1. Alabdulkareem A, Alhakbani N, Al-Nafjan A. A Systematic Review of Research on Robot-Assisted Therapy for Children with Autism. Sensors (Basel, Switzerland). 2022; 22(3).

Recent studies have shown that children with autism may be interested in playing with an interactive robot. Moreover, the robot can engage these children in ways that demonstrate essential aspects of human interaction, guiding them in therapeutic sessions to practice more complex forms of interaction found in social human-to-human interactions. We review published articles on robot-assisted autism therapy (RAAT) to understand the trends in research on this type of therapy for children with autism and to provide practitioners and researchers with insights and possible future directions in the field. Specifically, we analyze 38 articles, all of which are refereed journal articles, that were indexed on Web of Science from 2009 onward, and discuss the distribution of the articles by publication year, article type, database and journal, research field, robot type, participant age range, and target behaviors. Overall, the results show considerable growth in the number of journal publications on RAAT, reflecting increased interest in the use of robot technology in autism therapy as a salient and legitimate research area. Factors, such as new advances in artificial intelligence techniques and machine learning, have spurred this growth.

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2. Alharthi A, Alhazmi S, Alburae N, Bahieldin A. The Human Gut Microbiome as a Potential Factor in Autism Spectrum Disorder. International journal of molecular sciences. 2022; 23(3).

The high prevalence of gastrointestinal (GI) disorders among autism spectrum disorder (ASD) patients has prompted scientists to look into the gut microbiota as a putative trigger in ASD pathogenesis. Thus, many studies have linked the gut microbial dysbiosis that is frequently observed in ASD patients with the modulation of brain function and social behavior, but little is known about this connection and its contribution to the etiology of ASD. This present review highlights the potential role of the microbiota-gut-brain axis in autism. In particular, it focuses on how gut microbiota dysbiosis may impact gut permeability, immune function, and the microbial metabolites in autistic people. We further discuss recent findings supporting the possible role of the gut microbiome in initiating epigenetic modifications and consider the potential role of this pathway in influencing the severity of ASD. Lastly, we summarize recent updates in microbiota-targeted therapies such as probiotics, prebiotics, dietary supplements, fecal microbiota transplantation, and microbiota transfer therapy. The findings of this paper reveal new insights into possible therapeutic interventions that may be used to reduce and cure ASD-related symptoms. However, well-designed research studies using large sample sizes are still required in this area of study.

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3. Almurashi H, Bouaziz R, Alharthi W, Al-Sarem M, Hadwan M, Kammoun S. Augmented Reality, Serious Games and Picture Exchange Communication System for People with ASD: Systematic Literature Review and Future Directions. Sensors (Basel, Switzerland). 2022; 22(3).

For people with Autism Spectrum Disorder (ASD), using technological tools, such as augmented reality (AR) and serious games remain a new and unexplored option. To attract people with ASD who have communicative, social, emotional and attention deficit disorders to behavioral treatments, an attractive environment is needed that ensures continuity during treatment. The aim of the current work is to efficiently examine systematic reviews and relevant primary studies on ASD solutions from 2015 to 2020, particularly those using the traditional Picture Exchange Communication System (PECS), the application of augmented reality and those that propose serious games, thereby providing an overview of existing evidence and to identify strategies for future research. Five databases were searched for keywords that may be included within the broad Autism Spectrum Disorder ‘ASD’ umbrella term, alongside ‘augmented reality’, ‘serious games’ and ‘PECS’. We screened 1799 titles and abstracts, read, and retained 12 reviews and 43 studies. The studies scrutinized in our systematic review were examined to answer four primary and four sub-research questions, which we formulated to better understand general trends in the use of approaches for attracting people with ASD to behavioral therapies. Additionally, our systematic review also presents ongoing issues in this area of research and suggests promising future research directions. Our review is useful to researchers in this field as it facilitates the comparison of existing studies with work currently being conducted, based on the availability of a wide range of studies in three different areas (AR, SG and PECS).

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4. Barua PD, Vicnesh J, Gururajan R, Oh SL, Palmer E, Azizan MM, Kadri NA, Acharya UR. Artificial Intelligence Enabled Personalised Assistive Tools to Enhance Education of Children with Neurodevelopmental Disorders-A Review. International journal of environmental research and public health. 2022; 19(3).

Mental disorders (MDs) with onset in childhood or adolescence include neurodevelopmental disorders (NDDs) (intellectual disability and specific learning disabilities, such as dyslexia, attention deficit disorder (ADHD), and autism spectrum disorders (ASD)), as well as a broad range of mental health disorders (MHDs), including anxiety, depressive, stress-related and psychotic disorders. There is a high co-morbidity of NDDs and MHDs. Globally, there have been dramatic increases in the diagnosis of childhood-onset mental disorders, with a 2- to 3-fold rise in prevalence for several MHDs in the US over the past 20 years. Depending on the type of MD, children often grapple with social and communication deficits and difficulties adapting to changes in their environment, which can impact their ability to learn effectively. To improve outcomes for children, it is important to provide timely and effective interventions. This review summarises the range and effectiveness of AI-assisted tools, developed using machine learning models, which have been applied to address learning challenges in students with a range of NDDs. Our review summarises the evidence that AI tools can be successfully used to improve social interaction and supportive education. Based on the limitations of existing AI tools, we provide recommendations for the development of future AI tools with a focus on providing personalised learning for individuals with NDDs.

