Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis.

Circular RNAs (circRNAs) constitute a family of transcripts with unique structures and still largely unknown functions. Their biogenesis, which proceeds via a back-splicing reaction, is fairly well characterized, whereas their role in the modulation of physiologically relevant processes is still unclear. Here we performed expression profiling of circRNAs during in vitro differentiation of murine and human myoblasts, and we identified conserved species regulated in myogenesis and altered in Duchenne muscular dystrophy. A high-content functional genomic screen allowed the study of their functional role in muscle differentiation. One of them, circ-ZNF609, resulted in specifically controlling myoblast proliferation. Circ-ZNF609 contains an open reading frame spanning from the start codon, in common with the linear transcript, and terminating at an in-frame STOP codon, created upon circularization. Circ-ZNF609 is associated with heavy polysomes, and it is translated into a protein in a splicing-dependent and cap-independent manner, providing an example of a protein-coding circRNA in eukaryotes.

Linking caregiving quality during infancy to brain activity in early childhood and later executive function.

There is no relationship more vital than the one a child shares with their primary caregivers early in development. Yet many children worldwide are raised in settings that lack the warmth, connection, and stimulation provided by a responsive primary caregiver. In this study, we used data from the Bucharest Early Intervention Project (BEIP), a longitudinal study of institutionally-reared and family-reared children, to test how caregiving quality during infancy is associated with average EEG power over the first 3.5 years of life in alpha, beta, and theta frequency bands, and associations with later executive function (EF) at age 8 years. The sample comprised 189 children (129 institutionally-reared; 60 family-reared) who contributed data on observed caregiving quality during infancy (baseline; average age of 22 months), resting EEG power at baseline, 30, and 42 months, and performance-based data on a series of EF tasks at 8 years. Using Bayesian estimation, observed caregiving quality at baseline was marginally linked with higher average alpha and beta power, and lower theta power, from baseline to 42 months. In turn, higher average beta power and lower average theta power were marginally associated with higher EF at 8 years. In indirect effects models, higher caregiving quality at baseline was associated with higher EF at 8 years, with a marginal indirect effect through average theta power from baseline to 42 months. Variation in the quality of the early caregiving environment may be associated with later executive function, which is partially underpinned by individual differences in brain activity during early childhood. RESEARCH HIGHLIGHTS: Examined associations between caregiving quality during infancy, brain activity during early childhood, and executive function during mid-childhood in sample of never-institutionalized and institutionally-reared children. Significant associations between higher quality caregiving during infancy and higher executive function during middle childhood. Marginal associations between caregiving quality during infancy and brain activity during early childhood. Marginal associations between brain activity during early childhood and executive function during mid-childhood.

Integrating photonics with silicon nanoelectronics for the next generation of systems on a chip.

Electronic and photonic technologies have transformed our lives-from computing and mobile devices, to information technology and the internet. Our future demands in these fields require innovation in each technology separately, but also depend on our ability to harness their complementary physics through integrated solutions1,2. This goal is hindered by the fact that most silicon nanotechnologies-which enable our processors, computer memory, communications chips and image sensors-rely on bulk silicon substrates, a cost-effective solution with an abundant supply chain, but with substantial limitations for the integration of photonic functions. Here we introduce photonics into bulk silicon complementary metal-oxide-semiconductor (CMOS) chips using a layer of polycrystalline silicon deposited on silicon oxide (glass) islands fabricated alongside transistors. We use this single deposited layer to realize optical waveguides and resonators, high-speed optical modulators and sensitive avalanche photodetectors. We integrated this photonic platform with a 65-nanometre-transistor bulk CMOS process technology inside a 300-millimetre-diameter-wafer microelectronics foundry. We then implemented integrated high-speed optical transceivers in this platform that operate at ten gigabits per second, composed of millions of transistors, and arrayed on a single optical bus for wavelength division multiplexing, to address the demand for high-bandwidth optical interconnects in data centres and high-performance computing3,4. By decoupling the formation of photonic devices from that of transistors, this integration approach can achieve many of the goals of multi-chip solutions 5 , but with the performance, complexity and scalability of 'systems on a chip'1,6-8. As transistors smaller than ten nanometres across become commercially available 9 , and as new nanotechnologies emerge10,11, this approach could provide a way to integrate photonics with state-of-the-art nanoelectronics.

