1. Alho J, Samuelsson JG, Khan S, Mamashli F, Bharadwaj H, Losh A, McGuiggan NM, Graham S, Nayal Z, Perrachione TK, Joseph RM, Stoodley CJ, Hämäläinen MS, Kenet T. Both stronger and weaker cerebro-cerebellar functional connectivity patterns during processing of spoken sentences in autism spectrum disorder. Human brain mapping. 2023.

Cerebellar differences have long been documented in autism spectrum disorder (ASD), yet the extent to which such differences might impact language processing in ASD remains unknown. To investigate this, we recorded brain activity with magnetoencephalography (MEG) while ASD and age-matched typically developing (TD) children passively processed spoken meaningful English and meaningless Jabberwocky sentences. Using a novel source localization approach that allows higher resolution MEG source localization of cerebellar activity, we found that, unlike TD children, ASD children showed no difference between evoked responses to meaningful versus meaningless sentences in right cerebellar lobule VI. ASD children also had atypically weak functional connectivity in the meaningful versus meaningless speech condition between right cerebellar lobule VI and several left-hemisphere sensorimotor and language regions in later time windows. In contrast, ASD children had atypically strong functional connectivity for in the meaningful versus meaningless speech condition between right cerebellar lobule VI and primary auditory cortical areas in an earlier time window. The atypical functional connectivity patterns in ASD correlated with ASD severity and the ability to inhibit involuntary attention. These findings align with a model where cerebro-cerebellar speech processing mechanisms in ASD are impacted by aberrant stimulus-driven attention, which could result from atypical temporal information and predictions of auditory sensory events by right cerebellar lobule VI.

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2. Alibutud R, Hansali S, Cao X, Zhou A, Mahaganapathy V, Azaro M, Gwin C, Wilson S, Buyske S, Bartlett CW, Flax JF, Brzustowicz LM, Xing J. Structural Variations Contribute to the Genetic Etiology of Autism Spectrum Disorder and Language Impairments. International journal of molecular sciences. 2023; 24(17).

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restrictive interests and/or repetitive behaviors and deficits in social interaction and communication. ASD is a multifactorial disease with a complex polygenic genetic architecture. Its genetic contributing factors are not yet fully understood, especially large structural variations (SVs). In this study, we aimed to assess the contribution of SVs, including copy number variants (CNVs), insertions, deletions, duplications, and mobile element insertions, to ASD and related language impairments in the New Jersey Language and Autism Genetics Study (NJLAGS) cohort. Within the cohort, ~77% of the families contain SVs that followed expected segregation or de novo patterns and passed our filtering criteria. These SVs affected 344 brain-expressed genes and can potentially contribute to the genetic etiology of the disorders. Gene Ontology and protein-protein interaction network analysis suggested several clusters of genes in different functional categories, such as neuronal development and histone modification machinery. Genes and biological processes identified in this study contribute to the understanding of ASD and related neurodevelopment disorders.

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3. Byrska A, Błażejczyk I, Faruga A, Potaczek M, Wilczyński KM, Janas-Kozik M. Patterns of Food Selectivity among Children with Autism Spectrum Disorder. Journal of clinical medicine. 2023; 12(17).

Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by food selectivity in a significant portion of the population. The nature of this selectivity remains unclear, with hypotheses suggesting associations with sensory disorders or stereotypical and repetitive patterns of activity and interests. This study aimed to determine the prevalence and nature of food selectivity traits in individuals with ASD compared with the neurotypical population. This study involved 219 participants, with 115 diagnosed with autism and 92 without. Twelve children undergoing diagnosis were excluded from the analyses. The findings revealed that food selectivity traits are more common in individuals with ASD, with differences in preferences mainly involving structure, color, taste, and serving method. Children with ASD had more food selectivity traits than those without, and the intake of certain food characteristics could be altered as they grow. Selectivity occurred for both sensory and stereotypical reasons, but stereotypical features significantly differentiated neurotypical individuals from those with ASD.

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4. Compañ-Gabucio LM, Ojeda-Belokon C, Torres-Collado L, García-de-la-Hera M. A Scoping Review of Tools to Assess Diet in Children and Adolescents with Autism Spectrum Disorder. Nutrients. 2023; 15(17).