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5. Belteki Z, Lumbreras R, Fico K, Haman E, Junge C. The Vocabulary of Infants with an Elevated Likelihood and Diagnosis of Autism Spectrum Disorder: A Systematic Review and Meta-Analysis of Infant Language Studies Using the CDI and MSEL. International journal of environmental research and public health. 2022; 19(3).

Diagnoses of autism spectrum disorder (ASD) are typically accompanied by atypical language development, which can be noticeable even before diagnosis. The siblings of children diagnosed with ASD are at elevated likelihood for ASD diagnosis and have been shown to have higher prevalence rates than the general population. In this paper, we systematically reviewed studies looking at the vocabulary size and development of infants with autism. One inclusion criterion was that infants were grouped either pre-diagnostically as elevated or typical likelihood or post-diagnostically as ASD or without ASD. This review focused on studies that tested infants up to 24 months of age and that assessed vocabulary either via the parent-completed MacArthur-Bates Communicative Developmental Inventory (CDI) or the clinician-administered Mullen Scales of Early Learning (MSEL). Our systematic search yielded 76 studies. A meta-analysis was performed on these studies that compared the vocabulary scores of EL and TL infants pre-diagnostically and the scores of ASD and non-ASD infants post-diagnostically. Both pre- and post-diagnostically, it was found that the EL and ASD infants had smaller vocabularies than their TL and non-ASD peers, respectively. The effect sizes across studies were heterogenous, prompting additional moderator analyses of age and sub-group analyses of the language measure used (CDI or MSEL) as potential moderators of the effect size. Age was found to be a moderator both in the pre- and post-diagnostical groups, however, language measure was not a moderator in either diagnostic group. Interpretations and future research directions are discussed based on these findings.

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6. Ben-Ari Y, Cherubini E. The GABA Polarity Shift and Bumetanide Treatment: Making Sense Requires Unbiased and Undogmatic Analysis. Cells. 2022; 11(3).

GABA depolarizes and often excites immature neurons in all animal species and brain structures investigated due to a developmentally regulated reduction in intracellular chloride concentration ([Cl(-)](i)) levels. The control of [Cl(-)](i) levels is mediated by the chloride cotransporters NKCC1 and KCC2, the former usually importing chloride and the latter exporting it. The GABA polarity shift has been extensively validated in several experimental conditions using often the NKCC1 chloride importer antagonist bumetanide. In spite of an intrinsic heterogeneity, this shift is abolished in many experimental conditions associated with developmental disorders including autism, Rett syndrome, fragile X syndrome, or maternal immune activation. Using bumetanide, an EMA- and FDA-approved agent, many clinical trials have shown promising results with the expected side effects. Kaila et al. have repeatedly challenged these experimental and clinical observations. Here, we reply to the recent reviews by Kaila et al. stressing that the GABA polarity shift is solidly accepted by the scientific community as a major discovery to understand brain development and that bumetanide has shown promising effects in clinical trials.

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7. Bharadwaj H, Mamashli F, Khan S, Singh R, Joseph RM, Losh A, Pawlyszyn S, McGuiggan NM, Graham S, Hämäläinen MS, Kenet T. Cortical signatures of auditory object binding in children with autism spectrum disorder are anomalous in concordance with behavior and diagnosis. PLoS biology. 2022; 20(2): e3001541.

Organizing sensory information into coherent perceptual objects is fundamental to everyday perception and communication. In the visual domain, indirect evidence from cortical responses suggests that children with autism spectrum disorder (ASD) have anomalous figure-ground segregation. While auditory processing abnormalities are common in ASD, especially in environments with multiple sound sources, to date, the question of scene segregation in ASD has not been directly investigated in audition. Using magnetoencephalography, we measured cortical responses to unattended (passively experienced) auditory stimuli while parametrically manipulating the degree of temporal coherence that facilitates auditory figure-ground segregation. Results from 21 children with ASD (aged 7-17 years) and 26 age- and IQ-matched typically developing children provide evidence that children with ASD show anomalous growth of cortical neural responses with increasing temporal coherence of the auditory figure. The documented neurophysiological abnormalities did not depend on age, and were reflected both in the response evoked by changes in temporal coherence of the auditory scene and in the associated induced gamma rhythms. Furthermore, the individual neural measures were predictive of diagnosis (83% accuracy) and also correlated with behavioral measures of ASD severity and auditory processing abnormalities. These findings offer new insight into the neural mechanisms underlying auditory perceptual deficits and sensory overload in ASD, and suggest that temporal-coherence-based auditory scene analysis and suprathreshold processing of coherent auditory objects may be atypical in ASD.

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8. Błaszczyk B, Miziak B, Pluta R, Czuczwar SJ. Epilepsy in Pregnancy-Management Principles and Focus on Valproate. International journal of molecular sciences. 2022; 23(3).

