Altered Cerebral Cortical Microstructure In Preterm Infants At Term-Equivalent Age Relative To Term-born Neonates

Even now the survival rate of premature infants is markedly increased with the improvement of neonatal treatment ability,the population still remain high and at risk of developing neonatal and long-term morbidities.Studies have shown that even in the absence of significant white matter damage,the normal development of the cortex in preterm infants may be impaired.Prematuration disrupts the critical periods of early neurodevelopment,such as the relocation of thalamocortical afferent tracts in cerebral cortex and the development of cortico-cortical short fiber connectivity,which could lead to the developmental delay of cortical microstructure and cognitive impairment later in life.For example,premature children had worse cognitive,language,and motor development,and had higher odds of developmental delay and worse overall social-emotional competence compared with term-born children.Studies have proved that there was a relationship between these functional and behavior outcome and abnormal brain structure,and they also considered brain development may differ between very preterm(VPT,<32 gestation weeks)infants and moderately-late preterm(MLPT,32-36 gestation weeks)infants due to exposure to diverse medical complications and risk factors during different stages of brain development.It is difficult to assess the developmental status of the nervous system due to the lack of specific signs and symptoms of the nervous system in early neonatal period.Therefore,neuroimaging examination is a primary manner for this population.However,few studies have directly targeted the very early microstructural alteration occurred in preterm infants’ cerebral cortex,on account of the relatively thin cortical structures and sensitivity of diffusion metrics to partial volume contamination.In addition,to what extend the cortical microstructure has altered in preterm at TEA relative to full-term neonates is still undescribed.To achieve this goal,we decided use GBSS(gray matter-based spatial statistics)derived from TBSS(tract-based spatial statistics)to detect the very early microstructural changes in gray matter in the preterm infants with advanced diffusion MRI technique and more sensitive NODDI model.38 preterm infants and 32 full-term neonates with no evidence of focal lesions on conventional MRI adopted from dHCP database were included in this study.Their birth ages range in GA from 24 to 42 weeks and they were divided into three groups according to birth age:18 VPT infants born from 24.57 to 31.86 GW,20 MLPT infants born from 32.71 to 36.86 GW and 32 FT neonates born between 37.14 and 42.14 GW.All of them scanned at 37 PMW to 45 PMW.By extracting the core skeleton voxels of cerebral cortex from the 70 individuals in the same standard space,we compared the differences between VPT and FT group and between MLPT and FT group voxel-wisely using FSL Randomise to determine significance with 5000 permutations and TFCE based on a general linear model design matrix.Significance was defined to be p<0.05 following FWE corrections for multiple comparisons.The results indicated that only NDI in NODDI model showed significant between-group differences,that is the neurite density of preterm infants in both groups were significantly lower than that of normal term infants,and the alteration degree and scale in VPT were lager than MLPT.There was no difference in ODI,which may suggest that the cytoarchitecture of cerebral cortex in preterm infants at TEA was similar to that of normal term infants.According to DTI parameters,MD,AD and RD showed significant increase in both VPT and MLPT and the different regions resembled that of NDI,which were mainly distributed in the higher-order association cortex,also some area in primary functional cortex.Surprisingly,FA in FT significantly increased in some frontal areas and posterior parietal cortex compared with VPT group.Besides,ROI-based analysis further confirmed the between-group differences in the above indicators,as well as the differences in the microstructure and development degree of different cortical regions.These early structural changes may be an important basis for developmental defects such as motor,cognitive and learning disabilities in preterm infants.This study quantitatively defined the alterations in cerebral cortex between premature infants at term-equivalent age and normal full-term neonates for the first time using advanced multi-shell diffusion weighted imaging and NODDI model by innovative GBSS method.Taken together,these results suggest that(1)prematuration disrupts the microstructure of neurocognitive regions and major sensory/motor areas of the cerebral cortex,especially the higher-order cortex associated with cognition,and the changes were more extensive in very preterm infants than in those born in the moderately-late preterm,(2)microstructural abnormalities observed in preterm infants may be related to underlying impairments in the density of neurites,degree of myelinization or the complexity of tissue rather than dendritic arborization,which cannot be identified by FA,(3)this method and technique provided a way for evaluating whether some neuroprotective drugs such as EPO were effective for maintaining the normal brain development of premature infants.The results also proved that NODDI could be used as a sensitive neuroimaging biomarker and was suitable for the study of development,aging and some neuropsychiatric diseases.