1. Alsufiani HM, Alkhanbashi AS, Laswad NAB, Bakhadher KK, Alghamdi SA, Tayeb HO, Tarazi FI. Zinc deficiency and supplementation in autism spectrum disorder and Phelan-McDermid syndrome. Journal of neuroscience research. 2022; 100(4): 970-8.

Approximately 1 in 36 children are diagnosed with autism spectrum disorder (ASD). The disorder is four times more common in males than in females. Zinc deficiency and mutations in SHANK2 and SHANK3 (members of a family of excitatory postsynaptic scaffolding proteins) are all risk factors that may contribute to the pathophysiology of the disease. The presence of shankopathies (loss of one copy of the SHANK3 gene) can lead to the development of Phelan-McDermid syndrome (PMDS)-a rare genetic disorder characterized by developmental delay, intellectual disability, poor motor tone, and ASD-like symptoms. We reviewed the relationship between zinc, ASD, and PMDS as well as the effect of zinc supplementation in improving symptoms of ASD and PMDS based on 22 studies published within 6 years (2015-2020). Zinc deficiency (assessed by either dietary intake, blood, hair, or tooth matrix) was shown to be highly prevalent in ASD and PMDS patients as well as in preclinical models of ASD and PMDS. Zinc supplements improved the behavioral deficits in animal models of ASD and PMDS. Clinical trials are still needed to validate the beneficial therapeutic effects of zinc supplements in ASD and PMDS patients.

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2. Bourne L, Mandy W, Bryant-Waugh R. Avoidant/restrictive food intake disorder and severe food selectivity in children and young people with autism: A scoping review. Developmental medicine and child neurology. 2022.

AIM: To assess the extent of the scientific literature on avoidant/restrictive food intake disorder (ARFID) in children and young people with autism in order to evaluate and synthesize the evidence on (a) the nature of feeding and eating difficulties in children and young people with autism; (b) the consequences of a severely restricted diet; and (c) what is known about effective treatment approaches. METHOD: PubMed and PsycInfo databases were searched, identifying 56 studies and a narrative synthesis was effected. RESULTS: The literature suggested that ARFID-like presentations are common in children and young people with autism, with severe consequences for physical and mental health. The three drivers mentioned in the DSM-5 criteria, namely a sensory-based avoidance, fear- or phobia-based restriction, and a lack of interest in eating, are present in this population, although sensory sensitivities are currently the most commonly described. Research suggests that ARFID symptoms in children and young people with autism can be amenable to treatment, with evidence that behavioural interventions are feasible and potentially effective in this population. INTERPRETATION: ARFID is a common and impactful problem among young people with autism but is currently under researched. Work is required to (a) identify the prevalence of ARFID in children and young people with autism; (b) uncover the key drivers of ARFID in this population; (c) adapt currently available interventions for use with children and young people with autism; and (d) rigorously test these interventions in clinical trials.

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3. Chawla A, McCullagh EA. Auditory Brain Stem Responses in the C57BL/6J Fragile X Syndrome-Knockout Mouse Model. Frontiers in integrative neuroscience. 2021; 15: 803483.

Sensory hypersensitivity, especially in the auditory system, is a common symptom in Fragile X syndrome (FXS), the most common monogenic form of intellectual disability. However, linking phenotypes across genetic background strains of mouse models has been a challenge and could underly some of the issues with translatability of drug studies to the human condition. This study is the first to characterize the auditory brain stem response (ABR), a minimally invasive physiological readout of early auditory processing that is also used in humans, in a commonly used mouse background strain model of FXS, C57BL/6J. We measured morphological features of pinna and head and used ABR to measure the hearing range, and monaural and binaural auditory responses in hemizygous males, homozygous females, and heterozygous females compared with those in wild-type mice. Consistent with previous study, we showed no difference in morphological parameters across genotypes or sexes. There was no significant difference in hearing range between the sexes or genotypes, however there was a trend towards high frequency hearing loss in male FXS mice. In contrast, female mice with homozygous FXS had a decreased amplitude of wave IV of the monaural ABR, while there was no difference in males for amplitudes and no change in latency of ABR waveforms across sexes and genotypes. Finally, males with FXS had an increased latency of the binaural interaction component (BIC) at 0 interaural timing difference compared with that in wild-type males. These findings further clarify auditory brain stem processing in FXS by adding more information across genetic background strains allowing for a better understanding of shared phenotypes.

