1. Aziz-Zadeh L, Mayer E, Labus J, Ringold S, Jayashankar A, Kilroy E, Butera C, Jacobs J, Tanartkit S, Joshi S, Dapretto M. Relationships between tryptophan-related gut metabolites, brain activity, and autism symptomatology. Res Sq;2024 (Jul 25)

Gut microbial metabolites have been theorized to play a causative role in the pathophysiology of autism spectrum disorder (ASD). This hypothesis is based on results from mechanistic preclinical studies and several correlational studies showing differences in gut microbial composition between ASD subjects and neurotypical (NT) controls. However, alterations in how the human brain interacts with the gut microbiome in ASD have not been examined. In this cross-sectional, case-control observational study, fecal metabolomics, task-based functional magnetic resonance imaging (fMRI), and behavioral assessments were obtained from 43 ASD and 41 NT children aged 8-17. The fMRI tasks were based on socio-emotional and sensory paradigms that commonly show strong evoked brain differences in ASD participants. General linear models and mediational modeling were applied to examine the links between tryptophan metabolism and evoked brain activity and behavior. Results indicated that fecal levels of specific tryptophan-related metabolites were associated with: 1) brain activity atypicalities in regions previously implicated in ASD (i.e., insula and cingulate); and 2) ASD severity and symptomatology (i.e., ADOS scores, disgust propensity, and sensory sensitivities). Importantly, activity in the mid-insula and mid-cingulate significantly mediated relationships between the microbial tryptophan metabolites, indolelactate and tryptophan betaine, and ASD severity and disgust sensitivity. To our knowledge, this is the first study to elucidate how interactions between gut metabolites and brain activity may impact autism symptomatology, particularly in functional brain pathways associated with vagal and interoceptive/emotion processing.

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2. Blakey AO, Eilenberg JS, Cardona N, Kizildag D, Broder-Fingert S, Feinberg E, Long KA. Family Involvement During Comprehensive Developmental Evaluations: Perspectives of Diverse Mothers. J Dev Behav Pediatr;2024 (Jul-Aug 01);45(4):e325-e333.

OBJECTIVE: Early diagnosis and social support postdiagnosis (i.e., family involvement) can lead to improved outcomes for children with autism spectrum disorder (ASD) and other developmental disorders. Children of minority ethnic and racial groups are typically diagnosed later in childhood compared with White children, contributing to disparities in outcomes. Research has not yet explored family involvement during comprehensive developmental evaluations nor accounted for cross-cultural differences in family roles and involvement. This qualitative study sought to characterize the nature and impact of family involvement during the developmental evaluation process among racially and ethnically marginalized mothers of children with developmental delays and possible ASD. METHODS: Mothers (N = 27) of children who had a positive autism screen during their 18- or 24-month well-child visit but did not receive an ASD diagnosis after comprehensive developmental evaluation participated in individual semi-structured interviews exploring experiences with developmental screening, related services, and family involvement/social support. Qualitative data were transcribed, coded, and analyzed using applied thematic analysis. Data were stratified by partner status (i.e., partnered vs. nonpartnered) to examine differences in support and family involvement across varying family compositions. RESULTS: Three qualitative themes emerged: (1) mothers sought family involvement when making decisions about pursuing developmental evaluations, (2) family involvement affected mothers’ navigation of logistical challenges, and (3) mothers involved family members for emotional support. Differences by partner status emerged in themes 1 and 2. CONCLUSION: Findings highlight benefits of and potential approaches to harnessing family involvement to support parents’ navigation of the developmental evaluation process and ultimately improve child outcomes.

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3. Chang S, Liu JJ, Zhao Y, Pang T, Zheng X, Song Z, Zhang A, Gao X, Luo L, Guo Y, Liu J, Yang L, Lu L. Whole-genome sequencing identifies novel genes for autism in Chinese trios. Sci China Life Sci;2024 (Aug 7)

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high genetic heritability but heterogeneity. Fully understanding its genetics requires whole-genome sequencing (WGS), but the ASD studies utilizing WGS data in Chinese population are limited. In this study, we present a WGS study for 334 individuals, including 112 ASD patients and their non-ASD parents. We identified 146 de novo variants in coding regions in 85 cases and 60 inherited variants in coding regions. By integrating these variants with an association model, we identified 33 potential risk genes (P<0.001) enriched in neuron and regulation related biological process. Besides the well-known ASD genes (SCN2A, NF1, SHANK3, CHD8 etc.), several high confidence genes were highlighted by a series of functional analyses, including CTNND1, DGKZ, LRP1, DDN, ZNF483, NR4A2, SMAD6, INTS1, and MRPL12, with more supported evidence from GO enrichment, expression and network analysis. We also integrated RNA-seq data to analyze the effect of the variants on the gene expression and found 12 genes in the individuals with the related variants had relatively biased expression. We further presented the clinical phenotypes of the proband carrying the risk genes in both our samples and Caucasian samples to show the effect of the risk genes on phenotype. Regarding variants in non-coding regions, a total of 74 de novo variants and 30 inherited variants were predicted as pathogenic with high confidence, which were mapped to specific genes or regulatory features. The number of de novo variants found in patient was significantly associated with the parents' ages at the birth of the child, and gender with trend. We also identified small de novo structural variants in ASD trios. The results in this study provided important evidence for understanding the genetic mechanism of ASD.

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4. Cleary M, West S, Kornhaber R, Johnston-Devin C, Thapa DK, McLean L, Hungerford C. ‘The Horse Weaves Magic’: Parents and Service Providers on the Benefits of Horse-Based Therapies for Autistic Children-an Australian Qualitative Study. Issues Ment Health Nurs;2024 (Aug 7):1-9.

