Human cortical neurogenesis is altered via glucocorticoid-mediated regulation of ZBTB16 expression.

Glucocorticoids are important for proper organ maturation, and their levels are tightly regulated during development. Here, we use human cerebral organoids and mice to study the cell-type-specific effects of glucocorticoids on neurogenesis. We show that glucocorticoids increase a specific type of basal progenitors (co-expressing PAX6 and EOMES) that has been shown to contribute to cortical expansion in gyrified species. This effect is mediated via the transcription factor ZBTB16 and leads to increased production of neurons. A phenome-wide Mendelian randomization analysis of an enhancer variant that moderates glucocorticoid-induced ZBTB16 levels reveals causal relationships with higher educational attainment and altered brain structure. The relationship with postnatal cognition is also supported by data from a prospective pregnancy cohort study. This work provides a cellular and molecular pathway for the effects of glucocorticoids on human neurogenesis that relates to lasting postnatal phenotypes.

Maternal social support during and after pregnancy and child cognitive ability: examining timing effects in two cohorts.

BACKGROUND: Maternal anxiety, depression, and stress during and after pregnancy are negatively associated with child cognitive development. However, the contribution of positive maternal experiences, such as social support, to child cognitive development has received less attention. Furthermore, how maternal experience of social support during specific developmental periods impacts child cognitive development is largely unknown. METHODS: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 5784) and the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study (PREDO; n = 420), we investigated the associations between maternal perceived social support during and after pregnancy and child's general cognitive ability at 8 years of age, assessed with the Wechsler Intelligence Scale for Children (WISC). Bayesian relevant life course modeling was used to investigate timing effects of maternal social support on child cognitive ability. RESULTS: In both cohorts, higher maternal perceived social support during pregnancy was associated with higher performance on the WISC, independent of sociodemographic factors and concurrent maternal symptoms of depression and anxiety. In ALSPAC, pregnancy emerged as a sensitive period for the effects of perceived social support on child cognitive ability, with a stronger effect of social support during pregnancy than after pregnancy on child cognitive ability. CONCLUSIONS: Our findings, supported from two prospective longitudinal cohorts, suggest a distinct role of maternal perceived social support during pregnancy for cognitive development in children. Our study suggests that interventions aimed at increasing maternal social support during pregnancy may be an important strategy for promoting maternal and child well-being.

Visual alertness and brain diffusion tensor imaging at term age predict neurocognitive development at preschool age in extremely preterm-born children.

INTRODUCTION: Cognitive development is characterized by the structural and functional maturation of the brain. Diffusion-weighted magnetic resonance imaging (dMRI) provides methods of investigating the brain structure and connectivity and their correlations with the neurocognitive outcome. Our aim was to examine the relationship between early visual abilities, brain white matter structures, and the later neurocognitive outcome. METHODS: This study included 20 infants who were born before 28 gestational weeks and followed until the age of 6.5 years. At term age, visual alertness was evaluated and dMRI was used to investigate the brain white matter structure using fractional anisotropy (FA) in tract-based spatial statistics analysis. The JHU DTI white matter atlas was used to locate the findings. The neuropsychological assessment was used to assess neurocognitive performance at 6.5 years. RESULTS: Optimal visual alertness at term age was significantly associated with better visuospatial processing (p < .05), sensorimotor functioning (p < .05), and social perception (p < .05) at 6.5 years of age. Optimal visual alertness related to higher FA values, and further, the FA values positively correlated with the neurocognitive outcome. The tract-based spatial differences in FA values were detected between children with optimal and nonoptimal visual alertness according to performance at 6.5 years. CONCLUSION: We provide neurobiological evidence for the global and tract-based spatial differences in the white matter maturation between extremely preterm children with optimal and nonoptimal visual alertness at term age and a link between white matter maturation, visual alertness and the neurocognitive outcome at 6.5 years proposing that early visual function is a building block for the later neurocognitive development.

Extremely preterm children and relationships of minor neurodevelopmental impairments at 6 years.

