The contactin-associated protein-like 2 (CNTNAP2) gene encodes for the CASPR2 protein, which plays an essential role in neurodevelopment. Mutations in CNTNAP2 are associated with neurodevelopmental disorders, including autism spectrum disorder and schizophrenia. Rats with a loss of function mutation in the Cntnap2 gene show increased acoustic startle response (ASR) and decreased prepulse inhibition (PPI). The neural basis of this altered auditory processing in Cntnap2 knock-out rats is currently unknown. Auditory brainstem recordings previously revealed no differences between the genotypes. The next step is to investigate brainstem structures outside of the primary auditory pathway that mediate ASR and PPI, which are the pontine reticular nucleus (PnC) and pedunculopontine tegmentum (PPTg), respectively. Multi-unit responses from the PnC and PPTg in vivo of the same rats revealed sex-specific effects of loss of CASPR2 expression on PnC activity, but no effects on PPTg activity. Female Cntnap2-/- rats showed considerably increased PnC firing rates compared with female wildtypes, whereas the difference between the genotypes was modest in male rats. In contrast, for both females and males we found meager differences between the genotypes for PPTg firing rates and inhibition of PnC firing rates, indicating that altered firing rates of these brainstem structures are not responsible for decreased PPI in Cntnap2-/- rats. We conclude that the auditory processing changes seen in Cntnap2-/- rats are associated with, but cannot be fully explained by, differences in PnC firing rates, and that a loss of function mutation in the Cntnap2 gene has differential effects depending on sex.

Despite the inclusion of catatonia as a specifier of autism spectrum disorder in DSM-5, we-a team of child and adolescent neuropsychiatrists who specialise in paediatric catatonia and neurodevelopmental disorders-have identified a number of issues with the diagnosis and clinical management of catatonia in our patients. In this Personal View, we summarise the literature regarding catatonia in people with neurodevelopmental disorders, including autism spectrum disorder, describe our concerns, and offer a novel approach to addressing important issues with current diagnostic and treatment paradigms. We emphasise the need for a measure to diagnose and monitor people with catatonia and their history of neurodevelopmental disorders. This measure should consider previous complex and underlying motor, medical, functional, and neurobehavioural symptoms. We propose two concepts for understanding catatonia that relate to the baseline status of an individual: the personalised score at baseline, an estimate of premorbid neurobehavioral and motor symptoms, and the catatonic deterioration from baseline, an estimate of current features that are due to catatonia rather than an underlying neurodevelopmental disorder. We hope this measure will provide a practical tool for clinicians and researchers working with this underserved and high-risk population.

Neuronal migration and morphogenesis are fundamental processes for cortical development. Their defects may cause abnormities in neural circuit formation and even neuropsychiatric disorders. Many proteins, especially layer-specific transcription factors and adhesion molecules, have been reported to regulate the processes. However, the involvement of non-coding RNAs in cortical development has not been extensively studied. Here, we identified microRNA-218 (miR-218) as a layer V-specific microRNA in mouse brains. Expression of miR-218 was elevated in patients with autism spectrum disorder (ASD) and schizophrenia. We found in this study that miR-218 overexpression in developing mouse cortex led to severe defects in radial migration, morphogenesis, and spatial distribution of the cortical neurons. Moreover, we identified Satb2, an upper-layer marker, as a molecular target repressed by miR-218. These results suggest an underlying mechanism of miR-218 involvement in neuropsychiatric disorders, and the interactions of layer-specific non-coding RNAs and proteins in regulating cortical development.

Preterm birth has been linked with increased incidence of autism spectrum disorder (ASD). Despite the remarkable difference in the clinical backgrounds between ASD children born preterm and term, cross-sectional studies have found no striking difference in their autistic traits. To highlight autistic traits related with preterm birth, children born very preterm (prospective birth cohort, n = 50) and term (case cohort, n = 16), who were diagnosed as "Autism" by the Autism Diagnostic Observation Schedule (ADOS), 2nd edition, were compared using the calibrated severity scores of ADOS-2 and T-scores of the Social Responsiveness Scale, 2nd edition. No significant difference was found in the calibrated severity scores between ASD children born preterm and term. There was a trend that T-scores were smaller for the preterm cohort, which did not reach a statistical significance. Even when detailed cross-sectional information was obtained using ADOS-2, no difference in autistic traits was observed between children born very preterm and term. Our findings were consistent with a previous study, which assessed the entire prospective cohort of children born very preterm and found no difference in original ADOS scores. Further studies are warranted to delineate how preterm birth affects the autistic traits and their parental perception in a large prospective cohort.

