1. Ceccherini I, Kurek KC, Weese-Mayer DE. Developmental disorders affecting the respiratory system: CCHS and ROHHAD. Handb Clin Neurol;2022;189:53-91.

Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) and Congenital Central Hypoventilation Syndrome (CCHS) are ultra-rare distinct clinical disorders with overlapping symptoms including altered respiratory control and autonomic regulation. Although both disorders have been considered for decades to be on the same spectrum with necessity of artificial ventilation as life-support, recent acquisition of specific knowledge concerning the genetic basis of CCHS coupled with an elusive etiology for ROHHAD have definitely established that the two disorders are different. CCHS is an autosomal dominant neurocristopathy characterized by alveolar hypoventilation resulting in hypoxemia/hypercarbia and features of autonomic nervous system dysregulation (ANSD), with presentation typically in the newborn period. It is caused by paired-like homeobox 2B (PHOX2B) variants, with known genotype-phenotype correlation but pathogenic mechanism(s) are yet unknown. ROHHAD is characterized by rapid weight gain, followed by hypothalamic dysfunction, then hypoventilation followed by ANSD, in seemingly normal children ages 1.5-7 years. Postmortem neuroanatomical studies, thorough clinical characterization, pathophysiological assessment, and extensive genetic inquiry have failed to identify a cause attributable to a traditional genetic basis, somatic mosaicism, epigenetic mechanism, environmental trigger, or other. To find the key to the ROHHAD pathogenesis and to improve its clinical management, in the present chapter, we have carefully compared CCHS and ROHHAD.

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2. Crippa A. Motor abilities as a possible specifier of autism: A response to Bhat (2021). Autism Res;2022 (Aug 29)

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3. Frehner SS, Dooley KT, Palumbo MC, Smith AL, Goodman MM, Bales KL, Freeman SM. Effect of sex and autism spectrum disorder on oxytocin receptor binding and mRNA expression in the dopaminergic pars compacta of the human substantia nigra. Philos Trans R Soc Lond B Biol Sci;2022 (Aug 29);377(1858):20210118.

Oxytocin is an endogenous neuropeptide hormone that influences social behaviour and bonding in mammals. Variations in oxytocin receptor (OXTR) expression may play a role in the social deficits seen in autism spectrum disorder. Previous studies from our laboratory found a dense population of OXTR in the human substantia nigra (SN), a basal ganglia structure in the midbrain that is important in both movement and reward pathways. Here, we explore whether differences in OXTR can be identified in the dopaminergic SN pars compacta of individuals with autism. Postmortem human brain tissue specimens were processed for OXTR autoradiography from four groups: males with autism, females with autism, typically developing (TD) males and TD females. We found that females with autism had significantly lower levels of OXTR than the other groups. To examine potential gene expression differences, we performed in situ hybridization in adjacent slides to visualize and quantify OXTR mRNA as well as mRNA for tyrosine hydroxylase. We found no differences in mRNA levels for either gene across the four groups. These results suggest that a dysregulation in local OXTR protein translation or increased OXTR internalization/recycling may contribute to the differences in social symptoms seen in females with autism. This article is part of the theme issue ‘Interplays between oxytocin and other neuromodulators in shaping complex social behaviours’.

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4. Hansford R, Ouellette-Kuntz H, Péfoyo AK, Martin L. COVID-19 precautions experienced by a sample of adults with intellectual and developmental disabilities. Ann Epidemiol;2022 (Aug 27);75:10-15.

PURPOSE: This study describes factors associated with COVID-19 precautions (i.e., self-isolation and the use of personal protective equipment) among a sample of adults with intellectual and developmental disabilities (IDD) in Ontario, Canada. METHODS: The sample included 756 home care recipients with IDD who did not test positive for COVID-19 between March 2020 and July 2021. Among these, some received COVID-19 precautions. Precaution data were obtained from a large metropolitan organization serving persons with IDD in Ontario, and linked to home care assessment data. Unadjusted and adjusted odds ratios with 95% confidence intervals were calculated using logistic regression models to examine the association between COVID-19 cautions and demographic and clinical factors. Effect modification and interactions were explored. RESULTS: One hundred twenty-seven (16.8%) home care clients experienced precautions. After adjustment, congregate setting, aggression, and limited mobility were significantly associated with COVID-19 precautions. Age modified the relationship between congregate setting and precautions. CONCLUSIONS: Pandemic responses need to recognize the impact on subgroups of adults with IDD, such as those living in congregate settings (including younger individuals) or engaging in responsive behaviors. How these precautions impacted individuals-in the short and long term-warrants further investigation.

