1. Al Dera H. Cellular and molecular mechanisms underlying autism spectrum disorders and associated comorbidities: A pathophysiological review. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022; 148: 112688.

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders that develop in early life due to interaction between several genetic and environmental factors and lead to alterations in brain function and structure. During the last decades, several mechanisms have been placed to explain the pathogenesis of autism. Unfortunately, these are reported in several studies and reviews which make it difficult to follow by the reader. In addition, some recent molecular mechanisms related to ASD have been unrevealed. This paper revises and highlights the major common molecular mechanisms responsible for the clinical symptoms seen in people with ASD, including the roles of common genetic factors and disorders, neuroinflammation, GABAergic signaling, and alterations in Ca(+2) signaling. Besides, it covers the major molecular mechanisms and signaling pathways involved in initiating the epileptic seizure, including the alterations in the GABAergic and glutamate signaling, vitamin and mineral deficiency, disorders of metabolism, and autoimmunity. Finally, this review also discusses sleep disorder patterns and the molecular mechanisms underlying them.

Lien vers le texte intégral (Open Access ou abonnement)

2. Chen X, Yao T, Cai J, Fu X, Li H, Wu J. Systemic inflammatory regulators and 7 major psychiatric disorders: A two-sample Mendelian randomization study. Progress in neuro-psychopharmacology & biological psychiatry. 2022; 116: 110534.

Systemic inflammation has been thought to play a considerable part in psychiatric disorders. However, the causal relationships between systemic inflammation and psychiatric disorders and the directions of the causal effects remain elusive and need further investigation. By leveraging the summary statistics of genome-wide association studies, the standard inverse variance weighted method was applied to assess the causal associations among 41 systemic inflammatory regulators and 7 major psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), anorexia nervosa (AN), autism spectrum disorder (ASD), bipolar disorder (BIP), major depression disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia (SCZ), within a two-sample bidirectional Mendelian randomization analysis. Additionally, the weighted median test and the Mendelian randomization pleiotropy residual sum and outlier test were conducted for sensitivity analyses. The results suggested a total of 15 unique systemic inflammatory regulators might be causally associated with disease risk, including 2 for ADHD, 4 for AN, 2 for ASD, 2 for MDD, 2 for OCD, and 5 for SCZ. Among them, the genetically predicted concentration of basic fibroblast growth factor was significantly related to AN at the Bonferroni-corrected threshold (Odds ratio = 0.403, 95% confidence interval = (0.261, 0.622), P = 4.03 × 10(-5)). Furthermore, the concentrations of 9 systemic inflammatory regulators might be influenced by neuropsychiatric disorders, including 2 by ADHD, 2 by BIP, 3 by MDD, and 2 by SCZ, and the causal effects of ASD, AN, and OCD need to be further assessed when more significant genetic variants are identified in the future. Overall, this study provides additional insights into the relationships between systemic inflammation and psychiatric disorders and may provide new clues regarding the aetiology, diagnosis and treatment of psychiatric disorders.

Lien vers le texte intégral (Open Access ou abonnement)

3. Fallahchai R, Fallahi M. Parental stress and dyadic adjustment among parents of children with ASD: Moderating effects of dyadic coping and perceived social support. Research in developmental disabilities. 2022; 123: 104192.

BACKGROUND: Previous studies examining the association between child behavior problems and parental stress have reported mixed results. AIM: This study aimed to explore the associations between child behavior problems and parental stress as well as parental stress and dyadic adjustment, and the moderating roles of stress communication, perceived partner supportive dyadic coping, and perceived social support in the relationship between parental stress and dyadic adjustment. METHODS AND PROCEDURES: Data were derived from 233 parents with at least one child with ASD from Iran. OUTCOMES AND RESULTS: The results demonstrated that child behavior problems were positively associated with parental stress whereas parental stress was negatively associated with dyadic adjustment. Furthermore, stress communication, perceived partner supportive dyadic coping, and perceived social support moderated the relationship between parental stress and dyadic adjustment. CONCLUSIONS: The current findings may attract the attention of clinicians and professionals who work with parents of children with ASD on the effect of stress and how to manage stress on these parents’ dyadic adjustment.

Lien vers le texte intégral (Open Access ou abonnement)

4. Kaiser S, Halvorsen MB. The Strengths and Difficulties Questionnaire self-report-, parent-, and teacher version in children with intellectual and developmental disabilities. Research in developmental disabilities. 2022; 123: 104194.

