E L S E V I E R Magnetic Resonance Materials in Physics, Biology and Medicine 14 (2002) 30-38

MAGMA M a g n e t i c Rt . '~;onance M a t e r i a t s ha P h y s i c s , B k f l o g y a n d M e d i c h a e

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www.elsevier.com/locate/magma

The magnitude of signal errors introduced by ISIS in quantitative 31p MRS

Maria Ljungberg a,b,c,, G6ran Starck a,~ Barbro VikhotT-Baaz a,c Magne Alpsten a Sven Ekholm b, Eva Forssell-Aronsson a

" Department oJ" Radiation Physics, G6tebot\g University, Sahlgrenska Universi O' Hospital, 413 45 G6tebo~, Sweden b Departn~ent Of Rac#ology, GOteborg UniversiO', Sah&renska Universi O, Hospital, 413 45 G6tebop;g, Swe~#n

Department of MSedical Physics and Biomedical Eng#wer#Tg, Sahlgrenska University Hos)oital, 413 45 G6teborg, Sweden

Received 19 February 2001; received in revised form 23 August 2001: accepted 3 September 2001

Abstract

It is well known that the quality of a quantitative 31p MRS measurement relies largely on the performance of the volume selection method, and that image selected in vivo spectroscopy (ISIS) sufPers from contaminating signal caused mostly by T1 smearing. However, these signal errors and their magnitude are seldom addressed in clinical studies. The aim of this study was therefore to investigate the magnitude of signal errors in -~P MRS when using ISIS. The results from the measurements with a homogeneous head phantom are as follows: at low TR/TI ratios the contamination increases rapidly, especially for small ( < 27 cm 3) VOI sizes; at TR/T1 1 the signal from a 27 cm 3 VOI was ~.0'/,, too high, and from an 8 cm 3 VOI 150% too high. The signal obtained from different VOI positions varied between 80 and 127%. The signal varied linearly with the ~P concentration in the object. However, a too high signal was obtained when the concentration was lower in the region of interest (inner container) than in the rest of the phantom. The agreement between the simulations and measurements shows that the results of this study are generally applicable to the measurement geometry and the ISIS experiment order rather than being specific for the MR system studied. The errors obtained both experimentally and in computer simulations are too large to be ignored in clinical studies using the ISIS pulse sequence. ~) 2002 Elsevier Science B.V. All rights reserved.

Kevwords: 3~p magnetic resonance spectroscopy; Volume selection; ISIS; Phantom; Quantification

1. Introduction

Reliable methods for quantitative in vivo MRS are essential for ' the use of MRS as a clinical method for diagnosis and assessment of therapy response. How- ever, both t h e MRS measurement technique and data analysis may introduce substantial errors in obtaining absolute, or even relative, quantitative MRS data [1,2].

It is well known that the quality of quantitative 3~p MRS measurements relies largely on the performance of the volume selection method. It is also well known that image selected in vivo spectroscopy (ISIS) suffers from contaminating the signal for measurements per- formed with TR < 3*T1. However, these signal errors are seldom addressed in clinical studies.

* Corresponding author. Tel.: +46-31-342~56; fax: +46-31- 411673.

E-mail address: maria.ljungberg@radlvs.gu.se (M. kjungberg).

The ISIS pulse sequence [3] is a multishot method, i.e. signals from several experiments are combined in such a way that signal fi'om VOI adds constructively and signal from regions outside the VOI should cancel. Each experiment is composed of a spin preparation, where none, one, two or three slice selective 180 ~ pulses select the VOI. These are followed by a non-selective 90 ~ detection pulse, i.e. signal is collected from the whole sensitivity region of the coil for each experiment. Theoretically, a perfect localization of a parallelepiped is then achieved. Detailed theory of ISIS has been described in Refs. [3-6].

In reality the acquired spectrum consists not only of signals from nuclei within the VOI, but also from nuclei outside the VOI. Factors that atTect the performance of the volume selection method ISIS are for example [4]: (a) the chemical shift, which affects the spatial region excited by the selective inversion pulses; (b) B1 inhomo-

1352-866102/$ - see front matter ,:~2' 2002 Elsevier Science B.V. All rights reserved.

