1. Aksoylu IS, Martin P, Robert F, Szkop KJ, Redmond NE, Bhattacharyya S, Wang J, Chen S, Beauchamp RL, Nobeli I, Pelletier J, Larsson O, Ramesh V. Translatome analysis of tuberous sclerosis complex 1 patient-derived neural progenitor cells reveals rapamycin-dependent and independent alterations. Molecular autism. 2023; 14(1): 39.

BACKGROUND: Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder caused by mutations in the TSC1 or TSC2 genes, with patients often exhibiting neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD) and intellectual disability. Hamartin (TSC1) and tuberin (TSC2) proteins form a complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. Loss of TSC1 or TSC2 activates mTORC1 that, among several targets, controls protein synthesis by inhibiting translational repressor eIF4E-binding proteins. Using TSC1 patient-derived neural progenitor cells (NPCs), we recently reported early ND phenotypic changes, including increased cell proliferation and altered neurite outgrowth in TSC1-null NPCs, which were unaffected by the mTORC1 inhibitor rapamycin. METHODS: Here, we used polysome profiling, which quantifies changes in mRNA abundance and translational efficiencies at a transcriptome-wide level, to compare CRISPR-edited TSC1-null with CRISPR-corrected TSC1-WT NPCs generated from one TSC donor (one clone/genotype). To assess the relevance of identified gene expression alterations, we performed polysome profiling in postmortem brains from ASD donors and age-matched controls. We further compared effects on translation of a subset of transcripts and rescue of early ND phenotypes in NPCs following inhibition of mTORC1 using the allosteric inhibitor rapamycin versus a third-generation bi-steric, mTORC1-selective inhibitor RMC-6272. RESULTS: Polysome profiling of NPCs revealed numerous TSC1-associated alterations in mRNA translation that were largely recapitulated in human ASD brains. Moreover, although rapamycin treatment partially reversed the TSC1-associated alterations in mRNA translation, most genes related to neural activity/synaptic regulation or ASD were rapamycin-insensitive. In contrast, treatment with RMC-6272 inhibited rapamycin-insensitive translation and reversed TSC1-associated early ND phenotypes including proliferation and neurite outgrowth that were unaffected by rapamycin. CONCLUSIONS: Our work reveals ample mRNA translation alterations in TSC1 patient-derived NPCs that recapitulate mRNA translation in ASD brain samples. Further, suppression of TSC1-associated but rapamycin-insensitive translation and ND phenotypes by RMC-6272 unveils potential implications for more efficient targeting of mTORC1 as a superior treatment strategy for TAND.

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2. Beasant L, Realpe A, Douglas S, Kenny L, Rai D, Mills N. Autistic adults’ views on the design and processes within randomised controlled trials: The APRiCoT study. Autism : the international journal of research and practice. 2023: 13623613231202432.

Large randomised controlled trials are used to test healthcare treatments. Yet there are no large randomised controlled trials on effective treatments for common mental health issues affecting autistic adults. The purpose of this study was to learn what autistic adults think about randomised controlled trials in preparation for a randomised controlled trial testing a medication for anxiety. This means we wanted to know their opinions about the way randomised controlled trials are done, such as how people are chosen to be in the study and how the study is carried out. We did this by talking to 49 autistic adults individually and asking them questions. We found that most of the people we talked to were okay with the way randomised controlled trials are done. They thought it was fair and they liked that it was based on evidence. However, some autistic people might find it hard to take part in randomised controlled trials. Some people did not like the uncertainty of not knowing what treatment they would receive in a randomised controlled trial. Others felt too vulnerable and may have had bad experiences with healthcare in the past. We found that it is important to involve autistic people early on and at every stage when designing a clinical trial. Care about how clear and precise the study communication is will build trust and improve access to research. Our study indicates that it is possible to conduct large randomised controlled trials with and for autistic people. This can ultimately contribute to the improvement of healthcare outcomes for this population.

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3. Boyd NK, Nguyen J, Khoshnood MM, Jiang T, Nguyen L, Mendez L, Spinazzi NA, Manning MA, Rafii MS, Santoro JD. Hypovitaminosis D in persons with Down syndrome and autism spectrum disorder. Journal of neurodevelopmental disorders. 2023; 15(1): 35.

BACKGROUND: Plasma levels of vitamin D have been reported to be low in persons with Down syndrome (DS) and existing data is limited to small and homogenous cohorts. This is of particular importance in persons with DS given the high rates of autoimmune disease in this population and the known relationship between vitamin D and immune function. This study sought to investigate vitamin D status in a multi-center cohort of individuals with DS and compare them to individuals with autism spectrum disorder (ASD) and neurotypical (NT) controls. METHODS: A retrospective, multi-center review was performed. The three sites were located at latitudes of 42.361145, 37.44466, and 34.05349. Patients were identified by the International Classification of Diseases (ICD)-9 or ICD-10 codes for DS, ASD, or well-child check visits for NT individuals. The first vitamin D 25-OH level recorded in the electronic medical record (EMR) was used in this study as it was felt to be the most reflective of a natural and non-supplemented state. Vitamin D 25-OH levels below 30 ng/mL were considered deficient. RESULTS: In total, 1624 individuals with DS, 5208 with ASD, and 30,775 NT controls were identified. Individuals with DS had the lowest mean level of vitamin D 25-OH at 20.67 ng/mL, compared to those with ASD (23.48 ng/mL) and NT controls (29.20 ng/mL) (p < 0.001, 95% CI: -8.97 to -6.44). A total of 399 (24.6%) individuals with DS were considered vitamin D deficient compared to 1472 (28.3%) with ASD and 12,397 (40.3%) NT controls (p < 0.001, 95% CI: -5.43 to -2.36). Individuals with DS with higher body mass index (BMI) were found to be more likely to have lower levels of vitamin D (p < 0.001, 95% CI: -0.3849 to -0.1509). Additionally, having both DS and a neurologic diagnosis increased the likelihood of having lower vitamin D levels (p < 0.001, 95% CI: -5.02 to -1.28). Individuals with DS and autoimmune disease were much more likely to have lower vitamin D levels (p < 0.001, 95% CI: -6.22 to -1.55). Similarly, a history of autoimmunity in a first-degree relative also increased the likelihood of having lower levels of vitamin D in persons with DS (p = 0.01, 95% CI: -2.45 to -0.63). CONCLUSIONS: Individuals with DS were noted to have hypovitaminosis D in comparison to individuals with ASD and NT controls. Associations between vitamin D deficiency and high BMI, personal autoimmunity, and familial autoimmunity were present in individuals with DS.

