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Brain asymmetry and development of healthy preterm infants within half-year-old: a diffusion MRI study based on ROI and fixel methods
Tingting Liu1, Weihao Zheng1, Yuqing You2, Ying Lv2, Weijun Chen2, Zhiyong Zhao1, Fusheng Gao2, Hongxi Zhang2, Chai Ji2, and Dan Wu1
1ZheJiang University, Hangzhou, China, 2Children's Hospital, ZheJiang University School of Medicine, Hangzhou, China

Synopsis

The present study aimed to investigate brain asymmetry of healthy preterm-born infants within half-year-old using high angular resolution diffusion MRI. ROI-based analysis revealed most brain regions showed significant asymmetry and the asymmetry changed with brain development. The MD-based lateralization index showed an center-versus-peripheral pattern with remarkable lateralization in the posterior cortex. Moreover, in contrast to the adult brain, we found a rightward asymmetry in language processing regions and leftward asymmetry in visuospatial processing regions. Besides, consistent leftward lateralization in white matter was observed at both ROI-based and fixel-based analysis. These findings advanced our understanding of brain asymmetry during early development.

Introduction

The human brain demonstrates anatomical and functional asymmetries of left and right hemispheres with high variability of individual differences, which are associated with functional specialization1-3. Several studies investigated the white matter (WM) asymmetry at the early age of life (1-4 months) using DTI and reported different asymmetric patterns in different brain regions4-6. However, how such asymmetry changes with brain development during infancy remained unexplored; and also the traditional DTI metrics may not provide a comprehensive picture of asymmetry in complex WM structures. In this study, we aimed to study the brain asymmetry of healthy preterm-born infants using high angular resolution diffusion MRI (HARDI) for systemic investigation of spatiotemporal pattern of brain asymmetry from term-equivalent age (TEA) to half-year-old, using both ROI-based and fixel-based analysis (FBA).

Methods

Data acquisition: Sixty-five healthy preterm-born infants (gestational age between 25.3-36.6 weeks) were included in this study under IRB approval and parental consent, with postmenstrual age (PMA) at scan ranging from TEA to 6-months (see clinical information in Table.1). Multi-shell HARDI data acquired on a Philips 3.0T Achieva system using a single-shot spin-echo EPI sequence with 32 noncolinear diffusion directions and two b-values of 800/1500 s/mm2, one pair of b0s with inverse phase-encoding directions, TR/TE=9652/115 ms, in-plane resolution=1.5×1.5 mm2, FOV=180×180 mm2, and 60 slices at a slice thickness of 2 mm.
Data processing: All diffusion data underwent intra-subject registration7,8, distortion correction, and eddy current correction9,10. Segmentation of the DTI data was achieved by transforming individual subjects to the JHU-neonate single brain atlas11,12. FA and MD in 63 paired symmetrical ROIs were extracted.
In order to use FBA for asymmetry analysis, the preprocessed diffusion images were left-right flipped, then FBA was performed between the native and flipped data following the MRtrix3 MSMT-CSD pipeline13,14. Participants were categorized into three groups based on PMA: TEA to 1 month, 1-3 months, 3-6 months. For each group, a specific fiber orientation distribution (FOD) template was generated, and fiber density (FD), fiber cross-section (FC), and fiber density and cross-section (FDC) were calculated for each group. Connectivity-based fixel enhancement and non-parametric permutation tests were performed15 to identify the fixels with significant group differences. The max FD and mean FC of each voxel were extracted for ROI-based analysis.
Statistical analysis: Paired test was performed for ROI-based analysis. Laterality index (LI) was calculated for each paired ROI with the formula ((left–right)/(left+right)*100), and positive/negative LI represented leftward/rightward asymmetry. Then ANCOVA was performed for detecting the relationship between the LI and age, with gender, body weight at birth, and gestational age at birth as covariates. The P values of ROI-based analysis were adjusted using the FDR method. The significance level was set to 0.05 for all analyses.

