1. Aishworiya R, Chi MH, Zafarullah M, Mendoza G, Ponzini MD, Kim K, Biag HMB, Thurman AJ, Abbeduto L, Hessl D, Randol JL, Bolduc FV, Jacquemont S, Lippé S, Hagerman P, Hagerman R, Schneider A, Tassone F. Intercorrelation of Molecular Biomarkers and Clinical Phenotype Measures in Fragile X Syndrome. Cells;2023 (Jul 24);12(14)

This study contributes to a greater understanding of the utility of molecular biomarkers to identify clinical phenotypes of fragile X syndrome (FXS). Correlations of baseline clinical trial data (molecular measures-FMR1 mRNA, CYFIP1 mRNA, MMP9 and FMRP protein expression levels, nonverbal IQ, body mass index and weight, language level, NIH Toolbox, adaptive behavior rating, autism, and other mental health correlates) of 59 participants with FXS ages of 6-32 years are reported. FMR1 mRNA expression levels correlated positively with adaptive functioning levels, expressive language, and specific NIH Toolbox measures. The findings of a positive correlation of MMP-9 levels with obesity, CYFIP1 mRNA with mood and autistic symptoms, and FMR1 mRNA expression level with better cognitive, language, and adaptive functions indicate potential biomarkers for specific FXS phenotypes. These may be potential markers for future clinical trials for targeted treatments of FXS.

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2. Ali K, Shah S, Hughes CE. In-the-Wild Affect Analysis of Children with ASD Using Heart Rate. Sensors (Basel);2023 (Jul 21);23(14)

Recognizing the affective state of children with autism spectrum disorder (ASD) in real-world settings poses challenges due to the varying head poses, illumination levels, occlusion and a lack of datasets annotated with emotions in in-the-wild scenarios. Understanding the emotional state of children with ASD is crucial for providing personalized interventions and support. Existing methods often rely on controlled lab environments, limiting their applicability to real-world scenarios. Hence, a framework that enables the recognition of affective states in children with ASD in uncontrolled settings is needed. This paper presents a framework for recognizing the affective state of children with ASD in an in-the-wild setting using heart rate (HR) information. More specifically, an algorithm is developed that can classify a participant’s emotion as positive, negative, or neutral by analyzing the heart rate signal acquired from a smartwatch. The heart rate data are obtained in real time using a smartwatch application while the child learns to code a robot and interacts with an avatar. The avatar assists the child in developing communication skills and programming the robot. In this paper, we also present a semi-automated annotation technique based on facial expression recognition for the heart rate data. The HR signal is analyzed to extract features that capture the emotional state of the child. Additionally, in this paper, the performance of a raw HR-signal-based emotion classification algorithm is compared with a classification approach based on features extracted from HR signals using discrete wavelet transform (DWT). The experimental results demonstrate that the proposed method achieves comparable performance to state-of-the-art HR-based emotion recognition techniques, despite being conducted in an uncontrolled setting rather than a controlled lab environment. The framework presented in this paper contributes to the real-world affect analysis of children with ASD using HR information. By enabling emotion recognition in uncontrolled settings, this approach has the potential to improve the monitoring and understanding of the emotional well-being of children with ASD in their daily lives.

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3. Babiec L, Wilkaniec A, Matuszewska M, Pałasz E, Cieślik M, Adamczyk A. Alterations of Purinergic Receptors Levels and Their Involvement in the Glial Cell Morphology in a Pre-Clinical Model of Autism Spectrum Disorders. Brain Sci;2023 (Jul 18);13(7)

Recent data suggest that defects in purinergic signalling are a common denominator of autism spectrum disorders (ASDs), though nothing is known about whether the disorder-related imbalance occurs at the receptor level. In this study, we investigated whether prenatal exposure to valproic acid (VPA) induces changes in purinergic receptor expression in adolescence and whether it corresponds to glial cell activation. Pregnant dams were subjected to an intraperitoneal injection of VPA at embryonic day 12.5. In the hippocampi of adolescent male VPA offspring, we observed an increase in the level of P2X1, with concomitant decreases in P2X7 and P2Y1 receptors. In contrast, in the cortex, the level of P2X1 was significantly reduced. Also, significant increases in cortical P2Y1 and P2Y12 receptors were detected. Additionally, we observed profound alterations in microglial cell numbers and morphology in the cortex of VPA animals, leading to the elevation of pro-inflammatory cytokine expression. The changes in glial cells were partially reduced via a single administration of a non-selective P2 receptor antagonist. These studies show the involvement of purinergic signalling imbalance in the modulation of brain inflammatory response induced via prenatal VPA exposure and may indicate that purinergic receptors are a novel target for pharmacological intervention in ASDs.

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4. Ballester P, Espadas C, Almenara S, Barrachina J, Muriel J, Ramos E, Toral N, Belda C, Peiró AM. CYP2D6 Genotype and Pharmacovigilance Impact on Autism Spectrum Disorder: A Naturalistic Study with Extreme Phenotype Analysis. Pharmaceuticals (Basel);2023 (Jul 3);16(7)

The long-term use of psychopharmacology medications in autism spectrum disorder (ASD) hitherto remains controversial due to a lack of evidence about safety and tolerability. In this regard, genotyping the metabolizing enzyme cytochrome P450 (CYP) 2D6, especially its extreme phenotypes, could help to prevent drug-related adverse reactions or adverse events (AEs). There are several medications warranting CYP2D6 screening that are consumed by people with ASD, such as risperidone and aripiprazole to name a few. A naturalistic observational study was carried out in participants with ASD to analyze the influence of the CYP2D6 phenotype in drug tolerability using a local pharmacovigilance system created for this study. In this case, AEs were identified from participants’ electronic health records (EHRs) and paper registries. Other variables were collected: socio-demographic information, comorbidities, and psychopharmacology prescriptions (polypharmacy defined as ≥4 simultaneous prescriptions) and doses. The genetic analysis included allelic discrimination (CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, and *41) and copy number variations. All of these were used to determine theoretical phenotypes of the metabolic profiles: poor (PM); intermediate (IM); normal (NM); and ultra-rapid (UM). Sex differences were analyzed. A total of 71 participants (30 ± 10 years old, 82% male, 45% CYP2D6 NM phenotype (32 participants)) with a median of 3 (IQR 2-4) comorbidities per person, mainly urinary incontinence (32%) and constipation (22%), were included. CYP2D6 UM showed the highest rate of polypharmacy, whilst, IM participants had the highest rates of neurological and psychiatric AEs, even worse if a CYP2D6 inhibitor drug was prescribed simultaneously. CYP2D6 pharmacogenomics and the monitoring of new antipsychotic prescriptions may make a difference in medication safety in adults with ASD. Particularly in those with psychopharmacology polymedication, it can help with AE avoidance and understanding.

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5. Cerchiari A, Giordani C, Franceschetti S, Mazzafoglia S, Carosi F, Pizza F, Bella GD, Raponi M, Tofani M. The Efficacy of the Global Intensive Feeding Therapy on Feeding and Swallowing Abilities in Children with Autism Spectrum Disorder: A Pilot Study. Children (Basel);2023 (Jul 19);10(7)

The present investigation aims to explore the efficacy of Global Intensive Feeding Therapy (GIFT) on feeding and swallowing abilities in children with autism spectrum disorder (ASD). GIFT was developed as an intensive rehabilitation approach, divided into 30 sessions for 2 weeks, three times a day. GIFT focused on (a) encouraging desensitization; (b) widening the food repertoire (in terms of both variety and quantity); (c) reducing inappropriate mealtime behaviors; and (d) encouraging the development of appropriate chewing and swallowing abilities. GIFT was preliminarily implemented among 11 children with a diagnosis of ASD. To measure the efficacy of GIFT, the Karaduman Chewing Performance Scale (KCPS), the Brief Autism Mealtime Behavior Inventory (BAMBI), and food repertoire were investigated using Wilcoxon signed-rank test in three different times: baseline (T1), after treatment (T2), and one month after treatment (T3). Using Bonferroni correction, statistically significant differences were found between T1 and T2 for behavioral issues, as measured with BAMBI (p = 0.007), as well as for chewing abilities as measured with KCPS (p = 0.005) and for food acceptance (p = 0.005). These improvements were maintained after a month of follow-up, thanks to the collaboration of families and/or primary caregivers. In conclusion, GIFT seems to be an effective approach to improving behavioral issues, food acceptance, and chewing abilities in children with ASD.

