Clinical, socio-demographic, and parental correlates of early autism traits in a community cohort of toddlers.

Identifying factors linked to autism traits in the general population may improve our understanding of the mechanisms underlying divergent neurodevelopment. In this study we assess whether factors increasing the likelihood of childhood autism are related to early autistic trait emergence, or if other exposures are more important. We used data from 536 toddlers from London (UK), collected at birth (gestational age at birth, sex, maternal body mass index, age, parental education, parental language, parental history of neurodevelopmental conditions) and at 18 months (parents cohabiting, measures of socio-economic deprivation, measures of maternal parenting style, and a measure of maternal depression). Autism traits were assessed using the Quantitative Checklist for Autism in Toddlers (Q-CHAT) at 18 months. A multivariable model explained 20% of Q-CHAT variance, with four individually significant variables (two measures of parenting style and two measures of socio-economic deprivation). In order to address variable collinearity we used principal component analysis, finding that a component which was positively correlated with Q-CHAT was also correlated to measures of parenting style and socio-economic deprivation. Our results show that parenting style and socio-economic deprivation correlate with the emergence of autism traits at age 18 months as measured with the Q-CHAT in a community sample.

Neonatal brain dynamic functional connectivity in term and preterm infants and its association with early childhood neurodevelopment.

Brain dynamic functional connectivity characterises transient connections between brain regions. Features of brain dynamics have been linked to emotion and cognition in adult individuals, and atypical patterns have been associated with neurodevelopmental conditions such as autism. Although reliable functional brain networks have been consistently identified in neonates, little is known about the early development of dynamic functional connectivity. In this study we characterise dynamic functional connectivity with functional magnetic resonance imaging (fMRI) in the first few weeks of postnatal life in term-born (n = 324) and preterm-born (n = 66) individuals. We show that a dynamic landscape of brain connectivity is already established by the time of birth in the human brain, characterised by six transient states of neonatal functional connectivity with changing dynamics through the neonatal period. The pattern of dynamic connectivity is atypical in preterm-born infants, and associated with atypical social, sensory, and repetitive behaviours measured by the Quantitative Checklist for Autism in Toddlers (Q-CHAT) scores at 18 months of age.

Longitudinal neonatal brain development and socio-demographic correlates of infant outcomes following preterm birth.

Preterm birth results in premature exposure of the brain to the extrauterine environment during a critical period of neurodevelopment. Consequently, infants born preterm are at a heightened risk of adverse behavioural outcomes in later life. We characterise longitudinal development of neonatal regional brain volume and functional connectivity in the first weeks following preterm birth, sociodemographic factors, and their respective relationships to psychomotor outcomes and psychopathology in toddlerhood. We study 121 infants born preterm who underwent magnetic resonance imaging shortly after birth, at term-equivalent age, or both. Longitudinal regional brain volume and functional connectivity were modelled as a function of psychopathology and psychomotor outcomes at 18 months. Better psychomotor functioning in toddlerhood was associated with greater relative right cerebellar volume and a more rapid decrease over time of sensorimotor degree centrality in the neonatal period. In contrast, increased 18-month psychopathology was associated with a more rapid decrease in relative regional subcortical volume. Furthermore, while socio-economic deprivation was related to both psychopathology and psychomotor outcomes, cognitively stimulating parenting predicted psychopathology only. Our study highlights the importance of longitudinal imaging to better predict toddler outcomes following preterm birth, as well as disparate environmental influences on separable facets of behavioural development in this population.

Development of neonatal brain functional centrality and alterations associated with preterm birth.

Formation of the functional connectome in early life underpins future learning and behavior. However, our understanding of how the functional organization of brain regions into interconnected hubs (centrality) matures in the early postnatal period is limited, especially in response to factors associated with adverse neurodevelopmental outcomes such as preterm birth. We characterized voxel-wise functional centrality (weighted degree) in 366 neonates from the Developing Human Connectome Project. We tested the hypothesis that functional centrality matures with age at scan in term-born babies and is disrupted by preterm birth. Finally, we asked whether neonatal functional centrality predicts general neurodevelopmental outcomes at 18 months. We report an age-related increase in functional centrality predominantly within visual regions and a decrease within the motor and auditory regions in term-born infants. Preterm-born infants scanned at term equivalent age had higher functional centrality predominantly within visual regions and lower measures in motor regions. Functional centrality was not related to outcome at 18 months old. Thus, preterm birth appears to affect functional centrality in regions undergoing substantial development during the perinatal period. Our work raises the question of whether these alterations are adaptive or disruptive and whether they predict neurodevelopmental characteristics that are more subtle or emerge later in life.

