1. Bagherzadeh-Azbari S, Lau GKB, Ouyang G, Zhou C, Hildebrandt A, Sommer W, Lui M. Multimodal Evidence of Atypical Processing of Eye Gaze and Facial Emotion in Children With Autistic Traits. Frontiers in human neuroscience. 2022; 16: 733852.

According to the shared signal hypothesis (SSH) the impact of facial expressions on emotion processing partially depends on whether the gaze is directed toward or away from the observer. In autism spectrum disorder (ASD) several aspects of face processing have been found to be atypical, including attention to eye gaze and the identification of emotional expressions. However, there is little research on how gaze direction affects emotional expression processing in typically developing (TD) individuals and in those with ASD. This question is investigated here in two multimodal experiments. Experiment 1 required processing eye gaze direction while faces differed in emotional expression. Forty-seven children (aged 9-12 years) participated. Their Autism Diagnostic Observation Schedule (ADOS) scores ranged from 0 to 6 in the experiment. Event-related potentials (ERPs) were sensitive to gaze direction and emotion, but emotion processing did not depend on gaze direction. However, for angry faces the gaze direction effect on the N170 amplitude, as typically observed in TD individuals, diminished with increasing ADOS score. For neutral expressions this correlation was not significant. Experiment 2 required explicit emotion classifications in a facial emotion composite task while eye gaze was manipulated incidentally. A group of 22 children with ASD was compared to a propensity score-matched group of TD children (mean age = 13 years). The same comparison was carried out for a subgroup of nine children with ASD who were less trained in social cognition, according to clinician’s report. The ASD group performed overall worse in emotion recognition than the TD group, independently of emotion or gaze direction. However, for disgust expressions, eye tracking data revealed that TD children fixated relatively longer on the eyes of the stimulus face with a direct gaze as compared with averted gaze. In children with ASD we observed no such modulation of fixation behavior as a function of gaze direction. Overall, the present findings from ERPs and eye tracking confirm the hypothesis of an impaired sensitivity to gaze direction in children with ASD or elevated autistic traits, at least for specific emotions. Therefore, we conclude that multimodal investigations of the interaction between emotional processing and stimulus gaze direction are promising to understand the characteristics of individuals differing along the autism trait dimension.

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2. Baranek GT, Sideris J, Chen YJ, Crais ER, Turner-Brown L, Watson LR. Early measurement of autism risk constructs in the general population: A new factor structure of the First Years Inventory (FYIv3.1) for ages 6-16 months. Autism research : official journal of the International Society for Autism Research. 2022.

Early detection of autism risk in the community is critical to increasing families’ access to early intervention, yet few measures have been developed and tested for the general population of infants <16 months to tap a broader range of autism risk constructs. This study aimed to (a) examine the factor structure of the First Years Inventory, version 3.1 (FYIv3.1), with a sample of 6454 infants 6-16 months, and (b) determine the ability of the resulting factors to discriminate clinical outcome groups at 3 years of age. The FYIv3.1 is a parent-report tool designed to detect early behavioral risk signs that may be associated with a later diagnosis of ASD and related neurodevelopmental conditions. Factor analytic models were used to determine the number of constructs and inter-factor correlations. Findings supported a seven-factor structure: communication, imitation and play (CIP); social attention and affective engagement (SAE); sensory hyperresponsiveness (HYPER); sensory hyporesponsiveness (HYPO); self-regulation in daily routines (SREG); sensory interests, repetitions, and seeking behaviors (SIRS); motor coordination and milestones (MCM). Mean comparisons on these factors demonstrated significant discrimination of the three outcome groups at age 3 years including those classified as having an ASD diagnosis and/or high autism symptoms, those classified as having other developmental disorders/conditions/concerns, and those classified with no known conditions/concerns. These findings support the validity and multidimensionality of early ASD risk constructs, as well as the potential use of the FYIv3.1 for phenotypic subtyping in the general population, and early detection in a broader age range of 6-16 months in future clinical studies. LAY SUMMARY: The FYIv3.1 is a 69-item parent-report questionnaire about infant behaviors that may indicate an elevated likelihood for later neurodevelopmental conditions such as autism. Analyses of responses from 6454 parents of infants 6-16 months indicated that items could be grouped reliably into seven categories. Compared to children with or without other developmental conditions, children in the outcome group with autism spectrum disorder and/or high autism symptoms at age three showed more behavioral risk signs in social-communication, sensory, and motor domains during infancy.

