1. Althammer F, Muscatelli F, Grinevich V, Schaaf CP. Oxytocin-based therapies for treatment of Prader-Willi and Schaaf-Yang syndromes: evidence, disappointments, and future research strategies. Transl Psychiatry;2022 (Aug 8);12(1):318.

The prosocial neuropeptide oxytocin is being developed as a potential treatment for various neuropsychiatric disorders including autism spectrum disorder (ASD). Early studies using intranasal oxytocin in patients with ASD yielded encouraging results and for some time, scientists and affected families placed high hopes on the use of intranasal oxytocin for behavioral therapy in ASD. However, a recent Phase III trial obtained negative results using intranasal oxytocin for the treatment of behavioral symptoms in children with ASD. Given the frequently observed autism-like behavioral phenotypes in Prader-Willi and Schaaf-Yang syndromes, it is unclear whether oxytocin treatment represents a viable option to treat behavioral symptoms in these diseases. Here we review the latest findings on intranasal OT treatment, Prader-Willi and Schaaf-Yang syndromes, and propose novel research strategies for tailored oxytocin-based therapies for affected individuals. Finally, we propose the critical period theory, which could explain why oxytocin-based treatment seems to be most efficient in infants, but not adolescents.

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2. Aslam AR, Hafeez N, Heidari H, Altaf MAB. Channels and Features Identification: A Review and a Machine-Learning Based Model With Large Scale Feature Extraction for Emotions and ASD Classification. Front Neurosci;2022;16:844851.

Autism Spectrum Disorder (ASD) is characterized by impairments in social and cognitive skills, emotional disorders, anxiety, and depression. The prolonged conventional ASD diagnosis raises the sheer need for early meaningful intervention. Recently different works have proposed potential for ASD diagnosis and intervention through emotions prediction using deep neural networks (DNN) and machine learning algorithms. However, these systems lack an extensive large-scale feature extraction (LSFE) analysis through multiple benchmark data sets. LSFE analysis is required to identify and utilize the most relevant features and channels for emotion recognition and ASD prediction. Considering these challenges, for the first time, we have analyzed and evaluated an extensive feature set to select the optimal features using LSFE and feature selection algorithms (FSA). A set of up to eight most suitable channels was identified using different best-case FSA. The subject-wise importance of channels and features is also identified. The proposed method provides the best-case accuracies, precision, and recall of 95, 92, and 90%, respectively, for emotions prediction using a linear support vector machine (LSVM) classifier. It also provides the best-case accuracy, precision, and recall of 100% for ASD classification. This work utilized the largest number of benchmark data sets (5) and subjects (99) for validation reported till now in the literature. The LSVM classification algorithm proposed and utilized in this work has significantly lower complexity than the DNN, convolutional neural network (CNN), Naïve Bayes, and dynamic graph CNN used in recent ASD and emotion prediction systems.

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3. Batton B, Kaplan R, Ellis K, Schmidt C, Nudelman E. Telehealth Training in Principles of Applied Behavior Analysis for Caregivers of Young Children with Autism Spectrum Disorders during the COVID-19 Pandemic. Educ Treat Children;2022 (Aug 2):1-5.

Following the outbreak of the COVID-19 pandemic, the U.S. government declared a state of emergency and many applied behavior analysis clinics temporarily closed. The current study described a pilot of an existing manualized caregiver behavior skills training, the Online and Applied System of Intervention Skills (OASIS), to promote telehealth caregiver training during the pandemic and facilitate the start of early intervention for families on waitlists. The OASIS telehealth curriculum trains caregivers to use applied behavior analysis with their children with autism spectrum disorder. Pre/post measures suggest that OASIS modestly improved parent knowledge, improved perceived quality of life, decreased stress, improved caregiver self-efficacy, and was viewed positively by participating families.

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4. Ben Youssef H, Halayem S, Ghazzai M, Jelili S, Ben Mansour H, Rajhi O, Taamallah A, Ennaifer S, Hajri M, Abbes ZS, Fakhfakh R, Nabli A, Bouden A. Validation of the Tunisian Empathy Scale for Children (TESC) in General Population and Children With Autism Spectrum Disorder. Front Psychiatry;2022;13:903966.

BACKGROUND: Several empathy assessment tests have been proposed worldwide but none of them took into account cultural variations that seem to affect empathic manifestations. The aim of this study was to create and validate an empathy assessment questionnaire for school-aged Tunisian children entitled « Tunisian Empathy Scale for Children » (TESC). METHODS: An evaluative cross-sectional study was conducted. The questionnaire was administered to parents of 197 neuro-typical children and 31 children with autism without associated intellectual deficits, aged between 7 and 12 years. Validation steps included: face validity, content validity, construct validity, and reliability study. A ROC curve analysis was used to investigate the diagnostic performance of the TESC. RESULTS: Face validity was verified with an expert panel. Content validity was examined, and 11 items were removed as irrelevant or not assessable by parents. Exploratory factor analysis extracted four domains that explained 43% of the total variance. All these domains were significantly correlated with the total score (p < 10(-3)) and are, respectively: empathic behaviors, affective empathy, cognitive empathy, and a combined affective and cognitive domain. The reliability study showed a satisfactory level of internal consistency of the TESC, with a Cronbach's alpha of 0.615.The diagnostic performance of the TESC in relation to autism was evaluated by the ROC curve with a sensitivity and specificity of 84.3 and 62.1%, respectively, for a total score of 16. CONCLUSION: A 15-item questionnaire assessing empathy in a multidimensional and culturally adapted way was obtained. The psychometric qualities of the TESC were satisfactory.

