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Very Selective Suppression Pulses for Clinical MRSIStudies of Brain and Prostate Cancer

Tuan-Khanh C. Tran,1 Daniel B. Vigneron,1* Napapon Sailasuta,2 James Tropp,2

Patrick Le Roux,2 John Kurhanewicz,1 Sarah Nelson,1 and Ralph Hurd2

Focal three-dimensional magnetic resonance spectroscopicimaging (3D MRSI) methods based on conventional point re-solved spectroscopy (PRESS) localization are compromised bythe geometric restrictions in volume prescription and by chemi-cal shift registration errors. Outer volume saturation (OVS)pulses have been applied to address the geometric limits, butconventional OVS pulses do little to overcome chemical shiftregistration error, are not particularly selective, and often leavesubstantial signals that can degrade the spectra of interest. Inthis paper, an optimized sequence of quadratic phase pulses isintroduced to provide very selective spatial suppression withimproved B 1 and T1 insensitivity. This method was then vali-dated in volunteer studies and in clinical 3D MRSI exams ofbrain tumors and prostate cancer. Magn Reson Med 43:23–33,2000. r 2000 Wiley-Liss, Inc.

Key words: magnetic resonance spectroscopy; MRI; prostate;OVS; saturation pulse; cancer; brain

Magnetic resonance spectroscopy in vivo, particularlyclinical spectroscopy, derives much of its efficacy from thedetection of signals spatially localized to a specific regionsof interest. This is typically accomplished by a combina-tion of methods including selective excitation and outervolume suppression (OVS). Despite a significant amount ofinnovation (1–9), OVS, at least as a primary localizationstrategy, has not become a method of choice in clinicalfocal spectroscopic exams. Successful clinical applicationof OVS in the form of ‘‘octagonal’’ saturation of subcutane-ous lipids in slice-based magnetic resonance spectro-graphic imaging (MRSI) of brain (2,8,10,11) has beendemonstrated, but was limited in practice to very long echotime (TE) studies and ignored the consequences of chemi-cal shift registration error. Also, the transition bands ofthese pulses were up to 1cm in width, and this poorselectivity often limits the effectiveness of these OVSpulses. It is often desirable to further constrain the volumeof interest and acquire MRSI studies at shorter TEs andwith surface or phased-array coils where the outer volumesuppression requirements are significantly increased. Qua-dratic phase pulse designs (12–14) have both very goodspatial selectivity and high effective bandwidths and may

provide the basic elements needed to overcome previousOVS limitations. As with water suppression (15), the use ofan optimized series of pulses may be required to achievethe necessary B1 and T1 insensitivity to meet these require-ments.

Three-dimensional proton magnetic resonance spectro-scopic imaging (3D MRSI) has been shown to provide anaccurate assessment of the presence and extent of braintumors (16–19) and prostate cancers (20,21). This meta-bolic imaging technique is now being used clinically sinceother modalities often cannot provide the critical determi-nation of cancer presence especially after therapy. Toobtain reliable clinical MRSI, it is necessary to obtain goodBo field homogeneity over the acquired region and toexclude signals from regions of high lipid concentrationsor susceptibility shifted water. To accomplish this, PRESS(22) localized spectroscopic imaging is typically used toselect a region of interest and to exclude regions ofsubcutaneous fat and surgical artifacts in the case of braintumor studies and periprostatic lipids and the rectum forprostate studies.

While this technique allows the acquisition of clinicalquality spectra in most cases, the inclusion of unwantedlipid or susceptibility-shifted water signals from the cor-ners or edges of the PRESS box can render unusable a largeportion of the spectral array. We have evaluated conven-tional OVS pulses to address these problems but havefound them to be suboptimal due to poor edge profiles, B1

and T1 sensitivity, and chemical shift registration errors. Inthis study, we have sought to improve this technique bydesigning short quadratic-phase pulses and by using shorttrains of these pulses to provide improved spatial suppres-sion with reduced dependence on B1 and T1. The clinicalapplicability of these very selective saturation (VSS) pulseswas then evaluated in 3D MRSI studies of patients withbrain tumors and prostate cancers.

METHODS

Pulse Design and Simulations

The B1- and T1-insensitive spatial suppression sequenceutilizes the VSS pulses (13). The characteristics of thesepulses are well suited for improving spatial selection inclinical MRSI studies. Unlike the conventional Shinnar-LeRoux (SLR) pulses, the VSS pulses are quadratic phasemodulated (linear frequency sweep) as well as amplitudemodulated to spread the energy evenly throughout theentire pulse duration. The use of quadratic phase modula-tion to reduce the peak value of the time domain functionfor a given frequency spectrum has been a classical tool insignal processing (23) and has had practical applicationsfor decades (radar technology, ultrasound imaging, music

1Magnetic Resonance Science Center, University of California, San Francisco,San Francisco, California.2General Electric Medical Systems, Fremont, California.Grant sponsor: National Institutes of Health; Grant number: R01 CA59897;Grant sponsor: American Cancer Society; Grant number: RPG-93–023–06-CCE.*Correspondence to: Daniel B. Vigneron, Magnetic Resonance Science Cen-ter, Box 1290, University of California, San Francisco, 1 Irving Street, RoomAC-109, San Francisco, CA 94143-1290.E-mail: [email protected] 14 July 1999; revised 23 September 1999; accepted 27 September1999.

