1. Berent I, Theodore RM, Valencia E. Autism attenuates the perception of the mind-body divide. Proceedings of the National Academy of Sciences of the United States of America. 2022; 119(49): e2211628119.

People are intuitive Dualists-they tacitly consider the mind as ethereal, distinct from the body. Here we ask whether Dualism emerges naturally from the conflicting core principles that guide reasoning about objects, on the one hand, and about the minds of agents (theory of mind, ToM), on the other. To address this question, we explore Dualist reasoning in autism spectrum disorder (ASD)-a congenital disorder known to compromise ToM. If Dualism arises from ToM, then ASD ought to attenuate Dualism and promote Physicalism. In line with this prediction, Experiment 1 shows that, compared to controls, people with ASD are more likely to view psychological traits as embodied-as likely to manifest in a replica of one’s body. Experiment 2 demonstrates that, unlike controls, people with ASD do not consider thoughts as disembodied-as persistent in the afterlife (upon the body’s demise). If ASD promotes the perception of the psyche as embodied, and if (per Essentialism) embodiment suggests innateness, then ASD should further promote Nativism-this bias is shown in Experiment 3. Finally, Experiment 4 demonstrates that, in neurotypical (NT) participants, difficulties with ToM correlate with Physicalism. These results are the first to show that ASD attenuates Dualist reasoning and to link Dualism to ToM. These conclusions suggest that the mind-body distinction might be natural for people to entertain.

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2. Chen Y, Tang E, Ding H, Zhang Y. Auditory Pitch Perception in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. Journal of speech, language, and hearing research : JSLHR. 2022: 1-21.

PURPOSE: Pitch plays an important role in auditory perception of music and language. This study provides a systematic review with meta-analysis to investigate whether individuals with autism spectrum disorder (ASD) have enhanced pitch processing ability and to identify the potential factors associated with processing differences between ASD and neurotypicals. METHOD: We conducted a systematic search through six major electronic databases focusing on the studies that used nonspeech stimuli to provide a qualitative and quantitative assessment across existing studies on pitch perception in autism. We identified potential participant- and methodology-related moderators and conducted metaregression analyses using mixed-effects models. RESULTS: On the basis of 22 studies with a total of 464 participants with ASD, we obtained a small-to-medium positive effect size (g = 0.26) in support of enhanced pitch perception in ASD. Moreover, the mean age and nonverbal IQ of participants were found to significantly moderate the between-studies heterogeneity. CONCLUSIONS: Our study provides the first meta-analysis on auditory pitch perception in ASD and demonstrates the existence of different developmental trajectories between autistic individuals and neurotypicals. In addition to age, nonverbal ability is found to be a significant contributor to the lower level/local processing bias in ASD. We highlight the need for further investigation of pitch perception in ASD under challenging listening conditions. Future neurophysiological and brain imaging studies with a longitudinal design are also needed to better understand the underlying neural mechanisms of atypical pitch processing in ASD and to help guide auditory-based interventions for improving language and social functioning. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.21614271.

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3. Cipriani C, Giudice M, Petrone V, Fanelli M, Minutolo A, Miele MT, Toschi N, Maracchioni C, Siracusano M, Benvenuto A, Coniglio A, Curatolo P, Mazzone L, Sandro G, Garaci E, Sinibaldi-Vallebona P, Matteucci C, Balestrieri E. Modulation of human endogenous retroviruses and cytokines expression in peripheral blood mononuclear cells from autistic children and their parents. Retrovirology. 2022; 19(1): 26.

