1. Côté V, Lalancette È, Knoth IS, Côté L, Agbogba K, Vannasing P, Major P, Barlaam F, Michaud J, Lippé S. {{Distinct Patterns of Repetition Suppression in Fragile X Syndrome, Down Syndrome, Tuberous Sclerosis Complex and Mutations in SYNGAP1}}. {Brain Res}. 2020: 147205.
Sensory processing is the gateway to information processing and more complex processes such as learning. Alterations in sensory processing is a common phenotype of many genetic syndromes associated with intellectual disability (ID). It is currently unknown whether sensory processing alterations converge or diverge on brain responses between syndromes. Here, we compare for the first time four genetic conditions with ID using the same basic sensory learning paradigm. One hundred and five participants, aged between 3 to 30 years old, composing four clinical ID groups and one control group, were recruited : Fragile X syndrome (FXS; n=14), tuberous sclerosis complex (TSC; n=9), Down syndrome (DS; n=19), SYNGAP1 mutations (n=8) and Neurotypical controls (NT; n=55)). All groups included female and male participants. Brain responses were recorded using electroencephalography (EEG) during an audio-visual task that involved three repetitions of the pronunciation of the phoneme /a/. Event Related Potentials (ERP) were used to: 1) compare peak-to-peak amplitudes between groups, 2) evaluate the presence of repetition suppression within each group and 3) compare the relative repetition suppression between groups. Our results revealed larger overall amplitudes in FXS. A repetition suppression (RS) pattern was found in the NT group, FXS and DS, suggesting spared repetition suppression in a multimodal task in these two ID syndromes. Interestingly, FXS presented a stronger RS on one peak-to-peak value in comparison with the NT. The results of our study reveal the distinctiveness of ERP and RS brain responses in ID syndromes. Further studies should be conducted to understand the molecular mechanisms involved in these patterns of responses.
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2. Dohrn S, Luebbert C, Lehmkemper K, Kyeremateng SO, Degenhardt M, Sadowski G. {{Solvent influence on the phase behavior and glass transition of ASDs}}. {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV}. 2020.
Understanding the long-term stability of amorphous solid dispersions (ASDs) is important for their successful approval for market. ASD stability does not only depend on the interplay between the active pharmaceutical ingredient (API) and the polymer in the final formulation but may already be disadvantageously affected by process steps during the production (e.g. selection of inappropriate solvent for spray drying). Residual solvent can affect the API solubility in the polymer, molecular mobility (by influencing the glass-transition temperature) and induce liquid-liquid phase separation. Enhanced mobility in the ASD due to residual solvent can promote recrystallization in ASDs. The removal of residual solvent can be expensive, time-consuming, and usually requires secondary drying procedures to fulfil the regulatory requirements. The aim of this work is to predict the API solubility in polymer-solvent mixtures, solvent influence on the glass transition, and the occurrence of liquid-liquid phase separation of solvent-loaded ASDs using the thermodynamic model PC-SAFT and to experimentally validate these predictions. ASDs containing the APIs ritonavir or naproxen and the polymers poly(vinyl pyrrolidone), poly (vinyl pyrrolidone- co- vinyl acetate), or hydroxypropyl methylcellulose acetate succinate were spray-dried using the solvents acetone, ethanol, and dichloromethane. API solubility, sorption behavior, liquid-liquid phase separation and glass transition in the ternary API/polymer/solvent mixtures were predicted based on the binary phase behavior between API/solvent, API/polymer, and polymer/solvent and successfully validated experimentally using dynamic vapor sorption (DVS), and Raman spectroscopy. Thus, the presented methodology allows for an in-silico selection of appropriate solvent systems for solvent-based ASD preparation based on a limited amount of experimental data for binary systems only.
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3. Hosozawa M, Mandy W, Cable N, Flouri E. {{The Role of Decision-Making in Psychological Wellbeing and Risky Behaviours in Autistic Adolescents Without ADHD: Longitudinal Evidence from the UK Millennium Cohort Study}}. {J Autism Dev Disord}. 2020.
