1. Alharthi AG, Alzahrani SM. Multi-Slice Generation sMRI and fMRI for Autism Spectrum Disorder Diagnosis Using 3D-CNN and Vision Transformers. Brain sciences. 2023; 13(11).

Researchers have explored various potential indicators of ASD, including changes in brain structure and activity, genetics, and immune system abnormalities, but no definitive indicator has been found yet. Therefore, this study aims to investigate ASD indicators using two types of magnetic resonance images (MRI), structural (sMRI) and functional (fMRI), and to address the issue of limited data availability. Transfer learning is a valuable technique when working with limited data, as it utilizes knowledge gained from a pre-trained model in a domain with abundant data. This study proposed the use of four vision transformers namely ConvNeXT, MobileNet, Swin, and ViT using sMRI modalities. The study also investigated the use of a 3D-CNN model with sMRI and fMRI modalities. Our experiments involved different methods of generating data and extracting slices from raw 3D sMRI and 4D fMRI scans along the axial, coronal, and sagittal brain planes. To evaluate our methods, we utilized a standard neuroimaging dataset called NYU from the ABIDE repository to classify ASD subjects from typical control subjects. The performance of our models was evaluated against several baselines including studies that implemented VGG and ResNet transfer learning models. Our experimental results validate the effectiveness of the proposed multi-slice generation with the 3D-CNN and transfer learning methods as they achieved state-of-the-art results. In particular, results from 50-middle slices from the fMRI and 3D-CNN showed a profound promise in ASD classifiability as it obtained a maximum accuracy of 0.8710 and F1-score of 0.8261 when using the mean of 4D images across the axial, coronal, and sagittal. Additionally, the use of the whole slices in fMRI except the beginnings and the ends of brain views helped to reduce irrelevant information and showed good performance of 0.8387 accuracy and 0.7727 F1-score. Lastly, the transfer learning with the ConvNeXt model achieved results higher than other transformers when using 50-middle slices sMRI along the axial, coronal, and sagittal planes.

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2. Al-Hendawi M, Hussein E, Al Ghafri B, Bulut S. A Scoping Review of Studies on Assistive Technology Interventions and Their Impact on Individuals with Autism Spectrum Disorder in Arab Countries. Children (Basel, Switzerland). 2023; 10(11).

The rising prevalence of autism spectrum disorder (ASD) in Arab countries necessitates evidence-based interventions. Assistive technology (AT) presents a promising approach. However, data on the pervasiveness of AT use and its effectiveness for individuals with ASD, specifically within Arab countries, remain scarce. OBJECTIVE: To review the current literature on the AT interventions and outcomes reported for individuals with ASD in Arab countries. METHODS: A scoping review adhering to PRISMA guidelines was undertaken to explore the utilization of AT, segmented into three categories: low-technology (low-tech), mid-technology (mid-tech), and high-technology (high-tech) devices. RESULTS: Twelve studies had a pooled sample of 1547 participants, primarily male school-aged children with ASD. The AT applications evaluated ranged from low-tech visual schedules and support to high-tech virtual reality systems. Studies have reported the potential benefits of AT in improving communication, social, academic, adaptive, and functional abilities; however, comparative evidence between AT interventions is limited. The identified barriers to the adoption of AT included caregiver uncertainty about the use of AT and a lack of awareness of AT among professionals and the Arab community in general. CONCLUSION: Available studies suggest that the adoption of AT can enhance the skills of individuals with ASD in Arab countries. However, more rigorous studies across diverse demographic groups and Arab national regions are needed to strengthen the evidence base and provide appropriate recommendations.

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3. Alhowikan AM, Elamin NE, Aldayel SS, AlSiddiqi SA, Alrowais FS, Hassan WM, El-Ansary A, Alghamdi FA, Al-Ayadhi LY. Children with Autism Spectrum Disorder Exhibit Elevated Physical Activity and Reduced Sedentary Behavior. Brain sciences. 2023; 13(11).

According to previous research, individuals with autism spectrum disorder (ASD) have lower levels of physical activity than their typically developed (TD) counterparts. There have been conflicting reports about physical activity (PA) levels in people with ASD. Given the conflicting evidence, further investigation is required. We believe that evaluating PA in individuals with ASD is critical in order to offer PA intervention plans aiming at increasing their health-related physical fitness on a daily, systematic, and individualized basis. In the current study, an ActiGraph monitor (GT3X+) was used to accurately measure PA and sedentary activity in 21 children with autism aged 6.43 ± 2.29 years and 30 TD children aged 7.2 ± 3.14 years. Our data indicated that while the light and moderate activity counts were not significantly different between the two groups, the vigorous activity was significantly higher in ASD compared to TD. This finding was attributed to ASD characteristic stereotypy and self-stimulating behaviors. The significantly higher vigorous PA is discussed in relation to altered neurochemistry, oxidative stress, and neuroinflammation as etiological mechanisms in ASD. This research provides a better understanding of the status of PA participation in individuals with ASD.