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6. Croom K, Rumschlag JA, Erickson MA, Binder DK, Razak KA. Developmental delays in cortical auditory temporal processing in a mouse model of Fragile X syndrome. J Neurodev Disord;2023 (Jul 29);15(1):23.

BACKGROUND: Autism spectrum disorders (ASD) encompass a wide array of debilitating symptoms, including sensory dysfunction and delayed language development. Auditory temporal processing is crucial for speech perception and language development. Abnormal development of temporal processing may account for the language impairments associated with ASD. Very little is known about the development of temporal processing in any animal model of ASD. METHODS: In the current study, we quantify auditory temporal processing throughout development in the Fmr1 knock-out (KO) mouse model of Fragile X Syndrome (FXS), a leading genetic cause of intellectual disability and ASD-associated behaviors. Using epidural electrodes in awake and freely moving wildtype (WT) and KO mice, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (gap-ASSR) paradigm. Mice were recorded at three different ages in a cross sectional design: postnatal (p)21, p30 and p60. Recordings were obtained from both auditory and frontal cortices. The gap-ASSR requires underlying neural generators to synchronize responses to gaps of different widths embedded in noise, providing an objective measure of temporal processing across genotypes and age groups. RESULTS: We present evidence that the frontal, but not auditory, cortex shows significant temporal processing deficits at p21 and p30, with poor ability to phase lock to rapid gaps in noise. Temporal processing was similar in both genotypes in adult mice. ERP amplitudes were larger in Fmr1 KO mice in both auditory and frontal cortex, consistent with ERP data in humans with FXS. CONCLUSIONS: These data indicate cortical region-specific delays in temporal processing development in Fmr1 KO mice. Developmental delays in the ability of frontal cortex to follow rapid changes in sounds may shape language delays in FXS, and more broadly in ASD.

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7. de la Rubia Ortí JE, Moneti C, Serrano-Ballesteros P, Castellano G, Bayona-Babiloni R, Carriquí-Suárez AB, Motos-Muñoz M, Proaño B, Benlloch M. Liposomal Epigallocatechin-3-Gallate for the Treatment of Intestinal Dysbiosis in Children with Autism Spectrum Disorder: A Comprehensive Review. Nutrients;2023 (Jul 24);15(14)

Autism Spectrum Disorder (ASD) is characterized by varying degrees of difficulty in social interaction and communication. These deficits are often associated with gastrointestinal symptoms, indicating alterations in both intestinal microbiota composition and metabolic activities. The intestinal microbiota influences the function and development of the nervous system. In individuals with ASD, there is an increase in bacterial genera such as Clostridium, as well as species involved in the synthesis of branched-chain amino acids (BCAA) like Prevotella copri. Conversely, decreased amounts of Akkermansia muciniphila and Bifidobacterium spp. are observed. Epigallocatechin-3-gallate (EGCG) is one of the polyphenols with the greatest beneficial activity on microbial growth, and its consumption is associated with reduced psychological distress. Therefore, the objective of this review is to analyze how EGCG and its metabolites can improve the microbial dysbiosis present in ASD and its impact on the pathology. The analysis reveals that EGCG inhibits the growth of pathogenic bacteria like Clostridium perfringens and Clostridium difficile. Moreover, it increases the abundance of Bifidobacterium spp. and Akkermansia spp. As a result, EGCG demonstrates efficacy in increasing the production of metabolites involved in maintaining epithelial integrity and improving brain function. This identifies EGCG as highly promising for complementary treatment in ASD.

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8. Dell’Osso L, Amatori G, Muti D, Giovannoni F, Parri F, Violi M, Cremone IM, Carpita B. Autism Spectrum, Hikikomori Syndrome and Internet Gaming Disorder: Is There a Link?. Brain Sci;2023 (Jul 23);13(7)

The aim of this study is to review the available literature investigating the relationship between hikikomori, a pathological condition characterized by severe social withdrawal or isolation, autism spectrum disorder (ASD) and Internet gaming disorder (IGD). Studies on the relationship between ASD and IGD have found significant positive correlations between these two conditions. Individuals with ASD would appear to be at risk of developing a problematic use of the Internet, which, to the right extent, would represent a useful tool for social interaction and cognitive development. Even subjects with hikikomori, in whom rarefied interpersonal relationships and social isolation could be balanced by the use of online connections, appear to be at high risk of developing IGD. On the other hand, the finding of significant autistic traits in populations with hikikomori could lead to considering this psychopathological condition as a particular presentation of autism spectrum, a hypothesis that requires further investigation.

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9. Dong Q, Li J, Ju Y, Xiao C, Li K, Shi B, Zheng W, Zhang Y. Altered Relationship between Functional Connectivity and Fiber-Bundle Structure in High-Functioning Male Adults with Autism Spectrum Disorder. Brain Sci;2023 (Jul 20);13(7)

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterized by abnormalities in structure and function of the brain. However, how ASD affects the relationship between fiber-bundle microstructures and functional connectivity (FC) remains unclear. Here, we analyzed structural and functional images of 26 high-functioning adult males with ASD, alongside 26 age-, gender-, and full-scale IQ-matched typically developing controls (TDCs) from the BNI dataset in the ABIDE database. We utilized fixel-based analysis to extract microstructural information from fiber tracts, which was then used to predict FC using a multilinear model. Our results revealed that the structure-function relationships in both ASD and TDC cohorts were strongly aligned in the primary cortex but decoupled in the high-order cortex, and the ASD patients exhibited reduced structure-function relationships throughout the cortex compared to the TDCs. Furthermore, we observed that the disrupted relationships in ASD were primarily driven by alterations in FC rather than fiber-bundle microstructures. The structure-function relationships in the left superior parietal cortex, right precentral and inferior temporal cortices, and bilateral insula could predict individual differences in clinical symptoms of ASD patients. These findings underscore the significance of altered relationships between fiber-bundle microstructures and FC in the etiology of ASD.

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10. Dunham-Carr K, Feldman JI, Simon DM, Edmunds SR, Tu A, Kuang W, Conrad JG, Santapuram P, Wallace MT, Woynaroski TG. The Processing of Audiovisual Speech Is Linked with Vocabulary in Autistic and Nonautistic Children: An ERP Study. Brain Sci;2023 (Jul 8);13(7)

Explaining individual differences in vocabulary in autism is critical, as understanding and using words to communicate are key predictors of long-term outcomes for autistic individuals. Differences in audiovisual speech processing may explain variability in vocabulary in autism. The efficiency of audiovisual speech processing can be indexed via amplitude suppression, wherein the amplitude of the event-related potential (ERP) is reduced at the P2 component in response to audiovisual speech compared to auditory-only speech. This study used electroencephalography (EEG) to measure P2 amplitudes in response to auditory-only and audiovisual speech and norm-referenced, standardized assessments to measure vocabulary in 25 autistic and 25 nonautistic children to determine whether amplitude suppression (a) differs or (b) explains variability in vocabulary in autistic and nonautistic children. A series of regression analyses evaluated associations between amplitude suppression and vocabulary scores. Both groups demonstrated P2 amplitude suppression, on average, in response to audiovisual speech relative to auditory-only speech. Between-group differences in mean amplitude suppression were nonsignificant. Individual differences in amplitude suppression were positively associated with expressive vocabulary through receptive vocabulary, as evidenced by a significant indirect effect observed across groups. The results suggest that efficiency of audiovisual speech processing may explain variance in vocabulary in autism.

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11. Federman D, Blustein A, Rabinowitch TC. Mapping the Physical Language of Children Diagnosed with Autism: A Preliminary Study. Children (Basel);2023 (Jun 21);10(7)

Children diagnosed with autism spectrum disorder have a unique motor profile, characterized by, for example, unusual posture or compulsive use of the body. However, not much is known about specific characteristics of their physical language, such as their movement direction, their self-touch pattern, etc., and even less is known about these characteristics with regard to their typically developing siblings. In this first of its kind study, we attempted to map the physical language of children diagnosed with autism spectrum disorder and to compare it to their typically developing siblings. To this end, we recruited 12 pairs of siblings, comprising one sibling with a diagnosis of autism and one sibling who is typically developing. The siblings were asked to play for 10 min and were videotaped throughout the interaction. We evaluated the siblings’ physical language using Laban’s movement analysis. We found significant and substantial differences between the physical language of the children diagnosed with autism and their typically developing siblings. The results are discussed in terms of the implications of the differences in physical language between the two populations and how movement analysis could be important for interventions in order to improve the communication and social abilities of ASD children.

