Abstract 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.

IntroductionBehavioral outcomes may be suboptimal in school-age children and adolescents with congenital heart disease (CHD). However, little is known about the behavioral outcomes of preschool children with CHD. This study aimed to compare behavioural outcomes in preschool children with CHD and controls, and to investigate the impact of a cognitively stimulating home environment on these outcomes.MethodsCross-sectional case-control study based on parent-rated questionnaires assessing child behavior and cognitively stimulating opportunities in the home environment in 56 preschool children (4–6 years) with CHD and 215 control participants. Validated questionnaires were used to assess temperament (Child Behavior Questionnaire), autism traits (Social Communication Questionnaire), ADHD symptoms (ADHD-Rating Scale-IV), empathy (EmQue), and behavioral difficulties (Strengths and Difficulties Questionnaire). Higher scores on these measures indicate more severe difficulties. The Cognitively Stimulating Parenting Scale was used to assess the presence of cognitive stimulating opportunities in the home environment.ResultsUnivariate robust regression analyses showed that children with CHD compared to controls had higher levels of age-adjusted hyperactivity/impulsivity (B = −0.339, p = 0.032), hyperactivity/inattention (B = −0.390, p = 0.032) and peer relationship problems (B = −0.298, p = 0.045), after controlling for gestational age at birth, sex and neighborhood deprivation, with results surviving false discovery rate correction. We did not find any differences between children with CHD and controls in the other behavioral measures assessed. Group (CHD or control) significantly moderated the relationship between cognitively stimulating opportunities at home and selective behavioral outcomes: hyperactivity/impulsivity, inattention and peer problems. More cognitively stimulating opportunities at home were associated with more favorable behavioral outcomes in children with CHD (hyperactivity/impulsivity: B = −0.092, p < 0.001; hyperactivity/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; hyperactivity/inattention: B = −0.019, p = 0.225; peer problems: B = −0.002, p = 0.911).ConclusionsCompared to controls, and after adjusting for potential confounders, preschool children with CHD have more hyperactivity/impulsivity, inattention and peer relationship problems. Fewer behavioral problems were associated with a more cognitively stimulating home environment, highlighting this modifiable factor as a promising target for future longitudinal research.

Maternal diabetes and obesity are established risk factors for adverse offspring health. Emerging evidence suggests that these fetal programming effects vary by sex, yet it remains unclear whether these factors independently or interactively influence early brain development. This prospective study included 1,965 infants from six international cohorts. Infant MRI was used to derive subcortical volumes (thalamus, amygdala, hippocampus, pallidum, putamen, caudate). ComBat harmonization was applied. Multiple linear regression tested main and interaction effects of maternal obesity, maternal diabetes, and sex, controlling for covariates with false discovery rate (FDR) corrections. Of the sample, 46

Quantitative MRI has characterised early human brain development primarily through measures of water mobility, leaving other biophysical properties of maturing tissue unexplored. Here we show that radiofrequency electrical conductivity, reflecting ionic composition, membrane density and extracellular geometry in addition to water content, can be extracted retrospectively and at scale from the phase of conventional MRI acquisitions, revealing a distinct dimension of early brain tissue maturation and state. Applying electrical property tomography to 888 neonatal MRI sessions (784 subjects, 26-45 weeks post-menstrual age) alongside infant and childhood data, we find that whole-brain conductivity declines steeply during the perinatal period and remains independently associated with age after adjustment for mean diffusivity and ventricular volume, confirming that it represents a distinct developmental signal that is not reducible to tissue water content alone. Preterm birth was associated with elevated conductivity at term-equivalent age, particularly in deep grey matter. In neonates with hypoxic-ischaemic encephalopathy (n = 25), conductivity was elevated while mean diffusivity was reduced within the same tissue compartments, a dissociation indicating that these measures capture mechanistically distinct aspects of the tissue response to injury. These findings establish radiofrequency electrical properties as a new biophysical window on perinatal brain maturation and its perturbation by injury, extending quantitative MRI beyond measures of water mobility.

Prenatal air pollution exposure is associated with altered neurodevelopmental outcomes in childhood. It is unknown whether specific infant characteristics or prenatal exposure windows influence the relationship between prenatal exposure and neurodevelopmental outcomes. We studied 498 (262 male) toddlers born at 23+6-43+4 gestational weeks (125 born <37+0 weeks) who were recruited to the developing human connectome project. We characterised the association between average prenatal exposure to particulate matter [PM2.5 and PM10] and nitrogen dioxide (NO2) across gestation in each trimester modelled using maternal residential postcode, and cognitive, language and motor abilities assessed with the Bayley Scales of Infant and Toddler Development-3rd edition (age at assessment 17.3-34.5 months). Higher first trimester exposure to all pollutants was associated with lower language scores in toddlerhood adjusting for sex, ethnic group, maternal pregnancy complications, gestational age at birth, birth-weight z-score, home language environment and socioeconomic deprivation. Moderation analyses revealed higher exposure to all pollutants across gestation was associated with lower motor scores in preterm infants adjusting for sex, birth-weight z-score, ethnic group, maternal pregnancy complications, socioeconomic deprivation and duration of respiratory support. Increased air pollution exposure early in pregnancy is associated with altered early language development. Preterm infants demonstrate increased vulnerability to the adverse effects of gestational pollutant exposure on motor development in early childhood. Maternal exposure to air pollution during pregnancy is a potentially modifiable risk factor and reductions may improve neurodevelopmental outcomes. KEY POINTS: The effect of prenatal air pollution exposure on neurodevelopment in toddlers was examined. Higher 1st trimester exposure was associated with lower language scores. Higher exposure across gestation was associated with worse motor skills in very preterm infants.