Magnetic Resonance in Medicine 43:23–33 (2000)

23r 2000 Wiley-Liss, Inc.

synthesizer, etc.). This idea has been adapted by MRphysicists to obtain pulses with lower radio frequency (rf)peak power and better selectivity (12–14).

Classically, phased SLR pulses (24) are designed bychoosing a pulse profile with the desired response profile.The SLR polynomials A and B are then calculated andsolved for their roots. By inverting the roots of the A and Bpolynomials and applying an appropriate scaling factor,the response profile is the same as obtained with theoriginal pulse profile. For N roots that fall within theselected band, there can be 2N possible rf pulses, all havingthe same response profile. However, inverting the roots ofthe A and/or B polynomials can lead to very different pulseprofiles (24). By iteratively inverting the roots, one cansearch for the permutations that give the least rf peakpower. Le Roux and co-workers have demonstrated aneffective finite impulse response (FIR) filter design algo-rithm based on a weighted-least-mean-squares (WLMS)algorithm that efficiently searches for the minimum rf peakpulse with a specified target phase function (13). In thismethod, only the B filter is modulated. The target phasefunction used in the design of the VSS pulses is quadratic.In general, the transition width (0.95 . Mxy/Mo . 0.05) isinversely proportional to the pulse duration. Lengtheningthe pulse duration while maintaining the same pass band(FWHM) can increase the selectivity, defined as the ratiobetween the pass band and transition width. This can beeasily done for quadratic phase pulses without increasingrf peak power since the B1 magnitude is relatively constantthroughout the pulse duration. Despite their short durationand small in-band equi-ripple (equal amplitude), theypossess large excitation bandwidths and narrow transitionbands (sharper edge profiles). VSS pulses have been cre-ated with selectivity as high as 80, which is over 20-foldhigher than typical minimum phase suppression pulses(13).

In general, sharper spatial transition widths come at thecost of longer pulse duration or thinner saturation bands.The longer pulse duration results in pulses with less rfpeak power, hence are suitable for low B1 excitationsystems. The amplitude and frequency profiles of the VSSpulse are shown in Fig. 1. The high performance of the VSSpulses comes at a cost of nonlinear phase response. Fortu-nately, this is irrelevant for the case of suppression pulseswhere dephasing of the spin magnetization is desirable.The parameters of the VSS pulses used in the B1- andT1-insensitive sequence are: tp 5 3 msec, B1 5 0.15 G for anominal 90° pulse, pass bandwidth 5 6 kHz, in-bandripple 5 1%, outer-band ripple 5 1%, transition band 5350 Hz. The selectivity of this pulse was 17 giving atransition width of 1.8 mm for a 30-mm suppression band.This is much sharper than using the conventional OVSpulse which had a spatial transition band of 11.4 mm (seeFig. 2). An even more selective 3-msec VSS pulses could begenerated, but the peak power requirements would behigher, and we opted for these pulse design criteria toallow flip angles of up to 140° without exceeding peakpower limitations.

Since insensitivity to T1 and B1 is desirable in suppres-sion sequences, numerical simulations were performedusing Matlab (Matlab v5.2 MathWorks) to determine theoptimal flip angles and spacings for the three VSS pulses.

The shaped rf pulses were represented as trains of jpiece-wise constant subpulses. The overall complex rota-tion matrix of the successive rf subpulses is given by:

R 5 RjRj21 . . . R2R1

where RJ is the complex rotation matrix of each individualconstant subpulse. The final magnetization is subse-quently determined by applying the overall rotation matrixon the initial spin magnetization. The effect of crushergradients was simulated by numerically zeroing the trans-verse components of magnetization following each pulse.Relaxation was ignored during the pulses, and appliednumerically in the interpulse intervals.

In our strategy for simulation, the residual longitudinalmagnetization was minimized by varying the flip angle ofeach pulse while holding the other two constant. Residuallongitudinal magnetizations were calculated for T1 valuesranging between 0.1–1.2 sec, which spans the physiologicT1 values for lipids and water. Numerical simulations werealso performed for other pulses: (i) 5-msec SLR optimizedOVS pulse, (ii) 1-msec 90° three-lobed sinc, and (iii)4-msec 90° four-lobed sinc-gauss. Theoretical suppressionprofiles (residual longitudinal magnetization) of thesepulses were determined and compared to the 3-msec VSSpulse designed for this study.

FIG. 1. The amplitude and frequency profile of the 3-msec, 6-kHzvery selective suppression (VSS) pulse. The pulse is modulated inamplitude (a) and frequency (b) to spread the energy depositionevenly throughout the entire pulse duration.

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Data Acquisition

All spectra were obtained on a GE Signa 1.5T Echospeedsystem with phased-array and spectroscopy capability. TheVSS pulses were inserted just before the PRESS excitationpulses (22) in the modified PRESS-CSI sequence that wehave been using for clinical MRSI studies of brain andprostate cancer (25,26). For a single suppression band, atrain of three 3-msec (750 points per pulse) VSS pulseswith accompanying crusher gradients was used to reducesensitivity to B1 and T1 variations. The total duration ofeach pulse train was approximately 12 msec. For a 30-mmsuppression band, the spatial transition width is 1.8 mm ascompared to 11.4 mm for conventional SLR optimizedOVS pulse. The pulse sequence was written to allow thesuppression band to be placed at any double-oblique angledepending on the specific requirements of each MRSIexam.