Autistic children and adolescents experience a range of co-morbidities, including diagnoses of mental illness. Animal-assisted therapies have advanced rapidly over recent years as an effective and accessible intervention for autistic children and adolescents with various health issues. Horses offer a unique opportunity for interaction as the young person can physically ride the animal, thus creating a therapy with different physical interactions from other animals. This qualitative study had two main aims: first, to understand parents’ experiences of their autistic child’s involvement with horse-based therapies; and second, to understand the experiences of the staff of organisations offering horse-based therapies to those on the autism spectrum. Twelve interviews were conducted with six parents across four interviews (four mothers and two fathers), and eight staff of equine therapy services in eight individual interviews, to understand their perceptions of the child’s experience with horse riding and the perceived mental health impacts. Three emergent themes were prominent among parents and service providers alike: physical and social benefits, including health, self-management skills and social skills; protecting mental health; and recommendations for improvements and accessibility of horse-based therapies. Specifically, service providers with long-standing associations with horse-based therapies saw the actual and potential benefits of horse-based therapies for autistic children, particularly in promoting happiness, calm, resilience, and good mental health.

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5. Dessus-Gilbert ML, Nourredine M, Zimmer L, Rolland B, Geoffray MM, Auffret M, Jurek L. NMDA antagonist agents for the treatment of symptoms in autism spectrum disorder: a systematic review and meta-analysis. Front Pharmacol;2024;15:1395867.

AIMS: This systematic review and meta-analysis aimed to assess the efficacy of NMDA antagonists in ASD (Autism Spectrum Disorder) on the core (communication and social interaction, repetitive behavior) and associated symptoms (irritability) of ASD, as well as their safety. METHODS: PubMed, CENTRAL, CINHAL, EMBASE, and PsycINFO databases were searched until November 2023. Two authors independently selected the studies and extracted data. Randomized controlled trials assessing the efficacy of NMDA receptor antagonists in participants with ASD aged <18 years were included. The quality of the studies was assessed using the Risk of Bias-2 tool. A random-effect meta-analysis model was used to calculate standardized mean differences (SMD) or odds ratios (OR) using meta package in R. RESULTS: This systematic review included ten studies (588 participants). Most studies did not report scales assessing core symptoms of ASD. Meta-analysis of efficacy on ASD core symptoms included three studies (248 participants). NMDA antagonists were not superior to placebo [SMD = 0.29; CI 95% (-1,94; 1.35); I(2) = 0%]. NMDA antagonists was not superior to placebo concerning response (four studies, 189 participants) [OR = 2.4; CI 95% (0.69; 8.38); I(2) = 35%]. Meta-analysis of efficacy on irritability included three studies (186 participants); NMDA antagonists were not superior to placebo [MD irritability = -1.94; CI 95% (-4.66; 0.77); I(2) = 0%]. Compared with placebo, significantly more participants in the NMDA antagonist group reported at least one adverse event (five studies, 310 participants) [OR = 2.04; CI 95% (1.17; 3.57); I(2) = 0%]. CONCLUSION: Current evidence does not support the effectiveness of NMDA antagonists in the treatment of ASD symptoms or irritability. Further research is needed due to the limited and low quality data available. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018110399.

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6. Galazka MA, Thorsson M, Lundin Kleberg J, Hadjikhani N, Åsberg Johnels J. Pupil contagion variation with gaze, arousal, and autistic traits. Sci Rep;2024 (Aug 7);14(1):18282.

Pupillary contagion occurs when one’s pupil size unconsciously adapts to the pupil size of an observed individual and is presumed to reflect the transfer of arousal. Importantly, when estimating pupil contagion, low level stimuli properties need to be controlled for, to ensure that observations of pupillary changes are due to internal change in arousal rather than the external differences between stimuli. Here, naturalistic images of children’s faces depicting either small or large pupils were presented to a group of children and adolescents with a wide range of autistic traits, a third of whom had been diagnosed with autism. We examined the extent to which pupillary contagion reflects autonomic nervous system reaction through pupil size change, heart rate and skin conductance response. Our second aim was to determine the association between arousal reaction to stimuli and degree of autistic traits. Results show that pupil contagion and concomitant heart rate change, but not skin conductance change, was evident when gaze was restricted to the eye region of face stimuli. A positive association was also observed between pupillary contagion and autistic traits when participants’ gaze was constrained to the eye region. Findings add to a broader understanding of the mechanisms underlying pupillary contagion and its association with autism.

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7. Ha YW, Kim TH, Kang DR, Park KS, Shin DC, Cho J, Kim C. Estimation of Attributable Risk and Direct Medical and Non-Medical Costs of Major Mental Disorders Associated With Air Pollution Exposures Among Children and Adolescents in the Republic of Korea, 2011-2019. J Korean Med Sci;2024 (Aug 5);39(30):e218.

BACKGROUND: Recent studies have reported the burden of attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and depressive disorder. Also, there is mounting evidence on the effects of environmental factors, such as ambient air pollution, on these disorders among children and adolescents. However, few studies have evaluated the burden of mental disorders attributable to air pollution exposure in children and adolescents. METHODS: We estimated the risk ratios of major mental disorders (ADHD, ASD, and depressive disorder) associated with air pollutants among children and adolescents using time-series data (2011-2019) obtained from a nationwide air pollution monitoring network and healthcare utilization claims data in the Republic of Korea. Based on the estimated risk ratios, we determined the population attributable fraction (PAF) and calculated the medical costs of major mental disorders attributable to air pollution. RESULTS: A total of 33,598 patients were diagnosed with major mental disorders during 9 years. The PAFs for all the major mental disorders were estimated at 6.9% (particulate matter < 10 μm [PM(10)]), 3.7% (PM(2.5)), and 2.2% (sulfur dioxide [SO(2)]). The PAF of PM(10) was highest for depressive disorder (9.2%), followed by ASD (8.4%) and ADHD (5.2%). The direct medical costs of all major mental disorders attributable to PM(10) and SO(2) decreased during the study period. CONCLUSION: This study assessed the burden of major mental disorders attributable to air pollution exposure in children and adolescents. We found that PM(10,) PM(2.5), and SO(2) attributed 7%, 4%, and 2% respectively, to the risk of major mental disorders among children and adolescents.

