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Background: The diagnosis of attention-deficit/hyperactivity disorder (ADHD) in adolescence and adulthood is particularly challenging because retrospective confirmation of previous childhood ADHD is mandatory. Therefore, collecting valid diagnostic information about behavior at school is important. Primary school reports often contain descriptions of academic performance and social behaviors associated with ADHD criteria. Yet, there is no systematic approach available how to assess such reports quantitatively, and therefore, there is also no study on how valid such an approach could predict an ADHD diagnosis., Methods: We examined primary school reports from Germany (ADHD: n = 1197, typically developing controls: n = 656) for semantic references to ICD-10/DSM-5 main and sub-criteria of ADHD. Descriptions were assessed on a quantitative scale (blinded clinical expert rating) for disorder-associated behaviors (symptoms scale) as well as for desired, adaptive behaviors (competencies scale) according to these criteria. The scores of these developed scales have been summarized to summary scores. Scores were analyzed using linear mixed models, and sensitivity and specificity were estimated using receiver operating characteristics (ROC)., Results: Ratings showed highly significant differences between school reports of children with and without ADHD. For the summary scores, both symptoms and competencies scales showed high diagnostic accuracy (ROC area under the curve at least 0.96) with best discrimination when combining both into an integrated index (sensitivity and specificity > 0.97)., Conclusions: Our findings suggest that systematic quantitative analysis of primary school reports should be further explored to construct a valid instrument for retrospective assessment of childhood ADHD criteria to aid the diagnostic process in adolescents and adults., (© 2024. The Author(s).)

Difficulties in emotion regulation (ER) are thought to contribute to the development and maintenance of major depression (MD) in adolescents. In healthy adults, a task-based training of ER has previously proven effective to reduce stress, but no such studies are available for MD. It is also unclear whether findings can be generalized onto adolescent populations. The final sample consisted of n = 70 adolescents with MD, who were randomized to a task-based ER training ( n = 36) or a control training ( n = 34). Across four sessions, the ER group was trained to downregulate negative affect to negative images via reappraisal, while the control group was instructed to attend the images. Rumination, stress-, and affect-related measures were assessed as primary outcomes, behavioral and neurophysiological responses (late positive potential, LPP), as secondary outcomes. The trial was preregistered at clinicaltrials.gov (NCT03957850). While there was no significant differential effect of the ER training on primary outcomes, we found small to moderate effects on rumination in the ER group, but not the control group. During reappraisal (compared to attend), the ER group showed an unexpected increase of the LPP during the first, but not during later training sessions. Although replication in large, multicenter trials is needed, our findings on effect sizes suggest that ER training might be promising to decrease rumination in adolescent MD. The LPP increase at the first session may represent cognitive effort, which was successfully reduced over the sessions. Future studies should research whether training effects transfer to daily life and are durable over a longer time period. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Altered nonverbal communication patterns especially with regard to gaze interactions are commonly reported for persons with autism spectrum disorder (ASD). In this study we investigate and differentiate for the first time the interplay of attention allocation, the establishment of shared focus (eye contact and joint attention) and the recognition of intentions in gaze interactions in adults with ASD compared to control persons. Participants interacted via gaze with a virtual character (VC), who they believed was controlled by another person. Participants were instructed to ascertain whether their partner was trying to interact with them. In fact, the VC was fully algorithm-controlled and showed either interactive or non-interactive gaze behavior. Participants with ASD were specifically impaired in ascertaining whether their partner was trying to interact with them or not as compared to participants without ASD whereas neither the allocation of attention nor the ability to establish a shared focus were affected. Thus, perception and production of gaze cues seem preserved while the evaluation of gaze cues appeared to be impaired. An additional exploratory analysis suggests that especially the interpretation of contingencies between the interactants' actions are altered in ASD and should be investigated more closely., (© 2024. The Author(s).)

The Prechtl General Movements Assessment (GMA) has become a clinician and researcher toolbox for evaluating neurodevelopment in early infancy. Given that it involves the observation of infant movements from video recordings, utilising smartphone applications to obtain these recordings seems like the natural progression for the field. In this review, we look back on the development of apps for acquiring general movement videos, describe the application and research studies of available apps, and discuss future directions of mobile solutions and their usability in research and clinical practice. We emphasise the importance of understanding the background that has led to these developments while introducing new technologies, including the barriers and facilitators along the pathway. The GMApp and Baby Moves apps were the first ones developed to increase accessibility of the GMA, with two further apps, NeuroMotion and InMotion , designed since. The Baby Moves app has been applied most frequently. For the mobile future of GMA, we advocate collaboration to boost the field's progression and to reduce research waste. We propose future collaborative solutions, including standardisation of cross-site data collection, adaptation to local context and privacy laws, employment of user feedback, and sustainable IT structures enabling continuous software updating.

