1. Alostaz J, Baker JK, Fenning RM, Neece CL, Zeedyk S. Parental coping as a buffer between child factors and emotion-related parenting in families of children with autism spectrum disorder. Journal of family psychology : JFP : journal of the Division of Family Psychology of the American Psychological Association (Division 43). 2022; 36(1): 153-8.

Parents of children with autism spectrum disorder (ASD) experience high levels of stress related to their children’s symptoms and comorbid behavior problems. Adaptive parental coping in response to child-related stressors is proposed to serve a buffering function, and yet, little research has examined whether coping actually moderates associations between child factors and parent outcomes in this population. The few studies to do so have focused on parent well-being as the primary outcome and have not considered the degree to which child-related stressors may affect parenting and contribute to maladaptive transactional parent-child processes over time. The present study tested whether adaptive parental coping was associated with reduced associations between higher levels of child ASD symptoms and comorbid externalizing problems and poorer quality parent reactions to child negative emotions in 63 families of children with ASD. Parents reported on their children’s externalizing problems, their own coping behavior, and their reactions to their children’s negative emotions, and child ASD symptoms were measured through direct testing. Adaptive coping-primarily active planning-moderated the association between children’s behavior problems and supportive parent reactions such that parents of children with more externalizing problems reported less supportive reactions, but only when adaptive coping was low. Child ASD symptoms did not significantly relate to parent reactions, and coping did not moderate these associations. This cross-sectional study is the first to identify parental coping as a potential protective factor for parenting behavior in families of children with ASD and comorbid behavior problems. Implications for future longitudinal research are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

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2. Bhavnani S, Lockwood Estrin G, Arora R, Kumar D, Kakra M, Vajaratkar V, Juneja M, Gulati S, Patel V, Green J, Divan G. « I was Confused … and Still am » Barriers Impacting the Help-Seeking Pathway for an Autism Diagnosis in Urban North India: A Mixed Methods Study. Journal of autism and developmental disorders. 2022; 52(4): 1778-88.

Timely recognition of autism in children is integral to improve developmental outcomes. This study used mixed-methods (84 case-registers and 20 in-depth interviews with caregivers of children with a diagnosis of autism) to explore the extent to which the nature of parental concerns and prior knowledge of developmental disorders impact the time between symptom recognition and autism diagnosis, and the contextual family, societal and health-system related factors that impede the autism help-seeking pathway. Lack of awareness of age-appropriate child developmental milestones, apparent amongst the community and health professionals, contributed to a 1.5-year delay between parental concerns and autism diagnosis. Recommendations to shorten this help-seeking pathway include harnessing the potential of non-specialist workers to increase awareness and enable developmental monitoring of young children through scalable tools.

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3. Çıkı K, Yıldız Y, Yücel Yılmaz D, Pektaş E, Tokatlı A, Özgül RK, Sivri HS, Dursun A. DNACJ12 deficiency in patients with unexplained hyperphenylalaninemia: two new patients and a novel variant. Metabolic brain disease. 2021; 36(6): 1405-10.

In addition to tetrahydrobiopterin deficiencies and phenylalanine hydroxylase deficiency (phenylketonuria) due to PAH variants, the deficiency of the co-chaperone protein DNAJC12 was identified in 2017 as a novel cause of inherited hyperphenylalaninemia, revealing the genetic etiology in previously unresolved cases. In this study, we aimed to investigate DNAJC12 deficiency in non-tetrahydrobiopterin-deficient persistent hyperphenylalaninemia cases without biallelic PAH variants in a single pediatric metabolic center. It was determined retrospectively that 471 patients with non-tetrahydrobiopterin deficiency-hyperphenylalaninemia had undergone PAH gene sequencing and 451 patients had biallelic variants in PAH. DNAJC12 sequencing was performed in the remaining 20 patients, identifying a previously reported homozygous splice-site variant (c.158-2A > T) in one patient with axial hypotonia and developmental delay, and a novel, homozygous c.404del (p.Arg135Lysfs*21) frameshift variant in an asymptomatic patient. In segregation analysis, the asymptomatic patient’s both parents were also found to be homozygous for this variant and hyperphenylalaninemic. The parents may have had academic difficulties but intellectual disability could not be confirmed due to lack of cooperation. The symptomatic patient significantly benefited from treatment with sapropterin dihydrochloride and neurotransmitter precursors. DNAJC12 deficiency might be responsible for approximately 10% or more of cases with unexplained hyperphenylalaninemia. The phenotypic spectrum is broad, ranging from early infantile hypotonia to incidental diagnosis in adulthood. Similar to tetrahydrobiopterin deficiencies, early diagnosis and treatment with sapropterin dihydrochloride and neurotransmitter precursors can be beneficial, supporting the analysis of DNACJ12 gene in patients with unexplained hyperphenylalaninemia.

