1. Ahring PK, Liao VWY, Gardella E, Johannesen KM, Krey I, Selmer KK, Stadheim BF, Davis H, Peinhardt C, Koko M, Coorg RK, Syrbe S, Bertsche A, Santiago-Sim T, Diemer T, Fenger CD, Platzer K, Eichler EE, Lerche H, Lemke JR, Chebib M, Møller RS. Gain-of-function variants in GABRD reveal a novel pathway for neurodevelopmental disorders and epilepsy. Brain;2022 (May 24);145(4):1299-1309.

A potential link between GABRD encoding the δ subunit of extrasynaptic GABAA receptors and neurodevelopmental disorders has largely been disregarded due to conflicting conclusions from early studies. However, we identified seven heterozygous missense GABRD variants in 10 patients with neurodevelopmental disorders and generalized epilepsy. One variant occurred in two sibs of healthy parents with presumed somatic mosaicism, another segregated with the disease in three affected family members, and the remaining five occurred de novo in sporadic patients. Electrophysiological measurements were used to determine the functional consequence of the seven missense δ subunit variants in receptor combinations of α1β3δ and α4β2δ GABAA receptors. This was accompanied by analysis of electroclinical phenotypes of the affected individuals. We determined that five of the seven variants caused altered function of the resulting α1β3δ and α4β2δ GABAA receptors. Surprisingly, four of the five variants led to gain-of-function effects, whereas one led to a loss-of-function effect. The stark differences between the gain-of-function and loss-of function effects were mirrored by the clinical phenotypes. Six patients with gain-of-function variants shared common phenotypes: neurodevelopmental disorders with behavioural issues, various degrees of intellectual disability, generalized epilepsy with atypical absences and generalized myoclonic and/or bilateral tonic-clonic seizures. The EEG showed qualitative analogies among the different gain-of-function variant carriers consisting of focal slowing in the occipital regions often preceding irregular generalized epileptiform discharges, with frontal predominance. In contrast, the one patient carrying a loss-of-function variant had normal intelligence and no seizure history, but has a diagnosis of autism spectrum disorder and suffers from elevated internalizing psychiatric symptoms. We hypothesize that increase in tonic GABA-evoked current levels mediated by δ-containing extrasynaptic GABAA receptors lead to abnormal neurotransmission, which represent a novel mechanism for severe neurodevelopmental disorders. In support of this, the electroclinical findings for the gain-of-function GABRD variants resemble the phenotypic spectrum reported in patients with missense SLC6A1 (GABA uptake transporter) variants. This also indicates that the phenomenon of extrasynaptic receptor overactivity is observed in a broader range of patients with neurodevelopmental disorders, because SLC6A1 loss-of-function variants also lead to overactive extrasynaptic δ-containing GABAA receptors. These findings have implications when selecting potential treatment options, as a substantial portion of available antiseizure medication act by enhancing GABAergic function either directly or indirectly, which could exacerbate symptoms in patients with gain-of-function GABRD variants.

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2. Bader O, Fuchs T. Gestalt Perception and the Experience of the Social Space in Autism: A Case Study. Psychopathology;2022 (May 24):1-8.

Phenomenological approaches suggest that the bodily presence of others has a profound influence on the experience of social spaces. This intimate relationship is particularly evident in mental disorders. Investigations into the nature of intersubjectivity in various pathologies indicate that modifications to the capacity for social perception play a key role in determining the manners in which the social space is experienced and felt. This paper aims to examine the interviewing relation of social perception and the experience of space and its consequences in autism spectrum disorder (ASD). This is done through a phenomenologically informed analysis of the functioning of social perception in ASD. Our account proposes that the atypical socio-perceptual patterns exhibited by people with autism significantly reduce the capacity to grasp the context of the situation, which facilitates and intensifies negative feelings that are intertwined with the experience of social spaces. This novel understanding draws on the idea that ASD involves a fundamental difficulty to establish a gestalt perception of social scenes. The evidence we discuss suggests that this anomaly in the operation of social perception also modulates the experience of the social space. Failing to perceive the wholeness of the situation means that people with autism often experience the social space as unfamiliar, confusing, uncertain, and unsafe, rather than feeling familiar and understood in the embodied presence of others. As a result, autistic subjects may experience difficulty evaluating the outcomes of hazardous circumstances, which poses a risk to their well-being, particularly in borderline situations. This suggestion is elaborated through the tragic occurrences that led to the killing of Eyad al-Hallaq, a 32-year-old Palestinian with autism.

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3. Brian J, Solish A, Dowds E, Roth I, Bernardi K, Perry K, Daoud S, Jilderda S, MacWilliam S, Smith IM, Zwaigenbaum L, Bryson S. « Going Mobile »-increasing the reach of parent-mediated intervention for toddlers with ASD via group-based and virtual delivery. J Autism Dev Disord;2022 (May 24):1-14.