In behavioral research and clinical practice video data has rarely been shared or pooled across sites due to ethical concerns of confidentiality, although the need of shared large-scaled datasets remains increasing. This demand is even more imperative when data-heavy computer-based approaches are involved. To share data while abiding by privacy protection rules, a critical question arises whether efforts at data de-identification reduce data utility? We addressed this question by showcasing an established and video-based diagnostic tool for detecting neurological deficits. We demonstrated for the first time that, for analyzing infant neuromotor functions, pseudonymization by face-blurring video recordings is a viable approach. The redaction did not affect classification accuracy for either human assessors or artificial intelligence methods, suggesting an adequate and easy-to-apply solution for sharing behavioral video data. Our work shall encourage more innovative solutions to share and merge stand-alone video datasets into large data pools to advance science and public health., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Humans synchronize with one another to foster successful interactions. Here, we use a multimodal data fusion approach with the aim of elucidating the neurobiological mechanisms by which interpersonal neural synchronization (INS) occurs. Our meta-analysis of 22 functional magnetic resonance imaging and 69 near-infrared spectroscopy hyperscanning experiments (740 and 3721 subjects) revealed robust brain regional correlates of INS in the right temporoparietal junction and left ventral prefrontal cortex. Integrating this meta-analytic information with public databases, biobehavioral and brain-functional association analyses suggested that INS involves sensory-integrative hubs with functional connections to mentalizing and attention networks. On the molecular and genetic levels, we found INS to be associated with GABAergic neurotransmission and layer IV/V neuronal circuits, protracted developmental gene expression patterns, and disorders of neurodevelopment. Although limited by the indirect nature of phenotypic-molecular association analyses, our findings generate new testable hypotheses on the neurobiological basis of INS., Competing Interests: Conflicts of interest SHK is an employee of MEDIACC GmbH, Berlin, Germany, an independent clinical research organization, and received payments to consult with Mendi Innovations AB, Stockholm, Sweden. LB receives commissions for fNIRS visualizations. The remaining authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Diagnostic assessment of ASD requires substantial clinical experience and is particularly difficult in the context of other disorders with behavioral symptoms in the domain of social interaction and communication. Observation measures such as the Autism Diagnostic Observation Schedule (ADOS) do not take into account such co-occurring disorders., Method: We used a well-characterized clinical sample of individuals (n = 1,251) that had received detailed outpatient evaluation for the presence of an ASD diagnosis (n = 481) and covered a range of additional overlapping diagnoses, including anxiety-related disorders (ANX, n = 122), ADHD (n = 439), and conduct disorder (CD, n = 194). We focused on ADOS module 3, covering the age range with particular high prevalence of such differential diagnoses. We used machine learning (ML) and trained random forest models on ADOS single item scores to predict a clinical best-estimate diagnosis of ASD in the context of these differential diagnoses (ASD vs. ANX, ASD vs. ADHD, ASD vs. CD), in the context of co-occurring ADHD, and an unspecific model using all available data. We employed nested cross-validation for an unbiased estimate of classification performance and made available a Webapp to showcase the results and feasibility for translation into clinical practice., Results: We obtained very good overall sensitivity (0.89-0.94) and specificity (0.87-0.89). In particular for individuals with less severe symptoms, our models showed increases of up to 35% in sensitivity or specificity. Furthermore, we analyzed item importance profiles of the ANX, ADHD, and CD models in comparison with the unspecific model revealing distinct patterns of importance for specific ADOS items with respect to differential diagnoses., Conclusions: ML-based diagnostic classification may improve clinical decisions by utilizing the full range of information from detailed diagnostic observation instruments such as the ADOS. Importantly, this strategy might be of particular relevance for older children with less severe symptoms for whom the diagnostic decision is often particularly difficult., (© 2022 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Introduction: Theory of mind (ToM) is important for social interactions and typical development and has been found to be impaired in patients with anorexia nervosa (AN) and bulimia nervosa (BN). Hypoactivation in frontotemporal brain regions seems to be the underlying neural mechanism in AN while whole-brain analyses in BN are lacking., Methods: We used the well-validated social recognition task fMRI paradigm to assess ToM in a total of 72 female adolescents (16 BN, 18 AN and 38 matched healthy controls [HC])., Results: Compared to HC BN , patients with BN showed hyperactivity during ToM-activity in the right frontal pole, middle temporal gyrus and left temporal pole and differed fundamentally from hypoactivation in these regions observed in patients with AN before and after short-term weight rehabilitation. Interaction and overlap analyses confirmed that similar regions were affected in opposite directions in both diseases. Hyperactivations in BN in the right middle temporal gyrus and right frontal pole were associated with clinical BN-severity markers binging and purging frequency., Discussion: The hyperactivation in BN suggest different underlying neural mechanisms for ToM compared to AN. Hyperactivity might correspond to a different but also ineffective cognitive style in patients with BN when approaching social interactions. These important transdiagnostic differences are relevant for future brain-targeted therapeutic approaches., (© 2022 The Authors. European Eating Disorders Review published by Eating Disorders Association and John Wiley & Sons Ltd.)

