1. Abdallah S, Seeling A, Poreh A. B – 15 Additional Insights of the Factor Structure of the Autism Spectrum Adaptive Scale Questionnaire. Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists. 2023.

OBJECTIVE: Autism spectrum condition(s) (ASC) a neurodevelopmental disorder with limited research on the etiological basis. Thus, diagnoses are given based on an individual’s behavior. However, the process of receiving a diagnosis can be difficult to procure. Having an accurate self-report scale for diagnosing ASC is important, and current scales have limitations. This study aims to assess the factor structure of a new scale developed by the authors, the Autism Spectrum Adaptive Scale Questionnaire (ASAS-Q). METHODS: 994 adult volunteers with and without history of ASC were recruited via Research Match (391 with autism, 594 without autism). We ran an Exploratory Factor Analysis (EFA), which suggested three factors. Using a loading value cutoff of above 0.4, items that either did not load onto any factor or cross loaded were deleted. The final analysis converged in six iterations. Finally, we ran a reliability analysis to test the internal consistency. RESULTS: In its current experimental form, ASAS-Q has 38 items. Bartlett’s tests of sphericity was significant (χ2 (780) = 24860.18, p = 0.000) and the Kaiser-Meyer-Olkin (KMO) measure of sampling adequacy indicated a high relationship among variables (KMO = 0.97). These tests indicated that a factor analytic model was acceptable for this dataset. Cronbach’s Alpha indicated that the ASAS-Q has excellent internal consistency overall (α = 0.97) as well as among each of the three subscales: (1) (α = 0.87), (2) (α = 0.90), and (3) (α = 0.94). CONCLUSION: These findings indicate that the ASAS-Q may serve as a useful new self-report scale for diagnosing ASC in adults.

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2. Abdallah S, Seeling A, Poreh A. B – 14 Facial Affect Recognition among Individuals with Autism Spectrum Conditions (ASC) Compared to Individuals without ASC. Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists. 2023.

OBJECTIVE: This study aims to assess whether individuals with autism spectrum conditions (ASC) are less effective in recognizing facial affect (emotions) when compared to other individuals. METHODS: 1675 adult volunteers (ages 18+) were recruited via Research Match. All participants were asked to indicate their mental health history and were placed into one of two groups: (1) individuals with ASC (n = 586) and (2) individuals without ASC (n = 1089). Both groups took the Ekman Friesen Picture of Facial Affect scale (POFA). The POFA scale consists of 110 grayscale photos who posed with seven facial expressions: happy, sad, angry, fearful, surprise, disgust, and neutral. Participants were instructed to choose which emotion the photos best represented. Using the scoring manual, we recoded the participant’s responses to represent whether they accurately determined the emotion presented in each photo. Next, we computed a total score for each emotion. Finally, we conducted an Independent Samples T-test for each of the emotions to compare the mean of each group’s accuracy in determining the correct emotions. RESULTS: For all emotions, the ASD group was significantly less accurate in determining facial affect compared to the control group. Happy: t(1673) = 3.50, p = <0.001. Sad: t(1673) = 3.10, p = 0.002. Angry: t(1673) = 3.57, p = <0.001. Fearful: t(1673) = 3.55, p = <0.001. Surprised: t(1673) = 3.48, p = <0.001. Neutral: t(1673) = 5.60, p = <0.001. CONCLUSION: These findings indicate that individuals with ASC may be less accurate in determining facial affect when compared to individuals without ASC.

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3. Abdallah S, Seeling A, Poreh A. B – 16 Prevalence of Comorbid Diagnoses among Individuals with a Clinical Vs. Self-Diagnosis of Autism Spectrum Conditions (ASC). Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists. 2023.

OBJECTIVE: The evolution of ASC has changed drastically since its initial conceptualization. Therefore, it is possible that numerous individuals remain undiagnosed and untreated based on lack of knowledge about this condition. Diagnoses of ASC often include multiple other detrimental comorbid disorders. To elucidate whether the issue of underdiagnosis is relevant, it is important to determine if there are individuals who believe they qualify for a diagnosis of ASC, who remain undiagnosed. This study aims to compare the prevalence of comorbid diagnoses between individuals diagnosed by a clinician with those who self-report having ASC. METHODS: 391 adults who self-reported have ASC (ages 18+) were recruited via Research Match. The call for subjects stated that the study was looking for individuals with a diagnosis of ASC to participate. Volunteers were asked to indicate if they were diagnosed with ASC, and if so, from whom they were diagnosed. One of the options for who gave the diagnosis was « self ». Finally, participants were asked to indicate any comorbid diagnoses they had. RESULTS: Of the 391 participants, 180 self-reported having ASC, and 211 participants indicated that they were diagnosed by a clinician. A one-way ANOVA was significant, indicating significant differences among groups, F(5,389) = 2.84, p = 0.016. Specifically, those who were diagnosed by a psychiatrist (M = 4.41) had significantly more comorbid diagnoses when compared with those who were self-diagnosed (M = 3.62). CONCLUSION: As 180 participants who claimed to have ASC were not clinically diagnosed, the results suggest that under-diagnoses of this condition may be prevalent.

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4. Ali MT, Gebreil A, ElNakieb Y, Elnakib A, Shalaby A, Mahmoud A, Sleman A, Giridharan GA, Barnes G, Elbaz AS. A personalized classification of behavioral severity of autism spectrum disorder using a comprehensive machine learning framework. Scientific reports. 2023; 13(1): 17048.

Autism Spectrum Disorder (ASD) is characterized as a neurodevelopmental disorder with a heterogeneous nature, influenced by genetics and exhibiting diverse clinical presentations. In this study, we dissect Autism Spectrum Disorder (ASD) into its behavioral components, mirroring the diagnostic process used in clinical settings. Morphological features are extracted from magnetic resonance imaging (MRI) scans, found in the publicly available dataset ABIDE II, identifying the most discriminative features that differentiate ASD within various behavioral domains. Then, each subject is categorized as having severe, moderate, or mild ASD, or typical neurodevelopment (TD), based on the behavioral domains of the Social Responsiveness Scale (SRS). Through this study, multiple artificial intelligence (AI) models are utilized for feature selection and classifying each ASD severity and behavioural group. A multivariate feature selection algorithm, investigating four different classifiers with linear and non-linear hypotheses, is applied iteratively while shuffling the training-validation subjects to find the set of cortical regions with statistically significant association with ASD. A set of six classifiers are optimized and trained on the selected set of features using 5-fold cross-validation for the purpose of severity classification for each behavioural group. Our AI-based model achieved an average accuracy of 96%, computed as the mean accuracy across the top-performing AI models for feature selection and severity classification across the different behavioral groups. The proposed AI model has the ability to accurately differentiate between the functionalities of specific brain regions, such as the left and right caudal middle frontal regions. We propose an AI-based model that dissects ASD into behavioral components. For each behavioral component, the AI-based model is capable of identifying the brain regions which are associated with ASD as well as utilizing those regions for diagnosis. The proposed system can increase the speed and accuracy of the diagnostic process and result in improved outcomes for individuals with ASD, highlighting the potential of AI in this area.

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5. Al-Mazidi SH. The Physiology of Cognition in Autism Spectrum Disorder: Current and Future Challenges. Cureus. 2023; 15(10): e46581.

