Genetic association study of childhood aggression across raters, instruments, and age

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association metaanalysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis AGGoverall was 3.31% (SE= 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P= 1.6E-06), PCDH7 (P= 2.0E-06), and IPO13 (P= 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations rg among rater-specific assessment of AGG ranged from rg= 0.46 between self- and teacher-assessment to rg= 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range |rg|: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg=∼-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |rg| : 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.</p

I Won't Do EMDR! The Use of the "Sleeping Dogs" Method to Overcome Children's Resistance to EMDR Therapy

This article provides a comprehensive review of the challenges faced by chronically abused children and their treatment providers. The main aim of this pilot study was to explore whether chronically traumatized children, who presented as unable or unwilling to engage in eye movement desensitization and reprocessing (EMDR) therapy, could be prepared with the "Sleeping Dogs" method to complete EMDR therapy. The second aim was to determine whether there was sufficient reduction in posttraumatic stress symptoms to enable positive placement decisions. Participants were 14 children, age 3–9 years (M = 5.1), refusing to participate in EMDR therapy. All were living in residential care (n = 12) or with foster families (n = 2) and were considered stuck cases because of their severe problems. With the treatment package of "Sleeping Dogs" plus EMDR therapy, all children completed EMDR therapy in an average of 7.57 sessions leading to the resolution of all identified traumatic memories. At posttest, the Trauma Symptom Checklist for Young Children showed a significant reduction of scores on the Intrusion and Depression subscales. Two thirds of the children (n = 8) who were in residential care at study onset were placed in foster families within 2 months after the last session, some even during treatment. This is the first study on the "Sleeping Dogs" method and even though the limited sample size and research design restricts generalization of results, the present findings suggest important directions for future study

Executive function as a mediator in the link between single or complex trauma and posttraumatic stress in children and adolescents

In this study, we examined whether there is a mediating role of executive function (EF) in the relationship between trauma exposure and posttraumatic stress in youth. Children and adolescents exposed to trauma were recruited at an academic center for child psychiatry in The Netherlands. The total sample consisted of 119 children from 9 to 17 years old (M = 13.65, SD = 2.45). Based on retrospective life event information, the sample was divided into three groups: a single trauma group (n = 41), a complex trauma group (n = 38), and a control group that was not exposed to traumatic events (n = 40). Our findings revealed that youth exposed to complex trauma had more deficits in EF compared to youth in the single trauma and control groups. EF was found to partly mediate posttraumatic stress symptoms for youth exposed to complex trauma, but not for youth exposed to single trauma. Youth exposed to complex trauma showed more deficits in EF, which was in turn associated with higher levels of posttraumatic stress symptoms. Our findings provide partial support for the role of EF in mediating posttraumatic stress outcomes for youth exposed to complex trauma. This points to the important role of EF in the etiology and treatment of complexly traumatized yout

Individual prediction of trauma-focused psychotherapy response in youth with posttraumatic stress disorder using resting-state functional connectivity

Randomized controlled trials have shown efficacy of trauma-focused psychotherapies in youth with posttraumatic stress disorder (PTSD). However, response varies considerably among individuals. Currently, no biomarkers are available to assist clinicians in identifying youth who are most likely to benefit from treatment. In this study, we investigated whether resting-state functional magnetic resonance imaging (rs-fMRI) could distinguish between responders and non-responders on the group- and individual patient level. Pre-treatment rs-fMRI was recorded in 40 youth (ages 8–17 years) with (partial) PTSD before trauma-focused psychotherapy. Change in symptom severity from pre- to post-treatment was assessed using the Clinician-Administered PTSD scale for Children and Adolescents to divide participants into responders (≥30% symptom reduction) and non-responders. Functional networks were identified using meta-independent component analysis. Group-differences within- and between-network connectivity between responders and non-responders were tested using permutation testing. Individual predictions were made using multivariate, cross-validated support vector machine classification. A network centered on the bilateral superior temporal gyrus predicted treatment response for individual patients with 76% accuracy (pFWE = 0.02, 87% sensitivity, 65% specificity, area-under-receiver-operator-curve of 0.82). Functional connectivity between the frontoparietal and sensorimotor network was significantly stronger in non-responders (t = 5.35, pFWE = 0.01) on the group-level. Within-network connectivity was not significantly different between groups. This study provides proof-of-concept evidence for the feasibility to predict trauma-focused psychotherapy response in youth with PTSD at an individual-level. Future studies are required to test if larger cohorts could increase accuracy and to test further generalizability of the prediction models

Pretreatment cortisol predicts trauma-focused psychotherapy response in youth with (partial) posttraumatic stress disorder

