1. Abakumow M, Przybylski M, Słoma M, Markowska O, Sowa K, Jaśkiewicz P, Kowalczuk K. Aggressive and Autoaggressive Behaviors in Patients with Autism Spectrum Disorder in Correlation with Middle Cerebral Artery Flow Velocity. J Pers Med;2024 (Sep 22);14(9)

Background/Objectives The purpose of this study was to see whether there is a correlation between the behavior of autism spectrum disorder patients and brain abnormalities based on the velocity of blood flow in the MCA (middle cerebral artery). Methods: The use of HAP (High Altitude Protection) suits, which are used in aviation, to treat patients with ASD (autism spectrum disorder) causes significant changes in their functioning and physiological processes. These changes are not only noted in psychological tests but are observed in cerebral blood flow using transcranial Doppler ultrasound of the MCA. Results The results of this study made it possible to distinguish two groups with different flow velocities, which can be characterized as flows of less than 80 cm/s and flows of more than 80 cm/s. In addition, it was shown that in patients with elevated blood flow velocity, aggressive behaviors account for 86.96%, while self-aggressive behaviors account for 65.2%. On the other hand, in the case of patients with reduced flow velocity, i.e., less than 80 cm/s, the rate of aggressive behavior is 20% and that of self-aggressive behavior is 50%. The experiment showed that after therapy, there is a normalization of blood flow, which increased in the case of patients with a reduced flow rate below 80 cm/s and, in the case of elevated blood velocity after therapy, decreased towards normal levels. Conclusions The observed rate of normalization of flow velocities in the MCA translated into significant changes in the behavior and functioning of patients in the neurotypical direction, which was noticeable in the psychological tests conducted.

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2. Anastasescu CM, Gheorman V, Stoicanescu EC, Popescu F, Gheorman V, Udriștoiu I. Immunological Biomarkers in Autism Spectrum Disorder: The Role of TNF-Alpha and Dependent Trends in Serum IL-6 and CXCL8. Life (Basel);2024 (Sep 22);14(9)

BACKGROUND: Autism spectrum disorder (ASD) has seen a rise in prevalence, and the immune system’s role in brain development is increasingly recognized. This study investigates the relationship between immune dysregulation and ASD by examining serum concentrations of interleukin 6 (IL-6), interleukin 8 (CXCL8), and tumor necrosis factor alpha (TNF-alpha) in children. METHODS: Serum samples from 45 children with ASD and 30 controls, aged 2 to 12 years, were analyzed using electrochemiluminescence, chemiluminescent microparticle immunoassay, and chemiluminescent immunoassay. ASD symptoms were assessed using the Autism Spectrum Rating Scale (ASRS) and Social Communication Questionnaire (SCQ). RESULTS: No significant correlation was observed between CXCL8 levels and ASD. IL-6 levels showed a trend toward elevation in boys with ASD. TNF-alpha levels were significantly higher in children with ASD under 5 years compared to older children and controls, though no correlation with symptom severity was found. CONCLUSIONS: TNF-alpha may be a potential biomarker for early ASD detection, especially in younger children. Further research on larger cohorts is needed to understand the role of immune dysregulation in ASD.

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3. Buffle P, Cavadini T, Ortega ML, Armijos C, Soto P, Gentaz E, Crane L. Journeys towards accessing an autism diagnosis and associated support: A survey of families of autistic children in Ecuador. Autism;2024 (Sep 28):13623613241281029.

There has been much research about the experiences of families of autistic children as they navigate the process of accessing a diagnosis and associated support. However, most of this work has been conducted in Europe, the United States, and Australia. In this study, we examined the experiences of 767 families in Ecuador via an in-depth survey. Of the families we surveyed, 651 had children whose journeys resulted in them receiving a formal autism diagnosis. Most families realized that their children might have developmental differences when they were between the ages of 6 and 48 months, after which they tended to seek support from a professional fairly quickly (i.e. within 6 months). Most families consulted with several different professionals before they accessed a diagnosis for their children, with children tending to receive a diagnosis before the age of 48 months. Families often reported negative emotions around their children’s diagnostic and post-diagnostic journeys, which were commonly related to the lack of information and services available to them. We hope that through gaining a greater understanding of the experiences of families of autistic children in Ecuador, these findings can be used to inform public policies that lead to the development of supports and services that better meet the needs of autistic people and their families in this context.

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4. Capelli E, Crippa A, Riboldi EM, Beretta C, Siri E, Cassa M, Molteni M, Riva V. Prospective Interrelation Between Sensory Sensitivity and Fine Motor Skills During the First 18 Months Predicts Later Autistic Features. Dev Sci;2024 (Sep 28):e13573.

Sensory features are included in the diagnostic criteria of autism and atypical sensory responsiveness may produce « cascading effects » on later development. Similarly, autistic individuals often struggle with motor coordination and early delays in the motor domain appear to be linked to later development. However, the longitudinal interrelation between early sensory profiles and motor features on later socio-communicative skills remains to be defined. This study aimed to investigate whether sensory sensitivity impacts fine motor abilities and vice versa from 12 to 18 months of age and to examine how sensory-motor interplay would be associated with later autistic traits at 24-36 months of age. The sample included 118 infant siblings of autistic children recruited at 12 months of age. Sensory sensitivity and eye-hand coordination were assessed at 12 and 18 months of age and autistic traits were evaluated at 24-36 months of age. Cross-lagged panel analysis revealed significant within-domain effects for sensory sensitivity and eye-hand coordination from 12 to 18 months. Furthermore, a significant association between these two domains on later autistic traits was found. In analyzing the longitudinal bidirectional relationship, we found that lower eye-hand coordination skills at 12 months predicted later sensory sensitivity at 18 months, and in turn, social communication skills at 24-36 months. The present study offers new empirical evidence supporting the potential clinical value of including sensory and motor measures besides social communication skills within early autism surveillance programs.

