Introduction The dynamic nature and complexity of the cellular events that take place during the last trimester of pregnancy make the developing cortex particularly vulnerable to perturbations. Abrupt interruption to normal gestation can lead to significant deviations to many of these processes, resulting in atypical trajectory of cortical maturation in preterm birth survivors. Methods We sought to first map typical cortical micro- and macrostructure development using invivo MRI in a large sample of healthy term-born infants scanned after birth ( n = 259). Then we offer a comprehensive characterization of the cortical consequences of preterm birth in 76 preterm infants scanned at term-equivalent age (37–44 weeks postmenstrual age). We describe the group-average atypicality, the heterogeneity across individual preterm infants, and relate individual deviations from normative development to age at birth and neurodevelopment at 18 months. Results In the term-born neonatal brain, we observed heterogeneous and regionally specific associations between age at scan and measures of cortical morphology and microstructure, including rapid surface expansion, greater cortical thickness, lower cortical anisotropy and higher neurite orientation dispersion. By term-equivalent age, preterm infants had on average increased cortical tissue water content and reduced neurite density index in the posterior parts of the cortex, and greater cortical thickness anteriorly compared to term-born infants. While individual preterm infants were more likely to show extreme deviations (over 3.1 standard deviations) from normative cortical maturation compared to term-born infants, these extreme deviations were highly variable and showed very little spatial overlap between individuals. Measures of regional cortical development were associated with age at birth, but not with neurodevelopment at 18 months. Conclusion We showed that preterm birth alters cortical micro- and macrostructural maturation near the time of full-term birth. Deviations from normative development were highly variable between individual preterm infants.

The Developing Human Connectome Project (dHCP) is an Open Science project which provides the first large sample of neonatal functional MRI (fMRI) data with high temporal and spatial resolution. This data enables mapping of intrinsic functional connectivity between spatially distributed brain regions under normal and adverse perinatal circumstances, offering a framework to study the ontogeny of large-scale brain organisation in humans. Here, we characterise in unprecedented detail the maturation and integrity of resting-state networks (RSNs) at normal term age in 337 infants (including 65 born preterm).First, we applied group independent component analysis (ICA) to define 11 RSNs in term-born infants scanned at 43.5-44.5 weeks postmenstrual age (PMA). Adult-like topography was observed in RSNs encompassing primary sensorimotor, visual and auditory cortices. Among six higher-order, association RSNs, analogues of the adult networks for language and ocular control were identified, but a complete default mode network precursor was not. Next, we regressed the subject-level datasets from an independent cohort of infants scanned at 37-43.5 weeks PMA against the group-level RSNs to test for the effects of age, sex and preterm birth.Brain mapping in term-born infants revealed areas of positive association with age across four of six association RSNs, indicating active maturation in functional connectivity from 37 to 43.5 weeks PMA. Female infants showed increased connectivity in inferotemporal regions of the visual association network. Preterm birth was associated with striking impairments of functional connectivity across all RSNs in a dose-dependent manner; conversely, connectivity of the superior parietal lobules within the lateral motor network was abnormally increased in preterm infants, suggesting a possible mechanism for specific difficulties such as developmental coordination disorder which occur frequently in preterm children.Overall, we find a robust, modular, symmetrical functional brain organisation at normal term age. A complete set of adult-equivalent primary RSNs is already instated, alongside emerging connectivity in immature association RSNs, consistent with a primary-to-higher-order ontogenetic sequence of brain development. The early developmental disruption imposed by preterm birth is associated with extensive alterations in functional connectivity.

Background Very preterm birth is associated with an increased risk of childhood psychopathology and cognitive deficits. However, the extent to which these developmental problems associated with preterm birth are amenable to environmental factors or determined by neurobiology at birth remains unclear. Methods We derived neonatal brain structural covariance networks using non-negative matrix factorization in 384 very preterm infants (median gestational age [range], 30.29 [23.57–32.86] weeks) who underwent magnetic resonance imaging at term-equivalent age (median postmenstrual age, 42.57 [37.86–44.86] weeks). Principal component analysis was performed on 32 behavioral and cognitive measures assessed at preschool age ( n = 206; median age, 4.65 [4.19–7.17] years) to identify components of childhood psychopathology and cognition. The Cognitively Stimulating Parenting Scale assessed the level of cognitively stimulating experiences available to the child at home. Results Cognitively stimulating parenting was associated with reduced expression of a component reflecting developmental psychopathology and executive dysfunction consistent with the preterm phenotype (inattention-hyperactivity, autism spectrum behaviors, and lower executive function scores). In contrast, a component reflecting better general cognitive abilities was associated with larger neonatal gray matter volume in regions centered on key nodes of the salience network, but not with cognitively stimulating parenting. Conclusions Our results suggest that while neonatal brain structure likely influences cognitive abilities in very preterm children, the severity of behavioral symptoms that are typically observed in these children is sensitive to a cognitively stimulating home environment. Very preterm children may derive meaningful mental health benefits from access to cognitively stimulating experiences during childhood.

