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This article is part of a Special 15th Anniversary Issue. [ABSTRACT FROM AUTHOR]

Abstract The human cerebellum plays an essential role in motor control, is involved in cognitive function (i.e., attention, working memory, and language), and helps to regulate emotional responses. Quantitative in-vivo assessment of the cerebellum is important in the study of several neurological diseases including cerebellar ataxia, autism, and schizophrenia. Different structural subdivisions of the cerebellum have been shown to correlate with differing pathologies. To further understand these pathologies, it is helpful to automatically parcellate the cerebellum at the highest fidelity possible. In this paper, we coordinated with colleagues around the world to evaluate automated cerebellum parcellation algorithms on two clinical cohorts showing that the cerebellum can be parcellated to a high accuracy by newer methods. We characterize these various methods at four hierarchical levels: coarse (i.e., whole cerebellum and gross structures), lobe, subdivisions of the vermis, and the lobules. Due to the number of labels, the hierarchy of labels, the number of algorithms, and the two cohorts, we have restricted our analyses to the Dice measure of overlap. Under these conditions, machine learning based methods provide a collection of strategies that are efficient and deliver parcellations of a high standard across both cohorts, surpassing previous work in the area. In conjunction with the rank-sum computation, we identified an overall winning method. Highlights • First paper to evaluate the state-of-the-art in cerebellum parcellation. • Presenting results on both Adult and Pediatric Cohorts. • Adult Cohort contains healthy controls, and patients with either symptoms of cerebellar dysfunction or SCA 6. • Pediatric Cohort contains healthy controls, and patients with ADHD or Autism. [ABSTRACT FROM AUTHOR]

There is common agreement that many disorders of the central nervous system are ‘complex’, that is, there are many potential factors that influence the development of the disease, underlying mechanisms, and successful treatment. Most of these disorders, unfortunately, have no cure at the present time, and therapeutic strategies often have debilitating side effects. Interestingly, some of the ‘complexities’ of one disorder are found in another, and the similarities are often network defects. It seems likely that more discussions of these commonalities could advance our understanding and, therefore, have clinical implications or translational impact. With this in mind, the Fourth International Halifax Epilepsy Conference and Retreat was held as described in the prior paper, and this companion paper focuses on the second half of the meeting. Leaders in various subspecialties of epilepsy research were asked to address aging and dementia or psychosis in people with epilepsy (PWE). Commonalities between autism, depression, aging and dementia, psychosis, and epilepsy were the focus of the presentations and discussion. In the last session, additional experts commented on new conceptualization of translational epilepsy research efforts. Here, the presentations are reviewed, and salient points are highlighted. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) affects a significant number of individuals in the United States, with the prevalence continuing to grow. A significant proportion of individuals with ASD have comorbid medical conditions such as epilepsy. In fact, treatment-resistant epilepsy appears to have a higher prevalence in children with ASD than in children without ASD, suggesting that current antiepileptic treatments may be suboptimal in controlling seizures in many individuals with ASD. Many individuals with ASD also appear to have underlying metabolic conditions. Metabolic conditions such as mitochondrial disease and dysfunction and abnormalities in cerebral folate metabolism may affect a substantial number of children with ASD, while other metabolic conditions that have been associated with ASD such as disorders of creatine, cholesterol, pyridoxine, biotin, carnitine, γ-aminobutyric acid, purine, pyrimidine, and amino acid metabolism and urea cycle disorders have also been associated with ASD without the prevalence clearly known. Interestingly, all of these metabolic conditions have been associated with epilepsy in children with ASD. The identification and treatment of these disorders could improve the underlying metabolic derangements and potentially improve behavior and seizure frequency and/or severity in these individuals. This paper provides an overview of these metabolic disorders in the context of ASD and discusses their characteristics, diagnostic testing, and treatment with concentration on mitochondrial disorders. To this end, this paper aims to help optimize the diagnosis and treatment of children with ASD and epilepsy. This article is part of a Special Issue entitled “Autism and Epilepsy”. [ABSTRACT FROM AUTHOR]