M. Ljungberg et al./ Magnetic Resonance Materials in Physics, Biology and Medicine 14 (2002) 30-38 31

geneity, which degrades the volume selection perfor- mance and decreases the signal-to-noise ratio; (c) T1 smearing, i.e. a TR/T1 < 5 in combination with a non- perfect detection pulse. The amount of contamination is also dependent on the experiment order used [5]; and (d) T2 relaxation during the inversion pulses, which not only causes a degraded magnetization profile but also increases the contamination.

The aim. of this study was to quantify signal errors due to some previously described, but in clinical studies seldom addressed, problems that occur in quantitative ~P MRS measurem.ents using ISIS. The signal depen- dence of the TR/T1 ratio, the VOI size, the VOI position and the concentration were studied both with MRS measurements and computer simulations.

2. Mater ia l and methods

2.1. Computer simulations

Computer simulations were performed with a pro- gram written in mathcad (MathSoft Inc., USA) that calculates signal from an ISIS experiment, including the contamination caused by T1 smearing. This program has been described earlier [6].

The ISIS simulation begins with a spin preparation, i.e. zero, one, two or three slice selective inversion pulses. The number of inversions that affects each of the subvolumes is calculated for each of the ISIS exper- iments in the experiment order. The inversion pulses are assumed ideal since the inversion pulse angle does not influence the contamination due to T1 smearing [3]. The detection pulse causes a transfer of all, or parts of, the z-magnetization to the :qv-plane. If the detection pulse angle differs from 90 ~ some magnetization re- mains in the z-direction immediately after the detection pulse. During the remaining part of the repetition time, TR, the z-magnetization will be affected by T1 relax- ation. The z-magnetization at the end of the repetition time is transferred to the next experiment. The amount of signal-detected in each experiment is proportional to the magnetization that is transferred to the xv-plane by the detection pulse. For each subvolume the signal fi'om one ISIS acquisition is calculated as the sum of the signals for each of the eight ISIS experiments added using the add/subtract scheme (A/S).

In the computer simulations the detection pulse is always an ideal block pulse, but with a variable pulse angle. When comparing results from computer simula- tions with results from measurements with an adiabatic detection pulse, we found that the measured contami- nation from different regions in an object were similar to the simulated results using a block shaped detection pulse with an angle of 100 ~ (data not shown). The simulations were therefore pert:orm_ed with this detec- tion pulse angle.

2.2. Measurements

2.2.1. M R system

31p MRS measurements were performed on a Philips S15/ACSII 1.5 T horizontal whole body MR system with a bore size of 56 cm (Pt~ilips, The Netherlands). The MR system was equipped with software release 3.6.3. A standard 3~p quadrature transmit/receive head coil (Philips, The Netherlands), which was of a mirror birdcage design, was used for all measurements. The ISIS experiment order implemented in the system [7] is given in Table 1. All measurements were performed with adiabatic hyperbolic secant inversion pulses [8] and an adiabatic hyperbolic secant detection pulse [9].

2.2.2. Signal evaluation

The MRS signals were dc-corrected, apodized with an exponential filter with a line-broadening equal to the F W H M (full-width-at-half-maximum)of the unfiltered peak, Fourier transformed, phase corrected and basline corrected using a linear fourth degree polynomial. The signal values were then measured as the area between two manually set cursors.

2.2.3. Phanto , Ts

Three different phantoms were used to simulate 3~P MRS measurements of the brain. The phantom con- tainer used for the measurement of integrated signal from a homogeneously distributed substance was a 2 1 glass sphere. The container was filled with difl:erent solutions for different measurements, but they all con- tained saline solution, orthophosphoric acid (85% H3PO4) (Merck KGaA, Darmstadt Germany) and NiC12-6H20 (E. Merck, Darmstadt, Germany). The amount of NiC1, was varied to obtain a suitable T1 value. The amount of H3PO4 was varied to obtain a reasonable signal-to-noise ratio in a limited measure- ment time. This phantom was used if nothing else is stated. The linearity of concentration measurements were performed with a two-compartment phantom and a point source phantom was used for signal profile measurements of the VOI sensitivity [10-12].

Table I The experiment order used in the measurements and the computer simulations [7]

Experiment no. Inversion order xyz A/S

1 000 + 2 111 3 101 + 4 001 5 110 + 6 I00 7 011 + 8 010

32 M. L/ungberg et al . / Magnetic Resonance Materials in Physics, Biology and Medichw 14 (2002) 30--38

2.2.4. TI measurements" To estimate the T1 values of the measured solutions,

an inversion recovery measurement series was per- formed with 5-6 different inversion times. The peak areas were determined and fitted to the theoretical expression of the T1 relaxation using a least-square fit algorithm.