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4. Alwetaid MY, Almanaa TN, Bakheet SA, Ansari MA, Nadeem A, Attia SM, Hussein MH, Ahmad SF. Aflatoxin B(1) Exposure Aggravates Neurobehavioral Deficits and Immune Dysfunctions of Th1, Th9, Th17, Th22, and T Regulatory Cell-Related Transcription Factor Signaling in the BTBR T(+)Itpr3(tf)/J Mouse Model of Autism. Brain sciences. 2023; 13(11).

Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by impaired communication, reciprocal social interactions, restricted sociability deficits, and stereotyped behavioral patterns. Environmental factors and genetic susceptibility have been implicated in an increased risk of ASD. Aflatoxin B(1) (AFB(1)) is a typical contaminant of food and feed that causes severe immune dysfunction in humans and animals. Nevertheless, the impact of ASD on behavioral and immunological responses has not been thoroughly examined. To investigate this phenomenon, we subjected BTBR T(+)Itpr3(tf)/J (BTBR) mice to AFB(1) and evaluated their marble-burying and self-grooming behaviors and their sociability. The exposure to AFB(1) resulted in a notable escalation in marble-burying and self-grooming activities while concurrently leading to a decline in social contacts. In addition, we investigated the potential molecular mechanisms that underlie the impact of AFB(1) on the production of Th1 (IFN-γ, STAT1, and T-bet), Th9 (IL-9 and IRF4), Th17 (IL-17A, IL-21, RORγT, and STAT3), Th22 (IL-22, AhR, and TNF-α), and T regulatory (Treg) (IL-10, TGF-β1, and FoxP3) cells in the spleen. This was achieved using RT-PCR and Western blot analyses to assess mRNA and protein expression in brain tissue. The exposure to AFB(1) resulted in a significant upregulation of various immune-related factors, including IFN-γ, STAT1, T-bet, IL-9, IRF4, IL-17A, IL-21, RORγ, STAT3, IL-22, AhR, and TNF-α in BTBR mice. Conversely, the production of IL-10, TGF-β1, and FoxP3 by CD4(+) T cells was observed to be downregulated. Exposure to AFB(1) demonstrated a notable rise in Th1/Th9/Th22/Th17 levels and a decrease in mRNA and protein expression of Treg. The results above underscore the significance of AFB(1) exposure in intensifying neurobehavioral and immunological abnormalities in BTBR mice, hence indicating the necessity for a more comprehensive investigation into the contribution of AFB(1) to the development of ASD.

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5. Artuso C, Belacchi C. Implicit Grammatical Gender Representation in Italian Children with Autism without Intellectual/Language Disorder. Children (Basel, Switzerland). 2023; 10(11).

Grammatical language development in individuals with autism (without intellectual/language impairment) is mostly qualitatively comparable to language development in typically developing children of the same age. The majority of tasks used to study grammatical development require explicit performance (use of verbal language). Here, we administered an implicit categorization task (by biological sex) to understand which markers children use to implicitly infer grammatical gender representation in Italian (a gendered language where grammatical gender can be inferred via a determiner and/or word ending). Participants were asked to categorize photos of animals, relying on the names that differed in regard to the grammatical markers involved (i.e., lexical semantic, phonological, syntactic or phonological + syntactic). Children with autism displayed the same patterns observed in typically developing children: the lexical-semantic marker was categorized more accurately, followed in decreasing order by the phonological-syntactic marker and the phonological marker. The syntactic marker was the most difficult to categorize for both groups. In addition, children with autism showed an advantage in grammatical gender representation when using formal/grammatical markers than when using lexical/semantic markers. Such an implicit assessment allows for the investigation of more nuanced linguistic representations other than those expressed by traditional assessments.

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6. Assiri MA, Albekairi TH, Ansari MA, Nadeem A, Attia SM, Bakheet SA, Shahid M, Aldossari AA, Almutairi MM, Almanaa TN, Alwetaid MY, Ahmad SF. The Exposure to Lead (Pb) Exacerbates Immunological Abnormalities in BTBR T(+) Itpr(3tf)/J Mice through the Regulation of Signaling Pathways Relevant to T Cells. International journal of molecular sciences. 2023; 24(22).

Autism spectrum disorder (ASD) is a common neurodevelopmental illness characterized by abnormal social interactions, communication difficulties, and repetitive and limited behaviors or interests. The BTBR T(+) Itpr3(tf)/J (BTBR) mice have been used extensively to research the ASD-like phenotype. Lead (Pb) is a hazardous chemical linked to organ damage in the human body. It is regarded as one of the most common metal exposure sources and has been connected to the development of neurological abnormalities. We used flow cytometry to investigate the molecular mechanism behind the effect of Pb exposure on subsets of CD4(+) T cells in the spleen expressing IFN-γ, T-bet, STAT1, STAT4, IL-9, IRF4, IL-22, AhR, IL-10, and Foxp3. Furthermore, using RT-PCR, we studied the effect of Pb on the expression of numerous genes in brain tissue, including IFN-γ, T-bet, STAT1, STAT4, IL-9, IRF4, IL-22, AhR, IL-10, and Foxp3. Pb exposure increased the population of CD4(+)IFN-γ(+), CD4(+)T-bet(+), CD4(+)STAT1(+), CD4(+)STAT4(+), CD4(+)IL-9(+), CD4(+)IRF4(+), CD4(+)IL-22(+), and CD4(+)AhR(+) cells in BTBR mice. In contrast, CD4(+)IL-10(+) and CD4(+)Foxp3(+) cells were downregulated in the spleen cells of Pb-exposed BTBR mice compared to those treated with vehicle. Furthermore, Pb exposure led to a significant increase in IFN-γ, T-bet, STAT1, STAT4, IL-9, IRF4, IL-22, and AhR mRNA expression in BTBR mice. In contrast, IL-10 and Foxp3 mRNA expression was significantly lower in those treated with the vehicle. Our data suggest that Pb exposure exacerbates immunological dysfunctions associated with ASD. These data imply that Pb exposure may increase the risk of ASD.