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5. Bogdanova OV, Bogdanov VB, Pizano A, Bouvard M, Cazalets JR, Mellen N, Amestoy A. The Current View on the Paradox of Pain in Autism Spectrum Disorders. Front Psychiatry;2022;13:910824.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, which affects 1 in 44 children and may cause severe disabilities. Besides socio-communicational difficulties and repetitive behaviors, ASD also presents as atypical sensorimotor function and pain reactivity. While chronic pain is a frequent co-morbidity in autism, pain management in this population is often insufficient because of difficulties in pain evaluation, worsening their prognosis and perhaps driving higher mortality rates. Previous observations have tended to oversimplify the experience of pain in autism as being insensitive to painful stimuli. Various findings in the past 15 years have challenged and complicated this dogma. However, a relatively small number of studies investigates the physiological correlates of pain reactivity in ASD. We explore the possibility that atypical pain perception in people with ASD is mediated by alterations in pain perception, transmission, expression and modulation, and through interactions between these processes. These complex interactions may account for the great variability and sometimes contradictory findings from the studies. A growing body of evidence is challenging the idea of alterations in pain processing in ASD due to a single factor, and calls for an integrative view. We propose a model of the pain cycle that includes the interplay between the molecular and neurophysiological pathways of pain processing and it conscious appraisal that may interfere with pain reactivity and coping in autism. The role of social factors in pain-induced response is also discussed. Pain assessment in clinical care is mostly based on subjective rather than objective measures. This review clarifies the strong need for a consistent methodology, and describes innovative tools to cope with the heterogeneity of pain expression in ASD, enabling individualized assessment. Multiple measures, including self-reporting, informant reporting, clinician-assessed, and purely physiological metrics may provide more consistent results. An integrative view on the regulation of the pain cycle offers a more robust framework to characterize the experience of pain in autism.

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6. Castro-Kemp S, Orcid AM. Silver linings of the Covid-19 pandemic… for some! Comparing Experiences and Social demographic characteristics of autistic and non-autistic children with SEND in England. J Autism Dev Disord;2022 (Aug 9):1-12.

Several studies on the impact of Covid-19 on children’s wellbeing have been published, including for those with Special Educational Needs and Disabilities. However, limited evidence is available on who these children may be, their socioeconomic background, age, gender or type of school attended. This study examines the role of socio-demographic characteristics on the experiences of Autistic Children, compared to non-Autistic children, to assess the detrimental impact of the pandemic, but also potential silver linings. Primary-school aged Autistic children were more likely to mention a silver lining (for mental health), as well as younger non-Autistic children from more affluent backgrounds. Similar effects were observed for older non-Autistic boys with special needs attending mainstream settings (regarding physical health).

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7. Chen S, Zhao J, Hu X, Tang L, Li J, Wu D, Yan T, Xu L, Chen M, Huang S, Hao Y. Children neuropsychological and behavioral scale-revision 2016 in the early detection of autism spectrum disorder. Front Psychiatry;2022;13:893226.

BACKGROUND: The Children Neuropsychological and Behavioral Scale-Revision 2016 (CNBS-R2016) is a widely used developmental assessment tool for children aged 0-6 years in China. The communication warning behavior subscale of CNBS-R2016 is used to assess the symptoms of autism spectrum disorder (ASD), and its value of >30 points indicates ASD based on CNBS-R2016. However, we observed that children with relatively lower values were also diagnosed with ASD later on in clinical practice. Thus, this study aimed to identify the suitable cutoff value for ASD screening recommended by the communication warning behavior of CNBS-R2016. MATERIALS AND METHODS: A total of 90 typically developing (TD) children and 316 children with developmental disorders such as ASD, developmental language disorder (DLD), and global developmental delay (GDD; 130 in the ASD group, 100 in the DLD group, and 86 in the GDD group) were enrolled in this study. All subjects were evaluated based on the CNBS-R2016. The newly recommended cutoff value of communication warning behavior for screening ASD was analyzed with receiver operating curves. RESULTS: Children in the ASD group presented with lower developmental levels than TD, DLD, and GDD groups in overall developmental quotient assessed by CNBS-R2016. We compared the consistency between the scores of communication warning behavior subscale and Autism Behavior Checklist (ABC), Childhood Autism Rating Scale (CARS), Autism Diagnostic Observation Schedule, second edition (ADOS-2), and clinical diagnosis for the classification of ASD at a value of 30 based on the previously and newly recommended cutoff value of 12 by the CNBS-R2016. The Kappa values between the communication warning behavior and ABC, CARS, ADOS-2, and clinical diagnosis were 0.494, 0.476, 0.137, and 0.529, respectively, with an agreement rate of 76.90%, 76.26%, 52.03%, and 82.27%, respectively, when the cutoff point was 30. The corresponding Kappa values were 0.891, 0.816, 0.613, and 0.844, respectively, and the corresponding agreement rate was 94.62%, 90.82%, 90.54%, and 93.10%, respectively, when the cutoff point was 12. CONCLUSION: The communication warning behavior subscale of CNBS-R2016 is important for screening ASD. When the communication warning behavior score is 12 points or greater, considerable attention and further comprehensive diagnostic evaluation for ASD are required to achieve the early detection and diagnosis of ASD in children.

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8. Chen SK, Hsu LM, Chiu NC, Saleh W, Pai CW, Chen PL. Injury in Children with Developmental Disorders: A 1:1 Nested Case-Control Study Using Multiple Datasets in Taiwan. Int J Environ Res Public Health;2022 (Aug 9);19(16)

Although past studies have identified predictors related to child injuries with developmental disorders, national-level research in Asia is limited. The objective of this study was to explore the risk factors for child injuries with developmental disorders in Taiwan using a national-level integrated database for the period between 2004-2015 (The Maternal and Child Health Database, National Health Insurance Research Database, Census Registry, and Indigenous Household Registration). Children younger than 12 years old who had records of visiting the ER or being hospitalized due to injury or without injury were included in this study. A 1:1 nested case-control study (injury vs. noninjury) to examine the risk factors for child injury with developmental disorder was performed. A total of 2,167,930 children were enrolled. The risk factors were associated with repeated ER visits or hospitalization: being indigenous (adjusted odds ratio [AOR]: 1.51; CI: 1.45-1.57); having a developmental disorder (AOR: 1.74; CI: 1.70-1.78); and having parents with illicit drug use (AOR: 1.48; CI: 1.32-1.66), alcohol abuse (AOR: 1.21; CI: 1.07-1.37), or a history of mental illness (AOR: 1.43; CI: 1.41-1.46). Being indigenous, having developmental disorders, and having parents with history of illicit drug use, alcohol abuse, or mental illness were predictors related to injuries in children.

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9. Chen YL, Schneider M, Patten K. Exploring the role of interpersonal contexts in peer relationships among autistic and non-autistic youth in integrated education. Front Psychol;2022;13:946651.

