1. Allgar V, Wright B, Taylor A, Couter AL, Phillips H. Diagnosing Autism Spectrum Disorders in Deaf Children Using Two Standardised Assessment Instruments: The ADIR-Deaf Adaptation and the ADOS-2 Deaf Adaptation. Journal of clinical medicine. 2021; 10(19).

The aim was to investigate the agreement between the ADI-R Deaf adaptation and ADOS-2 Deaf adaptation overall diagnostic categorisation for autism (AUT) and a wider threshold to include autism spectrum (ASD) in a cohort of deaf children with and without ASD. We compared results of the instruments used on their own and when combined and propose standard criteria for the combined use of the ADI-R Deaf adaptation and ADOS-2 Deaf adaptation for use with deaf children. In total, 116 deaf children had a Gold standard NICE guideline assessment; 58 diagnosed with ASD and 58 without ASD, and for both groups a blinded informant based ADI-R Deaf adaptation and direct assessment using the ADOS-2 Deaf adaptation were separately completed. There was moderate agreement between the ADI-R Deaf adaptation and ADOS-2 Deaf adaptation for the wider threshold of ASD (Kappa, 0.433). To achieve the lowest number of false negatives, the most successful assessment tool approach is using the wider threshold of ASD with either ADI-R Deaf adaptation or ADOS-2-Deaf adaptation (95% sensitivity). This compares with 88% for the ADI-R Deaf adaptation alone and 74% for the ADOS-2-Deaf adaptation alone (wider threshold of ASD). To achieve a low number of false positives, the most successful assessment tool approach is a combination of ADI-R Deaf adaptation and ADOS-2- Deaf adaptation (using the narrow threshold of autism for both) (95% specificity). This compares with 83% for the ADI-R Deaf adaptation alone and 81% for the ADOS-2-Deaf adaptation (narrow threshold) alone. This combination is therefore recommended in specialist clinics for diagnostic assessment in deaf children.

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2. Andrade C. Gestational and Neurodevelopmental Outcomes Associated With Antipsychotic Drug Exposure During Pregnancy. The Journal of clinical psychiatry. 2021; 82(5).

Exposure to psychotropic drugs during pregnancy may adversely affect gestational and neurodevelopmental outcomes in many different ways. Much literature on the subject exists for antidepressant drug exposure. In contrast, the literature on antipsychotic drug exposure during pregnancy is relatively thin; this is a situation in which the underlying psychiatric disorder, the context of use, and the associated risks must all be understood. In this context, a large (n = 411,251 mother-child pairs), population-based, retrospective observational cohort study with 8-10 years of follow-up examined pregnancy (preterm birth, small for gestational age) and neurodevelopmental (attention-deficit/hyperactivity disorder [ADHD], autism spectrum disorder [ASD]) outcomes after gestational exposure to antipsychotic medications. The study found that, when exposed vs unexposed pregnancies were compared, gestational exposure to antipsychotics was associated with a small but significantly increased risk of preterm birth; there was no significant increase in the risk of small for gestational age, ADHD, or ASD. When pregnancies with gestational vs (only) pregestational (pre-pregnancy) exposure to antipsychotics were compared, and when exposed vs unexposed siblings were compared, gestational antipsychotic exposure was not associated with a significantly increased risk of any of these adverse outcomes. Pregnancies with only pregestational exposure were associated with all of the adverse outcomes (except ASD) relative to pregnancies in women with no antipsychotic exposure at any time. In antipsychotic-unexposed pregnancies, mothers with psychiatric disorders were more likely to have children with ADHD or ASD (but not preterm birth or small for gestational age) relative to mothers without psychiatric disorders. The findings of the study appear reassuring. However, there are many concerns about the study, some of which are potentially serious. The findings of the study should therefore be interpreted with caution, and decisions about antipsychotic use during pregnancy should continue to be made on a case-by-case basis, in consultation with the patient and her family. In most cases of women with major mental illness, the risk-benefit ratio is likely to favor continuation of antipsychotics during pregnancy.

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3. Babinet MN, Cublier M, Demily C, Michael GA. Eye Direction Detection and Perception as Premises of a Social Brain: A Narrative Review of Behavioral and Neural Data. Cognitive, affective & behavioral neuroscience. 2022; 22(1): 1-20.

The eyes and the gaze are important stimuli for social interaction in humans. Impaired recognition of facial identity, facial emotions, and inference of the intentions of others may result from difficulties in extracting information relevant to the eye region, mainly the direction of gaze. Therefore, a review of these data is of interest. Behavioral data demonstrating the importance of the eye region and how humans respond to gaze direction are reviewed narratively, and several theoretical models on how visual information on gaze is processed are discussed to propose a unified hypothesis. Several issues that have not yet been investigated are identified. The authors tentatively suggest experiments that might help progress research in this area. The neural aspects are subsequently reviewed to best describe the low-level and higher-level visual information processing stages in the targeted subcortical and cortical areas. A specific neural network is proposed on the basis of the literature. Various gray areas, such as the temporality of the processing of visual information, the question of salience priority, and the coordination between the two hemispheres, remain unclear and require further investigations. Finally, disordered gaze direction detection mechanisms and their consequences on social cognition and behavior are discussed as key deficiencies in several conditions, such as autism spectrum disorder, 22q11.2 deletion, schizophrenia, and social anxiety disorder. This narrative review provides significant additional data showing that the detection and perception of someone’s gaze is an essential part of the development of our social brain.