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7. Carpita B, Cremone IM, Nardi B, Amatori G, Bonelli C, Massimetti E, Casagrande D, Pini S, Dell’Osso L. Implications of Social Anxiety Symptoms in Adults with Autism Spectrum Disorder: Is There a Predictive Role of Interpersonal Sensitivity and Substance Abuse?. Brain sciences. 2023; 13(11).

Social anxiety disorder (SAD) has been frequently reported by subjects with Autism Spectrum Disorder (ASD). However, interestingly, the overlap between social anxiety and autistic traits may sometimes impede ASD diagnosis in subjects without intellectual or language impairment. The aim of the present work was to evaluate the presence and correlates of social phobic features among subjects with ASD, with a specific focus on evaluating which social anxiety symptoms may be statistically predictive of an ASD diagnosis. With this purpose, 48 subjects with ASD and 48 gender- and age- matched healthy controls (HCs) were recruited and assessed with the SHY-SV and the AdAS Spectrum questionnaires. Results highlighted higher scores in all SHY-SV Spectrum domains and total scores for the ASD group. Moreover, AdAS Spectrum scores were significantly correlated with all SHY-SV domain and total scores. A logistic regression analysis highlighted the SHY-SV Interpersonal sensitivity and Substance Abuse domains scores as significant positive predictors of an ASD diagnosis. These results confirm the link between ASD and SAD. Because of this association, particular attention should be paid to subjects with high interpersonal sensitivity traits and substance abuse problems.

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8. Caruana N, Nalepka P, Perez GA, Inkley C, Munro C, Rapaport H, Brett S, Kaplan DM, Richardson MJ, Pellicano E. Autistic young people adaptively use gaze to facilitate joint attention during multi-gestural dyadic interactions. Autism : the international journal of research and practice. 2023: 13623613231211967.

Autistic people have been said to have ‘problems’ with joint attention, that is, looking where someone else is looking. Past studies of joint attention have used tasks that require autistic people to continuously look at and respond to eye-gaze cues. But joint attention can also be done using other social cues, like pointing. This study looked at whether autistic and non-autistic young people use another person’s eye gaze during joint attention in a task that did not require them to look at their partner’s face. In the task, each participant worked together with their partner to find a computer-generated object in virtual reality. Sometimes the participant had to help guide their partner to the object, and other times, they followed their partner’s lead. Participants were told to point to guide one another but were not told to use eye gaze. Both autistic and non-autistic participants often looked at their partner’s face during joint attention interactions and were faster to respond to their partner’s hand-pointing when the partner also looked at the object before pointing. This shows that autistic people can and do use information from another person’s eyes, even when they don’t have to. It is possible that, by not forcing autistic young people to look at their partner’s face and eyes, they were better able to gather information from their partner’s face when needed, without being overwhelmed. This shows how important it is to design tasks that provide autistic people with opportunities to show what they can do.

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9. Choi J, Shin B, Choi BS. The Effect of Discrimination on the Daily Life Satisfaction of People with Developmental Disability: Parallel Multiple Mediating Effect of Social Involvement and Self-Esteem. Medicina (Kaunas, Lithuania). 2023; 59(11).

Background and Objectives: People with developmental disabilities are exposed to discrimination and it affects their daily life satisfaction. The purpose of this study is to examine the parallel mediating effect of social involvement and self-esteem on the relationship between discrimination and the daily life satisfaction of people with developmental disabilities to improve their daily life satisfaction. Materials and Methods: This study used raw data of participants with intellectual disabilities and autism spectrum disorder from a national panel survey of employment for the disabled second-wave fifth survey. First, correlations among variables were identified to determine whether variables are in a relationship, and then PROCESS Macro was conducted to identify the relationship between discrimination and daily life satisfaction and the parallel mediating effect of social involvement and self-esteem. Results: Discrimination had a significant negative effect on daily life satisfaction and it was found that social involvement and self-esteem have a significant mediating effect that lowers the effect size of discrimination on daily life satisfaction. Specifically, it was found that self-esteem had a more mediating effect than social involvement. Conclusions: To increase the daily life satisfaction of people with developmental disabilities, the potential need to not only decrease discrimination but also increase their social involvement and self-esteem should be considered.