BACKGROUND:Children born very preterm (VPT; ≤32 weeks' gestation) are at higher risk of developing behavioural problems, encompassing socio-emotional processing and attention, compared to term-born children. This study aimed to examine multi-dimensional predictors of late childhood behavioural and psychiatric outcomes in very preterm children, using longitudinal clinical, environmental, and cognitive measures. METHODS:Participants were 153 VPT children previously enrolled in the Evaluation of Preterm Imaging study who underwent neuropsychological assessments at 18-24 months, 4-7 years and 8-11 years as part of the Brain Immunity and Psychopathology following very Preterm birth (BIPP) study. Predictors of late childhood behavioural and psychiatric outcomes were investigated, including clinical, environmental, cognitive, and behavioural measures in toddlerhood and early childhood. Parallel analysis and exploratory factor analysis were conducted to define outcome variables. A prediction model using elastic-net regularisation and repeated nested cross-validation was applied to evaluate the predictive strength of these variables. RESULTS:Factor analysis revealed two key outcome factors in late childhood: externalising and internalising-socio-emotional problems. The strongest predictors of externalising problems were response inhibition, effortful control and internalising symptoms in early childhood (cross-validated R2=.256). The strongest predictors of internalising problems were autism traits and poor cognitive flexibility in early childhood (cross-validated R2=.123). Cross-validation demonstrated robust prediction models, with higher accuracy for externalising symptoms. CONCLUSIONS:Early childhood cognitive and behavioural outcomes predicted late childhood behavioural and psychiatric outcomes in very preterm children. These findings underscore the importance of early interventions targeting cognitive development and behavioural regulation to mitigate long-term psychiatric risks in very preterm children.

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.

Introduction:Recent genome-wide association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with subcortical brain volumes. These studies have been undertaken in largely adult cohorts. In this work we explore the role of common genetic variability in fetal and perinatal brain development. We investigate how genetic variation, known to be associated with adult subcortical brain volume, affects the infant subcortical brain. Methods:We examine the influence of specific genetic loci and genome-wide polygenic scores on development of the fetal brain. Using a cohort of 208 term-born infants from the Developing Human Connectome Project, we ask whether eight SNPs, previously associated with adult subcortical brain volumes, show similar associations at birth. In addition, we compute genome-wide polygenic scores for the amygdala, brainstem, caudate, hippocampus, pallidum, putamen and thalamus and ask whether these scores are associated with the corresponding neonatal brain volumes. Results:We find that the association between SNP rs945270 and putamen volume, seen in adults, is present at birth (p = 3.67 × 10-3, β = 0.13, SE = 0.04). We also show that neonatal hippocampal, brainstem, putamen and thalamic volumes are all significantly associated with the genome-wide polygenic scores for their corresponding adult subcortical brain volume. Conclusions:Our results suggest that common genetic variation, important in shaping adult subcortical brain volume, also plays a significant role in fetal and perinatal brain development.

Large diffusion-weighted brain MRI (dMRI) studies in neonates are crucial for developmental neuroscience. Our aim was to investigate the utility of ComBat, an empirical Bayes tool for multisite harmonization, in removing site effects from white matter (WM) dMRI measures in healthy infants born at 37 gestational weeks+0 days-42 weeks+6 days from the Theirworld Edinburgh Birth Cohort (n=86) and Developing Human Connectome Project (n=287).Skeletonized fractional anisotropy (FA), mean, axial and radial diffusivity (MD, AD, RD) maps were harmonized. Differences between voxel-wise metrics, skeleton means and histogram widths (5th-95th percentile) were assessed before and after harmonization, as well as variance associated with gestational age at birth and scan.Before harmonization, large cohort differences were observed. Harmonization removed all voxel-wise differences from MD maps and all metric means and histogram widths, however small voxel-wise differences (<1.5% of voxels) remained in FA, AD and RD. We detected significant relationships between GA at birth and all metrics. When comparing single site and multisite harmonized datasets of equal sample sizes, harmonized data resulted in smaller standardized regression coefficients.ComBat could enable unprecedented sample sizes in developmental neuroscience, offering new horizons for biomarker discovery and validation, understanding typical and atypical brain development, and assessing neuroprotective therapies.

