASL) can be used to measure per-fusion without the use of contrast agents (1–4). ASL isencumbered by its intrinsically low signal-to-noise ratio(SNR), due to the small volume fraction of vessels com-pared to tissue in the human brain, typically 3–5%. None-theless, this technique is widely used in various researchareas to quantify perfusion noninvasively since ASL offersthe possibility of yielding quantitative perfusion values ina more direct way compared to contrast-enhanced mea-surements. However, reliable quantification is still a greatchallenge and currently limits the clinical usefulness.

In EPI-based ASL techniques, several signal averages areused to achieve sufficient SNR in perfusion measurements.As an alternative approach to raising SNR, considerationcan be given to using single-shot 3D EPI (echo volumnarimaging (5)). The intrinsically higher sensitivity in 3Dimaging compared to 2D multislice single-shot imaging isdue to the larger number of signals sampled in each voxel.In 2D multislice EPI, one can define M signals/image and Nindependently acquired images. In comparison, 3D single-shot EPI (EVI) acquires a larger number of signals perimage equal to N � M, with N partitioned slices obtained

with the second phase encoded image axis. While thehigher SNR of EVI would be highly desirable for ASL, EVIhas more severe image distortions, blurring, signal loss,and artifacts than EPI. The poor image quality of EVI is dueto its longer echo train in the presence of T2* decay, whichincreases sensitivity to field inhomogeneity and suscepti-bility compared to EPI. This has made EVI essentiallyuseless as a readout sequence for most applications. Thedevelopment of single-shot 3D GRASE could improve theSNR of ASL techniques similar to EVI but without thesevere distortions and other image quality problems inher-ent to EVI (6). The CPMG spin echo sequence, being anintegral component of the 3D GRASE sequence, wouldpreserve signal amplitude in long echo trains far betterthan the rapid T2* decays of EPI and EVI.

In addition to SNR problems, major issues in quantita-tive perfusion measurements using ASL, which might re-sult in inaccurate perfusion values, are contamination ofthe microvascular perfusion with macrovascular flow anddifferent arrival times for the labeled blood in differentregions (bolus arrival time, BAT). There are many publi-cations that address these issues, e.g., “crusher gradients”were suggested for suppression of intravascular blood sig-nal (7). Here, the faster flowing spins in the arteries aredephased by gradient pulses without fully refocused firstmoments. Nevertheless, the required strength of these gra-dients is difficult to estimate and time consuming to de-termine experimentally. Other techniques acquire the im-ages after the labeled blood has (presumably) left the ar-teries. In continuous ASL this can be done by delaying theimage acquisition to longer inflow times (2), whereas inpulsed ASL the length of the bolus is limited by the ap-plication of additional saturation pulses upstream fromthe imaging slice a certain time before image acquisitionbegins (QUIPSS II (3) and Q2TIPS (4)). However, all thesetechniques have in common that the SNR of the resultingperfusion images, which is already intrinsically low, isdecreased even further.

The second problem, the variance of the BAT for differ-ent regions of the human brain, is also addressed by theabove-mentioned presaturation-based techniques QUIPSSII and Q2TIPS. Since the labeled blood bolus does notreach each region of the brain at the same time, the imageacquisition must be delayed to later TIs to ensure that thebolus has arrived in all areas of a particular slice at thetime of acquisition. This might pose a problem in com-monly used multislice 2D EPI imaging where each slice ismeasured at different inflow times TI after labeling of theblood. Slices are acquired in a sequential or interleavedmanner and usually assume an inflow from inferior tosuperior slices, which may not be true for the vascularphysiology of the human brain.

Advanced MRI Technologies, Sebastopol, California, U.S.A.Grant sponsor: National Center for Research Resources; Contract grant num-ber: NIH R01RR13618–01A1.*Correspondence to: Matthias Gunther, Advanced MRI Technologies,652 Petaluma Avenue, Sebastopol, CA 95472, U.S.A. E-mail:[email protected] 16 June 2004; revised 14 February 2005; accepted 11 March 2005.DOI 10.1002/mrm.20580Published online in Wiley InterScience (www.interscience.wiley.com).

