Fixel-based analysis reveals alterations is brain microstructure and macrostructure of preterm-born infants at term equivalent age

Abstract

Preterm birth causes significant disruption in ongoing brain development, frequently resulting in adverse neurodevelopmental outcomes. Brain imaging using diffusion MRI may provide valuable insight into microstructural properties of the developing brain. The aim of this study was to establish whether the recently introduced fixel-based analysis method, with its associated measures of fibre density (FD), fibre bundle cross-section (FC), and fibre density and bundle cross-section (FDC), is suitable for the investigation of the preterm infant brain at term equivalent age. High-angular resolution diffusion weighted images (HARDI) of 55 preterm-born infants and 20 term-born infants, scanned around term-equivalent age, were included in this study (3 T, 64 directions, b = 2000 s/mm²). Postmenstrual age at the time of MRI, and intracranial volume (FC and FDC only), were identified as confounding variables. Gestational age at birth was correlated with all fixel measures in the splenium of the corpus callosum. Compared to term-born infants, preterm infants showed reduced FD, FC, and FDC in a number of regions, including the corpus callosum, anterior commissure, cortico-spinal tract, optic radiations, and cingulum. Preterm infants with minimal macroscopic brain abnormality showed more extensive reductions than preterm infants without any macroscopic brain abnormality; however, little differences were observed between preterm infants with no and with minimal brain abnormality. FC showed significant reductions in preterm versus term infants outside regions identified with FD and FDC, highlighting the complementary role of these measures. Fixel-based analysis identified both microstructural and macrostructural abnormalities in preterm born infants, providing a more complete picture of early brain development than previous diffusion tensor imaging (DTI) based approaches.

Keywords: Diffusion; Fixel-based analysis; Neonate; Prematurity.

Fig. 1

FOD template and analysis mask. Top: A study specific FOD template was generated from 10 preterm and 10 term infants (selected randomly). Bottom: fibre density, fibre cross-section, and fibre density and cross-section metrics were statistically analysed for fixels with an FOD amplitude exceeding 0.3. Note that fixels perpendicular to the plane of view are not visible (e.g. in the corpus callosum in mid-sagittal view). Colour indicates the orientation of the FOD/fixel orientation (red: left-right, blue: inferior-superior, green: anterior-posterior). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Correlation between fixel metrics and postmenstrual age (PMA) and intracranial volume (ICV). p-values are overlaid on the total voxelwise FD map. FD, FC, and FDC are positively correlated with PMA and ICV. The correlation between FC and FDC and ICV remains significant throughout the brain when correcting for PMA.

Fig. 3

Correlation between fixel metrics and gestational age (GA) at birth. p-values are overlaid on the total voxelwise FD map. FD, FC, and FDC are positively correlated with GA in the splenium of the corpus callosum. For all measurements, PMA was included as a confounding variable. For FC and FDC, intracranial volume was additionally included as a confounding variable.

Fig. 4

Comparison between infant groups. p-values are overlaid on the total voxelwise FD map. Top panel: fibre density (FD), middle panel: fibre cross-section (FC), bottom panel: fibre density and cross-section (FDC). In each panel: A: preterm infants compared to term-born infants; B: preterm infants with no brain abnormality compared to term-born infants; C: preterm infants with minimal brain abnormality compared to term-born infants; D: preterm infants with minimal brain abnormality compared to preterm infants with no brain abnormality.

Fig. 5

Changes in fixel measures during brain development. Grey circles indicate axons (grey level indicates degree of diffusion restriction), black circumference indicates myelination. As myelination increases, axons are pushed further apart. Top: If myelination does not affect the diffusion restriction, a decrease in FD is expected, together with an increase in FC. Bottom: If myelination increases diffusion restriction (potentially due to a slowing in the exchange rate between intra-axonal and extra-axonal space), an increase in FD could be observed.