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8. Harvey S, Liyanagamage D, Pal T, Klockars A, Levine AS, Olszewski PK. Palatable solution overconsumption in the Cntnap2-/- murine model of autism: a link with oxytocin. Neuroreport;2024 (Aug 7)

Dysregulated appetite is common in autism spectrum disorder (ASD) and it includes excessive interest in tasty foods. Overconsumption of palatable fluids has been found in the valproic acid-induced ASD rat. Though ASD has a strong genetic component, the link between ASD-related genes and appetite for palatable foods remains elusive. We focused on the CNTNAP2 gene whose deletion in mice recapitulates human ASD symptoms. We investigated whether Cntnap2-/- male mice consume greater amounts of palatable 10% sucrose, 0.1% saccharin, and 4.1% intralipid solutions offered in episodic meals either in a no-choice paradigm or a two-bottle choice test. We examined how sucrose intake affects c-Fos immunoreactivity in feeding-related brain areas. Finally, we determined doses at which intraperitoneal oxytocin decreases sucrose intake in mutants. In the single-bottle tests, Cntnap2-/- mice drank more sucrose, saccharin, and intralipid compared to WTs. Given a choice between two tastants, Cntnap2-/- mice had a higher preference for sucrose than intralipid. While the standard 1 mg/kg oxytocin dose reduced sucrose intake in WTs, a low oxytocin dose (0.1 mg/kg) decreased sucrose intake in Cntnap2-/- mice. Sucrose intake induced a more robust c-Fos response in wild-type (WT) than Cntnap2-/- mice in the reward and hypothalamic sites and it increased the percentage of Fos-immunoreactivity oxytocin neurons in WTs, but not in mutants. We conclude that Cntnap2-/- mice overconsume palatable solutions, especially sucrose, beyond levels seen in WTs. This excessive consumption is associated with blunted c-Fos immunoreactivity in feeding-related brain sites, and it can be reversed by low-dose oxytocin.

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9. Jaicks CCD. Evaluating the Benefits of Occupational Therapy in Children With Autism Spectrum Disorder Using the Autism Behavior Checklist. Cureus;2024 (Jul);16(7):e64012.

INTRODUCTION AND OBJECTIVE: Autism spectrum disorder (ASD) is a neurodevelopmental disorder typically manifesting before the age of three years, characterized by significant impairments in social interaction and communication, as well as restricted and repetitive patterns of interests and activities. In our study, we assessed the benefits of sensory integration therapy in children with ASD using the Autism Behavior Checklist (ABC), focusing on improvements in sensory processing, relationship-building, language skills, and social and self-care abilities. METHOD: The study was conducted with 40 children aged three to nine years, diagnosed with ASD, and whose parents provided consent for their participation in therapy between December 2022 and March 2023 at the Private Adana Metro Hospital Child Psychiatry Clinic. The ages and genders of the patients were recorded. Before occupational therapy, after five sessions of occupational therapy, and after 10 sessions of occupational therapy, the ABC test was administered under the supervision of a child psychiatrist and an occupational therapist. The results were recorded, and statistical analyses were performed. RESULTS: In the ABC test conducted after 10 sessions, a decreasing trend was observed in sensory, relationship-building, body and object usage, language skills, social and self-care, and total scale scores compared to pre-occupational therapy test scores (p < 0.000). DISCUSSION AND CONCLUSION: Occupational therapy improves sensory skills, relationship-building skills, body and object usage abilities, language skills, and social and self-care skills.

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10. Kearly A, Hluchan M, Brazeel C, Lane JT, Oputa J, Baio J, Cree RA, Cheng Q, Wray A, Payne C, Gerling J, Pham T, Ekart S. Health Service Utilization Patterns Among Medicaid Enrollees With Intellectual and Developmental Disabilities Before and During the COVID-19 Pandemic: Implications for Pandemic Response and Recovery Efforts. J Public Health Manag Pract;2024 (Aug 5)

OBJECTIVES: To assess the impact of COVID-19 on health service utilization of adults with intellectual and developmental disabilities (IDDs) through an analysis of Medicaid claims data. DESIGN: Retrospective cohort study of Medicaid claims. SETTING AND PARTICIPANTS: Medicaid members aged 25 to 64 years from January 1, 2018, to March 31, 2021, from the states of Louisiana, Pennsylvania, and Wyoming. INTERVENTION: We analyzed data from two 12-month time periods (pre-COVID-19 and during COVID-19) and assessed the potential impact of the COVID-19 pandemic on health service utilization and service intensity for 3 cohorts: (1) IDD with preexisting mental health diagnoses, (2) IDD without mental health diagnoses, and (3) all other Medicaid members. MAIN OUTCOME MEASURE: Health service utilization determined by specific claims data classifications. RESULTS: The analysis showed reduced utilization for nonmental health service types with differing utilization patterns for IDD with preexisting mental health diagnoses, IDD without mental health diagnoses, and all other Medicaid members. Change in utilization varied, however, for mental health service types. Measures of service intensity showed decreased numbers of members utilizing services across most service types and increased Medicaid claims per person across most mental health service categories but decreased Medicaid claims per person for most nonmental health services. CONCLUSIONS: Results suggest a need for mental health services among all Medicaid members during the COVID-19 pandemic. By anticipating these needs, communities may be able to expand outreach to Medicaid members through enhanced case management, medication checks, and telemedicine options.

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11. Kristofik A, Demps KL. Reimagining Support for Autistic Indigenous Children in the United States: Addressing Under-Identification and Service Gaps. Neuropsychiatr Dis Treat;2024;20:1503-1511.

