1. Accelerating progress on early childhood development for children under 5 years with disabilities by 2030. The Lancet Global health. 2022; 10(3): e438-e44.

The likelihood of a newborn child dying before their fifth birthday (under-5 mortality rate) is universally acknowledged as a reflection of the social, economic, health, and environmental conditions in which children (and the rest of society) live, but little is known about the likelihood of a newborn child having a lifelong disability before their fifth birthday if he or she survives. Available data show that globally the likelihood of a child having a disability before their fifth birthday was ten times higher than the likelihood of dying (377•2 vs 38•2 per 1000 livebirths) in 2019. However, disability funding declined by 11•4% between 2007 and 2016, and only 2% of the estimated US$79•1 billion invested in early childhood development during this period was spent on disabilities. This funding pattern has not improved since 2016. This paper highlights the urgent need to prioritise early childhood development for the beneficiaries of global child survival initiatives who have lifelong disabilities, especially in low-income and middle-income countries, as envisioned by the Sustainable Development Goals agenda. This endeavour would entail disability-focused programming and monitoring approaches, economic analysis of interventions services, and substantial funding to redress the present inequalities among this cohort of children by 2030.

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2. Ayash TA, Vancolen SY, Allard MJ, Sébire G. C-section of Preclinical Animal Model of Chorioamnionitis Triggered by Group B Streptococcus (GBS). Journal of visualized experiments : JoVE. 2021; (178).

Group B Streptococcus (GBS) is one of the most common bacteria isolated during human pregnancy. It is a leading cause of placental infection/inflammation, termed chorioamnionitis. Chorioamnionitis exposes the developing fetus to a high risk of organ injuries, perinatal morbidity, and mortality, as well as life-long neurobehavioral impairments and other non-neurological developmental issues. The two most frequent subtypes of GBS isolates from maternal and fetal tissues are serotypes Ia (13%-23%) and III (25%-53%). Our lab has developed and characterized a rat model of GBS-induced chorioamnionitis to study subsequent impacts on the central nervous system of the developing fetus and to understand underlying mechanistic aspects. This article presents the design as well as uses of the preclinical rat model, which closely reproduces the hallmark of GBS-induced chorioamnionitis in humans. This article aims to help scientists reproduce the experimental design as well as to provide support through examples of troubleshooting. The present model may also contribute to potential discoveries through uncovering causes, mechanisms, and novel therapeutic avenues, which remain unsettled in many developmental impairments arising from chorioamnionitis. Furthermore, the use of this model may be extended to the studies of perinatal non-neurological common and severe morbidities affecting, for instance, the retina, bowel, lung, and kidney. The main interest of this research is in the field of GBS-induced fetal neurodevelopmental impairments such as cerebral palsy (CP), attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). The rationale supporting this model is presented in this article, followed by procedures and results.

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3. Berry-Kravis E, Filipink RA, Frye RE, Golla S, Morris SM, Andrews H, Choo TH, Kaufmann WE. Seizures in Fragile X Syndrome: Associations and Longitudinal Analysis of a Large Clinic-Based Cohort. Frontiers in pediatrics. 2021; 9: 736255.

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability, learning disability, and autism spectrum disorder, is associated with an increased prevalence of certain medical conditions including seizures. The goal of this study was to better understand seizures in individuals with FXS using the Fragile X Online Registry with Accessible Research Database, a multisite observational study initiated in 2012 involving FXS clinics in the Fragile X Clinic and Research Consortium. Seizure data were available for 1,607 participants, mostly male (77%) and white (74.5%). The overall prevalence of at least one seizure was 12%, with this rate being significantly higher in males than females (13.7 vs. 6.2%, p < 0.001). As compared to individuals with FXS without seizures, those with seizures were more likely to have autism spectrum disorder, current sleep apnea, later acquisition of expressive language, more severe intellectual disability, hyperactivity, irritability, and stereotyped movements. The mean age of seizure onset was 6.4 (SD 6.1) years of age with the great majority (>80%) having onset of seizures which was before 10. For those with epilepsy, about half (52%) had seizures for more than 3 years. This group was found to have greater cognitive and language impairment, but not behavioral disruptions, compared with those with seizures for <3 years. Antiepileptic drugs were more often used in males (60.6%) than females (34.8%), and females more often required more than one medication. The most commonly used anticonvulsants were oxcarbazepine, valproic acid, lamotrigine, and levetiracetam. The current study is the largest and first longitudinal study ever conducted to describe seizures in FXS. Overall, this study confirms previous reports of seizures in FXS and extends previous findings by further defining the cognitive and behavioral phenotype of those with epilepsy in FXS. Future studies should further investigate the natural history of seizures in FXS and the characteristics of seizures in FXS in adulthood.

