1. Barik K, Watanabe K, Bhattacharya J, Saha G. A Fusion-Based Machine Learning Approach for Autism Detection in Young Children Using Magnetoencephalography Signals. J Autism Dev Disord;2022 (Oct 3)

In this study, we aimed to find biomarkers of autism in young children. We recorded magnetoencephalography (MEG) in thirty children (4-7 years) with autism and thirty age, gender-matched controls while they were watching cartoons. We focused on characterizing neural oscillations by amplitude (power spectral density, PSD) and phase (preferred phase angle, PPA). Machine learning based classifier showed a higher classification accuracy (88%) for PPA features than PSD features (82%). Further, by a novel fusion method combining PSD and PPA features, we achieved an average classification accuracy of 94% and 98% for feature-level and score-level fusion, respectively. These findings reveal discriminatory patterns of neural oscillations of autism in young children and provide novel insight into autism pathophysiology.

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2. Bottema-Beutel K, LaPoint SC, Kim SY, Mohiuddin S, Yu Q, McKinnon R. An evaluation of intervention research for transition-age autistic youth. Autism;2022 (Oct 3):13623613221128761.

In this study, we assess the quality of intervention research that focuses on autistic youth who are 14-22 years old. We found 193 different studies on this topic, and carefully reviewed them. Most of these studies tested strategies that were behavioral. This means that they used procedures like prompting and rewards to change participants’ behavior. We found that the majority of studies had problems that make it hard to determine whether or not the intervention worked. The problems related to how researchers designed their studies, and how they measured the study outcomes. We also found that researchers rarely tried to find out if the strategies they studied had unintended negative effects for participants. Because of these issues, we make suggestions for how researchers might design better studies that will let people know how well the strategies worked.

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3. Bradshaw J, Shi D, Federico A, Klaiman C, Saulnier C. The Pull-to-Sit Task: Examining Infant Postural Development in Autism Spectrum Disorder. J Pediatr;2022 (Oct 3)

OBJECTIVE: To evaluate the predictive relation between early trajectories of postural and head control during a pull-to-sit task and later autism diagnostic and developmental outcomes. STUDY DESIGN: Using a prospective longitudinal design, postural skills in N=100 infants at elevated and low familial likelihood of ASD were evaluated using a pull-to-sit task monthly from age 1-6 months. At 24 months, infants were seen for a developmental and diagnostic evaluation completed by examiners masked to participant group. Latent growth curve models were used to compare early trajectories of pull-to-sit performance for infants later diagnosed with ASD and typically developing infants and predict developmental outcomes. RESULTS: Pull-to-sit trajectories did not differ for elevated likelihood infants or infants with ASD when compared with low likelihood and typically developing infants, but infants with ASD were more likely to exhibit at head lag by age 4 months. In addition, pull-to-sit trajectories predicted social and speech skills two years later. CONCLUSIONS: These findings highlight the role of very early pull-to-sit skills for later social and language outcomes. Atypical postural development and persistent presence of head lag may be important early indicators of social and language vulnerabilities, including ASD.

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4. Canu D, Ioannou C, Müller K, Martin B, Fleischhaker C, Biscaldi M, Beauducel A, Smyrnis N, van Elst LT, Klein C. Evidence towards a continuum of impairment across neurodevelopmental disorders from basic ocular-motor tasks. Sci Rep;2022 (Oct 3);12(1):16521.

Findings of genetic overlap between Schizophrenia, Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) contributed to a renewed conceptualization of these disorders as laying on a continuum based on aetiological, pathophysiological and neurodevelopmental features. Given that cognitive impairments are core to their pathophysiology, we compared patients with schizophrenia, ADHD, ASD, and controls on ocular-motor and manual-motor tasks, challenging crucial cognitive processes. Group comparisons revealed inhibition deficits common to all disorders, increased intra-subject variability in schizophrenia and, to a lesser extent, ADHD as well as slowed processing in schizophrenia. Patterns of deviancies from controls exhibited strong correlations, along with differences that posited schizophrenia as the most impaired group, followed by ASD and ADHD. While vector correlations point towards a common neurodevelopmental continuum of impairment, vector levels suggest differences in the severity of such impairment. These findings argue towards a dimensional approach to Neurodevelopmental Disorders’ pathophysiological mechanisms.

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5. Chen G, Yu B, Tan S, Tan J, Jia X, Zhang Q, Zhang X, Jiang Q, Hua Y, Han Y, Luo S, Hoekzema K, Bernier RA, Earl RK, Kurtz-Nelson EC, Idleburg MJ, Madan-Khetarpal S, Clark R, Sebastian J, Fernandez-Jaen A, Alvarez S, King SD, Ramos LL, Santos MLS, Martin DM, Brooks D, Symonds JD, Cutcutache I, Pan Q, Hu Z, Yuan L, Eichler EE, Xia K, Guo H. GIGYF1 disruption associates with autism and impaired IGF-1R signaling. J Clin Invest;2022 (Oct 3);132(19)

