1. Almasri J, Barazi A, King KS, Walther-Antonio MRS, Wang Z, Murad MH, Murray JA, Absah I. Peripartum Antibiotics Exposure and the Risk of Autoimmune and Autism Disorders in the Offspring. Avicenna journal of medicine. 2021; 11(3): 118-25.

Background As the use of antibiotics during the peripartum period increases, the incidence of autoimmune disorders and autism spectrum disorders (ASDs) is also increasing. In this study, we aim to assess if antibiotic exposure during the peripartum period affects the incidence of autoimmune diseases and ASD in the offspring. Methods We identified children (< 18 years of age) born in Olmsted County from January 1, 2003 through December 31, 2012. Offspring with celiac disease (CD), inflammatory bowel disease (IBD), or ASD diagnoses were matched to two controls on birth date, index date, mother's age at delivery, and sex. Data from the mother's medical records were retrieved to determine peripartum antibiotics use. Results A total of 242 cases and 484 matched controls were included in this study. Median age at the last follow-up was 11.3 years (range: 0.5-14.9), 73% were males in both groups. Odds of CD diagnosis was not statistically different between vaginal delivery with antibiotics compared with vaginal delivery with no antibiotics (odds ratio [OR] = 0.76, 95% confidence interval [CI]: 0.32-1.85), similarly in IBD (OR = 2.41, 95% CI: 0.53-10.98) and ASD (OR = 1.00, 95% CI:0.55-1.79). Preeclampsia or eclampsia was associated with offspring CD (OR = 3.20, 95% CI: 1.05-9.78). Smoking history and diabetes mellitus were associated with offspring ASD (OR = 1.84, 95% CI: 1.22-2.77 and OR = 2.01, 95% CI: 1.03-3.91, respectively). Conclusion In this cohort, we found no statistically significant association between peripartum antibiotics exposure and the development of CD, IBD, or ASD.

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2. Arthur T, Harris D, Buckingham G, Brosnan M, Wilson M, Williams G, Vine S. An examination of active inference in autistic adults using immersive virtual reality. Scientific reports. 2021; 11(1): 20377.

The integration of prior expectations, sensory information, and environmental volatility is proposed to be atypical in Autism Spectrum Disorder, yet few studies have tested these predictive processes in active movement tasks. To address this gap in the research, we used an immersive virtual-reality racquetball paradigm to explore how visual sampling behaviours and movement kinematics are adjusted in relation to unexpected, uncertain, and volatile changes in environmental statistics. We found that prior expectations concerning ball ‘bounciness’ affected sensorimotor control in both autistic and neurotypical participants, with all individuals using prediction-driven gaze strategies to track the virtual ball. However, autistic participants showed substantial differences in visuomotor behaviour when environmental conditions were more volatile. Specifically, uncertainty-related performance difficulties in these conditions were accompanied by atypical movement kinematics and visual sampling responses. Results support proposals that autistic people overestimate the volatility of sensory environments, and suggest that context-sensitive differences in active inference could explain a range of movement-related difficulties in autism.

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3. Borie AM, Muscatelli F, Desarménien MG, Jeanneteau F. [Vasopressin: An effective treatment for autism spectrum disorders?]. Medecine sciences : M/S. 2021; 37(10): 848-50.

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4. Bourne MJ, Smeltzer SC, Kelly MM. Healthcare inequities among adults with developmental disability: An integrative review with implications for nursing education. Nurse education in practice. 2021; 57: 103225.

AIM: This integrative review synthesized research on the healthcare inequities experienced by adults with developmental disability in the United States and discussed implications for nursing education. BACKGROUND: Individuals with developmental disability are living longer with chronic comorbidities and experience healthcare inequities. METHOD: Application of inclusion criteria to database and ancestry searches resulted in 26 articles that were assessed for quality and analyzed thematically. RESULTS: Three categories of inequity were identified: knowledge deficits, communication challenges and poor quality of care. Knowledge deficits and communication challenges can lead to frustration, errors and unmet needs. Poor quality of care encompasses the decreased availability and access to services, limited health promotion participation and higher rates of hospitalizations and complications for adults with developmental disability. CONCLUSION: Healthcare inequities may be reduced by targeting patient and provider knowledge. Inclusion of developmental disability content and clinical experiences in nursing education may improve care and reduce inequities for this underserved population.