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4. Brian J, Drmic I, Roncadin C, Dowds E, Shaver C, Smith IM, Zwaigenbaum L, Sacrey LR, Bryson SE. Effectiveness of a parent-mediated intervention for toddlers with autism spectrum disorder: Evidence from a large community implementation. Autism : the international journal of research and practice. 2022: 13623613211068934.

In an effort to increase access to intervention as early as possible for toddlers with autism spectrum disorder or signs thereof, many researchers have developed interventions that can be delivered by parents in their own homes. These parent-mediated approaches have gained a lot of research attention in recent years and have been found to be helpful in terms of parent and toddler learning. Several studies have used a rigorous research design (a randomized controlled trial) to show that parent-mediated intervention can work under ideal well-controlled conditions. To build on this evidence, we also need to examine whether parent-mediated interventions can be taught well through community service providers and delivered in more « real-world » conditions. This study used a research-community partnership to provide a parent-mediated intervention (called the Social ABCs) to 179 families (mean toddler age was 25 months; ranging from 14 to 34 months). Almost 90% of the families completed the 12-week program and 70% returned for a follow-up assessment 3 months later. Analyses showed that parents learned the strategies that were designed to help them support their toddlers’ development. Also, toddlers made gains in their language, communication, and social skills. Importantly, parents’ use of the strategies was related to toddlers’ skill gains, suggesting that the use of the strategies made a difference for the toddlers. Findings support the use of parent-mediated intervention in this very young age group and suggest that such intervention approaches should be made available for community delivery.

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5. Libdeh AA, Brenner L, Quigg M. Recurrent Dissociative Fugue Episodes in a Child With Autism Spectrum Disorder. Clinical pediatrics. 2022; 61(3): 253-5.

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6. Mordaunt CE, Mouat JS, Schmidt RJ, LaSalle JM. Comethyl: a network-based methylome approach to investigate the multivariate nature of health and disease. Briefings in bioinformatics. 2022; 23(2).

Health outcomes are frequently shaped by difficult to dissect inter-relationships between biological, behavioral, social and environmental factors. DNA methylation patterns reflect such multivariate intersections, providing a rich source of novel biomarkers and insight into disease etiologies. Recent advances in whole-genome bisulfite sequencing enable investigation of DNA methylation over all genomic CpGs, but existing bioinformatic approaches lack accessible system-level tools. Here, we develop the R package Comethyl, for weighted gene correlation network analysis of user-defined genomic regions that generates modules of comethylated regions, which are then tested for correlations with multivariate sample traits. First, regions are defined by CpG genomic location or regulatory annotation and filtered based on CpG count, sequencing depth and variability. Next, correlation networks are used to find modules of interconnected nodes using methylation values within the selected regions. Each module containing multiple comethylated regions is reduced in complexity to a single eigennode value, which is then tested for correlations with experimental metadata. Comethyl has the ability to cover the noncoding regulatory regions of the genome with high relevance to interpretation of genome-wide association studies and integration with other types of epigenomic data. We demonstrate the utility of Comethyl on a dataset of male cord blood samples from newborns later diagnosed with autism spectrum disorder (ASD) versus typical development. Comethyl successfully identified an ASD-associated module containing regions mapped to genes enriched for brain glial functions. Comethyl is expected to be useful in uncovering the multivariate nature of health disparities for a variety of common disorders. Comethyl is available at github.com/cemordaunt/comethyl with complete documentation and example analyses.