The double empathy problem theory posits that autistic social difficulties emerge from an interpersonal misalignment in social experiences and expectations between autistic and non-autistic people. Supporting this, emerging research reveals better social outcomes in interactions within than across neurotypes among autistic and non-autistic people, emphasizing the need to examine the role of the interpersonal context in autistic social outcomes. However, research on peer relationships among autistic youth primarily focuses on individual characteristics in isolation from the interpersonal context. To address this, this preliminary study explored the effects of student-peer neurotype match on peer relationships among autistic and non-autistic youth in an integrated educational setting. We plotted the peer relationship networks among youth in a school club based on systematic observations of peer interactions over eight 45-min sessions. Descriptive network statistics (node degree and strength) showed that both autistic and non-autistic youth had more and stronger peer relationships with their same- than cross-neurotype peers. Assortativity coefficients revealed a tendency for youth to connect with peers of the same neurotype, rather than with peers with similar social popularity or activity. We further modeled the effects of student-peer neurotype match on peer relationships using exponential random graph models. The findings suggested that student-peer neurotype match predicted the total strength of peer relationships above and beyond the effects of student neurotype, individual heterogeneity in social popularity and activity, and the tendency of mutuality in social relationships. We discussed the strengths and limitations of this study and the implications for future research and inclusion practice.

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10. Helsel BC, Foster RNS, Sherman J, Ptomey LT, Montgomery RN, Washburn RA, Donnelly JE. A Remotely Delivered Yoga Intervention for Adolescents with Autism Spectrum Disorder: Feasibility and Effectiveness for Improving Skills Related to Physical Activity. J Autism Dev Disord;2022 (Aug 8)

This study evaluated the feasibility of remotely delivered yoga for improving four physical activity-related skills: motor skills, strength, balance, and flexibility in adolescents with autism spectrum disorder (ASD). Nineteen of 20 participants enrolled (age 13.2 ± 2.2 years; 60% male) completed the 12-week intervention and attended 83% of the scheduled yoga sessions. Overall, physical activity-related skills improved pre to post intervention (Φ = 0.90, p = 0.005, 95% CI 0.72-1.0). Specifically, significant increases in leg strength (12.5%, p = 0.039), flexibility (40.3%, p = 0.008), and dynamic balance on the right (11.1%, p = 0.001) and left legs (8.1%, p = 0.003) were observed across 12 weeks. These results demonstrate the feasibility and potential effectiveness of yoga to improve physical activity-related skills in adolescents with ASD.

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11. Ilijoski B, Ackovska N, Zorcec T, Popeska Z. Extending Robot Therapy for Children with Autism Using Mobile and Web Application. Sensors (Basel);2022 (Aug 9);22(16)

Robot treatments for children with autism have proven to be successful and effective. However, the resources needed for the treatments do not always meet the needs of the children. We overcame the lack of equipment and staff by extending the concept of robot therapy using a web and mobile application. This application enables greater availability and personification of the therapy itself. Its use in the majority of respondents contributes to improving their condition. This approach increases the flexibility of the therapy itself and makes it more accessible, enabling the patients to progress more rapidly. Although the robotic treatment presented in this paper is specific to children with autism, this approach can be generalized and applied to other areas where there are similar types of therapies.

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12. Kasahara S, Takao C, Matsudaira K, Sato N, Tu TTH, Niwa SI, Uchida K, Toyofuku A. Case report: Treatment of persistent atypical odontalgia with attention deficit hyperactivity disorder and autism spectrum disorder with risperidone and atomoxetine. Front Pain Res (Lausanne);2022;3:926946.

Chronic pain has recently been associated with developmental disorders [autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD)]. Regarding chronic pain in adulthood, fibromyalgia, migraine, and chronic low back pain have been associated with ADHD. The ICD-11 disease classification categorizes these pain diseases as chronic primary pain, suggesting high comorbidity with developmental disorders in chronic primary pain. Atypical odontalgia (AO) is a persistent tooth pain that occurs in the absence of any of the usual dental causes, most of which are triggered by dental treatment. Conditions characterized by tooth pain with no apparent cause are also classified as chronic primary pain. Approximately half the patients with AO are diagnosed with psychiatric disorders; the most common are depression (15.4%) and anxiety disorders (10.1%). However, there are no reports on neurodevelopmental disorders comorbid with AO. In the present study, we report a case of a 46-year-old man with numerous complaints (e.g., occlusal instability, difficulty eating, difficulty speaking), who took work leave due to worsening of his symptoms after periodontal scaling (« gingival recession » and « aggressive periodontal treatment ») and frequently expressed dissatisfaction and anger at the hospital, making the dental treatment difficult. After a referral to a psychiatrist specializing in chronic pain, AO and previously undiagnosed comorbidity of ASD and ADHD were confirmed. Atypical antipsychotic risperidone for ASD irritability and an ADHD medication, atomoxetine dramatically reduced anger, pain, anxiety, depression, and pain catastrophizing thoughts, leading to reduced obsession with his symptoms and less frequent complaints. After risperidone (1 mg/day) + atomoxetine (120 mg/day) were ultimately prescribed after adjustment, he was able to return to work 226 days after initiation of psychiatric treatment. Recent studies show that comorbidity of developmental disorders in patients with chronic pain is likely to be undetected. Clinicians should include screening for ASD and ADHD not only in cases of fibromyalgia, migraine, and chronic low back pain, but also in orofacial pain such as AO and other treatments for chronic primary pain. For patients diagnosed with ASD or ADHD, an effective drug therapy for ASD and ADHD should be considered.