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12. Ferencova N, Visnovcova Z, Ondrejka I, Hrtanek I, Bujnakova I, Kovacova V, Macejova A, Tonhajzerova I. Peripheral Inflammatory Markers in Autism Spectrum Disorder and Attention Deficit/Hyperactivity Disorder at Adolescent Age. Int J Mol Sci;2023 (Jul 20);24(14)

Autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) are associated with immune dysregulation. We aimed to estimate the pro- and anti-inflammatory activity/balance in ASD and ADHD patients at a little-studied adolescent age with respect to sex. We evaluated 20 ASD patients (5 girls, average age: 12.4 ± 1.9 y), 20 ADHD patients (5 girls, average age: 13.4 ± 1.8 y), and 20 age- and gender-matched controls (average age: 13.2 ± 1.9 y). The evaluated parameters included (1) white blood cells (WBCs), neutrophils, monocytes, lymphocytes, platelets, platelet distribution width (PDW), mean platelet volume, and derived ratios, as well as (2) cytokines-interferon-gamma, interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, and IL-10, tumor necrosis factor-alpha (TNF-α), and derived profiles and ratios. ASD adolescents showed higher levels of WBC, monocytes, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, and IL-10, macrophages (M)1 profile, and anti-inflammatory profile than the controls, with ASD males showing higher monocytes, IL-6 and IL-10, anti-inflammatory profile, and a lower T-helper (Th)1/Th2+T-regulatory cell ratio than control males. The ADHD adolescents showed higher levels of PDW, IL-1β and IL-6, TNF-α, M1 profile, proinflammatory profile, and pro-/anti-inflammatory ratio than the controls, with ADHD females showing a higher TNF-α and pro-/anti-inflammatory ratio than the control females and ADHD males showing higher levels of IL-1β and IL-6, TNF-α, and M1 profile than the control males. Immune dysregulation appeared to be different for both neurodevelopmental disorders in adolescence.

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13. Ferraguto C, Bouleau Y, Peineau T, Dulon D, Pietropaolo S. Hyperacusis in the Adult Fmr1-KO Mouse Model of Fragile X Syndrome: The Therapeutic Relevance of Cochlear Alterations and BKCa Channels. Int J Mol Sci;2023 (Jul 24);24(14)

Hyperacusis, i.e., an increased sensitivity to sounds, is described in several neurodevelopmental disorders (NDDs), including Fragile X Syndrome (FXS). The mechanisms underlying hyperacusis in FXS are still largely unknown and effective therapies are lacking. Big conductance calcium-activated potassium (BKCa) channels were proposed as a therapeutic target to treat several behavioral disturbances in FXS preclinical models, but their role in mediating their auditory alterations was not specifically addressed. Furthermore, studies on the acoustic phenotypes of FXS animal models mostly focused on central rather than peripheral auditory pathways. Here, we provided an extensive characterization of the peripheral auditory phenotype of the Fmr1-knockout (KO) mouse model of FXS at adulthood. We also assessed whether the acute administration of Chlorzoxazone, a BKCa agonist, could rescue the auditory abnormalities of adult mutant mice. Fmr1-KO mice both at 3 and 6 months showed a hyperacusis-like startle phenotype with paradoxically reduced auditory brainstem responses associated with a loss of ribbon synapses in the inner hair cells (IHCs) compared to their wild-type (WT) littermates. BKCa expression was markedly reduced in the IHCs of KOs compared to WT mice, but only at 6 months, when Chlorzoxazone rescued mutant auditory dysfunction. Our findings highlight the age-dependent and progressive contribution of peripheral mechanisms and BKCa channels to adult hyperacusis in FXS, suggesting a novel therapeutic target to treat auditory dysfunction in NDDs.

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14. Frankovich J, Nanda H, Mellins ED, Jyonouchi H, Boles RG, Walker SJ, Gaitanis J, Frye RE. Synchrony 2022: The Role of Neuroinflammation in Behavioral Exacerbations in Autism Spectrum Disorder. J Pers Med;2023 (Jul 13);13(7)

The BRAIN Foundation (Pleasanton, CA) hosted Synchrony 2022, a medical conference focusing on research for treatments to benefit individuals with neurodevelopmental disorders (NDD), including those with autism spectrum disorders (ASD) […].

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15. Frasch MG, Yoon BJ, Helbing DL, Snir G, Antonelli MC, Bauer R. Autism Spectrum Disorder: A Neuro-Immunometabolic Hypothesis of the Developmental Origins. Biology (Basel);2023 (Jun 26);12(7)

Fetal neuroinflammation and prenatal stress (PS) may contribute to lifelong neurological disabilities. Astrocytes and microglia, among the brain’s non-neuronal « glia » cell populations, play a pivotal role in neurodevelopment and predisposition to and initiation of disease throughout lifespan. One of the most common neurodevelopmental disorders manifesting between 1-4 years of age is the autism spectrum disorder (ASD). A pathological glial-neuronal interplay is thought to increase the risk for clinical manifestation of ASD in at-risk children, but the mechanisms remain poorly understood, and integrative, multi-scale models are needed. We propose a model that integrates the data across the scales of physiological organization, from genome to phenotype, and provides a foundation to explain the disparate findings on the genomic level. We hypothesize that via gene-environment interactions, fetal neuroinflammation and PS may reprogram glial immunometabolic phenotypes that impact neurodevelopment and neurobehavior. Drawing on genomic data from the recently published series of ovine and rodent glial transcriptome analyses with fetuses exposed to neuroinflammation or PS, we conducted an analysis on the Simons Foundation Autism Research Initiative (SFARI) Gene database. We confirmed 21 gene hits. Using unsupervised statistical network analysis, we then identified six clusters of probable protein-protein interactions mapping onto the immunometabolic and stress response networks and epigenetic memory. These findings support our hypothesis. We discuss the implications for ASD etiology, early detection, and novel therapeutic approaches. We conclude with delineation of the next steps to verify our model on the individual gene level in an assumption-free manner. The proposed model is of interest for the multidisciplinary community of stakeholders engaged in ASD research, the development of novel pharmacological and non-pharmacological treatments, early prevention, and detection as well as for policy makers.

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16. Gaitanis J, Nie D, Hou T, Frye R. Developmental Regression Followed by Epilepsy and Aggression: A New Syndrome in Autism Spectrum Disorder?. J Pers Med;2023 (Jun 26);13(7)

Autism spectrum disorder (ASD) with regression (ASD-R) involves the loss of previously attained developmental milestones, typically during the first or second year of life. As children age, it is not uncommon for them to develop comorbid conditions such as aggressive behaviors or epilepsy, which can inhibit habilitation in language and social function. In this paper, we hypothesize that aggressive behaviors and epilepsy more commonly develop in patients with ASD-R than in those without a history of regression (ASD-NR). We conducted a retrospective review of non-syndromic patients with ASD over 12 years of age and compared the rates of epilepsy and aggression between ASD-R and ASD-NR patients. Patients with ASD-R, as compared to ASD-NR patients, demonstrated non-significantly higher rates of epilepsy (51.8% vs. 38.1%, p = 0.1335) and aggressive behaviors (73.2% vs. 57.1%, p = 0.0673) when evaluated separately. The rates for combined epilepsy and aggression, however, were statistically significant when comparing ASD-R versus ASD patients (44.5% vs. 23.8%, p = 0.0163). These results suggest that epilepsy with aggression is more common in ASD-R as compared to ASD-NR patients. When considering the impact of epilepsy and aggression on quality of life, these co-morbidities effectively cause a second regression in patients who experienced an earlier regression as toddlers. A larger, prospective trial is recommended to confirm these associations and further define the timeline in which these characteristics develop from early childhood to adolescence.

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17. Gasser B, Escher G, Calin AE, Deppeler M, Marchon M, Kurz J, Mohaupt M. Are steroid hormones and autistic traits affected by metformin? First insights from a pilot. Compr Psychoneuroendocrinol;2023 (Nov);16:100196.

