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Cell specific anisotropy with double diffusion encoding spectroscopy in the human brain at 7T1Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark, 2C. J. Gorter Center for High Field MRI, Leiden University Medical Center, Leiden, Netherlands
Synopsis
The measurement of intracellular metabolite mobility with diffusion weighted spectroscopy (DWS) provides a cell-specific probe for microstructure. Measurements in animals and humans with conventional one dimensional diffusion encoding and model-guided analysis suggest that the main component of the intracellular space of both neurons and astrocytes comprises mainly anisotropic fibrous geometries. In this study we performed double diffusion encoded spectroscopy (DDES) in the human brain as a direct probe of anisotropic intracellular diffusion. As expected, our results support a main fibrous component but the results also suggest a more complex geometry of astrocytes that could include isotropic compartments.
Introduction
Unlike diffusion weighted imaging (DWI), metabolite mobility measured with diffusion weighted spectroscopy (DWS) provides a probe to cell-specific microstructure1. In particular, the intracellular diffusivity of the neuronal/axonal NAA has been demonstrated to be particularly useful for characterization of the intraneuronal/axonal space in healthy and diseased tissue2,3. In contrast to water mobility, simpler biophysical models may also be used to interpret metabolite diffusion and to obtain accurate cytomorphological information4–7. We recently leveraged those findings to introduce powder averaged DWS to account for the unknown macroscopic orientational distribution of fibers8. Those analyses, however, assume that disperse anisotropic domains fully account for the non-monoexponential signal attenuation in a single diffusion encoding (SDE) sequence. Double diffusion encoding (DDE) or multidimensional diffusion encoding (MDE) overcomes this assumption and provides a direct probe to underlying microscopic anisotropy in disordered tissues9,10. The cosinusoidal signal modulation with respect to the relative angle θ between two separated diffusion weighting gradient encodings is the hallmark of microscopic anisotropy11. The method has recently been adopted for imaging using different approaches and enables the measurement of microscopic fractional anisotropy (µFA)12,13. µFA is related to the conventional FA value from DTI analysis but unbiased by the underlying macroscopic fiber architecture. DDE was recently combined with DWS in mice and demonstrated a strong underlying anisotropy in all brain metabolites14. In this work we apply double diffusion encoding spectroscopy (DDES) in human studies.Methods
Data acquisition: Experiments were performed on 5 healthy volunteers (41 ± 19 y/o). Data were acquired on a Philips 7T whole body MRI scanner (Philips, Cleveland OH, USA), equipped with a volume transmit/32-channel receive head coil ((Nova Medical, Wilmington MA, USA)). The sLASER-based DDSE sequence diagram is shown in (fig 1A). A volume of interest of 3(A-P)×2(R-L)×1.5(F-H) cm3 was positioned on a parietal region containing mostly white matter (fig 1B). TR/TE = 5000/185ms. For each diffusion weighting block, the single gradient duration was (δ/2) = 15.5 ms, bipolar gap (τ) = 10 ms and Δ = 45 ms. The direction of the first gradient was set to [1,1,-0.5] and the second gradient was given in 12 equally spaced directions, tracing a circle that included [1,1,-0.5]. The resulting b was 7192 s/mm2, and each condition was repeated 24 times for a total acquisition time of 25 minutes. Analysis: The individual spectra were corrected for eddy currents and phase and frequency variations. Water, tNAA, pCho and tCr levels were quantified for b=0 and at b=7192 s/mm2 for each θ value using LCmodel15. We initially assume fully disperse Gaussian domains and fitted the θ modulation from an ensemble of uniformly rotated axisymmetric diffusion tensors to the normalized data with respect to the longitudinal and transversal diffusivities DL and DT. µFA was calculated as a conventional FA based on those diffusivities.Results
The tNAA, pCho and tCr peaks were clearly visible in all spectra with a cosinusoidal θ modulation with quantifiable peaks within a CRLB up to 8% (fig 2). The normalized metabolite levels and the model fit are shown for a single subject and the group mean in fig 3. Fitted model parameters (DL, DT and derived µFA) are shown in fig 4.Discussion and Conclusion
Metabolite diffusivities were comparable to values presented earlier with SDE in mice and human7,8 and DDE in mice16. The astrocytic PCho diffusivity showed somewhat lower µFA compared to the neuronal tNAA signal, suggesting an additional contribution from isotropic cell bodies in white matter that could provide a potential marker of disease progression, e.g. of glial reactivity in response to neuroinflammation. Water µFA was close to the tNAA values reflecting that fast extracellular components are filtered out at this relatively high b-value. We deliberately placed the VOI in a region with known high fiber dispersion but effects from residual macroscopic anisotropy cannot be fully excluded. This can be addressed with model approaches or extended gradient orientation schemes to provide more robust powder averages17,18. Time dependent effects should be considered at the short mixing times used in our setup and would be manifested as a signal difference between the parallel and antiparallel conditions θ = 0° and 180°. This was not observed and we thus expect those effects to be small with the current gradient timings. However, this effect could provide additional information and can be explored with a range of mixing times or tuned/detuned gradient pulses as previously done in DDE and MDE settings19,20. We will in future experiments also consider a range of b-values to fully separate variances related to anisotropy and isotropic heterogeneity21.Acknowledgements
This work is supported by the Danish Council for Independent Research (4093-00280A and 4093-00280B).References
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