Charlotte A. M. Cecil

Amygdala Response to Preattentive Masked Fear in Children With Conduct Problems: The Role of Callous-Unemotional Traits

OBJECTIVE In children with conduct problems, high levels of callous-unemotional traits are associated with amygdala hypoactivity to consciously perceived fear, while low levels of callous-unemotional traits may be associated with amygdala hyperactivity. Behavioral data suggest that fear processing deficits in children with high callous-unemotional traits may extend to stimuli presented below conscious awareness (preattentively). The authors investigated the neural basis of this effect. Amygdala involvement was predicted on the basis of its role in preattentive affective processing in healthy adults and its dysfunction in previous studies of conduct problems. METHOD Functional MRI was used to measure neural responses to fearful and calm faces presented preattentively (for 17 ms followed by backward masking) in boys with conduct problems and high callous-unemotional traits (N=15), conduct problems and low callous-unemotional traits (N=15), and typically developing comparison boys (N=16). Amygdala response to fearful and calm faces was predicted to differentiate groups, with the greatest response in boys with conduct problems and low callous-unemotional traits and the lowest in boys with conduct problems and high callous-unemotional traits. RESULTS In the right amygdala, a greater amygdala response was seen in boys with conduct problems and low callous-unemotional traits than in those with high callous-unemotional traits. The findings were not explained by symptom levels of conduct disorder, attention-deficit hyperactivity disorder, anxiety, or depression. CONCLUSIONS These data demonstrate differential amygdala activity to preattentively presented fear in children with conduct problems grouped by callous-unemotional traits, with high levels associated with lower amygdala reactivity. The studys findings complement increasing evidence suggesting that callous-unemotional traits are an important specifier in the classification of children with conduct problems.

Environmental risk, Oxytocin Receptor Gene (OXTR) methylation and youth callous-unemotional traits: a 13-year longitudinal study.

Youth with high callous-unemotional traits (CU) are at risk for early-onset and persistent conduct problems. Research suggests that there may be different developmental pathways to CU (genetic/constitutional vs environmental), and that the absence or presence of co-occurring internalizing problems is a key marker. However, it is unclear whether such a distinction is valid. Intermediate phenotypes such as DNA methylation, an epigenetic modification regulating gene expression, may help to clarify etiological pathways. This is the first study to examine prospective inter-relationships between environmental risk (prenatal/postnatal) and DNA methylation (birth, age 7 and 9) in the prediction of CU (age 13), for youth low vs high in internalizing problems. We focused on DNA methylation in the vicinity of the oxytocin receptor (OXTR) gene as it has been previously implicated in CU. Participants were 84 youth with early-onset and persistent conduct problems drawn from the Avon Longitudinal Study of Parents and Children. For youth with low internalizing problems (46%), we found that (i) OXTR methylation at birth associated with higher CU (age 13) as well as decreased experience of victimization during childhood (evocative epigenetic-environment correlation; birth–age 7), (ii) higher prenatal parental risks (maternal psychopathology, criminal behaviors, substance use) associated with higher OXTR methylation at birth and (iii) OXTR methylation levels were more stable across time (birth–age 9). In contrast, for youth with high internalizing problems, CU were associated with prenatal risks of an interpersonal nature (that is, intimate partner violence, family conflict) but not OXTR methylation. Findings support the existence of distinct developmental pathways to CU.

Association between maladaptive parenting and child self-control over time: cross-lagged study using a monozygotic twin difference design

BACKGROUND Harsh parenting practices and negative parental feelings may be environmental risk factors for low self-control in children. Children may also evoke certain parenting reactions. AIMS To investigate the longitudinal relationship between parenting and self-control, as well as associated outcomes within the monozygotic (MZ) twin differences framework. METHOD Longitudinal MZ twin differences analysis was conducted on a community sample of 5184 twins using data from ages 3, 4, 7 and 9 years. Outcomes related to self-control and parenting were analysed at age 12 years. RESULTS Non-shared environmental effects of parenting on the development of self-control and an evocative effect of child self-control on parenting were found. Harsh parenting predicted conduct problems for both boys and girls. Self-control at age 9 predicted conduct problems and emotional difficulties at age 12. CONCLUSIONS Parenting and child self-control affect one another, highlighting the potential of early interventions that target parents and children simultaneously.