Publisher Correction: Integrating photonics with silicon nanoelectronics for the next generation of systems on a chip.

In this Letter, owing to an error during the production process, the author affiliations were listed incorrectly. Affiliation number 5 (Colleges of Nanoscale Science and Engineering, State University of New York (SUNY)) was repeated, and affiliation numbers 6-8 were incorrect. In addition, the phrase "two oxide thickness variants" should have been "two gate oxide thickness variants". These errors have all been corrected online.

Threat, Emotion Dysregulation, and Parenting in a Clinical Sample of Children with Disruptive Behaviour.

Early-life adversity is associated with the development of internalizing and externalizing problems in children. Despite this, there is a need to understand the mechanisms linking these experiences to psychopathology, especially in clinical samples. This cross-sectional study tested emotion dysregulation as a mechanism linking early-life threat to psychopathology in a clinical sample of children with disruptive behavior problems. We also explored parental positive reinforcement as a protective factor in these pathways. A clinical sample of 606 children aged 6-12 years, referred to a mental healthcare hospital, were included. Parent-reported child threat, and parent- and teacher-reported child emotion dysregulation and psychopathology, were collected. Path analysis was used to explore the mediating effect of emotion dysregulation in the relation between threat and psychopathology. The moderating effects of parental positive reinforcement were explored through moderated-mediation analyses. Emotion dysregulation partially mediated the association between threat and both internalizing (ß = .18, P = .006) and externalizing (ß = .19, P = .002) problems. Positive reinforcement did not buffer the association between threat and emotion dysregulation (ß = .09, P = .62) or the association between emotion dysregulation and internalizing (ß = - .003, P = .20) or externalizing (ß = - .002, P = .35). Poor emotion regulation may be a transdiagnostic mechanism linking early-threat with internalizing and externalizing problems in clinic-referred children with disruptive behaviors. Factors aside from parental positive reinforcement should be explored as protective factors in these pathways, including those directly implicated in the purported mechanisms linking these factors over time.

Maternal major depression during early pregnancy is associated with impaired child executive functioning at 4.5 years of age.

BACKGROUND: Maternal depression is a serious condition that affects up to 1 in 7 pregnancies. Despite evidence linking maternal depression to pregnancy complications and adverse fetal outcomes, there remain large gaps in its identification and treatment. More work is needed to define the specific timing and severity of depression that most urgently requires intervention, where feasible, to protect maternal health and the developing fetus. OBJECTIVE: This study aimed to examine whether the timing and severity of maternal depression and/or anxiety during pregnancy affect child executive functioning at age 4.5 years. Executive functioning in the preschool years is a strong predictor of both school readiness and long-term quality of life. STUDY DESIGN: This longitudinal observational pregnancy cohort study included a sample of 323 mother-child dyads taking part in the Ontario Birth Study, an open pregnancy cohort in Toronto, Ontario, Canada. Maternal symptoms of depression and anxiety were assessed at 12 to 16 and 28 to 32 weeks of gestation and at the time of child testing at age 4.5 years using the 4-item Patient Health Questionnaire. Child executive functioning was measured during a home visit using standardized computerized administration of the Flanker test (a measure of attention) and the Dimensional Change Card Sort (a measure of cognitive flexibility). Stepwise linear regressions, controlling for possible confounding variables, were used to assess the predictive value of continuous measures of maternal depression and/or anxiety symptoms at each assessment time on the Flanker test and Dimensional Change Card Sort. Posthoc general linear models were used to assess whether maternal depression severity categories (no symptom, mild symptoms, or probable major depressive disorder) were helpful in identifying children at risk. RESULTS: Across all children, after controlling for potential confounds, greater maternal depressive symptoms at weeks 12 to 16 weeks of gestation predicted worse performance on both the Flanker test (ΔR2=0.058; P<.001) and the Dimensional Change Card Sort (ΔR2=0.017; P=.018). Posthoc general linear modeling further demonstrated that the children of mothers meeting the screening criteria for major depression in early pregnancy scored 11.3% lower on the Flanker test and 9.8% lower on the Dimensional Change Card Sort than the children of mothers without maternal depressive symptoms in early pregnancy. Mild depressive symptoms had no significant effect on executive function scores. There was no significant effect of anxiety symptoms or maternal antidepressant use in early pregnancy or pandemic conditions or maternal symptoms in later pregnancy or at the time of child testing on either the Flanker or Dimensional Change Card Sort results. CONCLUSION: This study demonstrated that fetal exposure to maternal major depression, but not milder forms of depression, at 12 to 16 weeks of gestation is associated with impaired executive functioning in the preschool years. Child executive functioning is crucial for school readiness and predicts long-term quality of life. This emphasizes an urgent need to improve the recognition and treatment of maternal major depression, particularly in early pregnancy, to limit its negative effects on the patient and on child cognitive development.