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5. Costache ME, Gioia F, Vanello N, Greco A, Lefebvre F, Capobianco A, Weibel S, Weiner L. Exploring Emotion Control and Alexithymia in Autistic Adults: An Ecological Momentary Assessment Study. J Autism Dev Disord;2024 (Sep 27)

Difficulties in controlling emotions – a proxy for emotion dysregulation (ED)-and difficulties in expressing feelings in words-‘absence of emotion labelling’ or alexithymia-co-exist in autism and contribute to elevated levels of impulsive and suicidal behaviour. To date, studies linking the two phenomena have relied on retrospective self-reported measures, lacking support for generalizability to real-life situations. The present study investigated in vivo emotion labelling and its impact on emotion control in 29 autistic adults without intellectual disability (ASC) and 28 neurotypical (NT) individuals of similar age, sex, and educational level. Participants were trained in an Ecological Momentary Assessment (EMA) to label their emotions, the arousal dimension, and their emotion control via smartphone over a one-week period. Findings showed that the ASC group experienced more instances of ‘having an emotion that I cannot name’ and, when they were able to label their emotions, they reported higher rates of negative and conflicting (simultaneously positive and negative) emotions. In both groups, the absence of emotion labelling, and intense negative emotions were associated with impaired emotion control. However, the association between lack of emotional awareness-‘I have no emotion’-and impaired emotion control was only evident in ASC individuals. Our study highlights a nuanced facet of emotional processing in the ASC population. Further research is needed to gain a deeper understanding of the complex relationship between ED and alexithymia in autism.

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6. Dong S, Li Z, Li Y, Liu A. On the Optimal Combination of Elliptically Distributed Biomarkers to Improve Diagnostic Accuracy. Genes (Basel);2024 (Aug 30);15(9)

Diagnostic biomarkers play a critical role in biomedical research, particularly for the diagnosis and prediction of diseases, etc. To enhance diagnostic accuracy, extensive research about combining multiple biomarkers has been developed based on the multivariate normality, which is often not true in practice, as most biomarkers follow distributions that deviate from normality. While the likelihood ratio combination is recognized to be the optimal approach, it is complicated to calculate. To achieve a more accurate and effective combination of biomarkers, especially when these biomarkers deviate from normality, we propose using a receiver operating characteristic (ROC) curve methodology based on the optimal combination of elliptically distributed biomarkers. In this paper, we derive the ROC curve function for the elliptical likelihood ratio combination. Further, proceeding from the derived best combinations of biomarkers, we propose an efficient technique via nonparametric maximum likelihood estimate (NPMLE) to build empirical estimation. Simulation results show that the proposed elliptical combination method consistently provided better performance, demonstrating its robustness in handling various distribution types of biomarkers. We apply the proposed method to two real datasets: Autism/autism spectrum disorder (ASD) and neural tube defects (NTD). In both applications, the elliptical likelihood ratio combination improves the AUC value compared to the multivariate normal likelihood ratio combination and the best linear combination.

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7. Fernández Cerero J, Montenegro Rueda M, López Meneses E. The Impact of Parental Involvement on the Educational Development of Students with Autism Spectrum Disorder. Children (Basel);2024 (Aug 30);11(9)

BACKGROUND/OBJECTIVES: Parental involvement is vital for the academic success and overall development of students, particularly those with Autism Spectrum Disorder (ASD), who face unique educational challenges. This study investigates the influence of parental involvement on the academic performance and school adjustment of students with ASD, focusing on the interplay of cultural identity and first language in their educational and social growth. The research also seeks to identify the challenges parents face and the strategies they use to support their children. METHOD: Employing a qualitative, interpretive approach, this study involved 42 parents of secondary school students with ASD in Seville, Spain. Data collection included in-depth interviews and focus group discussions, allowing for a comprehensive understanding of parental experiences. RESULTS: The study found that active parental involvement greatly enhances students’ academic performance and emotional well-being. Key strategies include creating structured home environments, utilizing assistive technologies, and fostering open communication with school staff. However, parents reported significant challenges, including limited school resources, communication barriers with educators, and a lack of ASD-specific training for teachers and parents. These challenges often hinder their ability to fully support their children’s education. CONCLUSIONS: Active parental involvement is crucial for the educational success of students with ASD. The findings highlight the need for improved communication between schools and families, increased resources, and targeted ASD training for both teachers and parents. Additionally, the study advocates for greater investment in assistive technologies to better support students with ASD. Addressing these needs could significantly improve the educational experiences and outcomes for these students.

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8. Grot M, Białek-Dratwa A, Krupa-Kotara K, Grajek M, Nigowski M, Szczepańska E, Kowalski O. Negative Aspects of Dietary Habits in Children and Adolescents with Autism Spectrum Disorders. Nutrients;2024 (Sep 11);16(18)

BACKGROUND/OBJECTIVES: Diet therapy is a key component of a holistic approach to the physiological and psychological health of children with autism spectrum disorders. A personalized diet, tailored to clinical symptoms, yields positive therapeutic effects. The aim of this study was to assess the intake of specific food groups and the dietary methods used among children and adolescents with autism. METHODS: This study included 141 patients from neuropediatric centers diagnosed with autism spectrum disorders. Inclusion criteria were parental consent for the study, age of the child, and autism diagnosis. The research tool was a custom questionnaire covering patients’ demographic data, type of disorder, and a qualitative analysis of the dietary habits of selected products. RESULTS: The predominant dietary models were the basic diet (n = 26; 72.22%) and the elimination diet (n = 9; 25%), with a higher application rate among children with autism spectrum disorders. Aversion to specific foods/products was more prevalent in children with autism (n = 79; 75.24%) compared to those with other neurodevelopmental disorders (n = 10; 27.78%). Snacking between meals was significantly more common among the overall neuropediatric patient group (n = 140; 99.29%), with fruit purees (n = 33; 23.57%) and fruits (n = 28; 20%) being the most frequently consumed snacks. CONCLUSIONS: The qualitative analysis of dietary habits revealed selective food aversions and eating disorders due to a narrow range of frequently consumed products within dietary groups.

