1. Berg LM, Gurr C, Leyhausen J, Seelemeyer H, Bletsch A, Schaefer T, Pretzsch CM, Oakley B, Loth E, Floris DL, Buitelaar JK, Beckmann CF, Banaschewski T, Charman T, Jones EJH, Tillmann J, Chatham CH, Bourgeron T, Murphy DG, Ecker C. The neuroanatomical substrates of autism and ADHD and their link to putative genomic underpinnings. Molecular autism. 2023; 14(1): 36.

BACKGROUND: Autism spectrum disorders (ASD) are neurodevelopmental conditions accompanied by differences in brain development. Neuroanatomical differences in autism are variable across individuals and likely underpin distinct clinical phenotypes. To parse heterogeneity, it is essential to establish how the neurobiology of ASD is modulated by differences associated with co-occurring conditions, such as attention-deficit/hyperactivity disorder (ADHD). This study aimed to (1) investigate between-group differences in autistic individuals with and without co-occurring ADHD, and to (2) link these variances to putative genomic underpinnings. METHODS: We examined differences in cortical thickness (CT) and surface area (SA) and their genomic associations in a sample of 533 individuals from the Longitudinal European Autism Project. Using a general linear model including main effects of autism and ADHD, and an ASD-by-ADHD interaction, we examined to which degree ADHD modulates the autism-related neuroanatomy. Further, leveraging the spatial gene expression data of the Allen Human Brain Atlas, we identified genes whose spatial expression patterns resemble our neuroimaging findings. RESULTS: In addition to significant main effects for ASD and ADHD in fronto-temporal, limbic, and occipital regions, we observed a significant ASD-by-ADHD interaction in the left precentral gyrus and the right frontal gyrus for measures of CT and SA, respectively. Moreover, individuals with ASD + ADHD differed in CT to those without. Both main effects and the interaction were enriched for ASD-but not for ADHD-related genes. LIMITATIONS: Although we employed a multicenter design to overcome single-site recruitment limitations, our sample size of N = 25 individuals in the ADHD only group is relatively small compared to the other subgroups, which limits the generalizability of the results. Also, we assigned subjects into ADHD positive groupings according to the DSM-5 rating scale. While this is sufficient for obtaining a research diagnosis of ADHD, our approach did not take into account for how long the symptoms have been present, which is typically considered when assessing ADHD in the clinical setting. CONCLUSION: Thus, our findings suggest that the neuroanatomy of ASD is significantly modulated by ADHD, and that autistic individuals with co-occurring ADHD may have specific neuroanatomical underpinnings potentially mediated by atypical gene expression.

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2. Dell’Osso L, Massoni L, Battaglini S, De Felice C, Nardi B, Amatori G, Cremone IM, Carpita B. Emotional dysregulation as a part of the autism spectrum continuum: a literature review from late childhood to adulthood. Frontiers in psychiatry. 2023; 14: 1234518.

The concept of emotional dysregulation (ED) has recently gained interest in the scientific literature and is commonly defined as the inability to use the modulatory mechanisms involved in emotion regulation, resulting in a functioning meaningfully below the baseline. Even though the data available are still limited, an increasing number of studies have hypothesized a promoting role for some of the core features of autism spectrum disorder (ASD) in the development of ED, in particular being repetitive behaviors, social difficulties and alexythimia. In this framework, the purpose of this study was to review the literature that is currently available about presence and correlates of ED in young adults with autism spectrum conditions as well as to offer some insights about possible implications for illness trajectories. The data reported seems to point to a shared etiology between ED and repetitive/restricted ASD symptoms, with perseveration features serving as the foundation for the inability to control one’s emotions. In this context, a neurodevelopmental basis for ED could be consistent with the transnosographic conceptualization of ASD, which hypothesizes a potential neurodevelopmental basis for several psychiatric disorders, whose autistic traits would be the phenotypical presentation.

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3. Drahota A, Sridhar A, Moskowitz LJ, Kerns CM, Soorya L, Wainer A, Cohn E, Lerner MD. Community-based care for autistic youth: community providers’ reported use of treatment practices in the United States. Frontiers in psychiatry. 2023; 14: 1212084.