To demonstrate the efficacy of the suppression scheme,the PRESS box was placed to include a small portion ofadjacent lipids layer. In both brain and prostate studies,tilting of the suppression band was done at a double-oblique angle as deemed necessary. This allows the re-moval of frequency-shifted subcutaneous lipids near theskull or periprostatic fats.

Prior to 3D MRSI acquisition, single-voxel water andlipid suppressed spectra with and without the VSS suppres-sion band were collected. In some cases, minor adjust-ments to the position, tilt angle, and thickness of the VSSband were performed to minimize the residual water andlipid resonances. Automatic shimming typically producedwater linewidths of 5 Hz as determined from the unsup-pressed water spectrum.

Brain Volunteers and Tumor Patients

For volunteer and brain tumor studies, a conventionaltransmit/receive head coil was used. For surface coil brainMRSI study, a 5-inch GE coil was used to receive, and rfexcitation was achieved using the body coil. Prior tospectroscopy in volunteers high-resolution 3D MR imagesfrom the entire head were acquired using spoiled gradientrecalled echo (SPGR) sequence (45° flip angle, TR/TE 34/6msec, 120 slices, 1.5 mm thick, 256 3192 matrix). The 3DMR images served to guide the placement of the PRESSbox. Conventional outer-volume saturation (SLR opti-mized OVS) bands were applied to all six sides of thePRESS box. PRESS volume selection and frequency-selective excitation were accomplished by the applicationof spectral/spatial pulses in most studies except for theshort TE MRSI exam where standard 90 and 180 rf pulseswere used. Previous studies indicated a suppression factorof 104 for water and lipid resonances using the spectral/spatial pulses (26). The spectral/spatial pulse used in thesebrain exams was 30 msec long with a chemical-shift passband of 218 Hz to include resonances from choline tolactate. The acquisition parameters used in the brain MRSIstudies were: 1250 Hz spectral width, 512 points, 8 3 8 3 8phase encoding steps, 1 sec repetition time, 144 msec echotime, 1 NEX, CSI resolution of 1.0 cm3, and a totalacquisition time of 8.5 min.

For shorter echo time MRSI studies (TE 5 35 msec),CHESS (27) was employed for solvent suppression prior toPRESS selection. The flip angle of the last CHESS pulsewas optimized experimentally prior to acquisition of theMRSI data. The rest of the protocol was the same asdescribed above.

Prostate Cancer Patients

For prostate cancer studies, excitation was provided by thebody coil and reception by the combined pelvic andendorectal coil array. Commercial inflatable endorectalcoils were used (Medrad, Pittsburg, PA). For 3D MRSIstudies of prostate cancer, the BASING pulse scheme (25)was used to provide water and lipid suppression. Prior toPRESS box selection, a train of three VSS pulses separatedby crusher gradients was added to provide spatial suppres-sion. Crusher gradients were applied to dephase the spinmagnetization from unwanted regions prior to PRESS boxexcitation.

Frequency-selective suppression of water and lipids wasperformed by the usage of notch-filter BASING pulses asdescribed previously (25). For the dual BASING inversionpulses, the pulse duration and inversion bandwidth were25 msec and 130 Hz, respectively. For the prostate studiesthe acquisition parameters were: spectral width 5 1250 Hz,number of points 5 512, 16 3 8 3 8 phase-encoding steps,TR 5 1 sec, TE 5 130 msec, 1 NEX, CSI resolution 5 0.34cm3, and total acquisition time 5 17 min.

Data Processing

All 3D MRSI data were processed off-line on a SunUltraSparc 10 (Sun Microsystems, Mountain View, CA)using custom-designed software and a graphical displayinterface designed in IDL v5.0 (Research Systems, Boulder,

FIG. 2. Comparisons between the VSS pulse and other outervolume suppression (OVS) pulses. Theoretical suppression profilesof the 3-msec 90° very selective suppression (VSS) pulse (thick solidline), 120° VSS pulse (thin solid line), 5-msec SLR optimized OVSpulse (dotted line), and 4-msec 90° four-lobed sinc-gauss (dashedline). The VSS pulse offers a much sharper edge profile thantraditional OVS pulses. For a 3-cm suppression band, the transitionwidth of the VSS and SLR optimized OVS bands are 1.8 mm and 11.4mm, respectively. Despite the short duration, and small in-bandequi-ripple, the VSS pulse possesses a large excitation bandwidth(. 6 kHz) and a narrow transition width (sharper edge profile). Theprofile rectangularity and large bandwidth of the VSS pulse make itan excellent choice for outer volume suppression.

Very Selective Saturation Pulses in MRSI 25

CO). The MR images and 3D MRSI data were analyticallycorrected for the reception profile of the coil where appro-priate (16, 28–30). The 3D MRSI data were apodized with a2-Hz Lorentzian function, Fourier transformed in the tem-poral and spatial domains, phased, baseline corrected, andfrequency aligned. Two-dimensional MRSI grids were over-laid on the MR images to mark the location of the PRESSbox and MRSI spectral arrays.