Autism spectrum disorder (ASD) represents a group of neurodevelopmental phenotypes with a strong genetic component. An excess of likely gene-disruptive (LGD) mutations in GIGYF1 was implicated in ASD. Here, we report that GIGYF1 is the second-most mutated gene among known ASD high-confidence risk genes. We investigated the inheritance of 46 GIGYF1 LGD variants, including the highly recurrent mutation c.333del:p.L111Rfs*234. Inherited GIGYF1 heterozygous LGD variants were 1.8 times more common than de novo mutations. Among individuals with ASD, cognitive impairments were less likely in those with GIGYF1 LGD variants relative to those with other high-confidence gene mutations. Using a Gigyf1 conditional KO mouse model, we showed that haploinsufficiency in the developing brain led to social impairments without significant cognitive impairments. In contrast, homozygous mice showed more severe social disability as well as cognitive impairments. Gigyf1 deficiency in mice led to a reduction in the number of upper-layer cortical neurons, accompanied by a decrease in proliferation and increase in differentiation of neural progenitor cells. We showed that GIGYF1 regulated the recycling of IGF-1R to the cell surface. KO of GIGYF1 led to a decreased level of IGF-1R on the cell surface, disrupting the IGF-1R/ERK signaling pathway. In summary, our findings show that GIGYF1 is a regulator of IGF-1R recycling. Haploinsufficiency of GIGYF1 was associated with autistic behavior, likely through interference with IGF-1R/ERK signaling pathway.

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6. Coulter-Thompson EI, Matthews DD, Applegate J, Broder-Fingert S, Dubé K. Health Care Bias and Discrimination Experienced by Lesbian, Gay, Bisexual, Transgender, and Queer Parents of Children With Developmental Disabilities: A Qualitative Inquiry in the United States. J Pediatr Health Care;2022 (Sep 29)

INTRODUCTION: This study explored the impact of health care (HC) bias and discrimination on lesbian, gay, bisexual, transgender, and queer (LGBTQ) parents and their children with disabilities in the United States, including the timing of developmental screening and diagnosis. METHOD: We conducted semistructured interviews with 16 LGBTQ parents of children with developmental concerns or disabilities recruited through a prior national survey. Interviews were transcribed and analyzed using a combined inductive and deductive approach. RESULTS: Discrimination types reported included noninclusive forms, disclosure challenges, and providers dismissing nongestational parents and diverse families. Few parents reported screening and diagnosis delays. Parents’ recommendations included: avoiding assumptions, honoring family diversity, increasing LGBTQ family support, improving HC forms, increasing antibias training, and convening a learning community. DISCUSSION: Our study advances the knowledge around HC bias and discrimination among LGBTQ parents of children with disabilities. Findings highlight the need for increased LGBTQ-affirming family support and research representing LGBTQ family diversity in U.S. health care.

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7. de Oliveira DS, Brandão AI, Vale TC. Fragile X-associated tremor or ataxia syndrome in a patient with difficulty walking, falls, a tremor, and erectile dysfunction. Lancet;2022 (Oct 1);400(10358):1144.

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8. Elliott T, Floyd James K, Coleman KJ, Skrine Jeffers K, Nau CL, Choi K. Cross-sectional Comparison of Disparities by Race Using White vs Hispanic as Reference Among Children and Youths With Developmental Disabilities Referred for Speech Therapy. JAMA Netw Open;2022 (Oct 3);5(10):e2234453.

IMPORTANCE: Health care research on racial disparities among children and youths has historically used the White race as a reference category with which other racial and ethnic groups are compared, which may inadvertently set up Whiteness as a standard for health. OBJECTIVE: To compare 2 interpretations of an analysis of racial disparities in speech therapy receipt among children and youths with developmental disabilities: a traditional, White-referenced analysis and a Hispanic majority-referenced analysis. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used multiple logistic regression to analyze speech therapy referrals for children, adolescents, and transition age youths in an integrated health care system in Southern California from 2017 to 2020. Eligible participants were children and youths up to age 26 years with 1 or more diagnosed intellectual or developmental disability (eg, autism spectrum disorder, speech or language delay, developmental delay, Down syndrome, and others). EXPOSURES: Child or youth race and ethnicity as reported by parents or caregivers (Asian, Black and African American, Hispanic and Latinx, American Indian or Alaskan Native, Native Hawaiian or Pacific Islander, White, multiple, and other). MAIN OUTCOMES AND MEASURES: Receipt of speech therapy within 1 year of referral. RESULTS: A total 66 402 referrals were included; 65 833 referrals (99.1%) were for children under age 17 years, 47 323 (71.3%) were for boys, and 39 959 (60.2%) were commercially insured. A majority of participants were identified as Hispanic (36 705 [55.3%]); 6167 (9.3%) were identified as Asian, 4810 (7.2%) as Black, and 14 951 (22.5%) as White. In the traditional racial disparities model where the reference category was White, referrals of children and youths who identified as Hispanic, Black, Pacific Islander, and other had lower odds of actual receipt of speech therapy compared with referrals for White children and youths (Hispanic: OR, 0.79; 95% CI, 0.75-0.83; Black: OR, 0.72; 95% CI, 0.66-0.78; Pacific Islander: OR, 0.74; 95% CI, 0.57-0.98). When using the majority race group (Hispanic) as the reference category, referrals for children and youths who identified as White (OR, 1.26; 95% CI, 1.20-1.30), Asian (OR, 1.21; 95% CI, 1.12-1.30), and multiracial (OR, 1.35; 95% CI, 1.08-1.71) had higher odds of resulting in actual service receipt in comparison with referrals for Hispanic children and youths. CONCLUSIONS AND RELEVANCE: The cross-sectional study demonstrates the value of decentering Whiteness in interpreting racial disparities research and considering racial differences against multiple referents. Racial disparities researchers should consider investigating multiple between-group differences instead of exclusively using White as the default reference category.