INTRODUCTION: To illustrate the landscape of community-based care for autistic youth in the United States, we identified transdisciplinary psychosocial intervention practice sets that community providers report utilizing to care for this population, and examined characteristics associated with provider-reported utilization. METHODS: The Usual Care for Autism Study (UCAS) Survey assessed provider demographics and provider-reported use of transdisciplinary practices for common ASD co-occurring problems: social difficulties, externalizing behaviors, and anxiety. Community practitioners (N = 701) from allied health, behavioral, education, medical, mental health and other disciplines who treat or work with autistic youth (7-22 years) participated. RESULTS: Exploratory factor analysis yielded four factors: Consequence-Based Strategies (CBS), Cognitive-Behavioral and Therapy Strategies (CBTS), Antecedent-Based Strategies (ABS), and Teaching Strategies (TS). Providers across disciplines reported utilizing ABS more often than other sets. Providers from behavioral disciplines, with less than 4-year or Master degrees, or with more experience reported the most use of ABS, CBS and CBTS. Medical and behavioral providers reported the most use of TS. Setting and child characteristics were associated with practice set use, indicating variability by disability and client socioeconomic status. DISCUSSION: Findings reflect the complexity and inconsistency of the service landscape for autistic youth across the U.S. Only by understanding the service landscape and predictors of practice utilization, can researchers, policymakers, provider groups, and the autistic community facilitate effective implementation strategy development and use to ultimately improve community-based care.

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4. Estrugo Y, Bar Yehuda S, Bauminger-Zviely N. Pathways to peer interaction in ASD and TD through individual and dyadic joint-action motor abilities. Frontiers in psychology. 2023; 14: 1234376.

PURPOSE: Any social engagement, especially with peers, requires children’s effective activation of social and motor mechanisms. Children and adolescents with autism spectrum disorder (ASD) often display dysfunctions both in individual motor functioning (e.g., fine/gross) and in dyadic joint action (JA), where two partners coordinate movement toward a shared goal. Yet, these mechanisms’ contribution to peer interaction has been underexplored. METHOD: This study examined the contribution of individual motor functioning and JA performance to peer interaction (cooperation, attentiveness, social engagement, and dyadic quality), while comparing children and adolescents’ (youngsters) with ASD versus those with typical development (TD). RESULTS: Results indicated more competent peer interaction in TD than in ASD. Interestingly, only the ASD group showed significant maturation with age for social engagement and dyadic interaction quality, calls for further examination of developmental trajectories. However, even the oldest participants with ASD continued to lag behind the youngest TD group. Also, findings indicated that better individual motor functioning and JA performance explained better peer interactive competence; yet, the contribution of individual motor functioning to social cooperation and dyadic quality was moderated by JA performance. Thus, youngsters’ individual motor system was found to be an important contributor to peer interaction in those with low to moderate JA coordination capabilities, but not for those with high JA. CONCLUSION: Results emphasize possible distinct contributions of each motor mechanism and their interaction for facilitating social interaction, hence, encouraging incorporation of individual and dyadic motor skills explicitly into social interaction interventions for youngsters ASD.

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5. Fuentes J, Parellada M, Georgoula C, Oliveira G, Marret S, Crutel V, Albarran C, Lambert E, Pénélaud PF, Ravel D, Ben Ari Y. Bumetanide oral solution for the treatment of children and adolescents with autism spectrum disorder: Results from two randomized phase III studies. Autism research : official journal of the International Society for Autism Research. 2023.

The efficacy and safety of bumetanide oral solution for the treatment of autism spectrum disorder (ASD) in children and adolescents was evaluated in two international, multi-center, randomized, double-blind, placebo-controlled phase III trials; one enrolled patients aged 7-17 years (SIGN 1 trial) and the other enrolled younger patients aged 2-6 years (SIGN 2). In both studies, patients were randomized to receive bumetanide oral solution twice daily (BID) or placebo BID during a 6-month double-blind treatment period. The primary endpoint was change in Childhood Autism Rating Scale 2 (CARS2) total raw score from baseline to Week 26. Key secondary endpoints included changes in Social Responsiveness Scale-2, Clinical Global Impression Scale, and Vineland Adaptive Behavior Scale. Each study enrolled 211 patients (bumetanide, n = 107; placebo, n = 104). Both studies were terminated early due to absence of any significant difference between bumetanide and placebo in the overall studied populations. In both studies, CARS2 total raw score decreased from baseline to Week 26 in the bumetanide and placebo groups, with no statistically significant difference between groups. No differences were observed between treatment groups for any of the secondary efficacy endpoints in either study. In both studies, treatment-emergent adverse events that occurred more frequently with bumetanide than placebo included thirst, polyuria, hypokalemia, and dry mouth. These large phase III trials failed to demonstrate a benefit of bumetanide for the treatment of pediatric ASD compared with placebo. Consequently, the sponsor has discontinued the development of bumetanide for the treatment of this condition. Trial registration: https://clinicaltrials.gov: SIGN 1: NCT03715166; SIGN 2: NCT03715153.