BACKGROUND: Putative pathogenic effects mediated by human endogenous retroviruses (HERVs) in neurological and psychiatric disorders in humans have been extensively described. HERVs may alter the development of the brain by means of several mechanisms, including modulation of gene expression, alteration of DNA stability, and activation of immune system. We recently demonstrated that autistic children and their mothers share high expression levels of some HERVs and cytokines in peripheral blood mononuclear cells (PBMCs) ex vivo, suggesting a close mother-child association in Autism Spectrum Disorder (ASD). RESULTS: In the present study, PBMCs from autistic children and their parents were exposed to stimulating factors (Interleukin-2/Phytohaemagglutinin) or drugs, as Valproic acid and Efavirenz. The results show that HERVs and cytokines expression can be modulated in vitro by different stimuli in PBMCs from autistic children and their mothers, while no significant changes were found in PBMCs ASD fathers or in controls individuals. In particular, in vitro exposure to interleukin-2/Phytohaemagglutinin or valproic acid induces the expression of several HERVs and cytokines while Efavirenz inhibits them. CONCLUSION: Herein we show that autistic children and their mothers share an intrinsic responsiveness to in vitro microenvironmental changes in expressing HERVs and pro-inflammatory cytokines. Remarkably, the antiretroviral drug Efavirenz restores the expression of specific HERV families to values similar to those of the controls, also reducing the expression of proinflammatory cytokines but keeping the regulatory ones high. Our findings open new perspectives to study the role of HERVs in the biological mechanisms underlying Autism.

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4. Gibson CA, Sullivan DK, Ptomey LT, Rice AM, Donnelly JE. Interviews with parents of adolescents with intellectual and developmental disabilities in a weight management study. Journal of applied research in intellectual disabilities : JARID. 2022.

BACKGROUND: Adolescents and young adults with intellectual and developmental disabilities are at risk of obesity. Parents influence their diet and physical activity behaviours and therefore, can play important roles in weight management. The aims of this qualitative study were to explore parents’ experiences assisting their son or daughter to participate in a weight management study. METHODS: Interviews were completed at 6 months with 27 parents whose adolescent or young adult had completed the weight loss portion of an 18-month weight management study. Interviews were recorded, transcribed and thematic analysis performed. RESULTS: Parents shared insights about how well program components worked with their family, and what strategies worked best to adopt healthier dietary choices and become more physically active. The importance of meeting regularly with someone outside the family to encourage healthier habits was stressed. CONCLUSIONS: Future weight management studies should involve parents and their adolescents to help tailor strategies and adapt intervention approaches.

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5. Hung KC, Chen JY, Hsing CH, Hsu CW, Liu PH, Chang YJ, Chen JY, Chiu SF, Sun CK. Association of labor epidural analgesia exposure with long-term risk of autism spectrum disorder in offspring: A meta-analysis of observational studies. Autism : the international journal of research and practice. 2022: 13623613221138690.

A previous meta-analysis has demonstrated a superior analgesic efficacy of epidural analgesia (e.g. labor epidural analgesia) in comparison with non-epidural approaches. The widely accepted safety of labor epidural analgesia also endorses its current popularity in obstetric practice. However, the results of a recent large-scale longitudinal study that demonstrated a significant increase in risk of autism spectrum disorder in offspring from mothers with labor epidural analgesia exposure have raised some concerns over the safety of its use. The current meta-analysis aimed at examining the strength of evidence regarding this issue based on updated clinical data. Through systematically reviewing seven eligible observational studies involving 4,021,406 children from electronic databases, our results showed a slight but statistically significant increase in risk of autism spectrum disorder in children with exposure to labor epidural analgesia compared with those without. The finding was consistent in subgroup analysis focusing on siblings and children delivered vaginally. Nevertheless, despite the tendency of an increased risk of autism spectrum disorder in children exposed to labor epidural analgesia <4 h, this effect was not observed in those exposed to labor epidural analgesia >8 h (data from two studies). In conclusion, the level of evidence linking labor epidural analgesia to autism spectrum disorder development in offspring was very low based on the latest data because of the small effect size and the finding of a lack of cumulative dose-response effect in the current analysis. Further studies are warranted to provide an insight into this issue.

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6. Krishnamurthy K, Chan MMY, Han YMY. Neural substrates underlying effortful control deficit in autism spectrum disorder: a meta-analysis of fMRI studies. Scientific reports. 2022; 12(1): 20603.