Family-based care buffers the stress sensitizing effect of early deprivation on executive functioning difficulties in adolescence.

We examined whether family care following early-life deprivation buffered the association between stressful life events (SLEs) and executive functioning (EF) in adolescence. In early childhood, 136 institutionally reared children were randomly assigned to foster care or care-as-usual; 72 never-institutionalized children served as a comparison group. At age 16 years, adolescents (n = 143; 54% female; 67.1% Romanian) self-reported recent SLEs, completed a battery of memory and EF tasks, and completed a go/nogo task in which mediofrontal theta power (MFTP) was measured using electroencephalogram. More independent SLEs predicted lower EF and more dependent SLEs predicted lower MFTP, but only among adolescents with prolonged early deprivation. Findings provide preliminary evidence that family care following early deprivation may facilitate resilience against stress during adolescence on EF.

The Use of Tissue-on-Chip Technology to Focus the Search for Extracellular Vesicle miRNA Biomarkers in Thyroid Disease.

Small extracellular vesicles (sEVs) contain microRNAs (miRNAs) which have potential to act as disease-specific biomarkers. The current study uses an established method to maintain human thyroid tissue ex vivo on a tissue-on-chip device, allowing the collection, isolation and interrogation of the sEVs released directly from thyroid tissue. sEVs were analysed for differences in miRNA levels released from benign thyroid tissue, Graves' disease tissue and papillary thyroid cancer (PTC), using miRNA sequencing and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to identify potential biomarkers of disease. Thyroid biopsies from patients with benign tissue (n = 5), Graves' disease (n = 5) and PTC (n = 5) were perfused with medium containing sEV-depleted serum for 6 days on the tissue-on-chip device. During incubation, the effluents were collected and ultracentrifuged to isolate sEVs; miRNA was extracted and sequenced (miRNASeq). Out of the 15 samples, 14 passed the quality control and miRNASeq analysis detected significantly higher expression of miR-375-3p, miR-7-5p, miR-382-5p and miR-127-3p in the sEVs isolated from Graves' tissue compared to those from benign tissue (false discovery rate; FDR p < 0.05). Similarly, miR-375-3p and miR-7-5p were also detected at a higher level in the Graves' tissue sEVs compared to the PTC tissue sEVs (FDR p < 0.05). No significant differences were observed between miRNA in sEVs from PTC vs. those from benign tissue. These results were supported by Quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR). The novel findings demonstrate that the tissue-on-chip technology is a robust method for isolating sEVs directly from the tissue of interest, which has permitted the identification of four miRNAs, with which further investigation could be used as biomarkers or therapeutic targets within thyroid disease.

Linking early maternal input during shared reading to later theory of mind through receptive language and executive function: A within- and between-family design.

This study explored whether early maternal input during shared reading predicted later theory of mind (ToM) understanding through children's receptive language and executive function (EF). Maternal input plays a prominent role in the development of children's language skills, which are crucial for both EF and ToM development. There is also an abundance of behavioral evidence suggesting a directional link from EF to ToM. This relation raises the possibility of a cognitive cascade in which maternal input during shared reading promotes ToM development sequentially through receptive language and EF. The sample included 656 children clustered within 328 ethnically and sociodemographically diverse families. The shared reading sessions occurred when the younger and older siblings were 1.5 and 4 years old, respectively. Receptive language, EF, and ToM were measured when the siblings were approximately 5 years old to account for age differences. Multilevel modeling using Bayesian estimation was used to account for the effect of family-wide confounds (i.e., shared between the siblings in the family) while isolating child-specific processes (i.e., unique to each child within the family). The results supported two indirect paths from shared reading to children's ToM: one through receptive language alone and another that operated sequentially through receptive language and EF. These paths were observed only at the family level. These findings emphasize the importance of maternal input during early shared reading for cognitive development and suggest a cascade from maternal input to ToM via language and EF during the preschool period.

