High-gradient diffusion MRI reveals distinct estimates of axon diameter index within different white matter tracts in the in vivo human brain

Abstract

Axon diameter and density are important microstructural metrics that offer valuable insight into the structural organization of white matter throughout the human brain. We report the systematic acquisition and analysis of a comprehensive diffusion MRI data set acquired with 300 mT/m maximum gradient strength in a cohort of 20 healthy human subjects that yields distinct and consistent patterns of axon diameter index in white matter tracts of arbitrary orientation. We use a straightforward, previously validated approach to estimating indices of axon diameter and volume fraction that involves interpolating the diffusion signal perpendicular to the principal fiber orientation and fitting a three-compartment model of intra-axonal, extra-axonal and free water diffusion. The resultant maps confirm the presence of larger diameter indices in the body of corpus callosum compared to the genu and splenium, as previously reported, and show larger axon diameter index in the corticospinal tracts compared to adjacent white matter tracts such as the cingulum. An anterior-to-posterior gradient in axon diameter index is also observed, with smaller diameter indices in the frontal lobes and larger diameter indices in the parieto-occipital white matter. These observations are consistent with known trends from prior histologic studies in humans and non-human primates. Rather than serving as fully quantitative measures of axon diameter and density, our results may be considered as axon diameter- and volume fraction-weighted images that appear to be modulated by the underlying microstructure and may capture broad trends in axonal size and packing density, acknowledging that the precise origin of such modulation requires further investigation that will be facilitated by the availability of high gradient strengths for in vivo human imaging.

Keywords: Axon diameter index; Diffusion; Human brain; In vivo; MRI.

Figure B1.

Simulated and experimental diffusion signal decays plotted for (a–c) a region-of-interest (ROI) in the superior longitudinal fasciculus (volume-weighted effective axon diameter of 3.7 m calculated from histograms derived from electron micrographs in Liewald et al. (Liewald et al. 2014)and restricted volume fraction of 0.21 calculated from fitting Equation A1 to the experimental data) compared to (d–f) an ROI in the uncinate fasciculus (volume-weighted effective axon diameter of 2.4 m calculated from histograms derived from electron micrographs in Liewald et al. and restricted volume fraction of 0.30 calculated from fitting Equation A1 to the experimental data). In (a) and (d), the predicted total diffusion-weighted signal S(q, ) is a weighted sum of the signal due to (b, e) hindered and (c, f) restricted water. The restricted diffusion signal is calculated from the effective axon diameter derived from electron microscopy. At high q-values, the contribution to the tail of S(q, ) is dominated by restricted diffusion presumed to arise from the intra-axonal space.

Fig. 1

Flowchart outlining the axon diameter index analysis stream. Using the diffusion-weighted images for the shortest diffusion time, the orientation distribution functions (ODFs) were first reconstructed in each voxel using generalized q-sampling imaging analysis. The principal fiber orientations (black arrow) were calculated for each ODF. The diffusion signals were then resampled to the equator perpendicular to the primary fiber orientation and averaged to obtain the mean signal perpendicular to the principal fiber orientation. A three-compartment model of intra-axonal, extra-axonal, and free water diffusion was fitted to the mean perpendicular signal to obtain estimates of axon diameter and restricted volume fraction

Fig. 2

Representative sagittal slices through the right corticospinal tract (highlighted by green arrowheads) from the maps of axon diameter index (a, b), restricted volume fraction (c, d), and orientation dispersion index (ODI) (e, f) at 2 mm (a, c, e) and 2.4 mm (b, d, f) isotropic resolution in separate scan sessions in the same healthy subject

Fig. 3

Group averaged maps of (a–c) axon diameter index estimates and (d–f) restricted volume fraction estimates averaged across 20 healthy subjects, shown in coronal (a, d), sagittal (b, e) and axial views (c, f). The location of the corticospinal tract is highlighted by the green arrowheads and displayed in the probabilistic tractography maps in the top left corner of each sub-figure for reference

Fig. 4

Mean and standard deviation of the (b) mean axon diameter index and (c) mean restricted volume fraction estimates of the 20 major white matter tracts from the JHU white matter atlas (a) averaged across 20 healthy subjects.

Fig. 5

Mean and standard deviation of the (a) mean axon diameter index and (b) mean restricted volume fraction estimates of the anterior and posterior parts of six selected major white matter tracts from the JHU white matter atlas averaged across 20 healthy subjects. The six white matter tracts included the left and right internal capsule, left and right corona radiata, and left and right cingulum.