An estimated 60 million people worldwide suffer from epilepsy, half of whom are women. About one-third of women with epilepsy are of childbearing age. The childbirth rate in women with epilepsy is about 20-40% lower compared to that of the general population, which may be partly due to a lower number of these women being in relationships. Lower fertility in women with epilepsy may be linked to the disease itself, but it is mainly a result of the treatment provided. Valproate, as an antiepileptic drug inhibiting histone deacetylases, may affect the expression of genes associated with cell cycle control and cellular differentiation. Evidently, this drug is associated with the risk of malformations although other antiepileptic drugs (AEDs) may also trigger birth defects, however, to a lower degree. Valproate (and to a certain degree other AEDs) may induce autism spectrum disorders and attention deficit hyperactivity disorder. The main mechanism responsible for all negative effects of prenatal exposure to valproate seems inhibition of histone deacetylases. Animal studies show a reduction in the expression of genes involved in social behavior and an increase in hippocampal cytokines. Valproate-induced oxidative stress may also contribute to neural tube defects. Interestingly, paternal exposure to this AED in mice may trigger neurodevelopmental disorders as well although a population-based cohort study does not confirm this effect. To lower the risk of congenital malformations and neurodevelopmental disorders, a single AED at the optimal dose and supplementation with folic acid is recommended. VPA should be avoided in women of childbearing age and especially during pregnancy.

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9. Błażewicz A, Grywalska E, Macek P, Mertowska P, Mertowski S, Wojnicka J, Durante N, Makarewicz A. Research into the Association of Cadmium and Manganese Excretion with Thyroid Function and Behavioral Areas in Adolescents with Autism Spectrum Disorders. Journal of clinical medicine. 2022; 11(3).

Thyroid dysfunction and toxic metal exposure have been linked to the increased risk of autism spectrum disorders (ASD); however, the relationship between those factors remains unclear. We aimed to evaluate the relationship between the serum level of hormones, namely thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), and urinary cadmium (U-Cd) and urinary manganese (U-Mn), in patients with ASD. The study group consisted of 129 adolescents with ASD, and the control group consisted of 86 healthy persons. Ion chromatography with spectrophotometric detection (IC-UV/ViS) was used to quantitatively determine Cd and Mn in all 24-h urine samples. These results indicate that severity of certain symptoms in autism is associated with thyroid function. Correlation analysis between Childhood Autism Rating Scale (CARS) results and the content of both U-Mn and U-Cd as well as fT3, fT4 and TSH values in ASD patients showed significantly positive correlation of CARS7 (visual reaction) with fT3 and fT4 and a negative correlation with TSH for the whole study group. In the group of adolescents over 14 years of age, it was also observed that CARS10 (anxiety reaction) negatively correlates with serum TSH levels, and among younger individuals, CARS9 (near receptor responsiveness, taste, smell) positively correlates with TSH.

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10. Cassidy S, Au-Yeung S, Robertson A, Cogger-Ward H, Richards G, Allison C, Bradley L, Kenny R, O’Connor R, Mosse D, Rodgers J, Baron-Cohen S. Autism and autistic traits in those who died by suicide in England. The British journal of psychiatry : the journal of mental science. 2022: 1-9.

BACKGROUND: Autism and autistic traits are risk factors for suicidal behaviour. AIMS: To explore the prevalence of autism (diagnosed and undiagnosed) in those who died by suicide, and identify risk factors for suicide in this group. METHOD: Stage 1: 372 coroners’ inquest records, covering the period 1 January 2014 to 31 December 2017 from two regions of England, were analysed for evidence that the person who died had diagnosed autism or undiagnosed possible autism (elevated autistic traits), and identified risk markers. Stage 2: 29 follow-up interviews with the next of kin of those who died gathered further evidence of autism and autistic traits using validated autism screening and diagnostic tools. RESULTS: Stage 1: evidence of autism (10.8%) was significantly higher in those who died by suicide than the 1.1% prevalence expected in the UK general alive population (odds ratio (OR) = 11.08, 95% CI 3.92-31.31). Stage 2: 5 (17.2%) of the follow-up sample had evidence of autism identified from the coroners’ records in stage 1. We identified evidence of undiagnosed possible autism in an additional 7 (24.1%) individuals, giving a total of 12 (41.4%); significantly higher than expected in the general alive population (1.1%) (OR = 19.76, 95% CI 2.36-165.84). Characteristics of those who died were largely similar regardless of evidence of autism, with groups experiencing a comparably high number of multiple risk markers before they died. CONCLUSIONS: Elevated autistic traits are significantly over-represented in those who die by suicide.

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11. Diaz Heijtz R, Gressens P, Swann JR. Targeting microbial metabolites to treat autism. Nature medicine. 2022; 28(3): 448-50.

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12. Fanelli G, Franke B, De Witte W, Ruisch IH, Haavik J, van Gils V, Jansen WJ, Vos SJB, Lind L, Buitelaar JK, Banaschewski T, Dalsgaard S, Serretti A, Mota NR, Poelmans G, Bralten J. Insulinopathies of the brain? Genetic overlap between somatic insulin-related and neuropsychiatric disorders. Translational psychiatry. 2022; 12(1): 59.

