Cronobacter sakazakii is an opportunistic foodborne pathogen known to cause severe neonatal infections. However, its subclinical effects on human health remain largely unexplored. Here, we report that intestinal colonization by Cronobacter is potentially correlated with human neurobehavioral alterations in the absence of bacterial translocation across host barriers. Analysis of fecal microbiota from the children in GUSTO cohort revealed that Cronobacter abundance was significantly and positively correlated with their emotional reactivity and affective problem scores, suggesting an association between gut Cronobacter colonization and emotional dysfunction. Using a zebrafish larvae model, we demonstrated that enteric colonization by C. sakazakii ATCC 25944 triggered a distinctive bending phenotype and locomotor instability, indicative of central nervous system (CNS) disturbance. Multi-omics profiling revealed upregulation of genes related to circadian rhythm (e.g., per2, nr1d1, nr1d2) and neuropsychiatric markers (hint1), alongside metabolic dysregulation involving lipid classes linked to neurodegenerative stress. Random mutagenesis coupled with whole-genome sequencing identified modifier variants in genes associated with lipopolysaccharide (LPS) biosynthesis and fimbrial adhesion, which attenuated the neurotoxic phenotype. LPS isolated from wild-type C. sakazakii, but not from mutants, reproduced the CNS impairment phenotype, highlighting its crucial virulence role. Collectively, our findings provide the first evidence that enteric Cronobacter colonization may affect human emotional development via gut-derived LPS signaling, emphasizing its underestimated role in the gut-brain axis and neurobehavioral health.

BACKGROUND:The influence of plasma DHA and overall omega-3 (n-3) long-chain PUFA (LC-PUFA) on child cognitive development is unclear. OBJECTIVES:We examined if plasma LC-PUFA concentrations are prospectively associated with academic performance in primary school children and if diet patterns modulate the relationship. METHODS:Children were from the Growing Up in Singapore Toward healthy Outcomes cohort. Fasting LC-PUFA concentrations were measured using nuclear magnetic resonance spectroscopy at age 8 y (n = 557). Dietary patterns were derived using principal component analysis from a validated food frequency questionnaire at age 7 y. Academic performance was assessed using the Wechsler Individual Achievement Test-III at age 9 y (n = 288) and the primary school leaving examination (PSLE) at age 12 y (n = 408). The relationships of LC-PUFAs to academic performance scores were examined using multivariable linear regression models. RESULTS:Percent DHA at age 8 y was associated with higher reading fluency {β [95% confidence interval (CI)] = 3.54 (0.52, 6.56), P = 0.022} and spelling scores [4.49 (0.02, 8.95); P = 0.021] at age 9 y, and lower PSLE scores [β (95% CI) =-1.43 (-2.68, -0.618); P = 0.025] (indicating better performance) at age 12 y. However, these associations were attenuated after adjusting for an unhealthy dietary pattern. Total n-3 LC-PUFA at age 8 y was associated with higher reading fluency [β (95% CI) =1.55 (0.03, 3.07); P = 0.046] scores at age 9 y, and lower PSLE scores [β (95% CI) =-0.83 (-1.42, -0.24); P = 0.006] at age 12 y. The association with PSLE scores remained significant even after adjusting for healthy or unhealthy dietary patterns [β (95% CI) =-0.68 (-1.29, -0.08); P = 0.028]. CONCLUSIONS:Higher plasma total n-3 LC-PUFA and DHA were prospectively associated with better academic performance in primary school children, but the relationship with DHA was modulated by an unhealthy dietary pattern. The results suggest that beyond DHA, total n-3 LC-PUFA status plays a significant role in the cognitive development of children.

