Children with maltreatment exposure exhibit rumination-like spontaneous thought patterns: association with symptoms of depression, subcallosal cingulate cortex thickness, and cortisol levels.

BACKGROUND: Childhood maltreatment is associated with pervasive risk for depression. However, the immediate cognitive and neural mechanisms that mediate this risk during development are unknown. We here studied the impact of maltreatment on self-generated thought (SGT) patterns and their association with depressive symptoms, subcallosal cingulate cortex (SCC) thickness, and cortisol levels in children. METHODS: We recruited 183 children aged 6-12 years, 96 of which were exposed to maltreatment. Children performed a mind wandering task to elicit SGTs. A subgroup of children underwent structural magnetic resonance imaging (N = 155) for SCC thickness analyses and saliva collection for quantification of free cortisol concentrations (N = 126) was collected. Using network analysis, we assessed thought networks and compared these networks between children with and without maltreatment exposure. Using multilevel analyses, we then tested the association between thought networks of children with maltreatment exposure with depressive symptoms, SCC thickness, and cortisol levels. RESULTS: Children exposed to maltreatment generated fewer positively valenced thoughts. Network analysis revealed rumination-like thought patterns in children with maltreatment exposure, which were associated with depressive symptoms, SCC thickness, and cortisol levels. Children with maltreatment exposure further exhibited decreased future-self thought coupling, which was associated with depressive symptoms, while other-related and past-oriented thoughts had the greatest importance within the network. CONCLUSIONS: Using a novel network analytic approach, we provide evidence that children exposed to maltreatment exhibit ruminative clustering of thoughts, which is associated with depressive symptoms and neurobiological correlates of depression. Our results provide a specific target for clinical translation to design early interventions for middle childhood. Targeting thought patterns in children with maltreatment exposure may be an effective strategy to effectively mitigate depression risk early in life.

The pediatric buccal epigenetic clock identifies significant ageing acceleration in children with internalizing disorder and maltreatment exposure.

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 (F1,147 = 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.

Childhood adversity correlates with stable changes in DNA methylation trajectories in children and converges with epigenetic signatures of prenatal stress.

Childhood maltreatment (CM) is an established major risk factor for a number of negative health outcomes later in life. While epigenetic mechanisms, such as DNA methylation (DNAm), have been proposed as a means of embedding this environmental risk factor, little is known about its timing and trajectory, especially in very young children. It is also not clear whether additional environmental adversities, often experienced by these children, converge on similar DNAm changes. Here, we calculated a cumulative adversity score, which additionally to CM includes socioeconomic status (SES), other life events, parental psychopathology and epigenetic biomarkers of prenatal smoking and alcohol consumption. We investigated the effects of CM alone as well as the adversity score on longitudinal DNAm trajectories in the Berlin Longitudinal Child Study. This is a cohort of 173 children aged 3-5 years at baseline of whom 86 were exposed to CM. These children were followed-up for 2 years with extensive psychometric and biological assessments as well as saliva collection at 5 time points providing genome-wide DNAm levels. Overall, only a few DNAm patterns were stable over this timeframe, but less than 10 DNAm regions showed significant changes. At baseline, neither CM nor the adversity score associated with DNAm changes. However, in 6 differentially methylated regions (DMRs), CM and the adversity score significantly moderated DNAm trajectories over time. A number of these DMRs have previously been associated with adverse prenatal exposures. In our study, children exposed to CM also presented with epigenetic signatures indicative of increased prenatal exposure to tobacco and alcohol, as compared to non-CM exposed children. These epigenetic signatures of prenatal exposure strongly correlate with DNAm regions associated with CM and the adversity score. Finally, weighted correlation network analysis revealed a module of CpGs exclusively associated with CM. While our study identifies DNAm loci specifically associated with CM, especially within long non-coding RNAs, the majority of associations were found with the adversity score with convergent association with indicators of adverse prenatal exposures. This study highlights the importance of mapping not only of the epigenome but also the exposome and extending the observational timeframe to well before birth.

Validating the construct of aberrant salience in schizophrenia - Behavioral evidence for an automatic process.

Suspecting significance behind ordinary events is a common feature in psychosis and it is assumed to occur due to aberrant salience attribution. The Salience Attribution Test (SAT; Roiser et al., 2009) measures aberrant salience as a bias towards one out of two equally reinforced cue features as opposed to adaptive salience towards features indicating high reinforcement. This is the first study to validate the latent constructs involved in salience attribution in patients. Forty-nine schizophrenia patients and forty-four healthy individuals completed the SAT, a novel implicit salience paradigm (ISP), a reversal learning task and a neuropsychological test battery. First, groups were compared on raw measures. Second and within patients, these were correlated and then used for a principal component analysis (PCA). Third, sum scores matching the correlation and component pattern were correlated with psychopathology. Compared to healthy individuals, patients exhibited more implicit aberrant salience in the SAT and ISP and less implicit and explicit adaptive salience attribution in the SAT. Implicit aberrant salience from the SAT and ISP positively correlated with each other and negatively with reversal learning. Whereas explicit aberrant salience was associated with cognition, implicit and explicit adaptive salience were positively correlated. A similar pattern emerged in the PCA and implicit aberrant salience was associated with negative symptoms. Taken together, implicit aberrant salience from the SAT and ISP seems to reflect an automatic process that is independent from deficient salience ascription to relevant events. Its positive correlation with negative symptoms might reflect motivational deficits present in chronic schizophrenia patients.