1. Adochiei FC, Arghir SN, Adochiei IR, Argatu FC, Seritan GC, Alexandrescu B. The Power of Play: Strategies for Enhancing Development in Children with Autism Spectrum Disorders. Sensors (Basel). 2024; 24(20).

The increasing prevalence of autism spectrum disorder (ASD) underscores its significant impact on individuals and the importance of early intervention. ASD affects various aspects of life, including education, emotional development, and social interactions. Besides traditional therapeutic approaches, a novel strategy incorporating digital games has been introduced. Four games developed using Makey Makey and Scratch aim to enhance cognitive skills in children with ASD. This approach facilitates emotional and intellectual development, tracks progress, and offers personalized and engaging interventions. This study demonstrated significant improvements in memory and concentration among participants, with an average improvement of 23.38 points. The most notable enhancements were observed in children aged 10, who showed an average improvement of 25.67 points. Additionally, female participants exhibited a slightly higher average improvement compared to males. The Memory Maze game also effectively enhanced cognitive skills in children with different types of ADHD. Children with the Hyperactive-Impulsive type showed the highest average improvement, with 25.00 points, followed by those with the Combined type, with 24.15 points, and the Inattentive type, with 23.53 points. These findings highlight the potential use of these tools in both ASD and ADHD therapy, providing a structured and enjoyable learning environment that supports cognitive development and therapeutic outcomes.

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2. Al Kheraif AA, Adam TR, Wasi A, Alhassoun RK, Haddadi RM, Alnamlah M. Impact of Virtual Reality Intervention on Anxiety and Level of Cooperation in Children and Adolescents with Autism Spectrum Disorder during the Dental Examination. J Clin Med. 2024; 13(20).

Background: Individuals with Autism Spectrum Disorder (ASD) frequently encounter increased levels of anxiety and display resistant behaviors during dental examinations, which negatively affects their oral care and maintenance. This study employed a cross-sectional design to evaluate the impact of virtual reality (VR) intervention on the anxiety and level of cooperation in children and adolescents with ASD during dental examinations. Methods: A total of 140 participants diagnosed with ASD, aged from 4- to 18-years-old, were selected from two specialized ASD management centers in Riyadh/Saudi Arabia. The participants were randomly allocated into either the control group or the VR group. Control group participants were subjected to a conventional dental examination, while the VR group utilized VR intervention to immerse themselves in a simulated natural and soothing environment. The Venham anxiety and behavior scale (VABS) was utilized to measure anxiety levels, while the Frankl behavior rating scale (FBRS) was employed to assess the level of cooperation. Data were analyzed using a Mann-Whitney U test with a significance level of p < 0.05. Results: The baseline anxiety and level of cooperation between the groups were comparable (p > 0.05). During the dental examination, the VR group had significantly reduced anxiety scores (2.48 ± 1.76) compared to the control group (1.50 ± 1.74) (p < 0.001). Regarding the level of cooperation, the VR group exhibited significantly greater levels of cooperation (3.41 ± 0.96) than the control group (2.86 ± 1.03) (p = 0.002). Conclusions: These findings suggest that VR intervention is a successful technique for decreasing anxiety and enhancing cooperation among children with ASD during dental examination. Integrating VR technology in dental environments can potentially improve the dental experience and results for children diagnosed with ASD.

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3. Alayoubi AM, Alfadhli F, Mehnaz, Albalawi AM, Ramzan K, Jelani M, Basit S. A homozygous variant in ARHGAP39 is associated with lethal cerebellar vermis hypoplasia in a consanguineous Saudi family. Sci Rep. 2024; 14(1): 25291.

Cerebellar vermis hypoplasia refers to a varying degree of incomplete development of the cerebellum and vermis. A Saudi family with four affected individuals with cerebellar vermis hypoplasia, facial dysmorphology, visual impairment, skeletal, and cardiac abnormalities was ascertained in this study. Three out of four patients could not survive longer and had died in early infancy. Genetic analysis of the youngest affected was performed by genome-wide homozygosity mapping coupled with whole exome sequencing (WES), followed by Sanger validation. Genome-wide genotyping analysis mapped the phenotype to chromosome 8q24.3. Using an autosomal recessive model, considering deleterious variants with minor allele frequency of less than 0.001 in WES data, a homozygous missense variant (NM_025251.2; ARHGAP39; c.1301G > T; p.Cys434Phe) was selected as a potential candidate for the phenotype. The variant (c.1301G > T) in the ARHGAP39 is in the region of homozygosity on chromosome 8q24.3. ARHGAP39 is a Rho GTPase-activating protein 39 and has been known to regulate apoptosis, cell migration, neurogenesis, and cerebral and hippocampal dendritic spine morphology. Mice homozygous for arhgap39 knockouts have shown premature embryonic lethality. Our findings present the first ever human phenotype associated with ARHGAP39 alteration.

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4. André ML, Maintenant C. About the relationship between executive function, theory of mind, and language abilities in children with autism: a systematic review. Appl Neuropsychol Child. 2024: 1-18.

A systematic review guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) procedure was used to evaluate the assumption that executive functions play a role in the relationship between theory of mind and language abilities in autism spectrum disorder. A total of 141 papers published in English between 2012 and 2023 were selected in databases, and of which 10 articles met inclusion criteria. Results showed that executive functions could be a predictor of theory of mind even when controlling for general language scores and age. However, results on syntactic language were not sufficient to completely validate the hypothesis that syntax could explain the relationship between theory of mind and executive functions in children with autism.

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5. Bled C, Guillon Q, Mottron L, Soulieres I, Bouvet L. Evaluation of a Visual Cognitive Style in Autism: A Cluster Analysis. J Autism Dev Disord. 2024.