Eating is considered one of the activities of daily living most affected by autism spectrum disorder (ASD) in children and adolescents and, therefore, needs to be thoroughly assessed using specific tools. The aim of this scoping review was to describe the most widely used tool to assess diet in children and adolescents with ASD. A search was conducted on PubMed, Scopus, EMBASE, Web of Science and PsycINFO databases. Two authors screened the articles and included all randomized or non-randomized studies published in English or Spanish in the last five years in which the diet of children and adolescents with ASD was assessed. Fifteen studies were included in this review. Mealtime behaviour was the most assessed variable in the included studies (n = 7). Thirteen different assessment tools were identified to evaluate the diet of children and adolescents with ASD, mainly at ages 2-12 (n = 11). The Brief Assessment scale for Mealtime Behavior in Children (BAMBI) and 24-h recalls were the most commonly used dietary assessment tools in the included studies. Our results can help professionals in the selection of an optimal scale to assess diet in children and adolescents with ASD.

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5. Dwyer P, Williams ZJ, Vukusic S, Saron CD, Rivera SM. Habituation of auditory responses in young autistic and neurotypical children. Autism research : official journal of the International Society for Autism Research. 2023.

Prior studies suggest that habituation of sensory responses is reduced in autism and that diminished habituation could be related to atypical autistic sensory experiences, for example, by causing brain responses to aversive stimuli to remain strong over time instead of being suppressed. While many prior studies exploring habituation in autism have repeatedly presented identical stimuli, other studies suggest group differences can still be observed in habituation to intermittent stimuli. The present study explored habituation of electrophysiological responses to auditory complex tones of varying intensities (50-80 dB SPL), presented passively in an interleaved manner, in a well-characterized sample of 127 autistic (M(DQ)  = 65.41, SD = 20.54) and 79 typically developing (M(DQ)  = 106.02, SD = 11.50) children between 2 and 5 years old. Habituation was quantified as changes in the amplitudes of single-trial responses to tones of each intensity over the course of the experiment. Habituation of the auditory N2 response was substantially reduced in autistic participants as compared to typically developing controls, although diagnostic groups did not clearly differ in habituation of the P1 response. Interestingly, the P1 habituated less to loud 80 dB sounds than softer sounds, whereas the N2 habituated less to soft 50 dB sounds than louder sounds. No associations were found between electrophysiological habituation and cognitive ability or participants’ caregiver-reported sound tolerance (Sensory Profile Hyperacusis Index). The results present study results extend prior research suggesting habituation of certain sensory responses is reduced in autism; however, they also suggest that habituation differences observed using this study’s paradigm might not be a primary driver of autistic participants’ real-world sound intolerance.

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6. Fowler SP, Gimeno Ruiz de Porras D, Swartz MD, Stigler Granados P, Heilbrun LP, Palmer RF. Daily Early-Life Exposures to Diet Soda and Aspartame Are Associated with Autism in Males: A Case-Control Study. Nutrients. 2023; 15(17).

Since its introduction, aspartame-the leading sweetener in U.S. diet sodas (DS)-has been reported to cause neurological problems in some users. In prospective studies, the offspring of mothers who consumed diet sodas/beverages (DSB) daily during pregnancy experienced increased health problems. We hypothesized that gestational/early-life exposure to ≥1 DS/day (DS(early)) or equivalent aspartame (ASP(early): ≥177 mg/day) increases autism risk. The case-control Autism Tooth Fairy Study obtained retrospective dietary recalls for DSB and aspartame consumption during pregnancy/breastfeeding from the mothers of 235 offspring with autism spectrum disorder (ASD: cases) and 121 neurotypically developing offspring (controls). The exposure odds ratios (ORs) for DS(early) and ASP(early) were computed for autism, ASD, and the non-regressive conditions of each. Among males, the DS(early) odds were tripled for autism (OR = 3.1; 95% CI: 1.02, 9.7) and non-regressive autism (OR = 3.5; 95% CI: 1.1, 11.1); the ASP(early) odds were even higher: OR = 3.4 (95% CI: 1.1, 10.4) and 3.7 (95% CI: 1.2, 11.8), respectively (p < 0.05 for each). The ORs for non-regressive ASD in males were almost tripled but were not statistically significant: DS(early) OR = 2.7 (95% CI: 0.9, 8.4); ASP(early) OR = 2.9 (95% CI: 0.9, 8.8). No statistically significant associations were found in females. Our findings contribute to the growing literature raising concerns about potential offspring harm from maternal DSB/aspartame intake in pregnancy.