Evidence supports early intervention for toddlers with ASD, but barriers to access remain, including system costs, workforce constraints, and a range of family socio-demographic factors. An urgent need exists for innovative models that maximize resource efficiency and promote widespread timely access. We examined uptake and outcomes from 82 families participating in a parent-mediated intervention comprising group-based learning and individual coaching, delivered either in-person (n = 45) or virtually (n = 37). Parents from diverse linguistic, ethnic, and educational backgrounds gained intervention skills and toddlers evidenced significant social-communication gains. Few differences emerged across socio-demographic factors or delivery conditions. Findings highlight the feasibility, acceptability, and promise of group-based learning when combined with individual coaching, with added potential to increase program reach via virtual delivery.

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4. Cao LH, He HJ, Zhao YY, Wang ZZ, Jia XY, Srivastava K, Miao MS, Li XM. Food Allergy-Induced Autism-Like Behavior is Associated with Gut Microbiota and Brain mTOR Signaling. J Asthma Allergy;2022;15:645-664.

PURPOSE: Food allergy-induced autism-like behavior has been increasing for decades, but the causal drivers of this association are unclear. We sought to test the association of gut microbiota and mammalian/mechanistic target of rapamycin (mTOR) signaling with cow’s milk allergy (CMA)-induced autism pathogenesis. METHODS: Mice were sensitized intragastrically with whey protein containing cholera toxin before sensitization on intraperitoneal injection with whey-containing alum, followed by intragastric allergen challenge to induce experimental CMA. The food allergic immune responses, ASD-like behavioral tests and changes in the mTOR signaling pathway and gut microbial community structure were performed. RESULTS: CMA mice showed autism-like behavioral abnormalities and several distinct biomarkers. These include increased levels of 5-hydroxymethylcytosine (5-hmC) in the hypothalamus; c-Fos were predominantly located in the region of the lateral orbital prefrontal cortex (PFC), but not ventral; decreased serotonin 1A in amygdala and PFC. CMA mice exhibited a specific microbiota signature characterized by coordinate changes in the abundance of taxa of several bacterial genera, including the Lactobacillus. Interestingly, the changes were accompanied by promoted mTOR signaling in the brain of CMA mice. CONCLUSION: We found that disease-associated microbiota and mTOR activation may thus play a pathogenic role in the intestinal, immunological, and psychiatric Autism Spectrum Disorder (ASD)-like symptoms seen in CAM associated autism. However, this is only a preliminary study, and their mechanisms require further investigation.

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5. Castellani J, Kimbute O, Makasi C, Mrango ZE, Paulus ATG, Evers S, Hardy P, Sumner T, Keiya A, Mihaylova B, Faiz MA, Gomes M. Daily Life and Challenges Faced By Households With Permanent Childhood Developmental Disability in Rural Tanzania – A Qualitative Study. J Dev Phys Disabil;2022 (Jun);34(3):471-490.

Severe developmental disability in children affects the life of the child and entire household. We conducted a qualitative study to understand how caregivers manage severe developmental disabilities in children in rural Africa. Families and six children (out of 15 children) who had serious permanent sequelae from a cerebral infection in Handeni, Tanzania, were contacted and invited to a workshop to recount their experience living with severe developmental disabilities. After consent, individual interviews were conducted first through recording of individual digital stories and then through individual semi-structured interviews. Pre-determined key categories were used to analyse the data. Our results showed that developmental disabilities required constant care and reduced the autonomy of the children. Schooling had not been attempted or was halted because of learning problems or inability to meet specialized school costs. Parents were under constant physical, emotional and financial stress. Their occupational earnings decreased. Some families sold their assets to survive. Others began to rely on relatives. Understanding the consequences of developmental disability helps to identify where social support should be focused and improved.

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6. Caubit X, Gubellini P, Roubertoux PL, Carlier M, Molitor J, Chabbert D, Metwaly M, Salin P, Fatmi A, Belaidouni Y, Brosse L, Kerkerian-Le Goff L, Fasano L. Correction: Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors. Transl Psychiatry;2022 (May 23);12(1):211.

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7. Cervantes PE, Brown DS, Horwitz SM. Suicidal ideation and intentional self-inflicted injury in autism spectrum disorder and intellectual disability: An examination of trends in youth emergency department visits in the United States from 2006 to 2014. Autism;2022 (May 24):13623613221091316.

Youth suicide is a major problem in the United States and globally, but little is known about suicide risk in autistic youth and youth with intellectual disability specifically. Using data from the National Emergency Department Sample, which is the largest database of emergency department visits in the United States, we found that emergency department visits with a suicidal ideation or intentional self-inflicted injury diagnosis were more common in autistic youth and youth with intellectual disability than in youth without these diagnoses (i.e. the comparison group). This was true when examining both suicidal ideation diagnoses and intentional self-inflicted injury diagnoses at emergency department visits. In addition, the number of emergency department visits with a suicidal ideation or intentional self-inflicted injury diagnosis increased more from 2006 to 2014 in autistic youth and youth with intellectual disability compared with the comparison group. We also found both similarities and differences when examining factors, such as age, sex, and co-occurring mental health conditions, related to emergency department visits with a suicidal ideation or intentional self-inflicted injury diagnosis across groups that may be helpful for understanding suicide risk. It is urgent that we improve our understanding, assessment, and treatment of suicidality and self-harm in these groups through more research and clinical efforts.