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4. Beker S, Foxe JJ, Molholm S. Oscillatory entrainment mechanisms and anticipatory predictive processes in children with autism spectrum disorder. Journal of neurophysiology. 2021; 126(5): 1783-98.

Anticipating near-future events is fundamental to adaptive behavior, whereby neural processing of predictable stimuli is significantly facilitated relative to nonpredictable events. Neural oscillations appear to be a key anticipatory mechanism by which processing of upcoming stimuli is modified, and they often entrain to rhythmic environmental sequences. Clinical and anecdotal observations have led to the hypothesis that people with autism spectrum disorder (ASD) may have deficits in generating predictions, and as such, a candidate neural mechanism may be failure to adequately entrain neural activity to repetitive environmental patterns, to facilitate temporal predictions. We tested this hypothesis by interrogating temporal predictions and rhythmic entrainment using behavioral and electrophysiological approaches. We recorded high-density electroencephalography in children with ASD and typically developing (TD) age- and IQ-matched controls, while they reacted to an auditory target as quickly as possible. This auditory event was either preceded by predictive rhythmic visual cues or was not preceded by any cue. Both ASD and control groups presented comparable behavioral facilitation in response to the Cue versus No-Cue condition, challenging the hypothesis that children with ASD have deficits in generating temporal predictions. Analyses of the electrophysiological data, in contrast, revealed significantly reduced neural entrainment to the visual cues and altered anticipatory processes in the ASD group. This was the case despite intact stimulus-evoked visual responses. These results support intact behavioral temporal prediction in response to a cue in ASD, in the face of altered neural entrainment and anticipatory processes.NEW & NOTEWORTHY We examined behavioral and EEG indices of predictive processing in children with ASD to rhythmically predictable stimuli. Although behavioral measures of predictive processing and evoked neural responses were intact in the ASD group, neurophysiological measures of preparatory activity and entrainment were impaired. When sensory events are presented in a predictable temporal pattern, performance and neuronal responses in ASD may be governed more by the occurrence of the events themselves and less by their anticipated timing.

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5. Ellul P, Rosenzwajg M, Peyre H, Fourcade G, Mariotti-Ferrandiz E, Trebossen V, Klatzmann D, Delorme R. Regulatory T lymphocytes/Th17 lymphocytes imbalance in autism spectrum disorders: evidence from a meta-analysis. Molecular autism. 2021; 12(1): 68.

BACKGROUND: Immune system dysfunction has been proposed to play a critical role in the pathophysiology of autism spectrum disorders (ASD). Conflicting reports of lymphocyte subpopulation abnormalities have been described in numerous studies of patients with ASD. To better define lymphocytes abnormalities in ASD, we performed a meta-analysis of the lymphocyte profiles from subjects with ASD. METHODS: We used the PRISMA recommendations to query PubMed, Embase, PsychoINFO, BIOSIS, Science Direct, Cochrane CENTRAL, and Clinicaltrials.gov for terms related to clinical diagnosis of ASD and to lymphocytes’ populations. We selected studies exploring lymphocyte subpopulations in children with ASD. The search protocol has been registered in the international Prospective Register of Systematic Reviews (CRD42019121473). RESULTS: We selected 13 studies gathering 388 ASD patients and 326 healthy controls. A significant decrease in the CD4+ lymphocyte was found in ASD patients compared to controls [- 1.51 (95% CI - 2.99; - 0.04) p = 0.04] (I(2) = 96% [95% CI 94.6, 97.7], p < 0.01). No significant difference was found for the CD8+ T, B and natural killer lymphocytes. Considering the CD4+ subpopulation, there was a significant decrease in regulatory T lymphocytes (Tregs) in ASD patients (n = 114) compared to controls (n = 107) [- 3.09 (95% CI - 4.41; - 1.76) p = 0.0001]; (I(2) = 90.9%, [95% CI 76.2, 96.5], p < 0.0001) associated with an increase oin the Th17 lymphocytes (ASD; n = 147 controls; n = 128) [2.23 (95% CI 0.79; 3.66) p = 0,002] (I(2) = 95.1% [95% CI 90.4, 97.5], p < 0.0001). LIMITATIONS: Several factors inducing heterogeneity should be considered. First, differences in the staining method may be responsible for a part in the heterogeneity of results. Second, ASD population is also by itself heterogeneous, underlying the need of studying sub-groups that are more homogeneous. CONCLUSION: Our meta-analysis indicates defects in CD4+ lymphocytes, specifically decrease oin Tregs and increase in Th17 in ASD patients and supports the development of targeted immunotherapies in the field of ASD.