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4. Chamtouri M, Gaddour N, Merghni A, Mastouri M, Arboleya S, de Los Reyes-Gavilán CG. Age and severity-dependent gut microbiota alterations in Tunisian children with autism spectrum disorder. Scientific reports. 2023; 13(1): 18218.

Alterations in gut microbiota and short chain fatty acids (SCFA) have been reported in autism spectrum disorder (ASD). We analysed the gut microbiota and fecal SCFA in Tunisian autistic children from 4 to 10 years, and results were compared to those obtained from a group of siblings (SIB) and children from the general population (GP). ASD patients presented different gut microbiota profiles compared to SIB and GP, with differences in the levels of Bifidobacterium and Collinsella occurring in younger children (4-7 years) and that tend to be attenuated at older ages (8-10 years). The lower abundance of Bifidobacterium is the key feature of the microbiota composition associated with severe autism. ASD patients presented significantly higher levels of propionic and valeric acids than GP at 4-7 years, but these differences disappeared at 8-10 years. To the best of our knowledge, this is the first study on the gut microbiota profile of Tunisian autistic children using a metataxonomic approach. This exploratory study reveals more pronounced gut microbiota alterations at early than at advanced ages in ASD. Although we did not account for multiple testing, our findings suggest that early interventions might mitigate gut disorders and cognitive and neurodevelopment impairment associated to ASD.

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5. Davidson A, Pfeiffer B. Community Participation Challenges for Young Adults with Autism Spectrum Disorders During COVID-19 A Photovoice Study. Community mental health journal. 2023.

Autistic Individuals with or without co-occurring Mental Health Conditions Experience Challenges with Community Participation that can Affect Quality of life. These Challenges Involve, but are not Limited to, Transportation, Finances, Accessibility, Attitude towards Participation, and Infrastructure Issues. COVID-19 Added a new Layer of Community Participation Barriers for all Individuals, Especially Autistic Individuals. The purpose of this study is to understand the perceived community participation barriers and facilitators encountered by autistic individuals during a public health crisis using the Photovoice methodology. The study will compare these perceptions of autistic individuals with and without co-occurring mental health conditions during a public health crisis to determine if any distinctions can be determined. Photovoice, an established qualitative outreach methodology, was the foundation for the methods. Participants completed a narrative answering the question « what is a barrier or facilitator to your community participation? » Data were analyzed using grounded theory. Seventeen autistic participants with a mean age of 23 completed the Photovoice study. Eleven (65%) reported at least one co- occurring mental health condition. Data analysis resulted in two major themes COVID-19 and Transportation; and six subthemes access, safety, technology, leisure, shared experiences, and sensory. Autistic individuals with and without co-occurring mental health conditions chose to identify barriers more than facilitators. Participants without co-occurring mental health conditions viewed COVID-19 as a facilitator almost twice as often as those without. Participants with co-occurring mental health conditions reported transportation more as a barrier than those without. In this study conducted during COVID-19 regulations, autistic individuals identified COVID-19 and transportation as the primary barriers to community participation. COVID-19 was identified as both a barrier and a facilitator. Autistic individuals identified that COVID-19 enabled more on-line participation. Autistic individuals with co-occurring mental health conditions can experience a greater increase in symptoms when daily routines and participation are affected. Disruption and changes in participation for the autistic community during the COVID-19 pandemic can have future implications on this population’s ability to reintroduce themselves into community participation. Identified facilitators; technology, shared experiences, and leisure are useful tools to combat the participation barriers.

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6. Desalegn AA, van der Ent W, Lenters V, Iszatt N, Stigum H, Lyche JL, Berg V, Kirstein-Smardzewska KJ, Esguerra CV, Eggesbø M. Perinatal exposure to potential endocrine disrupting chemicals and autism spectrum disorder: From Norwegian birth cohort to zebrafish studies. Environment international. 2023; 181: 108271.

