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Metabolite-cycling at 14.1T: sequence implementation and initial explorations using SPECIAL and diffusion-weighted SPECIAL
Jessie Mosso1,2, André Döring1,2, Roland Kreis3,4, Cristina Cudalbu1,2, and Bernard Lanz1,2
1CIBM Center for Biomedical Imaging, Lausanne, Switzerland, 2Animal Imaging and Technology, EPFL, Lausanne, Switzerland, 3Magnetic Resonance Methodology, Institute of Diagnostic and Interventional Neuroradiology, University of Bern, Bern, Switzerland, 4Translational Imaging Center, sitem-insel, Bern, Switzerland

Synopsis

Keywords: Spectroscopy, Brain, MRS, metabolite-cycling, sequence development, SPECIAL, diffusion, DW-MRS, downfield

Motivation: Water suppression leads to saturation of exchanging protons which biases metabolite concentration estimates and prevents the study of downfield resonances in the 1H spectrum.

Goal(s): Apply metabolite-cycling (MC) to study these resonances with high sensitivity using the short-TE, full-intensity SPECIAL sequence at ultra-high field on an animal scanner.

Approach: The MC pulse was optimized for 14.1T. MC SPECIAL and MC diffusion-weighted SPECIAL were implemented and tested in vivo.

Results: Underestimation of specific upfield metabolite concentrations with water-suppressed SPECIAL compared to MC SPECIAL was observed. Downfield resonances attribution was further validated with diffusion-weighted acquisitions, uniquely showing the presence of macromolecules in the 6.5-7.5ppm region.

Impact: The introduction of metabolite-cycling in the short echo-time, full intensity SPECIAL and diffusion-weighted SPECIAL 1H MRS sequences at 14.1T paves the way for in-depth exploration of the downfield resonances of the 1H spectrum with high sensitivity on animal scanners.

Introduction

1H MRS sequences usually employ water suppression techniques such as VAPOR1 to observe upfield metabolites (< 4.7 ppm) 10000 times less concentrated than water. Water suppression (WS) RF pulses lead to indirect saturation of resonances with exchanging protons2 and direct, undesired saturation of resonances close to the water signal at 4.7 ppm. Metabolite-cycling (MC) has been introduced to circumvent these effects by alternatively inverting the upfield and downfield regions of the spectrum without water pre-saturation3. Combined with STEAM and sLASER sequences, MC enabled in-depth exploration of downfield resonances (> 4.7 ppm) of the 1H MRS spectrum3–6.
SPECIAL localization7,8 enables short echo-time (TE) acquisitions with full-magnetization, which in turn improves the quantification of short T2 and J-coupled metabolites.
In this work, we combined the semi-adiabatic SPECIAL localization with MC at 14.1T, both in the single-voxel semi-adiabatic SPECIAL sequence and in the recently proposed diffusion-weighted (DW-) SPECIAL sequence9. Doing so, we benefitted from the high sensitivity offered by short TEs and ultra-high magnetic field and aimed at 1) evaluating the bias introduced by WS pulses in the upfield metabolite concentration estimates, and 2) exploring the downfield region of the 1H MRS spectrum both with single-voxel MRS (SVS) and DW-MRS.

Methods

The SPECIAL and DW-SPECIAL sequence diagrams are presented in Fig 1. The MC RF pulse was optimized for 14.1T (Fig 2) and inserted before the first 90° pulse in each sequence. The downfield/upfield inversions are applied consecutively, resulting in a 4-shot sequence (Fig 1D).
SVS: N=2 male Wistar rats were scanned with VAPOR WS SPECIAL and with MC SPECIAL to compare upfield resonances quantification (15.6µL voxel, striatum, TE=9.3ms, 256 shots, TR=4s) (Fig 3). N=5 rats were scanned with MC SPECIAL in the same conditions to investigate the downfield region (Fig 4). Spectral registration10 was performed on the water region on each 4 (for MC) or 2 (for WS) subsets of shots individually. The basis set was simulated with NMRScopeB/jMRUI11, the macromolecules (MM) acquired in the striatum with metabolite nulling by double-inversion recovery (TI1/TI2=2200/850ms) and residual metabolites removed12. Metabolite concentrations from WS SPECIAL and MC SPECIAL were referenced to the same separately-acquired water signal and corrected for water (T2 at 14.1T in the striatum: 29ms) versus metabolites T2 relaxation.
DW-MRS: N=1 rat was scanned with MC DW-SPECIAL (175µL voxel, centre of the brain, 6 b-values between 0.05 to 20ms/µm2, TE/TR/Δ/δ=18.5/3000/43/3ms, Δ/δ: diffusion gradient spacing/duration). Spectral registration was performed either on the water region or the upfield region to compare the two processing strategies.