BACKGROUND:Preventive interventions in the form of parenting support can reduce the risk of mental disorders in children. Summarising the effectiveness of parenting interventions across different levels of prevention can inform the prioritisation of the intervention. OBJECTIVES:We conducted a meta-review of systematic reviews and meta-analyses on universal, selective and indicated parenting interventions to prevent adverse mental health outcomes in youth. STUDY SELECTION AND ANALYSIS:PubMed, Ovid, Embase and PsycNet were searched. Systematic reviews consisting of randomised controlled trials of preventative parenting interventions were included. We provided a narrative synthesis of the results and assessed the quantity and quality of evidence for each level of prevention (ie, universal, selective, indicated) and mental health outcome. FINDINGS:We identified 32 systematic reviews and meta-analyses, which included 354 randomised controlled trials, consisting of over 74 558 children and adolescents. Universal parenting interventions were effective in delaying the initiation of alcohol and cannabis use, but did not have consistent findings in preventing disruptive behaviour and mood disorders. Selective interventions were predominantly beneficial for disruptive behavioural problems across a variety of risk factors. Indicated interventions found substantial and consistent evidence for reducing problems in children with behavioural problems. Caution is warranted when interpreting findings, as the overall confidence rating of most reviews was very low, especially in the reporting of study selection and justifying exclusions in the AMSTAR-2. CONCLUSIONS:Our findings highlight the need for robust evidence synthesis. Despite the limitations of the current evidence base, parenting interventions hold promise for preventing mental health disorders.

OBJECTIVE:Exposure to maltreatment in childhood increases risk for mental health difficulties across generations, affecting the development of offspring. In particular, maternal exposure to childhood maltreatment can shape the neurobiological development of offspring, especially in brain regions implicated in emotional health. However, relevant studies are cross-sectional, limiting understanding of how maternal childhood maltreatment might affect offspring neurodevelopment. METHOD:Using data from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study, the authors investigated whether maternal report of childhood maltreatment was related to the development of offspring amygdala volume across 4 time points (ages 4.5-10.5 years; 1,143 scans from 430 children), how maltreatment-related alterations in amygdala volume development were related to anxiety symptoms in children at age 10.5 years (n = 267), and whether these associations differed by offspring sex. RESULTS:Greater maternal childhood maltreatment was associated with larger amygdala volume in girls at ages 4.5 to 10.5 years, which, in turn, was associated with lower levels of anxiety symptoms at age 10.5 years in girls, but not in boys. Maternal childhood maltreatment was not associated with the development of amygdala volume in boys. CONCLUSION:These findings support the formulation that maternal childhood maltreatment has a sex-differentiated effect on brain development and mental health outcomes of offspring. These results advance understanding of the effects of maternal childhood maltreatment on children's brain development and risk for psychopathology. PLAIN LANGUAGE SUMMARY:This study examined the effects of maternal childhood maltreatment on the development of the amygdala in their children. Using data from 430 children who participated in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study, the authors found that maternal childhood maltreatment predicted larger amygdala volumes in female children across the ages of 4 to 10 years. Larger amygdala volumes in these girls were associated with fewer anxiety symptoms at age 10. These findings suggest that mothers' own childhood experiences can impact brain development and emotional health of their offspring, particularly in girls.

Infants frequently experience sleep problems in early childhood. Poor infant sleep can impact not only infants’ cognitive development but also maternal sleep and maternal mental health. Studies have reported associations between infant sleep and maternal sleep and between infant sleep and maternal depression. However, methods utilized in these studies are unable to disentangle the directionality of these relationships. The purpose of this study was to assess the bi-directional relationships between child sleep, maternal sleep, and maternal depression in the first two years of life in a multi-ethnic Asian cohort. Data were drawn from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. Child nighttime sleep duration, maternal sleep (PSQI), and maternal depression scores (BDI) were assessed at 26 weeks gestational age, and when the child was 3, 12, and 24 months old in 1,131 children. We used autoregressive latent trajectory modeling with structured residuals (ALT-SR) to assess associations. Higher maternal depression scores at 3 months were predictive of longer nighttime sleep duration when the child was 12 months (BDI3mo → ChildSleep12mo:ѰStandardized = 0.04, p = .01), but at other timepoints this cross-lagged relationship was not significant, (BDIprenatal → ChildSleep3mo: ѰStandardized = 0.02, p = .49; BDI12mo → ChildSleep24mo: ѰStandardized = 0.03, p = .07). In addition, better maternal sleep at 3 months predicted longer nighttime child sleep duration at 12 months (PSQI3mo → ChildSleep12mo: ѰStandardized = − 0.08, p = 0.01), but not at other timepoints (PSQIprenatal → BISQ3mo: ѰStandardized = -0.06, p = .29; PSQI12mo → ChildSleep24mo: ѰStandardized = -0.05, p = 0.18). When using methods that properly differentiate between-person and within-person effects, we found that higher maternal depression scores were protective of infant sleep, but infant sleep did not affect maternal sleep or depression scores.