This study examined the development of decision-making and its association with psychological wellbeing and risky behaviours in adolescents with and without autism. Participants included 270 autistic and 9,713 typically developing adolescents. In both samples, those with a diagnosis of attention-deficit/hyperactivity disorder (ADHD) were excluded. Data came from the Millennium Cohort Study, a nationally representative population-based birth cohort. Decision-making was assessed using the Cambridge Gambling Task at ages 11 and 14. Psychological wellbeing (happiness, self-esteem, depressive symptoms and self-harm) and risky/antisocial behaviours were self-reported at age 14. After adjusting for sex, cognitive ability, spatial working memory, socioeconomic status and pubertal status, autistic adolescents showed comparable quality of decision-making to that of their peers at both ages but also a more deliberative decision-making style as they aged. Only in autistic adolescents was this decision-making style associated with positive outcomes.
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4. Mansour Y, Ahmed SN, Kulesza R. {{Abnormal morphology and subcortical projections to the medial geniculate in an animal model of autism}}. {Experimental brain research}. 2020.
Auditory dysfunction, including hypersensitivity and tinnitus, is a common symptom of autism spectrum disorder (ASD). Prenatal exposure to the antiseizure medication valproic acid (VPA) significantly increases the risk of ASD in humans and similar exposure is utilized as an animal model of ASD in rodents. Animals exposed to VPA in utero have abnormal activity in their auditory cortex in response to sounds, fewer neurons, abnormal neuronal morphology, reduced expression of calcium-binding proteins, and reduced ascending projections to the central nucleus of the inferior colliculus. Unfortunately, these previous studies of central auditory circuits neglect the medial geniculate (MG), which serves as an important auditory relay from the midbrain to the auditory cortex. Here, we examine the structure and connectivity of the medial geniculate (MG) in rats prenatally exposed to VPA. Our results indicate that VPA exposure results in significantly smaller and fewer neurons in the ventral and medial nuclei of the MG. Furthermore, injections of the retrograde tract tracer fluorogold (FG) in the MG result in significantly fewer FG+ neurons in the inferior colliculus, superior olivary complex, and ventral cochlear nucleus. Together, we interpret these findings to indicate that VPA exposure results in hypoplasia throughout the auditory circuits and that VPA has a differential impact on some long-range axonal projections from brainstem centers to the thalamus. Together, our findings support the widespread impact of VPA on neurons and sensory circuits in the developing brain.
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5. Mingins JE, Tarver J, Waite J, Jones C, Surtees AD. {{Anxiety and intellectual functioning in autistic children: A systematic review and meta-analysis}}. {Autism}. 2020: 1362361320953253.
Autistic children often experience higher levels of anxiety than their peers. It can be difficult to diagnose and treat anxiety disorders in autistic children, in part because of the high degree of variability in their underlying abilities and presentations. Some evidence suggests that autistic children with higher intelligence (as measured by intelligence quotient) experience higher levels of anxiety than autistic children with lower intelligence. However, the evidence is inconsistent, with other papers not finding a difference or finding higher levels of anxiety in autistic children with lower intelligence. In this article, we review existing literature to see whether autistic children with higher intelligence quotients have higher anxiety than autistic children with lower intelligence quotients. A systematic search of the literature was conducted which identified 49 papers on the topic. The methods of all the papers were reviewed using an objective quality assessment framework. When combining the data statistically, there was evidence that autistic children with higher intelligence quotients are more anxious than autistic children with lower intelligence quotients. The quality review raised common weaknesses across studies. Most importantly, few studies used measures of anxiety that have been shown to be valid for children with very low intelligence quotients. Similarly, many studies used measures of anxiety that have not been shown to be valid for autistic children. These factors are important because autistic children and those with low intelligence quotient may experience or understand anxiety differently. Future research should use fully validated measures to test whether high intelligence quotient is associated with high levels of anxiety in autistic children.
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6. Mughal R, Hill CM, Joyce A, Dimitriou D. {{Sleep and Cognition in Children with Fetal Alcohol Spectrum Disorders (FASD) and Children with Autism Spectrum Disorders (ASD)}}. {Brain Sci}. 2020; 10(11).