Cognitive impairment is among the most challenging characteristics of autism spectrum disorder (ASD). Although ASD is one of the common neurodevelopmental disorders, we are still behind in diagnosing and treating cognitive impairment in ASD. Cognitive impairment in ASD varies, meaning it could be at the sensory perception level to cognitive processing, learning, and memory. There are no diagnostic criteria for cognitive impairment that are specific to ASD. The leading causes of cognitive impairment in ASD could be neurological, immune, and gastrointestinal dysfunction. Immune dysfunction might lead to neuroinflammation, affecting neural connectivity, glutamate/gamma-aminobutyric acid (GABA) balance, and plasticity. The gut-brain axes are essential in the developing brain. Special retinal changes have recently been detected in ASD, which need clinical investigation to find their possible role in early diagnosis. Early intervention is crucial for ASD cognitive dysfunction. Due to the heterogeneity of the disease, the clinical manifestation of ASD makes it difficult for clinicians to develop gold-standard diagnostic and therapeutic criteria. We suggest a triad for diagnosis, which includes clinical tests for immune and gastrointestinal dysfunction biomarkers, clinical examination for the retina, and an objective neurocognitive evaluation for ASD, and to develop a treatment strategy involving these three aspects. Developing clear treatment criteria for cognitive impairment for ASD would improve the quality of life of ASD people and their caregivers and would delay or prevent dementia-related disorders in ASD people.

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6. Ba-Shammakh SA, Al-Zughali EA, Al-Bustanji SM. When the Gut Tells a Story: Bezoars in a Neglected Autistic Child. Cureus. 2023; 15(9): e44775.

This case study delves into the unique presentation of bezoars in a 14-year-old autistic female who exhibited chronic diarrhea and abdominal pain. While trichobezoars, masses formed from ingested hair, are rare, they are predominantly seen in young females and are associated with psychiatric conditions. Through rigorous diagnostic procedures, including a computed tomography imaging of the abdomen and pelvis (CTAP) scan, fecal impaction, and multiple bezoars, including hair and non-biological items, were identified. The background revealed significant neglect, emphasizing the importance of a comprehensive approach that integrates medical, surgical, and psychosocial care.

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7. Cabrales A, Saenz MG, Cartwright JE. H – 16 Providing Care to Spanish-Speaking Families in an Autism Clinic: Insights from Bilingual Spanish-English Speaking Trainees. Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists. 2023.

OBJECTIVE: Bilingual trainees at the Center for Autism Care (CAC) present insights from working with Spanish-speaking families with the integration of an interpreter during an autism evaluation. METHOD: Two Spanish-English speaking clinical psychology trainees observed evaluations conducted by the supervising psychologist via Spanish-English interpreters. Trainees gathered observational data through a frequency count of interpretation difficulties within the course of six evaluations for autism spectrum disorder (ASD) thus far. The observations included an interpreter who frequently works at CAC and other professional interpreters who serve Children’s Health clinics. A frequency count for type of error and content of error was collected within evaluations supported by various interpreters. RESULTS: A total of 41 errors in interpretation were observed across six autism evaluations during consent, interview, and feedback. Errors were categorized into types of errors (e.g., truncated message, incorrect interpretation, direct question from family, and direct clarification from interpreter) and content of errors (e.g., routines, restricted and repetitive behaviors, social communication, and comorbid diagnoses). 68.3% of interpretation errors included semantic content specific to ASD or discussion of comorbid diagnoses. 44% of interpretation errors consisted of a message being truncated. CONCLUSION(S): Findings indicate that the bulk of interpretation errors occurred when interpreting autism-specific terms. Despite limited encounters, our observations indicate that interpretation of patient-specific information, including specialized diagnostic details of ASD, is most susceptible to misinterpretation. Future directions may include exploring the utility of a handout to support interpreter knowledge of specialized terms to ensure Spanish-speaking families receive optimal care.

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8. Carollo-DuPrey G, Yañez JJ, Fernandez VG. H – 55 Socially Responsible Neuropsychology (SRN) in Action: the Role of Neuropsychology in Autism Spectrum Disorder (ASD) Care, a Case Study of a Bilingual Latino Patient. Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists. 2023.

OBJECTIVE: Latinx children with ASD are diagnosed 1-3 years later than their White counterparts and typically present with more severe symptoms at the time of assessment. Systemic barriers include language barriers, limited literacy about ASD, mental health stigma, mistrust in healthcare. Latinx children are at greater risk of misdiagnosis, delayed access to special education, limiting early intervention. Within neuropsychology, there are limited bicultural/bilingual neuropsychologists trained in autism evaluations, few Spanish ASD diagnostic tools, no bilingual norms, and little understanding regarding neuropsychologists’ role in providing autism evaluations to culturally/linguistically diverse children. This social injustice results in unmet needs and inequities in ASD care for Latinx children. We aim to illustrate how the SRN model increases equitable ASD care amongst Latinx children. METHOD: SRN model was utilized in 11-year-old bilingual Latinx male by applying culturally responsive interview to identify systemic barriers and language use, and a model of language proficiency testing. Testing was primarily in English after verbal fluency measures established language dominance. Clinical decision making identified the need for autism evaluation using Autism Diagnostic Observation Schedule (ADOS-2). RESULTS: His cognitive profile showed word reading and motor inefficiencies. ADOS-2 identified deficits in communication, reciprocal social interaction, restricted and repetitive behavior. Neuropsychological assessment confirmed ASD and Developmental Coordination Disorder diagnosis. CONCLUSION: His unremarkable neurocognitive profile suggested compensatory strategies may have masked symptoms. This case highlights need for bicultural/bilingual neuropsychologists with experience providing comprehensive ASD evaluations to practice from equitable framework, using the SRN model to enhance early detection, treatment recommendations, and advocacy for access to culturally/linguistically appropriate resources.

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9. Chen C, Cheng Y, Wu CT, Chiang CH, Wong CC, Huang CM, Martínez RM, Tzeng OJL, Fan YT. A sensory signature of unaffected biological parents predicts the risk of autism in their offspring. Psychiatry and clinical neurosciences. 2023.

AIM: Despite the emphasis on sensory dysfunction phenotypes in the revised diagnostic criteria for autism spectrum disorder (ASD), there has been limited research, particularly in the field of neurobiology, investigating the concordance in sensory features between individuals with ASD and their genetic relatives. Therefore, our objective was to examine whether neurobehavioral sensory patterns could serve as endophenotypic markers for ASD. METHODS: We combined questionnaire- and lab-based sensory evaluations with sensory fMRI measures to examine the patterns of sensory responsivity in 30 clinically diagnosed with ASD, 26 matched controls (CON), and 48 biological parents for both groups (27 parents of individuals with ASD [P-ASD] and 21 for individuals with CON [P-CON]). RESULTS: The ASD and P-ASD groups had higher sensory responsivity and rated sensory stimuli as more unpleasant than the CON and P-CON groups, respectively. They also exhibited greater hemodynamic responses within the sensory cortices. Overlapping activations were observed within these sensory cortices in the ASD and P-ASD groups. Using a machine learning approach with robust prediction models across cohorts, we demonstrated that the sensory profile of biological parents accurately predicted the likelihood of their offspring having ASD, achieving a prediction accuracy of 71.4%. CONCLUSIONS: These findings provide support for hereditary basis of sensory alterations in ASD and suggest a potential avenue to improve ASD diagnosis by utilizing the sensory signature of biological parents, especially in families with a high risk of ASD. This approach holds promising prospects for early detection, even before the birth of the offspring. This article is protected by copyright. All rights reserved.

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10. Dai Y, Deng T, Chen M, Huang B, Ji Y, Feng Y, Liu S, Zhong D, Zhang T, Zhang L. Improving early detection, diagnosis and intervention for children with autism spectrum disorder: A cross-sectional survey in China. Research in developmental disabilities. 2023; 142: 104616.