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10. Fu B, Li S, Lao Z, Yuan B, Liang Y, He W, Sun W, He H. Multi-sensor and multi-platform retrieval of water chlorophyll a concentration in karst wetlands using transfer learning frameworks with ASD, UAV, and Planet CubeSate reflectance data. The Science of the total environment. 2023; 901: 165963.

China has one of the widest distributions of carbonate rocks in the world. Karst wetland is a special and important ecosystem of carbonate rock regions. Chlorophyll-a (Chla) concentration is a key indicator of eutrophication, and could quantitatively evaluate water quality status of karst wetland. However, the spectral reflectance characteristics of the water bodies of karst wetland are not yet clear, resulting in remote sensing retrieval of Chla with great challenges. This study is a pioneer in utilizing field-based full-spectrum hyperspectral data to reveal the spectral response characteristics of karst wetland water body and determine the sensitive spectral bands of Chla. We further evaluated the Chla retrieval performance of multi-platform spectral data between Analytical Spectral Device (ASD), Unmanned aerial vehicle (UAV), and PlanetScope (Planet). We proposed two multi-sensor weighted integration strategies and two transfer learning frameworks for estimating water Chla from the largest karst wetland in China by combing a partial least square with adaptive ensemble algorithms. The results showed that: (1) In the range of 500-850 nm, the spectral reflectance of water bodies in the karst wetland was overall 0.001-0.105 higher than the inland water bodies, and the sensitive spectral ranges of water Chla focus on 603-778 nm; (2) UAV images outperformed ASD and Planet data, and produced the highest inversion accuracy (R(2) = 0.670) for water Chla in karst wetland; (3) Multi-sensor weighted integration retrieval methods improved the Chla estimation accuracy (R(2) = 0.716). Integration retrieval methods with the different weights produced the better Chla estimation accuracy than that of methods with the equal weights; (4) The transfer learning methods from ASD to UAV platform provided the better retrieval performance (the average R(2) = 0.669) than that of methods from UAV to Planet platform. The transfer learning methods obtained the highest estimation accuracy of Chla (R(2) = 0.814) when the ratio of the training and test data in the target domain was 7:3. The transfer learning methods produced the higher estimation accuracies with the distribution of the absolute residuals between predicted and measured values <20.957 mg/m(3) compared to the multi-sensor weighted integration retrieval methods, which demonstrated that transfer learning is more suitable for estimating Chla in karst wetland water bodies using multi-platform and multi-sensor data. The results provide a scientific basis for the protection and sustainable development of karst wetlands.

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11. Guiducci L, Cabiati M, Santocchi E, Prosperi M, Morales MA, Muratori F, Randazzo E, Federico G, Calderoni S, Del Ry S. Expression of miRNAs in Pre-Schoolers with Autism Spectrum Disorders Compared with Typically Developing Peers and Its Effects after Probiotic Supplementation. Journal of clinical medicine. 2023; 12(22).

Alteration of the microbiota-gut-brain axis has been recently recognized as a possible contributor to the physiopathology of autism spectrum disorder (ASD). In this context, microRNA (miRNAs) dysfunction, implicated both in several neuropathological conditions including ASD and in different gastrointestinal disorders (GIDs), could represent an important modulating factor. In this contextual framework, we studied the transcriptional profile of specific circulating miRNAs associated with both ASD (miR-197-5p, miR-424-5p, miR-500a-5p, miR-664a-5p) and GID (miR-21-5p, miR-320a-5p, miR-31-5p, miR-223-5p) in a group of pre-schoolers with ASD and in typically developing (TD) peers. In the ASD group, we also assessed the same miRNAs after a 6-month supplementation with probiotics and their correlation with plasma levels of zonulin and lactoferrin. At baseline, the expression of miRNAs involved in ASD were significantly reduced in ASD pre-schoolers vs. TD controls. Regarding the miRNAs involved in GID, the expression levels of miR-320-5p, miR-31-5p, and miR-223-5p were significantly higher in ASD than in TD subjects, whereas miR-21-5p showed significantly reduced expression in the ASD group vs. TD group. Supplementation with probiotics did not significantly change the expression of miRNAs in the ASD population. We found a significative negative correlation between zonulin and miR-197-5p and miR-21-5p at baseline, as well as between lactoferrin and miR-223-5p after 6 months of probiotic supplementation. Our study confirms the presence of an altered profile of the miRNAs investigated in ASD versus TD peers that was not modified by supplementation with probiotics.

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12. Jones MK, Sone BJ, Grauzer J, Sudec L, Kaat A, Roberts MY. Characterizing mechanisms of caregiver-mediated naturalistic developmental behavioral interventions for autistic toddlers: A randomized clinical trial. Autism : the international journal of research and practice. 2023: 13623613231213283.

Caregiver-mediated early interventions support caregivers’ use of strategies to improve their young autistic child’s communication. In the current clinical trial, we sought to isolate the most effective strategies to improve short-term and long-term child communication outcomes. Results demonstrated how children may benefit from caregiver prompts to facilitate long-term language outcomes. In conclusion, the current study improves our understanding of how early intervention facilitates child communication outcomes.