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3. Bauer V, Bouchara T, Bourdot P. Extended Reality Guidelines for Supporting Autism Interventions Based on Stakeholders’ Needs. Journal of autism and developmental disorders. 2022.

While Extended Reality (XR) autism research, ranging from Augmented to Virtual Reality, focuses on socio-emotional abilities and autistic children requiring low support, common interventions address the entire spectrum and focus on other abilities, including perceptual abilities. Based on these observations, this paper first addresses common practitioners’ interventions, and then suggests XR use cases and guidelines to better support them. To do so, 34 interviews were conducted with stakeholders, mainly including practitioners, and then analyzed. Emerging XR use cases were compared with the findings from two former systematic literature reviews, and emerging design guidelines were compared with the findings from a literature survey that we conducted. Findings suggest that collaborative XR sensory-based and mediation approaches could benefit the entire spectrum.

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4. Bhandari R, Paliwal JK, Kuhad A. Enhanced Bioavailability & higher Uptake of Brain-targeted Surface Engineered Delivery System of Naringenin developed as a therapeutic for Autism Spectrum Disorder. Current drug delivery. 2022.

BACKGROUND: Neuroinflammation occurring as a result of oxidative and nitrosative stress is associated with various neurological disorders and involves generation of pro-inflammatory cytokines as well as activation of microglia. Dietary phytochemicals are a safer and valuable adjunct neurotherapeutic agents which can be added to the therapeutic regimen. These compounds provide neuroprotection by modulation of various signaling pathways. INTRODUCTION: Naringenin (NGN) is a phytochemical having low oral bioavailability because of poor solubility, and adding to this limitation is enhanced efflux by P-glycoprotein transporters in neuroinflammatory diseases. METHODS: Hence, as a solution for these limitations, Naringenin encapsulated poly-lactic-co-glycolic acid (PLGA) nanocarriers were developed utilizing nanoprecipitation technique and were coated with 1% glutathione (GSH) and 1% Tween 80 to enhance brain delivery. RESULTS: Coated as well as uncoated NGN-PLGA nanoparticles (NGN-PLGA-NPs) were spherical, monodisperse, stable, non-toxic with a particle size of less than 200 nm and negative zeta-potential values, 80% entrapment efficiency, and sustained drug release of 81.8% (uncoated), 80.13 and 78.43% (coated) respectively in 24 hours. FT-IR, DSC, PXRD, and NMR confirmed the drug encapsulation and coating over nanoparticles. In-vivo brain uptake showed greater fluorescence intensity of the coated nanoparticles in the brain than uncoated nanoparticles. In addition, there was a 2.33 fold increase in bioavailability after coating compared to naringenin suspension and enhanced brain uptake. CONCLUSION: Present studies indicate sustained and targeted brain delivery of Naringenin via the ligand-coated delivery system by inhibition of enhanced P-glycoprotein (P-gp) efflux occurring due to neuroinflammation in Autism Spectrum Disorders.

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5. Breach MR, Dye CN, Galan A, Lenz KM. Prenatal allergic inflammation in rats programs the developmental trajectory of dendritic spine patterning in brain regions associated with cognitive and social behavior. Brain, behavior, and immunity. 2022; 102: 279-91.

