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Changes in neonatal regional brain volume associated with preterm birth and perinatal factors1Murdoch Children's Research Institute, Melbourne, Australia, 2Dept of Medicine, Monash University, Melbourne, Australia, 3Florey Institute of Neuroscience and Mental Health, Melbourne, Australia, 4The Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia, 5Dept of Newborn Medicine, Harvard Medical School, Boston, MA, United States, 6Dept of Radiology, Harvard Medical School, Boston, MA, United States, 7Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Australia, 8Dept of Paediatrics, The University of Melbourne, Melbourne, Australia, 9Neonatal services, Royal Women's Hospital, Melbourne, Australia, 10Dept of Obstetrics and Gynaecology, The University of Melbourne, Melbourne, Australia, 11Dept of Physiotherapy, The University of Melbourne, Melbourne, Australia
Synopsis
In a cohort of 285 preterm and term infants at term equivalent age, associations were investigated between gestational age (GA) at birth, perinatal factors, and volumes of 100 regions of the M-CRIB neonatal brain atlas. Volumes increased with increasing GA in some regions, and decreased with increasing GA in other regions including primary visual, motor and somatosensory cortices. Robust increases in many regional volumes were found for birthweight standard deviation score, and male sex. These results provide increased insight into the complex array of correlates of preterm birth.
Background
Preterm birth is associated with altered brain development, with younger gestational age (GA) at birth often1, though not always2, associated with greater brain volume reduction. Such volume alterations at term equivalent age (TEA) have been found with differing magnitude across different brain regions3,4, although this has mostly been investigated with regards to whole tissue volumes and large-scale subdivisions. Given the specialised roles different cortical and subcortical regions play in neurological functioning, local volume reductions might have implications for specific functional outcomes5. In addition to degree of prematurity, many other perinatal factors have been found to influence brain structure and development6. We aimed to elucidate associations between GA at birth and volume at TEA of each of the 100 regions in the Melbourne Children’s Regional Infant Brain (M-CRIB)7 atlas, in neonates born at a range of GAs between extremely preterm to term. We also aimed to identify associations between perinatal factors (fetal growth (reflected in birthweight SD score), sex, multiple birth, early postnatal growth, social risk) and volume of each M-CRIB region; both in univariable analyses, and secondary multivariable analyses controlling for other perinatal factors.Methods
226 preterm and 59 term-born infants (GA at birth 24.6 - 42.1 weeks; 145 female) were scanned at TEA during unsedated natural sleep, on a 3T Siemens Magnetom Trio Tim scanner with a 12-channel circular polarised volume extremity coil at the Royal Children’s Hospital, Melbourne, Australia. T2-weighted images were acquired with a transverse T2 restore turbo spin echo sequence with 1 x 1 x 1 mm isotropic voxels (zero-filled interpolated to 0.5 x 0.5 x 1 mm), flip angle = 120°, TR = 8910 ms, TE = 152 ms, FOV = 192 x 192 mm, matrix = 384 x 384. Data on perinatal factors were obtained by chart review. Images were bias-corrected using N4ITK8 and brain extracted using BET9. Each of the T2-weighted and segmentation images from the M-CRIB atlas were registered to each T2-weighted image in the current sample using ANTS10. PSTAPLE11 was then used to apply the M-CRIB labels to each brain. Regional volumes were calculated. Linear regressions with generalised estimating equations and likelihood ratio tests were performed to investigate whether GA at birth or perinatal factors were associated with regional volumes at TEA.Results
GA at birth was associated with lower volumes at TEA in some regions (see Figure 1) including bilateral cerebral white matter, bilateral middle temporal gyrus, left lateral orbitofrontal cortex, bilateral amygdalae and pallidum, left nucleus accumbens, inferior posterior cerebellar vermis, and brainstem. In other regions, younger GA at birth was associated with higher volumes, including anterior cerebellar vermis, bilateral precentral gyri, left postcentral gyrus, bilateral pericalcarine area and cuneus, left dorsal and medial frontal and parietal regions, right ventrolateral frontal and medial parietal regions, and bilateral precuneus. Higher birthweight SD score and male sex were generally associated with higher volumes in nearly all regions, both before and after adjusting for the remaining perinatal factors (Figure 2). Greater postnatal growth was generally associated with higher volumes in many regions, after adjusting for the remaining perinatal factors. Multiple birth was associated with higher volumes in a small number of regions, after adjusting for the remaining perinatal factors. There was no evidence for associations between social risk and brain volumes.Discussion
The increased volume with increasing GA seen in many regions is consistent with earlier findings of increased volume with GA for multiple tissue types and regions in TEA infants1,4,6,12. Findings of several regions with increased volume at TEA associated with increased prematurity were unexpected. Interestingly, these regions included bilateral primary motor cortex, left primary somatosensory cortex, and bilateral primary visual cortex. Speculatively, this may reflect increased cortical development in response to increased sensory input and unrestricted motor output with greater time ex-utero. It is apparent that previous results of a positive relationship between GA at birth and overall tissue volumes may mask more nuanced and bidirectional regional volume differences. Associations between birthweight SD score and volume, and male sex and volume in many regions, appear independent of GA at birth, and are consistent in direction with those seen in the literature2,13,14. The current findings add to the literature by clarifying regional associations in finer detail.Conclusions
These results elucidate regional brain volume differences associated with prematurity and perinatal factors at a more detailed parcellated level than previously reported, and contribute to understanding the complex array of correlates of preterm birth.Acknowledgements
We gratefully acknowledge support from members of the Victorian Infant Brain Studies (VIBeS) group, Developmental Imaging group, and Melbourne Children’s MRI Centre at the Murdoch Children’s Research Institute, and thank the families who participated in the study. This work was supported in part by the Australian National Health and Medical Research Council (NHMRC) (Project Grant ID 1028822 and 1024516; Centre of Clinical Research Excellence Grant ID 546519; Centre of Research Excellence Grant ID 1060733; Senior Research Fellowship ID 1081288 to P.J.A.; Early Career Fellowship ID 1053787 to J.L.Y.C., ID 1053767 to A.J.S., ID 1012236 to D.K.T.; Career Development Fellowship ID 1108714 to A.J.S., ID 1085754 to D.K.T.), Murdoch Children’s Research Institute Clinical Sciences Theme Grant, the Royal Children’s Hospital, the Department of Paediatrics at the University of Melbourne, the Victorian Government Operational Infrastructure Support Program, and The Royal Children’s Hospital FoundationReferences
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