Background Studies reporting accelerated ageing in children with affective disorders or maltreatment exposure have relied on algorithms for estimating epigenetic age derived from adult samples. These algorithms have limited validity for epigenetic age estimation during early development. We here use a pediatric buccal epigenetic (PedBE) clock to predict DNA methylation-based ageing deviation in children with and without internalizing disorder and assess the moderating effect of maltreatment exposure. We further conduct a gene set enrichment analysis to assess the contribution of glucocorticoid signaling to PedBE clock-based results. Method DNA was isolated from saliva of 158 children [73 girls, 85 boys; mean age (SD) = 4.25 (0.8) years] including children with internalizing disorder and maltreatment exposure. Epigenetic age was estimated based on DNA methylation across 94 CpGs of the PedBE clock. Residuals of epigenetic age regressed against chronological age were contrasted between children with and without internalizing disorder. Maltreatment was coded in 3 severity levels and entered in a moderation model. Genome-wide dexamethasone-responsive CpGs were derived from an independent sample and enrichment of these CpGs within the PedBE clock was identified. Results Children with internalizing disorder exhibited significant acceleration of epigenetic ageing as compared to children without internalizing disorder (F 1,147 = 6.67, p = .011). This association was significantly moderated by maltreatment severity (b = 0.49, 95% CI [0.073, 0.909], t = 2.322, p = .022). Children with internalizing disorder who had experienced maltreatment exhibited ageing acceleration relative to children with no internalizing disorder (1–2 categories: b = 0.50, 95% CI [0.170, 0.821], t = 3.008, p = .003; 3 or more categories: b = 0.99, 95% CI [0.380, 1.593], t = 3.215, p = .002). Children with internalizing disorder who were not exposed to maltreatment did not show epigenetic ageing acceleration. There was significant enrichment of dexamethasone-responsive CpGs within the PedBE clock (OR = 4.36, p = 1.65*10–6). Among the 94 CpGs of the PedBE clock, 18 (19%) were responsive to dexamethasone. Conclusion Using the novel PedBE clock, we show that internalizing disorder is associated with accelerated epigenetic ageing in early childhood. This association is moderated by maltreatment severity and may, in part, be driven by glucocorticoids. Identifying developmental drivers of accelerated epigenetic ageing after maltreatment will be critical to devise early targeted interventions.

Previous research suggests that intense, emotional pictures at fixation elicit an early posterior negativity (EPN) and a late positive potential (LPP) despite manipulations of spatial inattention and perceptual load. However, if high emotional intensity protects against such manipulations, then these manipulations should reduce emotional effects on EPN and LPP more strongly for medium than for intense emotional pictures. To test this prediction, pictures that were high negative, medium negative, or neutral were shown at fixation, and a small letter string was superimposed on the picture center. When participants attended the pictures, there were clear emotional effects on EPN and LPP. When participants attended the letter string, the emotional effects on LPP decreased; this decrease was smaller for medium than for high negative pictures. Thus, opposite of predictions, spatial inattention reduced the emotional effects more strongly for high than for medium negative pictures. As a manipulation of perceptual load, participants performed the letter task with one, three, or six relevant letters. Irrespective of load, EPN and LPP were similar for high and medium negative pictures. Our findings suggest that high negative valence does not protect EPN and LPP more strongly from effects of spatial inattention and perceptual load than does medium negative valence.

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Environmental enrichment, particularly during the early life phases of enhanced neuroplasticity, can stimulate cognitive development. However, individuals exhibit considerable variation in their response to environmental enrichment. Recent evidence suggests that certain neurophenotypes such as hippocampal size may index inter-individual differences in sensitivity to environmental conditions. We conducted a prospective, longitudinal investigation in a cohort of 75 mother-child dyads to investigate whether neonatal hippocampal volume moderates the effects of the postnatal environment on cognitive development. Newborn hippocampal volume was quantified shortly after birth (26.2 ± 12.5 days) by structural MRI. Measures of infant environmental enrichment (assessed by the IT-HOME) and cognitive state (assessed by the Bayley-III) were obtained at 6 months of age (6.09 ± 1.43 months). The interaction between neonatal hippocampal volume and enrichment predicted infant cognitive development ( b = 0.01, 95 % CI [0.00, 0.02], t = 2.08, p = .04), suggesting that exposure to a stimulating environment had a larger beneficial effect on cognitive outcomes among infants with a larger hippocampus as neonates. Our findings suggest that the effects of the postnatal environment on infant cognitive development are conditioned, in part, upon characteristics of the newborn brain, and that newborn hippocampal volume is a candidate neurophenotype in this context.