The prevalence of somatic insulinopathies, like metabolic syndrome (MetS), obesity, and type 2 diabetes mellitus (T2DM), is higher in Alzheimer’s disease (AD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). Dysregulation of insulin signalling has been implicated in these neuropsychiatric disorders, and shared genetic factors might partly underlie this observed multimorbidity. We investigated the genetic overlap between AD, ASD, and OCD with MetS, obesity, and T2DM by estimating pairwise global genetic correlations using the summary statistics of the largest available genome-wide association studies for these phenotypes. Having tested these hypotheses, other potential brain « insulinopathies » were also explored by estimating the genetic relationship of six additional neuropsychiatric disorders with nine insulin-related diseases/traits. Stratified covariance analyses were then performed to investigate the contribution of insulin-related gene sets. Significant negative genetic correlations were found between OCD and MetS (r(g) = -0.315, p = 3.9 × 10(-8)), OCD and obesity (r(g) = -0.379, p = 3.4 × 10(-5)), and OCD and T2DM (r(g) = -0.172, p = 3 × 10(-4)). Significant genetic correlations with insulin-related phenotypes were also found for anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, and schizophrenia (p < 6.17 × 10(-4)). Stratified analyses showed negative genetic covariances between AD, ASD, OCD, ADHD, AN, bipolar disorder, schizophrenia and somatic insulinopathies through gene sets related to insulin signalling and insulin receptor recycling, and positive genetic covariances between AN and T2DM, as well as ADHD and MetS through gene sets related to insulin processing/secretion (p < 2.06 × 10(-4)). Overall, our findings suggest the existence of two clusters of neuropsychiatric disorders, in which the genetics of insulin-related diseases/traits may exert divergent pleiotropic effects. These results represent a starting point for a new research line on "insulinopathies" of the brain.

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13. Fridell A, Norrman HN, Girke L, Bölte S. Effects of the Early Phase of COVID-19 on the Autistic Community in Sweden: A Qualitative Multi-Informant Study Linking to ICF. International journal of environmental research and public health. 2022; 19(3).

While the COVID-19 pandemic is ongoing, early outcome studies indicate severe and pervasive global effects of the pandemic and associated measures to prevent the spread of the virus. General population studies, as well as insight into the outcomes for particular groups, will be necessary in order to mitigate potentially long-term effects as well as to prepare for future epidemics or pandemics. The pandemic conditions have been marked by rapid and abrupt changes and unpredictability which are circumstances that leave the autistic population particularly vulnerable to adverse outcomes following the distinctive features of the diagnosis. Studies are only beginning to delineate the outcomes of the global autism community and the present study adds to these findings by providing a local, multi-perspective, qualitative analysis of the lived experiences of the Swedish autism community. In this study, autistic youth and adults, caregivers of autistic individuals, as well as representatives of Swedish interest organizations were interviewed. Thematic analysis was performed on the population as a whole and patterns of results were formalized according to the International Classification of Function, Disability and Health (ICF-CY). Participants report wide-ranging adverse outcomes of the pandemic relating to mental health and access to support, participation in daily activities and socialization, education, and work as well as parental resources. However, participants also report positive outcomes relating to a reduction in specific social and everyday demands, and normalization of lived experiences. Additionally, interviews outlined some strategies used to cope during pandemic conditions. Implications of these findings are discussed.

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14. Grant S, Norton S, Weiland RF, Scheeren AM, Begeer S, Hoekstra RA. Autism and chronic ill health: an observational study of symptoms and diagnoses of central sensitivity syndromes in autistic adults. Molecular autism. 2022; 13(1): 7.

BACKGROUND: Autistic adults, particularly women, are more likely to experience chronic ill health than the general population. Central sensitivity syndromes (CSS) are a group of related conditions that are thought to include an underlying sensitisation of the central nervous system; heightened sensory sensitivity is a common feature. Anecdotal evidence suggests autistic adults may be more prone to developing a CSS. This study aimed to investigate the occurrence of CSS diagnoses and symptoms in autistic adults, and to explore whether CSS symptoms were related to autistic traits, mental health, sensory sensitivity, or gender. METHODS: The full sample of participants included 973 autistic adults (410 men, 563 women, mean age = 44.6) registered at the Netherlands Autism Register, who completed questionnaires assessing autistic traits, sensory sensitivity, CSS, physical and mental health symptoms. The reliability and validity of the Central Sensitization Inventory (CSI) in an autistic sample was established using exploratory and confirmatory factor analyses. Chi(2) analyses, independent t-tests, hierarchical regression and path analysis were used to analyse relationships between CSS symptoms, autistic traits, measures of mental health and wellbeing, sensory sensitivity, age and gender. RESULTS: 21% of participants reported one or more CSS diagnosis, and 60% scored at or above the clinical cut-off for a CSS. Autistic women were more likely to report a CSS diagnosis and experienced more CSS symptoms than men. Sensory sensitivity, anxiety, age and gender were significant predictors of CSS symptoms, with sensory sensitivity and anxiety fully mediating the relationship between autistic traits and CSS symptoms. LIMITATIONS: Although this study included a large sample of autistic adults, we did not have a control group or a CSS only group. We also could not include a non-binary group due to lack of statistical power. CONCLUSIONS: CSS diagnoses and symptoms appear to be very common in the autistic population. Increased awareness of an association between autism and central sensitisation should inform clinicians and guide diagnostic practice, particularly for women where CSS are common and autism under recognised.