A basic tenet of Attachment Theory describes a species-wide tendency to search out an attachment figure in times of distress. Expectations of support, or lack thereof, may provide a template for socioemotional functioning. This study investigated potential concurrent predictors (i.e. time spent with one's mother and parenting style) and socioemotional correlates of children's verbally expressed preferences for their mothers (i.e. maternal preference) during hypothetical attachment- and affiliation-related situations in 185 Southeast Asian children aged 3-6 years (95 boys). Though children in the current study were cared for by several caregivers, results here suggest they nevertheless prefer their mothers. Maternal time spent did not significantly predict preferences. However, authoritative parenting style scores did. Maternal preferences predicted higher child prosocial, but not problematic behavior. Implications for future work discerning the role of mothers in children's lives are discussed.

Abstract Early life experiences shape individuals. Environmental enrichment, an experimental paradigm used to study the effect of increased environmental complexity and novelty in animal models, has long been recognised for its broad effect on nervous system function and behaviour. In adult rodents, structural changes in the brain due to enriched environments are well documented, notably in the hippocampus. However, the effect of environmental enrichment on the developing brain during early life is not well understood. This study aims to investigate how environmental enrichment affects brain development during the critical perinatal period, and how such effects compare to those observed during adulthood. We use high-resolution MRI to measure the brain structure of mouse neonates at postnatal day 7, born either in an enriched or a standard environment. We show that rodents exhibit brain structure differences as early as postnatal day 7. However, the regional changes observed differ from those in adulthood: hippocampal changes are limited, but changes in the hindbrain, the dorsal striatum, and the medial habenula are strong. Given the lack of direct interaction between neonates and the environment at P7, we hypothesised that maternal care may mediate these effects. We show that maternal care differs between enriched and standard environments, that maternal care correlates with brain structure changes in the neonates, and that maternal care and enriched environment affect brain structure similarly. This suggests that early changes in brain structure due to environmental enrichment are at least partly mediated by maternal care. This study provides novel insight into the differential effect of enriched environment on early brain development in rodents.

This study aimed to assess the associations between the frequency of episodes of disorders of arousal (sleepwalking and sleep terrors) and emotional-behavioural problems in a longitudinal cohort of healthy children aged 4 and 5 years. Mother-child dyads (N = 345) were recruited during pregnancy for a longitudinal cohort study. Mothers completed validated questionnaires when children were 4 and 5 years old. Linear regressions assessed (1) the concurrent association between the frequency of disorders of arousal episodes (i.e., sleepwalking and sleep terrors) and emotional-behavioural problems in children at 4 and 5; and (2) the association between the frequency of disorders of arousal episodes at 4 and emotional-behavioural problems at 5. Models included the following covariates: child's sex, child's nighttime sleep duration, socioeconomic status and maternal depressive symptoms. More frequent episodes of disorders of arousal at age 4 were significantly associated with more concurrent internalising (B = 2.659, p = 0.001), and externalising problems (B = 2.740, p = 0.006). At age 5, the frequency of episodes was not associated with concurrent internalising and externalising problems (p > 0.05). More frequent episodes at age 4 were associated with more externalising problems at 5 (B = 2.462, p = 0.039). Although sleep terrors and sleepwalking are often benign, our results show that even in a non-clinical cohort, these sleep phenomena can be associated with emotional-behavioural problems in children as young as 4. While the mere presence of sleep terrors or sleepwalking is not alarming, screening for emotional-behavioural problems seems appropriate for children with frequent episodes.