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9. Guerini FR, Bolognesi E, Mensi MM, Zanette M, Agliardi C, Zanzottera M, Chiappedi M, Annunziata S, García-García F, Cavallini A, Clerici M. HLA-A, -B, -C and -DRB1 Association with Autism Spectrum Disorder Risk: A Sex-Related Analysis in Italian ASD Children and Their Siblings. Int J Mol Sci;2024 (Sep 12);25(18)

Autism Spectrum disorders (ASD) are diagnosed more often in males than in females, by a ratio of about 3:1; this is likely to be due to a difference in risk burden between the sexes and/or to « compensatory skills » in females, that may delay the diagnosis of ASD. Identifying specific risk factors for ASD in females may be important in facilitating early diagnosis. We investigated whether HLA- class I: -A, -B, -C and class II -DRB1 alleles, which have been suggested to play a role in the development of ASD, can be considered as sex-related risk/protective markers towards the ASD. We performed HLA allele genotyping in 178 Italian children with ASD, 94 healthy siblings, and their parents. HLA allele distribution was compared between children with ASD, sex-matched healthy siblings, and a cohort of healthy controls (HC) enrolled in the Italian bone marrow donor registry. Allele transmission from parents to children with ASD and their siblings was also assessed. Our findings suggest that HLA-A*02, B*38, and C*12 alleles are more frequently carried by females with ASD compared to both HC and healthy female siblings, indicating these alleles as potential risk factors for ASD in females. Conversely, the HLA-A*03 allele was more commonly transmitted to healthy female siblings, suggesting it might have a protective effect. Additionally, the HLA-B*44 allele was found to be more prevalent in boys with ASD, indicating it is a potential risk factor for male patients. This is the first Italian study of sex-related HLA association with ASD. If confirmed, these results could facilitate early ASD diagnosis in female patients, allowing earlier interventions, which are crucial in the management of neurodevelopmental disorders.

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10. Huda E, Hawker P, Cibralic S, John JR, Hussain A, Diaz AM, Eapen V. Screening tools for autism in culturally and linguistically diverse paediatric populations: a systematic review. BMC Pediatr;2024 (Sep 28);24(1):610.

BACKGROUND: Autism Spectrum Disorder (ASD) has varying prevalence rates worldwide, often higher in culturally diverse populations. Cultural differences can affect autism symptom recognition. Language barriers and differing healthcare attitudes may delay diagnosis and intervention. Most autism screening tools were developed in Western, predominantly Caucasian populations, and their appropriateness in culturally and linguistically diverse (CALD) contexts remains uncertain. There is a lack of comprehensive data on the accuracy of these tools in identifying autism in culturally and linguistically diverse groups. Consequently, it is unclear whether current screening tools are culturally sensitive and appropriate. METHODS: A research protocol was registered in PROSPERO (CRD42022367308). A comprehensive search of literature published from inception to October 2022 was conducted using the following databases: PubMed, Medline Complete, Scopus, PsychInfo and CINAHL Complete. The articles were screened using pre-determined inclusion and exclusion criteria. Data extracted included participant demographics, screening tool psychometric properties (validity, reliability, accuracy) and acceptability. A narrative synthesis approach was used. RESULTS: From the initial retrieval of 2310 citations, 51 articles were included for analysis. The studies were conducted in 32 different countries with screening tools in the following languages: Chinese, Spanish, Korean, Turkish, Arabic, Kurdish, Persian, Serbian, Italian, French, Sinhala, Taiwanese, Finnish, Northern Soho, Albanian, German, Japanese, Vietnamese, Farsi, Greek and English. There was no data on acceptability of the screening tools in CALD populations. Validity, reliability, and accuracy ranged from poor to excellent with consistently high performance by screening tools devised within the populations they are intended for. CONCLUSIONS: The review evaluated autism screening tools in culturally diverse populations, with a focus on validity, reliability, and acceptability. It highlighted variations in the effectiveness of these tools across different cultures, with high performance by tools devised specifically for the intended population, emphasizing the need for culturally sensitive screening tools. Further research is needed to improve culturally specific, reliable autism screening tools for equitable assessment and intervention in diverse communities.

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11. Ipsiroglu OS, Pandher PK, Hill O, McWilliams S, Braschel M, Edwards K, Friedlander R, Keys E, Kuo C, Lewis MS, Richardson A, Wagner AL, Wensley D. Iron Deficiency and Restless Sleep/Wake Behaviors in Neurodevelopmental Disorders and Mental Health Conditions. Nutrients;2024 (Sep 11);16(18)

Iron deficiency (ID) and restlessness are associated with sleep/wake-disorders (e.g., restless legs syndrome (RLS)) and neurodevelopmental disorders (attention deficit/hyperactivity and autism spectrum disorders (ADHD; ASD)). However, a standardized approach to assessing ID and restlessness is missing. We reviewed iron status and family sleep/ID history data collected at a sleep/wake behavior clinic under a quality improvement/quality assurance project. Restlessness was explored through patient and parental narratives and a ‘suggested clinical immobilization test’. Of 199 patients, 94% had ID, with 43% having a family history of ID. ADHD (46%) and ASD (45%) were common conditions, along with chronic insomnia (61%), sleep-disordered breathing (50%), and parasomnias (22%). In unadjusted analysis, a family history of ID increased the odds (95% CI) of familial RLS (OR: 5.98, p = 0.0002, [2.35-15.2]), insomnia/DIMS (OR: 3.44, p = 0.0084, [1.37-8.64]), and RLS (OR: 7.00, p = 0.01, [1.49-32.93]) in patients with ADHD, and of insomnia/DIMS (OR: 4.77, p = 0.0014, [1.82-12.5]), RLS/PLMS (OR: 5.83, p = 0.009, [1.54-22.1]), RLS (OR: 4.05, p = 0.01, [1.33-12.3]), and familial RLS (OR: 2.82, p = 0.02, [1.17-6.81]) in patients with ASD. ID and restlessness were characteristics of ADHD and ASD, and a family history of ID increased the risk of sleep/wake-disorders. These findings highlight the need to integrate comprehensive blood work and family history to capture ID in children and adolescents with restless behaviors.

