1. Erratum to: From autism to Zoom®: Spina bifida advocacy, care, education, and research in a changing world. J Pediatr Rehabil Med;2023 (Mar 3)

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2. Arslan A, Fang Z, Wang M, Tan Y, Cheng Z, Chen X, Guan Y, L JP, Yoo B, Bejerano G, Peltz G. Analysis of structural variation among inbred mouse strains. BMC Genomics;2023 (Mar 2);24(1):97.

BACKGROUND: ‘Long read’ sequencing methods have been used to identify previously uncharacterized structural variants that cause human genetic diseases. Therefore, we investigated whether long read sequencing could facilitate genetic analysis of murine models for human diseases. RESULTS: The genomes of six inbred strains (BTBR T + Itpr3tf/J, 129Sv1/J, C57BL/6/J, Balb/c/J, A/J, SJL/J) were analyzed using long read sequencing. Our results revealed that (i) Structural variants are very abundant within the genome of inbred strains (4.8 per gene) and (ii) that we cannot accurately infer whether structural variants are present using conventional short read genomic sequence data, even when nearby SNP alleles are known. The advantage of having a more complete map was demonstrated by analyzing the genomic sequence of BTBR mice. Based upon this analysis, knockin mice were generated and used to characterize a BTBR-unique 8-bp deletion within Draxin that contributes to the BTBR neuroanatomic abnormalities, which resemble human autism spectrum disorder. CONCLUSION: A more complete map of the pattern of genetic variation among inbred strains, which is produced by long read genomic sequencing of the genomes of additional inbred strains, could facilitate genetic discovery when murine models of human diseases are analyzed.

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3. Bogéa Ribeiro L, da Silva Filho M. Systematic Review on EEG Analysis to Diagnose and Treat Autism by Evaluating Functional Connectivity and Spectral Power. Neuropsychiatr Dis Treat;2023;19:415-424.

An abnormality in neural connectivity is linked to autism spectrum disorder (ASD). There is no way to test the concept of neural connectivity empirically. According to recent network theory and time series analysis findings, electroencephalography (EEG) can assess neural network architecture, a sign of activity in the brain. This systematic review aims to evaluate functional connectivity and spectral power using EEG signals. EEG records the brain activity of an individual by displaying wavy lines that depict brain cells’ communication through electrical impulses. EEG can diagnose various brain disorders, including epilepsy and related seizure illness, brain dysfunction, tumors, and damage. We found 21 studies using two of the most common EEG analysis methods: functional connectivity and spectral power. ASD and non-ASD individuals were found to differ significantly in all selected papers. Due to high heterogeneity in the outcomes, generalizations cannot be drawn, and no single method is currently beneficial as a diagnostic tool. For ASD subtype delineation, the lack of research prevented the evaluation of these techniques as diagnostic tools. These findings confirm the presence of abnormalities in the EEG in ASD, but they are insufficient to diagnose. Our study suggests that EEG is useful in diagnosing ASD by evaluating entropy in the brain. Researchers may be able to develop new diagnostic methods for ASD which focuses on particular stimuli and brainwaves if they conduct more extensive studies with higher numbers and more rigorous study designs.

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4. Eckes T, Buhlmann U, Holling HD, Möllmann A. Comprehensive ABA-based interventions in the treatment of children with autism spectrum disorder – a meta-analysis. BMC Psychiatry;2023 (Mar 2);23(1):133.

BACKGROUND: Many studies display promising results for interventions that are based on Applied Behavior Analysis (ABA) in the treatment of autism spectrum disorder (ASD). METHODS: This meta-analysis assessed the effects of such treatments on developmental outcomes in children with ASD and on parental stress based on 11 studies with 632 participants. RESULTS: Compared to treatment as usual, minimal or no treatment, comprehensive ABA-based interventions showed medium effects for intellectual functioning (standardized mean difference SMD = 0.51, 95% CI [0.09; 0.92]) and adaptive behavior (SMD = 0.37, 95% CI [0.03; 0.70]). Language abilities, symptom severity or parental stress did not improve beyond the improvement in control groups. Moderator analyses indicate that language abilities at intake could influence the effect sizes and the influence of treatment intensity might decrease with older age. CONCLUSIONS: Practical implications and limitations are discussed.