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6. Fernandes G, Mishra PK, Nawaz MS, Donlin-Asp PG, Rahman MM, Hazra A, Kedia S, Kayenaat A, Songara D, Wyllie DJA, Schuman EM, Kind PC, Chattarji S. Correction of amygdalar dysfunction in a rat model of fragile X syndrome. Cell reports. 2021; 37(2): 109805.

Fragile X syndrome (FXS), a commonly inherited form of autism and intellectual disability, is associated with emotional symptoms that implicate dysfunction of the amygdala. However, current understanding of the pathogenesis of the disease is based primarily on studies in the hippocampus and neocortex, where FXS defects have been corrected by inhibiting group I metabotropic glutamate receptors (mGluRs). Here, we observe that activation, rather than inhibition, of mGluRs in the basolateral amygdala reverses impairments in a rat model of FXS. FXS rats exhibit deficient recall of auditory conditioned fear, which is accompanied by a range of in vitro and in vivo deficits in synaptic transmission and plasticity. We find presynaptic mGluR5 in the amygdala, activation of which reverses deficient synaptic transmission and plasticity, thereby restoring normal fear learning in FXS rats. This highlights the importance of modifying the prevailing mGluR-based framework for therapeutic strategies to include circuit-specific differences in FXS pathophysiology.

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7. Fisher PR, Allan CY, Sanislav O, Atkinson A, Ngoei KRW, Kemp BE, Storey E, Loesch DZ, Annesley SJ. Relationships between Mitochondrial Function, AMPK, and TORC1 Signaling in Lymphoblasts with Premutation Alleles of the FMR1 Gene. International journal of molecular sciences. 2021; 22(19).

The X-linked FMR1 gene contains a non-coding trinucleotide repeat in its 5′ region that, in normal, healthy individuals contains 20-44 copies. Large expansions of this region (>200 copies) cause fragile X syndrome (FXS), but expansions of 55-199 copies (referred to as premutation alleles) predispose carriers to a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome (FXTAS). The cytopathological mechanisms underlying FXTAS are poorly understood, but abnormalities in mitochondrial function are believed to play a role. We previously reported that lymphoblastoid cell lines (LCLs, or lymphoblasts) of premutation carriers have elevated mitochondrial respiratory activities. In the carriers, especially those not clinically affected with FXTAS, AMP-activated protein kinase (AMPK) activity was shown to be elevated. In the FXTAS patients, however, it was negatively correlated with brain white matter lesions, suggesting a protective role in the molecular mechanisms. Here, we report an enlarged and extended study of mitochondrial function and associated cellular stress-signaling pathways in lymphoblasts isolated from male and female premutation carriers, regardless of their clinical status, and healthy controls. The results confirmed the elevation of AMPK and mitochondrial respiratory activities and reduction in reactive O(2) species (ROS) levels in premutation cells and revealed for the first time that target of rapamycin complex I (TORC1) activities are reduced. Extensive correlation, multiple regression, and principal components analysis revealed the best fitting statistical explanations of these changes in terms of the other variables measured. These suggested which variables might be the most « proximal » regulators of the others in the extensive network of known causal interactions amongst the measured parameters of mitochondrial function and cellular stress signaling. In the resulting model, the premutation alleles activate AMPK and inhibit both TORC1 and ROS production, the reduced TORC1 activity contributes to activation of AMPK and of nonmitochondrial metabolism, and the higher AMPK activity results in elevated catabolic metabolism, mitochondrial respiration, and ATP steady state levels. In addition, the results suggest a separate CGG repeat number-dependent elevation of TORC1 activity that is insufficient to overcome the inhibition of TORC1 in premutation cells but may presage the previously reported activation of TORC1 in FXS cells.

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8. Gao K, Sun Y, Niu S, Wang L. Unified framework for early stage status prediction of autism based on infant structural magnetic resonance imaging. Autism research : official journal of the International Society for Autism Research. 2021; 14(12): 2512-23.

Autism, or autism spectrum disorder (ASD), is a developmental disability that is diagnosed at about 2 years of age based on abnormal behaviors. Existing neuroimaging-based methods for the prediction of ASD typically focus on functional magnetic resonance imaging (fMRI); however, most of these fMRI-based studies include subjects older than 5 years of age. Due to challenges in the application of fMRI for infants, structural magnetic resonance imaging (sMRI) has increasingly received attention in the field for early status prediction of ASD. In this study, we propose an automated prediction framework based on infant sMRI at about 24 months of age. Specifically, by leveraging an infant-dedicated pipeline, iBEAT V2.0 Cloud, we derived segmentation and parcellation maps from infant sMRI. We employed a convolutional neural network to extract features from pairwise maps and a Siamese network to distinguish whether paired subjects were from the same or different classes. As compared to T1w imaging without segmentation and parcellation maps, our proposed approach with segmentation and parcellation maps yielded greater sensitivity, specificity, and accuracy of ASD prediction, which was validated using two datasets with different imaging protocols/scanners and was confirmed by receiver operating characteristic analysis. Furthermore, comparison with state-of-the-art methods demonstrated the superior effectiveness and robustness of the proposed method. Finally, attention maps were generated to identify subject-specific autism effects, supporting the reasonability of the predictive results. Collectively, these findings demonstrate the utility of our unified framework for the early-stage status prediction of ASD by sMRI. LAY SUMMARY: The status prediction of autism spectrum disorder (ASD) at an early age is highly desirable, as early intervention may significantly reduce autism symptoms. However, current methods for diagnosing young children are limited to behavioral assays. In this study, we propose an automated method for ASD status prediction at the age of 24 months that uses infant structural magnetic resonance imaging to identify neural features.

