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

Abstract

Infants with congenital heart disease are at risk of neurodevelopmental impairments, the origins of which are currently unclear. This study aimed to characterize 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 before surgery on a 3T 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-Third Edition. We assessed the relationship between atypicality indices, cerebral oxygen delivery and cognitive and motor outcome. Additionally, 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 before 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.

Keywords: MRI; brain; cognition; congenital heart disease; dHCP.

Graphical Abstract

Figure 1

Volumetric brain development in neonates with CHD. Shaded areas represent ±1, 2 and 3 standard deviations from the normative model mean, separately for female and male infants. TTV = total tissue volume; GM = grey matter; WM = white matter; R = right; L = left.

Figure 2

Associations between cognitive scores and atypicality indices. Box plots showing the relationship between cognitive composite score and (A) left thalamus, (B) right thalamus, (C) left caudate, (G) right caudate, (H) and left lentiform atypicality indices across the whole sample. Scatter plots showing cognitive composite score residuals plotted against (D) left thalamus, (E) right thalamus, (F) left caudate, (I) right caudate and (J) left lentiform AI residuals across the whole sample. Residuals are corrected for the index of multiple deprivations.

Figure 3

The relationship between CDO₂ and cognitive composite scores mediated by atypicality indices. Path diagrams showing the indirect relationship between CDO₂ and cognitive composite score mediated by (A) left thalamus, (B) right thalamus, (C) left caudate nucleus and (D) right caudate nucleus atypicality indices across the whole sample. Standardized regression coefficients are reported; numbers in brackets show P-value. *P < 0.05; **P < 0.01. ACME = average causal mediation effect; CDO₂ = cerebral oxygen delivery.