2.2.5. TR/T1 3~p MRS measurements were performed to investi-

gate the signal contamination for a low TR/T1 ratio. Two VOI sizes were used, 27 and 8 cm 3. The VOI was positioned centrally in the homogeneous phantom.. Measurements of 27 crn 3 were performed with a T1 of 6.7 s, and for the 8 cm 3 two measurements were per- formed where T1 wag 0.7 and 6.7 s. The H3PO 4 concen- tration was 400 mM. Each measurement started with eight excitation dummies and eight dummy ISIS experi- ments, i.e. one full ISIS experiment order without signal acquisition. For each TR/T1 ratio (range 0.2-8.9) 144 experiments were averaged. Computer simulations cal- culating the effect of T1 smearing was also performed for the two VOI sizes. The signal, both measured and simulated, was divided by the factor ( 1 - e -TRwl) to correct for the signal decrease due to partial saturation (T1 correction). The T1 corrected signal was nornqal- ized to the signal strength measured or simulated with a TR/T1 > 5, since the amount of contamination due to T l smearing is negligible at such a high TR/T1 ratio.

2.2.6. VOI size The 31p MRS signal was measured for different VOI

sizes and a number of fixed TR/T1 ratios. The 2 1 phantom was filled with saline solution, 1200 mM H aDO4 and NiC12 to a T I of 1.6 s. The measurements were preceded by dummy ISIS experiments to reach steady state before acquiring the signal. In each mea- surement 160 signal acquisitions were averaged for each VOI size and TR/T1 ratio. The signal values were T1 corrected. To be able to compare the amount of con- taminatiorr in each measurement an extra measurement was performed with a VOI surrounding the sphere, i.e. a measurement free from signal contamination. The signal was also normalized to correct the difference in the signal generating volume.

Normalized signal

_ _ VOI signal/VOI volume �9 100% Signal from the sphere/Sphere volume

2.2. 7. VOI position The variation in the 3~p MRS signal strength for

different positions of the VOI was studied in the homo- geneous phantom. The phantom container was filled with saline solution, 200 mM H3POa and 1.5 mM NiCI~. T1 was determined to 0.6 s and TR was chosen

to be 0.8 s, which was the shortest TR possible. The phantom was positioned as close as possible to the iso-centre of the magnet and an 8 cm 3 VOI was posi- tioned in 19 different positions, all well within the phantom. The VOIs were positioned with a distance from the center of the phantom of 40 mm in one, two or three directions. The signal obtained was normalized to the mean of these 19 measurements. To rule out that the signal variations could be caused by time dependent instabilities in the MR system, 19 identical measure- ments were performed with the VOI placed centrally in the phantom.

To study how different VOI positions influence the signal contamination due to T1 smearing computer simulations were performed with TR/T1 = 1.3. To be able to compare the simulation results with the mea- sured results, the simulated signal values were compen- sated for the measured coil sensitivity in all the three directions. The coil sensitivity was measured previously using a small signal source (volume 0.08 cm 3) that was stepwise moved along the x-, y- and z-axis (step size 1 mm). In each position, a non-volume selective measure- ment was performed [13].

2.2.8. 31p concentration The phantom consisted of a spherical container (7.5

cm radius) containing saline solution, 10 mM H3PO4 and NiC12. Inside this phantom, a small sphere (4 crn diameter) was fixed containing saline solution, NiC12 and a variable concentration of H3PO4 (0 mM to 20 raM). T1 was measured to 1.1 s. Two different mea- surement series were performed, one with a 5 x 5 x 5 cm VOI surrounding the inner sphere and another with a 3.5 x 3.5 x 3.5 cm VOI placed entirely inside the small sphere. TR was equal to T1 and 960 signal acquisitions were averaged for each concentration. Dummy ISIS experiments were performed in order to reach z-magnetization steady state before the signal acquisition. The signal strength measured for 20 mM were for both VOI sizes used for the normalization of the measurement results. This normalization is based on the assumption that contaminating signal contribu- tions would be small, as the concentration in the inner sphere is higher than outside.