The Picture Exchange Communication System (PECS) is the conventional pedagogical approach for developing the communication skills of children with autism, and research has supported the approach׳s great effectiveness in its communicative utilization of picture cards. Unfortunately, the paper-based approach׳s effectiveness is hampered by the time-consuming and complex preparation process of manually creating and managing these picture cards for use between the children and their caregivers. This paper presents iCAN, a tablet-based system that adopts the successful aspects of the traditional PECS approach while incorporating advantageous features such as support for digital, visualization, and voice capabilities, improved portability due to its smaller form factor on a tablet, and image-capturing capabilities for expanding the flexibility of content creation. We deployed our system onto eleven children participants – whom are diagnosed with moderate to severe autism – and their primary caregivers over a span of four weeks, and our results demonstrated that iCAN reduced content-preparation time by over 70% while also enhancing children with autism׳s willingness to learn and interact with others. [ABSTRACT FROM AUTHOR]

Neurological Music Therapy uses live music to improve the sensorimotor regulation of children with severe autism. However, they often lack musical training and their impairments limit their interactions with musical instruments. In this paper, we present our co-design work that led to the BendableSound prototype: an elastic multisensory surface encouraging users to practice coordination movements when touching a fabric to play sounds. We present the results of a formative study conducted with 18 teachers showing BendableSound was perceived as “usable” and “attractive”. Then, we present a deployment study with 24 children with severe autism showing BendableSound is “easy to use” and may potentially have therapeutic benefits regarding attention and motor development. We propose a set of design insights that could guide the design of natural user interfaces, particularly elastic multisensory surfaces. We close with a discussion and directions for future work. [ABSTRACT FROM AUTHOR]

• Augmented reality agent-based social game in the emotional development of children with autism. • Interdisciplinary research using psychology, computer vision, and mixed reality interaction. • Children with autism can express basic facial expressions better in augmented reality. • Augmented reality agents can improve children's retention and engagement in intervention games. • Augmented reality agents can evoke active social behaviors in children with autism. Children with autism spectrum disorder (ASD) experience impaired emotional development, which severely affects their social communication. Although some assistive technologies are effective in helping children with ASD to improve their social skills, they are generally considered to be unable to engage children in real-world social situations. This paper presents "FaceMe," which is a virtual agent social game based on an augmented reality (AR) technology that supports children's emotional development. FaceMe uses a virtual agent, a set of tangible toolkits, and multilevel game mechanics to teach children about basic facial expressions in social scenarios and improve their emotional and communication skills. Empirical results show that the FaceMe virtual agent evoked active social behaviors in children with ASD who subsequently improved their ability to understand facial expressions. The FaceMe design guidelines for creating the virtual agent in the context of AR are presented, which opens up an interesting domain for future games using AR to support children's learning. [ABSTRACT FROM AUTHOR]

Children with severe autism lack of the eye-body coordination skills which are needed to conduct aimed limb movements. Physical therapy relies on the repetition of limb movements that demands children with severe autism to aim for a visual target. But their movements during physical therapies are most of the time aimless, and they found the visual stimuli confusing and not engaging. Exergames could support motor therapies as they combine game technology with exercise activity. This technology can offer a natural interaction and use multisensory stimuli appropriate to keep children with autism focused during motor therapeutic interventions. In this paper, we hypothesize that exergames supporting motor therapeutic interventions and alleviating such attention and motor challenges could help children with severe autism to develop the necessary coordination skills needed to follow up visual targets. We present a 7-weeks evaluation study of the deployment of an exergame supporting the practice of eye-body coordination exercises. Seven children with severe autism and three psychotherapists participated in the study. Our results indicate children with severe autism maintained their attention for the total duration of the therapy, reduced their aimless limb movements and developed aimed limb movements, as a result of weeks of usage of the exergame. We close discussing challenges for existing clinical practice from a design and clinical point of view. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD), a condition defined along a continuum of socio-communicative difficulties, is associated with unique patterns of memory functioning including difficulties with autobiographical memory (AM). AM refers to memory for information related to the self and personally experienced events and has a strong social function. The current paper reviews empirical studies assessing AM among individuals with ASD across the lifespan. Results support that both children and adults with ASD manifest AM difficulties characterized by (a) reduced specificity, (b) less elaborated and detailed AM narratives, (c) lower AM coherence, and (d) increased reliance on scaffolding for retrieval. Individuals with ASD also demonstrate intact AM for certain memory indices and show evidence of using compensatory strategies to facilitate retrieval. Results are interpreted in relation to models of typically developing AM and broad memory theory, as well as models of information processing specific to ASD. To advance knowledge of how AM develops within the context of ASD, a developmental psychopathology perspective is applied to the consideration of candidate processes underlying developing AM among individuals with ASD. Future research should consider support for mechanisms that promote AM performance at multiple ecological levels. Limitations, clinical implications for intervention, and future directions are discussed. [ABSTRACT FROM AUTHOR]

