Atypical Arousal Regulation in Children With Autism but Not With Attention-Deficit/Hyperactivity Disorder as Indicated by Pupillometric Measures of Locus Coeruleus Activity.

BACKGROUND: Atypical arousal regulation may explain slower mean reaction time (MRT) in autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder compared with typical development. The locus coeruleus-norepinephrine system (LC-NE) underlies arousal regulation and adapts its activity to the utility of a task. LC-NE tonic and phasic activity are indexed by baseline pupil size (BPS) and stimulus-evoked pupillary response (SEPR). METHODS: The study assessed pupillometry in ASD (n = 31, 3 female/28 male), attention-deficit/hyperactivity disorder (n = 28, 3 female/25 male), and typically developing control subjects (n = 31, 16 female/15 male) during a visuospatial reaction-time task that manipulates arousal by conditions with low and high task utility. We estimated linear mixed models of BPS, SEPR, and MRT in a per-trial analysis to investigate arousal regulation of task performance. RESULTS: Slower MRT occurred in the ASD group compared with the typically developing control group during low-utility conditions while controlling for dimensional ASD and attention-deficit/hyperactivity disorder symptoms. In low-utility conditions, BPS and SEPR were inversely related and both were associated with faster MRT. Increased ASD symptoms across groups were associated with higher BPS during low-utility conditions. Changes in BPS and SEPR between task-utility conditions were smaller in the ASD group. CONCLUSIONS: Slower visuospatial task performance in ASD is specific to low task utility. Arousal was associated with task performance and showed altered activity in ASD. Increased BPS during low-utility conditions suggested increased LC-NE tonic activity as an ASD symptom marker in children. Smaller changes in BPS and SEPR in ASD indicated attenuated LC-NE activity adaptation in response to high-utility conditions. Slower performance and atypical arousal regulation are probably associated with attenuated LC-NE activity adaptation.

The Revised Children's Communication Checklist-2 (CCC-R): Factor Structure and Psychometric Evaluation.

The Children's Communication Checklist-2 (CCC-2) is often applied to assess pragmatic language impairment which is highly prevalent in autism spectrum disorder (ASD) and several mental health conditions. We replicated previous findings on the limited applicability of the CCC-2 in clinical samples and the inconsistent findings concerning the factor structure. The aim of the present study was, thus, to develop a concise, simplified, and revised version of the CCC-2 in a large German-speaking sample. Four groups of children and adolescents aged 4 to 17 years were included: ASD (n = 195), intellectual disability (ID, n = 83), diverse mental health conditions (MHC, n = 144) and a typically developing control group (TD, n = 417). We reduced the original number of items from 70 to 39, based on item analysis, exploratory factor analysis and the exclusion of communication-unrelated items. The revised version, CCC-R (α = 0.96), consists of two empirically derived factors: a pragmatic-language (α = 0.96) and a grammatical-semantic-language factor (α = 0.93). All clinical groups (ASD, ID, and MHC) had significantly increased CCC-R total scores, with the highest scores being in the neurodevelopmental disorder groups (ASD and ID). In addition, we found group-specific patterns of elevated pragmatic-language scores in the ASD group and grammatical-semantic scores in the ID group. The CCC-R was comparable to the CCC-2 in distinguishing ASD from the other groups. The CCC-R is proposed as a simplified and easily applied, clinical questionnaire for caregivers, assessing pragmatic language impairments across neurodevelopmental disorders and mental health conditions. LAY SUMMARY: The CCC-2 is a questionnaire designed to identify children who have problems in the social use of language, however, it is limited in its clinical application and exhibits inconsistent factors. We have created a shorter and simpler version of the CCC-2 that we have called the CCC-R which overcomes the previous limitations of the CCC-2. It consists of two subscales: pragmatic language and grammatical-semantic language. The CCC-R can be used as a short and clinically relevant caregiver questionnaire which assesses pragmatic language impairments in children and adolescents. Autism Res 2021, 14: 759-772. © 2021 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals LLC.

Repetitive Behavior in Children and Adolescents: Psychometric Properties of the German Version of the Repetitive Behavior Scale-Revised.

