1. Aran A, Cayam Rand D. Cannabinoid treatment for the symptoms of autism spectrum disorder. Expert Opin Emerg Drugs;2024 (Jan 16)

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting approximately 3% of school-age children. The core symptoms are deficits in social communication and restricted and repetitive patterns of behavior. Associated problems in cognition, language, behavior, sleep and mood are prevalent. Currently, no established pharmacological treatment exists for core ASD symptoms. Risperidone and aripiprazole are used to manage associated irritability, but their effectiveness is limited and adverse events are common. AREAS COVERED: This mini-review summarizes existing scientific literature and ongoing clinical trials concerning cannabinoid treatment for ASD. Uncontrolled case series have documented improvements in both core ASD symptoms and related behavioral challenges in children treated with cannabis extracts rich in cannabidiol (CBD). Placebo-controlled studies involving CBD-rich cannabis extracts and/or pure CBD in children with ASD have demonstrated mixed efficacy results. A similar outcome was observed in a placebo-controlled study of pure CBD addressing social avoidance in Fragile X syndrome. Importantly, these studies have shown relatively high safety and tolerability. EXPERT OPINION: While current clinical data suggest the potential of CBD and CBD-rich cannabis extract in managing core and behavioral deficits in ASD, it is prudent to await the results of ongoing placebo-controlled trials before considering CBD treatment for ASD.

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2. Barnhardt E, Coury DL. Family-systems interventions for families of people with an intellectual disability or who are autistic show potential, but further research is needed. Evid Based Nurs;2024 (Jan 16)

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3. Bogatova D, Smirnakis SM, Palagina G. Tug-of-Peace: Visual Rivalry and Atypical Visual Motion Processing in MECP2 Duplication Syndrome of Autism. eNeuro;2024 (Jan);11(1)

Extracting common patterns of neural circuit computations in the autism spectrum and confirming them as a cause of specific core traits of autism is the first step toward identifying cell-level and circuit-level targets for effective clinical intervention. Studies in humans with autism have identified functional links and common anatomic substrates between core restricted behavioral repertoire, cognitive rigidity, and overstability of visual percepts during visual rivalry. To study these processes with single-cell precision and comprehensive neuronal population coverage, we developed the visual bistable perception paradigm for mice based on ambiguous moving plaid patterns consisting of two transparent gratings drifting at an angle of 120°. This results in spontaneous reversals of the perception between local component motion (plaid perceived as two separate moving grating components) and integrated global pattern motion (plaid perceived as a fused moving texture). This robust paradigm does not depend on the explicit report of the mouse, since the direction of the optokinetic nystagmus (OKN) is used to infer the dominant percept. Using this paradigm, we found that the rate of perceptual reversals between global and local motion interpretations is reduced in the methyl-CpG-binding protein 2 duplication syndrome (MECP2-ds) mouse model of autism. Moreover, the stability of local motion percepts is greatly increased in MECP2-ds mice at the expense of global motion percepts. Thus, our model reproduces a subclass of the core features in human autism (reduced rate of visual rivalry and atypical perception of visual motion). This further offers a well-controlled approach for dissecting neuronal circuits underlying these core features.

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4. Chadwick W, Angulo-Herrera I, Cogram P, Deacon RJM, Mason DJ, Brown D, Roberts I, O’Donovan DJ, Tranfaglia MR, Guilliams T, Thompson NT. A novel combination treatment for fragile X syndrome predicted using computational methods. Brain Commun;2024;6(1):fcad353.