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9. Geschwind DH. Oxytocin for Autism Spectrum Disorder – Down, but Not Out. The New England journal of medicine. 2021; 385(16): 1524-5.

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10. Janšáková K, Kyselicová K, Ostatníková D, Repiská G. Potential of Salivary Biomarkers in Autism Research: A Systematic Review. International journal of molecular sciences. 2021; 22(19).

The diagnostic process for autism spectrum disorders (ASD) is based on a behavioral analysis of the suspected individual. Despite intensive research, no specific and valid biomarker has been identified for ASD, but saliva, with its advantages such as non-invasive collection, could serve as a suitable alternative to other body fluids. As a source of nucleic acid of both human and microbial origin, protein and non-protein molecules, saliva offers a complex view on the current state of the organism. Additionally, the use of salivary markers seems to be less complicated not only for ASD screening but also for revealing the etiopathogenesis of ASD, since enrolling neurotypical counterparts willing to participate in studies may be more feasible. The aim of the presented review is to provide an overview of the current research performed on saliva in relation to ASD, mutual complementing, and discrepancies that result in difficulties applying the observed markers in clinical practice. We emphasize the methodological limitations of saliva collection and processing as well as the lack of information regarding ASD diagnosis, which is critically discussed.

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11. Kaysheva AL, Isaeva AI, Pleshakova TO, Shumov ID, Valueva AA, Ershova MO, Ivanova IA, Ziborov VS, Iourov IY, Vorsanova SG, Ryabtsev SV, Archakov AI, Ivanov YD. Detection of Circulating Serum microRNA/Protein Complexes in ASD Using Functionalized Chips for an Atomic Force Microscope. Molecules (Basel, Switzerland). 2021; 26(19).

MicroRNAs, which circulate in blood, are characterized by high diagnostic value; in biomedical research, they can be considered as candidate markers of various diseases. Mature microRNAs of glial cells and neurons can cross the blood-brain barrier and can be detected in the serum of patients with autism spectrum disorders (ASD) as components of macrovesicles, macromolecular protein and low-density lipoprotein particles. In our present study, we have proposed an approach, in which microRNAs in protein complexes can be concentrated on the surface of AFM chips with oligonucleotide molecular probes, specific against the target microRNAs. MicroRNAs, associated with the development of ASD in children, were selected as targets. The chips with immobilized molecular probes were incubated in serum samples of ASD patients and healthy volunteers. By atomic force microscopy (AFM), objects on the AFM chip surface have been revealed after incubation in the serum samples. The height of these objects amounted to 10 nm and 6 nm in the case of samples of ASD patients and healthy volunteers, respectively. MALDI-TOF-MS analysis of protein components on the chip surface allowed us to identify several cell proteins. These proteins are involved in the binding of nucleic acids (GBG10, RT24, RALYL), in the organization of proteasomes and nucleosomes (PSA4, NP1L4), and participate in the functioning of the channel of active potassium transport (KCNE5, KCNV2).

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12. Kim SY, Lecavalier L. Evaluating the Use of Self-reported Measures in Autistic Individuals in the Context of Psychiatric Assessment: A Systematic Review. Journal of autism and developmental disorders. 2021.

The current review examined the use of self-report measures in autistic individuals in the context of psychiatric assessments. It focused on inter-rater agreement, internal consistency, test-retest reliability, and criterion validity with clinical diagnoses. It also gathered information on constructs measured, the nature of the samples, and the quality of the studies. Thirty-six out of 10,557 studies met inclusion criteria. We found that the majority of studies (1) targeted young people with average or above average cognitive abilities, (2) measured anxiety symptoms, and (3) evaluated parent-child agreement. More studies are needed on individuals with lower cognitive abilities, adults, and other constructs. Studies assessing criterion validity and test-retest reliability are also needed.

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13. Mahony C, O’Ryan C. Convergent Canonical Pathways in Autism Spectrum Disorder from Proteomic, Transcriptomic and DNA Methylation Data. International journal of molecular sciences. 2021; 22(19).

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with extensive genetic and aetiological heterogeneity. While the underlying molecular mechanisms involved remain unclear, significant progress has been facilitated by recent advances in high-throughput transcriptomic, epigenomic and proteomic technologies. Here, we review recently published ASD proteomic data and compare proteomic functional enrichment signatures with those of transcriptomic and epigenomic data. We identify canonical pathways that are consistently implicated in ASD molecular data and find an enrichment of pathways involved in mitochondrial metabolism and neurogenesis. We identify a subset of differentially expressed proteins that are supported by ASD transcriptomic and DNA methylation data. Furthermore, these differentially expressed proteins are enriched for disease phenotype pathways associated with ASD aetiology. These proteins converge on protein-protein interaction networks that regulate cell proliferation and differentiation, metabolism, and inflammation, which demonstrates a link between canonical pathways, biological processes and the ASD phenotype. This review highlights how proteomics can uncover potential molecular mechanisms to explain a link between mitochondrial dysfunction and neurodevelopmental pathology.