Results

In the first half-of-year, the brain of infants demonstrated extensive regions with structural asymmetry. A distinct center-versus-peripheral asymmetry pattern was observed in MD, namely, leftward lateralization in the neocortex and rightward asymmetry in the central brain (Fig.1A), while the asymmetry patterns of FA, FD, and FC maps were more complicated (Fig.1B and Fig.2). In addition, the posterior brain demonstrated more remarkable lateralization compared with the anterior brain in all metric maps. Regionally, language processing regions showed a rightward asymmetry, while visuo-spatial processing regions exhibited leftward lateralization in FA, FD, and FC maps. Most WM regions were lateralized to the left in FA, FD, and FC maps (corresponding to rightward lateralization in MD).
The LIs of several regions demonstrated significant developmental changes. For example, the LIs of the precuneus and postcentral gyrus showed increased asymmetry with age, indicating completing visual and somatosensory functions (Fig.3). LI of inferior frontal gyrus of FA, FD, and FC maps consistently demonstrated a shift from leftward to rightward lateralization.
At the fixel level, extensive white matter structures showed constant leftward asymmetry in both FD and FDC maps with an inside-to-outside developmental change (Fig.4). The lateralized areas were more localized in the central brain and major WM tracts at TEA-1 month, but extended to peripheral and subcortical WM at 1-3 months and further increased at 3-6 months. Moreover, once the subcortical WM developed asymmetry, its degree of asymmetry was higher than that of the central brain.

Discussion

This study, for the first time, investigated the whole-brain asymmetry of infants within half-a-year with comprehensive ROI-based and fixel-based analysis. Results revealed a center-versus-peripheral asymmetry pattern in the MD measurement and inside-to-outside asymmetry changes with brain development based on FBA. We also found 1) the posterior brain demonstrated more established function specialization compared with the anterior brain, which is in accordance with the development trend of the brain from dorsal to rostrum16; 2) the rightward asymmetry in language processing regions and leftward asymmetry in visuospatial processing regions is opposite to the adult1,17-19, similar to the findings in another infant study20; 3) leftward lateralization of the WM was found from both ROI-based analysis and FBA, while FBA demonstrated more extensive differences. Moreover, brain asymmetry actively changes with development in terms of the degree (LI), lateralization (leftward versus rightward), and spatial distribution (inside-to-outside).

Conclusion

In summary, the results revealed important spatiotemporal asymmetry patterns in early life, and the lateralization changed with age, which contributed to the understanding of brain development during infancy.

Acknowledgements

This work was supported by the Ministry of Science and Technology of the People’s Republic of China (2018YFE0114600), National Natural Science Foundation of China (61801424, 81971606, 91859201, 61801421, and 81971605), Fundamental Research Funds for the Central Universities of China (2019QNA5024 and 2019FZJD005)), and Scientific Research Fund of Zhejiang Provincial Education Department (Y201431325).

References

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Figures

Table 1: Clinical and demographic information of the study population, including gestation age (GA) at birth, postmenstrual age (PMA) at scan, body weight at birth and scan, body length at birth and scan, head circumference at scan, delivery, Apgar score at 1 and 5 minutes, maternal age at birth.

Figure 1. Regions with significant left/right difference after multiple comparison correction, based on MD (A) and FA (B). LIs of all 63 regions were plotted on the left (A1 and B1), with the positive values indicating leftward asymmetry and negative values indicating rightward asymmetry. *p < 0.05 by pairwise t-test. Regions with significant asymmetry were overlaid on the corresponding MD and FA maps in sagittal and axial views, with the color bar indicating the LI. Positive values (red) represented leftward asymmetry, and negative values (blue) represented rightward asymmetry.

Figure 2. Regions with significant left/right difference after multiple comparison correction, based on FD (A) and FC (B). LIs of all 63 regions were plotted on the left (A1 and B1), with the positive values indicating leftward asymmetry and negative values indicating rightward asymmetry. *p < 0.05 by pairwise t-test. Regions with significant asymmetry were overlaid on the corresponding FD and FC maps in sagittal and axial views, with the colorbar indicating the LI. Positive values (red) represented leftward asymmetry, and negative values (blue) represented rightward asymmetry.

Figure 3. (A1-A4) Changes of LI with age for MD (green), FA (blue), FC (purple), and FD (red) measurements. Only the ROIs showing significant correlation between PMA and LI are plotted. (B1-B4) Developmental changes of MD, FA, FC, and FD measurements in left and right ROIs during PMA of 40-62 weeks, for the selected regions corresponding to (A1-A4). Carmine triangles represent the left regions, and grey circles represent the right regions. The ROI locations are highlighted in the inset figures for each plot.

Figure 4. FBA revealed extensive WM regions with significant asymmetry in terms of FDC. The three rows from top to bottom show results for TEA-1month, 1-3 months, 3-6 months, respectively. The color bar indicates the LI, with positive values (red) represent leftward asymmetry, and negative values (blue) represent rightward asymmetry. A clear inside-to-outside developmental change can be identified, with the lateralization primarily localizes in the central brain and major WM at TEA, but extend to peripheral and subcortical WM at 1-3 months which further increased at 3-6 months.

Proc. Intl. Soc. Mag. Reson. Med. 29 (2021)
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