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8. Choueiri R, Garrison WT, Tokatli V. Early Identification of Autism Spectrum Disorder (ASD): Strategies for Use in Local Communities. Indian J Pediatr;2022 (May 23):1-10.

Early diagnosis of autism spectrum disorder (ASD) is essential for improved outcomes. There is a paucity of data on the prevalence of ASD in low- and middle-income countries (LMIC), but early identification may be further delayed in those communities. In this paper, recent studies on strategies for the early detection of ASD, and the prevalence of ASD in LMIC are reviewed. The limitations that can arise in the early identification of ASD in LMIC communities are discussed, and screening tools and strategies that can be helpful are identified. The goal is to recommend models that are culturally appropriate and scientifically valid, easily integrated within community settings while strengthening community systems and reducing disparities in the early identification of ASD. Starting locally by simplifying and demystifying the ASD identification process and building community connections will inform global researchers and policymakers while making a difference in the lives of the children and families affected by ASD.

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9. Desroches ML, Fisher K, Ailey S, Stych J, McMillan S, Horan P, Marsden D, Trip H, Wilson N. Supporting the needs of people with intellectual and developmental disabilities 1 year into the COVID-19 pandemic: An international, mixed methods study of nurses’ perspectives. J Policy Pract Intellect Disabil;2022 (Mar);19(1):48-63.

As the largest public health crisis within a century, the COVID-19 pandemic has caused long-term disruption in the support systems of people with intellectual and developmental disabilities (IDD) across the globe. The purpose of this study was to investigate challenges and ameliorative strategies to supporting the basic care needs of people with IDD 1 year into the pandemic, as experienced by nurses who specialize in IDD nursing. We surveyed a convenience sample of 369 nurses from across North America, Europe, and Australasia using a 52-item online questionnaire. Descriptive statistics were used to rank the greatest challenges and the degree of support available to nurses, and manifest content analysis was used to analyze open-ended responses related to ongoing challenges and ameliorative strategies. Results of descriptive analyses revealed consistent findings across global regions in terms of the challenges faced by nurses; the greatest challenges related to supporting or enabling socialization with family/friends, ensuring adequate day programming or educational services, identifying/planning alternative entertainment activities, ensuring adequate staffing of familiar support workers and caregivers, and managing challenging behaviors related to change in daily routine and activities. Nurses described a considerable degree of support offered by their organizations in terms of flexibility in scheduling related to family obligations and paid time off for COVID-19-related isolation and quarantine. Content analysis of open-ended survey responses revealed numerous challenges related to: (1) client socialization, meaningful activity, and mental/behavioral health; (2) interpreting, keeping up with, and helping others to understand COVID-19 guidelines; (3) access to, quality of, and continuity of care; and (4) COVID-19 fatigue and the influence of time. Overall, our study highlights ongoing issues with access to care and support, exacerbated by the pandemic, and the importance of having meaningful activity and socialization for overall well-being of people with IDD during a long-term public health crisis.

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10. Gowda VK, Srinivasan VM. A Treatable Cause of Global Developmental Delay with Autism Spectrum Disorder Due to Cobalamin Related Remethylation Disorder. Indian J Pediatr;2022 (May 23)

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11. He R. The Intervention of Music Therapy on Behavioral Training of High-Functioning Autistic Children under Intelligent Health Monitoring. Appl Bionics Biomech;2022;2022:5766617.

Autism is a serious and widespread developmental disorder in children. With the increase of autistic children every year, it is necessary to study a set of effective music therapy activities that can penetrate into life to help autistic children’s rehabilitation training. This paper aims to study the behavioral training of high-functioning autistic children with music therapy intervention under intelligent health monitoring. The autistic children were selected and divided into experimental group and control group. According to the psychological and physiological characteristics of five autistic children aged 5-7 years in the experimental group, the music therapy activity plan was designed, and the experimental intervention was carried out by combining individual music therapy and group music therapy. Compared with the control group, this paper explores the effect of music on the treatment of children with autism. The experimental results of this paper show that the language, social, cognitive, and behavioral problems of autistic children under music therapy under intelligent health monitoring have been significantly improved, and their emotional response ability has improved the most, increasing by 34%. Communication ability was next, increased by 20.3%; motor coordination ability increased by 20%; and cognitive ability improved by 11%. It can be explained that the four aspects of language, social interaction, cognition, and behavior have been significantly improved after music therapy.

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12. Heller Murray ES, Segawa J, Karahanoglu FI, Tocci C, Tourville JA, Nieto-Castanon A, Tager-Flusberg H, Manoach DS, Guenther FH. Increased Intra-Subject Variability of Neural Activity During Speech Production in People with Autism Spectrum Disorder. Res Autism Spectr Disord;2022 (Jun);94

BACKGROUND: Communication difficulties are a core deficit in many people with autism spectrum disorder (ASD). The current study evaluated neural activation in participants with ASD and neurotypical (NT) controls during a speech production task. METHODS: Neural activities of participants with ASD (N = 15, M = 16.7 years, language abilities ranged from low verbal abilities to verbally fluent) and NT controls (N = 12, M = 17.1 years) was examined using functional magnetic resonance imaging with a sparse-sampling paradigm. RESULTS: There were no differences between the ASD and NT groups in average speech activation or inter-subject run-to-run variability in speech activation. Intra-subject run-to-run neural variability was greater in the ASD group and was positively correlated with autism severity in cortical areas associated with speech. CONCLUSIONS: These findings highlight the importance of understanding intra-subject neural variability in participants with ASD.