Children with Fetal Alcohol Spectrum Disorders (FASD) and Autism Spectrum Disorders (ASD) experience significantly higher rates of sleep disturbances than their typically developing peers. However, little is known about the association between sleep and the cognitive phenotype in these clinical populations. Structural damage affecting cortical and subcortical connectivity occurs as a result of prenatal alcohol exposure in children with FASD, whilst it is believed an abundance of short-range connectivity explains the phenotypic manifestations of childhood ASD. These underlying neural structural and connectivity differences manifest as cognitive patterns, with some shared and some unique characteristics between FASD and ASD. This is the first study to examine sleep and its association with cognition in individuals with FASD, and to compare sleep in individuals with FASD and ASD. We assessed children aged 6-12 years with a diagnosis of FASD (n = 29), ASD (n = 21), and Typically Developing (TD) children (n = 46) using actigraphy (CamNTech Actiwatch 8), digit span tests of working memory (Weschler Intelligence Scale), tests of nonverbal mental age (MA; Ravens Standard Progressive Matrices), receptive vocabulary (British Picture Vocabulary Scale), and a choice reaction time (CRT) task. Children with FASD and ASD presented with significantly shorter total sleep duration, lower sleep efficiency, and more nocturnal wakings than their TD peers. Sleep was significantly associated with scores on the cognitive tests in all three groups. Our findings support the growing body of work asserting that sleep is significant to cognitive functioning in these neurodevelopmental conditions; however, more research is needed to determine cause and effect.
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7. Northrup JB, Leezenbaum NB, Campbell SB. {{Observed Social Emotional Behavior at 22 Months Predicts a Later ASD Diagnosis in High-Risk Siblings}}. {J Autism Dev Disord}. 2020.
Social engagement, pretend play, and concern for another’s distress represent fundamental features of typical social-emotional development in the second year. Children with autism spectrum disorder (ASD) display delays and deficits in these areas, and research on toddlers at heightened risk for ASD (HR; younger siblings of children with ASD) indicates these deficits may be apparent in toddlerhood. Prior research has examined these aspects of social-emotional development individually in HR toddlers. The present paper examines them jointly as predictors of ASD. We show that social engagement, pretend play, and empathic concern at 22-months each contribute uniquely to predicting later ASD diagnosis with high specificity and moderate sensitivity. Results have important implications for early diagnosis and intervention in young children with ASD.
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8. Osos JA, Plavnick JB, Avendaño SM. {{Assessing Video Enhanced Activity Schedules to Teach Social Skills to Children with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2020.
Social communication deficits are one of the two core characteristics demonstrated by individuals with autism spectrum disorder (ASD) and require explicit instruction as soon as the deficit is discovered. The present investigation examined the use of video-enhanced activity schedules using tablet technology for teaching social interaction to children with ASD. A multiple probe across participants design was used to teach four preschool aged participants with ASD to show something they had accomplished to peers, and to demonstrate specific social conventions when doing so. An adapted alternating treatment design was also used to compare the differential effects of video enhanced activity schedules to electronic schedules without video. Two participants acquired social skills faster in the video enhanced activity schedule condition, and the other two participants learned at a comparable rate across interventions.
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9. Pau P, Westphalen M. {{Copper deficiency myelopathy and autism spectrum disorder}}. {Journal of paediatrics and child health}. 2020.
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10. Siller M. {{Editorial: Individualizing Interventions for Young Children With Autism: Embracing the Next Generation of Intervention Research}}. {J Am Acad Child Adolesc Psychiatry}. 2020.
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11. Sulaiman R, Wang M, Ren X. {{Exposure to Aluminum, Cadmium, and Mercury and Autism Spectrum Disorder in Children: A Systematic Review and Meta-Analysis}}. {Chemical research in toxicology}. 2020; 33(11): 2699-718.
