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Recent advances in the genetics of neurodevelopmental disorders (NDDs) have identified the transcription factor FOXP2 as one of numerous risk genes, e.g. in autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). FOXP2 function is suggested to be involved in GABAergic signalling and numerous studies demonstrate that GABAergic function is altered in NDDs, thus disrupting the excitation/inhibition balance. Interestingly, GABAergic signalling components, including glutamate-decarboxylase 1 (Gad1) and GABA receptors, are putative transcriptional targets of FOXP2. However, the specific role of FOXP2 in the pathomechanism of NDDs remains elusive. Here we test the hypothesis that Foxp2 affects behavioural dimensions via GABAergic signalling using zebrafish as model organism. We demonstrate that foxp2 is expressed by a subset of GABAergic neurons located in brain regions involved in motor functions, including the subpallium, posterior tuberculum, thalamus and medulla oblongata. Using CRISPR/Cas9 gene-editing we generated a novel foxp2 zebrafish loss-of-function mutant that exhibits increased locomotor activity. Further, genetic and/or pharmacological disruption of Gad1 or GABA-A receptors causes increased locomotor activity, resembling the phenotype of foxp2 mutants. Application of muscimol, a GABA-A receptor agonist, rescues the hyperactive phenotype induced by the foxp2 loss-of-function. By reverse translation of the therapeutic effect on hyperactive behaviour exerted by methylphenidate, we note that application of methylphenidate evokes different responses in wildtype compared to foxp2 or gad1b loss-of-function animals. Together, our findings support the hypothesis that foxp2 regulates locomotor activity via GABAergic signalling. This provides one targetable mechanism, which may contribute to behavioural phenotypes commonly observed in NDDs.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a complex genetic background, hampering identification of underlying genetic risk factors. We hypothesized that combining linkage analysis and whole-exome sequencing (WES) in multi-generation pedigrees with multiple affected individuals can point toward novel ADHD genes. Three families with multiple ADHD-affected members (Ntotal = 70) and apparent dominant inheritance pattern were included in this study. Genotyping was performed in 37 family members, and WES was additionally carried out in 10 of those. Linkage analysis was performed using multi-point analysis in Superlink Online SNP 1.1. From prioritized linkage regions with a LOD score ≥ 2, a total of 24 genes harboring rare variants were selected. Those genes were taken forward and were jointly analyzed in gene-set analyses of exome-chip data using the MAGMA software in an independent sample of patients with persistent ADHD and healthy controls (N = 9365). The gene-set including all 24 genes together, and particularly the gene-set from one of the three families (12 genes), were significantly associated with persistent ADHD in this sample. Among the latter, gene-wide analysis for the AAED1 gene reached significance. A rare variant (rs151326868) within AAED1 segregated with ADHD in one of the families. The analytic strategy followed here is an effective approach for identifying novel ADHD risk genes. Additionally, this study suggests that both rare and more frequent variants in multiple genes act together in contributing to ADHD risk, even in individual multi-case families.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that often persists into adulthood. Core symptoms of ADHD, such as impulsivity, are caused by an interaction of genetic and environmental factors. Epigenetic modifications of DNA, such as DNA methylation, are thought to mediate the interplay of these factors. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in brain serotonin synthesis. The TPH2 gene has frequently been investigated in relation to ADHD, e.g., showing that TPH2 G-703T (rs4570625) polymorphism influences response control and prefrontal signaling in ADHD patients. In this (epi)genetic imaging study we examined 144 children and adolescents (74 patients, 14 females) using fMRI at rest and during performing a waiting impulsivity (WI) paradigm. Both, TPH2 G-703T (rs4570625) genotype and DNA methylation in the 5' untranslated region (5'UTR) of TPH2 were associated with wavelet variance in fronto-parietal regions and behavioral performance, taking TPH2 genotype into account. In detail, comparisons between genotypes of patients and controls revealed highest wavelet variance and longest reaction times in patients carrying the T allele [indicative for a gene-dosage effect, i.e., the WI phenotype is a direct result of the cumulative effect of ADHD and TPH2 variation]. Regressions revealed a significant effect on one specific DNA methylation site in ADHD patients but not controls, in terms of a significant prediction of wavelet variance in fronto-parietal regions as well as premature responses. By the example of the TPH2 G-703T (rs4570625) polymorphism, we provide insight into how interactive genetic and DNA methylation affect the ADHD and/or impulsive endophenotype.

