Synopsis

Keywords: Microstructure, Relaxometry, myelin, white matter, orientation dependence, fiber direction, BedpostX, myelin water fraction, myelin water imaging

Previous work suggests myelin water fraction (MWF) may be fibre orientation dependent. We compared MWF to fiber angle (from diffusion tensor imaging (DTI)) in white matter (WM) from 16 healthy participants using BedpostX to estimate the number of fiber directions. MWF vs. fiber angle graphs showed trends which varied between participants, suggesting that real myelination differences may be at least partly responsible for apparent orientation dependence of MWF. There were little obvious differences between trends with 1, 2, or 3+ fiber orientations in WM, suggesting number of fibers directions within a voxel does not impact orientation dependence.

Background

Myelin Water Fraction (MWF) is a Myelin Water Imaging (MWI) metric that has been used to quantify myelin pathology in many diseases (e.g. multiple sclerosis¹, concussion², stroke³). Recent work has suggested that MWF measurements may depend on the orientation of white matter (WM) fibers with respect to the main magnetic field, B₀⁴. To investigate orientation dependence, it is common to use the principal eigenvector from diffusion tensor imaging (DTI) to solve for the angle between the fiber orientation and B₀^4,5. However, up to 90% of voxels in WM may have multiple fiber directions⁶. It is difficult to disentangle whether MWI is truly orientation dependent, or if the myelin content varies such that it tends to be higher in tracts oriented in particular directions, or if both factors contribute to the measured MWF.

Objectives

Investigate orientation dependence of MWF, as well as the impact of the number of fiber directions on changes in MWF with orientation in WM of healthy participants.

Methods

Data Collection: Sixteen healthy participants (mean age: 34y, age range: 22-67y, 7M/9F) underwent 3T MRI (Philips Achieva) to collect MWI (48-echo Gradient and Spin Echo, TR/TE=1073/8ms, resolution = 1x1x2.5mm³)⁷, diffusion (99 directions, b values = 0–1500, TR/TE=4798/79ms, voxel size = 2×2×2mm³)⁸, and 3DT₁ (TR/TE/TI=3000/3.5/926ms, resolution = 1x1x1mm³).

Analysis: Voxel-wise MWF maps (T₂<40ms) were made using NNLS^9,10. Diffusion data was eddy current corrected and smoothed (FSL toolbox¹¹). BedpostX^12,13 was used to extract the number of fiber directions in each voxel, using a threshold of 0.05 on each fiber signal volume fraction⁶. The primary eigenvector of diffusion data was extracted (FSL DTIFIT¹¹) to determine the angle between the primary eigenvector and B₀ (restricted to 0°-90°). 3DT₁ scans were registered to MNI standard space (FNIRT^11,15). WM ROIs from the JHU White Matter Labels atlas (anterior/posterior/superior corona radiata, anterior/posterior/retrolenticular part of the internal capsule, body/genu/splenium of the corpus callosum, cerebral peduncle, cingulum hippocampus, external capsule, posterior thalamic radiation, sagittal stratum, superior fronto-occipital fasciculus) were registered to 3DT₁ space¹⁶. The MWF map and diffusion scans were registered to 3DT₁ (MWF: FLIRT, diffusion: epireg from FSL toolbox¹¹). The MWF maps and WM ROIs were registered to diffusion space (inverse epireg registration matrix from diffusion to 3DT₁ space). The diffusion registered 3DT1 scans were segmented to produce WM masks (FAST¹⁴). ROIs were excluded if they contained <100 voxels. MWF was binned in 1° increments and the mean MWF was plotted, color coding points based on the number of fiber directions present. Plots were visually assessed to see patterns between participants.

Results and Discussion

Figure 1 displays representative MWF, number of fibers, and angle maps.

MWF vs. angle plots in all WM (Figure 2) followed a trend similar to that seen in Birkl et al. with minimum around the magic angle⁴. In some plots, voxels with 3+ fiber directions had higher MWF than voxels with 2 fiber directions across the whole angle range, indicating that higher MWF is seen with more complex fiber orientations. In other plots, voxels with just 1 fiber direction looked more scattered with no clear trend; this could be due to fewer voxels in white matter having 1 fiber direction (12% of voxels).

Example MWF vs. angle plots are shown in the Splenium of the Corpus Callosum (CCS) (Figure 3), Posterior Corona Radiata (PCR) (Figure 4), and Anterior Corona Radiata (ACR) (Figure 5). Overall, it was more difficult to see patterns in separate WM ROIs as they had fewer voxels and a smaller range of angles. Plots from 5 healthy participants in the CCS, PCR, and ACR are shown as they had enough voxels to see overarching trends and were representative of the trends in the whole dataset. In the CCS, most participants showed increasing MWF with angle (participants 4, 12, 13), while some showed a scattered (participant 5) and flat appearance (participant 8). Most PCR plots showed a downwards trend in MWF vs. angle (participants 1,7), while a few showed more scattered distributions (participants 6, 10, 15). In the PCR, some participants had different angle ranges (participants 1 vs. 15), which may be contributing to differing trends between MWF and angle. This may be due to varying head positions of participants in the scanner. In the ACR, there were upwards trends (participant 1 and 2), flat scattered shapes (participant 10, 11) and downwards trends (participant 13). Most regions showed no difference between voxels with 1, 2, or 3+ fiber directions suggesting number of fiber directions does not impact the apparent orientation dependence of MWF.

Conclusion

Differences between participants in WM ROIs suggest that changes in MWF with fiber orientation may be partly due to real changes in myelin content. Similar trends between number of fiber curves in WM suggest that number of fibers has little effect on orientation dependence. Work by Alderson et al. looked at the effect of fiber orientation on MWF by rotating ex vivo brain tissue and found no consistent changes with MWF over 3 orientations¹⁷. Further work investigating the effect of orientation on MWF from actual myelin changes by moving participants’ heads in vivo and rotating ex vivo tissue samples with a larger sample of angles is needed.

Acknowledgements

TSJ was funded by an endMS Master’s Studentship award from the Multiple Sclerosis Society of Canada. Thank you to the MRI technologists at the UBC MRI Research Center. This work was conducted on the traditional, ancestral, and unceded (stolen) territories of Coast Salish Peoples, including the territories of the xwməθkwəy̓əm (Musqueam), Skwxwú7mesh (Squamish), Stó:lō and Səl̓ílwətaʔ/Selilwitulh (Tsleil- Waututh) Nations. As settler scholars who live and work on this land, we think its important to continue work understanding and dismantling how educational institutions participate in colonization.

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