BACKGROUND: Detection and diagnosis of autism spectrum disorder (ASD) are prerequisites for early interventions. However, few studies focused on this topic. AIM: This study aims to characterize the timing from symptom detection to intervention in children with ASD and identify predictors of age at ASD diagnosis, presence of intervention, and the time lag between detection and diagnosis. METHODS AND PROCEDURES: A cross-sectional survey was conducted with 303 parents (111 fathers and 192 mothers, 21-54 years) of children with ASD in Guangzhou, China. OUTCOMES AND RESULTS: The median time from symptom observation to the first doctor visit was 3 months, while the time to ASD diagnosis averaged 6 months. Most children (76.24 %) were diagnosed within one year after detection, and 25.58 % had no intervention after diagnosis. Predictors of earlier ASD diagnosis included ASD-related symptoms identified at an older age, less serious symptoms, and initial symptoms with atypical motor development and sensory anomalies. ASD-related symptoms observed at an older age, initial symptoms with social deficits, sensory anomalies, and without language impairment, primary caregivers other than parents, families with lower income, and less social support utilization increased the odds of a time lag between detection and diagnosis. Children with fathers having lower education were less likely to receive interventions. CONCLUSIONS AND IMPLICATIONS: Earlier ASD identification and intervention might be facilitated by health education on typical symptoms of ASD for parents with young children and incorporating ASD screening during routine health examinations for children. For children whose primary caregivers are not their parents and from lower-income families, additional support may be required for timely diagnosis after reporting ASD-related symptoms. Moreover, more intervention supports are expected for children whose fathers have lower education levels. Helping families take full advantage of support is also important for early diagnosis and intervention.

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11. Deng PY, Kumar A, Cavalli V, Klyachko VA. Circuit-based intervention corrects excessive dentate gyrus output in the Fragile X mouse model. bioRxiv : the preprint server for biology. 2023.

Abnormal cellular and circuit excitability is believed to drive many core phenotypes in fragile X syndrome (FXS). The dentate gyrus is a brain area performing critical computations essential for learning and memory. However, little is known about dentate circuit defects and their mechanisms in FXS. Understanding dentate circuit dysfunction in FXS has been complicated by the presence of two types of excitatory neurons, the granule cells and mossy cells. Here we report that loss of FMRP markedly decreased excitability of dentate mossy cells, a change opposite to all other known excitability defects in excitatory neurons in FXS. This mossy cell hypo-excitability is caused by increased Kv7 function in Fmr1 KO mice. By reducing the excitatory drive onto local hilar interneurons, hypo-excitability of mossy cells results in increased excitation/inhibition ratio in granule cells and thus paradoxically leads to excessive dentate output. Circuit-wide inhibition of Kv7 channels in Fmr1 KO mice increases inhibitory drive onto granule cells and normalizes the dentate output in response to physiologically relevant theta-gamma coupling stimulation. Our study suggests that circuit-based interventions may provide a promising strategy in this disorder to bypass irreconcilable excitability defects in different cell types and restore their pathophysiological consequences at the circuit level.

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12. Devonshire A, Tuinstra K, Kuwabara H, Durham P. B – 10 The Effect of Gestational Age on Development of Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder. Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists. 2023.

OBJECTIVE: Studies show individuals with comorbid neurodevelopmental disorders of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) have poorer emotional, behavioral, and cognitive outcomes. While preterm birth (< 37 weeks) is an identified risk factor for ASD and ADHD, it is important to consider gestational age (ga) as it relates to the development of comorbid ASD/ADHD (ASD/ADHD). The current study aims to understand the relationship between level of prematurity (LoP) and neurodevelopmental disorders. METHOD: Participants included 10,711 children/adolescents (52.5% male) from the Environmental Influences on Child Health Outcomes (ECHO) Program. LoP was categorized as Extremely Preterm (36 weeks). Chi-square analysis was conducted to examine the relationship between LoP and neurodevelopmental disorder diagnoses as indicated in medical records. Logistic regression was also conducted to analyze the relationship between ga (weeks) and neurodevelopmental disorder diagnosis. RESULTS: 1521 individuals were diagnosed with ASD (n = 537), ADHD (n = 778), or ASD/ADHD (n = 206); ga ranged from 22 to 43 weeks. Results indicated the relationship between LoP and diagnoses was significant, ꭓ2(9, 10,771) = 148.31, p < 0.001. Extremely Preterm individuals were more likely than Full-term individuals to have ASD, ADHD, or ASD/ADHD. It was found that the odds of having a neurodevelopmental disorder decreased by 5.8% per 1-week ga increase (95% CI[-0.069, -0.048]). CONCLUSION: Results indicate gestational age is associated with greater risk of neurodevelopmental disorders, including comorbid ASD/ADHD. Improved understanding of the association between level of prematurity and comorbid ASD/ADHD diagnoses may help inform early intervention services enhancing children's outcomes throughout the lifespan.

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13. Dhossche D, de Billy C, Laurent-Levinson C, Le Normand MT, Recasens C, Robel L, Philippe A. Early-onset catatonia associated with SHANK3 mutations: looking at the autism spectrum through the prism of psychomotor phenomena. Frontiers in psychiatry. 2023; 14: 1186555.

BACKGROUND: Individuals with Phelan-McDermid syndrome (PMS) present with a wide range of diagnoses: autism spectrum disorder, intellectual disability, or schizophrenia. Differences in the genetic background could explain these different neurodevelopmental trajectories. However, a more parsimonious hypothesis is to consider that they may be the same phenotypic entity. Catatonic disturbances occasionally reported from adolescence onwards in PMS prompts exploration of the hypothesis that this clinical entity may be an early-onset form of catatonia. The largest cohort of children with childhood catatonia was studied by the Wernicke-Kleist-Leonhard school (WKL school), which regards catatonia as a collection of qualitative abnormalities of psychomotricity that predominantly affecting involuntary motricity (reactive and expressive). The aim of this study was to investigate the presence of psychomotor signs in three young adults carrying a mutation or intragenic deletion of the SHANK3 gene through the prism of the WKL school conception of catatonia. METHODS: This study was designed as an exploratory case study. Current and childhood psychomotor phenomena were investigated through semi-structured interviews with the parents, direct interaction with the participants, and the study of documents reporting observations of the participants at school or by other healthcare professionals. RESULTS: The findings show catatonic manifestations from childhood that evolved into a chronic form, with possible phases of sub-acute exacerbations starting from adolescence. CONCLUSION: The presence of catatonic symptoms from childhood associated with autistic traits leads us to consider that this singular entity fundamentally related to SHANK3 mutations could be a form of early-onset catatonia. Further case studies are needed to confirm our observations.

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14. Edwards N, Combrinck C, McCaughey-Chapman A, Connor B. Directly reprogrammed fragile X syndrome dorsal forebrain precursor cells generate cortical neurons exhibiting impaired neuronal maturation. Frontiers in cellular neuroscience. 2023; 17: 1254412.

INTRODUCTION: The neurodevelopmental disorder fragile X syndrome (FXS) is the most common monogenic cause of intellectual disability associated with autism spectrum disorder. Inaccessibility to developing human brain cells is a major barrier to studying FXS. Direct-to-neural precursor reprogramming provides a unique platform to investigate the developmental profile of FXS-associated phenotypes throughout neural precursor and neuron generation, at a temporal resolution not afforded by post-mortem tissue and in a patient-specific context not represented in rodent models. Direct reprogramming also circumvents the protracted culture times and low efficiency of current induced pluripotent stem cell strategies. METHODS: We have developed a chemically modified mRNA (cmRNA) -based direct reprogramming protocol to generate dorsal forebrain precursors (hiDFPs) from FXS patient-derived fibroblasts, with subsequent differentiation to glutamatergic cortical neurons and astrocytes. RESULTS: We observed differential expression of mature neuronal markers suggesting impaired neuronal development and maturation in FXS- hiDFP-derived neurons compared to controls. FXS- hiDFP-derived cortical neurons exhibited dendritic growth and arborization deficits characterized by reduced neurite length and branching consistent with impaired neuronal maturation. Furthermore, FXS- hiDFP-derived neurons exhibited a significant decrease in the density of pre- and post- synaptic proteins and reduced glutamate-induced calcium activity, suggesting impaired excitatory synapse development and functional maturation. We also observed a reduced yield of FXS- hiDFP-derived neurons with a significant increase in FXS-affected astrocytes. DISCUSSION: This study represents the first reported derivation of FXS-affected cortical neurons following direct reprogramming of patient fibroblasts to dorsal forebrain precursors and subsequently neurons that recapitulate the key molecular hallmarks of FXS as it occurs in human tissue. We propose that direct to hiDFP reprogramming provides a unique platform for further study into the pathogenesis of FXS as well as the identification and screening of new drug targets for the treatment of FXS.

