1. Benabderrahmane B, Gharzouli M, Benlecheb A. A novel multi-modal model to assist the diagnosis of autism spectrum disorder using eye-tracking data. Health Inf Sci Syst;2024 (Dec);12(1):40.

BACKGROUND AND OBJECTIVE: Timely and accurate detection of Autism Spectrum Disorder (ASD) is essential for early intervention and improved patient outcomes. This study aims to harness the power of machine learning (ML) techniques to improve ASD detection by incorporating temporal eye-tracking data. We developed a novel ML model to leverage eye scan paths, sequences of distances of eye movement, and a sequence of fixation durations, enhancing the temporal aspect of the analysis for more effective ASD identification. METHODS: We utilized a dataset of eye-tracking data without augmentation to train our ML model, which consists of a CNN-GRU-ANN architecture. The model was trained using gaze maps, the sequences of distances between eye fixations, and durations of fixations and saccades. Additionally, we employed a validation dataset to assess the model’s performance and compare it with other works. RESULTS: Our ML model demonstrated superior performance in ASD detection compared to the VGG-16 model. By incorporating temporal information from eye-tracking data, our model achieved higher accuracy, precision, and recall. The novel addition of sequence-based features allowed our model to effectively distinguish between ASD and typically developing individuals, achieving an impressive precision value of 93.10% on the validation dataset. CONCLUSION: This study presents an ML-based approach to ASD detection by utilizing machine learning techniques and incorporating temporal eye-tracking data. Our findings highlight the potential of temporal analysis for improved ASD detection and provide a promising direction for further advancements in the field of eye-tracking-based diagnosis and intervention for neurodevelopmental disorders.

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2. Benazzato C, Lojudice F, Pöehlchen F, Leite PEC, Manucci AC, Van der Linden V, Jungmann P, Sogayar MC, Bruni-Cardoso A, Russo FB, Beltrão-Braga P. Zika virus vertical transmission induces neuroinflammation and synapse impairment in brain cells derived from children born with Congenital Zika Syndrome. Sci Rep;2024 (Aug 3);14(1):18002.

Zika virus (ZIKV) infection was first reported in 2015 in Brazil as causing microcephaly and other developmental abnormalities in newborns, leading to the identification of Congenital Zika Syndrome (CZS). Viral infections have been considered an environmental risk factor for neurodevelopmental disorders outcome, such as Autism Spectrum Disorder (ASD). Moreover, not only the infection per se, but maternal immune system activation during pregnancy, has been linked to fetal neurodevelopmental disorders. To understand the impact of ZIKV vertical infection on brain development, we derived induced pluripotent stem cells (iPSC) from Brazilian children born with CZS, some of the patients also being diagnosed with ASD. Comparing iPSC-derived neurons from CZS with a control group, we found lower levels of pre- and postsynaptic proteins and reduced functional synapses by puncta co-localization. Furthermore, neurons and astrocytes derived from the CZS group showed decreased glutamate levels. Additionally, the CZS group exhibited elevated levels of cytokine production, one of which being IL-6, already associated with the ASD phenotype. These preliminary findings suggest that ZIKV vertical infection may cause long-lasting disruptions in brain development during fetal stages, even in the absence of the virus after birth. These disruptions could contribute to neurodevelopmental disorders manifestations such as ASD. Our study contributes with novel knowledge of the CZS outcomes and paves the way for clinical validation and the development of potential interventions to mitigate the impact of ZIKV vertical infection on neurodevelopment.

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3. Chen YJ, Sideris J, Watson LR, Crais ER, Baranek GT. Developmental Impacts of Early Sensory Patterns on School-Age Adaptive, Maladaptive, and Participation Outcomes in Autistic and Non-autistic Children. J Autism Dev Disord;2024 (Aug 2)

Early sensory differences may cascade into later social-communication difficulties in autism, yet their impacts on broader functional outcomes have remained understudied. This study aimed to conduct a comprehensive investigation into the longitudinal impacts of sensory patterns, including sensory hyperresponsiveness, hyporesponsiveness, and sensory repetitions/seeking behavior, on various school-age outcome domains among a community sample of children with autistic and non-autistic conditions. We prospectively followed 1,517 children with caregiver-reported sensory questionnaires across three timepoints from infancy to school age. A subsample (n = 389; 88 with reported autism diagnosis/concerns) was further assessed with adaptive, maladaptive and participation outcome measures at age 6-7. Structural equation modeling approaches were used to evaluate the multivariate associations between latent growth parameters (i.e., intercepts and slopes) of sensory patterns and school-age outcomes. Increasing sensory hyperresponsiveness was directly associated with poorer adaptive/maladaptive outcomes and indirectly with lower participation in activities with higher functional demands across settings at school age. Elevated sensory hyporesponsiveness was associated with lower adaptive functioning, more externalizing problems, and lower classroom participation. Trajectories of sensory patterns accounted for more unique variances in adaptive functioning and participation in daily life settings with higher functional and environmental demands among autistic children compared to their non-autistic peers.