Associations between Early Psychosocial Deprivation, Cognitive and Psychiatric Morbidity, and Risk-taking Behavior in Adolescence.

OBJECTIVE: Early psychosocial deprivation increases the risk of later cognitive and psychiatric problems, but not all deprived children show these difficulties. Here, we examine the extent to which psychosocial deprivation increases the risk of later cognitive and psychiatric difficulties and the downstream consequences of this for risk-taking behavior in adolescence. METHOD: Children abandoned to institutions early in life were randomly assigned to care-as-usual or a foster care intervention during infancy. A separate group of never-institutionalized children was recruited as a comparison sample. The current follow-up study included 165 children (51% female), 113 with a history of institutionalization and 52 with no such history. At age 12, caregivers reported on children's psychiatric difficulties, and their IQ was assessed by standardized testing. At 16 years, risk-taking behavior was assessed from youth self-reports. RESULTS: Latent profile analysis revealed three subgroups of children with varying levels of cognitive and psychiatric difficulties: Low-Morbidity (n = 104, 62.7%), Medium-Morbidity (n = 46, 27.9%), and High-Morbidity (n = 15, 9.4%). Nearly half of the institutionalized children belonged to the High- or Medium-Morbidity subgroups; and institutionally-reared children were significantly more likely to belong to one of these profiles than never-institutionalized children. Compared to the Low-Morbidity subgroup, membership in the Medium-Morbidity profile was associated with higher levels of risk-taking behavior at age 16 years. CONCLUSIONS: Children who experience psychosocial deprivation are considerably more likely to present with elevated cognitive and psychiatric difficulties in early adolescence and, for some children, this elevation is linked to heightened risk-taking behavior in later adolescence.

Long-term effects of institutional rearing, foster care, and brain activity on memory and executive functioning.

Children experiencing psychosocial deprivation as a result of early institutional rearing demonstrate many difficulties with memory and executive functioning (EF). To date, there is scant evidence that foster care placement remediates these difficulties during childhood. The current study examined longitudinal trajectories of memory and EF from childhood to adolescence in the Bucharest Early Intervention Project, a randomized controlled trial of foster care for institutionally reared children. We demonstrate that both ever- and never-institutionalized children show age-related improvements on several measures of memory and EF from age 8 to 16. Distinct patterns were observed for different domains of functioning: (i) Early-emerging disparities in attention and short-term visual memory, as well as spatial planning and problem solving, between ever- and never-institutionalized children persisted through adolescence; (ii) the gap in spatial working memory between ever- and never-institutionalized children widened by adolescence; and (iii) early difficulties in visual-spatial memory and new learning among children in foster care were mitigated by adolescence. Secondary analyses showed that higher resting EEG alpha power at age 8 predicted better EF outcomes in several domains at age 8, 12, and 16. These results suggest that early institutional rearing has enduring consequences for the development of memory and EF, with the possibility of catch-up among previously institutionalized children who start out with higher levels of problems. Finally, interindividual differences in brain activity relate to memory and EF across ages, thus highlighting one potential biological pathway through which early neglect impacts long-term cognitive functioning.

Heightened sensitivity to the caregiving environment during adolescence: implications for recovery following early-life adversity.