Restricted repetitive behaviors (RRBs) are a core feature of autism spectrum disorders (ASD) and further occur in intellectual disability (ID), mental disorders (MD), and in typically developed people (TD). There is a need of a valid and reliable measure to record RRBs as transdiagnostic symptom, which captures RRBs heterogeneity and evaluates severity. The Repetitive Behavior Scale-Revised (RBS-R) is an established screening instrument for RRBs, but was predominantly limited to ASD samples. We examined the psychometric properties of the German version of the RBS-R in 948 participants with ASD, ID, MD and TD aged 4 to 17 years. The suitability was proofed delivering a four-factor solution, good internal consistency, external validity as well as group, age, and sex effects.

Pupil dilation during visuospatial orienting differentiates between autism spectrum disorder and attention-deficit/hyperactivity disorder.

BACKGROUND: Previous research demonstrated atypical attention in children with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Regarding visual orienting, findings suggest a differential impairment: Atypical orienting to relatively unexpected targets in ASD, and atypical processing of alerting cues in ADHD. The locus coeruleus-norepinephrine (LC-NE) system plays an important role in exploiting alerting cues to increase attention and task performance. The present study's aim was to examine differential subcortical processes underlying visual orienting in ASD and ADHD with pupil dilation (PD) as index of LC activity. METHODS: Pupil dilation (PD) progression metrics during visual orienting were calculated for task-evoked PD locked to cue, stimulus onset, and behavioral response. Group differences in PD and reaction time (RT) were compared between children with ASD without ADHD (ASD-) (N = 18), ADHD without ASD (ADHD-) (N = 28), both disorders (ASD + ADHD) (N = 14), and typically developing children (TD) (N = 31) using linear mixed models (LMM). To further explore the modulatory role of the LC-NE system group differences in the effect of task-evoked PD metrics on RT were examined exploratively. RESULTS: ASD (+ADHD) showed slower orienting responses to relatively unexpected spatial target stimuli as compared to TD, which was accompanied by higher PD amplitudes relative to ADHD- and TD. In ADHD-, shorter cue-evoked PD latencies relative to ASD-, ASD + ADHD, and TD were found. Group differences in the effect of cue- and stimulus-evoked PD amplitudes on RT were found in ASD- relative to TD. CONCLUSIONS: Study findings provide new evidence for a specific role of the LC-NE system in impaired reflexive orienting responses in ASD, and atypical visual processing of alerting cues in ADHD.

Attention as neurocognitive endophenotype of ADHD across the life span: a family study.

Endophenotypes mediate pathways between genetic variations and the psychiatric phenotype, or share genetic risk with the psychiatric phenotype. Identifying endophenotypes is an important step to unravel disease pathways underlying complex psychiatric phenotypes such as ADHD. Potential viable endophenotypes for ADHD across the lifespan are neurocognitive measures of basic attention functions, such as sustained attention, and executive attention functions (EF), such as inhibition. The present study evaluated the endophenotype criteria of familiality and state-independency for measures of basic attention and EF in affected- and unaffected parents of children with ADHD (N = 139), and typically developing children (N = 60). In addition, the added value of neurocognitive measures relative to questionnaire data in genetically informed designs was explored by comparing the intergenerational transmission of neurocognitive measures to those of ADHD symptom scores. Results revealed small-to-medium-sized familial effects of ADHD for reaction time measures of EF components and state-independency given familial effects. Parent-child correlations as estimates of intergenerational transmission of those neurocognitive measures were not higher than those of behavioral ADHD symptom ratings. Taken together, our results argue against neurocognitive measures as pivotal endophenotypes for ADHD across the lifespan. If studied as neurocognitive endophenotypes of ADHD in adults, reaction time measures of executive-rather than basic attention function-seem to be more sensitive.

Sensitivity and Specificity of the ADOS-2 Algorithm in a Large German Sample.

The aim of the present study was to establish diagnostic validity of the new algorithm of the Autism Diagnostic Observation Scale, the ADOS-2, to differentiate between ASD and other clinically relevant psychiatric and developmental disorders in a large German sample. Validity of ADOS and ADOS-2 diagnostic algorithms was established in 826 individuals (n = 455 autism, n = 216 autism spectrum, n = 155 non-ASD patients) by receiver operating curves. Confidence intervals overlapped largely for ADOS and ADOS-2 algorithms, confirming diagnostic validity of both algorithms. Adding information of the Social Communication Questionnaire and the Social Responsiveness Scale resulted in slightly improved classification rates for autism in Module 4. We thus replicated previous findings of the diagnostic validity of the ADOS-2 algorithms.

Neural modulation of social reinforcement learning by intranasal oxytocin in male adults with high-functioning autism spectrum disorder: a randomized trial.