RESULTS

Spatially Selective Excitation Pulses for Outer VolumeSuppression

The very selective saturation (VSS) pulses used in thisstudy for spatial suppression are amplitude and frequencymodulated as shown in Fig. 1. The excitation profile of the3 msec VSS pulse demonstrated very high selectivity (passband/transition band 5 17) as compared to the 5-msec SLRoptimized pulse used on GE clinical scanners for OVS(selectivity 5 2.64) (Fig. 2). Even though the VSS pulse hasshorter pulse duration (3 msec) than the SLR optimizedOVS pulse (5 msec), its pass band is 4.5 times larger (6 kHzas compared to 1.3 kHz). This results in greatly reducedchemical shift errors. Also, for a suppression band of30-mm, the 3-msec VSS pulse demonstrated a spatialtransition width of 1.8 mm, whereas for the SLR-type OVSpulse, the spatial transition width was 11.4 mm.

Figure 2 shows the theoretical suppression profiles for a3-cm spatial suppression band of four pulses: a) a 3-msec90° VSS pulse, b) a 3-msec 120° VSS pulse, c) a 5-msec SLRoptimized 90° pulse used as standard OVS pulse on GEclinical scanners, and d) a 4-msec four-lobed sinc-gauss.Table 1 lists the pulse profile parameters for these pulses.Note the much sharper edge profiles provided by the VSSpulses. The higher selectivity and reduced chemical shiftmisregistration of the VSS pulses are great advantages forthe exclusion of neighboring lipid regions in clinical MRSIapplications.

B1- and T1-Insensitive Optimization of VSS Sequence

In order to improve B1- and T1-insensitivity for the VSSscheme, we used a train of pulses with varying flip anglesthat is similar in concept to methods used to improve watersuppression schemes (15). In this study, three VSS pulseswere used to increase B1 and T1 insensitivity while keepingthe train duration much shorter than the T1 recovery timefor the lipid resonances. The VSS pulses were insertedbetween the last CHESS pulse and the 90° selective pulseof the PRESS sequence (Fig. 3). This extra pulse period didnot increase the repetition time (TR 5 1 sec) typically usedin these MRSI exams. However, the flip angle of the last

CHESS pulse had to be increased to account for T1 relax-ation of water during the additional time period.

For a single suppression band, the optimal pulse anglecombination for the three VSS pulses was 86°-94°-116° asdetermined from B1- and T1-insensitive numerical simula-tions (Fig. 4). The total duration of the spatially selectiveVSS sequence was 12 msec for each suppression band. Forthe case of two non-overlapping suppression bands, VSSpulses were interleaved with each VSS pulse pair sepa-rated by a crusher gradient. This reduced the total timerequired while maintaining excellent suppression factors.

Results from phantom experiments depicted in Fig. 5showed the effectiveness of the VSS sequence in suppress-ing lipid signals from regions within and adjacent to thePRESS selected volume. In this example, the phantomconsisted of a spherical container filled with a solution of

Table 1Theoretical Pulse Profiles of Selected OVS Pulses

90° VSS 90° SLR90°

four-lobedsinc-gauss

Duration 3 msec 5 msec 4 msecPass band 6 kHz 1.3 kHz 2 kHzTransition band 350 Hz 500 Hz 800 HzSelectivity 17 2.6 2.5

FIG. 3. Pulse timing diagram for the VSS spectral/spatial PRESS.The VSS pulses are played out prior to PRESS selection. Thespectral/spatial 180° pulses provide both spatial and frequencyselection to suppress the water signal. For short echo times, aCHESS sequence is used instead for water suppression. The VSSpulses then are placed between the third CHESS pulse and the 90°PRESS pulse. Due to the short duration of the VSS pulses (3 msec)and the required crusher gradients (1–1.5 msec), many VSS pulsescan be inserted during this long delay without significantly affectingthe water suppression.

FIG. 4. B1 and T1 map of residual longitudinal magnetization. Thesequence simulated consisted of three VSS pulses separated byshort crusher gradients with the first two applied at a 90° flip angle.The contour map showed the residual magnetization (Mz/Mo) as afunction of T1 and flip angle of the third VSS pulse. The pulse anglecombination of 86°-94°-116° degrees was found to be the mostinsensitive to B1 and T1 variations.

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choline, creatine, and N-acetyl aspartate (NAA) at nearphysiological concentrations. A small cup containing pea-nut oil mimicking a subcutaneous fat layer was inserted inthe spherical phantom. The PRESS-selected box was posi-tioned to include a few millimeters of the oil layer. The 3DMRSI data were acquired with and without the VSS bandplaced to suppress signals from the oil layer. As shown inFig. 5a, inclusion of the oil layer in the PRESS box resultedin enormous lipid signals in the coincident voxels andappreciable lipid peaks throughout the entire spectralarray due to the point spread function of the MRSI sam-pling. However, with the application of the VSS band,virtually all of the lipid signals were removed. No lipidpeaks were detectable in the other voxels. Also due thehigh bandwidth (6 kHz) of the VSS pulses no chemicalshift misregistration was observed.