Effortful control comprises attentional control, inhibitory control, and cognitive flexibility subprocesses. Effortful control is impaired in individuals with autism spectrum disorder, yet its neural underpinnings remain elusive. By conducting a coordinate-based meta-analysis, this study compared the brain activation patterns between autism and typically developing individuals and examined the effect of age on brain activation in each effortful control subprocesses. Meta-analytic results from 22 studies revealed that, individuals with autism showed hypoactivation in the default mode network for tasks tapping inhibitory control functioning (threshold-free cluster enhancement p < 0.001). When these individuals perform tasks tapping attentional control and cognitive flexibility, they exhibited aberrant activation in various brain networks including default mode network, dorsal attention, frontoparietal, visual and somatomotor networks (uncorrected ps < 0.005). Meta-regression analyses revealed that brain regions within the default mode network showed a significant decreasing trend in activation with increasing age (uncorrected p < 0.05). In summary, individuals with autism showed aberrant activation patterns across multiple brain functional networks during all cognitive tasks supporting effortful control, with some regions showing a decrease in activation with increasing age.

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7. Kumar H, Diwan V, Sharma B. Protective Effect of Nimodipine Against Valproic-acid Induced Biochemical and Behavioral Phenotypes of Autism. Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology. 2022; 20(4): 725-36.

OBJECTIVE: Present study was designed to investigate behavioral and biochemical role of nimodipine in prenatal valproic acid (Pre-VPA) induced autism in rats. METHODS: Valproic acid was utilized to induce autistic phenotypes in Wistar rats. The rats were assessed for social behavior. Hippocampus and prefrontal cortex (PFC) were utilized for various biochemical assessments, whereas cerebellum was used to assess blood brain barrier (BBB) permeability. RESULTS: Pre-VPA rats showed reduction social interaction. Pre-VPA administration were decreased PFC levels of interleukin- 10 (IL-10), and glutathione along with hippocampus cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF). Also, the animals have shown increase in PFC levels of IL-6, tumor necrosis factor-α, thiobarbituric acid reactive substance, Evans blue leakage and water content. Nimodipine countered Pre-VPA administered reduction in social interaction, CREB, BDNF, inflammation, oxidative stress, BBB permeability. CONCLUSION: Pre-VPA has induced autistic phenotype, which were attenuated by nimodipine in rats. Nimodipine and other calcium channel blockers should further investigate to check the management of autism.

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8. Majerczyk D, Ayad EG, Brewton KL, Saing P, Hart PC. Systemic maternal inflammation promotes ASD via IL-6 and IFN-γ. Bioscience reports. 2022; 42(11).

Autism spectrum disorder (ASD) is a neurological disorder that manifests during early development, impacting individuals through their ways of communicating, social behaviors, and their ability to perform day-to-day activities. There have been different proposed mechanisms on how ASD precipitates within a patient, one of which being the impact cytokines have on fetal development once a mother’s immune system has been activated (referred to as maternal immune activation, MIA). The occurrence of ASD has long been associated with elevated levels of several cytokines, including interleukin-6 (IL-6) and interferon gamma (IFN-γ). These proinflammatory cytokines can achieve high systemic levels in response to immune activating pathogens from various extrinsic sources. Transfer of cytokines such as IL-6 across the placental barrier allows accumulation in the fetus, potentially inducing neuroinflammation and consequently altering neurodevelopmental processes. Individuals who have been later diagnosed with ASD have been observed to have elevated levels of IL-6 and other proinflammatory cytokines during gestation. Moreover, the outcome of MIA has been associated with neurological effects such as impaired social interaction and an increase in repetitive behavior in animal models, supporting a mechanistic link between gestational inflammation and development of ASD-like characteristics. The present review attempts to provide a concise overview of the available preclinical and clinical data that suggest cross-talk between IL-6 and IFN-γ through both extrinsic and intrinsic factors as a central mechanism of MIA that may promote the development of ASD.

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9. Miao C, Du L, Zhang Y, Jia F, Shan L. Novel de novo ZNF148 truncating variant causing autism spectrum disorder, attention deficit hyperactivity disorder and intellectual disability. Clinical genetics. 2022.