Sleep problems and alterations in circadian rhythmicity have been widely reported in attention-deficit/hyperactivity disorder (ADHD) patients, but studies covering the full 24h-motor-activity patterns to explore whole-day activity cycles are scarce. Furthermore, correlates and predictors of (hyper-)activity patterns are largely unknown. A subsample of 74 children (6–12 years) with ADHD ( n  = 35) participating in the multicenter study ESCAlife and n  = 39 controls recruited in one center were assessed using 24h-actigraphy for two weeks. Functional linear modeling (FLM) was applied to the actigraphy data and further post-hoc correlational analyses were conducted. FLM revealed no significant differences in 24h-actigraphy profiles between children with and without ADHD, but differentiated between ADHD presentations (combined vs. inattentive) around sleep onset time (around 8:00p.m.) on free days. In the ADHD group, the 24h-actigraphy profiles were associated with measures of the chronotype and early regulation problems in toddler age; in the control group, with daylight exposure. Finding 24h-activity profile differences between ADHD presentations, but not between ADHD and control children as in classical analyses of sleep-onset latency suggests that comprehensive 24h-FLM analyses and focused sleep-related analyses of actigraphy data capture complementary aspects altered in ADHD and its presentations. Another limitation is that the majority of children with ADHD were medicated. However, actigraphy may still prove valuable as a supplementary diagnostic tool in clinical ADHD assessment.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that often persists into adulthood. Core symptoms of ADHD, such as impulsivity, are caused by an interaction of genetic and environmental factors. Epigenetic modifications of DNA, such as DNA methylation, are thought to mediate the interplay of these factors. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in brain serotonin synthesis. The TPH2 gene has frequently been investigated in relation to ADHD, e.g., showing that TPH2 G-703T (rs4570625) polymorphism influences response control and prefrontal signaling in ADHD patients. In this (epi)genetic imaging study we examined 144 children and adolescents (74 patients, 14 females) using fMRI at rest and during performing a waiting impulsivity (WI) paradigm. Both, TPH2 G-703T (rs4570625) genotype and DNA methylation in the 5’ untranslated region (5’UTR) of TPH2 were associated with wavelet variance in fronto-parietal regions and behavioral performance, taking TPH2 genotype into account. In detail, comparisons between genotypes of patients and controls revealed highest wavelet variance and longest reaction times in patients carrying the T allele [indicative for a gene-dosage effect, i.e., the WI phenotype is a direct result of the cumulative effect of ADHD and TPH2 variation]. Regressions revealed a significant effect on one specific DNA methylation site in ADHD patients but not controls, in terms of a significant prediction of wavelet variance in fronto-parietal regions as well as premature responses. By the example of the TPH2 G-703T (rs4570625) polymorphism, we provide insight into how interactive genetic and DNA methylation affect the ADHD and/or impulsive endophenotype.

Objective Effective suicide prevention for adolescents is urgently needed but difficult, as suicide models lack a focus on age-specific influencing factors such as emotional dysregulation. Moreover, examined predictors often do not specifically consider the contribution to the severity of suicidality. To determine which adolescents are at high risk of more severe suicidality, we examined the association between emotional dysregulation and severity of suicidality directly as well as indirectly via depressiveness and nonsuicidal self-injury. Method Adolescents from 18 high schools in Bavaria were included in this cross-sectional and questionnaire-based study as part of a larger prevention study. Data were collected between November 2021 and March 2022 and were analyzed from January 2023 to April 2023. Students in the 6th or 7th grade of high school (11–14 years) were eligible to participate. A total of 2350 adolescents were surveyed and data from 2117 students were used for the analyses after excluding incomplete data sets. Our main outcome variable was severity of suicidality ( Paykel Suicide Scale, PSS ). Additionally, we assessed emotional dysregulation ( Difficulties in Emotion Regulation Scale, DERS-SF ), depressiveness ( Patient Health Questionnaire, PHQ-9 ) and nonsuicidal self-injury ( Deliberate Self-Harm Inventory, DSHI ). Results In total, 2117 adolescents (51.6% female; mean age, 12.31 years [standard deviation: 0.67]) were included in the structural equation model (SEM). Due to a clear gender-specific influence, the model was calculated separately for male and female adolescents. For male adolescents, there was a significant indirect association between emotional dysregulation and severity of suicidality, mediated by depressiveness (β = 0.15, SE  = .03, p  = .008). For female adolescents, there was a significant direct path from emotional dysregulation to severity of suicidality and also indirect paths via depressiveness (β = 0.12, SE  = .05, p  = 0.02) and NSSI (β = 0.18, SE  = .04, p  < .001). Conclusions Our results suggest that gender-related risk markers in 11–14-year-olds need to be included in future suicide models to increase their predictive power. According to our findings, early detection and prevention interventions based on emotion regulation skills might be enhanced by including gender-specific adjustments for the co-occurrence of emotional dysregulation, depressiveness, and nonsuicidal self-injury in girls and the co-occurrence of emotional dysregulation and depressiveness in boys.