To navigate the social world, humans heavily rely on gaze for non-verbal communication as it conveys information in a highly dynamic and complex, yet concise manner: For instance, humans utilize gaze effortlessly to direct and infer the attention of a possible interaction partner. Many traditional paradigms in social gaze research though rely on static ways of assessing gaze interaction, e.g., by using images or prerecorded videos as stimulus material. Emerging gaze contingent paradigms, in which algorithmically controlled virtual characters can respond flexibly to the gaze behavior of humans, provide high ecological validity. Ideally, these are based on models of human behavior which allow for precise, parameterized characterization of behavior, and should include variable interactive settings and different communicative states of the interacting agents. The present study provides a complete definition and empirical description of a behavioral parameter space of human gaze behavior in extended gaze encounters. To this end, we (i) modeled a shared 2D virtual environment on a computer screen in which a human could interact via gaze with an agent and simultaneously presented objects to create instances of joint attention and (ii) determined quantitatively the free model parameters (temporal and probabilistic) of behavior within this environment to provide a first complete, detailed description of the behavioral parameter space governing joint attention. This knowledge is essential to enable the modeling of interacting agents with a high degree of ecological validity, be it for cognitive studies or applications in human-robot interaction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hartz, Guth, Jording, Vogeley and Schulte-Rüther.)

Brain-to-brain synchrony has been proposed as an important mechanism underlying social interaction. While first findings indicate that it may be modulated in children with autism spectrum disorder (ASD), no study to date has investigated the influence of different interaction partners and task characteristics. Using functional near-infrared spectroscopy hyperscanning, we assessed brain-to-brain synchrony in 41 male typically developing (TD) children (8-18 years; control sample), as well as 18 children with ASD and age-matched TD children (matched sample), while performing cooperative and competitive tasks with their parents and an adult stranger. Dyads were instructed either to respond jointly in response to a target (cooperation) or to respond faster than the other player (competition). Wavelet coherence was calculated for oxy- and deoxyhemoglobin brain signals. In the control sample, a widespread enhanced coherence was observed for parent-child competition, and a more localized coherence for parent-child cooperation in the frontopolar cortex. While behaviorally, children with ASD showed a lower motor synchrony than children in the TD group, no significant group differences were observed on the neural level. In order to identify biomarkers for typical and atypical social interactions in the long run, more research is needed to investigate the neurobiological underpinnings of reduced synchrony in ASD., (© The Author(s) 2020. Published by Oxford University Press.)

Cognitive flexibility helps us to navigate through our ever-changing environment and has often been examined by reversal learning paradigms. Performance in reversal learning can be modeled using computational modeling which allows for the specification of biologically plausible models to infer psychological mechanisms. Although such models are increasingly used in cognitive neuroscience, developmental approaches are still scarce. Additionally, though most reversal learning paradigms have a comparable design regarding timing and feedback contingencies, the type of feedback differs substantially between studies. The present study used hierarchical Gaussian filter modeling to investigate cognitive flexibility in reversal learning in children and adolescents and the effect of various feedback types. The results demonstrate that children make more overall errors and regressive errors (when a previously learned response rule is chosen instead of the new correct response after the initial shift to the new correct target), but less perseverative errors (when a previously learned response set continues to be used despite a reversal) adolescents. Analyses of the extracted model parameters of the winning model revealed that children seem to use new and conflicting information less readily than adolescents to update their stimulus-reward associations. Furthermore, more subclinical rigidity in everyday life (parent-ratings) is related to less explorative choice behavior during the probabilistic reversal learning task. Taken together, this study provides first-time data on the development of the underlying processes of cognitive flexibility using computational modeling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Weiss, Kruppa, Fink, Herpertz-Dahlmann, Konrad and Schulte-Rüther.)

