1. Uncovering links between parental inflammatory bowel disease and autism in children. Nat Med;2022 (Jul 13):1-2.

Findings from a nationwide cohort study in Sweden, polygenic risk score analyses in a general population-based cohort in the United Kingdom, Mendelian randomization analyses and genetic correlation (linkage disequilibrium) analyses suggest a link between parental diagnosis of and genetic liability to inflammatory bowel disease and autism in children.

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2. Adams HC, Zlomke KR, Rossetti KG. Finding Benefit and Feeling Strain in Parenting a Child with Autism Spectrum Disorder. J Autism Dev Disord;2022 (Jul 11)

Female caregivers of children with autism spectrum disorder (ASD) often report higher levels of psychological distress related to increased levels of caregiver strain, as well as frequency and severity of child problem behaviors (CPB). However, despite reported distress, caregivers have also reported benefits. A sample of n = 259 female caregivers of children with ASD completed online surveys assessing CPB, caregiver strain, psychological distress, and benefit finding. Results suggest that objective caregiver strain is a significant mediator between CPB and caregiver distress. Benefit finding, however, was not found to be a significant moderator. These findings inform theoretical applications and provide implications for future research in the development of interventions to enhance functioning in female caregivers.

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3. Alberts LB, Kettering TL. Preliminary Development and Testing of the Risk Assessment Checklist for Self-Injury in Autism-Medical (RACSA-M). J Dr Nurs Pract;2022 (Jul 1);15(2):75-83.

Self-injurious behavior (SIB) is a major treatment focus for clinicians treating children with autism spectrum disorder (ASD). A review of the literature identified medical conditions that may be risk factors for an individual engaging in SIB. This study involved the creation and preliminary validation of a standardized assessment checklist: Risk Assessment Checklist for Self-Injury in Autism-Medical (RASCA-M) for the physical, behavioral, and diagnostic evaluation of non-verbal children with autism and SIB living in a residential setting. Preliminary content validity, criterion-related validity, and interobserver agreement were established. The RACSA-M is a promising instrument to assess underlying medical issues in non-verbal children with ASD and SIB.

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4. Alder ML, Johnson CR, Zauszniewski JA, Malow BA, Burant CJ, Scahill L. Feasibility of Actigraphy for Evaluating Sleep and Daytime Physical Activity in Children with Autism Spectrum Disorder. J Autism Dev Disord;2022 (Jul 13)

This research evaluated the feasibility of actigraphy to measure sleep and physical activity in children (ages 2-8 years) with autism spectrum disorder (ASD). We also explored associations between sleep and physical activity. Validated screening measures established eligibility. Questionnaires, diaries, and 5 days and 5 nights of actigraphy monitoring were used to collect data. Of the 32 children enrolled, 27 (84.4%) completed actigraphy monitoring. Based on the median steps per day, children with high physical activity had lower total sleep time and more disruptive behaviors than children with low physical activity. Findings support the feasibility of using actigraphy to measure sleep and physical activity in children with ASD. Larger studies are needed to evaluate interactions of physical activity on sleep in this population.

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5. Alpay M, Yucel F. Changes of Cerebellar Cortex in a Valproic Acid-Induced Rat Model of Autism. Int J Dev Neurosci;2022 (Jul 13)

In this study, 32 male Sprague-Dawley rats (8 for each group) were used in total to examine the effects of valproic acid on rat cerebellum. It was determined that the experimental group received valproic acid (600mg/kg) on embryonic day 15 and postnatal day 11, whereas the control group was treated with saline on the same days. Moreover, on the postnatal 30(th) day, the cerebellums of all pups were removed and prepared for light and electron microscopy. The numerical density of granule cells in the cerebellum of experimental groups of rats increased whereas the numerical density of Purkinje cells decreased. Furthermore, the granule cells had a smaller mean nuclear diameter in one of the experimental groups while the Purkinje cells had in both experimental groups than those in the comparison group. Thus, the numerical density of synaptic discs and their mean diameter in the cerebellar granular layer of experimental groups were significantly decreased compared to the corresponding controls; also, the synapse-to-neurons ratio, a parameter indicating interneural connectivity, was the same. Consequently, it was seen that valproic acid administration to pups in prenatal or early postnatal days causes changes in number of neurons and synapses in the cerebellum of rats.