Background As one of the most commonly diagnosed psychiatric disorders in children and adolescents, reliable prevalence data on attention-deficit/hyperactivity disorder (ADHD) is highly relevant to health policy and health care planning. However, routine data and parental diagnosis reports from surveys − as important data sources on child ADHD − often differ. This study investigates whether parental psychosocial factors are associated with parental diagnosis reporting in German parents whose child is registered with an administrative ADHD diagnosis (ICD-10 F90.0-9) with their statutory health insurance. We expected more parental burden to be associated with a lower likelihood of a parental diagnosis report. Methods Parents of 5,461 children and adolescents who presented with an administrative ADHD diagnosis in 2020 answered online questions about their child’s ADHD diagnosis and various psychosocial characteristics, including parental strain, parental psychological problems, parental ADHD diagnosis, family cohesion and parental health literacy. Chi-square tests and unadjusted linear regressions were used to analyze group differences in parental psychosocial characteristics between parents who reported the ADHD diagnosis and those who did not. Binary logistic regressions were conducted to predict the parental report of their child’s ADHD diagnosis in the survey. Results Group comparisons revealed that parents who reported their child’s ADHD diagnosis displayed significantly more parental strain, more psychological problems, higher rates of maternal and paternal ADHD, lower levels of family cohesion and lower health literacy than parents who did not report their child’s ADHD diagnosis. The results were partly confirmed in multivariate analysis, where maternal (OR = 3.18) and paternal ADHD (OR = 2.94) turned out to be the strongest predictor of a parental diagnosis report. Conclusions Contrary to our expectations, parental psychosocial burden, in particular parental ADHD diagnosis, increased the likelihood of a parental report of their child’s ADHD diagnosis, which may point to a greater sensitivity and awareness of affected parents towards their child’s ADHD. The findings suggest that differences in the diagnosis prevalence of child ADHD between routine and survey data may vary as a function of parental psychosocial factors.

Avoidance-based emotion regulation plays a central role in the development and maintenance of anxiety disorders across the life span. However, measures for children that account for different avoidance strategies, are scarce. Derived from Gross’ Process Model of Emotion Regulation, the Bochum Assessment of Avoidance-based Emotion Regulation for Children (BAER-C) was developed to assess avoidance strategies (cognitive avoidance, behavioural avoidance, verbal reassurance, and social reassurance) and reappraisal in anticipatory anxious situations. In the present study, the BAER-C was administered to 129 school children aged 8 to 14 and 199 children with anxiety disorders aged 8 to 16 and their parents, along with established measures on anxiety, psychopathology, and emotion regulation. Factor structure, internal consistency, convergent, divergent and construct validity were analysed. Results of the anxious sample showed a satisfactory internal consistency (McDonald’s ω = .94) for all scales as well as positive correlations with anxiety symptoms (all rs > .17, all ps < .05). Factor analysis supported a five-factor model. This model was confirmed in the student sample. Children with an anxiety disorder scored higher on behavioural avoidance, verbal reassurance, and social reassurance than school children ( F (5,304) = 12.63, p = .003, η p 2 = .17). Results for construct validity were ambiguous. Our analyses suggest that the BAER-C is a promising theory-based new instrument to reliably assess different avoidance strategies in children. More research is needed to further analyse construct validity with other emotion regulation questionnaires.

Background Non-suicidal self-injury (NSSI) has become a substantial public health problem. NSSI is a high-risk marker for the development and persistence of mental health problems, shows high rates of morbidity and mortality, and causes substantial health care costs. Thus, there is an urgent need for action to develop universal prevention programs for NSSI before adolescents begin to show this dangerous behavior. Currently, however, universal prevention programs are lacking. Methods The main objective of the present study is to evaluate a newly developed universal prevention program (“DUDE – Du und deine Emotionen / You and your emotions”), based on a skills-based approach in schools, in 3200 young adolescents (age 11–14 years). The effectiveness of DUDE will be investigated in a cluster-randomized controlled trial (RCT) in schools ( N = 16). All groups will receive a minimal intervention called “Stress-free through the school day” as a mental health literacy program to prevent burnout in school. The treatment group ( N = 1600; 8 schools) will additionally undergo the universal prevention program DUDE and will be divided into treatment group 1 (DUDE conducted by trained clinical psychologists; N = 800; 4 schools) and treatment group 2 (DUDE conducted by trained teachers; N = 800; 4 schools). The active control group ( N = 1600; 8 schools) will only receive the mental health literacy prevention. Besides baseline assessment (T0), measurements will occur at the end of the treatment (T1) and at 6- (T2) and 12-month (T3) follow-up evaluations. The main outcome is the occurrence of NSSI within the last 6 months assessed by a short version of the Deliberate Self-Harm Inventory (DSHI-9) at the 1-year follow-up (primary endpoint; T3). Secondary outcomes are emotion regulation, suicidality, health-related quality of life, self-esteem, and comorbid psychopathology and willingness to change. Discussion DUDE is tailored to diminish the incidence of NSSI and to prevent its possible long-term consequences (e.g., suicidality) in adolescents. It is easy to access in the school environment. Furthermore, DUDE is a comprehensive approach to improve mental health via improved emotion regulation. Trial registration German Clinical Trials Register (DRKS) DRKS00018945. Registered on 01 April 2020, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00018945