Aim: This study investigated minor impairments in neurological, sensorimotor, and neuropsychological functioning in extremely preterm-born (EPT) children compared to term-born children. The aim was to explore the most affected domains and to visualize their co-occurrences in relationship maps. Methods: A prospective cohort of 56 EPT children (35 boys) and 37 term-born controls (19 boys) were assessed at a median age of 6 years 7 months with Touwen Neurological Examination, Movement Assessment Battery for Children, 2nd edition (MABC-2), Sensory Integration and Praxis Test (SIPT), and a Developmental Neuropsychological Assessment, 2nd edition (NEPSY-II). Altogether 20 test domains were used to illustrate the frequency of impaired test performances with a bar chart profile and to construct relationship maps of co-occurring impairments. Results: The EPT children were more likely to perform inferiorly compared to the term-born controls across all assessments, with a wider variance and more co-occurring impairments. When aggregating all impaired test domains, 45% of the EPT children had more impaired domains than any term-born child (more than five domains, p < 0.001). Relationship maps showed that minor neurological dysfunction (MND), NEPSY-II design copying, and SIPT finger identification constituted the most prominent relationship of co-occurring impairments in both groups. However, it was ten times more likely in the EPT group. Another relationship of co-occurring MND, impairment in NEPSY-II design copying, and NEPSY-II imitation of hand positions was present in the EPT group only. Interpretation: Multiple minor impairments accumulate among EPT children at six years, suggesting that EPT children and their families may need support and timely multi-professional interventions throughout infancy and childhood.

Newborn Neurobehavior Is Related to Later Neurodevelopment and Social Cognition Skills in Extremely Preterm-Born Children: A Prospective Longitudinal Cohort Study.

Objective: The aim of this study was to evaluate the ability of the neonatal neurobehavioral characteristics to act as an indicator for later neurodevelopment and neurocognitive performance. Methods: Sixty-six infants born extremely preterm (<28 gestational weeks) were followed until 6.5 years. Neurobehavior at term age was assessed by the behavior subscale of the Hammersmith Neonatal Neurological Examination (HNNE) using dichotomic rating, optimal, and non-optimal. The Griffiths Mental Developmental Scales (GMDS) at 2 years, and the Wechsler Intelligence Scales at 6.5 years, and a Neuropsychological Assessment at 6.5 years were used to assess neurodevelopment and neurocognitive performance including social cognition skills. Results: An optimal auditory orientation at term age was associated with better developmental quotients (DQ) in Personal-Social, and Hearing-Language GMDS subscale at 2 years (p < 0.05). An optimal visual alertness was associated with better Total (p < 0.01), Locomotor (p < 0.001), and Eye-Hand Coordination (p < 0.01) DQs at 2 years, and with sensorimotor function (p < 0.001) and social perception (p < 0.01) tests at 6.5 years. Conclusion: The neurobehavioral characteristics of newborns might serve as a precursor of social cognition skills and the HNNE behavior subscale offers a tool to identify infants at risk for later deficits in neurodevelopment and social cognition.

Associations of antenatal glucocorticoid exposure with mental health in children.

BACKGROUND: Synthetic glucocorticoids, to enhance fetal maturation, are a standard treatment when preterm birth before 34 gestational weeks is imminent. While morbidity- and mortality-related benefits may outweigh potential neurodevelopmental harms in children born preterm (<37 gestational weeks), this may not hold true when pregnancy continues to term (⩾37 gestational weeks). We studied the association of antenatal betamethasone exposure on child mental health in preterm and term children. METHODS: We included 4708 women and their children, born 2006-2010, from the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction Study with information on both antenatal betamethasone treatment and child mental and behavioral disorders from the Finnish Hospital Discharge Register from the child's birth to 31 December 2016. Additional follow-up data on mother-reported psychiatric problems and developmental milestones were available for 2640 children at 3.5 (s.d. = 0.07) years-of-age. RESULTS: Of the children, 187 were born preterm (61 betamethasone-exposed) and 4521 at term (56 betamethasone-exposed). The prevalence of any mental and behavioral, psychological development, emotional and behavioral, and comorbid disorders was higher in the betamethasone-exposed, compared to non-exposed children [odds ratio 2.76 (95% confidence interval 1.76-4.32), 3.61 (2.19-5.95), 3.29 (1.86-5.82), and 6.04 (3.25-11.27), respectively]. Levels of psychiatric problems and prevalence of failure to meet the age-appropriate development in personal-social skills were also higher in mother-reports of betamethasone-exposed children. These associations did not vary significantly between preterm and term children. CONCLUSIONS: Antenatal betamethasone exposure may be associated with mental health problems in children born preterm and in those who end up being born at term.