Autism spectrum disorder (ASD) is a complex neurobehavioral disorder that is believed to be multifactorial in origin. As the incidence of ASD is rising along with industrialization, and because certain metals have been linked to neurological problems, it is important to consider whether such metals may play a role in the development of ASD. Previously, we performed a meta-analysis of existing literature to examine the potential link between inorganic arsenic and lead exposure and ASD. This is a continuation of that study investigating the association of the exposure to aluminum (Al), cadmium (Cd), and mercury (Hg) and ASD. These metals were chosen because they are abundant in our environment, are known to cause neurological problems in humans, and have multiple published studies examining their potential links with ASD. Following the same approach as our previous paper, we conducted a systematic review of the existing literature and performed a meta-analysis to evaluate the current evidence regarding these metals and their potential relationship with autism. We reviewed 18 studies on Al, 18 on Cd, and 23 on Hg, and the individual studies showed inconsistent results. When the measurements were integrated into the meta-analysis, we found significant associations between all the metals and ASD, but the associations were not always in the same direction. Levels of Hg in hair, urine, and blood were all positively associated with ASD. Levels of Al in hair and urine were positively associated with ASD, while levels of Al in blood were negatively associated. In comparison, levels of Cd in hair and urine were negatively associated with ASD. These results imply that, while these metals are all neurotoxic, their impact on the development of ASD and their modes of action could be different. Further research is warranted to examine the longitudinal effects of these toxic metals on the risk of ASD, to assess the critical period when exposure may affect development, and to investigate potential factors that may enhance or ameliorate the effect of metals. Overall, these findings support policies that advocate limiting exposure to neurotoxic metals, particularly for pregnant women and young children, in order to help reduce the rising incidence of ASD.
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12. Vallée A, Lecarpentier Y, Guillevin R, Vallée JN. {{The influence of circadian rhythms and aerobic glycolysis in autism spectrum disorder}}. {Translational psychiatry}. 2020; 10(1): 400.
Intellectual abilities and their clinical presentations are extremely heterogeneous in autism spectrum disorder (ASD). The main causes of ASD remain unclear. ASD is frequently associated with sleep disorders. Biologic rhythms are complex systems interacting with the environment and controlling several physiological pathways, including brain development and behavioral processes. Recent findings have shown that the deregulation of the core clock neurodevelopmental signaling is correlated with ASD clinical presentation. One of the main pathways involved in developmental cognitive disorders is the canonical WNT/β-catenin pathway. Circadian clocks have a main role in some tissues by driving circadian expression of genes involved in physiologic and metabolic functions. In ASD, the increase of the canonical WNT/β-catenin pathway is enhancing by the dysregulation of circadian rhythms. ASD progression is associated with a major metabolic reprogramming, initiated by aberrant WNT/β-catenin pathway, the aerobic glycolysis. This review focuses on the interest of circadian rhythms dysregulation in metabolic reprogramming in ASD through the aberrant upregulation of the canonical WNT/β-catenin pathway.
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13. Vitiello B. {{Editorial: Targeting the Core Symptoms of Autism Spectrum Disorder With Mechanism-based}}. {J Am Acad Child Adolesc Psychiatry}. 2020.
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14. Wagley N, Lajiness-O’Neill R, Hay JSF, Bowyer SM, Ugolini M, Kovelman I, Brennan JR. {{Predictive processing during a naturalistic statistical learning task in ASD}}. {eNeuro}. 2020.
Children’s sensitivity to regularities within the linguistic stream, such as the likelihood that syllables co-occur, is foundational to speech segmentation and language acquisition. Yet, little is known about the neurocognitive mechanisms underlying speech segmentation in typical development and in neurodevelopmental disorders that impact language acquisition such as Autism Spectrum Disorder (ASD). Here, we investigate the neural signals of statistical learning in 15 human participants (children ages 8-12) with a clinical diagnosis of ASD and 14 age- and gender-matched typically developing peers. We tracked the evoked neural responses to syllable sequences in a naturalistic statistical learning corpus using magnetoencephalography (MEG) in the left primary auditory cortex, posterior superior temporal gyrus, and inferior frontal gyrus, across three repetitions of the passage. In typically developing children, we observed a neural index of learning in all three regions of interest, measured by the change in evoked response amplitude as a function of syllable surprisal across passage repetitions. As surprisal increased, the amplitude of the neural response increased; this sensitivity emerged after repeated exposure to the corpus. Children with ASD did not show this pattern of learning in all three regions. We discuss two possible hypotheses related to children’s sensitivity to bottom-up sensory deficits and difficulty with top-down incremental processing.Significance Statement Language acquisition involves segmenting the continuous speech stream into sounds, syllables, and words. Learning these units relies on both the properties of the input, as well as emerging high-order cognitive mechanisms that guide learning from the top-down. We examined the neurobiology underlying the integration of top-down and bottom-up information in statistical speech segmentation in children with and without ASD. We offer evidence of neural and behavioral effects of syllable-to-syllable processing in speech segmentation that differ in typically developing children from children with a clinical diagnosis of ASD. Our findings inform developmental and cognitive theories of language acquisition by examining the computational nature of speech segmentation across different populations of learners.