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6. Ash RT, Palagina G, Fernandez-Leon JA, Park J, Seilheimer R, Lee S, Sabharwal J, Reyes F, Wang J, Lu D, Sarfraz M, Froudarakis E, Tolias AS, Wu SM, Smirnakis SM. Increased reliability of visually-evoked activity in area V1 of the MECP2-duplication mouse model of autism. J Neurosci;2022 (Jul 13)

Atypical sensory processing is now thought to be a core feature of the autism spectrum. Influential theories have proposed that both increased and decreased neural response reliability within sensory systems could underlie altered sensory processing in autism. Here, we report evidence for abnormally increased reliability of visual-evoked responses in layer 2/3 neurons of adult male and female primary visual cortex in the MECP2-duplication syndrome animal model of autism. Increased response reliability was due in part to decreased response amplitude, decreased fluctuations in endogenous activity, and an abnormal decoupling of visual-evoked activity from endogenous activity. Similar to what was observed neuronally, the optokinetic reflex occurred more reliably at low contrasts in mutant mice compared to controls. Retinal responses did not explain our observations. These data suggest that the circuit mechanisms for combining sensory-evoked and endogenous signal and noise processes may be altered in this form of syndromic autism.SIGNIFICANT STATEMENT:Atypical sensory processing is now thought to be a core feature of the autism spectrum. Influential theories have proposed that both increased and decreased neural response reliability within sensory systems could underlie altered sensory processing in autism. Here, we report evidence for abnormally increased reliability of visual-evoked responses in primary visual cortex of the animal model for MECP2-duplication syndrome, a high-penetrance single-gene cause of autism. Visual-evoked activity was abnormally decoupled from endogenous activity in mutant mice, suggesting in line with the influential « hypo-priors » theory of autism that sensory priors embedded in endogenous activity may have less influence on perception in autism.

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7. Bove M, Schiavone S, Tucci P, Sikora V, Dimonte S, Colia AL, Morgese MG, Trabace L. Ketamine administration in early postnatal life as a tool for mimicking Autism Spectrum Disorders core symptoms. Prog Neuropsychopharmacol Biol Psychiatry;2022 (Jul 13);117:110560.

Autism Spectrum Disorders (ASD) core symptoms include deficits of social interaction, stereotyped behaviours, dysfunction in language and communication. Beyond them, several additional symptoms, such as cognitive impairment, anxiety-like states and hyperactivity are often occurring, mainly overlapping with other neuropsychiatric diseases. To untangle mechanisms underlying ASD etiology, and to identify possible pharmacological approaches, different factors, such as environmental, immunological and genetic ones, need to be considered. In this context, ASD animal models, aiming to reproduce the wide range of behavioural phenotypes of this uniquely human disorder, represent a very useful tool. Ketamine administration in early postnatal life of mice has already been studied as a suitable animal model resembling psychotic-like symptoms. Here, we investigated whether ketamine administration, at postnatal days 7, 9 and 11, might induce behavioural features able to mimic ASD typical symptoms in adult mice. To this aim, we developed a 4-days behavioural tests battery, including Marble Burying, Hole Board, Olfactory and Social tests, to assess repetitive and stereotyped behaviour, social deficits and anxiety-like symptoms. Moreover, by using this mouse model, we performed neurochemical and biomolecular analyses, quantifying neurotransmitters belonging to excitatory-inhibitory pathways, such as glutamate, glutamine and gamma-aminobutyric acid (GABA), as well as immune activation biomarkers related to ASD, such as CD11b and glial fibrillary acidic protein (GFAP), in the hippocampus and amygdala. Possible alterations in levels of brain-derived neurotrophic factor (BDNF) expression in the hippocampus and amygdala were also evaluated. Our results showed an increase in stereotyped behaviours, together with social impairments and anxiety-like behaviour in adult mice, receiving ketamine administration in early postnatal life. In addition, we found decreased BDNF and enhanced GFAP hippocampal expression levels, accompanied by elevations in glutamate amount, as well as reduction in GABA content in amygdala and hippocampus. In conclusion, early ketamine administration may represent a suitable animal model of ASD, exhibiting face validity to mimic specific ASD symptoms, such as social deficits, repetitive repertoire and anxiety-like behaviour.

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8. Chiu HM, Chen CT, Tsai CH, Li HJ, Wu CC, Huang CY, Chen KL. Theory of Mind Predicts Social Interaction in Children with Autism Spectrum Disorder: A Two-Year Follow-Up Study. J Autism Dev Disord;2022 (Jul 13)

This two-year follow-up study examined the predictive relationships of theory of mind (ToM) to social interaction by reciprocal social behaviors (RSBs) and social functioning (SF) in 106 children with ASD. The results of the path analysis showed that the earlier ToM predicted children’s current component RSBs (B = 3.53, SE = 1.86, p = 0.039) and the current SF (B = 1.79-1.87, SE = 0.03-0.34, p < 0.001). The aloof and passive social interaction styles predicted fewer turn-taking of RSBs (B =  - 48.77 to - 111.17, p < 0.001) and fewer components of RSBs (B =  - 36.30 to - 81.41, p < 0.001). This finding provides empirical evidence that ToM predicts social interaction in children with ASD.

