Association of prenatal diagnosis of critical congenital heart disease with postnatal brain development and the risk of brain injury

IMPORTANCE: The relationship of prenatal diagnosis of critical congenital heart disease (CHD) with brain injury and brain development is unknown. Given limited improvement of CHD outcomes with prenatal diagnosis, the effect of prenatal diagnosis on brain health may reveal additional benefits. OBJECTIVE: To compare the prevalence of preoperative and postoperative brain injury and the trajectory of brain development in neonates with prenatal vs postnatal diagnosis of CHD. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of term newborns with critical CHD recruited consecutively from 2001 to 2013 at the University of California, San Francisco and the University of British Columbia. Term newborns with critical CHD were studied with brain magnetic resonance imaging preoperatively and postoperatively to determine brain injury severity and microstructural brain development with diffusion tensor imaging by measuring fractional anisotropy and the apparent diffusion coefficient. Comparisons of magnetic resonance imaging findings and clinical variables were made between prenatal and postnatal diagnosis of critical CHD. A total of 153 patients with transposition of the great arteries and single ventricle physiology were included in this analysis. MAIN OUTCOMES AND MEASURES: The presence of brain injury on the preoperative brain magnetic resonance imaging and the trajectory of postnatal brain microstructural development. RESULTS: Among 153 patients (67% male), 96 had transposition of the great arteries and 57 had single ventricle physiology. The presence of brain injury was significantly higher in patients with postnatal diagnosis of critical CHD (41 of 86 [48%]) than in those with prenatal diagnosis (16 of 67 [24%]) (P = .003). Patients with prenatal diagnosis demonstrated faster brain development in white matter fractional anisotropy (rate of increase, 2.2%; 95% CI, 0.1%-4.2%; P = .04) and gray matter apparent diffusion coefficient (rate of decrease, 0.6%; 95%CI, 0.1%-1.2%; P = .02). Patients with prenatal diagnosis had lower birth weight (mean, 3184.5 g; 95%CI, 3050.3–3318.6) than those with postnatal diagnosis (mean, 3397.6 g; 95%CI, 3277.6–3517.6) (P = .02). Those with prenatal diagnosis had an earlier estimated gestational age at delivery (mean, 38.6 weeks; 95%CI, 38.2–38.9) than those with postnatal diagnosis (mean, 39.1 weeks; 95%CI, 38.8–39.5) (P = .03). CONCLUSIONS AND RELEVANCE: Newborns with prenatal diagnosis of single ventricle physiology and transposition of the great arteries demonstrate less preoperative brain injury and more robust microstructural brain development than those with postnatal diagnosis. These results are likely secondary to improved cardiovascular stability. The impact of these findings on neurodevelopmental outcomes warrants further study

Quantitative assessment of white matter injury in preterm neonates: Association with outcomes.

OBJECTIVE: To quantitatively assess white matter injury (WMI) volume and location in very preterm neonates, and to examine the association of lesion volume and location with 18-month neurodevelopmental outcomes. METHODS: Volume and location of WMI was quantified on MRI in 216 neonates (median gestational age 27.9 weeks) who had motor, cognitive, and language assessments at 18 months corrected age (CA). Neonates were scanned at 32.1 postmenstrual weeks (median) and 68 (31.5%) had WMI; of 66 survivors, 58 (87.9%) had MRI and 18-month outcomes. WMI was manually segmented and transformed into a common image space, accounting for intersubject anatomical variability. Probability maps describing the likelihood of a lesion predicting adverse 18-month outcomes were developed. RESULTS: WMI occurs in a characteristic topology, with most lesions occurring in the periventricular central region, followed by posterior and frontal regions. Irrespective of lesion location, greater WMI volumes predicted poor motor outcomes ( CONCLUSIONS: The predictive value of frontal lobe WMI volume highlights the importance of lesion location when considering the neurodevelopmental significance of WMI. Frontal lobe lesions are of particular concern

Automatic segmentation of the hippocampus for preterm neonates from early-in-life to term-equivalent age.