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12. Itahashi T, Yamashita A, Takahara Y, Yahata N, Aoki YY, Fujino J, Yoshihara Y, Nakamura M, Aoki R, Okimura T, Ohta H, Sakai Y, Takamura M, Ichikawa N, Okada G, Okada N, Kasai K, Tanaka SC, Imamizu H, Kato N, Okamoto Y, Takahashi H, Kawato M, Yamashita O, Hashimoto RI. Generalizable and transportable resting-state neural signatures characterized by functional networks, neurotransmitters, and clinical symptoms in autism. Mol Psychiatry;2024 (Sep 28)

Autism spectrum disorder (ASD) is a lifelong condition with elusive biological mechanisms. The complexity of factors, including inter-site and developmental differences, hinders the development of a generalizable neuroimaging classifier for ASD. Here, we developed a classifier for ASD using a large-scale, multisite resting-state fMRI dataset of 730 Japanese adults, aiming to capture neural signatures that reflect pathophysiology at the functional network level, neurotransmitters, and clinical symptoms of the autistic brain. Our adult ASD classifier was successfully generalized to adults in the United States, Belgium, and Japan. The classifier further demonstrated its successful transportability to children and adolescents. The classifier contained 141 functional connections (FCs) that were important for discriminating individuals with ASD from typically developing controls. These FCs and their terminal brain regions were associated with difficulties in social interaction and dopamine and serotonin, respectively. Finally, we mapped attention-deficit/hyperactivity disorder (ADHD), schizophrenia (SCZ), and major depressive disorder (MDD) onto the biological axis defined by the ASD classifier. ADHD and SCZ, but not MDD, were located proximate to ASD on the biological dimensions. Our results revealed functional signatures of the ASD brain, grounded in molecular characteristics and clinical symptoms, achieving generalizability and transportability applicable to the evaluation of the biological continuity of related diseases.

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13. Jaschke AC, Howlin C, Pool J, Greenberg YD, Atkinson R, Kovalova A, Merriam E, Pallás-Ferrer I, Williams S, Moore C, Hayden K, Allison C, Odell-Miller H, Baron-Cohen S. Study protocol of a randomized control trial on the effectiveness of improvisational music therapy for autistic children. BMC Psychiatry;2024 (Sep 27);24(1):637.

BACKGROUND: Music therapy is the clinical use of musical interventions to improve mental and physical health across multiple domains, including social communication. Autistic children, who have difficulties in social communication and often increased anxiety, tend to show a strong preference for music, because it can be structured and systematic, and therefore more predictable than social interaction. This makes music therapy a promising medium for therapeutic support and intervention. Previous clinical trials of music therapy compared to traditional therapy for autistic children have shown encouraging but nevertheless mixed results. KEY AIMS: The primary aim is to conduct a randomised controlled trial (RCT) of improvisational music therapy for autistic children and test its effectiveness in at improving social communication and wellbeing, and to reduce anxiety. RESEARCH PLAN: The RCT will be conducted with 200 autistic children in the UK aged 7 to 11 years old. Participants will be randomly assigned to either improvisational music therapy or support as usual. The trial will be an assessor-blind, pragmatic two-arm cluster RCT comparing the impact of 12-weeks of improvisational music therapy in addition to support as usual, vs. support as usual for autistic children. METHODS: Researchers who are blind to which arm the children are in will conduct assessments and obtain data via caregiver reports. The primary outcome will be the absolute change in the total score of the Brief Observation of Social Communication Change (BOSCC) assessed at baseline, T1 (13 weeks) and T2 (39 weeks) follow-ups. The BOSCC consists of specific items that were developed to identify changes in social-communication behaviours. Secondary outcome measures include: (1) Parent reported anxiety scale for youth with ASD (Note that we do not use the term ‘ASD’ or Autism Spectrum Disorder, because many autistic people feel it is stigmatising. Instead, we use the term ‘autism’) (PRAS-ASD) (2) Young Child Outcome Rating Scale, for wellbeing (YCORS), (3) Strengths and Difficulties Questionnaire (SDQ); and (4) Vineland Adaptive Behaviour Scale (VABS). (5) The Children’s Communication Checklist-2 (CCC-2) will be completed to evaluate pragmatic speech with fluent speakers only; (6) The Music Engagement Scale (MES); and (7) Assessment of the Quality of Relationship (AQR) will be used to evaluate the child-therapist relationships using video-analysis of music therapy sessions. Additional data will be collected by administering the Wechsler Abbreviated Scale of Intelligence (WASI-II), Music at Home Questionnaire (M@H), and children’s versions of the Empathy Quotient (EQ) and Systemizing Quotient (SQ). Audio and video data from the therapy sessions will be collected and analysed (using both human and computer-based feature-coding, e.g., machine learning and AI-driven methods) to identify how music and non-musical interactions foster change throughout the therapy. DISCUSSION: This study aims to observe if the interactions, engagement, and therapeutic modalities fostered during music therapy sessions can translate to non-musical contexts and improve autistic children’s social communication skills, identifying possible mediating factors contributing to the effectiveness of music therapy, potentially informing policy making and governance. TRIAL REGISTRATION: This randomised control trial is registered with the NIH U.S. National Library of Medicine: https://clinicaltrials.gov/search?term=NCT06016621 , clinicalTrials.gov Identifier: NCT0601662, Registration Date 19th August 2023.

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14. Kim SW, Lee H, Song DY, Lee GH, Ji J, Park JW, Han JH, Lee JW, Byun HJ, Son JH, Kim YR, Lee Y, Kim J, Jung A, Lee J, Kim E, Kim SH, Lee JH, Satterstrom FK, Girirajan S, Børglum AD, Grove J, Kim E, Werling DM, Yoo HJ, An JY. Whole genome sequencing analysis identifies sex differences of familial pattern contributing to phenotypic diversity in autism. Genome Med;2024 (Sep 27);16(1):114.