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13. Kim H, Woo RS, Yang EJ, Kim HB, Jo EH, Lee S, Im H, Kim S, Kim HS. Transcriptomic analysis in the striatum reveals the involvement of Nurr1 in the social behavior of prenatally valproic acid-exposed male mice. Transl Psychiatry;2022 (Aug 9);12(1):324.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that exhibits neurobehavioral deficits characterized by abnormalities in social interactions, deficits in communication as well as restricted interests, and repetitive behaviors. The basal ganglia is one of the brain regions implicated as dysfunctional in ASD. In particular, the defects in corticostriatal function have been reported to be involved in the pathogenesis of ASD. Surface deformation of the striatum in the brains of patients with ASD and their correlation with behavioral symptoms was reported in magnetic resonance imaging (MRI) studies. We demonstrated that prenatal valproic acid (VPA) exposure induced synaptic and molecular changes and decreased neuronal activity in the striatum. Using RNA sequencing (RNA-Seq), we analyzed transcriptome alterations in striatal tissues from 10-week-old prenatally VPA-exposed BALB/c male mice. Among the upregulated genes, Nurr1 was significantly upregulated in striatal tissues from prenatally VPA-exposed mice. Viral knockdown of Nurr1 by shRNA significantly rescued the reduction in dendritic spine density and the number of mature dendritic spines in the striatum and markedly improved social deficits in prenatally VPA-exposed mice. In addition, treatment with amodiaquine, which is a known ligand for Nurr1, mimicked the social deficits and synaptic abnormalities in saline-exposed mice as observed in prenatally VPA-exposed mice. Furthermore, PatDp+/- mice, a commonly used ASD genetic mouse model, also showed increased levels of Nurr1 in the striatum. Taken together, these results suggest that the increase in Nurr1 expression in the striatum is a mechanism related to the changes in synaptic deficits and behavioral phenotypes of the VPA-induced ASD mouse model.

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14. Kloidt B, Blatz L, Flemming M, von Spee L, Giersdorf M. [Challenges and Influencial Factors in Autism-Specific Diagnostics in Toddlers]. Z Kinder Jugendpsychiatr Psychother;2022 (Aug 9)

Challenges and Influencial Factors in Autism-Specific Diagnostics in Toddlers Abstract. Objective: What are the particular challenges that make early diagnosis of young children difficult in the clinical routine? What recommendations can be derived from this in practice? Methods: Our interdisciplinary social pediatric team examined 31 toddlers aged 2 to 3 years twice in intervals of 6-9 months in the for outpatient diagnostics regarding suspected autism spectrum disorder (ASD). In addition, we conducted an online survey with further experts. Results: After the first anamnestic interview, 8 of the 31 (26 %) children were diagnosed with a differential diagnosis of ASD. Comorbid disorders, familial peculiarities, and challenges posed by the examination setting and anamnesis made a reliable clinical classification difficult. Conclusion: In our experience, many toddlers can only receive a valid diagnosis after a follow-up examination after starting one or more therapies and regularly carrying out these therapies over a period of 6-9 months and possibly also after structural changes have taken place (care in nursery, implementation of youth welfare measures, or similar).

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15. Leonard H, Whitehouse A, Jacoby P, Benke T, Demarest S, Saldaris J, Wong K, Reddihough D, Williams K, Downs J. Quality of life beyond diagnosis in intellectual disability – Latent profiling. Res Dev Disabil;2022 (Oct);129:104322.

OBJECTIVE: To compare quality of life (QOL) across diagnoses associated with intellectual disability, construct QOL profiles and evaluate membership by diagnostic group, function and comorbidities. METHOD: Primary caregivers of 526 children with intellectual disability (age 5-18 years) and a diagnosis of cerebral palsy, autism spectrum disorder, Down syndrome, CDKL5 deficiency disorder or Rett syndrome completed the Quality of Life Inventory-Disability (QI-Disability) questionnaire. Latent profile analysis of the QI-Disability domain scores was conducted. RESULTS: The mean (SD) total QOL score was 67.8 (13.4), ranging from 60.3 (14.6) for CDD to 77.5 (11.7) for Down syndrome. Three classes describing domain scores were identified: Class 1 was characterised by higher domain scores overall but poorer negative emotions scores; Class 2 by average to high scores for most domains but low independence scores; and Class 3 was characterised by low positive emotions, social interaction, and leisure and the outdoors scores, and extremely low independence scores. The majority of individuals with autism spectrum disorder and Down syndrome belonged to Class 1 and the majority with CDKL5 deficiency disorder belonged to Class 3. Those with better functional abilities (verbal communication and independent walking were predominately members of Class 1 and those with frequent seizures were more often members of Class 2 and 3. CONCLUSION: The profiles illustrated variation in QOL across a diverse group of children. QOL evaluations illustrate areas where interventions could improve QOL and provide advice to families as to where efforts may be best directed.

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16. Levy Y. ASD-Time for a paradigm shift. Front Psychiatry;2022;13:956351.

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17. Li S, Tang Z, Jin N, Yang Q, Liu G, Liu T, Hu J, Liu S, Wang P, Hao J, Zhang Z, Zhang X, Li J, Wang X, Li Z, Wang Y, Yang B, Ma L. Uncovering Brain Differences in Preschoolers and Young Adolescents with Autism Spectrum Disorder Using Deep Learning. Int J Neural Syst;2022 (Sep);32(9):2250044.

Identifying brain abnormalities in autism spectrum disorder (ASD) is critical for early diagnosis and intervention. To explore brain differences in ASD and typical development (TD) individuals by detecting structural features using T1-weighted magnetic resonance imaging (MRI), we developed a deep learning-based approach, three-dimensional (3D)-ResNet with inception (I-ResNet), to identify participants with ASD and TD and propose a gradient-based backtracking method to pinpoint image areas that I-ResNet uses more heavily for classification. The proposed method was implemented in a preschool dataset with 110 participants and a public autism brain imaging data exchange (ABIDE) dataset with 1099 participants. An extra epilepsy dataset with 200 participants with clear degeneration in the parahippocampal area was applied as a verification and an extension. Among the datasets, we detected nine brain areas that differed significantly between ASD and TD. From the ROC in PASD and ABIDE, the sensitivity was 0.88 and 0.86, specificity was 0.75 and 0.62, and area under the curve was 0.787 and 0.856. In a word, I-ResNet with gradient-based backtracking could identify brain differences between ASD and TD. This study provides an alternative computer-aided technique for helping physicians to diagnose and screen children with an potential risk of ASD with deep learning model.

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18. Little LM, Ausderau K, Freuler A, Sideris J, Baranek GT. Caregiver Strategies to Sensory Features for Children With Autism and Developmental Disabilities. Front Psychol;2022;13:905154.

