1. Acton R, Imberman S, Lovenheim M. Do Health Insurance Mandates Spillover to Education? Evidence from Michigan’s Autism Insurance Mandate. Journal of health economics. 2021; 80: 102489.

Social programs and mandates are usually studied in isolation, but unintended spillovers to other areas can impact individual behavior and social welfare. We examine the presence of spillovers from health care policy to the education sector by studying how health insurance coverage affects the education of students with Autism Spectrum Disorder (ASD). We leverage a state mandate that increased insurance coverage of ASD-related services, which often are provided by both the private sector and within public schools. The mandate primarily affected coverage for children with private health insurance, so we proxy for private insurance coverage with students’ economic disadvantage status and estimate effects via triple-differences. While we find little change in ASD identification, the mandate crowds-out special education supports for students with ASD. A lack of short-run impact on achievement supports our crowd-out interpretation and indicates that the mandate had little net effect on the academic achievement of ASD students.

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2. Ansell BRE, Thomas SN, Bonelli R, Munro JE, Freytag S, Bahlo M. A survey of RNA editing at single-cell resolution links interneurons to schizophrenia and autism. RNA (New York, NY). 2021; 27(12): 1482-96.

Conversion of adenosine to inosine in RNA by ADAR enzymes, termed « RNA editing, » is essential for healthy brain development. Editing is dysregulated in neuropsychiatric diseases, but has not yet been investigated at scale at the level of individual neurons. We quantified RNA editing sites in nuclear transcriptomes of 3055 neurons from six cortical regions of a neurotypical female donor, and found 41,930 sites present in at least ten nuclei. Most sites were located within Alu repeats in introns or 3′ UTRs, and approximately 80% were cataloged in public RNA editing databases. We identified 9285 putative novel editing sites, 29% of which were also detectable in unrelated donors. Intersection with results from bulk RNA-seq studies provided cell-type and spatial context for 1730 sites that are differentially edited in schizophrenic brain donors, and 910 such sites in autistic donors. Autism-related genes were also enriched with editing sites predicted to modify RNA structure. Inhibitory neurons showed higher overall transcriptome editing than excitatory neurons, and the highest editing rates were observed in the frontal cortex. We used generalized linear models to identify differentially edited sites and genes between cell types. Twenty nine genes were preferentially edited in excitatory neurons, and 43 genes were edited more heavily in inhibitory neurons, including RBFOX1, its target genes, and genes in the autism-associated Prader-Willi locus (15q11). The abundance of SNORD115/116 genes from locus 15q11 was positively associated with editing activity across the transcriptome. We contend that insufficient editing of autism-related genes in inhibitory neurons may contribute to the specific perturbation of those cells in autism.

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3. Bloch C, Burghof L, Lehnhardt FG, Vogeley K, Falter-Wagner C. Author Correction: Alexithymia traits outweigh autism traits in the explanation of depression in adults with autism. Scientific reports. 2021; 11(1): 18900.

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4. Brant B, Stern T, Shekhidem HA, Mizrahi L, Rosh I, Stern Y, Ofer P, Asleh A, Umanah GKE, Jada R, Levy NS, Levy AP, Stern S. IQSEC2 mutation associated with epilepsy, intellectual disability, and autism results in hyperexcitability of patient-derived neurons and deficient synaptic transmission. Molecular psychiatry. 2021; 26(12): 7498-508.

Mutations in the IQSEC2 gene are associated with drug-resistant, multifocal infantile and childhood epilepsy; autism; and severe intellectual disability (ID). We used induced pluripotent stem cell (iPSC) technology to obtain hippocampal neurons to investigate the neuropathology of IQSEC2-mediated disease. The neurons were characterized at three-time points during differentiation to assess developmental progression. We showed that immature IQSEC2 mutant dentate gyrus (DG) granule neurons were extremely hyperexcitable, exhibiting increased sodium and potassium currents compared to those of CRISPR-Cas9-corrected isogenic controls, and displayed dysregulation of genes involved in differentiation and development. Immature IQSEC2 mutant cultured neurons exhibited a marked reduction in the number of inhibitory neurons, which contributed further to hyperexcitability. As the mutant neurons aged, they became hypoexcitable, exhibiting reduced sodium and potassium currents and a reduction in the rate of synaptic and network activity, and showed dysregulation of genes involved in synaptic transmission and neuronal differentiation. Mature IQSEC2 mutant neurons were less viable than wild-type mature neurons and had reduced expression of surface AMPA receptors. Our studies provide mechanistic insights into severe infantile epilepsy and neurodevelopmental delay associated with this mutation and present a human model for studying IQSEC2 mutations in vitro.

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5. DaWalt LS, Fielding-Gebhardt H, Fleming KK, Warren SF, Brady N. Change in Behavior Problems from Childhood Through Adolescence for Children with Fragile X Syndrome. Journal of autism and developmental disorders. 2021: 1-11.