Results and Discussion

Fig 2 shows the results of the MC pulse optimization at 14.1T, performed following refs3,5, based on the initial pulse of Hwang et al.13. Pulse duration tp and RF peak amplitude ν1,max were chosen to reach the desired inversion bandwidth (2400Hz, 4 ppm at 14.1T) and transition bandwidth (100Hz) (Fig 2A,B). The longer the pulse, the more robust bwinv to ν1,max inhomogeneities, expected with surface coils, guiding the choice for a long tp among the possible choices (Fig 2C). The final combination of parameters was: ν1,max=1700Hz, tp=36ms, ±350Hz offset with respect to water frequency.
Fig 3A shows the comparison between WS and MC SPECIAL in the striatum of two animals. Good upfield spectral quality and efficient water suppression were obtained with both sequences, the downfield region with MC SPECIAL featuring additional resonances. Cr, PCr, Gln and Glu concentrations are systematically underestimated with WS SPECIAL compared to MC SPECIAL, possibly caused by magnetization transfer on metabolites pools linked to solid-like macromolecules (Fig 3B).
Fig 4 shows a tentative assignment of the downfield resonances in the striatum (ATP, Gln, PCr, Glc, NAA, GSH, MM) based on literature4,14,15. The resonance at 5.8 ppm, possibly blood-borne urea16, was highly variable between animals.
Fig 5A shows upfield, downfield and water diffusion spectra acquired in one animal with MC DW-SPECIAL, of good quality up to the highest b=20ms/µm2 used. The downfield resonances between 6.5 and 7.5 ppm barely decay, suggesting the presence of macromolecules in this region. Spectral registration and intensity scaling applied on water or on upfield metabolites perform similarly at correcting high b-value spectra and better than without any correction (Fig 5B). For human experiments more prone to motion artefacts or with poorer shimming conditions, alignment of the ISIS shots based on MC water rather than on metabolites could become crucial.

Conclusion

A short TE (DW-)SPECIAL combined with MC at 14.1T was successfully implemented. With their high sensitivity, the two sequences enable further exploration of the downfield region enhanced by diffusion measurements, and improved accuracy of 1H MRS upfield metabolite concentrations estimation.

Acknowledgements

This project was supported by the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 813120 (INSPiRE-MED), the SNSF projects no 310030_173222, 310030_201218 and the Leenaards and Jeantet Foundations. We acknowledge access to the facilities and expertise of the CIBM Center for Biomedical Imaging founded and supported by Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Ecole polytechnique fédérale de Lausanne (EPFL), University of Geneva (UNIGE) and Geneva University Hospitals (HUG).

References

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Figures

Fig 1 – Metabolite-cycled SPECIAL (A) and metabolite-cycled DW-SPECIAL (B) sequence design. Pulse details: MC pulse (36 ms, bandwidth (BW) = 2400 Hz, frequency factor 2 as defined in ref5, offset 350 Hz), adiabatic hyperbolic secant (2 ms, BW = 10 kHz), asymmetric P10 90° (0.5 ms, BW = 13.5 kHz, 18% refocusing factor), square 90° pulse (0.1 ms, BW = 12.8 kHz). SPECIAL localization RF pulses: blue. Gradients: blue – volume selection, red – diffusion, grey – spoilers. The downfield/upfield inversion profiles of the MC pulse are shown in C and the shots combination in D.

Fig 2 – Optimization of the MC RF pulse for 14.1T based on numerical solutions of the Bloch equations without relaxation. Inversion (bwinv) (A) and transition bandwidth (bwtrans) (B) as a function of pulse duration tp and RF peak amplitude ν1,max. The black squares correspond to the target bwinv = 2400 Hz ± 100 Hz and bwtrans = 100 Hz ± 1 Hz and the red lines to the chosen combination of tp and ν1,max. C: Effect of achieved ν1,max on bwinv depending on the pulse duration. The frequency factor that multiplies the initial bandwidth of the composite MC pulse was set to 2.

Fig 3 – Comparison between WS SPECIAL (red) and MC SPECIAL (blue) (TE = 9.3 ms) with respect to spectral quality of the upfield/downfield regions and water suppression efficiency (A), and upfield metabolites concentration estimates in the striatum of two animals (B). In panel B, metabolites for which the concentrations derived from WS SPECIAL are underestimated compared to the ones from MC SPECIAL are highlighted with black boxes. Cr and PCr are well separable (3.9 ppm) thanks to a good shim in the striatum (water linewidth: 15-17Hz). 2 Hz Lorentzian line broadening for display.

Fig 4 – Downfield region (5-9 ppm) from 5 animals measured with MC SPECIAL (TE = 9.3 ms) in the striatum, overlapped (A) and averaged (B). Tentative peak assignment based on literature4,14–16 on the averaged spectra (B). In brackets, the chemical shift of the resonances in ppm. 5 Hz Lorentzian line broadening for display.

Fig 5 – Diffusion set up to b = 20 ms/µm2 with MC DW-SPECIAL in one animal, for upfield, downfield and water (A). Effects on the NAA signal intensity at b = 20 ms/µm2 (maximum amplitude indicated by a dashed line) when spectral registration is performed on the water signal (blue), on the upfield metabolites signal (pink) or not at all (purple) (B). 2 and 5 Hz Lorentzian line broadening for display of upfield and downfield spectra, respectively.

Proc. Intl. Soc. Mag. Reson. Med. 32 (2024)
0252
DOI: https://doi.org/10.58530/2024/0252