Intrinsic and extrinsic contributors to subregional thalamic volume loss in multiple sclerosis

Abstract

Objective: To evaluate the intrinsic and extrinsic microstructural factors contributing to atrophy within individual thalamic subregions in multiple sclerosis using in vivo high-gradient diffusion MRI.

Methods: In this cross-sectional study, 41 people with multiple sclerosis and 34 age and sex-matched healthy controls underwent 3T MRI with up to 300 mT/m gradients using a multi-shell diffusion protocol consisting of eight b-values and diffusion time of 19 ms. Each thalamus was parcellated into 25 subregions for volume determination and diffusion metric estimation. The soma and neurite density imaging model was applied to obtain estimates of intra-neurite, intra-soma, and extra-cellular signal fractions for each subregion and within structurally connected white matter trajectories and cortex.

Results: Multiple sclerosis-related volume loss was more pronounced in posterior/medial subregions than anterior/ventral subregions. Intra-soma signal fraction was lower in multiple sclerosis, reflecting reduced cell body density, while the extra-cellular signal fraction was higher, reflecting greater extra-cellular space, both of which were observed more in posterior/medial subregions than anterior/ventral subregions. Lower intra-neurite signal fraction in connected normal-appearing white matter and lower intra-soma signal fraction of structurally connected cortex were associated with reduced subregional thalamic volumes. Intrinsic and extrinsic microstructural measures independently related to subregional volume with heterogeneity across atrophy-prone thalamic nuclei. Extrinsic microstructural alterations predicted left anteroventral, intrinsic microstructural alterations predicted bilateral medial pulvinar, and both intrinsic and extrinsic factors predicted lateral geniculate and medial mediodorsal volumes.

Interpretation: Our results might be reflective of the involvement of anterograde and retrograde degeneration from white matter demyelination and cerebrospinal fluid-mediated damage in subregional thalamic volume loss.

Figure 1

Visualization of thalamic subregions included in our study. Thalamic subregions included in the analysis, shown for right thalamus on axial T1‐weighted scans: AV, anteroventral; CL, central lateral; CM, central medial; CeM, centromedian; LD, laterodorsal; LGN, lateral geniculate; LP, lateral posterior; LSg, limitans suprageniculate; MDl, lateral mediodorsal; MDm, medial mediodorsal; MGN, medial geniculate; MVRe, reuniens medial ventral; Pf, parafascicular; PuA, anterior pulvinar; PuI, inferior pulvinar; PuL, lateral pulvinar; PuM, medial pulvinar; VA, ventral anterior; VAmc, magnocellular ventral anterior; VLa, anterior ventral lateral; VLp, posterior ventral lateral; VPL, ventral posterolateral. *Thalamic subregions showing a significant association between either intrinsic or extrinsic microstructure and its normalized volume, as further highlighted in the results section (Table 5).

Figure 2

Normalized volumes across thalamic subregions showing multiple sclerosis‐related volume loss. Z‐score distribution of normalized volumes of thalamic subregions that show multiple sclerosis‐related volume loss is shown as violin plot (left) and as spatial representations on axial slices (right). Significant Z‐score differences are marked by brackets in the violin plot: *p < 0.05, **p < 0.01. AV, anteroventral; CM, central medial; LGN, lateral geniculate; LP, lateral posterior; MDl, lateral mediodorsal; MDm, medial mediodorsal; MGN, medial geniculate; MVRe, reuniens medial ventral; PuA, anterior pulvinar; PuI, inferior pulvinar; PuM, medial pulvinar; VA, ventral anterior; VAmc, magnocellular ventral anterior; VLp, posterior ventral lateral; VPL, ventral posterolateral.

Figure 3

Intra‐soma and extra‐cellular signal fraction across thalamic subregions showing multiple sclerosis‐related volume loss and microstructural changes. Z‐score distribution of intra‐soma (A) and extra‐cellular (B) signal fraction of thalamic subregions that show multiple sclerosis‐related microstructural changes are shown as violin plots (left) and as spatial representations in a graph against normalized volumes (center) and on axial slices (right). Significant Z‐score differences are marked by brackets in the violin plot: *p < 0.05, **p < 0.01, ***p < 0.001. AV, anteroventral; CM, central medial; LGN, lateral geniculate; LP, lateral posterior; MDl, lateral mediodorsal; MDm, medial mediodorsal; MGN, medial geniculate; MVRe, reuniens medial ventral; PuA, anterior pulvinar; PuI, inferior pulvinar; PuM, medial pulvinar; VA, ventral anterior; VAmc, magnocellular ventral anterior; VLp, posterior ventral lateral; VPL, ventral posterolateral.