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5. Fell LA, Albright CM, Kryszak EM, Butter E, Kuhlthau KA. Provider Perspectives on Telehealth Services for Children with Autism Spectrum Disorder During the COVID-19 Pandemic. Acad Pediatr;2023 (Mar 3)

OBJECTIVE: The purpose of the current study was to explore provider perspectives on the strengths and challenges of telehealth services (e.g., behavioral interventions, physical, speech, and occupational therapy, medication management) for children with ASD during COVID-19 related shutdowns. METHODS: From September 2020 to May 2021, we conducted qualitative interviews with 35 providers across multiple disciplines from 17 sites in the Autism Care Network. Qualitative data was analyzed using a framework approach and common themes were identified. RESULTS: Providers across clinical disciplines identified strengths of the virtual model, such as its flexibility and the opportunity it provided to see children in their home environment. They also indicated that some interventions worked better virtually than others, and that there were several factors that impacted their success. Respondents were generally satisfied providing parent-mediated interventions but expressed mixed satisfaction in using telehealth for direct-to-patient care. CONCLUSIONS: Results suggest that telehealth services for children with ASD could be a helpful tool in decreasing barriers and improving service delivery, especially when tailored to the individual needs of the patient. More research is needed on the factors contributing to its success in order to eventually inform clinical guidelines regarding the prioritization of children seen for in-person visits.

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6. Fusaroli R, Weed E, Rocca R, Fein D, Naigles L. Caregiver linguistic alignment to autistic and typically developing children: A natural language processing approach illuminates the interactive components of language development. Cognition;2023 (Mar 3);236:105422.

BACKGROUND: Language development is a highly interactive activity. However, most research on linguistic environment has focused on the quantity and complexity of linguistic input to children, with current models showing that complexity facilitates language in both typically developing (TD) and autistic children. AIMS: After reviewing existing work on caregiver engagement of children’s utterances, we aim to operationalize such engagement with automated measures of linguistic alignment, thereby providing scalable tools to assess caregivers’ active reuse of their children’s language. By assessing the presence of alignment, its sensitivity to the child’s individual differences and how well it predicts language development beyond current models across the two groups, we showcase the usefulness of the approach and provide initial empirical foundations for further conceptual and empirical investigations. METHODS: We measure lexical, syntactic and semantic types of caregiver alignment in a longitudinal corpus involving 32 adult-autistic child and 35 adult-TD child dyads, with children between 2 and 5 years of age. We assess the extent to which caregivers repeat their children’s words, syntax, and semantics, and whether these repetitions predict language development beyond more standard predictors. RESULTS: Caregivers tend to re-use their child’s language in a way that is related to the child’s individual, primarily linguistic, differences. Caregivers’ alignment provides unique information improving our ability to predict future language development in both typical and autistic children. CONCLUSIONS: We provide evidence that language development also relies on interactive conversational processes, previously understudied. We share carefully detailed methods, and open-source scripts so as to systematically extend our approach to new contexts and languages.

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7. Kim JY, Kim W, Lee KH. The role of microRNAs in the molecular link between circadian rhythm and autism spectrum disorder. Anim Cells Syst (Seoul);2023;27(1):38-52.

Circadian rhythm regulates physiological cycles of awareness and sleepiness. Melatonin production is primarily regulated by circadian regulation of gene expression and is involved in sleep homeostasis. If the circadian rhythm is abnormal, sleep disorders, such as insomnia and several other diseases, can occur. The term ‘autism spectrum disorder (ASD)’ is used to characterize people who exhibit a certain set of repetitive behaviors, severely constrained interests, social deficits, and/or sensory behaviors that start very early in life. Because many patients with ASD suffer from sleep disorders, sleep disorders and melatonin dysregulation are attracting attention for their potential roles in ASD. ASD is caused by abnormalities during the neurodevelopmental processes owing to various genetic or environmental factors. Recently, the role of microRNAs (miRNAs) in circadian rhythm and ASD have gained attraction. We hypothesized that the relationship between circadian rhythm and ASD could be explained by miRNAs that can regulate or be regulated by either or both. In this study, we introduced a possible molecular link between circadian rhythm and ASD. We performed a thorough literature review to understand their complexity.