Cognitive style refers to how individuals perceive their environment and solve problems. Among various cognitive styles documented, verbal and visual styles, including object versus spatial cognition, have been widely studied. « Thinking in pictures » is often associated with autism and characterized by enhanced performance and autonomy of certain perceptual areas. This study aimed to characterize the cognitive style of autistic individuals, focusing on this visual « thinking in pictures » style. We assessed 43 autistic and 42 non-autistic adults using the Object Spatial Imagery Verbal Questionnaire to evaluate three dimensions of their cognitive style: visual object, visual spatial, and verbal. Using a cluster analysis, we identified cognitive style profiles. We then examined manifestations of cognitive style within these profiles, including mental imagery abilities (with the Mental Rotation Test), the vividness of mental images (with the Vividness of Visual Imagery Questionnaire), language abilities (with the Mill Hill vocabulary test), and synesthetic experiences. Our results revealed three distinct cognitive profiles: a visual profile characterized by significant mental imagery and vivid mental images, a visuo-spatial profile associated with strong abilities to manipulate mental images but lower vividness of mental images, and a verbal profile with lower spatial imagery and manipulation abilities. While all profiles were observed in autistic individuals, the visual cognitive profile was the most common. Additionally, we found synesthesia to be more prevalent in the autistic population compared to the non-autistic population. This study confirms that, while not exclusive, a visual cognitive style is prevalent among autistic individuals.

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6. Camino-Alarcón J, Robles-Bello MA, Valencia-Naranjo N, Sarhani-Robles A. A Systematic Review of Treatment for Children with Autism Spectrum Disorder: The Sensory Processing and Sensory Integration Approach. Children (Basel). 2024; 11(10).

BACKGROUND/OBJECTIVES: The prevalence of the diagnosis of autism spectrum disorder (ASD) has been increasing globally, necessitating updates to the Diagnostic and Statistical Manual of Mental Disorders with respect to ASD diagnosis. It is now recognised that ASD is related to sensory processing disorder, and sensory integration is considered a suitable intervention for treating children diagnosed with ASD. METHODS: This paper provides a systematic review on a timeline from 2013 to 2023, based on the PRISMA model. Evidence was sought in the academic search engines Pubmed, Scielo, Eric, Dialnet, Springer, Base Search and Google Scholar, which produced 16 articles according to the inclusion criteria. RESULTS: According to the results of this review, intervention with sensory integration in infants with ASD meets the criteria to be considered an evidence-based practice. The studies reviewed focused mainly on clinical settings and, therefore, we highlight the urgent need for further research to evaluate the effectiveness of sensory integration interventions in naturalistic settings such as homes and schools. CONCLUSIONS: This will help to obtain more representative data on how these interventions affect the daily lives of children with ASD.

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7. Carson WEt, Major S, Akkineni H, Fung H, Peters E, Carpenter KLH, Dawson G, Carlson DE. Model selection to achieve reproducible associations between resting state EEG features and autism. Sci Rep. 2024; 14(1): 25301.

A concern in the field of autism electroencephalography (EEG) biomarker discovery is their lack of reproducibility. In the present study, we considered the problem of learning reproducible associations between multiple features of resting state (RS) neural activity and autism, using EEG data collected during a RS paradigm from 36 to 96 month-old children diagnosed with autism (N = 224) and neurotypical children (N = 69). Specifically, EEG spectral power and functional connectivity features were used as inputs to a regularized generalized linear model trained to predict diagnostic group (autism versus neurotypical). To evaluate our model, we proposed a procedure that quantified both the predictive generalization and reproducibility of learned associations produced by the model. When prioritizing both model predictive performance and reproducibility of associations, a highly reproducible profile of associations emerged. This profile revealed a distinct pattern of increased gamma power and connectivity in occipital and posterior midline regions associated with an autism diagnosis. Conversely, model selection based on predictive performance alone resulted in non-robust associations. Finally, we built a custom machine learning model that further empirically improved robustness of learned associations. Our results highlight the need for model selection criteria that maximize the scientific utility provided by reproducibility instead of predictive performance.

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8. Dame C, Viellard M, Elissalde SN, Pergeline H, Grandgeorge P, Garie LA, Solla F, Martino S, Avenel E, Salle-Collemiche X, Fernandez A, Poinso F, Jouve E, Guivarch J. Developmental Profile of Children with Autism Spectrum Disorder Versus Social Communication Disorder: A Pilot Study. Children (Basel). 2024; 11(10).

BACKGROUND: Social Communication Disorder (SCD), introduced in the DSM-5, is distinguished from Autism Spectrum Disorder (ASD) by the absence of restricted and repetitive behaviors or interests (RRBIs). AIM: To compare the adaptive, sensory, communication, and cognitive profiles of children with ASD and SCD. METHODS: The assessments of nine children with SCD and ten with ASD were compared with either Fisher’s Exact Test or the Mann-Whitney Test. Assessments included the Vineland Adaptive Behavior Scales, the Autism Diagnostic Observation Schedule (ADOS), the Short Sensory Profile, Bishop’s Children’s Communication Checklist, a pragmatics evaluation, and the Wechsler Intelligence Scale for Children IV. RESULTS: The total ADOS score and the second subtotal « Restricted and Repetitive Behaviors » were significantly higher (p = 0.022) in the ASD group than in the SCD group. The Vineland standard score for the « Socialization » domain was significantly lower (p = 0.037) in the ASD group (mean: 51 +/- 19) than in the SCD group (mean: 80 +/- 28). The working memory index score was also significantly lower (p = 0.013) in the ASD group compared to the SCD group. CONCLUSIONS: While ASD and SCD share similarities in communication and pragmatic difficulties, some distinctions have been identified, e.g. in executive functioning and the impact on socialization, which may be linked to the absence of RRBIs in SCD. These findings highlight the challenges posed by this nosographic separation during diagnostic evaluations due to the scarcity of discriminative tools.

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9. De Jesus Cintron K, Yang X. Neuroticism Mediates the Association between Autistic Traits and Choice Reaction Time among Young Adults. Behav Sci (Basel). 2024; 14(10).

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that influences an individual’s cognitive functions and social interaction. While most studies have focused on children and adolescents diagnosed with ASD, elevated levels of autistic traits in subclinical populations may also influence individuals’ daily functioning. Autistic traits are also linked to the Big Five personality. In particular, neuroticism (emotion instability) has been shown to be positively associated with autistic traits, which may contribute to behavioral symptoms of autistic traits. The present study aimed to investigate the association between autistic symptoms and sensorimotor processing among a subclinical population. One hundred young adults (M(age) = 20.32 years; SD = 3.69 years; 69 female) completed a choice reaction time (RT) task, and their behavioral performance was analyzed using the ex-Gaussian modeling. The Autism Quotient (AQ) and the Ten-Item Personality Inventory (TIPI) were used to assess autistic traits and neuroticism, respectively. The mediation analysis was conducted to examine the behavioral mechanism through which autistic traits influence sensorimotor processing. The results showed that the AQ score was negatively correlated with RT and positively correlated with neuroticism score. Importantly, the mediation analysis indicated an indirect effect, suggesting that neuroticism mediates the association between the AQ score and RT. The findings indicated a possible mechanism of the association between autistic traits and sensorimotor responses and suggested that neuroticism should be included as an intervention target for ASD. The present study contributes to the research on autistic traits and has practical implications for future intervention programs to improve daily functioning among individuals with ASD.