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7. Jönemo J, Abramian D, Eklund A. Evaluation of Augmentation Methods in Classifying Autism Spectrum Disorders from fMRI Data with 3D Convolutional Neural Networks. Diagnostics (Basel, Switzerland). 2023; 13(17).

Classifying subjects as healthy or diseased using neuroimaging data has gained a lot of attention during the last 10 years, and recently, different deep learning approaches have been used. Despite this fact, there has not been any investigation regarding how 3D augmentation can help to create larger datasets, required to train deep networks with millions of parameters. In this study, deep learning was applied to derivatives from resting state functional MRI data, to investigate how different 3D augmentation techniques affect the test accuracy. Specifically, resting state derivatives from 1112 subjects in ABIDE (Autism Brain Imaging Data Exchange) preprocessed were used to train a 3D convolutional neural network (CNN) to classify each subject according to presence or absence of autism spectrum disorder. The results show that augmentation only provide minor improvements to the test accuracy.

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8. Kissine M, Saint-Denis A, Mottron L. Language acquisition can be truly atypical in autism: Beyond joint attention. Neuroscience and biobehavioral reviews. 2023; 153: 105384.

Language profiles in autism are variable and atypical, with frequent speech onset delays, but also, in some cases, unusually steep growth of structural language skills. Joint attention is often seen as a major predictor of language in autism, even though low joint attention is a core characteristic of autism, independent of language levels. In this systematic review of 71 studies, we ask whether, in autism, joint attention predicts advanced or only early language skills, and whether it may be independent of language outcomes. We consider only conservative estimates, and flag studies that include heterogenous samples or no control for non-verbal cognition. Our review suggests that joint attention plays a pivotal role for the emergence of language, but is also consistent with the idea that some autistic children may acquire language independently of joint attention skills. We propose that language in autism should not necessarily be modelled as a quantitative or chronological deviation from typical language development, and outline directions to bring autistic individuals’ atypicality within the focus of scientific inquiry.

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9. Oge-Enver E, Isat E, Cansever MS, Zubarioglu T, Yilmaz G, Cebi MN, Aktuglu-Zeybek C, Kiykim E. Urinary neopterin and biopterin indicate that inflammation has a role in autism spectrum disorder. Metabolic brain disease. 2023.

Inflammation is thought to be involved in the pathogenesis of autism spectrum disorder (ASD). Pteridine metabolites are biomarkers of inflammation that increase on immune system activation. In this study, we investigated the urinary pteridine metabolites in ASD patients as a possible biomarker for immune activation and inflammation. This observational, cross-sectional, prospective study collected urine samples from 212 patients with ASD and 68 age- and sex-matched healthy individuals. Urine neopterin (NE) and biopterin (BIO) levels were measured. Patients who had chronic disorders, active infection at the time of sampling, or high C-reactive protein levels were excluded. The urine NE and BIO concentrations were determined by high-performance liquid chromatography. The ratios of both NE and BIO to creatinine (CRE) were used to standardise the measurements. The NE/CRE and NE/BIO levels were significantly higher in ASD patients than controls. Univariate and multivariate models revealed a significant increase in NE/CRE and NE/BIO in ASD patients. There was a significant relationship between the NE/BIO [average area under the curve (AUC) = 0.717; range: 0.637-0.797] and NE/CRE (average AUC = 0.756; range: 0.684-0.828) ratios, which distinguished individuals with ASD from controls. The elevated NE/CRE and NE/BIO ratios suggest that inflammation and T cell-mediated immunity are involved in the pathophysiology of autism. NE/BIO could serve as a diagnostic inflammatory marker in the pathogenesis of ASD.

