White matter alterations and cognitive outcomes in children born very low birth weight

Abstract

Background: Very low birth weight (VLBW) infants are at risk for disrupted white matter maturation, yet little is known about the contributing factors, particularly at preschool-age when cognitive difficulties begin to emerge. We examined white matter microstructure in five-year-old VLBW and full-term (FT) children, and its association with cognitive outcomes and birth weight.

Methods: Multi-shell diffusion and MR images were obtained for 41 VLBW (mean birth weight: 1028.6 ± 256.8 g) and 26 FT (3295.4 ± 493.9 g) children. Fractional anisotropy (FA), radial diffusivity (RD), neurite orientation dispersion index (ODI) and density index (NDI) were estimated using diffusion tensor and neurite orientation dispersion and density imaging models. Between-group analyses used a general linear model with group and sex as explanatory variables. Within-group associations between white matter microstructure, cognitive outcomes and birth weight were also investigated.

Results: VLBW compared to FT children showed lower FA and NDI across widespread white matter regions. Smaller clusters of atypical ODI were also found in VLBW children. Within-group analyses in FT children revealed that lower RD and higher NDI were associated with vocabulary acquisition and working memory. In VLBW children, higher FA and NDI, and lower RD and ODI, were associated with improved processing speed. In both groups, FA was positively associated with birth weight.

Conclusions: Our findings demonstrate white matter alterations in young VLBW children, including widespread reductions in axon density that may reflect sustained myelination disruptions. The associations with cognitive outcomes may also highlight which of the VLBW children are at higher risk for later cognitive difficulties.

Keywords: Children; Cognition; Diffusion tensor imaging; Very low birth weight; White matter.

Fig. 1

FA and NODDI between-group results. A. Blue areas represent regions in which FA was significantly lower in VLBW compared to FT children. Significant regions included the body of the corpus callosum and posterior limb of the internal capsule. B. Voxels with significantly lower NDI in VLBW children are indicated in blue. Significant regions included the corpus callosum (genu, splenium), retrolenticular part of the internal capsule, corona radiata, posterior thalamic radiation and superior longitudinal fasciculus. C. Voxels in red depict regions with increased ODI in VLBW children including the corpus callosum and posterior limb of the internal capsule. Blue areas are regions with reduced ODI in VLBW children including the superior and posterior corona radiata and the superior longitudinal fasciculus. Significance was held at p_corr < 0.05. Colour bars indicate p-values. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Sensitivity analysis for between-group contrast: excluding VLBW children with a history of brain injury (n = 5). A. Blue areas represent regions along the white matter skeleton in which FA was reduced in VLBW compared to FT children B. Voxels with reduced NDI in VLBW children are indicated in blue. C. Voxels in red depict regions with increased ODI in VLBW children, whereas blue areas are regions with reduced ODI in VLBW compared to FT children. Significance was held at p_corr < 0.05. Colour bars indicate p-values. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Sensitivity analysis for between-group contrast: excluding VLBW children who were not IQ-matched to FT controls (n = 7). A. Blue areas represent regions along the white matter skeleton in which FA was reduced in VLBW compared to FT children B. Voxels with reduced neurite density in VLBW children are indicated in blue. C. Voxels in red depict regions with increased ODI in VLBW children, whereas blue areas are regions with reduced ODI in VLBW compared to FT children. Significance was held at p_corr < 0.05. Colour bars indicate p-values. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Sensitivity analysis for between-group contrast: matching a sub-sample of VLBW (n = 28) and FT children (n = 24) on maternal education levels. A. Blue areas represent regions along the white matter skeleton in which FA was reduced in VLBW compared to FT children B. Red areas represent voxels with higher RD values in VLBW children. C. Voxels with reduced NDI in VLBW children are indicated in blue. D. Voxels in red depict regions with increased ODI in VLBW children, whereas blue areas are regions with reduced ODI in VLBW compared to FT children. Significance was held at p_corr < 0.05. Colour bars indicate p-values. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

Within-group associations between DTI and NODDI metrics with cognitive outcomes. A. The red areas represent regions in which a significant positive association between NDI and vocabulary acquisition scores was found in FT children. B. Blue areas represent regions with a negative association between RD and working memory in FT children. C. Significant positive associations between NDI and processing speed in VLBW children are represented by red areas. D. Significant negative associations between RD and processing speed in VLBW children are shown in blue. Significance was held at p_corr < 0.05. Colour bars indicate p-values. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 6

Within-group associations between FA and birth weight. Significant positive association was found between birth weight and FA in VLBW (left side; 3A) and FT groups (right side; 3B). Significance was held at p_corr < 0.05 and significant voxels are displayed in red. Colour bars indicate p-values. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)