It is now recognised that autism spectrum disorder (ASD) and personality disorders (PDs) have a variety of factors in common. However, the exact nature of the relationship between ASD and the PDs remains unclear. The overlapping symptom profiles of ASD and PDs can lead to diagnostic uncertainty - features of ASD and PD can be misattributed and easily lead to misdiagnosis of ASD patients. Since differentiating between ASD and PD is such a complex task, it has been argued that there is a need for additional understanding and markers for facilitating diagnostic procedures. There is an urgent need to explore, first, how clinicians make diagnostic decisions and, second, how to effectively deal with the challenges and difficulties they face when making decisions. Also, where there are clear overlaps, how do clinicians choose how to attribute labels in order to understand the person.

Influence from bias is unavoidable in clinical decision-making, and mental health assessment seems particularly vulnerable. Individuals with intellectual disabilities have increased risk of developing co-occurring mental disorder. Due to the inherent difficulties associated with intellectual disabilities, assessment of mental health in this population often relies on a different set of strategies, and it is unclear how these may affect risk of bias. In this theoretical paper, we apply recent conceptualisations of bias in clinical decision-making to the specific challenges and strategies in mental health assessment in intellectual disabilities. We suggest that clinical decision-making in these assessments is particularly vulnerable to bias, including sources of bias present in mental health assessment in the general population, as well as potential sources of bias which may be specific to assessments in this population. It follows that to manage potential bias, triangulating information from multi-informant, multi-method, interdisciplinary assessment strategies is likely to be necessary.

Autistic adults are at high risk for co-occurring mental health problems and need access to effective and appropriate mental health treatment. However, the relative effectiveness or acceptability of specific mental health strategies among autistic adults has not been previously examined. The current study sought to gain a deeper understanding of autistic adults' experiences and preferences regarding mental health strategies using a mixed methods approach. Autistic adults (n = 303, ages 21-77) completed online surveys and open-ended questions about their mental health and therapy experiences. Most (88.8%) had participated in therapy, with cognitive approaches being the most common. Regarding overall therapy experiences, qualitative analyses revealed 4 primary themes and 9 subthemes. Therapist acceptance and understanding were seen as critical for therapy success and many participants felt that therapy was helpful for personal growth. However, many participants found that talking in session was challenging and noted that aspects of the session format affected their ability to engage in therapy. Regarding specific strategies, 4 cross-cutting themes and 8 strategy-specific subthemes were identified. A variety of strategies were seen as helpful for reducing anxiety and improving mood. However, autistic adults reported trouble generalizing strategies to daily life and found some techniques to be difficult to implement due, in part, to their unique autism-related needs. As the first study of its kind, the results underscore the importance of establishing a safe and accepting therapeutic relationship, providing accommodations to support communication needs, and considering individual differences and preferences when selecting mental health strategies for autistic clients.

There is credible evidence that environmental factors influence individual risk and/or severity of autism spectrum disorders (hereafter referred to as autism). While it is likely that environmental chemicals contribute to the etiology of autism via multiple mechanisms, identifying specific environmental factors that confer risk for autism and understanding how they contribute to the etiology of autism has been challenging, in part because the influence of environmental chemicals likely varies depending on the genetic substrate of the exposed individual. Current research efforts are focused on elucidating the mechanisms by which environmental chemicals interact with autism genetic susceptibilities to adversely impact neurodevelopment. The goal is to not only generate insights regarding the pathophysiology of autism, but also inform the development of screening platforms to identify specific environmental factors and gene×environment (G×E) interactions that modify autism risk. Data from such studies are needed to support development of intervention strategies for mitigating the burden of this neurodevelopmental condition on individuals, their families and society. In this review, we discuss environmental chemicals identified as putative autism risk factors and proposed mechanisms by which G×E interactions influence autism risk and/or severity using polychlorinated biphenyls (PCBs) as an example.

Background: Atypical eating behaviors and feeding issues are common in children with autism spectrum disorder (ASD). Aim: This study aims to evaluate the nutritional status and eating behavior of the ASD and typically developing groups. Methods: A case-control study was conducted from January to April 2019 in Nghe An, Vietnam. A total of 93 children in each group participated in the study with their main caregivers. We applied the Children's Eating Behavior Inventory (CEBI) to evaluate the eating behaviors of children. Results: Overweight and obesity in ASD children accounted for 41.9%. The CEBI score and %CEBI of the ASD group was higher than that of the control group (104.0 ± 14.2 and 91.3 ± 8.3; 24.1 ± 21.4 and 5.0 ± 11.8, respectively). Most of the adverse mealtime behaviors of ASD children focused on excessive duration (52.7%), distraction (40.9%), and food refusal (39.8%). In total 88.2% of caregivers had to comfort their ASD children at every meal, followed by threatening, scolding, or punishing children if they refused to eat (57.0%). Conclusion: Being overweight/obese and having eating behavior difficulties were prevalent among ASD children in Vietnam. Safer alternatives, such as lifestyle measures and seeking help from a nutritional therapist, can help ASD children reduce weight and modify their erroneous feeding habits.