ZNF148 gene is a Krüppel-type transcription factor that has transcriptional regulatory function. Heterozygous variant in ZNF148 gene causes an intellectual disability syndrome characterized by global developmental delay, absence or hypoplasia of corpus callosum, wide intracerebral ventricles, and dysmorphic facial features, while its associations with ASD and ADHD have not been reported. We report a new patient with intellectual disability (ID), autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). The patient had a novel heterozygous truncating variant c.1818dupC (p.Lys607Glnfs*11) in the ZNF148 gene. This variation produces a ZNF148 truncated protein with a deletion of the C-terminal activation domain and may destabilize the protein by affecting the transcriptional activation function. Brain MRI shows normal brain development. Here, we identify a novel ZNF148 heterozygous truncating variant in a patient with distinct phenotypes of ASD and ADHD, which expands the genotype-phenotype spectrum of ZNF148, and indicates ZNF148 is also a potential target gene for ASD. This article is protected by copyright. All rights reserved.

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10. Nenonene EK, Trottier-Lavoie M, Marchais M, Bastien A, Gilbert I, Macaulay A, Khandjian EW, Luciano AM, Lodde V, Viger R, Robert C. Roles of the cumulus-oocyte transzonal network and the Fragile X protein family in oocyte competence. Reproduction (Cambridge, England). 2022.

The determinants of oocyte developmental competence have puzzled scientists for decades. It is known that follicular conditions can nurture the production of a high-quality oocyte, but the underlying mechanisms remain unknown. Somatic cumulus cells most proximal to the oocyte are known to have cellular extensions that reach across the zona pellucida and contact with the oocyte plasma membrane. Herein, it was found that transzonal projections (TZPs) network quality is associated with developmental competence. Knowing that ribonucleo-particles are abundant within TZPs, the distribution of RNA binding proteins were studied. The Fragile X-Related Proteins (FMRP, FXR1P, and FXR2P) and two partnering protein families, namely cytoplasmic FMRP interacting protein (CYFIP) and nuclear FMRP interacting protein (NUFIP), exhibited distinctive patterns consistent with roles in regulating mRNA packaging, transport and translation. Expression of GFP-FMRP fusion protein in cumulus cells showed active granule formation and their transport and transfer through filipodia connecting with neighboring cells. Near the projections’ ends was found the cytoskeletal anchoring protein Filamin A and active protein synthesis sites. This study highlights key proteins involved in delivering mRNA to the oocyte. Thus, cumulus cells appear to indeed support the development of high-quality oocytes via the transzonal network.

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11. Persichetti AS, Shao J, Gotts SJ, Martin A. Maladaptive Laterality in Cortical Networks Related to Social Communication in Autism Spectrum Disorder. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2022; 42(48): 9045-52.

Neuroimaging studies of individuals with autism spectrum disorders (ASDs) consistently find an aberrant pattern of reduced laterality in brain networks that support functions related to social communication and language. However, it is unclear how the underlying functional organization of these brain networks is altered in ASD individuals. We tested four models of reduced laterality in a social communication network in 70 ASD individuals (14 females) and a control group of the same number of tightly matched typically developing (TD) individuals (19 females) using high-quality resting-state fMRI data and a method of measuring patterns of functional laterality across the brain. We found that a functionally defined social communication network exhibited the typical pattern of left laterality in both groups, whereas there was a significant increase in within- relative to across-hemisphere connectivity of homotopic regions in the right hemisphere in ASD individuals. Furthermore, greater within- relative to across-hemisphere connectivity in the left hemisphere was positively correlated with a measure of verbal ability in both groups, whereas greater within- relative to across-hemisphere connectivity in the right hemisphere in ASD, but not TD, individuals was negatively correlated with the same verbal measure. Crucially, these differences in patterns of laterality were not found in two other functional networks and were specifically correlated to a measure of verbal ability but not metrics of other core components of the ASD phenotype. These results suggest that previous reports of reduced laterality in social communication regions in ASD is because of the two hemispheres functioning more independently than seen in TD individuals, with the atypical right-hemisphere network component being maladaptive.SIGNIFICANCE STATEMENT A consistent neuroimaging finding in individuals with ASD is an aberrant pattern of reduced laterality of the brain networks that support functions related to social communication and language. We tested four models of reduced laterality in a social communication network in ASD individuals and a TD control group using high-quality resting-state fMRI data. Our results suggest that reduced laterality of social communication regions in ASD may be because of the two hemispheres functioning more independently than seen in TD individuals, with atypically greater within- than across-hemisphere connectivity in the right hemisphere being maladaptive.