Reduced social motivation is a hallmark of individuals with autism spectrum disorders (ASDs). Although the exact neural mechanisms are unclear, oxytocin has been shown to enhance motivation and attention to social stimuli, suggesting a potential to augment social reinforcement learning as the central mechanism of behavioral interventions in ASD. We tested how reinforcement learning in social contexts and associated reward prediction error (RPE) signals in the nucleus accumbens (NAcc) were modulated by intranasal oxytocin. Male adults with a childhood diagnosis of ASD (n = 15) and healthy controls (n = 24; aged 18-26 years) performed a probabilistic reinforcement learning task during functional magnetic resonance imaging in a single-center (research center in Germany), randomized double-blind, placebo-controlled cross-over trial. The interventions were intranasal oxytocin (Syntocinon®, Novartis; 10 puffs = 20 international units (IUs) per treatment) and placebo spray. Using computational modeling of behavioral data, trial-by-trial RPE signals were assessed and related to brain activation in NAcc during reinforcing feedback in social and non-social contexts. The order of oxytocin/placebo was randomized for 60 participants. Twenty-one participants were excluded from analyses, leaving 39 for the final analysis. Behaviorally, individuals with ASD showed enhanced learning under oxytocin when the learning target as well as feedback was social as compared to non-social (social vs. non-social target: 87.09% vs. 71.29%, 95% confidence interval (CI): 7.28-24.33, p = .003; social vs. non-social feedback: 81.00% vs. 71.29%, 95% CI: 2.81-16.61, p = .027). Correspondingly, oxytocin enhanced the correlation of the RPE signal with NAcc activation during social (vs. non-social) feedback in ASD (3.48 vs. -1.12, respectively, 95% CI: 2.98-6.22, p = .000), whereas in controls, this effect was found in the placebo condition (2.90 vs. -1.14, respectively, 95% CI: 1.07-7.01, p = .010). In ASD, a similar pattern emerged when the learning target was social (3.00 vs. -0.64, respectively, 95% CI: -0.13 to 7.41, p = .057), whereas controls showed a reduced correlation for social learning targets under oxytocin (-0.70 vs. 2.72, respectively, 95% CI: -5.86 to 0.98, p = .008). The current data suggest that intranasal oxytocin has the potential to enhance social reinforcement learning in ASD. Future studies are warranted that investigate whether oxytocin can potentiate social learning when combined with behavioral therapies, resulting in greater treatment benefits than traditional behavior-only approaches.

Facilitation of biological motion processing by group-based autism specific social skills training.

Abnormalities in neurophysiological correlates of social perception are a well-known feature of autism spectrum disorder (ASD). However, little is known if and how ASD specific behavioral interventions may affect neural processing in ASD. The aim of the current study was to investigate for the first time, whether the group-based social skills training SOSTA-FRA would elicit changes in neurophysiological correlates of social perception in high-functioning ASD individuals aged 8-17 years. Event-related potentials (ERPs) of a facial emotion recognition (FER) and a biological motion perception task were examined. ERPs were compared between a randomized intervention and a treatment as usual group at three time points (baseline, post-intervention, and at 3 months follow-up). A reduction of P100 amplitude in the right hemisphere and a trend toward reduced N200 latency in the biological motion task were found after the training only in the intervention group, whereas behavioral performance remained stable. Change in N200 latencies and parent-rated social responsiveness showed small but statistically nonsignificant correlations. No changes were observed regarding FER. Results indicate that the intervention changed neural correlates of social perception in ASD. Especially neural correlates of biological motion perception, which is an important prerequisite for successful social interaction, were sensitive to change. ERPs of social perception tasks that are impaired in ASD can well be used to objectively measure neural processing improvement by behavioral intervention. Autism Res 2018, 11: 1376-1387. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: It is well known that people with autism spectrum disorder (ASD) process social information differently than other people and that these differences can also be seen in their brain activity. We also know that behavioral therapies, such as group-based social skills trainings can help people with ASD improve their behavior. But it is unclear how therapy changes social processing in the brain. The aim of our study was therefore to examine how neural processing of social stimuli changed after behavioral intervention. Comparing a group of children and adolescents that received the group-based social skills training SOSTA-FRA to a control group we found that the neural processing of human motion became faster and involved less brain resources after the intervention, while behavioral performance remained stable. No changes were seen for the processing of emotional facial expressions. We recommend that future studies should also analyze changes in brain function as well as behavioral changes as a secondary therapy outcome parameter.