Magnetic Resonance in Medicine 54:491–498 (2005)

© 2005 Wiley-Liss, Inc. 491

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In this work, we present a single-shot 3D imaging tech-nique whose SNR is high enough to acquire up to 18 sliceswith fairly good resolution in less than 2 min. This largereduction in imaging time results from the enormous im-provement in data acquisition efficiency since the whole3D image set is acquired after each ASL preparation. Usinga labeling and saturation scheme based on FAIR (1) andQ2TIPS (3,4) the presented technique allows the acquisi-tion of quantitative perfusion maps of almost the wholebrain at a resolution of 2.5 � 3.4 � 5.0 mm3 in less than2 min.

MATERIALS AND METHODS

A clinical 1.5-T scanner (Magnetom Sonata, Siemens, Er-langen, Germany) was used for imaging. Maximum gradi-ent strength was 40 mT/m with a slew rate of 200 mT/m/ms.

In typical ASL experiments the signal differences be-tween the label and the control images are of the order ofa few percent, which makes the MR scanner adjustmentineffective for the extracted blood signal. To overcome thisproblem background suppression techniques (8,9) weresuggested using multiple nonselective inversion pulses tonull the signal of the stationary tissue while leaving thesignal of the labeled blood untouched (for perfect pulses).For a given inflow time TI the following analytical solutionof the signal equations given in Ref. (8) was used to nulltwo components with T1 relaxations rates R1opt and0.5�R1opt using two inversion pulses at time �1 and �2:

�1.2(TI) � TI

�2

R1opt� ln��1

2�

14� � �1

2�

14� � e� 1/2 � TI � R1opt�. [1]

For the measurements an R1opt value of 500 ms was as-sumed. For an inflow time of 1800 ms the nulling of themagnetization was calculated to occur after 1700 ms toreduce artifacts due to different signs of the signal ofcomponents not matching R1opt and 0.5�R1opt. The posi-tions of the nonselective inversion pulses are then 751 and1471 ms after the labeling pulse.

A technique related to Q2TIPS (4) was applied withmultiple saturation pulses (thickness of saturation slabwas 40 mm) using the FAIR spin labeling scheme (1). Thestandard Q2TIPS method uses off-resonance saturationpulses relative to the imaging slab to produce a singlesaturation band proximal to the acquired slices before theimage readout takes place. This allows limiting the lengthof the labeled blood bolus and efficiently reduces intra-arterial blood signal in the resulting perfusion images. Inprinciple, the defined length of the labeled blood bolusalso allows quantification of microvascular perfusion. Incontrary, the proposed technique uses modulated satura-tion pulses, which result in two saturation bands on bothsides of the imaging slab. This suppresses intravascularblood flowing into the imaging slab from not only one butalso from both sides, thus also reducing the signal of mostvenous vessels. Furthermore, the image quality of the sin-gle-shot readout module can be improved by reducing thenecessary oversampling in the 3D encode direction to

avoid aliasing. The resulting slab profile with and withoutsaturation pulses was measured by exchanging the 3Dencode and the phase encode directions. This allows formore precise measurement of the profile.

The total inflow time was chosen to be 1600 ms with aduration TS of 700 ms. A single-shot 3D-GRASE sequencewas used as readout (see Fig. 1). Twenty-four repetitionswere applied (acquisition time: 2 min). Magnitude imagesafter nonselective and slice-selective inversion were aver-aged and subtracted to yield the perfusion images.

The resolution relevant parameters of the single shot 3D-GRASE sequence were matrix size 128 � 41, reconstructed to256 � 80, field of view 320 � 140 mm, nominal 18 partitions,no oversampling, partition thickness 6 mm, 5/8 Fourier en-coding was used to reduce the number of measured parti-tions to 11. Thus, a resolution of 2.5 � 3.4 � 6.0 mm3 wasachieved. Other parameters include echo time TE � 41 ms,repetition time TR � 2500 ms, total echo train length: 451echoes acquired within 480 ms (net sampling time: 312 ms),inter-RF spacing � 41 ms, bandwidth � 1446 Hz, off-reso-nance fat-saturation pulse. Readout, phase encode, and 3Dencode directions were anterior–posterior, left–right, andhead–feet, respectively. Each partition was acquired by asingle EPI echo train. Peripheral nerve stimulation was less-ened by decreasing the number of phase encoding steps perpartition, effectively reducing the duration of continuousgradient switching. Perfusion was quantified using the equa-tion given in Ref. (4).

