Localized, gradient-reversed ultrafast z-spectroscopy in vivo at 7T
Neil Wilson1, Kevin D'Aquilla1, Catherine Debrosse1, Hari Hariharan1, and Ravinder Reddy1

1Department of Radiology, Center for Magnetic Resonance and Optical Imaging (CMROI), University of Pennsylvania, Philadelphia, PA, United States

### Synopsis

Ultrafast z-spectroscopy can be collected by saturating the nuclear spins with an RF pulse in the presence of a gradient, effectively encoding the offset frequency spatially across a voxel and allowing full z-spectra to be collected in a single shot. When asymmetry analysis is applied, frequencies on one physical side of the voxel are compared with those on the other physical side. This can be a problem if there is inhomogeneity or partial voluming. By acquiring an additional z-spectrum with the gradient polarity reversed, mixed z-spectra can be created in which the positive and negative offset frequencies come from the same side of the voxel. This method is more robust to inhomogeneity and partial voluming typically found in vivo as demonstrated here with studies on 7T in human brain.

### Purpose

To collect ultrafast z-spectra in vivo at 7T where voxel homogeneity cannot be assured.

### Introduction

CEST contrast is generated by selective saturation of a labile proton group and measurement of the subsequent reduction in water signal.1 Standard methods collect a single offset frequency per acquisition which leads to a trade-off between spectral resolution and scan time.

Saturating in the presence of a gradient spreads the offset frequency spatially across a voxel. Effectively, each voxel is split into slivers that are encoded for each offset frequency. This encoding is resolved by applying a similar gradient during readout and allows for ultrafast2 collection of a full z-spectrum in a single shot and has been applied in vitro3,4,5 and recently, localized in vivo in human brain (UCEPR)6. Spectral resolution is determined by the number of readout points and does not affect overall scan time. In conventional z-spectroscopy, inhomogeneity and partial volume effects are averaged over the entire voxel for each frequency, whereas in ultrafast z-spectroscopy (UFZS), different offsets experience different effects, resulting in unpredictable errors in analysis.

Here, we demonstrate an extension to UCEPR6 that makes it more robust to voxel inhomogeneity and partial volume effects by acquiring an additional scan with the saturating gradient polarity reversed. Reversing the gradient polarity reverses the direction of offset frequencies relative to isocenter. Physical locations that were saturated at a positive offset originally are saturated at a negative offset during reversal. We call this approach gradient-reversed ultrafast z-spectroscopy (GRUFZS).

### Methods

The pulse sequence is a modified version of PRESS in which excitation was performed with a hard, nonselective 90o pulse followed by three slice selective refocusing pulses and is shown in Fig 1. Saturation used Hanning-filtered rectangular pulses with a total saturation time of 800 ms with peak B1 power 220 Hz. The saturation pulse was frequency shifted such that the voxel center was on resonance and the saturation bandwidth was $\pm$5 ppm over the voxel. The readout was oversampled by a factor of 10 to ensure adequate sampling of T2*-weighted gradient echo. TR/TE = 8000/30 ms. Voxel size was 15x15x15 mm3. Scans without saturation were acquired and used to normalize for proton density differences across the voxel. All scans were taken on a Siemens 7T whole body scanner.

Time domain data was filtered using a binary threshold at the noise level since the readout was much longer than the actual echo duration. Data was Fourier transformed to the spatial/z-spectral domain and normalized with the unsaturated scan. Mixed z-spectra were created by taking the positive offset frequencies from the positive polarity scan and combining with the negative offset frequencies from the negative polarity scan and vice versa. $\text{MTR}_{asym}$ values were calculated and normalized by the negative offset intensity.

### Results and Discussion

Figure 2 shows an example reconstruction for a cortical white matter voxel. The white matter voxel shown is fairly homogeneous with little partial voluming. Nevertheless, the asymmetry plots from the mixed z-spectra in Fig 2g are much closer than those from the acquired spectra in Fig 2f. For an inhomogeneous voxel with significant partial voluming, UFZS results in widely different, sometimes negative asymmetry values depending on the gradient polarity as shown in Fig 3f. The mixed asymmetry plots calculated from GRUFZS in Fig 3g show much better agreement, especially farther from water.

Table 1 shows results of different voxel placements as well as different ultrafast directions and compares to conventional z-spectroscopy. It is clear that regular UFZS fails in many of the cases since $\text{MTR}_{asym}$ can be positive or negative depending on the gradient polarity choice, while GRUFZS values are much closer and consistently reflect positive asymmetry values.

Conventional z-spectroscopy at the same digital spectral resolution as GRUFZS would take 25x longer, and though there is an SNR penalty associated with ultrafast scanning, the high sensitivity of CEST along with the large voxel sizes here mean that SNR is not a limiting factor. Compared to previously-reported UFZS, GRUFZS requires additional scans. However, there is no associated penalty in scanning efficiency since the mixed z-spectra can be averaged to give a single $\text{MTR}_{asym}$ value. Alternatively, the mixed z-spectra can be kept separate, as they are effectively acquired from two adjacent half voxels.

### Conclusion

We have presented a method to acquire ultrafast z-spectra in vivo that requires only an additional scan with the gradient polarity reversed. The improved tolerance to inhomogeneity and partial voluming is evident in the asymmetry plots of the mixed z-spectra compared to the originally acquired ones. This method offers a fast, robust way to record full z-spectra in vivo.

### Acknowledgements

This work was supported by the National Institute of Health through grant number P41-EB015893 and the National Institute of Neurological Disorders and Stroke through Award Number R01NS087516.

### References

[1] Wol ff SD, Balaban RS. NMR imaging of labile proton exchange. Journal of Magnetic Resonance 1990;86:164-169.

[2] Frydman L, Scherf T, Lupulescu A. The acquisition of multidimensional NMR spectra withina single scan. Proceedings of the National Academy of Sciences 2002;99:15858-15862.

[3] Swanson SD. Broadband excitation and detection of cross-relaxation NMR spectra. Journal of Magnetic Resonance 1991;95:615-618.

[4] Xu X, Lee JS, Jerschow A. Ultrafast Scanning of Exchangeable Sites by NMR Spectroscopy. Angewandte Chemie International Edition 2013;52:8281-8284.

[5] Dopfert J, Witte C, Schroder L. Slice-selective gradient-encoded CEST spectroscopy for monitoringdynamic parameters and high-throughput sample characterization. Journal of Magnetic Resonance 2013;237:34-39.

[6] Liu Z, Dimitrov IE, Lenkinski RE, Hajibeigi A, Vinogradov E. UCEPR: Ultrafast localized CEST-spectroscopy with PRESS in phantoms and in vivo. Magnetic Resonance in Medicine 2015;Early View.

### Figures

Table 1: Comparison of $\text{MTR}_{asym}$ values between mixed z-spectra (dubbed Left and Right) and acquired z-spectra (Positive and Negative) in GRUFZS as well as with conventional z-spectroscopy (Conv) for white matter (WM), thalamus, and prefrontal cortex voxel placement. GRUFZS is shown with the ultrafast direction varied (x,y,z).