BACKGROUND: Whole-genome sequencing (WGS) analyses have found higher genetic burden in autistic females compared to males, supporting higher liability threshold in females. However, genomic evidence of sex differences has been limited to European ancestry to date and little is known about how genetic variation leads to autism-related traits within families across sex. METHODS: To address this gap, we present WGS data of Korean autism families (n = 2255) and a Korean general population sample (n = 2500), the largest WGS data of East Asian ancestry. We analyzed sex differences in genetic burden and compared with cohorts of European ancestry (n = 15,839). Further, with extensively collected family-wise Korean autism phenotype data (n = 3730), we investigated sex differences in phenotypic scores and gene-phenotype associations within family. RESULTS: We observed robust female enrichment of de novo protein-truncating variants in autistic individuals across cohorts. However, sex differences in polygenic burden varied across cohorts and we found that the differential proportion of comorbid intellectual disability and severe autism symptoms mainly drove these variations. In siblings, males of autistic females exhibited the most severe social communication deficits. Female siblings exhibited lower phenotypic severity despite the higher polygenic burden than male siblings. Mothers also showed higher tolerance for polygenic burden than fathers, supporting higher liability threshold in females. CONCLUSIONS: Our findings indicate that genetic liability in autism is both sex- and phenotype-dependent, expanding the current understanding of autism’s genetic complexity. Our work further suggests that family-based assessments of sex differences can help unravel underlying sex-differential liability in autism.

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15. Li H, Zhang Q, Duan T, Li J, Shi L, Hua Q, Li D, Ji GJ, Wang K, Zhu C. Sex differences in brain functional specialization and interhemispheric cooperation among children with autism spectrum disorders. Sci Rep;2024 (Sep 27);14(1):22096.

The prevalence of autism spectrum disorders (ASDs) differs substantially between males and females, suggesting that sex-related neurodevelopmental factors are central to ASD pathogenesis. Numerous studies have suggested that abnormal brain specialization patterns and poor regional cooperation contribute to ASD pathogenesis, but relatively little is known about the related sex differences. Therefore, this study examined sex differences in brain functional specialization and cooperation among children with ASD. The autonomy index (AI) and connectivity between functionally homotopic voxels (CFH) derived from resting-state functional magnetic resonance imaging (rs-fMRI) were compared between 58 male and 13 female children with ASD. In addition, correlations were examined between regional CFH values showing significant sex differences and symptom scores on the autism behavior checklist (ABC) and childhood autism rating scale (CARS). Male children with ASD demonstrated significantly greater CFH in the left fusiform gyrus (FG) and right opercular part of the inferior frontal gyrus (IFGoperc) than female children with ASD. In addition, the CFH value of the left FG in male children with ASD was negatively correlated with total ABC score and subscale scores for sensory and social abilities. In contrast, no sex differences were detected in brain specialization. These regional abnormalities in interhemispheric cooperation among male children with ASD may provide clues to the neural mechanisms underlying sex differences in ASD symptomatology and prevalence. Autism spectrum disorders, sex, resting-state functional magnetic resonance imaging, cerebral specialization, interhemispheric cooperation.

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16. Montanaro FAM, Alfieri P, Caciolo C, Spano G, Bosco A, Vicari S. Effects of a combined neuropsychological and cognitive behavioral group therapy on young adults with Fragile X Syndrome: An explorative study. Res Dev Disabil;2024 (Sep 26);154:104839.

BACKGROUND: Fragile X Syndrome (FXS) is an X-linked neurodevelopmental disorder that leads to intellectual disability (ID) along with cognitive-behavioral difficulties. Research on psychosocial treatments in individuals FXS and ID is still lacking. This study aimed to investigate the effectiveness of a combined neuropsychological and cognitive behavioral group therapy (nCBT) among young adults with FXS. METHOD: Ten young adults diagnosed with FXS took part in the second stage intervention of « Corp-osa-Mente » (CoM II), a group nCBT program previously outlined by Montanaro and colleagues in an earlier study, with the participants being the same as in the previous research. This report details the outcomes of an additional twelve-month group sections aimed at enhancing the ability to manage emotions and the socio-communicative skills of these young adults. Caregivers completed measures of adaptive functioning, emotional and behavior problems, executive function, communication skills and family quality of life at pre-treatment (T0) and post-treatment (T1). RESULTS: CoM II showed a decrease in depressive and anxiety symptoms from T0 to T1, along with increased socio-pragmatic and communication skills from pre-test to post-test intervention. Additionally, our analysis revealed improvements in the adapative behavior of participants and in the family quality of life. CONCLUSIONS: These preliminary findings suggest that young adults with FXS and ID experienced positive outcomes through participation in CoM II, a group nCBT. However, it is recommended to undertake additional methodologically rigorous studies, such as randomized controlled trials (RCTs), to substantiate these initially promising findings.

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17. Nabors L, Bauer A, Ayers K, Workman B, Butsch Kovacic M, Lee SY. A Short-Term Evaluation of the Eat and Exercise to Win Program for Adults with Intellectual and Developmental Disabilities. Nutrients;2024 (Sep 16);16(18)

(1) Study Aim: Adults with intellectual and developmental disabilities (IDD) face a multitude of chronic health risks related to obesity, including diabetes and heart disease. Day adult service programs offer unique opportunities for improving and monitoring the health of this vulnerable group. To promote exercise and healthy eating habits among adults with IDD, the Eat and Exercise to Win Program (EE-2-Win) was offered weekly at two locations over 8-9 months. (2) Methods: Using daily logs, staff assessed outcomes of 26 program participants, including changes in knowledge, eating and exercise habits, and water consumption. Participants’ weights were measured, and their lunches were photographed at baseline and 3 months. (3) Results: While participants’ weights did not significantly differ at 3 months, assessing photographs indicated that participants’ lunches included more fruits and vegetables. Staff surveys indicated that participants had greater knowledge of MyPlate and were consuming more water at three months. Survey responses indicated that staff perceived the program to be valuable overall, and challenges in learning and assessment were reported given differences in the cognitive abilities of adults with IDD. Staff also suggested engaging home caregivers in the program, as they often make dietary decisions. (4) Conclusions: Overall, results confirmed that the EE-2-Win Program positively impacted healthy eating and exercise. Future work, however, with both staff and caregivers is needed to further optimize the program.