Allergic inflammation during pregnancy increases risk for a diagnosis of neurodevelopmental disorders such as Attention Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) in the offspring. Previously, we found a model of such inflammation, allergy-induced maternal immune activation (MIA), produced symptoms analogous to those associated with neurodevelopmental disorders in rats, including reduced juvenile play behavior, hyperactivity, and cognitive inflexibility. These behaviors were preceded by perinatal changes in microglia colonization and phenotype in multiple relevant brain regions. Given the role that microglia play in synaptic patterning as well as evidence for altered synaptic architecture in neurodevelopmental disorders, we investigated whether allergic MIA altered the dynamics of dendritic spine patterning throughout key regions of the rat forebrain across neurodevelopment. Adult virgin female rats were sensitized to the allergen, ovalbumin, with alum adjuvant, bred, and allergically challenged on gestational day 15. Brain tissue was collected from male and female offspring on postnatal days (P) 5, 15, 30, and 100-120 and processed for Golgi-Cox staining. Mean dendritic spine density was calculated for neurons in brain regions associated with cognition and social behavior, including the medial prefrontal cortex (mPFC), basal ganglia, septum, nucleus accumbens (NAc), and amygdala. Allergic MIA reduced dendritic spine density in the neonatal (P5) and juvenile (P15) mPFC, but these mPFC spine deficits were normalized by P30. Allergic inflammation reduced spine density in the septum of juvenile (P30) rats, with an interaction suggesting increased density in males and reduced density in females. MIA-induced reductions in spine density were also found in the female basal ganglia at P15, as well as in the NAc at P30. Conversely, MIA-induced increases were found in the NAc in adulthood. While amygdala dendritic spine density was generally unaffected throughout development, MIA reduced density in both medial and basolateral subregions in adult offspring. Correlational analyses revealed disruption to amygdala-related networks in the neonatal animals and cortico-striatal related networks in juvenile and adult animals in a sex-specific manner. Collectively, these data suggest that communication within and between these cognitive and social brain regions may be altered dynamically throughout development after prenatal exposure to allergic inflammation. They also provide a basis for future intervention studies targeted at rescuing spine and behavior changes via immunomodulatory treatments.

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6. Camodeca A. Diagnostic Utility of the Gilliam Autism Rating Scales-3rd Edition Parent Report in Clinically Referred Children. Journal of autism and developmental disorders. 2022.

There is limited research regarding the Gilliam Autism Rating Scales-3rd Edition (GARS-3) despite its extensive use. A comprehensive diagnostic evaluation, including the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2) was provided to 186 clinically referred children suspected of autism ([Formula: see text] age = 8.98; Autism [AUT] n = 87; Not Autism [NOT] n = 99). Mean difference analyses, Logistic Regressions, and ROC analyses were non-significant for both Autism Index scores. The author-suggested cutoff score of 70 correctly classified approximately 47% of participants, with false positive rates = 82.83-87.88%. ADOS-2 correlations were significantly lower vis-à-vis the standardization sample. The Social Interaction subscale demonstrated weak, marginal results, and sensitivity/specificity could not be optimized. In its current form, the GARS-3 does not demonstrate adequate criterion validity for use in assessment of complex community samples.

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7. Chawarska K, Lewkowicz D, Feiner H, Macari S, Vernetti A. Attention to audiovisual speech does not facilitate language acquisition in infants with familial history of autism. Journal of child psychology and psychiatry, and allied disciplines. 2022.

