Measuring compartmental T2-orientational dependence in human brain white matter using a tiltable RF coil and diffusion-T2 correlation MRI.

The anisotropy of brain white matter microstructure manifests itself in orientational-dependence of various MRI contrasts, and can result in significant quantification biases if ignored. Understanding the origins of this orientation-dependence could enhance the interpretation of MRI signal changes in development, ageing and disease and ultimately improve clinical diagnosis. Using a novel experimental setup, this work studies the contributions of the intra- and extra-axonal water to the orientation-dependence of one of the most clinically-studied parameters, apparent transverse relaxation T2. Specifically, a tiltable receive coil is interfaced with an ultra-strong gradient MRI scanner to acquire multidimensional MRI data with an unprecedented range of acquisition parameters. Using this setup, compartmental T2 can be disentangled based on differences in diffusional-anisotropy, and its orientation-dependence further elucidated by re-orienting the head with respect to the main magnetic field B→0. A dependence of (compartmental) T2 on the fibre orientation w.r.t. B→0 was observed, and further quantified using characteristic representations for susceptibility- and magic angle effects. Across white matter, anisotropy effects were dominated by the extra-axonal water signal, while the intra-axonal water signal decay varied less with fibre-orientation. Moreover, the results suggest that the stronger extra-axonal T2 orientation-dependence is dominated by magnetic susceptibility effects (presumably from the myelin sheath) while the weaker intra-axonal T2 orientation-dependence may be driven by a combination of microstructural effects. Even though the current design of the tiltable coil only offers a modest range of angles, the results demonstrate an overall effect of tilt and serve as a proof-of-concept motivating further hardware development to facilitate experiments that explore orientational anisotropy. These observations have the potential to lead to white matter microstructural models with increased compartmental sensitivity to disease, and can have direct consequences for longitudinal and group-wise T2- and diffusion-MRI data analysis, where the effect of head-orientation in the scanner is commonly ignored.

Probing the myelin water compartment with a saturation-recovery, multi-echo gradient-recalled echo sequence.

PURPOSE: To investigate the effect of varying levels of T1 -weighting on the evolution of the complex signal from white matter in a multi-echo gradient-recalled echo (mGRE) saturation-recovery sequence. THEORY AND METHODS: Analysis of the complex signal evolution in an mGRE sequence allows the contributions from short- and long- T2∗ components to be separated, thus providing a measure of the relative strength of signals from the myelin water, and the external and intra-axonal compartments. Here we evaluated the effect of different levels of T1 -weighting on these signals, expecting that the previously reported, short T1 of the myelin water would lead to a relative enhancement of the myelin water signal in the presence of signal saturation. Complex, saturation-recovery mGRE data from the splenium of the corpus callosum from 5 healthy volunteers were preprocessed using a frequency difference mapping (FDM) approach and analyzed using the 3-pool model of complex signal evolution in white matter. RESULTS: An increase in the apparent T1 as a function of echo time was demonstrated, but this increase was an order of magnitude smaller than that expected from previously reported myelin water T1 -values. This suggests the presence of magnetization transfer and exchange effects which counteract the T1 -weighting. CONCLUSION: Variation of the B1+ amplitude in a saturation-recovery mGRE sequence can be used to modulate the relative strength of signals from the different compartments in white matter, but the modulation is less than predicted from previously reported T1 -values.

Strong diffusion gradients allow the separation of intra- and extra-axonal gradient-echo signals in the human brain.

The quantification of brain white matter properties is a key area of application of Magnetic Resonance Imaging (MRI), with much effort focused on using MR techniques to quantify tissue microstructure. While diffusion MRI probes white matter (WM) microstructure by characterising the sensitivity of Brownian motion of water molecules to anisotropic structures, susceptibility-based techniques probe the tissue microstructure by observing the effect of interaction between the tissue and the magnetic field. Here, we unify these two complementary approaches by combining ultra-strong (300mT/m) gradients with a novel Diffusion-Filtered Asymmetric Spin Echo (D-FASE) technique. Using D-FASE we can separately assess the evolution of the intra- and extra-axonal signals under the action of susceptibility effects, revealing differences in the behaviour in different fibre tracts. We observed that the effective relaxation rate of the ASE signal in the corpus callosum decreases with increasing b-value in all subjects (from 17.1±0.7s-1 at b=0s/mm2 to 14.6±0.7s-1 at b=4800s/mm2), while this dependence on b in the corticospinal tract is less pronounced (from 12.0±1.1s-1 at b=0s/mm2 to 10.7±0.5s-1 at b=4800s/mm2). Voxelwise analysis of the signal evolution with respect to b-factor and acquisition delay using a microscopic model demonstrated differences in gradient echo signal evolution between the intra- and extra-axonal pools.

The impact of head orientation with respect to B0 on diffusion tensor MRI measures.