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6. Gonzales S, Zhao JZ, Choi NY, Acharya P, Jeong S, Lee MY. SOX7: Novel Autistic Gene Identified by Analysis of Multi-Omics Data. Research square. 2023.

Background Despite thousands of variants identified by genome-wide association studies (GWAS) to be associated with autism spectrum disorder (ASD), it is unclear which mutations are causal because most are noncoding. Consequently, reliable diagnostic biomarkers are lacking. RNA-seq analysis captures biomolecular complexity that GWAS cannot by considering transcriptomic patterns. Therefore, integrating DNA and RNA testing may reveal causal genes and useful biomarkers for ASD. Methods We performed gene-based association studies using an adaptive test method with GWAS summary statistics from two large Psychiatric Genomics Consortium (PGC) datasets (ASD2019: 18,382 cases and 27,969 controls; ASD2017: 6,197 cases and 7,377 controls). We also investigated differential expression for genes identified with the adaptive test using an RNA-seq dataset (GSE30573: 3 cases and 3 controls) and DESeq2. Results We identified 5 genes significantly associated with ASD in ASD2019 (KIZ-AS1, p = 8.67×10 (- 10) ; KIZ, p = 1.16×10 (- 9) ; XRN2, p = 7.73×10 (- 9) ; SOX7, p = 2.22×10 (- 7) ; LOC101929229 (also known as PINX1-DT), p = 2.14×10 (- 6) ). Two of the five genes were replicated in ASD2017: SOX7 (p = 0.00087) and LOC101929229 (p = 0.009), and KIZ was close to the replication boundary of replication (p = 0.06). We identified significant expression differences for SOX7 (p = 0.0017, adjusted p = 0.0085), LOC101929229 (p = 5.83×10 (- 7) , adjusted p = 1.18×10 (- 5) ), and KIZ (p = 0.00099, adjusted p = 0.0055). SOX7 encodes a transcription factor that regulates developmental pathways, alterations in which may contribute to ASD. Limitations: The limitation of the gene-based analysis is the reliance on a reference population for estimating linkage disequilibrium between variants. The similarity of this reference population to the population of study is crucial to the accuracy of many gene-based analyses, including those performed in this study. As a result, the extent of our findings is limited to European populations, as this was our reference of choice. Future work includes a tighter integration of DNA and RNA information as well as extensions to non-European populations that have been under-researched. Conclusions These findings suggest that SOX7 and its related SOX family genes encode transcription factors that are critical to the downregulation of the canonical Wnt/\(\beta\)-catenin signaling pathway, an important developmental signaling pathway, providing credence to the biologic plausibility of the association between gene SOX7 and autism spectrum disorder.

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7. Hayden J, Ahearne C, Wienand L, Vaish S, McCallion N, Hayes BC. Autistic traits at neurodevelopmental assessment for very preterm infants. Irish medical journal. 2023; 116(8): 828.

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8. Hernandez AM, Michael O, Canning G, Joshi M, Osuna A, Locke J. Educators’ experiences and reflections on the implementation of evidence-based practices for autistic students in public schools during the COVID-19 pandemic. Implementation research and practice. 2023; 4: 26334895231189197.