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5. Huebschman JL, Monterrey CA, Foster DM, Omoregie CC, Cakir AE, Sevilla-Gutierrez A, Chow EC, Essoh A, Guo Y, Smith LN. The role of the dorsal striatum in a mouse model for fragile X syndrome: Behavioral and dendritic spine assessment. Brain Res;2022 (Aug 25):148060.

Fragile X syndrome (FXS), a leading monogenic cause of autism spectrum disorders (ASDs), typically occurs as the result of a mutation silencing the Fmr1 gene, preventing production of the fragile X messenger ribonucleoprotein (FMRP). FXS is characterized, in part, by hyperactivity, impaired behavioral flexibility, and the development of repetitive, or stereotyped, behaviors. While these phenotypes are influenced by striatal activity, few studies have examined FXS or FMRP in the context of striatal function. Here, we report enhanced repetitive behaviors in Fmr1 knockout (KO) compared to wild type (WT) mice according to multiple measures, including quantity and intensity of stereotypic behaviors in an open field and nose poking activity in an unbaited hole board test. However, using a baited version of the hole board assay, we see that KO mice do show some behavioral flexibility in that they make changes in their nose poking behavior following familiarization with an appetitive bait. By contrast, repeated exposure to cocaine (15 mg/kg) promotes repetitive behavior in both WT and KO mice, in a manner mostly independent of genotype. Branch length alterations in medium spiny neurons (MSNs) of the dorsolateral striatum (DLS) are similar between WT cocaine-treated and KO saline-treated mice, possibly suggesting shared synaptic mechanisms. Overall, we suggest that scoring open field behavior is a sensitive measure for repetitive sensory-motor behaviors in Fmr1 KO mice. In addition, our findings show that synaptic contacts onto MSNs in the DLS should be examined in conjunction with measures of stereotypical behavior.

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6. Lord JS, Gay SM, Harper KM, Nikolova VD, Smith KM, Moy SS, Diering GH. Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice. Mol Autism;2022 (Aug 29);13(1):35.

BACKGROUND: Patients with autism spectrum disorder (ASD) experience high rates of sleep disruption beginning early in life; however, the developmental consequences of this disruption are not understood. We examined sleep behavior and the consequences of sleep disruption in developing mice bearing C-terminal truncation mutation in the high-confidence ASD risk gene SHANK3 (Shank3ΔC). We hypothesized that sleep disruption may be an early sign of developmental divergence, and that clinically relevant Shank3(WT/ΔC) mice may be at increased risk of lasting deleterious outcomes following early life sleep disruption. METHODS: We recorded sleep behavior in developing Shank3(ΔC/ΔC), Shank3(WT/ΔC), and wild-type siblings of both sexes using a noninvasive home-cage monitoring system. Separately, litters of Shank3(WT/ΔC) and wild-type littermates were exposed to automated mechanical sleep disruption for 7 days prior to weaning (early life sleep disruption: ELSD) or post-adolescence (PASD) or undisturbed control (CON) conditions. All groups underwent standard behavioral testing as adults. RESULTS: Male and female Shank3(ΔC/ΔC) mice slept significantly less than wild-type and Shank3(WT/ΔC) siblings shortly after weaning, with increasing sleep fragmentation in adolescence, indicating that sleep disruption has a developmental onset in this ASD model. ELSD treatment interacted with genetic vulnerability in Shank3(WT/ΔC) mice, resulting in lasting, sex-specific changes in behavior, whereas wild-type siblings were largely resilient to these effects. Male ELSD Shank3(WT/ΔC) subjects demonstrated significant changes in sociability, sensory processing, and locomotion, while female ELSD Shank3(WT/ΔC) subjects had a significant reduction in risk aversion. CON Shank3(WT/ΔC) mice, PASD mice, and all wild-type mice demonstrated typical behavioral responses in most tests. LIMITATIONS: This study tested the interaction between developmental sleep disruption and genetic vulnerability using a single ASD mouse model: Shank3ΔC (deletion of exon 21). The broader implications of this work should be supported by additional studies using ASD model mice with distinct genetic vulnerabilities. CONCLUSION: Our study shows that sleep disruption during sensitive periods of early life interacts with underlying genetic vulnerability to drive lasting and sex-specific changes in behavior. As individuals progress through maturation, they gain resilience to the lasting effects of sleep disruption. This work highlights developmental sleep disruption as an important vulnerability in ASD susceptibility.

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7. Ramirez JM, Karlen-Amarante M, Wang JJ, Huff A, Burgraff N. Breathing disturbances in Rett syndrome. Handb Clin Neurol;2022;189:139-151.

