Microstructural Alterations in Projection and Association Fibers in Neonatal Hypoxia-Ischemia

Abstract

Background: Diffusion MRI (dMRI) is known to be sensitive to hypoxic-ischemic encephalopathy (HIE). However, existing dMRI studies used simple diffusion tensor metrics and focused only on a few selected cerebral regions, which cannot provide a comprehensive picture of microstructural injury.

Purpose: To systematically characterize the microstructural alterations in mild, moderate, and severe HIE neonates compared to healthy neonates with advanced dMRI using region of interest (ROI), tract, and fixel-based analyses.

Study type: Prospective.

Population: A total of 42 neonates (24 males and 18 females).

Field strength/sequence: 3-T, diffusion-weighted echo-planar imaging.

Assessment: Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), fiber density (FD), fiber cross-section (FC), and fiber density and cross-section (FDC) were calculated in 40 ROIs and 6 tracts. Fixel-based analysis was performed to assess group differences in individual fiber components within a voxel (fixel).

Statistical tests: One-way analysis of covariance (ANCOVA) to compare dMRI metrics among severe/moderate/mild HIE and control groups and general linear model for fixel-wise group differences (age, sex, and body weight as covariates). Adjusted P value < 0.05 was considered statistically significant.

Results: For severe HIE, ROI-based analysis revealed widespread regions, including the deep nuclei and white matter with reduced FA, while in moderate injury, only FC was decreased around the posterior watershed zones. Tract-based analysis demonstrated significantly reduced FA, FD, and FC in the right inferior fronto-occipital fasciculus (IFOF), right inferior longitudinal fasciculus (ILF), and splenium of corpus callosum (SCC) in moderate HIE, and in right IFOF and left anterior thalamic radiation (ATR) in mild HIE. Correspondingly, we found altered fixels in the right middle-posterior IFOF and ILF, and in the central-to-right part of SCC in moderate HIE.

Data conclusion: For severe HIE, extensive microstructural injury was identified. For moderate-mild HIE, association fiber injury in posterior watershed area with a rightward lateralization was found.

Evidence level: 1 TECHNICAL EFFICACY: Stage 3.

Keywords: diffusion MRI; fixel; hypoxic-ischemic encephalopathy; microstructural alternation; region of interest; tract.

FIGURE 1:

Flowchart shows participant enrollment. * outlier means one or more of the dMRI metrics were outside 3-fold of standard deviation of this group. dMRI = diffusion magnetic resonance imaging; HIE = hypoxic-ischemic encephalopathy.

FIGURE 2:

Pipeline of dMRI-based analysis of mild, moderate, and HIE neonates at ROI, tract and fixel levels. (a) For all subjects, tensor-based (FA, MD, RD, AD) and fixel-based (FD, FC, FDC) metrics were calculated. Affine and nonlinear registrations between individual subjects and the JHU atlas were performed for brain segmentation. In template space, averaged metrics were calculated in each ROI for statistical comparison between control group and mild-to-severe HIE groups. (b) Six tracts (ATR, IFOF, GCC, CST, ILF, SCC) were obtained for each subject, which were sampled in 100 segments to obtain the along-tract profiles. For each segment along the tract, statistical comparison was performed between the control and injury groups. (c) FOD were estimated for each subject and a FOD template was obtained, based on which, the microstructural metrics were calculated and transformed to fixel. Then, statistical analysis was performed in the fixel space for the tracts that were found significantly altered. IFOF = inferior fronto-occipital fasciculus; ILF = inferior longitudinal fasciculus; ATR = anterior thalamic radiation; CST = corticospinal tract; GCC = genu of corpus callosum; SCC = splenium of corpus callosum.

FIGURE 3:

The WM and deep GM ROIs showing statistically different dMRI metrics in HIE neonates. (a) Percentage differences in the ROIs with statistically lower FA in the severe HIE group compared to the controls, overlaid on the T1-weighted image. (b) FA values in representative ROIs of the severe HIE and control groups. (c) Percentage differences in the ROIs with statistically lower FC in the moderate HIE group compared to the controls, overlaid on the T1-weighted image. (d) FC values in selected ROIs that were statistically different between moderate HIE and control groups. Adjusted *P < 0.05. CC = corpus callosum; CR = coronal radiate; BG = basal ganglia; EC = external capsule; HP = hippocampus; ALIC = anterior limb of internal capsule; PLIC = posterior limb of internal capsule; RPIC = retrolenticular part of internal capsule; ST = stria terminalis; PTR = posterior thalamic radiation; SFOF = superior fronto-occipital fasciculus; Thal = thalamus; SS = sagittal stratum; L = left; R = right.

FIGURE 4:

Along-tract statistics for the right IFOF in moderate HIE group. (a) The trunk region of IFOF was evenly segmented into 100 segments from posterior to anterior brain. (b) The statistics of each segment illustrated as 1-P (corrected) were mapped onto the tract for FA, FD, FC, and FDC metrics. (c) The along-tract FA, FD, FC, and FDC values were plotted as group mean ± standard deviation in the moderate HIE and control groups. (d,e) The −log(P) values from the group comparison at each segment along the tract for the different dMRI metrics. The segments showing statistically significant group differences were underlined by red lines in (d).

FIGURE 5:

Along-tract statistics for the right ILF in moderate HIE group. (a) The trunk region of ILF was evenly segmented into 100 segments from posterior to anterior brain. (b) The statistics of each segment illustrated as 1-P (corrected) were mapped onto the tract for FA, FD, FC, and FDC metrics. (c) The along-tract FA, FD, FC, and FDC values were plotted as group mean ± standard deviation in the moderate HIE and control groups. (d,e) The −log(p) values from the group comparison at each segment along the tract for the different dMRI metrics. The segments showing statistically significant group differences were underlined by red lines in (d).

FIGURE 6:

Fixels showing statistical differences between moderate HIE and controls in FA (a), FC (b), FD (c), and FDC (d) measurements. The fixels located in the right IFOF and right ILF (the two tracts were anatomically connected in the posterior sections) were shown in axial and sagittal views (first and second columns), and those in the SCC were shown in the third column. Corrected P values were mapped onto the fixels. fIFOF = inferior fronto-occipital fasciculus; ILF = inferior longitudinal fasciculus; SCC = splenium of corpus callosum.