Maternal perinatal mental health and offspring academic achievement at age 16:the mediating role of childhood executive function

Background: Elucidating risk pathways for under-achieving at school can inform strategies to reduce the number of adolescents leaving school without passing grades in core subjects. Maternal depression can compromise the quality of parental care and is associated with multiple negative child outcomes. However, only a few small studies have investigated the association between perinatal maternal depression and poor academic achievement in adolescence. The pathways to explain the risks are also unclear. Method: Prospective observational data from 5,801 parents and adolescents taking part in a large UK population cohort (Avon-Longitudinal-Study-of-Parents-and-Children) were used to test associations between maternal and paternal depression and anxiety in the perinatal period, executive function (EF) at age 8, and academic achievement at the end of compulsory school at age 16. Results: Adolescents of postnatally depressed mothers were 1.5 times (1.19, 1.94, p = .001) as likely as adolescents of nondepressed mothers to fail to achieve a ‘pass’ grade in math; antenatal anxiety was also an independent predictor of poor math. Disruption in different components of EF explained small but significant proportions of these associations: attentional control explained 16% (4%, 27%, p < .001) of the association with postnatal depression, and working memory explained 17% (13%, 30%, p = .003) of the association with antenatal anxiety. A similar pattern was seen for language grades, but associations were confounded by maternal education. There was no evidence that paternal factors were independently associated with impaired child EF or adolescent exams. Conclusion: Maternal postnatal depression and antenatal anxiety are risk factors for adolescents underachieving in math. Preventing, identifying, and treating maternal mental health in the perinatal period could, therefore, potentially increase adolescents’ academic achievement. Different aspects of EF partially mediated these associations. Further work is needed, but if these pathways are causal, improving EF could reduce underachievement in math

The nature and structure of maternal parenting practices and infant behaviors in U.S. national and international samples

Methods: Twenty maternal parenting practices and 15 behaviors of their 5½-month-old infants in a U.S. national sample (N = 360) and 9 international samples (N = 653) were microcoded from videorecords of naturalistic interactions at home and aggregated into domains. Altogether, the samples were recruited from Argentina, Belgium, Brazil, France, Israel, Italy, Japan, Kenya, as well as the United States. Background and Rationale: A previous test of three competing models of the nature and structure of the maternal parenting practices supported a hybrid 2 factor/6 domain model as superior to a 1-factor dimensional model and a multi-factor style model: Maternal parenting practices are structured into nurture, physical, social, didactic, material, and language domains undergirded by dyadic and extradyadic factors. Infant behaviors were organized into physical, social, exploration, nondistress vocalization, and distress communication domains. The current study sought to examine links connecting these previously identified maternal domains and factors with infant behavior domains using structural equation models. Results: Mothers' dyadic factor is associated with infant social behaviors with mother; and mothers' extradyadic factor and encouragement of infant physical development are associated with infant exploration of their immediate physical environment and physical development. Infant distress communication (and less nondistress vocalization) is associated with more maternal nurturing. Discussion: Mothers' parenting practices in the middle of the first year of infant life are commonly structured and adapted to specific needs and developmental tasks of infants. Evaluations of mother-infant interactions with national and international samples permit a wide yet judicious analysis of common vs. specific models of mother-infant relationships

Foundations of attention sharing: orienting and responding to attention in term and preterm 5-month-old infants

Attention is the gateway to perceptual, cognitive, and socioemotional development in humans. We observed 104 5-month-old term and preterm infants and their mothers in social interactions to address three questions about the role of maturation in orienting and responding to attention. We used a fine-grained coding system to allow parallel comparisons across infant and maternal orienting, and sequential analysis to evaluate infant and maternal responding to attention. Orienting and responding to attention differed for attention to people versus objects, as did the relations between maturity and attention. We conclude that maturity contributes to orienting and responding to attention and that orienting and responding to attention are specific rather than homogenous. We discuss the implications of these conclusions for future studies of how attention influences cognitive and communicative development