INTRODUCTION: The hippocampus, a medial temporal lobe structure central to learning and memory, is particularly vulnerable in preterm-born neonates. To date, segmentation of the hippocampus for preterm-born neonates has not yet been performed early-in-life (shortly after birth when clinically stable). The present study focuses on the development and validation of an automatic segmentation protocol that is based on the MAGeT-Brain (Multiple Automatically Generated Templates) algorithm to delineate the hippocampi of preterm neonates on their brain MRIs acquired at not only term-equivalent age but also early-in-life. METHODS: First, we present a three-step manual segmentation protocol to delineate the hippocampus for preterm neonates and apply this protocol on 22 early-in-life and 22 term images. These manual segmentations are considered the gold standard in assessing the automatic segmentations. MAGeT-Brain, automatic hippocampal segmentation pipeline, requires only a small number of input atlases and reduces the registration and resampling errors by employing an intermediate template library. We assess the segmentation accuracy of MAGeT-Brain in three validation studies, evaluate the hippocampal growth from early-in-life to term-equivalent age, and study the effect of preterm birth on the hippocampal volume. The first experiment thoroughly validates MAGeT-Brain segmentation in three sets of 10-fold Monte Carlo cross-validation (MCCV) analyses with 187 different groups of input atlases and templates. The second experiment segments the neonatal hippocampi on 168 early-in-life and 154 term images and evaluates the hippocampal growth rate of 125 infants from early-in-life to term-equivalent age. The third experiment analyzes the effect of gestational age (GA) at birth on the average hippocampal volume at early-in-life and term-equivalent age using linear regression. RESULTS: The final segmentations demonstrate that MAGeT-Brain consistently provides accurate segmentations in comparison to manually derived gold standards (mean Dice\u27s Kappa \u3e 0.79 and Euclidean distance CONCLUSIONS: MAGeT-Brain is capable of segmenting hippocampi accurately in preterm neonates, even at early-in-life. Hippocampal asymmetry with a larger right side is demonstrated on early-in-life images, suggesting that this phenomenon has its onset in the 3rd trimester of gestation. Hippocampal volume assessed at the time of early-in-life and term-equivalent age is linearly associated with GA at birth, whereby smaller volumes are associated with earlier birth

White matter injury predicts disrupted functional connectivity and microstructure in very preterm born neonates

© 2018 The Authors Objective: To determine whether the spatial extent and location of early-identified punctate white matter injury (WMI) is associated with regionally-specific disruptions in thalamocortical-connectivity in very-preterm born neonates. Methods: 37 very-preterm born neonates (median gestational age: 28.1 weeks; interquartile range [IQR]: 27–30) underwent early MRI (median age 32.9 weeks; IQR: 32–35), and WMI was identified in 13 (35%) neonates. Structural T1-weighted, resting-state functional Magnetic Resonance Imaging (rs-fMRI, n = 34) and Diffusion Tensor Imaging (DTI, n = 31) sequences were acquired using 3 T-MRI. A probabilistic map of WMI was developed for the 13 neonates demonstrating brain injury. A neonatal atlas was applied to the WMI maps, rs-fMRI and DTI analyses to extract volumetric, functional and microstructural data from regionally-specific brain areas. Associations of thalamocortical-network strength and alterations in fractional anisotropy (FA, a measure of white-matter microstructure) with WMI volume were assessed in general linear models, adjusting for age at scan and cerebral volumes. Results: WMI volume in the superior (β = −0.007; p =.02) and posterior corona radiata (β = −0.01; p =.01), posterior thalamic radiations (β = −0.01; p =.005) and superior longitudinal fasciculus (β = −0.02; p =.001) was associated with reduced connectivity strength between thalamus and parietal resting-state networks. WMI volume in the left (β = −0.02; p =.02) and right superior corona radiata (β = −0.03; p =.008), left posterior corona radiata (β = −0.03; p =.01), corpus callosum (β = −0.11; p \u3c.0001) and right superior longitudinal fasciculus (β = −0.02; p =.02) was associated with functional connectivity strength between thalamic and sensorimotor networks. Increased WMI volume was also associated with decreased FA values in the corpus callosum (β = −0.004, p =.015). Conclusions: Regionally-specific alterations in early functional and structural network complexity resulting from WMI may underlie impaired outcomes

White matter injury in term neonates with congenital heart diseases: Topology & comparison with preterm newborns