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7. Owens AP, Mathias CJ, Iodice V. Autonomic Dysfunction in Autism Spectrum Disorder. Frontiers in integrative neuroscience. 2021; 15: 787037.

Background: There have been previous reports of enhanced sympathoexcitation in autism spectrum disorder (ASD). However, there has been no formal investigation of autonomic dysfunction in ASD. Also, the joint hypermobile form of Ehlers-Danlos syndrome (hE-DS) that maybe overrepresented in ASD and orthostatic related autonomic dysfunction. This study examined the comorbidity of ASD, autonomic dysfunction and hE-DS in two UK autonomic national referral centers. Proven, documented and globally accepted clinical autonomic investigations were used to assess neuro-cardiovascular autonomic function in a cohort of ASD subjects and in age-matched healthy controls. Methods: Clinical data from 28 referrals with a confirmed diagnosis of ASD over a 10-year period were compared with 19 age-matched healthy controls. Autonomic function was determined using methods established in the centers previously described in detail. Results: 20/28 ASD had a diagnosed autonomic condition; 9 had the postural tachycardia syndrome (PoTS), 4 PoTS and vasovagal syncope (VVS), 3 experienced presyncope, 1 essential hyperhidrosis, 1 orthostatic hypotension, 1 VVS alone and 1 a combination of PoTS, VVS and essential hyperhidrosis. 16/20 ASD with autonomic dysfunction had hE-DS. In ASD, basal heart rate and responses to orthostatic tests of autonomic function were elevated, supporting previous findings of increased sympathoexcitation. However, sympathetic vasoconstriction was impaired in ASD. Conclusion: Intermittent neuro-cardiovascular autonomic dysfunction affecting heart rate and blood pressure was over-represented in ASD. There is a strong association with hE-DS. Autonomic dysfunction may further impair quality of life in ASD, particularly in those unable to adequately express their experience of autonomic symptoms.

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8. Polprapreut Y, Kerr SJ, Trairatvorakul P. Positive Parenting Styles Tied to Less Unmet Dental Needs in Children with Developmental Disabilities. Journal of autism and developmental disorders. 2022.

This study aimed to identify factors, particularly positive parenting styles, associated with unmet dental needs, defined as no dental visit for the past 12 months, in children with developmental disabilities (DD). Participants included 263 primary caregivers of children with DD. Children exposed to less positive parenting styles were more than two times (aOR, 2.19, 95%CI, 1.12-4.32) more likely to have unmet dental needs. Children who were male (aOR, 1.88, 95%CI, 1.04-3.41), aged < 4 years (aOR, 2.95, 95%CI, 1.2-7.27) or aged ≥ 11 years (aOR, 2.65, 95%CI, 1.25-5.64), had higher illness severity (aOR, 2.04, 95%CI, 1.09-3.81), had primary caregivers with less than or equal to high school education (aOR, 2.45, 95%CI, 1.13-5.30) were also more likely to have unmet dental needs.

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9. Regev O, Hadar A, Meiri G, Flusser H, Michaelovski A, Dinstein I, Hershkovitz R, Menashe I. Association between ultrasonography foetal anomalies and autism spectrum disorder. Brain : a journal of neurology. 2022.

