Autism beyond diagnostic categories: characterization of autistic phenotypes in schizophrenia.

BACKGROUND: Behavioral phenotypical continua from health to disease suggest common underlying mechanisms with quantitative rather than qualitative differences. Until recently, autism spectrum disorders and schizophrenia were considered distinct nosologic entities. However, emerging evidence contributes to the blurring of symptomatic and genetic boundaries between these conditions. The present study aimed at quantifying behavioral phenotypes shared by autism spectrum disorders and schizophrenia to prepare the ground for biological pathway analyses. METHODS: Specific items of the Positive and Negative Syndrome Scale were employed and summed up to form a dimensional autism severity score (PAUSS). The score was created in a schizophrenia sample (N = 1156) and validated in adult high-functioning autism spectrum disorder (ASD) patients (N = 165). To this end, the Autism Diagnostic Observation Schedule (ADOS), the Autism (AQ) and Empathy Quotient (EQ) self-rating questionnaires were applied back to back with the newly developed PAUSS. RESULTS: PAUSS differentiated between ASD, schizophrenia and a disease-control sample and substantially correlated with the Autism Diagnostic Observation Schedule. Patients with ADOS scores ≥12 obtained highest, those with scores <7 lowest PAUSS values. AQ and EQ were not found to vary dependent on ADOS diagnosis. ROC curves for ADOS and PAUSS resulted in AuC values of 0.9 and 0.8, whereas AQ and EQ performed at chance level in the prediction of ASD. CONCLUSIONS: This work underscores the convergence of schizophrenia negative symptoms and autistic phenotypes. PAUSS evolved as a measure capturing the continuous nature of autistic behaviors. The definition of extreme-groups based on the dimensional PAUSS may permit future investigations of genetic constellations modulating autistic phenotypes.

From gene to brain to behavior: schizophrenia-associated variation in AMBRA1 alters impulsivity-related traits.

Recently, genome-wide association between schizophrenia and an intronic variant in AMBRA1 (rs11819869) was reported. Additionally, in a reverse genetic approach in adult healthy subjects, risk allele carriers showed a higher medial prefrontal cortex blood oxygen level-dependent (BOLD) response during a flanker task examining motor inhibition as an aspect of impulsivity. To test whether this finding can be expanded to further aspects of impulsivity, we analysed the effects of the rs11819869 genotype on impulsivity-related traits on a behavioral, temperament and neural level in a large sample of healthy adolescents. We consider this reverse genetic approach specifically suited for use in a healthy adolescent sample, as these individuals comprise those who will eventually develop mental disorders in which impulsivity is implicated. Healthy adolescents from the IMAGEN study were included in the neuropsychological analysis (n = 848) and a functional magnetic resonance imaging (fMRI) task (n = 512). Various aspects of impulsivity were assessed using the Temperament and Character Inventory-Revised, the Substance Use Risk Profile Scale, the Cambridge Cognition Neuropsychological Test Automated Battery, and the Stop Signal Task (SST) in the fMRI paradigm. On a behavioral level, increased delay aversion was observed in risk allele carriers. Furthermore, risk allele carriers showed a higher BOLD response in an orbito-frontal target region during the SST, which declined to trend status after Family Wise Error correction. Our findings support the hypothesis that the schizophrenia-related risk variant of rs11819869 is involved in various aspects of impulsivity, and that this involvement occurs on a behavioral as well as an imaging genetics level.

The risk variant in ODZ4 for bipolar disorder impacts on amygdala activation during reward processing.

OBJECTIVES: Bipolar disorder is a severe mood disorder, which normally begins during adolescence or early adulthood and has a heritability of up to 80%. The largest genome-wide association analysis of bipolar disorder recently identified a new genome-wide associated variant in OZD4 (rs12576775). The aim of the present study was to further elucidate the role of this risk variant in the disease process using an imaging genetics approach. As increased amygdala and striatal responses during the processing of reward and emotion are characteristic for bipolar disorder patients, it was tested whether the risk variant has an influence on this endophenotype in healthy adolescents. METHODS: We examined the impact of the risk variant rs12576775 on functional magnetic resonance imaging data in an adolescent sample (N = 485). Differential activation between carriers of the risk allele (G-allele) and homozygous A-allele carriers in the amygdala and the striatum during a modification of the monetary incentive delay task (examining reward) and a face task (examining emotion) was analyzed. RESULTS: Carriers of the risk allele showed an increased blood oxygen level-dependent response in the amygdala during reward sensitivity (p = 0.05) and reward expectation (p < 0.05) but not during the face task. No significant group differences were found in the striatum during both reward and emotion processing. CONCLUSION: Our results indicate that the ODZ4 risk variant influences reward processing in the amygdala. Alterations in the processing of emotion may have different underlying mechanisms and need to be further examined.

Fostering socio-emotional competencies in children on the autism spectrum using a parent-assisted serious game: A multicenter randomized controlled trial.