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9. Chu MC, Wu HF, Lee CW, Chung YJ, Chi H, Chen PS, Lin HC. Generational synaptic functions of GABA(A) receptor β3 subunit deteriorations in an animal model of social deficit. J Biomed Sci;2022 (Jul 11);29(1):51.

BACKGROUND: Disruption of normal brain development is implicated in numerous psychiatric disorders with neurodevelopmental origins, including autism spectrum disorder (ASD). Widespread abnormalities in brain structure and functions caused by dysregulations of neurodevelopmental processes has been recently shown to exert adverse effects across generations. An imbalance between excitatory/inhibitory (E/I) transmission is the putative hypothesis of ASD pathogenesis, supporting by the specific implications of inhibitory γ-aminobutyric acid (GABA)ergic system in autistic individuals and animal models of ASD. However, the contribution of GABAergic system in the neuropathophysiology across generations of ASD is still unknown. Here, we uncover profound alterations in the expression and function of GABA(A) receptors (GABA(A)Rs) in the amygdala across generations of the VPA-induced animal model of ASD. METHODS: The F2 generation was produced by mating an F1 VPA-induced male offspring with naïve females after a single injection of VPA on embryonic day (E12.5) in F0. Autism-like behaviors were assessed by animal behavior tests. Expression and functional properties of GABA(A)Rs and related proteins were examined by using western blotting and electrophysiological techniques. RESULTS: Social deficit, repetitive behavior, and emotional comorbidities were demonstrated across two generations of the VPA-induced offspring. Decreased synaptic GABA(A)R and gephyrin levels, and inhibitory transmission were found in the amygdala from two generations of the VPA-induced offspring with greater reductions in the F2 generation. Weaker association of gephyrin with GABA(A)R was shown in the F2 generation than the F1 generation. Moreover, dysregulated NMDA-induced enhancements of gephyrin and GABA(A)R at the synapse in the VPA-induced offspring was worsened in the F2 generation than the F1 generation. Elevated glutamatergic modifications were additionally shown across generations of the VPA-induced offspring without generation difference. CONCLUSIONS: Taken together, these findings revealed the E/I synaptic abnormalities in the amygdala from two generations of the VPA-induced offspring with GABAergic deteriorations in the F2 generation, suggesting a potential therapeutic role of the GABAergic system to generational pathophysiology of ASD.

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10. da Cruz FM. Multimodal interaction analysis of non-lexical vocalisations in low-verbal autistic children. Clin Linguist Phon;2022 (Jul 13):1-22.

This article analyses non-lexical vocalisations produced by low-verbal autistic children. Seven dyads of naturalistic interactions between non-autistic adults and low-verbal autistic children over five years old were analysed from a multimodal conversation analysis perspective. Data were extracted from an audio-visual corpus of interactions in institutional (school) and non-institutional settings (home). The data are in Brazilian Portuguese. The videos are visualised using the ELAN tool and transcribed. The analyses showed that in some cases participants did not reach a mutual understanding of the semantic meaning of non-lexical vocalisations, while in other cases, the meanings of vocalisations emerged between the participants in the multimodal process of sense-making in their embodied context. A microanalysis of where these vocalisations occurred and their multimodal aspects (linguistics, bodily, material, and spatial) suggests that: a) such occurrences are both initiated by the autistic child and responsive to the non-autistic interlocutor’s turn; b) some vocalisations play an important role in the sequential organisation of the interaction, promoting the maintenance of intersubjective of low verbal children; and c) non-autistic adult interlocutors perform a varied set of actions, recycling, incorporating, retaking, assigning meaning, and repairing the non-lexical vocalisations produced by autistic children. The indexical analysis shows how communicative ecologies create meaning. This study thus contributes to our understanding of the interactional behaviour of these children and their interlocutors.

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11. Liu X, Wang Z, Zhang X, Zhang D, Yang Q, Hu P, Li F. LncRNA MEG3 activates CDH2 expression by recruitment of EP300 in valproic acid-induced autism spectrum disorder. Neurosci Lett;2022 (Jul 13);783:136726.