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15. Goodson R, Wagner J, Sandritter T, Staggs VS, Soden S, Nadler C. Pharmacogenetic Testing in Patients with Autism Spectrum Disorder Evaluated in a Precision Medicine Clinic. Journal of developmental and behavioral pediatrics : JDBP. 2023; 44(8): e505-e10.

OBJECTIVE: This study investigated outcomes of pharmacogenetic testing of youth with autism spectrum disorder (ASD) referred to a precision medicine clinic and explored associations between patient characteristics and pharmacogenomic testing results. METHODS: Records for patients diagnosed with ASD and subsequently referred to a pediatric hospital’s precision medicine clinic between July 1, 2010, and June 30, 2020, were reviewed. Pharmacogenetic testing results were abstracted focusing on CYP2D6 and CYP2C19. In addition, we compiled counts of patients’ co-occurring diagnoses, histories of adverse drug reactions (ADRs), previously trialed ineffective medications, and previous psychiatric medication changes. Logistic regression models were fit to examine CYP2C19 and CYP2D6 metabolizer status as functions of patient demographics and prereferral medication histories. RESULTS: Of 202 patients (mean age = 12.18 yrs), 66% were referred to precision medicine because of poor medication response. Among patients with pharmacogenomic testing results for CYP2D6, 9% were classified as poor metabolizers; among patients with results for CYP2C19, 10% were classified as rapid/ultrarapid metabolizers. Patient demographics and medication response history did not predict pharmacogenomic results. However, the number of co-occurring diagnoses positively predicted the number of nonpsychiatric ADRs and a higher probability of CYP2D6 poor metabolizer status; moreover, nonpsychiatric ADRs positively predicted CYP2C19 rapid/ultrarapid metabolizer status. CONCLUSION: In one of the largest reported samples of youth with ASD clinically referred for pharmacogenetic testing, we observed high variability in medication response and yield for actionable results. Our findings suggest potential clinical utility for pharmacogenetic testing and introduce possible clinical profiles associated with metabolizer status.

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16. Griffin A, Chen M, Tiwari VK. Dissection of cellular disruptions in autism spectrum disorder comorbidities. The European journal of neuroscience. 2023: e16155.

Up to 80% of children with autism spectrum disorder have at least one other neuropsychiatric comorbidity. The causes of such disorders are highly genetic, yet many studies fail to take analysis further than risk gene discovery to see cellular and mechanistic changes occurring. Therefore, the goal of this study was to unveil novel gene expression signatures involved in important neurodevelopmental processes that, when disrupted, lead to each of the autism comorbidities of interest. We achieved this by analysing a single-nuclei RNA sequencing dataset with prefrontal cortex samples from autism spectrum disorder plus comorbidities for differentially expressed genes. The highest number of alterations was seen in excitatory neurons, which also showed differential population and cell-cell interactions across disorders and an increase in expression of genes involved in neurodevelopmental pathways. Interestingly, the group without comorbidities displayed an increase in neuron-neuron interactions yet a decrease in population number, suggesting a major rewiring of neuronal connections. Further analysis of the topmost significant genes from this cell type in developing prefrontal cortex datasets revealed interesting expression trajectories corresponding to important time points during corticogenesis. This further identified four novel candidate genes that show a potential link to developmental pathways that may contribute to autism and its comorbidities when dysregulated. The study provides a better understanding of co-occurring conditions at a transcriptomic and cell-type level and thereby aid future research in providing earlier diagnosis, care and intervention.

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17. Iffland M, Livingstone N, Jorgensen M, Hazell P, Gillies D. Pharmacological intervention for irritability, aggression, and self-injury in autism spectrum disorder (ASD). The Cochrane database of systematic reviews. 2023; 10(10): Cd011769.

BACKGROUND: Pharmacological interventions are frequently used for people with autism spectrum disorder (ASD) to manage behaviours of concern, including irritability, aggression, and self-injury. Some pharmacological interventions might help treat some behaviours of concern, but can also have adverse effects (AEs). OBJECTIVES: To assess the effectiveness and AEs of pharmacological interventions for managing the behaviours of irritability, aggression, and self-injury in ASD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, 11 other databases and two trials registers up to June 2022. We also searched reference lists of relevant studies, and contacted study authors, experts and pharmaceutical companies. SELECTION CRITERIA: We included randomised controlled trials of participants of any age with a clinical diagnosis of ASD, that compared any pharmacological intervention to an alternative drug, standard care, placebo, or wait-list control. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Primary outcomes were behaviours of concern in ASD, (irritability, aggression and self-injury); and AEs. Secondary outcomes were quality of life, and tolerability and acceptability. Two review authors independently assessed each study for risk of bias, and used GRADE to judge the certainty of the evidence for each outcome. MAIN RESULTS: We included 131 studies involving 7014 participants in this review. We identified 26 studies as awaiting classification and 25 as ongoing. Most studies involved children (53 studies involved only children under 13 years), children and adolescents (37 studies), adolescents only (2 studies) children and adults (16 studies), or adults only (23 studies). All included studies compared a pharmacological intervention to a placebo or to another pharmacological intervention. Atypical antipsychotics versus placebo At short-term follow-up (up to 6 months), atypical antipsychotics probably reduce irritability compared to placebo (standardised mean difference (SMD) -0.90, 95% confidence interval (CI) -1.25 to -0.55, 12 studies, 973 participants; moderate-certainty evidence), which may indicate a large effect. However, there was no clear evidence of a difference in aggression between groups (SMD -0.44, 95% CI -0.89 to 0.01; 1 study, 77 participants; very low-certainty evidence). Atypical antipsychotics may also reduce self-injury (SMD -1.43, 95% CI -2.24 to -0.61; 1 study, 30 participants; low-certainty evidence), possibly indicating a large effect. There may be higher rates of neurological AEs (dizziness, fatigue, sedation, somnolence, and tremor) in the intervention group (low-certainty evidence), but there was no clear evidence of an effect on other neurological AEs. Increased appetite may be higher in the intervention group (low-certainty evidence), but we found no clear evidence of an effect on other metabolic AEs. There was no clear evidence of differences between groups in musculoskeletal or psychological AEs. Neurohormones versus placebo At short-term follow-up, neurohormones may have minimal to no clear effect on irritability when compared to placebo (SMD -0.18, 95% CI -0.37 to -0.00; 8 studies; 466 participants; very low-certainty evidence), although the evidence is very uncertain. No data were reported for aggression or self -injury. Neurohormones may reduce the risk of headaches slightly in the intervention group, although the evidence is very uncertain. There was no clear evidence of an effect of neurohormones on any other neurological AEs, nor on any psychological, metabolic, or musculoskeletal AEs (low- and very low-certainty evidence). Attention-deficit hyperactivity disorder (ADHD)-related medications versus placebo At short-term follow-up, ADHD-related medications may reduce irritability slightly (SMD -0.20, 95% CI -0.40 to -0.01; 10 studies, 400 participants; low-certainty evidence), which may indicate a small effect. However, there was no clear evidence that ADHD-related medications have an effect on self-injury (SMD -0.62, 95% CI -1.63 to 0.39; 1 study, 16 participants; very low-certainty evidence). No data were reported for aggression. Rates of neurological AEs (drowsiness, emotional AEs, fatigue, headache, insomnia, and irritability), metabolic AEs (decreased appetite) and psychological AEs (depression) may be higher in the intervention group, although the evidence is very uncertain (very low-certainty evidence). There was no evidence of a difference between groups for any other metabolic, neurological, or psychological AEs (very low-certainty evidence). No data were reported for musculoskeletal AEs. Antidepressants versus placebo At short-term follow-up, there was no clear evidence that antidepressants have an effect on irritability (SMD -0.06, 95% CI -0.30 to 0.18; 3 studies, 267 participants; low-certainty evidence). No data for aggression or self-injury were reported or could be included in the analysis. Rates of metabolic AEs (decreased energy) may be higher in participants receiving antidepressants (very low-certainty evidence), although no other metabolic AEs showed clear evidence of a difference. Rates of neurological AEs (decreased attention) and psychological AEs (impulsive behaviour and stereotypy) may also be higher in the intervention group (very low-certainty evidence) although the evidence is very uncertain. There was no clear evidence of any difference in the other metabolic, neurological, or psychological AEs (very low-certainty evidence), nor between groups in musculoskeletal AEs (very low-certainty evidence). Risk of bias We rated most of the studies across the four comparisons at unclear overall risk of bias due to having multiple domains rated as unclear, very few rated as low across all domains, and most having at least one domain rated as high risk of bias. AUTHORS’ CONCLUSIONS: Evidence suggests that atypical antipsychotics probably reduce irritability, ADHD-related medications may reduce irritability slightly, and neurohormones may have little to no effect on irritability in the short term in people with ASD. There was some evidence that atypical antipsychotics may reduce self-injury in the short term, although the evidence is uncertain. There was no clear evidence that antidepressants had an effect on irritability. There was also little to no difference in aggression between atypical antipsychotics and placebo, or self-injury between ADHD-related medications and placebo. However, there was some evidence that atypical antipsychotics may result in a large reduction in self-injury, although the evidence is uncertain. No data were reported (or could be used) for self-injury or aggression for neurohormones versus placebo. Studies reported a wide range of potential AEs. Atypical antipsychotics and ADHD-related medications in particular were associated with an increased risk of metabolic and neurological AEs, although the evidence is uncertain for atypical antipsychotics and very uncertain for ADHD-related medications. The other drug classes had minimal or no associated AEs.