Altered working memory-related brain responses and white matter microstructure in extremely preterm-born children at school age.

Preterm birth poses a risk for neurocognitive and behavioral development. Preterm children, who have not been diagnosed with neurological or cognitive deficits, enter normal schools and are expected to succeed as their term-born peers. Here we tested the hypotheses that despite an uneventful development after preterm birth, these children might exhibit subtle abnormalities in brain function and white-matter microstructure at school-age. We recruited 7.5-year-old children born extremely prematurely (<28 weeks' gestation), and age- and gender-matched term-born controls (≥37 weeks' gestation). We applied fMRI during working-memory (WM) tasks, and investigated white-matter microstructure with diffusion tensor imaging. Compared with controls, preterm-born children performed WM tasks less accurately, had reduced activation in several right prefrontal areas, and weaker deactivation of right temporal lobe areas. The weaker prefrontal activation correlated with poorer WM performance. Preterm-born children had higher fractional anisotropy (FA) and lower diffusivity than controls in several white-matter areas, and in the posterior cerebellum, the higher FA associated with poorer visuospatial test scores. In controls, higher FA and lower diffusivity correlated with faster WM performance. Together these findings demonstrate weaker WM-related brain activations and altered white matter microstructure in children born extremely preterm, who had normal global cognitive ability.

Sensory-motor performance in seven-year-old children born extremely preterm.

BACKGROUND: Children born preterm are prone to motor problems. Research on their motor performance has, however, rarely been integrated with sensory processing. AIM: To examine sensory-motor performance in children born extremely preterm (EPT). METHOD: In a longitudinal prospective cohort study, 49 EPT (born <28 gestational weeks; 32 boys and 17 girls) and 33 term-born (16 boys and 17 girls) children were assessed with six individual subtests from the Sensory Integration and Praxis Tests at the age of 7.0 to 7.3 years. RESULTS: The rate of test z-scores indicating dysfunction [from -2 standard deviations (SD) to < -1 SD for mild and < -2 SD for moderate-to-severe] was significantly higher in EPT children than in term-born children in all the subtests. When comparing mean performance adjusted for gender and mother's education, EPT children performed worse than term-born children in Design Copying (z-score difference - 0.83; 95% confidence interval -1.32 to -0.34), Motor Accuracy (-0.82; -1.26 to -0.38), Postural Praxis (-0.95; -1.45 to -0.45), Manual Form Perception (-0.59; -1.12 to -0.06), and Finger Identification (-0.88; -1.45 to -0.31). Additional adjustment for Full-Scale Intelligence Quotient rendered difference in Manual Form Perception non-significant. CONCLUSION: Seven-year-old EPT children perform worse than their term-born peers in tests for visual-motor, somatosensory, and motor planning performance.

Maternal depressive symptoms during and after pregnancy are associated with attention-deficit/hyperactivity disorder symptoms in their 3- to 6-year-old children.