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12. Politano D, Gana S, Pezzotti E, Berardinelli A, Pasca L, Carmen Barbero V, Pichiecchio A, Maria Valente E, Errichiello E. A novel variant in NEUROD2 in a patient with Rett-like phenotype points to Glu130 codon as a mutational hotspot. Brain & development. 2022.

BACKGROUND: NEUROD2, encoding the neurogenic differentiation factor 2, is essential for neurodevelopment. To date, heterozygous missense variants in this gene have been identified in eight patients (from six unrelated families) with epileptic encephalopathy and developmental delay. CASE REPORT: We describe a child with initial clinical suspicion of Rett/Rett-like syndrome, in whom exome sequencing detected a novel de novo variant (c.388G > A, p.Glu130Lys) in NEUROD2. Interestingly, a missense change affecting the same codon, c.388G > C (p.Glu130Gln), was previously identified in other two patients. CONCLUSIONS: Our results suggest that Glu130 might represent a potential mutational hotspot of NEUROD2. Furthermore, the clinical findings (especially the absence of clinically overt seizures) strengthen the NEUROD2-phenotypic spectrum, implying that developmental delay may also manifest isolatedly. We suggest inclusion of NEUROD2-associated developmental and epileptic encephalopathies (DEEs) in the differential diagnosis of atypical Rett syndrome as well as gene panels related to autism spectrum disorder.

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13. Poteet B, Ali N, Bellcross C, Sherman SL, Espinel W, Hipp H, Allen EG. The diagnostic experience of women with fragile X-associated primary ovarian insufficiency (FXPOI). Journal of assisted reproduction and genetics. 2022.

PURPOSE: The fragile X premutation occurs when there are 55-200 CGG repeats in the 5′ UTR of the FMR1 gene. An estimated 1 in 148 women carry a premutation, with 20-30% of these individuals at risk for fragile X-associated primary ovarian insufficiency (FXPOI). Diagnostic experiences of FXPOI have not previously been included in the literature, limiting insight on experiences surrounding the diagnosis. This study identifies barriers and facilitators to receiving a FXPOI diagnosis and follow-up care, which can inform care and possibly improve quality of life. METHODS: We conducted qualitative interviews with 24 women with FXPOI exploring how FMR1 screening, physician education, and supportive care impacted their experience. Three subgroups were compared: women diagnosed through family history who have biological children, women diagnosed through family history who do not have biological children, and women diagnosed through symptoms of POI. RESULTS: Themes from interviews included hopes for broader clinician awareness of FXPOI, clear guidelines for clinical treatment, and proper fertility workups to expand reproductive options prior to POI onset. Participants also spoke of difficulty finding centralized sources of care. CONCLUSIONS: Our results indicate a lack of optimal care of women with a premutation particularly with respect to FMR1 screening for molecular diagnosis, short- and long-term centralized treatment, and clinical and emotional support. The creation of a « FXPOI health navigator » could serve as a centralized resource for the premutation patient population, assisting in connection to optimal treatment and appropriate referrals, including genetic counseling, mental health resources, advocacy organizations, and better-informed physicians.

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14. Price KM, Wigg KG, Eising E, Feng Y, Blokland K, Wilkinson M, Kerr EN, Guger SL, Fisher SE, Lovett MW, Strug LJ, Barr CL. Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities. Translational psychiatry. 2022; 12(1): 495.

Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)-GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10(-2), threshold = 2.5 × 10(-2)). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10(-2)). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10(-4)). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.

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15. Saure E, Castrén M, Mikkola K, Salmi J. Intellectual disabilities moderate sex/gender differences in autism spectrum disorder: a systematic review and meta-analysis. Journal of intellectual disability research : JIDR. 2022.

BACKGROUND: Girls/women with autism spectrum disorder (ASD) are suggested to exhibit different symptom profiles than boys/men with ASD. Accumulating evidence suggests that intellectual disability (ID) may affect sex/gender differences in ASD. However, a systematic review and meta-analysis on this topic is missing. METHODS: Two databases (MEDLINE and PsycINFO) were used to search for studies reporting sex/gender differences (girls/women versus boys/men) in social communication and interaction, restrictive and repetitive behaviour and interests (RRBIs), sensory processing, and linguistic and motor abilities in ASD. The final sample consisted of 79 studies. The meta-analysis was performed with Review Manager using a random-effects model. Participants with ASD without and with ID were analysed as separate subgroups, and the effects in these two subgroups were also compared with each other. RESULTS: Girls/women with ASD without ID displayed fewer RRBIs, more sensory symptoms and less problems in linguistic abilities than their boys/men counterparts. In contrast, girls/women with ASD with ID displayed more social difficulties and RRBIs, poorer linguistic abilities and more motor problems than boys/men with ASD with ID. Comparisons of groups of participants with ASD without ID versus participants with ASD with ID confirmed differences in sex/gender effects on social difficulties, sensory processing, linguistic abilities and motor abilities. CONCLUSIONS: Our results clearly suggest that the female phenotype of ASD is moderated by ID. Among individuals with ASD with ID, girls/women seem to be more severely affected than boys/men, whereas among individuals with ASD without ID, girls/women with ASD may have less symptoms than boys/men. Such phenotypic differences could be a potential cause of underrecognition of girls/women with ASD, and it is also possible that observed phenotypic differences may reflect underdiagnosing of girls/women with ASD.

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16. Skjegstad CL, Trevor C, Swanborough H, Roswandowitz C, Mokros A, Habermeyer E, Frühholz S. Psychopathic and autistic traits differentially influence the neural mechanisms of social cognition from communication signals. Translational psychiatry. 2022; 12(1): 494.

Psychopathy is associated with severe deviations in social behavior and cognition. While previous research described such cognitive and neural alterations in the processing of rather specific social information from human expressions, some open questions remain concerning central and differential neurocognitive deficits underlying psychopathic behavior. Here we investigated three rather unexplored factors to explain these deficits, first, by assessing psychopathy subtypes in social cognition, second, by investigating the discrimination of social communication sounds (speech, non-speech) from other non-social sounds, and third, by determining the neural overlap in social cognition impairments with autistic traits, given potential common deficits in the processing of communicative voice signals. The study was exploratory with a focus on how psychopathic and autistic traits differentially influence the function of social cognitive and affective brain networks in response to social voice stimuli. We used a parametric data analysis approach from a sample of 113 participants (47 male, 66 female) with ages ranging between 18 and 40 years (mean 25.59, SD 4.79). Our data revealed four important findings. First, we found a phenotypical overlap between secondary but not primary psychopathy with autistic traits. Second, primary psychopathy showed various neural deficits in neural voice processing nodes (speech, non-speech voices) and in brain systems for social cognition (mirroring, mentalizing, empathy, emotional contagion). Primary psychopathy also showed deficits in the basal ganglia (BG) system that seems specific to the social decoding of communicative voice signals. Third, neural deviations in secondary psychopathy were restricted to social mirroring and mentalizing impairments, but with additional and so far undescribed deficits at the level of auditory sensory processing, potentially concerning deficits in ventral auditory stream mechanisms (auditory object identification). Fourth, high autistic traits also revealed neural deviations in sensory cortices, but rather in the dorsal auditory processing streams (communicative context encoding). Taken together, social cognition of voice signals shows considerable deviations in psychopathy, with differential and newly described deficits in the BG system in primary psychopathy and at the neural level of sensory processing in secondary psychopathy. These deficits seem especially triggered during the social cognition from vocal communication signals.