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5. Bozoglan B, Kumar S. Parenting Styles, Parenting Stress and Hours Spent Online as Predictors of Child Internet Addiction Among Children with Autism. Journal of autism and developmental disorders. 2021.

The current study examined the association between hours spent online (HOS), positive parenting, negative parenting, autism parental stress and Internet addiction among Singapore based boys and girls (aged 6 to 14 years old) with Autism Spectrum Disorder (ASD). The research participants included 59 parents (41 females and 18 males) aged between 28 and 74 years old (mean age 37.95). Results indicated HOS, negative parenting and autism parenting stress predicted 54.8% of the total variance in Child Internet Addiction scores of children with ASD. Autism parental stress was the most significant predictor explaining 25.3% of the total variance with time spent online explaining another 23.5% and negative parenting predicted 6%. Positive parenting was not found to be significant. The findings reinforce the importance of according greater consideration for the role of parents when working with such children.

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6. Cameron KL, Allison K, McGinley JL, Fini NA, Cheong JLY, Spittle AJ. Feasibility of a Dance PaRticipation intervention for Extremely prEterm children with Motor Impairment at prEschool age (Dance PREEMIE). Early human development. 2021; 163: 105482.

BACKGROUND: Physical activity (PA) participation provides opportunities for preschool-age children to improve motor skills. This is especially important for children born extremely preterm (EP) or extremely low birthweight (ELBW) who are at greater risk of motor impairment, and are participating less frequently in PA, compared with children born at term. There is limited evidence on improving PA participation for this population. METHODS: This case series design study evaluated the feasibility of a Dance PaRticipation intervention for Extremely prEterm children with Motor Impairment at prEschool age (Dance PREEMIE), a community-based dance class intervention aiming to improve PA participation. Children born EP/ELBW with motor impairment were recruited at 3 years’ corrected age. Dance teachers were recruited from community dance schools and provided with study-specific training. Intervention feasibility was assessed using; recruitment capability, class attendance, child involvement and enjoyment, teacher self-efficacy, and implementation fidelity. RESULTS: Ten children and seven dance teachers were recruited. Most children (n = 7) attended >75% of classes. Children enjoyed the classes and were mostly ‘somewhat-very’ or ‘very’ involved. Teachers reported improved self-efficacy for teaching dance to children with motor impairment after attending the training day. CONCLUSION: Further research is warranted to evaluate the efficacy of Dance PREEMIE in larger samples.

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7. Frye RE, Lionnard L, Singh I, Karim MA, Chajra H, Frechet M, Kissa K, Racine V, Ammanamanchi A, McCarty PJ, Delhey L, Tippett M, Rose S, Aouacheria A. Mitochondrial morphology is associated with respiratory chain uncoupling in autism spectrum disorder. Translational psychiatry. 2021; 11(1): 527.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is associated with unique changes in mitochondrial metabolism, including elevated respiration rates and morphological alterations. We examined electron transport chain (ETC) complex activity in fibroblasts derived from 18 children with ASD as well as mitochondrial morphology measurements in fibroblasts derived from the ASD participants and four typically developing controls. In ASD participants, symptoms severity was measured by the Social Responsiveness Scale and Aberrant Behavior Checklist. Mixed-model regression demonstrated that alterations in mitochondrial morphology were associated with both ETC Complex I+III and IV activity as well as the difference between ETC Complex I+III and IV activity. The subgroup of ASD participants with relative elevation in Complex IV activity demonstrated more typical mitochondrial morphology and milder ASD related symptoms. This study is limited by sample size given the invasive nature of obtaining fibroblasts from children. Furthermore, since mitochondrial function is heterogenous across tissues, the result may be specific to fibroblast respiration. Previous studies have separately described elevated ETC Complex IV activity and changes in mitochondrial morphology in cells derived from children with ASD but this is the first study to link these two findings in mitochondrial metabolism. The association between a difference in ETC complex I+III and IV activity and normal morphology suggests that mitochondrial in individuals with ASD may require ETC uncoupling to function optimally. Further studies should assess the molecular mechanisms behind these unique metabolic changes.Trial registration: Protocols used in this study were registered in clinicaltrials.gov as NCT02000284 and NCT02003170.