Postnatal maternal depressive symptoms and behavioural outcomes in term-born and preterm-born toddlers: a longitudinal UK community cohort study.

OBJECTIVES: To examine the association between maternal depressive symptoms in the immediate postnatal period and offspring's behavioural outcomes in a large cohort of term-born and preterm-born toddlers. DESIGN AND PARTICIPANTS: Data were drawn from the Developing Human Connectome Project. Maternal postnatal depressive symptoms were assessed at term-equivalent age, and children's outcomes were evaluated at a median corrected age of 18.4 months (range 17.3-24.3). EXPOSURE AND OUTCOMES: Preterm birth was defined as <37 weeks completed gestation. Maternal depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale (EPDS). Toddlers' outcome measures were parent-rated Child Behaviour Checklist 11/2-5 Total (CBCL) and Quantitative Checklist for Autism in Toddlers (Q-CHAT) scores. Toddlers' cognition was assessed with the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). RESULTS: Higher maternal EPDS scores were associated with toddlers' higher CBCL (B=0.93, 95% CI 0.43 to 1.44, p<0.001, f2=0.05) and Q-CHAT scores (B=0.27, 95% CI 0.03 to 0.52, p=0.031, f2=0.01). Maternal EPDS, toddlers' CBCL and Q-CHAT scores did not differ between preterm (n=97; 19.1% of the total sample) and term participants. Maternal EPDS score did not disproportionately affect preterm children with respect to CBCL or Q-CHAT scores. CONCLUSIONS: Our findings indicate that children whose mothers reported increased depressive symptoms in the early postnatal period, including subclinical symptoms, exhibit more parent-reported behavioural problems in toddlerhood. These associations were independent of gestational age. Further research is needed to confirm the clinical significance of these findings.

Maternal depressive symptoms, neonatal white matter, and toddler social-emotional development.

Maternal prenatal depression is associated with increased likelihood of neurodevelopmental and psychiatric conditions in offspring. The relationship between maternal depression and offspring outcome may be mediated by in-utero changes in brain development. Recent advances in magnetic resonance imaging (MRI) have enabled in vivo investigations of neonatal brains, minimising the effect of postnatal influences. The aim of this study was to examine associations between maternal prenatal depressive symptoms, infant white matter, and toddler behaviour. 413 mother-infant dyads enrolled in the developing Human Connectome Project. Mothers completed the Edinburgh Postnatal Depression Scale (median = 5, range = 0-28, n = 52 scores ≥ 11). Infants (n = 223 male) (median gestational age at birth = 40 weeks, range 32.14-42.29) underwent MRI (median postmenstrual age at scan = 41.29 weeks, range 36.57-44.71). Fixel-based fibre metrics (mean fibre density, fibre cross-section, and fibre density modulated by cross-section) were calculated from diffusion imaging data in the left and right uncinate fasciculi and cingulum bundle. For n = 311, internalising and externalising behaviour, and social-emotional abilities were reported at a median corrected age of 18 months (range 17-24). Statistical analysis used multiple linear regression and mediation analysis with bootstrapping. Maternal depressive symptoms were positively associated with infant fibre density in the left (B = 0.0005, p = 0.003, q = 0.027) and right (B = 0.0006, p = 0.003, q = 0.027) uncinate fasciculus, with left uncinate fasciculus fibre density, in turn, positively associated with social-emotional abilities in toddlerhood (B = 105.70, p = 0.0007, q = 0.004). In a mediation analysis, higher maternal depressive symptoms predicted toddler social-emotional difficulties (B = 0.342, t(307) = 3.003, p = 0.003), but this relationship was not mediated by fibre density in the left uncinate fasciculus (Sobel test p = 0.143, bootstrapped indirect effect = 0.035, SE = 0.02, 95% CI: [-0.01, 0.08]). There was no evidence of an association between maternal depressive and cingulum fibre properties. These findings suggest that maternal perinatal depressive symptoms are associated with neonatal uncinate fasciculi microstructure, but not fibre bundle size, and toddler behaviour.

The Developing Human Connectome Project Neonatal Data Release.

