1. Baker A, Bean A, Cargill LP, Lyle S. Within arm’s reach: The role of proximity in speech generating device use of ambulatory children with autism. International journal of speech-language pathology. 2022; 24(1): 88-96.

Purpose: Augmentative and Alternative Communication (AAC) provides an alternative means of communication for individuals who are unable to effectively communicate using spoken language. The present study seeks to investigate the role of proximity in facilitating AAC (specifically Speech Generating Devices; SGD) use in a homogeneous population: ambulatory school-aged children with autism spectrum disorder (ASD).Method: Twelve school-age children with ASD who use an SGD as their primary mode of communication participated in the study. The percentage of time the child was within the proximity of their device was calculated over nine videotaped sessions and data logging provided information regarding device use over an 18-week period.Result: Children were in proximity to their device 65% of the time. There was a significant positive correlation between percentage of time in proximity to device and the average minutes of device use on the day video recorded. Exploratory analyses revealed that communicative abilities may be more connected to proximity than school context.Conclusion: These results support the importance of developing a program for assuring device proximity in order to encourage consistent device use in minimally verbal ambulatory school-age children with ASD.

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2. Bochet A, Sperdin HF, Rihs TA, Kojovic N, Franchini M, Jan RK, Michel CM, Schaer M. Early alterations of large-scale brain networks temporal dynamics in young children with autism. Communications biology. 2021; 4(1): 968.

Autism spectrum disorders (ASD) are associated with disruption of large-scale brain network. Recently, we found that directed functional connectivity alterations of social brain networks are a core component of atypical brain development at early developmental stages in ASD. Here, we investigated the spatio-temporal dynamics of whole-brain neuronal networks at a subsecond scale in 113 toddlers and preschoolers (66 with ASD) using an EEG microstate approach. We first determined the predominant microstates using established clustering methods. We identified five predominant microstate (labeled as microstate classes A-E) with significant differences in the temporal dynamics of microstate class B between the groups in terms of increased appearance and prolonged duration. Using Markov chains, we found differences in the dynamic syntax between several maps in toddlers and preschoolers with ASD compared to their TD peers. Finally, exploratory analysis of brain-behavioral relationships within the ASD group suggested that the temporal dynamics of some maps were related to conditions comorbid to ASD during early developmental stages.

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3. Chen H, Yang T, Chen J, Chen L, Dai Y, Zhang J, Li L, Jia F, Wu L, Hao Y, Ke X, Yi M, Hong Q, Chen J, Fang S, Wang Y, Wang Q, Jin C, Li T. Sleep problems in children with autism spectrum disorder: a multicenter survey. BMC psychiatry. 2021; 21(1): 406.

BACKGROUND: High prevalence of sleep problems have been reported in children with Autism Spectrum Disorder (ASD). This study aims to investigate the sleep conditions of ASD children in China, and explore the relationship between the common sleep problems and core symptoms and developmental levels. METHODS: Using a cross-sectional design, we included 2 to 7-year-old children from 13 cities in China: 1310 with ASD and 1158 with typically-developing (TD) children. The neurodevelopmental level was evaluated with the revised Children Neuropsychological and Behavior Scale (CNBS-R2016). ASD were diagnosed with DSM-5 and Child Autism Rating Scale (CARS). the Social Responsiveness Scale (SRS), the Autism Behavior Checklist (ABC) and the communication warning behavior sub-scale in CNBS-R2016 valued autism behaviors. The children’ s sleep habits questionnaire (CSHQ) assessed sleep conditions. RESULTS: The prevalence of sleep disorders in ASD children was significantly higher than that in TD (67.4% vs. 51%, p < 0.01), and among them the four dimensions with the highest prevalence of sleep problems were bedtime resistance (25.6%), sleep anxiety (22.7%), sleep onset delay (17.9%) and daytime sleepiness (14.7%). ASD children with sleep onset delay or sleep anxiety had higher ABC, SRS scores and higher scores on communication warning behavior with sleep anxiety, with daytime sleepiness had higher ABC, SRS and CARS scores, and with bedtime resistance had higher SRS total scores. Differences in the neurodevelopmental level were not significant. CONCLUSION: Children with ASD have a higher prevalence of sleep problems. Bedtime resistance, anxiety, sleep onset delay and daytime sleepiness may be related to the core symptoms, but not be related to the developmental level in ASD children. In the clinic, sleep assessment should be included in the routine of ASD visits, and during the intervention, sleep hygiene education is as important as the treatment of biological factors. TRIAL REGISTRATION: The study was approved by the ethics committee of the Children's Hospital of Chongqing Medical University, Approval Number: (2018) IRB (STUDY) NO. 121, and registered in the Chinese Clinical Trial Registry (Registration number: ChiCTR2000031194 ).