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10. Downs J, Wong K, Leonard H. Associations between genotype, phenotype and behaviours measured by the Rett syndrome behaviour questionnaire in Rett syndrome. J Neurodev Disord. 2024; 16(1): 59.

INTRODUCTION: Rett syndrome (RTT) is a rare neurodevelopmental disorder with developmental impairments, comorbidities, and abnormal behaviours such as hand stereotypies and emotional features. The Rett Syndrome Behaviour Questionnaire (RSBQ) was developed to describe the behavioural and emotional features of RTT. Little is known how RSBQ scores are associated with genetic and clinical characteristics in RTT. This study investigated relationships between genotype, age, walking, hand function, sleep, and RSBQ total and subscale scores in RTT. METHODS: This is a cross-sectional analysis of data collected in the Australian Rett Syndrome Database and the International Rett Syndrome Phenotype Database. Parent caregivers completed the RSBQ and Sleep Disturbance Scale for Children [subscales for disorders of initiating and maintaining sleep (DIMS), disorders of excessive somnolence (DOES)], and provided information on age, variant type, functional abilities (mobility, hand function), seizure frequency and gastrointestinal problems. Associations between the RSBQ scores and the independent variables were modelled using linear regression. RESULTS: Data were available for 365 individuals with RTT [median (range) age 17.8 (2.9-51.9) years, 2 males]. Compared to adults, 2- to 12-year-old children had higher mean Total, Night-time Behaviour and Fear/Anxiety scores. Compared to individuals with a C-terminal deletion, individuals with the p.Arg255* variant had higher mean Total and Night-time Behaviours scores, whereas the p.Arg294* variant had higher mean Mood scores. Individuals with intermediate mobility and hand function abilities had a higher mean Total score. Total RSBQ and subscale scores were similar across categories for seizures, constipation, and reflux, but were higher with abnormal DIMS and abnormal DOES scores. CONCLUSION: Except for associations with sleep, the RSBQ measures the behavioural phenotype rather than clinical severity in RTT, as traditionally conceptualised in terms of functional abilities and comorbidities. When designing clinical trials, the RSBQ needs to be complemented by other outcome measures to assess specific core functions and associated comorbidities in RTT.

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11. Fischbacher L, Dodds RL, Tien IS. Teaching Parents via Online Asynchronous Training to Use Speech-Generating Devices with Their Autistic Children: A Pilot Study. Children (Basel). 2024; 11(10).

Background/Objectives: Telepractice interventions have been found to alleviate barriers families face when seeking communication interventions. This study is a multiple-baseline single-subject design that measures parent communication opportunities and parent responsiveness to determine if parent training through online modules created for parents of children with communication support needs can be effective for training parents of autistic children with communication support needs. Methods: This study replicates work by utilizing online training used as well as the same variables and definitions. This study expands the original study by providing the children with speech-generating devices (SGDs). SGDs are an assistive technology tool to increase language production and give access to language to minimally verbal autistic people. A central difference between this study and study is that the only training parents received was the online modules and written instructions to set up the SGD. Results: Overall, the POWR modules appear to positively impact the communication opportunities provided by the parent during play and activities, increase child communication, and improve parent proficiency in implementing the POWR strategy. Conclusions: There is a need for a larger single-case study or a randomized control trial to replicate these findings. Additional instruction may be needed for parents of children with autism around responsive interactions. This study adds to innovative ways of providing family-centered training and access to AAC for those with barriers to service.

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12. Hagiwara S, Shiohama T, Takahashi S, Ishikawa M, Kawashima Y, Sato H, Sawada D, Uchida T, Uchikawa H, Kobayashi H, Shiota M, Nabatame S, Tsujimura K, Hamada H, Suzuki K. Comprehensive High-Depth Proteomic Analysis of Plasma Extracellular Vesicles Containing Preparations in Rett Syndrome. Biomedicines. 2024; 12(10).

Backgroud: Rett syndrome is a neurodevelopmental disorder that affects 1 in 10,000 females. Various treatments have been explored; however, no effective treatments have been reported to date, except for trofinetide, a synthetic analog of glycine-proline-glutamic acid, which was approved by the FDA in 2023. Serological biomarkers that correlate with the disease status of RTT are needed to promote early diagnosis and to develop novel agents. Methods: In this study, we performed a high-depth proteomic analysis of extracellular vesicles containing preparations extracted from patient plasma samples to identify novel biomarkers. Results: We identified 33 upregulated and 17 downregulated candidate proteins among a total of 4273 proteins in RTT compared to the healthy controls. Among these, UBE3B was predominantly increased in patients with Rett syndrome and exhibited a strong correlation with the clinical severity score, indicating the severity of the disease. Conclusions: We demonstrated that the proteomics of high-depth extracellular vesicles containing preparations in rare diseases could be valuable in identifying new disease biomarkers and understanding their pathophysiology.

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13. Horecka-Lewitowicz A, Lewitowicz W, Wawszczak-Kasza M, Lim H, Lewitowicz P. Autism Spectrum Disorder Pathogenesis-A Cross-Sectional Literature Review Emphasizing Molecular Aspects. Int J Mol Sci. 2024; 25(20).