Whole-brain fMRI signals are a subject of intense interest: variance in the global fMRI signal (the spatial mean of all signals in the brain) indexes subject arousal, and psychiatric conditions such as schizophrenia and autism have been characterized by differences in the global fMRI signal. Further, vigorous debates exist on whether global signals ought to be removed from fMRI data. However, surprisingly little research has focused on the empirical properties of whole-brain fMRI signals. Here we map the spatial and temporal properties of the global signal, individually, in 1000+ fMRI scans. Variance in the global fMRI signal is strongly linked to head motion, to hardware artifacts, and to respiratory patterns and their attendant physiologic changes. Many techniques used to prepare fMRI data for analysis fail to remove these uninteresting kinds of global signal fluctuations. Thus, many studies include, at the time of analysis, prominent global effects of yawns, breathing changes, and head motion, among other signals. Such artifacts will mimic dynamic neural activity and will spuriously alter signal covariance throughout the brain. Methods capable of isolating and removing global artifactual variance while preserving putative “neural” variance are needed; this paper adopts no position on the topic of global signal regression. [ABSTRACT FROM AUTHOR]

The mental states of other people are components of the external world that modulate the activity of our sensory epithelia. Recent probabilistic frameworks that cast perception as unconscious inference on the external causes of sensory input can thus be expanded to enfold the brain’s representation of others’ mental states. This paper examines this subject in the context of the debate concerning the extent to which we have perceptual awareness of other minds. In particular, we suggest that the notion of perceptual presence helps to refine this debate: are others’ mental states experienced as veridical qualities of the perceptual world around us? This experiential aspect of social cognition may be central to conditions such as autism spectrum disorder, where representations of others’ mental states seem to be selectively compromised. Importantly, recent work ties perceptual presence to the counterfactual predictions of hierarchical generative models that are suggested to perform unconscious inference in the brain. This enables a characterisation of mental state representations in terms of their associated counterfactual predictions, allowing a distinction between spontaneous and explicit forms of mentalising within the framework of predictive processing. This leads to a hypothesis that social cognition in autism spectrum disorder is characterised by a diminished set of counterfactual predictions and the reduced perceptual presence of others’ mental states. [ABSTRACT FROM AUTHOR]

The controversies that have arisen in endeavoring to establish the nature of the relationships between autism and epilepsy might be summarized in a few simple questions, most of which do not yet have clear, complete answers. Does epilepsy cause autism? Does autism cause epilepsy? Are there underlying brain mechanisms that predispose to both conditions? What is the role of genetics in this regard? What is the importance of prenatal, perinatal, and postnatal environmental factors? Do any of the proposed relationships between autism and epilepsy provide insight into useful management or treatment? Is the prognosis of either autism or epilepsy different when the other condition is also present? What is the role of additional comorbidities, such as intellectual impairment or attention deficit hyperactivity disorder, in the relationship between the two conditions and in influencing treatment choices? From the evidence currently available, it would appear that epilepsy can rarely be the cause of autistic features but is not the cause of autism in most cases. There is currently no credible mechanism for suggesting that autism might cause epilepsy. There is strong evidence for an underlying predisposition for both conditions, particularly arising from genetic investigations. However, many issues remain unresolved. Considering the amount of research that has been published in this area, it is surprising that so few definitive answers have been established. The papers in this issue’s special section provide additional insights into the relationships between autism and epilepsy; while they do not provide answers to all the questions, they represent considerable progress in this area and, at the very least, give some strong indication of what research might, in the future, provide such answers. [ABSTRACT FROM AUTHOR]