BACKGROUND: The etiology of autism spectrum disorder (ASD) is multifactorial, involving genetic and environmental contributors such as endocrine-disrupting chemicals (EDCs). OBJECTIVE: To evaluate the association between perinatal exposure to 27 potential EDCs and ASD among Norwegian children, and to further examine the neurodevelopmental toxicity of associated chemicals using zebrafish embryos and larvae. METHOD: 1,199 mothers enrolled in the prospective birth-cohort (HUMIS, 2002-2009) study. Breastmilk levels of 27 chemicals were measured: polychlorinated biphenyls, organochlorine pesticides, polybrominated diphenyl ethers, and perfluoroalkyl substances as a proxy for perinatal exposure. We employed multivariable logistic regression to determine association, utilized elastic net logistic regression as variable selection method, and conducted an in vivo study with zebrafish larvae to confirm the neurodevelopmental effect. RESULTS: A total of 20 children had specialist confirmed diagnosis of autism among 1,199 mother-child pairs in this study. β-Hexachlorocyclohexane (β-HCH) was the only chemical associated with ASD, after adjusting for 26 other chemicals. Mothers with the highest levels of β-HCH in their milk had a significant increased risk of having a child with ASD (OR = 1.82, 95 % CI: 1.20, 2.77 for an interquartile range increase in ln-transformed β-HCH concentration). The median concentration of β-HCH in breast milk was 4.37 ng/g lipid (interquartile range: 2.92-6.47), and the estimated daily intake (EDI) for Norwegian children through breastfeeding was 0.03 µg/kg of body weight. The neurodevelopmental and social behavioral effects of β-HCH were established in zebrafish embryos and larvae across various concentrations, with further analysis suggesting that perturbation of dopaminergic neuron development may underlie the neurotoxicity associated with β-HCH. CONCLUSIONS: Prenatal exposure to β-HCH was associated with an increased risk of specialist-confirmed diagnoses of ASD among Norwegian children, and the EDI surpasses the established threshold. Zebrafish experiments confirm β-HCH neurotoxicity, suggesting dopaminergic neuron disruption as a potential underlying mechanism.

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7. Dong H, Chen D, Chen Y, Tang Y, Yin D, Li X. A multi-task learning model with reinforcement optimization for ASD comorbidity discrimination. Computer methods and programs in biomedicine. 2023; 243: 107865.

How to discriminate the comorbidities in autism spectrum disorder (ASD) population has long been an intriguing and challenging issue in neuroscience and neurology practices. Taking attention deficit hyperactivity disorder (ADHD) for example, electroencephalogram (EEG) analysis has alleviated the problem caused by the task of evaluation of similar behaviors of subjects with ASD, ADHD and ASD+ADHD, which requires a very high expertise to reach any concrete conclusions. However, the performance of ASD comorbidity discrimination is still limited by two major difficulties 1) crucial EEG features regarding ASD and ASD+ADHD largely overlap, and 2) reliable data for model training are routinely insufficient. This study proposes a multi-task learning method with « reinforcement optimization » (namely RO-MLT) working in a two-fold manner: 1)Modeling for Discrimination: a multi-task CNN model maintains the target discrimination task (ASD vs. ASD+ADHD) with the aid of the auxiliary task (ASD vs. Typically Developed (TD)), which is designed to mitigate the aforementioned difficulties on model training; and 2) Reinforcement Optimization: a reinforcement learning algorithm enhances the model’s feature extraction and fusion capabilities by optimizing its shared structure. Experimental results based on resting-state EEG that collected from 150 ASD, ASD+ADHD or TD children with the RO-MLT method against the state-of-the-art counterparts indicate that RO-MLT is far superior in terms of all performance indicators (e.g., accuracy). Ablation experiments also show that introduction of multi-task learning and reinforcement optimization can achieve a performance boost-up by 11.07%, a gain even higher than the sums of introduction of two individual techniques to the model design.

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8. Ilen L, Feller C, Schneider M. Cognitive emotion regulation difficulties increase affective reactivity to daily-life stress in autistic adolescents and young adults. Autism : the international journal of research and practice. 2023: 13623613231204829.

Previous research has shown that autistic individuals report high levels of perceived stress and have an increased likelihood of developing mental health difficulties. Increase in individuals’ negative emotions in relation to perceived stress (i.e. affective reactivity to stress) is a known risk factor for mental health difficulties. In this study, we investigated perceived daily stress and affective reactivity to stress in autistic (n = 39, age = 18.4) and non-autistic (n = 55, age = 18.1) adolescents and young adults. We used the ecological momentary assessment, a technique that allows to assess individuals repeatedly in their daily life using their smartphone. Moreover, participants filled a questionnaire to evaluate the strategies they use to regulate emotions when faced with difficulties. Finally, a clinical interview and a parent-report questionnaire were used to assess mental health symptoms. Autistic youth reported higher levels of perceived daily stress compared with non-autistic peers. Moreover, they showed increased affective reactivity to stress related to their daily activities. Autistic participants reported more emotion regulation difficulties (e.g. more repetitive thinking of difficulties) compared with non-autistic participants. Difficulties in emotion regulation increased negative emotions in relation to stress and might contribute to the severity of mental health symptoms. We conclude that adolescents and young adults with autism report high perceived stress in their daily lives. To minimize the negative impact of stress and the development of mental health symptoms, people supporting autistic young people could focus on stress management skills and the strategies that the youth use to manage emotions.

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9. Kaufmann WE. CDKL5 deficiency disorder: At the intersection between Rett syndrome and developmental epileptic encephalopathies. Developmental medicine and child neurology. 2023.

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10. Kostanian D, Rebreikina A, Voinova V, Sysoeva O. Effect of presentation rate on auditory processing in Rett syndrome: event-related potential study. Molecular autism. 2023; 14(1): 40.