In addition to these high-resolution images a lower re-solved time series at multiple TIs (200 to 2400 ms, 200-msincrements) was acquired with a saturation time TS of100 ms. The short TS of the times series is solely used toavoid infolding instead of suppressing vascular blood wa-ter signal. The time series were used to estimate the time ofthe arrival of the labeled blood in each voxel of each slice,which is customarily named BAT. The resolution relevantparameters of the single-shot 3D-GRASE sequence withlower spatial resolution were matrix size 64 � 36, recon-structed to 128 � 72, field of view 256 � 144 mm, nominal24 partitions without oversampling, partition thickness4.5 mm; 5/8 Fourier encoding was used to reduce thenumber of measured partitions to 15. Thus, an almost

FIG. 1. Schematic display of the arterial spin labeling sequencewith single-shot 3D-GRASE readout.

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isotropic resolution of 4.0 � 4.0 � 4.5 mm was achieved.Other parameters include echo time TE � 55 ms, repeti-tion time TR � 3000 ms, total echo train length: 615 echoesacquired within 430 ms, inter-RF spacing � 27 ms, band-width � 2442 Hz, off-resonance fat saturation pulse. Eightrepetitions per TI were applied (acquisition time: 48 s).Thus, total measurement time of time series was 9 min36 s.

Perfusion and BAT were estimated by fitting four param-eters (perfusion and BAT of microvascular and arterialcomponents) of a model to the data of this times series Themodel function allows the separation of macrovascularfrom microvascular perfusion and consists of two compo-nents that model the arterial (10) and microvascular (stan-dard kinetic model (11)) signal behavior separately. Mini-mum, maximum, mean, and SD of the mean BAT wereextracted from the maps of the microvascular component.Only pixels with a calculated perfusion value of 20% ofthe maximum perfusion were considered for the estima-tion of the BAT statistics. The resulting BAT map wasmedian filtered in plane (filter size 3 � 3) to reduce noisein the minimum and maximum value estimations.

Standard Q2TIPS perfusion images with gradient echoEPI (GE-EPI) readout were acquired to compare the SNR ofboth readout modules. A single slice was measured withthe same size and position of the ASL relevant saturationand inversion regions. Number of repetitions and thereforetotal measurement time was the same for both 3D-GRASEand 2D EPI sequences. Identical in-plane resolution waschosen by using same field of view and matrix size as inthe 3D-GRASE sequence but with a smaller bandwidth of700 Hz/pixel and two different slice thicknesses. Onematched the nominal slice thickness of the 3D-GRASEASL (4.5 mm) and the other was acquired with twice thenominal slice thickness (10 mm). The total echo trainduration was 80 ms with a TE of 35 ms.

The whole experiment took 16 min. Five healthy volun-teers (three male, two female, 33–51 years old) were ex-amined.

RESULTS

The proposed 3D-GRASE ASL sequence resulted in high-quality perfusion-weighted images with a high SNR com-pared to 2D EPI ASL in all measured subjects.

Figure 2 shows perfusion images of all five subjects withTS of 700 ms for slices 5–13 of 18 slices. No major contri-bution of intra-arterial blood spins is present except forsubject 5 with slightly increased signal in arteries. Theimages show very good SNR, which results from the longoverall sampling time compared to conventional readoutmodules. The mean calculated CBF of gray matter was62 � 15 mL/100 g/min. The mean SNR in gray matter in allsubjects ranged from 7.5 to 15.8 with a mean of 13. Indi-vidual values are shown in Table 1 along with the corre-sponding values for both EPI measurements. The wholedata set for subject 2 is presented in Fig. 3 with multipla-nar reconstruction for transverse, sagittal, and coronalslices along with a sagittal localizer image that depicts theposition of the labeling and imaging slabs.

The effective 3D slab was measured using a water phan-tom. The result with and without modulated saturation

pulses is shown in Fig. 4. The graph displays the result fora TS of 700 ms but does not change significantly for TSranging from 100 to 2000 ms. A tremendous reduction ofoverlap is achieved, allowing a reduction in the amount ofoversampling necessary to avoid aliasing to almost zero. Inaddition, a more homogenous profile for all slices withinthe 3D imaging slab is achieved, thus yielding an optimalSNR for almost all slices except the two outer ones.