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9. Fiksinski AM, Hoftman GD, Vorstman JAS, Bearden CE. A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome. Mol Psychiatry;2022 (Oct 3)

Recently, increasing numbers of rare pathogenic genetic variants have been identified that are associated with variably elevated risks of a range of neurodevelopmental outcomes, notably including Autism Spectrum Disorders (ASD), Schizophrenia Spectrum Disorders (SSD), and Intellectual Disability (ID). This review is organized along three main questions: First, how can we unify the exclusively descriptive basis of our current psychiatric diagnostic classification system with the recognition of an identifiable, highly penetrant genetic risk factor in an increasing proportion of patients with ASD or SSD? Second, what can be learned from studies of individuals with ASD or SSD who share a common genetic basis? And third, what accounts for the observed variable penetrance and pleiotropy of neuropsychiatric phenotypes in individuals with the same pathogenic variant? In this review, we focus on findings of clinical and preclinical studies of the 22q11.2 deletion syndrome (22q11DS). This particular variant is not only one of the most common among the increasing list of known rare pathogenic variants, but also one that benefits from a relatively long research history. Consequently, 22q11DS is an appealing model as it allows us to: (1) elucidate specific genotype-phenotype associations, (2) prospectively study behaviorally defined classifications, such as ASD or SSD, in the context of a known, well-characterized genetic basis, and (3) elucidate mechanisms underpinning variable penetrance and pleiotropy, phenomena with far-reaching ramifications for research and clinical practice. We discuss how findings from animal and in vitro studies relate to observations in human studies and can help elucidate factors, including genetic, environmental, and stochastic, that impact the expression of neuropsychiatric phenotypes in 22q11DS, and how this may inform mechanisms underlying neurodevelopmental expression in the general population. We conclude with research priorities for the field, which may pave the way for novel therapeutics.

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10. Haligheri G, Johnson T, Kathol M, Kuzava L, Goth N, Staggs VS, Donnelly JE, Ptomey LT, Forsha D. Early cardiac dysfunction in obese adolescents with Down syndrome or autism. Cardiol Young;2022 (Oct 3):1-8.

BACKGROUND: Obesity in adolescents with intellectual and developmental disabilities) occurs at twice the frequency as their typically developing peers. Typically developing adolescents with obesity have abnormal cardiac function (as measured by strain echocardiography) and cardiac mass, but the effects of obesity on cardiac health in adolescents with Down syndrome or autism spectrum disorder are unknown. The purpose of this study was to evaluate the impact of body mass index on cardiac function in adolescents with Down syndrome or autism. METHODS: Adolescents (age 12-21 years) with Down syndrome (n = 28), autism (n = 33), and age-/sex-matched typically developing controls (n = 15) received an echocardiogram optimised for strain analysis at a single timepoint. Measures of ventricular function, mass, and size were collected. Regression modelling evaluated the impact of body mass index and intellectual and developmental disabilities diagnosis on these cardiac measures. RESULTS: In regression modelling, an elevated body mass index z-score was associated with diminished systolic biventricular function by global strain (left ventricular longitudinal strain β 0.87, P < 0.001; left ventricular circumferential strain β 0.57, p 0.003; right ventricular longitudinal strain β 0.63, P < 0.001). Diminished left ventricular diastolic function by early diastolic strain rate was also associated with elevated body mass index (global longitudinal end-diastolic strain rate β -0.7, P < 0.001). No association was found between traditional (non-strain) measures of systolic and diastolic ventricular function and body mass index z-score. CONCLUSIONS: Obesity in adolescents with Down syndrome or autism negatively impacts cardiac function as measured by echocardiographic strain analysis that was not detected by traditional parameters.

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11. Lacroix A, Proteau-Lemieux M, Côté S, Near J, Hui SCN, Edden RAE, Lippé S, Çaku A, Corbin F, Lepage JF. Multimodal assessment of the GABA system in patients with fragile-X syndrome and neurofibromatosis of type 1. Neurobiol Dis;2022 (Oct 3);174:105881.

Fragile-X syndrome (FXS) and Neurofibromatosis of type 1 (NF-1) are two monogenic disorders sharing neurobehavioral symptoms and pathophysiological mechanisms. Namely, preclinical models of both conditions show overactivity of the mTOR signaling pathway as well as GABAergic alterations. However, despite its potential clinical relevance for these disorders, the GABAergic system has not been systematically studied in humans. In the present study, we used an extensive transcranial magnetic stimulation (TMS) assessment battery in combination with magnetic resonance spectroscopy (MRS) to provide a comprehensive picture of the main inhibitory neurotransmitter system in patients with FXS and NF1. Forty-three participants took part in the TMS session (15 FXS, 10 NF1, 18 controls) and 36 in the MRS session (11 FXS, 14 NF1, 11 controls). Results show that, in comparison to healthy control participants, individuals with FXS and NF1 display lower GABA concentration levels as measured with MRS. TMS result show that FXS patients present increased GABA(B)-mediated inhibition compared to controls and NF1 patients, and that GABA(A)-mediated intracortical inhibition was associated with increased excitability specifically in the FXS groups. In line with previous reports, correlational analyses between MRS and TMS measures did not show significant relationships between GABA-related metrics, but several TMS measures correlated with glutamate+glutamine (Glx) levels assessed with MRS. Overall, these results suggest a partial overlap in neurophysiological alterations involving the GABA system in NF1 and FXS, and support the hypothesis that MRS and TMS assess different aspects of the neurotransmitter systems.

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12. Marrus N, Botteron KN, Hawks Z, Pruett JR, Elison JT, Jackson JJ, Markson L, Eggebrecht AT, Burrows CA, Zwaigenbaum L, Dager SR, Estes AM, Hazlett HC, Schultz RT, Piven J, Constantino JN. Social motivation in infancy is associated with familial recurrence of ASD. Dev Psychopathol;2022 (Oct 3):1-11.