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18. Johnson CR, Barto L, Worley S, Rothstein R, Alder ML. Telehealth parent training for sleep disturbances in young children with autism spectrum disorder: A randomized controlled trial. Sleep medicine. 2023; 111: 208-19.

BACKGROUND AND PURPOSE: Young children with autism spectrum disorder (autism) have bedtime and sleep disturbances at much higher frequency and persistency than their neurotypical counterparts. Hence, access to early, effective treatment is critical in view of the importance of sleep in early childhood. Telehealth delivery could be a means to expand access to such early treatment if efficacious. The aim of this randomized control trial (RCT) was to compare a manualized, telehealth delivered, behaviorally based sleep parent training (SPT) intervention for parents of young children with autism and sleep disturbances to a control condition, a telehealth delivered parent education program with one sleep focused session (SPE). We hypothesized that the SPT group would show more improvements on child measures of sleep outcome measures, and daytime behaviors and parent measures of stress and sense of competence. We further aimed to explore the overall feasibility of telehealth delivery of SPT and SPE. PARTICIPANTS AND METHODS: Parents of 77 young children, ages 2-7 years, with autism and co-occurring sleep disturbances were enrolled in this study. Participants were randomized to either SPT or a comparison arm that included non-sleep related parent education except for one session. Each participant was individually administered a 5 session program delivered over 10 weeks. Outcome measures, including child sleep measures, child daytime behavior and parent stress and sense of competency were collected at weeks 5 and 10 after the baseline time point. Feasibility indicators (treatment fidelity, parent adherence, and parent attendance), and safety measures were also collected. RESULTS: Of 77 randomized participants, data were available for 36 participants randomized to SPT and 38 participants randomized to SPE. The mean age was 3 years, 8 months. Results support the efficacy of this manualized SPT intervention for bedtime and sleep disturbances. Sleep outcome measures were significantly improved in the SPT group compared to SPE on the Modified Simonds & Parraga Sleep Questionnaire-Composite Sleep Index (MSPSQ – CSI) (p < 0.001) with a large effect size of 0.83 at week 10. Positive response to treatment, as determined from the Clinical Global Impression-Improvement scale (CGI-I) at week 10 was observed in 56% of SPT participants compared to 32% in SPE (p = 0.037). There were no significant group differences in either the ABC-I as measure of daytime behaviors or in parental stress. There were group differences in favor of SPT over SPE on the PSOC, a measure of parent sense of competency. Feasibility and safety were further demonstrated with telehealth delivery. CONCLUSIONS: This RCT demonstrated the efficacy of a telehealth delivered parent training intervention for bedtime and sleep disturbances in young autistic children compared to an active control condition. Further, parents in SPT reported more confidence in their parenting role than those in the SPE group, but SPT did not result in overall decreases in parental stress. Telehealth delivery allowed for a much broader reach with enrolled participants from 24 states. This study supports a telehealth approach to a manualized behavioral parent mediated intervention for sleep disturbance in young autistic children and offers an alternative to in-person delivered approaches. This telehealth delivery has the potential to improve access for families who have a young autistic child with sleep disturbances. Given the small sample size, determining predictors and moderators of treatment response was not possible and should be examined in a larger trial.

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19. Kars S, Akı E. Relationship between play skills and sensory processing in children with autism. Applied neuropsychology Child. 2023: 1-11.

Play skills in children with autism are limited due to autism symptoms. It is important to determine the effect of sensory processing skill, which is one of these symptoms, on play skills. Therefore, we aimed to investigate of the relationship between play skills and sensory processing of children with autism. A total of 58 children with autism (n = 29) and typically developing children (n = 29) participated. We used the Sensory Profile and the Revised Knox Preschool Play Scale. Spearman’s correlation coefficient was used. Children with autism demonstrated a significantly lower developmental play age and were rated lower on all dimensions of the RKPPS than typically developing children. Moreover, the results of this study showed that there are complex correlations between play skills and sensory processing in children with autism. Sensory processing and play skills have complex relationships in children with autism.

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20. Kim J, Jung MW, Lee D. Reward learning improves social signal processing in autism model mice. Cell reports. 2023; 42(10): 113228.

Social and reward signal processing and their association are critical elements of social motivation. Despite the use of reward learning to improve the social interactions of patients with autism spectrum disorder (ASD), the underlying neural mechanisms are unknown. Here, we found different yet conjunct neuronal representations of social and reward signals in the mouse medial prefrontal cortex (mPFC). We also found that social signal processing is selectively disrupted, whereas reward signal processing is intact in the mPFC of Shank2-knockout mice, a mouse model of ASD. Furthermore, reward learning not only allows Shank2-knockout mice to associate social stimuli with reward availability, but it also rescues the impaired social signal processing. These findings provide insights into the neural basis for the therapeutic use of reward learning in ASD.

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21. Lassalle-Pérez A, Guzmán-Millán R, Ocasio-Quiñonez IT. H – 20 Barreras En El Diagnóstico Temprano Del Trastorno Del Espectro Autista En Féminas De 2 a 17 Años. Una Revisión Sistemática. Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists. 2023.