Background: While neonates have no sophisticated language skills, the neural basis for acquiring this function is assumed to already be present at birth. Receptive language is measurable by 6 months of age and meaningful speech production by 10-18 months of age. Fiber tracts supporting language processing include the corpus callosum (CC), which plays a key role in the hemispheric lateralization of language; the left arcuate fasciculus (AF), which is associated with syntactic processing; and the right AF, which plays a role in prosody and semantics. We examined if neonatal maturation of these fiber tracts is associated with receptive language development at 12 months of age. Methods: Diffusion-weighted imaging (DWI) was performed in 86 infants at 26.6 ± 12.2 days post-birth. Receptive language was assessed via the MacArthur-Bates Communicative Development Inventory at 12 months of age. Tract-based fractional anisotropy (FA) was determined using the NA-MIC atlas-based fiber analysis toolkit. Associations between neonatal regional FA, adjusted for gestational age at birth and age at scan, and language development at 12 months of age were tested using ANOVA models. Results: After multiple comparisons correction, higher neonatal FA was positively associated with receptive language at 12 months of age within the genu (p < 0.001), rostrum (p < 0.001), and tapetum (p < 0.001) of the CC and the left fronto-parietal AF (p = 0.008). No significant clusters were found in the right AF. Conclusion: Microstructural development of the CC and the AF in the newborn is associated with receptive language at 12 months of age, demonstrating that interindividual variation in white matter microstructure is relevant for later language development, and indicating that the neural foundation for language processing is laid well ahead of the majority of language acquisition. This suggests that some origins of impaired language development may lie in the intrauterine and potentially neonatal period of life. Understanding how interindividual differences in neonatal brain maturity

Exposure to child maltreatment increases the risk for psychiatric and physical diseases. Inflammation has been proposed as a mechanism through which early adverse experiences become biologically embedded. However, most studies providing evidence for the link between early adverse exposures and inflammation have been retrospective or cross-sectional in design, or did not assess inflammation immediately after maltreatment in young children. In the present study we investigated the association between childhood maltreatment and salivary C-reactive protein (CRP) concentrations in a population of N = 173 children, 3–5 years of age, who were recruited in the immediate aftermath of maltreatment and followed-up longitudinally every 6 months over a period of 2 years. We found that the association between maltreatment and CRP concentrations was significantly moderated by child sex, such that in girls, CRP concentrations were higher in the maltreated compared to the control group, and this difference was stable across the 2-year follow-up-period, while in boys, there was no association between maltreatment and CRP. Our findings suggest that the effect of maltreatment on inflammation may already emerge right after exposure at a very young age in girls and manifest over time. Our study provides important evidence for the development of personalized, early interventions strategies targeting the early-life period.

Objective The immediate impact of child maltreatment on health and developmental trajectories over time is unknown. Longitudinal studies starting in the direct aftermath of exposure with repeated follow‐up are needed. Method We assessed health and developmental outcomes in 6‐month intervals over 2 years in 173 children, aged 3–5 years at study entry, including 86 children with exposure to emotional and physical abuse or neglect within 6 months and 87 nonmaltreated children. Assessments included clinician‐administered, self‐ and parent‐report measures of psychiatric and behavioral symptoms, development, and physical health. Linear mixed models and latent growth curve analyses were used to contrast trajectories between groups and to investigate the impact of maltreatment features on trajectories. Results Maltreated children exhibited greater numbers of psychiatric diagnoses (b = 1.998, p < .001), externalizing (b = 13.29, p < .001) and internalizing (b = 11.70, p < .001) symptoms, impairments in cognitive (b = −11.586, p < .001), verbal (b = −10.687, p < .001), and motor development (b = −7.904, p = .006), and greater numbers of medical symptoms (b = 1.021, p < .001) compared to nonmaltreated children across all time‐points. Lifetime maltreatment severity and/or age at earliest maltreatment exposure predicted adverse outcomes over time. Conclusion The profound, immediate, and stable impact of maltreatment on health and developmental trajectories supports a biological embedding model and provides foundation to scrutinize the precise underlying mechanisms. Such knowledge will enable the development of early risk markers and mechanism‐driven interventions that mitigate adverse trajectories in maltreated children.

Early‐life stress (ELS), such as childhood abuse and neglect is a well‐established risk factor for the development of psychiatric and medical conditions. In the present chapter, we will focus on the biological embedding of maltreatment during development, which is thought to underlie the increased long‐term risk for several disorders. Specifically, we will discuss the effects of ELS on the functioning of the main stress regulatory systems resulting in a persistent dysregulation of stress processing. Further, we will discuss findings that focus on structural and functional changes of brain regions that are involved in the regulation of stress and emotion. Given that some individuals remain resilient despite of significant exposure to ELS, whereas others develop disorders, we next focus on factors that mediate the emergence of interindividual differences in the effects of ELS including the role of sensitive periods, sex, and the individual genotype. Finally, we will discuss more recent insights into the molecular mechanisms of gene regulation by stress that may account for the development of altered stress responsiveness and risk for psychiatric and medical disorders after ELS, including epigenetic programming with long‐term impact on gene expression. We will conclude this chapter by discussing the implications of insights from neurobiological research on the long‐term consequences of ELS for novel diagnostic and therapeutic approaches to prevent or reverse the detrimental long‐term consequences and thereby reduce the manifestation of negative health outcomes in these victims.