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8. Klusek J, Will E, Moser C, Hills K, Thurman AJ, Abbeduto L, Roberts JE. Predictors, Parental Views, and Concordance Across Diagnostic Sources of Autism in Male Youth with Fragile X Syndrome: Clinical Best Estimate and Community Diagnoses. Res Child Adolesc Psychopathol;2023 (Mar 3)

Persons with fragile X syndrome (FXS) with cooccurring autism spectrum disorder (ASD) are at risk for poorer educational, medical, employment, and independent living outcomes. Thus, the identification of ASD in those with FXS is fundamental to ensuring access to appropriate supports to achieve good quality of life. Yet, optimal diagnostic methods and the exact rate of ASD comorbidity remains controversial, and description of ASD identification in the community in FXS has been limited. This study characterized ASD in a sample of 49 male youth with FXS across multiple diagnostic sources: parent-reported community diagnoses, classification derived from ADOS-2 and ADI-R thresholds, and clinical best-estimate classifications from an expert multidisciplinary team. High concordance was found between ADOS-2/ADI-R and clinical best estimate classifications, with both methods supporting ASD in ~ 75% of male youth with FXS. In contrast, 31% had a community diagnosis. Findings supported gross under-identification of ASD in male youth with FXS in community settings; 60% of those who met clinical best estimate criteria for ASD had not received a diagnosis in the community. Moreover, community diagnoses were poorly aligned with the presence of ASD symptoms as perceived by parents and professionals and, unlike clinical best estimate diagnoses, were not associated with cognitive, behavioral, or language features. Findings highlight under-identification of ASD in community settings as a significant barrier to service access for male youth with FXS. Clinical recommendations should emphasize the benefits of seeking a professional ASD evaluation for children with FXS who are noted to display key ASD symptoms.

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9. Marsack-Topolewski C, Milberger S, Janks E, Anderson N, Bray M, Samuel PS. Evaluation of peer-mediated systems navigation for ageing families of individuals with developmental disabilities. J Intellect Disabil Res;2023 (Mar 3)

BACKGROUND: As individuals with intellectual and developmental disabilities (I/DD) age, services often diminish, with many family caregivers experiencing challenges finding and navigating services. The purpose of this study was to examine the benefits of a state-wide family support project for ageing caregivers (50+) of adults with I/DD in accessing and using services. METHOD: A one-group pre-test-post-test design was used to determine if participation in the MI-OCEAN intervention grounded in the Family Quality of Life (FQOL) theory reduced ageing caregivers’ (n = 82) perceptions of barriers to accessing, using and needing formal services. RESULTS: After participating in the study, there was a reduction in reported barriers to accessing services. There was also greater use and reduced need for 10 of the 23 listed formal services. CONCLUSIONS: Findings indicate that a peer-mediated intervention grounded in FQOL theory can be beneficial in empowering ageing caregivers by reducing perceived barriers to accessing services and increasing their use of advocacy and support services.

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10. Mei L, Hu C, Li D, Wang Y, Li H, Zhang K, Zhou B, Zhu R, Hagerman RJ, Xu X, Xu Q. The incidence and clinical characteristics of fragile X syndrome in China. Front Pediatr;2023;11:1064104.

INTRODUCTION: Fragile X syndrome (FXS) is a X-linked neurodevelopmental disorder (NDD). This study aims to investigate the incidence of FXS in Chinese children and analyze the comprehensive clinical characteristics of these FXS children. METHODS: Children diagnosed with idiopathic NDD were recruited between 2016 and 2021 from the department of Child Health Care, Children’s Hospital of Fudan University. We combined tetraplet-primed PCR-capillary electrophoresis and whole exome sequencing (WES)/panel or array-based comparative genomic hybridization (array-CGH) to identify the size of the CGG repeats and the mutations or copy number variations (CNVs) in the genome and in FMR1. The clinical features of FXS children were analyzed according to pediatricians’ recording, parental questionnaires, the results of examinations and follow-up. RESULTS: The incidence of FXS in Chinese children with idiopathic NDD was 2.4% (42/1753) and in those with FXS, 2.38% had a deletion (1/42). Here, we present the clinical characteristics of 36 children with FXS. Overweight was observed in two boys. The average intelligence quotient (IQ)/development quotient (DQ) of all FXS patients was 48. The average ages of meaningful words and walking alone were 2 years and 10 months and 1 year and 7 months, respectively. The most frequent repetitive behavior was stimulated by hyperarousal to sensory stimulation. On social aspects, social withdrawal, social anxiety, and shyness accounted for 75%, 58%, and 56% of the total number of children, respectively. Approximately 60% of FXS children in this cohort were emotionally labile and prone to temper tantrums. Self-injury and aggression toward others could also be observed, at 19% and 28%, respectively. The most frequent behavioral problem was attention-deficit hyperactivity disorder (ADHD) seen in 64% and the most common facial features were a narrow and elongated face and large or prominent ears in 92% of patients. DISCUSSION: Screening of FMR1 full mutation provides the possibility for patients’ further medical supports and the clinical features of FXS children obtained in this study will increase the understanding and diagnosis of FXS.