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10. Pedersen EM, Agerbo E, Plana-Ripoll O, Steinbach J, Krebs MD, Hougaard DM, Werge T, Nordentoft M, Børglum AD, Musliner KL, Ganna A, Schork AJ, Mortensen PB, McGrath JJ, Privé F, Vilhjálmsson BJ. ADuLT: An efficient and robust time-to-event GWAS. Nature communications. 2023; 14(1): 5553.

Proportional hazards models have been proposed to analyse time-to-event phenotypes in genome-wide association studies (GWAS). However, little is known about the ability of proportional hazards models to identify genetic associations under different generative models and when ascertainment is present. Here we propose the age-dependent liability threshold (ADuLT) model as an alternative to a Cox regression based GWAS, here represented by SPACox. We compare ADuLT, SPACox, and standard case-control GWAS in simulations under two generative models and with varying degrees of ascertainment as well as in the iPSYCH cohort. We find Cox regression GWAS to be underpowered when cases are strongly ascertained (cases are oversampled by a factor 5), regardless of the generative model used. ADuLT is robust to ascertainment in all simulated scenarios. Then, we analyse four psychiatric disorders in iPSYCH, ADHD, Autism, Depression, and Schizophrenia, with a strong case-ascertainment. Across these psychiatric disorders, ADuLT identifies 20 independent genome-wide significant associations, case-control GWAS finds 17, and SPACox finds 8, which is consistent with simulation results. As more genetic data are being linked to electronic health records, robust GWAS methods that can make use of age-of-onset information will help increase power in analyses for common health outcomes.

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11. Poulsen R, Dwyer P, Gassner D, Heyworth M, Williams ZJ. The INSAR Community Collaborator Request: Using community-academic partnerships to enhance outcomes of participatory autism research. Autism research : official journal of the International Society for Autism Research. 2023.

Participatory approaches, in which researchers work together with members of the autism community (e.g., autistic people, family members, caregivers, or other stakeholders) to design, conduct, and disseminate research, have become increasingly prominent within the field of autism research over the past decade. Despite growing academic and community interest in conducting participatory studies, stakeholder collaboration remains infrequent in autism research, at least partially due to systemic barriers. To help reduce barriers to engaging in participatory autism research, the International Society for Autism Research (INSAR) Autistic Researchers Committee has launched the INSAR Community Collaborator Request (ICCR; https://www.autism-insar.org/page/iccr), a platform on the INSAR website that allows autism researchers conducting participatory research to seek out stakeholder collaborators from the autism community (including both autistic people and their family members/caregivers, as relevant to a given research project). Interested stakeholders also have the opportunity to subscribe to ICCR posts, allowing them to be alerted of new opportunities for collaboration and potentially increasing their involvement in autism research. Overall, the ICCR provides a venue to connect autism researchers with potential community collaborators, reducing barriers to participatory autism research and increasing the frequency of successful community-academic partnerships within the field. We are hopeful that in the long term, such changes will lead to greater alignment between research outputs and the goals of the greater autism community, and consequently an increase in the overall quality and relevance of autism research.

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12. Prillinger K, Radev ST, Amador de Lara G, Werneck-Rohrer S, Plener PL, Poustka L, Konicar L. Effects of Transcranial Direct Current Stimulation on Social Attention Patterns and Emotion Recognition Ability in Male Adolescents with Autism Spectrum Disorder. Journal of clinical medicine. 2023; 12(17).

Autism Spectrum Disorder (ASD) is characterized by impairments in social cognition including emotion recognition (ER) abilities. Common symptoms include unusual patterns of visual social attention, which are investigated as early developmental biomarkers for ASD. Transcranial Direct Current Stimulation (tDCS) has shown promising results in influencing social functioning in individuals with ASD. However, the effects of tDCS on social attention patterns and ER ability in adolescents with ASD remain unclear. This double-blind, sham-controlled, randomized clinical trial examined the effects of repeated sessions of tDCS on gaze behavior and ER ability in 22 male adolescents diagnosed with ASD. Participants received either 20 min of 2 mA active tDCS or sham stimulation for 10 days and an intra-stimulation training. Social allocation patterns were assessed using eye-tracking paradigms, including ER tasks. Our results indicated no tDCS-specific effects. Both groups showed improvements in ER and more frequent, faster, and longer fixations on the eyes than the mouth, and on social than nonsocial areas. In tasks with low social content, fixating the mouth seemed to increase ER accuracy. Understanding the effects of tDCS on social functioning in adolescents with ASD holds promise for the development of targeted interventions to improve their social cognition abilities.