INTRODUCTION: In 2020, the COVID-19 pandemic forced many schools to close their doors and transition to remote learning, disrupting how autistic students received school-based services and support. While school structure changes were challenging for all students, autistic students were uniquely affected, considering their reliance on predictability and routine; moreover, education settings are where most autistic children receive services. Much has been studied regarding the use of evidence-based practices (EBPs) for autistic students in traditional school settings, yet little is known about how educators use EBPs in remote learning environments in the wake of the COVID-19 pandemic. METHOD: In this study, we explore educators’ experiences with EBP implementation at the height of the pandemic and educators’ reflections of its impact on autistic students and their school systems. Qualitative data were collected from 81 educators (general educators, special educators, and paraeducators) in semi-structured interviews regarding EBP use at the onset of the pandemic. RESULTS: Four themes emerged from interviews: (1) pandemic and remote learning environment challenges to inclusion and EBP use; (2) EBP use adaptations for remote learning environments; (3) pandemic and remote learning environment benefits for EBP use; and (4) considerations for EBP use beyond the pandemic. CONCLUSION: These findings elucidate educators’ experiences using EBPs during the COVID-19 pandemic and highlight important areas of consideration for autism-focused EBP implementation as remote instruction continues to be a learning format. More research is needed to understand how to best implement EBPs for autistic students in this emerging instruction context. The COVID-19 pandemic forced many schools to shift to remote or hybrid learning, which impacted how autistic students received school-based services. School settings are where most autistic children receive support and accommodations. Evidence-based practices (EBPs) are strategies shown by high-quality research to support autistic children, and there are strong efforts to increase the use of EBPs in schools. While much is known about how autism-focused EBPs are used in traditional classroom settings, little is known about how these practices are used in remote learning environments. This paper explored educators’ experiences using EBPs at the height of the pandemic and educators’ reflections of its impact on autistic students and their school systems. Interviews with general educators, special educators, and paraeducators revealed important information. There were pandemic-specific and remote learning environment challenges to inclusion and EBP use. Many educators reported making adaptations to EBPs when instruction was pivoted to remote learning. While there were challenges to remote instruction, there were also pandemic- and remote learning environment-related benefits for EBP use. Educators also reflected on considerations for EBP use beyond the pandemic, including more educator training opportunities to support EBP use in remote settings. Considering the rise in remote and hybrid learning settings, future research should explore how to support educators, autistic students, and their caregivers in remote setting EBP use. eng.

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9. Hooshmandi M, Sharma V, Thörn Perez C, Sood R, Krimbacher K, Wong C, Lister KC, Ureña Guzmán A, Bartley TD, Rocha C, Maussion G, Nadler E, Roque PM, Gantois I, Popic J, Lévesque M, Kaufman RJ, Avoli M, Sanz E, Nader K, Hagerman RJ, Durcan TM, Costa-Mattioli M, Prager-Khoutorsky M, Lacaille JC, Martinez-Cerdeno V, Gibson JR, Huber KM, Sonenberg N, Gkogkas CG, Khoutorsky A. Excitatory neuron-specific suppression of the integrated stress response contributes to autism-related phenotypes in fragile X syndrome. Neuron. 2023; 111(19): 3028-40.e6.

Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2α phosphorylation (p-eIF2α), is suppressed in excitatory, but not inhibitory, neurons in a mouse model of fragile X syndrome (FXS; Fmr1(-/y)). We further show that the decrease in p-eIF2α is mediated via activation of mTORC1. Genetic reduction of p-eIF2α only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1(-/y) mice, restoration of p-eIF2α solely in excitatory neurons reverses elevated protein synthesis and rescues autism-related phenotypes. Thus, we reveal a previously unknown causal relationship between excitatory neuron-specific translational control via the ISR pathway, general protein synthesis, and core phenotypes reminiscent of autism in a mouse model of FXS.

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10. Kantor J, Smrčková A, de Goumoëns V, Munn Z, Svobodová Z, Klugar M. Experience of having a sibling with autism spectrum disorder: a systematic review protocol. JBI evidence synthesis. 2023.

OBJECTIVE: This qualitative systematic review aims to understand the experiences of neurotypical siblings of a person with autism spectrum disorder (ASD). INTRODUCTION: ASD influences communication and social interaction with other people and has a significant impact on family relationships. The experiences of siblings range from the positive, such as development of increased empathy and ability to cope with challenges, to experiences that are more negative, such as a higher risk of bullying. In many countries, neurotypical siblings are marginalized and don’t receive adequate support to cope with the increased challenges. INCLUSION CRITERIA: This review will consider qualitative studies exploring the experiences of siblings of a person with ASD. There are no limitations regarding age, gender, sex, or length of relationship with the sibling. We will consider studies from all countries and contexts. METHODS: This study will be conducted according to JBI methodology for qualitative reviews. A 3-step search strategy will be used to find published and unpublished studies in the following sources: MEDLINE, CINAHL, APA PsycINFO, Scopus, SocINDEX, Web of Science, Embase, ERIC, ProQuest Dissertations and Theses, Open Dissertations, and Google Scholar (first 100 records). There will be no search limitations on the publication period or language, but only studies with an English-language abstract/title will be considered for inclusion. Screening, data extraction, and data synthesis will be conducted by 2 independent reviewers.

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11. Ketcheson LR, Pitchford EA, Wentz FC, Loetzner F. Trajectories of physical activity among autistic children and their caregivers: Outcomes of a virtual 1-year longitudinal intervention. Disability and health journal. 2023: 101538.