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13. Jurin A, Šimleša S, Cepanec M. Parental perception of the process of communicating a diagnosis of autism spectrum disorder in the Republic of Croatia. Clin Child Psychol Psychiatry;2022 (May 23):13591045221105191.

The process of communicating a diagnosis of an autism spectrum disorder (ASD) stands out as the first important factor when confronting parents with such a diagnosis for their child. The situation in which a child is diagnosed with ASD is viewed as certainly one of the most stressful moments for parents. Previous research has indicated several factors that affect the positivity of parents’ experiences. Therefore, the aim of the current study was to examine the experiences of parents in the Republic of Croatia concerning the process of communicating a diagnosis of ASD to them and to show the satisfaction level of parents with the characteristics of this procedure. The study involved 52 parents of children who were either suspected of having or diagnosed with ASD. For the purposes of the research, a questionnaire was constructed. The results showed a relatively high degree of parental satisfaction with the process of communicating a diagnosis of ASD. A significant correlation was found between parental satisfaction and the presence of positive characteristics in both the diagnostic process and communicating the diagnosis. However, the results also indicated that there is much room for improvement regarding the conditions and manner of expressing this unwanted news.

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14. Khalifa N, Hawken ER, Bickle A, Cabrera M, Heath T, Drury A, Jones J, Ayub M. The use of transcranial direct current stimulation (tDCS) to reduce impulsivity and aggression in adults with mild intellectual developmental disabilities: the tDCS-RIADD randomised controlled trial protocol. Trials;2022 (May 23);23(1):431.

BACKGROUND: Challenging behaviours, in particular aggressive behaviours, are prevalent among people with intellectual developmental disabilities. Predictors of challenging behaviours are numerous, including past history of aggression, poor coping skills and impulsivity. Factors like motor or rapid-response impulsivity (RRI) have neurobiological underpinnings that may be amenable to change via neuromodulation using non-invasive brain stimulation techniques like transcranial direct current stimulation (tDCS). METHODS: This study aims to determine the efficacy of anodal tDCS in reducing RRI and incidents of aggression in people with intellectual developmental disabilities (IDD) in residential or hospital settings. Using a single blind, randomised, sham-controlled trial design, adults with IDD, with a history of impulsivity leading to aggression, will be randomised to receive either repetitive anodal or sham tDCS applied to the left dorsolateral prefrontal cortex. Outcome measures assessing impulsivity and aggression will be collected for up to 1 month following the last tDCS session. DISCUSSION: The results of this study may pave the way for developing targeted interventions for impulsivity and aggressive behaviours in people with IDD.

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15. Kim JA, Kwon WK, Kim JW, Jang JH. Variation spectrum of MECP2 in Korean patients with Rett and Rett-like syndrome: a literature review and reevaluation of variants based on the ClinGen guideline. J Hum Genet;2022 (May 24)

Rett syndrome (RTT) is a progressive neurodevelopmental disorder caused by variants in MECP2. Emerging evidence of ethnic specificity of genetic variations has allowed precise diagnostic approaches with tailored therapies. In this study, we reviewed the variation spectrum of MECP2 in Korean RTT(-like) patients and compared it with previous reports in multiple ethnic groups. We reevaluated variants found in Korean RTT patients according to the new Clinical Genome Resource guideline to reinterpret and reclassify variants of uncertain significance in MECP2. Among 377 cases, 56 (14.9%) showed pathogenic variants, and three novel variants, p.(Ala277Argfs*7), p.(Ala378Glyfs*8), and p.(Arg270_Ser332del), were identified. Comprehensive data from Korea revealed an overall consistent variation spectrum with those from other ethnicities. Through the reevaluation of variants, nine that previously had insufficient evidence for pathogenicity were reclassified into pathogenic variants. Our study provided insight on the genetic contribution of MECP2 in RTT and a useful background for genetic counseling in the Korean population.