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4. Feng S, Gong Y, Xia L, Lang Y, Shen Y, Li H, Feng W, Chen F, Chen Y. Calcium Hexacyanoferrate (III) Nanocatalyst Enables Redox Homeostasis for Autism Spectrum Disorder Treatment. Adv Mater;2024 (Aug 3):e2405655.

Autism spectrum disorder (ASD) is a multifaced neurodevelopmental disorder with considerable heterogeneity, in which over-generated reactive oxygen species (ROS) induce a cascade of pathological changes, including cellular apoptosis and inflammatory responses. Given the complex etiology of ASD, no effective treatment is available for ASD. In this work, a specific catalytic nanoenzyme, calcium hexacyanoferrate (III) nanocatalysts (CaH NCs), is designed and engineered for efficient ASD treatment. CaH NCs can mimic the activities of natural enzymes including superoxide dismutase, peroxidase, catalase, and glutathione peroxidase, which mitigates intracellular excessive ROS and regulates redox equilibrium. These CaH NCs modulate mitochondrial membrane potential, elevate B-cell lymphoma-2 levels, and suppress pro-apoptotic proteins, including Caspase-3 and B-cell lymphoma-2-associated X, thus effectively reducing cellular apoptosis. Importantly, CaH NCs alleviate inflammation by upregulating anti-inflammatory cytokine interleukin-10 and downregulating pro-inflammatory factors, resulting in attenuated activation of microglial and astrocytic and subsequent reduction in neuroinflammation. Subsequently, CaH NCs enhance social abilities, decrease anxiety levels, ameliorate repetitive behaviors, and improve learning and memory in ASD animal models through inflammation regulation and apoptosis inhibition. The CaH NCs in managing and preventing ASD represents a paradigm shift in autism treatment, paving the alternative but efficient way for clinical interventions in neurological conditions.

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5. Lee JP, Chang YH, Tseng YL, Chou TL, Chien YL. Pupillary response during social emotion tasks in autism spectrum disorder. Autism Res;2024 (Aug 2)

Autistic individuals encounter challenges in recognizing emotional expressions of others. Pupillary response has been proposed as an indicator of arousal dysregulation or cognitive load. The pupillary response of autistic individuals during socio-affective tasks remains unclear. This study investigated pupillary response in autistic adults when viewing emotional faces/eyes and recognizing emotions during the Reading the Mind in the Eyes Test (RMET) and watching interpersonal touch scenes in the social touch task. The study included 98 participants diagnosed with autism spectrum disorder and 37 typically developing controls (TD). Pupil size was measured using the Tobii X2-30 Eye Tracker. The results showed that autistic adults had larger maximal pupil sizes, smaller minimal pupil sizes, and greater change rates of pupil size, particularly during the RMET Eyes task. Clinical correlations revealed that attention switching difficulty positively correlated with mean pupil size in TD participants, while social communication deficits positively correlated with mean pupil size in autistic participants. In conclusion, our findings suggest atypical pupillary responses in autistic adults during socio-affective tasks, indicating heightened cognitive demand. Further investigation is necessary to understand the underlying mechanisms and their association with autistic traits.

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6. McMahon CM, McClain MB, Haverkamp CR, Harris B. Re-Evaluating the Appropriateness of the « Don’t Know » Response Option: Guessing Rate as a Source of Systematic Error on Autism Knowledge Assessments. J Autism Dev Disord;2024 (Aug 3)

Several autism knowledge assessments include « don’t know » as a response option. The inclusion of this response option may lead to systematic error, such that participants’ guessing rate affects the measurement of their autism knowledge. This study examines both predictors of guessing rate for autism knowledge and predictors of autism knowledge, including guessing rate. School-based professionals (n = 396) completed the Autism Spectrum Knowledge Scale Professional Version-Revised (ASKSP-R; McClain et al, Journal of Autism and Developmental Disorders 50(3):998-1006, 2020). and the Autism Stigma and Knowledge Questionnaire (ASK-Q; Harrison et al, Journal of Autism and Developmental Disorders 47(10):3281-3295, 2017). Both assessments include « don’t know » as a response option. Guessing rate was the strongest predictor of autism knowledge across both the ASKSP-R and the ASK-Q assessments. For the ASKSP-R, participants who were school psychologists, practicing for more years, had more autism-related clinical experiences, and who personally knew an autistic person had a higher guessing rate. School psychologists and participants who worked with more autistic students scored higher in autism knowledge. For the ASK-Q, participants with greater self-perceived autism knowledge had a higher guessing rate. Participants with a doctorate degree, who personally knew an autistic person, and who worked with more autistic students scored higher in autism knowledge. Guessing rate can be a source of systematic error on autism knowledge assessments. Potential solutions to correct for guessing rate are examined and recommended for future use.