Although the original purpose of this article was to provide a comprehensive review of services provided for autistic children among Indigenous communities in Texas, USA, the authors’ encounter with a significant paucity in availability of data and relevant reports on Indigenous services for ASD spurred the choice of a perspective article instead as it allows a more critical view into the pitfalls surrounding the state of autism services. The meager documentation availability presents a dilemma for both researchers and Indigenous communities since it often leads to misrepresentations of data, and limits understanding of existing support systems. This perspective article addresses these issues and serves to highlight the complexity of collecting data among Indigenous populations across the United States. Specifically, it emphasizes the challenges faced in Texas, shedding light on the various barriers such as variations in cultural identity, government trust, cultural awareness, and disability identity that impede data-collection efforts in providing effective services to Indigenous populations. We advocate for a radical transformation in understanding how to approach and report the prevalence of possible ASD autism among Indigenous children to provide effective and tailored services. Ultimately, this transformation aims to secure the necessary data to provide services that effectively complement the existing support systems within individual Indigenous communities to enable their fullest and most equitable participation in society. The discussion calls for a comprehensive roadmap to achieve the goal of increasing Indigenous data collection and availability while the conclusion outlines a suggested roadmap to achieve the goals of increasing data generation and available services to Indigenous communities, and ultimately, improving services for Indigenous children with ASD in Texas and their families.

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12. Kuramitsu A, Ohi K, Shioiri T. Associations of polygenic risk scores differentiating attention-deficit hyperactivity disorder from autism spectrum disorder with cognitive and cortical alterations in Schizophrenia patients. Eur Child Adolesc Psychiatry;2024 (Aug 7)

Schizophrenia (SCZ) is a clinically and genetically heterogeneous disorder that shares genetic factors with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). A genome-wide association study (GWAS) differentiating ADHD from ASD was performed recently. In this study, we investigated whether polygenic risk scores (PRSs) differentiating ASD from ADHD are associated with cognitive impairments and alterations in cortical structures in SCZ patients. Based on the GWAS data (9,315 ASD and 11,964 ADHD patients), PRSs differentiating ADHD from ASD (indicating a greater risk of ADHD and a lower risk of ASD) were calculated for SCZ patients (n = 168). Cognitive performance, including verbal comprehension (VC), perceptual organization (PO), working memory (WM), and processing speed (PS), was assessed using the WAIS-III (n = 145). The surface areas and cortical thicknesses of 34 bilateral brain regions were extracted using FreeSurfer (n = 126). We examined the associations of these PRSs with cognitive performance and cortical structures in SCZ patients. Among the four cognitive domains, a higher PRS, indicating a greater risk of ADHD, was associated with impaired WM in SCZ patients (beta=-0.21, p = 0.012). A lower PRS, indicating a greater risk of ASD, was associated with decreased surface areas of the left medial orbitofrontal (beta = 0.21, p = 8.29 × 10(- 4)), left entorhinal (beta = 0.21, p = 0.025), left postcentral (beta = 0.18, p = 7.52 × 10(- 3)), right fusiform (beta = 0.17, p = 6.64 × 10(- 3)), and left fusiform cortices (beta = 0.17, p = 7.77 × 10(- 3)) in SCZ patients. A higher PRS, indicating a greater risk of ADHD, was associated with decreased cortical thickness in the bilateral transverse temporal regions (left, beta=-0.17, p = 0.039; right, beta=-0.17, p = 0.045). Our study revealed a relationship between genetic factors that differentiate ADHD patients from ASD patients and both cortical structure and cognitive performance in SCZ patients. These findings suggest that the heterogeneity of SCZ might be partly derived from genetic factors related to neurodevelopmental and psychiatric disorders other than SCZ.

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13. Lawson RJ, Lipovsek NJ, Brown SP, Jena AK, Osko JJ, Ransdell JL. Selective deletion of Tsc1 from mouse cerebellar Purkinje neurons drives sex-specific behavioral impairments linked to autism. bioRxiv;2024 (Aug 7)

There is a striking sex bias in the prevalence and severity of autism spectrum disorder (ASD) with 80% of diagnoses occurring in males. Because the molecular etiology of ASD is likely combinatorial, including interactions across multiple genetic and environmental factors, it is difficult to investigate the physiological mechanisms driving sex-specific differences. Loss of function mutations in TSC1 result in dysregulated mTORC1 signaling and underlie a multi-system disorder known as tuberous sclerosis (TSC). Interestingly, more than 50% of individuals diagnosed with TSC are also diagnosed with ASD, making TSC mutations one of the most prevalent monogenic causes of ASD. Mice harboring targeted deletion of Tsc1 selectively in cerebellar Purkinje neurons, referred to here as Tsc1 (mut/mut) , have multiple ASD-linked behavioral impairments, including deficits in social interactions, motor coordination, and vocalizations. However, these ASD-linked behavioral deficits have only been investigated using male Tsc1 (mut/mut) animals. Here, we used cohorts of male and female Tsc1 (mut/mut) animals to determine if behavioral impairments, previously identified in this model, are similar across sex. Specifically, we measured balance and motor coordination and social interaction behaviors in two age groups across sex. W e determined balance and motor coordination deficits are similar in male and female Tsc1 (mut/mut) mice, and that deficits in the firing of Tsc1 (mut/mut) Purkinje neurons located in the cerebellar vermis are also similar across sex. However, impairments in social approach behavior were found to be significantly more severe in Tsc1 (mut/mut) males compared to females. These results indicate the selective deletion of Tsc1 in Purkinje neurons differentially impairs cerebellar circuits based on sex.