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16. Kushima M, Yamagata Z. Screen Timing May Be More Likely Than Screen Time to Be Associated With the Risk of Autism Spectrum Disorder-Reply. JAMA Pediatr;2022 (May 23)

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17. Lin YH, Lin SH, Gau SS. Screen Timing May Be More Likely Than Screen Time to Be Associated With the Risk of Autism Spectrum Disorder. JAMA Pediatr;2022 (May 23)

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18. Meng J, Han L, Zheng N, Wang T, Xu H, Jiang Y, Wang Z, Liu Z, Zheng Q, Zhang X, Luo H, Can D, Lu J, Zhang YW. Microglial Tmem59 Deficiency Impairs Phagocytosis of Synapse and Leads to Autism-Like Behaviors in Mice. J Neurosci;2022 (May 20)

Synaptic abnormality is an important pathologic feature of autism spectrum disorders (ASDs) and responsible for various behavioral defects in these neurodevelopmental disorders. Microglia are the major immune cells in the brain and also play an important role in synapse refinement. Although dysregulated synaptic pruning by microglia during the brain development has been associated with ASDs, the underlying mechanism has yet to be fully elucidated. Herein, we observed that expression of Transmembrane protein 59 (TMEM59), a protein recently shown to regulate microglial function, was decreased in autistic patients. Furthermore, we found that both male and female mice with either complete or microglia-specific loss of Tmem59 developed ASD-like behaviors. Microglial TMEM59-deficient mice also exhibited enhanced excitatory synaptic transmission, increased dendritic spine density, and elevated levels of excitatory synaptic proteins in synaptosomes. TMEM59-deficient microglia had impaired capacity for synapse engulfment both in vivo and in vitro. Moreover, we demonstrated that TMEM59 interacted with the C1q receptor CD93 and TMEM59 deficiency promoted CD93 protein degradation in microglia. Downregulation of CD93 in microglia also impaired synapse engulfment. These findings identify a crucial role of TMEM59 in modulating microglial function on synapse refinement during brain development and suggest that TMEM59 deficiency may contribute to ASDs through disrupting phagocytosis of excitatory synapse and thus distorting the excitatory-inhibitory (E/I) neuronal activity balance.SIGNIFICANCE STATEMENTMicroglia play an important role in synapse refinement. Dysregulated synaptic pruning by microglia during brain development has been associated with autism spectrum disorders (ASDs). However, the underlying mechanism has yet to be fully elucidated. Herein, we observe that the expression of Transmembrane protein 59 (TMEM59), an autophagy-related protein, is decreased in autistic patients. Moreover, we find ASD-like behaviors in mice with complete loss and with microglia-specific loss of Tmem59 Mechanistic studies reveal that TMEM59 deficiency in microglia impairs their synapse engulfment ability likely through destabilizing the C1q receptor CD93, thereby leading to enhanced excitatory neurotransmission and increased dendritic spine density. Our findings demonstrate a crucial role of microglial TMEM59 in early neuronal development and provide new insight into the etiology of ASDs.

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19. Morris SL, Vollmer TR. The matching law provides a quantitative description of social time allocation in children with autism. J Appl Behav Anal;2022 (May 24)

Recent research has developed and evaluated assessments of sociability in which time allocation near or away from an adult who initiates social interactions is used to characterize the participant as social, indifferent, or avoidant of social interaction. Though these qualitative outcomes have been useful, no studies have evaluated methods of obtaining more quantitative measures of sociability. The matching law has been demonstrated to describe a wide range of human behavior and may also be useful in describing social time allocation. We adapted the matching law and assessment of sociability procedures with the aim of providing a more precise, quantitative measure of sociability. We fitted the matching equation to the social time allocation data of 8 children with autism spectrum disorder. The equation was effective in quantifying sociability, accounted for a large proportion of variance in participants’ behavior, did so equally well for participants who were social and avoidant, and provided a more sensitive measure relative to those used in previous research. The implications of this methodology, its potential utility, and directions for future research are discussed.

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20. Nakahara K, Michikawa T, Morokuma S, Hamada N, Ogawa M, Kato K, Sanefuji M, Shibata E, Tsuji M, Shimono M, Kawamoto T, Ohga S, Kusuhara K. Association of physical activity and sleep habits during pregnancy with autistic spectrum disorder in 3-year-old infants. Commun Med (Lond);2022;2:35.

BACKGROUND: We hypothesized that maternal lifestyle factors, such as physical activity and sleep habits, may be associated with autism spectrum disorder (ASD) in infants. This study aimed to investigate the association between maternal physical activity and sleep before and during pregnancy with infant ASD diagnosed by the age of 3 years. METHODS: We used the data from the Japan Environment and Children’s Study between 2011 and 2014. The study included 103,060 pregnant women, among which, 69,969 women were analyzed. Participants were asked about their physical activity and sleep before and during pregnancy using questionnaires during pregnancy. Maternal physical activity was estimated using the international physical activity questionnaire. Based on the levels of physical activity before or during pregnancy, the participants were divided into five groups. Maternal sleep was analyzed based on sleep duration and bedtime. The outcome was diagnosis of ASD in 3-year-old infants. RESULTS: In mothers with higher physical activity levels during pregnancy, the risk ratios (RR) for ASD in their 3-year-old infants were lower (RR = 0.61, 95% confidence interval (CI) = 0.42-0.90). In contrast, too short (<6 h) and too long (>10 h) sleep durations during pregnancy were associated with higher risk ratios for ASD than 7-8 h sleep duration (too short: RR = 1.87, 95% CI = 1.21-2.90; too long: RR = 1.56, 95% CI = 1.00-2.48). These associations were not observed before pregnancy. CONCLUSION: Maternal physical activity and sleep duration during pregnancy may be associated with ASD in infants.