Introduction: Major depression (MD) often has its onset during adolescence and is associated with significant morbidity and mortality. One important factor for the development and maintenance of adolescent MD are disturbances in emotion regulation and the underlying neural processes. Cognitive reappraisal (CR) is a particular adaptive emotion regulation strategy. Previously, it has been shown in healthy adults that a task-based training in CR is efficient to reduce negative affect, and that these effects translate into everyday life.This randomised controlled trial examines for the first time whether a task-based training in CR proves effective in MD adolescents. Specifically, we will investigate whether the CR training improves the ability to downregulate negative affect in MD individuals as assessed by behavioural and neurobiological indices, and whether training effects generalise outside the laboratory., Methods and Analysis: Adolescents with MD will be randomly allocated to a group that either receives a task-based training in CR or a control training. Both involve four training sessions over a time period of 2 weeks. In the CR training, participants will be instructed to downregulate negative affective responses to negative pictures via CR, while the control training involves picture viewing. During the training sessions, the Late Positive Potential, gaze fixations on negative picture aspects and affective responses to pictures will be collected. Before and after the training programmes, and at a 2-week follow-up, overall negative and positive affect, rumination and perceived stress will be assessed as primary outcomes. Analyses of variance will be conducted to test the effectiveness of the CR training with regard to both primary outcomes and task-based behavioural and neurobiological parameters., Ethics and Dissemination: The study was approved by the Ethics Committee of the Medical Faculty of the LMU Munich, Germany. The results will be published in peer-reviewed journals and disseminated through conferences, social media and public events., Trial Registration Details: ClinicalTrials.gov NCT03957850, registered 21 st May 2019; URL: https://clinicaltrials.gov/ct2/show/NCT03957850., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Autism spectrum disorders (ASD) are highly heritable and are characterized by deficits in social communication and restricted and repetitive behaviors. Twin studies on phenotypic subdomains suggest a differing underlying genetic etiology. Studying genetic variation explaining phenotypic variance will help to identify specific underlying pathomechanisms. We investigated the effect of common variation on ASD subdomains in two cohorts including >2500 individuals. Based on the Autism Diagnostic Interview-Revised (ADI-R), we identified and confirmed six subdomains with a SNP-based genetic heritability h 2 SNP  = 0.2-0.4. The subdomains nonverbal communication (NVC), social interaction (SI), and peer interaction (PI) shared genetic risk factors, while the subdomains of repetitive sensory-motor behavior (RB) and restricted interests (RI) were genetically independent of each other. The polygenic risk score (PRS) for ASD as categorical diagnosis explained 2.3-3.3% of the variance of SI, joint attention (JA), and PI, 4.5% for RI, 1.2% of RB, but only 0.7% of NVC. We report eight genome-wide significant hits-partially replicating previous findings-and 292 known and novel candidate genes. The underlying biological mechanisms were related to neuronal transmission and development. At the SNP and gene level, all subdomains showed overlap, with the exception of RB. However, no overlap was observed at the functional level. In summary, the ADI-R algorithm-derived subdomains related to social communication show a shared genetic etiology in contrast to restricted and repetitive behaviors. The ASD-specific PRS overlapped only partially, suggesting an additional role of specific common variation in shaping the phenotypic expression of ASD subdomains.

Background: A deficit in empathy has repeatedly been described in individuals with conduct disorder (CD), and in particular in those with callous unemotional traits. Until now, little is known about the neural basis of empathy in children and adolescents with early onset conduct disorder. The aim of this study was to examine neural responses during empathizing in children and adolescents with CD with a task that allowed to differentiate between the judgment of the emotional states of other people and the own emotional response to other people's emotional state. Moreover, we investigated associations of callous-unemotional traits and neural activations during empathizing. Methods: Using functional magnetic resonance imaging (fMRI) we investigated 14 boys with early onset CD and 15 typically developing (TDC) age matched controls between 8 and 16 years of age. Happy and sad faces were presented, and participants were asked to either infer the emotional state from the face (other-task) or to judge their own emotional response (self-task). A perceptual decision on faces was used as a control task. Individual empathic abilities and callous unemotional traits were assessed. Results: During the other task, TDC boys showed significantly larger right amygdala responses than CD boys. Higher empathic abilities (as assessed with the Bryant Index of Empathy) were associated with higher responses in the right amygdala within the CD boys and across the entire sample. Moreover, across the entire sample, callous-unemotional traits were negatively related to the BOLD-response in the right amygdala. CD boys showed larger responses in the dorsal and ventral medial prefrontal cortex across tasks and increased activation in dorsal medial prefrontal cortex specifically during the self-conditions, which were also related to empathic abilities within the CD boys. Conclusions: The data emphasize the important role of the amygdala in empathy related emotional processing. Diminished amygdala responses and their association with low empathy suggest a pivotal influence of impaired amygdala processing in early-onset CD, in particular for deficits in empathic behavior and related callous-unemotional-traits. Elevated response in the medial prefrontal cortex in boys with CD point toward increased involvement of brain areas related to self-referential processing and cognitive empathy during empathizing., (Copyright © 2020 von Polier, Greimel, Konrad, Großheinrich, Kohls, Vloet, Herpertz-Dahlmann and Schulte-Rüther.)

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.

A negative mood-congruent attention bias has been consistently observed, for example, in clinical studies on major depression. This bias is assumed to be dysfunctional in that it supports maintaining a sad mood, whereas a potentially adaptive role has largely been neglected. Previous experiments involving sad mood induction techniques found a negative mood-congruent attention bias specifically for young individuals, explained by an adaptive need for information transfer in the service of mood regulation. In the present study we investigated the attentional bias in typically developing children (aged 6-12 years) when happy and sad moods were induced. Crucially, we manipulated the age (adult vs. child) of the displayed pairs of facial expressions depicting sadness, anger, fear and happiness. The results indicate that sad children indeed exhibited a mood specific attention bias toward sad facial expressions. Additionally, this bias was more pronounced for adult faces. Results are discussed in the context of an information gain which should be stronger when looking at adult faces due to their more expansive life experience. These findings bear implications for both research methods and future interventions.