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8. Huang L, Wang J, Liang G, Gao Y, Jin SY, Hu J, Yang X, Lao J, Chen J, Luo ZC, Fan C, Xiong L, Zhu X, Gao TM, Zhong M, Yang X. Upregulated NMDAR-mediated GABAergic transmission underlies autistic-like deficits in Htr3a knockout mice. Theranostics. 2021; 11(19): 9296-310.

Mutations in serotonin pathway genes, especially the serotonergic receptor subunit gene HTR3A, are associated with autism. However, the association of HTR3A deficiency with autism and the underlying mechanisms remain unknown. Methods: The Htr3a knockout (KO) mice were generated using transcription activator-like effector nuclease technology. Various behavior tests, including social interaction, social approach task, olfactory habituation/dishabituation, self-grooming, novel object recognition, contextual fear conditioning, elevated plus maze, open field and seizure susceptibility, were performed to assess the phenotypes. Transcriptome sequencing was carried out to search for molecular network and pathways underlying the phenotypes. Electrophysiological recordings, immunoblotting, immunofluorescence staining, immunoprecipitation, and quantitative real-time PCR were performed to verify the potential mechanisms. The N-methyl-D-aspartate receptor (NMDAR) antagonist memantine was used to treat the KO mice for rescuing the phenotypes. Results: The Htr3a KO mouse model showed three phenotypic domains: autistic-like behaviors (including impaired social behavior, cognitive deficits, and increased repetitive self-grooming), impaired memory, and attenuated susceptibility to pentylenetetrazol-induced seizures. We observed enhanced action potential-driven γ-aminobutyric acid-ergic (GABAergic) transmission in pyramidal neurons and decreased excitatory/inhibitory (E/I) ratio using the patch-clamp recording. Transcriptome sequencing on the hippocampus revealed the converged pathways of the dysregulated molecular networks underlying three phenotypic domains with upregulation of NMDAR. We speculated that Htr3a KO promotes an increase in GABA release through NMDAR upregulation. The electrophysiological recordings on hippocampal parvalbumin-positive (PV(+)) interneuron revealed increased NMDAR current and NMDAR-dependent excitability. The NMDAR antagonist memantine could rescue GABAergic transmission in the hippocampus and ameliorate autistic-like behaviors of the KO mice. Conclusion: Our data indicated that upregulation of the NMDAR in PV(+) interneurons may play a critical role in regulating GABAergic input to pyramidal neurons and maybe involve in the pathogenesis of autism associated with HTR3A deficiency. Therefore, we suggest that the NMDAR system could be considered potential therapeutic target for autism.

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9. Liang Y, Liu B, Zhang H. A Convolutional Neural Network Combined With Prototype Learning Framework for Brain Functional Network Classification of Autism Spectrum Disorder. IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society. 2021; 29: 2193-202.