LncRNAs partake in the biological processes contributing to development of autism spectrum disorder (ASD). The aim of the present study is to investigate the effects of lncRNA maternally expressed gene 3 (MEG3) on viability and apoptosis of hippocampal neurons from ASD rats. Rats with ASD were induced using valproic acid (VPA) with normal saline (NS) as control. We performed microarray analysis on hippocampal tissues of NS rats and ASD rats to screen the differentially expressed lncRNAs. MEG3 loss in rats alleviated the impairment of learning and memory abilities induced by VPA, and promoted neuronal viability and inhibited apoptosis. MEG3 could recruit the transcription factor E1A binding protein p300 (EP300) in the nucleus and promote the cadherin 2 (CDH2) expression. CDH2 depletion in rats ameliorated the impairment of learning and memory capacities in ASD rats. After upregulation of CDH2 in neurons with sh-MEG3, we found diminished viability and increased apoptosis in hippocampal neurons of ASD rats. Taken together, MEG3 supports activation of CDH2 via EP300, thus repressing the viability of hippocampal neurons. Therefore, MEG3 upregulation may be partially responsible for the pathogenesis of ASD.

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12. Long J, Lu F, Yang S, Zhang Q, Chen X, Pang Y, Wang M, He B, Liu H, Duan X, Chen H, Ye S. Different functional connectivity optimal frequency in autism compared with healthy controls and the relationship with social communication deficits: Evidence from gene expression and behavior symptom analyses. Hum Brain Mapp;2022 (Jul 13)

Studies have reported that different brain regions/connections possess distinct frequency properties, which are related to brain function. Previous studies have proposed altered brain activity frequency and frequency-specific functional connectivity (FC) patterns in autism spectrum disorder (ASD), implying the varied dominant frequency of FC in ASD. However, the difference of the dominant frequency of FC between ASD and healthy controls (HCs) remains unclear. In the present study, the dominant frequency of FC was measured by FC optimal frequency, which was defined as the intermediate of the frequency bin at which the FC strength could reach the maximum. A multivariate pattern analysis was conducted to determine whether the FC optimal frequency in ASD differs from that in HCs. Partial least squares regression (PLSR) and enrichment analyses were conducted to determine the relationship between the FC optimal frequency difference of ASD/HCs and cortical gene expression. PLSR analyses were also performed to explore the relationship between FC optimal frequency and the clinical symptoms of ASD. Results showed a significant difference of FC optimal frequency between ASD and HCs. Some genes whose cortical expression patterns are related to the FC optimal frequency difference of ASD/HCs were enriched for social communication problems. Meanwhile, the FC optimal frequency in ASD was significantly related to social communication symptoms. These results may help us understand the neuro-mechanism of the social communication deficits in ASD.

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13. Melo X, Marôco JL, Pinto R, Angarten VG, Coimbra M, Correia D, Roque M, Reis JF, Santos V, Fernhall B, Santa-Clara H. The Acute Effect of Maximal Exercise on Arterial Stiffness in Adults with and without Intellectual and Developmental Disabilities. Appl Physiol Nutr Metab;2022 (Jul 12)

PURPOSE: We compared central and peripheral arterial stiffness response patterns between persons with and without intellectual and developmental disabilities (IDD) of different age groups at rest and following a cardiopulmonary exercise test (CPET). METHODS: 15 young adults with and without IDD, and 15 middle-aged adults without IDD performed a CPET. Central and peripheral arterial stiffness were measured at rest and following CPET using estimates of carotid-femoral (cfPWV), carotid-radial (crPWV), and carotid-ankle (cdPWV) pulse wave velocity derived from piezoelectric mechano-transducers. RESULTS: cfPWV remained unchanged following CPET in adults with and without IDD but increased in middle-aged adults (d= 0.85; 95% CI: 0.27 to 1.42 m.s-1, p= 0.005), whereas cdPWV was similarly reduced (d= -0.77; 95% CI: -1.06 to -0.48 m.s-1, p< 0.001) in all groups. crPWV remained unchanged in all groups. These results were independent of exercise-related changes in mean arterial pressure. Overall group differences suggested that persons with IDD (d = - 1.78; 95% CI: -3.20 to -0.37 m.s-1, p= 0.009) and without IDD (d = -1.84; 95% CI: -3.26 to -0.43 m.s-1, p= 0.007) had lower cfPWV than middle-aged adults. CONCLUSION: We found no evidence of early vascular aging and diminished vascular reserve following CPET in adults with IDD.