Background:As the global climate crisis persists, it becomes increasingly important to understand how exposure to environmental toxins can affect the developing brain. Although researchers are beginning to document links between prenatal exposure to air pollution and brain structure, it is not clear when these associations emerge. Methods:We leveraged data from the GUSTO (Growing Up Toward Healthy Outcomes in Singapore) longitudinal birth cohort study to examine prenatal exposure to air pollution and brain development during childhood. Spatiotemporally interpolated prenatal exposure to particulate matter <2.5 μm was averaged across each prenatal week. Structural magnetic resonance imaging data were obtained when children were ages 4.5, 6.0, 7.5, and 10.5 years (N = 325, 47.7% female) and segmented with FreeSurfer 7.1. A subset of parents completed the Child Behavior Checklist at the final assessment (n = 195, 46.7% female). We used latent growth modeling to estimate a slope of hippocampal volume growth in each hemisphere from ages 4.5 to 10.5 years, adjusted for intracranial volume. Results:Distributed lag models indicated that late gestational exposure (during weeks 36-40) was associated with slower hippocampal growth in both hemispheres. Importantly, we also found that faster hippocampal volume growth in the right hemisphere was associated with more externalizing and attention problems at 10.5 years. Conclusions:Future research should examine mechanisms that may underlie or contribute to these associations. These findings underscore the importance of efforts to reduce pollution, particularly for pregnant people and their children.

BACKGROUND:The impact of maternal mental health on child eating beyond infancy is understudied. This study explores whether maternal feeding practices and concerns mediate the association between maternal depression and anxiety symptoms and eating behaviours at age three years. METHODS:Data from 409 mother-child dyads in the Growing Up in Singapore Towards healthy Outcomes cohort were analysed. Maternal mental health was assessed using the Beck Depression Inventory-II and State-Trait Anxiety Inventory, feeding practices and concerns with the Preschooler Feeding Questionnaire, and child eating behaviours with the Children's Eating Behaviour Questionnaire. Structural equation modelling was used to test pathways. RESULTS:Depression symptoms in mothers showed direct and indirect links to child eating behaviours. For example, maternal depression symptoms were directly associated with enjoyment of food (B = 0.011, p = 0.015) and indirectly with food responsiveness (B = 0.004, p = 0.034) via use of food to calm the child. Anxiety symptoms, however, had only indirect associations with child eating behaviours through maternal feeding concerns, not practices. For example, maternal anxiety symptoms were indirectly linked with food responsiveness through perceived difficulty in feeding (B = -0.001, p = 0.011). CONCLUSIONS:Depression and anxiety symptoms influence children's eating behaviours differently. Anxiety symptoms were linked with child eating behaviours only through maternal feeding concerns, whereas depression symptoms were linked with child eating behaviours both directly and indirectly via feeding to calm the child. As maternal anxiety symptoms are linked with more child eating concerns, the validity of mother-reported child eating behaviours requires consideration.

Background and objectives The presence of sleep bruxism (SB) has been associated with internalizing symptoms and sleep disturbances in school-aged children and adolescents. While manifestations of SB often start earlier in development, there is a lack of studies investigating such an association in younger age groups. Therefore, we assessed the association between SB frequency and (1) internalizing symptoms (anxiety and depression) and (2) sleep disturbances in preschoolers. Methods The study comprised 340 mother-child dyads from a longitudinal cohort. Inclusion criteria were full-term pregnancy (>36 weeks), absence of birth complications, absence of severe health issues, and completion of essential measures for the present study. Mothers completed the Children's Sleep Habits Questionnaire when their child was four and five years old. Generalized estimating equation models were used to investigate our main objectives. The models included family socioeconomic status, child's sex, time, child's nighttime sleep duration, and maternal depressive symptoms as covariables. Results More frequent possible SB was associated with more anxiety (B = 0.682, p = 0.009) and depressive symptoms (B = 0.439, p = 0.02) in preschoolers. More frequent possible SB was also associated with more sleep anxiety (B = 0.450, p = 0.002) and bedtime resistance (B = 0.489, p = 0.01) but not with sleep onset delay, sleep duration, and night wakings (p > 0.05). Conclusions Frequent possible SB episodes in preschoolers may be an indicator of depressive and anxiety difficulties during this developmental period. Bedtime manifestations of internalizing difficulties (bedtime resistance and sleep anxiety) paired with frequent SB in children should warrant further assessment for depressive and anxiety symptoms in preschoolers.