Multiple evidence support the prenatal predisposition of autism spectrum disorder (ASD). Nevertheless, robust data about abnormalities in fetuses later developing into children diagnosed with ASD are lacking. Prenatal ultrasound is an excellent tool to study abnormal fetal development as it frequently used to monitor fetal growth and identify fetal anomalies throughout pregnancy. We conducted a retrospective case-sibling-control study of children diagnosed with ASD (cases); their own typically developing, closest-in-age siblings (TDS); and typically developing children from the general population (TDP), matched by year of birth, sex and ethnicity to investigate the association between ultrasonography fetal anomalies (UFAs) and ASD. The case group was drawn from all children diagnosed with ASD enrolled at the Azrieli National Center of Autism and Neurodevelopment Research. Fetal ultrasound data from the fetal anatomy survey were obtained from prenatal ultrasound clinics of Clalit Health Services (CHS) in southern Israel. The study comprised 659 children: 229 ASD, 201 TDS, and 229 TDP. UFAs were found in 29.3% of ASD cases vs. only 15.9% and 9.6% in the TDS and TDP groups (aOR = 2.23, 95%CI = 1.32-3.78, and aOR = 3.50, 95%CI = 2.07-5.91, respectively). Multiple co-occurring UFAs were significantly more prevalent among ASD cases. UFAs in the urinary system, heart, and head&brain were the most significantly associated with ASD diagnosis (aORUrinary =2.08, 95%CI = 0.96-4.50 and aORUrinary = 2.90, 95%CI = 1.41-5.95; aORHeart = 3.72, 95%CI = 1.50-9.24 and aORHeart = 8.67, 95%CI = 2.62-28.63; and aORHead&Brain = 1.96, 95%CI = 0.72-5.30 and aORHead&Brain = 4.67, 95%CI = 1.34-16.24; vs. TDS and TDP, respectively). ASD females had significantly more UFAs than ASD males (43.1% vs. 25.3%, p = 0.013) and a higher prevalence of multiple co-occurring UFAs (15.7% vs. 4.5%, p = 0.011). No sex differences were seen among TDS and TDP controls. ASD fetuses were characterized by a narrower head and a relatively wider ocular-distance vs. TDP fetuses (ORBPD = 0.81, 95%CI = 0.70-0.94, and aOROcular-Distance = 1.29, 95%CI = 1.06-1.57). UFAs were associated with more severe ASD symptoms. Our findings shed important light on the abnormal multiorgan embryonic development of ASD and suggest fetal ultrasonography biomarkers for ASD.

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10. Riva V, Riboldi EM, Dondena C, Piazza C, Molteni M, Cantiani C. Atypical ERP responses to audiovisual speech integration and sensory responsiveness in infants at risk for autism spectrum disorder. Infancy : the official journal of the International Society on Infant Studies. 2022; 27(2): 369-88.

Atypical sensory responses are included in the diagnostic criteria of autism spectrum disorder (ASD). Autistic individuals perform poorly during conditions that require integration across multiple sensory modalities such as audiovisual (AV) integration. Previous research investigated neural processing of AV integration in infancy. Yet, this has never been studied in infants at higher likelihood of later ASD (HR) using neurophysiological (EEG/ERP) techniques. In this study, we investigated whether ERP measures of AV integration differentiate HR infants from low-risk (LR) infants and whether early AV integration abilities are associated with clinical measures of sensory responsiveness. At age 12 months, AV integration in HR (n = 21) and LR infants (n = 19) was characterized in a novel ERP paradigm measuring the McGurk effect, and clinical measures of sensory responsiveness were evaluated. Different brain responses over the left temporal area emerge between HR and LR infants, specifically when AV stimuli cannot be integrated into a fusible percept. Furthermore, ERP responses related to integration of AV incongruent stimuli were found to be associated with sensory responsiveness, with reduced effects of AV incongruency being associated with reduced sensory reactivity. These data suggest that early identification of AV deficits may pave the way to innovative therapeutic strategies for the autistic symptomatology. Further replications in independent cohorts are needed for generalizability of findings.

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11. Schelinski S, Tabas A, von Kriegstein K. Altered processing of communication signals in the subcortical auditory sensory pathway in autism. Human brain mapping. 2022; 43(6): 1955-72.