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4. Denier N, Steinberg G, van Elst LT, Bracht T. The role of head circumference and cerebral volumes to phenotype male adults with autism spectrum disorder. Brain and behavior. 2022; 12(3): e2460.

BACKGROUND: Autism spectrum disorder (ASD) has been repeatedly associated with enlargements of head circumference in children with ASD. However, it is unclear if these enlargements persist into adulthood. This is the first study to investigate head circumference in a large sample of adults with ASD. METHODS: We apply a fully automated magnetic resonance imaging (MRI) based measurement approach to compute head circumference by combining 3D and 2D image processing. Head circumference was compared between male adults with ASD (n = 120) and healthy male controls (n = 136), from the Autism Brain Imaging Data Exchange (ABIDE) database. To explain which brain alterations drive our results, secondary analyses were performed for 10 additional morphological brain metrics. RESULTS: ASD subjects showed an increase in head circumference (p = .0018). In addition, ASD patients had increased ventricular surface area (SA) (p = .0013). Intracranial volume, subarachnoidal cerebrospinal fluid (CSF) volume, and gray matter volume explained 50% of head circumference variance. Using a linear support vector machine, we gained an ASD classification accuracy of 73% (sensitivity 92%, specificity 68%) using head circumference and brain-morphological metrics as input features. Head circumference, ventricular SA, ventricular CSF volume, and ventricular asymmetry index contributed to 85% of feature weighting relevant for classification. CONCLUSION: Our results suggest that head circumference increases in males with ASD persist into adulthood. Results may be driven by morphological alterations of ventricular CSF. The presented approach for an automated head circumference measurement allows for the retrospective investigation of large MRI datasets in neuropsychiatric disorders.

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5. Gowen E, Crane L, Falter-Wagner CM. Editorial: Autism: Innovations and Future Directions in Psychological Research. Frontiers in psychology. 2021; 12: 832008.

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6. Le Bras A. New insights into Rett syndrome. Lab animal. 2022; 51(2): 43.

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7. Mandy W. Six ideas about how to address the autism mental health crisis. Autism : the international journal of research and practice. 2022; 26(2): 289-92.

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8. Nordahl CW, Andrews DS, Dwyer P, Waizbard-Bartov E, Restrepo B, Lee JK, Heath B, Saron C, Rivera SM, Solomon M, Ashwood P, Amaral DG. The Autism Phenome Project: Toward Identifying Clinically Meaningful Subgroups of Autism. Frontiers in neuroscience. 2021; 15: 786220.

One of the most universally accepted facts about autism is that it is heterogenous. Individuals diagnosed with autism spectrum disorder have a wide range of behavioral presentations and a variety of co-occurring medical and mental health conditions. The identification of more homogenous subgroups is likely to lead to a better understanding of etiologies as well as more targeted interventions and treatments. In 2006, we initiated the UC Davis MIND Institute Autism Phenome Project (APP) with the overarching goal of identifying clinically meaningful subtypes of autism. This ongoing longitudinal multidisciplinary study now includes over 400 children and involves comprehensive medical, behavioral, and neuroimaging assessments from early childhood through adolescence (2-19 years of age). We have employed several strategies to identify sub-populations within autistic individuals: subgrouping by neural, biological, behavioral or clinical characteristics as well as by developmental trajectories. In this Mini Review, we summarize findings to date from the APP cohort and describe progress made toward identifying meaningful subgroups of autism.

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9. Okazaki S, Kimura R, Otsuka I, Funabiki Y, Murai T, Hishimoto A. Epigenetic clock analysis and increased plasminogen activator inhibitor-1 in high-functioning autism spectrum disorder. PloS one. 2022; 17(2): e0263478.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by impaired social communication and behavioral problems. An increased risk of premature mortality has been observed in individuals with ASD. Therefore, we hypothesized that biological aging is accelerated in individuals with ASD. Recently, several studies have established genome-wide DNA methylation (DNAm) profiles as ‘epigenetic clocks’ that can estimate biological aging. In addition, ASD has been associated with differential DNAm patterns. METHODS: We used two independent datasets from blood samples consisting of adult patients with high-functioning ASD and controls: the 1st cohort (38 ASD cases and 31 controls) and the 2nd cohort (6 ASD cases and 10 controls). We explored well-studied epigenetic clocks such as HorvathAge, HannumAge, SkinBloodAge, PhenoAge, GrimAge, and DNAm-based telomere length (DNAmTL). In addition, we investigated seven DNAm-based age-related plasma proteins, including plasminogen activator inhibitor-1 (PAI-1), and smoking status, which are the components of GrimAge. RESULTS: Compared to controls, individuals with ASD in the 1st cohort, but not in the 2nd cohort, exhibited a trend for increased GrimAge acceleration and a significant increase of PAI-1 levels. A meta-analysis showed significantly increased PAI-1 levels in individuals with ASD compared to controls. CONCLUSION: Our findings suggest there is no epigenetic age acceleration in the blood of individuals with ASD. However, this study provides novel evidence regarding increased plasma PAI-1 levels in individuals with high-functioning ASD. These findings suggest PAI-1 may be a biomarker for high-functioning ASD, however, larger studies based on epigenetic clocks and PAI-1 will be necessary to confirm these findings.