BACKGROUND: Due to familial liability, siblings of children with ASD exhibit elevated risk for language delays. The processes contributing to language delays in this population remain unclear. METHODS: Considering well-established links between attention to dynamic audiovisual cues inherent in a speaker’s face and speech processing, we investigated if attention to a speaker’s face and mouth differs in 12-month-old infants at high familial risk for ASD but without ASD diagnosis (hr-sib; n = 91) and in infants at low familial risk (lr-sib; n = 62) for ASD and whether attention at 12 months predicts language outcomes at 18 months. RESULTS: At 12 months, hr-sib and lr-sib infants did not differ in attention to face (p = .14), mouth preference (p = .30), or in receptive and expressive language scores (p = .36, p = .33). At 18 months, the hr-sib infants had lower receptive (p = .01) but not expressive (p = .84) language scores than the lr-sib infants. In the lr-sib infants, greater attention to the face (p = .022) and a mouth preference (p = .025) contributed to better language outcomes at 18 months. In the hr-sib infants, neither attention to the face nor a mouth preference was associated with language outcomes at 18 months. CONCLUSIONS: Unlike low-risk infants, high-risk infants do not appear to benefit from audiovisual prosodic and speech cues in the service of language acquisition despite intact attention to these cues. We propose that impaired processing of audiovisual cues may constitute the link between genetic risk factors and poor language outcomes observed across the autism risk spectrum and may represent a promising endophenotype in autism.

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8. Feng X, Li K, Jiang Q, Zhang Y, Gong Z, Zhi H, Yu J, Li W, Li J. Traditional Chinese medicine intervention for autism spectrum disorders: A protocol for systematic review and network meta-analysis. Medicine. 2022; 101(9): e28957.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication, social interaction, and restrictive or repetitive behaviors. Traditional Chinese medicine (TCM) has been used in the clinical management of ASD, especially in mainland China, where studies have shown promising efficacy. However, this remains to be further explored and clarified. Therefore, the purpose of this study was to evaluate the effectiveness and safety of conventional treatment-based TCM interventions for ASD. METHOD: The study will be conducted from January 2022, and the following electronic databases will be searched: China Biological Medicine Database, Chinese Scientific Journals Database, Wan Fang database, and China National Knowledge Infrastructure, the Cochrane Library, Web of Science, PubMed, and EMBASE Database. Only randomized controlled trials of TCM interventions for ASD will be included. The Autism Diagnostic Observation Scale, Autism Diagnostic Interview-Revised, and Childhood Autism Rating Scale will be the primary outcome indicators. The methodological quality of this Bayesian-based network meta-analysis will be performed using the « Risk of Bias » tool. Stata 14.0 and WinBUGS 1.4.3 will be used to analyze the data. In addition, assessment of heterogeneity, inconsistency, subgroups, sensitivity, and publication bias will be conducted using the Cochrane Collaboration’s tools. RESULTS: The results of this study will be submitted to a peer-reviewed journal for publication. CONCLUSION: This study will help patients recover better, provide clinical evidence for practitioners, and promote the use of TCM in ASD interventions.

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9. Jiang S, Xiao L, Sun Y, He M, Gao C, Zhu C, Chang H, Ding J, Li W, Wang Y, Sun T, Wang F. The GABAB receptor agonist STX209 reverses the autism‑like behaviour in an animal model of autism induced by prenatal exposure to valproic acid. Molecular medicine reports. 2022; 25(5).

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition characterized by impaired social interaction, compromised communication, and restrictive or stereotyped behaviours and interests. Due to the complex pathophysiology of ASD, there are currently no available medical therapies for improving the associated social deficits. Consequently, the present study investigated the effects of STX209, a selective γ‑aminobutyric acid type B receptor (GABABR2) agonist, on an environmental rodent model of autism. The mouse model of autism induced by prenatal exposure to valproic acid (VPA) was used to assess the therapeutic potential of STX209 on autism‑like behaviour in the present study. This study investigated the effects of STX209 on VPA model mice via behavioral testing and revealed a significant reversal of core/associated autism‑like behavior, including sociability and preference for social novelty, novelty recognition, locomotion and exploration activity and marble‑burying deficit. This may be associated with STX209 correcting dendritic arborization, spine density and GABABR2 expression in hippocampus of VPA model mice. However, expression of glutamic acid decarboxylase 65/67 in the hippocampus were not altered by STX209. The present results demonstrated that STX209 administration ameliorated autism‑like symptoms in mice exposed to VPA prenatally, suggesting that autism‑like symptoms in children with a history of prenatal VPA exposure may also benefit from treatment with the GABABR2 agonist STX209.