BACKGROUND: Adolescence has been proposed to be a period of heightened sensitivity to environmental influence. If true, adolescence may present a window of opportunity for recovery for children exposed to early-life adversity. Recent evidence supports adolescent recalibration of stress response systems following early-life adversity. However, it is unknown whether similar recovery occurs in other domains of functioning in adolescence. METHODS: We use data from the Bucharest Early Intervention Project - a randomized controlled trial of foster care for children raised in psychosocially depriving institutions - to examine the associations of the caregiving environment with reward processing, executive functioning, and internalizing and externalizing psychopathology at ages 8, 12, and 16 years, and evaluate whether these associations change across development. RESULTS: Higher quality caregiving in adolescence was associated with greater reward responsivity and lower levels of internalizing and externalizing symptoms, after covarying for the early-life caregiving environment. The associations of caregiving with executive function and internalizing and externalizing symptoms varied by age and were strongest at age 16 relative to ages 8 and 12 years. This heightened sensitivity to caregiving in adolescence was observed in both children with and without exposure to early psychosocial neglect. CONCLUSIONS: Adolescence may be a period of heightened sensitivity to the caregiving environment, at least for some domains of functioning. For children who experience early psychosocial deprivation, this developmental period may be a window of opportunity for recovery of some functions. Albeit correlational, these findings suggest that it may be possible to reverse or remediate some of the lasting effects of early-life adversity with interventions that target caregiving during adolescence.

Single-chip microprocessor that communicates directly using light.

Data transport across short electrical wires is limited by both bandwidth and power density, which creates a performance bottleneck for semiconductor microchips in modern computer systems--from mobile phones to large-scale data centres. These limitations can be overcome by using optical communications based on chip-scale electronic-photonic systems enabled by silicon-based nanophotonic devices. However, combining electronics and photonics on the same chip has proved challenging, owing to microchip manufacturing conflicts between electronics and photonics. Consequently, current electronic-photonic chips are limited to niche manufacturing processes and include only a few optical devices alongside simple circuits. Here we report an electronic-photonic system on a single chip integrating over 70 million transistors and 850 photonic components that work together to provide logic, memory, and interconnect functions. This system is a realization of a microprocessor that uses on-chip photonic devices to directly communicate with other chips using light. To integrate electronics and photonics at the scale of a microprocessor chip, we adopt a 'zero-change' approach to the integration of photonics. Instead of developing a custom process to enable the fabrication of photonics, which would complicate or eliminate the possibility of integration with state-of-the-art transistors at large scale and at high yield, we design optical devices using a standard microelectronics foundry process that is used for modern microprocessors. This demonstration could represent the beginning of an era of chip-scale electronic-photonic systems with the potential to transform computing system architectures, enabling more powerful computers, from network infrastructure to data centres and supercomputers.

Global deficits in executive functioning are transdiagnostic mediators between severe childhood neglect and psychopathology in adolescence.

BACKGROUND: Children reared in institutions experience profound deprivation that is associated with both heightened levels of psychopathology and deficits in executive functioning (EF). It is unclear whether deficits in EF among institutionally-reared children serve as a vulnerability factor that increases risk for later psychopathology. It is also unclear whether this putative association between EF and psychopathology is transdiagnostic (i.e. cuts across domains of psychopathology), or specific to a given syndrome. Thus, we examined whether global deficits in EF mediate the association between severe childhood neglect and general v. specific psychopathology in adolescence. METHODS: The sample consisted of 188 children from the Bucharest Early Intervention Project, a longitudinal study examining the brain and behavioral development of children reared in Romanian institutions and a comparison group of never-institutionalized children. EF was assessed at age 8, 12, and 16 using a well-validated measure of neuropsychological functioning. Psychopathology was measured as general (P) and specific internalizing (INT) and externalizing (EXT) factors at age 12 and 16. RESULTS: Institutionally-reared children had lower global EF and higher general psychopathology (P) at all ages compared to never-institutionalized children. Longitudinal path analysis revealed that the effect of institutionalization on P at age 16 operated indirectly through poorer EF from ages 8 to 12. No indirect effects involving EF were observed for INT or EXT at age 16. CONCLUSIONS: We conclude that stable, global deficits in EF serve as a cognitive endophenotype that increases transdiagnostic vulnerability to psychopathology in adolescence among those who have experienced profound early neglect.

Social communication deficits following early-life deprivation and relation to psychopathology: a randomized clinical trial of foster care.