• We examined emotion recognition in ASD across visual and auditory domains. • ASD is associated with general emotion recognition deficits for human faces. • Emotion-specific deficits were observed for music and speech prosody in ASD. • Autistic adults showed more pronounced deficits in emotion recognition than children. • Deficits were consistently observed for verbal but not nonverbal tasks in ASD. An expanding literature has investigated emotion recognition across visual and auditory modalities in autism spectrum disorder (ASD). Findings, however, have been highly variable. The present work systematically reviewed and quantitatively synthesised a large body of literature, in order to determine whether autistic individuals differ from their neurotypical counterparts in emotion recognition across human face, nonhuman face, speech, and music domains. To identify eligible studies, the literature was searched using Embase, Medline, PubMed, Web of Science, and Google Scholar. Synthesising data from 72 papers, results showed a general difficulty with emotion recognition accuracy in ASD, while autistic individuals also showed longer response times than their neurotypical counterparts for a subset of emotions (i.e., anger, fear, sadness, and the six-emotion composite). These impairments were shown to be robust as they were not driven by differences in stimulus presentation time restriction and IQ matching, though the severity of impairments was less pronounced for a subset of emotions when full-scale IQ matching (i.e., anger, fear, happiness, sadness, and disgust) and verbal IQ matching (i.e., anger, fear, sadness, and disgust) had been undertaken. The heterogeneity among studies arose from a combination of sample characteristics (i.e., age but not IQ) and experimental design (i.e., stimulus domain and task demand) parameters. Specifically, we show that (i) impairments were more pronounced in autistic adults; (ii) full-scale, verbal, and nonverbal IQ did not moderate impairments; (iii) emotion-general impairments were found for human faces but emotion-specific impairments were observed for speech prosody (i.e., anger, happiness, and disgust) and music (i.e., fear and sadness), while no impairment was observed for nonhuman faces; (iv) impairments were found across emotions for verbal but not nonverbal tasks. Importantly, further research on the recognition of prosodic, musical, and nonhuman facial emotions is warranted, as the current findings are disproportionately influenced by studies on human faces. Future studies should also continue to explore the different emotion processing strategies employed by autistic individuals, which could be fundamental to promoting fulfilling emotional experiences in real life. [ABSTRACT FROM AUTHOR]

Abstract: Among its many roles in body and brain, oxytocin influences social behavior. Understanding the precise nature of this influence is crucial, both within the broader theoretical context of neurobiology, social neuroscience and brain evolution, but also within a clinical context of disorders such as anxiety, schizophrenia, and autism. Research exploring oxytocin''s role in human social behavior is difficult owing to its release in both body and brain and its interactive effects with other hormones and neuromodulators. Additional difficulties are due to the intricacies of the blood–brain barrier and oxytocin''s instability, which creates measurement issues. Questions concerning how to interpret behavioral results of human experiments manipulating oxytocin are thus made all the more pressing. The current paper discusses several such questions. We highlight unresolved fundamental issues about what exactly happens when oxytocin is administered intranasally, whether such oxytocin does in fact reach appropriate receptors in brain, and whether central or peripheral influences account for the observed behavioral effects. We also highlight the deeper conceptual issue of whether the human data should be narrowly interpreted as implicating a specific role for oxytocin in complex social cognition, such a generosity, trust, or mentalizing, or more broadly interpreted as implicating a lower-level general effect on general states and dispositions, such as anxiety and social motivation. Using several influential studies, we show how seemingly specific, higher-level social-cognitive effects can emerge via a process by which oxytocin''s broad influence is channeled into a specific social behavior in a context of an appropriate social and research setting. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. [Copyright &y& Elsevier]

Abstract: The imaginative abilities of children on the autistic spectrum are reportedly impaired compared to typically developing children. This study explored computer mediated story construction in children with autism and typically developing peers. The purpose was to explore expressive writing ability, as a measure of imagination. Ten pairs of individually matched children (one typically developing and one child on the autistic spectrum) aged between seven and nine created reality and fantasy based stories using Bubble Dialogue software. The study provided a brief starting point for the stories, relying on the imaginative capabilities of the children to develop the stories beyond the story opening. The study contributes to the literature as an alternative to paper based studies of imagination given the known appeal of technology to most children, particularly children on the autistic spectrum (). This study found that the children with autism were as able as the typically developing children to engage with the task, although qualitative differences in their responses were recorded. [Copyright &y& Elsevier]