Double disadvantage: the influence of childhood maltreatment and community violence exposure on adolescent mental health

BACKGROUND Childhood maltreatment is a key risk factor for maladjustment and psychopathology. Although maltreated youth are more likely to experience community violence, both forms of adversity are generally examined separately. Consequently, little is known about the unique and interactive effects that characterize maltreatment and community violence exposure (CVE) on mental health. METHODS Latent Profile Analysis (LPA) was applied to data from a community sample of high-risk adolescents and young adults (n = 204, M = 18.85) to categorize groups of participants with similar patterns of childhood (i.e. past) maltreatment exposure. Associations between childhood maltreatment, CVE and mental health outcomes were then explored using multivariate regression and moderation analyses. RESULTS Latent Profile Analysis identified three groups of individuals with low, moderate and severe levels of childhood maltreatment. Maltreatment was associated with more internalizing, externalizing, and trauma-related symptoms. By contrast, CVE showed independent associations with only externalizing and trauma-related symptoms. Typically, childhood maltreatment and CVE exerted additive effects; however, these forms of adversity interacted to predict levels of anger. CONCLUSIONS Exposure to maltreatment and community violence is associated with increased levels of clinical symptoms. However, while maltreatment is associated with increased symptoms across a broad range of mental health domains, the impact of community violence is more constrained, suggesting that these environmental risk factors differentially impact mental health functioning.

Epigenetic profiling of ADHD symptoms trajectories: A prospective, methylome-wide study

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent developmental disorder, associated with a range of long-term impairments. Variation in DNA methylation, an epigenetic mechanism, is implicated in both neurobiological functioning and psychiatric health. However, the potential role of DNA methylation in ADHD symptoms is currently unclear. In this study, we examined data from the Avon Longitudinal Study of Parents and Children (ALSPAC)—specifically the subsample forming the Accessible Resource for Integrated Epigenomics Studies (ARIES)—that includes (1) peripheral measures of DNA methylation (Illumina 450k) at birth (n=817, 49% male) and age 7 (n=892, 50% male) and (2) trajectories of ADHD symptoms (7–15 years). We first employed a genome-wide analysis to test whether DNA methylation at birth associates with later ADHD trajectories; and then followed up at age 7 to investigate the stability of associations across early childhood. We found that DNA methylation at birth differentiated ADHD trajectories across multiple genomic locations, including probes annotated to SKI (involved in neural tube development), ZNF544 (previously implicated in ADHD), ST3GAL3 (linked to intellectual disability) and PEX2 (related to perixosomal processes). None of these probes maintained an association with ADHD trajectories at age 7. Findings lend novel insights into the epigenetic landscape of ADHD symptoms, highlighting the potential importance of DNA methylation variation in genes related to neurodevelopmental and peroxisomal processes that play a key role in the maturation and stability of cortical circuits.

Neural responses to fearful eyes in children with conduct problems and varying levels of callous-unemotional traits