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4. Fletcher S, Pawliuk C, Ip A, Huh L, Rassekh SR, Oberlander TF, Siden H. Medicinal cannabis in children and adolescents with autism spectrum disorder: A scoping review. Child: care, health and development. 2022; 48(1): 33-44.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition estimated to affect 1 in 66 children in Canada and 1 in 270 individuals worldwide. As effective therapies for the management of ASD core and associated symptoms are limited, parents are increasingly turning to clinicians for advice regarding the use of medicinal cannabis to manage behavioural disturbances. OBJECTIVE: The objective of this scoping review was to identify and map symptoms, outcomes and adverse events related to medicinal cannabis treatment for ASD-related behaviours. METHODS: Ovid MEDLINE, Embase, CINAHL, PsycInfo, Web of Science Core Collection, Google Scholar and grey literature sources were searched up to 5 January 2020 for studies. Included studies met the following criteria: (1) investigate the use of medicinal cannabis, (2) at least 50% participants had ASD, (3) at least 50% of the study population was 0-18 years old and (4) any study design (published or unpublished). RESULTS: We identified eight completed and five ongoing studies meeting the inclusion criteria. All studies reported substantial behaviour and symptom improvement on medicinal cannabis, with 61% to 93% of subjects showing benefit. In the three studies reporting on concomitant psychotropic medication usage and with cannabis use, up to 80% of participants observed a reduction in concurrent medication use. Adverse events related to cannabis use were reported in up to 27% of participants related, and two participants had psychotic events. CONCLUSIONS: Early reports regarding medicinal cannabis in paediatric ASD symptom management are presented as positive; the evidence, however, is limited to very few retrospective cohort and observational studies. Evidence of safety and efficacy from prospective clinical trials is needed.

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5. Holzinger D, Weber C, Bölte S, Fellinger J, Hofer J. Correction to: Assessment of Autism Spectrum Disorder in Deaf Adults with Intellectual Disability: Feasibility and Psychometric Properties of an Adapted Version of the Autism Diagnostic Observation Schedule (ADOS-2). Journal of autism and developmental disorders. 2021.

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6. Khuller K, Yigit G, Martínez Grijalva C, Altmüller J, Thiele H, Nürnberg P, Elcioglu NH, Yeter B, Hehr U, Stein A, Della Marina A, Köninger A, Depienne C, Kaiser FJ, Wollnik B, Kuechler A. MFSD2A-associated primary microcephaly – Expanding the clinical and mutational spectrum of this ultra-rare disease. European journal of medical genetics. 2021; 64(10): 104310.

MFSD2A, a member of the major facilitator superfamily (MFS), is a transmembrane transporter responsible for the uptake of specific essential fatty acids through the blood-brain barrier (BBB) to the brain. The transporter is crucial for early embryonic brain development and a major factor in the formation and maintenance of the BBB. Mfsd2a-knockout mice show a leakage of the BBB in early embryonic stages and develop a phenotype characterized by microcephaly, cognitive impairment, and anxiety. So far, homozygous or compound heterozygous MFSD2A mutations in humans have only been reported in 13 different families with a total of 28 affected individuals. The phenotypical spectrum of patients with MFSD2A variants is rather broad but all patients present with microcephaly and severe intellectual disability, absent or limited speech, and walking difficulties. Severely affected patients develop seizures and show brain malformations and have, above all, a profound developmental delay hardly reaching any developmental motor milestones. Here, we report on two unrelated individuals with novel homozygous variants in the MFSD2A gene, presenting with severe primary microcephaly, brain malformations, profound developmental delay, and epilepsy, including hypsarrhythmia. Our findings extend the mutational spectrum of the bi-allelic MFSD2A variants causing autosomal recessive primary microcephaly type 15 and broaden the phenotypic spectrum associated with these pathogenic variants emphasizing the role of MFSD2A in early brain development.

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7. Maddox BB, Dickson KS, Stadnick NA, Mandell DS, Brookman-Frazee L. Mental Health Services for Autistic Individuals Across the Lifespan: Recent Advances and Current Gaps. Current psychiatry reports. 2021; 23(10): 66.