Abstract: This paper presents a paradigm for generating a quantifiable marker of pathology that supports diagnosis and provides a potential biomarker of neuropsychiatric disorders, such as autism spectrum disorder (ASD). This is achieved by creating high-dimensional nonlinear pattern classifiers using support vector machines (SVM), that learn the underlying pattern of pathology using numerous atlas-based regional features extracted from diffusion tensor imaging (DTI) data. These classifiers, in addition to providing insight into the group separation between patients and controls, are applicable on a single subject basis and have the potential to aid in diagnosis by assigning a probabilistic abnormality score to each subject that quantifies the degree of pathology and can be used in combination with other clinical scores to aid in diagnostic decision. They also produce a ranking of regions that contribute most to the group classification and separation, thereby providing a neurobiological insight into the pathology. As an illustrative application of the general framework for creating diffusion based abnormality classifiers we create classifiers for a dataset consisting of 45 children with ASD (mean age 10.5±2.5yr) as compared to 30 typically developing (TD) controls (mean age 10.3±2.5yr). Based on the abnormality scores, a distinction between the ASD population and TD controls was achieved with 80% leave one out (LOO) cross-validation accuracy with high significance of p<0.001, ~84% specificity and ~74% sensitivity. Regions that contributed to this abnormality score involved fractional anisotropy (FA) differences mainly in right occipital regions as well as in left superior longitudinal fasciculus, external and internal capsule while mean diffusivity (MD) discriminates were observed primarily in right occipital gyrus and right temporal white matter. [Copyright &y& Elsevier]

Abstract: Successful communication requires that individuals attend to the perspective of their conversational partners and use this information to modify their behavior accordingly. This paper presents a framework by which to understand children’s communicative perspective-taking skills and, within this framework, outlines three routes by which children’s communicative perspective-taking performance can be disrupted. First, children may have difficulty in communicative contexts due to deficits in mentalizing ability whereby they are unable to appreciate another’s perspective. Second, children may have intact mentalizing abilities but do not have the cognitive skills to support the use of this information when generating communicative behaviors. Third, decreased social exposure may lead to exacerbated deficits in either mentalizing ability or the use of mentalistic information within communicative contexts. Patterns within both typical and atypical populations (i.e., autism, ADHD, and mood disorders) are reviewed. [Copyright &y& Elsevier]

Abstract: Motion artefacts are an important but often disregarded problem in diffusion-weighted imaging, which can readily lead to corrupt diffusion model estimations. The new processing method proposed in this paper uses robust tensor estimation that is spatially informed to efficiently detect the most frequently occurring artefacts, namely those that result from head and cardiac motion. Simulations demonstrate that the method is more robust and accurate than previous methods. The tensor estimates are more accurate in motion artefact-free conditions, less sensitive to increases in artefact magnitude and more resistant to increasing artefact frequency. Evaluation with real diffusion-weighted (DW) imaging data shows that the method works excellently, even for datasets with a high degree of motion that otherwise need to be discarded. The method is not limited to diffusion tensor imaging but also yields objective artefact reflecting weights that can be used to inform subsequent processing or estimation of higher-order diffusion models. [Copyright &y& Elsevier]

Abstract: Executive dysfunction is a characteristic impairment of individuals with Autism Spectrum Disorders (ASD). However whether such deficits are related to autism per se, or to associated intellectual disability is unclear. This paper examines executive functions in a group of children with ASD (N =54, all IQ⩾70) in relation to a typically developing control group individually matched on the basis of age, gender, IQ and vocabulary. Significant impairments in the inhibition of prepotent responses (Stroop, Junior Hayling Test) and planning (Tower of London) were reported for children with ASD, with preserved performance for mental flexibility (Wisconsin Card Sorting Task) and generativity (Verbal Fluency). Atypical age-related patterns of performance were reported on tasks tapping response inhibition and self-monitoring for children with ASD compared to controls. The disparity between these and previous research findings are discussed. A multidimensional notion of executive functions is proposed, with difficulties in planning, the inhibition of prepotent responses and self-monitoring reflecting characteristic features of ASD that are independent of IQ and verbal ability, and relatively stable across the childhood years. [Copyright &y& Elsevier]