BACKGROUND: Caregivers of children with autism spectrum disorders (ASD) and developmental disabilities (DD) implement myriad strategies to support their children during daily activities and routines, which are laden with sensory stimuli. Children’s sensory features are often characterized by three patterns of response (i.e., hyperresponsiveness, hyporesponsiveness, sensory seeking), and little is known about how caregivers’ strategies differ among these patterns. Therefore, we used a mixed methods analysis to examine the complex interplay between children’s sensory response patterns, child characteristics (diagnosis, chronological age, mental age), and caregiver strategies. Specifically, we examined how children’s sensory response pattern scores were associated with caregiver strategies within sensory response pattern and at the item level. Lastly, we described the differential strategies implemented by caregivers of children with ASD and DD by sensory response pattern. MATERIALS AND METHODS: Participants included children with ASD (n = 77) and DD (n = 40) aged 2-10 years. Caregivers completed the Sensory Experiences Questionnaire-2.1. A convergent parallel mixed methods approach was used to analyze data. RESULTS: Children’s sensory response pattern scores were significantly, positively associated with caregiver strategies within each sensory pattern (hyperresponsiveness, hyporesponsiveness, seeking); however, child mental age, and chronological age were not significantly related to the rate of caregiver strategies across patterns. While caregivers of children with ASD reported using more strategies, child diagnosis did not moderate the association between child sensory response pattern scores and the rate of caregiver strategies used. Item analysis demonstrated specific child behaviors in response to sensory stimuli that elicited high rates of strategies among caregivers. Qualitative analysis revealed distinct themes characterized caregiver strategies within each sensory pattern for children with ASD and DD. CONCLUSION: Our findings demonstrated specificity of caregiver strategies to children’s sensory response patterns in the context of families’ everyday lives, which were not contingent on child diagnosis, mental age, or chronological age, thereby highlighting universal qualities of caregiving for young children who experience varying levels of sensory challenges. Targeted intervention approaches may differentially incorporate types of strategies based on sensory response patterns to more optimally facilitate children’s activity participation.

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19. Lv S, Xing Y, Xu Y, Liu L, Zhu H, Ye Q, Wang C, Zou X, Deng H. The role of caregiver gestures and gesture-related responses of toddlers with autism spectrum disorder. Front Psychiatry;2022;13:895029.

Autism spectrum disorder (ASD) is characterized by social communicative abnormalities. Deficits and delays in gestural communication are among the early deficits of ASD and also a major social modality in early caregiver-toddler interaction. Caregiver gestures have an important role in the cognitive and social development of children with ASD. Thus, it is urgent to further explore the role of caregiver gestures in early caregiver-toddler interaction. In this cross-sectional study, we observed the caregivers’ gestures and responses of toddlers aged between 18 and 24 months during play (ASD = 44, TD = 29) and dining activities (ASD = 34, TD = 27). By observing the different frequencies and patterns of gestures by the caregiver-child interaction and the different proportions of children’s responses to the caregiver’s gestures, we found that, compared to caregivers of typically developing toddlers, caregivers of toddlers with ASD had fewer synchronized gestures and more unsynchronized gestures in the play activity and more supplementary gestures in dining activity. Toddlers with ASD produced more social responses to caregivers’ synchronized gestures, whereas the use of synchronized gestures by the caregivers in caregiver-toddler interaction had a positive influence on social responses to toddlers with ASD. The findings suggest that effective use of gestures by caregivers during caregiver-toddler activities can improve children’s social responses.

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20. Nair N, Hegarty JP, 2nd, Cirstea CM, Gu M, Appling CB, Beversdorf DQ. Relationship Between MR Spectroscopy-Detected Glutamatergic Neurometabolites and Changes in Social Behaviors in a Pilot Open-Label Trial of Memantine for Adults With Autism Spectrum Disorder. Front Psychiatry;2022;13:898006.

BACKGROUND: The neurobiology underlying ASD is largely unknown but altered neural excitability/inhibitory ratios have been reported. Memantine is an N-methyl-D-aspartate (NMDA) glutamatergic antagonist studied for the treatment of core ASD symptoms, with mixed results. We examined whether glutamatergic levels were associated with and predicted response to memantine in an exploratory pilot study. METHODS: Ten adult participants with ASD underwent proton magnetic resonance spectroscopy ((1)H-MRS) imaging at baseline and behavioral assessments before and after 12-weeks of open-label memantine. Post-treatment scores on Clinical Global Impressions-Improvement (CGI-I) for social interaction were the primary outcome measure, and scores on the Social Responsiveness Scale (SRS) were included as a secondary outcome. LCModel was used to quantify the concentrations of Point RESolved Spectroscopy-detected glutamate+glutamine (Glx) (and other neurometabolites, i.e., N-acetylaspartate, NAA; creatine+phosphocreatine, Cr+PCr, and myo-inositol, Ins), within the left dorsolateral prefrontal cortex (LDLPFC) and right (R) posterolateral cerebellum. SPM was used to perform brain tissue segmentation within the spectroscopic voxels. CGI-I scores post-treatment were used to classify the participants into two groups, responders (scores 1-3; n = 5) and non-responders (scores 4-7, or withdrew due to increase behaviors; n = 5). Independent samples t-tests, partial correlations and linear hierarchical regression models (SPSS) were used to determine between-group differences in neurometabolite concentrations and associations between neurometabolites and behavioral scores. RESULTS: Responders and non-responders did not significantly differ in Glx levels in any region of interest, but differed in NAA levels in LDLPFC (higher in responders vs. non-responders). Although changes in CGI-I social scores were not correlated with Glx in any region of interest, the linear hierarchical regression did reveal that Glx and Ins levels in LDLPFC were predictors of post-treatment CGI-I social scores. Changes in SRS scores were correlated with baseline Cr+PCr levels in the LDLPFC. DISCUSSION: Our pilot data suggest that baseline Glx, a marker of glutamatergic neurotransmission, did not directly predict response to memantine for social outcomes in adults with ASD. However, interactions between Glx and the neurometabolite associated with glial integrity (Ins) may help predict treatment response. Further, those with highest baseline NAA, a putative neuronal marker, and Cr+pCr, a brain energy metabolism marker, were the best responders. These preliminary results may explain some of the mixed results reported in previous memantine trials in ASD. Future studies will need to examine these results in a larger sample.