The application of deep learning methods in brain disease diagnosis is becoming a new research hotspot. This study constructed brain functional networks based on the functional magnetic resonance imaging (fMRI) data, and proposed a novel convolutional neural network combined with a prototype learning (CNNPL) framework to classify brain functional networks for the diagnosis of autism spectrum disorder (ASD). At the bottom of CNNPL, traditional CNN was employed as the basic feature extractor, while at the top of CNNPL multiple prototypes were automatically learnt on the features to represent different categories. A generalized prototype loss based on distance cross-entropy was proposed to jointly learn the parameters of the CNN feature extractor and the prototypes. The classification was implemented with prototype matching. A transfer learning strategy was introduced to our CNNPL for weight initialization in the subsequent fine-tuning phase to promote model training. We conducted systematic experiments on the aggregate multi-sites ASD dataset. Experimental results revealed that our model outperforms the current state-of-the-art methods in ASD classification and can reliably learn inter-site biomarkers, indicating the robustness of our model on large-scale dataset with inter-site variability. Furthermore, our model demonstrated robust learning capability for high-level organization of brain functionality. Our study also identified important brain regions as biomarkers associated with ASD classification. Together, our proposed model provides a promising solution for learning and classifying brain functional networks, and thus contributes to the biomarker extraction and imaging diagnosis of ASD.

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10. Murch O, Jain V, Benneche A, Metcalfe K, Hobson E, Prescott K, Chandler K, Ghali N, Carmichael J, Foulds NC, Paulsen J, Smeland MF, Berland S, Fry AE. Further delineation of the clinical spectrum of White-Sutton syndrome: 12 new individuals and a review of the literature. European journal of human genetics : EJHG. 2022; 30(1): 95-100.

White-Sutton syndrome (WHSUS) is a neurodevelopmental disorder caused by heterozygous loss-of-function variants in POGZ. Through the Deciphering Developmental Disorders study and clinical testing, we identified 12 individuals from 10 families with pathogenic or likely pathogenic variants in POGZ (eight de novo and two inherited). Most individuals had delayed development and/or intellectual disability. We analyzed the clinical findings in our series and combined it with data from 89 previously reported individuals. The results demonstrate WHSUS is associated with variable developmental delay or intellectual disability, increased risk of obesity, visual defects, craniofacial dysmorphism, sensorineural hearing loss, feeding problems, seizures, and structural brain malformations. Our series includes further individuals with rod-cone dystrophy, cleft lip and palate, congenital diaphragmatic hernia, and duplicated renal drainage system, suggesting these are rare complications of WHSUS. In addition, we describe an individual with a novel, de novo missense variant in POGZ and features of WHSUS. Our work further delineates the phenotypic spectrum of WHSUS highlighting the variable severity of this disorder and the observation of familial pathogenic POGZ variants.

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11. Pirbhoy PS, Jonak CR, Syed R, Argueta DA, Perez PA, Wiley MB, Hessamian K, Lovelace JW, Razak KA, DiPatrizio NV, Ethell IM, Binder DK. Increased 2-arachidonoyl-sn-glycerol levels normalize cortical responses to sound and improve behaviors in Fmr1 KO mice. Journal of neurodevelopmental disorders. 2021; 13(1): 47.

BACKGROUND: Individuals with Fragile X syndrome (FXS) and autism spectrum disorder (ASD) exhibit an array of symptoms, including sociability deficits, increased anxiety, hyperactivity, and sensory hyperexcitability. It is unclear how endocannabinoid (eCB) modulation can be targeted to alleviate neurophysiological abnormalities in FXS as behavioral research reveals benefits to inhibiting cannabinoid (CB) receptor activation and increasing endocannabinoid ligand levels. Here, we hypothesize that enhancement of 2-arachidonoyl-sn-glycerol (2-AG) in Fragile X mental retardation 1 gene knock-out (Fmr1 KO) mice may reduce cortical hyperexcitability and behavioral abnormalities observed in FXS. METHODS: To test whether an increase in 2-AG levels normalized cortical responses in a mouse model of FXS, animals were subjected to electroencephalography (EEG) recording and behavioral assessment following treatment with JZL-184, an irreversible inhibitor of monoacylglycerol lipase (MAGL). Assessment of 2-AG was performed using lipidomic analysis in conjunction with various doses and time points post-administration of JZL-184. Baseline electrocortical activity and evoked responses to sound stimuli were measured using a 30-channel multielectrode array (MEA) in adult male mice before, 4 h, and 1 day post-intraperitoneal injection of JZL-184 or vehicle. Behavior assessment was done using the open field and elevated plus maze 4 h post-treatment. RESULTS: Lipidomic analysis showed that 8 mg/kg JZL-184 significantly increased the levels of 2-AG in the auditory cortex of both Fmr1 KO and WT mice 4 h post-treatment compared to vehicle controls. EEG recordings revealed a reduction in the abnormally enhanced baseline gamma-band power in Fmr1 KO mice and significantly improved evoked synchronization to auditory stimuli in the gamma-band range post-JZL-184 treatment. JZL-184 treatment also ameliorated anxiety-like and hyperactivity phenotypes in Fmr1 KO mice. CONCLUSIONS: Overall, these results indicate that increasing 2-AG levels may serve as a potential therapeutic approach to normalize cortical responses and improve behavioral outcomes in FXS and possibly other ASDs.