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10. Paulsen B, Velasco S, Kedaigle AJ, Pigoni M, Quadrato G, Deo AJ, Adiconis X, Uzquiano A, Sartore R, Yang SM, Simmons SK, Symvoulidis P, Kim K, Tsafou K, Podury A, Abbate C, Tucewicz A, Smith SN, Albanese A, Barrett L, Sanjana NE, Shi X, Chung K, Lage K, Boyden ES, Regev A, Levin JZ, Arlotta P. Autism genes converge on asynchronous development of shared neuron classes. Nature. 2022; 602(7896): 268-73.

Genetic risk for autism spectrum disorder (ASD) is associated with hundreds of genes spanning a wide range of biological functions(1-6). The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals(7,8). Here we used organoid models of the human cerebral cortex to identify cell-type-specific developmental abnormalities that result from haploinsufficiency in three ASD risk genes-SUV420H1 (also known as KMT5B), ARID1B and CHD8-in multiple cell lines from different donors, using single-cell RNA-sequencing (scRNA-seq) analysis of more than 745,000 cells and proteomic analysis of individual organoids, to identify phenotypic convergence. Each of the three mutations confers asynchronous development of two main cortical neuronal lineages-γ-aminobutyric-acid-releasing (GABAergic) neurons and deep-layer excitatory projection neurons-but acts through largely distinct molecular pathways. Although these phenotypes are consistent across cell lines, their expressivity is influenced by the individual genomic context, in a manner that is dependent on both the risk gene and the developmental defect. Calcium imaging in intact organoids shows that these early-stage developmental changes are followed by abnormal circuit activity. This research uncovers cell-type-specific neurodevelopmental abnormalities that are shared across ASD risk genes and are finely modulated by human genomic context, finding convergence in the neurobiological basis of how different risk genes contribute to ASD pathology.

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11. Posar A, Visconti P. Early Motor Impairment in Children with Autism Spectrum Disorder. Turkish archives of pediatrics. 2021; 56(6): 646-7.

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12. Qu X, Lee LC, Ladd-Acosta C, Hong X, Ji Y, Kalb LG, Volk HE, Wang X. Association between atopic diseases and neurodevelopmental disabilities in a longitudinal birth cohort. Autism research : official journal of the International Society for Autism Research. 2022; 15(4): 740-50.

Reports on the association between the prevalence of atopic diseases and neurodevelopmental disabilities (NDs) have been inconsistent in the literature. We investigated whether autism spectrum disorder (ASD), attention deficit-hyperactivity disorders (ADHD), and other NDs are more prevalent in children with asthma, atopic dermatitis (AD) and allergic rhinitis (AR) compared to those without specific atopic conditions. A total of 2580 children enrolled at birth were followed prospectively, of which 119 have ASD, 423 have ADHD, 765 have other NDs, and 1273 have no NDs. Atopic diseases and NDs were defined based on physician diagnoses in electronic medical records. Logistic regressions adjusting for maternal and child characteristics estimated the associations between NDs (i.e., ASD, ADHD, and other NDs) and asthma, AD and AR, respectively. Children with asthma, AD or AR had a greater likelihood of having ADHD or other NDs compared with children without specific atopic conditions. The association between ASD and asthma diminished after adjusting for maternal and child factors. Either mothers or children having atopic conditions and both mothers and children with atopic conditions were associated with a higher prevalence of ADHD in children, compared with neither mothers nor children having atopic conditions. Children diagnosed with multiple atopic diseases were more likely to have NDs compared with those without or with only one type of atopic disease. In conclusion, in this U.S. urban birth cohort, children with atopic diseases had a higher co-morbidity of NDs. The findings have implications for etiologic research that searches for common early life antecedents of NDs and atopic conditions. Findings from this study also should raise awareness among health care providers and parents about the possible co-occurrence of both NDs and atopic conditions, which calls for coordinated efforts to screen, prevent and manage NDs and atopic conditions.