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14. Li BZ, Poleg S, Ridenour M, Tollin D, Lei T, Klug A. Computational model for synthesizing auditory brainstem responses to assess neuronal alterations in aging and autistic animal models. bioRxiv;2024 (Aug 7)

The auditory brainstem response (ABR) is a widely used objective electrophysiology measure for non-invasively assessing auditory function and neural activities in the auditory brainstem, but its ability to reflect detailed neuronal processes is limited due to the averaging nature of the electroencephalogram recordings. This study addresses this limitation by developing a computational model of the auditory brainstem which is capable of synthesizing ABR traces based on a large, population scale neural extrapolation of a spiking neuronal network of auditory brainstem neural circuitry. The model was able to recapitulate alterations in ABR waveform morphology that have been shown to be present in two medical conditions: animal models of autism and aging. Moreover, in both of these conditions, these ABR alterations are caused by known distinct changes in auditory brainstem physiology, and the model could recapitulate these changes. In the autism model, the simulation revealed myelin deficits and hyperexcitability, which caused a decreased wave III amplitude and a prolonged wave III-V interval, consistent with experimentally recorded ABRs in Fmr1-KO mice. In the aging model, the model recapitulated ABRs recorded in aged gerbils and indicated a reduction in activity in the medial nucleus of the trapezoid body (MNTB), a finding validated by confocal imaging data. These results demonstrate not only the model’s accuracy but also its capability of linking features of ABR morphologies to underlying neuronal properties and suggesting follow-up physiological experiments. SIGNIFICANCE STATEMENT: This study presents a novel computational model of the auditory brainstem, capable of synthesizing auditory brainstem response (ABR) traces by simulating large-scale neuronal activities. Addressing limitations of traditional ABR measurements, the model links ABR waveform features to underlying neuronal properties. Validated using empirical ABRs from animal models of autism and aging, the model accurately reproduced observed ABR alterations, revealing influences of myelin deficits and hyperexcitability in Fragile X syndrome, and degraded inhibitory activity in aging. These findings, supported by experimental data, demonstrate the model’s potential for predicting changes in auditory brainstem physiology and guiding further physiological investigations, thus advancing our understanding of auditory neural processes.

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15. Limbers CA, Zeleznik T, Beuley G, Milliken A, Hernandez E, Ryan-Pettes SR. Age of Autism Spectrum Disorder Diagnosis and Patient-Centered Medical Home Components. J Clin Psychol Med Settings;2024 (Aug 7)

Early diagnosis of autism spectrum disorder (ASD) in children facilitates the provision of services and enhances opportunities for improving functioning via intervention. To date, limited studies have examined whether age of ASD diagnosis is associated with components of care of the patient-centered medical home (PCMH), a model of health care that emphasizes centralized, accessible, and coordinated care. The objective of the current study was to evaluate the associations between components of the PCMH and age of ASD diagnosis while controlling for associated clinical and socio-demographic factors, in a national sample of children 17 years and younger with ASD. The present study was a cross-sectional, observational study. Participants were caregivers of 1,193 children ages with ASD from the 2020 National Survey of Children’s Health (NSCH). Hierarchical multiple linear regression analysis was run with age of ASD diagnosis as the criterion variable in two regression models. The binary composite medical home proxy variable was investigated as well as the five individual medical home components (usual source of care, personal doctor or nurse, family-centered care, care coordination, able to obtain referrals when needed). In the first regression analysis, the overall PCMH proxy variable was significantly correlated with the age of ASD diagnosis (standardized beta coefficient = -.08; p < .01). Of the five components of the PCMH assessed in the second regression model, only usual source of sick care was significantly associated with the age of ASD diagnosis (standardized beta coefficient = -.11; p < .01). Having a usual source of sick care may be an important factor in receiving an earlier ASD diagnosis for children and adolescents.

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16. Luo Y, Wang L, Cao Y, Shen Y, Gu Y, Wang L. Reduced excitatory activity in the developing mPFC mediates a PV(H)-to-PV(L) transition and impaired social cognition in autism spectrum disorders. Transl Psychiatry;2024 (Aug 6);14(1):325.

Understanding the neuropathogenesis of impaired social cognition in autism spectrum disorders (ASD) is challenging. Altered cortical parvalbumin-positive (PV(+)) interneurons have been consistently observed in ASD, but their roles and the underlying mechanisms remain poorly understood. In our study, we observed a downward-shifted spectrum of PV expression in the developing medial prefrontal cortex (mPFC) of ASD mouse models due to decreased activity of PV(+) neurons. Surprisingly, chemogenetically suppressing PV(+) neuron activity during postnatal development failed to induce ASD-like behaviors. In contrast, lowering excitatory activity in the developing mPFC not only dampened the activity state and PV expression of individual PV(+) neurons, but also replicated ASD-like social deficits. Furthermore, enhancing excitation, but not PV(+) interneuron-mediated inhibition, rescued social deficits in ASD mouse models. Collectively, our findings propose that reduced excitatory activity in the developing mPFC may serve as a shared local circuitry mechanism triggering alterations in PV(+) interneurons and mediating impaired social functions in ASD.

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17. Mendes M, Chen DZ, Engchuan W, Leal TP, Thiruvahindrapuram B, Trost B, Howe JL, Pellecchia G, Nalpathamkalam T, Alexandrova R, Salazar NB, McKee EA, Alfaro NR, Lai MC, Bandres-Ciga S, Roshandel D, Bradley CA, Anagnostou E, Sun L, Scherer SW. Chromosome X-Wide Common Variant Association Study (XWAS) in Autism Spectrum Disorder. medRxiv;2024 (Jul 18)