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14. Netser S, Nahardiya G, Weiss-Dicker G, Dadush R, Goussha Y, John SR, Taub M, Werber Y, Sapir N, Yovel Y, Harony-Nicolas H, Buxbaum JD, Cohen L, Crammer K, Wagner S. TrackUSF, a novel tool for automated ultrasonic vocalization analysis, reveals modified calls in a rat model of autism. BMC Biol;2022 (Jul 12);20(1):159.

BACKGROUND: Various mammalian species emit ultrasonic vocalizations (USVs), which reflect their emotional state and mediate social interactions. USVs are usually analyzed by manual or semi-automated methodologies that categorize discrete USVs according to their structure in the frequency-time domains. This laborious analysis hinders the effective use of USVs as a readout for high-throughput analysis of behavioral changes in animals. RESULTS: Here we present a novel automated open-source tool that utilizes a different approach towards USV analysis, termed TrackUSF. To validate TrackUSF, we analyzed calls from different animal species, namely mice, rats, and bats, recorded in various settings and compared the results with a manual analysis by a trained observer. We found that TrackUSF detected the majority of USVs, with less than 1% of false-positive detections. We then employed TrackUSF to analyze social vocalizations in Shank3-deficient rats, a rat model of autism, and revealed that these vocalizations exhibit a spectrum of deviations from appetitive calls towards aversive calls. CONCLUSIONS: TrackUSF is a simple and easy-to-use system that may be used for a high-throughput comparison of ultrasonic vocalizations between groups of animals of any kind in any setting, with no prior assumptions.

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15. Niarchou M, Singer EV, Straub P, Malow BA, Davis LK. Investigating the genetic pathways of insomnia in Autism Spectrum Disorder. Res Dev Disabil;2022 (Jul 9);128:104299.

BACKGROUND: Sleep problems are common in children with autism spectrum disorder (autism). There is sparse research to date to examine whether insomnia in people with autism is related to autism genetics or insomnia genetics. Moreover, there is a lack of research examining whether circadian-rhythm related genes share potential pathways with autism. AIMS: To address this research gap, we tested whether polygenic scores of insomnia or autism are related to risk of insomnia in people with autism, and whether the circadian genes are associated with insomnia in people with autism. METHODS AND PROCEDURES: We tested these questions using the phenotypically and genotypically rich MSSNG dataset (N = 1049) as well as incorporating in the analyses data from the Vanderbilt University Biobank (BioVU) (N = 349). OUTCOMES AND RESULTS: In our meta-analyzed sample, there was no evidence of associations between the polygenic scores (PGS) for insomnia and a clinical diagnosis of insomnia, or between the PGS of autism and insomnia. We also did not find evidence of a greater burden of rare and disruptive variation in the melatonin and circadian genes in individuals with autism and insomnia compared to individuals with autism without insomnia. CONCLUSIONS AND IMPLICATIONS: Overall, we did not find evidence for strong effects of genetic scores influencing sleep in people with autism, however, we cannot rule out the possibility that smaller genetic effects may play a role in sleep problems. Our study indicated the need for a larger collection of data on sleep problems and sleep quality among people with autism.

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16. Rahdar M, Hajisoltani R, Davoudi S, Asaad Karimi S, Borjkhani M, Ahli Khatibi V, Hosseinmardi N, Behzadi G, Janahmadi M. Alterations in the intrinsic discharge activity of CA1 pyramidal neurons associated with possible changes in the NADPH diaphorase activity in a rat model of autism induced by prenatal exposure to valproic acid. Brain Res;2022 (Jul 13):148013.

Autism spectrum disorder is a neurodevelopmental disorder characterized by sensory abnormalities, social skills impairment and cognitive deficits. Although recent evidence indicated that induction of autism-like behavior in animal models causes abnormal neuronal excitability, the impact of autism on neuronal properties is still an important issue. Thus, new findings at the cellular level may shed light on the pathophysiology of autism and may help to find effective treatment strategies. Here, we investigated the behavioral, electrophysiological and histochemical impacts of prenatal exposure to valproic acid (VPA) in rats. Findings revealed that VPA exposure caused a significant increase in the hot plate response latency. The novel object recognition ability was also impaired in VPA-exposed rats. Along with these behavioral alterations, neurons from VPA-exposed animals exhibited altered excitability features in response to depolarizing current injections relative to control neurons. In the VPA-exposed group, these changes consisted of a significant increase in the amplitude, evoked firing frequency and the steady-state standard deviation of spike timing of action potentials (APs). Moreover, the half-width, the AHP amplitude and the decay time constant of APs were significantly decreased in this group. These changes in the evoked electrophysiological properties were accompanied by intrinsic hyperexcitability and lower spike-frequency adaptation and also a significant increase in the number of NADPH-diaphorase stained neurons in the hippocampal CA1 area of the VPA-exposed rats. Taken together, findings demonstrate that abnormal nociception and recognition memory is associated with alterations in the neuronal responsiveness and nitrergic system in a rat model of autism-like.