Humans substantially rely on non-verbal cues in their communication and interaction with others. The eyes represent a "simultaneous input-output device": While we observe others and obtain information about their mental states (including feelings, thoughts, and intentions-to-act), our gaze simultaneously provides information about our own attention and inner experiences. This substantiates its pivotal role for the coordination of communication. The communicative and coordinative capacities - and their phylogenetic and ontogenetic impacts - become fully apparent in triadic interactions constituted in its simplest form by two persons and an object. Technological advances have sparked renewed interest in social gaze and provide new methodological approaches. Here we introduce the 'Social Gaze Space' as a new conceptual framework for the systematic study of gaze behavior during social information processing. It covers all possible categorical states, namely 'partner-oriented,' 'object-oriented,' 'introspective,' 'initiating joint attention,' and 'responding joint attention.' Different combinations of these states explain several interpersonal phenomena. We argue that this taxonomy distinguishes the most relevant interactional states along their distinctive features, and will showcase the implications for prominent social gaze phenomena. The taxonomy allows to identify research desiderates that have been neglected so far. We argue for a systematic investigation of these phenomena and discuss some related methodological issues.

Background: Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis., Methods: In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0·0156., Findings: Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohen's d=-0·15), amygdala (d=-0·19), caudate (d=-0·11), hippocampus (d=-0·11), putamen (d=-0·14), and intracranial volume (d=-0·10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0·95) and thalamus (p=0·39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (<15 years) versus adults (>21 years): in the accumbens (Cohen's d=-0·19 vs -0·10), amygdala (d=-0·18 vs -0·14), caudate (d=-0·13 vs -0·07), hippocampus (d=-0·12 vs -0·06), putamen (d=-0·18 vs -0·08), and intracranial volume (d=-0·14 vs 0·01). There was no difference between children and adults for the pallidum (p=0·79) or thalamus (p=0·89). Case-control differences in adults were non-significant (all p>0·03). Psychostimulant medication use (all p>0·15) or symptom scores (all p>0·02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0·5)., Interpretation: With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes., Funding: National Institutes of Health., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

It has been suggested that an early deficit in the human mirror neuron system (MNS) is an important feature of autism. Recent findings related to simple hand and finger movements do not support a general dysfunction of the MNS in autism. Studies investigating facial actions (e.g., emotional expressions) have been more consistent, however, mostly relied on passive observation tasks. We used a new variant of a compatibility task for the assessment of automatic facial mimicry responses that allowed for simultaneous control of attention to facial stimuli. We used facial electromyography in 18 children and adolescents with Autism spectrum disorder (ASD) and 18 typically developing controls (TDCs). We observed a robust compatibility effect in ASD, that is, the execution of a facial expression was facilitated if a congruent facial expression was observed. Time course analysis of RT distributions and comparison to a classic compatibility task (symbolic Simon task) revealed that the facial compatibility effect appeared early and increased with time, suggesting fast and sustained activation of motor codes during observation of facial expressions. We observed a negative correlation of the compatibility effect with age across participants and in ASD, and a positive correlation between self-rated empathy and congruency for smiling faces in TDC but not in ASD. This pattern of results suggests that basic motor mimicry is intact in ASD, but is not associated with complex social cognitive abilities such as emotion understanding and empathy. Autism Res 2017, 10: 298-310. © 2016 International Society for Autism Research, Wiley Periodicals, Inc., (© 2016 International Society for Autism Research, Wiley Periodicals, Inc.)

Reward processing plays a major role in goal-directed behavior and motivation. On the neural level, it is mediated by a complex network of brain structures called the dopaminergic reward system. In the last decade, neuroscientific researchers have become increasingly interested in aspects of social interaction that are experienced as rewarding. Recent neuroimaging studies have provided evidence that the reward system mediates the processing of social stimuli in a manner analogous to nonsocial rewards and thus motivates social behavior. In this context, the neuropeptide oxytocin is assumed to play a key role by activating dopaminergic reward pathways in response to social cues, inducing the rewarding quality of social interactions. Alterations in the dopaminergic reward system have been found in several psychiatric disorders that are accompanied by social interaction and motivation problems, for example autism, attention deficit/hyperactivity disorder, addiction disorders, and schizophrenia.