Autism Spectrum Disorder (ASD) displays a notable male bias in prevalence. Research into rare (<0.1) genetic variants on the X chromosome has implicated over 20 genes in ASD pathogenesis, such as MECP2, DDX3X, and DMD. The "female protective effect" in ASD suggests that females may require a higher genetic burden to manifest similar symptoms as males, yet the mechanisms remain unclear. Despite technological advances in genomics, the complexity of the biological nature of sex chromosomes leave them underrepresented in genome-wide studies. Here, we conducted an X chromosome-wide association study (XWAS) using whole-genome sequencing data from 6,873 individuals with ASD (82% males) across Autism Speaks MSSNG, Simons Simplex Cohort SSC, and Simons Foundation Powering Autism Research SPARK, alongside 8,981 population controls (43% males). We analyzed 418,652 X-chromosome variants, identifying 59 associated with ASD (p-values 7.9×10(-6) to 1.51×10(-5)), surpassing Bonferroni-corrected thresholds. Key findings include significant regions on chrXp22.2 (lead SNP=rs12687599, p=3.57×10(-7)) harboring ASB9/ASB11, and another encompassing DDX53/PTCHD1-AS long non-coding RNA (lead SNP=rs5926125, p=9.47×10(-6)). When mapping genes within 10kb of the 59 most significantly associated SNPs, 91 genes were found, 17 of which yielded association with ASD (GRPR, AP1S2, DDX53, HDAC8, PCDH19, PTCHD1, PCDH11X, PTCHD1-AS, DMD, SYAP1, CNKSR2, GLRA2, OFD1, CDKL5, GPRASP2, NXF5, SH3KBP1). FGF13 emerged as a novel X-linked ASD candidate gene, highlighted by sex-specific differences in minor allele frequencies. These results reveal significant new insights into X chromosome biology in ASD, confirming and nominating genes and pathways for further investigation.

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18. Meuffels SA, Kuijpers-Jagtman AM, Tjoa STH, Carvajal Monroy PL. Orthodontic aligner therapy outcomes in children with autism spectrum disorder. Int J Paediatr Dent;2024 (Aug 6)

BACKGROUND: Children with autism spectrum disorder (ASD) face unique challenges in oral care. Aligner therapy offers a promising alternative to conventional approaches for this patient group. AIM: To evaluate orthodontic aligner therapy outcomes in children with ASD using the Peer Assessment Rating (PAR) Index and the Index of Complexity, Outcome, and Need (ICON), and to investigate whether concomitant disorders affect ICON, PAR scores, and treatment duration. DESIGN: Two calibrated observers assessed digital dental casts and intraoral pictures of 37 children with ASD before (T0) and after (T1) their treatment. At T0, the participants’ average age was 12.9 years (SD = 1.68); at T1, post-therapy, the average age was 14.9 years (SD = 1.51). All participants underwent orthodontic aligner therapy. Statistical methods employed in this study included descriptive analysis, Wilcoxon tests, and univariate linear regression. RESULTS: Posttreatment, median ICON scores decreased significantly from 74 to 14, and median PAR scores from 36 to 8 (p < .0001), demonstrating "excellent to substantial" improvement in 89.2% (n = 33) of the children. Comorbidities, present in 62% of patients, did not significantly affect treatment duration (22.6 ± 11.02 months). CONCLUSION: Children with ASD significantly benefit from orthodontic aligner therapy, emphasizing the need for tailored orthodontic care.

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19. Mohammad S, Gentreau M, Dubol M, Rukh G, Mwinyi J, Schiöth HB. Association of polygenic scores for autism with volumetric MRI phenotypes in cerebellum and brainstem in adults. Mol Autism;2024 (Aug 7);15(1):34.

Previous research on autism spectrum disorders (ASD) have showed important volumetric alterations in the cerebellum and brainstem. Most of these studies are however limited to case-control studies with small clinical samples and including mainly children or adolescents. Herein, we aimed to explore the association between the cumulative genetic load (polygenic risk score, PRS) for ASD and volumetric alterations in the cerebellum and brainstem, as well as global brain tissue volumes of the brain among adults at the population level. We utilized the latest genome-wide association study of ASD by the Psychiatric Genetics Consortium (18,381 cases, 27,969 controls) and constructed the ASD PRS in an independent cohort, the UK Biobank. Regression analyses controlled for multiple comparisons with the false-discovery rate (FDR) at 5% were performed to investigate the association between ASD PRS and forty-four brain magnetic resonance imaging (MRI) phenotypes among ~ 31,000 participants. Primary analyses included sixteen MRI phenotypes: total volumes of the brain, cerebrospinal fluid (CSF), grey matter (GM), white matter (WM), GM of whole cerebellum, brainstem, and ten regions of the cerebellum (I_IV, V, VI, VIIb, VIIIa, VIIIb, IX, X, CrusI and CrusII). Secondary analyses included twenty-eight MRI phenotypes: the sub-regional volumes of cerebellum including the GM of the vermis and both left and right lobules of each cerebellar region. ASD PRS were significantly associated with the volumes of seven brain areas, whereby higher PRS were associated to reduced volumes of the whole brain, WM, brainstem, and cerebellar regions I-IV, IX, and X, and an increased volume of the CSF. Three sub-regional volumes including the left cerebellar lobule I-IV, cerebellar vermes VIIIb, and X were significantly and negatively associated with ASD PRS. The study highlights a substantial connection between susceptibility to ASD, its underlying genetic etiology, and neuroanatomical alterations of the adult brain.

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20. O’Brien K, Agostino J, Ciszek K, Douglas KA. Risk of behavioural and developmental difficulties in early childhood in the Australian Capital Territory. Child Care Health Dev;2024 (Sep);50(5):e13314.

AIM: We aimed to estimate the prevalence of risk for developmental and behavioural problems for children in their first year of full-time primary education in the Australian Capital Territory (ACT). METHODS: We conducted an analysis of the 2014-2017 Kindergarten Health Check (KHC), an annual series of complete enumeration surveys of all children in their first year of full-time primary education in the ACT. Risk for developmental and behavioural problems was determined using the Parents’ Evaluation of Developmental Status (PEDS) questionnaire. RESULTS: 19 414 children (mean age 5.56 years; 51.4% boys; 2.3% Aboriginal and Torres Strait Islander; 18.4% quintile of greatest relative disadvantage) who participated in the 2014-2017 KHC were included in the study (87%). More than half of ACT children in their first year of primary education had low/no developmental risk identified through the PEDS questionnaire, with 1 in 10 at high risk. CONCLUSIONS: Those more likely to have a high risk PEDS score were boys, those from the areas experiencing relative disadvantage, and Aboriginal and Torres Strait Islander children. While we can identify children at risk through screening, the greater challenge remains to identify and address the underlying causes of healthy inequalities, even within highly socioeconomically advantaged communities.