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17. Rodriguez L, Morley-Fletcher A, Winter H, Buie T. « Evaluation of gastroesophageal reflux disease in children on the autism spectrum: a study evaluating the tolerance and utility of the BRAVO wireless pH monitoring ». J Pediatr Gastroenterol Nutr;2022 (Jul 13)

OBJECTIVE: Children on the autism spectrum disorder (ASD) may express pain or discomfort through stereotypic or self-injurious behaviors. Gastroesophageal reflux disease (GERD) may be challenging to diagnose in a child who is non-verbal or has impaired communication skills, diagnostic testing for GERD may be the only way to establish the diagnosis. We report our experience using the BRAVO wireless pH monitoring device for the evaluation of GERD in this patient population. METHODS: Tolerance and feasibility as well as pH parameters and symptom correlation of the BRAVO pH were evaluated retrospectively in ASD children and compared it to a large cohort of non-ASD children. Only patients with studies lasting >24 hours were included. RESULTS: A total of 172 patients were included, 27 of those were diagnosed with autism (median age 11 years, 17 male). We found no difference in age and weight between both groups but there was a male predominance in the autism group (p=0.007). We found no difference in the ability to complete at least 24 hours of study duration between both groups (24/27 or 89% in ASD vs. 133/145 or 92% non-ASD patients, p=0.632). We also found no difference in the median reflux index on the worst day (p=0.27) or the average of both days (p=0.75), BRAVO pH parameters and the proportion of abnormal studies between ASD and non-ASD children. When evaluating the overall symptom correlation with GER episodes we did not find a difference between both groups, but we did find a higher symptom correlation for GER symptom during supine position in ASD children. Study was performed for behavioral indication in 11 ASD children, all had normal esophageal mucosa but 4 of those had an abnormal BRAVO pH study.No significant side effects were reported during the study, only 2 patients (one non-ASD and one ASD) complained of self-limited chest pain. CONCLUSIONS: BRAVO wireless pH is well tolerated and feasible in evaluating GER and behavioral symptoms in ASD children and provides a reasonable alternative to standard trans-nasal pH monitoring.

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18. Seguin D, Pac S, Wang J, Nicolson R, Martinez-Trujillo J, Anagnostou E, Lerch JP, Hammill C, Schachar R, Crosbie J, Kelley E, Ayub M, Brian J, Liu X, Arnold PD, Georgiades S, Duerden EG. Amygdala subnuclei volumes and anxiety behaviors in children and adolescents with autism spectrum disorder, attention deficit hyperactivity disorder, and obsessive-compulsive disorder. Hum Brain Mapp;2022 (Jul 12)

Alterations in the structural maturation of the amygdala subnuclei volumes are associated with anxiety behaviors in adults and children with neurodevelopmental and associated disorders. This study investigated the relationship between amygdala subnuclei volumes and anxiety in 233 children and adolescents (mean age = 11.02 years; standard deviation = 3.17) with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and children with obsessive compulsive disorder (OCD), as well as typically developing (TD) children. Parents completed the Child Behavior Checklist (CBCL), and the children underwent structural MRI at 3 T. FreeSurfer software was used to automatically segment the amygdala subnuclei. A general linear model revealed that children and adolescents with ASD, ADHD, and OCD had higher anxiety scores compared to TD children (p < .001). A subsequent interaction analysis revealed that children with ASD (B = 0.09, p < .0001) and children with OCD (B = 0.1, p < .0001) who had high anxiety had larger right central nuclei volumes compared with TD children. Similar results were obtained for the right anterior amygdaloid area. Amygdala subnuclei volumes may be key to identifying children with neurodevelopmental disorders or those with OCD who are at high risk for anxiety. Findings may inform the development of targeted behavioral interventions to address anxiety behaviors and to assess the downstream effects of such interventions.