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21. Peng L, Liu X, Ma D, Chen X, Xu X, Gao X. The Altered Pattern of the Functional Connectome Related to Pathological Biomarkers in Individuals for Autism Spectrum Disorder Identification. Front Neurosci;2022;16:913377.

OBJECTIVE: Autism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by the development of multiple symptoms, with incidences rapidly increasing worldwide. An important step in the early diagnosis of ASD is to identify informative biomarkers. Currently, the use of functional brain network (FBN) is deemed important for extracting data on brain imaging biomarkers. Unfortunately, most existing studies have reported the utilization of the information from the connection to train the classifier; such an approach ignores the topological information and, in turn, limits its performance. Thus, effective utilization of the FBN provides insights for improving the diagnostic performance. METHODS: We propose the combination of the information derived from both FBN and its corresponding graph theory measurements to identify and distinguish ASD from normal controls (NCs). Specifically, a multi-kernel support vector machine (MK-SVM) was used to combine multiple types of information. RESULTS: The experimental results illustrate that the combination of information from multiple connectome features (i.e., functional connections and graph measurements) can provide a superior identification performance with an area under the receiver operating characteristic curve (ROC) of 0.9191 and an accuracy of 82.60%. Furthermore, the graph theoretical analysis illustrates that the significant nodal graph measurements and consensus connections exists mostly in the salience network (SN), default mode network (DMN), attention network, frontoparietal network, and social network. CONCLUSION: This work provides insights into potential neuroimaging biomarkers that may be used for the diagnosis of ASD and offers a new perspective for the exploration of the brain pathophysiology of ASD through machine learning.

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22. Petriv T, Tatarchuk M, Skuratov A, Rybachuk O, Tsymbaliuk V. Safety of Combined Autistic Spectrum Disorders Treatment with Umbilical Cord Mesenchymal Stem Cells Application: Clinical Investigation. Stem Cells Transl Med;2021 (Sep 1);10(S1):S10.

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23. Qu J, Liu Z, Li L, Zou Z, He Z, Zhou L, Luo Y, Zhang M, Ye J. Efficacy and Safety of Stem Cell Therapy in Children With Autism Spectrum Disorders: A Systematic Review and Meta-Analysis. Front Pediatr;2022;10:897398.

AIM: There is insufficient evidence regarding the efficacy and safety of stem cell therapy for autism spectrum disorders. We performed the first meta-analysis of stem cell therapy for autism spectrum disorders in children to provide evidence for clinical rehabilitation. METHODS: The data source includes PubMed/Medline, Web of Science, EMBASE, Cochrane Library and China Academic Journal, from inception to 24th JULY 2021. After sifting through the literature, the Cochrane tool was applied to assess the risk of bias. Finally, we extracted data from these studies and calculated pooled efficacy and safety. RESULTS: 5 studies that met the inclusion criteria were included in current analysis. Meta-analysis was performed using rehabilitation therapy as the reference standard. Data showed that the Childhood Autism Rating Scale score of stem cell group was striking lower than the control group (WMD: -5.96; 95%CI [-8.87, -3.06]; p < 0.0001). The Clinical Global Impression score consolidated effect size RR = 1.01, 95%CI [0.87, 1.18], Z = 0.14 (p = 0.89), the effective rate for The Clinical Global Impression was 62% and 60% in the stem cell group and the control group, respectively. The occurrence events of adverse reactions in each group (RR = 1.55; 95%CI = 0.60 to 3.98; p = 0.36), there was no significant difference in the incidence of adverse reactions between the stem cell group and the control group. CONCLUSIONS: The results of this meta-analysis suggested that stem cell therapy for children with autism might be safe and effective. However, the evidence was compromised by the limitations in current study size, lacking standardized injection routes and doses of stem cells, as well as shortages in diagnostic tools and long period follow-up studies. Hence, it calls for more studies to systematically confirm the efficacy and safety of stem cell therapy for children with autism spectrum disorders.

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24. Roshini R, Jason BM, Marta IG. Increased context adjustment is associated with auditory sensitivities but not with autistic traits. Autism Res;2022 (May 24)

Bayesian models of autism suggest that alterations in context-sensitive prediction error weighting may underpin sensory perceptual alterations, such as hypersensitivities. We used an auditory oddball paradigm with pure tones arising from high or low uncertainty contexts to determine whether autistic individuals display differences in context adjustment relative to neurotypicals. We did not find group differences in early prediction error responses indexed by mismatch negativity. A dimensional approach revealed a positive correlation between context-dependent prediction errors and subjective reports of auditory sensitivities, but not with autistic traits. These findings suggest that autism studies may benefit from accounting for sensory sensitivities in group comparisons. LAY SUMMARY: We aimed to understand if autistic and non-autistic groups showed differences in their electrical brain activity measured by electroencephalography (EEG) when listening to surprising tones infrequently embedded in a statistical pattern. We found no differences between the autistic and the non-autistic group in their EEG response to the surprising sound even if the pattern switched, indicating their ability to learn a pattern. We did find that, as subjective sensory sensitivities (but not autistic traits) increased, there were increasingly large differences between the EEG responses to surprising tones that were embedded in the different statistical patterns of tones. These findings show that perceptual alterations may be a function of sensory sensitivities, but not necessarily autistic traits. We suggest that future EEG studies in autism may benefit from accounting for sensory sensitivities.