The etiology of autism spectrum disorder (ASD) has not yet been completely elucidated. Through time, multiple attempts have been made to uncover the causes of ASD. Different theories have been proposed, such as being caused by alterations in the gut-brain axis with an emphasis on gut dysbiosis, post-vaccine complications, and genetic or even autoimmune causes. In this review, we present data covering the main streams that focus on ASD etiology. Data collection occurred in many countries covering ethnically diverse subjects. Moreover, we aimed to show how the progress in genetic techniques influences the explanation of medical White Papers in the ASD area. There is no single evidence-based pathway that results in symptoms of ASD. Patient management has constantly only been symptomatic, and there is no ASD screening apart from symptom-based diagnosis and parent-mediated interventions. Multigene sequencing or epigenetic alterations hold promise in solving the disjointed molecular puzzle. Further research is needed, especially in the field of biogenetics and metabolomic aspects, because young children constitute the patient group most affected by ASD. In summary, to date, molecular research has confirmed multigene dysfunction as the causative factor of ASD, the multigene model with metabolomic influence would explain the heterogeneity in ASD, and it is proposed that ion channel dysfunction could play a core role in ASD pathogenesis.

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14. Hotez E, Phan JM, Truong DM. Addressing Stigma-Related Health Disparities for Autistic Individuals Through Cultural Competemility: Insights from Research and Lived Experience. Curr Psychiatry Rep. 2024.

PURPOSE OF REVIEW: Autistic individuals experience disproportionate stigma across the life course in interpersonal, healthcare, and educational contexts. These experiences contribute to negative health and healthcare outcomes for this population. This paper seeks to describe autistic individuals’ experiences of stigma and marginalization; discuss frameworks such as Campinha-Bacote’s innovative concept of cultural competemility and its relevance to autistic populations; offer recommendations to healthcare providers based on this framework; and apply theory to practice in a case study. RECENT FINDINGS: Autistic individuals increasingly understand autism as an important aspect of their identity. There are, however, few culturally informed healthcare efforts that reflect this understanding. As a result, efforts to address stigma-related health disparities for this population have limited effectiveness. In this manuscript, we highlight opportunities within clinical encounters, medical training, healthcare offices and systems, and research to provide higher quality culturally informed care to autistic populations and address stigma-related health disparities.

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15. Josselsohn A, Zhao Y, Espinoza D, Hollander E. Oxytocin in neurodevelopmental disorders: Autism spectrum disorder and Prader-Willi syndrome. Pharmacol Ther. 2024: 108734.

This manuscript reviews recent work on oxytocin and its use in neurodevelopmental disorders including spectrum disorder (ASD) and Prader-Willi syndrome (PWS). Oxytocin is involved in social recognition, bonding, maternal behaviors, anxiety, food motivation, and hyperphagia. While the pathophysiology of ASD and PWS involve abnormalities in the oxytocin system, clinical trials have shown discrepant results in the effectiveness of oxytocin as a treatment for core symptoms associated with these disorders. In this review, we outline oxytocin’s clinical pharmacology, safety considerations, and results in recent clinical trials. We propose that oxytocin may be most beneficial in these populations if dosed in a dynamic regimen (PRN) and paired with social interventions.

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16. Lasota A. The Mediating Role of Social Interactions and Early Psychopathological Symptoms in the Relationship Between Empathy and Prosociality in Young Children with ASD and Neurotypical Peers. J Autism Dev Disord. 2024.

This study examined the relationship between empathy, prosocial behaviour, social interactions and early psychopathological symptoms (internalising and externalising behaviours) in children with autism spectrum disorder (ASD) and typically developing (TD) children. A total of 506 parents of children aged 18-48 months participated in this study. The parents of 92 children with ASD and 414 neurotypical children completed the Empathy Questionnaire, the Child Prosocial Behaviour Questionnaire, and the Emotional and Social Development Questionnaire. The results confirmed the direct relationship between empathy and prosocial behaviour in both groups. However, the findings showed a different pattern of the indirect relationship between empathy and prosociality through the social dimensions in the children with ASD compared to their typically developing peers. In the children with ASD, there was only one significant indirect path from empathy to prosocial behaviour – through internalising behaviours (anxiety). Anxiety also played a moderating role in this relationship. The higher the anxiety, the stronger the relationship between empathy and prosociality. In the neurotypical group, social interactions were a significant mediator, strengthening the relationship between empathy and prosocial behaviour. Externalising behaviours weakened this relationship. Intergroup and gender differences were also examined. These findings may have practical implications for social skills training programmes based on behavioural interventions by highlighting the importance of prosocial behaviour for social interaction and protection against psychopathological problems in children with autism and typically developing children.

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17. Liu L, Li S, Tian L, Yao X, Ling Y, Chen J, Wang G, Yang Y. The Impact of Cues on Joint Attention in Children with Autism Spectrum Disorder: An Eye-Tracking Study in Virtual Games. Behav Sci (Basel). 2024; 14(10).

Joint attention (JA), a core deficit in children with autism spectrum disorder (ASD), is crucial for social interaction, emotional understanding, and cognitive development. This study aims to compare and analyze the eye-tracking data of ASD and typically developing children (TDC) during virtual games, exploring how different cue types affect JA performance in ASD children. A total of 31 TDC and 40 ASD children participated in the study. Using eye-tracking devices, we recorded the children’s eye movements as they played virtual games, selecting the correct target based on cues provided by virtual characters. Our findings revealed that different cue types significantly impacted the game scores of ASD children but had no significant effect on TDC, highlighting a notable disparity between the two groups. ASD children showed a lower fixation frequency, irregular fixation paths, and increased attention to non-target objects compared to TDC. Interestingly, among the three cue types, ASD children exhibited a preference for the third type, leading to longer fixation on the region of interest and higher game scores. These results underscore the importance of cue selection in enhancing JA in ASD children. This study provides novel insights into the JA deficits in ASD children and offers a scientific basis for the development of targeted and individualized intervention programs.

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18. Marangelo C, Vernocchi P, Del Chierico F, Scanu M, Marsiglia R, Petrolo E, Fucà E, Guerrera S, Valeri G, Vicari S, Putignani L. Stratification of Gut Microbiota Profiling Based on Autism Neuropsychological Assessments. Microorganisms. 2024; 12(10).