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13. Simpson K, Adams D. Brief Report: Covid Restrictions had Positive and Negative Impacts on Schooling for Students on the Autism Spectrum. Journal of autism and developmental disorders. 2022: 1-7.

The COVID-19 pandemic (2020) resulted in school closures and changes to school delivery. The aim of this study was to explore how these changes impacted on children on the autism spectrum. As part of an online survey, parents (n = 180) of school-aged children (9.3-16.5 years) on the autism spectrum in Australia were asked an open-ended question on how the COVID-19 pandemic had impacted on their child’s education experience. Nearly half (48%) of the parents reported only negative impacts, 26% only positive impacts, 12% a mix of positive and negative impacts, and 9% little or no impact. Parents identified that school restrictions impacted on more than their child’s learning. These findings highlight areas to consider when supporting autism-friendly learning.

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14. Vaiouli P, Luminet O, Panayiotou G. Alexithymic and autistic traits in children and adolescents: A systematic review of the current state of knowledge. Autism : the international journal of research and practice. 2022; 26(2): 308-16.

In this study, we aim to explore the ability of autistic children to process emotions and respond to a range of feelings in relation to a triad of difficulties known as alexithymia, namely children’s difficulties to recognize, describe, and distinguish emotions. Alexithymia is common in autistic adults but we know very little about children. To understand this condition better, within a large group of studies, first we study the extent to which alexithymia difficulties are present in autistic children. In reviewing the literature, we also present the assessment measures implemented in each study, their limitations, and potential effects on our understanding of findings. This knowledge will help us understand the extent to which alexithymia is present in autistic children and how it may be related to their emotional difficulties. Also, it will allow us to further detect challenges early on in children’s lives so that we recommend interventions that teach autistic children how to recognize, describe, and distinguish emotions in themselves and in others. Such interventions may include family members of autistic children to assist interactions with their child. Supporting children from an early age will help them develop skills that will ready them for school and life and it will enhance their ability to build supportive relationships and meet their fullest potential.

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15. Vanderplow AM, Kermath BA, Bernhardt CR, Gums KT, Seablom EN, Radcliff AB, Ewald AC, Jones MV, Baker TL, Watters JJ, Cahill ME. A feature of maternal sleep apnea during gestation causes autism-relevant neuronal and behavioral phenotypes in offspring. PLoS biology. 2022; 20(2): e3001502.

Mounting epidemiologic and scientific evidence indicates that many psychiatric disorders originate from a complex interplay between genetics and early life experiences, particularly in the womb. Despite decades of research, our understanding of the precise prenatal and perinatal experiences that increase susceptibility to neurodevelopmental disorders remains incomplete. Sleep apnea (SA) is increasingly common during pregnancy and is characterized by recurrent partial or complete cessations in breathing during sleep. SA causes pathological drops in blood oxygen levels (intermittent hypoxia, IH), often hundreds of times each night. Although SA is known to cause adverse pregnancy and neonatal outcomes, the long-term consequences of maternal SA during pregnancy on brain-based behavioral outcomes and associated neuronal functioning in the offspring remain unknown. We developed a rat model of maternal SA during pregnancy by exposing dams to IH, a hallmark feature of SA, during gestational days 10 to 21 and investigated the consequences on the offspring’s forebrain synaptic structure, synaptic function, and behavioral phenotypes across multiples stages of development. Our findings represent a rare example of prenatal factors causing sexually dimorphic behavioral phenotypes associated with excessive (rather than reduced) synapse numbers and implicate hyperactivity of the mammalian target of rapamycin (mTOR) pathway in contributing to the behavioral aberrations. These findings have implications for neuropsychiatric disorders typified by superfluous synapse maintenance that are believed to result, at least in part, from largely unknown insults to the maternal environment.

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16. Virues-Ortega J, McKay NS, McCormack JC, Lopez N, Liu R, Kirk I. A callosal biomarker of behavioral intervention outcomes for autism spectrum disorder? A case-control feasibility study with diffusion tensor imaging. PloS one. 2022; 17(2): e0262563.