Computer simulations were performed to study how T1 smearing affects the linearity of concentration. Two VOI sizes were simulated: 125 and 27 cm 3. The concen- tration outside the VOI was set to 10 mM and the concentration inside the VOI was varied between 0 and 20 raM. The simulations were performed with a TR equal to T1 and a detection pulse angle of 100 ~

For each measurement and simulation the equation for the straight line was calculated by a least squares fit to the signal values. The result is given as the point of intersection and the slope of the line.

M. Ljungberg et al./ Magnetic Resonance Materia/s in Physics, Biology and Medicine 14 (2002) 30-38 33

600

g 500

400 r~

= 300

.~ 200 r

100 Z

....... . .

i . . . . . . i i i ' ! i I i i i . . . . . . . . . . . . . . . . . . i

0 1 2 3 4 5 6 7 8 9 10

TI~T1

8 c m 3 V O l T 1 = 6 . 7 s

8 c m 3 V O I T I = 0 . 7 s - - N - - 2 7 c m 3 V O I T 1 = 6 . 7 s

---4,-- S i m u l a t e d s i g n a l 8 c m 3 V O I

" " < S i m u l a t e d s i g n a l 27 c m 3 V O I

Fig. 1. The normalized signal strength as a function of TR/T1 ratio for two different VOl sizes, 8 cm 3 (diamonds) and 27 cm 3 (crosses). Solid line denotes measurements and dotted lines computer simulations. For the small VOI two measurements were performed, one with a T1 of 0.7 s (white diamonds) and another with T1 of 6.7 s (black diamonds). All signal values were T1 corrected. The SEM for the data-points varies between 0.4 a lad TM / ,., . /,, of the normalized signal strength

2.2.9. Signal pr@'le , z easure , lents

Signal profile measurements were performed to study if the signal profile shape and position was the same for different VOI sizes. If the transition zones proportionally take a larger share for small VOI sizes, then the contamination will increase or the selectivity will decrease. The phantom used for signal profile measurements has been described earlier [10]. The phantom consists of a small signal source that can be remotely positioned along a diameter in a spherical outer container. The signal source was a piston with a cylindrical cavity with 1 mm height and 10-mm diame- ter [17]. The cavity was filled with concentrated H3PO 4 with a T1 of 1 s at 3~p MRS. The outer sphere was filled with saline solution, Gd-DTPA and MnCI to obtain a-T1 of 0.8 s and a T2 of 0.2 s for ~H MRS [14].

The signal profiles were measured in the x direction tar the two different VOI sizes: 30 x 30 x 30 and 10 x 30 x 30 mm (x x y x :). The signal source was moved stepwise through the VOI, which was positioned cen- trally in the phantom. The step size was 1 mm for the 30 mm profile and 0.5 mm for the 10 mm profile. The VOI size in the 3"- and --directions was 30 mm in both profile measurements to include the signal source in the VOI in these directions. All signal values were normalized to the signal strength measured in position 0 mm without volume selection. The full-width-at-half- maximum (FWHM), the mid position and the extent of the transition regions (20-80% of maximum signal value) were estimated t;or the signal profiles [11].

3. R e s u l t s

The study of" the signal strength as a function of the TR/T1 ratio shows that the T1 corrected signal strength increased for decreasing TR/T1 ratios (Fig. 1). The simulated and measured signal shows the same behav- ior, but the simulated signal was lower than the mea- sured signal for the 8 cm 3 VOI and larger than the measured for the 27 cm 3 VOI. The measured contami-

"3i3o/ nation was _,,,.,, for the 27 cm s VOI and between 120 and 150% for the 8 c m 3 VOI measured with a TR/T1 - - 1 .

Fig. 2 shows the measured and simulated signal values for different VOI sizes. For a TR equal to T1 and a VOI size of 27 cm s the measured signal was 37% higher than expected. For a VOI of 1 c m 3 the measured signal was about 2400'71, higher than expected for a TR equal to T1.

The measured 3 1 p MRS signal fl"om each VOI posi- tion studied in the homogeneous phantom is shown in Fig. 3. The signal varied between 96 and 103% due to time-dependent signal variations in the MR system. The measured signal varied for the different VOI posi- tions between 80 and 127% of the mean signal value for all the 19 positions. The simulated signal values ranged from 91 to 111% when only the signal variations due to different degrees of contamination caused by T1 smear- ing was taken into account. If the simulation results were compensated far the measured coil inhomogeneity then the simulated signal values would range between

9Y~,. 77 and 11 o

34 M. Ljungberg et al . / Magnetic Resonance Materiab in Physics, Biology and Mech'cine 14 (~002) 30-38

The results from the concentration linearity measure- ments and the simulations are shown in Fig. 4.