Autism spectrum disorder (ASD) is a neurodevelopmental disorder. Investigations of gut microbiota (GM) play an important role in deciphering disease severity and symptoms. Overall, we stratified 70 ASD patients by neuropsychological assessment, based on Calibrated Severity Scores (CSSs) of the Autism Diagnostic Observation Schedule-Second edition (ADOS-2), Child Behavior Checklist (CBCL) and intelligent quotient/developmental quotient (IQ/DQ) parameters. Hence, metataxonomy and PICRUSt-based KEGG predictions of fecal GM were assessed for each clinical subset. Here, 60% of ASD patients showed mild to moderate autism, while the remaining 40% showed severe symptoms; 23% showed no clinical symptoms, 21% had a risk of behavior problems and 56% had clinical symptoms based on the CBCL, which assesses internalizing problems; further, 52% had no clinical symptoms, 21% showed risk, and 26% had clinical symptoms classified by CBCL externalizing problems. Considering the total CBCL index, 34% showed no clinical symptoms, 13% showed risk, and 52% had clinical symptoms. Here, 70% of ASD patients showed cognitive impairment/developmental delay (CI/DD). The GM of ASDs with severe autism was characterized by an increase in Veillonella, a decrease in Monoglobus pectinilyticus and a higher microbial dysbiosis index (MDI) when compared to mild-moderate ASDs. Patients at risk for behavior problems and showing clinical symptoms were characterized by a GM with an increase of Clostridium, Eggerthella, Blautia, Intestinibacter, Coprococcus, Ruminococcus, Onthenecus and Bariatricus, respectively. Peptidoglycan biosynthesis and biofilm formation KEGGs characterized patients with clinical symptoms, while potential microbiota-activated PPAR-γ-signaling was seen in CI/DD patients. This evidence derived from GM profiling may be used to further improve ASD understanding, leasing to a better comprehension of the neurological phenotype.

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19. Mourad J, Daniels K, Bogaerts K, Desseilles M, Bonnechère B. Innovative Digital Phenotyping Method to Assess Body Representations in Autistic Adults: A Perspective on Multisensor Evaluation. Sensors (Basel). 2024; 24(20).

In this perspective paper, we propose a novel tech-driven method to evaluate body representations (BRs) in autistic individuals. Our goal is to deepen understanding of this complex condition by gaining continuous and real-time insights through digital phenotyping into the behavior of autistic adults. Our innovative method combines cross-sectional and longitudinal data gathering techniques to investigate and identify digital phenotypes related to BRs in autistic adults, diverging from traditional approaches. We incorporate ecological momentary assessment and time series data to capture the dynamic nature of real-life events for these individuals. Statistical techniques, including multivariate regression, time series analysis, and machine learning algorithms, offer a detailed comprehension of the complex elements that influence BRs. Ethical considerations and participant involvement in the development of this method are emphasized, while challenges, such as varying technological adoption rates and usability concerns, are acknowledged. This innovative method not only introduces a novel vision for evaluating BRs but also shows promise in integrating traditional and dynamic assessment approaches, fostering a more supportive atmosphere for autistic individuals during assessments compared to conventional methods.

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20. Müller A, Bába É B, Židek P, Lengyel A, Lakó JH, Laoues-Czimbalmos N, Molnár A, Boda E. The Experiences of Motor Skill Development in Children with Autism Spectrum Disorder (ASD) Reflected through Parental Responses. Children (Basel). 2024; 11(10).

Background/Objectives: Understanding movement development in children with autism spectrum disorder (ASD) is critical for creating effective intervention strategies. This study aims to explore parental perspectives on the movement development of children with ASD, focusing on identifying common challenges and successful strategies. The objective is to analyze the experiences of parents to highlight the most effective approaches to support motor, communication, and social skills development in these children. Methods: Using a qualitative approach, we conducted in-depth interviews with parents of children with ASD. The data were analyzed using open and selective coding to identify key themes related to movement development challenges and strategies. The analysis included cross-referencing with the existing literature to support parental insights. Results: This study identified several key themes, including communication barriers, social interaction difficulties, and the importance of personalized movement programs. Parents reported significant challenges in understanding and addressing their children’s movement needs, particularly in group settings. However, activities such as water programs, music and dance, and animal-assisted therapies were found to be highly engaging. Motivation was a critical factor, with rewards and active parental involvement enhancing participation. Conclusions: This study highlights the crucial role of a supportive environment, including professional guidance and family support, in the success of movement development programs.

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21. O’Connor M, Griffin C, Corrigan J, Somers C, Delaney M, Larkin F. Autism spectrum disorder (ASD) presentations among referrals to a child and adolescent mental health service (CAMHS) inpatient unit in Ireland. Clin Child Psychol Psychiatry. 2024: 13591045241295419.

This retrospective chart review aimed to identify the intersection between young people with Autism Spectrum Disorder (ASD)’s needs and CAMHS inpatient service needs. A retrospective chart review was conducted on all referrals to a CAMHS inpatient unit over three years (n = 352). Referrals which specified a formal diagnosis or suspected diagnosis of ASD were identified (n = 111), and basic demographic data were collected. Young people with either a formal or suspected diagnosis of ASD referred to the unit presented with a wide range of co-occurring conditions. Of these young people, 30 were admitted to the unit and only 6 of them were engaged with an ASD specialist service. Young people with diagnosed or suspected ASD were more likely to be admitted if they presented with suicidality. Males with diagnosed or suspected ASD were more likely to have a diagnosis of OCD while females with diagnosed or suspected ASD were more likely to present with eating and feeding disorders and personality development difficulties. Findings highlight the lack of a clear care pathway for young people with co-occurring autism or suspected autism and complex mental health problems. Many children and adolescents who are referred to Child and Adolescent Mental Health Services (CAMHS) inpatient units may also have autism spectrum disorder (ASD). It is important that we understand their needs and how best services can support them. METHODS: In this study, we reviewed the files of all young people referred to a CAMHS inpatient service over a 3 year period (n = 352), and identified those where the young person had a diagnosis of ASD, or where the referring clinician suspected the young person may have had autism (n = 111). We collected details about their demographics, the mental health difficulties with which they presented, and the services that were supporting them. RESULTS: We found that young people with either a formal or suspected diagnosis of ASD referred to the unit presented with a wide range of co-occurring conditions. Of these young people, 30 were admitted to the unit and only 6 of them were engaged with an ASD specialist service. Young people with diagnosed or suspected ASD were more likely to be admitted if they presented with suicidality. Males with diagnosed or suspected ASD were more likely to have a diagnosis of OCD while females with diagnosed or suspected ASD were more likely to present with eating and feeding disorders and personality development difficulties. CONCLUSION: Presentations of confirmed and suspected ASD represented a significant number of referrals for inpatient care. This means that it is important for mental health services to work alongside disability services to ensure that the needs of these young people are met. eng.