Tentative results from feasibility analyses are critical for planning future randomized control trials (RCTs) in the emerging field of neural biomarkers of behavioral interventions. The current feasibility study used MRI-derived diffusion imaging data to investigate whether it would be possible to identify neural biomarkers of a behavioral intervention among people diagnosed with autism spectrum disorder (ASD). The corpus callosum has been linked to cognitive processing and callosal abnormalities have been previously found in people diagnosed with ASD. We used a case-control design to evaluate the association between the type of intervention people diagnosed with ASD had previously received and their current white matter integrity in the corpus callosum. Twenty-six children and adolescents with ASD, with and without a history of parent-managed behavioral intervention, underwent an MRI scan with a diffusion data acquisition sequence. We conducted tract-based spatial statistics and a region of interest analysis. The fractional anisotropy values (believed to indicate white matter integrity) in the posterior corpus callosum was significantly different across cases (exposed to parent-managed behavioral intervention) and controls (not exposed to parent-managed behavioral intervention). The effect was modulated by the intensity of the behavioral intervention according to a dose-response relationship. The current feasibility case-control study provides the basis for estimating the statistical power required for future RCTs in this field. In addition, the study demonstrated the effectiveness of purposely-developed motion control protocols and helped to identify regions of interest candidates. Potential clinical applications of diffusion tensor imaging in the evaluation of treatment outcomes in ASD are discussed.

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17. Wang L, Liang X, Jiang B, Wu Q, Jiang L. What Ability Can Predict Mathematics Performance in Typically Developing Preschoolers and Those with Autism Spectrum Disorder?. Journal of autism and developmental disorders. 2022.

Research evaluating predictors of mathematics ability in preschoolers with autism spectrum disorder (ASD) is scarce and inconclusive. The present study first compared the mathematics ability and cognitive abilities of preschoolers with ASD and age-matched typically developing (TD) peers. Then, we examined the relative contributions of cognitive abilities to the mathematics ability of preschoolers with ASD and TD. The results show that compared to those of their age-matched TD peers, the mathematics and cognitive abilities of preschoolers with ASD were impaired. The predictors of mathematics ability were found to differ among preschoolers with ASD and their age-matched TD peers. For TD preschoolers, the domain-specific approximate number system (ANS) was the key predictor of mathematics ability. For preschoolers with ASD, domain-general working memory (WM) was most important.

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18. Yan H, Siegel L, Breitbart S, Gorodetsky C, Fasano A, Rahim A, Loh A, Kulkarni AV, Ibrahim GM. An open-label prospective pilot trial of nucleus accumbens deep brain stimulation for children with autism spectrum disorder and severe, refractory self-injurious behavior: study protocol. Pilot and feasibility studies. 2022; 8(1): 24.

BACKGROUND: Children and youth with autism spectrum disorder (ASD) may manifest self-injurious behaviors (SIB) that may become severe and refractory with limited pharmacologic or behavioral treatment options. Here, we present the protocol of a prospective, mixed-methods study to assess the safety and efficacy of deep brain stimulation (DBS) of the nucleus accumbens (NAcc) for children and youth with ASD and severe, refractory SIB. METHODS: This is a prospective, single-center, single-cohort, open-label, non-randomized pilot trial of 6 patients. Participants will be recruited through specialized behavioral clinics with persistent severe and refractory SIB following standard and intensive interventions. Following NAcc-DBS, participants will be enrolled in the study for 12 months. The primary objectives of the study are safety and feasibility, assessed by rate of recruitment and identification of factors impacting adherence to follow-up and study protocol. Potential treatment efficacy will be assessed by changes in the Children’s Yale-Brown Obsessive-Compulsive Scale in ASD (CYBOCS-ASD), the Behavior Problems Index (BPI), the Inventory of Statements about Self-Injury (ISAS) and the Repetitive Behavior Scale-Revised (RBS-R) questionnaires. Additional clinical outcomes will be assessed, including measures of participant and caregiver quality of life, actigraph measurements, and positron emission tomography (PET) changes following DBS. DISCUSSION: This study will be the first to evaluate the effect of DBS of the NAcc on a pediatric population in a controlled, prospective trial. Secondary outcomes will improve the understanding of behavioral, neuro-imaging, and electrophysiologic changes in children with ASD and SIB treated with DBS. This trial will provide an estimated effect size of NAcc-DBS for severe refractory SIB in children with ASD in preparation for future comparative trials. TRIAL REGISTRATION: Registration on ClinicalTrials.gov was completed on 12 June 2019 with the Identifier: NCT03982888 .

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