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21. Ramirez M, Badayeva Y, Yeung J, Wu J, Abdalla-Wyse A, Yang E, Trost B, Scherer SW, Goldowitz D. Temporal analysis of enhancers during mouse cerebellar development reveals dynamic and novel regulatory functions. Elife;2022 (Aug 9);11

We have identified active enhancers in the mouse cerebellum at embryonic and postnatal stages which provides a view of novel enhancers active during cerebellar development. The majority of cerebellar enhancers have dynamic activity between embryonic and postnatal development. Cerebellar enhancers were enriched for neural transcription factor binding sites with temporally specific expression. Putative gene targets displayed spatially restricted expression patterns, indicating cell-type specific expression regulation. Functional analysis of target genes indicated that enhancers regulate processes spanning several developmental epochs such as specification, differentiation and maturation. We use these analyses to discover one novel regulator and one novel marker of cerebellar development: Bhlhe22 and Pax3, respectively. We identified an enrichment of de novo mutations and variants associated with autism spectrum disorder in cerebellar enhancers. Furthermore, by comparing our data with relevant brain development ENCODE histone profiles and cerebellar single-cell datasets we have been able to generalize and expand on the presented analyses, respectively. We have made the results of our analyses available online in the Developing Mouse Cerebellum Enhancer Atlas, where our dataset can be efficiently queried, curated and exported by the scientific community to facilitate future research efforts. Our study provides a valuable resource for studying the dynamics of gene expression regulation by enhancers in the developing cerebellum and delivers a rich dataset of novel gene-enhancer associations providing a basis for future in-depth studies in the cerebellum.

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22. Salehinejad MA, Ghanavati E, Glinski B, Hallajian AH, Azarkolah A. A systematic review of randomized controlled trials on efficacy and safety of transcranial direct current stimulation in major neurodevelopmental disorders: ADHD, autism, and dyslexia. Brain Behav;2022 (Aug 8):e2724.

OBJECTIVE: Among the target groups in child and adolescent psychiatry, transcranial direct current stimulation (tDCS) has been more applied in neurodevelopmental disorders specifically, attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and dyslexia. This systematic review aims to provide the latest update on published randomized-controlled trials applying tDCS in these disorders for evaluating its efficacy and safety. METHODS: Based on a pre-registered protocol (PROSPERO: CRD42022321430) and using the PRISMA approach, a literature search identified 35 randomized controlled trials investigating the effects of tDCS on children and adolescents with ADHD (n = 17), ASD (n = 11), and dyslexia (n = 7). RESULTS: In ADHD, prefrontal anodal tDCS is reported more effective compared to stimulation of the right inferior frontal gyrus. Similarly in ASD, prefrontal anodal tDCS was found effective for improving behavioral problems. In dyslexia, stimulating temporoparietal regions was the most common and effective protocol. In ASD and dyslexia, all tDCS studies found an improvement in at least one of the outcome variables while 64.7% of studies (11 of 17) in ADHD found a similar effect. About 88% of all tDCS studies with a multi-session design in 3 disorders (16 of 18) reported a significant improvement in one or all outcome variables after the intervention. Randomized, double-blind, controlled trials consisted of around 70.5%, 36.3%, and 57.1% of tDCS studies in ADHD, ASD, and dyslexia, respectively. tDCS was found safe with no reported serious side effects in 6587 sessions conducted on 745 children and adolescents across 35 studies. CONCLUSION: tDCS was found safe and partially effective. For evaluation of clinical utility, larger randomized controlled trials with a double-blind design and follow-up measurements are required. Titration studies that systematically evaluate different stimulation intensities, duration, and electrode placement are lacking.

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23. Savage TA, Bowers A. Dignity of Risk, Intellectual/Developmental Disabilities, and Living in the Community. Perspect Biol Med;2022;65(2):262-273.

Historically, people with intellectual/developmental disabilities (IDD) lived in institutions with little contact with the community. Having a label of « mental retardation » meant they were incapable of living and working outside of the institution. These individuals were protected from risk and harms and had little input into how they lived their lives. Perske (1972) challenged the idea that persons with IDD necessarily had to be protected from the harms one faces in daily life. He championed the principle of « dignity of risk, » respecting their right to weigh risks and harms of their choices. Over time, federal, state, and local agencies embraced the idea that people with IDD should be integrated into communities and receive supports so they may live their lives to the fullest. This article discusses how a community agency worked with their clients with IDD to balance their personal liberties with acceptable risks as they live and work in the community. Approaches such as the use of a Risk Committee or the empowerment of direct care workers in assessing risks are described through case illustrations.

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24. Seidler GR, Knaus ME, Beyene TJ, Ahmad H, Lu PL, Gasior AC, Halaweish I, Wood RJ. Impact of Neurodevelopmental Disorders on Bowel Management Outcomes in Children with Functional Constipation. J Pediatr Gastroenterol Nutr;2022 (Sep 1);75(3):286-292.

OBJECTIVES: Patients experiencing functional constipation (FC) can participate in structured bowel management programs (BMPs) to manage constipation or fecal incontinence when standard management fails. We sought to evaluate the efficacy of BMPs for children with FC with and without neurodevelopmental disorders. METHODS: We performed a retrospective review of children with FC who participated in our BMP from 2014 to 2021. Stool/urinary continence, bowel regimen, surgical history, parent-reported outcomes measures (PROMs: Cleveland Clinic Constipation Score, Baylor Continence Scale, Vancouver Symptom Score for Dysfunctional Elimination), and Pediatric Quality of Life Inventory (PedsQL) were assessed pre- and at least 9 months post-BMP. RESULTS: The cohort included 156 patients with a median age of 9 years and follow-up of 627 days (IQR: 389-808 days). Two sub-cohorts included patients with FC only (69%) and FC plus a neurodevelopmental disorder (31%): 59% attention-deficit/hyperactivity disorder, 33% autism spectrum disorder, and 8% obsessive-compulsive disorder. Both groups had significantly improved follow-up bowel movement frequency and continence (39%-90% neurodevelopmental, 44%-82% FC only, P < 0.001) and urinary continence (65%-90% neurodevelopmental, 69%-91% FC only, P < 0.02). There was a significant improvement in most of the PROMs at follow-up. Both groups experienced a clinically meaningful improvement in overall PedsQL scores (pre- and postBMP difference of >4.5). CONCLUSIONS: Patients with FC with and without a neurodevelopmental disorder had significant improvement in stool and urinary continence after undergoing a BMP. Further studies are needed to see if this improvement is durable over a longer period of time in this challenging cohort.