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22. Obuchi C, Kawase T, Sasame Y, Yamamoto Y, Sasaki K, Iwasaki J, Okamoto H, Kaga K. Traits of Developmental Disorders in Adults With Listening Difficulties Without Diagnosis of Autism Spectrum Disorder And/or Attention-Deficit/Hyperactivity Disorder. J Clin Med. 2024; 13(20).

Background: Some individuals have a normal audiogram but have listening difficulties (LiD). As many studies have investigated the relationship between listening and developmental disorders, the traits of developmental disorders might explain the symptoms of LiD. In this study, we examined the traits of developmental disorders of adults with LiD to help clarify the cause of LiD symptoms. Methods: In total, 60 adults with LiD and 57 adults without LiD were included. Participants completed a questionnaire for the autism spectrum quotient (AQ) test, the Adult Attention-Deficit Hyperactivity Disorder Self-Rating Scale (A-ADHD), the Adolescent/Adult Sensory Profile (SP), and the severity of subjective LiD in daily life. Results: Before analysis, we excluded participants with LiD who were already diagnosed or met the criteria for autism spectrum disorder (ASD) or ADHD, and the results of the remaining 30 participants (50.0%) with LiD were analyzed. Adults with LiD showed higher scores than those without LiD in the AQ. Attention switching in the AQ and attention ability in the A-ADHD scale were correlated with the severity of LiD symptoms in everyday life. The AQ scores were also significantly correlated with subscales of the SP. Conclusions: Adults with LiD showed greater autistic traits than those without LiD; therefore, LiD symptoms are possibly related to autistic symptoms. Furthermore, adults with LiD might have attention disorder traits of both ASD and ADHD and sensory processing problems. These findings suggest that the attention problems in adults with LiD noted in previous studies might be related to these traits of developmental disorders.

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23. Sánchez Suárez A, Martínez Menéndez B, Escolar Escamilla E, Martínez Sarries FJ, Esparza Garrido MI, Gil-Fournier B, Ramiro León S, Rubio Gribble B, Quesada Espinosa JF, Alcaraz Romero AJ. Whole Exome Sequencing and Panel-Based Analysis in 176 Spanish Children with Neurodevelopmental Disorders: Focus on Autism Spectrum Disorder and/or Intellectual Disability/Global Developmental Delay. Genes (Basel). 2024; 15(10).

BACKGROUND: Neurodevelopmental disorders (NDDs) represent a significant challenge in pediatric genetics, often requiring advanced diagnostic tools for the accurate identification of genetic variants. OBJECTIVES: To determine the diagnostic yield of whole exome sequencing (WES) with targeted gene panels in children with neurodevelopmental disorders (NDDs). METHODS: This observational, prospective study included a total of 176 Spanish-speaking pediatric patients with neurodevelopmental disorders (NDDs), encompassing intellectual disability (ID), global developmental delay (GDD), and/or autism spectrum disorder (ASD). Participants were recruited from January 2019 to January 2023 at a University Hospital in Madrid, Spain. Clinical and sociodemographic variables were recorded, along with genetic study results. The age range of the subjects was 9 months to 16 years, and the percentage of males was 72.1%. The diagnostic yield of whole exome sequencing (WES) was calculated both before and after parental testing via Sanger DNA sequencing. RESULTS: The study included 176 children: 67 (38.1%) with ID, 62 (35.2%) with ASD, and 47 (26.7%) with ASD + ID. The diagnostic yield of proband-only exome sequencing was 12.5% (22/176). By group, the diagnostic yield of proband-only exome sequencing was 3.2% in the ASD, 12.7% in the ASD + ID, and 20.8% in the ID group. Variants of uncertain significance (VUS) were found in 39.8% (70/176). After parental testing, some variants were reclassified as « likely pathogenic », increasing the diagnostic yield by 4.6%, with an overall diagnostic yield of 17.1%. Diagnostic yield was higher in patients with syndromic ID (70.6%% vs. 29.4%; p = 0.036). CONCLUSIONS: A sequential approach utilizing WES followed by panel-based analysis, starting with the index case and, when appropriate, including the parents, proves to be a cost-effective strategy. WES is particularly suitable for complex conditions, as it allows for the identification of potentially causative genes beyond those covered by targeted panels, providing a more comprehensive analysis. Including parental testing enhances the diagnostic yield and improves accuracy, especially in cases with variants of uncertain significance (VUS), thereby advancing our understanding of NDDs.

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24. Scanu M, Del Chierico F, Marsiglia R, Toto F, Guerrera S, Valeri G, Vicari S, Putignani L. Correction of Batch Effect in Gut Microbiota Profiling of ASD Cohorts from Different Geographical Origins. Biomedicines. 2024; 12(10).

BACKGROUND: To date, there have been numerous metataxonomic studies on gut microbiota (GM) profiling based on the analyses of data from public repositories. However, differences in study population and wet and dry pipelines have produced discordant results. Herein, we propose a biostatistical approach to remove these batch effects for the GM characterization in the case of autism spectrum disorders (ASDs). METHODS: An original dataset of GM profiles from patients with ASD was ecologically characterized and compared with GM public digital profiles of age-matched neurotypical controls (NCs). Also, GM data from seven case-control studies on ASD were retrieved from the NCBI platform and exploited for analysis. Hence, on each dataset, conditional quantile regression (CQR) was performed to reduce the batch effects originating from both technical and geographical confounders affecting the GM-related data. This method was further applied to the whole dataset matrix, obtained by merging all datasets. The ASD GM markers were identified by the random forest (RF) model. RESULTS: We observed a different GM profile in patients with ASD compared with NC subjects. Moreover, a significant reduction of technical- and geographical-dependent batch effects in all datasets was achieved. We identified Bacteroides_H, Faecalibacterium, Gemmiger_A_73129, Blautia_A_141781, Bifidobacterium_388775, and Phocaeicola_A_858004 as robust GM bacterial biomarkers of ASD. Finally, our validation approach provided evidence of the validity of the QCR method, showing high values of accuracy, specificity, sensitivity, and AUC-ROC. CONCLUSIONS: Herein, we proposed an updated biostatistical approach to reduce the technical and geographical batch effects that may negatively affect the description of bacterial composition in microbiota studies.