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4. Desarkar P, Rajji TK, Ameis SH, Blumberger DM, Lai MC, Lunsky Y, Daskalakis ZJ. Assessing and stabilizing atypical plasticity in autism spectrum disorder using rTMS: Results from a proof-of-principle study. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2021.

OBJECTIVES: Emerging evidence implicates atypical plasticity in the neurophysiology of autism spectrum disorder (ASD). Specifically, autistic people demonstrated hyperplasticity in response to theta-burst stimulation (TBS). We hypothesized that autistic adults would display hyperplasticity to TBS and that repetitive transcranial magnetic stimulation (rTMS) – which potentiates brain inhibitory mechanisms – would ‘stabilize’ hyperplasticity. METHODS: Using a randomized, cross-over design, plasticity was assessed using TBS in the left motor cortex (M1) in 31 autistic adults and 30 sex-, intelligence quotient-, and age-matched controls. Autistic adults (n = 29) were further randomized (1:1) to receive a single session of active (n = 14) or sham (n = 15) rTMS (6000 pulses at 20 Hz) over left M1 and plasticity was reassessed on the next day following rTMS. RESULTS: Both long-term potentiation (LTP) and long-term depression (LTD) were significantly increased in the ASD group, indicating hyperplasticity. Active, but not sham rTMS, attenuated LTD in autistic adults. CONCLUSIONS: We provided further evidence for the presence of brain hyperplasticity in ASD. To our knowledge, this is the first study to show preliminary evidence that an excessive LTD in ASD can be ‘stabilized’ using rTMS. Such ‘stabilizing’ effect of rTMS on LTP was not observed, likely due to small sample size or a more specific ‘attenuating’ effect of rTMS on LTD, compared to LTP. SIGNIFICANCE: These findings indicate atypical brain inhibitory mechanisms behind hyperplasticity in ASD. Utilizing a larger sample, future replication studies could investigate therapeutic opportunities of ‘mechanism-driven’ rTMS.

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5. Emmons KA, Kc Lee A, Estes A, Dager S, Larson E, McCloy DR, St John T, Lau BK. Auditory Attention Deployment in Young Adults with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2022; 52(4): 1752-61.

Difficulty listening in noisy environments is a common complaint of individuals with autism spectrum disorder (ASD). However, the mechanisms underlying such auditory processing challenges are unknown. This preliminary study investigated auditory attention deployment in adults with ASD. Participants were instructed to maintain or switch attention between two simultaneous speech streams in three conditions: location (co-located versus ± 30° separation), voice (same voice versus male-female contrast), and both cues together. Results showed that individuals with ASD can selectively direct attention using location or voice cues, but performance was best when both cues were present. In comparison to neurotypical adults, overall performance was less accurate across all conditions. These findings warrant further investigation into auditory attention deployment differences in individuals with ASD.

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6. Ide-Okochi A, Funayama H, Asada Y. Pediatric dentists’ perspectives of children with special health care needs in Japan: developmental disabilities, phobia, maltreatment, and multidisciplinary collaboration. BMC pediatrics. 2021; 21(1): 240.

BACKGROUND: The number of children diagnosed with developmental disabilities (DDs) or other chronic difficulties has risen. However, each professional’s awareness of children with developmental, emotional and behavioural difficulties may differ, allowing their special needs to be overlooked at child health checkups until secondary difficulties appear. Therefore, it is necessary to explore the multi-professional views of children with such chronic difficulties. This study investigates pediatric dentists’ perception of children with potential chronic difficulties. METHODS: Interviews were conducted with 21 pediatric dentists, and the transcripts were analyzed using grounded theory to develop categories for the theoretical assessment. RESULTS: Four themes emerged regarding the children with potential chronic difficulties: children exhibiting possible DDs with awkward social communication and interaction; severe rampant caries possibly derived from maltreatment; dental phobia possibly derived from mental health problems; a complicated home environment where their mothers exhibit poor oral health literacy. CONCLUSIONS: This study’s findings imply that participants’ concept of children of concern included the risks of poor oral health and mental health problems that other healthcare professionals might overlook. It is recommended that multidisciplinary professionals engaging in child health checkups be aware of children’s oral and mental health status as well as potential DDs and child maltreatment.