BACKGROUND: Participation in regular physical activity (PA) is a critical component of overall well-being. However, opportunities to engage in health-enhancing PA for families who have an autistic child are relatively obsolete. A virtual PA intervention has the potential to address many participation barriers and represents a timely opportunity to promote positive trajectories of PA among vulnerable populations. OBJECTIVE: To examine PA trajectories during a one-year virtual intervention for autistic children and their caregiver and to explore relationships in activity participation within child-caregiver dyads. METHODS: Twenty-nine families, including autistic children and their caregiver participated in the full intervention. Caregivers completed questionnaires to measure PA behavior at baseline and four-month intervals throughout the intervention. RESULTS: Reported PA significantly increased among autistic children and caregivers during the intervention. No association in PA was observed within dyads at baseline, but moderate relationships were observed during the intervention. CONCLUSION: Findings demonstrate the initial effectiveness of a virtual PA intervention for autistic children and their caregiver.

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12. Kuruppath P, Xue L, Pouille F, Jones ST, Schoppa NE. Hyperexcitability in the olfactory bulb and impaired fine odor discrimination in the Fmr1 KO mouse model of fragile X syndrome. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2023.

Fragile X syndrome (FXS) is the single most common monogenetic cause of autism spectrum disorders in humans. FXS is caused by loss of expression of the Fragile X mental retardation protein (FMRP), an mRNA-binding protein encoded on the X chromosome involved in suppressing protein translation. Sensory processing deficits have been a major focus of studies of FXS in both humans and rodent models of FXS, but olfactory deficits remain poorly understood. Here we conducted experiments in wild-type and Fmr1 KO (Fmr1(-/y) ) mice (males) that lack expression of the gene encoding FMRP to assess olfactory circuit and behavioral abnormalities. In patch-clamp recordings conducted in slices of the olfactory bulb, output mitral cells (MCs) in Fmr1 KO mice displayed greatly enhanced excitation under baseline conditions, as evidenced by a much higher rate of occurrence of spontaneous network-level events known as long-lasting depolarizations (LLDs). The higher probability of spontaneous LLDs, which appeared to be due to a decrease in GABAergic synaptic inhibition in glomeruli leading to more feedforward excitation, caused a reduction in the reliability of stimulation-evoked responses in MCs. In addition, in a go/no-go operant discrimination paradigm, we found that Fmr1 KO mice displayed impaired discrimination of odors in difficult tasks that involved odor mixtures but not altered discrimination of monomolecular odors. We suggest that the Fmr1 KO-induced reduction in MC response reliability is one plausible mechanism for the impaired fine odor discrimination.Significance StatementFragile X syndrome (FXS) in humans is associated with a range of debilitating deficits including aberrant sensory processing. One sensory system that has received comparatively little attention in studies in animal models of FXS is olfaction. Here, we report the first comprehensive physiological analysis of circuit defects in the olfactory bulb in the commonly-used Fmr1 knockout (KO) mouse model of FXS. Our studies indicate that Fmr1 KO alters the local excitation/inhibition balance in the bulb – similar to what Fmr1 KO does in other brain circuits – but through a novel mechanism that involves enhanced feedforward excitation. Furthermore, Fmr1 KO mice display behavioral impairments in fine odor discrimination, an effect that may be explained by changes in neural response reliability.

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13. Liu Z, Xin B, Smith IN, Sency V, Szekely J, Alkelai A, Shuldiner A, Efthymiou S, Rajabi F, Coury S, Brownstein CA, Rudnik-Schöneborn S, Bruel AL, Thevenon J, Zeidler S, Jayakar P, Schmidt A, Cremer K, Engels H, Peters SO, Zaki MS, Duan R, Zhu C, Xu Y, Gao C, Sepulveda-Morales T, Maroofian R, Alkhawaja IA, Khawaja M, Alhalasah H, Houlden H, Madden JA, Turchetti V, Marafi D, Agrawal PB, Schatz U, Rotenberg A, Rotenberg J, Mancini GMS, Bakhtiari S, Kruer M, Thiffault I, Hirsch S, Hempel M, Stühn LG, Haack TB, Posey JE, Lupski JR, Lee H, Sarn NB, Eng C, Gonzaga-Jauregui C, Zhang B, Wang H. Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features. Human molecular genetics. 2023; 32(20): 2981-95.

Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that PPP1R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that PPP1R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.

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14. Longhurst P, Burnette CB. Challenges and opportunities for conceptualizing intuitive eating in autistic people. The International journal of eating disorders. 2023.