BACKGROUND: Rett syndrome (RS) is a rare neurodevelopmental disorder characterized by mutations in the MECP2 gene. Patients with RS have severe motor abnormalities and are often unable to walk, use hands and speak. The preservation of perceptual and cognitive functions is hard to assess, while clinicians and care-givers point out that these patients need more time to process information than typically developing peers. Neurophysiological correlates of auditory processing have been also found to be distorted in RS, but sound presentation rates were relatively quick in these studies (stimulus onset asynchrony, SOA < 1000 ms). As auditory event-related potential (ERP) is typically increased with prolongation of SOA we aim to study if SOA prolongation might compensate for observed abnormalities. METHODS: We presented a repetitive stimulus (1000 Hz) at three different SOAs of 900 ms, 1800 ms, and 3600 ms in children with RS (N = 24, Mean age = 9.0 ± 3.1) and their typical development (TD) peers (N = 27, Mean age = 9.7 ± 3.4) while recording 28-channels electroencephalogram, EEG. Some RS participants (n = 10) did not show clear ERP and were excluded from the analysis. RESULTS: Major ERP components (here assessed as N1P1 and P2N1 peak-to-peak values) were smaller at SOA 900 than at longer SOAs in both groups, pointing out that the basic mechanism of adaptation in the auditory system is preserved in at least in RS patients with evident ERPs. At the same time the latencies of these components were significantly delayed in the RS than in TD. Moreover, late components (P2N1 and N2P2) were drastically reduced in Rett syndrome irrespective of the SOA, suggesting a largely affected mechanism of integration of upcoming sensory input with memory. Moreover, developmental stagnation of auditory ERP characterized patients with RS: absence of typical P2N1 enlargement and P1 and N1 shortening with age at least for shortest SOA. LIMITATIONS: We could not figure out the cause for the high percentage of no-evident ERP RS participants and our final sample of the RS group was rather small. Also, our study did not include a control clinical group. CONCLUSIONS: Thus, auditory ERPs inform us about abnormalities within auditory processing that cannot be fully overcomed by slowing presentation rate.

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11. Lilley R, Rapaport H, Poulsen R, Yudell M, Pellicano E. Contributing to an autism biobank: Diverse perspectives from autistic participants, family members and researchers. Autism : the international journal of research and practice. 2023: 13623613231203938.

A lot of autism research has focused on finding genes that might cause autism. To conduct these genetic studies, researchers have created ‘biobanks’ – collections of biological samples (such as blood, saliva, urine, stool and hair) and other health information (such as cognitive assessments and medical histories). Our study focused on the Australian Autism Biobank, which collected biological and health information from almost 1000 Australian autistic children and their families. We wanted to know what people thought about giving their information to the Biobank and why they chose to do so. We spoke to 71 people who gave to the Biobank, including 18 autistic adolescents and young adults, 46 of their parents and seven of their siblings. We also spoke to six researchers who worked on the Biobank project. We found that people were interested in giving their information to the Biobank so they could understand why some people were autistic. Some people felt knowing why could help them make choices about having children in the future. People also wanted to be involved in the Biobank because they believed it could be a resource that could help others in the future. They also trusted that scientists would keep their information safe and were keen to know how that information might be used in the future. Our findings show that people have lots of different views about autism biobanks. We suggest researchers should listen to these different views as they develop their work.

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12. Lin X, Wang G, Shen S, Zhan J. Advances in the Diagnosis and Treatment of Autism Spectrum Disorders in Children. Alternative therapies in health and medicine. 2023.

OBJECTIVE: This study aims to review recent developments in the diagnosis and treatment of Autism Spectrum Disorder (ASD )and provide insights for its clinical management. METHODS: The literatures were researched fro the pubmed, Wanfang and CNKI. We searched for research on the etiology, pathogenesis, diagnosis (screening and evaluation), and treatment of Autism spectrum disorder. When selecting papers to be included, priority should be given to randomized clinical trials, systematic evaluations, meta-analyses, clinical practice guidelines, and articles related to general medical readers. RESULTS: ASD is a widely present neurodevelopmental disorder characterized by social and communication difficulties, narrow interests, and repetitive behavior, accompanied by symptoms such as irritability, self-harm, attention deficit hyperactivity disorder (ADHD), and sleep problems. Irritability, self-harm, ADHD, and sleep problems are common accompanying symptoms that contribute to the challenges faced by individuals with ASD. At present, there is no fully effective treatment method for ASD, and key factors affecting the prognosis of ASD include early diagnosis time, early language communication level, intelligence level, disease severity, comorbidities, family participation, appropriate intervention, and social support. Therefore, early individualized long-term comprehensive training and drug therapy, hyperbaric oxygen therapy, and combined family participation can improve the prognosis of pediatric patients. Before selecting treatment plans for children, collecting as much information as possible about various treatment methods and choosing personalized treatment plans based on the child’s developmental assessment level is necessary. In addition, the treatment of ASD is also influenced by factors such as family economic status, parental mentality, and social environment. During the training process, it is important to be family-centered, tolerant, and understand children’s behavior. CONCLUSION: It is significant to take effective treatment measures to improve the quality of life and prognosis of children with autism spectrum disorders.

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13. Minagawa Y, Hata M, Yamamoto E, Tsuzuki D, Morimoto S. Inter-brain synchrony during mother-infant interactive parenting in 3-4-month-old infants with and without an elevated likelihood of autism spectrum disorder. Cerebral cortex (New York, NY : 1991). 2023.

Maternal bonding for mammalian infants is critical for their survival. Additionally, it is important for human infants’ development into social creatures. However, despite the ample neurobiological evidence of attachment for the mother’s brain, the interplay of this system in infants is poorly understood. We aimed to identify the neural substrates of synchrony in mothers and infants under three interactive conditions and compare the differences between groups with (n = 16) and without (n = 71) an elevated likelihood of autism spectrum disorder by examining the inter-brain synchrony between mothers and their 3-4-month-old infants. Mother-infant hyperscanning with functional near-infrared spectroscopy was performed during breastfeeding and while each of the mother and experimenter was holding the infants. The results showed almost no group differences, with both groups demonstrating the strongest inter-brain coupling for breastfeeding. The cerebral foci underlying these couplings differed between mothers and infants: the ventral prefrontal cortex, focusing on the right orbitofrontal cortex, in the mother and the left temporoparietal junction in the infant were chiefly involved in connecting the two brains. Furthermore, these synchronizations revealed many significant correlations with behavioral measures, including subsequent language development. The maternal reward-motivational system and the infant’s elementary mentalization system seem to underlie mother-infant coupling during breastfeeding.