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25. Salehi F, Jaloli M, Coben R, Nasrabadi AM. Estimating brain effective connectivity from EEG signals of patients with autism disorder and healthy individuals by reducing volume conduction effect. Cogn Neurodyn;2022 (Jun);16(3):519-529.

Studying brain connectivity has shed light on understanding brain functions. Electroencephalogram signals recorded from the scalp surface comprise inter-dependent multi-channel signals each of which is a linear combination of simultaneously active brain sources as well as adjacent non-brain sources whose activity is widely volume conducted to the scalp through overlapping patterns. Evaluation of brain connectivity based on multivariate autoregressive (MVAR) model identification from neurological time series can be a proper tool for brain signal analysis. However, the MVAR model only considers the lagged influences between time series while ignoring the instantaneous effects (zero-lagged interactions) among simultaneously recorded neurological signals. Hence predicting instant interactions may result in fake connectivity, which may lead to misinterpreting in results. In this study, we aim to find instantaneous effects from coefficients of the MVAR model acquired using an ADALINE neural network and investigate the efficiency of the proposed algorithm by applying it to a simulated signal. We show that our coefficients are estimated accurately from channels of the simulated signal. Moreover, we apply the proposed method on a dataset of a group of 18 healthy children and 10 children with autism by comparing their effective connectivity estimated by direct directed transfer function method using new and old coefficients. Finally, to show the efficiency of the algorithm we exploit the support vector machine method for classifying the dataset. We show that there is a significant improvement in the results obtained from the proposed method.

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26. Slanzi CM, Vollmer TR, Iwata BA, Kronfli FR, Williams LP, Perez BC. Further evaluation of functional analysis screening methods in early autism intervention. J Appl Behav Anal;2022 (May 24)

A goal of some functional analysis (FA) variations is to reduce assessment time while still maintaining efficacy. This may be especially important when conducting FAs in early intervention programs, where time is a crucial commodity. To that end, we evaluated a model for using the results of the no-interaction condition as a screening for behavioral function and to guide selection of FA test conditions with 20 participants (22 assessments) aged 3 to 7 years old. We used the no-interaction condition to develop hypotheses for both automatic reinforcement and socially mediated reinforcement. The outcome of the no-interaction condition guided the selection of test conditions for the remainder of the FA. We also incorporated methods from prior FA studies (e.g., divided attention) to modify the test conditions. We obtained differentiated results in 91% of assessments, all within 70 min and, as such, extended evidence that an FA can be completed in little time without sacrificing efficacy.

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27. Stickley A, Shirama A, Kamio Y, Takahashi H, Inagawa T, Saito A, Sumiyoshi T. Association between autistic traits and binge drinking: Findings from Japan. Soc Psychiatry Psychiatr Epidemiol;2022 (May 24)

PURPOSE: Substance misuse may be elevated in some individuals with autism spectrum disorder (ASD). As yet, however, little is known about the association between autistic traits (AT) and substance use/misuse in adults. This study examined the association between AT and binge drinking (BD) among individuals in Japan. METHODS: Data were analyzed from 1452 individuals aged 18 and above collected during an online survey in February 2021. Self-reported information was obtained on BD assessed as consuming 5 or more (males) or 4 or more (females) drinks containing any kind of alcohol within a 2-h period. AT were assessed with the Japanese version of the Autism Spectrum Quotient – the AQ-J-10. Logistic regression analysis was used to examine associations. RESULTS: The prevalence of past-month BD was significantly higher in individuals with AT compared to those without AT (42.7% > 27.6%). In a fully adjusted analysis that controlled for mental health (anxiety, depression) and attention-deficit/hyperactivity disorder symptoms, individuals with AT had significantly higher odds for BD once a week or more often (OR: 1.54, 95%CI: 1.04-2.29). AT were also associated with significantly higher odds for BD among women (OR: 2.27, 95%CI: 1.08-4.76), and those aged 18-34 (OR: 2.37, 95%CI: 1.09-5.18) and aged 60 and above (OR: 2.15, 95%CI: 1.02-4.53). CONCLUSION: Individuals with AT have higher odds for BD. Increased efforts to detect alcohol use/misuse in adults with AT and AT in adults misusing alcohol may be efficacious in efforts to manage symptoms and eliminate harmful alcohol misuse.

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28. Sullivan WF, Björne P, Heng J, Northway R. Ethics framework and recommendations to support capabilities of people with intellectual and developmental disabilities during pandemics. J Policy Pract Intellect Disabil;2022 (Mar);19(1):116-124.