BACKGROUND: Different lines of evidence imply that metformin could alter steroid hormone homeostasis and thereby improve social impairment. Here, we tried to correlate the impact of metformin treatment on alterations in steroid hormones and autism spectrum traits before versus after treatment with metformin. MATERIAL & METHODS: Urine steroid hormones were measured using gas chromatography mass spectrometry in 12 male subjects (54.2 ± 9.1 years, 177.3 ± 4.1 cm, 80 ± 10.4 kg) and 7 female subjects (64.14 ± 18.0 years, 162.7 ± 4.1 cm, 76.1 ± 10.4 kg). Furthermore, a questionnaire on autism spectrum traits (Autism Spectrum Questionnaire]) was administered prior to and after metformin treatment. RESULTS: Overall, a decrease of steroid hormones were detected, which were most pronounced in the metabolites of corticosterone, deoxycortisol, cortisol, as well as androgens. These remained after Bonferroni correction (three classes: glucocorticoid, mineralocorticoid, androgens). No effect on autism spectrum traits (social skills, attention switching skills, attention to detail skills, communication skills, imagination skills), was identified pre versus post metformin treatment. DISCUSSION: The decreased steroid hormone levels are based on different mechanisms; one effect is likely via mitochondria, another effect via activated protein kinase prior to post treatment. The finding on autistic traits must be taxed as negative and do not directly provide an argument for using metformin in the treatment of autism.

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18. Golubiani G, van Agen L, Tsverava L, Solomonia R, Müller M. Mitochondrial Proteome Changes in Rett Syndrome. Biology (Basel);2023 (Jul 3);12(7)

Rett syndrome (RTT) is a genetic neurodevelopmental disorder with mutations in the X-chromosomal MECP2 (methyl-CpG-binding protein 2) gene. Most patients are young girls. For 7-18 months after birth, they hardly present any symptoms; later they develop mental problems, a lack of communication, irregular sleep and breathing, motor dysfunction, hand stereotypies, and seizures. The complex pathology involves mitochondrial structure and function. Mecp2(-/y) hippocampal astrocytes show increased mitochondrial contents. Neurons and glia suffer from oxidative stress, a lack of ATP, and increased hypoxia vulnerability. This spectrum of changes demands comprehensive molecular studies of mitochondria to further define their pathogenic role in RTT. Therefore, we applied a comparative proteomic approach for the first time to study the entity of mitochondrial proteins in a mouse model of RTT. In the neocortex and hippocampus of symptomatic male mice, two-dimensional gel electrophoresis and subsequent mass-spectrometry identified various differentially expressed mitochondrial proteins, including components of respiratory chain complexes I and III and the ATP-synthase FoF1 complex. The NADH-ubiquinone oxidoreductase 75 kDa subunit, NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, NADH dehydrogenase [ubiquinone] flavoprotein 2, cytochrome b-c1 complex subunit 1, and ATP synthase subunit d are upregulated either in the hippocampus alone or both the hippocampus and neocortex of Mecp2(-/y) mice. Furthermore, the regulatory mitochondrial proteins mitofusin-1, HSP60, and 14-3-3 protein theta are decreased in the Mecp2(-/y) neocortex. The expressional changes identified provide further details of the altered mitochondrial function and morphology in RTT. They emphasize brain-region-specific alterations of the mitochondrial proteome and support the notion of a metabolic component of this devastating disorder.

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19. Griffioen RE, van Boxtel GJM, Verheggen T, Enders-Slegers MJ, Van Der Steen S. Group Changes in Cortisol and Heart Rate Variability of Children with Down Syndrome and Children with Autism Spectrum Disorder during Dog-Assisted Therapy. Children (Basel);2023 (Jul 11);10(7)

Dog-assisted therapy is hypothesized to lower stress in children with autism spectrum disorder (ASD) and children with Down syndrome (DS), which may be visible on a physiological level. In this study, we measured heart rate variability (HRV) and salivary cortisol of 20 children with DS or ASD at the beginning and end of six weekly sessions of dog-assisted therapy. We found a decrease of cortisol levels during single sessions, but no overall effect after six sessions (six weeks). The effect of dog-assisted therapy on the increase of HRV could not be confirmed. This study is one of the first to use physiological measurements to test the effects of DAT.

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20. Gundogdu BS, Gaitanis J, Adams JB, Rossignol DA, Frye RE. Age-Related Changes in Epilepsy Characteristics and Response to Antiepileptic Treatment in Autism Spectrum Disorders. J Pers Med;2023 (Jul 21);13(7)

Despite the high prevalence of epilepsy in individuals with autism spectrum disorder (ASD), there is little information regarding whether seizure characteristics and treatment effectiveness change across age. Using an online survey, seizure characteristics, effectiveness of antiepileptic treatments, comorbidities, potential etiologies, and ASD diagnosis were collected from individuals with ASD and seizures. We previously reported overall general patterns of treatment effectiveness but did not examine the effect of seizure characteristics or age on antiepileptic treatment effectiveness. Such information would improve the personalized medicine approach to the treatment of seizures in ASD. Survey data from 570 individuals with ASD and clinical seizures were analyzed. Seizure severity (seizure/week) decreased with age of onset of seizures, plateauing in adolescence, with a greater reduction in generalized tonic-clonic (GTC) seizures with age. Seizure severity was worse in those with genetic disorders, neurodevelopmental regression (NDR) and poor sleep maintenance. Carbamazepine and oxcarbazepine were reported to be more effective when seizures started in later childhood, while surgery and the Atkins/modified Atkins Diet (A/MAD) were reported to be more effective when seizures started early in life. A/MAD and the ketogenic diet were reported to be more effective in those with NDR. Interestingly, atypical Landau-Kleffner syndrome was associated with mitochondrial dysfunction and NDR, suggesting a novel syndrome. These interesting findings need to be verified in independent, prospectively collected cohorts, but nonetheless, these data provide insights into novel relationships that may assist in a better understanding of epilepsy in ASD and provide insight into personalizing epilepsy care in ASD.

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21. Harwood V, Baron A, Kleinman D, Campanelli L, Irwin J, Landi N. Event-Related Potentials in Assessing Visual Speech Cues in the Broader Autism Phenotype: Evidence from a Phonemic Restoration Paradigm. Brain Sci;2023 (Jun 30);13(7)

Audiovisual speech perception includes the simultaneous processing of auditory and visual speech. Deficits in audiovisual speech perception are reported in autistic individuals; however, less is known regarding audiovisual speech perception within the broader autism phenotype (BAP), which includes individuals with elevated, yet subclinical, levels of autistic traits. We investigate the neural indices of audiovisual speech perception in adults exhibiting a range of autism-like traits using event-related potentials (ERPs) in a phonemic restoration paradigm. In this paradigm, we consider conditions where speech articulators (mouth and jaw) are present (AV condition) and obscured by a pixelated mask (PX condition). These two face conditions were included in both passive (simply viewing a speaking face) and active (participants were required to press a button for a specific consonant-vowel stimulus) experiments. The results revealed an N100 ERP component which was present for all listening contexts and conditions; however, it was attenuated in the active AV condition where participants were able to view the speaker’s face, including the mouth and jaw. The P300 ERP component was present within the active experiment only, and significantly greater within the AV condition compared to the PX condition. This suggests increased neural effort for detecting deviant stimuli when visible articulation was present and visual influence on perception. Finally, the P300 response was negatively correlated with autism-like traits, suggesting that higher autistic traits were associated with generally smaller P300 responses in the active AV and PX conditions. The conclusions support the finding that atypical audiovisual processing may be characteristic of the BAP in adults.

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22. Helmy E, Elnakib A, ElNakieb Y, Khudri M, Abdelrahim M, Yousaf J, Ghazal M, Contractor S, Barnes GN, El-Baz A. Role of Artificial Intelligence for Autism Diagnosis Using DTI and fMRI: A Survey. Biomedicines;2023 (Jun 29);11(7)

Autism spectrum disorder (ASD) is a wide range of diseases characterized by difficulties with social skills, repetitive activities, speech, and nonverbal communication. The Centers for Disease Control (CDC) estimates that 1 in 44 American children currently suffer from ASD. The current gold standard for ASD diagnosis is based on behavior observational tests by clinicians, which suffer from being subjective and time-consuming and afford only late detection (a child must have a mental age of at least two to apply for an observation report). Alternatively, brain imaging-more specifically, magnetic resonance imaging (MRI)-has proven its ability to assist in fast, objective, and early ASD diagnosis and detection. With the recent advances in artificial intelligence (AI) and machine learning (ML) techniques, sufficient tools have been developed for both automated ASD diagnosis and early detection. More recently, the development of deep learning (DL), a young subfield of AI based on artificial neural networks (ANNs), has successfully enabled the processing of brain MRI data with improved ASD diagnostic abilities. This survey focuses on the role of AI in autism diagnostics and detection based on two basic MRI modalities: diffusion tensor imaging (DTI) and functional MRI (fMRI). In addition, the survey outlines the basic findings of DTI and fMRI in autism. Furthermore, recent techniques for ASD detection using DTI and fMRI are summarized and discussed. Finally, emerging tendencies are described. The results of this study show how useful AI is for early, subjective ASD detection and diagnosis. More AI solutions that have the potential to be used in healthcare settings will be introduced in the future.