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21. Posar A, Visconti P. Possible Overestimation of Comorbid Oppositional Defiant Disorder in Autism Spectrum Disorder. Turk Arch Pediatr;2024 (Mar 7);59(3):330-331.

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22. Qiu L, Liang C, Kochunov P, Hutchison KE, Sui J, Jiang R, Zhi D, Vergara VM, Yang X, Zhang D, Fu Z, Bustillo JR, Qi S, Calhoun VD. Associations of alcohol and tobacco use with psychotic, depressive and developmental disorders revealed via multimodal neuroimaging. Transl Psychiatry;2024 (Aug 7);14(1):326.

People affected by psychotic, depressive and developmental disorders are at a higher risk for alcohol and tobacco use. However, the further associations between alcohol/tobacco use and symptoms/cognition in these disorders remain unexplored. We identified multimodal brain networks involving alcohol use (n = 707) and tobacco use (n = 281) via supervised multimodal fusion and evaluated if these networks affected symptoms and cognition in people with psychotic (schizophrenia/schizoaffective disorder/bipolar, n = 178/134/143), depressive (major depressive disorder, n = 260) and developmental (autism spectrum disorder/attention deficit hyperactivity disorder, n = 421/346) disorders. Alcohol and tobacco use scores were used as references to guide functional and structural imaging fusion to identify alcohol/tobacco use associated multimodal patterns. Correlation analyses between the extracted brain features and symptoms or cognition were performed to evaluate the relationships between alcohol/tobacco use with symptoms/cognition in 6 psychiatric disorders. Results showed that (1) the default mode network (DMN) and salience network (SN) were associated with alcohol use, whereas the DMN and fronto-limbic network (FLN) were associated with tobacco use; (2) the DMN and fronto-basal ganglia (FBG) related to alcohol/tobacco use were correlated with symptom and cognition in psychosis; (3) the middle temporal cortex related to alcohol/tobacco use was associated with cognition in depression; (4) the DMN related to alcohol/tobacco use was related to symptom, whereas the SN and limbic system (LB) were related to cognition in developmental disorders. In summary, alcohol and tobacco use were associated with structural and functional abnormalities in DMN, SN and FLN and had significant associations with cognition and symptoms in psychotic, depressive and developmental disorders likely via different brain networks. Further understanding of these relationships may assist clinicians in the development of future approaches to improve symptoms and cognition among psychotic, depressive and developmental disorders.

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23. Sepehri Bonab H, Ebrahimi Sani S, Behzadnia B. The Impact of Virtual Reality Intervention on Emotion Regulation and Executive Functions in Autistic Children. Games Health J;2024 (Aug 7)

Introduction: Autistic children may encounter difficulties in managing emotions and executive functions (EFs), which can contribute to mental and health challenges. Recognizing physical activities as a potential strategy for enhancing emotion regulation (ER), this study aims to investigate the efficacy of a virtual reality (VR)-based physical exercise program in improving ER and EFs among children with autism spectrum disorder (ASD). Materials and Methods: Forty boys diagnosed with ASD, aged 7 to 10 years, were randomly assigned to two groups: a VR intervention group (n = 20) and a control group (n = 20). The intervention group participated in a VR program, while the control group solely concentrated on engaging in sedentary and inactive video gaming. EFs were evaluated through the utilization of both the flanker task and the Wisconsin card sorting task, both administered initially at baseline and subsequently after an 8-week interval. In addition, the parents of the children completed the Emotion Regulation Checklist to evaluate their ER skills. Results: According to the results, a significant difference was observed between the two groups in terms of EFs and the ability to regulate emotion (P < 0.05). The intervention group demonstrated a notable improvement in ER skills and exhibited superior executive functioning abilities compared with the control group. Conclusion: It appears that VR exercises can serve as a preliminary trial to enhance EFs and ER in children with autism. In addition, they may prove effective as complementary interventions to traditional educational strategies in preventing future challenges associated with ASD.

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24. Silva FAE, J PM, Mira Coelho A. Evaluation of the Behavioral Effect of Psychostimulants in Children with Autism Spectrum Disorder: A Cross-Sectional Study. Neuropediatrics;2024 (Aug 6)

BACKGROUND:  Autism spectrum disorder (ASD) is often accompanied by comorbid conditions such as attention deficit hyperactivity disorder and epilepsy. In this context, patients are often treated with psychostimulants in an attempt to control behavioral symptoms. This study aims to understand the behavioral effects of psychostimulants in children with ASD and investigate if interictal epileptiform discharges on electroencephalogram (EEG) can act as a modifying factor in this behavior. METHODS:  Sixty-eight patients with ASD who were being accompanied in the Department of Child and Adolescent Psychiatry of the Centro Hospitalar Universitário de São João and had previously done an EEG assessment answered a questionnaire regarding their behavioral response to psychostimulants. RESULTS:  In total, 47.4% of patients reported improved agitation, 56.1% enhanced concentration, and 8.8% improved sleep. Conversely, 28.1% experienced worsened agitation, 15.8% worsened concentration, and 17.5% worsened sleep. The remaining reported no alterations. The age of diagnosis correlated significantly with improved agitation, with a higher diagnosis age being associated with a higher probability of improvement. Extended-release methylphenidate and genetic variations were significantly associated with worsening of agitation. Regarding speech, 86% exhibited no changes, while 14% showed alterations, mostly, 87.5%, characterized as negative. For other behavioral alterations, 45.6% reported negative changes, 3.5% reported positive changes, and 50.9% reported no additional alterations. Female gender was significantly associated with other negative behavioral changes. A significant correlation was found between treatment duration and the probability of improvement in agitation, concentration, and other behavioral changes.

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25. Song Y, Kim J, Choi Y, Lee JH, Cheong J, Park W. Oral hygiene changes & compliance with telemonitoring device in individuals with intellectual/developmental disabilities: a randomized controlled crossover trial. Clin Oral Investig;2024 (Aug 7);28(9):471.