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14. Mitchell L, Vellanki B, Tang L, Hunter K, Finnegan A, Swartz JJ, Huchko M. Contraceptive Provision to Women With Intellectual and Developmental Disabilities Enrolled in Medicaid. Obstetrics and gynecology. 2023.

OBJECTIVE: To compare contraceptive provision to women with and without intellectual and developmental disabilities enrolled in North Carolina Medicaid. METHODS: Our retrospective cohort study used 2019 North Carolina Medicaid claims to identify women aged 15-44 years with and without intellectual and developmental disabilities at risk for pregnancy who were continuously enrolled during 2019 or had Family Planning Medicaid with at least one claim. We calculated the proportion in each cohort who received 1) most or moderately effective contraception, 2) long-acting reversible contraception, 3) short-acting contraception, and 4) individual methods. We classified contraceptive receipt by procedure type and disaggregated across sociodemographic characteristics. Adjusting for age, race, ethnicity, and urban or rural setting, we constructed logistic regression models to estimate most or moderately effective contraceptive provision odds by intellectual and developmental disability status and by level or type of intellectual and developmental disability. We performed subanalyses to estimate co-occurrence of provision and menstrual disorders. RESULTS: Among 9,508 women with intellectual and developmental disabilities and 299,978 without, a significantly smaller proportion with intellectual and developmental disabilities received most or moderately effective contraception (30.1% vs 36.3%, P<.001). With the exception of injectable contraception, this trend was consistent across all measures and remained statistically significant after controlling for race, ethnicity, age, and urban or rural status (adjusted odds ratio 0.75, 95% CI 0.72-0.79; P<.001). Among those who received most or moderately effective contraception, a significantly greater proportion of women with intellectual and developmental disabilities had co-occurring menstrual disorders (31.3% vs 24.3%, P<.001). CONCLUSION: These findings suggest disparities in contraceptive provision and potential differences in clinical indication by intellectual and developmental disability status. Future studies should investigate reasons for and barriers to contraceptive use among women with intellectual and developmental disabilities.

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15. Musokhranova U, Grau C, Vergara C, Rodríguez-Pascau L, Xiol C, Castells AA, Alcántara S, Rodríguez-Pombo P, Pizcueta P, Martinell M, García-Cazorla A, Oyarzábal A. Mitochondrial modulation with leriglitazone as a potential treatment for Rett syndrome. Journal of translational medicine. 2023; 21(1): 756.

BACKGROUND: Rett syndrome is a neuropediatric disease occurring due to mutations in MECP2 and characterized by a regression in the neuronal development following a normal postnatal growth, which results in the loss of acquired capabilities such as speech or purposeful usage of hands. While altered neurotransmission and brain development are the center of its pathophysiology, alterations in mitochondrial performance have been previously outlined, shaping it as an attractive target for the disease treatment. METHODS: We have thoroughly described mitochondrial performance in two Rett models, patients’ primary fibroblasts and female Mecp2(tm1.1Bird-/+) mice brain, discriminating between different brain areas. The characterization was made according to their bioenergetics function, oxidative stress, network dynamics or ultrastructure. Building on that, we have studied the effect of leriglitazone, a PPARγ agonist, in the modulation of mitochondrial performance. For that, we treated Rett female mice with 75 mg/kg/day leriglitazone from weaning until sacrifice at 7 months, studying both the mitochondrial performance changes and their consequences on the mice phenotype. Finally, we studied its effect on neuroinflammation based on the presence of reactive glia by immunohistochemistry and through a cytokine panel. RESULTS: We have described mitochondrial alterations in Rett fibroblasts regarding both shape and bioenergetic functions, as they displayed less interconnected and shorter mitochondria and reduced ATP production along with increased oxidative stress. The bioenergetic alterations were recalled in Rett mice models, being especially significant in cerebellum, already detectable in pre-symptomatic stages. Treatment with leriglitazone recovered the bioenergetic alterations both in Rett fibroblasts and female mice and exerted an anti-inflammatory effect in the latest, resulting in the amelioration of the mice phenotype both in general condition and exploratory activity. CONCLUSIONS: Our studies confirm the mitochondrial dysfunction in Rett syndrome, setting the differences through brain areas and disease stages. Its modulation through leriglitazone is a potential treatment for this disorder, along with other diseases with mitochondrial involvement. This work constitutes the preclinical necessary evidence to lead to a clinical trial.

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16. Norris JE, Prosser R, Remington A, Crane L, Maras K. Disclosing an autism diagnosis improves ratings of candidate performance in employment interviews. Autism : the international journal of research and practice. 2023: 13623613231203739.

Employment interviews are challenging for many autistic people, for example, due to difficulties with interpreting questions. Autistic people also have differences in non-verbal communication, such as emotional expression, eye-contact, and gestures, with research showing that these factors negatively affect first impressions. Some studies have shown that perceptions of autistic people are more positive when the person observing them, such as an interviewer, is already aware of their diagnosis. However, previous research has not studied how disclosing one’s autism diagnosis affects perceptions of a candidate undergoing a full employment interview. Participants in this study acted as raters, who watched a video of an autistic person undergoing a mock employment interview with a researcher, and then rated their overall impressions of them on factors important to real-world hiring decisions, such as confidence, motivation, and knowledgeability. Prior to watching the interview, raters were either (1) not aware of the interviewee’s diagnosis, (2) made aware of their diagnosis, or (3) made aware of their diagnosis and provided with additional information about autism, such as differences in behaviours and communication. The results show that disclosing an autism diagnosis improved ratings compared to not disclosing the diagnosis. Providing additional information about autism alongside the diagnostic label did not improve ratings further. The findings are important for employers and autistic people; employers should consider improving procedures by which autistic people can disclose their diagnosis prior to interview should they wish, and autistic people may wish to consider the potential benefits of disclosing their diagnosis.

