Anthony David Edwards

Background and aim: Very preterm birth (VPT; ≤32 weeks’ gestation) is associated with an increased risk of later psychiatric disorders, including psychosis. Although psychosis typically emerges in adulthood, subclinical early signs along the psychosis continuum, such as psychotic-like experiences (PLEs), can be observed much earlier. We therefore aimed to study PLEs in childhood in VPT individuals recruited from a clinical cohort compared with full-term (FT) controls. We subsequently investigated whether findings could be replicated in an independent population-based cohort. Methods: Primary analyses were conducted in the Brain, Immunity and Psychopathology (BIPP) study, including 197 children born VPT recruited through Neonatal Intensive Care Units and 72 FT controls assessed at a mean age of 10.50±1.77 years. Between-group differences in PLEs were then examined in the Adolescent Brain Cognitive Development (ABCD) study, including 149 children born VPT and 9519 FT controls assessed at a mean age of 9.94 ± 0.63 years. PLEs were assessed using the Prodromal Questionnaire-Brief Child Version (PQ-BC), yielding frequency and distress-related scores for both the total scale and three specific domains (unusual thought content, perceptual abnormalities, disorganised speech). Regression models tested associations between birth status (VPT and control) and PQ-BC scores adjusting for age, sex, and socio-economic status, with secondary models additionally adjusting for cognitive ability and broader psychopathology. Pooled analyses examined cohort effects (BIPP and ABCD) and cohort-by-group status (VPT and control) interactions. Results: In BIPP, VPT birth was associated with higher PQ-BC total (β=1.61, p=0.004) and distress scores (β=0.78, p=0.039), with the strongest and most consistent associations observed for perceptual abnormalities across total score (sum of endorsed items), distressing items, and distress severity scores (all p≤0.01). These associations were attenuated but largely persisted after adjustment for cognitive ability and broader psychopathology, particularly for perceptual abnormalities. In ABCD, VPT birth was not significantly associated with global or domain-specific PQ-BC outcomes. Discussion: VPT birth is associated with increased vulnerability to PLEs in childhood, particularly in the domain of perceptual abnormalities. The lack of clear replication in the population-based ABCD cohort may reflect differences in the composition of its VPT subgroup, which may not fully represent VPT individuals typically seen in clinical cohorts.

Background: Brain development is altered in neonates with congenital heart disease (CHD), with well‐characterised reductions in regional brain volumes and enlargement of CSF spaces. However, perioperative morphological changes remain incompletely understood. Purpose: To identify brain regions showing spatial patterns of coordinated expansion and contraction that differ between neonates with CHD after cardiac intervention and controls, assess perioperative changes and effects of perioperative risk factors, using Structural Covariance Component (SCC) analysis. Study Type: Prospective. Population: Forty‐one neonates with CHD (male = 20) who underwent cardiac surgery or catheterization and 359 healthy neonates (male = 185). Field Strength and Sequence: 3T T2‐weighted turbo‐spin‐echo sequence. Assessment: Images were motion‐corrected and reconstructed using a neonatal algorithm. Jacobian determinants calculated from non‐linear image registration to a template were input into an Independent Component Analysis to identify SCCs ( N = 40). SCC weightings were extracted, reflecting the degree to which the covariance pattern is expressed per neonate. Statistical Tests: Postoperative SCC weightings were compared to those of controls using a general linear model or robust regression. Perioperative change was assessed using a linear mixed effects model, and associations between perioperative differences and age at surgery, cardiopulmonary bypass duration, and postoperative pediatric intensive care unit stay were assessed using partial Spearman's rank correlation. Analyses were adjusted for covariates and corrected for multiple comparisons using False Discovery Rate, significant at p < 0.05. Results: Sixteen of the 40 SCCs showed significant differences between neonates with CHD after surgery and controls, including white matter, cortical‐ and deep gray matter, brainstem, and CSF ( f ² _partial = 0.02–0.04), with seven also showing significant perioperative change ( f ² _partial < 0.01–0.27). An additional nine SCCs only showed significant perioperative change ( f ² _partial < 0.01–0.14). Perioperative risk factors were not associated with perioperative change ( p > 0.463). Data Conclusion: This work highlights region‐specific postoperative alterations and perioperative changes in brain morphology of neonates with CHD. Evidence Level: 1. Technical Efficacy: Stage 3.