Reduction of Lipid Contamination in Brain 3D MRSI WithVSS Pulses

To validate the suppression efficiency of the B1- andT1-insensitive VSS sequence, MRSI results from a volun-teer brain study obtained with and without the VSS pulseswere compared. In this study, the PRESS box was placed topartially include the subcutaneous lipid layer (Fig. 6). The3D MRSI data acquired without the VSS band showedmany spectra with distorted baselines due to the large lipidsignals (Fig. 6b). By placing a VSS band to remove signalsfrom the subcutaneous lipid layer, lipid contamination wasvirtually removed (Fig. 6c). For most studies, a single VSSband was sufficient. This is particularly true for tumorslocated near the skull, where full coverage of the tumorwould often force the partial inclusion of the subcutaneous

lipid layer in the PRESS box. Typically, to avoid thesubcutaneous fat layer, PRESS boxes are chosen whichresult in incomplete coverage of this region. This wouldresult in partial coverage of a tumor mass such as the onedepicted in Fig. 7. For full coverage, the chosen PRESS-selected box unavoidably included a portion of the subcu-taneous fat. Without the oblique VSS band, MRSI spectrashowed severe baseline distortion (figure not shown). Byapplying an oblique VSS band across the unwanted fatregion, lipid signals were markedly reduced. All spectraexhibited well-resolved resonances from relevant metabo-lites. The use of the VSS sequence was also validated forshort echo time (TE 35 msec) MRSI acquisitions employingCHESS water suppression. Brain 3D MRSI results fromvolunteer at short TE (35 msec) demonstrated good suppres-sion of water and minimal detection of lipid signals (figurenot shown).

We have applied these pulses in over 10 brain tumorclinical MRSI studies and now use them routinely. Figure 7showed MRSI results from a brain tumor patient where 3DMRSI coverage significantly benefited from usage of anoblique VSS band. This patient was a 47-year-old womanwith recurrent/residual oligoastrocytoma grade 3 using theWorld Health Organization II (WHO-II) grading criteria.The patient had a long history of a variety of treatments,including radiation therapy, surgical resection, and mul-tiple chemotherapy treatments. The MRI/MRSI exam wasrequested to obtain an assessment of extent of viable tumorto assist in subsequent treatment decisions. Due to theprevious therapies, MRI alone poorly provides the identifi-cation of viable tumor since contrast enhancing necrosiscan be indistinguishable from tumor and some regions of

FIG. 5. Phantom experiments demonstrating the effectiveness of the B1- and T1-insensitive VSS sequence. The phantom consists of aspherical container filled with a solution of choline, creatine, and NAA at near physiological concentrations. A cup of peanut oil was inserted intothe spherical phantom to mimic a subcutaneous fat layer. The PRESS-selected box (6 3 6 3 4 cm3) was positioned to include a few millimetersof the oil layer at the top. 3D MRSI data (8 3 8 3 8 phase encoding steps and voxel resolution of 1 cm3) were acquired using thespectral/spatial PRESS (TR/TE 1000/144 msec) sequence with and without the VSS band. Selected MRSI spectra (magnitude mode) areshown from nine voxels within the PRESS-selected box at the oil/water interface (a) without, and (b) with a VSS band to remove signals fromthe oil layer. Notice that all lipid signals were suppressed to the noise level, hence did not spread to other voxels. The suppression factor in thiscase is greater than 500.


a b cFIG. 6. Application of B1- and T1-insensitive VSS sequence to 3D MRSI of the brain in volunteers. a: MR image showing the positions of thePRESS box (white box) and VSS band (black line). b: The inclusion of subcutaneous lipids at the left side of the PRESS box caused spectraldistortions throughout the entire spectral array (white grid). c: The VSS band was placed to reduce the lipid contamination. The black lineindicated the edge of the VSS band. All voxels within the left two columns showed virtually complete suppression of lipid signals.

FIG. 7. Clinical brain tumor application of the VSS pulses. a: SPGR image (TR/TE 34/8 msec, 256 3 192 matrix, 45° flip angle, 1.5 mm thick)displayed the PRESS box (white) placement to obtain full coverage of the tumor mass. Notice that the PRESS-selected box included thesubcutaneous lipid layer at the bottom-right corner. b: By chopping the corner of the PRESS box (black line indicated edge of suppressionband) containing the subcutaneous lipid layer using the B1- and T1-insensitive VSS sequence, lipid signals were excluded from the MRSI data.Note the elevated choline levels in the region of viable tumor and the absence of all metabolite levels indicating necrosis in some regions of theenhancing mass.

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tumor often do not enhance. Based on the MRI/MRSI data,the region of contrast enhancement contained predomi-nantly necrotic tissues as indicated by the lack of observ-able metabolite resonances in the corresponding MR spec-tra. In the contralateral hemisphere, normal metabolitelevels were detected. The region of viable tumor, as indi-cated by highly elevated choline levels and reduced NAA,extended anteriorly and medially beyond the contrastenhancing lesion. The addition of the oblique VSS bandallowed improved spatial coverage, which was critical forthe metabolic assessment of residual tumor extent in thisheterogeneous mass lesion.

Use of VSS Pulses in Surface Coil Brain MRSI

The VSS suppression sequence can also greatly benefit 3DMRSI spectra obtained using surface or phased-array coilswith inhomogeneous reception profiles. Due to the drop-off in signal reception intensity of surface coil, spinsadjacent to the coil surface give rise to increased signalintensities. This presents a serious problem for humanbrain studies using surface or phased-array coils where thesubcutaneous lipids are close to the coil, and lipid contami-nation can severely affect MRSI even if the fat region isminimally excited (Fig. 8b). The addition of the VSSsuppression band significantly reduced lipid contamina-tion in this study (Fig. 8c).