As mentioned above, 2D EPI ASL was acquired for SNRcomparison in all five subjects with identical parameters asfor the 3D-GRASE ASL. In each subject a region of interest(ROI) was selected consisting of white matter, gray matter,and air, respectively. Mean values were calculated based onthe ROI values of each of the five subjects. Mean SNR in graymatter for the 3D-GRASE ASL, 2D EPI ASL (4.5 mm), and 2DEPI ASL (10 mm) was 13 � 3.5, 4.7 � 1.3, and 8.9 � 2.2,respectively. The ratio between 3D-GRASE ASL and the 2DEPI ASL techniques (4.5 and 10 mm) was 2.8 � 0.4 and 1.5 �0.4, respectively. Figure 5 shows a representative set of per-fusion images of the three acquisitions.

The estimation of BAT in all five healthy human sub-jects gave mean arrivals times with a range from 500 to850 ms in gray matter for all slices within the volume. Theresults of one subject are visualized in Fig. 6, which showsa graph of minimum, maximum, and mean BAT for allslices along with the BAT calculated maps. Slice-by-slicevariation of the maximum value was larger compared tothe minimum and the mean values. White matter BAT wasmore difficult to estimate and was typically 400 to 600 mslater than gray matter BAT. But even the top-most slicesshowed moderate gray matter BAT with the labeled bloodarriving no later than 850 ms and as early as 450 ms in allsubjects. In-plane changes of gray matter BAT were of theorder of 500 ms. However, in all five subjects the earliestBAT of the upper slices was generally smaller than themean of the lower slices; as well, the latest BAT of thelower slices was longer than the mean BAT in the upperslices.

DISCUSSION

A noninvasive perfusion measurement with ASL was im-plemented based on the FAIR labeling scheme and aQ2TIPS-like extension. A higher SNR could be achievedwith a single-shot 3D GRASE readout module compared tomultislice 2D gradient-echo readouts like EPI and spirals,which are commonly used. A background suppressiontechnique reduces motion sensitivity in the difference im-ages.

Q2TIPS uses multiple saturation pulses upstream of theimaging region to attenuate signal from inflowing intra-arterial blood spins. In contrast, our proposed techniqueuses modulated saturation pulses to produce a saturationband on each side of the imaging slab. Therefore, suppres-sion of intravascular blood spins works for both arterialand venous inflow since these modulated saturationpulses operate regardless of inflow direction. Furthermore,aliasing artifacts in the 3D-encoding direction are reducedtremendously after application of the modulated satura-tion pulses since the signal outside the imaging slab isnulled directly before readout. This allows a reduction inthe oversampling usually employed to avoid infolding.

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After proper selection of the measurement parameters nooversampling at all was used. Therefore, the entire ac-quired signal is used to form the image, thus increasingimage quality and coverage.

A large advantage of single-shot 3D techniques is thatthe whole image volume is acquired at the same inflowtime TI. All partitions acquired throughout the echo trainhave the same amount of perfusion weighting since thereis only one excitation pulse, which specifies the actual TI.This fact is not hampered by the application of multiplerefocusing pulses, which refocus only the existing excitedmagnetization, whereas the free induction decay signalwill be dephased by gradient spoiler pulses (see Fig. 1).Therefore, any labeled blood entering the image volumeafter application of the excitation pulse will not contributeto the acquired signal.

Comparison of image quality between single-shot 3D-GRASE and 2D GE-EPI acquisitions revealed much lessdistortion with the 3D-GRASE because of the higher band-width of the readout. The total readout duration per 2Dslice was 72 ms in 2D GE-EPI compared to 33 ms in3D-GRASE.

Furthermore, comparison of the SNR of the resultingperfusion images acquired with single-shot 3D-GRASEand 2D-EPI readout show a 2.8-fold higher SNR for 3D-GRASE ASL. A factor of �312/59 � 2.3 is expected due tothe total sum of the sampling period, which is approxi-mately five times longer in the case of the 3D-GRASEreadout (net sampling time 312 ms) compared to the 2D-EPI sequence (net sampling time 59 ms). The SNR gain dueto the different echo formation (the 3D-GRASE sequenceuses spin echo with a TE of 41 ms and the EPI sequence aGE with TE � 35 ms) is minor. For typical relaxationvalues of arterial blood (e.g., T2 � 200 ms, T2* � 100 ms)this gain would be 1.13. Taking this into account, a totalgain in SNR of 2.6 is expected. There is a trade-off betweenSNR and resolution in the slice-select direction (through-plane resolution) in the 3D-GRASE technique due to theinherent decay of the magnetization (dominated by T2-relaxation). The true resolution on the slice-select axis ofthe image with the parameters presented here is at mosthalf the nominal due to the magnetization decay. Resolu-tion enhancements could be achieved, e.g., by modelingthe flip-angles of the refocusing pulses to account for the

FIG. 2. Nine slices of 18 for all five subjects at inflow times TI � 1600 ms and TS � 700 ms. The acquisition time for each complete 3Ddata set was 2 min.