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10. Kondoleon NP, Kanaan C, Hansen J, Kapadia SR. Use of an Amplatzer ASD Occlusion Device for the Closure of an Ascending Aortic Pseudoaneurysm Presenting as Hemoptysis. Journal of interventional cardiology. 2022; 2022: 9809289.

Aortic pseudoaneurysms can commonly be caused by previous thoracic surgery, trauma, and infection, quickly becoming life-threatening if ruptured. This pathology is typically asymptomatic and incidentally found on imaging; however, few cases have outlined hemoptysis as a presenting symptom for aortic pseudoaneurysms. Traditionally, management of these patients included surgical correction; however, percutaneous approaches have emerged as a safe alternative, helping to reduce the risk of morbidity and mortality associated with surgical correction. This report seeks to describe a case in which hemoptysis was the symptom unveiling the finding of a thoracic ascending aortic pseudoaneurysm and the use of an Amplatzer atrial septal defect (ASD) occlusion device as a viable option to safely resolve the disease process.

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11. Li TS, Gau SS, Chou TL. Exploring social emotion processing in autism: evaluating the reading the mind in the eyes test using network analysis. BMC psychiatry. 2022; 22(1): 161.

BACKGROUND: Features of autism spectrum disorder (ASD) include difficulties in processing and interpreting socioemotional information. The « Reading the Mind in the Eyes » test (RMET) is a validated measurement for processing socioemotional ability. However, previous RMET studies did not explore patterns of incorrect answers and the emotional valence of the test items. This study used the Taiwanese version of the RMET and the network analysis methods to examine the differences in underlying mechanisms of socioemotional processes between 30 males with autism spectrum disorder (ASD) (mean age = 18 years) and 30 healthy control males (mean age = 17 years). For each test item, a picture of a person’s eyes and partial face was shown with four words describing the emotional status on picture corners. Participants were instructed to choose one of the four words that best matched the person’s thinking or feeling. We further classified the words into three valences of emotional categories to examine socioemotional processes. RESULTS: Our results showed that ASD males performed poorer on the RMET than the controls. ASD males had higher network density and in-degree scores, especially in negative words, than control males. CONCLUSIONS: The findings suggest that males with ASD might have deficits in mapping the best emotional concept words to the target item, especially for processing negative emotion.

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12. McDougle CJ, Thom RP, Ravichandran CT, Palumbo ML, Politte LC, Mullett JE, Keary CJ, Erickson CA, Stigler KA, Mathieu-Frasier L, Posey DJ. A randomized double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in children and adolescents with autism spectrum disorder. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2022; 47(6): 1263-70.

This study was a 10-week double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in youth with autism spectrum disorder (ASD). Participants were ages 5 to 17 years with ASD and clinically significant anxiety (Pediatric Anxiety Rating Scale [PARS] score ≥10). Thirty participants were randomized to mirtazapine (7.5-45 mg/day) or placebo in a 2:1 ratio. The co-primary outcome measures were the PARS and the Clinical Global Impressions-Improvement subscale (CGI-I). Mirtazapine resulted in a statistically significant within group decrease in anxiety on the PARS (ES 1.76, p < 0.001). The improvement in PARS score for mirtazapine versus placebo was clinically meaningful but not statistically significant (ES = 0.63, p = 0.64). Forty-seven percent of participants assigned to mirtazapine (95% CI 22%: 74%) and 20% assigned to placebo (95% CI 2%: 60%) were rated "much improved" (CGI-I = 2) or "very much improved" (CGI-I = 1) for anxiety, p = 0.46. No statistically significant differences in mean 10-week changes between mirtazapine and placebo occurred on any outcome measure. There were no statistically significant differences in adverse effect frequency between mirtazapine and placebo. The results are consistent with mirtazapine's safety and tolerability and meet three of four pre-specified indicators of efficacy (statistically significant change in total PARS score for mirtazapine, numerically greater reduction in total PARS score for mirtazapine than placebo, numerically higher number of responders to mirtazapine than placebo, but not greater than 50% of participants receiving mirtazapine rated as responders). Implementation of a larger randomized controlled trial of mirtazapine for the treatment of anxiety in this population is supported.Clinical trial registration information: Mirtazapine Treatment of Anxiety in Children and Adolescents with Pervasive Developmental Disorders; https://clinicaltrials.gov ; NCT01302964.