OBJETIVO: Estudio dirigido a identificar las posibles diferencias de sexo en la presentación y diagnóstico del Trastorno Del Espectro Autista (TEA). El TEA es un desorden del neurodesarrollo, con el cual uno de cada 44 niños/as es diagnosticado en Estados Unidos. Se estima que los niños presentan una probabilidad mayor de ser diagnosticados que las niñas. SELECCIÓN DE DATA: Se realizó una revisión sistemática para conocer las barreras en el diagnóstico temprano del TEA en féminas de 2 a 17 años. Ésta se limitó a revisiones de literatura, estudios descriptivos y transeccionales, entre los años 2019-2023. Se realizó una búsqueda en las bases de datos de PubMed, ResearchGate, y Google Scholar, para los meses de enero a abril del 2023. Se utilizaron los siguientes términos « autismo, féminas, señales tempranas, niñez temprana ». Se identificaron 93,516 artículos, luego del proceso de filtración se evaluaron 20 y 4 cumplieron con los criterios de inclusión. Se analizaron los detalles de publicación, constructo, muestra, medidas de análisis y diagnóstico. El avalúo de calidad se realizó utilizando las guías de QUADAS-2. SÍNTESIS DE DATA: La búsqueda arrojó una muestra de 4 artículos sobre las barreras y diferencias de sexo en el TEA y diagnóstico temprano. Se identificaron 4 temas principales basados en la neurociencia, como atención social, percepción táctil y funcionamiento cerebral. CONCLUSIÓN: Se evidenciaron diferencias significativas por sexo en síntomas y procesos cerebrales, que aportan a la teoría de un fenotipo femenino del TEA. Estos estudios son de carácter exploratorio y se requiere investigación empírica representativa para lograr conclusiones significativas.

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22. Lopes-Herrera SA, Costa DGS, Santos TRD, Martins A. Comparison between the socio-educational profiles of children with verbal and non-verbal Autism Spectrum Disorder. CoDAS. 2023; 35(5): e20210317.

PURPOSE: Compare the psychoeducational profiles of children with verbal and non-verbal Autism Spectrum Disorder (ASD). METHODS: Cross-sectional study conducted with a sample of 30 children with a medical diagnosis of ASD (15 verbal and 15 non-verbal) aged 2-9 years. The Psychoeducational Profile-Revised (PEP-R) scale was applied to assess the children’s development. The data were analyzed quantitatively and comparatively. Analysis of covariance (ANCOVA) was performed to evaluate the compatibility between the groups regarding the scores obtained in each PEP-R area, with chronological age as the covariate, and Student’s t-Test was used for the independent samples (p≤0.001). RESULTS: The scores in the different areas of the PEP-R were higher in the verbal group, with associations between language development and cognitive and social adaptive skills in the studied sample. Comparison between the groups showed a lower profile of the non-verbal group, with statistically significant differences in the areas of imitation, perception, gross and fine motor coordination, eye-hand coordination, cognitive performance, and verbal performance. CONCLUSION: The goal of comparing the psychoeducational profiles of verbal and non-verbal ASD children was reached, and statistically significant differences were observed. The children with non-verbal ASD presented a lower psychoeducational profile compared with that of verbal ASD children. Further studies with larger samples, delimited age groups, and more specific tests in each developmental area are suggested.

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23. Mammarella V, Orecchio S, Cameli N, Occhipinti S, Marcucci L, De Meo G, Innocenti A, Ferri R, Bruni O. Using pharmacotherapy to address sleep disturbances in autism spectrum disorders. Expert review of neurotherapeutics. 2023: 1-16.

INTRODUCTION: Sleep disorders are the second most common medical comorbidity in autism spectrum disorder (ASD), with effects on daytime behavior and functioning, mood and anxiety, and autism core features. In children with ASD, insomnia also has a negative impact on the whole family’s quality of life. Therefore, treatment of sleep disturbances should be considered as a primary goal in the management of ASD patients, and it is important to clarify the scientific evidence to inappropriate treatments. AREAS COVERED: The authors review the current literature concerning the pharmacological treatment options for the management of sleep-related disorders in patients with ASD (aged 0-18 years) using the PubMed and Cochrane Library databases with the search terms: autism, autistic, autism spectrum disorder, ASD, drug, drug therapy, drug intervention, drug treatment, pharmacotherapy, pharmacological treatment, pharmacological therapy, pharmacological intervention, sleep, sleep disturbance, and sleep disorder. EXPERT OPINION: Currently, clinicians tend to select medications for the treatment of sleep disorders in ASD based on the first-hand experience of psychiatrists and pediatricians as well as expert opinion. Nevertheless, at the present time, the only compound for which there is sufficient evidence is melatonin, although antihistamines, trazodone, clonidine, ramelteon, gabapentin, or suvorexant can also be considered for selection.

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24. McKern N, Dargue N, Sweller N. Comparing gesture frequency between autistic and neurotypical individuals: A systematic review and meta-analysis. Psychological bulletin. 2023.

While diagnostic assessments for autism routinely screen for reduced frequency of gestures, evidence supporting reduced gesture production in autism is inconsistent. This systematic review and meta-analysis aimed to clarify differences in frequency of gestures between autistic and neurotypical individuals. Included studies compared frequency of gestures between autistic and neurotypical individuals. Database searches (APA PsycInfo, ERIC, MEDLINE, ProQuest Dissertations and Theses Global) and a call for unpublished data on the International Society for Gesture Studies listserv identified research from January 1994 to March 2023. Study quality was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Quasi-Experimental Designs. Quantitative synthesis involved a narrative review of all findings and meta-analysis of articles allowing effect size calculations, stratified by the type of gesture. Thirty-one articles comparing frequency of gestures between 701 autistic and 860 neurotypical individuals were included in the narrative review, 25 of which were also included in the meta-analysis. Compared to neurotypical individuals, meta-analyses found that autistic individuals produced significantly less total, deictic, and emblematic gestures. While the number of iconic gestures appeared comparable between groups, studies investigating iconic gestures exhibited an almost equal trend of both positive and negative effect sizes, which were mostly nonsignificant. The way gesture production was measured, age, observer familiarity, and task structure (but not overall study quality) moderated the effect size, albeit inconsistently across the types of gestures. Findings have implications relating to profiling gesture use in diagnostic assessments for autism and highlight gaps in our understanding of differences in gesture production in autism. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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25. Montaser J, Umeano L, Pujari HP, Nasiri SMZ, Parisapogu A, Shah A, Khan S. Correlations Between the Development of Social Anxiety and Individuals With Autism Spectrum Disorder: A Systematic Review. Cureus. 2023; 15(9): e44841.

It is well established that people with autism spectrum disorder (ASD) have significantly higher rates of social anxiety, given that most autistic individuals experience socio-communication impairments, a deficit in social competence, and their experience in social engagement situations often leads to discomfort in social settings. Literature also finds that individuals on the spectrum are often at a higher risk of developing social anxiety, which is often misinterpreted as social anxiety disorder (SAD) leading to delays in the clinical diagnosis of ASD. Hence, an improved understanding of specific factors that put ASD individuals at risk of developing social anxiety will aid research to differentiate between social anxiety among individuals with ASD compared to non-ASD individuals facing social anxiety in general. This systematic review study focuses on empirical literature that provides evidence for reasons contributing to social anxiety among individuals with ASD. Following the systematic review methodology, the study evaluates 10 research papers. The results revealed several correlations that can be useful in helping explain why individuals with ASD are at a higher risk of developing SAD. Individuals with ASD often suffer severe social anxiety because they struggle to understand social cues, maintain eye contact, interpret non-verbal cues like facial expressions or body language, or participate in reciprocal conversation. Other cognitive factors include a preference toward predictable situations, intolerance for uncertainty, and a tendency toward rigid thinking patterns. Unpredictability in social settings often heightens anxiety levels in ASD individuals, making them avoid such situations. Other risk factors include emotional recognition impairments and reduced social competence. These findings serve as a guide to developing better intervention strategies to help individuals with ASD to overcome social anxiety.

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26. Murphy KE, Duncan B, Sperringer JE, Zhang E, Haberman V, Wyatt EV, Maness P. Ankyrin B promotes developmental spine regulation in the mouse prefrontal cortex. Cerebral cortex (New York, NY : 1991). 2023; 33(20): 10634-48.