Pre-diagnostic deficits in social motivation are hypothesized to contribute to autism spectrum disorder (ASD), a heritable neurodevelopmental condition. We evaluated psychometric properties of a social motivation index (SMI) using parent-report item-level data from 597 participants in a prospective cohort of infant siblings at high and low familial risk for ASD. We tested whether lower SMI scores at 6, 12, and 24 months were associated with a 24-month ASD diagnosis and whether social motivation’s course differed relative to familial ASD liability. The SMI displayed good internal consistency and temporal stability. Children diagnosed with ASD displayed lower mean SMI T-scores at all ages and a decrease in mean T-scores across age. Lower group-level 6-month scores corresponded with higher familial ASD liability. Among high-risk infants, strong decline in SMI T-scores was associated with 10-fold odds of diagnosis. Infant social motivation is quantifiable by parental report, differentiates children with versus without later ASD by age 6 months, and tracks with familial ASD liability, consistent with a diagnostic and susceptibility marker of ASD. Early decrements and decline in social motivation indicate increased likelihood of ASD, highlighting social motivation’s importance to risk assessment and clarification of the ontogeny of ASD.

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13. Millen C. The Reality of Accessing Care for Autism Spectrum Disorder. J Pediatr Health Care;2022 (Sep 29)

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14. Monk R, Whitehouse AJO, Waddington H. The use of language in autism research. Trends Neurosci;2022 (Sep 27)

The past three decades have seen a major shift in our understanding of the strong links between autism and identity. These developments have called for careful consideration of the language used to describe autism. Here, we briefly discuss some of these deliberations and provide guidance to researchers around language use in autism research.

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15. Namli Z, Tamam L, Demirkol ME, Karaytuğ MO, Sun T. The Relationship Among Autistic Traits, Impulsivity, and Functionality in Patients With Obsessive-Compulsive Disorder. J Nerv Ment Dis;2022 (Oct 3)

Obsessive-compulsive disorder (OCD) is a chronic mental disorder that causes disabilities. This study investigated the relationship among impulsivity, autistic traits, and disabilities in patients with OCD. We included 88 patients with OCD and 90 healthy volunteers without any mental disorders. The participants were evaluated using the Yale-Brown Obsessive-Compulsive Scale, Autism Spectrum Quotient (AQ), Barratt Impulsiveness Scale-11 (BIS-11), and World Health Organization Disability Assessment Schedule (WHODAS 2.0). Regression analyses revealed that AQ-attention switching and BIS-attentional subscale scores were associated with WHODAS-overall score in the OCD group (p = 0.017 and p = 0.034, respectively). In the OCD group, AQ total, social skills, and communication subdomain scores partially mediated the relationship between impulsivity and disability. BIS total, attentional, and nonplanning subscale scores partially mediated the relationship between autistic traits and disability. Developing new treatment strategies for cognitive recovery, in addition to traditional treatment approaches in patients with OCD, may help increase functionality in patients with OCD.

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16. Nielsen TC, Nassar N, Shand AW, Jones HF, Han VX, Patel S, Guastella AJ, Dale RC, Lain SJ. Association of maternal autoimmune disease and early childhood infections with offspring autism spectrum disorder: A population-based cohort study. Autism Res;2022 (Oct 3)

The aim of this study was to examine potential synergistic effects between maternal autoimmune disease and early childhood infections and their association with autism spectrum disorder (ASD) in offspring. Both exposures have been associated with increased risk of ASD in previous studies, but potential synergistic effects remain underexplored. We conducted a population-based cohort study of singleton children born at term gestation (37-41 weeks) in New South Wales, Australia from January 2002 to December 2008. Maternal autoimmune diagnoses and childhood infections before age 2 years were identified from linked maternal and child hospital admissions, and ASD diagnoses by age 9 years were identified from linked disability services data. Multivariable logistic regression assessed the association between each exposure and ASD and additive interaction between exposures, controlling for potential confounders. A total of 18,451 children exposed to maternal autoimmune disease were propensity score matched (1:2) to 36,902 unexposed children. Any maternal autoimmune disease (adjusted odds ratio (aOR) 1.25, 95% confidence interval (CI) 1.07-1.47) and any childhood infection before age 2 years (aOR 1.38, 95% CI 1.15-1.67) were each associated with ASD. However, there was no evidence of additive interaction between the two exposures (relative excess risk due to interaction [RERI] 0.128, 95% CI -0.418-0.675) resulting in increased odds of ASD in offspring. Future studies could examine potential interactions between other sources of maternal immune activation and childhood infection and impact on ASD and other neurodevelopmental disorders. LAY SUMMARY: Inflammation during pregnancy and in early childhood may influence how a child’s brain develops, increasing the risk of autism spectrum disorder (ASD). In this study, we found that having a mother with an autoimmune disease and being admitted to hospital with an infection before age two each increased a child’s odds of ASD. However, children with maternal autoimmune disease and an infection did not experience any additional increase in risk from having both exposures together.