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7. Khodaverdi M, Rahdar M, Davoudi S, Hajisoltani R, Tavassoli Z, Ghasemi Z, Amini AE, Hosseinmardi N, Behzadi G, Janahmadi M. 5-HT7 receptor activation rescues impaired synaptic plasticity in an autistic-like rat model induced by prenatal VPA exposure. Neurobiology of learning and memory. 2021; 183: 107462.

Autism spectrum disorder (ASD) is a severe life-long neuropsychiatric disorder. Alterations and imbalance of several neurochemical systems may be involved in ASD pathophysiology, of them, serotonergic neurotransmission dysfunction and deficiency may underlie behavioral abnormalities associated with ASD. However, the functional importance of serotonergic receptors, particularly 5HT7 receptors in ASD pathology remains poorly defined. Serotonin receptor subtype 7 (5-HT7R) plays a direct regulatory role in the development and also for the mature function of the brain, therefore, further studies are necessary to elucidate the role of these receptors in the etiology of autism. To address this issue, we combined here behavioral, electrophysiological methods to further characterize the contribution of 5-HT7Rs in the prenatal valproic acid (VPA) exposure-induced impairment in synaptic plasticity and their impact on the associated behavioral changes. This may help to unravel the underlying cellular mechanisms involved in ASD and can lead to new treatment and/or prevention therapies based on the role of the serotonergic system for autism. Findings revealed that compared to control, autistic-like offspring showed increased anxiety-like behavior, reduced social interaction, decreased locomotor activity, and impaired identification of the novel object. However, administration of 5-HT7Rs agonist, LP-211, for 7 consecutive days before testing from postnatal day 21 to 27 reversed all behavioral deficits induced by prenatal exposure to VPA in offspring. Also, both short-term depression and long-term potentiation were impaired in the autistic-like pups, but activation of 5-HT7Rs rescued the LTP impairment in the autistic-like group so that there was no significant difference between the two groups. Blockade of 5-HT7Rs caused LTP impairment following HFS in the autistic-like group. Besides, there was a significant difference in LTD induction following SB-269970 application between the control and the autistic-like groups measured at first 10 min following TPS. Moreover, both the number and the size of retrograde fast blue-labelled neurons in the raphe nuclei were reduced. Overall, these results provide for the first time, as far as we know, functional evidence for the restorative role of 5-HT7Rs activation against prenatal VPA exposure induced behavioral deficits and hippocampal synaptic plasticity impairment. Therefore, these receptors could be a potential and promising pharmacotherapy target for the treatment of autism.

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8. Koire A, Katsonis P, Kim YW, Buchovecky C, Wilson SJ, Lichtarge O. A method to delineate de novo missense variants across pathways prioritizes genes linked to autism. Science translational medicine. 2021; 13(594).

Genotype-phenotype relationships shape health and population fitness but remain difficult to predict and interpret. Here, we apply an evolutionary action method to de novo missense variants in whole-exome sequences of individuals with autism spectrum disorder (ASD) to unravel genes and pathways connected to ASD. Evolutionary action predicts the impact of missense variants on protein function by measuring the fitness effect based on phylogenetic distances and substitution odds in homologous gene sequences. By examining de novo missense variants in 2384 individuals with ASD (probands) compared to matched siblings without ASD, we found missense variants in 398 genes representing 23 pathways that were biased toward higher evolutionary action scores than expected by random chance; these pathways were involved in axonogenesis, synaptic transmission, and neurodevelopment. The predicted fitness impact of de novo and inherited missense variants in candidate genes correlated with the IQ of individuals with ASD, even for new gene candidates. Taking an evolutionary action method, we detected those missense variants most likely to contribute to ASD pathogenesis and elucidated their phenotypic impact. This approach could be applied to integrate missense variants across a patient cohort to identify genes contributing to a shared phenotype in other complex diseases.

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9. Lin N, Liu K, Feng J, Chen R, Ying Y, Lv D, Zhou Y, Xu H. Development and validation of a postoperative delirium prediction model for pediatric patients: A prospective, observational, single-center study. Medicine. 2021; 100(20): e25894.