Prenatal infection increases risk for neurodevelopmental disorders such as autism in offspring. In rodents, prenatal administration of the viral mimic Polyinosinic: polycytidylic acid (Poly I: C) allows for investigation of developmental consequences of gestational sickness on offspring social behavior and neural circuit function. Because maternal immune activation (MIA) disrupts cortical development and sociability, we examined approach and avoidance in a rat social affective preference (SAP) task. Following maternal Poly I:C (0.5 mg/kg) injection on gestational day 12.5, male adult offspring (PN 60-64) exhibited atypical social interactions with stressed conspecifics whereas female SAP behavior was unaffected by maternal Poly I:C. Social responses to stressed conspecifics depend upon the insular cortex where corticotropin releasing factor (CRF) modulates synaptic transmission and SAP behavior. We characterized insular field excitatory postsynaptic potentials (fEPSP) in adult offspring of Poly I:C or control treated dams. Male MIA offspring showed decreased sensitivity to CRF (300 nM) while female MIA offspring showed greater sensitivity to CRF compared to sham offspring. These sex specific effects appear to be behaviorally relevant as CRF injected into the insula of male and female rats prior to social exploration testing had no effect in MIA male offspring but increased social interaction in female MIA offspring. We examined the cellular distribution of CRF receptor mRNA but found no effect of maternal Poly I:C in the insula. Together, these experiments reveal sex specific effects of prenatal infection on offspring responses to social affective stimuli and identify insular CRF signaling as a novel neurobiological substrate for autism risk.

Current explanatory models of negative symptoms in schizophrenia have suggested the role of social cognition in symptom formation and maintenance. This study examined a core aspect of social cognition, namely social perception, and its association with clinical manifestations in 22q11.2 deletion syndrome (22q11DS), a genetic model of schizophrenia. We used an eye-tracking device to analyze developmental trajectories of complex and dynamic social scenes exploration in 58 participants with 22q11DS compared to 79 typically developing controls. Participants with 22q11DS showed divergent patterns of social scene exploration compared to healthy individuals from childhood to adulthood. We evidenced a more scattered gaze pattern and a lower number of shared gaze foci compared to healthy controls. Associations with negative symptoms, anxiety level, and face recognition were observed. Findings reveal abnormal visual exploration of complex social information from childhood to adulthood in 22q11DS. Atypical gaze patterns appear related to clinical manifestations in this syndrome.

Autism spectrum disorder (ASD) is one common psychiatric illness that manifests in neurological and developmental disorders, which can last throughout a person's life and cause challenges in social interaction, communication, and behavior. Since the standard ASD diagnosis is highly based on the symptoms of the disease, it is difficult to make an early diagnosis to take the best cure opportunity. Compared to the standard methods, functional brain network (FBN) could reveal the statistical dependence among neural architectures in brains and provide potential biomarkers for the early neuro-disease diagnosis and treatment of some neurological disorders. However, there are few FBN estimation methods that take into account the noise during the data acquiring process, resulting in poor quality of FBN and thus poor diagnosis results. To address such issues, we provide a brand-new approach for estimating FBNs under a noise modeling framework. In particular, we introduce a noise term to model the representation errors and impose a regularizer to incorporate noise prior into FBNs estimation. More importantly, the proposed method can be formulated as conducting traditional FBN estimation based on transformed fMRI data, which means the traditional methods can be elegantly modified to support noise modeling. That is, we provide a plug-and-play noise module capable of being embedded into different methods and adjusted according to different noise priors. In the end, we conduct abundant experiments to identify ASD from normal controls (NCs) based on the constructed FBNs to illustrate the effectiveness and flexibility of the proposed method. Consequently, we achieved up to 13.04% classification accuracy improvement compared with the baseline methods.