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15. Khera R, Mehan S, Bhalla S, Kumar S, Alshammari A, Alharbi M, Sadhu SS. Guggulsterone Mediated JAK/STAT and PPAR-Gamma Modulation Prevents Neurobehavioral and Neurochemical Abnormalities in Propionic Acid-Induced Experimental Model of Autism. Molecules (Basel, Switzerland). 2022; 27(3).

Autism spectrum disorder is a neurodevelopmental disorder marked by repetitive behaviour, challenges in verbal and non-verbal communication, poor socio-emotional health, and cognitive impairment. An increased level of signal transducer and activator of transcription 3 (STAT3) and a decreased level of peroxisome proliferator-activated receptor (PPAR) gamma have been linked to autism pathogenesis. Guggulsterone (GST) has a neuroprotective effect on autistic conditions by modulating these signalling pathways. Consequently, the primary objective of this study was to examine potential neuroprotective properties of GST by modulating JAK/STAT and PPAR-gamma levels in intracerebroventricular propionic acid (ICV PPA) induced experimental model of autism in adult rats. In this study, the first 11 days of ICV-PPA injections in rats resulted in autism-like behavioural, neurochemical, morphological, and histopathological changes. The above modifications were also observed in various biological samples, including brain homogenate, CSF, and blood plasma. GST was also observed to improve autism-like behavioural impairments in autistic rats treated with PPA, including locomotion, neuromuscular coordination, depression-like behaviour, spatial memory, cognition, and body weight. Prolonged GST treatment also restored neurochemical deficits in a dose-dependent manner. Chronic PPA administration increased STAT3 and decreased PPAR gamma in autistic rat brain, CSF, and blood plasma samples, which were reversed by GST. GST also restored the gross and histopathological alterations in PPA-treated rat brains. Our results indicate the neuroprotective effects of GST in preventing autism-related behavioural and neurochemical alterations.

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16. Kodera K, Matsui H. Zebrafish, Medaka and Turquoise Killifish for Understanding Human Neurodegenerative/Neurodevelopmental Disorders. International journal of molecular sciences. 2022; 23(3).

In recent years, small fishes such as zebrafish and medaka have been widely recognized as model animals. They have high homology in genetics and tissue structure with humans and unique features that mammalian model animals do not have, such as transparency of embryos and larvae, a small body size and ease of experiments, including genetic manipulation. Zebrafish and medaka have been used extensively in the field of neurology, especially to unveil the mechanisms of neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, and recently, these fishes have also been utilized to understand neurodevelopmental disorders such as autism spectrum disorder. The turquoise killifish has emerged as a new and unique model animal, especially for ageing research due to its unique life cycle, and this fish also seems to be useful for age-related neurological diseases. These small fishes are excellent animal models for the analysis of human neurological disorders and are expected to play increasing roles in this field. Here, we introduce various applications of these model fishes to improve our understanding of human neurological disorders.

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17. Myers RK, Labows C, Yerys BE, McDonald CC, Sartin EB, Mollen CJ, Curry AE. Transition to Adulthood for Autistic Adolescents: Topics Discussed by Healthcare Providers With Autistic Patients and Families. The Journal of adolescent health : official publication of the Society for Adolescent Medicine. 2022; 70(5): 829-32.

PURPOSE: We surveyed healthcare providers to determine the extent to which they discuss transition-to-adulthood topics with autistic patients without intellectual disabilities. METHODS: Seventy-four healthcare providers in the Philadelphia area reported on the patient age at which they begin transition conversations, topics covered, and provider comfort. We calculated the proportion of providers who endorsed each transition topic, overall and by clinical setting. RESULTS: Providers initiated transition-related conversations at a median age of 16 years (IQR: 14, 18), with over half reporting they were « somewhat » or « a little » comfortable with discussions. Nearly all providers discussed at least one healthcare, well-being, and mental health topic, while basic need-related discussions were limited. DISCUSSION: Results suggest providers may delay and feel poorly prepared to provide anticipatory guidance to autistic patients for transition to adulthood. Future efforts to enhance the available resources and preparation available to providers are essential to meet autistic patients’ needs.

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18. Offermans JE, de Bruin EI, Lange AMC, Middeldorp CM, Wesseldijk LW, Boomsma DI, Dieleman GC, Bögels SM, van Steensel FJA. The Development and Validation of a Subscale for the School-Age Child Behavior CheckList to Screen for Autism Spectrum Disorder. Journal of autism and developmental disorders. 2022.