Postnatal regulation of dendritic spine formation and refinement in cortical pyramidal neurons is critical for excitatory/inhibitory balance in neocortical networks. Recent studies have identified a selective spine pruning mechanism in the mouse prefrontal cortex mediated by class 3 Semaphorins and the L1 cell adhesion molecules, neuron-glia related cell adhesion molecule, Close Homolog of L1, and L1. L1 cell adhesion molecules bind Ankyrin B, an actin-spectrin adaptor encoded by Ankyrin2, a high-confidence gene for autism spectrum disorder. In a new inducible mouse model (Nex1Cre-ERT2: Ank2flox: RCE), Ankyrin2 deletion in early postnatal pyramidal neurons increased spine density on apical dendrites in prefrontal cortex layer 2/3 of homozygous and heterozygous Ankyrin2-deficient mice. In contrast, Ankyrin2 deletion in adulthood had no effect on spine density. Sema3F-induced spine pruning was impaired in cortical neuron cultures from Ankyrin B-null mice and was rescued by re-expression of the 220 kDa Ankyrin B isoform but not 440 kDa Ankyrin B. Ankyrin B bound to neuron-glia related CAM at a cytoplasmic domain motif (FIGQY1231), and mutation to FIGQH inhibited binding, impairing Sema3F-induced spine pruning in neuronal cultures. Identification of a novel function for Ankyrin B in dendritic spine regulation provides insight into cortical circuit development, as well as potential molecular deficiencies in autism spectrum disorder.

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27. Rahmatullah N, Schmitt LM, De Stefano L, Post S, Robledo J, Chaudhari GR, Pedapati E, Erickson CA, Portera-Cailliau C, Goel A. Hypersensitivity to distractors in Fragile X syndrome from loss of modulation of cortical VIP interneurons. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2023.

Attention deficit is one of the most prominent and disabling symptoms in Fragile X Syndrome (FXS). Hypersensitivity to sensory stimuli contributes to attention difficulties by overwhelming and/or distracting affected individuals, which disrupts activities of daily living at home and learning at school. We find that auditory or visual distractors selectively impair visual discrimination performance in humans and mice with FXS, but not their typically developing controls. In both species, males and females were examined. Vasoactive intestinal polypeptide (VIP) neurons were significantly modulated by incorrect responses in the post-stimulus period during early distractor trials in WT mice, consistent with their known role as ‘error’ signals. Strikingly, however, VIP cells from Fmr1(-/-) mice showed little modulation in error trials, and this correlated with their poor performance on the distractor task. Thus, VIP interneurons and their reduced modulatory influence on pyramidal cells, could be a potential therapeutic target for attentional difficulties in FXS.Significance StatementSensory hypersensitivity, impulsivity, and persistent inattention are among the most consistent clinical features of FXS, all of which impede daily functioning and create barriers to learning. However, the neural mechanisms underlying sensory over-reactivity remain elusive. To overcome a significant challenge in translational FXS research we demonstrate a compelling alignment of sensory over-reactivity in both humans with FXS and Fmr1(-/-) mice (the principal animal model of FXS) using a novel analogous distractor task. Two photon microscopy in mice reveal that dysfunctional VIP cells contribute to susceptibility to distractors. Implementing research efforts we describe here, can help identify dysfunctional neural mechanisms associated not only with sensory issues, but broader impairments, including those in learning and cognition.

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28. Ramirez AM, Kent GW, Kern J, Pyykkonen B, Shepardson K, Wenzel B. A – 177 The Self-Concept Scale of Conners Adult Rating Scale in the Diagnosis of Autism Spectrum Disorder in Adults. Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists. 2023.

OBJECTIVE: Self-report scales are beneficial in identifying symptoms of Autism Spectrum Disorder (ASD) in adults (Hayashi et al., 2021; Hull et al., 2019). Symptoms of ASD and attention-deficit/hyperactivity disorder (ADHD) overlap significantly even without dual-diagnosis (Nakagawa et al., 2021). The Conners Adult ADHD Rating Scale (CAARS) is a reliable and valid screening tool when identifying ADHD in adults, 78% sensitivity and 56% specificity (Abbass et al., 2021). Distinguishing features of ASD include restricted repetitive behaviors (RRB) and social interaction and communication deficits (SIC) (American Psychiatric Association, 2022). In adults, CAARS has shown a moderate correlation of RRB with the inattention (IA) and hyperactivity/impulsivity (HI) of ADHD; SIC moderately correlates with IA and mildly with HI. This study explores group differences when comparing Self-Concept (SC) Scale of CAARS in those diagnosed with ASD from clinical comparisons. DATA SELECTION: Data composed of 93 adult participants, 7 diagnosed with ASD, were extracted from a midwest neuropsychological outpatient clinic and analyzed to determine the sensitivity of CAARS-SC in diagnosing ASD. DATA SYNTHESIS: Independent t-Test identified no significant effect for diagnosis, t(91) = -0.301, p = 0.764, despite those in the ASD group (M = 62.00, SD = 12.432) endorsing more concerns than those without the diagnosis (M = 60.47, SD = 12.996). CONCLUSION: This study did not identify significant group differences on the CAARS-SC when comparing those diagnosed with ASD to the clinical comparisons. Further implications and limitations will be explored to distinguish ASD from overlapping diagnoses to employ appropriate treatment and future psychometric research directions.

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29. Shamji J, Erickson CS. B – 21 What Does BASC-3 Tell us about ASD in Females. Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists. 2023.

OBJECTIVE: This study explored parent endorsements on Behavior Assessment System for Children, Third Edition (BASC-3) for females diagnosed with Autism Spectrum Disorder (ASD) and how they differ by age group. METHOD: Data for 121 females (mean age 9.94) was collected between 2022 and 2023 for ages 2-5 (N = 21), 6-11 (N = 55), and 12-21(N = 45). Participants (White = 66%, Hispanic = 12%, Black = 5%, Biracial = 10%, and other = 5.8%) at a private group practice serving suburban and rural counties completed a standard neuropsychological evaluation for ASD. Seven subscales from the BASC-3 were analyzed; four subscales with strong theoretical relationships with ASD and three exploratory scales. RESULTS: A between-subjects ANOVA was conducted to compare the effect of age on BASC-3 for selected subscales. There was a significant effect of age on Externalizing Problems [F(2, 118) = 9.01, p < 0.001, η2 = 0.13], Internalizing Problems [F(2, 118) = 6.63, p = 0.002, η2 = 0.10], Atypicality [F(2, 118) = 15.07, p < 0.001, η2 = 0.20], and Adaptive Skills [F(2, 118) = 4.39, p = 0.015, η2 = 0.07]. Post hoc comparisons indicated significant differences across age groups on most scales, but especially for 6-11 ages. However, no significant differences were noted for Withdrawal, Developmental Social Disorder, and ASD probability. CONCLUSION: Age plays a significant role in the symptomatic presentation of ASD. Parents endorse more problematic behaviors for ages 6 to 11 than other age groups. Moreover, atypicality was the only subscale that showed differential elevations, but all theoretically relevant subscales were at risk. Females with ASD are equally as likely to demonstrate internalizing and externalizing behaviors.