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13. Mische Lawson L, Foster L, Hodges M, Murphy M, O’Neal M, Peters L. Effects of Sensory Garments on Sleep of Children with Autism Spectrum Disorder. Occupational therapy international. 2022; 2022: 2941655.

OBJECTIVE: The purpose of this study is to assess the effectiveness of the use of sensory garments for improving sleep in children with autism spectrum disorder. METHOD: Using a single-subject ABAB reversal design, the researchers evaluated the effectiveness of a sensory garment on sleep duration, sleep latency, and parental stress related to a child’s sleep. Four children aged 4-10 participated. We measured sleep duration and sleep latency using the Garmin watches and parent-report sleep logs, parent stress using the Parenting Stress Index Short Form, and sleep behaviors using the Children’s Sleep Habits Questionnaire. Results/Discussion. Data showed variable effects on sleep duration and latency across children. The oldest child with the hyposensitive sensory patterns experienced the greatest sleep improvements. All parents experienced stress from daily life, and some reported increased stress due to study participation. Future research is recommended to further investigate the effectiveness of sensory garments on sleep for children with ASD. Therapists are encouraged to evaluate children’s development and sensory preferences prior to recommending sensory garments for sleep.

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14. Mouat JS, LaSalle JM. The Promise of DNA Methylation in Understanding Multigenerational Factors in Autism Spectrum Disorders. Frontiers in genetics. 2022; 13: 831221.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by impairments in social reciprocity and communication, restrictive interests, and repetitive behaviors. Most cases of ASD arise from a confluence of genetic susceptibility and environmental risk factors, whose interactions can be studied through epigenetic mechanisms such as DNA methylation. While various parental factors are known to increase risk for ASD, several studies have indicated that grandparental and great-grandparental factors may also contribute. In animal studies, gestational exposure to certain environmental factors, such as insecticides, medications, and social stress, increases risk for altered behavioral phenotypes in multiple subsequent generations. Changes in DNA methylation, gene expression, and chromatin accessibility often accompany these altered behavioral phenotypes, with changes often appearing in genes that are important for neurodevelopment or have been previously implicated in ASD. One hypothesized mechanism for these phenotypic and methylation changes includes the transmission of DNA methylation marks at individual chromosomal loci from parent to offspring and beyond, called multigenerational epigenetic inheritance. Alternatively, intermediate metabolic phenotypes in the parental generation may confer risk from the original grandparental exposure to risk for ASD in grandchildren, mediated by DNA methylation. While hypothesized mechanisms require further research, the potential for multigenerational epigenetics assessments of ASD risk has implications for precision medicine as the field attempts to address the variable etiology and clinical signs of ASD by incorporating genetic, environmental, and lifestyle factors. In this review, we discuss the promise of multigenerational DNA methylation investigations in understanding the complex etiology of ASD.

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15. Ng-Cordell E, Wardell V, Stewardson C, Kerns CM. Anxiety and Trauma-Related Disorders in Children on the Autism Spectrum. Current psychiatry reports. 2022; 24(3): 171-80.

PURPOSE OF REVIEW: To summarize recent findings regarding anxiety and trauma-related disorders in children diagnosed with autism spectrum disorder (autism), focusing on the distinct ways in which these conditions may be expressed, as well as advances in evidence-based assessment and treatment. RECENT FINDINGS: Current findings suggest both anxiety and trauma-related disorders may be more prevalent, yet more complicated to address in autistic relative to non-autistic children. Overlapping symptoms and distinct manifestations of these disorders pose challenges for the accurate identification, assessment, and treatment of anxiety and trauma-related disorders in autistic children. Emerging evidence recommends adapting traditional assessment and treatment approaches to better meet the needs of autistic children. Recent research suggests autism-centered conceptualizations, which accommodate complexity in how anxiety and trauma-related disorders are experienced and expressed by autistic people, are needed to enhance the psychiatric care of this population.