OBJECTIVE: Serious games are a promising means of fostering socio-emotional skills in children on the autism spectrum (AS). However, empathy and related constructs have not yet been addressed comprehensively and together with emotion recognition, and there is a lack of randomized controlled trials (RCT) to investigate skill maintenance and the transfer to functional behavior. METHOD: The manualized, parent-assisted serious game Zirkus Empathico (ZE) was tested against an active control group, in a six-week multicenter RCT. Eighty-two children aged 5-10 years on the AS were assessed at baseline, post-treatment, and three-month follow-up. Empathy and emotion recognition skills were defined as the primary outcomes. The secondary outcomes included measures of emotional awareness, emotion regulation, autism social symptomatology (Social Responsiveness Scale), and subjective therapy goals. RESULTS: Training effects were observed after the intervention for empathy (d = 0.71) and emotion recognition (d = 0.50), but not at follow-up. Moderate effects on emotional awareness, emotion regulation, and autism social symptomatology were indicated by the short and mid-term assessments. Parents reported treatment goal attainment and positive training transfer. CONCLUSION: While a six-week training with ZE failed to induce lasting changes in empathy and emotion recognition, it may be effective for improving emotional awareness and emotion regulation, and mitigate general autism symptomatology. CLINICAL TRIAL REGISTRATION INFORMATION: Zirkus Empathico - Promoting socioemotional competencies in 5- to 10-year-old children with autism spectrum conditions using a computer-based training program; https://www.drks.de/; DRKS-ID: DRKS00009337; Universal Trial Number (UTN): U1111-1175-5451.

COMT Val158Met Polymorphism and Social Impairment Interactively Affect Attention-Deficit Hyperactivity Symptoms in Healthy Adolescents.

The dopaminergic system has been shown to have substantial effects on the etiology of attention-deficit hyperactivity disorder (ADHD). However, while some studies found a significant direct effect, others did not. In this context, social behavior might play an important role as a factor that is related both to the dopaminergic system and ADHD. In a large epidemiological sample of adolescents (N = 462; 16-17 years), we assessed the level of ADHD symptoms using the Strengths and Difficulties Questionnaire, social behavior using the Social Responsiveness Scale, and the allelic distribution of the dopaminergic catechol-O-methyltransferase (COMT) Val158Met polymorphism. We found a significant association between COMT and social impairment, insofar as Met-allele carriers showed increased levels of social impairment. Moreover, social impairment significantly determined an association between COMT and ADHD (explained variance: 19.09%). This effect did not significantly differ between males and females. COMT and social impairment might interactively affect ADHD symptomatology, and could thus represent significant gene-phenotypic risk factors for ADHD symptomatology. This might have interesting implications for prevention and intervention strategies with a focus on social behavior in genetically at-risk individuals.

Neurofeedback of Slow Cortical Potentials in Children with Attention-Deficit/Hyperactivity Disorder: A Multicenter Randomized Trial Controlling for Unspecific Effects.

Background: Neurofeedback (NF) in children with attention-deficit/hyperactivity disorder (ADHD) has been investigated in a series of studies over the last years. Previous studies did not unanimously support NF as a treatment in ADHD. Most studies did not control for unspecific treatment effects and did not demonstrate that self-regulation took place. The present study examined the efficacy of NF in comparison to electromyographic (EMG) feedback to control for unspecific effects of the treatment, and assessed self-regulation of slow cortical potentials (SCPs). Methods: A total of 150 children aged 7-9 years diagnosed with ADHD (82% male; 43% medicated) were randomized to 25 sessions of feedback of SCPs (NF) or feedback of coordination of the supraspinatus muscles (EMG). The primary endpoint was the change in parents' ratings of ADHD core symptoms 4 weeks after the end of treatment compared to pre-tests. Results: Children in both groups showed reduced ADHD-core symptoms (NF 0.3, 95% CI -0.42 to -0.18; EMG 0.13, 95% CI -0.26 to -0.01). NF showed a significant superiority over EMG (treatment difference 0.17, 95% CI 0.02-0.3, p = 0.02). This yielded an effect size (ES) of d = 0.57 without and 0.40 with baseline observation carried forward (BOCF). The sensitivity analysis confirmed the primary result. Successful self-regulation of brain activity was observed only in NF. As a secondary result teachers reported no superior improvement from NF compared to EMG, but within-group analysis revealed effects of NF on the global ADHD score, inattention, and impulsivity. In contrast, EMG feedback did not result in changes despite more pronounced self-regulation learning. Conclusions: Based on the primary parent-rated outcome NF proved to be superior to a semi-active EMG feedback treatment. The study supports the feasibility and efficacy of NF in a large sample of children with ADHD, based on both specific and unspecific effects. Trial Register: Current controlled trials ISRCTN76187185, registered 5 February 2009.

Impact of ADHD symptoms on autism spectrum disorder symptom severity.

Despite the official exclusion criteria for autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) in the DSM-IV and ICD-10, patients with ASD often show ADHD symptoms. We aimed to examine the potential influence of ADHD symptoms on autistic psychopathology in a large sample of patients with ASD. We tested the hypothesis that patients with ASD and an additional ADHD (ASD+) would show a higher severity of autistic symptoms than those with ASD only (ASD-). We measured autistic symptoms using the autism diagnostic observation schedule (ADOS-G), the autism diagnostic interview (ADI-R), and the social responsiveness scale (SRS). To measure overall psychopathology and ADHD symptoms, we used the child behavior checklist (CBCL) and the ADHD rating scale (FBB-ADHS), respectively. Group differences between the ASD+ and the ASD- group (group division was conducted according to the results of the FBB-ADHS) were calculated using a univariate analysis of variance (ANOVA). The ASD+ group showed a greater severity of autistic symptoms than the ASD- group, measured by the SRS and the ADI-R. Especially in the social interaction subscale (ADI-R), a significantly higher symptom severity was found in the ASD+ group. No significant group differences were found regarding autistic symptoms measured by the ADOS-G. Patients with ASD and an additional ADHD expressed a stronger severity of autistic symptoms than patients with ASD only. According to our results, the possibility of a co-diagnosis of ADS and ADHD, as is being planned in the DSM-5, is in line with earlier studies, is highly reasonable, will simplify research, and have therapeutic implications.