Maternal depressive symptoms during pregnancy have been associated with child behavioural symptoms of attention-deficit/hyperactivity disorder (ADHD) in early childhood. However, it remains unclear if depressive symptoms throughout pregnancy are more harmful to the child than depressive symptoms only during certain times, and if maternal depressive symptoms after pregnancy add to or mediate any prenatal effects. 1,779 mother-child dyads participated in the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study. Mothers filled in the Center of Epidemiological Studies Depression Scale biweekly from 12+0-13+6 to 38+0-39+6 weeks+days of gestation or delivery, and the Beck Depression Inventory-II and the Conners' Hyperactivity Index at the child's age of 3 to 6 years (mean 3.8 years, standard deviation [SD] 0.5). Maternal depressive symptoms were highly stable throughout pregnancy, and children of mothers with consistently high depressive symptoms showed higher average levels (mean difference = 0.46 SD units, 95% Confidence Interval [CI] 0.36, 0.56, p < 0.001 compared to the low group), and proportion (32.1% vs. 14.7%) and odds (odds ratio = 2.80, 95% CI 2.20, 3.57, p < 0.001) of clinically significant ADHD symptoms. These associations were not explained by the effects of maternal depressive symptoms after pregnancy, which both added to and partially mediated the prenatal effects. Maternal depressive symptoms throughout pregnancy are associated with increased ADHD symptomatology in young children. Maternal depressive symptoms after pregnancy add to, but only partially mediate, the prenatal effects. Preventive interventions suited for the pregnancy period may benefit both maternal and offspring mental health.

Self-Reported Mental Health Problems Among Adults Born Preterm: A Meta-analysis.

CONTEXT: Preterm birth increases the risk for mental disorders in adulthood, yet findings on self-reported or subclinical mental health problems are mixed. OBJECTIVE: To study self-reported mental health problems among adults born preterm at very low birth weight (VLBW; ≤1500 g) compared with term controls in an individual participant data meta-analysis. DATA SOURCES: Adults Born Preterm International Collaboration. STUDY SELECTION: Studies that compared self-reported mental health problems using the Achenbach Young Adult Self Report or Adult Self Report between adults born preterm at VLBW (n = 747) and at term (n = 1512). DATA EXTRACTION: We obtained individual participant data from 6 study cohorts and compared preterm and control groups by mixed random coefficient linear and Tobit regression. RESULTS: Adults born preterm reported more internalizing (pooled ß = .06; 95% confidence interval .01 to .11) and avoidant personality problems (.11; .05 to .17), and less externalizing (-.10; -.15 to -.06), rule breaking (-.10; -.15 to -.05), intrusive behavior (-.14; -.19 to -.09), and antisocial personality problems (-.09; -.14 to -.04) than controls. Group differences did not systematically vary by sex, intrauterine growth pattern, neurosensory impairments, or study cohort. LIMITATIONS: Exclusively self-reported data are not confirmed by alternative data sources. CONCLUSIONS: Self-reports of adults born preterm at VLBW reveal a heightened risk for internalizing problems and socially avoidant personality traits together with a lowered risk for externalizing problem types. Our findings support the view that preterm birth constitutes an early vulnerability factor with long-term consequences on the individual into adulthood.

Lack of Cortical Correlates of Response Inhibition in 6-Year-Olds Born Extremely Preterm - Evidence from a Go/NoGo Task in Magnetoencephalographic Recordings.

Children born extremely preterm (EPT) may have difficulties in response inhibition, but the neural basis of such problems is unknown. We recorded magnetoencephalography (MEG) during a somatosensory Go/NoGo task in 6-year-old children born EPT (n = 22) and in children born full term (FT; n = 21). The children received tactile stimuli randomly to their left little (target) and index (non-target) finger and were instructed to squeeze a soft toy with the opposite hand every time they felt a stimulus on the little finger. Behaviorally, the EPT children performed worse than the FT children, both in responding to the target finger stimulation and in refraining from responding to the non-target finger stimulation. In MEG, after the non-target finger stimulation (i.e., during the response inhibition), the sensorimotor alpha oscillation levels in the contralateral-to-squeeze hemisphere were elevated in the FT children when compared with a condition with corresponding stimulation but no task (instead the children were listening to a story and not attending to the fingers). This NoGo task effect was absent in the EPT children. Further, in the sensorimotor cortex contralateral to the tactile stimulation, the post-stimulus suppression was less pronounced in the EPT than FT children. We suggest that the missing NoGo task effect and lower suppression of sensorimotor oscillations are markers of deficient functioning of the sensorimotor networks in the EPT children.