Fragile X syndrome is a neurodevelopmental disorder caused by silencing of the fragile X messenger ribonucleotide gene. Patients display a wide spectrum of symptoms ranging from intellectual and learning disabilities to behavioural challenges including autism spectrum disorder. In addition to this, patients also display a diversity of symptoms due to mosaicism. These factors make fragile X syndrome a difficult syndrome to manage and suggest that a single targeted therapeutic approach cannot address all the symptoms. To this end, we utilized Healx’s data-driven drug discovery platform to identify a treatment strategy to address the wide range of diverse symptoms among patients. Computational methods identified the combination of ibudilast and gaboxadol as a treatment for several pathophysiological targets that could potentially reverse multiple symptoms associated with fragile X syndrome. Ibudilast is an approved broad-spectrum phosphodiesterase inhibitor, selective against both phosphodiesterase 4 and phosphodiesterase 10, and has demonstrated to have several beneficial effects in the brain. Gaboxadol is a GABA(A) receptor agonist, selective against the delta subunit, which has previously displayed encouraging results in a fragile X syndrome clinical trial. Alterations in GABA and cyclic adenosine monophosphate metabolism have long since been associated with the pathophysiology of fragile X syndrome; however, targeting both pathways simultaneously has never been investigated. Both drugs have a good safety and tolerability profile in the clinic making them attractive candidates for repurposing. We set out to explore whether the combination of ibudilast and gaboxadol could demonstrate therapeutic efficacy in a fragile X syndrome mouse model. We found that daily treatment with ibudilast significantly enhanced the ability of fragile X syndrome mice to perform a number of different cognitive assays while gaboxadol treatment improved behaviours such as hyperactivity, aggression, stereotypy and anxiety. Importantly, when ibudilast and gaboxadol were co-administered, the cognitive deficits as well as the aforementioned behaviours were rescued. Moreover, this combination treatment showed no evidence of tolerance, and no adverse effects were reported following chronic dosing. This work demonstrates for the first time that by targeting multiple pathways, with a combination treatment, we were able to rescue more phenotypes in a fragile X syndrome mouse model than either ibudilast or gaboxadol could achieve as monotherapies. This combination treatment approach holds promise for addressing the wide spectrum of diverse symptoms in this heterogeneous patient population and may have therapeutic potential for idiopathic autism.

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5. Cirillo N. Diagnosis of Autism. Jama;2024 (Jan 16);331(3):259.

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6. da Silva GCB, Firmino RT, Nóbrega WFS, d’Ávila S. Oral habits, sociopsychological orthodontic needs, and sociodemographic factors perceived by caregivers impact oral health-related quality of life in children with and without autism?. Int J Paediatr Dent;2024 (Jan 16)

BACKGROUND: Caregivers play a crucial role in assessing the oral health-related quality of life (OHRQoL) of young individuals with autism spectrum disorder (ASD). AIM: This study assessed the impact of sociodemographic and oral conditions on OHRQoL and family dynamics in young individuals with and without autism, as perceived by guardians. DESIGN: This comparative cross-sectional study included young individuals aged 6 to 14 years and their guardians. Data were collected at a specialized institution and dental schools. Guardians completed the Parental-Caregiver Perceptions Questionnaire (P-CPQ), Family Impact Scale (FIS), and sociodemographic and oral habits questionnaires. The sociopsychological need for orthodontic treatment was assessed using the Index of Orthodontic Treatment Need (IOTN). RESULTS: The sample included 144 youths and caregivers. The ASD group had higher P-CPQ and FIS scores. Factors associated with poorer perceived OHRQoL included higher youth age, lower caregiver education, higher IOTN scores, teeth clenching (RR = 1.20; 95% CI: 1.01-1.41), and lip sucking. Lower parental education (RR = 1.75; 95% CI: 1.10-2.80) and higher IOTN scores from the caregiver’s perspective impacted family dynamics. CONCLUSION: Caregivers of young individuals with ASD perceived a lower OHRQoL, and families in this group were more affected by sociodemographic and oral conditions.

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7. Groenman AP, van der Oord S, Geurts HM. Navigating adolescence: pubertal development in autism spectrum conditions and its relation to mental health. Arch Womens Ment Health;2024 (Jan 16)

Adolescence is a period of social, psychological, and physiological change, including the onset of puberty. Differential pubertal onset has been linked to a myriad of problems, including mental health problems. Therefore, we aim to investigate deviating pubertal development in autism, and whether this is more pronounced in girls than in boys. A total of 68 individuals (n(ASC) = 34, n(COM) (comparisons) = 34) aged 12 to 16 years were administered test concerning pubertal development and mental health (i.e., sensory sensitivity, autistic traits, depression, anxiety, and externalizing problems). Frequentist and Bayesian ANOVA was used to examine deviations in pubertal development in ASC and possible sex effects. Regression analyses was used to test whether this asynchronicity was linked to mental health problems. Our (frequentist and Bayesian) analyses revealed earlier onset and slower development of pubertal development in ASC but we did not find any sex differences. Maturation disparity was linked to higher mental health problems in ASC, but not in COM. No sex differences in the relation with mental health outcomes was found. We found evidence for a slower development of « true » puberty in those with ASC compared to those without. Moreover, we show that disparities in pubertal development are related to mental health in ASC, suggesting a greater impact on mental health in autistic than in non-autistic teens. Longitudinal studies are necessary to elucidate important developmental trajectories in puberty in neurodiverse populations.