BACKGROUND Children with conduct problems (CP) are a heterogeneous group. Those with high levels of callous-unemotional traits (CP/HCU) appear emotionally under-reactive at behavioural and neural levels whereas those with low levels of CU traits (CP/LCU) appear emotionally over-reactive, compared with typically developing (TD) controls. Investigating the degree to which these patterns of emotional reactivity are malleable may have important translational implications. Instructing participants with CP/HCU to focus on the eyes of fearful faces (i.e. the most salient feature) can ameliorate their fear-recognition deficits, but it is unknown whether this is mediated by amygdala response. It is also unknown whether focusing on fearful eyes is associated with increased amygdala reactivity in CP/LCU. METHOD Functional magnetic resonance imaging (fMRI) was used to measure neural responses to fearful and calm faces in children with CP/HCU, CP/LCU and TD controls (n = 17 per group). On half of trials participants looked for a blue dot anywhere within target faces; on the other half, participants were directed to focus on the eye region. RESULTS Reaction time (RT) data showed that CP/LCU were selectively slowed in the fear/eyes condition. For the same condition, CP/LCU also showed increased amygdala and subgenual anterior cingulate cortex (sgACC)/orbitofrontal cortex (OFC) responses compared with TD controls. RT and amygdala response to fear/eyes were correlated in CP/LCU only. No effects of focusing on the eye region were observed in CP/HCU. CONCLUSIONS These data extend the evidence base suggesting that CU traits index meaningful heterogeneity in conduct problems. Focusing on regulating reactive emotional responses may be a fruitful strategy for children with CP/LCU.

Disentangling the mental health impact of childhood abuse and neglect.

It is unclear whether maltreatment types exert common or specific effects on mental health. In the current study, we aimed to systematically characterize the unique, shared and cumulative effects of maltreatment types on psychiatric symptoms, using data drawn from a community sample of high-risk youth (n=204, M=18.85). Analyses controlled for a range of potentially confounding variables, including socio-demographic variables, neighbourhood deprivation and levels of community violence exposure. Outcome measures included multi-informant reports of internalizing difficulties, as well as data on externalizing problems and trauma-related symptoms. We found that (i) consistent with previous studies, maltreatment types were highly interrelated and frequently co-occurred; (ii) symptom severity linearly increased with the number of maltreatment types experienced (more so for self-report vs informant ratings); and (iii) while most forms of maltreatment were significantly associated with mental health outcomes when examined individually, few unique effects were observed when modelling maltreatment types simultaneously, pointing to an important role of shared variance in driving maltreatment effects on mental health. Emotional abuse emerged as the main independent predictor of psychiatric symptomatology - over and above other maltreatment types - and this effect was comparable for males and females (i.e. no significant interaction with sex). Findings contribute to a better understanding of heterogeneity in individual responses to maltreatment.

An epigenome-wide association meta-analysis of prenatal maternal stress in neonates: A model approach for replication

ABSTRACT Prenatal maternal stress exposure has been associated with neonatal differential DNA methylation. However, the available evidence in humans is largely based on candidate gene methylation studies, where only a few CpG sites were evaluated. The aim of this study was to examine the association between prenatal exposure to maternal stress and offspring genome-wide cord blood methylation using different methods. First, we conducted a meta-analysis and follow-up pathway analyses. Second, we used novel region discovery methods [i.e., differentially methylated regions (DMRs) analyses]. To this end, we used data from two independent population-based studies, the Generation R Study (n = 912) and the Avon Longitudinal Study of Parents and Children (ALSPAC, n = 828), to (i) measure genome-wide DNA methylation in cord blood and (ii) extract a prenatal maternal stress composite. The meta-analysis (ntotal = 1,740) revealed no epigenome-wide (meta P <1.00e-07) associations of prenatal maternal stress exposure with neonatal differential DNA methylation. Follow-up analyses of the top hits derived from our epigenome-wide meta-analysis (meta P <1.00e-04) indicated an over-representation of the methyltransferase activity pathway. We identified no Bonferroni-corrected (P <1.00e-06) DMRs associated with prenatal maternal stress exposure. Combining data from two independent population-based samples in an epigenome-wide meta-analysis, the current study indicates that there are no large effects of prenatal maternal stress exposure on neonatal DNA methylation. Such replication efforts are essential in the search for robust associations, whether derived from candidate gene methylation or epigenome-wide studies.