The Developing Human Connectome Project has created a large open science resource which provides researchers with data for investigating typical and atypical brain development across the perinatal period. It has collected 1228 multimodal magnetic resonance imaging (MRI) brain datasets from 1173 fetal and/or neonatal participants, together with collateral demographic, clinical, family, neurocognitive and genomic data from 1173 participants, together with collateral demographic, clinical, family, neurocognitive and genomic data. All subjects were studied in utero and/or soon after birth on a single MRI scanner using specially developed scanning sequences which included novel motion-tolerant imaging methods. Imaging data are complemented by rich demographic, clinical, neurodevelopmental, and genomic information. The project is now releasing a large set of neonatal data; fetal data will be described and released separately. This release includes scans from 783 infants of whom: 583 were healthy infants born at term; as well as preterm infants; and infants at high risk of atypical neurocognitive development. Many infants were imaged more than once to provide longitudinal data, and the total number of datasets being released is 887. We now describe the dHCP image acquisition and processing protocols, summarize the available imaging and collateral data, and provide information on how the data can be accessed.

Predicting age and clinical risk from the neonatal connectome.

The development of perinatal brain connectivity underpins motor, cognitive and behavioural abilities in later life. Diffusion MRI allows the characterisation of subtle inter-individual differences in structural brain connectivity. Individual brain connectivity maps (connectomes) are by nature high in dimensionality and complex to interpret. Machine learning methods are a powerful tool to uncover properties of the connectome which are not readily visible and can give us clues as to how and why individual developmental trajectories differ. In this manuscript we used Deep Neural Networks and Random Forests to predict demographic and neurodevelopmental characteristics from neonatal structural connectomes in a large sample of babies (n = 524) from the developing Human Connectome Project. We achieved an accurate prediction of post menstrual age (PMA) at scan in term-born infants (mean absolute error (MAE) = 0.72 weeks, r = 0.83 and p < 0.001). We also achieved good accuracy when predicting gestational age at birth in a cohort of term and preterm babies scanned at term equivalent age (MAE = 2.21 weeks, r = 0.82, p < 0.001). We subsequently used sensitivity analysis to obtain feature relevance from our prediction models, with the most important connections for prediction of PMA and GA found to predominantly involve frontal and temporal regions, thalami, and basal ganglia. From our models of PMA at scan for infants born at term, we computed a brain maturation index (predicted age minus actual age) of individual preterm neonates and found a significant correlation between this index and motor outcome at 18 months corrected age. Our results demonstrate the applicability of machine learning techniques in analyses of the neonatal connectome and suggest that a neural substrate of brain maturation with implications for future neurodevelopment is detectable at term equivalent age from the neonatal connectome.

Neonatal multi-modal cortical profiles predict 18-month developmental outcomes.

Developmental delays in infanthood often persist, turning into life-long difficulties, and coming at great cost for the individual and community. By examining the developing brain and its relation to developmental outcomes we can start to elucidate how the emergence of brain circuits is manifested in variability of infant motor, cognitive and behavioural capacities. In this study, we examined if cortical structural covariance at birth, indexing coordinated development, is related to later infant behaviour. We included 193 healthy term-born infants from the Developing Human Connectome Project (dHCP). An individual cortical connectivity matrix derived from morphological and microstructural features was computed for each subject (morphometric similarity networks, MSNs) and was used as input for the prediction of behavioural scores at 18 months using Connectome-Based Predictive Modeling (CPM). Neonatal MSNs successfully predicted social-emotional performance. Predictive edges were distributed between and within known functional cortical divisions with a specific important role for primary and posterior cortical regions. These results reveal that multi-modal neonatal cortical profiles showing coordinated maturation are related to developmental outcomes and that network organization at birth provides an early infrastructure for future functional skills.

Early Childhood Temperamental Trajectories following Very Preterm Birth and Their Association with Parenting Style.

Childhood temperament is an early characteristic shaping later life adjustment. However, little is currently known about the stability of early temperament and its susceptibility to the environment in children born very preterm (VPT; <33 weeks' gestation). Here, we investigated infant-to-childhood temperamental trajectories, and their interaction with parental practices, in VPT children. Maternal reports of infant temperament were collected in 190 infants (mean age: 11.27 months; range 9−18 months) enrolled in the longitudinal Evaluation of Preterm Imaging (ePrime; Eudra: CT 2009-011602-42) study, using the ePrime questionnaire on infant temperament. At 4−7 years of age, further assessments of child temperament (Children's Behavior Questionnaire­Very Short Form) and parenting style (Arnold's Parenting Scale) were conducted. Results showed that more difficult temperament in infancy was associated with increased Negative Affectivity in childhood, regardless of parenting practices. This lends support to the stability of early temperamental traits reflecting negative emotionality. In contrast, a lax parenting style moderated the relationship between easy infant temperament and Negative Affectivity at 4−7 years, such that an easier infant temperament was increasingly associated with higher childhood Negative Affectivity scores as parental laxness increased. These results highlight a potential vulnerability of VPT infants considered by their mothers to be easy to handle, as they may be more susceptible to the effects of suboptimal parenting in childhood.