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13. Leontiadis LJ, Trompoukis G, Felemegkas P, Tsotsokou G, Miliou A, Papatheodoropoulos C. Increased Inhibition May Contribute to Maintaining Normal Network Function in the Ventral Hippocampus of a Fmr1-Targeted Transgenic Rat Model of Fragile X Syndrome. Brain sciences. 2023; 13(11).

A common neurobiological mechanism in several neurodevelopmental disorders, including fragile X syndrome (FXS), is alterations in the balance between excitation and inhibition in the brain. It is thought that in the hippocampus, as in other brain regions, FXS is associated with increased excitability and reduced inhibition. However, it is still not known whether these changes apply to both the dorsal and ventral hippocampus, which appear to be differently involved in neurodegenerative disorders. Using a Fmr1 knock-out (KO) rat model of FXS, we found increased neuronal excitability in both the dorsal and ventral KO hippocampus and increased excitatory synaptic transmission in the dorsal hippocampus. Interestingly, synaptic inhibition is significantly increased in the ventral but not the dorsal KO hippocampus. Furthermore, the ventral KO hippocampus displays increased expression of the α1GABA(A) receptor subtype and a remarkably reduced rate of epileptiform discharges induced by magnesium-free medium. In contrast, the dorsal KO hippocampus displays an increased rate of epileptiform discharges and similar expression of α1GABA(A) receptors compared with the dorsal WT hippocampus. Blockade of α5GABA(A) receptors by L-655,708 did not affect epileptiform discharges in any genotype or hippocampal segment, and the expression of α5GABA(A) receptors did not differ between WT and KO hippocampus. These results suggest that the increased excitability of the dorsal KO hippocampus contributes to its heightened tendency to epileptiform discharges, while the increased phasic inhibition in the Fmr1-KO ventral hippocampus may represent a homeostatic mechanism that compensates for the increased excitability reducing its vulnerability to epileptic activity.

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14. Miranda-Lourenço C, Rosa J, Rei N, Belo RF, Lopes AL, Silva D, Vieira C, Magalhães-Cardoso T, Viais R, Correia-de-Sá P, Sebastião AM, Diógenes MJ. Adenosinergic System and BDNF Signaling Changes as a Cross-Sectional Feature of RTT: Characterization of Mecp2 Heterozygous Mouse Females. International journal of molecular sciences. 2023; 24(22).

Rett Syndrome is an X-linked neurodevelopmental disorder (RTT; OMIM#312750) associated to MECP2 mutations. MeCP2 dysfunction is seen as one cause for the deficiencies found in brain-derived neurotrophic factor (BDNF) signaling, since BDNF is one of the genes under MeCP2 jurisdiction. BDNF signaling is also dependent on the proper function of the adenosinergic system. Indeed, both BDNF signaling and the adenosinergic system are altered in Mecp2-null mice (Mecp2(-/y)), a representative model of severe manifestation of RTT. Considering that symptoms severity largely differs among RTT patients, we set out to investigate the BDNF and ADO signaling modifications in Mecp2 heterozygous female mice (Mecp2(+/-)) presenting a less severe phenotype. Symptomatic Mecp2(+/-) mice have lower BDNF levels in the cortex and hippocampus. This is accompanied by a loss of BDNF-induced facilitation of hippocampal long-term potentiation (LTP), which could be restored upon selective activation of adenosine A(2A) receptors (A(2A)R). While no differences were observed in the amount of adenosine in the cortex and hippocampus of Mecp2(+/-) mice compared with healthy littermates, the density of the A(1)R and A(2A)R subtype receptors was, respectively, upregulated and downregulated in the hippocampus. Data suggest that significant changes in BDNF and adenosine signaling pathways are present in an RTT model with a milder disease phenotype: Mecp2(+/-) female animals. These features strengthen the theory that boosting adenosinergic activity may be a valid therapeutic strategy for RTT patients, regardless of their genetic penetrance.

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15. Razzak R, Li J, He S, Sokhadze E. Investigating Sex-Based Neural Differences in Autism and Their Extended Reality Intervention Implications. Brain sciences. 2023; 13(11).

Autism Spectrum Disorder (ASD) affects millions of individuals worldwide, and there is growing interest in the use of extended reality (XR) technologies for intervention. Despite the promising potential of XR interventions, there remain gaps in our understanding of the neurobiological mechanisms underlying ASD, particularly in relation to sex-based differences. This scoping review synthesizes the current research on brain activity patterns in ASD, emphasizing the implications for XR interventions and neurofeedback therapy. We examine the brain regions commonly affected by ASD, the potential benefits and drawbacks of XR technologies, and the implications of sex-specific differences for designing effective interventions. Our findings underscore the need for ongoing research into the neurobiological underpinnings of ASD and sex-based differences, as well as the importance of developing tailored interventions that consider the unique needs and experiences of autistic individuals.

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16. Russell LA, Tinker SC, Rice CE, Ryerson AB, Gonzalez MG. Variation in identifying children and adolescents with disability and developmental disability in population-based public health surveys. Disability and health journal. 2023: 101556.