Concurrent and longitudinal contribution of exposure to bullying in childhood to mental health: the role of vulnerability and resilience

Importance Exposure to bullying is associated with poor mental health. However, the degree to which observed associations reflect direct detrimental contributions of exposure to bullying to mental health remains uncertain, as noncausal relationships may arise from genetic and environmental confounding (eg, preexisting vulnerabilities). Determining to what extent exposure to bullying contributes to mental health is an important concern, with implications for primary and secondary interventions. Objective To characterize the concurrent and longitudinal contribution of exposure to bullying to mental health in childhood and adolescence using a twin differences design to strengthen causal inference. Design, Setting, and Participants Participants were drawn from the Twins Early Development Study, a population-based cohort recruited from population records of births in England and Wales between January 1, 1994, and December 31, 1996. Data collection took place when the participants were between 11 and 16 years of age from December 1, 2005, to January 31, 2013. Data analysis was conducted from January 1, 2016, to June 20, 2017. Exposures Participants completed the Multidimensional Peer-Victimization Scale at 11 and 14 years of age. Main Outcomes and Measures Mental health assessments at 11 and 16 years of age included anxiety, depression, hyperactivity and impulsivity, inattention, conduct problems, and psychotic-like experiences (eg, paranoid thoughts or cognitive disorganization). Results The 11 108 twins included in the final sample (5894 girls and 5214 boys) were a mean age of 11.3 years at the first assessment and 16.3 years at the last assessment. The most stringent twin differences estimates (monozygotic) were consistent with causal contribution of exposure to bullying at 11 years to concurrent anxiety, depression, hyperactivity and impulsivity, inattention, and conduct problems. Effects decreased over time; that is, substantial concurrent contributions to anxiety (&bgr; = 0.27; 95% CI, 0.22-0.33) persisted for 2 years (&bgr; = 0.12; 95% CI, 0.04-0.20) but not 5 years. Direct contributions to paranoid thoughts and cognitive disorganization persisted for 5 years. Conclusions and Relevance This study is the largest to date to characterize the contribution of exposure to bullying in childhood to mental health using a twin differences design and multi-informant, multiscale data. Stringent evidence of the direct detrimental contribution of exposure to bullying in childhood to mental health is provided. Findings also suggest that childhood exposure to bullying may partly be viewed as a symptom of preexisting vulnerabilities. Finally, the dissipation of effects over time for many outcomes highlights the potential for resilience in children who were bullied. In addition to programs that aim to reduce exposure to bullying, interventions may benefit from addressing preexisting vulnerabilities and focus on resilience.

Prenatal unhealthy diet, insulin-like growth factor 2 gene (IGF2) methylation, and attention deficit hyperactivity disorder symptoms in youth with early-onset conduct problems

Background Conduct problems (CP) and attention deficit hyperactivity disorder (ADHD) are often comorbid and have each been linked to ‘unhealthy diet’. Early‐life diet also associates with DNA methylation of the insulin‐like growth factor 2 gene (IGF2), involved in fetal and neural development. We investigated the degree to which prenatal high‐fat and ‐sugar diet might relate to ADHD symptoms via IGF2 DNA methylation for early‐onset persistent (EOP) versus low CP youth. Methods Participants were 164 youth with EOP (n = 83) versus low (n = 81) CP drawn from the Avon Longitudinal Study of Parents and Children. We assessed if the interrelationships between high‐fat and ‐sugar diet (prenatal, postnatal), IGF2 methylation (birth and age 7, collected from blood), and ADHD symptoms (age 7–13) differed for EOP versus low CP youth. Results Prenatal ‘unhealthy diet’ was positively associated with IGF2 methylation at birth for both the EOP and low CP youth. For EOP only: (a) higher IGF2 methylation predicted ADHD symptoms; and (b) prenatal ‘unhealthy diet’ was associated with higher ADHD symptoms indirectly via higher IGF2 methylation. Conclusions Preventing ‘unhealthy diet’ in pregnancy might reduce the risk of ADHD symptoms in EOP youth via lower offspring IGF2 methylation.