PURPOSE OF REVIEW: This synthesis of recent mental health services research with autistic individuals presents significant advances, current gaps, and recommendations for improving mental healthcare for this population. RECENT FINDINGS: Recent advances include improved understanding of co-occurring mental health conditions among autistic individuals, a growing evidence base for interventions to address them, the development and implementation of new service models to support mental health for this population, and a substantial increase in mental health services and implementation research focused on autism. Ongoing challenges include a lack of mental health interventions designed for community implementation with autistic individuals, limited workforce capacity, complex and disconnected service systems, and racial, ethnic, and socioeconomic disparities in accessibility and quality of mental health services. Despite the advances in our understanding of mental health needs and mental health services for autistic individuals, several critical gaps remain. We encourage future efforts to develop and test interventions that can be used in community settings, train and incentivize the workforce to provide them, realign policies and funding with best practice, and embrace an equity-focused approach to autism research and care.

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8. Quadt L, Garfinkel SN, Mulcahy JS, Larsson DE, Silva M, Jones AM, Strauss C, Critchley HD. Interoceptive training to target anxiety in autistic adults (ADIE): A single-center, superiority randomized controlled trial. EClinicalMedicine. 2021; 39: 101042.

BACKGROUND: This trial tested if a novel therapy, Aligning Dimensions of Interoceptive Experience (ADIE), reduces anxiety in autistic adults. ADIE targets the association of anxiety with mismatch between subjective and behavioral measures of an individual’s interoceptive sensitivity to bodily signals, including heartbeats. METHODS: In this superiority randomized controlled trial, autistic adults (18-65 years) from clinical and community settings in Southern England were randomly assigned (1:1) to receive six sessions of ADIE or an active ‘exteroceptive’ control therapy (emotional prosody identification). Researchers conducting outcome assessments were blind to allocation. ADIE combines two modified heartbeat detection tasks with performance feedback and physical activity manipulation that transiently increases cardiac arousal. Participants were followed-up one-week (T1) and 3-months post-intervention (T2). The primary outcome was Spielberger Trait Anxiety Score (STAI-T) at T2. Outcomes were assessed on an intention-to-treat basis using multiple imputation for dealing with missing values. This trial was registered at International Standard Randomized Controlled Trial Registry, ISRCTN14848787. FINDINGS: Between July 01, 2017, and December 31, 2019, 121 participants were randomly allocated to ADIE (n = 61) or prosody (n = 60) intervention groups. Data at T1 was provided by 85 (70%) participants (46 [75%] ADIE; 39 [65%] prosody). Data at T2 was provided by 61 (50%) participants (36 [59%] ADIE; 25 [42%] prosody). One adverse event (cardiac anxiety following ADIE) was recorded. A statistically significant group effect of ADIE on trait anxiety continued at T2 (estimated mean difference 3•23 [95% CI 1•13 to 5•29]; d = 0•30 [95% CI 0•09 to 0•51]; p = 0•005) with 31% of ADIE group participants meeting trial criteria for recovery (compared to 16% in the control group). INTERPRETATION: ADIE can reduce anxiety in autistic adults, putatively improving regulatory control over internal stimuli. With little reliance on language and emotional insight, ADIE may constitute an inclusive intervention. FUNDING MQ: Transforming Mental Health PsyImpact Grant.

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9. Shea LL, Cooper D, Wilson AB. Preventing and improving interactions between autistic individuals and the criminal justice system: A roadmap for research. Autism research : official journal of the International Society for Autism Research. 2021; 14(10): 2053-60.

Researchers have identified that autistic individuals are encountering the criminal justice system as victims, offenders, and witnesses at high rates. The prevalence of autism spectrum disorder (ASD) is increasing and generating a comprehensive approach to addressing criminal justice system involvement among autistic individuals is a timely and urgent need. Revisions to an established framework generated for use among individuals with mental health diagnoses, the sequential Intercept Model (SIM), were produced by an international consortium of interdisciplinary stakeholders presenting a new opportunity to identify gaps in ASD research and generate preventive solutions across the criminal justice system. The revised SIM maps each criminal justice system component, or Intercept, and includes paths for the experiences of autistic individuals as victims or witnesses to crimes as well as offenders to catalyze new and interdisciplinary research, policy, and practice efforts. As the field of ASD research continues to grow, the revised SIM is a promising pathway to avoiding siloed research approaches, including diverse autistic voices, and contributing to international dialogue about criminal justice reform at a critical juncture. LAY SUMMARY: Autistic individuals are encountering the criminal justice system as victims, offenders, and witnesses at high rates. A revised version of the SIM generated by an international consortium provides a cohesive framework to ensure research focused on this topic extends across the criminal justice system. Preventing and improving interactions between autistic individuals and the criminal justice system is an urgent research, policy, and practice need.