Cheek swabs, heterogeneous samples consisting primarily of buccal epithelial cells, are widely used in pediatric DNA methylation studies and biomarker creation. However, the decrease in buccal proportion with age in adults remains unexamined in childhood. We analyzed cheek swabs from 4626 typically developing children 2-months to 20-years-old. Estimated buccal proportion declined throughout childhood with both increasing chronological and predicted epigenetic age. However, buccal proportion did not associate with age throughout adolescence. Variability in buccal proportion increased with age through the entire developmental range. These trends held inversely true for neutrophil proportions. Correcting for buccal proportion attenuated the weak association with PedBE age acceleration to non-significance during initial estimation. Notably, correcting for buccal proportion attenuated the association of PedBE age acceleration with obsessive-compulsive disorder and strengthened the association with diurnal cortisol slope. Thus, the age-related change in children’s oral cells is a crucial consideration for cell type-sensitive research. Cheek swabs are widely used in pediatric epigenetic studies, but changes in their cellular composition with age are unclear. Here the authors show that buccal epithelial cells decline with age until adolescence, then stabilize, while variability increases with age, impacting the precision of tools like the PedBE clock in pediatric epigenetics.

Amygdala-hippocampal connectivity is a promising area of study for an understanding of the neurobiological mechanisms of depression. In this study, we examined the association between amygdala-hippocampal connectivity and depressive symptoms in children with a specific focus on the subnuclei level. We then examined whether self-concept mediated brain-behavior associations. Resting-state functional magnetic resonance imaging (fMRI) was performed at age 7.5 years (N = 319), followed by self-reported depressive symptoms and self-concept between ages 8.5 and 10.5 years, using the Children’s Depression Inventory (CDI-2) and Piers-Harris Children’s Self-Concept Scale (PHCSC) respectively. We conducted multiple regression analyses to examine the associations between the amygdala-hippocampus resting-state functional connectivity (RSFC) and CDI scores, first at the whole-region level and subsequently at the subnuclear level. Mediation analyses were then performed to explore the mediating role of self-concept in these brain-behavior associations. We observed a significant association between left amygdala-anterior hippocampus connectivity and CDI total scores, primarily driven by the left superficial amygdala. Further exploration at sub-symptomatic levels highlighted an association with negative cognition. Finally, self-concept mediated the association between left amygdala-anterior hippocampus connectivity and depressive symptoms in children. This study provided valuable insights into the associations among amygdala-hippocampal subnuclei connectivity, childhood depressive symptoms, and self-concept. Diminished left superficial amygdala-anterior hippocampus connectivity may serve as an early biomarker to identify depressive symptoms, particularly in children with negative cognition problems.