Executive functioning (EF) processes are essential for adaptive and flexible responding to the demands and complexities of everyday life. Conversely, if impaired, these processes are a key transdiagnostic risk factor that cuts across autism and a range of other neurodevelopmental (NDD) and neuropsychiatric (NPD) conditions. However, there are currently no freely available informant-report measures that comprehensively characterize non-affective (e.g., working memory, response inhibition, and set shifting) and affective (e.g., emotion regulation) EF subdomains. This study describes the development, refinement, and initial psychometric evaluation of a new 52-item Executive Functioning Scale (EFS). Two independent data collections yielded exploratory (n = 2004, 169 with autism, ages 2-17) and confirmatory (n = 954, 74 with autism, ages 2-17) samples. Exploratory Structural Equation Modeling (ESEM) model with six specific factors that closely matched hypothesized executive functioning subdomains of working memory and sequencing, response inhibition, set-shifting, processing speed, emotion regulation, and risk avoidance, and one general factor, showed the best fit to the data and invariance across age, sex, race, and ethnicity groups. Model reliability and internal consistency were excellent for the general factor (ω = 0.98; α = 0.97) and specific factors (ω ≥ 0.89-0.96; α ≥ 0.84-0.94). Conditional reliability estimates indicated excellent reliability (≥0.90) for the total EF scale and adequate or better reliability (≥0.70) for subscale scores. With further replication, the EFS has excellent potential for wide adoption across research and clinical contexts.

The number of children diagnosed with autism spectrum disorders (ASD) worldwide has increased rapidly in the past decade and China is no exception. Yet the identity development of Chinese parents of children with ASD is little understood. This study employed an ethics of care perspective to explore the identity of parents of children with ASD as shaped in their social-cultural context in mainland China.

The GRIN2B-related neurodevelopmental disorder is a rare disease caused by mutations in the GRIN2B gene, which encodes the GluN2B subunit of NMDA receptors. Most individuals with GRIN2B-related neurodevelopmental disorder present with intellectual disability and developmental delay. Motor impairments, autism spectrum disorder, and epilepsy are also common. A large number of pathogenic de novo mutations have been identified in GRIN2B. However, it is not yet known how these variants lead to the clinical symptoms of the disease. Recent research has begun to address this issue. Here, we describe key experimental approaches that have been used to better understand the pathophysiology of this disease. We discuss the impact of several distinct pathogenic GRIN2B variants on NMDA receptor properties. We then critically review pivotal studies examining the synaptic and neurodevelopmental phenotypes observed when disease-associated GluN2B variants are expressed in neurons. These data provide compelling evidence that various GluN2B mutants interfere with neuronal differentiation, dendrite morphogenesis, synaptogenesis, and synaptic plasticity. Finally, we identify important open questions and considerations for future studies aimed at understanding this complex disease. Together, the existing data provide insight into the pathophysiological mechanisms that underlie GRIN2B-related neurodevelopmental disorder and emphasize the importance of comparing the effects of individual, disease-associated variants. Understanding the molecular, cellular and circuit phenotypes produced by a wide range of GRIN2B variants should lead to the identification of core neurodevelopmental phenotypes that characterize the disease and lead to its symptoms. This information could help guide the development and application of effective therapeutic strategies for treating individuals with GRIN2B-related neurodevelopmental disorder.

Historical evidence from stimulation and lesion studies in animals and humans demonstrated a close association between the hypothalamus and typical and atypical socioemotional behavior. A central hypothalamic contribution to regulation of socioemotional responses was also provided indirectly by studies on oxytocin and arginine vasopressin. However, a limited number of studies have so far directly investigated the contribution of the hypothalamus in human socioemotional behavior. To reconsider the functional role of the evolutionarily conserved hypothalamic region in regulating human social behavior, here I provide a synthesis of neuroimaging investigations showing that the hypothalamus is involved in multiple and diverse facets of human socioemotional behavior through widespread functional interactions with other cortical and subcortical regions. These neuroimaging findings are then integrated with recent optogenetics studies in animals demonstrating that the hypothalamus plays a more active role in eliciting socioemotional responses and is not simply a downstream effector of higher-level brain systems. Building on the aforementioned evidence, the hypothalamus is argued to substantially contribute to a continuum of human socioemotional behaviors promoting survival and preservation of the species that extends from exploratory and approaching responses facilitating social bonding to aggressive and avoidance responses aimed to protect and defend formed relationships.

Autism is a highly heritable, heterogeneous, neurodevelopmental condition. Large-scale genetic studies, predominantly focussing on simplex families and clinical diagnoses of autism have identified hundreds of genes associated with autism. Yet, the contribution of these classes of genes to multiplex families and autistic traits still warrants investigation. Here, we conducted whole-genome sequencing of 21 highly multiplex autism families, with at least three autistic individuals in each family, to prioritise genes associated with autism. Using a combination of both autistic traits and clinical diagnosis of autism, we identify rare variants in genes associated with autism, and related neurodevelopmental conditions in multiple families. We identify a modest excess of these variants in autistic individuals compared to individuals without an autism diagnosis. Finally, we identify a convergence of the genes identified in molecular pathways related to development and neurogenesis. In sum, our analysis provides initial evidence to demonstrate the value of integrating autism diagnosis and autistic traits to prioritise genes.