In this study, we examined trajectories of specific domains of behavior problems (i.e., attention problems, depression/anxiety, and aggressive behavior) from age 6 to 18 in a sample of 55 children with fragile X syndrome. We also examined autism status and early parenting as predictors of subsequent behavioral trajectories. We found that attention problems and aggressive behavior declined steadily from childhood through adolescence whereas anxious/depressed behavior demonstrated relative stability over the same period. Youth with highly flexible mothers displayed more optional trajectories of improvement in attention problems.

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6. Hoyt CR, Varughese TE, Erickson J, Haffner N, Luo L, L’Hotta AJ, Yeager L, King AA. Developmental delay in infants and toddlers with sickle cell disease: a systematic review. Developmental medicine and child neurology. 2022; 64(2): 168-75.

AIM: To summarize developmental delay among infants and toddlers with sickle cell disease (SCD). METHOD: This systematic review included studies that reported developmental outcomes of children with SCD between 0 months and 48 months of age and followed standards set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Ten studies were included, describing 596 unique developmental assessments. The rate of developmental delay ranged from 17.5% to 50% and increased with age. Cognition was the only domain included in all studies and the most frequently identified delay. One study reported that more severe SCD genotypes predicted worse development, while five studies reported no difference in rates of developmental delay across genotypes. INTERPRETATION: These findings emphasize the need for standardized screening to identify children with SCD at risk of delay at a young age to facilitate appropriate referrals for therapeutic intervention. Frequent and comprehensive developmental screening is necessary among all SCD genotypes.

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7. Mencer S, Kartawy M, Lendenfeld F, Soluh H, Tripathi MK, Khaliulin I, Amal H. Proteomics of autism and Alzheimer’s mouse models reveal common alterations in mTOR signaling pathway. Translational psychiatry. 2021; 11(1): 480.

Autism spectrum disorder (ASD) and Alzheimer’s disease (AD) are two different neurological disorders that share common clinical features, such as language impairment, executive functions, and motor problems. A genetic convergence has been proposed as well. However, the molecular mechanisms of these pathologies are still not well understood. Protein S-nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modification, targets key proteins implicated in synaptic and neuronal functions. Previously, we have shown that NO and SNO are involved in the InsG3680(+/+) ASD and P301S AD mouse models. Here, we performed large-scale computational biology analysis of the SNO-proteome followed by biochemical validation to decipher the shared mechanisms between the pathologies. This analysis pointed to the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway as one of the shared molecular mechanisms. Activation of mTOR in the cortex of both mouse models was confirmed by western blots that showed increased phosphorylation of RPS6, a major substrate of mTORC1. Other molecular alterations affected by SNO and shared between the two mouse models, such as synaptic-associated processes, PKA signaling, and cytoskeleton-related processes were also detected. This is the first study to decipher the SNO-related shared mechanisms between SHANK3 and MAPT mutations. Understanding the involvement of SNO in neurological disorders and its intersection between ASD and AD might help developing an effective novel therapy for both neuropathologies.

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8. Northcutt KV, Leal-Medina TS, Yoon YS. Early postnatal hypothyroidism reduces juvenile play behavior, but prenatal hypothyroidism compensates for these effects. Physiology & behavior. 2021; 241: 113594.

Perinatal hypothyroidism causes long-lasting effects on behavior, including hyperactivity, cognitive delays/deficits, and a reduction in anxiety. Although there is some evidence that hypothyroidism during fetal development in humans has been associated with later autism spectrum disorder diagnosis or autism-like traits, the relationships between early thyroid hormones and social behaviors are largely unknown. Previously, we found that a moderate dose of the hypothyroid-inducing drug methimazole during embryonic and postnatal development dramatically increased juvenile play in male and female rats. The goal of the current study was to determine the extent to which thyroid hormones act in prenatal or postnatal development to organize later social behaviors. Subjects were exposed to methimazole in the drinking water during prenatal (embryonic day 12 to birth), postnatal (birth to postnatal day 23), or pre- and postnatal development; control animals received regular drinking water throughout the experiment. They were tested for play behavior as juveniles (P30-32). We found an interaction between pre- and postnatal methimazole administration such that postnatal hypothyroidism decreased some play behaviors, whereas sustained pre- and postnatal hypothyroidism restored play to control levels. The effects were similar in males and females. To our knowledge, this is the first report of an interaction between pre- and postnatal hypothyroidism on later behavior. The complexity of the timing of these effects may help explain why epidemiological studies have not consistently found a relationship between gestational hypothyroidism and later behavior.

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9. Tomaszewski B, Klinger LG, Pugliese CE. Self-Determination in Autistic Transition-Aged Youth without Intellectual Disability. Journal of autism and developmental disorders. 2021.

Self-determination refers to an individual’s capacity and opportunities to act as a causal agent in their own lives to make choices, decisions, and set goals. The current study examined self- and parent-reports of the AIR Self-Determination Scale in transition-aged autistic youth (Based on stakeholder preferences, we use identity-first(autistic) or neutral language (on the autism spectrum) (Bottema-Beutel in JAMA 3:18-29, 2020)). Autistic youth completed depression and executive function measures, and parents rated their child’s social-communication and executive function difficulties. Despite differences between youth and parent reports, both youth and their parents reported lower self-determination skills (capacity) than opportunities to practice self-determined behaviors. Both depression and executive function skills were related to self-determination capacity, highlighting potential intervention targets for transition-aged youth to facilitate increased self-determination and potentially improved adult outcomes.