Diffusion tensor MRI (DT-MRI) remains the most commonly used approach to characterise white matter (WM) anisotropy. However, DT estimates may be affected by tissue orientation w.r.t. B→0 due to local gradients and intrinsic T2 orientation dependence induced by the microstructure. This work aimed to investigate whether and how diffusion tensor MRI-derived measures depend on the orientation of the head with respect to the static magnetic field, B→0. By simulating WM as two compartments, we demonstrated that compartmental T2 anisotropy can induce the dependence of diffusion tensor measures on the angle between WM fibres and the magnetic field. In in vivo experiments, reduced radial diffusivity and increased axial diffusivity were observed in white matter fibres perpendicular to B→0 compared to those parallel to B→0. Fractional anisotropy varied by up to 20% as a function of the angle between WM fibres and the orientation of the main magnetic field. To conclude, fibre orientation w.r.t. B→0 is responsible for up to 7% variance in diffusion tensor measures across the whole brain white matter from all subjects and head orientations. Fibre orientation w.r.t. B→0 may introduce additional variance in clinical research studies using diffusion tensor imaging, particularly when it is difficult to control for (e.g., fetal or neonatal imaging, or when the trajectories of fibres change due to, e.g., space occupying lesions).

Practical considerations of diffusion-weighted MRS with ultra-strong diffusion gradients.

Introduction: Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) offers improved cellular specificity to microstructure-compared to water-based methods alone-but spatial resolution and SNR is severely reduced and slow-diffusing metabolites necessitate higher b-values to accurately characterize their diffusion properties. Ultra-strong gradients allow access to higher b-values per-unit time, higher SNR for a given b-value, and shorter diffusion times, but introduce additional challenges such as eddy-current artefacts, gradient non-uniformity, and mechanical vibrations. Methods: In this work, we present initial DW-MRS data acquired on a 3T Siemens Connectom scanner equipped with ultra-strong (300 mT/m) gradients. We explore the practical issues associated with this manner of acquisition, the steps that may be taken to mitigate their impact on the data, and the potential benefits of ultra-strong gradients for DW-MRS. An in-house DW-PRESS sequence and data processing pipeline were developed to mitigate the impact of these confounds. The interaction of TE, b-value, and maximum gradient amplitude was investigated using simulations and pilot data, whereby maximum gradient amplitude was restricted. Furthermore, two DW-MRS voxels in grey and white matter were acquired using ultra-strong gradients and high b-values. Results: Simulations suggest T2-based SNR gains that are experimentally confirmed. Ultra-strong gradient acquisitions exhibit similar artefact profiles to those of lower gradient amplitude, suggesting adequate performance of artefact mitigation strategies. Gradient field non-uniformity influenced ADC estimates by up to 4% when left uncorrected. ADC and Kurtosis estimates for tNAA, tCho, and tCr align with previously published literature. Discussion: In conclusion, we successfully implemented acquisition and data processing strategies for ultra-strong gradient DW-MRS and results indicate that confounding effects of the strong gradient system can be ameliorated, while achieving shorter diffusion times and improved metabolite SNR.

Multi-compartment analysis of the complex gradient-echo signal quantifies myelin breakdown in premanifest Huntington's disease.

White matter (WM) alterations have been identified as a relevant pathological feature of Huntington's disease (HD). Increasing evidence suggests that WM changes in this disorder are due to alterations in myelin-associated biological processes. Multi-compartmental analysis of the complex gradient-echo MRI signal evolution in WM has been shown to quantify myelin in vivo, therefore pointing to the potential of this technique for the study of WM myelin changes in health and disease. This study first characterized the reproducibility of metrics derived from the complex multi-echo gradient-recalled echo (mGRE) signal across the corpus callosum in healthy participants, finding highest reproducibility in the posterior callosal segment. Subsequently, the same analysis pipeline was applied in this callosal region in a sample of premanifest HD patients (n = 19) and age, sex and education matched healthy controls (n = 21). In particular, we focused on two myelin-associated derivatives: i. the myelin water signal fraction (fm), a parameter dependent on myelin content; and ii. The difference in frequency between myelin and intra-axonal water pools (Δω), a parameter dependent on the ratio between the inner and the outer axonal radii. fm was found to be lower in HD patients (ß = -0.13, p = 0.03), while Δω did not show a group effect. Performance in tests of working memory, executive function, social cognition and movement was also assessed, and a greater age-related decline in executive function was detected in HD patients (ß = -0.06, p = 0.006), replicating previous evidence of executive dysfunction in HD. Finally, the correlation between fm, executive function, and proximity to disease onset was explored in patients, and a positive correlation between executive function and fm was detected (r = 0.542; p = 0.02). This study emphasises the potential of complex mGRE signal analysis for aiding understanding of HD pathogenesis and progression. Moreover, expanding on evidence from pathology and animal studies, it provides novel in vivo evidence supporting myelin breakdown as an early feature of HD.