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10. Shum KK, Wong RM, Au AH, Au TK. Autism spectrum disorder screening in Chinese-language preschools. Autism : the international journal of research and practice. 2022; 26(2): 545-51.

The 13-item Classroom Observation Scale is an autism spectrum disorder screening tool for teachers and non-clinically trained observers to make real-time observation of children’s peer interaction (or the lack thereof) in regular preschool classrooms. The Classroom Observation Scale was originally developed in English and validated with ethnically diverse preschoolers at English-speaking international schools serving families from middle to middle-upper socioeconomic backgrounds in Hong Kong. These private schools can usually afford a higher teacher-student ratio, which is not typical for most preschools. This study, therefore, investigated whether the Classroom Observation Scale is ecologically valid when used by Chinese teachers with teacher-student ratios typically found in less-resourced preschools. We found that the Classroom Observation Scale reliably helped observers with little or no clinical training-research assistants with just a few hours of Classroom Observation Scale training and preschool teachers with an hour of briefing-to identify children in their first year of Chinese-language preschool who were more likely than their peers to have autism spectrum disorder. Reliability estimates of Classroom Observation Scale-Teacher and Classroom Observation Scale-Researcher in this study were comparable to those for the original English Classroom Observation Scale. Our results provided further evidence on the versatility and ecological validity of the Classroom Observation Scale for use by preschool teachers and non-clinically trained observers in the early identification of children with autism spectrum disorder in community settings.

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11. Song L, Wen W, Liu J, Jin X, Yang J. Inflammatory state and autism-like behavioral phenotype of offspring induced by maternal exposure to low-dose chemical mixtures during pregnancy in mice. Zhejiang da xue xue bao Yi xue ban = Journal of Zhejiang University Medical sciences. 2021; 50(3): 279-89.

To investigate the effects of maternal exposure to 13 chemicals mixture (CM) during pregnancy on pregnancy outcome and health status of maternal/offspring mice. C57BL/6 pregnant mice were given drinking water containing carbaryl dimethoate glyphosate methomyl methyl parathion triadimefon aspartame sodium benzoate calcium disodium ethylene diamine tetra-acetate ethylparaben butylparaben bisphenol A and acacia gum The effects of CM exposure on pregnancy outcome, health status of dams/offspring, levels of circulating inflammatory cytokines in dams/offspring and emotional related behaviors of offspring were evaluated. CM exposure during pregnancy had no significant effect on pregnancy outcome, liver function, body weight of the dams in late pregnancy and uterine/ovarian weight after delivery, however, it led to an increase in maternal serum IFN-γ level （<0.05）. CM exposure during pregnancy had no significant effect on the liver function of offspring, but increased the serum IFN-γ, prefrontal cortex IFN-γ, and TNF-α and hippocampus IFN-γ levels in the offspring（all <0.01）. In addition, the offspring of CM group showed significant abnormal emotion-related (autism-like) behaviors in adulthood, especially in male offspring. Low dose CM exposure during pregnancy may induce inflammation status in dams/offspring, and lead to autism-like behaviors in offspring, indicating the potential effects of low dose CM exposure on human maternal and infant health. OBJECTIVE: To investigate the effects of maternal exposure to 13 chemicals mixture (CM) during pregnancy on pregnancy outcome and health status of maternal/offspring mice. METHODS: C57BL/6 pregnant mice were given drinking water containing carbaryl 0.0075 mg/kg, dimethoate 0.001 mg/kg, glyphosate 0.5 mg/kg, methomyl 0.0025 mg/kg, methyl parathion 0.003 mg/kg, triadimefon 0.03 mg/kg, aspartame 40 mg/kg, sodium benzoate 5 mg/kg, calcium disodium ethylene diamine tetra-acetate 2.5 mg/kg, ethylparaben 10 mg/kg, butylparaben 0.5 mg/kg, bisphenol A 0.004 mg/kg and acacia gum 34 mg/kg. The effects of CM exposure on pregnancy outcome, health status of dams/offspring, levels of circulating inflammatory cytokines in dams/offspring and emotional related behaviors of offspring were evaluated. RESULTS: CM exposure during pregnancy had no significant effect on pregnancy outcome, liver function, body weight of the dams in late pregnancy and uterine/ovarian weight after delivery, however, it led to an increase in maternal serum IFN-γ level （ P<0.05）. CM exposure during pregnancy had no significant effect on the liver function of offspring, but increased the serum IFN-γ, prefrontal cortex IFN-γ, IL-6 and TNF-α and hippocampus IFN-γ levels in the offspring（all P<0.01）. In addition, the offspring of CM group showed significant abnormal emotion-related (autism-like) behaviors in adulthood, especially in male offspring. CONCLUSION: Low dose CM exposure during pregnancy may induce inflammation status in dams/offspring, and lead to autism-like behaviors in offspring, indicating the potential effects of low dose CM exposure on human maternal and infant health. eng.