Neural Correlates of Explicit Versus Implicit Facial Emotion Processing in ASD.

The underlying neural mechanisms of implicit and explicit facial emotion recognition (FER) were studied in children and adolescents with autism spectrum disorder (ASD) compared to matched typically developing controls (TDC). EEG was obtained from N = 21 ASD and N = 16 TDC. Task performance, visual (P100, N170) and cognitive (late positive potential) event-related-potentials, as well as coherence were compared across groups. TDC showed a task-dependent increase and a stronger lateralization of P100 amplitude during the explicit task and task-dependent modulation of intra-hemispheric coherence in the beta band. In contrast, the ASD group showed no task dependent modulation. Results indicate disruptions in early visual processing and top-down attentional processes as contributing factors to FER deficits in ASD.

[Pre- and perinatal risk factors in autism spectrum disorder and attention deficit/hyperactivity disorder]. / Prä- und perinatale Risikofaktoren bei Autismus-Spektrum-Störung und Aktivitäts- und Aufmerksamkeitsstörung.

Objective: Epidemiological studies indicate the relevance of pre- and perinatal risk factors for the genesis of attention deficit/hyperactivity disorder and autism spectrum disorder. This study compares potential risk factors in a clinical sample of children with ADHD, ASD, the combination of both diseases, ADHD and oppositional defiant or conduct disorder (ADHD & ODD/CD) and examined whether the existence of additional risk factors promotes the occurrence of combined diseases. Method: We compared the pre- and perinatal risk factors of 341 patients (299 boys, 42 girls) from a clinical population, differentiating between children with ADHD (n=80), ASD (n=122), ADHD & ASD (n=55), or ADHD & ODD/CD (n=84). Results: We observed a higher rate of maternal smoking, a higher rate of migration, and lower parental education among the children with ADHD & ODD/CD compared to those with ASD or ADHD. The rate of migration background was higher among the children with ASD compared to children with ADHD. Miscarriage was a specific risk factor for ADHD & ASD. Conclusion: Numerous risk factors described in epidemiological studies occurred only rarely in our clinical sample. The distribution of most risk factors was comparable between the examined diseases.

Classifying Autism Spectrum Disorders by ADI-R: Subtypes or Severity Gradient?

To reduce phenotypic heterogeneity of Autism spectrum disorders (ASD) and add to the current diagnostic discussion this study aimed at identifying clinically meaningful ASD subgroups. Cluster analyses were used to describe empirically derived groups based on the Autism Diagnostic Interview-revised (ADI-R) in a large sample of n = 463 individuals with ASD aged 3-21. Three clusters were observed. Most severely affected individuals regarding all core symptoms were allocated to cluster 2. Cluster 3 comprised moderate symptom severity of social communication impairments (SCI) and less stereotyped repetitive behavior (RRB). Minor SCI and relatively more RRB characterized cluster 1. This study offers support for both, a symptom profile, and a gradient model of ASD within the spectrum due to the sample included.

Group-based cognitive behavioural psychotherapy for children and adolescents with ASD: the randomized, multicentre, controlled SOSTA-net trial.

BACKGROUND: Group-based psychotherapy in Autism Spectrum Disorder (ASD) has predominantly been studied in the United States by small studies in school-aged children without long-term follow-up. We report results of a large, confirmatory, multicentre randomized-controlled phase-III trial in children and adolescents studying the ASD specific, manualized group-based cognitive behavioural SOSTA-FRA approach. METHODS: High-functioning ASD individuals aged 8-19 years old were randomized to 12 sessions SOSTA-FRA or treatment as usual. Primary outcomes were change in total raw score of the parent-rated Social Responsiveness Scale (pSRS) between baseline (T2) and end of intervention (T4), and between T2 and 3 months after end of intervention (T5). TRIAL REGISTRATION: ISRCTN94863788. RESULTS: Between 20/5/2010 and 14/2/2013, n = 320 ASD patients were screened, n = 228 patients were randomized, and N = 209 analysed. Mean pSRS difference between groups at T4 was -6.5 (95% CI -11.6 to - 1.4; p = .013), and at T5 -6.4 (-11.5 to -1.3, p = .015). Pre-treatment SRS and IQ were positively associated with stronger improvement at T4 and T5. CONCLUSIONS: Short-term ASD-specific add-on group-based psychotherapy has shown postintervention efficacy with regard to parent-rated social responsiveness predominantly in male high-functioning children and adolescents with ASD. Future studies should implement blinded standardized observational measures of peer-related social interaction.