Use of VSS Pulses for 3D MRSI of the Prostate

The utility of the VSS suppression sequence extendsbeyond its application to brain tumor studies. We used theVSS sequence in over 10 prostate cancer studies, and thepreliminary results from prostate cancer studies demon-strate its importance for clinical MRSI studies to minimizewater and lipid contamination and conform the PRESS

selection more closely to the shape of the prostate. In 3DMRSI prostate studies, the periprostatic lipids near therectal wall are often frequency-shifted due to the suscepti-bility difference at the air-tissue interface. This placed thelipid signals within the pass band of the frequency-selective water/lipid pulses (25) resulting in unsuppressedlipid contamination. The PRESS box is often chosen to bemore anterior than desirable in order to avoid severe lipidcontamination. Since the PRESS-selected box was definedby pulses with transition bands of several millimeters, thepoor edge profile forced the PRESS box to be positioned afew millimeters away from the rectal wall and full coverageof the prostate gland was not possible. However, with theuse of an oblique VSS band with its high bandwidth andnarrow spatial transition width, the PRESS-VSS selectedregion could encompass the prostate (Fig. 9) withoutappreciable lipid contamination. This 65-year-old patientwith biopsy-positive cancer (Gleason score 3 1 3) wasreferred for MRI/MRSI to obtain an assessment of thespatial extent of the cancer prior to radiation therapy. TheMRI/MRSI provides an anatomic/metabolic assessment ofcancer extent that can be very valuable to the radiationoncologist for treatment choice, tailoring therapy to aspecific individual and following treatment response. Inthis case, the addition of the oblique VSS band allowed theinterpretation of seven 3D MRSI voxels, which were other-wise not interpretable due to the presence of enormouslipid peaks. Of these seven voxels, four indicated thepresence of prostate cancer based on reduced citrate andincreased choline levels. Therefore, the addition of theVSS band in this case resulted in a much better assessmentof the extent of the cancer, which is often a criticalassessment for optimal clinical management of this dis-ease.

a

b cFIG. 8. Reduction of subcutaneous lipid contamination in surface coil MRSI studies. In surface coil brain MRSI studies, lipid contaminationcan be severe due to the strong reception of the lipid signals proximal to the coil. a: MR image of a volunteer brain acquired using a 5-inchsurface coil. b: Inclusion of the subcutaneous lipids at the bottom of the PRESS box caused significant baseline distortion in all voxels. c: AVSS band positioned at the bottom of the PRESS box eliminated most of the lipid contamination.


DISCUSSION

In this paper, we have demonstrated the applicability ofthe short pulse duration (3 msec or less) very selectivesuppression (VSS) pulses (13) to serve as spatial-saturationpulses in MRSI studies of brain and prostate cancer. Due tothe large bandwidths of these VSS pulses (<6 kHz orhigher), the edges of the suppression bands were virtuallyunaffected by chemical shift misregistration. The VSSpulses provided selective suppression within the PRESS-selected box to exclude unwanted regions. This allowedthe minimization of chemical shift errors, maximized theexcitation volume of interest to include as many voxelsaround the tumor mass as possible, and eliminated lipidsignals from adjacent fat layers while maintaining the truelipid spatial distribution in the tumors.

Recent studies have established the clinical utility ofusing the metabolic information provided by 3D MRSI todifferentiate cancer form necrosis, benign and healthytissue (16–19). However, the inclusion of adjacent adiposetissues within the PRESS-selected region can severelydegrade data quality. In the case of brain tumor exams, thesubcutaneous lipid layer adjacent to the skull can give riseto significant baseline distortion and artifactual peaks inthe clinical MRSI spectra. The typical solution is to choosean excitation volume away from the lipid layer. This,however, often prevents full coverage of the tumor mass. Tocircumvent this problem, spatial-selective suppressionpulses were used to remove the outer-volume lipid signalsfrom the 3D MRSI spectral array.

In the past, several groups have employed OVS se-quences (1–9) to conform the volume of interest (VOI).

These sequences utilized optimized pulses or specialexcitation schemes to shape the excitation volume to theregion of interest. Due to nonrectangular suppressionprofiles of these pulses, residual unsuppressed water andlipid signals at the bands’ edges could give rise to signifi-cant signal contamination in spectroscopic imaging. In thispaper, we demonstrated the applicability of the veryselective saturation (VSS) pulses (13) to serve as OVSpulses in MRSI studies of brain and prostate cancer.

These VSS pulses provide significant advantages overprevious spatial suppression pulses. Duyn et al. (2) used a4-msec sinc-gauss pulses for outer-volume saturation (PB <2 kHz, TB < 800 Hz). The suppression profiles obtainedusing this pulse or other common OVS pulses demon-strated much poorer transition profiles with selectivities(pass band/transition band) several-fold less than for theVSS pulses. Shungu and Glickson (8) employed the Projec-tion Presaturation (PROPRE) proposed by Singh et al. (7,9)to shape the excitation box to the region of interest usingthe low flip angle 1-msec three-lobed sinc pulses (PB < 4kHz, TB < 2 kHz). The ability to conform the selectedregion to user-defined shapes was impressive, however,chemical shift misregistration could be a limiting factor inmany applications due to the narrow bandwidth of thepulses used. The high bandwidth of the VSS pulses greatlyreduces these chemical shift errors and can improve manyclinical MRSI applications.