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17. O’Nions E, McKechnie DG, Long C, Mandy W, Stott J. How can autistic adults be supported in primary care?. The British journal of general practice : the journal of the Royal College of General Practitioners. 2023; 73(736): 518-21.

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18. Pan PY, Yeh CB. Characteristic Similarities of Irritability Between Autism and Disruptive Mood Dysregulation Disorder. Journal of child and adolescent psychopharmacology. 2023.

Objective: Irritability in children with autism spectrum disorder (ASD) is prominent and often leads to distress to both autistic children and their families. However, the nature of irritability in autism and the difference from nonautistic children have rarely been examined. This study aimed to investigate the clinical characteristics of irritability in autism, and to compare the symptom profiles with those of disruptive mood dysregulation disorder (DMDD) in nonautistic children. Methods: Fifty-six children aged 7-17 years (mean age 10.36 ± 3.05) were recruited into this study (21 with DMDD, 21 with high-functioning autism [hfASD], and 14 healthy volunteers [HV]). Their parents completed the Aberrant Behavior Checklist-Irritability (ABC-I) subscale and the Strengths and Difficulties Questionnaire (SDQ) parent report form. The ABC-I subscale was analyzed as a whole and broken into subsets (ABC-I-Irritability, ABC-I-Agitation, and ABC-I-Crying). The symptom profiles of irritability and the association with psychosocial difficulties were compared between groups. Results: The ABC-I-Irritability scores of children with hfASD closely matched to those of children with DMDD. In addition, both DMDD and hfASD groups could be differentiated from HV group in five of the six items except « depressed mood. » However, in the ABC-I-Agitation scale, children with DMDD, but not hfASD, had higher scores in « Aggressive to other patients and staff » and « Stamps feet while banging objects or slamming doors » than HV. Regarding psychosocial outcomes, irritability in children with DMDD and hfASD were associated with emotional problems as measured by the SDQ. Moreover, irritability in DMDD was associated with conduct problems, and the hfASD group exhibited the similar trend. Conclusions: Symptom profiles of irritability and the associated emotional and conduct problems in children with hfASD were similar to those of DMDD in the nonautistic population. Future studies are warranted to explore the underlying neurophysiological mechanisms of irritability between autistic and nonautistic children for further insight into the nature of irritability in autism.

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19. Qin Y, Zhang XY, Liu Y, Ma Z, Tao S, Li Y, Peng R, Wang F, Wang J, Feng J, Qiu Z, Jin L, Wang H, Gong X. Downregulation of mGluR1-mediated signaling underlying autistic-like core symptoms in Shank1 P1812L-knock-in mice. Translational psychiatry. 2023; 13(1): 329.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms that consist of social deficits and repetitive behaviors. Unfortunately, no effective medication is available thus far to target the core symptoms of ASD, since the pathogenesis remains largely unknown. To investigate the pathogenesis of the core symptoms in ASD, we constructed Shank1 P1812L-knock-in (KI) mice corresponding to a recurrent ASD-related mutation, SHANK1 P1806L, to achieve construct validity and face validity. Shank1 P1812L-KI heterozygous (HET) mice presented with social deficits and repetitive behaviors without the presence of confounding comorbidities. HET mice also exhibited downregulation of metabotropic glutamate receptor (mGluR1) and associated signals, along with structural abnormalities in the dendritic spines and postsynaptic densities. Combined with findings from Shank1 R882H-KI mice, our study confirms that mGluR1-mediated signaling dysfunction is a pivotal mechanism underlying the core symptoms of ASD. Interestingly, Shank1 P1812L-KI homozygous (HOM) mice manifested behavioral signs of impaired long-term memory rather than autistic-like core traits; thus, their phenotype was markedly different from that of Shank1 P1812L-KI HET mice. Correspondingly, at the molecular level, Shank1 P1812L-KI HOM displayed upregulation of AMPA receptor (GluA2)-related signals. The different patterns of protein changes in HOM and HET mice may explain the differences in behaviors. Our study emphasizes the universality of mGluR1-signaling hypofunction in the pathogenesis of the core symptoms in ASD, providing a potential target for therapeutic drugs. The precise correspondence between genotype and phenotype, as shown in HOM and HET mice, indicates the importance of reproducing disease-related genotypes in mouse models.

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20. Ruck P, Morris HT, Thikkurissy S. Case report of an extra-oral cutaneous sinus tract of endodontic origin in a patient with autism spectrum disorder. Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry. 2023.

BACKGROUND AND OVERVIEW: Extraoral cutaneous sinus tracts (EOCST) are often misdiagnosed due to their unexpected appearance without history of odontogenic pain, discomfort, or cellulitis. Diagnosis can be further confounded in those with sensory processing difficulties since patients can have a hypersensitivity to sensory input, but simultaneously demonstrate hyposensitivity and indifference toward pain. EOCST misdiagnosis and resultant mismanagement can lead to multiple surgical excisions, biopsies, and elongated antibiotic regimens, with eventual lesion recurrence. CASE DESCRIPTION: A 19-year-old white male with autism spectrum disorder in the period of transitional dental care presented with a history of a chronic EOCST. The patient required sedation for evaluation, biopsy, and was initially managed by infectious disease under the impression of an actinomycosis infection. The patient completed a twelve-month course of antibiotic therapy with subsequent lesion re-occurrence. Eventually, the diagnosis of an EOCST of dental origin was confirmed. It was determined that pulpal necrosis was due to localized dental trauma of the lower left central incisor, as a result of a self-injurious behavior. Root canal treatment eventually led to the resolution of the lesion. It took three years from initial clinical presentation for the resolution of the lesion. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Collaboration between the medical and dental healthcare team in diagnosis and treatment planning for a patient with special needs is essential to ensure prompt and appropriate care for this patient group.