Objective: Recent evidence has suggested an increased rate of comorbid ADHD and subclinical attentional impairments in bulimia nervosa (BN) patients. However, little is known regarding the underlying neural mechanisms of attentional functions in BN., Method: Twenty BN patients and twenty age- and weight-matched healthy controls (HC) were investigated using a modified version of the Attention Network Task (ANT) in an fMRI study. This design enabled an investigation of the neural mechanisms associated with the three attention networks involved in alerting, reorienting and executive attention., Results: The BN patients showed hyperactivation in parieto-occipital regions and reduced deactivation of default-mode-network (DMN) areas during alerting compared with HCs. Posterior cingulate activation during alerting correlated with the severity of eating-disorder symptoms within the patient group. Conversely, BN patients showed hypoactivation during reorienting and executive attention in anterior cingulate regions, the temporo-parietal junction (TPJ) and parahippocampus compared with HCs, which was negatively associated with global ADHD symptoms and impulsivity, respectively., Discussion: Our findings demonstrate altered brain mechanisms in BN associated with all three attentional networks. Failure to deactivate the DMN and increased parieto-occipital activation required for alerting might be associated with a constant preoccupation with food or body image-related thoughts. Hypoactivation of executive control networks and TPJ might increase the likelihood of inattentive and impulsive behaviors and poor emotion regulation. Thus, dysfunction in the attentional network in BN goes beyond an altered executive attentional domain and needs to be considered in the diagnosis and treatment of BN., Competing Interests: JS, MH, BD, MSR, and TL report no financial relationships with commercial interests. KK has received speaking fees from Lilly, Novartis, and Medice. BHD and KK have an investigator-initiated trial (IIT) with Vivor AG on the effects of polyunsaturated fatty acids on brain maturation in children with and without ADHD. None of the above authors is employed by a commercial company. No commercial company was involved in this study in any way. None of the authors receive financial contributions related to an increased sale of any of their products. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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., (© 2015 Association for Child and Adolescent Mental Health.)

The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

Findings on face identity and facial emotion recognition in autism spectrum disorder (ASD) are inconclusive. Moreover, little is known about the developmental trajectory of face processing skills in ASD. Taking a developmental perspective, the aim of this study was to extend previous findings on face processing skills in a sample of adolescents and adults with ASD. N = 38 adolescents and adults (13-49 years) with high-functioning ASD and n = 37 typically developing (TD) control subjects matched for age and IQ participated in the study. Moreover, n = 18 TD children between the ages of 8 and 12 were included to address the question whether face processing skills in ASD follow a delayed developmental pattern. Face processing skills were assessed using computerized tasks of face identity recognition (FR) and identification of facial emotions (IFE). ASD subjects showed impaired performance on several parameters of the FR and IFE task compared to TD control adolescents and adults. Whereas TD adolescents and adults outperformed TD children in both tasks, performance in ASD adolescents and adults was similar to the group of TD children. Within the groups of ASD and control adolescents and adults, no age-related changes in performance were found. Our findings corroborate and extend previous studies showing that ASD is characterised by broad impairments in the ability to process faces. These impairments seem to reflect a developmentally delayed pattern that remains stable throughout adolescence and adulthood.

In typical development, empathic abilities continue to refine during adolescence and early adulthood. Children and adolescents with autism spectrum disorders (ASD) show deficits in empathy, whereas adults with ASD may have developed compensatory strategies. We aimed at comparing developmental trajectories in the neural mechanisms underlying empathy in individuals with ASD and typically developing control (TDC) subjects. Using an explicit empathizing paradigm and functional magnetic resonance imaging, 27 participants with ASD and 27 TDC aged 12-31 years were investigated. Participants were asked to empathize with emotional faces and to either infer the face's emotional state (other-task) or to judge their own emotional response (self-task). Differential age-dependent changes were evident during the self-task in the right dorsolateral prefrontal cortex, right medial prefrontal cortex, right inferior parietal cortex, right anterior insula and occipital cortex. Age-dependent decreases in neural activation in TDC were paralleled by either increasing or unchanged age-dependent activation in ASD. These data suggest ASD-associated deviations in the developmental trajectories of self-related processing during empathizing. In TDC, age-dependent modulations of brain areas may reflect the 'fine-tuning' of cortical networks by reduction of task-unspecific brain activity. Increased age-related activation in individuals with ASD may indicate the development of compensatory mechanisms., (© The Author (2013). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Imitation of facial expressions engages the putative human mirror neuron system as well as the insula and the amygdala as part of the limbic system. The specific function of the latter two regions during emotional actions is still under debate. The current study investigated brain responses during imitation of positive in comparison to non-emotional facial expressions. Differences in brain activation of the amygdala and insula were additionally examined during observation and execution of facial expressions. Participants imitated, executed and observed happy and non-emotional facial expressions, as well as neutral faces. During imitation, higher right hemispheric activation emerged in the happy compared to the non-emotional condition in the right anterior insula and the right amygdala, in addition to the pre-supplementary motor area, middle temporal gyrus and the inferior frontal gyrus. Region-of-interest analyses revealed that the right insula was more strongly recruited by (i) imitation and execution than by observation of facial expressions, that (ii) the insula was significantly stronger activated by happy than by non-emotional facial expressions during observation and imitation and that (iii) the activation differences in the right amygdala between happy and non-emotional facial expressions were increased during imitation and execution, in comparison to sole observation. We suggest that the insula and the amygdala contribute specifically to the happy emotional connotation of the facial expressions depending on the task. The pattern of the insula activity might reflect increased bodily awareness during active execution compared to passive observation and during visual processing of the happy compared to non-emotional facial expressions. The activation specific for the happy facial expression of the amygdala during motor tasks, but not in the observation condition, might reflect increased autonomic activity or feedback from facial muscles to the amygdala.