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T2-decay (12) or by multiplying each partition by a correc-tion factor. Both techniques benefit from the fact that oneT1/T2 compartment (arterial blood) dominates the finaldifference images. Blood within the microvasculature hasshorter T1 and T2 relaxation times and will not undergofull decay correction, resulting in slightly worse resolutionenhancement. However, both techniques will lower theSNR by either reducing the signal in earlier partitions(flip-angle adjustment) or amplifying the noise by leverag-ing the later partitions (correction factor).

The estimation of BAT shows that the assumption thatthe mean value would increase from bottom to top in thehuman brain as suggested in various publications is only

reasonable for a certain part of the brain, namely the upperpart. However, it can be seen in Fig. 6 that there is a largeregion of the brain where the blood seems to reach themicrovasculature at almost the same time, regardless of thedistance from the place of labeling. The minimum BATshows the same trend as the mean BAT while the maxi-mum BAT shows large slice-by-slice variations. Thismight result from the automated processing of the data. Asmentioned above, only pixels with a perfusion of at least20% of the maximum perfusion value were considered.Thus, BAT statistics are dominated by gray matter perfu-sion. In some slices, the estimate of the maximum BATvalue reflects white matter BAT while in other slices the

Table 1Mean SNR and CBF Measurement of All Five Subjects

Subject SequenceMean SNRgray matter

Mean SNRwhite matter

Mean CBF gray matter(ml/100 g/min)

Mean CBF white matter(ml/100 g/min)

1 3D-GRASE 15.8 4.2 76 � 15 20 � 92D-EPI 4.5 mm 5.2 1.3 67 � 27 17 � 132D-EPI 10 mm 10.3 1.6 71 � 19 11 � 9

2 3D-GRASE 15.8 5.6 71 � 14 25 � 72D-EPI 4.5 mm 6.2 1.5 76 � 25 18 � 92D-EPI 10 mm 11.3 2.7 71 � 21 17 � 6

3 3D-GRASE 14.2 4.3 62 � 12 19 � 62D-EPI 4.5 mm 5.1 1.3 72 � 19 18 � 62D-EPI 10 mm 9.3 1.9 68 � 14 14 � 7

4 3D-GRASE 11.8 3.8 53 � 12 17 � 82D-EPI 4.5 mm 4.0 1.5 49 � 17 18 � 92D-EPI 10 mm 7.7 1.6 56 � 11 12 � 7

5 3D-GRASE 7.5 3.3 47 � 21 21 � 82D-EPI 4.5 mm 2.9 1.1 50 � 27 20 � 92D-EPI 10 mm 5.8 1.6 49 � 18 13 � 7

mean 3D-GRASE 13.0 � 3.5 4.2 � 0.9 62 � 12 20 � 32D-EPI 4.5 mm 4.7 � 1.3 1.3 � 0.2 63 � 12 18 � 12D-EPI 10 mm 8.9 � 2.2 1.9 � 0.5 63 � 10 20 � 3

FIG. 3. Transverse, sagittal, and coronal crosssection of the data set shown in Fig. 2. The positionof the labeling slice (cross-hatched box withpointed line) and the imaging slab (bold line) isshown on a localizer image.

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maximum BAT value lies in gray matter. However, hand-drawn regions of interest revealed large variations of graymatter BAT even within a transverse slice. These measure-ments suggest that 3D imaging techniques can be used asreadout in ASL techniques without sacrificing the accu-racy of the measurement if appropriate measurement pa-rameters are chosen. In contrast, multislice 2D imagingtechniques, which acquire the slice in a sequential (orworse, interleaved) manner, might underestimate perfu-sion in certain regions due to different inflow times foreach slice. This might also hold true for some QUIPSS IIderivatives with 2D multislice acquisition where the as-sumption that the labeled blood bolus arrives at the lowerslices first is not necessarily met. Images could be acquiredat different inflow times to improve quantification accu-racy and reliability for both 2D and 3D imaging tech-niques. Low-resolution images would be sufficient to en-sure that the labeled blood has arrived at the capillaries atthe time of the image acquisition.