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23. Herath M, Cho E, Marklund U, Franks AE, Bornstein JC, Hill-Yardin EL. Quantitative Spatial Analysis of Neuroligin-3 mRNA Expression in the Enteric Nervous System Reveals a Potential Role in Neuronal-Glial Synapses and Reduced Expression in Nlgn3(R451C) Mice. Biomolecules;2023 (Jun 30);13(7)

Mutations in the Neuroligin-3 (Nlgn3) gene are implicated in autism spectrum disorder (ASD) and gastrointestinal (GI) dysfunction, but cellular Nlgn3 expression in the enteric nervous system remains to be characterised. We combined RNAScope in situ hybridization and immunofluorescence to measure Nlgn3 mRNA expression in cholinergic and VIP-expressing submucosal neurons, nitrergic and calretinin-containing myenteric neurons and glial cells in both WT and Nlgn3(R451C) mutant mice. We measured Nlgn3 mRNA neuronal and glial expression via quantitative three-dimensional image analysis. To validate dual RNAScope/immunofluorescence data, we interrogated available single-cell RNA sequencing (scRNASeq) data to assess for Nlgn3, Nlgn1, Nlgn2 and their binding partners, Nrxn1-3, MGDA1 and MGDA2, in enteric neural subsets. Most submucosal and myenteric neurons expressed Nlgn3 mRNA. In contrast to other Nlgns and binding partners, Nlgn3 was strongly expressed in enteric glia, suggesting a role for neuroligin-3 in mediating enteric neuron-glia interactions. The autism-associated R451C mutation reduces Nlgn3 mRNA expression in cholinergic but not in VIPergic submucosal neurons. In the myenteric plexus, Nlgn3 mRNA levels are reduced in calretinin, nNOS-labelled neurons and S100 β -labelled glia. We provide a comprehensive cellular profile for neuroligin-3 expression in ileal neuronal subpopulations of mice expressing the R451C autism-associated mutation in Nlgn3, which may contribute to the understanding of the pathophysiology of GI dysfunction in ASD.

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24. Herrera-Mejía J, Campos-Vega R, Wall-Medrano A, Jiménez-Vega F. A Two-Step Single Plex PCR Method for Evaluating Key Colonic Microbiota Markers in Young Mexicans with Autism Spectrum Disorders: Protocol and Pilot Epidemiological Application. Diagnostics (Basel);2023 (Jul 17);13(14)

Many neurological disorders have a distinctive colonic microbiome (CM) signature. Particularly, children with autism spectrum disorders (ASD) exhibit a very dissimilar CM when compared to neurotypical (NT) ones, mostly at the species level. Thus far, knowledge on this matter comes from high-throughput (yet very expensive and time-consuming) analytical platforms, such as massive high-throughput sequencing of bacterial 16S rRNA. Here, pure (260/280 nm, ~1.85) stool DNA samples (200 ng.µL(-1)) from 48 participants [39 ASD, 9 NT; 3-13 y] were used to amplify four candidate differential CM markers [Bacteroides fragilis (BF), Faecalibacterium prausnitzii (FP), Desulfovibrio vulgaris (DV), Akkermansia muciniphila (AM)], using micro-organism-specific oligonucleotide primers [265 bp (BF), 198 bp (FP), 196 bp (DV), 327 bp (AM)] and a standardized two-step [low (step 1: °Tm-5 °C) to high (stage 2: °Tm-0 °C) astringent annealing] PCR protocol (2S-PCR). The method was sensitive enough to differentiate all CM biomarkers in the studied stool donors [↑ abundance: NT (BF, FP, AM), ASD (DV)], and phylogenetic analysis confirmed the primers’ specificity.

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25. Lamboglia A, Romano R, Valente D, Berardi A, Cavalli G, Giovannone F, Sogos C, Tofani M, Galeoto G. Brief Autism Mealtime Behavior Inventory (BAMBI): Italian Translation and Validation. Children (Basel);2023 (Jul 11);10(7)

Food selectivity is among the most common problems for children with Autism Spectrum Disorder (ASD). The present study aims to validate the Brief Autism Mealtime Behavior Inventory (BAMBI) in an Italian population of children with ASD. BAMBI was translated and cross-culturally adapted following international guidelines, then we investigated internal consistency as measured by Cronbach’s alpha and test-retest reliability, as measured by the Intraclass Correlation Coefficient (ICC) in a sample of both children with ASD and with typical development (TD). A total of 131 children were recruited in a clinical and community sample. Internal consistency revealed significant data for both TD and ASD children, with a Cronbach’s Alpha of 0.86 and 0.71, respectively. Test-retest reliability showed excellent values for each item of the BAMBI (range 0.83-1.00). Furthermore, we investigated differences in gender and body max index; however, no significant differences were found among groups. In conclusion, the Italian version of the BAMBI showed good internal consistency and test-retest reliability and it can be used for clinical and research purposes.

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26. Leharanger M, Rodriguez Martinez EA, Balédent O, Vandromme L. Familiarization with Mixed Reality for Individuals with Autism Spectrum Disorder: An Eye Tracking Study. Sensors (Basel);2023 (Jul 11);23(14)

Mixed Reality (MR) technology is experiencing significant growth in the industrial and healthcare sectors. The headset HoloLens 2 displays virtual objects (in the form of holograms) in the user’s environment in real-time. Individuals with Autism Spectrum Disorder (ASD) exhibit, according to the DSM-5, persistent deficits in communication and social interaction, as well as a different sensitivity compared to neurotypical (NT) individuals. This study aims to propose a method for familiarizing eleven individuals with severe ASD with the HoloLens 2 headset and the use of MR technology through a tutorial. The secondary objective is to obtain quantitative learning indicators in MR, such as execution speed and eye tracking (ET), by comparing individuals with ASD to neurotypical individuals. We observed that 81.81% of individuals with ASD successfully familiarized themselves with MR after several sessions. Furthermore, the visual activity of individuals with ASD did not differ from that of neurotypical individuals when they successfully familiarized themselves. This study thus offers new perspectives on skill acquisition indicators useful for supporting neurodevelopmental disorders. It contributes to a better understanding of the neural mechanisms underlying learning in MR for individuals with ASD.

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27. Levkova M, Chervenkov T, Pancheva R. Genus-Level Analysis of Gut Microbiota in Children with Autism Spectrum Disorder: A Mini Review. Children (Basel);2023 (Jun 23);10(7)

Autism is a global health problem, probably due to a combination of genetic and environmental factors. There is emerging data that the gut microbiome of autistic children differs from the one of typically developing children and it is important to know which bacterial genera may be related to autism. We searched different databases using specific keywords and inclusion criteria and identified the top ten bacterial genera from the selected articles that were significantly different between the studied patients and control subjects studied. A total of 34 studies that met the inclusion criteria were identified. The genera Bacteroides, Bifidobacterium, Clostridium, Coprococcus, Faecalibacterium, Lachnospira, Prevotella, Ruminococcus, Streptococcus, and Blautia exhibited the most substantial data indicating that their fluctuations in the gastrointestinal tract could be linked to the etiology of autism. It is probable that autism symptoms are influenced by both increased levels of harmful bacteria and decreased levels of beneficial bacteria. Interestingly, these genera demonstrated varying patterns of increased or decreased levels across different articles. To validate and eliminate the sources of this fluctuation, further research is needed. Consequently, future investigations on the causes of autism should prioritize the examination of the bacterial genera discussed in this publication.