The measured signal profile for the 30 mm VOI (Fig. 5) had an F W H M of 30.0 ram, the profile center position was - 0 . 3 mm and the transition zones were 3.4 mm. The corresponding values for the 10 ml-n VOI profile (Fig. 5) were a F W H M of 10.1 mm, a VOI centre position of - 0 . 4 and 1.6 mm transition zones. The signal strength at the profile plateau was 76% of the non-volume selective measurement for the 30 mm VOI and 69% for the 10 mm VOI.

4. Discuss ion

The accuracy of quantitative measurements with 31p MRS relies largely on the performance of the volume selection method used. The volume selection perfor- mance is dependent on the object and the location of the selected volume in the object. Errors can therefore be introduced when comparing signal values obtained from different locations and time periods. It is also irnportant to remember that the contaminating signal cannot be removed or corrected for during spectrum processing, since the concentration distribution in the object is unknown.

Three major calibration methods have been sug- gested for the determination of concentration with in vivo 3~p MRS. (I) Internal standard with known con- centration that occurs naturally in the object. (II) A phantom measured in conjunction with the original measurement with conditions as close to the clinical

measurement as possible [15]. (III) Small external phan- tom including a standard substance, which is measured at the same time as the actual measurement [16]. This method can also be combined with method II [17]. If the volume selection method used suffers from the contaminating signal from regions outside the VOI then all three calibration methods can experience errors. In the case of using an internal standard, the object size and position in the coil is the same, but the concentra- tion distribution of the standard substance and the metabolite of interest may differ and may therefore cause errors in the concentration determination. An- other uncertainty arises because the concentration of the internal standard substance is usually not exactly known and only a part of the substance might be ' N M R visible'. With a small external standard, no contamination is obtained as the source has a small volume and all signal from this volume is acquired. However, the position of the external standard in the coil is not the same as the object, i.e. experiences a different B1 field strength. Using a large phantom the problem with a different concentration distribution is the same as an internal standard, but this method also has the drawback with different object geometry, i.e. the regions from where contamination is acquired is not of the same size and shape as in the original measurement.

ISIS is one of the most commonly used volume selection method for in vivo 31p MRS. Several studies have shown that ISIS suffers from contamination [4- 7,11,12]. Computer simulations performed by Burger et al. [5] and Ljungberg et al. [6] show that the experiment

2500

2000

I . - 1500 r ~

~a0

r~

1000 N

x._

500 z

1.0 1.5

. . . . . . . I T " i ' I I J .... l

2.0 2.5 3.0 3.5 4.0 4.5 5.0 VOI side (cm)

Simulations: --@--TR=T1 --1---TR=2T1 ---&-- TR=3T1 --'X-- TR=5T1

Measurements--~--- TR=T1 ---[:3-- TR=2T1 ~ TR=3T1 - - X - - TR=5T1

Fig. 2. The normalized signal strength as a function of VOI side for a cubic VOI. Four different TR/T1 ratios were measured, TR = T1 (diamonds), TR = 2T1 (boxes), TR = 3TI (triangles) and TR = 5T1 (crosses). Solid line denotes measurements and dotted lines computer simulations. Error bars show _+ SEM.

M. L]ungberg et al . / Magnetic Resonance Materials in Physics, Biology and Medicine 14 (2002) 30-,38 35

130

120 v

110

~oo

. , i

~-'~ 90

�9 ~,,,t

60

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ~ ~ �9

o ; ; . . . . . . . . ;i ... . . . . . . . . . . . . ; . . . . . . . . . . . . . . . . . . . . . .

0

Position relative coil centre (x,y,z in cm)

0 measured signal ~simulated signal corrected for coil sensitivity in x,y and z-direction

Fig. 3. The signal strength as a function of VOI position in a homogeneous head phantom. The v-axis is given as normalized signal strength, where 100% is the mean of the signal values measured in all 19 positions. The x-axis is given as VOI position as (x,y,:) cm from the phantom centre. The simulated signal values, corrected for coil inhomogeneity, are denoted with black diamonds. The dotted lines show minimum and maximum signal values obtained when evaluating the MR system instabilities during the same length of time as the measurements. Error bars show + SEM.

order implemented in the MR system used suffers from contaminating signal caused by T1 smearing if TR/ T1 < 5 in the measurements. The contamination mea- sured will not be the same for an MR system with another experiment order.