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21. Rudling M, Nyström P, Bussu G, Bölte S, Falck-Ytter T. Infant responses to direct gaze and associations to autism: A live eye-tracking study. Autism : the international journal of research and practice. 2023: 13623613231203037.

When other people look directly towards us, we often respond by looking back at them, and such direct-gaze responses are important for establishing eye contact. Atypical eye contact is common in autism, but how and when this aspect of autism develops is not well understood. Here, we studied whether how much and how quickly infants respond to others’ direct gaze is associated with autism in toddlerhood. We did this by measuring direct-gaze responses in a playful social interaction using live eye tracking. The study included 169 infants, of whom 129 had an elevated likelihood of developing autism due to having a first-degree family member with the condition, and 40 with typical likelihood of autism. In the elevated likelihood group, 35 were diagnosed with autism spectrum disorder at 3 years of age, and 94 were not. The results showed that infants in all three groups tended to increase their looking towards the adult’s face after the adult looked directly at them. However, neither how much nor how quickly the infants responded to direct gaze by looking back at the adult reliably differentiated the infants with or without subsequent autism. While infants in the elevated likelihood of autism and subsequent diagnosis group tended to look away quicker from faces with direct gaze than infants in the typical likelihood group, this measure did not differentiate between the two elevated likelihood groups. We interpret the results as supporting the view that atypical direct-gaze responses are not early markers of autism.

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22. Schnitzler T, Korn C, S CH, Fuchs T. Emotion recognition in autism spectrum condition during the COVID-19 pandemic. Autism : the international journal of research and practice. 2023: 13623613231203306.

In the COVID-19 pandemic, wearing face masks became mandatory to prevent the spread of the virus. However, they restrict the ability to recognize emotions to the upper part of the face. Since individuals with autism spectrum condition often tend to look at the lower half of the face, they may be particularly restricted in emotion recognition by people wearing masks, since they are now forced to look at the upper half of the face. The current study compared the recognition of facially expressed emotions between individuals with and without autism spectrum condition. Each photo was shown in three types, once uncovered, once with face mask, and once with sunglasses. Our results revealed a reduction in accuracy of individuals with autism spectrum condition at recognizing emotions in all three stimulus types and exhibited more difficulties distinguishing anger, fear, pride, and embarrassment. During the emotion recognition task, there was no difference in which facial areas the groups looked at. We did not find evidence that the disadvantages of individuals with autism spectrum condition in emotion recognition were due to looking at different areas of the face.

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23. Sureshkumar BM, Zonneveld KLM. An evaluation of video-prompting procedures via telehealth to teach first aid skills to children with intellectual and developmental disabilities. Journal of applied behavior analysis. 2023.

Unintentional injuries are one of the leading causes of morbidity and mortality among children with intellectual and developmental disabilities (IDD). First aid training involves teaching critical first aid skills, some of which are designed to treat unintentional injuries. To date, no study has (a) evaluated the effects of a video-prompting procedure to teach first aid skills to children with IDD or (b) attempted to teach these skills to children by using a telehealth delivery format. We used a concurrent multiple-baseline-across-skills design to evaluate the efficacy of a video-prompting procedure via telehealth to teach five children with IDD to perform first aid on themselves for insect stings, minor cuts, and minor burns under simulated conditions. For all participants, our procedure produced large improvements that maintained for a minimum of 4 weeks. Furthermore, the effects of the training generalized to novel confederates for all participants, and these effects maintained for a minimum of 4 weeks.

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24. Tang H, Chen X, Huang S, Yin G, Wang X, Shen G. Targeting the gut-microbiota-brain axis in irritable bowel disease to improve cognitive function – recent knowledge and emerging therapeutic opportunities. Reviews in the neurosciences. 2023; 34(7): 763-73.

The brain-gut axis forms a bidirectional communication system between the gastrointestinal (GI) tract and cognitive brain areas. Disturbances to this system in disease states such as inflammatory bowel disease have consequences for neuronal activity and subsequent cognitive function. The gut-microbiota-brain axis refers to the communication between gut-resident bacteria and the brain. This circuits exists to detect gut microorganisms and relay information to specific areas of the central nervous system (CNS) that in turn, regulate gut physiology. Changes in both the stability and diversity of the gut microbiota have been implicated in several neuronal disorders, including depression, autism spectrum disorder Parkinson’s disease, Alzheimer’s disease and multiple sclerosis. Correcting this imbalance with medicinal herbs, the metabolic products of dysregulated bacteria and probiotics have shown hope for the treatment of these neuronal disorders. In this review, we focus on recent advances in our understanding of the intricate connections between the gut-microbiota and the brain. We discuss the contribution of gut microbiota to neuronal disorders and the tangible links between diseases of the GI tract with cognitive function and behaviour. In this regard, we focus on irritable bowel syndrome (IBS) given its strong links to brain function and anxiety disorders. This adds to the growing body of evidence supporting targeted therapeutic strategies to modulate the gut microbiota for the treatment of brain/mental-health-related disease.

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25. Yang Y, Yang R, Kang B, Qian S, He X, Zhang X. Single-cell long-read sequencing in human cerebral organoids uncovers cell-type-specific and autism-associated exons. Cell reports. 2023; 42(11): 113335.