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18. Panzeri D, Perina M, Biffi E, Semino M, Diella E, Caprì T. Effects of Immersive Virtual Reality with Treadmill in Subjects with Rett Syndrome: A Pilot Study. Children (Basel);2024 (Sep 11);11(9)

BACKGROUND/OBJECTIVES: Rett syndrome is a rare neurodevelopmental disorder that can severely affect motor functioning, particularly walking. Previous training programs proposed treadmills as tools to increase walking endurance of patients with Rett syndrome, but these trainings did not include virtual reality (VR). The aim of this study was to assess the feasibility of a short treadmill training coupled to VR in girls with Rett syndrome. METHODS: Nine patients with Rett syndrome underwent a 3-day treadmill walking program performed in semi-immersive VR. During the training, the happiness index and performance metrics were collected. At the end of the training parents filled out the Suitability Evaluation Questionnaire (SEQ) and, when feasible, patients underwent a gait assessment. RESULTS: All the subjects recruited performed the three GRAIL sessions and parents showed a good satisfaction and considered the integration of treadmill and VR a good possibility for future rehabilitative programs. Participants showed greater satisfaction in environments requiring walking and their attention increased during training sessions, hypothesizing the feasibility of longer trainings with treadmill and VR. Data collected from gait analysis provided insights, although preliminary, concerning differences in gait pattern amongst the recruited subjects. CONCLUSIONS: Despite the small sample size and limited training duration, the paper suggests that a walking training with a treadmill combined with VR can represent a new strategy for Rett rehabilitation.

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19. Pérez-Cabral ID, Bernal-Mercado AT, Islas-Rubio AR, Suárez-Jiménez GM, Robles-García M, Puebla-Duarte AL, Del-Toro-Sánchez CL. Exploring Dietary Interventions in Autism Spectrum Disorder. Foods;2024 (Sep 23);13(18)

Autism spectrum disorder (ASD) involves social communication difficulties and repetitive behaviors, and it has a growing prevalence worldwide. Symptoms include cognitive impairments, gastrointestinal (GI) issues, feeding difficulties, and psychological problems. A significant concern in ASD is food selectivity, leading to nutrient deficiencies. Common GI issues in ASD, such as constipation and irritable bowel syndrome, stem from abnormal gut flora and immune system dysregulation. Sensory sensitivities and behavioral challenges exacerbate these problems, correlating with neurological symptom severity. Children with ASD also exhibit higher oxidative stress due to low antioxidant levels like glutathione. Therapeutic diets, including ketogenic, high-antioxidant, gluten-free and casein-free, and probiotic-rich diets, show potential in managing ASD symptoms like behavior, communication, GI issues, and oxidative stress, though the evidence is limited. Various studies have focused on different populations, but there is increasing concern about the impact among children. This review aims to highlight the food preferences of the ASD population, analyze the effect of the physicochemical and nutritional properties of foods on the selectivity in its consumption, GI problems, and antioxidant deficiencies in individuals with ASD, and evaluate the effectiveness of therapeutic diets, including diets rich in antioxidants, gluten-free and casein-free, ketogenic and essential fatty acids, and probiotic-rich diets in managing these challenges.

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20. Qi SY, Zhang SJ, Lin LL, Li YR, Chen JG, Ni YC, Du X, Zhang J, Ge P, Liu GH, Wu JY, Lin S, Gong M, Lin JW, Chen LF, He LL, Lin D. Quantifying attention in children with intellectual and developmental disabilities through multicenter electrooculogram signal analysis. Sci Rep;2024 (Sep 27);14(1):22186.

In a multicenter case-control investigation, we assessed the efficacy of the Electrooculogram Signal Analysis (EOG-SA) method, which integrates attention-related visual evocation, electrooculography, and nonlinear analysis, for distinguishing between intellectual and developmental disabilities (IDD) and typical development (TD) in children. Analyzing 127 participants (63 IDD, 64 TD), we applied nonlinear dynamics for feature extraction. Results indicated EOG-SA’s capability to distinguish IDD, with higher template thresholds and Correlation Dimension values correlating with clinical severity. The template threshold proved a robust indicator, with higher values denoting severe IDD. Discriminative metrics showed areas under the curve of 0.91 (template threshold) and 0.85/0.91 (D2), with sensitivities and specificities of 77.6%/95.9% and 93.5%/71.0%, respectively. EOG-SA emerges as a promising tool, offering interpretable neural biomarkers for early and nuanced diagnosis of IDD.

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21. Rodríguez-Jiménez T, Martínez-González AE. Relationships between Anxiety, Repetitive Behavior and Parenting Stress: A Comparative Study between Individuals with Autism from Spain and Colombia. Brain Sci;2024 (Sep 9);14(9)

The present study analyzed the association between anxiety, repetitive behavior and parental stress in individuals with autism from Spain (n = 60, mean age = 8.52, SD = 4.41) and Colombia (n = 58, mean age = 10.29, SD = 4.98). Similarly, differences in anxiety, repetitive behavior and parental stress between both countries were analyzed. Outcomes revealed a strong relationship between anxiety and repetitive behavior in both populations. Furthermore, moderate positive associations were observed between anxiety, repetitive behavior and parental stress in the Spanish sample. However, parental stress was found to be moderately and negatively related with anxiety and repetitive behavior in the Colombian sample. Finally, no differences were found in anxiety and repetitive behavior between countries, but differences did emerge for parental stress which was found to be higher in the Colombian sample. In conclusion, differences in parental stress may be due to regional differences in socio-health resources, socio-economics, parenting styles, etc.