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10. Trujillo JP, Özyürek A, Kan CC, Sheftel-Simanova I, Bekkering H. Differences in the production and perception of communicative kinematics in autism. Autism research : official journal of the International Society for Autism Research. 2021; 14(12): 2640-53.

In human communication, social intentions and meaning are often revealed in the way we move. In this study, we investigate the flexibility of human communication in terms of kinematic modulation in a clinical population, namely, autistic individuals. The aim of this study was twofold: to assess (a) whether communicatively relevant kinematic features of gestures differ between autistic and neurotypical individuals, and (b) if autistic individuals use communicative kinematic modulation to support gesture recognition. We tested autistic and neurotypical individuals on a silent gesture production task and a gesture comprehension task. We measured movement during the gesture production task using a Kinect motion tracking device in order to determine if autistic individuals differed from neurotypical individuals in their gesture kinematics. For the gesture comprehension task, we assessed whether autistic individuals used communicatively relevant kinematic cues to support recognition. This was done by using stick-light figures as stimuli and testing for a correlation between the kinematics of these videos and recognition performance. We found that (a) silent gestures produced by autistic and neurotypical individuals differ in communicatively relevant kinematic features, such as the number of meaningful holds between movements, and (b) while autistic individuals are overall unimpaired at recognizing gestures, they processed repetition and complexity, measured as the amount of submovements perceived, differently than neurotypicals do. These findings highlight how subtle aspects of neurotypical behavior can be experienced differently by autistic individuals. They further demonstrate the relationship between movement kinematics and social interaction in high-functioning autistic individuals. LAY SUMMARY: Hand gestures are an important part of how we communicate, and the way that we move when gesturing can influence how easy a gesture is to understand. We studied how autistic and typical individuals produce and recognize hand gestures, and how this relates to movement characteristics. We found that autistic individuals moved differently when gesturing compared to typical individuals. In addition, while autistic individuals were not worse at recognizing gestures, they differed from typical individuals in how they interpreted certain movement characteristics.

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11. Van Damme T, Vancampfort D, Thoen A, Sanchez CPR, Van Biesen D. Evaluation of the Developmental Coordination Questionnaire (DCDQ) as a Screening Instrument for Co-occurring Motor Problems in Children with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2021.

Although motor problems are highly prevalent in children with autism spectrum disorder (ASD), they remain underdiagnosed. Questionnaire-based screening for motor problems could optimize current clinical practice. This study aimed to examine the psychometric properties of the developmental coordination disorder questionnaire (DCDQ) to screen for co-occurring motor problems in individuals with ASD (n = 115; aged 5-15 years). Results indicated an excellent internal consistency; concurrent and discriminant validity with the Movement Assessment Battery for Children, second edition. Sensitivity was excellent, but specificity was lower. The positive and negative predictive values indicate that the DCDQ can be used to detect motor problems in children with ASD and can exclude the presence of developmental coordination disorder.

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12. Weir E, Allison C, Baron-Cohen S. The sexual health, orientation, and activity of autistic adolescents and adults. Autism research : official journal of the International Society for Autism Research. 2021; 14(11): 2342-54.

Small studies suggest significant differences between autistic and nonautistic individuals regarding sexual orientation and behavior. We administered an anonymized, online survey to n = 2386 adults (n = 1183 autistic) aged 16-90 years to describe sexual activity, risk of sexually transmitted infections (STIs), and sexual orientation. Autistic individuals are less likely to report sexually activity or heterosexuality compared to nonautistic individuals, but more likely to self-report asexuality or an ‘other’ sexuality. Overall, autistic, and nonautistic groups did not differ in age of sexual activity onset or contraction of STIs. When evaluating sex differences, autistic males are uniquely more likely to be bisexual (compared to nonautistic males); conversely, autistic females are uniquely more likely to be homosexual (compared to nonautistic females). Thus, both autistic males and females may express a wider range of sexual orientations in different sex-specific patterns than general population peers. When comparing autistic males and females directly, females are more likely to have diverse sexual orientations (except for homosexuality) and engage in sexual activity, are less likely to identify as heterosexual, and have a lower mean age at which they first begin engaging in sexual activity. This is the largest study of sexual orientation of autistic adults. Sexual education and sexual health screenings of all children, adolescents, and adults (including autistic individuals) must remain priorities; healthcare professionals should use language that affirms a diversity of sexual orientations and supports autistic individuals who may have increased risks (affecting mental health, physical health, and healthcare quality) due to stress and discrimination from this intersectionality. LAY SUMMARY: This is the largest study on the sexual activity, orientation, and health of autistic adults. This study reaffirms that the majority of autistic adults are interested in sexual relationships and engage in sexual activity. Sexual education and sexual health screenings must remain a priority for all individuals, including those with autism; healthcare professionals should be aware that autistic patients may be more likely to identify as Lesbian, Gay, Bisexual, Trans, Queer, Asexual, and other identities not listed here (LGBTQA+) which may put them at greater risk of mental and physical health difficulties due to discrimination.

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