Background: Despite availability of effective trauma-focused psychotherapies, treatment non-response in youth with (partial) posttraumatic stress disorder remains substantial. Studies in adult PTSD have suggested that cortisol is associated with treatment outcome. Furthermore, cortisol prior to treatment could be used to predict treatment success. However, there is a lack of comparable studies in youth with (partial) PTSD. The objective of the current study was therefore to test whether cortisol prior to treatment would differ between treatment responders and non-responders and would positively predict the extent of clinical improvement in youth with (partial) PTSD. Methods: Youth aged 8–18 with PTSD (79.2%) or partial PTSD (20.8%) were treated with 8 sessions of either trauma-focused cognitive behavioral therapy (TF-CBT) or eye movement desensitization and reprocessing (EMDR). Prior to treatment initiation, salivary cortisol was measured in treatment responders (n = 23) and treatment non-responders (n = 30) at 10 and 1 min before and 10, 20 and 30 min after personalized trauma script driven imagery (SDI). The cortisol stress response (>1.5 nmol/L increase from baseline) and basal cortisol secretion was assessed during the SDI procedure. We hypothesized that treatment responders would display higher cortisol levels caused by increased cortisol reactivity prior to trauma-focused psychotherapy relative to psychotherapy non-responders and higher cortisol levels would positively predict the extent of clinical improvement. Results: Script driven imagery did not induce a cortisol stress response in all but two participants. Prior to treatment responders showed significantly higher basal cortisol secretion during SDI compared to treatment non-responders. This effect remained significant after controlling for gender. Higher pre-treatment basal cortisol secretion further positively predicted the extent of clinical improvement during trauma-focused psychotherapy. Conclusion: Because SDI failed to provoke a cortisol stress response in our sample, the question if cortisol reactivity differs between treatment responders and non-responders remains inconclusive. However, our results do suggest that higher pretreatment basal cortisol secretion forms a potential indicator of prospective trauma-focused psychotherapy response in youth with (partial) PTSD. Although, the amount of uniquely explained variance in clinical improvement by pre-treatment cortisol secretion is limited and still renders insufficient basis for clinical applicability, these findings do suggest directions for future studies to delineate the mechanisms of treatment success in youth with (partial) PTS

Distinct saliva DNA methylation profiles in relation to treatment outcome in youth with posttraumatic stress disorder

Abstract In youth with posttraumatic stress disorder (PTSD) non-response rates after treatment are often high. Epigenetic mechanisms such as DNA methylation (DNAm) have previously been linked to PTSD pathogenesis, additionally DNAm may affect response to (psychological) therapies. Besides investigating the direct link between DNAm and treatment response, it might be helpful to investigate the link between DNAm and previously associated biological mechanisms with treatment outcome. Thereby gaining a deeper molecular understanding of how psychotherapy (reflecting a change in the environment) relates to epigenetic changes and the adaptability of individuals. To date, limited research is done in clinical samples and no studies have been conducted in youth. Therefore we conducted a study in a Dutch cohort of youth with and without PTSD (n = 87, age 8–18 years). We examined the cross-sectional and longitudinal changes of saliva-based genome-wide DNA methylation (DNAm) levels, and salivary cortisol secretion. The last might reflect possible abbreviations on the hypothalamic–pituitary– adrenal (HPA) axis. The HPA-axis is previously linked to DNAm and the development and recovery of PTSD. Youth were treated with 8 sessions of either Eye Movement Reprocessing Therapy (EMDR) or Trauma Focused Cognitive behavioral Therapy (TF-CBT). Our epigenome wide approach showed distinct methylation between treatment responders and non-responders on C18orf63 gene post-treatment. This genomic region is related to the PAX5 gene, involved in neurodevelopment and inflammation response. Additionally, our targeted approach indicated that there were longitudinal DNAm changes in successfully treated youth at the CRHR2 gene. Methylation at this gene was further correlated with cortisol secretion pre- and post-treatment. Awaiting replication, findings of this first study in youth point to molecular pathways involved in stress response and neuroplasticity to be associated with treatment response

Diagnosing selective mutism: a critical review of measures for clinical practice and research

Selective mutism (SM) is an anxiety disorder (prevalence 1–2%), characterized by the consistent absence of speaking in specific situations (e.g., in school), while adequately speaking in other situations (e.g., at home). SM can have a debilitating impact on the psychosocial and academic functioning in childhood. The use of psychometrically sound and cross-culturally valid instruments is urgently needed. The aim of this paper is to identify and review the available assessment instruments for screening or diagnosing the core SM symptomatology. We conducted a systematic search in 6 databases. We identified 1469 studies from the last decade and investigated the measures having been used in a diagnostic assessment of SM. Studies were included if original data on the assessment or treatment of SM were reported. It was found that 38% of published studies on SM reporting original data did not report the use of any standardized or objective measure to investigate the core symptomatology. The results showed that many different questionnaires, interviews and observational instruments were used, many of these only once. The Selective Mutism Questionnaire (SMQ), Anxiety Disorders Interview Schedule (ADIS) and School Speech Questionnaire (SSQ) were used most often. Psychometric data on these instruments are emerging. Beyond these commonly used instruments, more recent developed instruments, such as the Frankfurt Scale of SM (FSSM) and the Teacher Telephone Interview for SM (TTI-SM), are described, as well as several interesting observational measures. The strengths and weaknesses of the instruments are discussed and recommendations are made for their use in clinical practice and research

The Validation of the Selective Mutism Questionnaire for Use in the Dutch Population

Selective mutism (SM) is an anxiety disorder in children/adolescents, characterized by the absence of speaking in specific social situations, mostly at school. The selective mutism questionnaire (SMQ) is a parent report, internationally used to assess SM symptomatology and treatment outcomes. Since no assessment instrument for SM was available in the Netherlands, our aim was to investigate the psychometric properties of the Dutch translation of the SMQ, through reliability, confirmatory factor, and ROC analyses conducted on data obtained in 303 children (ages 3–17 years; clinical SM group n = 106, control group n = 197). The SMQ turned out to be highly reliable (α = 0.96 in the combined sample; 0.83 within the clinical group) and followed the expected factor structure. We conclude that the Dutch version of the SMQ is a reliable and valid tool both as a screening and clinical instrument to assess SM in Dutch speaking children