Autism spectrum disorder (ASD) is characterised by social communication difficulties. These difficulties have been mainly explained by cognitive, motivational, and emotional alterations in ASD. The communication difficulties could, however, also be associated with altered sensory processing of communication signals. Here, we assessed the functional integrity of auditory sensory pathway nuclei in ASD in three independent functional magnetic resonance imaging experiments. We focused on two aspects of auditory communication that are impaired in ASD: voice identity perception, and recognising speech-in-noise. We found reduced processing in adults with ASD as compared to typically developed control groups (pairwise matched on sex, age, and full-scale IQ) in the central midbrain structure of the auditory pathway (inferior colliculus [IC]). The right IC responded less in the ASD as compared to the control group for voice identity, in contrast to speech recognition. The right IC also responded less in the ASD as compared to the control group when passively listening to vocal in contrast to non-vocal sounds. Within the control group, the left and right IC responded more when recognising speech-in-noise as compared to when recognising speech without additional noise. In the ASD group, this was only the case in the left, but not the right IC. The results show that communication signal processing in ASD is associated with reduced subcortical sensory functioning in the midbrain. The results highlight the importance of considering sensory processing alterations in explaining communication difficulties, which are at the core of ASD.

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12. Shaffer R, Thurman AJ, Ronco L, Cadavid D, Raines S, Kim SH. Social communication in fragile X syndrome: pilot examination of the Brief Observation of Social Communication Change (BOSCC). Journal of neurodevelopmental disorders. 2022; 14(1): 4.

BACKGROUND: Social communication is a key area of difficulty in fragile X syndrome (FXS) and there are not yet adequate outcome measurement tools. Appropriate outcome measures for FXS have been identified as a key area of research interest in order to evaluate future therapeutic trials. The Brief Observation of Social Communication Change-Minimally Verbal (BOSCC-MV), an outcome measure with strong psychometrics developed for autism spectrum disorder, has promise as an outcome measure to assess social communication change with FXS participants. METHODS: We examined the BOSCC-MV via central coders in this multi-site-trial to assess its appropriateness for FXS. Eighteen minimally verbal males ages 3-12 years were enrolled and assessed on two consecutive days and 7 participants completed a third visit 6 months later. We examined test-retest reliability, inter-rater reliability, and both convergent and divergent validity with standard clinical measures including the Autism Diagnostic and Observation Schedule-2, Vineland 3, Social Responsiveness Scale, and the Aberrant Behavior Checklist. RESULTS: The BOSCC-MV in FXS demonstrated strong inter-rater and test-retest reliability, comparable to previous trials in idiopathic ASD. Strong convergent validity was found with Autism Diagnostic Observation Schedule-2 and Vineland-3. Divergent validity was demonstrated between BOSCC-MV and unrelated measures. CONCLUSIONS: The BOSCC-MV shows promise as a FXS social communication outcome measure, warranting further large-scale evaluation.

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13. Siqueira E, Obiols-Guardia A, Jorge-Torres OC, Oliveira-Mateos C, Soler M, Ramesh-Kumar D, Setién F, van Rossum D, Pascual-Alonso A, Xiol C, Ivan C, Shimizu M, Armstrong J, Calin GA, Pasterkamp RJ, Esteller M, Guil S. Analysis of the circRNA and T-UCR populations identifies convergent pathways in mouse and human models of Rett syndrome. Molecular therapy Nucleic acids. 2022; 27: 621-44.

Noncoding RNAs play regulatory roles in physiopathology, but their involvement in neurodevelopmental diseases is poorly understood. Rett syndrome is a severe, progressive neurodevelopmental disorder linked to loss-of-function mutations of the MeCP2 gene for which no cure is yet available. Analysis of the noncoding RNA profile corresponding to the brain-abundant circular RNA (circRNA) and transcribed-ultraconserved region (T-UCR) populations in a mouse model of the disease reveals widespread dysregulation and enrichment in glutamatergic excitatory signaling and microtubule cytoskeleton pathways of the corresponding host genes. Proteomic analysis of hippocampal samples from affected individuals confirms abnormal levels of several cytoskeleton-related proteins together with key alterations in neurotransmission. Importantly, the glutamate receptor GRIA3 gene displays altered biogenesis in affected individuals and in vitro human cells and is influenced by expression of two ultraconserved RNAs. We also describe post-transcriptional regulation of SIRT2 by circRNAs, which modulates acetylation and total protein levels of GluR-1. As a consequence, both regulatory mechanisms converge on the biogenesis of AMPA receptors, with an effect on neuronal differentiation. In both cases, the noncoding RNAs antagonize MeCP2-directed regulation. Our findings indicate that noncoding transcripts may contribute to key alterations in Rett syndrome and are not only useful tools for revealing dysregulated processes but also molecules of biomarker value.