Results on grey matter (GM) structural alterations in autism spectrum disorder (ASD) are inconclusive. Moreover, little is known about age effects on brain-structure abnormalities in ASD beyond childhood. Here, we aimed to examine regional GM volumes in a large sample of children, adolescents, and adults with ASD. Magnetic resonance imaging scans were obtained in 47 male ASD subjects and 51 matched healthy controls aged 8-50 years. We used whole-brain voxel-based morphometry to first assess group differences in regional GM volume across age. Moreover, taking a cross-sectional approach, group differences in age effects on regional GM volume were investigated. Compared to controls, ASD subjects showed reduced GM volumes in the anterior cingulate cortex, posterior superior temporal sulcus, and middle temporal gyrus. Investigation of group differences in age effects on regional GM volume revealed complex, region-specific alterations in ASD. While GM volumes in the amygdala, temporoparietal junction, septal nucleus and middle cingulate cortex increased in a negative quadratic fashion in both groups, data indicated that GM volume curves in ASD subjects were shifted to the left along the age axis. Moreover, while GM volume in the right precentral gyrus decreased linearly with age in ASD individuals, GM volume development in controls followed a U-shaped pattern. Based on a large sample, our voxel-based morphometry results on group differences in regional GM volumes help to resolve inconclusive findings from previous studies in ASD. Results on age-related changes of regional GM volumes suggest that ASD is characterized by complex alterations in lifetime trajectories of several brain regions that underpin social-cognitive and motor functions.

Although it has been suggested that social deficits of autism spectrum disorders (ASDs) are related to reward circuitry dysfunction, very little is known about the neural reward mechanisms in ASD. In the current functional magnetic resonance imaging study, we investigated brain activations in response to both social and monetary reward in a group of children with ASD, relative to matched controls. Participants with ASD showed the expected hypoactivation in the mesocorticolimbic circuitry in response to both reward types. In particular, diminished activation in the nucleus accumbens was observed when money, but not when social reward, was at stake, whereas the amygdala and anterior cingulate cortex were hypoactivated within the ASD group in response to both rewards. These data indicate that the reward circuitry is compromised in ASD in social as well as in non-social, i.e. monetary conditions, which likely contributes to atypical motivated behaviour. Taken together, with incentives used in this study sample, there is evidence for a general reward dysfunction in ASD. However, more ecologically valid social reward paradigms are needed to fully understand, whether there is any domain specificity to the reward deficit that appears evident in ASD, which would be most consistent with the ASD social phenotype.

Previous studies have shown overlapping neural activations for observation and execution or imitation of emotional facial expressions. These shared representations have been assumed to provide indirect evidence for a human mirror neuron system, which is suggested to be a prerequisite of action comprehension. We aimed at clarifying whether shared representations in and beyond human mirror areas are specifically activated by affective facial expressions or whether they are activated by facial expressions independent of the emotional meaning. During neuroimaging, participants observed and executed happy and non-emotional facial expressions. Shared representations were revealed for happy facial expressions in the pars opercularis, the precentral gyrus, in the superior temporal gyrus/medial temporal gyrus (MTG), in the pre-supplementary motor area and in the right amygdala. All areas showed less pronounced activation in the non-emotional condition. When directly compared, significant stronger neural responses emerged for happy facial expressions in the pre-supplementary motor area and in the MTG than for non-emotional stimuli. We assume that activation of shared representations depends on the affect and (social) relevance of the facial expression. The pre-supplementary motor area is a core-shared representation-structure supporting observation and execution of affective contagious facial expressions and might have a modulatory role during the preparation of executing happy facial expressions.