Differential effects of mTOR inhibition and dietary ketosis in a mouse model of subacute necrotizing encephalomyelopathy

Genetic mitochondrial diseases are the most frequent cause of inherited metabolic disorders and one of the most prevalent causes of heritable neurological disease. Leigh syndrome is the most common clinical presentation of pediatric mitochondrial disease, typically appearing in the first few years of life, and involving severe multisystem pathologies. Clinical care for Leigh syndrome patients is difficult, complicated by the wide range of symptoms including characteristic progressive CNS lesion, metabolic sequelae, and epileptic seizures, which can be intractable to standard management. While no proven therapies yet exist for the underlying mitochondrial disease, a ketogenic diet has led to some reports of success in managing mitochondrial epilepsies, with ketosis reducing seizure risk and severity. The impact of ketosis on other aspects of disease progression in Leigh syndrome has not been studied, however, and a rigorous study of the impact of ketosis on seizures in mitochondrial disease is lacking. Conversely, preclinical efforts have identified the intracellular nutrient signaling regulator mTOR as a promising therapeutic target, with data suggesting the benefits are mediated by metabolic changes. mTOR inhibition alleviates epilepsies arising from defects in TSC, an mTOR regulator, but the therapeutic potential of mTOR inhibition in seizures related to primary mitochondrial dysfunction is unknown. Given that ketogenic diet is used clinically in the setting of mitochondrial disease, and mTOR inhibition is in clinical trials for intractable pediatric epilepsies of diverse causal origins, a direct experimental assessment of their effects is imperative. Here, we define the impact of dietary ketosis on survival and CNS disease in the Ndufs4(KO) mouse model of Leigh syndrome and the therapeutic potential of both dietary ketosis and mTOR inhibition on seizures in this model. These data provide timely insight into two important clinical interventions

Maternal postnatal depression and offspring depression at age 24 years in a UK-birth cohort: the mediating role of maternal nurturing behaviours concerning feeding, crying and sleeping

Background: Maternal postnatal depression (PND) is a risk factor for offspring depression in adulthood. However, few longitudinal studies have examined the role of maternal nurturing parenting behaviours in the association between maternal PND and offspring depression in adulthood. Methods: We examined pathways from maternal PND measured using self-reported Edinburgh Postnatal Depression Scale at 8 weeks to offspring ICD-10 depression diagnosed using the Clinical Interview Schedule-Revised computerised assessment at 24 years through maternal-reported nurturing behaviours concerning feeding, sleeping and crying measured from pregnancy to age 3 years 6 months in 5,881 members of the UK-based birth cohort study, the Avon Longitudinal Study of Parents and Children. Results: The fully adjusted model revealed an indirect effect from PND to adult offspring depression through the combination of all parenting factors (probit regression coefficient [B]=0.038, 95% confidence interval [CI] 0.005, 0.071); however, there was no evidence of a direct effect from early maternal PND to offspring depression once the indirect effect via parenting factors was accounted for (B=0.009, 95%CI -0.075, 0.093). Specificity analyses revealed indirect effects through maternal worries about feeding (B=0.019, 95%CI 0.003, 0.035, p=0.010) and maternal perceptions and responses to crying (B=0.018, 95%CI 0.004, 0.032, p=0.012). Conclusions: The adverse impact of maternal PND on offspring depression in early adulthood was explained by maternal nurturing behaviours concerning feeding, crying and sleeping in early childhood. Residual confounding and measurement error likely limit reliable conclusions. If found causal, interventions providing support to reduce worries around maternal nurturing behaviours and treating depression could reduce adverse outcomes in adult offspring of depressed mothers

Maternal postnatal depressive symptoms and offspring emotional and behavioral development at age 7 years in a U.K. birth cohort: The role of paternal involvement