Although intuitive eating (IE) has become an increasingly adopted intervention target, current conceptualisations of IE have yet to pivot away from (neuro)normative physiology and phenomenology. Autistic individuals commonly report disordered eating behaviours and/or poorer well-being but appear to benefit from adaptive interventions using an affirmative approach. This article uses autism as a case example to summarise challenges related to IE’s prevailing conceptualisation, before proposing how future research and current practice can be extended to the autistic population. Scholars are encouraged to evaluate the full 10-principal IE framework while utilising a participatory-led approach. We argue that research using a mixed methods design is urgently needed to comprehensively explore the (re)conceptualisation of IE in autistic people. While IE shows promise for producing positive outcomes in the autistic population, we discuss the potential challenges for research and practice due to its current emphasis on accurate interoception, emotional awareness and processing, and executive functioning. This suggests the need for research and practice to integrate autistic needs and experiences into future developments with an affirmative approach. Public Significance: IE is an effective intervention for reducing disordered eating behaviours. Autistic individuals commonly present disordered eating behaviours and have unique nutritional needs which often require intervention. However, there is limited understanding of IE among the autistic population. Research-informed definitions involving autistic perspectives will support translating the IE framework to this underrepresented population.

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15. Perez Y, Velmeshev D, Wang L, White M, Siebert C, Baltazar J, Dutton NG, Wang S, Haeussler M, Chamberlain S, Kriegstein A. Single cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism. bioRxiv : the preprint server for biology. 2023.

Duplication 15q (dup15q) syndrome is the most common genetic cause of autism spectrum disorder (ASD). Due to a higher genetic and phenotypic homogeneity compared to idiopathic autism, dup15q syndrome provides a well-defined setting to investigate ASD mechanisms. Previous bulk gene expression studies identified shared molecular changes in ASD. However, how cell type specific changes compare across different autism subtypes and how they change during development is largely unknown. In this study, we used single cell and single nucleus mRNA sequencing of dup15q cortical organoids from patient iPSCs, as well as post-mortem patient brain samples. We find cell-type specific dysregulated programs that underlie dup15q pathogenesis, which we validate by spatial resolved transcriptomics using brain tissue samples. We find degraded identity and vulnerability of deep-layer neurons in fetal stage organoids and highlight increased molecular burden of postmortem upper-layer neurons implicated in synaptic signaling, a finding shared between idiopathic ASD and dup15q syndrome. Gene co-expression network analysis of organoid and postmortem excitatory neurons uncovers modules enriched with autism risk genes. Organoid developmental modules were involved in transcription regulation via chromatin remodeling, while postmortem modules were associated with synaptic transmission and plasticity. The findings reveal a shifting landscape of ASD cellular vulnerability during brain development.

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16. Romero-Galisteo RP, Pinero-Pinto E, Palomo-Carrión R, Luque-Moreno C, Molina-Torres G, González-Sánchez M. Translation, cross-cultural adaptation and validation of the Rett syndrome motor evaluation scale (RESMES): Spanish version. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2023; 47: 72-9.

OBJECTIVE: To develop a Spanish version of the Rett Syndrome Motor Evaluation Scale (RESMES) for the locomotor function of Rett Syndrome (RTT) using a transcultural methodology. METHODS: The RESMES was cross-culturally adaptated and validated in the Spanish language (RESMES-sp). This study was divided into two well-differentiated phases: 1) a cross-cultural translation and adaptation; 2) psychometric characteristics analysis of the RESMES-sp (reliability, test-retest, construct validity, criteria validity, error measurements). For criteria validity, PAINAD questionnaire, the scoliosis values and PedsQL™, were used. RESULTS: A total of 63 girls and women diagnosed with RTT participated in this validation study. The total value of the RESMES-sp correlates significantly with all its dimensions, with the correlation value oscillating between 0.645 and 0.939. The correlation value with PAINAD ranges between 0.439 and 0.805; the scoliosis values ranges between 0.245 and 0.564; with PedsQOL™ questionnaire, the correlation values range between 0.273 and 0.663 for the PedsQL™ dimensions, and between 0.447 and 0.648 for the total value of PedsQOL™ questionnaire. The reliability values of Crombach’s alpha ranged between 0.897 and 0.998 for the intra-observer analyses and between 0.904 and 0.998 for the inter-observer reliability. The SEM showed a value of 2,829, while the MDC90 showed a value of 6601. The Exploratory Factor Analysis showed 6 factors and values of variance of 86.163%. CONCLUSIONS: The Spanish version of the RESMES is a reliable and valid tool for the functional assessment and follow-up of patients with RTT.