The first aim of this study was to construct/validate a subscale-with cut-offs considering gender/age differences-for the school-age Child Behavior CheckList (CBCL) to screen for Autism Spectrum Disorder (ASD) applying both data-driven (N = 1666) and clinician-expert (N = 15) approaches. Further, we compared these to previously established CBCL ASD profiles/subscales and DSM-oriented subscales. The second aim was to cross-validate results in two truly independent samples (N = 2445 and 886). Despite relatively low discriminative power of all subscales in the cross-validation samples, results indicated that the data-driven subscale had the best potential to screen for ASD and a similar screening potential as the DSM-oriented subscales. Given beneficial implications for pediatric/clinical practice, we encourage colleagues to continue the validation of this CBCL ASD subscale.

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19. Romano A, Ippolito E, Risoli C, Malerba E, Favetta M, Sancesario A, Lotan M, Moran DS. Intensive Postural and Motor Activity Program Reduces Scoliosis Progression in People with Rett Syndrome. Journal of clinical medicine. 2022; 11(3).

BACKGROUND: A scoliosis prevalence of 94% was reported in the population with Rett syndrome (RTT), with an annual progression rate of 14 to 21° Cobb which may result in pain, loss of sitting balance, deterioration of motor skills, and lung disfunction. This paper describes the efficacy of an intensive conservative individualized physical and postural activity program in preventing scoliosis curvature progression in patients with RTT. METHODS: Twenty subjects diagnosed with RTT and scoliosis were recruited, and an individualized intensive daily physical activity program was developed for each participant. Each program was conducted for six months by participants’ primary caregivers in their daily living environment. Fortnightly remote supervision of the program implementation was provided by an expert therapist. Pre- and post-intervention radiographs and motor functioning were analyzed. RESULTS: An averaged progression of +1.7° ± 8.7° Cobb, over one year (12.3 ± 3.5 months) was observed in our group, together with motor function improvements. A relation between curve progression and motor skill improvement was observed. CONCLUSIONS: The intervention prevented scoliosis progression in our group. The achievement of functional motor improvements could enable better body segment control and muscle balancing, with a protective effect on scoliosis progression. The intervention was effective for individuals with RTT across various ages and severity levels. Individual characteristics of each participant and the details of their activity program are described.

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20. Rujeedawa T, Zaman SH. The Diagnosis and Management of Autism Spectrum Disorder (ASD) in Adult Females in the Presence or Absence of an Intellectual Disability. International journal of environmental research and public health. 2022; 19(3).

We review the reasons for the greater male predominance in the diagnosis of autism spectrum disorder in the non-intellectual disabled population and compare it to autism diagnosed in intellectually disabled individuals. Accurate and timely diagnosis is important, as it reduces health inequalities. Females often present later for the diagnosis. The differences are in core features, such as in social reciprocal interaction through ‘camouflaging’ and restricted repetitive behaviours, that are less noticeable in females and are potentially explained by the biological differences (female protective effect theory) and/or differences in presentation between the two sexes (female autism phenotype theory). Females more often present with internalising co-occurring conditions than males. We review these theories, highlighting the key differences and the impact of a diagnosis on females. We review methods to potentially improve diagnosis in females along with current and future management strategies.

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21. Santos S, Ferreira H, Martins J, Gonçalves J, Castelo-Branco M. Male sex bias in early and late onset neurodevelopmental disorders: Shared aspects and differences in Autism Spectrum Disorder, Attention Deficit/hyperactivity Disorder, and Schizophrenia. Neuroscience and biobehavioral reviews. 2022; 135: 104577.

Neurodevelopmental disorders are characterized by relatively early onset, with temporal variations across conditions. These lifelong conditions lead to social and communication impairments, and cognitive deficits. In recent years, the importance of biological sex as a vital factor determining behavioural and cognitive vulnerability has been substantiated with a direct impact on both diagnosis and therapeutic response. Several theories have been raised as an attempt to explain psychiatric sex bias. These include the extreme male brain theory, female protective effect, maternal stress, and perinatal inflammation. Here, we address this issue in the context of three important neurodevelopmental disorders where male bias exists into variable extents: autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ). Sex differences in behaviour and brain organization are reviewed both for patient and animal research, in the context of molecular theories that may explain differential disease vulnerability. Accumulating evidence suggests a complex mechanistic scenario, with genetic predisposition and endocrine and environmental factors as interacting components governing disease onset, progression, and severity.

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22. Sekułowicz M, Kwiatkowski P, Manor-Binyamini I, Boroń-Krupińska K, Cieślik B. The Effect of Personality, Disability, and Family Functioning on Burnout among Mothers of Children with Autism: A Path Analysis. International journal of environmental research and public health. 2022; 19(3).