BACKGROUND: The term « developmental disability » (DD) is inconsistently defined and applied depending on purpose and across sources, including in legislation. OBJECTIVE: This project aimed to identify existing definitions of disability and DD and to determine the extent to which each definition could be operationalized to produce prevalence estimates using data from U.S. national surveys. METHODS: Using data among children <18 years from the 2016-2018 National Health Interview Survey (NHIS) and National Survey of Children's Health (NSCH), we estimated the prevalence of two definitions of disability (Washington Group Short Set on Functioning, American Community Survey) and seven definitions of DD [Health and Human Services (ever/current), Developmental Disabilities Assistance and Bill of Rights Act of 2000 (1+, 2+, or 3+ components), and Diagnostic and Statistical Manual of Mental Disorders, 5th ed (ever/current)]. Complex sample design variables and weights were used to calculate nationally representative prevalence. RESULTS: Disability (NHIS: 5.2-6.3%; NSCH: 9.2-11.9%) and DD prevalence (NHIS: 0.6-18.0% and NSCH: 0.2-22.2%) varied depending on the definition and data source. For the same definition, NSCH prevalence estimates tended to be higher than NHIS estimates. CONCLUSIONS: The substantial variability in estimated prevalence of disability and DD among children in the United States may be in part due to the surveys not representing all components of each definition. Different or additional questions in national surveys may better capture existing definitions of disability and DD. Considering the data collection goals may help determine the optimal definition to provide useful information for public health action.

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17. Saban-Bezalel R, Avni E, Ben-Itzchak E, Zachor DA. Relationship between Parental Concerns about Social-Emotional Reciprocity Deficits and Their Children’s Final ASD Diagnosis. Children (Basel, Switzerland). 2023; 10(11).

Concerns raised by parents regarding their child’s development are compatible with the child’s final diagnosis of autism spectrum disorder. A better understanding of the relationship between parental concerns and a final diagnosis of autism spectrum disorder is therefore critical. In the current study, we compared the frequencies of parental concerns related to DSM-5 criteria for autism spectrum disorder between pair-matched groups with and without a final diagnosis of autism spectrum disorder and determined which parental concerns predicted a final diagnosis of autism spectrum disorder. The cohort included 80 participants (48-154 months of age, IQ > 70) assessed for a possible autism spectrum disorder diagnosis. Parental concerns were retrieved from the free-description portion of the introductory questions of the Autism Diagnostic Interview-Revised and analyzed to assess whether they corresponded to any of the seven DSM-5 criteria for ASD. The two groups only differed in the frequency of parental concerns relating to deficits in social-emotional reciprocity. Parents of children diagnosed with autism spectrum disorder were four times as likely to report deficits in social-emotional reciprocity. This finding highlights the significance of parental concerns regarding deficits in social-emotional reciprocity in predicting a final diagnosis of autism spectrum disorder.

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18. Sandoval-Talamantes AK, Tenorio-Castaño JA, Santos-Simarro F, Adán C, Fernández-Elvira M, García-Fernández L, Muñoz Y, Lapunzina P, Nevado J. NGS Custom Panel Implementation in Patients with Non-Syndromic Autism Spectrum Disorders in the Clinical Routine of a Tertiary Hospital. Genes. 2023; 14(11).

Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders characterized by deficiencies in communication, social interaction, and repetitive and restrictive behaviors. The discovery of genetic involvement in the etiology of ASD has made this condition a strong candidate for genome-based diagnostic tests. Next-generation sequencing (NGS) is useful for the detection of variants in the sequence of different genes in ASD patients. Herein, we present the implementation of a personalized NGS panel for autism (AutismSeq) for patients with essential ASD over a prospective period of four years in the clinical routine of a tertiary hospital. The cohort is composed of 48 individuals, older than 3 years, who met the DSM-5 (The Diagnostic and Statistical Manual of Mental Disorders) diagnostic criteria for ASD. The NGS customized panel (AutismSeq) turned out to be a tool with good diagnostic efficacy in routine clinical care, where we detected 12 « pathogenic » (including pathogenic, likely pathogenic, and VUS (variant of uncertain significance) possibly pathogenic variations) in 11 individuals, and 11 VUS in 10 individuals, which had previously been negative for chromosomal microarray analysis and other previous genetic studies, such as karyotype, fragile-X, or MLPA/FISH (Multiplex Ligation dependent Probe Amplification/Fluorescence in situ hybridization) analysis. Our results demonstrate the high genetic and clinical heterogeneity of individuals with ASD and the current difficulty of molecular diagnosis. Our study also shows that an NGS-customized panel might be useful for diagnosing patients with essential/primary autism and that it is cost-effective for most genetic laboratories.

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19. Serra G, Mainas F, Golosio B, Retico A, Oliva P. Effect of data harmonization of multicentric dataset in ASD/TD classification. Brain informatics. 2023; 10(1): 32.