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17. Penna HM, Paiva APM, Romano AJM, Alves RL, Junior PDN, Módolo NSP. Comparison between oral midazolam versus oral ketamine plus midazolam as preanesthetic medication in autism spectrum disorder: double-blind randomized clinical trial. Braz J Anesthesiol;2022 (Sep 29)

BACKGROUND: Conventional dental care is often impossible in patients with Autism Spectrum Disorder (ASD). Non-collaborative behaviors, sometimes associated with aggressiveness, are usual justifications for premedication in this population. Thereby, this research focuses on the effects of oral midazolam versus oral ketamine plus midazolam as preanesthetic medication in ASD. METHODS: The sample included 64 persons with ASD, aged 2-59 years, scheduled for dental care under general anesthesia. The primary objective of this study was to compare degrees of sedation between two parallel, double-blinded, equally proportional groups randomized to receive oral midazolam (0.5 mg.kg(-1), maximum 15 mg) or oral midazolam (0.5 mg.kg(-1)) associated with oral S(+)-ketamine (3 mg.kg(-1), maximum 300 mg). The secondary outcomes were the need of physical stabilization to obtain intravenous line, awakening time, and occurrence of adverse events. RESULTS: According to the dichotomous analysis of sedation level (Ramsay score 1 and 2 versus Ramsay ≥ 3), oral association of S(+)-ketamine and midazolam improved sedation, with increased probability of Ramsay ≥ 3, Relative Risk (RR) = 3.2 (95% Confidence Interval [95% CI] = 1.32 to 7.76) compared to midazolam alone. Combined treatment also made it easier to obtain venous access without physical stabilization, RR = 2.05 (95% CI = 1.14 to 3.68). There were no differences between groups regarding awakening time and the occurrence of adverse events. CONCLUSION: The association of oral S(+)-ketamine with midazolam provides better preanesthetic sedation rates than midazolam alone and facilitates intravenous line access in patients with autism.

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18. Pfender EJ, Wittenberg E, Kerr AM, Goldsmith JV. Family Communication in Autism Spectrum Disorder: Applying the Family Caregiver Communication Typology to Parent Caregivers. Health Commun;2022 (Oct 3):1-11.

Parents of children with Autism Spectrum Disorder (ASD) experience greater stress and caregiver burden than parents of children with other disabilities. To cope with the stress of long-term caregiving, they rely on professionals for support and guidance. However, parents continue to report unmet communication and support needs. To inform tailored communication for parents of a child with ASD, this study used the existing Family Caregiver Communication Typology framework which identifies four caregiver communication types (manager, carrier, partner, and lone) and their unique communication and support needs. In-depth, structured interviews were conducted with parents (n = 22) and ASD professionals (n = 28) to explore communication characteristics of ASD parent caregivers. A thematic analysis revealed communication behaviors among four ASD parent caregiver types, further validating the typology. Future research is needed to develop targeted interventions for improving family-centered care based on ASD parent caregiver types.

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19. Procyshyn TL, Lombardo MV, Lai MC, Jassim N, Auyeung B, Crockford SK, Deakin JB, Soubramanian S, Sule A, Terburg D, Baron-Cohen S, Bethlehem RAI. Oxytocin enhances basolateral amygdala activation and functional connectivity while processing emotional faces: preliminary findings in autistic vs non-autistic women. Soc Cogn Affect Neurosci;2022 (Oct 3);17(10):929-938.

Oxytocin is hypothesized to promote social interactions by enhancing the salience of social stimuli. While previous neuroimaging studies have reported that oxytocin enhances amygdala activation to face stimuli in autistic men, effects in autistic women remain unclear. In this study, the influence of intranasal oxytocin on activation and functional connectivity of the basolateral amygdala-the brain’s ‘salience detector’-while processing emotional faces vs shapes was tested in 16 autistic and 21 non-autistic women by functional magnetic resonance imaging in a placebo-controlled, within-subject, cross-over design. In the placebo condition, minimal activation differences were observed between autistic and non-autistic women. However, significant drug × group interactions were observed for both basolateral amygdala activation and functional connectivity. Oxytocin increased left basolateral amygdala activation among autistic women (35-voxel cluster, Montreal Neurological Institute (MNI) coordinates of peak voxel = -22 -10 -28; mean change = +0.079%, t = 3.159, PTukey = 0.0166) but not among non-autistic women (mean change = +0.003%, t = 0.153, PTukey = 0.999). Furthermore, oxytocin increased functional connectivity of the right basolateral amygdala with brain regions associated with socio-emotional information processing in autistic women, but not in non-autistic women, attenuating group differences in the placebo condition. Taken together, these findings extend evidence of oxytocin’s effects on the amygdala to specifically include autistic women and specify the subregion of the effect.

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20. Richards Steed R, Bakian AV, Smith KR, Wan N, Brewer S, Medina R, VanDerslice J. Evidence of transgenerational effects on autism spectrum disorder using multigenerational space-time cluster detection. Int J Health Geogr;2022 (Oct 3);21(1):13.