This path analysis of mothers of children with autism aimed to investigate the relationship between maternal burnout and the mother’s subjective reporting of difficulty in childcare, family function, and personality traits. A total of 410 mothers of children with autism (mean age 39.03, SD 7.42) completed four questionnaires: Parental Burnout Measure (PBM-12), International Personality Item Pool-Big Five Markers (IPIP-BFM-20), Flexibility and Cohesion Evaluation Scales (FACES-IV), and a survey on childcare difficulties. Path analysis using two predetermined models was used to examine the interrelations. Both models fit the empirical data equally with a Root Mean Square Error of Approximation (RMSEA) index of 0.000 and a 90% confidence interval (model 1: 0.000-0.052; model 2: 0.000-0.059). Path analysis revealed similar fit indexes for both models: (a) burnout is a mediator between exogenous variables and family functioning, and (b) family functioning is an indirect mediator between exogenous variables and burnout. These findings suggest that increased maternal emotional instability (neuroticism) and conscientiousness can lead to increased family communication problems, which may further lead to a breakdown of the equilibrium in the family system, resulting in the mother’s dissatisfaction with family life and a consequent increased risk of maternal burnout.

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23. Stewart Campbell A, Needham BD, Meyer CR, Tan J, Conrad M, Preston GM, Bolognani F, Rao SG, Heussler H, Griffith R, Guastella AJ, Janes AC, Frederick B, Donabedian DH, Mazmanian SK. Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial. Nature medicine. 2022; 28(3): 528-34.

Autism spectrum disorder (ASD) is defined by hallmark behaviors involving reduced communication and social interaction as well as repetitive activities and restricted interests. ASD represents a broad spectrum, from minimally affected individuals to those requiring intense support, with additional manifestations often including anxiety, irritability/aggression and altered sensory processing. Gastrointestinal (GI) issues are also common in ASD, and studies have identified changes in the gut microbiome of individuals with ASD compared to control populations, complementing recent findings of differences in gut-derived metabolites in feces and circulation. However, a role for the GI tract or microbiome in ASD remains controversial. Here we report that an oral GI-restricted adsorbent (AB-2004) that has affinity for small aromatic or phenolic molecules relieves anxiety-like behaviors that are driven by a gut microbial metabolite in mice. Accordingly, a pilot human study was designed and completed to evaluate the safety of AB-2004 in an open-label, single-cohort, multiple-ascending-dose clinical trial that enrolled 30 adolescents with ASD and GI symptoms in New Zealand and Australia. AB-2004 was shown to have good safety and tolerability across all dose levels, and no drug-related serious adverse events were identified. Significant reductions in specific urinary and plasma levels of gut bacterial metabolites were observed between baseline and end of AB-2004 treatment, demonstrating likely target engagement. Furthermore, we observed improvements in multiple exploratory behavioral endpoints, most significantly in post hoc analysis of anxiety and irritability, as well as GI health, after 8 weeks of treatment. These results from an open-label study (trial registration no. ACTRN12618001956291) suggest that targeting gut-derived metabolites with an oral adsorbent is a safe and well-tolerated approach to improving symptoms associated with ASD, thereby emboldening larger placebo-controlled trials.

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24. Supekar K, de Los Angeles C, Ryali S, Cao K, Ma T, Menon V. Deep learning identifies robust gender differences in functional brain organization and their dissociable links to clinical symptoms in autism. The British journal of psychiatry : the journal of mental science. 2022: 1-8.

BACKGROUND: Autism spectrum disorder (ASD) is a highly heterogeneous disorder that affects nearly 1 in 189 females and 1 in 42 males. However, the neurobiological basis of gender differences in ASD is poorly understood, as most studies have neglected females and used methods ill-suited to capture such differences. AIMS: To identify robust functional brain organisation markers that distinguish between females and males with ASD and predict symptom severity. METHOD: We leveraged multiple neuroimaging cohorts (ASD n = 773) and developed a novel spatiotemporal deep neural network (stDNN), which uses spatiotemporal convolution on functional magnetic resonance imaging data to distinguish between groups. RESULTS: stDNN achieved consistently high classification accuracy in distinguishing between females and males with ASD. Notably, stDNN trained to distinguish between females and males with ASD could not distinguish between neurotypical females and males, suggesting that there are gender differences in the functional brain organisation in ASD that differ from normative gender differences. Brain features associated with motor, language and visuospatial attentional systems reliably distinguished between females and males with ASD. Crucially, these results were observed in a large multisite cohort and replicated in a fully independent cohort. Furthermore, brain features associated with the motor network’s primary motor cortex node predicted the severity of restricted/repetitive behaviours in females but not in males with ASD. CONCLUSIONS: Our replicable findings reveal that the brains of females and males with ASD are functionally organised differently, contributing to their clinical symptoms in distinct ways. They inform the development of gender-specific diagnoses and treatment strategies for ASD, and ultimately advance precision psychiatry.

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25. Varma M, Washington P, Chrisman B, Kline A, Leblanc E, Paskov K, Stockham N, Jung JY, Sun MW, Wall DP. Identification of Social Engagement Indicators Associated With Autism Spectrum Disorder Using a Game-Based Mobile App: Comparative Study of Gaze Fixation and Visual Scanning Methods. Journal of medical Internet research. 2022; 24(2): e31830.