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8. Haaf R, Brandi ML, Albantakis L, Lahnakoski JM, Henco L, Schilbach L. Peripheral oxytocin levels are linked to hypothalamic gray matter volume in autistic adults: a cross-sectional secondary data analysis. Sci Rep;2024 (Jan 16);14(1):1380.

Oxytocin (OXT) is known to modulate social behavior and cognition and has been discussed as pathophysiological and therapeutic factor for autism spectrum disorder (ASD). An accumulating body of evidence indicates the hypothalamus to be of particular importance with regard to the underlying neurobiology. Here we used a region of interest voxel-based morphometry (VBM) approach to investigate hypothalamic gray matter volume (GMV) in autistic (n = 29, age 36.03 ± 11.0) and non-autistic adults (n = 27, age 30.96 ± 11.2). Peripheral plasma OXT levels and the autism spectrum quotient (AQ) were used for correlation analyses. Results showed no differences in hypothalamic GMV in autistic compared to non-autistic adults but suggested a differential association between hypothalamic GMV and OXT levels, such that a positive association was found for the ASD group. In addition, hypothalamic GMV showed a positive association with autistic traits in the ASD group. Bearing in mind the limitations such as a relatively small sample size, a wide age range and a high rate of psychopharmacological treatment in the ASD sample, these results provide new preliminary evidence for a potentially important role of the HTH in ASD and its relationship to the OXT system, but also point towards the importance of interindividual differences.

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9. Jeong EH. Effects of school-based occupational therapy program for children with disabilities in elementary school in Korea: a case study. BMC Psychol;2024 (Jan 16);12(1):26.

BACKGROUND: The purpose of this case study was to explore the effects of a school-based occupational therapy on children’s attention, school adaptation, sensory processing, and motor function for children in special classes in elementary school in Korea. CASE PRESENTATION: The subjects of this study were a 7-year-old boy with autism spectrum disorder and a 9-year-old girl with intellectual disability. The school-based occupational therapy program consisted of 10 sessions and was conducted once a week for an hour and a half. The program consisted of classroom activities, use of school facilities, emotional management, and activities based on sensory integration, and was conducted as individual and group programs according to sessions. As a result of the study, all improved when the pre- and post-scores of the two children’s attention assessment, school adjustment scale, sensory processing evaluation tool for the children in school and BOT-2-SF were compared. CONCLUSIONS: Although the results from two cases cannot be generalized, the findings suggest the school-based occupational therapy program may help a positive effect on the school life of children with disabilities. Further investigation is necessary.

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10. Jones W, Klaiman C, Klin A. Diagnosis of Autism-Reply. Jama;2024 (Jan 16);331(3):259-260.

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11. Lyu TJ, Ma J, Zhang XY, Xie GG, Liu C, Du J, Xu YN, Yang DC, Cen C, Wang MY, Lyu NY, Wang Y, Zhang HQ. Deficiency of FRMD5 results in neurodevelopmental dysfunction and autistic-like behavior in mice. Mol Psychiatry;2024 (Jan 16)