Rett Syndrome is an X-linked neurological disorder characterized by behavioral and neurological regression, seizures, motor deficits, and dysautonomia. A particularly prominent presentation includes breathing abnormalities characterized by breathing irregularities, hyperventilation, repetitive breathholding during wakefulness, obstructive and central apneas during sleep, and abnormal responses to hypoxia and hypercapnia. The condition and pathology of the respiratory system is further complicated by dysfunctions of breathing-motor coordination, which is reflected in dysphagia. The discovery of the X-linked mutations in the MECP2 gene has transformed our understanding of the cellular and molecular mechanisms that are at the root of various clinical phenotypes. However, the genotype-phenotype relationship is complicated by various factors which include not only X-inactivation but also consequences of the intermittent hypoxia and oxidative stress associated with the breathing abnormalities.

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8. Stark EA. Empowering autistic academics. Nat Hum Behav;2022 (Aug 29)

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9. Torres C. NeuroTribes: The Legacy of Autism and the Future of Neurodiversity. J Dev Behav Pediatr;2022 (Aug 29)

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10. Yu L, Huang D, Wang S, Zhang Y. Reduced Neural Specialization for Word-level Linguistic Prosody in Children with Autism. J Autism Dev Disord;2022 (Aug 29)

Children with autism often show atypical brain lateralization for speech and language processing, however, it is unclear what linguistic component contributes to this phenomenon. Here we measured event-related potential (ERP) responses in 21 school-age autistic children and 25 age-matched neurotypical (NT) peers during listening to word-level prosodic stimuli. We found that both groups displayed larger late negative response (LNR) amplitude to native prosody than to nonnative prosody; however, unlike the NT group exhibiting left-lateralized LNR distinction of prosodic phonology, the autism group showed no evidence of LNR lateralization. Moreover, in both groups, the LNR effects were only present for prosodic phonology but not for phoneme-free prosodic acoustics. These results extended the findings of inadequate neural specialization for language in autism to sub-lexical prosodic structures.

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11. Yui K, Imataka G, Yoshihara S. Lipid-Based Molecules on Signaling Pathways in Autism Spectrum Disorder. Int J Mol Sci;2022 (Aug 29);23(17)

The signaling pathways associated with lipid metabolism contribute to the pathophysiology of autism spectrum disorder (ASD) and provide insights for devising new therapeutic strategies. Prostaglandin E2 is a membrane-derived lipid molecule that contributes to developing ASD associated with canonical Wnt signaling. Cyclooxygenase-2 plays a key role in neuroinflammation and is implicated in the pathogenesis of neurodevelopmental diseases, such as ASD. The endocannabinoid system maintains a balance between inflammatory and redox status and synaptic plasticity and is a potential target for ASD pathophysiology. Redox signaling refers to specific and usually reversible oxidation-reduction reactions, some of which are also involved in pathways accounting for the abnormal behavior observed in ASD. Redox signaling and redox status-sensitive transcription factors contribute to the pathophysiology of ASD. Cannabinoids regulate the redox balance by altering the levels and activity of antioxidant molecules via ROS-producing NADPH oxidase (NOX) and ROS-scavenging superoxide dismutase enzymes. These signaling cascades integrate a broad range of neurodevelopmental processes that may be involved in the pathophysiology of ASD. Based on these pathways, we highlight putative targets that may be used for devising novel therapeutic interventions for ASD.

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12. Zamani Esfahlani F, Byrge L, Tanner J, Sporns O, Kennedy DP, Betzel RF. Edge-centric analysis of time-varying functional brain networks with applications in autism spectrum disorder. Neuroimage;2022 (Aug 27);263:119591.

The interaction between brain regions changes over time, which can be characterized using time-varying functional connectivity (tvFC). The common approach to estimate tvFC uses sliding windows and offers limited temporal resolution. An alternative method is to use the recently proposed edge-centric approach, which enables the tracking of moment-to-moment changes in co-fluctuation patterns between pairs of brain regions. Here, we first examined the dynamic features of edge time series and compared them to those in the sliding window tvFC (sw-tvFC). Then, we used edge time series to compare subjects with autism spectrum disorder (ASD) and healthy controls (CN). Our results indicate that relative to sw-tvFC, edge time series captured rapid and bursty network-level fluctuations that synchronize across subjects during movie-watching. The results from the second part of the study suggested that the magnitude of peak amplitude in the collective co-fluctuations of brain regions (estimated as root sum square (RSS) of edge time series) is similar in CN and ASD. However, the trough-to-trough duration in RSS signal is greater in ASD, compared to CN. Furthermore, an edge-wise comparison of high-amplitude co-fluctuations showed that the within-network edges exhibited greater magnitude fluctuations in CN. Our findings suggest that high-amplitude co-fluctuations captured by edge time series provide details about the disruption of functional brain dynamics that could potentially be used in developing new biomarkers of mental disorders.

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