A way to avoid signal contamination for short repeti- tion-times was suggested in the original ISIS article [3]. The idea was to signal average each of the eight exper- iments separately and insert a sufficiently long relax- ation delay time when changing to the next ISIS experiment (i.e. experiment 1, 1, 1, 1, delay.time, exper- iment 2, 2, 2, 2, delay time ..... experiment 8, 8, 8, 8). There are however two practical drawbacks with this ISIS implementation. First, the localization of the VOI is not completed until the whole measurement is ended, i.e. it is sensitive for motion over long time periods (e.g. patient movement). Secondly, if the measurement has to be ended before planned, e.g. due to patient discom- fort, etc. then no useful signal is recorded since the localization of the VOI is not complete until all the eight experiments have been performed. This specific ISIS implementation is to our knowledge not imple- mented in any commercial clinical MR system today.

The phantom used for the integrated signal measure- ments had a volume of 2 1, which was larger than a medium head that often is about 1.5 1. This caused an overestimation of the contamination. Computer simula- tions of a spherical .object shows that this overestima- tion of the contamination is 8% of the signal from VOI /~or a TR/T1 = 1 and a 27 c m 3 VOl.

The T1 corrected signal strength increased consider- ably for decreasing TR/TI ratios. This signal increase is probably mainly caused by contamination due to T1 smearing, and increases further with a reduced TR [5,6]. The results show that a TR of at least 3*T1 should be used to avoid substantial signal contamina- tion. However, often in 3~p MRS of the brain a TR of 3 s is chosen. This is of the order of T1 for PCr, and approximately twice the T1 value for Pi. According to the present results, the contamination might be high (about 18% for a 27 cm 3 VOI and about 150% for a 8 cm 3 VOI for PCr). The contamination seems to be reasonable for VOI sizes >_ 27 cm 3. For a TR equal to T1 and a volume size of 1 cm 3 the signal was about 22 times higher than expected. Consequently, when small VOIs are used, e.g. for brain tumor measurements, one should at least use a long TR to reduce the amount of contamination.

The signal strength obtained from different VOI po- sitions varies theoretically if the measurement suffers from T1 smearing. This is caused by the geometry of the subvolumes created by ISIS, with different sizes for different VOI positions in the object (cf. Refs. [4-6]). As signal contamination in ISIS is created with both positive and negative signs, the degree of cancellation of signal contamination from different regions varies, also resulting in different signal strengths. The signal strength measured from a VOI may also be influenced by variations in the coil sensitivity. The coil used in the measurements was of a mirror birdcage design and the

36 M. L/ungberg et a l . / Magnetic Resonance Materials h7 Physics, Biology and Medicine 14 (2002) 30-38

sensitivity in the inner parts of the coil (cranial) was therefore higher than in the outer parts (caudal). We have also observed a small signal variation with posi- tion in the y-direction (anterior-posterior direction), where the signal strength posteriorly was a t:ew percent lower than anteriorly. To compare the simulations and the measurement results (Fig. 5) the simulated signal values were compensated for the coil inhomogeneity. The signal values from the measurements and the simu- lations were similar, even though they do not corre- spond perfectly. The trends are however the same, i.e. the major reason for signal variations is probably due to the different geometry when shifting the VOI posi- tion and coil homogeneity.

The concentration linearity measurements were per- formed with a phanfom geometry that is common in clinical brain examinations, i.e. a sphere in a sphere. The concentrations in vivo from the metabolites mea-

sured in 31p MRS is in the range of a few to 25 mM. The concentration in the outer sphere was therefore about the mid concentration in this range, and in the inner sphere, the concentration was varied within this range. The results from the measurements and simula- tions illustrate two different effects that might cause errors in the estimation of absolute concentrations. If the VOI circumscribes the tissue of interest, the concen- tration will be overestimated due to signal contributions from the corners of the VOI in the surrounding tissue, when the tissue of interest has a lower concentration than the surrounding tissue. If the VO! is inscribed in the tissue of interest a more correct concentration value is obtained (Fig. 4(a)), but a lower SNR is acquired since the VOI is smaller. The simulations, however, showed that a small VOI size might cause another type of error in the concentration value. The effect of T1 smearing will for a small VOI size cause a constant

20

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y=3.7+0.85x ~ ..... -~ ....