Individuals with autism spectrum disorder (ASD) often fail to attach context to their memories and are specifically impaired in processing social aspects of contextual information. The aim of the present study was to investigate the modulatory influence of social vs. non-social context on neural mechanisms during encoding in ASD. Using event-related fMRI, 13 boys with ASD and 13 typically developing boys comparable for age and IQ were investigated during encoding of neutral objects presented either with a social (faces) or a non-social (houses) context. A memory paradigm was then applied to identify brain activation patterns associated with encoding of subsequently recollected versus non-recollected objects. On the behavioural level, no significant between-group differences emerged. In particular, no differential effects of context on memory performance were observed. Neurally, however, context-specific group differences were observed in several brain regions. During encoding of subsequently recollected objects presented with a face, ASD subjects (compared to controls) showed reduced neural activation in the bilateral inferior frontal gyrus, bilateral middle frontal gyrus and right inferior parietal lobule. Neural activation in the right inferior frontal gyrus was positively correlated with memory performance in controls, but negatively in ASD individuals. During encoding of subsequently non-recollected objects presented in the non-social context, ASD subjects showed increased activation in the dorsal MPFC. Our findings suggest that in ASD subjects, fronto-parietal brain regions subserving memory formation and the association of contextual information are activated atypically when a social context is presented at encoding. The data add to findings from related research fields indicating that in ASD, socioemotional impairment extends into domains beyond social cognition. Increased activation in the dorsal MPFC in ASD individuals might reflect supervisory cognitive processes related to the suppression of a distracting non-social context., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Converging evidence suggests deficits in theory-of-mind (ToM) processing in patients with anorexia nervosa (AN). The present study aimed at elucidating the neural mechanisms underlying ToM-deficits in AN., Method: A total of 19 adolescent patients with AN and 21 age-matched controls were investigated using functional magnetic resonance imaging during performance of a ToM-task at two time points (in-patients: admission to hospital and discharge after weight recovery). Clinical outcomes in patients were determined 1 year after admission., Results: Irrespective of the time point, AN patients showed reduced activation in middle and anterior temporal cortex and in the medial prefrontal cortex. Hypoactivation in the medial prefrontal cortex at admission to hospital (T1) was correlated with clinical outcome at follow-up., Conclusions: Hypoactivation in the brain network supporting theory of mind may be associated with a social-cognitive endophenotype reflecting impairments of social functioning in anorexia nervosa which is predictive for a poor outcome at 1-year follow-up., (Copyright © 2012 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Social motivation deficit theories suggest that children with autism do not properly anticipate and appreciate the pleasure of social stimuli. In this study, we investigated event-related brain potentials evoked by cues that triggered social versus monetary reward anticipation in children with autism. Children with autism showed attenuated P3 activity in response to cues associated with a timely reaction to obtain a reward, irrespective of reward type. We attribute this atypical P3 activity in response to reward cues as reflective of diminished motivated attention to reward signals, a possible contributor to reduced social motivation in autism. Thus, our findings suggest a general reward processing deficit rather than a specific social reward dysfunction in autism.

Objective: A deficit in empathy has repeatedly been described as a central feature of autistic disorders. However, little is known about how adolescents with autism evaluate their own empathic abilities, and how their parents judge these skills. The present study assesses affective components of empathy via both self-report and parental report., Method: 18 boys with autism and 18 typically developing boys participated in the study. A German translation of the Bryant Index of Empathy was used for the self-assessment of empathy. Parents rated the empathic abilities of their sons using a German version of the Griffith Empathy Measure. Both questionnaires are comparable with regards to content and mainly tap into affective components of empathy., Results: Self-reports of empathy in adolescents with autism did not differ from controls. In contrast, parents of adolescents with autism judged their sons to be less empathic compared to parents of typically developing adolescents., Conclusions: The discrepancy between unimpaired self-reported empathy and parental report of impaired empathy in adolescents with autism might result from their difficulties in effectively conveying empathic feelings to other people. Alternatively, the results may be explained by impaired introspection on inner experiences in individuals with autism.

The present study aimed at identifying dysfunctions in brain networks that may underlie disturbed empathic behavior in autism spectrum disorders (ASD). During functional magnetic resonance imaging, subjects were asked to identify the emotional state observed in a facial stimulus (other-task) or to evaluate their own emotional response (self-task). Behaviorally, ASD subjects performed equally to the control group during the other-task, but showed less emotionally congruent responses in the self-task. Activations in brain regions related to theory of mind were observed in both groups. Activations of the medial prefrontal cortex (MPFC) were located in dorsal subregions in ASD subjects and in ventral areas in control subjects. During the self-task, ASD subjects activated an additional network of frontal and inferior temporal areas. Frontal areas previously associated with the human mirror system were activated in both tasks in control subjects, while ASD subjects recruited these areas during the self-task only. Activations in the ventral MPFC may provide the basis for one's "emotional bond" with other persons' emotions. Such atypical patterns of activation may underlie disturbed empathy in individuals with ASD. Subjects with ASD may use an atypical cognitive strategy to gain access to their own emotional state in response to other people's emotions.

The goal of the current studies was to examine perception-action interactions in a socially relevant domain. Social interactions are based on a mutual understanding of the emotions and actions of others. We assume that the perception of emotional actions also stimulates a parallel action preparation in the perceiver, underlining the common coding theory. We report two experiments aimed to examine whether the perception of socially relevant facial actions (e.g., happy vs. angry facial expressions) interact with the execution of such actions. More specifically, we use a stimulus-response compatibility paradigm, in which subjects responded to the gender of a face by either smiling or frowning while ignoring the fact that the presented face is also randomly either smiling or frowning. We measured reaction time (RT) as onset latency on the two large muscle groups used for smiling (zygomaticus major) and frowning (corrugator supercilii) using electromyography. Experiment 1 showed that on compatible trials, in which perceived facial expression and actually produced facial expression matched, RTs were shorter than on incompatible trials. Experiment 2 used pre-instructed (i.e., blocked) responses and replicated the compatibility effect, suggesting that the effect is functionally located not in response selection but in response initiation or execution. We discuss these results in relation to cognitive mechanisms of common coding of perception and action and to the human mirror neuron system., (Copyright © 2010 Elsevier Ltd. All rights reserved.)