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7. Orioli PA, Johnston C, Del Bigio JZ, Krebs VLJ, Pissolato M, Gibelli M, De Araujo OR, Francisco RPV, De Carvalho WB. Assessment of newborn neuropsychomotor development born with exposure to SARS-CoV-2 in the perinatal period using the Bayley III scale at 6 months of age. Clinics (Sao Paulo);2024;79:100460.

OBJECTIVE: This study aimed to evaluate the Neuropsychomotor Development (NPMD) of newborns exposed to SARS-CoV-2 in the perinatal period using the Bayley III scale at 6 months of age. METHODS: Childcare appointments were scheduled for the included newborns in the study. During the 6-month consultation, the Screening Test for Bayley III Scale and, based on it, children were classified as « low risk », « moderate risk » or « high risk » in the domains: of cognitive, receptive language, expressive language, fine motor, and gross motor. Those classified as « moderate risk »; or « high risk » received guidance about NPMD stimuli and were instructed to maintain follow-up. RESULTS: Only 13 (37.1 %) of the newborns were classified as low risk in receptive language and 18 (51.4 %) in gross motor skills, with the domains most affected. Prematurity was a risk for cognitive incompetence (moderate risk/high-risk classification) (coefficient: 1.89, Odds Ratio = 6.7, 95 % CI 1.3‒35, p = 0.02). Lower birth weight that 2.500g had a similar effect on cognitive incompetence (coefficient: 1.9, Odds Ratio = 6.2, 95 % CI 1.2‒32.2, p = 0.02). Exclusive breastfeeding at hospital discharge (n = 8) was protective for incompetence (high risk/moderate risk) in the language domain (coefficient -2.14, OR = 0.12, 95 % CI 0.02‒0.71, p = 0.02). CONCLUSIONS: The children included in the study must be monitored and their development monitored in order to clarify whether there is a relationship between the delay in NPMD and perinatal exposure to COVID-19, as delays were observed in these preliminary results.

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8. Oz M, Kury LA, Sadek B, Mahgoub MO. The role of nicotinic acetylcholine receptors in the pathophysiology and pharmacotherapy of autism spectrum disorder: Focus on α7 nicotinic receptors. Int J Biochem Cell Biol;2024 (Sep);174:106634.

Postmortem studies have revealed that brains of individuals with autism spectrum disorder (ASD) exhibit abnormalities in various components of the cholinergic system including cholinergic receptors, projections, and nuclei. Deletions in the 15q13.3 region which encompasses CHRNA7, the gene that encodes the α7-nACh receptor, have been linked to various neurodevelopmental disorders, including ASD. In addition, the involvement of α7-nACh receptors in biological phenomena known to play a role in the pathophysiology of ASD such as cognitive functions, learning, memory, neuroinflammation, and oxidative stress, as well as the excitation-inhibition balance in neuronal circuits and maternal immune activation have been reported in previous studies. Furthermore, evolving preclinical and clinical literature supports the potential therapeutic benefits of using selectively acting cholinergic compounds, particularly those targeting the α7-nACh receptor subtype, in the treatment of ASD. This study reviews the previous literature on the involvement of nACh receptors in the pathophysiology of ASD and focuses on the α7-nACh receptor as a potential therapeutic target.

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9. Schielen SJC, Pilmeyer J, Aldenkamp AP, Zinger S. The diagnosis of ASD with MRI: a systematic review and meta-analysis. Transl Psychiatry;2024 (Aug 2);14(1):318.