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14. Soriano LDH, Bullard L, Alvarez CH, Thurman AJ, Abbeduto L. Using telehealth-delivered procedures to collect a parent-implemented expressive language sampling narrative task in monolingual and bilingual families with Autism Spectrum Disorder: A pilot study. Frontiers in rehabilitation sciences. 2021; 2.

Language impairments are frequent, severe, and of prognostic value in autism spectrum disorder (ASD). Unfortunately, the evaluation of the efficacy of treatments targeting the language skills of those with ASD continues to be hindered by a lack of psychometrically sound outcome measures. Expressive Language Sampling (ELS) procedures offer a promising alternative to norm-referenced standardized tests for assessing expressive language in treatment studies. Until now, however, research on the validity and utility of ELS as outcome measures has been limited to administrations by a trained professional in a clinic setting and to use with English-speaking families. These limitations are a barrier for many families accessing the benefits of participation in treatment studies. The current study examines the feasibility of teaching native English-speaking parents (NESP) and native Spanish-speaking parents (NSSP) how to administer the ELS narrative task (ELS-N) to their sons and daughters with ASD (between ages 6 and 21) at home through telehealth-delivered procedures. The parent training was provided in the primary language of the participating parent (i.e., 11 NSSP and 11 NESP) and administered by the parent to the youth in the language that the parent reported to use to communicate with the youth at home (i.e., 9 Spanish and 13 English). Families were able to choose between using their own technology or be provided with the technology needed for participation. Of the 19 parents who completed the training, 16 learned to administer the ELS-N procedures. In addition, strong test-retest reliability and no practice effects over the 4-week interval were observed for ELS-N derived youth outcome measures (i.e., talkativeness, vocabulary, syntax, dysfluency, and intelligibility) for both NSSP and NESP. Results from this pilot study suggest that the home-based parent-implemented ELS-N procedures can be learned and administered at acceptable levels of fidelity by parents, with good test-retest reliability and limited practice effects observed in terms of outcome measures for youth with ASD. Implications for treatment studies and future directions are discussed.

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15. Vallés AS, Barrantes FJ. Dendritic spine membrane proteome and its alterations in autistic spectrum disorder. Advances in protein chemistry and structural biology. 2022; 128: 435-74.

Dendritic spines are small protrusions stemming from the dendritic shaft that constitute the primary specialization for receiving and processing excitatory neurotransmission in brain synapses. The disruption of dendritic spine function in several neurological and neuropsychiatric diseases leads to severe information-processing deficits with impairments in neuronal connectivity and plasticity. Spine dysregulation is usually accompanied by morphological alterations to spine shape, size and/or number that may occur at early pathophysiological stages and not necessarily be reflected in clinical manifestations. Autism spectrum disorder (ASD) is one such group of diseases involving changes in neuronal connectivity and abnormal morphology of dendritic spines on postsynaptic neurons. These alterations at the subcellular level correlate with molecular changes in the spine proteome, with alterations in the copy number, topography, or in severe cases in the phenotype of the molecular components, predominantly of those proteins involved in spine recognition and adhesion, reflected in abnormally short lifetimes of the synapse and compensatory increases in synaptic connections. Since cholinergic neurotransmission participates in the regulation of cognitive function (attention, memory, learning processes, cognitive flexibility, social interactions) brain acetylcholine receptors are likely to play an important role in the dysfunctional synapses in ASD, either directly or indirectly via the modulatory functions exerted on other neurotransmitter receptor proteins and spine-resident proteins.

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