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22. Rydzanicz M, Kuzniewska B, Magnowska M, Wójtowicz T, Stawikowska A, Hojka A, Borsuk E, Meyza K, Gewartowska O, Gruchota J, Miłek J, Wardaszka P, Chojnicka I, Kondrakiewicz L, Dymkowska D, Puścian A, Knapska E, Dziembowski A, Płoski R, Dziembowska M. Mutation in the mitochondrial chaperone TRAP1 leads to autism with more severe symptoms in males. EMBO Mol Med;2024 (Sep 27)

There is increasing evidence of mitochondrial dysfunction in autism spectrum disorders (ASD), but the causal relationships are unclear. In an ASD patient whose identical twin was unaffected, we identified a postzygotic mosaic mutation p.Q639* in the TRAP1 gene, which encodes a mitochondrial chaperone of the HSP90 family. Additional screening of 176 unrelated ASD probands revealed an identical TRAP1 variant in a male patient who had inherited it from a healthy mother. Notably, newly generated knock-in Trap1 p.Q641* mice display ASD-related behavioral abnormalities that are more pronounced in males than in females. Accordingly, Trap1 p.Q641* mutation also resulted in sex-specific changes in synaptic plasticity, the number of presynaptic mitochondria, and mitochondrial respiration. Thus, the TRAP1 p.Q639* mutation is the first example of a monogenic ASD caused by impaired mitochondrial protein homeostasis.

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23. Sanglakh Ghoochan Atigh A, Joghataei MT, Moradkhani S, Alizadeh Zarei M, Nazari MA. Early Auditory Temporal Processing Deficit in Children with Autism Spectrum Disorder: The Research Domain Criteria Framework. Brain Sci;2024 (Sep 3);14(9)

Altered sensory processing especially in the auditory system is considered a typical observation in children with autism spectrum disorder (ASD). Auditory temporal processing is known to be impaired in ASD children. Although research suggests that auditory temporal processing abnormalities could be responsible for the core aspects of ASD, few studies have examined early time processing and their results have been conflicting. The present event-related potential (ERP) study investigated the early neural responses to duration and inter-stimulus interval (ISI) deviants in nonspeech contexts in children with ASD and a control group of typically developing (TD) children matched in terms of age and IQ. A passive auditory oddball paradigm was employed to elicit the mismatch negativity (MMN) for change detection considering both the duration and ISI-based stimulus. The MMN results showed that the ASD group had a relatively diminished amplitude and significant delayed latency in response to duration deviants. The findings are finally discussed in terms of hyper-hyposensitivity of auditory processing and the fact that the observed patterns may potentially act as risk factors for ASD development within the research domain criteria (RDoC) framework.

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24. Sener EF, Dana H, Tahtasakal R, Taheri S, Rassoulzadegan M. Autism-Related Cc2d1a Heterozygous Mice: Increased Levels of miRNAs Retained in DNA/RNA Hybrid Profiles (R-Loop). Biomolecules;2024 (Sep 20);14(9)

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a highly variable expression of phenotypes (restricted interest or activity and repetitive behavior in communication and social interactions), genes (mutation), markers (alteration of transcription) and pathways. Loss of function of the CC2D1A gene appears to primarily affect the brain, leading to a range of behavioral problems in humans. In our study published in 2020, we found that the expressions of miR-19a-3p, miR-361-5p, miR-150-5p, miR-3613-3p, miR-126-3p and miR-499a-5p were downregulated in the serum samples of autistic patients, their families and mouse models (Cc2d1a +/- and valproic acid treated males). Here, acquired non-Mendelian hereditary character in a genetically defined mouse model of autism (Cc2d1a +/-) correlates with the transcriptional alteration of five miRNAs. We seek to test the hypothesis that miRNA levels vary by changes in RNA/DNA structure during development, thereby creating transcription alteration and cell memory. Behavioral tests were conducted on the offspring of Cc2d1a (+/-) mutant and control mice, such as novel object, social interaction, marble burying and tail suspension behavior. Two RNA fractions were isolated from mouse hippocampal tissues and sperm cells via standard TRIzol extraction: free RNA and the fraction of RNA bound to DNA in the form of a DNA/RNA hybrid (R-loop). The expression levels of miR-19a-3p, miR-361-5p, miR-150-5p, miR-126-3p and miR-499a-5p were investigated by quantitative real-time RT-PCR. We report differences in the distribution of five miRNAs in the hippocampus between male and female mice, particularly in colonies of Cc2d1a (+/-) mice. Furthermore, the number of miRNAs engaged in the DNA/RNA hybrid fraction is generally higher in the mutant pedigree than in the control group. On the other hand, in sperm, both fractions are at lower levels than in controls. R-loops contribute to the physiology and pathology of organisms including human disease. Here, we report a variation in five miRNA levels between gender and tissue. Our results suggest that the transcription levels of these five miRNAs are directly regulated by their RNA.

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25. Stahmer AC, Dufek S, Rogers SJ, Iosif AM. Study Protocol for a Cluster, Randomized, Controlled Community Effectiveness Trial of the Early Start Denver Model (ESDM) Compared to Community Early Behavioral Intervention (EBI) in Community Programs serving Young Autistic Children: Partnering for Autism: Learning more to improve Services (PALMS). BMC Psychol;2024 (Sep 28);12(1):513.