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17. Smith CJ, James S, Skepnek E, Leuthe E, Outhier LE, Avelar D, Barnes CC, Bacon E, Pierce K. Implementing the Get SET Early Model in a Community Setting to Lower the Age of ASD Diagnosis. Journal of developmental and behavioral pediatrics : JDBP. 2022; 43(9): 494-502.

OBJECTIVE: The objective of this study was to implement a validated, university-based early detection program, the Get SET Early model, in a community-based setting. Get SET was developed to improve Screening, Evaluation, and Treatment referral practices. Specifically, its purpose was to lower the age of diagnosis and enable toddlers with autism spectrum disorder (ASD) to begin treatment by 36 months. METHODS: One hundred nine pediatric health care providers were recruited to administer the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist at 12-month, 18-month, and 24-month well-baby visits and referred toddlers whose scores indicated the need for a developmental evaluation. Licensed psychologists were trained to provide diagnostic evaluations to toddlers as young as 12 months. Mean age of diagnosis was compared with current population rates. RESULTS: In 4 years, 45,504 screens were administered at well-baby visits, and 648 children were evaluated at least 1 time. The overall median age for ASD diagnosis was 22 months, which is significantly lower than the median age reported by the CDC (57 months). For children screened at 12 months, the age of first diagnosis was significantly lower at 15 months. Of the 350 children who completed at least 1 follow-up evaluation, 323 were diagnosed with ASD or another delay, and 239 (74%) were enrolled in a treatment program. CONCLUSION: Toddlers with ASD were diagnosed nearly 3 years earlier than the most recent CDC report, which allowed children to start a treatment program by 36 months. Overall, Get SET Early was an effective strategy for improving the current approach to screening, evaluation, and treatment. Efforts to demonstrate sustainability are underway.

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18. Urchs SGW, Tam A, Orban P, Moreau C, Benhajali Y, Nguyen HD, Evans AC, Bellec P. Functional connectivity subtypes associate robustly with ASD diagnosis. eLife. 2022; 11.

Our understanding of the changes in functional brain organization in autism is hampered by the extensive heterogeneity that characterizes this neurodevelopmental disorder. Data driven clustering offers a straightforward way to decompose autism heterogeneity into subtypes of connectivity and promises an unbiased framework to investigate behavioral symptoms and causative genetic factors. Yet, the robustness and generalizability of functional connectivity subtypes is unknown. Here, we show that a simple hierarchical cluster analysis can robustly relate a given individual and brain network to a connectivity subtype, but that continuous assignments are more robust than discrete ones. We also found that functional connectivity subtypes are moderately associated with the clinical diagnosis of autism, and these associations generalize to independent replication data. We explored systematically 18 different brain networks as we expected them to associate with different behavioral profiles as well as different key regions. Contrary to this prediction, autism functional connectivity subtypes converged on a common topography across different networks, consistent with a compression of the primary gradient of functional brain organization, as previously reported in the literature. Our results support the use of data driven clustering as a reliable data dimensionality reduction technique, where any given dimension only associates moderately with clinical manifestations.

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19. Wang X, Ling Z, Luo T, Zhou Q, Zhao G, Li B, Xia K, Li J. Severity of Autism Spectrum Disorder Symptoms Associated with de novo Variants and Pregnancy-Induced Hypertension. Journal of autism and developmental disorders. 2022.

Genetic factors, particularly, de novo variants (DNV), and an environment factor, exposure to pregnancy-induced hypertension (PIH), were reported to be associated with risk of autism spectrum disorder (ASD); however, how they jointly affect the severity of ASD symptom is unclear. We assessed the severity of core ASD symptoms affected by functional de novo variants or PIH. We selected phenotype data from Simon’s Simplex Collection database, used genotypes from previous studies, and created linear regression models. We found that ASD patients carrying DNV with PIH exposure had increased adaptive and cognitive ability, decreased social problems, and enhanced repetitive behaviors; however, there was no difference in patients without DNV between those with or without PIH exposure. In addition, the DNV genes carried by patients exposed to PIH were enriched in ubiquitin-dependent proteolytic processes, highlighting how candidate genes in pathways and environments interact. The results indicate the joint contribution of DNV and PIH to ASD.