Machine Learning (ML) is nowadays an essential tool in the analysis of Magnetic Resonance Imaging (MRI) data, in particular in the identification of brain correlates in neurological and neurodevelopmental disorders. ML requires datasets of appropriate size for training, which in neuroimaging are typically obtained collecting data from multiple acquisition centers. However, analyzing large multicentric datasets can introduce bias due to differences between acquisition centers. ComBat harmonization is commonly used to address batch effects, but it can lead to data leakage when the entire dataset is used to estimate model parameters. In this study, structural and functional MRI data from the Autism Brain Imaging Data Exchange (ABIDE) collection were used to classify subjects with Autism Spectrum Disorders (ASD) compared to Typical Developing controls (TD). We compared the classical approach (external harmonization) in which harmonization is performed before train/test split, with an harmonization calculated only on the train set (internal harmonization), and with the dataset with no harmonization. The results showed that harmonization using the whole dataset achieved higher discrimination performance, while non-harmonized data and harmonization using only the train set showed similar results, for both structural and connectivity features. We also showed that the higher performances of the external harmonization are not due to larger size of the sample for the estimation of the model and hence these improved performance with the entire dataset may be ascribed to data leakage. In order to prevent this leakage, it is recommended to define the harmonization model solely using the train set.

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20. Shah S, Sarasua SM, Boccuto L, Dean BC, Wang L. Brain Gene Co-Expression Network Analysis Identifies 22q13 Region Genes Associated with Autism, Intellectual Disability, Seizures, Language Impairment, and Hypotonia. Genes. 2023; 14(11).

Phelan-McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder caused by 22q13 region deletions or SHANK3 gene variants. Deletions vary in size and can affect other genes in addition to SHANK3. PMS is characterized by autism spectrum disorder (ASD), intellectual disability (ID), developmental delays, seizures, speech delay, hypotonia, and minor dysmorphic features. It is challenging to determine individual gene contributions due to variability in deletion sizes and clinical features. We implemented a genomic data mining approach for identifying and prioritizing the candidate genes in the 22q13 region for five phenotypes: ASD, ID, seizures, language impairment, and hypotonia. Weighted gene co-expression networks were constructed using the BrainSpan transcriptome dataset of a human brain. Bioinformatic analyses of the co-expression modules allowed us to select specific candidate genes, including EP300, TCF20, RBX1, XPNPEP3, PMM1, SCO2, BRD1, and SHANK3, for the common neurological phenotypes of PMS. The findings help understand the disease mechanisms and may provide novel therapeutic targets for the precise treatment of PMS.

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21. Thorsteinsdottir S, Olafsdottir AS, Traustadottir OU, Njardvik U. Changes in Anxiety following Taste Education Intervention: Fussy Eating Children with and without Neurodevelopmental Disorders. Nutrients. 2023; 15(22).

Despite the surge in studies on fussy eating in recent years, anxiety as an associated factor is generally not considered, even though children with fussy eating and those with neurodevelopmental disorders, including Autism Spectrum Disorder or Attention Deficit/Hyperactivity Disorder (ADHD) often have higher levels of anxiety than typically developing children. The current study investigated changes in anxiety scores during a Taste Education intervention, a seven-week school-based intervention for 71 children with fussy eating. Comparisons were made based on neurodevelopmental status (between children with (n = 30) and without (n = 41) neurodevelopmental disorders). Participants were paired based on age, sex, and neurodevelopmental disorder. The Multidimensional Anxiety Scale for Children (MASC) was administered at delayed intervention (for those waiting 7 weeks before starting the intervention), pre-intervention, post-intervention, and at six-month follow-up. Results did not indicate elevated anxiety based on mean MASC T-scores. MASC Total T-scores ranged from slightly elevated to average, decreasing significantly between pre-intervention and post-intervention, plateauing at six-month follow-up. Significant reductions between measurement points were seen for the physical symptoms, social anxiety, and separation anxiety subscales, but not for harm avoidance. Repeated measures analysis of variance with neurodevelopmental disorders as between-subjects factors did not reveal a significant interaction effect between neurodevelopmental disorders and changes in MASC Total score or subscales. The results indicated that our food-based intervention did not elevate MASC scores in fussy eating children, with or without neurodevelopmental disorders.

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22. Vilela J, Martiniano H, Marques AR, Santos JX, Asif M, Rasga C, Oliveira G, Vicente AM. Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis. Biomedicines. 2023; 11(11).

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by communication deficits and repetitive behavioral patterns. Hundreds of candidate genes have been implicated in ASD, including neurotransmission and synaptic (NS) genes; however, the genetic architecture of this disease is far from clear. In this study, we seek to clarify the biological processes affected by NS gene variants identified in individuals with ASD and the global networks that link those processes together. For a curated list of 1216 NS candidate genes, identified in multiple databases and the literature, we searched for ultra-rare (UR) loss-of-function (LoF) variants in the whole-exome sequencing dataset from the Autism Sequencing Consortium (N = 3938 cases). Filtering for population frequency was carried out using gnomAD (N = 60,146 controls). NS genes with UR LoF variants were used to construct a network of protein-protein interactions, and the network’s biological communities were identified by applying the Leiden algorithm. We further explored the expression enrichment of network genes in specific brain regions. We identified 356 variants in 208 genes, with a preponderance of UR LoF variants in the PDE11A and SYTL3 genes. Expression enrichment analysis highlighted several subcortical structures, particularly the basal ganglia. The interaction network defined seven network communities, clustering synaptic and neurotransmitter pathways with several ubiquitous processes that occur in multiple organs and systems. This approach also uncovered biological pathways that are not usually associated with ASD, such as brain cytochromes P450 and brain mitochondrial metabolism. Overall, the community analysis suggests that ASD involves the disruption of synaptic and neurotransmitter pathways but also ubiquitous, but less frequently implicated, biological processes.