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16. Stephenson KAJ, Power B, Malata D, Quill B, Murphy CC, Power WJ. Management of Keratoconus in Down Syndrome and Other Intellectual Disability. Cornea. 2022; 41(4): 456-61.

PURPOSE: The purpose of this study was to assess an intellectual disability (ID) cohort with keratoconus (KC) regarding ophthalmic (visual acuity and corneal tomography) and systemic characteristics and to describe an appropriate clinical algorithm for investigation and management of KC in this setting. METHODS: This was the retrospective cohort study of patients with ID (Down syndrome, autism, and other) in the cornea department of a tertiary referral ophthalmic hospital in Dublin, Ireland. Retrospective chart review was conducted on people with ID undergoing examination under anesthesia or crosslinking under general anesthetic. Key outcome data included corneal examination findings, corneal tomography, visual acuity, and examination findings (eg, type of ID, general anesthetic, and cardiac status). RESULTS: Mean age of the 24 patients was 31.9 years (66.7% male). ID type was Down syndrome (66.7%), autism (25%), and other (8.3%). KC was diagnosed in 98% of eyes, with 45.8% having untreatable advanced disease (57.1% of these bilateral), 39.6% amenable to corneal collagen crosslinking (35.7% of these bilateral), and 6.3% having corneal transplantation. Congenital heart defects were present in 37.5% of the Down syndrome group. There were no serious ocular or systemic adverse events. CONCLUSIONS: KC is strikingly prevalent in the ID population. Ireland has the highest rate of Down syndrome in Europe (26.3:10,000 live births). This group is rarely suitable for corneal transplantation, and corneal collagen crosslinking is an effective intervention to prevent progression to advanced KC in this already socially restricted group. We propose an algorithm for investigation/treatment and also recommend uniform pediatric KC screening/treatment in ID populations.

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17. Su WC, Amonkar N, Cleffi C, Srinivasan S, Bhat A. Neural Effects of Physical Activity and Movement Interventions in Individuals With Developmental Disabilities-A Systematic Review. Frontiers in psychiatry. 2022; 13: 794652.

Individuals with developmental disabilities present with perceptuo-motor, social communication, and cognitive impairments that often relate to underlying atypical brain structure and functioning. Physical activity/movement interventions improve behavioral performance of individuals with and without developmental disabilities. Majority of the evidence on potential neural mechanisms explaining the impact of physical activity/movement interventions is based on studies in individuals with typical development; there is a dearth of systematic reviews synthesizing the neural effects of physical activity/movement interventions in individuals with developmental disabilities. In this systematic review, we have gathered evidence on the neural effects of physical activity/movement interventions from 32 papers reporting substantial neural effects and behavioral improvements in individuals with developmental disabilities. Chronic intervention effects (multiple sessions) were greater than acute intervention effects (single session). Specifically, using electroencephalogram, functional magnetic resonance imaging, diffusion tensor imaging, and functional near-infrared spectroscopy, studies found physical activity/movement intervention-related changes in neural activity, indicating normalization of cortical arousal in individuals with attention-deficit /hyperactivity disorder (ADHD), increased social brain connectivity in individuals with autism spectrum disorder (ASD), and more efficient executive functioning processes in individuals with a wide range of other developmental disabilities. Despite promising results, more research is clearly needed in this area with larger sample sizes, using standardized neuroimaging tools/variables, and across multiple diagnoses to further explore the neural mechanisms underlying physical activity/movement interventions and to replicate findings from the present review.

