Investigating altered brain development in infants with congenital heart disease using tensor-based morphometry

Ng, Isabel H X; Bonthrone, Alexandra F; Kelly, Christopher; Cordero‐Grande, Lucilio; Hughes, Emer; Price, Anthony N.; Hutter, Jana; Victor, Suresh; Schuh, Andreas; Rueckert, Daniel; Hajnal, Joseph V.; Simpson, John; Edwards, A. David; Rutherford, Mary; Batalle, Dafnis; Counsell, Serena J.

doi:10.1038/s41598-020-72009-3

Cited by 24 publications

(30 citation statements)

References 96 publications

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“…Consistent with previous studies, 11 , 15 including in this cohort, 12 we observed that infants with CHD had reduced brain tissue volumes and increased extracerebral CSF before surgery. However, to our knowledge, this is the first use of a normative modelling approach to assess brain development in individual infants with CHD.…”

Section: Discussionsupporting

confidence: 92%

Individualized brain development and cognitive outcome in infants with congenital heart disease

Bonthrone

Dimitrova

Chew

et al. 2021

Brain Communications

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Infants with Congenital Heart Disease are at risk of neurodevelopmental impairments, the origins of which are currently unclear. The aim of this study was to characterise the relationship between neonatal brain development, cerebral oxygen delivery and neurodevelopmental outcome in infants with Congenital Heart Disease. A cohort of infants with serious or critical Congenital Heart Disease (N = 66; N = 62 born ≥37 weeks) underwent brain MRI prior to surgery on a 3 T scanner situated on the neonatal unit. T2-weighted images were segmented into brain regions using a neonatal-specific algorithm. We generated normative curves of typical volumetric brain development using a data-driven technique applied to 219 healthy infants from the Developing Human Connectome Project (dHCP). Atypicality indices, representing the degree of positive or negative deviation of a regional volume from the normative mean for a given gestational age, sex and postnatal age, were calculated for each infant with Congenital Heart Disease. Phase contrast angiography was acquired in 53 infants with Congenital Heart Disease and cerebral oxygen delivery was calculated. Cognitive and motor abilities were assessed at 22 months (N = 46) using the Bayley scales of Infant and Toddler Development—3rd Edition. We assessed the relationship between atypicality indices, cerebral oxygen delivery and cognitive and motor outcome. In addition, we examined whether cerebral oxygen delivery was associated with neurodevelopmental outcome through the mediating effect of brain volume. Negative atypicality indices in deep grey matter were associated with both reduced neonatal cerebral oxygen delivery and poorer cognitive abilities at 22 months across the whole sample. In infants with Congenital Heart Disease born ≥37 weeks negative cortical grey matter and total tissue volume atypicality indices, in addition to deep grey matter structures, were associated with poorer cognition. There was a significant indirect relationship between cerebral oxygen delivery and cognition through the mediating effect of negative deep grey matter atypicality indices across the whole sample. In infants born ≥37 weeks, cortical grey matter and total tissue volume atypicality indices were also mediators of this relationship. In summary, lower cognitive abilities in toddlers with Congenital Heart Disease were associated with smaller grey matter volumes prior to cardiac surgery. The aetiology of poor cognition may encompass poor cerebral oxygen delivery leading to impaired grey matter growth. Interventions to improve cerebral oxygen delivery may promote early brain growth and improve cognitive outcomes in infants with Congenital Heart Disease. Bonthrone et al. assessed individualized brain growth in infants with congenital heart disease compared to a large normative sample to determine atypicality indices in the patient group. Low cerebral oxygen delivery was associated with impaired grey matter development and resulted in poor cognitive outcome in this population.

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Section: Discussionsupporting

confidence: 92%

Individualized brain development and cognitive outcome in infants with congenital heart disease

Bonthrone

Dimitrova

Chew

et al. 2021

Brain Communications

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“…Similar to these findings, in a heterogenous sample of CHD infants, significant positive correlations were observed between CDO 2 and whole brain, cortical grey matter and deep grey matter volumes (26,27,31) along with cortical gyrification (26) and cortical microstructural development (27) . However, using tensor-based morphometry, after accounting for global brain size, no significant associations between CDO 2 and structural brain development at a voxel-wise level were identified (31). We suggest this reflects that either reduced CDO 2 impairs growth across the whole brain with no specific regional vulnerability to low CDO 2 in the neonatal period, or that there was insufficient statistical power in our study to determine voxel-wise differences related to CDO 2 after correcting for the many multiple comparisons undertaken in voxel-wise analyses.…”

Section: The Relationship Between Haemodynamic Factors and Brain Development In The Neonatal Periodsupporting

confidence: 78%

“…CDO 2 was significantly reduced in SVP and TGA infants compared to controls, pre-operative brain volume was significantly lower in the CHD sample and there was a significant positive association between CDO 2 and brain volumes (25). Similar to these findings, in a heterogenous sample of CHD infants, significant positive correlations were observed between CDO 2 and whole brain, cortical grey matter and deep grey matter volumes (26,27,31) along with cortical gyrification (26) and cortical microstructural development (27) . However, using tensor-based morphometry, after accounting for global brain size, no significant associations between CDO 2 and structural brain development at a voxel-wise level were identified (31).…”