Background: Very preterm (VPT) infants face an elevated risk of neurodevelopmental delays, yet early predictors of specific impairments are poorly understood. This study investigated how neonatal brain structure relates to neurodevelopmental delays in VPT toddlers. Methods: We analysed term-equivalent T2-weighted MRI scans from 352 VPT infants. Neurodevelopmental outcomes were assessed at 18–24 months using the Bayley Scales of Infant and Toddler Development-III. We used tensor-based morphometry to compare voxel-wise whole-brain volumes between infants with and without developmental delay. Results: Toddlers with motor delays showed significantly reduced volume in the left posterior cerebellum at term compared to those without motor delays, even after adjusting for other domains. No significant volumetric differences were observed for cognitive or language delays. Conclusion: Reduced cerebellar volume at term is associated with motor delay in VPT toddlers. These findings highlight the cerebellum’s key role in early motor development and the value of structural MRI for early risk stratification.

Background: Brain development is altered in neonates with congenital heart disease (CHD). However, development in the perioperative period remains incompletely understood. Purpose: This study used Structural Covariance Component (SCC) analysis to identify brain regions showing spatial patterns of coordinated expansion and contraction that differ between neonates with CHD after cardiac intervention and healthy controls, as well as pre-to postoperative changes and effects of perioperative risk factors. Study type: Prospective. Population: The cohort included 41 neonates with CHD who underwent cardiac surgery or catheterization and 359 healthy neonates. Field strength and sequence: 3 Tesla T2-weighted turbo-spin-echo sequence. Assessment: Brain MRI were motion-corrected and reconstructed using an established neonatal algorithm. Jacobian determinants calculated from non-linear registration of MRI to a neonatal template were input into an Independent Component Analysis to identify SCCs (N=40). SCC weightings were extracted, reflecting the degree to which the pattern of covariance is expressed in each neonate. Statistical tests: Postoperative SCC weightings were compared to healthy neonates using a general linear model or robust regression. Pre- and postoperative SCC weightings were compared using a linear mixed effect model. Pre- to postoperative differences were calculated and associations with age at surgery, cardiopulmonary bypass duration, and postoperative paediatric intensive care unit stay were assessed using partial spearman’s rank correlation. Analyses were adjusted for covariates and corrected for multiple comparisons using False Discovery Rate. Results: 16/40 SCCs showed significant differences between neonates with CHD after surgery and controls, including white matter, cortical- and deep grey matter, brainstem, and CSF regions, with seven also showing significant perioperative change. A further nine SCCs only showed significant perioperative change. Perioperative risk factors were not associated with perioperative change. Data conclusion: This data-driven approach highlights region-specific postoperative alterations and perioperative changes in brain morphology of neonates with CHD. Evidence level. 1. Technical Efficacy: Stage 3.

Objective: To compare intrathalamic morphometry in infants born preterm, with congenital heart disease (CHD) and typical controls and investigate associations with neurodevelopmental outcomes. Methods: 592 infants underwent T2-weighted brain MRI: 107 CHD [gestational age at birth (GA) ≥37.00 weeks], 126 preterm (GA 23.00-36.86), 359 controls (GA ≥37.00). We used data-driven structural covariance analysis to derive 8 components of coordinated expansion and contraction within the thalamus. Permutation testing was used to test associations between intrathalamic morphometry and group (control, CHD, preterm birth 2 ) in infants with CHD, and neurodevelopmental outcomes at 18-24 months. Results: Preterm infants born 2 was not associated with intrathalamic morphometry. Right posterior thalamus morphometry was associated with motor scores in preterm infants born 2 . Together, these findings suggest distinct thalamic phenotypes in prematurity and CHD.