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19. Siddiqua H, Akter Y, Uddin MN, Kumkum M, Hossain MA, Aziz MA, Ahmed MS, Chowdhury MA, Islam MS, Marzan LW. SHANK3 genetic polymorphism and susceptibility to ASD: evidence from molecular, in silico, and meta-analysis approaches. Mol Biol Rep;2022 (Jul 11)

BACKGROUND: The SHANK3 gene encodes a master synaptic scaffolding protein at the excitatory synapse’s postsynaptic density, which is predominantly responsible for constructing a synapse, maintaining synaptic structure, and functions. Recently, evidence from rare mutations and copy number variation provided an important clue about SHANK3 which acts as a strong candidate gene in the pathogenesis of Autism Spectrum Disorder (ASD). MATERIALS AND METHODS: To investigate potential allelic variants for the SHANK3 (rs9616915) gene as a genetic risk factor, we performed PCR-RFLP analysis and Sanger sequencing for 90 ASD and 90 healthy subjects. Moreover, to understand the functional and structural impacts of our selected non-synonymous SHANK3 SNP rs9616915, we have performed an in silico analysis. Subsequently, a meta-analysis of rs9616915 with a total of 6 eligible studies (including the present study) containing a total of 795 cases and 12,947 controls was obtained from a comprehensive online database search to evaluate the overall association with ASD. RESULTS: Our retrieved data, such as Pearson’s chi-square test (p = 0.081) as well as logistic regression analysis of co-dominant (p = 0.1131), dominant (p = 0.3656) and recessive models (p = 0.0569) speculated no significant association between rs9616915 and our studied sample. Interestingly, by in silico analysis, we have observed two hydrogen bonds between amino acids instead of one hydrogen bond in the protein structure of rs9616915, which indicates this mutant structure could affect the proteins’ stability. The findings of the meta-analysis revealed that four genetic association models were associated with ASD susceptibility. CONCLUSIONS: Our study suggested that targeted SHANK3 SNP of interest rs9616915 might not be associated with ASD in the southern part of the Bangladeshi population.

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20. Simcoe SM, Gilmour J, Garnett MS, Attwood T, Donovan C, Kelly AB. Are there gender-based variations in the presentation of Autism amongst female and male children?. J Autism Dev Disord;2022 (Jul 13)

The Questionnaire for Autism Spectrum Conditions (Q-ASC; Attwood, Garnett & Rynkiewicz, 2011) is one of the few screening instruments that includes items designed to assess female-specific ASD-Level 1 traits. This study examined the ability of a modified version of the Q-ASC (Q-ASC-M; Ormond et al., 2018) to differentiate children with and without ASD-Level 1. Participants included 111 parents of autistic children and 212 parents of neurotypical children (5-12 years). Results suggested that the gendered behaviour, sensory sensitivity, compliant behaviours, imagination, and imitation subscales differentiated autistic females from neurotypical females. Compared to autistic males, autistic females had higher scores on gendered behaviour, sensory sensitivity, social masking, and imitation. Results are discussed in relation to early detection of autistic female children.

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21. Taketomi T, Yasuda T, Morita R, Kim J, Shigeta Y, Eroglu C, Harada R, Tsuruta F. Autism-associated mutation in Hevin/Sparcl1 induces endoplasmic reticulum stress through structural instability. Sci Rep;2022 (Jul 13);12(1):11891.

Hevin is a secreted extracellular matrix protein that is encoded by the SPARCL1 gene. Recent studies have shown that Hevin plays an important role in regulating synaptogenesis and synaptic plasticity. Mutations in the SPARCL1 gene increase the risk of autism spectrum disorder (ASD). However, the molecular basis of how mutations in SPARCL1 increase the risk of ASD is not been fully understood. In this study, we show that one of the SPARCL1 mutations associated with ASD impairs normal Hevin secretion. We identified Hevin mutants lacking the EF-hand motif through analyzing ASD-related mice with vulnerable spliceosome functions. Hevin deletion mutants accumulate in the endoplasmic reticulum (ER), leading to the activation of unfolded protein responses. We also found that a single amino acid substitution of Trp(647) with Arg in the EF-hand motif associated with a familial case of ASD causes a similar phenotype in the EF-hand deletion mutant. Importantly, molecular dynamics (MD) simulation revealed that this single amino acid substitution triggers exposure of a hydrophobic amino acid to the surface, increasing the binding of Hevin with molecular chaperons, BIP. Taken together, these data suggest that the integrity of the EF-hand motif in Hevin is crucial for proper folding and that ASD-related mutations impair the export of Hevin from the ER. Our data provide a novel mechanism linking a point mutation in the SPARCL1 gene to the molecular and cellular characteristics involved in ASD.