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17. Rubenstein E, Tewolde S, Michals A, Fox M, Wang N. Prevalence of Autism Among Medicaid-Enrolled Adults. JAMA psychiatry. 2023.

IMPORTANCE: The reported prevalence of autism in children has consistently risen over the past 20 years. The concurrent implications for the adult Medicaid system, which insures autistic adults due to low income or disability, have not been studied. OBJECTIVE: To estimate the prevalence of adults identified as autistic in Medicaid claims data and to examine the prevalence by year, age, and race and ethnicity to understand enrollment patterns. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from a longitudinal Medicaid claims cohort of enrollees aged 18 years or older with a claim for autism at any point from January 1, 2011, to December 31, 2019, and an approximately 1% random sample of all adult Medicaid enrollees. The data were analyzed between February 22 and June 22, 2023. EXPOSURE: Adults enrolled in Medicaid with a claim for autism. MAIN OUTCOME AND MEASURES: Prevalence of autism per 1000 Medicaid enrollees for each year was calculated using denominator data from the Centers for Medicare & Medicaid Services weighted to nondisabled population demographic characteristics. Prevalence by race and ethnicity were calculated for study year 2019. RESULTS: Across 9 years, 403 028 unique adults had autism claims in their Medicaid records (25.7% female, 74.2% male, 3.3% Asian, 16.8% Black, 12.2% Hispanic, 0.8% Native American, 0.8% Pacific Islander, 74.3% White, and 4.2% of multiple races). Across all ages, autism prevalence increased from 4.2 per 1000 enrollees in 2011 to 9.5 per 1000 enrollees in 2019. The largest increase over the 9 years was in the 25- to 34-year age group (195%), and the smallest increase was in the 55- to 64-year age group (45%). The prevalence of White enrollees was at least 2 times that of the prevalence of every other racial group in all age categories. CONCLUSIONS AND RELEVANCE: The study findings suggest that despite difficulties in identifying autism in adults, there is a considerable and growing population of autistic adults enrolled in Medicaid. As children on the autism spectrum become autistic adults, Medicaid is an important insurance provider for an increasing number of autistic adults and can be a valuable resource for understanding the health of the autistic population.

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18. Shin T, Song JHT, Kosicki M, Kenny C, Beck SG, Kelley L, Qian X, Bonacina J, Papandile F, Antony I, Gonzalez D, Scotellaro J, Bushinsky EM, Andersen RE, Maury E, Pennacchio LA, Doan RN, Walsh CA. Rare variation in noncoding regions with evolutionary signatures contributes to autism spectrum disorder risk. medRxiv : the preprint server for health sciences. 2023.

Little is known about the role of noncoding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of noncoding regions: Human Accelerated Regions (HARs), which show signatures of positive selection in humans; experimentally validated neural Vista Enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole genome analysis of >16,600 samples and >4900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in a VE near SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved noncoding regions in ASD risk and suggest potential mechanisms of how changes in regulatory regions can modulate social behavior.

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19. Stahmer AC, Suhrheinrich J, Yu Y, Melgarejo M, Schetter P, Young GA. Implementation readiness for evidence-based autism practices in school systems. Implementation research and practice. 2023; 4: 26334895231199465.