Can autism spectrum disorders and social anxiety disorders be differentiated by the social responsiveness scale in children and adolescents?

Autism spectrum disorder (ASD) as well as social phobia (SP), and selective mutism (SM) are characterised by impaired social interaction. We assessed the validity of the Social Responsiveness Scale (SRS) to differentiate between ASD, and SP/SM. Raw scores were compared in 6-18 year old individuals with ASD (N = 60), SP (N = 38), SM (N = 43), and typically developed (N = 42). Sensitivity and specificity were examined. The three disorders showed overlapping SRS scores. Especially in boys with SM (ROC-AUC = .81), presence of ASD was overestimated by the SRS. A combination of three disorder specific questionnaires resulted in marginally improved diagnostic accuracy. For the clinically very relevant differential diagnosis of SP/SM, SRS results must be interpreted with caution.

Validity of the social responsiveness scale to differentiate between autism spectrum disorders and disruptive behaviour disorders.

Autism spectrum disorder (ASD) as well as oppositional defiant (ODD) and conduct disorder (CD) is characterised by difficulties in social interaction with peers. The Social Responsiveness Scale (SRS) measures reciprocal social behaviour in children and adolescents and was originally developed as a quantitative measure of autistic traits. In the present study, we compare parent-rated SRS scores in children with ODD, CD, and ASD and examine the diagnostic validity of the SRS alone and in combination with additional questionnaires to differentiate between groups. We hypothesize that the SRS better differentiates ASD and typically developing controls (TD) than ASD and the disruptive behaviour disorders ODD and CD. The sample consists of three clinical groups: ASD without comorbid intellectual delay (N = 55), ODD/CD (N = 55), and TD (N = 55), between 6 and 18 years. The groups were matched by age, sex, and IQ. SRS scores were compared for the three groups. Sensitivity and specificity of the SRS total and sub-scores were examined by receiver operating characteristics (ROC) analyses. Logistic regression analyses were calculated for estimating the rate of correctly specified individuals. The SRS differentiated excellently between ASD and TD (ROC-AUC = 1.00), but sensitivity and specificity were considerably lower when ASD was compared with ODD/CD (ROC-AUC = 0.82). A combination of three parent-rated questionnaires resulted in an improved validity to differentiate ASD and ODD/CD. For clinical screening purposes in children suspicious of ASD and/or ODD/CD, the SRS should be used in combination with additional disorder-specific questionnaires to improve the rate of correct classification of both disorders.

The group-based social skills training SOSTA-FRA in children and adolescents with high functioning autism spectrum disorder--study protocol of the randomised, multi-centre controlled SOSTA--net trial.

BACKGROUND: Group-based social skills training (SST) has repeatedly been recommended as treatment of choice in high-functioning autism spectrum disorder (HFASD). To date, no sufficiently powered randomised controlled trial has been performed to establish efficacy and safety of SST in children and adolescents with HFASD. In this randomised, multi-centre, controlled trial with 220 children and adolescents with HFASD it is hypothesized, that add-on group-based SST using the 12 weeks manualised SOSTA-FRA program will result in improved social responsiveness (measured by the parent rated social responsiveness scale, SRS) compared to treatment as usual (TAU). It is further expected, that parent and self reported anxiety and depressive symptoms will decline and pro-social behaviour will increase in the treatment group. A neurophysiological study in the Frankfurt HFASD subgroup will be performed pre- and post treatment to assess changes in neural function induced by SST versus TAU. METHODS/DESIGN: The SOSTA - net trial is designed as a prospective, randomised, multi-centre, controlled trial with two parallel groups. The primary outcome is change in SRS score directly after the intervention and at 3 months follow-up. Several secondary outcome measures are also obtained. The target sample consists of 220 individuals with ASD, included at the six study centres. DISCUSSION: This study is currently one of the largest trials on SST in children and adolescents with HFASD worldwide. Compared to recent randomised controlled studies, our study shows several advantages with regard to in- and exclusion criteria, study methods, and the therapeutic approach chosen, which can be easily implemented in non-university-based clinical settings. TRIAL REGISTRATION: ISRCTN94863788--SOSTA--net: Group-based social skills training in children and adolescents with high functioning autism spectrum disorder.