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28. Lin YC, Lin CH, Lin MC. The Association of Prenatal Antibiotic Use with Attention Deficit and Autism Spectrum Disorders: A Nationwide Cohort Study. Children (Basel);2023 (Jun 29);10(7)

(1) Background: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are common cognitive and behavioral disorders. Antibiotics are widely used in pregnant women and their newborns. The objective of this study was to examine the potential association between prenatal exposure to antibiotics and the risk of ADHD and ASD in childhood from a nationwide perspective. (2) Methods: The Taiwan National Health Insurance Research Database (NHIRD) was used as the primary data source. This nationwide cohort study included only first-time pregnancies. A total of 906,942 infants were enrolled. All infants were followed up for at least 6 years. The Cox regression model was applied for covariate control. (3) Results: Prenatal exposure to antibiotics was found to significantly increase the cumulative incidence of ADHD while having only a borderline effect on the cumulative incidence of ASD. Exposure to antibiotics during any of the three different gestational age ranges significantly increased the cumulative risk. However, only exposure after 34 weeks of gestation had a significant impact on the occurrence of ASD. The study also revealed a dose-dependent effect on the occurrence of ADHD but no effect on the occurrence of ASD. (4) Conclusions: This study suggests that prenatal exposure to antibiotics may increase the risk of developing ADHD and ASD later in life.

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29. Liu X, Zhao W, Qi Q, Luo X. A Survey on Autism Care, Diagnosis, and Intervention Based on Mobile Apps Focusing on Usability and Software Design. Sensors (Basel);2023 (Jul 9);23(14)

This article presents a systematic review on autism care, diagnosis, and intervention based on mobile apps running on smartphones and tablets. Here, the term « intervention » means a carefully planned set of activities with the objective of improving autism symptoms. We guide our review on related studies using five research questions. First, who benefits the most from these mobile apps? Second, what are the primary purposes of these mobile apps? Third, what mechanisms have been incorporated in these mobiles apps to improve usability? Fourth, what guidelines have been used in the design and implementation of these mobile apps? Fifth, what theories and frameworks have been used as the foundation for these mobile apps to ensure the intervention effectiveness? As can be seen from these research questions, we focus on the usability and software development of the mobile apps. Informed by the findings of these research questions, we propose a taxonomy for the mobile apps and their users. The mobile apps can be categorized into autism support apps, educational apps, teacher training apps, parental support apps, and data collection apps. The individuals with autism spectrum disorder (ASD) are the primary users of the first two categories of apps. Teachers of children with ASD are the primary users of the teacher training apps. Parents are the primary users of the parental support apps, while individuals with ASD are usually the primary users of the data collection apps and clinicians and autism researchers are the beneficiaries. Gamification, virtual reality, and autism-specific mechanisms have been used to improve the usability of the apps. User-centered design is the most popular approach for mobile app development. Augmentative and alternative communication, video modeling, and various behavior change practices have been used as the theoretical foundation for intervention efficacy.

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30. Lorena JE, Sandra PR. Description of Neuropsychological Profile in Patients with 22q11 Syndrome. Genes (Basel);2023 (Jun 26);14(7)

BACKGROUND: 22q11 deletion syndrome (SD22Q11) is a neurogenetic condition that is associated with a high risk of neurodevelopmental disorders and intellectual disability. People with SD22Q11, both children and adults, often experience significant difficulties in social interactions, as well as neurocognitive deficits, and have elevated rates of autism spectrum disorder (ASD). Despite this, the relationship between basic cognitive processes and cognitive ability in this population has not been well investigated. METHODS: the main objective of the present research is to describe the neurocognitive profile of people with SD22Q11 using standardized neuropsychological assessment instruments. For this purpose, a sample of 10 participants aged between 7 and 15 years was administered an assessment battery with the following tests: WISC-V, CELF-5, NEPSY-II, CSAT-R, CARAS-R, TP, MABC-2, BRIEF-2, SENA, DABAS, ABAS-II, SCQ, and ADOS-2. RESULTS: the results showed IQ scores in the borderline normal range, as well as difficulties in language functions, social skills, motor skills, and executive functions. CONCLUSIONS: an individualized assessment taking into account the globality of its expression, and a therapeutic approach adapted to the specific needs of children with this syndrome is essential.

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31. Matrone C, Ferretti G. Semaphorin 3A influences neuronal processes that are altered in patients with autism spectrum disorder: Potential diagnostic and therapeutic implications. Neurosci Biobehav Rev;2023 (Jul 29);153:105338.

Autism spectrum disorder (ASD) is a pervasive disorder that most frequently manifests in early childhood and lasts for their entire lifespan. Several behavioural traits characterise the phenotype of patients with ASD, including difficulties in reciprocal social communication as well as compulsive/repetitive stereotyped verbal and non-verbal behaviours. Although multiple hypotheses have been proposed to explain the aetiology of ASD and many resources have been used to improve our understanding of ASD, several aspects remain largely unexplored. Class 3 semaphorins (SEMA3) are secreted proteins involved in the organisation of structural and functional connectivity in the brain that regulate synaptic and dendritic development. Alterations in brain connectivity and aberrant neuronal development have been described in some patients with ASD. Mutations and polymorphisms in SEMA3A and alterations in its receptors and signalling have been associated with some neurological disorders such as schizophrenia and epilepsy, which are comorbidities in ASD, but also with ASD itself. In addition, SEMA3A is a key regulator of the immune response and neuroinflammatory processes, which have been found to be dysregulated in mothers of children who develop ASD and in affected patients. In this review, we highlight neurodevelopmental-related processes in which SEMA3A is involved, which are altered in ASD, and provide a viewpoint emphasising the development of strategies targeting changes in the SEMA3A signal to identify patterns of anomalies distinctive of ASD or to predict the prognosis of affected patients.

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32. Rocco K, Drobnyk W, Bruce S, Soumerai SB. Ayres Sensory Integration Therapy for a Child With Rett Syndrome: A Case Report. Clin Med Insights Pediatr;2023;17:11795565231188939.

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by severe dyspraxia, hand stereotypies, and sensory processing issues for which there is no known treatment. This case describes a child with classic RTT and the child’s responses to an Ayres Sensory Integration (ASI) treatment intervention (36 one-hour sessions, 3 per week). We coded and analyzed 36 detailed treatment notes to answer the following questions: What strategies and factors facilitated or interfered with participation in the intervention? What critical elements of treatment documentation might detect small changes in praxis and participation? How do patterns of motor or praxis milestones that emerge over time relate to this child’s level of participation? We observed an increase in participation when the therapist incorporated elements of neurodevelopmental treatment (NDT) and motor learning theory- treatment strategies commonly used with children who have neuromotor conditions. This increase in participation in the ASI intervention emerged at approximately the same time that the therapist documented acquisition of new motor and praxis skills. We observed the importance of using: lateral movement activities to develop weight-shifting and bilateral coordination, rotary play to increase trunk rotation and improve postural transitions, and rhythm to promote continuing or initiating actions. The documentation of the specific amounts of assistance and prompting needed during treatment sessions was an important tool for tracking small yet meaningful responses to treatment. This case illustrates a novel use of ASI intervention supplemented with strategies that developed foundational skills, and the emergence of praxis and participation in the therapeutic intervention. We suggest further research is needed to determine efficacy of ASI for other children with this rare disorder.

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33. Saleh Hodin NA, Chong SG, Bakar NA, Fahmi M, Ramlan NF, Hamid N, Fadzar M, Zulkifli AR, Norazhar AI, Mastuki SN, Faudzi SMM, Ibrahim WNW, Azmai MNA. Toxicity and teratogenicity effects of valproic acid on zebrafish (Danio rerio) embryos in relation to autism spectrum disorder. Birth Defects Res;2023 (Jul 28)

Valproic acid (VPA) is a widely prescribed antiepileptic drug with various medicinal efficacies. Accumulated evidence implied that prenatal exposure to VPA is highly associated with autism spectrum disorder (ASD). In this study, the zebrafish were exposed to a set of VPA concentrations (0, 5, 10, 20, 40, 80, 160, 320, 640, 1280, and 2560 μM) at 5 h post fertilization (hpf) to 120 hpf. The adverse effects of VPA were extensively studied through the evaluations on the mortality, heartbeats, spontaneous tail coiling, and hatching rate. Morphological observations were conducted at 120 hpf, following the exposure termination. Basic locomotor responses and anxiety-like behavioral alterations evaluated for behavioral impairments are the hallmark feature of ASD. The exposure to VPA at teratogenic concentrations reduced the aforementioned parameters in a dose-dependent manner (p ≤ .05). At the selected non-teratogenic concentrations of VPA, the treated larvae demonstrated profound alterations of basic locomotor responses. No significant changes of anxiety and thigmotactic behaviors were observed on the VPA-treated fish compared to the control (p ≥ .005). This study depicted that embryonic zebrafish exposure to VPA produced significant toxicity and teratogenicity effects as well as the alterations of basic behavioral responses. Overall, this study provides a fundamental insight of the toxicity effects at morphological and behavioral levels to facilitate the understanding of ASD mechanisms at different molecular levels.