BACKGROUND: Transgenerational epigenetic risks associated with complex health outcomes, such as autism spectrum disorder (ASD), have attracted increasing attention. Transgenerational environmental risk exposures with potential for epigenetic effects can be effectively identified using space-time clustering. Specifically applied to ancestors of individuals with disease outcomes, space-time clustering characterized for vulnerable developmental stages of growth can provide a measure of relative risk for disease outcomes in descendants. OBJECTIVES: (1) Identify space-time clusters of ancestors with a descendent with a clinical ASD diagnosis and matched controls. (2) Identify developmental windows of ancestors with the highest relative risk for ASD in descendants. (3) Identify how the relative risk may vary through the maternal or paternal line. METHODS: Family pedigrees linked to residential locations of ASD cases in Utah have been used to identify space-time clusters of ancestors. Control family pedigrees of none-cases based on age and sex have been matched to cases 2:1. The data have been categorized by maternal or paternal lineage at birth, childhood, and adolescence. A total of 3957 children, both parents, and maternal and paternal grandparents were identified. Bernoulli space-time binomial relative risk (RR) scan statistic was used to identify clusters. Monte Carlo simulation was used for statistical significance testing. RESULTS: Twenty statistically significant clusters were identified. Thirteen increased RR (> 1.0) space-time clusters were identified from the maternal and paternal lines at a p-value < 0.05. The paternal grandparents carry the greatest RR (2.86-2.96) during birth and childhood in the 1950's-1960, which represent the smallest size clusters, and occur in urban areas. Additionally, seven statistically significant clusters with RR < 1 were relatively large in area, covering more rural areas of the state. CONCLUSION: This study has identified statistically significant space-time clusters during critical developmental windows that are associated with ASD risk in descendants. The geographic space and time clusters family pedigrees with over 3 + generations, which we refer to as a person's geographic legacy, is a powerful tool for studying transgenerational effects that may be epigenetic in nature. Our novel use of space-time clustering can be applied to any disease where family pedigree data is available.

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21. Sakihara K, Kita Y, Suzuki K, Inagaki M. Modulation effects of the intact motor skills on the relationship between social skills and motion perceptions in children with autism spectrum disorder: A pilot study. Brain Dev;2022 (Sep 29)

BACKGROUND: An individual with autism spectrum disorder (ASD) has social skill, motor skill, and motion perception deficits. However, the relationship among them was not clarified. Therefore, this study aimed to evaluate the effects of motor skills on social skills and motion perception. METHODS: Five typically developed children and fourteen children with ASD participated in our study. The N200 component, a brain activity indicating motion perception, was induced in mid-temporal (MT/V5) brain area by watching a random dot kinematograph, and was recorded using a scalp electroencephalogram. Furthermore, the social responsiveness scale (SRS) indicating the social skill deficit, the developmental coordination disorder questionnaire (DCDQ) estimating the developmental coordination disorder (DCD), and the movement assessment battery for children second edition (MABC-2) indicating motor skills were recorded in the children with ASD. A hierarchical multiple regression analysis was conducted to examine the modulation effects of motor skills on the relationship between social skills and motion perception. The dependent variable was the N200 latency, and the independent variables were SRS, MABC-2, and combined MABC-2 and SRS. RESULTS: The N200 latency was more delayed in children with ASD relative that in typically developed children. Intact balance ability modulated the relationship between social skills and N200 latency in children with ASD. Within the high balance ability, when the social skills worsened, the N200 latency was shortened. CONCLUSIONS: This is the first report that intact motor skills could modulate the relationship between social skills and motion perception.

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22. Salvador-Garcia C, Valverde-Esteve T, Chiva-Bartoll O, Maravé-Vivas M. Dynamic balance improvement in children with Autism Spectrum Disorder after an extracurricular Service-Learning Physical Education program. Dev Neurorehabil;2022 (Oct 3):1-9.

This study aimed to examine the acute changes in dynamic balance Postural Control experienced by children with Autism Spectrum Disorder (ASD) who undertook a 6-month extracurricular Service-Learning Physical Education (PE) program. The study used a quasi-experimental design with 23 participants divided into an experimental group and a control group. Limits of Stability protocol was used to measure the children’s postural control. The results showed that the experimental group achieved statistically significant improvements. To conclude, this study provides substantial input about how extracurricular PE activities aimed at developing the general motor proficiency of ASD children can improve their dynamic balance.

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23. Song AY, Bakulski K, Feinberg JI, Newschaffer C, Croen LA, Hertz-Picciotto I, Schmidt RJ, Farzadegan H, Lyall K, Fallin MD, Volk HE, Ladd-Acosta C. Associations between accelerated parental biologic age, autism spectrum disorder, social traits, and developmental and cognitive outcomes in their children. Autism Res;2022 (Oct 3)

Parental age is a known risk factor for autism spectrum disorder (ASD), however, studies to identify the biologic changes underpinning this association are limited. In recent years, « epigenetic clock » algorithms have been developed to estimate biologic age and to evaluate how the epigenetic aging impacts health and disease. In this study, we examined the relationship between parental epigenetic aging and their child’s prospective risk of ASD and autism related quantitative traits in the Early Autism Risk Longitudinal Investigation study. Estimates of epigenetic age were computed using three robust clock algorithms and DNA methylation measures from the Infinium HumanMethylation450k platform for maternal blood and paternal blood specimens collected during pregnancy. Epigenetic age acceleration was defined as the residual of regressing chronological age on epigenetic age while accounting for cell type proportions. Multinomial logistic regression and linear regression models were completed adjusting for potential confounders for both maternal epigenetic age acceleration (n = 163) and paternal epigenetic age acceleration (n = 80). We found accelerated epigenetic aging in mothers estimated by Hannum’s clock was significantly associated with lower cognitive ability and function in offspring at 12 months, as measured by Mullen Scales of Early Learning scores (β = -1.66, 95% CI: -3.28, -0.04 for a one-unit increase). We also observed a marginal association between accelerated maternal epigenetic aging by Horvath’s clock and increased odds of ASD in offspring at 36 months of age (aOR = 1.12, 95% CI: 0.99, 1.26). By contrast, fathers accelerated aging was marginally associated with decreased ASD risk in their offspring (aOR = 0.83, 95% CI: 0.68, 1.01). Our findings suggest epigenetic aging could play a role in parental age risks on child brain development. LAY SUMMARY: Parental age is a risk factor for ASD; however, little is known about possible biologic aging changes that contribute to this association. We found that mothers with faster epigenetic aging and fathers with slower epigenetic aging, relative to their chronologic age, were at increased odds of having a child with ASD and/or decreased early learning, at 3 years of age. These findings suggest epigenetic aging in parents may play a role in neurodevelopment and ASD.