[ : ] . . - " "

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| = . , =

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C o n c e n t r a t i o n in the inner sphere ( m M )

20

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---A-- Simulated signal 125 cm 3 VOI . :~:" . . ; 2 : ' "

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0 5 10 15 20

C o n c e n t r a t i o n in the V O I ( m M )

Fig. 4. The results obtained from the concentration evaluation: (a) the results from the measurements: and (b) from the simulations. The signal values were fitted to a straight line with a least squares fit, and the equation for the line is denoted in the diagrams. Maximal SEM for the measurements was 0.3 a.u.

M. Ljzmgberg et al /Magnetic Resommce MateriaLs" in Physics.. Biology and Medicine 14 (20()2) 30-38 37

100

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20

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i := ,! {::

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Position (mm)

I d e a l V O I p r o f i l e ............ 30 mm . . . . . . . . I 0 mm

Measured V O l profile .... ~ . . . . 30 mm . . . I . . 1 0 mm

Fig. 5. Signal profiles for v o I sizes of 30 mm (white diamonds) and 10 mm (black boxes), respectively, in the x-direction. In the y- and _--direction the VOI was 30 mm in both measurements. TR was equal to T1. No chemical shiti displacement was present in the profiles. The maximum uncertainty in signal position and transition zones is 0.8 mm. The maximum uncertainty in the relative signal values is 3.9%.

signal contribution that only depends on the concentra- tion in the surrounding tissue (Fig. 4(b)), i.e. ti)r low concentrations in VOI the signal will be overestimated. A trade-off between these two errors has to be per- I:ormed as they oppose each other.

Signal profile measurements were performed to study if the VOI profile transition zones were proportional to the size of the VOI. The results seem to show a proportionally slightly larger transition zone fi~r the 10 mm VOI side than for the 30 mm VOI side. However, the number of points in the transition zone was few t:gr the 10 mm VOI size, and therefore the uncertainty in these figures is probably larger than those for the 30 mm VOI profile. Additionally, the signal source will broaden the transition region, as it is not a point source. The maximum broadening of the transition region should be of the size of the signal source, in this case 1 mm. A relatively larger transition region might be able to explain why the measured signal values increased faster than the simulated signal values for small VOI sizes. The signal strength of the plateau was lower for the small VOI (69%) than for the large VOI (76%). This signal loss might be caused by larger eddy currents due to the higher gradient strength used with the small VOI size. In the measurements performed in this study, both the gradient strength and the RF pulse bandwidth changed when changing VOI size from 10 to 30 mm.

The computer simulations did not fully predict the measured result, but the same type of behavior for the simulated and measured results were obtained. The simulations took only into account the contam_ination caused by T1 smearing, but other effects may also influence the signal strength, i.e. the coil homogeneity, T2 relaxation during the inversion pulses, and eddy

currents. However, since the same behavior is obtained T1 smearing is probably the main reason for contami- nation in these measurements.

This study has shown that with a measurement situa- tion close to the real in vivo situation (27 cm 3 VOI, TR = T1, 2 1 object, etc.) the errors introduced by the ISIS volume selection are of such a magnitude that quantitative measurements must be performed with great caution. The amount of contamination is strongly dependent on the ISIS experiment order used. T1 smearing seems to be the main source of contamination in in vivo 31p MRS using ISIS. If this is correct, then the ISIS experiment order is crucial for the measure- ment accuracy and the results of this study are gener- ally applicable to the measurement geometry and ISIS experiment order rather than specific for the MR sys- tem studied.

To our knowledge there is no ISIS experiment order implemented in any MR system today that does not suffer from contamination due to T1 smearing. The tolerable amount of contamination and other errors are due to the type of experiments performed. Since the signal changes obtained in in vivo MRS are low, the contamination should be less than a few percent of the total signal. This might be possible to achieve with an optimal experiment order [5] but only if the slice with contamination is chosen in a Pavorable direction. The most optimal ISIS sequence would probably be E-ISIS [6], which theoretically cause no contamination due to T1 smearing.

AcknoMedgements

This work was supported by the Swedish Medical Research Council (project no. 10433) and the Lundberg Foundation, G6teborg, Sweden.

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