Chronic stress is a causal antecedent condition for major depressive disorder and associates with altered patterns of neural connectivity. There are nevertheless important individual differences in susceptibility to chronic stress. How functional connectivity (FC) amongst interconnected, depression-related brain regions associates with resilience and susceptibility to chronic stress is largely unknown. We used resting-state functional magnetic resonance imaging (rs-fMRI) to examine FC between established depression-related regions in susceptible (SUS) and resilient (RES) adult mice following chronic social defeat stress (CSDS). Seed-seed FC analysis revealed that the ventral dentate gyrus (vDG) exhibited the greatest number of FC group differences with other stress-related limbic brain regions. SUS mice showed greater FC between the vDG and subcortical regions compared to both control (CON) or RES groups. Whole brain vDG seed-voxel analysis supported seed-seed findings in SUS mice but also indicated significantly decreased FC between the vDG and anterior cingulate area compared to CON mice. Interestingly, RES mice exhibited enhanced FC between the vDG and anterior cingulate area compared to SUS mice. Moreover, RES mice showed greater FC between the infralimbic prefrontal cortex and the nucleus accumbens shell compared to CON mice. These findings indicate unique differences in FC patterns in phenotypically distinct SUS and RES mice that could represent a neurobiological basis for depression, anxiety, and negative-coping behaviors that are associated with exposure to chronic stress.

INTRODUCTION:Dental caries is a biofilm-mediated, multifactorial disease of the dental hard tissues. Maternal psychosocial and behavioral factors can affect a child's risk for many chronic childhood conditions including dental caries. We examined the relationship between maternal psychological well-being during and after pregnancy on caries experience in 3-year-old offspring. METHODS:Using data from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study (N = 667), maternal psychological well-being including depressive symptoms (Edinburg Postnatal Depression scale [EPDS]), anxiety symptoms (State Trait Anxiety Inventory [STAI]), and sleep quality were measured. Offspring dental caries experience was defined as having at least one decayed, missing, and filled teeth or surface (dmft ≥1 vs. 0/dmfs ≥1 vs. 0). We estimated associations between maternal psychological well-being in the pre- and postnatal periods with offspring dental caries experience using logistic regression models adjusted for several maternal and child demographic and socioeconomic factors. RESULTS:The mean maternal age at delivery was 31 (SD: 5.1) years with ethnic distribution of 55% Chinese, 28% Malay, and 17% Indian; 8.6% of mothers had a prenatal EPDS score ≥15 indicating probable depression and 44% of the children had dmft ≥1. Children of mothers with high prenatal EPDS scores (≥15) had 1.57 times (95% CI: 0.85-2.93) the adjusted odds of dental caries experience as compared to children of mothers with prenatal EPDS score <15, although this association was not statistically significant. Moreover, children of mothers with consistently high/changing EPDS and STAI scores in the pre- and postnatal periods had adjusted odds of caries experience of 1.65 (95% CI: 1.01-2.72) and 1.24 (95% CI: 0.89-1.74), respectively, when compared to children whose mothers had consistently low EPDS and STAI scores, though only EPDS association was statistically significant. Associations with poor sleep quality followed a similar direction, although not statistically significant. CONCLUSION:While the current findings did not consistently demonstrate statistically significant associations, they suggest a potential role of maternal psychological well-being during and after pregnancy on children's oral health status.

ObjectiveTo identify parenting profiles among Singaporean mothers of young children and to examine the longitudinal implications of these profiles for children's well-being during middle childhood.BackgroundThe universality of traditional parenting styles (e.g., authoritative, authoritarian), established in Western contexts, and their implications for child well-being, has been called into question, with studies conducted with Asian populations suggesting these styles may not be universally applicable.MethodOur sample consisted of 411 mother-child dyads drawn from a prebirth cohort in Singapore, where mothers reported on their parenting at child age 4.5 years, and children reported on their evaluation of their mothers' parenting and their own depressive symptoms at ages 9 and 10 years, respectively.ResultsThree latent class profiles of maternal parenting emerged at child age 4.5 years: Supportive (high use of supportive practices and low use of harsh practices), Supportive-Harsh (high use of both supportive and harsh practices), and Unsupportive (moderate use of both supportive and harsh practices). Children of Unsupportive mothers reported greater maternal indifference at age 9 years and depressive symptoms at age 10 years compared to children of Supportive or Supportive-Harsh mothers. Children's evaluation of maternal indifference mediated the association between early maternal parenting profiles and later child depressive symptoms.ConclusionOur findings highlight the variation in parenting profiles in Singapore from well-established parenting styles, and the greater implications of supportive, compared to harsh, parenting practices for children's well-being.