Section: The Relationship Between Haemodynamic Factors and Brain Development In The Neonatal Periodsupporting

confidence: 62%

MRI studies of brain size and growth in individuals with congenital heart disease

Bonthrone¹,

Kelly²,

Ng³

et al. 2021

Transl Pediatr

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Congenital heart disease (CHD) is the most frequent congenital abnormality. Most infants born with CHD now survive. However, survivors of CHD are at increased risk of neurodevelopmental impairment, which may be due to impaired brain development in the fetal and neonatal period. Magnetic resonance imaging (MRI) provides objective measures of brain volume and growth. Here, we review MRI studies assessing brain volume and growth in individuals with CHD from the fetus to adolescence. Smaller brain volumes compared to healthy controls are evident from around 30 weeks gestation in fetuses with CHD and are accompanied by increased extracerebral cerebrospinal fluid. This impaired brain growth persists after birth and throughout childhood to adolescence. Risk factors for impaired brain growth include reduced cerebral oxygen delivery in utero, longer time to surgery and increased hospital stay. There is increasing evidence that smaller total and regional brain volumes in this group are associated with adverse neurodevelopmental outcome. However, to date, few studies have assessed the association between early measures of cerebral volume and neurodevelopmental outcome in later childhood. Large prospective multicentre studies are required to better characterise the relationship between brain volume and growth, clinical risk factors and subsequent cognitive, motor, and behavioural impairments in this at-risk population.

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“…including the CC, in fetuses with CHD before 32 weeks' gestation 24 . Reduced brain volumes in infants with CHD have also been described to persist postnatally in neonates prior to surgery 16,25 and in teenagers 36 , with a significant reduction in the isthmus 16 and the splenium 16,25 of the CC. Experimental data have shown that chronic exposure of the developing brain to low oxygen concentrations resulted in a smaller CC in rats 37 .…”

Section: Discussionmentioning

confidence: 99%

“…The CC is a well‐defined brain structure that can be measured reliably in the midsagittal plane using transvaginal neurosonography (NSG) 23 . Recent studies have shown significant reduction in CC volume in CHD fetuses 24 and neonates before surgery 16,25 . Likewise, CC size during the fetal period has been shown to be affected in high‐risk conditions such as intrauterine growth restriction (IUGR) and preterm birth 19,26,27 .…”

Section: Introductionmentioning

confidence: 99%

Corpus callosum size by neurosonography in fetuses with congenital heart defect and relationship with expected pattern of brain oxygen supply

Pérez‐Cruz

Gómez

Gibert

et al. 2022

Ultrasound in Obstet & Gyne

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Objective To evaluate corpus callosum (CC) size by neurosonography (NSG) in fetuses with an isolated major congenital heart defect (CHD) and explore the association of CC size with the expected pattern of in‐utero oxygen supply to the brain. Methods A total of 56 fetuses with postnatally confirmed isolated major CHD and 56 gestational‐age‐matched controls were included. Fetuses with CHD were stratified into two categories according to the main expected pattern of cerebral arterial oxygen supply: Class A, moderately to severely reduced oxygen supply (left outflow tract obstruction and transposition of the great arteries) and Class B, near normal or mildly impaired oxygenated blood supply to the brain (other CHD). Transvaginal NSG was performed at 32–36 weeks in all fetuses to evaluate CC length, CC total area and areas of CC subdivisions in the midsagittal plane. Results CHD fetuses had a significantly smaller CC area as compared to controls (7.91 ± 1.30 vs 9.01 ± 1.44 mm2; P < 0.001), which was more pronounced in the most posterior part of the CC. There was a significant linear trend for reduced CC total area across the three clinical groups, with CHD Class‐A cases showing more prominent changes (controls, 9.01 ± 1.44 vs CHD Class B, 8.18 ± 1.21 vs CHD Class A, 7.53 ± 1.33 mm2; P < 0.05). Conclusions Fetuses with major CHD had a smaller CC compared with controls, and the difference was more marked in the CHD subgroup with expected poorer brain oxygenation. Sonographic CC size could be a clinically feasible marker of abnormal white matter development in CHD. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

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Investigating altered brain development in infants with congenital heart disease using tensor-based morphometry

Cited by 24 publications

References 96 publications

Individualized brain development and cognitive outcome in infants with congenital heart disease

Individualized brain development and cognitive outcome in infants with congenital heart disease

MRI studies of brain size and growth in individuals with congenital heart disease

Corpus callosum size by neurosonography in fetuses with congenital heart defect and relationship with expected pattern of brain oxygen supply

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