Empathy involves both empathic ability and empathic motivation. An important topic has been how to measure empathic ability and motivation simultaneously in both clinical and non-clinical samples and across different cultures. The Empathy Components Questionnaire (ECQ) is a self-report questionnaire that measures empathic ability and motivation in a questionnaire. The current study aimed to validate the Mandarin Chinese version of the ECQ (ECQ-Chinese) in three Chinese samples. In study 1, a total of 538 Chinese participants (Sample 1) completed the ECQ-Chinese via an online survey, and existing measures of empathy and related constructs which were used for criterion validity. In study 2, a total of 104 participants (Sample 2) were recruited again from sample 1 and completed the ECQ-Chinese three weeks later to investigate test-retest reliability. In study 3, a further 324 participants (Sample 3) completed the ECQ-Chinese for confirmatory factor analysis. The results showed that the ECQ-Chinese has a good internal consistency reliability, split-half reliability, and criterion validity (Study 1), and a good test-retest reliability (Study 2). Further, Study 3 found that a 22-item ECQ-Chinese consisting of five subscales had a good construct validity, convergence validity and discriminate validity, demonstrating it to be a suitable tool for the measurement of empathic ability and motivation in Chinese samples and to carry out cross-cultural studies of empathy and its components.

Individuals with autism spectrum disorder can find behavioural flexibility challenging, often exhibited in terms of repetitive behaviours or restricted ranges of interests and activities. An inability to shift efficiently from one situation to another is connected with problems in daily life, and identifying factors associated with this ability may help develop teaching strategies to improve behavioural flexibility. Some existing findings imply shifting performance for individuals with autism spectrum disorder is better with nonverbal, compared to verbal, feedback - even for those with strong verbal abilities. Unfortunately, there are few behavioural examinations that further explore these findings, which is the aim of this study. In this study, 28 children with a diagnosis of autism spectrum disorder and 28 typically developing children matched on cognitive and verbal abilities learned to sort cards according to one out of a possible three dimensions (colour, shape and number), and then had to relearn the sorting rule. One group of typically developing children, and one group of autism spectrum disorder children, received verbal feedback on their performance, and one group received nonverbal feedback. Children with autism spectrum disorder learned an initial categorisation rule as fast as matched typically developing children, and there was little difference in the impact of the type of feedback on acquisition. However, on shifting the classification rule, children with autism spectrum disorder showed slower rates of learning the new rule, which was worse when verbal feedback was used compared to nonverbal feedback. This finding has implications for the interpretations of set-shifting performance and for classroom use of feedback strategies.

This study used data for 14.4 million individuals with 43.5 million emergency department visits from all hospitals in the state of New York to explore the association between suicide and non-fatal self-injury-related (self-injury) emergency department visits and autism spectrum disorder. Overall, we found that individuals with autism spectrum disorder had more emergency department visits and admissions through the emergency department, more years of emergency department utilization, and higher prevalence of mental health-related comorbidities. Individuals with autism spectrum disorder were also significantly more likely to have at least one self-injury-related emergency department visit compared to those without autism spectrum disorder. These results emphasize the need to raise awareness across both family caregivers and healthcare providers on the increased suicide and self-injury risks that individuals with autism spectrum disorder face and to improve care delivery practices. In addition, effort to promote and increase timely access to mental health care is an urgent priority for individuals with autism spectrum disorder.

The development of cognitive processes, such as attention control and learning, has been suggested to be altered in children with a diagnosis of autism spectrum disorder. However, nearly all of our understanding of the development of these cognitive processes comes from studies with school-aged or older children in high-income countries, and from research conducted in a controlled laboratory environment, thereby restricting the potential generalisability of results and away from the majority of the world's population. We need to expand our research to investigate abilities beyond these limited settings. We address shortcomings in the literature by (1) studying attention control and learning in an understudied population of children in a low- and middle-income country setting in India, (2) focusing research on a critical younger age group of children and (3) using portable eye-tracking technology that can be taken into communities and healthcare settings to increase the accessibility of research in hard-to-reach populations. Our results provide novel evidence on differences in attention control and learning responses in groups of children with and without a diagnosis of autism spectrum disorder. We show that learning responses in children that we assessed through a portable eye-tracking task, called the 'antisaccade task', may be specific to autism. This suggests that the methods we use may have the potential to identify and assess autism-specific traits across development, and be used in research in low-resource settings.