BACKGROUND: Children reared in institutions experience profound deprivation that is linked to impairments in social communication (SC). However, little is known about the long-term consequences of institutional rearing on SC through adolescence, and how SC deficits relate to broad-spectrum psychopathology. It is also unclear whether early removal from deprivation and placement into socially enriched environments remediates these difficulties. METHODS: Children reared in Romanian institutions from the Bucharest Early Intervention Project were randomly assigned to care as usual or foster care intervention in early childhood. An age- and sex-matched group of never-institutionalized children was also recruited. SC data from 208 children at age 8 and 129 children at 16 were collected using the Social Communication Questionnaire. Psychopathology was assessed as saved factor scores for general (P) and specific internalizing (INT) and externalizing (EXT) problems. We examined (a) whether institutional rearing is associated with continued SC deficits into adolescence; (b) whether early placement into foster care mitigates risk for SC problems; and (c) associations between SC and psychopathology from middle childhood (age 8) to adolescence (age 16). RESULTS: Findings suggest that: (a) institutionally-reared children have significantly more SC problems than never-institutionalized children at age 16; (b) children placed into foster care early in life have fewer problems with reciprocal social interaction compared to those with prolonged institutional rearing; and (c) deficits in SC at age 8 partially account for the link between institutional rearing and general psychopathology at age 16. CONCLUSIONS: Early deprivation is associated with impairments in SC that persist into adolescence, with evidence for the remedial benefit of family-based care in the domain of reciprocal social interaction. Moreover, deficits in SC among ever-institutionalized children in middle childhood may increase the risk of broad-spectrum psychopathology in adolescence, thus providing one putative target for early intervention to safeguard against later psychiatric problems.

The link between maternal and child verbal abilities: An indirect effect through maternal responsiveness.

Language abilities in early childhood show stability over time and play an important role in the development of other cognitive processes. Identifying modifiable environmental risk factors is important to informing prevention and early intervention efforts. Maternal verbal ability has been previously linked to child verbal ability. The current study examined whether maternal and child verbal abilities were linked indirectly through early childhood maternal responsiveness. Data come from a longitudinal birth cohort study. Participants included 133 mothers and their children recruited from maternity wards shortly after birth. Maternal verbal ability was measured using the Vocabulary subtest from the Wechsler Abbreviated Scale of Intelligence, Second Edition (child age 8 months). Child verbal ability was assessed using the Peabody Picture Vocabulary Test (36 months). A latent maternal responsiveness variable was estimated using three developmentally sensitive indicators; one during infancy (child age 8 months) and two when children were 36 months. Results of a structural equation model indicated a significant indirect effect from maternal verbal abilities to child verbal abilities through maternal responsiveness. This indirect path was significant even after inclusion of another indirect path from maternal executive functioning to child verbal ability through maternal responsiveness (which was not significant). Future studies will benefit from experimental, genetically sensitive and/or cross-lagged designs to allow for conclusions related to directionality and causality. This body of research has implications for the study of the intergenerational transmission of verbal abilities and associated skills, behaviours and adaptive outcomes.

Pathways to social-emotional functioning in the preschool period: The role of child temperament and maternal anxiety in boys and girls.

Individual differences in social-emotional functioning emerge early and have long-term implications for developmental adaptation and competency. Research is needed that specifies multiple early risk factors and outcomes simultaneously to demonstrate specificity. Using multigroup longitudinal path analysis in a sample of typically developing children (N = 541), we examined child temperament dimensions (surgency, negative affectivity, and regulation/effortful control) and maternal anxiety in infancy and age 2 as predictors of child externalizing, internalizing, dysregulation, and competence behaviors at age 3. Four primary patterns emerged. First, there was stability in temperament dimensions and maternal anxiety from infancy to age 3. Second, negative affectivity was implicated in internalizing problems and surgency in externalizing problems. Third, effortful control at age 2 was a potent mediator of maternal anxiety in infancy on age 3 outcomes. Fourth, there was suggestive evidence for transactional effects between maternal anxiety and child effortful control. Most pathways operated similarly for boys and girls, with some differences, particularly for surgency. These findings expand our understanding of the roles of specific temperamental domains and postnatal maternal anxiety in a range of social-emotional outcomes in the preschool period, and have implications for efforts to enhance the development of young children's social-emotional functioning and reduce risk for later psychopathology.

The prospective association between stressful life events and inflammation among adolescents with a history of early institutional rearing.