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23. Yildirim V, Simsek S, Cetin I, Dokuyucu R. Kynurenine, Kynurenic Acid, Quinolinic Acid and Interleukin-6 Levels in the Serum of Patients with Autism Spectrum Disorder. Medicina (Kaunas, Lithuania). 2023; 59(11).

Background and Objectives: It is known that inflammatory processes play a role in the pathogenesis of autism spectrum disorder (ASD). It is also reported that immune activation induces the kynurenine pathway (KP), as known as the tryptophan destruction pathway. In our study, we aimed to investigate whether the serum levels of KP products and interleukin (IL)-6 activating indolamine 2-3 dioxygenase (IDO) enzyme are different in healthy developing children and children with ASD. Materials and Methods: Forty-three ASD children aged 2-9 were included in this study. Forty-two healthy developing children, similar to the patient group in terms of age and gender, were selected as the control group. Serum levels of kynurenic acid, kynurenine, quinolinic acid and IL-6 were analyzed using the ELISA method. ASD severity was evaluated with the Autism Behavior Checklist (ABC). Results: The mean age of children with ASD was 42.4 ± 20.5 months, and that of healthy controls was 48.1 ± 15.8 months. While the serum levels of kynurenic acid, kynurenine and interleukin-6 were higher in the group with ASD (p < 0.05), there was no significant difference (p > 0.05) in terms of the quinolinic acid level. There was no significant difference between the ABC total and subscale scores of children with ASD and biochemical parameters (p > 0.05). Conclusions: We conclude that these biomarkers must be measured in all ASD cases. They may be important for the diagnosis of ASD.

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24. Yu J, Woo Y, Kim H, An S, Park SK, Jang SK. FMRP Enhances the Translation of 4EBP2 mRNA during Neuronal Differentiation. International journal of molecular sciences. 2023; 24(22).

FMRP is a multifunctional protein encoded by the Fragile X Messenger Ribonucleoprotein 1 gene (FMR1). The inactivation of the FMR1 gene results in fragile X syndrome (FXS), a serious neurodevelopmental disorder. FMRP deficiency causes abnormal neurite outgrowth, which is likely to lead to abnormal learning and memory capabilities. However, the mechanism of FMRP in modulating neuronal development remains unknown. We found that FMRP enhances the translation of 4EBP2, a neuron-specific form of 4EBPs that inactivates eIF4E by inhibiting the interaction between eIF4E and eIF4G. Depletion of 4EBP2 results in abnormal neurite outgrowth. Moreover, the impairment of neurite outgrowth upon FMRP depletion was overcome by the ectopic expression of 4EBP2. These results suggest that FMRP controls neuronal development by enhancing 4EBP2 expression at the translational level. In addition, treatment with 4EGI-1, a chemical that blocks eIF4E activity, restored neurite length in FMRP-depleted and 4EBP2-depleted cells. In conclusion, we discovered that 4EBP2 functions as a key downstream regulator of FMRP activity in neuronal development and that FMRP represses eIF4E activity by enhancing 4EBP2 translation.

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25. Zaccarelli-Magalhães J, Manes M, Féba LS, Abreu GR, Flório JC, Ricci EL, Felício LF, Spinosa HS. Do Autistic and Depressed Rats Express the Same Type of Maternal Care?. Neuroscience. 2023; 536: 72-8.

Autism is a neurodevelopmental disorder that is more frequently diagnosed in men. Nevertheless, through current diagnostic tools, women have also been found to be affected by this disorder, but in different ways. Few studies have been conducted regarding unique periods of life, such as motherhood. Yet, extant literature has already described the existence of a comorbidity between autism and postpartum depression. Thus, this study aimed to compare the maternal care sphere between two animal models of these diseases. Lactating rats were subdivided into three groups (n = 8 animals/group): 1) control dams; 2) maternal separation (MS) dams, separated from their litter for 3 h daily from lactating day (LD) 2-12 for postpartum depression induction; and 3) valproic acid (VPA) dams, which were the pups of dams treated with 400 mg/kg of VPA (i.p.) on gestational day 12.5 for autism induction. Maternal care tests were performed during lactation and, after weaning, dams were euthanized for the analysis of dopaminergic system on the prefrontal cortex. The results showed an impairment of maternal care of MS dams and an improvement of VPA dams, as well as alterations on dopaminergic system that corroborates the behavior data. These findings indicate that VPA dams express better maternal care, even with cognitive and socialization difficulties. This is probably due to a hyper-focus, as opposed to MS dams, which mimic the maternal care dysfunction expressed by women with postpartum depression.

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