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25. Sesso G, Bargnesi F, Mutti G, Berloffa S, Viglione V, Fantozzi P, Tolomei G, Guccione F, Muratori P, Milone A, Masi G. Extended-Release Lithium Treatment for Adolescents with Bipolar Disorder with or Without Comorbid Autism Spectrum Disorder: Protocol of a Longitudinal Prospective Naturalistic Study for the Assessment of Efficacy and Tolerability. J Clin Med. 2024; 13(20).

Background: Lithium is the gold-standard treatment for Bipolar Disorder (BD) in both adults and adolescents, effectively managing mood episodes and reducing suicide risk. While its efficacy in neurotypical youth is well established, its use in adolescents with Autism Spectrum Disorder (ASD) and comorbid BD remains under-researched. Here, we present the protocol for a study aiming to evaluate the efficacy and tolerability of Extended-Release Lithium Salts in treating adolescents with BD and comorbid ASD compared to neurotypical BD patients. Methods: This longitudinal prospective naturalistic comparative study will enroll lithium-naïve adolescents aged 12-18 with BD, with or without comorbid ASD, from the Department of Child and Adolescent Psychiatry and Psychopharmacology. Participants will be followed for six months while receiving Extended-Release Lithium Salts treatment. Primary outcomes will include mood instability, suicidality, emotional dysregulation, and aggression, assessed through a range of clinical rating scales and diagnostic tools at baseline, three months, and six months. Secondary outcomes will focus on the safety and tolerability of Extended-Release Lithium Salts, with measures including side effect ratings, physical exams, and laboratory tests. Results: We hypothesize that Extended-Release Lithium Salts will demonstrate non-inferiority in treating BD symptoms in adolescents with comorbid ASD compared to those without ASD. Conclusions: This study is poised to fill a significant gap in the literature by providing critical data on the use of lithium for adolescents with BD and ASD. Findings will inform clinical practice and future research, potentially guiding more personalized treatment approaches for this complex and vulnerable population.

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26. Thomas SD, Jayaprakash P, Marwan N, Aziz E, Kuder K, Łażewska D, Kieć-Kononowicz K, Sadek B. Alleviation of Autophagic Deficits and Neuroinflammation by Histamine H3 Receptor Antagonist E159 Ameliorates Autism-Related Behaviors in BTBR Mice. Pharmaceuticals (Basel). 2024; 17(10).

BACKGROUND/OBJECTIVES: Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by social interaction difficulties, repetitive behaviors, and immune dysregulation with elevated pro-inflammatory markers. Autophagic deficiency also contributes to social behavior deficits in ASD. Histamine H3 receptor (H3R) antagonism is a potential treatment strategy for brain disorders with features overlapping ASD, such as schizophrenia and Alzheimer’s disease. METHODS: This study investigated the effects of sub-chronic systemic treatment with the H3R antagonist E159 on social deficits, repetitive behaviors, neuroinflammation, and autophagic disruption in male BTBR mice. RESULTS: E159 (2.5, 5, and 10 mg/kg, i.p.) improved stereotypic repetitive behavior by reducing self-grooming time and enhancing spontaneous alternation in addition to attenuating social deficits. It also decreased pro-inflammatory cytokines in the cerebellum and hippocampus of treated BTBR mice. In BTBR mice, reduced expression of autophagy-related proteins LC3A/B and Beclin 1 was observed, which was elevated following treatment with E159, attenuating the disruption in autophagy. The co-administration with the H3R agonist MHA (10 mg/kg, i.p.) reversed these effects, highlighting the role of histaminergic neurotransmission in observed behavioral improvements. CONCLUSIONS: These preliminary findings suggest the therapeutic potential of H3R antagonists in targeting neuroinflammation and autophagic disruption to improve ASD-like behaviors.

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27. Villani C, Sacchetti G, Invernizzi RW. Boosting Serotonin Synthesis Is Not Sufficient to Improve Motor Coordination of Mecp2 Heterozygous Mouse Model of Rett Syndrome. Biomolecules. 2024; 14(10).

Motor deficit is a core symptom of Rett syndrome, a rare neurological disease caused in most cases by mutations of the methyl-CpG-binding protein2 (MECP2) gene. Serotonin reuptake inhibitors improve motor coordination in Mecp2 heterozygous (Het) mice and serotonin depletion prevented this effect. Here, we assess alterations in indole levels in various brain regions and whether boosting brain serotonin synthesis with the serotonin precursors tryptophan, 5-hydroxytryptophan and α-lactalbumin rescued motor coordination deficit of Mecp2 Het mice. Motor coordination was assessed in the accelerated rotarod during and after systemic administration of serotonin precursors for 2-3 weeks. Since no data are available, the effect of α-lactalbumin on tryptophan, serotonin and 5-hydroxyindoleacetic acid levels was evaluated in various brain regions in order to identify the dose of ALAC to evaluate on motor coordination. As compared to WT, Mecp2 Het mice show reduced levels of serotonin in the whole brain, hippocampus, brainstem and cerebral cortex, but not the striatum. Reduced levels of 5-hydroxyindoleacetic acid were observed in the hippocampus and brainstem. Doses of serotonin precursors increasing brain tryptophan and/or serotonin production and metabolism had no effect on motor coordination. The results indicate that boosting serotonin synthesis is not sufficient to improve motor coordination of Mecp2 Het mice.

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28. Viner HE, Yuill N, Costa AP, Radford H, Kornadt AE. A qualitative interview study on quality of life and ageing experiences of autistic adults. Commun Psychol. 2024; 2(1): 99.

Quality of life across the lifespan has been established as a key research priority by the autism community. Still relatively little is known about the quality of life and ageing experiences of older autistic adults. Most studies to date have used generic measures of quality of life which may not accurately capture the experiences of autistic people. The aim of this qualitative study was to understand how autistic adults experience and define quality of life as they age. We conducted semi-structured interviews with 16 autistic adults aged 40+ from the UK and Luxembourg. Using reflexive thematic analysis, we identified five themes that contribute to quality of life: (1) Diagnosis is pivotal, (2) Connection with others, (3) Autonomy over space and time, (4) ‘Paperwork of life’, (5) Vulnerability. This study identifies autism-specific aspects of quality of life and highlights ways in which ageing and autism intersect and impact quality of life.