BACKGROUND: The rising number of children identified with autism has led to exponential growth in for-profit applied behavior analysis (ABA) agencies and the use of highly structured approaches that may not be developmentally appropriate for young children. Multiple clinical trials support naturalistic developmental behavior interventions (NDBIs) that integrate ABA and developmental science and are considered best practices for young autistic children. The Early Start Denver Model (ESDM) is a comprehensive NDBI shown to improve social communication outcomes for young autistic children in several controlled efficacy studies. However, effectiveness data regarding NDBI use in community-based agencies are limited. METHODS: This study uses a community-partnered approach to test the effectiveness of ESDM compared to usual early behavioral intervention (EBI) for improving social communication and language in autistic children served by community agencies. This is a hybrid type 1 cluster-randomized controlled trial with 2 conditions: ESDM and EBI. In the intervention group, supervising providers will receive training in ESDM; in the control group, they will continue EBI as usual. We will enroll and randomize 100 supervisors (50 ESDM, 50 EBI) by region. Each supervisor enrolls 3 families of autistic children under age 5 (n = 300) and accompanying behavior technicians (n = 200). The primary outcome is child language and social communication at 6 and 12 months. Secondary outcomes include child adaptive behavior, caregiver use of ESDM strategies, and provider intervention fidelity. Child social motivation and caregiver fidelity will be tested as mediating variables. ESDM implementation determinants will be explored using mixed methods. DISCUSSION: This study will contribute novel knowledge on ESDM effectiveness, the variables that mediate and moderate child outcomes, and engagement of its mechanisms in community use. We expect results from this trial to increase community availability of this model and access to high-quality intervention for young autistic children, especially those who depend on publicly funded intervention services. Understanding implementation determinants will aid scale-up of effective models within communities. TRAIL REGISTRATION: Clinicaltrials.gov identifier number NCT06005285. Registered on August 21, 2023. PROTOCOL VERSION: Issue date 6 August 2024; Protocol amendment number: 02.

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26. Szabó J, Renczés E, Borbélyová V, Ostatníková D, Celec P. Assessing sociability using the Three-Chamber Social Interaction Test and the Reciprocal Interaction Test in a genetic mouse model of ASD. Behav Brain Funct;2024 (Sep 28);20(1):24.

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with heterogeneous symptomatology. Arguably, the most pervasive shortfall of ASD are the deficits in sociability and the animal models of the disorder are expected to exhibit such impairments. The most widely utilized behavioral task for assessing sociability in rodents is the Three-Chamber Social Interaction Test (SIT). However, SIT has been yielding inconsistent results in social interaction behavior across different rodent models of ASD, which could be pointing to the suboptimal methodology of the task. Here, we compared social behavior assessed in SIT and in another prominent sociability behavioral assay, Reciprocal Interaction Test (RCI), in a SH3 and multiple ankyrin repeated domains 3 (SHANK3) mouse model of ASD. Head-to-head comparison showed no association (p = 0.15, 0.25, 0.43) and a fixed bias (p = 0.01, < 0.001, < 0.001) in sociability assessment between the behavioral assays in both wild-type (WT) controls and Shank3B((-/-)) mice. Adult Shank3B((-/-)) mice of both sexes displayed normative sociability in SIT when compared to the WT controls (p = 0.74) but exhibited less than half of social interaction (p < 0.001) and almost three times more social disinterest (p < 0.001) when compared to WT mice in RCI. At least in the Shank3B((-/-)) mouse model of ASD, we presume RCI could be a preferable way of assessing social interaction compared to SIT. Considering the variability of animal models of ASD and the wide palette of tools available for the assessment of their behavior, a consensus approach would be needed for observational and interventional analyses.

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27. Szukiewicz D. Histaminergic System Activity in the Central Nervous System: The Role in Neurodevelopmental and Neurodegenerative Disorders. Int J Mol Sci;2024 (Sep 12);25(18)

Histamine (HA), a biogenic monoamine, exerts its pleiotropic effects through four H1R-H4R histamine receptors, which are also expressed in brain tissue. Together with the projections of HA-producing neurons located within the tuberomammillary nucleus (TMN), which innervate most areas of the brain, they constitute the histaminergic system. Thus, while remaining a mediator of the inflammatory reaction and immune system function, HA also acts as a neurotransmitter and a modulator of other neurotransmitter systems in the central nervous system (CNS). Although the detailed causes are still not fully understood, neuroinflammation seems to play a crucial role in the etiopathogenesis of both neurodevelopmental and neurodegenerative (neuropsychiatric) diseases, such as autism spectrum disorders (ASDs), attention-deficit/hyperactivity disorder (ADHD), Alzheimer’s disease (AD) and Parkinson’s disease (PD). Given the increasing prevalence/diagnosis of these disorders and their socioeconomic impact, the need to develop effective forms of therapy has focused researchers’ attention on the brain’s histaminergic activity and other related signaling pathways. This review presents the current state of knowledge concerning the involvement of HA and the histaminergic system within the CNS in the development of neurodevelopmental and neurodegenerative disorders. To this end, the roles of HA in neurotransmission, neuroinflammation, and neurodevelopment are also discussed.

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28. Xiong C, Zhang M, Yang H, Wei X, Zhao C, Zhang J. Modelling cell type-specific lncRNA regulatory network in autism with Cycle. BMC Bioinformatics;2024 (Sep 27);25(1):307.

BACKGROUND: Autism spectrum disorder (ASD) is a class of complex neurodevelopment disorders with high genetic heterogeneity. Long non-coding RNAs (lncRNAs) are vital regulators that perform specific functions within diverse cell types and play pivotal roles in neurological diseases including ASD. Therefore, exploring lncRNA regulation would contribute to deciphering ASD molecular mechanisms. Existing computational methods utilize bulk transcriptomics data to identify lncRNA regulation in all of samples, which could reveal the commonalities of lncRNA regulation in ASD, but ignore the specificity of lncRNA regulation across various cell types. RESULTS: Here, we present Cycle (Cell type-specific lncRNA regulatory network) to construct the landscape of cell type-specific lncRNA regulation in ASD. We have found that each ASD cell type is unique in lncRNA regulation, and more than one-third and all cell type-specific lncRNA regulatory networks are characterized as scale-free and small-world, respectively. Across 17 ASD cell types, we have discovered 19 rewired and 11 stable modules, along with eight rewired and three stable hubs within the constructed cell type-specific lncRNA regulatory networks. Enrichment analysis reveals that the discovered rewired and stable modules and hubs are closely related to ASD. Furthermore, more similar ASD cell types tend to be connected with higher strength in the constructed cell similarity network. Finally, the comparison results demonstrate that Cycle is a potential method for uncovering cell type-specific lncRNA regulation. CONCLUSION: Overall, these results illustrate that Cycle is a promising method to model the landscape of cell type-specific lncRNA regulation, and provides insights into understanding the heterogeneity of lncRNA regulation between various ASD cell types.

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