Abstract: This paper reviews the use of eye tracking measures (saccades, smooth-pursuit eye movements, fixations during scene and face perception, and pupillary dilation) to study typical and clinical populations of children and adolescents and evaluates the use of these measures. The studies are evaluated with a focus on points that may be of general interest to developmentalists (the contribution of contextual and temporal factors in performance, methods of analyzing age-related differences, and the role of the psychometric properties of the tests in interpretation of differences across age and clinical groups). Some limitations of eye tracking are pointed out (e.g., the nature of the relation between oculomotor and other motor systems, constraints in making inferences about the brain from psychophysiological data). Finally, the potential of eye tracking measures for probing normative and abnormal development is explored. [Copyright &y& Elsevier]

Abstract: In this paper, we attempt to make a distinction between egocentrism and allocentrism in social cognition, based on the distinction that is made in visuo-spatial perception. We propose that it makes a difference to mentalizing whether the other person can be understood using an egocentric (“you”) or an allocentric (“he/she/they”) stance. Within an egocentric stance, the other person is represented in relation to the self. By contrast, within an allocentric stance, the existence or mental state of the other person needs to be represented as independent from the self. We suggest here that people with Asperger syndrome suffer from a disconnection between a strong naïve egocentric stance and a highly abstract allocentric stance. We argue that the currently used distinction between first-person and third-person perspective-taking is orthogonal to the distinction between an egocentric and an allocentric stance and therefore cannot serve as a critical test of allocentrism. [Copyright &y& Elsevier]

Abstract: Empathy is a lay term that is becoming increasingly viewed as a unitary function within the field of cognitive neuroscience. In this paper, a selective review of the empathy literature is provided. It is argued from this literature that empathy is not a unitary system but rather a loose collection of partially dissociable neurocognitive systems. In particular, three main divisions can be made: cognitive empathy (or Theory of Mind), motor empathy, and emotional empathy. The two main psychiatric disorders associated with empathic dysfunction are considered: autism and psychopathy. It is argued that individuals with autism show difficulties with cognitive and motor empathy but less clear difficulties with respect to emotional empathy. In contrast, individuals with psychopathy show clear difficulties with a specific form of emotional empathy but no indications of impairment with cognitive and motor empathy. [Copyright &y& Elsevier]

Abstract: Sewards and Sewards (2002) argue that while computations necessary for object recognition occur throughout the ventral visual stream, object recognition awareness involves the anterior temporal lobe and the medial orbital prefrontal cortex. The present paper suggests, however, that the medial orbital prefrontal cortex has a unique contribution, namely that of producing a basic experience of a perceptual object. It is further argued that the mechanisms that produce this experience also result in making the object more important than its subparts and features. Finally, it is argued that a reduction in this importance may account for some perceptual difficulties in high-functioning autism. This view is consistent with evidence for early selective abnormalities in other systems involving the medial prefrontal cortex in autism. [Copyright &y& Elsevier]

In this paper studies of executive function in autism spectrum disorder are reviewed. Executive function is an umbrella term for functions such as planning, working memory, impulse control, inhibition, and shifting set, as well as for the initiation and monitoring of action. In this review, the focus will be on planning, inhibition, shifting set, generativity, and action monitoring. While it is known that these functions depend upon the frontal lobes, and particularly on prefrontal cortex, very little is known about neuroanatomical correlates of executive function in autism. The review acknowledges the complexity of investigating executive functions in autism, the possible influence of IQ on executive performance in these groups and the possibility of overlap between performance on tests of executive function in other neurodevelopmental disorders that are likely to involve congenital deficits in the frontal lobes, such as attention deficit hyperactivity disorder and Tourette''s syndrome. [Copyright &y& Elsevier]

Deficits in pragmatic language ability are common to a number of clinical populations, for example, right-hemisphere damage (RHD), Autism and traumatic brain injury (TBI). In these individuals the basic structural components of language may be intact, but the ability to use language to engage socially is impaired. Despite the nature of these difficulties being well documented, exactly what causes these difficulties is less clear. Furthermore, the current status of causal explanations for pragmatic difficulties across these populations is divergent and sometimes contradictory. This paper explores the empirical validity of three theories that attempt to explain pragmatic language impairment. It is recommended that a new, more convergent approach to investigating the causes of pragmatic language disability be adopted. [Copyright &y& Elsevier]