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11. Mesa A. Euphemism has no place in the pages of autism research. Autism Res;2023 (Mar 2)

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12. Minnigulova A, Davydova E, Pereverzeva D, Sorokin A, Tyushkevich S, Mamokhina U, Danilina K, Dragoy O, Arutiunian V. Corpus callosum organization and its implication to core and co-occurring symptoms of Autism Spectrum Disorder. Brain Struct Funct;2023 (Mar 3)

Autism Spectrum Disorder (ASD) is characterized by social interaction and communication deficits, repetitive behavior and often by co-occurring conditions such as language and non-verbal IQ development delays. Previous studies reported that those behavioral abnormalities can be associated with corpus callosum organization. However, little is known about the specific differences in white matter structure of the corpus callosum parts in children with ASD and TD peers and their relationships to core and co-occurring symptoms of ASD. The aim of the study was to investigate the volumetric and microstructural characteristics of the corpus callosum parts crucially involved in social, language, and non-verbal IQ behavior in primary-school-aged children with ASD and to assess the relationships between these characteristics and behavioral measures. 38 children (19 with ASD and 19 typically developing (TD) controls) were scanned using diffusion-weighted MRI and assessed with behavioral tests. The tractography of the corpus callosum parts were performed using Quantitative Imaging Toolkit software; diffusivity and volumetric measurements were extracted for the analysis. In the ASD group, fractional anisotropy (FA) was decreased across the supplementary motor area and the ventromedial prefrontal cortex, and axial diffusivity (AD) was reduced across each of the corpus callosum parts in comparison to the TD group. Importantly, the AD decrease was related to worse language skills and more severe autistic traits in individuals with ASD. The microstructure of the corpus callosum parts differs between children with and without ASD. Abnormalities in white matter organization of the corpus callosum parts are associated with core and co-occurring symptoms of ASD.

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13. Petrolini V, Jorba M, Vicente A. What does it take to be rigid? Reflections on the notion of rigidity in autism. Front Psychiatry;2023;14:1072362.

Characterizations of autism include multiple references to rigid or inflexible features, but the notion of rigidity itself has received little systematic discussion. In this paper we shed some light on the notion of rigidity in autism by identifying different facets of this phenomenon as discussed in the literature, such as fixed interests, insistence on sameness, inflexible adherence to routines, black-and-white mentality, intolerance of uncertainty, ritualized patterns of verbal and non-verbal behavior, literalism, and discomfort with change. Rigidity is typically approached in a disjointed fashion (i.e., facet by facet), although there are recent attempts at providing unifying explanations. Some of these attempts assume that the rigidity facets mainly relate to executive functioning: although such an approach is intuitively persuasive, we argue that there are equally plausible alternative explanations. We conclude by calling for more research on the different facets of rigidity and on how they cluster together in the autistic population, while suggesting some ways in which intervention could benefit from a finer-grained view of rigidity.

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14. Spinazzi NA, Santoro JD, Pawlowski K, Anzueto G, Howe YJ, Patel LR, Baumer NT. Co-occurring conditions in children with Down syndrome and autism: a retrospective study. J Neurodev Disord;2023 (Mar 2);15(1):9.