The pathophysiology of autism spectrum disorders (ASDs) is causally linked to postsynaptic scaffolding proteins, as evidenced by numerous large-scale genomic studies [1, 2] and in vitro and in vivo neurobiological studies of mutations in animal models [3, 4]. However, due to the distinct phenotypic and genetic heterogeneity observed in ASD patients, individual mutation genes account for only a small proportion (<2%) of cases [1, 5]. Recently, a human genetic study revealed a correlation between de novo variants in FERM domain-containing-5 (FRMD5) and neurodevelopmental abnormalities [6]. In this study, we demonstrate that deficiency of the scaffolding protein FRMD5 leads to neurodevelopmental dysfunction and ASD-like behavior in mice. FRMD5 deficiency results in morphological abnormalities in neurons and synaptic dysfunction in mice. Frmd5-deficient mice display learning and memory dysfunction, impaired social function, and increased repetitive stereotyped behavior. Mechanistically, tandem mass tag (TMT)-labeled quantitative proteomics revealed that FRMD5 deletion affects the distribution of synaptic proteins involved in the pathological process of ASD. Collectively, our findings delineate the critical role of FRMD5 in neurodevelopment and ASD pathophysiology, suggesting potential therapeutic implications for the treatment of ASD.

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12. Rojas-Velazquez D, Kidwai S, Kraneveld AD, Tonda A, Oberski D, Garssen J, Lopez-Rincon A. Methodology for biomarker discovery with reproducibility in microbiome data using machine learning. BMC Bioinformatics;2024 (Jan 15);25(1):26.

BACKGROUND: In recent years, human microbiome studies have received increasing attention as this field is considered a potential source for clinical applications. With the advancements in omics technologies and AI, research focused on the discovery for potential biomarkers in the human microbiome using machine learning tools has produced positive outcomes. Despite the promising results, several issues can still be found in these studies such as datasets with small number of samples, inconsistent results, lack of uniform processing and methodologies, and other additional factors lead to lack of reproducibility in biomedical research. In this work, we propose a methodology that combines the DADA2 pipeline for 16s rRNA sequences processing and the Recursive Ensemble Feature Selection (REFS) in multiple datasets to increase reproducibility and obtain robust and reliable results in biomedical research. RESULTS: Three experiments were performed analyzing microbiome data from patients/cases in Inflammatory Bowel Disease (IBD), Autism Spectrum Disorder (ASD), and Type 2 Diabetes (T2D). In each experiment, we found a biomarker signature in one dataset and applied to 2 other as further validation. The effectiveness of the proposed methodology was compared with other feature selection methods such as K-Best with F-score and random selection as a base line. The Area Under the Curve (AUC) was employed as a measure of diagnostic accuracy and used as a metric for comparing the results of the proposed methodology with other feature selection methods. Additionally, we use the Matthews Correlation Coefficient (MCC) as a metric to evaluate the performance of the methodology as well as for comparison with other feature selection methods. CONCLUSIONS: We developed a methodology for reproducible biomarker discovery for 16s rRNA microbiome sequence analysis, addressing the issues related with data dimensionality, inconsistent results and validation across independent datasets. The findings from the three experiments, across 9 different datasets, show that the proposed methodology achieved higher accuracy compared to other feature selection methods. This methodology is a first approach to increase reproducibility, to provide robust and reliable results.

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13. Srinivasan S, Marsan TN. Commentary on « Early Motor Delays During the First 2 Years of Life in Autism Spectrum Disorder: A Scoping Review ». Pediatr Phys Ther;2024 (Jan 1);36(1):36.

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14. Tsuji Y, Imaizumi S. Autistic traits and speech perception in social and non-social noises. Sci Rep;2024 (Jan 16);14(1):1414.

Individuals with the autism spectrum disorder (ASD) experience difficulties in perceiving speech in background noises with temporal dips; they also lack social orienting. We tested two hypotheses: (1) the higher the autistic traits, the lower the performance in the speech-in-noise test, and (2) individuals with high autistic traits experience greater difficulty in perceiving speech, especially in the non-vocal noise, because of their attentional bias toward non-vocal sounds. Thirty-eight female Japanese university students participated in an experiment measuring their ability to perceive speech in the presence of noise. Participants were asked to detect Japanese words embedded in vocal and non-vocal background noises with temporal dips. We found a marginally significant effect of autistic traits on speech perception performance, suggesting a trend that favors the first hypothesis. However, caution is needed in this interpretation because the null hypothesis is not rejected. No significant interaction was found between the types of background noise and autistic traits, indicating that the second hypothesis was not supported. This might be because individuals with high autistic traits in the general population have a weaker attentional bias toward non-vocal sounds than those with ASD or to the explicit instruction given to attend to the target speech.

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