[Display omitted] • Imbalance of GSH redox system is an key factor in the pathophysiology of ASD. • Existing data support a protective role of the GSH system in ASD development. • External modulation of GSH levels may be used in the treatment of ASD. • Therapeutic approaches by targeting the GSH system are discussed. This paper reviews the potential role of glutathione (GSH) in autism spectrum disorder (ASD). GSH plays a key role in the detoxification of xenobiotics and maintenance of balance in intracellular redox pathways. Recent data showed that imbalances in the GSH redox system are an important factor in the pathophysiology of ASD. Furthermore, ASD is accompanied by decreased concentrations of reduced GSH in part caused by oxidation of GSH into glutathione disulfide (GSSG). GSSG can react with protein sulfhydryl (SH) groups, thereby causing proteotoxic stress and other abnormalities in SH-containing enzymes in the brain and blood. Moreover, alterations in the GSH metabolism via its effects on redox-independent mechanisms are other processes associated with the pathophysiology of ASD. GSH-related regulation of glutamate receptors such as the N-methyl-D-aspartate receptor can contribute to glutamate excitotoxicity. Synergistic and antagonistic interactions between glutamate and GSH can result in neuronal dysfunction. These interactions can involve transcription factors of the immune pathway, such as activator protein 1 and nuclear factor (NF)-κB, thereby interacting with neuroinflammatory mechanisms, ultimately leading to neuronal damage. Neuronal apoptosis and mitochondrial dysfunction are recently outlined as significant factors linking GSH impairments with the pathophysiology of ASD. Moreover, GSH regulates the methylation of DNA and modulates epigenetics. Existing data support a protective role of the GSH system in ASD development. Future research should focus on the effects of GSH redox signaling in ASD and should explore new therapeutic approaches by targeting the GSH system. [ABSTRACT FROM AUTHOR]

Autism occurs more frequently in epilepsy, but is often not diagnosed. This could be due to a focus on medical issues, or because it presents differently from classic autism in its timing, phenotype, fluctuating profiles, and high level of comorbidity. Without a diagnosis, these children miss out on interventions that could modify outcome and their families and local teams will struggle to understand and support them. They also become a hidden group that does not participate in or benefit from research. This paper examined the issues and challenges of diagnosing autism in a population with a high-risk of epilepsy, drawing on more than 20 years' experience of a specialist multi-disciplinary Developmental Epilepsy Clinic (DEC). [ABSTRACT FROM AUTHOR]

• POMA is a TUI that runs on a tablet computer and interactive pretend play toys (iPPy) are used to interact with POMA. • Evaluation of POMA was carried out with children with ASD in Sri Lanka. • Children with mild ASD were more comfortable to play POMA than with moderate ASD. • Flat-surface structure of the iPPy toys prevents children from placing the toys correctly on the iPad screen. • A set of recommendations are provided to develop TUIs for children with ASD in low-resource regions. A Tangible User Interface (TUI) can bridge real-world physical objects with the digital world, which has much potential for children with ASD. However, at present, most TUIs have been developed for children in affluent countries. Such solutions may not be applicable for children with ASD in low resource countries like Sri Lanka. Therefore, we have designed a tablet-based, and cost-effective TUI called POMA (Picture to Object Mapping Activities) for supporting social and cognitive skills of Sri Lankan children with ASD. This paper presents the evaluation of POMA with 20 children with ASD (moderate: 6; mild: 14) and five special education teachers. Results show that both groups of children were able to play POMA accurately. However, children with moderate ASD required more time and help from the special education teachers to play POMA compared to children with mild ASD. This study identified several lessons for designing TUI, such as the importance of including audio prompts when the system is in idle state, using appropriate helper cues, using multiple types of reinforcements, easy-to-handle nature of the tangibles and the properties of them. Finally, we provide guidelines to overcome the issues for designing low-cost TUIs for children with ASD. [ABSTRACT FROM AUTHOR]

