MAGNETIC RESONANCE IN MEDICINE 17, 3-9 ( 1991 )

Quantitative Spectroscopy Using Multiple Surface Coil Probes

PETER STYLES

MRC Biochemical and Clinical Magnetic Resonance Unit. John Radclife Hospital, Headington, Oxford OX3 9DU. United Kingdom

Received September 4, 1990

The performance of the rotating frame localization method is discussed, with emphasis on performing the experiment and processing the data in the optimum manner. Studies on phantom samples are presented to illustrate various imperfections which affect the confidence that can be placed on acquired data. o 1991 Academic press, Inc.

INTRODUCTION

The aim of a localized spectroscopic investigation should be to obtain absolute metabolite concentrations from a precisely defined voxel containing some homoge- neous tissue type. The realities of the NMR measurement and the nonuniformity of human morphology render the realization of such an aim impossible in the majority of cases. However, the spectroscopist must still strive to understand and minimize the various uncertainties in his or her experimental technique.

In this laboratory we routinely apply the phase-modulated rotating frame method ( 1-3) to the study of a wide variety of tissues. Here are described certain experiments which have been performed to validate the method, and arrive at confidence limits for obtaining quantitative data from human studies. Although the rotating frame approach is not widely used, many of the problems are common to other experimental protocols. In particular, the well known “point spread function” effect occurs in all Fourier methods, as does the interdependence of sensitivity and spatial resolution.

METHODS

The way in which we implement the phase-modulated rotating frame localization has been reported elsewhere (3-5). Briefly, an approximately linear BI gradient is generated using a double surface coil probe in which a large transmitter coil is placed behind a smaller receiver coil (6, 7). Typically, the ratio of the two coil radii is 2.5, with the transmitter separated from the sample by a distance of 0.3rt (where r , is the transmitter coil radius). Passive tuning circuits using crossed diodes and a transmission line effect electrical isolation of the two coils (7) . In some cases, a proton coil is incorporated which takes the form of a rectangular “butterfly coil,” chosen because this shape does not inductively couple to the simple surface coil loops (8-10). This arrangement enables scout images to be obtained from the region underneath the probe assembly.

The pulse sequence for performing the rotating frame localization consists of an incremented pulse no, immediately followed by a nominal 90” pulse A, which tips

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4 PETER STYLES

the magnetization into the x’y’ plane, thus creating a two-dimensional data set in which B1 field strength (and hence position) is encoded into the phase of the received signal. Problems of phase twist are avoided by collecting two complete data sets with the phase of the X pulse either + y or - y (1 , 3-5). Subsequent processing in which one data set is reversed along the spatial axis prior to addition of the two data matrices results in a set of absorption mode spectra, each corresponding to a different position in the gradient B , field.

VERIFICATION OF PROBE PERFORMANCE

The performance of the rotating frame experiment is dependent on the characteristics of the probe, and several parameters need to be investigated.

Flatness of the B, je ld over the detected region. This parameter may be determined by using a phantom comprising several flat compartments, placed parallel to the probe, and extending laterally well beyond the outline of the receiver coil. Data obtained from such experiments have been presented elsewhere ( 5 , 1 I ), and demonstrate that excellent localization of flat sections is indeed possible.

Depth calibration. The variation of the field along the axis of a circular transmitter coil is given by

where r is the coil radius and x is the distance along the coil axis. However, this field profile could be modified by rf eddy currents. To measure the true spatial response, the rotating frame experiment can be performed on a large homogeneous phantom in the presence of a static Bo gradient applied in the direction of the probe axis. Thus the chemical shift dimension represents distance as defined by the static gradient, allowing for a direct determination of B1 gradient versus Bo gradient. By adjusting the conductivity of the phantom to mimic that of tissue, any modification of the B I profile will be detected. A typical data set may be found in Ref. (10) . As would be expected from other studies ( 1 2 ) , skin depth effects in the sample do not significantly affect the spatial calibration of our phosphorus probes operating at 32.7 MHz.