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14. Moore HL, Brice S, Powell L, Ingham B, Freeston M, Parr JR, Rodgers J. The Mediating Effects of Alexithymia, Intolerance of Uncertainty, and Anxiety on the Relationship Between Sensory Processing Differences and Restricted and Repetitive Behaviours in Autistic Adults. Journal of autism and developmental disorders. 2021.

Distress caused by sensory processing differences for autistic individuals may be reduced by repetitive behaviours (RRB), including repetitive motor (RMB) and insistence on sameness (ISB) behaviours. Intolerance of uncertainty (IU) and anxiety mediate the relationship between sensory processing and RRB in autistic children. We replicated this model in autistic adults, extending it to include alexithymia. Serial mediation, using data from 426 autistic adults, identified significant direct effects from sensory processing to RMB and ISB, and indirect effects through alexithymia-IU-anxiety for RMB, and IU alone, and alexithymia-IU for ISB. Different mechanisms may underpin RMB and ISB. Alexithymia alongside, IU and anxiety, should be considered when understanding the relationship between sensory processing and RRB, and when offering interventions to support autistic people.

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15. Mottron L, Bzdok D. Diagnosing as autistic people increasingly distant from prototypes lead neither to clinical benefit nor to the advancement of knowledge. Molecular psychiatry. 2022; 27(2): 773-5.

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16. Ozbaran B, Kose S, Barankoglu I, Dogan N. Inpatient Care Unit in Children and Adolescents With Autism Spectrum Disorder: Benefits, Difficulties, and Conditions of Hospitalization. The Journal of nervous and mental disease. 2022; 210(3): 206-11.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that affects social interactions and behavior. The number of children and adolescents with ASD treated in mental health services has been growing in recent years. Knowing clinical and familial characteristics of hospitalized patients with ASD and multidisciplinary approach are crucial for children and adolescents mental health professionals. In this study, 253 Turkish children and adolescents, with and without ASD, treated in psychiatry inpatient care unit were examined. Applied approaches such as medical consultation areas, psychiatric management of mothers, and pharmacological treatment during hospitalization, were studied. In addition to familial and clinical characteristics of patients with ASD, the benefits and the hospitalization conditions were evaluated. Patients with ASD showed a higher tendency on having relatives with a psychiatric disorder than the patients without ASD. A significant difference was found in terms of age, sex, and intellectual functioning, whereas length of stay did not differ drastically. Also, suicide attempts were significantly higher in patients without ASD than in patients with ASD. This study eases the management of hospitalized ASD patients with giving important information of clinical and familial characteristics.

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17. Pavez R, Diaz J, Arango-Lopez J, Ahumada D, Mendez-Sandoval C, Moreira F. Emo-mirror: a proposal to support emotion recognition in children with autism spectrum disorders. Neural computing & applications. 2021: 1-12.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined as persistent difficulty in maturing the socialization process. Health professionals have used traditional methods in the therapies performed on patients with the aim of improving the expression of emotions by patients. However, they have not been sufficient to detect the different emotions expressed in the face of people according to different sensations. Therefore, different artificial intelligence techniques have been applied to improve the results obtained in these therapies. In this article, we propose the construction of an intelligent mirror to recognize five basic emotions: angry, scared, sad, happy and neutral. This mirror uses convolutional neural networks to analyze the images that are captured by a camera and compare it with the one that the patient should perform, thus supporting the therapies performed by health professionals in children with ASD. The proposal presents the platform and computer architecture, as well as the evaluation by specialists under the technology acceptance model.

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18. Reis H, Eusébio I, Sousa M, Ferreira M, Pereira R, Dias S, Reis CI. Regul-A: A Technological Application for Sensory Regulation of Children with Autism Spectrum Disorder in the Home Context. International journal of environmental research and public health. 2021; 18(19).

(1) Background: Sensory processing disorder is now recognised as a core feature of autism spectrum disorder that influences children’s adaptive behaviours, which, in turn, may interfere with their participation in life situations. This study describes the process of developing a technological platform, in the form of an app, to help families regulate children with ASD, aged 3-6 years old, by applying sensory strategies to improve the child’s participation in daily routines in the home context. (2) Methods: A focus group formed by four specialised occupational therapists who intervene with children with ASD was selected in order to understand and discuss content that should be included in the app. At a later stage, a group of three was involved to ensure quality and veracity in technological platform elaboration. (3) Results: The purpose of the app, named Regul-A, is to help parents regulate children with ASD regarding their participation in home routines. The sensory strategies provided by the focus group in the three major occupations of the child were the first results obtained, followed by the development of the app structure. (4) Conclusions: The next phase of the study will be the use of the platform by families of children with ASD and occupational therapists. It is believed that, in the future, Regul-A will be used as a tool to gather, analyse and manage data on the occupational performance of children with ASD in the home context, particularly for activities of daily living, sleep, rest and play, facilitating the implementation of strategies and the sharing of information between parents and occupational therapists.