OBJECTIVE: Advances in mobile technology are helping with health management practices, and smart toothbrushes provide proper dental care by collecting and analyzing users’ toothbrushing data. The purpose of this study is to assess the effect of a telemonitoring device on oral hygiene management in individuals with intellectual or developmental disabilities and its role in promoting oral health. MATERIALS AND METHODS: Participants were split into two groups: one initially using the telemonitoring device (telemonitoring device/manual toothbrush) and the other using it later (manual toothbrush/telemonitoring device), with a one-month washout period. The study compared plaque index, halitosis, changes in oral microbiota, and guardian questionnaire responses between the groups. RESULTS: In period 1, the QHI index score significantly decreased from 1.93 to 0.83 in the group using the remote monitoring device, compared to an increase from 1.75 to 2.01 in the manual toothbrush group. Additionally, toothbrushing frequency, time, and cooperation increased by 0.82 ± 0.60, 0.82 ± 1.16, and 1.09 ± 0.94, respectively, with initial telemonitoring device use. However, these measures decreased by -1.45 ± 0.68, -1.09 ± 0.70, and - 1.00 ± 1.00 after switching to a manual toothbrush, and decreased by -0.64 ± 0.67, -0.27 ± 1.19, and 0.09 ± 0.94 overall, respectively. However, there were no significant differences in oral microbiota between the groups at these different time points. CONCLUSIONS: The study shows that telemonitoring devices effectively reduce plaque index and improve toothbrushing frequency, time, and cooperation. However, these benefits decrease after switching to a manual toothbrush. Follow-up is needed to assess satisfaction and compliance with telemonitoring device use. CLINICAL RELEVANCE: Using telemonitoring devices in the oral health management of individuals with intellectual and developmental disabilities can improve their oral health quality.

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26. Symeonides C, Vacy K, Thomson S, Tanner S, Chua HK, Dixit S, Mansell T, O’Hely M, Novakovic B, Herbstman JB, Wang S, Guo J, Chia J, Tran NT, Hwang SE, Britt K, Chen F, Kim TH, Reid CA, El-Bitar A, Bernasochi GB, Delbridge LMD, Harley VR, Yap YW, Dewey D, Love CJ, Burgner D, Tang MLK, Sly PD, Saffery R, Mueller JF, Rinehart N, Tonge B, Vuillermin P, Ponsonby AL, Boon WC. Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10HDA ameliorates the related mouse phenotype. Nat Commun;2024 (Aug 7);15(1):6367.

Male sex, early life chemical exposure and the brain aromatase enzyme have been implicated in autism spectrum disorder (ASD). In the Barwon Infant Study birth cohort (n = 1074), higher prenatal maternal bisphenol A (BPA) levels are associated with higher ASD symptoms at age 2 and diagnosis at age 9 only in males with low aromatase genetic pathway activity scores. Higher prenatal BPA levels are predictive of higher cord blood methylation across the CYP19A1 brain promoter I.f region (P = 0.009) and aromatase gene methylation mediates (P = 0.01) the link between higher prenatal BPA and brain-derived neurotrophic factor methylation, with independent cohort replication. BPA suppressed aromatase expression in vitro and in vivo. Male mice exposed to mid-gestation BPA or with aromatase knockout have ASD-like behaviors with structural and functional brain changes. 10-hydroxy-2-decenoic acid (10HDA), an estrogenic fatty acid alleviated these features and reversed detrimental neurodevelopmental gene expression. Here we demonstrate that prenatal BPA exposure is associated with impaired brain aromatase function and ASD-related behaviors and brain abnormalities in males that may be reversible through postnatal 10HDA intervention.

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27. Trayvick J, Barkley SB, McGowan A, Srivastava A, Peters AW, Cecchi GA, Foss-Feig JH, Corcoran CM. Speech and language patterns in autism: Towards natural language processing as a research and clinical tool. Psychiatry Res;2024 (Oct);340:116109.

Speech and language differences have long been described as important characteristics of autism spectrum disorder (ASD). Linguistic abnormalities range from prosodic differences in pitch, intensity, and rate of speech, to language idiosyncrasies and difficulties with pragmatics and reciprocal conversation. Heterogeneity of findings and a reliance on qualitative, subjective ratings, however, limit a full understanding of linguistic phenotypes in autism. This review summarizes evidence of both speech and language differences in ASD. We also describe recent advances in linguistic research, aided by automated methods and software like natural language processing (NLP) and speech analytic software. Such approaches allow for objective, quantitative measurement of speech and language patterns that may be more tractable and unbiased. Future research integrating both speech and language features and capturing « natural language » samples may yield a more comprehensive understanding of language differences in autism, offering potential implications for diagnosis, intervention, and research.

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28. Wang HC, Feldman DE. Degraded tactile coding in the Cntnap2 mouse model of autism. Cell Rep;2024 (Aug 27);43(8):114612.

Atypical sensory processing is common in autism, but how neural coding is disrupted in sensory cortex is unclear. We evaluate whisker touch coding in L2/3 of somatosensory cortex (S1) in Cntnap2(-/-) mice, which have reduced inhibition. This classically predicts excess pyramidal cell spiking, but this remains controversial, and other deficits may dominate. We find that c-fos expression is elevated in S1 of Cntnap2(-/-) mice under spontaneous activity conditions but is comparable to that of control mice after whisker stimulation, suggesting normal sensory-evoked spike rates. GCaMP8m imaging from L2/3 pyramidal cells shows no excess whisker responsiveness, but it does show multiple signs of degraded somatotopic coding. This includes broadened whisker-tuning curves, a blurred whisker map, and blunted whisker point representations. These disruptions are greater in noisy than in sparse sensory conditions. Tuning instability across days is also substantially elevated in Cntnap2(-/-). Thus, Cntnap2(-/-) mice show no excess sensory-evoked activity, but a degraded and unstable tactile code in S1.

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