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15. Wallace-Watkin C, Whitehouse AJO, Waddington H. {{Early Intervention Delivery Methods for New Zealand Children with Autism: Current Practices Versus Parental Preferences}}. {J Autism Dev Disord}. 2020.
Little is known about parent preferences regarding delivery methods of early interventions. This research examined, through parent report, the current and preferred delivery methods of seven common educational early interventions accessed by New Zealand children with autism spectrum disorder. Responses from 63 eligible participants were collected via an online questionnaire. Results suggested that four of the seven early intervention services were predominantly delivered through some form of professional advice to parents. Participants who were receiving at least one privately funded service were more likely to have at least one service delivered directly to their child. Parents’ most preferred delivery method for all early intervention services, except parent education programs, involved a professional working directly with their child.
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16. Winter AS, Fountain C, Cheslack-Postava K, Bearman PS. {{The social patterning of autism diagnoses reversed in California between 1992 and 2018}}. {Proceedings of the National Academy of Sciences of the United States of America}. 2020.
As rates of autism diagnosis increased dramatically over the past number of decades, prevalence rates were generally highest among Whites and among those of higher socioeconomic status (SES). Using a unique, population-level dataset, we find that rates of autism diagnosis continued to be on the rise in recent years, but who is diagnosed changed during the study period. Our data consist of birth records of all 13,272,573 children born in the state of California in 1992 through 2016 linked to autism caseload records for January 1992 through November 2019 from California’s Department of Developmental Services. California’s diagnosed autism incidence rate rose from 0.49 per 1,000 3-6 y olds in 1998 to 3.49 per 1,000 3-6 y olds in 2018, a 612% increase. However, diagnosed incidence rates did not rise uniformly across sociodemographic groups. By 2018, children of Black and Asian mothers were diagnosed at higher rates than children of non-Hispanic White mothers. Furthermore, among children of non-Hispanic White and Asian mothers, children of lower SES were diagnosed at higher rates than children of higher SES. These changes align with sociological theories of health disparities and contain important clues for more fully understanding the autism epidemic.
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17. Zhang W, Noland R, Chin S, Petkovic M, Zuniga R, Santarra B, Conklin B, Helen Hou H, Nagapudi K, Gruenhagen JA, Yehl P, Chen T. {{Impact of polymer type, ASD loading and polymer-drug ratio on ASD tablet disintegration and drug release}}. {International journal of pharmaceutics}. 2020: 120087.
Amorphous solid dispersion (ASD) has become an attractive strategy to enhance solubility and bioavailability of poorly water-soluble drugs. To facilitate oral administration, ASDs are commonly incorporated into tablets. Disintegration and drug release from ASD tablets are thus critical for achieving the inherent solubility advantage of amorphous drugs. In this work, the impact of polymer type, ASD loading in tablet and polymer-drug ratio in ASD on disintegration and drug release of ASD tablets was systematically studied. Two hydrophilic polymers PVPVA and HPMC and one relatively hydrophobic polymer HPMCAS were evaluated. Dissolution testing was performed, and disintegration time was recorded during dissolution testing. As ASD loading increased, tablet disintegration time increased for all three polymer-based ASD tablets, and this effect was more pronounced for hydrophilic polymer-based ASD tablets. As polymer-drug ratio increased, tablet disintegration time increased for hydrophilic polymer-based ASD tablets, however, it remained short and largely unchanged for HPMCAS-based ASD tablets. Consequently, at high ASD loadings or high polymer-drug ratios, HPMCAS-based ASD tablets showed faster drug release than PVPVA- or HPMC-based ASD tablets. These results were attributed to the differences between polymer hydrophilicities and viscosities of polymer aqueous solutions. This work is valuable for understanding the disintegration and drug release of ASD tablets and provides insight to ASD composition selection from downstream tablet formulation perspective.