QUIPSSII and derivatives have been shown to yieldperfusion images with good suppression of intra-arterialblood signal. To provide reliable perfusion data both tech-

niques make assumptions on the presence of labeled bloodwithin the capillaries of the imaging slab. The estimationof BAT presented in this work demonstrates that a largeslab of 100 mm can be acquired in a single shot withoutsacrificing the accuracy of quantitative perfusion measure-ment using QUIPSSII derivates. Therefore, single-shot 3Dacquisition of perfusion covering almost the whole brainmight be possible in a clinical setup. However, the smallvariation of BAT was only shown for healthy subjects.This may not be true for all people and is even less likelyfor the pathophysiology of stroke or tumor vascularity. Toincrease the accuracy and reliability of QUIPSSII-basedsequences by ensuring that the requirements of the tech-nique are met, a low-resolution time series might be help-ful, as mentioned above. This time series allows estima-tion of the hemodynamics of the inflowing labeled spinsand can act as a useful tool to adjust the parameters(namely, inflow time TI and saturation time TS) of aQUIPSSII-based sequence appropriately. Since the 3D-GRASE readout module presented here offers a fairly highSNR compared to standard multislice EPI readouts, thistime series could be acquired within a couple of minutes.However, further research is needed to establish a reliableprotocol.

A full 3D data set is acquired in each labeling cycle.This allows for real-time motion correction (13) to beused to reduce motion sensitivity. Here, each acquireddata set is compared to a reference data set and if motionis detected the gradient orientation of the followingacquisition is updated to correct for the mismatch. Stan-dard registration algorithms can further be used to reg-ister each data set for optimal results. In multislice 2Dimaging motion during the acquisition of the wholevolume can result in different orientations of adjacentslices, whereas in the single-shot 3D technique motionartifacts might arise. However, the total acquisition du-ration for the complete volume is shorter for the 3Dreadout than for the 2D technique, thus reducing theoverall probability of artifacts. Concerns might ariseabout flow effects during the CPMG echo train. UsingQUIPSSII the only signal is from microvasculatureblood, which has very low velocities and therefore neg-ligible displacements and phase shifts with no associ-ated flow artifacts.

FIG. 4. Effective slab profile of combined excitation and refocusingpulse with and without application of four modulated saturationpulses (total duration 48 ms). Nominal slab is 100 mm ranging from�50 to �50 mm. The large overlap is apparent when no saturationpulses are applied. With the use of modulated saturation pulses nooversampling is necessary to avoid aliasing.

FIG. 5. Comparison of 2D EPI ASL with aslice thickness of 4.5 mm (left) and 10 mm(middle) and 3D GRASE ASL with nominalslice thickness of 4.5 mm (right). Total mea-surement time (2 min) as well as in-planeresolution (2.5 � 3.4 mm) was identical forall sequences.

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CONCLUSION

The CPMG-based GRASE sequence allowed acquisition of18 perfusion images with a gray matter SNR of more than10 in less than 2 min at 1.5 T using single-shot 3D encod-ing. Since the sequence is based on a true single-shotreadout, the SNR of the resulting perfusion-weighted im-ages is optimal in terms of efficiency. By incorporating theCPMG sequence, the SNR is higher than conventionalgradient-echo-based EPI or spiral sequences, since thereadout time per voxel is up to six times longer. Unlike 2Dmultislice imaging, the 3D acquisition advantageously ob-tains contiguous slices with identical inversion times. To-gether these factors allow for an improvement in ASLimaging in terms of sequence efficiency, slice coverage,SNR, physiologic timing, substantially reduced measure-ment times, reduced distortions, and susceptibility arti-facts. A wide variety of 3D GRASE sequence variants thatincrease k-space coverage within the multiple refocusings

of a CPMG sequence will realize similar gains, includingspiral, propeller, and cylindrical trajectory variants. Inconclusion, single-shot 3D perfusion imaging by GRASEhas reached the point of clinically useful scan times andslice coverage.

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FIG. 6. Minimum (Œ), maximum (�), and mean (F) bolus arrival time for all slices. The BAT map of each slice is given on top of the graph.Only values where the perfusion was at least 20% of the maximal perfusion value of the data set were considered (for more information,see text).

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