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20. Wang YC, Chen CH, Yang CY, Ling P, Hsu KS. High-Fat Diet Exacerbates Autistic-Like Restricted Repetitive Behaviors and Social Abnormalities in CC2D1A Conditional Knockout Mice. Molecular neurobiology. 2022.

Autism spectrum disorder (ASD) represents a heterogeneous group of neurodevelopmental disorders characterized by deficits in social communication, social interaction, and the presence of restricted repetitive behaviors. The cause of ASD involves complex interactions between genetic and environmental factors. Haploinsufficiency of the Coiled-coil and C2 domain containing 1A (Cc2d1a) gene is causally linked to ASD, and obesity has been associated with worse outcomes for ASD. High-fat diet (HFD) feeding leads to the development of obesity and metabolic dysfunction; however, the effect of HFD on pre-existing autistic-like phenotypes remains to be clarified. Here, we report that male Cc2d1a conditional knockout (cKO) mice fed with HFD, from weaning onwards and throughout the experimental period, show a marked aggravation in autistic-like phenotypes, manifested in increased restricted repetitive behaviors and impaired performance in the preference for social novelty, but not in sociability and cognitive impairments assessed using the object location memory, novel object recognition, and Morris water maze tests. HFD feeding also results in increased numbers of reactive microglia and astrocytes, and exacerbates reductions in dendritic complexity and spine density of hippocampal CA1 pyramidal neurons. Furthermore, we demonstrate that chronic treatment with minocycline, a semisynthetic tetracycline-derived antibiotic, rescues the observed behavioral and morphological deficits in Cc2d1a cKO mice fed with HFD. Collectively, these findings highlight an aggravating role of HFD in pre-existing autistic-like phenotypes and suggest that minocycline treatment can alleviate abnormal neuronal morphology and behavioral symptoms associated with ASD resulted from the interplay between genetic and environmental risk factors.

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21. Weitlauf AS, Vehorn A, Miceli A, Pinnock T, Dada Y, Hine J, Warren Z. Black Families’ Experiences of Developmental Screening: Review of Well-Child Visits to Inform Enhanced Autism Spectrum Disorder Risk Assessment. Journal of developmental and behavioral pediatrics : JDBP. 2022; 43(9): 503-10.

OBJECTIVE: Black families face barriers to early diagnosis of autism spectrum disorder (ASD). Most work emphasizes systemic delays to diagnosis rather than how existing screening procedures may affect identification. Our goal was to examine pediatric care visits in which screening was most likely to occur to document behaviors of parents and providers. METHODS: We examined 18- to 36-month primary care visits in our electronic health record system (n = 99) of thirty-nine 4- and 8-year-old Black children later diagnosed with ASD. We extracted qualitative and quantitative data and engaged in consensus coding. We captured whether formal screening occurred, the content of concerns of parents and providers, and referral patterns for follow-up care or evaluation. RESULTS: Consistent with existing work, we found differences in parent and provider concerns and discrepancies in referral rates. Parents often endorsed concerns about language, sleeping or eating habits, behavior, or motor skills rather than ASD, but specific mention of ASD as a concern increased over time. Referrals for follow-up care were more likely when providers, not parents alone, expressed concerns about patient development. CONCLUSION: Pediatric providers cannot place the burden on families to raise autism concerns. Although some level of developmental risk was noted at most visits for children later diagnosed with ASD, referrals were only made when providers were also concerned, and most of these were for speech-language evaluation. Ongoing work is necessary to better understand how existing care systems interact with diverse families to inform the creation of inclusive screening practices that mitigate diagnostic delays.

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