Dysregulation of alternative splicing has been repeatedly associated with neurodevelopmental disorders, but the extent of cell-type-specific splicing in human neural development remains largely uncharted. Here, single-cell long-read sequencing in induced pluripotent stem cell (iPSC)-derived cerebral organoids identifies over 31,000 uncatalogued isoforms and 4,531 cell-type-specific splicing events. Long reads uncover coordinated splicing and cell-type-specific intron retention events, which are challenging to study with short reads. Retained neuronal introns are enriched in RNA splicing regulators, showing shorter lengths, higher GC contents, and weaker 5′ splice sites. We use this dataset to explore the biological processes underlying neurological disorders, focusing on autism. In comparison with prior transcriptomic data, we find that the splicing program in autistic brains is closer to the progenitor state than differentiated neurons. Furthermore, cell-type-specific exons harbor significantly more de novo mutations in autism probands than in siblings. Overall, these results highlight the importance of cell-type-specific splicing in autism and neuronal gene regulation.

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26. Zheng RM, Chan SP, Law EC, Chong SC, Aishworiya R. Validity and feasibility of using the Modified Checklist for Autism in Toddlers, Revised with Follow-Up (M-CHAT-R/F) in primary care clinics in Singapore. Autism : the international journal of research and practice. 2023: 13623613231205748.

Systematic screening for autism in early childhood has been suggested to improve eventual outcomes by facilitating earlier diagnosis and access to intervention. However, clinical implementation of screening has to take into account effectiveness and feasibility of use within a healthcare setting for accurate diagnosis of autism. In Singapore, autism screening using a structured screening tool is not currently employed as a part of routine well-child visits for children in primary care clinics. In this study, 5336 children (aged 17-20 months) were screened for autism using the Modified Checklist for Autism in Toddlers, Revised with Follow-Up (M-CHAT-R/F) during their 18-month well-child visit in seven primary care clinics. Screening and follow-up interviews were administered by nursing staff at each clinic. Children screened positive and a portion of those screened negative then underwent diagnostic assessments to determine whether they met the diagnostic criteria for autism. In total, 113 (2.1%) were screened positive, of which 54 (1.0%) met the criteria for autism. Children who screened positive and received a diagnosis accessed autism-specific intervention at an average age of 22 months. Nurses and physicians rated the acceptability and practicality of the M-CHAT-R/F highly. Therefore, the M-CHAT-R/F questionnaire was an effective and feasible tool for autism screening among 18-month-old children in this study. Future studies will be designed to determine the optimal age of screening and role of repeated screening in Singapore, as well as to better understand any potential improved outcomes nationwide compared with pre-implementation of autism screening.

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27. Zhou D, Liu Z, Gong G, Zhang Y, Lin L, Cai K, Xu H, Cong F, Li H, Chen A. Decreased Functional and Structural Connectivity is Associated with Core Symptom Improvement in Children with Autism Spectrum Disorder After Mini-basketball Training Program. Journal of autism and developmental disorders. 2023.

Exercise intervention has been proven helpful to ameliorate core symptoms of Autism Spectrum Disorder (ASD). However, the underlying mechanisms are not fully understood. In this study, we carried out a 12-week mini-basketball training program (MBTP) on ASD children and examined the changes of brain functional and structural networks before and after exercise intervention. We applied individual-based method to construct functional network and structural morphological network, and investigated their alterations following MBTP as well as their associations with the change in core symptom. Structural MRI and resting-state functional MRI data were obtained from 58 ASD children aged 3-12 years (experiment group: n = 32, control group: n = 26). ASD children who received MBTP intervention showed several distinguishable alternations compared to the control without special intervention. These included decreased functional connectivity within the sensorimotor network (SM) and between SM and the salience network, decreased morphological connectivity strength in a cortical-cortical network centered on the left inferior temporal gyrus, and a subcortical-cortical network centered on the left caudate. Particularly, the aforementioned functional and structural changes induced by MBTP were associated with core symptoms of ASD. Our findings suggested that MBTP intervention could be an effective approach to improve core symptoms in ASD children, decrease connectivity in both structure and function networks, and may drive the brain change towards normal-like neuroanatomy.

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28. Zyoud SH, Shakhshir M, Abushanab AS, Koni A, Shahwan M, Jairoun AA, Abu Taha A, Al-Jabi SW. Gut microbiota and autism spectrum disorders: where do we stand?. Gut pathogens. 2023; 15(1): 50.

BACKGROUND: Children with autism spectrum disorder (ASD) often have digestive problems and microbial imbalances in their guts, suggesting that these conditions may play a role in the development of the disorder. Scopus-based research on the gut microbiota and ASD was examined in this bibliometric analysis to shed light on the current state of research and identify potential hotspots for future work in this area. METHODS: We searched documents from the Scopus database and reference citation analysis to collect published data on the gut microbiota and ASD from 2003 to 2022. The downloaded document records were exported to VOSviewer v.1.6.19 to examine and visualize the collaboration between countries and determine the research hotspots. RESULTS: The search yielded 958 articles specifically dedicated to gut microbiota and ASD. The number of publications in this field increased rapidly after 2013, with a peak in 2022. The United States (n = 267; 27.87%) was the most active country, followed by China (n = 171; 17.85%) and Italy (n = 96; 10.02). International collaboration was observed, with the USA playing a central role. University College Cork, Ireland, was the most productive institution (n = 24; 2.51%). The National Natural Science Foundation of China was the most active funding agency (n = 76; 7.93%). Nutrients journal had the highest number of publications (n = 28; 2.92%). The articles related to gut microbiota and ASD were highly cited, with an h-index of 108. The research themes identified focused on the modulation of gut microbiota as a potential therapy for children with ASD and gut-brain axis dysfunction in ASD. CONCLUSIONS: In recent years, the study of gut microbiota and its association with ASD has garnered considerable interest as an emergent field of study. The results of this study substantially enhance our current understanding of the knowledge landscape in this field and illuminate potential avenues for future research. It is essential to emphasize the significance of devoting more resources to the newest and most promising research areas, such as investigating the potential therapeutic benefits of modulating the intestinal microbiota in children with ASD. This research has enormous potential and merits intensified focus and investigation.

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