Early adversity has been shown to sensitize individuals to the effects of later stress and enhance risk of psychopathology. Using a longitudinal randomized trial of foster care as an alternative to institutional care, we extend the stress sensitization hypothesis to examine whether early institutional rearing sensitizes individuals to stressful events in adolescence engendering chronic low-grade inflammation. At baseline, institutionalized children in Romania (ages 6-31 months) were randomly assigned to foster care or to remain in usual care within institutions. A group of never-institutionalized children was recruited as an in-country comparison sample. At ages 12 and 16, participants reported stressful events. At age 16, Interleukin-6 (IL-6) and C-reactive protein (CRP) were derived from blood spots. Among children assigned to care as usual, more stressful events at age 12, but not age 16, were associated with higher IL-6. In the same group, stressful events at age 16 were associated with higher CRP, though these effects attenuated after adjusting for covariates. These associations were not observed in the foster care or never-institutionalized groups. The findings suggest that heightened inflammation following stress exposure is one pathway through which early neglect could compromise physical health. In contrast, early family care might buffer against these risks.

Environmental determinants of physiological reactivity to stress: The interacting effects of early life deprivation, caregiving quality, and stressful life events.

Children who spend their early lives in institutions experience profound psychosocial deprivation that is associated with altered stress response system development. Here, we used data from a longitudinal randomized controlled trial of foster care for institutionally reared children to examine whether caregiving quality and stressful life events (SLEs) in early adolescence (age 12) influence patterns of hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) reactivity. Controlling for the effect of institutional care, higher caregiving quality at age 12 was associated with heightened cortisol and SNS reactivity. However, moderation analysis revealed that the latter effect was only observed among never-institutionalized children, whereas ever-institutionalized children demonstrated a persistently blunted SNS response regardless of recent caregiving quality. Among institutionally reared children, SLEs interacted with prior random assignment to foster care, such that those placed in foster care early in development had a SNS response that approximated never-institutionalized children when SLEs at age 12 were low. In contrast, SNS reactivity was persistently blunted among those with prolonged deprivation, regardless of recent SLEs. Early-life deprivation is associated with persistent blunting of stress response systems, but normalization may be achievable if SLEs are limited following placement into enriched family-based care.

Growth faltering is associated with altered brain functional connectivity and cognitive outcomes in urban Bangladeshi children exposed to early adversity.

BACKGROUND: Stunting affects more than 161 million children worldwide and can compromise cognitive development beginning early in childhood. There is a paucity of research using neuroimaging tools in conjunction with sensitive behavioral assays in low-income settings, which has hindered researchers' ability to explain how stunting impacts brain and behavioral development. We employed high-density EEG to examine associations among children's physical growth, brain functional connectivity (FC), and cognitive development. METHODS: We recruited participants from an urban impoverished neighborhood in Dhaka, Bangladesh. One infant cohort consisted of 92 infants whose height (length) was measured at 3, 4.5, and 6 months; EEG data were collected at 6 months; and cognitive outcomes were assessed using the Mullen Scales of Early Learning at 27 months. A second, older cohort consisted of 118 children whose height was measured at 24, 30, and 36 months; EEG data were collected at 36 months; and Intelligence Quotient (IQ) scores were assessed at 48 months. Height-for-age (HAZ) z-scores were calculated based on the World Health Organization standard. EEG FC in different frequency bands was calculated in the cortical source space. Linear regression and longitudinal path analysis were conducted to test the associations between variables, as well as the indirect effect of child growth on cognitive outcomes via brain FC. RESULTS: In the older cohort, we found that HAZ was negatively related to brain FC in the theta and beta frequency bands, which in turn was negatively related to children's IQ score at 48 months. Longitudinal path analysis showed an indirect effect of HAZ on children's IQ via brain FC in both the theta and beta bands. There were no associations between HAZ and brain FC or cognitive outcomes in the infant cohort. CONCLUSIONS: The association observed between child growth and brain FC may reflect a broad deleterious effect of malnutrition on children's brain development. The mediation effect of FC on the relation between child growth and later IQ provides the first evidence suggesting that brain FC may serve as a neural pathway by which biological adversity impacts cognitive development.