Learning in autism: implicitly superb

Background: Although autistic people have shown impairments in various learning and memory tasks, recent studies have reported mixed findings concerning implicit learning in ASD. Implicit skill learning, with its unconscious and statistical properties, underlies not only motor but also cognitive and social skills, and it therefore plays an important role from infancy to old age. Methodology/Principal findings: We investigated probabilistic implicit sequence learning and its consolidation in Autism Spectrum Disorder (ASD). Three groups of children participated: thirteen with high-functioning ASD, 14 age-matched controls, and 13 IQ-matched controls. All were tested on the Alternating Serial Reaction Time Task (ASRT), making it possible to separate general skill learning from sequence-specific learning. The ASRT task was repeated after 16 hours. We found that control and ASD children showed similar sequence-specific and general skill learning in the learning phase. Consolidation of skill learning and sequence-specific learning were also intact in the ASD compared to the control groups. Conclusions/Significance: These results suggest that autistic children can use the effects/results of implicit learning not only for a short period, but also for a longer stretch of time. Using these findings, therapists can design more effective educational and rehabilitation programs

DNA methylation signatures of aggression and closely related constructs : A meta-analysis of epigenome-wide studies across the lifespan

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 x 10(-7); Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.Peer reviewe

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10-7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.</p

Results of the experiment.

<p>RTs of Session 1 (epoch 1–4) and Session 2 (epoch 5) for ASD (A), IQ-matched (B) and AGE-matched (C) control groups. The RT differences between the high (open squares) and low frequency (filled squares) triplets indicate sequence-specific learning, whereas the decrease of reaction time (regardless of triplet type) indicates general skill learning. In Session 1 all groups showed significant sequence-specific and general skill learning. D) Offline changes of sequence-specific knowledge for all groups. The sequence learning effect (SLE) is the RT on low frequency minus RT on high frequency trials; this effect on the last epoch of Session 1 (Epoch 4) does not differ significantly from that of the first epoch of Session 2 (Epoch 5). E) Offline changes of general skill for all groups; there was no difference in overall RT between Epoch 4 and 5 for any group. Error bars indicate SEM.</p

General data of participants.

<p>The IQ-matched control group was significantly younger than the other two groups; and the mean IQ of the AGE-matched control group was the highest (* - p<0.05). The right-most column shows the number of participants in each group who showed significant sequence learning (determined by greater than zero RT difference in high minus low frequency triplets in the last epoch of Session 1).</p

Experiment design.

<p>There were two sessions in the experiment: a Learning Phase (Session 1) followed by a Testing Phase (Session 2) after a 16-hour delay.</p

The methylome in females with adolescent Conduct Disorder: Neural pathomechanisms and environmental risk factors

Conduct Disorder (CD) is an impairing psychiatric disorder of childhood and adolescence characterized by aggressive and dissocial behavior. Environmental factors such as maternal smoking during pregnancy, socio-economic status, trauma, or early life stress are associated with CD. Although the number of females with CD is rising in Western societies, CD is under-researched in female cohorts. We aimed at exploring the epigenetic signature of females with CD and its relation to psychosocial and environmental risk factors. We performed HpaII sensitive genome-wide methylation sequencing of 49 CD girls and 50 matched typically developing controls and linear regression models to identify differentially methylated CpG loci (tags) and regions. Significant tags and regions were mapped to the respective genes and tested for enrichment in pathways and brain developmental processes. Finally, epigenetic signatures were tested as mediators for CD-associated risk factors. We identified a 12% increased methylation 5’ of the neurite modulator SLITRK5 (FDR = 0.0046) in cases within a glucocorticoid receptor binding site. Functionally, methylation positively correlated with gene expression in lymphoblastoid cell lines. At systems-level, genes (uncorr. P < 0.01) were associated with development of neurons, neurite outgrowth or neuronal developmental processes. At gene expression level, the associated gene-networks are activated perinatally and during early childhood in neocortical regions, thalamus and striatum, and expressed in amygdala and hippocampus. Specifically, the epigenetic signatures of the gene network activated in the thalamus during early childhood correlated with the effect of parental education on CD status possibly mediating its protective effect. The differential methylation patterns identified in females with CD are likely to affect genes that are expressed in brain regions previously indicated in CD. We provide suggestive evidence that protective effects are likely mediated by epigenetic mechanisms impairing specific brain developmental networks and therefore exerting a long-term effect on neural functions in CD. Our results are exploratory and thus, further replication is needed

No association between oxytocin or prolactin gene variants and childhood-onset mood disorders

BACKGROUND: Oxytocin (OXT) and prolactin (PRL) are neuropeptide hormones that interact with the serotonin system and are involved in the stress response and social affiliation. In human studies, serum OXT and PRL levels have been associated with depression and related phenotypes. Our purpose was to determine if single nucleotide polymorphisms (SNPs) at the loci for OXT, PRL and their receptors, OXTR and PRLR, were associated with childhood-onset mood disorders (COMD). METHODS: Using 678 families in a family-based association design, we genotyped sixteen SNPs at OXT, PRL, OXTR and PRLR to test for association with COMD. RESULTS: No significant associations were found for SNPs in the OXTR, PRL, or PRLR genes. Two of three SNPs 3' of the OXT gene were associated with COMD (p ≤ 0.02), significant after spectral decomposition, but were not significant after additionally correcting for the number of genes tested. Supplementary analyses of parent-of-origin and proband sex effects for OXT SNPs by Fisher’s Exact test were not significant after Bonferroni correction. CONCLUSIONS: We have examined sixteen OXT and PRL system gene variants, with no evidence of statistically significant association after correction for multiple tests

Neuropsychological Subgroups of Emotion Processing in Youths With Conduct Disorder

Background: At the group level, youths with conduct disorder (CD) show deficient emotion processing across various tasks compared to typically developing controls (TDC). But little is known about neuropsychological subgroups within the CD population, the clinical correlates of emotion processing deficits [for instance, with regard to the presence or absence of the DSM-5 Limited Prosocial Emotions (LPE) specifier], and associated risk factors. Methods: 542 children and adolescents with CD (317 girls) and 710 TDCs (479 girls), aged 9–18 years, were included from the FemNAT-CD multisite study. All participants completed three neuropsychological tasks assessing emotion recognition, emotion learning, and emotion regulation. We used a self-report measure of callous-unemotional traits to create a proxy for the LPE specifier. Results: Relative to TDCs, youths with CD as a group performed worse in all three emotion domains. But using clinically based cut-off scores, we found poor emotion recognition skills in only 23% of the participants with CD, followed by emotion regulation deficits in 18%, and emotion learning deficits in 13% of the CD group. Critically, the majority of youths with CD (~56%) did not demonstrate any meaningful neuropsychological deficit, and only a very small proportion showed pervasive deficits across all three domains (~1%). Further analyses indicate that established DSM-5 subtypes of CD are not tightly linked to neurocognitive deficits in one particular emotion domain over another (i.e., emotion recognition deficits in CD+LPE vs. emotion regulation deficits in CD–LPE). Conclusions: Findings from this large-scale data set suggest substantial neuropsychological diversity in emotion processing in the CD population and, consequently, only a subgroup of youths with CD are likely to benefit from additional behavioral interventions specifically targeting emotion processing mechanisms