A growing body of knowledge highlights the negative impact of the COVID-19 pandemic on the health and well-being of many people with intellectual and developmental disabilities (IDDs) and their caregivers. The underlying reasons are not only due to biomedical factors but also ethical issues. They stem from longstanding and pervasive structural injustices and negative social attitudes that continue to devalue people with IDD and that underlie certain clinical decisions and frameworks for public-health policies during this pandemic. Unless these fundamental ethical shortcomings are addressed, pandemic responses will continue to undermine the human rights and well-being of people with IDD. This paper proposes an ethics framing for policy and practices regarding clinical care and public health based on Martha Nussbaum’s approach to Capability Theory. Such a framework can reorient healthcare professionals and healthcare systems to support the capabilities of people with IDD to protect, recover, and promote health and well-being. It could be applied during this pandemic and in planning for future pandemics. The paper presents some practical recommendations that follow from applying this framework.

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29. Yoshida S, Amamoto M, Takahashi T, Tomita I, Yuge K, Hara M, Iwama K, Matsumoto N, Matsuishi T. Perampanel markedly improved clinical seizures in a patient with a Rett-like phenotype and 960-kb deletion on chromosome 9q34.11 including the STXBP1. Clin Case Rep;2022 (May);10(5):e05811.

Intractable epilepsy was successfully controlled using perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptor antagonist, in a 27-year-old woman who presented with a Rett syndrome-like phenotype and novel 960-kb deletion involving syntaxin-binding protein 1 on chromosome 9q34.11. Perampanel may be an effective antiepileptic drug for intractable epilepsy associated with STXBP1 mutations.

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30. Zhao L, Li Y, Kou X, Chen B, Cao J, Li J, Zhang J, Wang H, Zhao J, Shi S. Stem Cells from Human Exfoliated Deciduous Teeth Ameliorate Autistic-Like Behaviors of SHANK3 Mutant Beagle Dogs. Stem Cells Transl Med;2022 (May 24)

Mesenchymal stem cell-based therapy has emerged as a great potential approach to treat individuals with autism spectrum disorders (ASD), a group of developmental disabilities characterized by impairments in social interaction and communication. Stem cells from human exfoliated deciduous teeth (SHED), holding earlier developing characteristics, have immune-modulatory and anti-inflammatory properties. To investigate whether SHED transplantation can rescue autistic-like symptoms in SHANK3 mutant beagle dogs, 12 SHANK3 mutant beagle dogs were randomly assigned into 2 groups according to their behavior evaluated by social interaction tests. Six mutant dogs received 6 intravenous infusions of SHED and were followed up for 3 months by testing social interaction and inflammatory cytokine levels. We found that infusion of SHED significantly improved impaired social novel preference of SHANK3 mutant beagle dogs at 1- and 3-month follow-ups. Social intimacies (following, sniffing, and licking) between mutant beagle dogs and human experimenters were partly improved. Stressed tail posture, indicating social stress, was also significantly alleviated. In addition, we showed that the levels of serum interferon-γ and interleukin-10 were notably increased and decreased, respectively, in SHANK3 mutant beagle dogs. Infusion of SHED was able to rescue altered interferon-γ and interleukin-10 levels. We failed to observe any serious adverse events after infusion of SHED. In summary, SHED transplantation may be a safe and effective therapy for ASD. The correction in the levels of serum interferon-γ and interleukin-10 may serve as an index to predict autistic severity and therapeutic outcomes.

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31. Zhao M, Havrilla J, Peng J, Drye M, Fecher M, Guthrie W, Tunc B, Schultz R, Wang K, Zhou Y. Development of a phenotype ontology for autism spectrum disorder by natural language processing on electronic health records. J Neurodev Disord;2022 (May 23);14(1):32.

BACKGROUND: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by restricted, repetitive behavior, and impaired social communication and interactions. However, significant challenges remain in diagnosing and subtyping ASD due in part to the lack of a validated, standardized vocabulary to characterize clinical phenotypic presentation of ASD. Although the human phenotype ontology (HPO) plays an important role in delineating nuanced phenotypes for rare genetic diseases, it is inadequate to capture characteristic of behavioral and psychiatric phenotypes for individuals with ASD. There is a clear need, therefore, for a well-established phenotype terminology set that can assist in characterization of ASD phenotypes from patients’ clinical narratives. METHODS: To address this challenge, we used natural language processing (NLP) techniques to identify and curate ASD phenotypic terms from high-quality unstructured clinical notes in the electronic health record (EHR) on 8499 individuals with ASD, 8177 individuals with non-ASD psychiatric disorders, and 8482 individuals without a documented psychiatric disorder. We further performed dimensional reduction clustering analysis to subgroup individuals with ASD, using nonnegative matrix factorization method. RESULTS: Through a note-processing pipeline that includes several steps of state-of-the-art NLP approaches, we identified 3336 ASD terms linking to 1943 unique medical concepts, which represents among the largest ASD terminology set to date. The extracted ASD terms were further organized in a formal ontology structure similar to the HPO. Clustering analysis showed that these terms could be used in a diagnostic pipeline to differentiate individuals with ASD from individuals with other psychiatric disorders. CONCLUSION: Our ASD phenotype ontology can assist clinicians and researchers in characterizing individuals with ASD, facilitating automated diagnosis, and subtyping individuals with ASD to facilitate personalized therapeutic decision-making.

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