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12. Stringer RN, Jurkovicova-Tarabova B, Souza IA, Ibrahim J, Vacik T, Fathalla WM, Hertecant J, Zamponi GW, Lacinova L, Weiss N. De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy. Molecular brain. 2021; 14(1): 126.

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873-4881 duplication) in the SCN8A gene and an inherited heterozygous variant (c.952G > A) in the CACNA1H gene encoding for Na(v)1.6 voltage-gated sodium and Ca(v)3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Na(v)1.6 and Ca(v)3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of SCN8A and CACNA1H, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.

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13. Vacher CM, Lacaille H, O’Reilly JJ, Salzbank J, Bakalar D, Sebaoui S, Liere P, Clarkson-Paredes C, Sasaki T, Sathyanesan A, Kratimenos P, Ellegood J, Lerch JP, Imamura Y, Popratiloff A, Hashimoto-Torii K, Gallo V, Schumacher M, Penn AA. Placental endocrine function shapes cerebellar development and social behavior. Nature neuroscience. 2021; 24(10): 1392-401.

Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders. Here we show that placenta allopregnanolone (ALLO), a progesterone-derived GABA-A receptor (GABA(A)R) modulator, reduction alters neurodevelopment in a sex-linked manner. A new conditional mouse model, in which the gene encoding ALLO’s synthetic enzyme (akr1c14) is specifically deleted in trophoblasts, directly demonstrated that placental ALLO insufficiency led to cerebellar white matter abnormalities that correlated with autistic-like behavior only in male offspring. A single injection of ALLO or muscimol, a GABA(A)R agonist, during late gestation abolished these alterations. Comparison of male and female human preterm infant cerebellum also showed sex-linked myelination marker alteration, suggesting similarities between mouse placental ALLO insufficiency and human preterm brain development. This study reveals a new role for a placental hormone in shaping brain regions and behaviors in a sex-linked manner. Placental hormone replacement might offer novel therapeutic opportunities to prevent later neurobehavioral disorders.

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14. Yu MC, Wang TM, Chiou YH, Yu MK, Lin CF, Chiu CY. Urine metabolic phenotyping in children with nocturnal enuresis and comorbid neurobehavioral disorders. Scientific reports. 2021; 11(1): 16592.

Nocturnal enuresis (NE) is a common problem among 10% school-aged children. The etiologies underlying childhood NE is complex and not fully understood nowadays. Nevertheless, increasing evidence suggests a potential link between neurobehavioral disorders and enuresis in children. In this study, we aimed to explore novel metabolomic insights into the pathophysiology of NE and also, its association with pediatric psychiatric problems. Urine collected from 41 bedwetting children and 27 healthy control children was analyzed by using (1)H-nuclear magnetic resonance spectroscopy from August 2017 to December 2018. At regular follow-up, there were 14 children with refractory NE having a diagnosis of attention deficient hyperactivity disorder (ADHD) or anxiety. Eventually, we identified eight significantly differential urinary metabolites and particularly increased urinary excretion of betaine, creatine and guanidinoacetate linked to glycine, serine and threonine metabolism were associated with a comorbidity of neurobehavioral disorders in refractory bedwetting children. Notably, based on physiological functions of betaine acting as a renal osmolyte and methyl group donor, we speculated its potential role in modulation of renal and/or central circadian clock systems, becoming a useful urinary metabolic marker in diagnosis of treatment-resistant NE in children affected by these two disorders.

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