Congenital heart disease (CHD) is associated with impaired early brain development and an increased risk of adverse neurodevelopmental outcomes. Previous studies have reported smaller hippocampal volumes in infants, children and adolescents with CHD. However, it is unclear whether specific subfields are differentially sensitive as hippocampal subfield morphometry has not been assessed in this population. The aims of this study were to test the hypothesis that infants with CHD deviate from typical hippocampal morphometry, using a normative modelling approach with reference data from 217 typically developing infants, and characterize the relationship between hippocampal morphometric measures and both cerebral oxygen delivery and neurodevelopmental outcomes in infants with CHD. Infants with CHD [60 preoperative and 29 postoperative, gestational age at birth median (range) 38.43 (36.71–40.57) weeks, postmenstrual age at scan 39.86 (37.14–45.71) weeks] and typically developing infants underwent brain MRI on a 3T scanner, and T2-weighted and inversion recovery T1-weighted imaging were acquired. Phase-contrast angiography was acquired in 53 infants with CHD before surgery, and cerebral oxygen delivery was calculated. Cognitive and motor abilities were assessed at 22 months (N = 52) using the Bayley Scales of Infant and Toddler Development-Third Edition. Volumes of the whole hippocampus, subiculum, cornu ammonis 1–4, dentate gyrus, and stratum radiatum lacunosum and moleculare were obtained by segmenting T1-weighted MRI data using a U-net model trained on infant data using HippUnfold. Normative curves were generated from the typically developing infants using two models: one for relative hippocampal volumes and one for hippocampal gyrification. Models accounted for the infant’s postmenstrual age at scan, postnatal age at scan and sex. The hippocampal gyrification model also accounted for hippocampal subfield volume. Z-scores representing the degree of positive or negative deviation from the normative mean were generated for infants with CHD. Relative volume z-scores were reduced for the bilateral cornu ammonis 4 and dentate gyrus (median Z-scores −0.45 to −0.82) and were increased for the left subiculum (mean Z-scores: preoperative 0.44; postoperative 0.51) in infants with CHD. Hippocampal gyrification was reduced in the bilateral subiculum, cornu ammonis 1–4 and dentate gyrus both pre- and postoperatively (mean Z-scores, −0.50 to −1.33). There was no significant relationship between preoperative hippocampal morphometric Z-scores and cerebral oxygen delivery or neurodevelopmental outcomes. Our findings suggest that hippocampal morphometry is altered in infants with CHD; however these effects are not uniform across the hippocampus.

Background: Behavioural outcomes may be suboptimal in school-age children and adolescents with congenital heart disease (CHD), but little is known about outcomes of preschool children. We aimed to compare the behavioural outcomes of preschool children with CHD with controls, and investigate whether a cognitively stimulating home environment impacts their outcomes. Methods: This is a cross-sectional case-control study of fifty-six preschool children (4-6 years) with CHD and 215 controls. Questionnaires were used to assess temperament (Child Behavior Questionnaire), autism traits (Social Communication Questionnaire), ADHD symptoms (ADHD-Rating Scale-IV), empathy (EmQue), and behavioural difficulties (Strengths and Difficulties Questionnaire). The Cognitively Stimulating Parenting Scale was used to assess home environment. Results: Univariate robust regression analyses showed that children with CHD compared to controls had higher levels of hyperactivity-impulsivity (B=-0.467 p=0.023), inattention (B=-0.450, p=0.023) and peer relationship problems (B=-0.504, p=0.023), after controlling for age at assessment, gestational age at birth, sex and neighbourhood deprivation, with results surviving false discovery rate correction. Group significantly moderated the relationship between cognitively stimulating opportunities at home and the outcomes that differed between the groups: hyperactivity-impulsivity, inattention and peer problems. More cognitively stimulating opportunities at home were associated with more favourable behavioural outcomes in children with CHD (hyperactivity-impulsivity: B=-0.092, p<0.001; inattention: B=-0.088, p<0.001; peer problems: B=-0.124, p<0.001) but not in controls (hyperactivity-impulsivity: B=-0.005, p=0.727; inattention: B=-0.019, p=0.225; peer problems: B=-0.002, p=0.911). Conclusions: Compared to controls, preschool children with CHD have more hyperactivity-impulsivity, inattention and peer relationship problems. These behavioural problems are mitigated by a cognitively stimulating home environment.