BACKGROUND: Down syndrome (DS) is one of the most common genetic causes of intellectual disability, and it is associated with an increased incidence of numerous co-occurring conditions. Autism spectrum disorder (ASD) is common in persons with DS, with rates reported as high as 39%. However, little is known regarding co-occurring conditions in children with both DS and ASD. METHODS: A single-center retrospective review of prospective longitudinally collected clinical data was performed. Any patient with a confirmed diagnosis of DS evaluated at a large, specialized Down Syndrome Program in a tertiary pediatric medical center between March 2018 and March 2022 was included. A standardized survey which included demographic and clinical questions was administered during each clinical evaluation. RESULTS: In total, 562 individuals with DS were included. The median age was 10 years (IQR: 6.18-13.92). Of this group, 72 (13%) had a co-occurring diagnosis of ASD (DS+ASD). Individuals with DS+ASD were more likely to be male (OR 2.23, CI 1.29-3.84) and had higher odds of a current or prior diagnosis of constipation (OR 2.19, CI 1.31-3.65), gastroesophageal reflux (OR 1.91, CI 1.14-3.21), behavioral feeding difficulties (OR 2.71, CI 1.02-7.19), infantile spasms (OR 6.03, CI 1.79-20.34) and scoliosis (OR 2.73, CI 1.16-6.40). There were lower odds of congenital heart disease in the DS+ASD group (OR 0.56, CI 0.34-0.93). There was no observed difference in prematurity or Neonatal Intensive Care Unit complications between groups. Individuals with DS+ASD had similar odds of having a history of congenital heart defect requiring surgery to those with DS only. Furthermore, there was no difference in rates of autoimmune thyroiditis or celiac disease. There was also no difference in rates of diagnosed co-occurring neurodevelopmental or mental health conditions in this cohort, including anxiety disorders and attention-deficit/hyperactivity disorder. CONCLUSIONS: This study identifies a variety of medical conditions which are more frequent in children with DS+ASD than DS alone, providing important information for the clinical management of these patients. Future research should investigate the role of some of these medical conditions in the development of ASD phenotypes, and whether there may be distinct genetic and metabolic contributions towards these conditions.

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15. Thom RP, McDougle CJ. Repetitive Thoughts and Behaviors in Autism Spectrum Disorder: A Symptom-Based Framework for Novel Therapeutics. ACS Chem Neurosci;2023 (Mar 3)

While the core symptoms of autism spectrum disorder include repetitive thoughts and repetitive behaviors, repetitive phenomena also occur in many other psychiatric disorders. Types of repetitive thoughts include preoccupations, ruminations, obsessions, overvalued ideas, and delusions. Types of repetitive behaviors include tics, stereotypies, compulsions, extrapyramidal symptoms, and automatisms. We provide a description of how to recognize and classify different types of repetitive thoughts and behaviors in autism spectrum disorder, providing clarity on which phenomena should be considered a core feature of autism spectrum disorder and which phenomena are indicative of a comorbid psychiatric disorder. Clinical features that can be used to differentiate types of repetitive thoughts include whether they are distressing and the degree of insight the individual has, while repetitive behaviors can be classified based on whether they are voluntary, goal-directed/purposeful, and rhythmic. We present the psychiatric differential diagnosis of repetitive phenomena within the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) framework. Careful clinical consideration of these transdiagnostic features of repetitive thoughts and behaviors can improve diagnostic accuracy and treatment outcomes, and influence future research.

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16. Tu G, Guo Y, Xiao R, Tang L, Hu M, Liao B. Effects of Exercise Training on the Phosphoproteomics of the Medial Prefrontal Cortex in Rats With Autism Spectrum Disorder Induced by Valproic Acid. Neurorehabil Neural Repair;2023 (Mar 1):15459683231152814.

BACKGROUND: The key neural pathological characteristics of autism spectrum disorder (ASD) include abnormal synaptic plasticity of the medial prefrontal cortex (mPFC). Exercise therapy is widely used to rehabilitate children with ASD, but its neurobiological mechanism is unclear. METHODS: To clarify whether the structural and molecular plasticity of synapses in the mPFC are related to improvement in ASD behavioral deficits after continuous exercise rehabilitation training, we applied phosphoproteomic, behavioral, morphological, and molecular biological methods to investigate the impact of exercise on the phosphoprotein expression profile and synaptic structure of the mPFC in valproic acid (VPA)-induced ASD rats. RESULTS: Exercise training differentially regulated the density, morphology, and ultrastructure of synapses in mPFC subregions in the VPA-induced ASD rats. In total, 1031 phosphopeptides were upregulated and 782 phosphopeptides were downregulated in the mPFC in the ASD group. After exercise training, 323 phosphopeptides were upregulated, and 1098 phosphopeptides were downregulated in the ASDE group. Interestingly, 101 upregulated and 33 downregulated phosphoproteins in the ASD group were reversed after exercise training, and these phosphoproteins were mostly involved in synapses. Consistent with the phosphoproteomics data, the total and phosphorylated levels of the proteins MARK1 and MYH10 were upregulated in the ASD group and reversed after exercise training. CONCLUSIONS: The differential structural plasticity of synapses in mPFC subregions may be the basic neural architecture of ASD behavioral abnormalities. The phosphoproteins involved in mPFC synapses, such as MARK1 and MYH10, may play important roles in the exercise rehabilitation effect on ASD-induced behavioral deficits and synaptic structural plasticity, which requires further investigation.