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18. Yehia L, Ni Y, Sadler T, Frazier TW, Eng C. Distinct metabolic profiles associated with autism spectrum disorder versus cancer in individuals with germline PTEN mutations. NPJ genomic medicine. 2022; 7(1): 16.

PTEN hamartoma tumor syndrome (PHTS), caused by germline PTEN mutations, has been associated with organ-specific cancers and autism spectrum disorder (ASD) and/or developmental delay (DD). Predicting precise clinical phenotypes in any one PHTS individual remains impossible. We conducted an untargeted metabolomics study on an age- and sex-matched series of PHTS individuals with ASD/DD, cancer, or both phenotypes. Using agnostic metabolomic-analyses from patient-derived lymphoblastoid cells and their spent media, we found 52 differentially abundant individual metabolites, 69 cell/media metabolite ratios, and 327 pair-wise metabotype (shared metabolic phenotype) ratios clearly distinguishing PHTS individuals based on phenotype. Network analysis based on significant metabolites pointed to hubs converging on PTEN-related insulin, MAPK, AMPK, and mTOR signaling cascades. Internal cross-validation of significant metabolites showed optimal overall accuracy in distinguishing PHTS individuals with ASD/DD versus those with cancer. Such metabolomic markers may enable more accurate risk predictions and prevention in individual PHTS patients at highest risk.

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19. Yu Y, Zhang B, Ji P, Zuo Z, Huang Y, Wang N, Liu C, Liu SJ, Zhao F. Changes to gut amino acid transporters and microbiome associated with increased E/I ratio in Chd8(+/-) mouse model of ASD-like behavior. Nature communications. 2022; 13(1): 1151.

Autism spectrum disorder (ASD), a group of neurodevelopmental disorders characterized by social communication deficits and stereotyped behaviors, may be associated with changes to the gut microbiota. However, how gut commensal bacteria modulate brain function in ASD remains unclear. Here, we used chromodomain helicase DNA-binding protein 8 (CHD8) haploinsufficient mice as a model of ASD to elucidate the pathways through which the host and gut microbiota interact with each other. We found that increased levels of amino acid transporters in the intestines of the mouse model of ASD contribute to the high level of serum glutamine and the increased excitation/inhibition (E/I) ratio in the brain. In addition, elevated α-defensin levels in the haploinsufficient mice resulted in dysregulation of the gut microbiota characterized by a reduced abundance of Bacteroides. Furthermore, supplementation with Bacteroides uniformis improved the ASD-like behaviors and restored the E/I ratio in the brain by decreasing intestinal amino acid transport and the serum glutamine levels. Our study demonstrates associations between changes in the gut microbiota and amino acid transporters, and ASD-like behavioral and electrophysiology phenotypes, in a mouse model.

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20. Zhang Q, Li T, Lin J, Zhang Y, Li F, Chen X, Wang X, Li Q. Deficiency of nde1 in zebrafish induces brain inflammatory responses and autism-like behavior. iScience. 2022; 25(3): 103876.

The cytoskeletal protein NDE1 plays an important role in chromosome segregation, neural precursor differentiation, and neuronal migration. Clinical studies have shown that NDE1 deficiency is associated with several neuropsychiatric disorders including autism. Here, we generated nde1 homologous deficiency zebrafish (nde1 (-/-) ) to elucidate the cellular molecular mechanisms behind it. nde1 (-/-) exhibit increased neurological apoptotic responses at early infancy, enlarged ventricles, and shrank valvula cerebelli in adult brain tissue. Behavioral analysis revealed that nde1 (-/-) displayed autism-like behavior traits such as increased locomotor activity and repetitive stereotype behaviors and impaired social and kin recognition behaviors. Furthermore, nde1 mRNA injection rescued apoptosis in early development, and minocycline treatment rescued impaired social behavior and overactive motor activity by inhibiting inflammatory cytokines. In this study, we revealed that nde1 homozygous deletion leads to abnormal neurological development with autism-related behavioral phenotypes and that inflammatory responses in the brain are an important molecular basis behind it.

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