Neonatal amygdala resting-state functional connectivity and socio-emotional development in very preterm children.

Very preterm children are more likely to exhibit difficulties in socio-emotional processing than their term-born peers. Emerging socio-emotional problems may be partly due to alterations in limbic system development associated with infants' early transition to extrauterine life. The amygdala is a key structure in this system and plays a critical role in various aspects of socio-emotional development, including emotion regulation. The current study tested the hypothesis that amygdala resting-state functional connectivity at term-equivalent age would be associated with socio-emotional outcomes in childhood. Participants were 129 very preterm infants (<33 weeks' gestation) who underwent resting-state functional MRI at term and received a neurodevelopmental assessment at 4-7 years (median = 4.64). Using the left and right amygdalae as seed regions, we investigated associations between whole-brain seed-based functional connectivity and three socio-emotional outcome factors which were derived using exploratory factor analysis (Emotion Moderation, Social Function and Empathy), controlling for sex, neonatal sickness, post-menstrual age at scan and social risk. Childhood Emotion Moderation scores were significantly associated with neonatal resting-state functional connectivity of the right amygdala with right parahippocampal gyrus and right middle occipital gyrus, as well as with functional connectivity of the left amygdala with the right thalamus. No significant associations were found between amygdalar resting-state functional connectivity and either Social Function or Empathy scores. The current findings show that amygdalar functional connectivity assessed at term is associated with later socio-emotional outcomes in very preterm children.

Effects of gestational age at birth on perinatal structural brain development in healthy term-born babies.

Infants born in early term (37-38 weeks gestation) experience slower neurodevelopment than those born at full term (40-41 weeks gestation). While this could be due to higher perinatal morbidity, gestational age at birth may also have a direct effect on the brain. Here we characterise brain volume and white matter correlates of gestational age at birth in healthy term-born neonates and their relationship to later neurodevelopmental outcome using T2 and diffusion weighted MRI acquired in the neonatal period from a cohort (n = 454) of healthy babies born at term age (>37 weeks gestation) and scanned between 1 and 41 days after birth. Images were analysed using tensor-based morphometry and tract-based spatial statistics. Neurodevelopment was assessed at age 18 months using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Infants born earlier had higher relative ventricular volume and lower relative brain volume in the deep grey matter, cerebellum and brainstem. Earlier birth was also associated with lower fractional anisotropy, higher mean, axial, and radial diffusivity in major white matter tracts. Gestational age at birth was positively associated with all Bayley-III subscales at age 18 months. Regression models predicting outcome from gestational age at birth were significantly improved after adding neuroimaging features associated with gestational age at birth. This work adds to the body of evidence of the impact of early term birth and highlights the importance of considering the effect of gestational age at birth in future neuroimaging studies including term-born babies.

Associations Between Neonatal Brain Structure, the Home Environment, and Childhood Outcomes Following Very Preterm Birth.

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.

Preterm birth alters the development of cortical microstructure and morphology at term-equivalent age.

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.

Neonatal White Matter Microstructure and Emotional Development during the Preschool Years in Children Who Were Born Very Preterm.

Children born very preterm (<33 weeks of gestation) are at a higher risk of developing socio-emotional difficulties compared with those born at term. In this longitudinal study, we tested the hypothesis that diffusion characteristics of white matter (WM) tracts implicated in socio-emotional processing assessed in the neonatal period are associated with socio-emotional development in 151 very preterm children previously enrolled into the Evaluation of Preterm Imaging study (EudraCT 2009-011602-42). All children underwent diffusion tensor imaging at term-equivalent age and fractional anisotropy (FA) was quantified in the uncinate fasciculus (UF), inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), and superior longitudinal fasciculus (SLF). Children's socio-emotional development was evaluated at preschool age (median = 4.63 years). Exploratory factor analysis conducted on the outcome variables revealed a three-factor structure, with latent constructs summarized as: "emotion moderation," "social function," and "empathy." Results of linear regression analyses, adjusting for full-scale IQ and clinical and socio-demographic variables, showed an association between lower FA in the right UF and higher "emotion moderation" scores (ß = -0.280; p < 0.001), which was mainly driven by negative affectivity scores (ß = -0.281; p = 0.001). Results further showed an association between higher full-scale IQ and better social functioning (ß = -0.334, p < 0.001). Girls had higher empathy scores than boys (ß = -0.341, p = 0.006). These findings suggest that early alterations of diffusion characteristics of the UF could represent a biological substrate underlying the link between very preterm birth and emotional dysregulation in childhood and beyond.