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13. Siracusano M, Arturi L, Riccioni A, Noto A, Mussap M, Mazzone L. Metabolomics: Perspectives on Clinical Employment in Autism Spectrum Disorder. International journal of molecular sciences. 2023; 24(17).

Precision medicine is imminent, and metabolomics is one of the main actors on stage. We summarize and discuss the current literature on the clinical application of metabolomic techniques as a possible tool to improve early diagnosis of autism spectrum disorder (ASD), to define clinical phenotypes and to identify co-occurring medical conditions. A review of the current literature was carried out after PubMed, Medline and Google Scholar were consulted. A total of 37 articles published in the period 2010-2022 was included. Selected studies involve as a whole 2079 individuals diagnosed with ASD (1625 males, 394 females; mean age of 10, 9 years), 51 with other psychiatric comorbidities (developmental delays), 182 at-risk individuals (siblings, those with genetic conditions) and 1530 healthy controls (TD). Metabolomics, reflecting the interplay between genetics and environment, represents an innovative and promising technique to approach ASD. The metabotype may mirror the clinical heterogeneity of an autistic condition; several metabolites can be expressions of dysregulated metabolic pathways thus liable of leading to clinical profiles. However, the employment of metabolomic analyses in clinical practice is far from being introduced, which means there is a need for further studies for the full transition of metabolomics from clinical research to clinical diagnostic routine.

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14. Utami KH, Yusof N, Garcia-Miralles M, Skotte NH, Nama S, Sampath P, Langley SR, Pouladi MA. Dysregulated COMT Expression in Fragile X Syndrome. Neuromolecular medicine. 2023.

Transcriptional and proteomics analyses in human fragile X syndrome (FXS) neurons identified markedly reduced expression of COMT, a key enzyme involved in the metabolism of catecholamines, including dopamine, epinephrine and norepinephrine. FXS is the most common genetic cause of intellectual disability and autism spectrum disorders. COMT encodes for catechol-o-methyltransferase and its association with neuropsychiatric disorders and cognitive function has been extensively studied. We observed a significantly reduced level of COMT in in FXS human neural progenitors and neurons, as well as hippocampal neurons from Fmr1 null mice. We show that deficits in COMT were associated with an altered response in an assay of dopaminergic activity in Fmr1 null mice. These findings demonstrate that loss of FMRP downregulates COMT expression and affects dopamine signaling in FXS, and supports the notion that targeting catecholamine metabolism may be useful in regulating certain neuropsychiatric aspects of FXS.

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15. Zafarullah M, Li J, Salemi MR, Phinney BS, Durbin-Johnson BP, Hagerman R, Hessl D, Rivera SM, Tassone F. Blood Proteome Profiling Reveals Biomarkers and Pathway Alterations in Fragile X PM at Risk for Developing FXTAS. International journal of molecular sciences. 2023; 24(17).

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the FMR1 premutation. Currently, it is not possible to determine when and if individual premutation carriers will develop FXTAS. Thus, with the aim to identify biomarkers for early diagnosis, development, and progression of FXTAS, along with associated dysregulated pathways, we performed blood proteomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct groups: those who developed symptoms of FXTAS (converters, CON) over time (at subsequent visits) and those who did not (non-converters, NCON). We compared these groups to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern blot and PCR analysis. The proteomic profile was obtained by liquid chromatography mass spectrometry (LC-MS/MS). We identified several significantly differentiated proteins between HC and the PM groups at Visit 1 (V1), Visit 2 (V2), and between the visits. We further reported the dysregulated protein pathways, including sphingolipid and amino acid metabolism. Our findings are in agreement with previous studies showing that pathways involved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered and appear to contribute to the development of FXTAS. Lastly, we compared the blood proteome of the PM who developed FXTAS over time with the CSF proteome of the FXTAS patients recently reported and found eight significantly differentially expressed proteins in common. To our knowledge, this is the first report of longitudinal proteomic profiling and the identification of unique biomarkers and dysregulated protein pathways in FXTAS.

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