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Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10-10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h2SNP = 0.34) when compared to ADHD without DBDs (h2SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (rg = 0.81) and anti-social behaviors (rg = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.
Oppositional defiant disorder and conduct disorder, collectively referred to as disruptive behavior disorders (DBDs), are prevalent psychiatric disorders in children. Early diagnosis of DBDs is crucial because they can increase the risks of other mental health and substance use disorders without appropriate psychosocial interventions and treatment. However, diagnosing DBDs is challenging as they are often comorbid with other disorders, such as attention-deficit/hyperactivity disorder, anxiety, and depression. In this study, a multimodal ensemble three-dimensional convolutional neural network (3D CNN) deep learning model was used to classify children with DBDs and typically developing children. The study participants included 419 females and 681 males, aged 108-131 months who were enrolled in the Adolescent Brain Cognitive Development Study. Children were grouped based on the presence of DBDs (n = 550) and typically developing (n = 550); assessments were based on the scores from the Child Behavior Checklist and on the Schedule for Affective Disorders and Schizophrenia for School-age Children-Present and Lifetime version for DSM-5. The diffusion, structural, and resting-state functional magnetic resonance imaging (rs-fMRI) data were used as input data to the 3D CNN. The model achieved 72% accuracy in classifying children with DBDs with 70% sensitivity, 72% specificity, and an F1-score of 70. In addition, the discriminative power of the classifier was investigated by identifying the cortical and subcortical regions primarily involved in the prediction of DBDs using a gradient-weighted class activation mapping method. The classification results were compared with those obtained using the three neuroimaging modalities individually, and a connectome-based graph CNN and a multi-scale recurrent neural network using only the rs-fMRI data.
This study compares teacher-reported prevalence rates for disruptive behavior disorders using DSM-IV, DSM-III-R, and DSM-III criteria within the same population of elementary school students and examines the relationships between DSM "subtypes" and academic performance, perceived behavior problems, and demographic variables.
Oppositional defiant disorder (ODD) is a frequent psychiatric disorder seen in children and adolescents with attention-deficit-hyperactivity disorder (ADHD). ODD is also a common antecedent to both affective disorders and aggressive behaviors. Although the heritability of ODD has been estimated to be around 0.60, there has been little research into the molecular genetics of ODD. The present study examined the association of irritable and defiant/vindictive dimensions and categorical subtypes of ODD (based on latent class analyses) with previously described specific polymorphisms (DRD4 exon3 VNTR, 5-HTTLPR, and seven OXTR SNPs) as well as with dopamine, serotonin, and oxytocin genes and pathways in a clinical sample of children and adolescents with ADHD. In addition, we performed a multivariate genome-wide association study (GWAS) of the aforementioned ODD dimensions and subtypes. Apart from adjusting the analyses for age and sex, we controlled for "parental ability to cope with disruptive behavior." None of the hypothesis-driven analyses revealed a significant association with ODD dimensions and subtypes. Inadequate parenting behavior was significantly associated with all ODD dimensions and subtypes, most strongly with defiant/vindictive behaviors. In addition, the GWAS did not result in genome-wide significant findings but bioinformatics and literature analyses revealed that the proteins encoded by 28 of the 53 top-ranked genes functionally interact in a molecular landscape centered around Beta-catenin signaling and involved in the regulation of neurite outgrowth. Our findings provide new insights into the molecular basis of ODD and inform future genetic studies of oppositional behavior. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
Of all psychiatric disorders, the disruptive behavior disorders (DBDs) are the most likely to predispose to substance dependence (SD). One possible underlying mechanism for this increased vulnerability is risky decision making. The aim of this study was to examine decision making in DBD adolescents with and without SD. Twenty-five DBD adolescents (19 males) with SD (DBD+SD), 28 DBD adolescents (23 males) without SD (DBD-SD) and 99 healthy controls (72 males) were included in the study. DBD adolescents with co-morbid attention deficit/ hyperactivity disorder (ADHD) were excluded. Risky decision making was investigated by assessing the number of disadvantageous choices in the Iowa gambling task. DBD+SD made significantly more risky choices than healthy controls and DBD-SD. Healthy controls and DBD-SD did not differ on risky decision making. These results suggest that risky decision making is a vulnerability factor for the development of SD in a subgroup of adolescents with DBD without ADHD.
