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MRS Extended by Oscillating Diffusion Gradients as a Probe for Investigation of Human Brain Tissue Microstructure1Depts. Radiology and Biomedical Research, Bern, Switzerland
Synopsis
Pulsed diffusion and oscillating diffusion gradients implemented in a semi-Laser sequence for measuring at long and short diffusion times were tested in a phantom and applied in vivo. Metabolite diffusion constants measured in human gray matter in 6 healthy volunteers at short diffusion times were significantly higher than those determined at long diffusion times, suggesting an enhanced sensitivity to diffusion on the cellular and subcellular level.
Introduction
Diffusion-weighted spectroscopy (DW-MRS) provides information on metabolite diffusion. Unlike water, metabolites probe intracellular space only and are partially specific to neuronal (e.g. Glu, NAA)1 or glial (e.g. Ins, Cho)1 cells. Hence, metabolite-specific diffusion is a tailored probe for cellular tissue microstructure. Depending on diffusion time (TD), apparent diffusion coefficients (ADCs) are affected by different dimensions and mechanisms of cellular barriers2. Pulsed gradient spin-echo (PGSE) sequences, commonly used, measure at long diffusion times (TD) (>50ms) where ADCs represent diffusion mostly along tissue fibers3,4. Use of oscillating gradient spin-echo (OGSE) sequences sensitive to short TD (<10ms) promises ADCs more specific to cellular and subcellular properties (e.g. tissue diameter, size, tortuosity)2,5. This work aims to demonstrate that OGSE can be combined with DW-MRS on clinical MR systems to study human brain at short TD to provide ADCs sensitive to a different cellular length scale than PGSE.Methods
A semi-Laser6 localization sequence (cf. Fig.1) was extended to include diffusion-weighting by OGSE7,8 and PGSE9 elements, sensitive to TDs <10ms and >50ms, respectively. To counteract limited diffusion-weighting for OGSE a stretching exponent α was included to increase the gradient area10. The effective TD for OGSE is calculated from the gradient modulation spectrum (Fourier transform of total diffusion gradient shape G(t)) by10
$$\omega_{eff}^{OGSE}=\frac{\int_{0}^{\infty}\omega|F(\omega)|^2 d\omega}{\int_{0}^{\infty}|F(\omega)|^2 d\omega} \qquad TD_{eff}^{OGSE}=\frac{1}{4\,\omega_{eff}^{OGSE}}$$
The diffusion-weighting b was calculated by integration of G(t)
$$ b = \int_{0}^{T}dt \left[ \gamma \int_{0}^{t}G(t') dt' \right]^2$$
The parameter space in terms of b-value and TD as accessible on a clinical scanner is shown in Fig.2 as function of echo time (TE) and number of oscillation-periods N. As example, |F(ω)|² is provided for the {TD[ms],b[s/mm²],N} combinations of {5.7,1560,1}, {8.3,4660,1} and {4.5,1560,4} at α=8. For our diffusion measurements, TEs 150 and 200ms were chosen (N=1). At equal TE, PGSE was applied with effective TDs of 107 and 155ms and maximal b-values of 1716 and 4140s/mm². Background diffusion-weighting arising from crusher and slice-selecting gradients for a typical VoI of 30x30x30mm³ was estimated to be merely 55s/mm². Adiabatic metabolite-cycling and selective inversion-recovery pulses were added before localization to acquire water and metabolites simultaneously and suppress CSF (TI=1200ms)11. The inherent water reference was applied for frequency, phase, eddy-current correction and motion-compensation12. The sLaser sequence with PGSE and OGSE at 8 different b-values was tested in a “braino” phantom (TE=150ms) filled with an aqueous solution of typical brain metabolites and applied in vivo (TE=200ms) in gray matter of six healthy volunteers (age: 45.0±13.1yrs). Measurements were performed on a 3T Siemens PRISMA scanner using a 20-channel headcoil. Spectra were fitted with FiTAID13, first independently to probe mono-exponentiality of the decay and second simultaneously imposing a mono-exponential DW signal decay together with spectral linear-combination-model fitting14. The metabolite basis sets were simulated for sLaser with VESPA using real pulse shapes15.
Results and Discussion
Fig.3A shows water and metabolite spectra acquired simultaneously in the phantom with OGSE at different diffusion-weighting. The signal attenuation (Fig.3B & 3C) is mono-exponential for both PGSE and OGSE, and yields almost identical ADCs compatible with free diffusion. The possible parameter space for application of OGSE in vivo is limited by available gradient strength, TE, TD and physiological safety restrictions (cf. Fig.2), where a tradeoff to reach adequate b-values (4660s/mm²) has to be taken with prolonged TD (8.3ms) and TE (200ms). Fig.4A shows exemplary metabolite spectra acquired with PGSE and OGSE in a single subject. The slower signal attenuation in case of PGSE is directly visible from spectral inspection. Increased ADCs are found for all metabolites using OGSE at short TD (cf. Fig.4B). The signal attenuation for individual metabolites is mono-exponential within the error estimates. The cohort ADCs derived from 2D simultaneous fitting are presented in Fig.5. A paired t-test reveals highly significant and significantly faster diffusion of Cr, PCho, NAA, mI, Gln, Glu, NAAG, sI and Tau for OGSE than PGSE. These results suggest that even for moderate TDs (5-10ms) the ADC sensitivity for the cellular compartment changes to smaller structures where not only diffusion along fibers, but also subcellular diffusion, contributes.Conclusion
A sLaser diffusion sequence with PGSE and OGSE was developed and successfully tested in vitro and applied in vivo. It is demonstrated in human brain that application of OGSE reveal significantly increased metabolite ADCs compared to PGSE, indicating an increased sensitivity to diffusion on the cellular and subcellular level at short TD. ADCs representing diffusion on this level (at short and ultra-short TD) are assumed to be more sensitive to cellular and subcellular changes in disease. We hope that later studies will confirm a higher sensitivity for patho-physiological ADC changes at short TD.Acknowledgements
This work is supported by the Swiss National Science Foundation (SNSF #320030‐175984).References
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