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12. Poleg S, Kourieh E, Ruban A, Shapira G, Shomron N, Barak B, Offen D. Behavioral aspects and neurobiological properties underlying medical cannabis treatment in Shank3 mouse model of autism spectrum disorder. Translational psychiatry. 2021; 11(1): 524.

Autism spectrum disorder (ASD) is a neurodevelopmental disease with a wide spectrum of manifestation. The core symptoms of ASD are persistent deficits in social communication, and restricted and repetitive patterns of behavior, interests, or activities. These are often accompanied by intellectual disabilities. At present, there is no designated effective treatment for the core symptoms and co-morbidities of ASD. Recently, interest is rising in medical cannabis as a treatment for ASD, with promising clinical data. However, there is a notable absence of basic pre-clinical research in this field. In this study, we investigate the behavioral and biochemical effects of long-term oral treatment with CBD-enriched medical cannabis oil in a human mutation-based Shank3 mouse model of ASD. Our findings show that this treatment alleviates anxiety and decreases repetitive grooming behavior by over 70% in treated mutant mice compared to non-treated mutant mice. Furthermore, we were able to uncover the involvement of CB1 receptor (CB1R) signaling in the Avidekel oil mechanism, alongside a mitigation of cerebrospinal fluid (CSF) glutamate concentrations. Subsequently, RNA sequencing (RNA seq) of cerebellar brain samples revealed changes in mRNA expression of several neurotransmission-related genes post-treatment. Finally, our results question the relevancy of CBD enrichment of medical cannabis for treating the core symptoms of ASD, and emphasize the importance of the THC component for alleviating deficits in repetitive and social behaviors in ASD.

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13. Simhal AK, Filho JOA, Segura P, Cloud J, Petkova E, Gallagher R, Castellanos FX, Colcombe S, Milham MP, Di Martino A. Predicting multiscan MRI outcomes in children with neurodevelopmental conditions following MRI simulator training. Developmental cognitive neuroscience. 2021; 52: 101009.

Pediatric brain imaging holds significant promise for understanding neurodevelopment. However, the requirement to remain still inside a noisy, enclosed scanner remains a challenge. Verbal or visual descriptions of the process, and/or practice in MRI simulators are the norm in preparing children. Yet, the factors predictive of successfully obtaining neuroimaging data remain unclear. We examined data from 250 children (6-12 years, 197 males) with autism and/or attention-deficit/hyperactivity disorder. Children completed systematic MRI simulator training aimed to habituate to the scanner environment and minimize head motion. An MRI session comprised multiple structural, resting-state, task and diffusion scans. Of the 201 children passing simulator training and attempting scanning, nearly all (94%) successfully completed the first structural scan in the sequence, and 88% also completed the following functional scan. The number of successful scans decreased as the sequence progressed. Multivariate analyses revealed that age was the strongest predictor of successful scans in the session, with younger children having lower success rates. After age, sensorimotor atypicalities contributed most to prediction. Results provide insights on factors to consider in designing pediatric brain imaging protocols.