The frequency-modulated pulse proposed by Kunz (6)provided a higher selectivity and larger bandwidth thanthe sinc and sinc-gauss pulses. However, for the samepulse duration, the VSS pulse’s selectivity is six times

FIG. 9. 3D MRSI studies of prostate cancer also benefit from the use of the VSS pulses to eliminate regions containing periprostatic lipids. a:MR image of the prostate showing the location of PRESS box and VSS band. b: Without the VSS band, voxels adjacent to the lipid layer(bottom right) displayed lipid contamination. c: Lipid signal intensities were greatly reduced using an oblique VSS band.

30 Tran et al.

higher than that attainable from Kunz’s design. There arecertain similarities between Kunz’s pulse and the VSSpulse. In both cases, the pulses have a quasi-linear fre-quency sweep with sharp excitation profiles and highbandwidths. However, these pulses were designed usingtwo very different approaches. In Kunz’s approach, ananalytical frequency domain function is numerically in-verted to obtain the time domain function that is theoreti-cally infinite in time and therefore needs to be truncated.Kunz reduced this signal to a 10-msec duration. TheFourier transform of this truncated function (which approxi-mates the flip angle response when the nutation angle islow; a 90° nutation is at the borderline of this hypothesis)results in an excitation profile, which is not exactly thesame as the initial analytical frequency function. Fornutation angles above 90°, the result is even less analyticalas the linearity assumption of the response fails. Further-more, due to the cutoff function used in this method toshape the excitation profile, truncating effects could leadto nonrectangularity of the slice profile (overshoot at theprofile’s edges). The pulses obtained in this manner havesignificantly lower peak rf power than an amplitude-modulated pulse. However, this design method does notnecessarily furnish pulses with the lowest possible rf peakpower.

Le Roux’s approach to design the VSS pulses does notuse the linearity assumption (13). Instead it employs theSLR inversion algorithm (31). This method is based on theweighted least mean squares (WLMS) algorithm whereby adesired phase function can be specified (13). This methodallows more flexibility than Kunz’s approach since thephase, pass band, transition band, ripples, and max peak rfpower can be specified. The solution obtained can beiterated to obtain the desired phase modulation functionand an equi-ripple profile without any truncation effects.For a given transition bandwidth, a Le Roux VSS pulserequires 1⁄6 of the pulse duration needed by Kunz’s design.This reduction in pulse length is essential for the trains ofpulses in B1- and T1-insensitive suppression scheme.

These quadratic phase VSS pulses have several character-istics that proved beneficial in improving the performanceof current MRSI pulse sequences. Despite the short pulseduration, large pass bandwidth, and sharp transition band,these pulses do not require enormous rf peak power. The rfamplitude of the 90° pulse was 0.15 G, which was compa-rable to other SLR pulses. This is feasible since the pulsewas designed to evenly spread the energy throughout theentire pulse duration. Numerical and experimental resultsindicated a spatial transition width of 1.8 mm for a 30-mmband. This is clearly much sharper than the edge profileachieved solely with PRESS box selection.

Like other saturation pulses, the amount of residualmagnetization is directly influenced by the inhomogeneityof the applied field. For a 10% B1 fluctuation, a single VSSpulse would suppress only 90% of the signal leaving 10%residual magnetization. While this might be an acceptablevalue in imaging experiments, in vivo MR spectroscopy ofmetabolites often demands better performance. With twoVSS pulses, the residual magnetization can be reducedfurther. The suppression factor is improved for increasednumber of VSS pulses at the cost of increased repetitiontime. Numerical simulations indicated that a compromised

value of three VSS pulses separated by short crushergradients could provide suppression factors of severalhundred fold (Fig. 4). Note that the transverse magnetiza-tion is not destroyed by the crusher gradients but is merelydephased. The orientations of the crusher gradients werechanged to avoid inadvertent refocusing of the transversemagnetization, which would give rise to stimulated ech-oes. To minimize T1 relaxation of the spins within thesuppressed region, all crusher gradients were kept as shortas possible, while maintaining the ability to dephase thetransverse magnetization sufficiently. Typical crusher gra-dient strengths used were 1 G/cm with durations rangingfrom 0.5 to 1.5 msec.

The suppression factor achieved with this B1- and T1-insensitive VSS sequence was 103-fold as determined fromphantom experiments. Lipid signals from unwanted regionwere practically suppressed without resorting to a longecho time. Also lipid peaks were detected in virtually all ofthe MRSI voxels acquired without the VSS pulse due to thenonideal point spread function. These lipid peaks wereeliminated in the VSS acquisition even without spatialfiltering (Fig. 5). This is important for medical applicationswhere assessment of lipid presence within the volume ofinterest is desired.

Experimental results from human brain 3D MRSI dis-played excellent suppression of all signals within the VSSband using the 86°-94°-116° pulsing scheme. The ability toremove the unwanted lipid contamination can be seen bycomparing Fig. 6b and 6c. Notice that signals from voxelswithin the VSS band were suppressed to the noise level.Even for short echo time MRSI, employing CHESS forwater suppression, the VSS sequence reduced the lipidcontamination drastically to reveal well-resolved signalsin most voxels. In brain tumor patients, this suppressionscheme can greatly increase the spatial coverage withoutincluding signals from subcutaneous lipids. This is particu-larly useful for cases where the tumor mass is located nearthe skull (Fig. 7a). In these cases, subcutaneous lipidsignals were virtually eliminated (Fig. 7b).