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34. Samadi SA, Biçak CA, Noori H, Abdalla B, Abdullah A, Ahmed L. Correction: Samadi et al. Autism Spectrum Disorder Diagnostic Criteria Changes and Impacts on the Diagnostic Scales-Utility of the 2nd and 3rd Versions of the Gilliam Autism Rating Scale (GARS). Brain Sci. 2022, 12, 537. Brain Sci;2023 (Jul 17);13(7)

In the original publication […].

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35. Sanderson KA, Aquino MD. ‘It’s a 24/7 Deal’: Parents of adults with intellectual and developmental disabilities discuss natural supports. J Appl Res Intellect Disabil;2023 (Jul 29)

BACKGROUND: Natural supports are widely used by adults with intellectual and developmental disabilities. However, little research has been conducted on this topic. This study adds to the literature by examining the role of parents as natural supporters, other members of the natural support network, challenges families face as they secure natural supports, and advice parents have for other families. METHOD: Twenty-three parents of adults with intellectual and developmental disabilities were interviewed. Data was analyzed using a constant comparative approach. RESULTS: Family members and friends were key natural supporters. However, parents provided the bulk of support. A hesitation with asking others for support was a common barrier to building natural support networks. Parents encouraged others to connect with families with similar circumstances. CONCLUSIONS: To ensure proper care for adults with intellectual and developmental disabilities, we must develop supports that meet family members’ needs and identify ways to strengthen natural support networks.

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36. Subashi E, Lemaire V, Petroni V, Pietropaolo S. The Impact of Mild Chronic Stress and Maternal Experience in the Fmr1 Mouse Model of Fragile X Syndrome. Int J Mol Sci;2023 (Jul 13);24(14)

Fragile X syndrome (FXS) is a pervasive developmental disorder and the most common monogenic cause of autism spectrum disorder (ASD). Female heterozygous (HET) carriers play a major role in the transmission of the pathology and present several FXS- and ASD-like behavioral alterations. Despite their clear genetic origins, FXS symptoms are known to be modulated by environmental factors, e.g., exposure to chronic stress, especially during critical life periods, such as pregnancy. Pregnancy, together with pups’ care, constitutes maternal experience, i.e., another powerful environmental factor affecting several neurobehavioral functions in females. Here we investigated the impact of maternal experience on the long-term effects of stress in Fmr1-HET female mice. Our findings demonstrated that the behavioral abnormalities of HET females, i.e., hyperactivity and memory deficits, were unaffected by stress or maternal experience. In contrast, stress, independently of maternal experience, induced the appearance of cognitive deficits in WT mice. Maternal experience increased anxiety levels in all mice and enhanced their corticosterone levels, concomitantly promoting the effects of stress on social communication and adrenal glands. In translational terms, these results advance our understanding of the environmental modulation of the behavioral alterations observed in FXS female carriers and highlight the long-term impact of maternal experience and its interactions with chronic stress.

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37. Talvio K, Wagner VA, Minkeviciene R, Kirkwood JS, Kulinich AO, Umemori J, Bhatia A, Hur M, Käkelä R, Ethell IM, Castrén ML. An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis. Commun Biol;2023 (Jul 29);6(1):789.

Cholesterol is an essential membrane structural component and steroid hormone precursor, and is involved in numerous signaling processes. Astrocytes regulate brain cholesterol homeostasis and they supply cholesterol to the needs of neurons. ATP-binding cassette transporter A1 (ABCA1) is the main cholesterol efflux transporter in astrocytes. Here we show dysregulated cholesterol homeostasis in astrocytes generated from human induced pluripotent stem cells (iPSCs) derived from males with fragile X syndrome (FXS), which is the most common cause of inherited intellectual disability. ABCA1 levels are reduced in FXS human and mouse astrocytes when compared with controls. Accumulation of cholesterol associates with increased desmosterol and polyunsaturated phospholipids in the lipidome of FXS mouse astrocytes. Abnormal astrocytic responses to cytokine exposure together with altered anti-inflammatory and cytokine profiles of human FXS astrocyte secretome suggest contribution of inflammatory factors to altered cholesterol homeostasis. Our results demonstrate changes of astrocytic lipid metabolism, which can critically regulate membrane properties and affect cholesterol transport in FXS astrocytes, providing target for therapy in FXS.

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38. Tilwani D, Bradshaw J, Sheth A, O’Reilly C. ECG Recordings as Predictors of Very Early Autism Likelihood: A Machine Learning Approach. Bioengineering (Basel);2023 (Jul 11);10(7)

In recent years, there has been a rise in the prevalence of autism spectrum disorder (ASD). The diagnosis of ASD requires behavioral observation and standardized testing completed by highly trained experts. Early intervention for ASD can begin as early as 1-2 years of age, but ASD diagnoses are not typically made until ages 2-5 years, thus delaying the start of intervention. There is an urgent need for non-invasive biomarkers to detect ASD in infancy. While previous research using physiological recordings has focused on brain-based biomarkers of ASD, this study investigated the potential of electrocardiogram (ECG) recordings as an ASD biomarker in 3-6-month-old infants. We recorded the heart activity of infants at typical and elevated familial likelihood for ASD during naturalistic interactions with objects and caregivers. After obtaining the ECG signals, features such as heart rate variability (HRV) and sympathetic and parasympathetic activities were extracted. Then we evaluated the effectiveness of multiple machine learning classifiers for classifying ASD likelihood. Our findings support our hypothesis that infant ECG signals contain important information about ASD familial likelihood. Amongthe various machine learning algorithms tested, KNN performed best according to sensitivity (0.70 ± 0.117), F1-score (0.689 ± 0.124), precision (0.717 ± 0.128), accuracy (0.70 ± 0.117, p-value = 0.02), and ROC (0.686 ± 0.122, p-value = 0.06). These results suggest that ECG signals contain relevant information about the likelihood of an infant developing ASD. Future studies should consider the potential of information contained in ECG, and other indices of autonomic control, for the development of biomarkers of ASD in infancy.

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39. Vörös D, Kiss O, Ollmann T, Mintál K, Péczely L, Zagoracz O, Kertes E, Kállai V, László BR, Berta B, Toth A, Lénárd L, László K. Intraamygdaloid Oxytocin Increases Time Spent on Social Interaction in Valproate-Induced Autism Animal Model. Biomedicines;2023 (Jun 23);11(7)

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder that affects about 1.5% of children worldwide. One of the core symptoms is impaired social interaction. Since proper treatment has not been found yet, an investigation of the exact pathophysiology of autism is essential. The valproate (VPA)-induced rat model can be an appropriate way to study autism. Oxytocin (OT) may amend some symptoms of ASD since it plays a key role in developing social relationships. In the present study, we investigated the effect of the intraamygdaloid OT on sham and intrauterine VPA-treated rats’ social interaction using Crawley’s social interaction test. Bilateral guide cannulae were implanted above the central nucleus of the amygdala (CeA), and intraamygdaloid microinjections were carried out before the test. Our results show that male Wistar rats prenatally exposed to VPA spent significantly less time on social interaction. Bilateral OT microinjection increased the time spent in the social zone; it also reached the level of sham-control animals. OT receptor antagonist blocked this effect of the OT but in itself did not significantly influence the behavior of the rats. Based on our results, we can establish that intraamygdaloid OT has significantly increased time spent on social interaction in the VPA-induced autism model, and its effect is receptor-specific.