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24. Song C, Wu L, Hong Y, Chen X, Zhu Z. Factors affecting knowledge of autism spectrum disorder among pediatric residents in eastern China: a cross-sectional study. BMC Med Educ;2022 (Oct 3);22(1):699.

BACKGROUND: There is a global increase in the prevalence of autism spectrum disorder (ASD). Early identification of ASD in children and intervention are key aspects in the management of ASD. However, early identification is partly dependent on knowledge on ASD among pediatricians. This study analyzed the extent of ASD knowledge and its underlying factors among pediatric residents in eastern China, to provide a reference for medical education reforms. METHODS: The study employed the Knowledge about Childhood Autism among Health Workers questionnaire. A total of 138 pediatric residents participated in the survey. Descriptive statistics were used to describe demographic characteristics and the four domains of the questionnaire. Univariate analysis was employed to assess impacts of the demographic characteristics on the questionnaire scores. On the other hand, multivariate regression analysis was used to analyze the correlation between the participants’ demographic characteristics and the questionnaire scores. RESULTS: The average ASD cognitive score of 138 respondents was 13.38 ± 4.48. The ASD cognitive scores in female pediatric residents were higher compared to that in males (p < 0.05). Residents who had obtained professional doctor qualification certificate were more than those without professional doctor qualification certificate (p < 0.05). The ASD knowledge in the group which did not have rotation in both departments was lower than in the group which had rotation in both departments (p < 0.05) as well as the group that had rotation in developmental and behavioral pediatrics department only (p < 0.05). Our multivariate linear regression model demonstrated significant statistical differences (p < 0.05), and showed that gender and systematic exposure to ASD knowledge had significant effects on cognitive scores (p < 0.05). CONCLUSION: Most participants had relatively low levels of awareness and knowledge about ASD, especially on ASD comorbidities and age of onset. Women, systematic learning of ASD knowledge in medical school, successful passing of the physician examination, and rotation in the developmental and behavioral pediatrics (DBP) department significantly influence the levels of ASD awareness and knowledge. It is, therefore, important to strengthen ASD education in medical students at the university level and make rotation in the DBP department a requisite for pediatric trainees.

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25. Tei S, Tanicha M, Itahashi T, Aoki YY, Ohta H, Qian C, Hashimoto RI, Nakamura M, Takahashi H, Kato N, Fujino J. Decision flexibilities in autism spectrum disorder: an fMRI study of moral dilemmas. Soc Cogn Affect Neurosci;2022 (Oct 3);17(10):904-911.

People make flexible decisions across a wide range of contexts to resolve social or moral conflicts. Individuals with autism spectrum disorder (ASD) frequently report difficulties in such behaviors, which hinders the flexibility in changing strategies during daily activities or adjustment of perspective during communication. However, the underlying mechanisms of this issue are insufficiently understood. This study aimed to investigate decision flexibility in ASD using a functional magnetic resonance imaging task that involved recognizing and resolving two types of moral dilemmas: cost-benefit analysis (CBA) and mitigating inevitable misconducts (MIM). The CBA session assessed the participants’ pitting of result-oriented outcomes against distressful harmful actions, whereas the MIM session assessed their pitting of the extenuation of a criminal sentence against a sympathetic situation of defendants suffering from violence or disease. The behavioral outcome in CBA-related flexibility was significantly lower in the ASD group compared to that of the typical development group. In the corresponding CBA contrast, activation in the left inferior frontal gyrus was lower in the ASD group. Meanwhile, in the MIM-related flexibility, there were no significant group differences in behavioral outcome or brain activity. Our findings add to our understanding of flexible decision-making in ASD.

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26. Tesfaye R, Huguet G, Schmilovich Z, Renne T, Loum MA, Douard E, Saci Z, Jean-Louis M, Martineau JL, Whelan R, Desrivieres S, Heinz A, Schumann G, Hayward C, Elsabbagh M, Jacquemont S. Investigating the contributions of circadian pathway and insomnia risk genes to autism and sleep disturbances. Transl Psychiatry;2022 (Oct 3);12(1):424.

Sleep disturbance is prevalent in youth with Autism Spectrum Disorder (ASD). Researchers have posited that circadian dysfunction may contribute to sleep problems or exacerbate ASD symptomatology. However, there is limited genetic evidence of this. It is also unclear how insomnia risk genes identified through GWAS in general populations are related to ASD and common sleep problems like insomnia traits in ASD. We investigated the contribution of copy number variants (CNVs) encompassing circadian pathway genes and insomnia risk genes to ASD risk as well as sleep disturbances in children with ASD. We studied 5860 ASD probands and 2092 unaffected siblings from the Simons Simplex Collection (SSC) and MSSNG database, as well as 7509 individuals from two unselected populations (IMAGEN and Generation Scotland). Sleep duration and insomnia symptoms were parent reported for SSC probands. We identified 335 and 616 rare CNVs encompassing circadian and insomnia risk genes respectively. Deletions and duplications with circadian genes were overrepresented in ASD probands compared to siblings and unselected controls. For insomnia-risk genes, deletions (not duplications) were associated with ASD in both cohorts. Results remained significant after adjusting for cognitive ability. CNVs containing circadian pathway and insomnia risk genes showed a stronger association with ASD, compared to CNVs containing other genes. Circadian genes did not influence sleep duration or insomnia traits in ASD. Insomnia risk genes intolerant to haploinsufficiency increased risk for insomnia when duplicated. CNVs encompassing circadian and insomnia risk genes increase ASD liability with little to no observable impacts on sleep disturbances.