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14. Zach V, Pieske-Kraigher E, Pieske B, Schneider M. Floppy interatrial septum mimicking an ASD: The role of left atrial pressure. Health science reports. 2021; 4(4): e415.

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15. Zhang Y, Sindermann C, Kendrick KM, Becker B, Montag C. Individual Differences in Tendencies Toward Internet Use Disorder, Internet Literacy and Their Link to Autistic Traits in Both China and Germany. Frontiers in psychiatry. 2021; 12: 638655.

Recent evidence demonstrates that Internet Use Disorder tendencies (IUD; formerly known as Internet Addiction) are associated with higher tendencies toward autistic traits. In the present study, we aimed to further explore this association between IUD tendencies and autistic traits in a large cohort of German and Chinese subjects (total N = 1,524; mostly student background) who completed the short Internet-Addiction-Test, the Autism-Spectrum-Quotient, and the Internet-Literacy-Questionnaire. Moreover, the present research also enabled us to study potential differences in the investigated variables between the Chinese and German cultures. First, the results indicated higher occurrence of IUD symptoms in China. Moreover, Chinese subjects scored significantly higher on all ILQ dimensions than German participants, with the exception of self-regulation where the reverse picture appeared. Second, results confirmed a positive association between IUD tendencies and autistic traits both in China and Germany, although effect sizes were low to medium (China: r = 0.19 vs. Germany: r = 0.36). Going beyond the literature, the present study also assessed individual differences in Internet Literacy and shows in how far variables such as technical expertise, production and interaction, reflection and critical analysis as well as self-regulation in the realm of the Internet usage influence the aforementioned association between IUD tendencies and autistic traits. Although the present study is limited by being of correlational nature it is discussed how the association between IUD tendencies and autistic traits might be explained.

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16. Zhu B, Deng F, Yan S, Huang K, Wu X, Tao X, Wang S, Tao F. Gestational diabetes mellitus, autistic traits and ADHD symptoms in toddlers: Placental inflammatory and oxidative stress cytokines do not play an intermediary role. Psychoneuroendocrinology. 2021; 134: 105435.

OBJECTIVE: To evaluate whether gestational diabetes mellitus (GDM) is associated with increased risks of autistic traits and attention deficit/hyperactivity disorder (ADHD) among offspring and whether placental inflammatory and oxidative stress cytokines play an intermediary role. METHODS: Based on a prospective cohort study from China, namely, the Ma’anshan Birth Cohort study (MABC), 3260 mother-child pairs were included. Autistic traits and ADHD symptoms among children were assessed at 18 months and 36 months, respectively. The mRNA expression levels of fourteen placental cytokines were determined using PCR. Logistic regression analysis was used to examine the associations between GDM and the risks of autistic traits or ADHD symptoms. Mediation analysis was used to assess the potential mediation effects of certain placental inflammatory factors. RESULTS: Of the 3260 children, 419 (12.85%) were exposed to GDM. The prevalence rates of autistic traits and ADHD symptoms were 13.86% and 6.4%, respectively. A 48.6% increased risk of autistic traits was observed among offspring born to mothers with GDM [odds ratio (OR) = 1.49, 95% confidence interval (95%CI): 1.11-2.00)], while no significant association was found in terms of ADHD symptoms. There were significant positive associations between GDM and IL-10 expression and between HIF1-α and CRP mRNA expression and a significant negative association between GDM and CD206 mRNA expression. The expression of MCP-1 mRNA was negatively associated with the risk of autistic traits [adjusted OR = 0.73 (95%CI: 0.73-0.55)]. The levels of TNF-α were positively associated with the risk of ADHD symptoms [OR = 2.11 (95%CI: 1.39-3.21)], while GRP78 was inversely associated with it [OR = 0.64 (95%CI: 0.44-0.94)]. However, none of the 14 placental cytokines was involved as a key mediator. CONCLUSION: Our findings suggest that GDM may act as a risk factor for autistic traits in offspring, while the biological mechanisms may not involve the 14 placental cytokines studied. No significant association between GDM and ADHD symptoms was observed.

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