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. ### Competing Interest Statement The authors have declared no competing interest. the National Institute for Health Research (NIHR) Medical Research Council, https://ror.org/03x94j517

INTRODUCTION:Older gestational age (GA) has been associated with more favourable cognitive outcomes in preterm children. Recent evidence suggests this may also apply to term-born children. This study aims to examine the association between GA and early neurodevelopmental outcomes in children born at term in China and the UK. METHODS:Participants were term-born children from two cohorts, the Sichuan Multi-stratified Infants and Early Life (SMILE) study in China and the Developing Human Connectome Project (dHCP) in the UK. Early cognitive outcomes were assessed at 6 months in the SMILE study, and at 18 months in the dHCP. Linear regression models were conducted to examine the association between GA at birth and early cognitive outcomes in each cohort separately. RESULTS:A sample of 1245 participants from the SMILE study and 406 participants for the dHCP were included in the analysis. In the SMILE study, longer GA was associated with better mental developmental (B = 2.47 [1.60, 3.34], P < .001) and psychomotor outcomes (B = 2.91 [2.01, 3.82], P < .001), after controlling for sex, parental education, family yearly income, maternal age, maternal depressive symptoms, and birth weight; in the dHCP, longer GA was associated with better cognitive (B = 1.35 [0.33, 2.37], P = .010) and motor outcomes (B = 1.49 [0.59, 2.39], P = .001), after controlling for sex, relative social deprivation, maternal depressive symptoms and birth weight. CONCLUSIONS:Older GA in term-born toddlers is associated with more favourable developmental outcomes across different cultural contexts.

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 submillimetre 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.

Pain is multidimensional, including sensory-discriminative, affective-motivational, and cognitive-evaluative components. Although the concept of pain is learned through life, it is not known when and how the brain networks that are required to encode these different dimensions of pain develop. Using the 2 largest available databases of brain magnetic resonance images—the developing Human Connectome Project and the Human Connectome Project—we have mapped the development of the pain connectome—the neural network required for pain perception—in infants from 26 to 42 weeks of postmenstrual age (PMA, n = 372), compared with adults (n = 98). Partial correlation analysis of resting BOLD signal between pairwise combinations of 12 pain-related brain regions showed that overall functional connectivity is significantly weaker before 32 weeks PMA compared with adults. However, over the following weeks, significantly different developmental trajectories emerge across pain connectome subnetworks. The first subnetwork to reach adult levels in strength and proportion of connections is the sensory-discriminative subnetwork (34-36 weeks PMA), followed by the affective-motivational subnetwork (36-38 weeks PMA), while the cognitive-evaluative subnetwork has still not reached adult levels at term. This study reveals a previously unknown pattern of early development of the infrastructure necessary to encode different components of pain experience. Newborn neural pathways required for mature pain processing in the brain are incomplete in newborns compared with adults, particularly regarding the emotional and evaluative aspects of pain. The rapid age-related changes suggest that pain processing, and consequently pain experience, changes rapidly over this developmental period and unlikely to be the same as in adults, even at term.

BACKGROUND:Altered structural brain development has been identified in fetuses with congenital heart disease (CHD), suggesting that the neurodevelopmental impairment observed later in life might originate in utero. There are many interacting factors that may perturb neurodevelopment during the fetal period and manifest as structural brain alterations, such as altered cerebral substrate delivery and aberrant fetal hemodynamics. METHODS AND RESULTS:We extracted structural covariance networks from the log Jacobian determinants of 435 in utero T2 weighted image magnetic resonance imaging scans, (n=67 controls, 368 with CHD) acquired during the third trimester. We fit general linear models to test whether age, sex, expected cerebral substrate delivery, and CHD diagnosis were significant predictors of structural covariance. We identified significant effects of age, sex, cerebral substrate delivery, and specific CHD diagnosis across a variety of structural covariance networks, including primary motor and sensory cortices, cerebellar regions, frontal cortex, extra-axial cerebrospinal fluid, thalamus, brainstem, and insula, consistent with widespread coordinated aberrant maturation of specific brain regions over the third trimester. CONCLUSIONS:Structural covariance networks offer a sensitive, data-driven approach to explore whole-brain structural changes without anatomical priors. We used them to stratify a heterogenous patient cohort with CHD, highlighting similarities and differences between diagnoses during fetal neurodevelopment. Although there was a clear effect of abnormal fetal hemodynamics on structural brain maturation, our results suggest that this alone does not explain all the variation in brain development between individuals with CHD.

Very preterm (VPT; < 33 weeks’ gestation) toddlers screening positively for autism spectrum conditions (ASC) may display heterogenous neurodevelopmental trajectories. Here we studied neonatal brain volumes and childhood ASC traits evaluated with the Social Responsiveness Scale (SRS-2) in VPT-born toddlers (N = 371; median age 20.17 months) sub-divided into three groups based on their Modified-Checklist for Autism in Toddlers scores. These were: those screening positively failing at least 2 critical items ( critical-positive ); failing any 3 items, but less than 2 critical items ( non-critical-positive ); and screening negatively. Critical-positive scorers had smaller neonatal cerebellar volumes compared to non-critical-positive and negative scorers. However, both positive screening groups exhibited higher childhood ASC traits compared to the negative screening group, suggesting distinct aetiological trajectories associated with ASC outcomes.