Neonatal Tract-Based Spatial Statistics Findings and Outcome in Preterm Infants

Discussion

In this study, TBSS, optimized for the neonatal brain,²² was used for the first time at TEA in preterm infants born before 31 weeks' gestation to assess the relationship between diffusion parameters and neurodevelopmental performance at 2 years of age. TBSS provides an objective and reproducible voxelwise survey of cerebral WM, which reveals features that are consistent across a group of subjects, and avoids subjective selection of locations of interest or hypothesis-based selections of WM regions.¹⁵ Using this approach, we have shown that higher FA in the CC at TEA was associated with better cognitive performance. In addition, a widespread association was demonstrated between FA in the major WM tracts and fine-motor performance whereas gross-motor scores were associated with FA values in the PLIC, fornix, and thalamus. The findings for total motor scores were similar to those for fine-motor scores, suggesting that our results for the total motor scores were largely influenced by fine-motor performance and not by gross-motor abilities.

The increase in FA with respect to better BSITD-III scores observed here was mainly driven by a decrease in RD. The relationship between diffusion measures (eg, FA and RD) and underlying WM microstructure is complex. The increase in FA observed with increasing maturation is largely due to a decrease in RD.^11,12 FA is largely dependent on axonal thickness, axonal attenuation, and myelination.^24,25 The development of oligodendroglia precursors induces anisotropy in WM in a process primarily driven by changes in RD.²⁶ At TEA, only the PLIC and the brain stem are myelinated,²⁷ so the reduction in FA in association with subsequent poor neurodevelopment demonstrated here probably represents deficits or delays in premyelination events such as increasing axonal thickness, alterations in axonal permeability, and premyelination wrapping of the oligodendrocyte around the axon.²⁸

We recognize that cognitive deficits are difficult to diagnose in early childhood and usually first become evident at school age.² Nevertheless, our findings of altered WM microstructure in the CC and impaired cognitive ability are supported by previous studies that assessed callosal macrostructure and demonstrated that reduced callosal volume on conventional MR imaging was related to impaired cognitive development in children and adolescents born prematurely.^29,30 Furthermore, Schmithorst et al³¹ observed a positive relationship between FA in association fibers and intelligence quotient in a healthy pediatric population, consistent with our findings of higher FA in association tracts and better neurocognitive performance.

Using a region-of-interest−based approach to assess DTI data, Rose et al³² examined FA in the anterior limb of the internal capsule, PLIC, and genu and splenium of the CC. They observed a relationship between FA in the PLIC at TEA and the psychomotor score of the BSITD-II at 18-month corrected age. Using TBSS to survey whole brain WM, we have shown that this relationship exists more extensively throughout the WM. The regions where we observed a positive correlation between fine-motor score and FA values were more extensive than those for gross-motor score. In addition to the PLIC and the corticospinal tracts, a correlation with FA was found in the association tracts, including the cingulum, fornix, uncinate fasciculus, and frontal WM.

The frontal lobes are involved in working memory, planning, monitoring, and organizing retrieval processes.³³ The uncinate fasciculus provides a corticocortical link between the frontal and temporal lobes and is thought to be important in episodic memory.³⁴ The cingulum is involved with high-order motor control and organization of motor-control processes.³⁵ Lesions in this region are associated with deficits in working-memory performance,³⁶ and reduced FA in the cingulum in schizophrenia is associated with attention and working-memory deficits.³⁷ The fornix connects the hippocampus to the hypothalamus, and lesions in this structure are associated with memory and learning dysfunctions.^38,39 These regions, therefore, are associated with working memory and manipulating information, processes that are assessed in the fine-motor component of the BSITD-III. In this study, we observed that better gross-motor function was related to a region of higher FA in the left PLIC, while decreased RD was correlated with gross-motor outcome in many regions throughout the brain. On examination of those voxels in the left PLIC showing a significant relationship between FA and gross-motor scores, we observed a strong positive correlation between AD and RD. These findings may explain the lack of association between FA and gross-motor scores, because an increase in both AD and RD could leave FA relatively unchanged.

Previous studies have used voxel-based approaches to assess the relationship between WM microstructure and performance in children who were born preterm. Skranes et al⁴⁰ assessed adolescents born prematurely and age-matched term-born controls. They found lower FA in the internal and external capsules, CC, and the inferior and superior longitudinal fasciculi in the preterm group. Most important, lower FA in these areas was related to worse performance on the visual-motor integration and the Grooved Pegboard tests. At 2 years of age, subscores of the Griffiths Mental Developmental Scales were related to FA in the CC, cingulum, fornix, anterior commissure, and the right uncinate fasciculus.¹⁷ Our results suggest that the relationship between WM integrity and neurodevelopment, demonstrated by others in children born prematurely, is already evident at TEA.

We were able to analyze only 56% of the DTI data. DTI data are inherently sensitive to artifacts due to patient motion. Although the infants were sedated and noise reduction was administered, some infants woke up during the DTI sequence. In addition, some data were acquired with a sensitivity encoding factor of 3, which resulted in a lower signal intensity–to-noise ratio and visible artifacts across the brain, so these datasets were rejected. Nevertheless, our study group was relatively large, consisting of 63 infants with data amenable to analysis by using TBSS. This study used DTI data acquired at 3T, which offers a higher signal intensity–to-noise ratio and allows improved spatial resolution than could be achieved at lower field strengths. However, at the resolution achievable in vivo, the imaging voxels will inevitably contain fiber populations with different orientations, resulting in a reduction in the measured FA.

A further limitation of this approach is that TBSS is not always able to assess WM where there is an abrupt change in direction of the fiber pathway, for example at the junction of tracts.¹⁵ Finally, these findings were restricted to preterm infants, without the possibility to compare the results with healthy full-term controls. We accept that the lack of healthy term-born controls is a limitation of this study. However, previous studies have already shown differences between preterm infants at term and healthy term-born controls.^9,16 Our aim here was to explore the relationship between WM injury and early neurodevelopmental performance in the preterm population.