Postoperative delirium is a serious complication that relates to poor outcomes. A risk prediction model could help the staff screen for children at high risk for postoperative delirium. Our study aimed to establish a postoperative delirium prediction model for pediatric patients and to verify the sensitivity and specificity of this model.Data were collected from a total of 1134 children (0-16yr) after major elective surgery between February 2020 to June 2020. Demographic and clinical data were collected to explore the risk factors. Multivariate logistic regression analysis was used to develop the model, and we assessed the predictive ability of the model by using the area under the receiver operating characteristics curve (AUROC). Further data were collected from another 100 patients in October 2020 to validate the model.Prevalence of postoperative delirium in this sample was 11.1%. The model consisted of 5 predictors, namely, age, developmental delay, type of surgery, pain, and dexmedetomidine. The AUROC was 0.889 (P < .001, 95% confidence interval (CI):0.857-0.921), with sensitivity and specificity of 0.754 and 0.867, and the Youden of 0.621. The model verification results showed the sensitivity of 0.667, the specificity of 0.955.Children undergoing surgery are at risk for developing delirium during the postoperative period, young age, developmental delay, otorhinolaryngology surgery, pain, and exposure to dexmedetomidine were associated with increased odds of delirium. Our study established a postoperative delirium prediction model for pediatric patients, which may be a base for development of strategies to prevent and treat postoperative delirium in children.

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10. Maitland CA, Rhodes S, O’Hare A, Stewart ME. Social identities and mental well-being in autistic adults. Autism : the international journal of research and practice. 2021; 25(6): 1771-83.

Social identities are groups that we are part of and influence how we think about ourselves. However, up until now there has been little examination of the groups that autistic people may belong to, and how these groups may influence their mental health. This survey-based study investigated whether autistic adults answer questions about social groups in a similar way to non-autistic non-autistic adults, including the types and number of social groups they may belong to, and whether these are associated with depression, anxiety and positive traits of mental well-being. In total, 184 autistic adults completed an online survey with questionnaires about their demographics, social groups and mental health. The results found that autistic adults reported on their social groups similarly to non-autistic people. There was a variety in the types and numbers of groups that autistic adults identified with. Some participants reported having no groups that they identified with, whereas others reported up to four groups. These included other autistic people, their family, friends, work colleagues and activity clubs among others. Autistic adults who felt connected with more groups reported better mental well-being. Feelings of connection to other autistic people and the family were also associated with better mental well-being. These results show that it is important for autistic people to be given opportunity to be part of groups that are meaningful to them, as this may be beneficial for their mental health.

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11. McBain RK, Cantor JH, Kofner A, Stein BD, Yu H. Brief Report: Medicaid Expansion and Growth in the Workforce for Autism Spectrum Disorder. Journal of autism and developmental disorders. 2022; 52(4): 1881-9.

Over 700,000 children throughout the U.S. have received insurance coverage through welcome mat effects of Medicaid expansion, including children with autism spectrum disorder (ASD). Utilizing health workforce data from the Health Resources and Services Administration, we examined workforce growth (2008-2017) among three types of health providers for children with ASD as a result of Medicaid expansion: child psychiatrists, board-certified behavioral analysts (BCBAs) and pediatricians. We found that state Medicaid expansion was associated with a 9% increase in BCBAs per 100,000 children one year after enactment, a 5% increase in child psychiatrists, and was not associated with growth in pediatricians. Results indicate the importance of new policies that directly address a shortage of providers for children with ASD.

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12. Schreiber JM, Wiggs E, Cuento R, Norato G, Dustin IH, Rolinski R, Austermuehle A, Zhou X, Inati SK, Gibson KM, Pearl PL, Theodore WH. A Randomized Controlled Trial of SGS-742, a γ-aminobutyric acid B (GABA-B) Receptor Antagonist, for Succinic Semialdehyde Dehydrogenase Deficiency. Journal of child neurology. 2021; 36(13-14): 1189-99.

We examined safety, tolerability, and efficacy of SGS-742, a γ-aminobutyric acid B (GABA-B) receptor antagonist, in patients with succinic semialdehyde dehydrogenase deficiency. This was a single-center randomized, double-blind crossover phase II clinical trial of SGS-742 versus placebo in patients with succinic semialdehyde dehydrogenase deficiency. Procedures included transcranial magnetic stimulation and the Adaptive Behavior Assessment Scale. Nineteen subjects were consented and enrolled; the mean age was 14.0 ± 7.5 years and 11 (58%) were female. We did not find a significant effect of SGS-742 on the Adaptive Behavior Assessment Scale score, motor threshold, and paired-pulse stimulation. The difference in recruitment curve slopes between treatment groups was 0.003 (P = .09). There was no significant difference in incidence of adverse effects between drug and placebo arms. SGS-742 failed to produce improved cognition and normalization of cortical excitability as measured by the Adaptive Behavior Assessment Scale and transcranial magnetic stimulation. Our data do not support the current use of SGS-742 in succinic semialdehyde dehydrogenase deficiency.Trial registry number NCT02019667. Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency. https://clinicaltrials.gov/ct2/show/NCT02019667.