Introduction: The structural correspondence of neurodevelopmental impairments related to intrauterine growth restriction (IUGR) that persists later in life remains elusive. Moreover, early postnatal stimulation strategies have been proposed to mitigate these effects. Long-term brain connectivity abnormalities in an IUGR rabbit model and the effects of early postnatal environmental enrichment (EE) were explored. Materials and Methods: IUGR was surgically induced in one horn, whereas the contralateral one produced the controls. Postnatally, a subgroup of IUGR animals was housed in an enriched environment. Functional assessment was performed at the neonatal and long-term periods. At the long-term period, structural brain connectivity was evaluated by means of diffusion-weighted brain magnetic resonance imaging and by histological assessment focused on the hippocampus. Results: IUGR animals displayed poorer functional results and presented altered whole-brain networks and decreased median fractional anisotropy in the hippocampus. Reduced density of dendritic spines and perineuronal nets from hippocampal neurons were also observed. Of note, IUGR animals exposed to enriched environment presented an improvement in terms of both function and structure. Conclusions: IUGR is associated with altered brain connectivity at the global and cellular level. A strategy based on early EE has the potential to restore the neurodevelopmental consequences of IUGR.

23 This study investigated the association between attention-deficit/hyperactivity disorder (ADHD) 24 symptomatology in preschool-aged children who were born very preterm (<32 weeks) and cognitive 25 outcomes, clinical risk and socio-demographic characteristics. 119 very preterm children who participated 26 in the Evaluation of Preterm Imaging Study at term-equivalent age were assessed at a mean age of 4.5 27 years. Parents completed the ADHD Rating Scale IV, a norm-referenced checklist that evaluates ADHD 28 symptomatology according to diagnostic criteria, and the Behavior Rating Inventory of Executive 29 Function-Preschool version. Children completed the Wechsler Preschool and Primary Scales of 30 Intelligence and the Forward Digit Span task. Longitudinal data including perinatal clinical, qualitative 31 MRI classification, socio-demographic variables and neurodevelopmental disabilities were investigated in 32 relation to ADHD symptomatology. All results were corrected for multiple comparisons using false 33 discovery rate. Results showed that although the proportion of very preterm children with clinically 34 significant ADHD did not differ from normative data after excluding those with neurodevelopmental 35 disabilities, 32.7% met criteria for subthreshold ADHD inattentive type and 33.6% for combined type, 36 which was higher than the expected 20% in normative samples. Higher ADHD symptom scores (all) were 37 associated with greater executive dysfunction (inhibitory self-control, flexibility, and emergent 38 metacognition, corrected p<0.001 for all tests). Higher inattentive ADHD symptom scores were 39 associated with lower IQ (ρ=-0.241, p=0.036) and higher perinatal clinical risk (more days on mechanical 40 ventilation (ρ=0.206, p=0.025) and more days on parenteral nutrition (ρ=0.223, p=0.015)). Higher 41 hyperactive ADHD symptom scores instead were associated with lower socio-economic status (ρ=0.278, 42 p=0.002). These results highlight the importance of monitoring and supporting the development of very 43 preterm children throughout the school years, as subthreshold ADHD symptoms represent risk factors for 44 psychosocial problems and for receiving a future clinical diagnosis of ADHD. 45 3 46 List of Abbreviations and Acronyms: 47 ADHD (Attention-deficit/hyperactivity disorder) 48 MRI (magnetic resonance imaging) 49 NDD (Neurodevelopmental disability) 50 51 52 53 54 55 56 57 58 59 60 4 61 Introduction 62 Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition which affects 5-7%63 of children, depending on the source of information used to reach a diagnosis (1, 2). Children who were 64 born very preterm (< 32 weeks of gestation) have a 2-to 3-fold increased risk of being diagnosed with 65 ADHD compared to their term born peers (4-fold risk in those born at < 26 weeks) (3-7). 66According to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-67 V), ADHD is characterized by two main symptom presentations, inattention and hyperactivity-68 impulsivit...