There is considerable variability in developmental outcomes of children whose mothers experience depression. Few longitudinal studies have examined contributions of paternal involvement in the association between maternal postnatal depression (PND) and offspring development. We examined pathways from maternal PND at 8 weeks (Edinburgh Postnatal Depression Scale; total score) to offspring emotional and behavioral development at 7 years (Strengths and Difficulties Questionnaire; total score) through behavioral, affective, and cognitive dimensions of paternal involvement in a U.K.-based birth cohort (Avon Longitudinal Study of Parents and Children; n = 3,434). Analyses were adjusted for baseline confounders and paternal PND (Edinburgh Postnatal Depression Scale; total score) as an intermediate confounder. Maternal PND was strongly associated with offspring development, but this association was not mediated by the combination of all indirect pathways through various dimensions of paternal involvement. Only father–child conflict emerged as a risk factor for adverse offspring development and as a mediator in the association between maternal PND and offspring development (albeit the effect size was small). If found causal, interventions that reduce father–child conflict may reduce the risk of adverse development in offspring of mothers with PND

A quantitative evaluation of thin slice sampling for parent-infant interactions

Behavioural coding is time-intensive and laborious. Thin slice sampling provides an alternative approach, aiming to alleviate the coding burden. However, little is understood about whether different behaviours coded over thin slices are comparable to those same behaviours over entire interactions. To provide quantitative evidence for the value of thin slice sampling for a variety of behaviours. We used data from three populations of parent-infant interactions: mother-infant dyads from the Grown in Wales (GiW) cohort (n = 31), mother-infant dyads from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (n = 14), and father-infant dyads from the ALSPAC cohort (n = 11). Mean infant ages were 13.8, 6.8, and 7.1 months, respectively. Interactions were coded using a comprehensive coding scheme comprised of 11–14 behavioural groups, with each group comprised of 3–13 mutually exclusive behaviours. We calculated frequencies of verbal and non-verbal behaviours, transition matrices (probability of transitioning between behaviours, e.g., from looking at the infant to looking at a distraction) and stationary distributions (long-term proportion of time spent within behavioural states) for 15 thin slices of full, 5-min interactions. Measures drawn from the full sessions were compared to those from 1-, 2-, 3- and 4-min slices. We identified many instances where thin slice sampling (i.e., < 5 min) was an appropriate coding method, although we observed significant variation across different behaviours. We thereby used this information to provide detailed guidance to researchers regarding how long to code for each behaviour depending on their objectives

Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome

Symmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of LS. Depleting leukocytes with a colony-stimulating factor 1 receptor inhibitor disrupted disease progression, including suppression of CNS lesion formation and a substantial extension of survival. Leukocyte depletion rescued diverse symptoms, including seizures, respiratory center function, hyperlactemia, and neurologic sequelae. These data reveal a mechanistic explanation for the beneficial effects of mTOR inhibition. More importantly, these findings dramatically alter our understanding of the pathogenesis of LS, demonstrating that immune involvement is causal in disease. This work has important implications for the mechanisms of mitochondrial disease and may lead to novel therapeutic strategies

Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics

Volatile anesthetics (VAs) are widely used in medicine, but the mechanisms underlying their effects remain ill-defined. Though routine anesthesia is safe in healthy individuals, instances of sensitivity are well documented, and there has been significant concern regarding the impact of VAs on neonatal brain development. Evidence indicates that VAs have multiple targets, with anesthetic and non-anesthetic effects mediated by neuroreceptors, ion channels, and the mitochondrial electron transport chain. Here, we characterize an unexpected metabolic effect of VAs in neonatal mice. Neonatal blood β-hydroxybutarate (β-HB) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia. β-HB in adults, including animals in dietary ketosis, is unaffected. Depletion of β-HB is mediated by citrate accumulation, malonyl-CoA production by acetyl-CoA carboxylase, and inhibition of fatty acid oxidation. Adults show similar significant changes to citrate and malonyl-CoA, but are insensitive to malonyl-CoA, displaying reduced metabolic flexibility compared to younger animals