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19. Rosales MR, Deng W, Nishiyori R, Vanderbilt DL, Smith BA. Leg Movement Rate before and after a Caregiver-Provided Intervention for Infants at Risk of Developmental Disability: A Pilot Study. Physical & occupational therapy in pediatrics. 2022; 42(3): 259-74.

AIM: Our purpose was to assess daily leg movement rate before and after a caregiver-provided in-home intervention for infants at risk for developmental disability. We also assessed adherence and quality of caregiver-child interaction. METHODS: Twelve infants, at risk for developmental disabilities, and their caregivers participated in an intervention focused on increasing leg movements. Intervention started between 3- and 6-months corrected age and ended once the infant was able to sit independently or at 9 months corrected age, whichever occurred first. Infants were assessed monthly. RESULTS: Infants at risk for developmental disabilities who were moving less than 1200 leg movements per hour awake at the start of the intervention increased their daily leg movement rate following the intervention (Median [range]: pre-1047 [506-1056], post- 1104 [655-1359], p = 0.040). Additionally, the caregivers had a high adherence (Median: 89%, Range: 11.43%-329.17%) and good quality of caregiver-child interaction (Median NCAST total: 46, Range: 34-59); and maintained similar amounts of adherence (p = 0.575) and quality of caregiver-child interaction (p = 0.432) throughout the intervention. CONCLUSION: This study provides preliminary evidence that leg movement rate has the potential to be used as an outcome measure to assess an infant’s progress and motor practice during an intervention.

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20. Scheerer NE, Curcin K, Stojanoski B, Anagnostou E, Nicolson R, Kelley E, Georgiades S, Liu X, Stevenson RA. Exploring sensory phenotypes in autism spectrum disorder. Molecular autism. 2021; 12(1): 67.

BACKGROUND: Atypical reactions to the sensory environment are often reported in autistic individuals, with a high degree of variability across the sensory modalities. These sensory differences have been shown to promote challenging behaviours and distress in autistic individuals and are predictive of other functions including motor, social, and cognitive abilities. Preliminary research suggests that specific sensory differences may cluster together within individuals creating discrete sensory phenotypes. However, the manner in which these sensory differences cluster, and whether the resulting phenotypes are associated with specific cognitive and social challenges is unclear. METHODS: Short sensory profile data from 599 autistic children and adults between the ages of 1 and 21 years were subjected to a K-means cluster analysis. Analysis of variances compared age, adaptive behaviour, and traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder across the resultant clusters. RESULTS: A five-cluster model was found to minimize error variance and produce five sensory phenotypes: (1) sensory adaptive, (2) generalized sensory differences, (3) taste and smell sensitivity, (4) under-responsive and sensation seeking, and (5) movement difficulties with low energy. Age, adaptive behaviour, and traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder were found to differ significantly across the five phenotypes. LIMITATIONS: The results were based on parent-report measures of sensory processing, adaptive behaviour, traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder, which may limit the generalizability of the findings. Further, not all measures are standardized, or psychometrically validated with an autism population. Autistic individuals with an intellectual disability were underrepresented in this sample. Further, as these data were obtained from established records from a large provincial database, not all measures were completed for all individuals. CONCLUSIONS: These findings suggest that sensory difficulties in autistic individuals can be clustered into sensory phenotypes, and that these phenotypes are associated with behavioural differences. Given the large degree of heterogeneity in sensory difficulties seen in the autistic population, these sensory phenotypes represent an effective way to parse that heterogeneity and create phenotypes that may aid in the development of effective treatments and interventions for sensory difficulties.

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21. Schuck RK, Tagavi DM, Baiden KMP, Dwyer P, Williams ZJ, Osuna A, Ferguson EF, Jimenez Muñoz M, Poyser SK, Johnson JF, Vernon TW. Neurodiversity and Autism Intervention: Reconciling Perspectives Through a Naturalistic Developmental Behavioral Intervention Framework. Journal of autism and developmental disorders. 2021.

Proponents of autism intervention and those of the neurodiversity movement often appear at odds, the former advocating for intensive treatments and the latter arguing that autism must be accepted as a form of diversity. The history of behavioral intervention has understandably outraged many in the Autistic community, though many still value supports focused on quality of life. This commentary argues that Naturalistic Developmental Behavioral Interventions (NDBIs) hold promise for bridging the gap between early intervention and the neurodiversity movement. However, we recognize NDBIs have much room to grow and suggest multiple strategies for improvement. We believe these updates are not only feasible for clinicians and researchers to implement but will ultimately lead to improved quality of life for Autistic individuals.

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22. Sikich L, Kolevzon A, King BH, McDougle CJ, Sanders KB, Kim SJ, Spanos M, Chandrasekhar T, Trelles MDP, Rockhill CM, Palumbo ML, Witters Cundiff A, Montgomery A, Siper P, Minjarez M, Nowinski LA, Marler S, Shuffrey LC, Alderman C, Weissman J, Zappone B, Mullett JE, Crosson H, Hong N, Siecinski SK, Giamberardino SN, Luo S, She L, Bhapkar M, Dean R, Scheer A, Johnson JL, Gregory SG, Veenstra-VanderWeele J. Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder. The New England journal of medicine. 2021; 385(16): 1462-73.