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25. Sherman HT, Liu K, Kwong K, Chan ST, Li AC, Kong XJ. Carbon monoxide (CO) correlates with symptom severity, autoimmunity, and responses to probiotics treatment in a cohort of children with autism spectrum disorder (ASD): a post-hoc analysis of a randomized controlled trial. BMC Psychiatry;2022 (Aug 8);22(1):536.

BACKGROUND: Inflammation, autoimmunity, and gut-brain axis have been implicated in the pathogenesis of autism spectrum disorder (ASD). Carboxyhemoglobin (SpCO) as a non-invasive measurement of inflammation has not been studied in individuals with ASD. We conducted this post-hoc study based on our published clinical trial to explore SpCO and its association with ASD severity, autoimmunity, and response to daily Lactobacillus plantarum probiotic supplementation. METHODS: In this study, we included 35 individuals with ASD aged 3-20 years from a previously published clinical trial of the probiotic Lactobacillus plantarum. Subjects were randomly assigned to receive daily Lactobacillus plantarum probiotic (6 × 10(10) CFUs) or a placebo for 16 weeks. The outcomes in this analysis include Social Responsiveness Scale (SRS), Aberrant Behavior Checklist second edition (ABC-2), Clinical Global Impression (CGI) scale, SpCO measured by CO-oximetry, fecal microbiome by 16 s rRNA sequencing, blood serum inflammatory markers, autoantibodies, and oxytocin (OT) by ELISA. We performed Kendall’s correlation to examine their interrelationships and used Wilcoxon rank-sum test to compare the means of all outcomes between the two groups at baseline and 16 weeks. RESULTS: Elevated levels of serum anti-tubulin, CaM kinase II, anti-dopamine receptor D1 (anti-D1), and SpCO were found in the majority of ASD subjects. ASD severity is correlated with SpCO (baseline, R = 0.38, p = 0.029), anti-lysoganglioside GM1 (R = 0.83, p = 0.022), anti-tubulin (R = 0.69, p = 0.042), and anti-D1 (R = 0.71, p = 0.045) in treatment group. CONCLUSIONS: The findings of the present study suggests that the easily administered and non-invasive SpCO test offers a potentially promising autoimmunity and inflammatory biomarker to screen/subgroup ASD and monitor the treatment response to probiotics. Furthermore, we propose that the associations between autoantibodies, gut microbiome profile, serum OT level, GI symptom severity, and ASD core symptom severity scores are specific to the usage of probiotic treatment in our subject cohort. Taken together, these results warrant further studies to improve ASD early diagnosis and treatment outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03337035 , registered November 8, 2017.

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26. Sinnamon JR, Jacobson ME, Yung JF, Fisk JR, Jeng S, McWeeney SK, Parmelee LK, Chan CN, Yee SP, Mandel G. Targeted RNA editing in brainstem alleviates respiratory dysfunction in a mouse model of Rett syndrome. Proc Natl Acad Sci U S A;2022 (Aug 16);119(33):e2206053119.

Rett syndrome is a neurological disease due to loss-of-function mutations in the transcription factor, Methyl CpG binding protein 2 (MECP2). Because overexpression of endogenous MECP2 also causes disease, we have exploited a targeted RNA-editing approach to repair patient mutations where levels of MECP2 protein will never exceed endogenous levels. Here, we have constructed adeno-associated viruses coexpressing a bioengineered wild-type ADAR2 catalytic domain (Editase(wt)) and either Mecp2-targeting or nontargeting gfp RNA guides. The viruses are introduced systemically into male mice containing a guanosine to adenosine mutation that eliminates MeCP2 protein and causes classic Rett syndrome in humans. We find that in the mutant mice injected with the Mecp2-targeting virus, the brainstem exhibits the highest RNA-editing frequency compared to other brain regions. The efficiency is sufficient to rescue MeCP2 expression and function in the brainstem of mice expressing the Mecp2-targeting virus. Correspondingly, we find that abnormal Rett-like respiratory patterns are alleviated, and survival is prolonged, compared to mice injected with the control gfp guide virus. The levels of RNA editing among most brain regions corresponds to the distribution of guide RNA rather than Editase(wt). Our results provide evidence that a targeted RNA-editing approach can alleviate a hallmark symptom in a mouse model of human disease.

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27. Takagi S, Hori H, Yamaguchi T, Ochi S, Nishida M, Maruo T, Takahashi H. Motor Functional Characteristics in Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorders: A Systematic Review. Neuropsychiatr Dis Treat;2022;18:1679-1695.

BACKGROUND: The development of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs) has various influences on physical abilities. Identification of specific physical abilities of people with ADHD/ASDs as biomarkers for diagnosing these conditions is necessary. Therefore, in the present review, we aimed firstly to extract the difference in physical abilities of people with ADHD or ASDs compared to those of normal individuals. Secondly, we aimed to extract the specific physical ability characteristics for identifying potential diagnostic biomarkers in people with ADHD/ASDs. METHODS: A systematic literature review was performed. The databases were searched for relevant articles on motor function deficits and characteristics of ADHD or ASD. RESULTS: Forty-one cross-sectional studies and three randomized controlled trials were identified, comprising 33 studies of ADHD, 10 studies of ASDs, and 1 study of both ADHD and ASDs. The quality of studies varied. Three types of physical activities/exercises were identified, including coordinated movement, resistance-type sports, and aerobic-type sports. People with ADHD/ASDs generally exhibited poorer physical abilities for all types of activities, possibly because of low levels of physical activity. Specifically, we found temporal discoordination of movement in ADHD and integration or synchronization of separate movements in ASDs. CONCLUSION: Specific deficits in physical ability may be attributed to ADHD/ASDs. However, there is not enough research on the physical abilities of people with ADHD and ASDs to clarify the specific deficits. Investigation of specific motor functions that characterize ADHD/ASDs should be facilitated.