Attention deficit-hyperactivity disorder (ADHD) is a neuropsychiatric disorder characterized by inappropriate and impaired levels of hyperactivity, impulsivity and inattention. Around 75% of adults with ADHD show comorbidity with other psychiatric disorders such as disruptive behavior disorders or substance use disorders (SUDs). Recently, there has been growing interest in studying the role of microRNAs (miRNAs) in the susceptibility to complex disorders. Interestingly, converging evidence suggests that single nucleotide polymorphisms (SNPs) within miRNAs or miRNA target sites may modulate the miRNA-mediated regulation of gene expression through the alteration of the miRNA maturation, structure or expression pattern as well as the silencing mechanisms of target genes. Genetic studies and animal models support the involvement of the serotonin receptor (HTR1B) in ADHD. We evaluated the contribution of one SNP in the miR-96 target site at HTR1B and eight tagSNPs within the genomic region containing this miRNA in 695 adults with ADHD (266 and 396 subjects with and without comorbid SUD, respectively), 403 subjects with SUD without life-time diagnosis of ADHD and 485 sex-matched controls from Spain. Single and multiple marker analyses revealed association between two SNPs located at the 3' region of miR-96 (rs2402959 and rs6965643) and ADHD without SUD. Our results provide preliminary evidence for the contribution of two sequence variants at the miR-183-96-182 cluster to ADHD without comorbid SUD, and emphasize the need to take comorbidities into account in genetic studies to minimize the effect of heterogeneity and to clarify these complex phenotypes.
Prenatal exposure to teratogenic substances, such as nicotine or alcohol, increases the risk of developing attention-deficit/hyperactivity disorder (ADHD). To date, studies examining this relationship have used symptom scales as outcome measures to assess the effect of prenatal exposure, and have not investigated the neurobiological pathways involved. This study explores the effect of prenatal exposure to cigarettes or alcohol on brain volume in children with ADHD and typically developing controls. Children with ADHD who had been exposed prenatally to either substance were individually matched to children with and without ADHD who had not been. Controls who had been exposed prenatally were also individually matched to controls who had not been. For prenatal exposure to both smoking and alcohol, we found a pattern where subjects with ADHD who had been exposed had the smallest brain volumes and unexposed controls had the largest, with intermediate volumes for unexposed subjects with ADHD. This effect was most pronounced for cerebellum. A similar reduction fell short of significance for controls who had been exposed to cigarettes, but not alcohol. Our results are consistent with an additive effect of prenatal exposure and ADHD on brain volume, with the effects most pronounced for cerebellum.
Visual-spatial Working Memory (WM) is the most impaired executive function in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Some suggest that deficits in executive functioning are caused by motivational deficits. However, there are no studies that investigate the effects of motivation on the visual-spatial WM of children with- and without ADHD. Studies examining this in executive functions other than WM, show inconsistent results. These inconsistencies may be related to differences in the reinforcement used. The effects of different reinforcers on WM performance were investigated in 30 children with ADHD and 31 non-ADHD controls. A visual-spatial WM task was administered in four reinforcement conditions: Feedback-only, 1 euro, 10 euros, and a computer-game version of the task. In the Feedback-only condition, children with ADHD performed worse on the WM measure than controls. Although incentives significantly improved the WM performance of children with ADHD, even the strongest incentives (10 euros and Gaming) were unable to normalize their performance. Feedback-only provided sufficient reinforcement for controls to reach optimal performance, while children with ADHD required extra reinforcement. Only children with ADHD showed a decrease in performance over time. Importantly, the strongest incentives (10 euros and Gaming) normalized persistence of performance in these children, whereas 1 euro had no such effect. Both executive and motivational deficits give rise to visual-spatial WM deficits in ADHD. Problems with task-persistence in ADHD result from motivational deficits. In ADHD-reinforcement studies and clinical practice (e.g., assessment), reinforcement intensity can be a confounding factor and should be taken into account. Gaming can be a cost-effective way to maximize performance in ADHD.
