Abnormal Microstructural Development of the Cerebral Cortex in Neonates With Congenital Heart Disease Is Associated With Impaired Cerebral Oxygen Delivery

Christopher J. Kelly, Daan Christiaens, Dafnis Batalle, Antonios Makropoulos, Lucilio Cordero-Grande, Johannes K. Steinweg, Jonathan O'Muircheartaigh, Hammad Khan, Geraint Lee, Suresh Victor, Daniel C. Alexander, Hui Zhang, John Simpson, Joseph V. Hajnal, A. David Edwards, Mary A. Rutherford, Serena J. Counsell*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


Background: Abnormal macrostructural development of the cerebral cortex has been associated with hypoxia in infants with congenital heart disease (CHD). Animal studies have suggested that hypoxia results in cortical dysmaturation at the cellular level. New magnetic resonance imaging techniques offer the potential to investigate the relationship between cerebral oxygen delivery and cortical microstructural development in newborn infants with CHD. Methods and Results: We measured cortical macrostructural and microstructural properties in 48 newborn infants with serious or critical CHD and 48 age-matched healthy controls. Cortical volume and gyrification index were calculated from high-resolution structural magnetic resonance imaging. Neurite density and orientation dispersion indices were modeled using high-angular-resolution diffusion magnetic resonance imaging. Cerebral oxygen delivery was estimated in infants with CHD using phase contrast magnetic resonance imaging and preductal pulse oximetry. We used gray matter–based spatial statistics to examine voxel-wise group differences in cortical microstructure. Microstructural development of the cortex was abnormal in 48 infants with CHD, with regions of increased fractional anisotropy and reduced orientation dispersion index compared with 48 healthy controls, correcting for gestational age at birth and scan (family-wise error corrected for multiple comparisons at P<0.05). Regions of reduced cortical orientation dispersion index in infants with CHD were related to impaired cerebral oxygen delivery (R2=0.637; n=39). Cortical orientation dispersion index was associated with the gyrification index (R2=0.589; P<0.001; n=48). Conclusions: This study suggests that the primary component of cerebral cortex dysmaturation in CHD is impaired dendritic arborization, which may underlie abnormal macrostructural findings reported in this population, and that the degree of impairment is related to reduced cerebral oxygen delivery.

Original languageEnglish
Article numbere009893
JournalJournal of the American Heart Association
Issue number5
Publication statusPublished - 5 Mar 2019
Externally publishedYes

Bibliographical note

Funding Information:
This research was funded by the British Heart Foundation (FS/15/55/31649) and Medical Research Council UK (MR/ L011530/1). This work received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/20072013)/ERC grant agreement no. 319456 (dHCP project), and was supported by the Wellcome Engineering and Physical Sciences Research Council Centre for Medical Engineering at Kings College London (WT 203148/Z/16/Z), MRC strategic grant MR/K006355/1, Medical Research Council Centre grant MR/N026063/1, and by the National Institute for Health Research Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and Kings College London. Dr O’Muirc-heartaigh is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (206675/Z/17/Z). The views expressed are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health.

Funding Information:
We are indebted to the families who supported this study. We thank the staff from the St Thomas’ Neonatal Intensive Care Unit; the Evelina London Children's Hospital Fetal and Paediatric Cardiology Departments; the Evelina London Paediatric Intensive Care Unit; the Centre for the Developing Brain at King's College London; our research radiologists, including Sophie Arulkumaran, Kelly Pegoretti, and Olivia Carney; our research radiographers, including Emer Hughes, Joanna Allsop, Ana Dos Santos Gomes, and Elaine Green; Jiaying Zhang for assistance with diffusion modeling; and our neonatal scanning team including Katy Vecchiato, Julia Wurie, José Bueno Conde, Maryann Sharma, Beatriz Santamaria, Camilla O'Keeffe, and Jacqueline Brandon, whose energy and expertise made this study possible.

Publisher Copyright:
© 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.


  • brain imaging
  • cerebral blood flow
  • congenital heart disease
  • development
  • magnetic resonance imaging


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