For both brain and prostate cancer studies, there is anincreasing demand for phased array or surface coil MRSIstudies to improve sensitivity. However, due to the proxim-ity of the subcutaneous or periprostatic fat to the coil, lipidcontamination is even a larger problem than for volumecoils. In these cases, the B1- and T1-insensitive VSS se-quence is important to alleviate the lipid contaminationproblem. Results from 3D MRSI studies of brain volunteeracquired using a 5-inch surface coil showed an 80%increase in voxels with usable spectra was attained withthe use of a VSS band (Fig. 8). For these studies, the lowpeak rf power of the current VSS pulses allowed the use ofbody coil excitation. In prostate cancer studies, a pelvic/endorectal phased-array coil is used for signal reception.Often, due to the tilted placement of the flexible endorectalcoil, the PRESS box was forced to include the periprostaticlipids (Fig. 9a) resulting in distorted spectral baseline (Fig.9b). In this case, an oblique VSS band significantly reducedthe spectral contamination caused by periprostatic lipidsignals (Fig. 9c), allowing the metabolic assessment of agreater volume of the prostate than was possible in theMRSI data acquired without the VSS band. While completeremoval of the lipid resonances was not achieved in all


cases, the lipid signal intensity was sufficiently reduced toavoid contamination over more than one voxel.

In the case of two nonoverlapping suppression bands,significant time reduction was possible by interleaving thesuppression pulses for the two suppression bands. Eachpair of interleaved VSS pulses was separated by a singlecrusher gradient. In this manner, recovery of the longitudi-nal magnetization is less than for the non-interleavedmode. The short total duration of the six suppressionpulses and three crusher gradients translated into animproved suppression factor for both suppression bands.Numerical simulations indicated that B1- and T1-insensitiv-ity was still achievable using the same pulse angle combi-nation. However, the suppression factor was slightly moresensitive to B1 and T1 than for the case of a singlesuppression band.

The complexity is drastically increased for the case oftwo overlapping suppression bands. While interleavingthe VSS pulses of the two suppression bands providedgood suppression at the nonoverlapped regions, incom-plete removal occurred within the overlapped regions dueto stimulated echoes caused by unwanted rephasing of thespin magnetization by the crusher gradients. Careful choicesof permuting crusher gradient orientations can significantreduce rephasing of the transverse magnetization. How-ever, insensitivity to B1 and T1 was no longer feasible giventhe current pulses and timings. In this case, the usage ofone or two longer (and also sharper) VSS pulses persuppression band might prove to be more efficient. Re-cently, Wiese and Posse (32) proposed a scheme to improvesuppression in regions of overlapping OVS bands. Thismethod might provide the necessary solution and will befurther examined. In addition, designs of new VSS pulsesas well as improved pulse schemes are necessary toimprove the suppression within overlapped regions with-out increasing the total duration.

Since multiple off-resonance VSS pulses are used, mag-netization transfer (MT) effects are a possibility for thisspatial suppression scheme. Dreher et al. (33) demon-strated the possibility of magnetization transfer for thecreatine/phosphocreatine (Cr/PCr) resonance of rat brainin vivo. A recent study, however, reported (34) no consis-tent variation in the signal intensity of creatine wasdetected in human brain. In our volunteer studies with andwithout the VSS pulses, we detected no significant changesin metabolite ratios indicating a lack of MT effects. Thismay be due to the short pulse duration of the VSS, whichwas three orders of magnitude less than the typical 3 secpulse duration used in the afore-mentioned magnetizationtransfer studies.

SUMMARY

MRSI results from brain and prostate demonstrated theeffectiveness of the very selective suppression pulses fordramatically reducing lipid contamination. These VSSpulses improved the performance of the MRSI sequenceused for clinical cancer studies at our institution. Thesepulses provided a much sharper spatial suppression withimproved B1 and T1 sensitivity as compared to conven-tional OVS pulses. The VSS MRSI data exhibited dramaticsuppression of the lipid signals, and well-resolved reso-

nances of all relevant metabolites. In brain tumor studies,this spatial suppression scheme was extremely valuable incases where the tumor is located near the subcutaneouslipid layer. In the prostate, the suppression bands removedlipid contamination originating from the periprostatic fat,including regions next to the air interface caused by theinflatable coil in the rectum. Furthermore, due to the largebandwidth of the suppression pulse (. 6 kHz), chemicalshift misregistration was negligible for these spatial suppres-sion bands.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the helpful discus-sions on pulse sequences with Dr. John Pauly (Stanford)and Dr. Olivier Beuf (MRSC). We also thank Drs. Mark Day,Roland Henry, Tracy McKnight, Sue Moyher-Noworolski,Mark Swanson, Valeska Scharen-Guivel, and Andre Bes-sette for collecting MRSI data of brain/prostate cancerpatients. Special thanks are due to the radiology technolo-gists, Evelyn Proctor, Niles Bruce, and Gary Ciciriello, fortheir assistance with the imaging sequences

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