Gestational age plays a crucial role in neurodevelopment, and individuals born very preterm (VPT; <32 weeks’ gestation) are at elevated risk for cognitive, behavioural and psychiatric problems across the lifespan. Better understanding of the impact of very preterm birth on cortical maturation trajectories could inform mechanistic insights into the origins of these sequelae. Here we compared cortical morphology between VPT individuals and full-term controls in three datasets spanning birth, childhood and adulthood. We identified a consistent cortical signature of VPT birth, characterized by reduced surface area and cortical folding in the frontal, temporal, parietal and insular regions, which persisted across development. Furthermore, in two large infant cohorts, we found that this cortical signature was significantly associated with neonatal clinical factors and with poorer motor outcomes at follow-up, suggesting its potential as a neuroimaging marker for long-term neurodevelopmental risk. Given that early motor development plays a key role in shaping infants’ interactions with the environment and supporting later cognitive and behavioural development, our findings provide insights into the neurobiological pathways linking VPT birth to subsequent neurodevelopmental difficulties.

Human cortical development leading up to and around birth is crucial for lifelong brain function. Cortical activity can be studied using BOLD fMRI, however, previously limited sensitivity and spatial specificity has constrained understanding of how its emergence relates to functional cortical circuitry and neurovascular development at the mesoscale. To resolve this, we used ultra-high-field 7 Tesla MRI to acquire sub-millimetre resolution BOLD-fMRI data from 40 newborns and 4 adults. In all subjects, passive right-hand movement elicited localised, positive BOLD responses in contralateral primary somatosensory cortex. In newborns, depth-specific BOLD responses were still evident in the thinner cortex, with developmental changes in response temporal features and amplitudes at different depths. This provides insight into key rapidly evolving factors in early cortical development including neuronal function, vascular architecture, and neurovascular coupling. Our framework and findings provide a foundation for future studies of emerging cortical circuitry and how disruption leads to adverse outcomes.

Lateralization is a fundamental principle of structural brain organization. In vivo imaging of brain asymmetry is essential for deciphering lateralized brain functions and their disruption in neurodevelopmental and neurodegenerative disorders. Here, we present a normative framework for benchmarking brain asymmetry across the lifespan, developed from an aggregated sample of 128 primary neuroimaging studies, including 177,701 scans from 138,231 individuals, jointly spanning the age range from 20 post menstrual weeks to 102 years. This resource includes comprehensive, hemisphere-specific brain growth charts for multiple neuroimaging phenotypes: regional cortical grey matter volume, thickness, surface area, and subcortical volumes. Our findings reveal distinct spatial patterns of asymmetry, with early leftward asymmetry observed in association cortices and late rightward asymmetry in sensory regions. These trajectories support theories of the neuroplasticity of asymmetry and the role of both genetic and environmental factors in shaping brain lateralization. Additionally, we provide tools to generate asymmetry centile scores, which allow the quantification of individual deviations from typical asymmetry throughout the lifespan and can be applied to unseen data or clinical populations. We demonstrate the utility of these models by highlighting group-level differences in asymmetry in autism spectrum disorder, schizophrenia, and Alzheimer’s disease, and exploring genetic correlations with hemispheric specialization. To facilitate further research, we have made this normative framework freely available as an interactive open-access resource (upon publication), offering an essential tool to advance both basic and clinical neuroscience.