BACKGROUND: The increase in the number of autistic children being identified has led to increased demand on public schools to provide high-quality services. Effectively scaling up evidence-based practice (EBP) use for autistic students is challenging, given the complicated organization of special education. Teachers have significant challenges implementing autism EBP with fidelity. Factors such as implementation leadership and climate and attitudes toward EBP are linked to successful EBP use and may vary at different levels of the education system. Examining mechanisms of successful implementation is a critical step to support scale-up. METHOD: In this observational study, conducted from September 2018 to March 2020, California school personnel (n = 2273) at multiple levels of the system completed surveys related to implementation climate, leadership, and attitudes toward EBP. Data were collected throughout California at the Special Education Local Plan Areas, County Office of Education, and district and school levels from educators and administrators working in public schools supporting autistic students. Multi-level modeling was conducted to characterize implementation readiness. RESULTS: Overall, implementation climate and leadership scores are low across levels with regional levels rated more positively than districts or schools. Attitudes toward EBP were moderate, with those working in schools having the poorest ratings and specialists/trainers and related service providers (e.g., speech-language pathologists) having the highest ratings. CONCLUSIONS: Outcomes provide a unique opportunity to compare implementation factors across organizational levels with a large, statewide sample. These data provide guidance for developing implementation interventions at multiple levels of the education system to increase readiness for effective scale-up of autism EBP in schools. Personnel and leaders at different organizational levels may need differentiated training targeting improved implementation climate and leadership. Personnel within districts and schools may experience a particular benefit from leadership support for EBP implementation. The increase in the number of autistic children being identified in schools is increasing. To address this, schools are trying to do a better job of using high-quality practices based on research. However, teachers have had difficulty using research-based strategies for autistic students the way the manuals indicate they should be used. This might be due to the complexity of the strategies or limited support from special education leadership and infrastructure. Research shows that leaders can be very important in helping teachers use effective strategies. Over 2200 school personnel in California, including administrators, professional development providers, teachers, and paraprofessionals completed surveys asking about how their leaders, schools, districts, and regions supported the use of research practices for autistic students. Overall, limited support is provided in special education, with regional agencies providing more support than districts or schools. These data suggest that school and district leaders need training in how to support educators in using autism-specific strategies. eng.

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20. Van Biesen D, Van Damme T, Morgulec-Adamowicz N, Buchholtz A, Anjum M, Healy S. A Systematic Review of Digital Interventions to Promote Physical Activity in People With Intellectual Disabilities and/or Autism. Adapted physical activity quarterly : APAQ. 2023: 1-21.

This systematic review synthesized the literature on digital health interventions for the promotion of physical activity (PA) among people with intellectual disabilities and/or autism. From an initial screening of 553 records, 10 studies underwent full-text review. Data were extracted relating to study, intervention, and sample characteristics and PA-related findings. Methodological quality was evaluated using the Crowe Critical Appraisal Tool. There were mixed findings pertaining to the effectiveness of digital health interventions for promoting PA among these populations. Positive results were reported for three of five active-video-game interventions, two of three social-media-based interventions, and one of two e-learning/multicomponent interventions. Digital health interventions can potentially be effective for promoting PA among people with intellectual disabilities and/or autism. However, the large variation in the samples and intervention types and a reliance on pre- and quasi-experimental research designs suggest that inferences should be made with caution and additional research is needed.

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21. Wang X, Delgado J, Marchesotti S, Kojovic N, Sperdin HF, Rihs TA, Schaer M, Giraud AL. Speech Reception in Young Children with Autism Is Selectively Indexed by a Neural Oscillation Coupling Anomaly. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2023; 43(40): 6779-95.

Communication difficulties are one of the core criteria in diagnosing autism spectrum disorder (ASD), and are often characterized by speech reception difficulties, whose biological underpinnings are not yet identified. This deficit could denote atypical neuronal ensemble activity, as reflected by neural oscillations. Atypical cross-frequency oscillation coupling, in particular, could disrupt the joint tracking and prediction of dynamic acoustic stimuli, a dual process that is essential for speech comprehension. Whether such oscillatory anomalies already exist in very young children with ASD, and with what specificity they relate to individual language reception capacity is unknown. We collected neural activity data using electroencephalography (EEG) in 64 very young children with and without ASD (mean age 3; 17 females, 47 males) while they were exposed to naturalistic-continuous speech. EEG power of frequency bands typically associated with phrase-level chunking (δ, 1-3 Hz), phonemic encoding (low-γ, 25-35 Hz), and top-down control (β, 12-20 Hz) were markedly reduced in ASD relative to typically developing (TD) children. Speech neural tracking by δ and θ (4-8 Hz) oscillations was also weaker in ASD compared with TD children. After controlling gaze-pattern differences, we found that the classical θ/γ coupling was replaced by an atypical β/γ coupling in children with ASD. This anomaly was the single most specific predictor of individual speech reception difficulties in ASD children. These findings suggest that early interventions (e.g., neurostimulation) targeting the disruption of β/γ coupling and the upregulation of θ/γ coupling could improve speech processing coordination in young children with ASD and help them engage in oral interactions.SIGNIFICANCE STATEMENT Very young children already present marked alterations of neural oscillatory activity in response to natural speech at the time of autism spectrum disorder (ASD) diagnosis. Hierarchical processing of phonemic-range and syllabic-range information (θ/γ coupling) is disrupted in ASD children. Abnormal bottom-up (low-γ) and top-down (low-β) coordination specifically predicts speech reception deficits in very young ASD children, and no other cognitive deficit.

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