The lateral spatial response. For most applications, we rely on the response of the surface coil receiver to determine the lateral extent of the sensitive region. This may be ascertained by experiments on concentric phantoms ( I 1 ). Alternatively, the profile in any desired direction may be determined in a similar manner to that described for depth calibration ( 10). Such experiments provide qualitative confirmation of computer simulations of offset double surface coil probes such as those performed by Ganvood and colleagues ( 13).

ADDITIONAL CONTROL OF SPATIAL PROFILE

In situations where the natural spatial response of the surface coil receiver does not provide adequate lateral localization, a hybrid localization method may be advanta- geous. We have investigated the efficacy of implementing noise pulses in conjunction with switched BO gradients (14, 1 5 ) to improve the lateral selectivity of our double surface coil probes. The pulses are computer generated by Fourier transformation of

MULTIPLE SURFACE COIL PROBES 5

white noise which has been zeroed over a specified bandwidth. Application of the pulse and associated Bo gradient prior to the rotating frame pulses serves to randomize the magnetization over a region determined by the bandwidth of the “frequency hole” and the gradient strength. This additional localization may be implemented along the two lateral directions, thus delineating a rectangular column of sample which is then further localized by the rotating frame protocol.

The method is demonstrated in Fig. 1. Setting the lateral localization to 4 cm in both x and y directions gives almost complete elimination of the signal from outside the central bottle, with a small reduction in the inner signal as expected when locating a rectangular (4-cm) sensitive volume within a circular (5-cm) cross-section object. Two features of the data require explanation: the peak at the front of the matrices arises from the calibration phantom within the receiver coil, and the small unsuppressed signal that remains in the superficial region comes from some of the “outer” phosphate which was trapped underneath the concave base of the “inner” bottle.

OPTIMIZATION OF DATA COLLECTION

In any Fourier imaging method, two adjacent positions will be resolved if the longest (or strongest) phase encoding period effects approximately one cycle difference at these points [a more detailed description can be found in Ref. ( 1 ) ] . As one increases this maximum encoding period, the acquired signal will decrease because signals from the various parts of the sample interfere destructively. Thus, spatial resolution can be obtained only at the expense of overall signal to noise as shown in Fig. 2. A further payoff between resolution and sensitivity can be achieved by appropriate windowing of the data set. Zero filling is also desirable as a means of extracting the maximum information from the data ( 1, 1 6 ) . Any such manipulations must be considered within the context of the “point spread function,” which describes the manner in which the signal from a point in space is spread through the frequency domain, leading to con- tamination of spectra by signals from unwanted regions. In the case of a smooth decaying window function, the signal becomes broader. When zero filling is employed, the rectangular window of data within a larger transformation block can result in serious truncation artifacts-the well-known sinc wiggles on either side of the desired response.

FIG. 1. The use of a hybrid B I / B o technique to improve localization. The sample comprised two concentric bottles, diameters 5 and 10 cm, each containing phosphate at the same concentration (acidic in the inner compartment, alkaline in the outer). The offset double surface coil probe had a receiver diameter of 6.5 cm and transmitter diameter of I5 cm. ( A ) Data obtained without any lateral discrimination. (B) Data obtained by applying noise pulses together with Bo gradients along the two axes perpendicular to the probe axis. The nominal lateral localization was a 4-cm rectangular column.

6 PETER STYLES

FIG. 2. Data acquired to assess the interdependence of sensitivity, resolution, and contamination. The sample comprised a large beaker containing inorganic phosphate with a void created by placing a l-cm- thick disk of plexiglass parallel to the coil. ( A ) Sixty-four pulse increments. ( B ) Thirty-two pulse increments. (C) Sixteen pulse increments. In each case, the data were apodized by a Gaussian truncated at 5% in the final increment, and zero filled to 128 points.

Combining these several factors, it becomes clear that the number of phase encoding steps should be sufficient only to achieve the required resolution. The data should then be windowed to reduce truncation effects to less than the noise level, and zero filled prior to the second Fourier transformation.