BACKGROUND: Autism spectrum disorder (ASD) is a widespread neurodevelopmental condition with a range of potential causes and symptoms. Standard diagnostic mechanisms for ASD, which involve lengthy parent questionnaires and clinical observation, often result in long waiting times for results. Recent advances in computer vision and mobile technology hold potential for speeding up the diagnostic process by enabling computational analysis of behavioral and social impairments from home videos. Such techniques can improve objectivity and contribute quantitatively to the diagnostic process. OBJECTIVE: In this work, we evaluate whether home videos collected from a game-based mobile app can be used to provide diagnostic insights into ASD. To the best of our knowledge, this is the first study attempting to identify potential social indicators of ASD from mobile phone videos without the use of eye-tracking hardware, manual annotations, and structured scenarios or clinical environments. METHODS: Here, we used a mobile health app to collect over 11 hours of video footage depicting 95 children engaged in gameplay in a natural home environment. We used automated data set annotations to analyze two social indicators that have previously been shown to differ between children with ASD and their neurotypical (NT) peers: (1) gaze fixation patterns, which represent regions of an individual’s visual focus and (2) visual scanning methods, which refer to the ways in which individuals scan their surrounding environment. We compared the gaze fixation and visual scanning methods used by children during a 90-second gameplay video to identify statistically significant differences between the 2 cohorts; we then trained a long short-term memory (LSTM) neural network to determine if gaze indicators could be predictive of ASD. RESULTS: Our results show that gaze fixation patterns differ between the 2 cohorts; specifically, we could identify 1 statistically significant region of fixation (P<.001). In addition, we also demonstrate that there are unique visual scanning patterns that exist for individuals with ASD when compared to NT children (P<.001). A deep learning model trained on coarse gaze fixation annotations demonstrates mild predictive power in identifying ASD. CONCLUSIONS: Ultimately, our study demonstrates that heterogeneous video data sets collected from mobile devices hold potential for quantifying visual patterns and providing insights into ASD. We show the importance of automated labeling techniques in generating large-scale data sets while simultaneously preserving the privacy of participants, and we demonstrate that specific social engagement indicators associated with ASD can be identified and characterized using such data.

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26. Wang J, Fröhlich H, Torres FB, Silva RL, Poschet G, Agarwal A, Rappold GA. Mitochondrial dysfunction and oxidative stress contribute to cognitive and motor impairment in FOXP1 syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2022; 119(8).

FOXP1 syndrome caused by haploinsufficiency of the forkhead box protein P1 (FOXP1) gene is a neurodevelopmental disorder that manifests motor dysfunction, intellectual disability, autism, and language impairment. In this study, we used a Foxp1 (+/-) mouse model to address whether cognitive and motor deficits in FOXP1 syndrome are associated with mitochondrial dysfunction and oxidative stress. Here, we show that genes with a role in mitochondrial biogenesis and dynamics (e.g., Foxo1, Pgc-1α, Tfam, Opa1, and Drp1) were dysregulated in the striatum of Foxp1 (+/-) mice at different postnatal stages. Furthermore, these animals exhibit a reduced mitochondrial membrane potential and complex I activity, as well as decreased expression of the antioxidants superoxide dismutase 2 (Sod2) and glutathione (GSH), resulting in increased oxidative stress and lipid peroxidation. These features can explain the reduced neurite branching, learning and memory, endurance, and motor coordination that we observed in these animals. Taken together, we provide strong evidence of mitochondrial dysfunction in Foxp1 (+/-) mice, suggesting that insufficient energy supply and excessive oxidative stress underlie the cognitive and motor impairment in FOXP1 deficiency.

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27. Xiao L, Wang M, Zhang W, Song Y, Zeng J, Li H, Yu H, Li L, Gao P, Yao P. Maternal diabetes-mediated RORA suppression contributes to gastrointestinal symptoms in autism-like mouse offspring. BMC neuroscience. 2022; 23(1): 8.

BACKGROUND: Retinoic acid-related orphan receptor alpha (RORA) has been reported to be suppressed in autistic patients and is associated with autism spectrum disorders (ASD), although the potential role and mechanism of RORA on gastrointestinal (GI) symptoms in ASD patients is still not reported. In this study, we aim to investigate the contribution of RORA to GI symptoms through a maternal diabetes-mediated autism-like mouse model. RESULTS: Male offspring of diabetic dams were treated with either superoxide dismutase (SOD) mimetic MnTBAP or RORA agonist SR1078, or were crossbred with intestine epithelial cells (IEC)-specific RORA knockout (RORA(-/-)) mouse. Gene expression, oxidative stress and inflammation were measured in brain tissues, peripheral blood mononuclear cells (PBMC) and IEC, and GI symptoms were evaluated. Our results showed that SOD mimetic MnTBAP completely, while RORA agonist SR1078 partly, reversed maternal diabetes-mediated oxidative stress and inflammation in the brain, PBMC and IEC, as well as GI symptoms, including intestine permeability and altered gut microbiota compositions. IEC-specific RORA deficiency either mimicked or worsened maternal diabetes-mediated GI symptoms as well as oxidative stress and inflammation in IEC, while there was little effect on maternal diabetes-mediated autism-like behaviors. CONCLUSIONS: We conclude that RORA suppression contributes to maternal diabetes-mediated GI symptoms in autism-like mouse offspring, this study provides a potential therapeutical target for maternal diabetes-mediated GI symptoms in offspring through RORA activation.

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