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27. Underwood JFG, DelPozo-Banos M, Frizzati A, Rai D, John A, Hall J. Neurological and psychiatric disorders among autistic adults: a population healthcare record study. Psychol Med;2022 (Oct 3):1-11.

BACKGROUND: Co-occurring psychiatric disorders are common in autism, with previous studies suggesting 54-94% of autistic individuals develop a mental health condition in their lifetime. Most studies have looked at clinically-recruited cohorts, or paediatric cohorts followed into adulthood, with less known about the autistic community at a population level. We therefore studied the prevalence of co-occurring psychiatric and neurological conditions in autistic individuals in a national sample. METHODS: This retrospective case-control study utilised the SAIL Databank to examine anonymised whole population electronic health record data from 2001 to 2016 in Wales, UK (N = 3.6 million). We investigated the prevalence of co-occurring psychiatric and selected neurological diagnoses in autistic adults’ records during the study period using International Classification of Diseases-10 and Read v2 clinical codes compared to general population controls matched for age, sex and deprivation. RESULTS: All psychiatric conditions examined were more common amongst adults with autism after adjusting for age, sex and deprivation. Prevalence of attention-deficit hyperactivity disorder (7.00%), bipolar disorder (2.50%), obsessive-compulsive disorder (3.02%), psychosis (18.30%) and schizophrenia (5.20%) were markedly elevated in those with autism, with corresponding odds ratios 8.24-10.74 times the general population. Depression (25.90%) and anxiety (22.40%) were also more prevalent, with epilepsy 9.21 times more common in autism. CONCLUSIONS: We found that a range of psychiatric conditions were more frequently recorded in autistic individuals. We add to understanding of under-reporting and diagnostic overshadowing in autism. With increasing awareness of autism, services should be cognisant of the psychiatric conditions that frequently co-occur in this population.

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28. Xing M, Zhang Q, Song W. GIGYF1-disturbed IGF-1R recycling: a potential contributor to autism spectrum disorder pathogenesis?. J Clin Invest;2022 (Oct 3);132(19)

Autism spectrum disorder (ASD) is a highly variable and heritable neurodevelopmental disease (NDD) with strong genetic underpinnings. In this issue of the JCI, Chen et al. analyzed 2 previously reported, large-scale sequenced ASD cohorts and reported that GIGYF1 is the second most mutated among ASD risk genes. In this issue of the JCI, Chen et al. used a conditional mouse model combined with molecular technologies based on human genetic analyses to determine the critical role of GIGYF1 in ASD. GIGYF1-deficiency affected the recycling of IGF-1R, thereby suppressing the IGF-1R/ERK signaling pathway. Disruption of GIGYF1 in the developing mouse brain led to social deficits and cognitive impairments. These findings extend our understanding of ASD pathogenesis and provide an avenue for developing potentially effective preventions and treatments for patients with ASD.

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29. Yun M, Kim E, Jung MW. Enhanced fear limits behavioral flexibility in Shank2-deficient mice. Mol Autism;2022 (Oct 3);13(1):40.

BACKGROUND: A core symptom of autism spectrum disorder (ASD) is repetitive and restrictive patterns of behavior. Cognitive inflexibility has been proposed as a potential basis for these symptoms of ASD. More generally, behavioral inflexibility has been proposed to underlie repetitive and restrictive behavior in ASD. Here, we investigated whether and how behavioral flexibility is compromised in a widely used animal model of ASD. METHODS: We compared the behavioral performance of Shank2-knockout mice and wild-type littermates in reversal learning employing a probabilistic classical trace conditioning paradigm. A conditioned stimulus (odor) was paired with an unconditioned appetitive (water, 6 µl) or aversive (air puff) stimulus in a probabilistic manner. We also compared air puff-induced eye closure responses of Shank2-knockout and wild-type mice. RESULTS: Male, but not female, Shank2-knockout mice showed impaired reversal learning when the expected outcomes consisted of a water reward and a strong air puff. Moreover, male, but not female, Shank2-knockout mice showed stronger anticipatory eye closure responses to the air puff compared to wild-type littermates, raising the possibility that the impairment might reflect enhanced fear. In support of this contention, male Shank2-knockout mice showed intact reversal learning when the strong air puff was replaced with a mild air puff and when the expected outcomes consisted of only rewards. LIMITATIONS: We examined behavioral flexibility in one behavioral task (reversal learning in a probabilistic classical trace conditioning paradigm) using one ASD mouse model (Shank2-knockout mice). Thus, future work is needed to clarify the extent to which our findings (that enhanced fear limits behavioral flexibility in ASD) can explain the behavioral inflexibility associated with ASD. Also, we examined only the relationship between fear and behavioral flexibility, leaving open the question of whether abnormalities in processes other than fear contribute to behavioral inflexibility in ASD. Finally, the neurobiological mechanisms linking Shank2-knockout and enhanced fear remain to be elucidated. CONCLUSIONS: Our results indicate that enhanced fear suppresses reversal learning in the presence of an intact capability to learn cue-outcome contingency changes in Shank2-knockout mice. Our findings suggest that behavioral flexibility might be seriously limited by abnormal emotional responses in ASD.

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