Background: Neonates with congenital heart disease (CHD) are at high risk of punctate white matter injury (WMI) and impaired brain development. We hypothesized that WMI in CHD neonates occurs in a characteristic distribution that shares topology with preterm WMI and that lower birth gestational age (GA) is associated with larger WMI volume. Objective: (1) To quantitatively assess the volume and location of WMI in CHD neonates across three centres. (2) To compare the volume and spatial distribution of WMI between term CHD neonates and preterm neonates using lesion mapping. Methods: In 216 term born CHD neonates from three prospective cohorts (mean birth GA: 39 weeks), WMI was identified in 86 neonates (UBC: 29; UCSF: 43; UCZ: 14) on pre- and/or post-operative T1 weighted MRI. WMI was manually segmented and volumes were calculated. A standard brain template was generated. Probabilistic WMI maps (total, pre- and post-operative) were developed in this common space. Using these maps, WMI in the term CHD neonates was compared with that in preterm neonates: 58 at early-in-life (mean postmenstrual age at scan 32.2 weeks); 41 at term-equivalent age (mean postmenstrual age at scan 40.1 weeks). Results: The total WMI volumes of CHD neonates across centres did not differ (p = 0.068): UBC (median = 84.6 mm 3 , IQR = 26–174.7 mm 3 ); UCSF (median = 104 mm 3 , IQR = 44–243 mm 3 ); UCZ (median = 121 mm 3 , IQR = 68–200.8 mm 3 ). The spatial distribution of WMI in CHD neonates showed strong concordance across centres with predilection for anterior and posterior rather than central lesions. Predominance of anterior lesions was apparent on the post-operative WMI map relative to the pre-operative map. Lower GA at birth predicted an increasing volume of WMI across the full cohort (41.1 mm 3 increase of WMI per week decrease in gestational age; 95% CI 11.5–70.8; p = 0.007), when accounting for centre and heart lesion. While WMI in term CHD and preterm neonates occurs most commonly in the intermediate zone/outer subventricular zone there is a paucity of central lesions in the CHD neonates relative to preterms. Conclusions: WMI in term neonates with CHD occurs in a characteristic topology. The spatial distribution of WMI in term neonates with CHD reflects the expected maturation of pre-oligodendrocytes such that the central regions are less vulnerable than in the preterm neonates

Interplay of brain structure and function in neonatal congenital heart disease

Objective: To evaluate whether structural and microstructural brain abnormalities in neonates with congenital heart disease (CHD) correlate with neuronal network dysfunction measured by analysis of EEG connectivity. Methods: We studied a prospective cohort of 20 neonates with CHD who underwent continuous EEG monitoring before surgery to assess functional brain maturation and network connectivity, structural magnetic resonance imaging (MRI) to determine the presence of brain injury and structural brain development, and diffusion tensor MRI to assess brain microstructural development. Results: Neonates with MRI brain injury and delayed structural and microstructural brain development demonstrated significantly stronger high-frequency (beta and gamma frequency band) connectivity. Furthermore, neonates with delayed microstructural brain development demonstrated significantly weaker low-frequency (delta, theta, alpha frequency band) connectivity. Neonates with brain injury also displayed delayed functional maturation of EEG background activity, characterized by greater background discontinuity. Interpretation: These data provide new evidence that early structural and microstructural developmental brain abnormalities can have immediate functional consequences that manifest as characteristic alterations of neuronal network connectivity. Such early perturbations of developing neuronal networks, if sustained, may be responsible for the persistent neurocognitive impairment prevalent in adolescent survivors of CHD. These foundational insights into the complex interplay between evolving brain structure and function may have relevance for a wide spectrum of neurological disorders manifesting early developmental brain injury

Plasma cholesterol levels and brain development in preterm newborns.

BackgroundTo assess whether postnatal plasma cholesterol levels are associated with microstructural and macrostructural regional brain development in preterm newborns.MethodsSixty preterm newborns (born 24-32 weeks gestational age) were assessed using MRI studies soon after birth and again at term-equivalent age. Blood samples were obtained within 7 days of each MRI scan to analyze for plasma cholesterol and lathosterol (a marker of endogenous cholesterol synthesis) levels. Outcomes were assessed at 3 years using the Bayley Scales of Infant Development, Third Edition.ResultsEarly plasma lathosterol levels were associated with increased axial and radial diffusivities and increased volume of the subcortical white matter. Early plasma cholesterol levels were associated with increased volume of the cerebellum. Early plasma lathosterol levels were associated with a 2-point decrease in motor scores at 3 years.ConclusionsHigher early endogenous cholesterol synthesis is associated with worse microstructural measures and larger volumes in the subcortical white matter that may signify regional edema and worse motor outcomes. Higher early cholesterol is associated with improved cerebellar volumes. Further work is needed to better understand how the balance of cholesterol supply and endogenous synthesis impacts preterm brain development, especially if these may be modifiable factors to improve outcomes