In recent years, there has been growing interest in investigating the effect of specific pharmacological treatments for ADHD not only on its core symptoms, but also on social skills in youths. This stands especially true for ADHD patients displaying impulsive aggressiveness and antisocial behaviors, being the comorbidity with Disruptive Behavior Disorders, one of the most frequently observed in clinical settings. This systematic review aimed to synthesize research findings on this topic following PRISMA guidelines and to identify gaps in current knowledge, future directions, and treatment implications. Search strategies included the following terms: ADHD; methylphenidate and other ADHD drugs; empathy, theory of mind and emotion recognition. Full-text articles were retrieved and data from individual studies were collected. Thirteen studies were finally included in our systematic review. Ten studies assessing changes in empathy and/or theory of mind in patients with ADHD treated after pharmacological interventions were identified. Similarly, seven partially overlapping studies assessing changes in emotion recognition were retrieved. Despite a great heterogeneity in the methodological characteristics of the included studies, most of them reported an improvement in emphatic and theory of mind abilities in youths with ADHD treated with psychostimulants and nonstimulant drugs, as well as positive but less consistent results about emotion recognition performances.
Electroencephalography (EEG) has been used to examine the possibility of dysfunctional brain activity in externalizing behavior, but findings across studies have been inconsistent. Furthermore, studies of attention-deficit/hyperactivity disorder (ADHD) versus other externalizing behaviors, such as disruptive behavior disorders or antisocial behavior, have developed parallel literatures. The purpose of the present study was to reconcile these two literatures. A meta-analysis of 62 studies of EEG power at rest in relationship to externalizing behaviors was performed. Results of the meta-analyses showed significantly higher delta (Hedges's g=0.25) and theta power (g=0.40) and lower beta power (g=-0.22) in externalizing participants compared to controls. Alpha (g=-0.26) and gamma power (g=-0.26) were marginally lower in externalizing samples. Results were not moderated by type of externalizing behavior. Overall, the results of the meta-analyses were consistent with the hypoarousal theory of externalizing behavior.
The Behavior and Mind Health (BeMIND) study is a population-based cohort study of adolescents and young adults from Dresden, Germany. The aim is to investigate psychological and behavioral factors linked to a range of mental disorders and health behaviors and their interaction with social-environmental and genetic/biologic factors.
Efforts to describe the current state of research are needed to advance the field of physical-mental multimorbidity (ie, the co-occurrence of at least one physical illness and at least one mental disorder) among children and youth. Our objective was to systematically explore the breadth of physical-mental multimorbidity research in children and youth and to provide an overview of existing literature topics.
Spontaneous eye blink rate is modulated by task demands and internal state, and is demonstrated to reflect central dopamine activity. Also, spontaneous eye blinks are strategically timed around salient stimuli. This study investigates whether children with attention deficit hyperactivity disorder (ADHD) show reduced blink rates, blink modulation and blink timing, and whether this is influenced by stimulant medication. The electrooculogram was measured in 18 typically developing children, 16 children with ADHD off methylphenidate (Mph), and 16 children with ADHD on Mph during a rest period and during performance of a 60-min visual selective attention task. Blink rate and timing was extracted from the electrooculogram. No evidence was found for aberrant blink rate or blink modulation in children with ADHD off Mph. All groups increased blink rates from rest to task, and no group differences were found in blink rate during rest and task, or in the modulation of blink rate from rest to task. Time-on task resulted in a similar increase in blink rates in all three groups. Stimulant medication appeared not to influence blink rate and blink modulation, except that in the ADHD off Mph group the blink rate was enhanced only under conditions with performance feedback. All groups inhibited blinks before stimulus presentation and strategically timed their blinks after the stimulus. Children with ADHD off Mph showed reduced blink inhibition before the stimulus; however, given the low incidence (<1Â % of the trials) and long latency this is not likely to impair their visual intake.
Most clinical trials of antipsychotics in children are brief, failing to address their long-term safety, particularly when taken concurrently with other psychotropics. This hypothesis-generating analysis evaluates potential correlates of weight gain in children receiving extended risperidone treatment.
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