• Autism symptoms and related psychological dimensions are tested within the context of maleness and femaleness. • 2nd trimester foetal testosterone levels are measured most accurately by amniocentesis. • Foetal testosterone plausibly affects autism symptoms, social and non-social cognition. • Its role on sex differences in play-styles is not supported. • More studies are required beyond the Baron-Cohen group to diminish the possibility of bias in the literature. Baron-Cohen (2002) proposed the Extreme Male Brain Theory (EMB) to suggest that foetal testosterone (FT) (1) is a component of the complex neurobiological aetiology of Autism Spectrum Disorder (ASD) and (2) accounts for its high male prevalence. The theory suggests that ASD is more common in males to an extreme manifestation of psychological maleness due to heightened testosterone exposure in the foetus. To assess the EMB theory by reviewing cohort studies that directly assayed FT levels at 12–24 weeks of gestation in relation to subsequent ASD symptoms, ASD-related cognitions, social outcomes and playstyles prior to adolescence. A systematic term to subject heading search was conducted on Web of Science, Embase, PsycINFO, 'Ovid Medline Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily and Ovid Medline', PsycARTICLES Full Text, and ProQuest up to December 2019. Studies that included the extraction of foetal fluid and children of both sexes were assessed in compliance with STROBE guidelines. Additional articles were obtained by reference list screening. 22 FT-assay studies (N = 2284) containing EMB-associated traits as dependent variables were identified, including ASD symptoms, ASD-related cognition, sociality and playstyles. Their STROBE ratings ranged from 50% to 86.4%. FT significantly accounted for ASD-related traits beyond the child's sex in 3 of 4 studies. 4 out of 9 papers looking at sexed ASD-related cognitive-styles and 2 of 3 examining social outcomes showed significant FT effect. 2 of 6 found that FT accounted for significant variance in behavioral indices that differ on average between the sexes. Chi-square tests (χ 2 2 , N = 22 = 4.46 , P <. 05) demonstrated that researchers affiliated with Baron-Cohen are significantly more likely to generate results fully supportive of EMB, with 25% (N = 3 , P <. 05) of positive findings produced by independent authors. Homogeneity of data did not account for this. The certainty with which FT was established as an agent in sexual differentiation varies by the psychological variable in question, but none of the conclusions were supported by an adequate number of studies. Nevertheless, this review yields the following preliminary conclusions, which can be tested in future research. FT plays a plausible role in driving social and non-social ASD-related cognition as well as ASD symptoms across the sexes. FT accounts for gender differences on eye contact frequency and value-laden proposition use and mediates the narrowing of interest toward systems and exerts sex-specific effects on numerical and language abilities, though these studies require independent replication. The role of FT on the differentiation of play is consistently non-significant. Where an effect exists, it is largely dwarfed by the effect of sex and hence it is equivocal that second trimester FT affects play. Biological implications for sex differences are considered and more lifespan longitudinal amniocentesis studies are suggested to pursue greater clarity in the empirical bases of EMB. [ABSTRACT FROM AUTHOR]

Mercury (Hg) is widely recognized as a neurotoxic metal, besides it can also act as a proinflammatory agent and immunostimulant, depending on individual exposure and susceptibility. Mercury exposure may arise from internal body pathways, such as via dental amalgams, preservatives in drugs and vaccines, and seafood consumption, or even from external pathways, i.e., occupational exposure, environmental pollution, and handling of metallic items and cosmetics containing Hg. In susceptible individuals, chronic low Hg exposure may trigger local and systemic inflammation, even exacerbating the already existing autoimmune response in patients with autoimmunity. Mercury exposure can trigger dysfunction of the autoimmune responses and aggravate immunotoxic effects associated with elevated serum autoantibodies titers. The purpose of the present review is to provide a critical overview of the many issues associated with Hg exposure and autoimmunity. In addition, the paper focuses on individual susceptibility and other health effects of Hg. • Mercury (Hg) is a proinflammatory agent and immunostimulant. • Exposure to Hg can trigger immunotoxic effects, inflammation, and autoimmune dysfunction. • In susceptible individuals, Hg may play a role in autoimmune diseases, including MS. • Characterization of epigenetic markers is needed to highlight individual predispositions to Hg-induced toxic outcomes. [ABSTRACT FROM AUTHOR]