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22. Tiwari R, Chakrabarty B. Autism Spectrum Disorder and Epilepsy: Exploring the Missing Links. Indian J Pediatr;2022 (Jul 12)

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23. Williams ZJ, Suzman E, Bordman SL, Markfeld JE, Kaiser SM, Dunham KA, Zoltowski AR, Failla MD, Cascio CJ, Woynaroski TG. Characterizing Interoceptive Differences in Autism: A Systematic Review and Meta-analysis of Case-control Studies. J Autism Dev Disord;2022 (Jul 11)

Interoception, the body’s perception of its own internal states, is thought to be altered in autism, though results of empirical studies have been inconsistent. The current study systematically reviewed and meta-analyzed the extant literature comparing interoceptive outcomes between autistic (AUT) and neurotypical (NT) individuals, determining which domains of interoception demonstrate robust between-group differences. A three-level Bayesian meta-analysis compared heartbeat counting performance, heartbeat discrimination performance, heartbeat counting confidence ratings, and self-reported interoceptive attention between AUT and NT groups (15 studies; n(AUT) = 467, n(NT) = 478). Autistic participants showed significantly reduced heartbeat counting performance [g = - 0.333, CrI(95%) (- 0.535, – 0.138)] and higher confidence in their heartbeat counting abilities [g = 0.430, CrI(95%) (0.123, 0.750)], but groups were equivalent on other meta-analyzed outcomes. Implications for future interoception research in autism are discussed.

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24. Xu S, Li M, Yang C, Fang X, Ye M, Wu Y, Yang B, Huang W, Li P, Ma X, Fu S, Yin Y, Tian J, Gan Y, Jiang G. Abnormal Degree Centrality in Children with Low-Function Autism Spectrum Disorders: A Sleeping-State Functional Magnetic Resonance Imaging Study. Neuropsychiatr Dis Treat;2022;18:1363-1374.

PURPOSE: This study used the graph-theory approach, degree centrality (DC) to analyze whole-brain functional networks at the voxel level in children with ASD, and investigated whether DC changes were correlated with any clinical variables in ASD children. METHODS: The current study included 86 children with ASD and 54 matched healthy subjects Aged 2-5.5 years. Next, chloral hydrate induced sleeping-state functional magnetic resonance imaging (ss-fMRI) datasets were acquired from these ASD and healthy subjects. For a given voxel, the DC was calculated by calculating the number of functional connections with significantly positive correlations at the individual level. Group differences were tested using two-sample t-tests (p < 0.01, AlphaSim corrected). Finally, relationships between abnormal DCs and clinical variables were investigated via Pearson's correlation analysis. RESULTS: Children with ASD exhibited low DC values in the right middle frontal gyrus (MFG) (p < 0.01, AlphaSim corrected). Furthermore, significantly negative correlations were established between the decreased average DC values within the right MFG in ASD children and the total ABC scores, as well as with two ABC subscales measuring highly relevant impairments in ASD (ie, stereotypes and object-use behaviors and difficulties in language). CONCLUSION: Taken together, the results of our ss-fMRI study suggest that abnormal DC may represent an important contribution to elucidation of the neuropathophysiological mechanisms of preschoolers with ASD.

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25. Yang MR, Yu M. [Structural Equation Modeling for Quality of Life of Mothers of Children with Developmental Disabilities: Focusing on the Self-Help Model]. J Korean Acad Nurs;2022 (Jun);52(3):308-323.

PURPOSE: This study aimed to construct and test a predictive model for the quality of life (QOL) in mothers of children with developmental disabilities (DB). The hypothesized model included severity of illness, distress, uncertainty, self-help, and parenting efficacy as influencing factors, QOL as a consequence based on the Braden’s Self-Help Model. METHODS: The data were collected through a direct and online surveys from 206 mothers in 8 locations, including welfare or daycare centers, developmental treatment centers, and The Parents’ Coalition for the Disabled located in two provinces of Korea. Data were analysed using SPSS/WIN 23.0 and AMOS 21.0 program. RESULTS: The fit indices of the predictive model satisfied recommended levels; χ² = 165.79 (p < .001), normed χ² (χ²/df) = 2.44, RMR = .04, RMSEA= .08, GFI = .90, AGFI = .85, NFI = .91, TLI = .93, CFI = .95. Among the variables, distress (β = - .46, p < .001), parenting efficacy (β = .22, p < .001), and self-help (β = .17, p = .018) had direct effects on QOL. Severity of illness (β = - .61, p = .010) and uncertainty (β = - .08, p = .014) showed indirect effects. The explanatory power of variables was 61.0%. CONCLUSION: The study results confirm the utility of Braden's Self-Help Model. They provide a theoretical basis for improving QOL in mothers of children with DB. Nursing intervention strategies that can relieve mothers' distress and uncertainty related to disease and enhance parenting efficacy and self-help behavior should be considered.

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