BACKGROUND: Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder. METHODS: We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ. RESULTS: Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was -3.7 in the oxytocin group and -3.5 in the placebo group (least-squares mean difference, -0.2; 95% confidence interval, -1.5 to 1.0; P = 0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks. (Funded by the National Institute of Child Health and Human Development; SOARS-B ClinicalTrials.gov number, NCT01944046.).

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23. Simone M, Margari L, Pompamea F, De Giacomo A, Gabellone A, Marzulli L, Palumbi R. Autism Spectrum Disorder and Duchenne Muscular Dystrophy: A Clinical Case on the Potential Role of the Dystrophin in Autism Neurobiology. Journal of clinical medicine. 2021; 10(19).

A diagnosis of autism spectrum disorder is reported in up to 19% of dystrophinopathies. However, over the last ten years, only a few papers have been published on this topic. Therefore, further studies are required to analyze this association in depth and ultimately to understand the role of the brain dystrophin isoform in the pathogenesis of ASD and other neurodevelopmental disorders. In this paper, we report a clinical case of a patient affected by ASD and Duchenne muscular dystrophy, who carries a large deletion of the dystrophin gene. Then we present a brief overview of the literature about similar cases and about the potential role of the dystrophin protein in the neurobiology of autism spectrum disorder.

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24. Soyer-Gobillard MO, Gaspari L, Paris F, Kalfa N, Hamamah S, Courtet P, Sultan C. Prenatal Exposure to Diethylstilbestrol and Multigenerational Psychiatric Disorders: An Informative Family. International journal of environmental research and public health. 2021; 18(19).

BACKGROUND: Psychiatric disorders in children exposed in utero to diethylstilbestrol (DES) are still debated. We report here the impact of DES prescribed to suppress lactation on the children born after such treatment and their progeny, focusing particularly on psychiatric disorders. CASE PRESENTATION: We report here an informative family in which one or more psychiatric problems (e.g., bipolarity, suicide attempts and suicide, eating disorders) were detected in all children of second-generation (DES-exposed children; n = 9), but for II-2 who died at the age of 26 years due to rupture of a congenital brain aneurysm, and were associated with non-psychiatric disorders (particularly, endometriosis and hypospadias). In the third generation, 10 out of 19 DES-exposed grandchildren had psychiatric disorders (autism spectrum disorder, bipolar disorder, dyspraxia and learning disabilities, mood and behavioral disorders, and eating disorders), often associated with comorbidities. In the fourth generation (7 DES-exposed great-grandchildren, aged between 0 and 18 years), one child had dyspraxia and autism spectrum disorder. The first daughter of the second generation (not exposed to DES) and her children and grandchildren did not have any psychiatric symptoms or comorbidities. CONCLUSIONS: To our knowledge, the high prevalence of psychiatric disorders of various severities in two, and likely three generations, including DES-free pregnancies and DES-exposed pregnancies from the same family, has never been reported. This work strengthens the hypothesis that in utero exposure to DES contributes to the pathogenesis of psychiatric disorders. It also highlights a multigenerational, and possibly transgenerational, effect of DES in neurodevelopment and psychiatric disorders.

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25. Thom RP, Pereira JA, Sipsock D, McDougle CJ. Recent Updates in Psychopharmacology for the Core and Associated Symptoms of Autism Spectrum Disorder. Current psychiatry reports. 2021; 23(12): 79.

PURPOSE OF REVIEW: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core deficits in social communication and restricted, repetitive patterns of behavior. This article aims to review the recent literature pertaining to psychopharmacology for the core and associated symptoms of ASD including social impairment, repetitive behaviors, irritability, and language impairment. RECENT FINDINGS: Recent medication trials targeting social impairment in ASD have focused on neuropeptides (oxytocin and vasopressin) and memantine. None of these three medications has demonstrated consistent benefit for social impairment in ASD; however, additional studies are underway. Two double-blind, placebo-controlled studies on selective serotonin reuptake inhibitors (SSRIs) provide evidence against the use of SSRIs for repetitive behaviors in youth with ASD. Preliminary studies have investigated cannabidiol (CBD) for irritability in ASD but further studies are needed to demonstrate safety and efficacy. Finally, three double-blind, placebo-controlled studies provide preliminary evidence for folinic acid for the treatment of verbal language deficits in children with ASD. The identification of safe and effective pharmacological treatments to ameliorate the core and associated symptoms of ASD has proven difficult.

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26. Toko M, Ohshita T, Kurashige T, Morino H, Kume K, Yamashita H, Sobue G, Iwasaki Y, Sone J, Kawakami H, Maruyama H. FXTAS is difficult to differentiate from neuronal intranuclear inclusion disease through skin biopsy: a case report. BMC neurology. 2021; 21(1): 396.