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30. Song Y, Hupfeld KE, Davies-Jenkins CW, Zöllner HJ, Murali-Manohar S, Abdul-Nashirudeen M, Crocetti D, Yedavalli V, Oeltzschner G, Alessi N, Batschelett MA, Puts NAJ, Mostofsky SH, Edden RAE. Brain Glutathione and GABA+ levels in autistic children. bioRxiv : the preprint server for biology. 2023.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication challenges and repetitive behaviors. Altered neurometabolite levels, including glutathione (GSH) and gamma-aminobutyric acid (GABA), have been proposed as potential contributors to the biology underlying ASD. This study investigated whether cerebral GSH or GABA levels differ between a large cohort of children aged 8-12 years with ASD (n=52) and typically developing children (TDC, n=49). A comprehensive analysis of GSH and GABA levels in multiple brain regions, including the primary motor cortex (SM1), thalamus (Thal), medial prefrontal cortex (mPFC), and supplementary motor area (SMA), was conducted using single-voxel HERMES MR spectroscopy at 3T. The results revealed no significant differences in cerebral GSH or GABA levels between the ASD and TDC groups across all examined regions. These findings suggest that the concentrations of GSH (an important antioxidant and neuromodulator) and GABA (a major inhibitory neurotransmitter) do not exhibit marked alterations in children with ASD compared to TDC. A statistically significant positive correlation was observed between GABA levels in the SM1 and Thal regions with ADHD inattention scores. No significant correlation was found between metabolite levels and hyper/impulsive scores of ADHD, measures of core ASD symptoms (ADOS-2, SRS-P) or adaptive behavior (ABAS-2). While both GSH and GABA have been implicated in various neurological disorders, the current study provides valuable insights into the specific context of ASD and highlights the need for further research to explore other neurochemical alterations that may contribute to the pathophysiology of this complex disorder. LAY SUMMARY: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication challenges and repetitive behaviors. Altered glutathione (GSH, an important antioxidant and neuromodulator) and gamma-aminobutyric acid (GABA, a major inhibitory neurotransmitter) levels have been proposed as potential contributors to the biology underlying ASD. Here, we used advanced edited Magnetic Resonance Spectroscopy (MRS) to measure levels of these low-concentration metabolites in four brain regions of a pediatric cohort. Contrary to our hypothesis, no significant difference was found between ASD and control subjects in either GSH or GABA levels in any brain region.

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31. Stafford C, Aronson R, Golden C, Willeumier K, Amen D. B – 22 Cerebral Blood Flow in Patients with Autism Spectrum Disorder. Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists. 2023.

OBJECTIVE: The current study aims to investigate whether hyperactivity is present in the parietal lobe of individuals with autism spectrum disorder (ASD). METHOD: The data for this study was derived from an archival SPECT database. Participants in the ASD group (n = 91, Mage = 10.07, 78% male, 20.9% female, 1.1% others) were like those in the control group (n = 2983, Mage = 12.20, 69.7% male, 30% female, 0.3% other). Multiple independent t-tests were performed between the ASD and control groups on CBF levels in the left and right sides of the parietal lobe. RESULTS: Statistically significant differences existed between the ASD and control groups on CBF levels as follows: left and right side of the cerebellum, frontal lobe, occipital lobe, temporal lobe, vermis, and subcortical areas. In all cases, CBF was higher in the control group than in the ASD group. DISCUSSION: Findings suggest lower CBF within these areas in individuals with ASD may lead to why children with ASD have difficulties regulating emotions, over sensitivity to auditory stimuli, hand posturing, toe walking, or repetitive behaviors (such as flapping). These areas with lower CBF also lead to poorer memory functioning; these findings may suggest children with ASD have limited ability to remember large amount of information which may suggest why children with ASD have specific interests.

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32. Uy NG, Weiss E, McGinley J, Stimmel M, Bronshteyn D, Masur D, Facchini R. B – 24 Neuropsychological Profile of a Child with ASD, ADHD, and Psychotic Features. Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists. 2023.

OBJECTIVE: Autism Spectrum Disorder (ASD), Attention Deficit-Hyperactivity Disorder (ADHD), and psychotic traits, although highly comorbid, have rarely been studied in children. Existing research indicates that impulsivity, comprehension difficulties, and inflexibility are overlapping symptoms within the ASD and ADHD populations. Adult research shows high comorbidity estimates between ASD and psychosis. Here we describe the neuropsychological profile of a 14-year-old boy with diagnoses of ASD and ADHD with psychotic features. We highlight the value of comprehensive and flexible neuropsychological assessment while integrating detailed testing, behavioral observations, and collateral report. METHODS: Medical history of this child included late-term and breech birth with his first Apgar score at expected level and his second score falling below expected level. Delayed acquisition of developmental milestones, learning difficulties, speech difficulties, anxiety, and hyperactivity, were reported. Auditory hallucinations triggered by stress were observed during evaluation. Comprehensive neuropsychological evaluation requires nonstandard exploration of cognitive domains and time-limited testing sessions to acquire robust estimates of functioning. RESULTS: Overall cognitive abilities were in the borderline range with highly variable academic performances (extremely low to average). All performances were grossly below age level and were significantly impacted by auditory hallucinations but were consistent with the diagnoses of ASD and ADHD. CONCLUSION: This case of a boy with ASD, ADHD, and auditory hallucinations demonstrates the diagnostic overlap among these conditions and the necessity for flexible neuropsychological testing, detailed behavioral observations and caregiver report in the assessment of overlapping clinical features. Multiple sources of data are required to identify patterns in symptomatology to inform differential diagnosis and comorbidities.

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33. Wang HC, Feldman DE. Degraded tactile coding in the Cntnap2 mouse model of autism. bioRxiv : the preprint server for biology. 2023.

Atypical sensory processing in autism involves altered neural circuit function and neural coding in sensory cortex, but the nature of coding disruption is poorly understood. We characterized neural coding in L2/3 of whisker somatosensory cortex (S1) of Cntnap2 (-/-) mice, an autism model with pronounced hypofunction of parvalbumin (PV) inhibitory circuits. We tested for both excess spiking, which is often hypothesized in autism models with reduced inhibition, and alterations in somatotopic coding, using c-fos immunostaining and 2-photon calcium imaging in awake mice. In Cntnap2 (-/-) mice, c- fos-(+) neuron density was elevated in L2/3 of S1 under spontaneous activity conditions, but comparable to control mice after whisker stimulation, suggesting that sensory-evoked spiking was relatively normal. 2-photon GCaMP8m imaging in L2/3 pyramidal cells revealed no increase in whisker-evoked response magnitude, but instead showed multiple signs of degraded somatotopic coding. These included broadening of whisker tuning curves, blurring of the whisker map, and blunting of the point representation of each whisker. These altered properties were more pronounced in noisy than sparse sensory conditions. Tuning instability, assessed over 2-3 weeks of longitudinal imaging, was also significantly increased in Cntnap2 (-/-) mice. Thus, Cntnap2 (-/-) mice show no excess spiking, but a degraded and unstable tactile code in S1.

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34. Yurdakul E, Barlas Y, Ulgen KO. Circadian clock crosstalks with autism. Brain and behavior. 2023: e3273.

BACKGROUND: The mechanism underlying autism spectrum disorder (ASD) remains incompletely understood, but researchers have identified over a thousand genes involved in complex interactions within the brain, nervous, and immune systems, particularly during the mechanism of brain development. Various contributory environmental effects including circadian rhythm have also been studied in ASD. Thus, capturing the global picture of the ASD-clock network in combined form is critical. METHODS: We reconstructed the protein-protein interaction network of ASD and circadian rhythm to understand the connection between autism and the circadian clock. A graph theoretical study is undertaken to evaluate whether the network attributes are biologically realistic. The gene ontology enrichment analyses provide information about the most important biological processes. RESULTS: This study takes a fresh look at metabolic mechanisms and the identification of potential key proteins/pathways (ribosome biogenesis, oxidative stress, insulin/IGF pathway, Wnt pathway, and mTOR pathway), as well as the effects of specific conditions (such as maternal stress or disruption of circadian rhythm) on the development of ASD due to environmental factors. CONCLUSION: Understanding the relationship between circadian rhythm and ASD provides insight into the involvement of these essential pathways in the pathogenesis/etiology of ASD, as well as potential early intervention options and chronotherapeutic strategies for treating or preventing the neurodevelopmental disorder.

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