Windowing (in the spatial dimension) may be achieved either by multiplying the acquired data by the appropriate function or by varying the number of accumulations at each pulse increment. These two approaches have previously been considered for the HASP method. Pekar er al. ( 1 7 ) show that improvement in sensitivity is possible by tailored acquisition rather than apodization of a data set collected with equal scans for each acquisition. With a window function f ( n ) (where the collected FIDs are numbered from 1 to n ) , it can be shown that the relative sensitivities of the two methods are

where the summations are from 1 to n , and AS: N / fi is the relative sensitivity of the apodization method compared to the tailored data acquisition technique. Taking as an example a Gaussian window truncated at 5% of its maximum value, the apodization of equal acquisitions reduces the sensitivity to about 83% of that obtained by tailoring the number of scans. Figure 3 shows the effects of different acquisition and processing strategies. The sample was a small “point source” phantom of phosphoric acid, and in each case, 32 pulse increments were collected and the data were zero filled in the spatial dimension to 128 complex points. Without any windowing (Fig. 2A), there is excellent spatial resolution, but significant sinc wiggles due to truncation effects. Ap- plying a Gaussian apodization gives rather less resolution, but improved signal to noise and an absence of truncation artifacts (Fig. 3B) . In Fig. 3C, the data have been acquired by tailoring the number of scans. Although the S : N ratio is now reduced, the acquisition required 266 scans instead of 5 12 in the previous case. Using the Bruker S : N routine, and correcting for the acquisition time, there is a measured im- provement in sensitivity of 20% as a consequence of tailoring the data acquisition.

MULTIPLE SURFACE COlL PROBES 7

FIG. 3. Effects of data acquisition and processing on resolution and sensitivity. The sample comprised a small sample of phosphoric acid. (A) Thirty-two pulse increments taking a total of 5 12 acquisitions; data zero filled to 128 points with no apodization in the spatial dimension. (B) As in (A) except that data are apodized with a Gaussian truncated at 5% in the final increment. ( C ) Data collected using 32 pulse increments, but with the number of acquisitions tailored according to the Gaussian used for ( B ) . This resulted in a total number of data acquisitions of 266.

ABSOLUTE QUANTIFICATION

In the absence of additional localization, the surface coil receiver is a very poor vehicle for achieving absolute quantification. If, however, the spatial origin of the signal is known, correction may be made for the inhomogeneity of the surface coil sensitivity. Where localization is effected by means of a B1 method, it is necessary to provide a calibration of the transmitter field to allow for probe loading effects. We incorporate a small glass vial containing diphenyl phosphate at the center of the receiver coil (9-11, 18). This serves two purposes. First, the spatial (i.e., B1) calibration can be determined from the position of the diphenyl phosphate signal in the final data matrix. Second, this phantom serves as an external concentration reference for deter- mining absolute metabolite concentrations. In extensive calibration experiments it has been interesting to note that the most significant error has been in the determination of the total signal from this reference. The problem stems from the uncertain linewidth and lineshape due to the standard being external to the main shimmed volume. Despite this difficulty, repeated phantom studies ( 1 9 ) have shown that concentrations (of the same order as found in vivo) may be determined with a coefficient of variation of less than 10%. These techniques have already proved to be valuable in measuring gray/ white matter differences and enzymatic rates in brain ( 18), and in detecting cellular damage in patients with paracetamol poisoning (20).

CONCLUSIONS

The accurate assessment of localized metabolic status is still a difficult problem due to the extreme insensitivity of the NMR phenomenon and the technological problems of performing artifact-free localized spectroscopy. Rotating frame methods offer one possible approach, particularly applicable in cases where relaxation times are short. This presentation has dealt with some of the performance characteristics which govern

8 PETER STYLES

the confidence that one can place on experimental findings. Finally, it seems likely that the routine measurement of concentrations rather than simple ratios will become increasingly important in determining metabolic abnormalities in human disease.

ACKNOWLEDGMENTS

The work presented here represents the efforts of many colleagues working under the direction of Professor George Radda. The reference list indicates the names of most of the contributors, but special thanks are due Dr. Jonathan Allis for his consistent help in understanding and improving our experimental protocols. This laboratory is funded by the Medical Research Council, the Department of Health, and the British Heart Foundation.

