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.

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.

Exploring cognitive, behavioral and autistic trait network topology in very preterm and term-born children.

Introduction: Compared to full-term (FT) born peers, children who were born very preterm (VPT; <32 weeks' gestation) are likely to display more cognitive and behavioral difficulties, including inattention, anxiety and socio-communication problems. In the published literature, such difficulties tend to be studied independently, thus failing to account for how different aspects of child development interact. The current study aimed to investigate children's cognitive and behavioral outcomes as interconnected, dynamically related facets of development that influence one another. Methods: Participants were 93 VPT and 55 FT children (median age 8.79 years). IQ was evaluated with the Wechsler Intelligence Scale for Children-4th edition (WISC-IV), autism spectrum condition (ASC) traits with the social responsiveness scale-2nd edition (SRS-2), behavioral and emotional problems with the strengths and difficulties questionnaire (SDQ), temperament with the temperament in middle childhood questionnaire (TMCQ) and executive function with the behavior rating inventory of executive functioning (BRIEF-2). Outcome measures were studied in VPT and FT children using Network Analysis, a method that graphically represents partial correlations between variables and yields information on each variable's propensity to form a bridge between other variables. Results: VPT and FT children exhibited marked topological differences. Bridges (i.e., the variables most connected to others) in the VPT group network were: conduct problems and difficulties with organizing and ordering their environment. In the FT group network, the most important bridges were: difficulties with initiating a task or activity and prosocial behaviors, and greater emotional problems, such as lower mood. Discussion: These findings highlight the importance of targeting different aspects of development to support VPT and FT children in person-based interventions.

Parsing brain-behavior heterogeneity in very preterm born children using integrated similarity networks.

Very preterm birth (VPT; ≤32 weeks' gestation) is associated with altered brain development and cognitive and behavioral difficulties across the lifespan. However, heterogeneity in outcomes among individuals born VPT makes it challenging to identify those most vulnerable to neurodevelopmental sequelae. Here, we aimed to stratify VPT children into distinct behavioral subgroups and explore between-subgroup differences in neonatal brain structure and function. 198 VPT children (98 females) previously enrolled in the Evaluation of Preterm Imaging Study (EudraCT 2009-011602-42) underwent Magnetic Resonance Imaging at term-equivalent age and neuropsychological assessments at 4-7 years. Using an integrative clustering approach, we combined neonatal socio-demographic, clinical factors and childhood socio-emotional and executive function outcomes, to identify distinct subgroups of children based on their similarity profiles in a multidimensional space. We characterized resultant subgroups using domain-specific outcomes (temperament, psychopathology, IQ and cognitively stimulating home environment) and explored between-subgroup differences in neonatal brain volumes (voxel-wise Tensor-Based-Morphometry), functional connectivity (voxel-wise degree centrality) and structural connectivity (Tract-Based-Spatial-Statistics). Results showed two- and three-cluster data-driven solutions. The two-cluster solution comprised a 'resilient' subgroup (lower psychopathology and higher IQ, executive function and socio-emotional scores) and an 'at-risk' subgroup (poorer behavioral and cognitive outcomes). No neuroimaging differences between the resilient and at-risk subgroups were found. The three-cluster solution showed an additional third 'intermediate' subgroup, displaying behavioral and cognitive outcomes intermediate between the resilient and at-risk subgroups. The resilient subgroup had the most cognitively stimulating home environment and the at-risk subgroup showed the highest neonatal clinical risk, while the intermediate subgroup showed the lowest clinical, but the highest socio-demographic risk. Compared to the intermediate subgroup, the resilient subgroup displayed larger neonatal insular and orbitofrontal volumes and stronger orbitofrontal functional connectivity, while the at-risk group showed widespread white matter microstructural alterations. These findings suggest that risk stratification following VPT birth is feasible and could be used translationally to guide personalized interventions aimed at promoting children's resilience.

Distinct Neurodevelopmental Trajectories in Groups of Very Preterm Children Screening Positively for Autism Spectrum Conditions.

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.

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.

Subcortical volume reduction and cortical thinning 3 months after switching to clozapine in treatment resistant schizophrenia.

The neurobiological effects of clozapine are under characterised. We examined the effects clozapine treatment on subcortical volume and cortical thickness and investigated whether macrostructural changes were linked to alterations in glutamate or N-acetylaspartate (NAA). Data were acquired in 24 patients with treatment-resistant schizophrenia before and 12 weeks after switching to clozapine. During clozapine treatment we observed reductions in caudate and putamen volume, lateral ventricle enlargement (P < 0.001), and reductions in thickness of the left inferior temporal cortex, left caudal middle frontal cortex, and the right temporal pole. Reductions in right caudate volume were associated with local reductions in NAA (P = 0.002). None of the morphometric changes were associated with changes in glutamate levels. These results indicate that clozapine treatment is associated with subcortical volume loss and cortical thinning and that at least some of these effects are linked to changes in neuronal or metabolic integrity.

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.

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.

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.

Exploring the relationship between maternal prenatal stress and brain structure in premature neonates.

BACKGROUND: Exposure to maternal stress in utero is associated with a range of adverse outcomes. We previously observed an association between maternal stress and white matter microstructure in a sample of infants born prematurely. In this study, we aimed to investigate the relationship between maternal trait anxiety, stressful life events and brain volumes. METHODS: 221 infants (114 males, 107 females) born prematurely (median gestational age = 30.43 weeks [range 23.57-32.86]) underwent magnetic resonance imaging around term-equivalent age (mean = 42.20 weeks, SD = 1.60). Brain volumes were extracted for the following regions of interest: frontal lobe, temporal lobe, amygdala, hippocampus, thalamus and normalized to total brain volume. Multiple linear regressions were conducted to investigate the relationship between maternal anxiety/stress and brain volumes, controlling for gestational age at birth, postmenstrual age at scan, socioeconomic status, sex, days on total parenteral nutrition. Additional exploratory Tensor Based Morphometry analyses were performed to obtain voxel-wise brain volume changes from Jacobian determinant maps. RESULTS AND CONCLUSION: In this large prospective study, we did not find evidence of a relationship between maternal prenatal stress or trait anxiety and brain volumes. This was the case for both the main analysis using a region-of-interest approach, and for the exploratory analysis using Jacobian determinant maps. We discuss these results in the context of conflicting evidence from previous studies and highlight the need for further research on premature infants, particularly including term-born controls.

The neurobiological correlates of cognitive outcomes in adolescence and adulthood following very preterm birth.

Very preterm birth (<33 weeks of gestation) has been associated with alterations in structural and functional brain development in regions that are believed to underlie a variety of cognitive processes. While such alterations have been often studied in the context of cognitive vulnerability, early disruption to programmed developmental processes may also lead to neuroplastic and functional adaptations, which support cognitive performance. In this review, we will focus on executive function and intelligence as the main cognitive outcomes following very preterm birth in adolescence and adulthood in relation to their structural and functional neurobiological correlates. The neuroimaging modalities we review provide quantitative assessments of brain morphology, white matter macro and micro-structure, structural and functional connectivity and haemodynamic responses associated with specific cognitive operations. Identifying the neurobiological underpinning of the long-term sequelae associated with very preterm birth may guide the development and implementation of targeted neurobehaviourally-informed interventions for those at high risk.