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29. Vivanti G, Algur Y, Ryan V, McClure LA, Fein D, Stahmer AC, Wieckowski AT, Robins DL. The Impact of Using Standardized Autism Screening on Referral to Specialist Evaluation for Young Children on the Autism Spectrum-A Cluster-Randomized Controlled Trial. J Am Acad Child Adolesc Psychiatry. 2024.

OBJECTIVE: We tested whether the implementation of standardized, high-fidelity screening for autism during routine well-child check-ups results in the following: increasing the number of children with suspected autism referred to diagnostic evaluation; lowering the age at which they are referred; and facilitating autism diagnosis for children across a more diverse range of demographic backgrounds and clinical presentations, including those with subtle manifestations. METHOD: As part of a multi-site cluster randomized trial, pediatric practices were randomly assigned to an experimental condition involving training and supervision in the universal, standardized, high-fidelity implementation of the Modified Checklist for Autism in Toddlers, Revised with Follow-Up (M-CHAT-R/F), or a usual care condition. Children in both conditions identified as having a high likelihood of autism during well-child visits were referred to a diagnostic evaluation conducted by clinicians naive to referral source. RESULTS: Children referred to the diagnostic evaluation from the practices in the experimental condition were more numerous (n = 186) and younger (mean age = 20.65 months) than those referred from the practices in the usual care condition (n = 39; mean age = 23.58 months). Children referred by experimental practices who received an autism diagnosis had milder clinical presentations across measures of cognitive, language, adaptive, and social-communication functioning, compared to those referred from usual care practices. Demographic characteristics were similar across groups. CONCLUSION: Standardized, high-fidelity implementation of autism screening during pediatric well-child visits facilitates the identification of children with high autism likelihood at a younger age, including those presenting with more subtle clinical manifestations. CLINICAL TRIAL REGISTRATION INFORMATION: Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes; https://clinicaltrials.gov/; NCT03333629.

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30. Wilczyński KM, Cichoń L, Stasik A, Kania K, Rodak N, Wizner M, Janas-Kozik M. An Analysis of the Time Required for the Diagnosis of ASD and the Factors Influencing Its Duration in a Sample of the Pediatric Population from Poland. J Clin Med. 2024; 13(20).

Background/Objectives: Early diagnosis of autism spectrum disorder (ASD) is a very important factor for improving the quality of life of people on the spectrum, but it still remains a major problem in Europe, especially concerning girls. In this study, we tried to answer the question of what factors affect the age of diagnosis in Poland. Additionally, we tried to establish the time between the first visit to the mental health center (MHC) and the diagnosis in this population, and what factors affect its length. Methods: 77 children were randomly recruited among the patients who came to local MHC at the Child and Family Health Centre in Sosnowiec. All participants were tested using the ADOS-2 protocol. In addition, the study used the TAS-20 test and BDI. Results: The mean age of the first enrollment in the MHC was 9.09 years for girls and 6.42 for the boys. The time needed to obtain a diagnosis from the first visit was consecutively 2.90 years and 4.29 years, but the difference was not statistically significant (p > 0.05). Obtaining a different psychiatric diagnosis did not affect the average time to diagnosis and the age of diagnosis. Conclusions: The results of the study indicate that the diagnosis of ASD is still a significant problem both in Poland and in the world. Obtaining an accurate diagnosis requires significant time, and it frequently involves consulting multiple specialists. The diagnostic process should be flexible, and the specialist should always take into account the axial symptoms but remain aware that the « overdiagnosis » of ASD can also have harmful consequences for the child.

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31. Yi T, Liu Y, Wei W, He S, Jin K. Microstructural abnormalities of the right hemisphere in preschool autism spectrum disorders. J Psychiatr Res. 2024; 180: 258-64.

BACKGROUND: This study aims to investigate microstructural abnormalities within and between hemispheres in preschool children with autism spectrum disorders (ASD) using diffusion basis spectrum imaging (DBSI). METHODS: A total of 35 ASD patients and 32 healthy controls (HC), matched for sex and age, underwent DBSI at 3T. We analyzed DBSI-derived indices of brain white matter using tract-based spatial statistics (TBSS) to compare ASD and HC groups. Support vector machine (SVM) classification was employed to evaluate the potential of positive DBSI parameters in distinguishing ASD patients. Additionally, correlation analyses were conducted to explore relationships between positive DBSI parameters and clinical scales. RESULTS: Patients in the ASD group exhibited significantly higher fiber ratios in the right brainstem tracts, increased radial diffusivity in the left superior longitudinal fasciculus, and reduced fractional anisotropy (FA) in various fiber tracts, including projection, commissural, and association fibers, compared to HC. Notably, the FA of the right cingulum correlated positively with the Gesell scale (r = 0.439, p = 0.008) and achieved a specificity of 90% in identifying ASD. CONCLUSION: The DBSI findings suggest asynchronous myelination in the right hemisphere and cerebellum in preschool ASD, with the FA value of the right cingulate gyrus appearing to be a reliable marker for ASD and may serve as a potential diagnostic parameter for preschool ASD.

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32. Zheng H, Liu J, Muraishi S. Optimal Arrangements and Local Anisotropy of {100} Guinier-Preston (GP) Zones by Parametric Dislocation Dynamics (PDD) Simulations. Materials (Basel). 2024; 17(20).

Stress-oriented precipitation and the resulting mechanical anisotropy have been widely studied over the decades. However, the local anisotropy of precipitates with specific orientations has been less thoroughly investigated. This study models the interaction between an edge dislocation source and {100} variants of Guinier-Preston (GP) zones in Al-Cu alloys using the parametric dislocation dynamics (PDD) method. Concentric geometrically necessary dislocation (GND) loops were employed to construct a line integral model for thin platelets. The simulations, conducted with our self-developed code based on Green’s function method and Eshelby inclusion theory revealed distinct strengthening behavior along the strong and weak directions for 60° GP zones, demonstrating anisotropic strengthening from the perspective of elastic interactions. Furthermore, the optimal inclined arrangement of the GP zone array was determined through elastic energy calculations, and these results were corroborated by TEM observations.

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