Incidental findings on brain MR imaging of asymptomatic term neonates in the Developing Human Connectome Project.

BACKGROUND: Interpretation of incidental findings on term neonatal MRI brain imaging can be challenging as there is a paucity of published normative data on asymptomatic term neonates. Reporting radiologists and clinicians need to be familiar with these incidental findings to avoid over-investigation and misinterpretation particularly in relation to neurodevelopmental outcome. This study aimed to determine the prevalence of incidental findings in a large group of asymptomatic term neonates participating in the Developing Human Connectome Project (dHCP) who were invited for neurodevelopmental assessment at 18 months. METHODS: We retrospectively reviewed MRI brain scans performed on 500 term neonates enrolled in the dHCP study between 2015 and 2019 with normal clinical examination. We reviewed the results of the Bayley Scales of Infant and Toddler Development (Bayley III) applied to participants who attended for neurodevelopmental follow-up at 18 months. Scores considered "delayed" if <70 on language, cognitive or motor scales. FINDINGS: Incidental findings were observed in 47% of term infants. Acute cerebral infarcts were incidentally noted in five neonates (1%). More common incidental findings included punctate white matter lesions (PWMLs) (12%) and caudothalamic subependymal cysts (10%). The most frequent incidental finding was intracranial haemorrhage (25%), particularly subdural haemorrhage (SDH). SDH and PWMLs were more common in infants delivered with ventouse-assistance versus other delivery methods.Neurodevelopmental results were available on 386/500 (77%). 14 infants had a language score < 70 (2 SD below the mean). Of the 386 infants with neurodevelopmental follow up at 18 months, group differences in motor and language scores between infants with and without incidental findings were not significant (p = 0·17 and p = 0·97 respectively). Group differences in cognitive scores at 18 months between infants with (median (interquartile range) -100 (95-105)) and without (100 (95-110)) incidental findings were of small effect size to suggest clinical significance (Cliff's d = 0·15; p<0·05). INTERPRETATION: Incidental findings are relatively common on brain MRI in asymptomatic term neonates, majority are clinically insignificant with normal neurodevelopment at 18 months. FUNDING: This work was supported by the European Research Council under the European Union's Seventh Framework Programme (FP7/20072013/ERC grant agreement no. [319456] dHCP project), by core funding from the Wellcome/EPSRC Centre for Medical Engineering [WT203148/Z/16/Z] and by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London and/or the NIHR Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Neurodevelopmental Outcomes following Intrauterine Growth Restriction and Very Preterm Birth.

OBJECTIVES: To evaluate whether intrauterine growth restriction (IUGR) adds further neurodevelopmental risk to that posed by very preterm birth alone in terms of alterations in brain growth and poorer toddlerhood outcomes. STUDY DESIGN: Participants were 314 infants of very preterm birth enrolled in the Evaluation of Preterm Imaging Study (e-Prime) who were subsequently followed up in toddlerhood. IUGR was identified postnatally from discharge records (n = 49) and defined according to prenatal evaluation of growth restriction confirmed by birth weight <10th percentile for gestational age and/or alterations in fetal Doppler. Appropriate for gestational age (AGA; n = 265) was defined as birth weight >10th percentile for gestational age at delivery. Infants underwent magnetic resonance imaging at term-equivalent age (median = 42 weeks); T2-weighted images were obtained for voxelwise gray matter volumes. Follow-up assessments were conducted at corrected median age of 22 months using the Bayley Scales of Infant and Toddler Development III and the Modified-Checklist for Autism in Toddlers. RESULTS: Infants of very preterm birth with IUGR displayed a relative volumetric decrease in gray matter in limbic regions and a relative increase in frontoinsular, temporal-parietal, and frontal areas compared with peers of very preterm birth who were AGA. At follow-up, toddlers born very preterm with IUGR had significantly lower cognitive (effect size = 0.42) and motor (effect size = 0.41) scores and were more likely to have a positive Modified-Checklist for Autism in Toddlers screening for autism (OR = 2.12) compared with peers of very preterm birth who were AGA. CONCLUSIONS: IUGR might confer a neurodevelopmental risk that is greater than that posed by very preterm alone, in terms of both alterations in brain growth and poorer toddlerhood outcomes.