REFERENCES

1. D. 1. HOULT, J . Magn. Reson. 33, 193 (1979). 2. S. J. Cox AND P. STYLES, J. Mugn. Reson. 40,209 (1980). 3. M. J. BLACKLEDGE, B. RAJAGOPALAN, R. D. OBERHAENSLI, N. M. BOLAS, P. STYLES, AND G. K.

4. M. J. BLACKLEDGE AND P. STYLES, J. Magn. Reson. 77,203 (1988). RADDA, Proc. Natl. Acad. Sci. USA 84,4283 ( 1987).

5 . M. J. BLACKLEDGE, P. STYLES, AND G. K. RADDA, J . Magn. Reson. 79, 176 ( 1988). 6. P. STYLES, C. A. SCOTT, A N D G. K. RADDA, Magn. Reson. Med. 2,402 ( 1985). 7. P. STYLES, NMR Biomed. 1,61 (1988). 8. J. H. BATTOCLETTI, R. E. HALBACH, A. SANCES, s. J. LARSON, R. L. BOWMAN, AND v. KUDRAVCEV,

Med. Biol. Eng. Comput. 17, 183 (1979).

Meeting, 1989,” p. 960. 9. P. STYLES, G. HOGAN, T. CADOUX-HUDSON, AND G. K. RADDA, in “Proceedings, SMRM, 8th Annual

10. P. STYLES, T. CADOUX-HUDSON, AND G. HOGAN, Magn. Reson. Med. Biol.. in press. 11. T. A. D. CADOUX-HUDSON, M. J. BLACKLEDGE, B. RAJAGOPALAN, D. J. TAYLOR, AND G. K. RADDA,

12. C. C. HANSTOCK, J. A. LUNT, AND P. s. ALLEN, Mugn. Reson. Med. 7,204 ( 1988). 13. M. GARWOOD, T. SCHLEICH, M. R. BENDALL, AND K. UGURBIL, SMRM Poster ( 1986). Relevant data

14. R. J. ORDIDGE, Mugn. Reson. Med. 5,93 (1987). 15. U. BOTTCHER, A. HASSE, D. NORRIS, AND D. LEIBFRITZ, in “Abstracts, 2nd European Congress of

16. R. FREEMAN, “A Handbook of Nuclear Magnetic Resonance,” Longman, Harlow, 1988. 17. J. PEKAR, J. S. LEIGH, AND B. CHANCE, J. Mugn. Reson. 64, 115 (1985). 18. T. A. CADOUX-HUDSON, M. J. BLACKLEDCE, AND G. K. RADDA, FASEB .I. 3,2660 ( 1989). 19. J. F. DUNN AND G. J. KEMP, personal communication. 20. R. M. DIXON, P. W. ANGUS, B. RAJAGOPALAN, AND G. K. RADDA, in “Abstracts, 7th European

Br. J. Cancer 60,430 (1989).

appears in Ref. ( 7).

NMR in Medicine and Biology, Berlin, 1988,” p. 27.

Congress of NMR in Medicine and Biology, Strasbourg, 1990,” p. 69.

DISCUSSION

Speuker: P. STYLES

Professor Hahn Would it be possible to utilize the “rotary saturation” effect to obtain calibration

information about the gradient values of Bo and BI fields? Professor Hahn then described the rotary saturation phenomenon. There was general

agreement about the interest of the idea, even if immediate applications were not readily identifiable.

MULTIPLE SURFACE COIL PROBES 9

Dr. Morris

volume (say 10 cm3), and what is the optimum size of surface coil?

Dr. Styles With our 6.5-cm-diameter receiver coil, we get usable phosphorus signals from

depths of up to about 6 cm. We have performed experiments which suggest that optimum coils should be rather smaller than is sometimes believed. We found that when sample losses dominate, and when considering sensitivity for unit sample volume, the coil should have a diameter approximately equal to the depth.

Dr. Garroway

theory for localization spectroscopy applications?

Dr. Styles We have no firsthand experience. However, maximum entropy has been applied

to the rotating frame protocol (Hore and Daniel, J . Mugn. Reson. 69, 386 ( 1986)). Both truncation and off-resonance artifacts can be successfully dealt with by this approach.

Can you tell us how far into the body it is possible to observe signals from a given

What is your experience with maximum entropy methods and linear prediction