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17. Zeif D, Yakobi O, Yechiam E. Choice behavior in autistic adults: What drives the extreme switching phenomenon?. PLoS One;2023;18(3):e0282296.

BACKGROUND: Previous studies reported that autistic adolescents and adults tend to exhibit extensive choice switching in repeated experiential tasks. However, a recent meta-analysis showed that this switching effect was non-significant across studies. Furthermore, the relevant psychological mechanisms remain unclear. We examined the robustness of the extreme choice-switching phenomenon, and whether it is driven by a learning impairment, feedback-related aspects (e.g., avoiding losses), or alternatively a different information sampling strategy. METHODS: We recruited an online sample of 114 US participants (57 autistic adults and 57 non-autistic). All participants performed the Iowa Gambling task, a four-option repeated choice task. Standard task blocks were followed by a trial block with no feedback. RESULTS: The findings replicate the extreme choice switching phenomenon (Cohen’s d = 0.48). Furthermore, the effect was found with no difference in average choice rates denoting no learning impairment, and was even observed in trial blocks with no feedback (d = 0.52). There was no evidence that the switching strategy of autistic individuals was more perseverative (i.e., that similar switching rates were used in subsequent trial blocks). When adding the current dataset to the meta-analysis, the choice switching phenomenon is significant across studies, d = 0.32. CONCLUSIONS: The findings suggest that the increased choice switching phenomenon in autism may be robust and that it represents a distinct information sampling strategy and not poor implicit learning (or a bias in the sensitivity to losses). Such extended sampling may underlie some of the phenomena previously attributed to poor learning.

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18. Zhang P, Omanska A, Ander BP, Gandal MJ, Stamova B, Schumann CM. Neuron-specific transcriptomic signatures indicate neuroinflammation and altered neuronal activity in ASD temporal cortex. Proc Natl Acad Sci U S A;2023 (Mar 7);120(10):e2206758120.

Autism spectrum disorder (ASD) is a highly heterogeneous disorder, yet transcriptomic profiling of bulk brain tissue has identified substantial convergence among dysregulated genes and pathways in ASD. However, this approach lacks cell-specific resolution. We performed comprehensive transcriptomic analyses on bulk tissue and laser-capture microdissected (LCM) neurons from 59 postmortem human brains (27 ASD and 32 controls) in the superior temporal gyrus (STG) of individuals ranging from 2 to 73 years of age. In bulk tissue, synaptic signaling, heat shock protein-related pathways, and RNA splicing were significantly altered in ASD. There was age-dependent dysregulation of genes involved in gamma aminobutyric acid (GABA) (GAD1 and GAD2) and glutamate (SLC38A1) signaling pathways. In LCM neurons, AP-1-mediated neuroinflammation and insulin/IGF-1 signaling pathways were upregulated in ASD, while mitochondrial function, ribosome, and spliceosome components were downregulated. GABA synthesizing enzymes GAD1 and GAD2 were both downregulated in ASD neurons. Mechanistic modeling suggested a direct link between inflammation and ASD in neurons, and prioritized inflammation-associated genes for future study. Alterations in small nucleolar RNAs (snoRNAs) associated with splicing events suggested interplay between snoRNA dysregulation and splicing disruption in neurons of individuals with ASD. Our findings supported the fundamental hypothesis of altered neuronal communication in ASD, demonstrated that inflammation was elevated at least in part in ASD neurons, and may reveal windows of opportunity for biotherapeutics to target the trajectory of gene expression and clinical manifestation of ASD throughout the human lifespan.

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