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Relationships between myelin development and neurodevelopmental outcomes in very preterm and typically developing children
Deanne K Thompson1,2,3,4, Joseph YM Yang2,3,5,6, Jian Chen2, Claire E Kelly1,2, Chris L Adamson2, Bonnie Alexander1,2, Lillian G Matthews7, Katherine J Lee1,3,8, Rod W Hunt1,3,9, Jeanie LY Cheong1,10,11, Megan Spencer-Smith1,12, Marc L Seal2,3, Terrie E Inder1,7, Lex W Doyle1,3,10,11, and Peter J Anderson1,12
1Victorian Infant Brain Studies, Murdoch Children's Research Institute, Parkville, Australia, 2Developmental Imaging, Murdoch Children's Research Institute, Parkville, Australia, 3Department of Paediatrics, University of Melbourne, Parkville, Australia, 4Florey Institute of Neuroscience and Mental Health, Parkville, Australia, 5Neuroscience Research, Murdoch Children’s Research Institute, Parkville, Australia, 6Department of Neurosurgery, the Royal Children’s Hospital, Parkville, Australia, 7Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States, 8Clinical Epidemiology & Biostatistics Unit, Murdoch Children’s Research Institute, Parkville, Australia, 9Neonatal Medicine, Royal Children’s Hospital, Parkville, Australia, 10Royal Women's Hospital, Parkville, Australia, 11Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Australia, 12Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Clayton, Australia

Synopsis

Children born very preterm have altered myelination compared with full-term controls, but whether the T1-T2 ratio is a sensitive measure for understanding neurodevelopmental functioning remains unknown. This study found that the T1-T2 ratio trajectory between 7 and 13 years of age in the uncinate fasciculus was related to IQ scores, and 13-year T1-T2 ratios in almost all white matter regions were associated with motor functioning in both birth groups. Myelin development assessed using the T1-T2 ratio appears to be sensitive to predicting some neurodevelopmental outcomes.

Introduction

Myelination begins late in fetal development, and continues into early adulthood.(1) Myelin mapping, using the T1-weighted and T2-weighted structural MRI images as a ratio, may provide insight into the maturity of myelin.(2,3) Children born very preterm (VP) are known to have developmental vulnerability of myelin.(4)

We have recently shown through a longitudinal study that VP children at 7 and 13 years of age have reduced T1-T2 ratios, predominantly in the white matter of the limbic system, compared with full-term (FT) children.(5) We hypothesise that this may explain some of the cognitive, learning, memory and behavioral problems VP children face.(6) We have also shown that VP children born small for gestational age have reduced T1-T2 ratios predominantly in the sensorimotor tracts,(5) and hypothesise that this may explain some of their reported motor problems.(7) However, it is unknown whether the T1-T2 ratio is related to these neurodevelopmental outcomes.

The aims of this study were to 1) examine associations between (a) the T1-T2 ratio at term-equivalent age, 7 or 13 years of age, or (b) the trajectories of T1-T2 ratio development between term and 13 years, and cognitive, learning and memory, behavioral and motor functioning at 13 years, and 2) assess whether these associations differed between the VP and FT groups.

Methods

VP children born <30 weeks’ gestation or very low birthweight (<1250 g) and FT controls (born ≥37 weeks’) underwent longitudinal T1 and T2-weighted brain MRI. 224 VP and 45 FT infants were scanned at term-equivalent age, 159 VP and 36 FT children at 7 years, and 140 VP and 48 FT children at 13 years corrected age, with 198 VP and 56 FT children having usable T1 and T2 scans at term-equivalent, 7 and/or 13 years of age.

T1- and T2-weighted images were first corrected for β1 bias field inhomogeneity(8) and brain extracted.(9) T1-T2 ratio whole brain myelin map images were then calculated. The myelin maps were parcellated into white matter regions of interest using the JHU neonatal(10) and adult(11) atlases. 47 brain regions were assessed across the 3 time-points.

Neurodevelopmental outcomes were collected at 13 years of age for intelligence quotient (IQ) using the Kaufman Brief Intelligence Test, Second Edition (KBIT-2), motor outcomes using the Movement Assessment Battery for Children, Second Edition (MABC-2), memory and learning using the California Verbal Learning Test, Children’s Version (CVLT-C), and behavior using the Strengths & Difficulties Questionnaire (SDQ).

Linear regression models were used to examine associations between T1-T2 ratios at each time-point, the rate of change in T1-T2 ratios from term-equivalent to 7 years and 7 to 13 years, and neurodevelopmental outcomes. A group-by-T1-T2 ratio interaction term was included, and all estimates were adjusted for sex, age at assessment, and social risk at 13 years. P-values were False Discovery Rate corrected.

Results

Increases in T1-T2 ratio between 7 and 13 years in the left uncinate fasciculus were associated with higher IQ (p=0.025), across both birth groups.

Higher T1-T2 ratios in all brain regions at 13 years of age were associated with better motor functioning (all p<0.026), except the fornix column and body, and superior cerebellar peduncles.

There were no associations between the T1-T2 ratio at or across any time-points with memory and learning or behavioral scores (all p>0.07).

Discussion and conclusion

In line with our hypotheses, we found that increasing T1-T2 ratio trajectories between 7 and 13 years in one of the limbic structures, the uncinate fasciculus, were associated with higher IQ at 13 years of age in both VP and FT children. This suggests that our previous findings of reduced myelin content in the limbic structures of VP children compared with FT children may have consequences for cognitive functioning.

Higher T1-T2 ratios at 13 years were also associated with better concurrent motor functioning, with no regional or birth group specificity. However, early measures of T1-T2 ratio at term-equivalent age did not appear to be sensitive to later functional outcomes.

Myelin development assessed using the T1-T2 ratio may help to explain poorer IQ and motor outcomes experienced by VP children at 13 years of age.

Acknowledgements

We would like to thank members of the Victorian Infant Brain Studies and Developmental Imaging groups the at the Murdoch Children Research Institute for ideas and support, Michael Kean and Radiographers at the Royal Children’s Hospital for the magnetic resonance images, and the families and children who participated in this study.

This study was supported by the Australian National Health and Medical Research Council (NHMRC) (Centre for Clinical Research Excellence 546519; Centre for Research Excellence 1060733; Project Grants 237117, 491209 & 1066555; Senior Research Fellowships 628371 & 1081288 to PJA; Career Development Fellowship 1085754 to DKT; Early Career Fellowship 1012236 to DKT), US National Institutes of Health HD058056, United Cerebral Palsy Foundation (USA), Leila Y. Mathers Charitable Foundation (USA), the Brown Foundation (USA), Murdoch Children’s Research Institute, the Royal Children’s Hospital, The Royal Children’s Hospital Foundation, Department of Paediatrics, The University of Melbourne and the Victorian Government's Operational Infrastructure Support Program.

References

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7. Murray E, Fernandes M, Fazel M, Kennedy SH, Villar J, Stein A. Differential effect of intrauterine growth restriction on childhood neurodevelopment: a systematic review. BJOG : an international journal of obstetrics and gynaecology 2015;122(8):1062-1072.

8. Tustison NJ, Avants BB, Cook PA, et al. N4ITK: improved N3 bias correction. IEEE Trans Med Imaging 2010;29(6):1310-1320.

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Proc. Intl. Soc. Mag. Reson. Med. 28 (2020)
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