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28. Taniya MA, Chung HJ, Al Mamun A, Alam S, Aziz MA, Emon NU, Islam MM, Hong SS, Podder BR, Ara Mimi A, Aktar Suchi S, Xiao J. Role of Gut Microbiome in Autism Spectrum Disorder and Its Therapeutic Regulation. Front Cell Infect Microbiol;2022;12:915701.

Autism spectrum disorder (ASD) is a neurological disorder that affects normal brain development. The recent finding of the microbiota-gut-brain axis indicates the bidirectional connection between our gut and brain, demonstrating that gut microbiota can influence many neurological disorders such as autism. Most autistic patients suffer from gastrointestinal (GI) symptoms. Many studies have shown that early colonization, mode of delivery, and antibiotic usage significantly affect the gut microbiome and the onset of autism. Microbial fermentation of plant-based fiber can produce different types of short-chain fatty acid (SCFA) that may have a beneficial or detrimental effect on the gut and neurological development of autistic patients. Several comprehensive studies of the gut microbiome and microbiota-gut-brain axis help to understand the mechanism that leads to the onset of neurological disorders and find possible treatments for autism. This review integrates the findings of recent years on the gut microbiota and ASD association, mainly focusing on the characterization of specific microbiota that leads to ASD and addressing potential therapeutic interventions to restore a healthy balance of gut microbiome composition that can treat autism-associated symptoms.

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29. Zhang W, Li D, Pang N, Jiang L, Li B, Ye F, He F, Chen S, Liu F, Peng J, Yin J, Yin F. The second-tier status of fragile X syndrome testing for unexplained intellectual disability/global developmental delay in the era of next-generation sequencing. Front Pediatr;2022;10:911805.

OBJECTIVE: Although many unexplained intellectual disability/global developmental delay (ID/GDD) individuals have benefited from the excellent detection yield of copy number variations and next-generation sequencing testing, many individuals still who suffer from ID/GDD of unexplained etiology. In this study, we investigated the applicability of fragile X syndrome (FXS) testing in unexplained ID/GDD individuals with negative or absent genetic testing. METHODS: In this study, we used the triplet repeat primed polymerase chain reaction to evaluate the value and application of fragile X testing in unexplained ID/GDD individuals with negative or absent genetic testing (n = 681) from three hospitals. RESULTS: Of the 681 ID/GDD individuals with negative or absent genetic testing results detected by FXS testing, 12 men and one woman were positive. This corresponded to a diagnostic yield of 1.9% for FXS testing in our cohort. All FXS individuals had either a family history of ID/GDD or suggestive clinical features. The detection yield of FXS testing in ID/GDD individuals who completed genetic testing (2.70%, 12/438) was significantly higher than in individuals without any genetic testing (0.40%, 1/243). CONCLUSIONS: This is the first report of FXS testing in ID/GDD individuals who lacked previous genetic testing, which promotes standardization of the FXS diagnostic process. These results highlight the utility of FXS testing of unexplained ID/GDD individuals with negative results from standard genetic testing. In the era of next-generation sequencing, FXS testing is more suitable as a second-tier choice and provides clinicians and geneticists with auxiliary references for tracing the etiology of ID/GDD.

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30. Zhang Y, Qin B, Wang L, Chen J, Cai J, Li T. Sex differences of language abilities of preschool children with autism spectrum disorder and their anatomical correlation with Broca and Wernicke areas. Front Pediatr;2022;10:762621.

OBJECTIVE: People with autism spectrum disorder (ASD) often have language difficulties. This study focuses on whether there are sex differences in language ability in children with ASD and aims to analyze whether such differences may arise from developmental imbalances in the anatomical structures of Broca and Wernicke areas. METHODS: The language development quotient (DQ) scores of Gesell Developmental Scale (GDS) and the scores of language communication of Childhood Autism Rating Scale (CARS) were used to judge the language ability, and the FREESURFER software extracted the anatomical structures of Broca and Wernicke areas on 3DT1 sequences. We analyzed the correlation between the anatomical structure of Broca/Wernicke areas and language abilities assessments. RESULTS: The study initially included 44 cases of ASD, with 36 males (81.8 %) and 8 females (18.2%), and the age range was 24-72 months. Males have better language abilities than females. Specifically, the GDS verbal DQ of males was significantly higher than that of females (56.50 ± 18.02 vs. 29.23 ± 6.67, p < 0.001). Broca thickness-L was positively correlated with verbal DQ scores in GDS (r = 0.382, p = 0.011) and lower than grade 2 and 3 on the CARS verbal communication grade 4 (5.76 ± 0.17 vs. 6.21 ± 0.30 and 6.11 ± 0.35), with statistically significant differences between groups (p < 0.05). CONCLUSION: There were sex differences in the language abilities of preschoolers with ASD, which may be due to an imbalance development of certain structures in Broca and Wernicke areas, especially Broca area.

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31. Zhao F, Zhang H, Wang P, Cui W, Xu K, Chen D, Hu M, Li Z, Geng X, Wei S. Oxytocin and serotonin in the modulation of neural function: Neurobiological underpinnings of autism-related behavior. Front Neurosci;2022;16:919890.

Autism spectrum disorders (ASD) is a group of generalized neurodevelopmental disorders. Its main clinical features are social communication disorder and repetitive stereotyped behavioral interest. The abnormal structure and function of brain network is the basis of social dysfunction and stereotyped performance in patients with autism spectrum disorder. The number of patients diagnosed with ASD has increased year by year, but there is a lack of effective intervention and treatment. Oxytocin has been revealed to effectively improve social cognitive function and significantly improve the social information processing ability, empathy ability and social communication ability of ASD patients. The change of serotonin level also been reported affecting the development of brain and causes ASD-like behavioral abnormalities, such as anxiety, depression like behavior, stereotyped behavior. Present review will focus on the research progress of serotonin and oxytocin in the pathogenesis, brain circuit changes and treatment of autism. Revealing the regulatory effect and neural mechanism of serotonin and oxytocin on patients with ASD is not only conducive to a deeper comprehension of the pathogenesis of ASD, but also has vital clinical significance.

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