Pro12Ala polymorphism of peroxisome proliferator activated receptor gamma 2 may be associated with adverse neurodevelopment in European preterm babies.

INTRODUCTION: Prematurity is the leading cause of death and disability in children under 5 years of age. Understanding the molecular mechanisms of the biological processes involved in preterm brain injury may help develop novel neuroprotective treatment strategies. A growing body of evidence suggest that peroxisome proliferator-activated receptor gamma (PPARγ) signaling is associated with inhibited brain development in preterm babies. The Ala allele of the Pro12Ala polymorphism of PPARγ2 decreases receptor binding affinity and consequently induces a reduction of PPARγ signaling. METHODS: In this study, we carried out a preliminary analysis of existing datasets to test the hypothesis that reduced transactivation capacity of PPARγ in the presence of the Ala variant of PPARγ2 may be associated with adverse neurodevelopment in preterm babies. The association between PPAR-γ2 Pro12Ala polymorphism and neurodevelopment at 18-24 months of age was assessed in two groups of European infants, 155 born before 33 weeks' gestation and 180 born later than 36 weeks' gestation using a linear regression model. The Bayley Scales of Infant and Toddler Development-3rd edition was administered to assess neurodevelopment at 18-24 months of age. RESULTS: We observed the Ala allele of the Pro12Ala polymorphism in 25% preterm infants and 20% term infants. The Ala allele of PPARγ2 was significantly associated with adverse cognitive (p = .019), language (p = .03), and motor development (p = 0.036) at 18-24 months of age after taking into consideration the duration of ventilation, gender, and index of multiple deprivation scores, but without correction for potential shared ancestry. There was no association between the PPAR-γ2 Pro12Ala polymorphism and neurodevelopment in term infants. CONCLUSIONS: These preliminary data suggest that PPARγ signaling in the presence of the Ala variant of PPARγ2 may be associated with adverse neurodevelopment in preterm infants suggesting that further studies are warranted.

Phenotyping the Preterm Brain: Characterizing Individual Deviations From Normative Volumetric Development in Two Large Infant Cohorts.

The diverse cerebral consequences of preterm birth create significant challenges for understanding pathogenesis or predicting later outcome. Instead of focusing on describing effects common to the group, comparing individual infants against robust normative data offers a powerful alternative to study brain maturation. Here we used Gaussian process regression to create normative curves characterizing brain volumetric development in 274 term-born infants, modeling for age at scan and sex. We then compared 89 preterm infants scanned at term-equivalent age with these normative charts, relating individual deviations from typical volumetric development to perinatal risk factors and later neurocognitive scores. To test generalizability, we used a second independent dataset comprising of 253 preterm infants scanned using different acquisition parameters and scanner. We describe rapid, nonuniform brain growth during the neonatal period. In both preterm cohorts, cerebral atypicalities were widespread, often multiple, and varied highly between individuals. Deviations from normative development were associated with respiratory support, nutrition, birth weight, and later neurocognition, demonstrating their clinical relevance. Group-level understanding of the preterm brain disguises a large degree of individual differences. We provide a method and normative dataset that offer a more precise characterization of the cerebral consequences of preterm birth by profiling the individual neonatal brain.

Functional thalamocortical connectivity at term equivalent age and outcome at 2 years in infants born preterm.

Infants born preterm are at high risk of long-term motor and neurocognitive deficits. In the majority of these infants structural MRI at the time of normal birth does not predict motor or cognitive outcomes accurately, and many infants without apparent brain lesions later develop motor and cognitive deficits. Thalamocortical connections are known to be necessary for normal brain function; they develop during late fetal life and are vulnerable to perinatal adversity. This study addressed the hypothesis that abnormalities in the functional connectivity between cortex and thalamus underlie neurocognitive impairments seen after preterm birth. Using resting state functional connectivity magnetic resonance imaging (fMRI) in a group of 102 very preterm infants without major focal brain lesions, we used partial correlations between thalamus and functionally-derived cortical areas to determine significant connectivity between cortical areas and thalamus, and correlated the parameter estimates of these connections with standardised neurocognitive assessments in each infant at 20 months of age. Pre-motor association cortex connectivity to thalamus correlates with motor function, while connectivity between primary sensory-motor cortex and thalamus correlates with cognitive scores. These results demonstrate the importance and vulnerability of functional thalamocortical connectivity development in the perinatal period for later neurocognitive functioning.