BACKGROUND: Both fragile X-associated tremor/ataxia syndrome (FXTAS) and late-onset neuronal intranuclear inclusion disease (NIID) show CGG/GGC trinucleotide repeat expansions. Differentiating these diseases are difficult because of the similarity in their clinical and radiological features. It is unclear that skin biopsy can distinguish NIID from FXTAS. We performed a skin biopsy in an FXTAS case with cognitive dysfunction and peripheral neuropathy without tremor, which was initially suspected to be NIID. CASE PRESENTATION: The patient underwent neurological assessment and examinations, including laboratory tests, electrophysiologic test, imaging, skin biopsy, and genetic test. A brain MRI showed hyperintensity lesions along the corticomedullary junction on diffusion-weighted imaging (DWI) in addition to middle cerebellar peduncle sign (MCP sign). We suspected NIID from the clinical picture and the radiological findings, and performed a skin biopsy. The skin biopsy specimen showed ubiquitin- and p62-positive intranuclear inclusions, suggesting NIID. However, a genetic analysis for NIID using repeat-primed polymerase chain reaction (RP-PCR) revealed no expansion detected in the Notch 2 N-terminal like C (NOTCH2NLC) gene. We then performed genetic analysis for FXTAS using RP-PCR, which revealed a repeat CGG/GGC expansion in the FMRP translational regulator 1 (FMR1) gene. The number of repeats was 83. We finally diagnosed the patient with FXTAS rather than NIID. CONCLUSIONS: For the differential diagnosis of FXTAS and NIID, a skin biopsy alone is insufficient; instead, genetic analysis, is essential. Further investigations in additional cases based on genetic analysis are needed to elucidate the clinical and pathological differences between FXTAS and NIID.

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27. Xiol C, Heredia M, Pascual-Alonso A, Oyarzabal A, Armstrong J. Technological Improvements in the Genetic Diagnosis of Rett Syndrome Spectrum Disorders. International journal of molecular sciences. 2021; 22(19).

Rett syndrome (RTT) is a severe neurodevelopmental disorder that constitutes the second most common cause of intellectual disability in females worldwide. In the past few years, the advancements in genetic diagnosis brought by next generation sequencing (NGS), have made it possible to identify more than 90 causative genes for RTT and significantly overlapping phenotypes (RTT spectrum disorders). Therefore, the clinical entity known as RTT is evolving towards a spectrum of overlapping phenotypes with great genetic heterogeneity. Hence, simultaneous multiple gene testing and thorough phenotypic characterization are mandatory to achieve a fast and accurate genetic diagnosis. In this review, we revise the evolution of the diagnostic process of RTT spectrum disorders in the past decades, and we discuss the effectiveness of state-of-the-art genetic testing options, such as clinical exome sequencing and whole exome sequencing. Moreover, we introduce recent technological advancements that will very soon contribute to the increase in diagnostic yield in patients with RTT spectrum disorders. Techniques such as whole genome sequencing, integration of data from several « omics », and mosaicism assessment will provide the tools for the detection and interpretation of genomic variants that will not only increase the diagnostic yield but also widen knowledge about the pathophysiology of these disorders.

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28. Yu R, Ahmed T, Jiang H, Zhou G, Zhang M, Lv L, Li B. Impact of Zinc Oxide Nanoparticles on the Composition of Gut Microbiota in Healthy and Autism Spectrum Disorder Children. Materials (Basel, Switzerland). 2021; 14(19).

Autism spectrum disorder (ASD) seriously affects children’s health, while the gut microbiome has been widely hypothesized to be involved in the regulation of ASD behavior. This study investigated and compared the number, diversity, and population structure of gut microbiota between healthy and ASD children and their susceptibility to zinc oxide nanoparticles (ZnONPs) based on the measurement of live cell number, living/dead bacterial staining test, flow cytometry observation and bacterial community analysis using 16S rRNA gene amplicon sequencing. The result of this present study revealed that ASD children not only significantly reduced the live cell number and the community diversity of gut bacteria, but also changed the gut bacterial community composition compared to the healthy children. In addition, this result revealed that ZnONPs significantly reduced the number of live bacterial cells in the gut of healthy children, but not in that of ASD children. In contrast, ZnONPs generally increased the gut bacterial community diversity in both ASD and healthy children, while a greater increase was found in ASD children than that of healthy children. Furthermore, this study successfully isolated and identified some representative nanoparticle-resistant bacteria based on the color, shape, and edge of colony as well as the 16S rDNA sequence analysis. The community of nanoparticle-resistant bacteria differed in between healthy and ASD children. Indeed, the representative strains 6-1, 6-2, 6-3 and 6-4 from healthy children were identified as Bacillus anthracis, Escherichia coli, Bacillus cereus and Escherichia coli with sequence similarity of 97.86%, 99.86%, 99.03% and 99.65%, respectively, while the representative strains 8-1, 8-2 and 8-3 from ASD children were identified as Bacillus cereus, with sequence similarities of 99.58%, 99.72% and 99.72%, respectively. Overall, this study demonstrated that ZnONPs caused a change in number, diversity, and species composition of gut bacteria, but differed in healthy and ASD children.

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