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13. Scibelli F, Fucà E, Guerrera S, Lupi E, Alfieri P, Valeri G, Vicari S. Clinical and individual features associated with maternal stress in young adolescents with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research. 2021; 14(9): 1935-47.

Parents of people with autism spectrum disorder experience both negative stressful and positive events. Several clinical and socio-demographic features of children on the autism spectrum have been associated with parenting stress in their families. However, there have been few studies that focus on adolescents and the role of cognitive impairment has rarely been addressed. The main aim of the present research is to explore associations between autism symptoms, cognitive impairment, emotional and behavioral problems, socio-demographic features, and maternal stress in a sample of young adolescents with Autism Spectrum Disorder with and without cognitive impairment. Cognitive impairment and emotional and behavioral problems are associated with maternal stress, while autism symptoms seem to play a minor role. Maternal education and occupation are only associated with maternal stress in the group with cognitive impairment, while maternal age is stress-associated in the group of adolescents without cognitive impairment. Age-related implications for intervention and future research directions are discussed. LAY SUMMARY: Parents of individuals on the autism spectrum are exposed to both negative stressful and enriching experiences during their parenthood. While the influence of several child characteristics and socio-demographic features on parental stress during childhood has been widely explored in past studies, studies on teenagers are limited. The aim of the present research is to explore the influence of several characteristics on maternal stress levels in families with teenagers on the autism spectrum. We found that cognitive impairment and emotional and behavioral problems are associated with maternal stress, while autism symptoms seem to play a minor role. Socio-demographic features are not associated with maternal stress. Broadly speaking, the subjective perception of parental distress in both groups is less related to teenagers’ characteristics then the perception of having a difficult interaction with the teenagers. We divided our participants into two groups (one group with cognitive impairment and the other group without). We found that mothers of teenagers with cognitive impairment are generally more stressed compared to the other group. Furthermore, we confirm that emotional and behavioral problems seem to play a major role in maternal stress (especially in the group without cognitive impairment), while autism symptoms seem to play a minor role. Furthermore, we found that maternal education/occupation and maternal age are associated with maternal stress in the group with and the group without cognitive impairment respectively. This research highlights the association between several variables and stress in mothers of adolescents on the spectrum. Results are discussed in the framework of previous findings highlighting the lack of adequate care and support services for families, especially for those of adolescents on the spectrum with cognitive impairment.

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14. Tochitani S, Furukawa T, Bando R, Kondo S, Ito T, Matsushima Y, Kojima T, Matsuzaki H, Fukuda A. GABAA Receptors and Maternally Derived Taurine Regulate the Temporal Specification of Progenitors of Excitatory Glutamatergic Neurons in the Mouse Developing Cortex. Cerebral cortex (New York, NY : 1991). 2021; 31(10): 4554-75.

Temporal specification of the neural progenitors (NPs) producing excitatory glutamatergic neurons is essential for histogenesis of the cerebral cortex. Neuroepithelial cells, the primary NPs, transit to radial glia (RG). To coincide with the transition, NPs start to differentiate into neurons, undergoing a switch from symmetric to asymmetric cell division. After the onset of neurogenesis, NPs produce layer-specific neurons in a defined order with precise timing. Here, we show that GABAA receptors (GABAARs) and taurine are involved in this regulatory mechanism. Foetal exposure to GABAAR-antagonists suppressed the transition to RG, switch to asymmetric division, and differentiation into upper-layer neurons. Foetal exposure to GABAAR-agonists caused the opposite effects. Mammalian foetuses are dependent on taurine derived from the mothers. GABA and taurine function as endogenous ligands for GABAARs. Ca2+ imaging showed that NPs principally responded to taurine but not GABA before E13. The histological phenotypes of the taurine transporter knockout mice resembled those of the mice foetally exposed to GABAAR-antagonists. Foetal exposure to GABAAR-modulators resulted in considerable alterations in offspring behavior like core symptoms of autism. These results show that taurine regulates the temporal specification of NPs and that disrupting the taurine-receptor interaction possibly leads to neurodevelopmental disorders.

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