While diagnosing autism spectrum disorder (ASD) based on an objective test is desired, the current diagnostic practice involves observation-based criteria. This study is a systematic review and meta-analysis of studies that aim to diagnose ASD using magnetic resonance imaging (MRI). The main objective is to describe the state of the art of diagnosing ASD using MRI in terms of performance metrics and interpretation. Furthermore, subgroups, including different MRI modalities and statistical heterogeneity, are analyzed. Studies that dichotomously diagnose individuals with ASD and healthy controls by analyses progressing from magnetic resonance imaging obtained in a resting state were systematically selected by two independent reviewers. Studies were sought on Web of Science and PubMed, which were last accessed on February 24, 2023. The included studies were assessed on quality and risk of bias using the revised Quality Assessment of Diagnostic Accuracy Studies tool. A bivariate random-effects model was used for syntheses. One hundred and thirty-four studies were included comprising 159 eligible experiments. Despite the overlap in the studied samples, an estimated 4982 unique participants consisting of 2439 individuals with ASD and 2543 healthy controls were included. The pooled summary estimates of diagnostic performance are 76.0% sensitivity (95% CI 74.1-77.8), 75.7% specificity (95% CI 74.0-77.4), and an area under curve of 0.823, but uncertainty in the study assessments limits confidence. The main limitations are heterogeneity and uncertainty about the generalization of diagnostic performance. Therefore, comparisons between subgroups were considered inappropriate. Despite the current limitations, methods progressing from MRI approach the diagnostic performance needed for clinical practice. The state of the art has obstacles but shows potential for future clinical application.

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10. Spencer SD, Pinciotti CM, Murphy C, Hertz A, Wiese AD, Wood JJ, Kendall PC, Storch EA. Concurrent Validity of the Anxiety Disorders Section of the Anxiety Disorder Interview Schedule- Autism Spectrum Addendum (ADIS-ASA) in Autistic Youth. J Autism Dev Disord;2024 (Aug 3)

PURPOSE: Examine the concurrent validity of specific Anxiety Disorders Section of the Anxiety Disorder Interview Schedule for DSM-IV-Autism Spectrum Addendum (ADIS-ASA)-Parent Interview in a sample of 167 autistic youth who met diagnostic criteria for an anxiety-related disorder (M(age) = 9.91; 78.4% male; 82% non-Hispanic; 77.67% White). METHODS: Concurrent validity of Diagnostic and Statistical Manual (DSM)-defined ADIS-ASA anxiety disorder diagnostic caseness was examined via relations with (a) parent-reported dimensions of youth anxiety symptomology and (b) dimensional measures of youth anxiety-related functional impairment, respectively, using logistic regression models and point-biserial correlations. RESULTS: Significant relations were found between separation anxiety disorder and social anxiety disorder (but not generalized anxiety disorder nor obsessive-compulsive disorder) caseness, respectively, and theoretically consistent facets of dimensional youth anxiety symptomology. Relations between ADIS-ASA diagnostic caseness and youth functional impairment-related variables revealed that only separation anxiety disorder demonstrated robust evidence of convergent validity. CONCLUSION: Despite mixed findings concerning relations between ADIS-ASA anxiety disorder diagnostic caseness and dimensional measures of anxiety severity and anxiety-related impairment, the present findings provide further support for the status of the ADIS-ASA as a gold standard for assessment of anxiety in autistic youth. This work also highlights the importance of continuing to improve precision in measurement of anxiety symptomology in autistic youth, with implications for clinical assessment.

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11. Starr AL, Fraser HB. A general principle governing neuronal evolution reveals a human-accelerated neuron type potentially underlying the high prevalence of autism in humans. bioRxiv;2024 (Aug 3)

The remarkable ability of a single genome sequence to encode a diverse collection of distinct cell types, including the thousands of cell types found in the mammalian brain, is a key characteristic of multicellular life. While it has been observed that some cell types are far more evolutionarily conserved than others, the factors driving these differences in evolutionary rate remain unknown. Here, we hypothesized that highly abundant neuronal cell types may be under greater selective constraint than rarer neuronal types, leading to variation in their rates of evolution. To test this, we leveraged recently published cross-species single-nucleus RNA-sequencing datasets from three distinct regions of the mammalian neocortex. We found a strikingly consistent relationship where more abundant neuronal subtypes show greater gene expression conservation between species, which replicated across three independent datasets covering >10(6) neurons from six species. Based on this principle, we discovered that the most abundant type of neocortical neurons-layer 2/3 intratelencephalic excitatory neurons-has evolved exceptionally quickly in the human lineage compared to other apes. Surprisingly, this accelerated evolution was accompanied by the dramatic down-regulation of autism-associated genes, which was likely driven by polygenic positive selection specific to the human lineage. In sum, we introduce a general principle governing neuronal evolution and suggest that the exceptionally high prevalence of autism in humans may be a direct result of natural selection for lower expression of a suite of genes that conferred a fitness benefit to our ancestors while also rendering an abundant class of neurons more sensitive to perturbation.

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