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40. Wang JY, Sonico GJ, Salcedo-Arellano MJ, Hagerman RJ, Martinez-Cerdeno V. A Postmortem MRI Study of Cerebrovascular Disease and Iron Content at End-Stage of Fragile X-Associated Tremor/Ataxia Syndrome. Cells;2023 (Jul 20);12(14)

Brain changes at the end-stage of fragile X-associated tremor/ataxia syndrome (FXTAS) are largely unknown due to mobility impairment. We conducted a postmortem MRI study of FXTAS to quantify cerebrovascular disease, brain atrophy and iron content, and examined their relationships using principal component analysis (PCA). Intracranial hemorrhage (ICH) was observed in 4/17 FXTAS cases, among which one was confirmed by histologic staining. Compared with seven control brains, FXTAS cases showed higher ratings of T2-hyperintensities (indicating cerebral small vessel disease) in the cerebellum, globus pallidus and frontoparietal white matter, and significant atrophy in the cerebellar white matter, red nucleus and dentate nucleus. PCA of FXTAS cases revealed negative associations of T2-hyperintensity ratings with anatomic volumes and iron content in the white matter, hippocampus and amygdala, that were independent from a highly correlated number of regions with ICH and iron content in subcortical nuclei. Post-hoc analysis confirmed PCA findings and further revealed increased iron content in the white matter, hippocampus and amygdala in FXTAS cases compared to controls, after adjusting for T2-hyperintensity ratings. These findings indicate that both ischemic and hemorrhagic brain damage may occur in FXTAS, with the former being marked by demyelination/iron depletion and atrophy, and the latter by ICH and iron accumulation in basal ganglia.

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41. Wong KM, Wegener E, Baradaran-Heravi A, Huppke B, Gärtner J, Huppke P. Evaluation of Novel Enhancer Compounds in Gentamicin-Mediated Readthrough of Nonsense Mutations in Rett Syndrome. Int J Mol Sci;2023 (Jul 19);24(14)

Rett syndrome (RTT), a severe X-linked neurodevelopmental disorder, is primarily caused by mutations in the methyl CpG binding protein 2 gene (MECP2). Over 35% RTT patients carry nonsense mutation in MECP2, making it a suitable candidate disease for nonsense suppression therapy. In our previous study, gentamicin was found to induce readthrough of MECP2 nonsense mutations with modest efficiency. Given the recent discovery of readthrough enhancers, CDX compounds, we herein evaluated the potentiation effect of CDX5-1, CDX5-288, and CDX6-180 on gentamicin-mediated readthrough efficiency in transfected HeLa cell lines bearing the four most common MECP2 nonsense mutations. We showed that all three CDX compounds potentiated gentamicin-mediated readthrough and increased full-length MeCP2 protein levels in cells expressing the R168X, R255X, R270X, and R294X nonsense mutations. Among all three CDX compounds, CDX5-288 was the most potent enhancer and enabled the use of reduced doses of gentamicin, thus mitigating the toxicity. Furthermore, we successfully demonstrated the upregulation of full-length Mecp2 protein expression in fibroblasts derived from Mecp2(R255X/Y) mice through combinatorial treatment. Taken together, findings demonstrate the feasibility of this combinatorial approach to nonsense suppression therapy for a subset of RTT patients.

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42. Xie Y, Sun J, Man W, Zhang Z, Zhang N. Personalized estimates of brain cortical structural variability in individuals with Autism spectrum disorder: the predictor of brain age and neurobiology relevance. Mol Autism;2023 (Jul 28);14(1):27.

BACKGROUND: Autism spectrum disorder (ASD) is a heritable condition related to brain development that affects a person’s perception and socialization with others. Here, we examined variability in the brain morphology in ASD children and adolescent individuals at the level of brain cortical structural profiles and the level of each brain regional measure. METHODS: We selected brain structural MRI data in 600 ASDs and 729 normal controls (NCs) from Autism Brain Imaging Data Exchange (ABIDE). The personalized estimate of similarity between gray matter volume (GMV) profiles of an individual to that of others in the same group was assessed by using the person-based similarity index (PBSI). Regional contributions to PBSI score were utilized for brain age gap estimation (BrainAGE) prediction model establishment, including support vector regression (SVR), relevance vector regression (RVR), and Gaussian process regression (GPR). The association between BrainAGE prediction in ASD and clinical performance was investigated. We further explored the related inter-regional profiles of gene expression from the Allen Human Brain Atlas with variability differences in the brain morphology between groups. RESULTS: The PBSI score of GMV was negatively related to age regardless of the sample group, and the PBSI score was significantly lower in ASDs than in NCs. The regional contributions to the PBSI score of 126 brain regions in ASDs showed significant differences compared to NCs. RVR model achieved the best performance for predicting brain age. Higher inter-individual brain morphology variability was related to increased brain age, specific to communication symptoms. A total of 430 genes belonging to various pathways were identified as associated with brain cortical morphometric variation. The pathways, including short-term memory, regulation of system process, and regulation of nervous system process, were dominated mainly by gene sets for manno midbrain neurotypes. LIMITATIONS: There is a sample mismatch between the gene expression data and brain imaging data from ABIDE. A larger sample size can contribute to the model training of BrainAGE and the validation of the results. CONCLUSIONS: ASD has personalized heterogeneity brain morphology. The brain age gap estimation and transcription-neuroimaging associations derived from this trait are replenished in an additional direction to boost the understanding of the ASD brain.

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43. Zhang C, Ma Y, Qiao L, Zhang L, Liu M. Learning to Fuse Multiple Brain Functional Networks for Automated Autism Identification. Biology (Basel);2023 (Jul 8);12(7)

Functional connectivity network (FCN) has become a popular tool to identify potential biomarkers for brain dysfunction, such as autism spectrum disorder (ASD). Due to its importance, researchers have proposed many methods to estimate FCNs from resting-state functional MRI (rs-fMRI) data. However, the existing FCN estimation methods usually only capture a single relationship between brain regions of interest (ROIs), e.g., linear correlation, nonlinear correlation, or higher-order correlation, thus failing to model the complex interaction among ROIs in the brain. Additionally, such traditional methods estimate FCNs in an unsupervised way, and the estimation process is independent of the downstream tasks, which makes it difficult to guarantee the optimal performance for ASD identification. To address these issues, in this paper, we propose a multi-FCN fusion framework for rs-fMRI-based ASD classification. Specifically, for each subject, we first estimate multiple FCNs using different methods to encode rich interactions among ROIs from different perspectives. Then, we use the label information (ASD vs. healthy control (HC)) to learn a set of fusion weights for measuring the importance/discrimination of those estimated FCNs. Finally, we apply the adaptively weighted fused FCN on the ABIDE dataset to identify subjects with ASD from HCs. The proposed FCN fusion framework is straightforward to implement and can significantly improve diagnostic accuracy compared to traditional and state-of-the-art methods.

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44. Zhang W, Johnson KR. Geographic Variation in Preventable Hospitalizations among US Children with Autism. Children (Basel);2023 (Jul 15);10(7)

There is a limited amount of research on geographic differences in preventable hospitalizations for ambulatory care sensitive conditions (ACSCs) among children with autism. The purpose of this study was to examine US regional differences in potentially preventable hospital admissions for pediatric inpatients diagnosed with autism. Hospital discharge data for six pediatric preventable conditions were obtained from the 2016-2019 National Inpatient Sample (NIS) under the US Agency for Healthcare Research and Quality. Geographic differences in preventable hospitalizations for children with autism were examined by US census regions and divisions. Multiple logistic regression analyses were conducted to examine child and clinical characteristics associated with ACSCs hospitalization across four US regions; the dependent variable was the likelihood of ACSCs hospitalization. Additionally, this study further explored the variation in preventable hospitalization among racial and ethnic groups for each region or division. Of the 138,305 autistic inpatients aged 2-17 years, about 10% had a primary diagnosis related to ACSCs. The results showed that the highest proportion of preventable hospitalizations for autistic children occurred in the middle Atlantic division of the northeast region. Racial differences were observed across all US regions, particularly in the northeast and south regions. Black children with autism were more likely to be hospitalized for ACSCs compared to White children with autism in three of the four US regions. Our results highlight the significant racial disparities in potentially avoidable hospitalizations among US children with autism. Examining geographic and racial differences in potentially avoidable hospitalizations could inform policy and practice while gaining a better understanding of pediatric patients with autism and where their families access health services. The findings of this study may help policymakers to identify where intervention is needed to tackle health inequities in the accessibility to quality primary care in the US. Further studies with more detailed investigation are recommended to better understand the mechanisms underlying these disparities, and to formulate effective regional policy and clinical practices while considering the unique needs and challenges of underserved children with autism.

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