BACKGROUND: The Strengths and Difficulties Questionnaire (SDQ) is a frequently used behavioral screening instrument. However, its psychometric properties have been rarely examined among children with intellectual and developmental disabilities (IDD). AIMS: The main aims of this study were to examine the internal consistency (i.e., McDonald’s Omega), the convergent validity (by correlating the Total difficulties score with the Aberrant Behavior Checklist [ABC]), the divergent validity (by correlating the Total difficulties score with the Vineland Adaptive Behavior Composite; VABS-II Total) and the factorial validity (by the means of confirmatory factor analyses [CFA]) of the SDQ self-report-, parent-, and teacher version in a sample of children with IDD. METHOD: Participants were 365 children and adolescents (males n = 238; 65 %) aged 4-18 years (M = 10.11, SD = 3.82) referred for a developmental/neurological assessment to the neuropediatric outpatient clinics in the specialist health services. The SDQ was filled inn by 115 children, 337 parents, and 248 teachers. RESULTS: McDonald’s Omega was overall lowest for the self-report version. Correlations of the SDQ Total difficulties score and the ABC subscales were strongest for the parent version. The results of the CFA indicated best model fit for the six-factor model that included a method factor for all three versions of the SDQ, however, model fit was overall not good. CONCLUSIONS: Further research that examines the psychometric properties of the SDQ among multiple informants in large samples of children with IDD is needed.

Lien vers le texte intégral (Open Access ou abonnement)

5. Kohlhoff J, Cibralic S, Hawes DJ, Eapen V. Oxytocin receptor gene (OXTR) polymorphisms and social, emotional and behavioral functioning in children and adolescents: A systematic narrative review. Neuroscience and biobehavioral reviews. 2022; 135: 104573.

This study systematically reviewed available evidence regarding associations between polymorphisms of the oxytocin receptor (OXTR) gene and socio-emotional and behavioral functioning in children and adolescents. The search yielded 69 articles, which were grouped into nine categories: depression, anxiety, and internalizing symptoms, alcohol abuse, borderline personality disorder, conduct disorder symptoms or diagnosis, autism spectrum disorder, attention deficit hyperactivity disorder, early childhood attachment and behavior, pro-social skills, and resilience. Direct and/or gene x environment interactions were identified in over half of the studies. ASD and conduct disorder (including callous unemotional traits) were the diagnoses that were most studied and for which there was the strongest evidence of direct links with OXTR polymorphisms. In most studies identifying gene x environment interactions, the candidate OXTR polymorphism was rs53576. Results suggest that OXTR polymorphisms are associated with social, emotional or behavioural functioning in children and adolescents. The mixed findings do, however, highlight the need for further research.

Lien vers le texte intégral (Open Access ou abonnement)

6. Landes SD, Wilmoth JM, McDonald KE, Smith AN. Racial-ethnic inequities in age at death among adults with/without intellectual and developmental disability in the United States. Preventive medicine. 2022; 156: 106985.

To identify potential differences in racial-ethnic inequities in mortality between adults with/without intellectual and developmental disability, we compared patterns in age at death by race-ethnic status among adults who did/did not have intellectual and developmental disability reported on their death certificate in the United States. Data were from the 2005-2017 U.S. Multiple Cause-of-Death Mortality files. Average age at death by racial-ethnic status was compared between adults, age 18 and older, with/without different types of intellectual and developmental disability reported on their death certificate (N = 32,760,741). A multiple descent pattern was observed among adults without intellectual or developmental disability, with age at death highest among Whites, followed by Asians, Hispanics and Blacks, then American Indians. In contrast, a bifurcated pattern was observed among adults with intellectual disability, with age at death highest among Whites, but lower and similar among all racial-ethnic minority groups. The severity of racial-ethnic inequities in age at death was most pronounced among adults with cerebral palsy. Policy makers and public health experts should be aware that racial-ethnic inequities are different for adults with intellectual and developmental disability – all minorities with intellectual and developmental disability are at greater risk of premature death than their White counterparts.

Lien vers le texte intégral (Open Access ou abonnement)

7. Macinska S, Jellema T. Memory for facial expressions on the autism spectrum: The influence of gaze direction and type of expression. Autism research : official journal of the International Society for Autism Research. 2022.

Face memory research in autism has largely neglected memory for facial expressions, in favor of memory for identity. This study in three experiments examined the role of gaze direction and type of expression on memory for facial expressions in relation to the autism spectrum. In the learning phase, four combinations of facial expressions (joy/anger) and gaze direction (toward/away), displayed by 16 different identities, were presented. In a subsequent surprise test the same identities were presented displaying neutral expressions, and the expression of each identity had to be recalled. In Experiment 1, typically-developed (TD) individuals with low and high Autism Quotient (AQ) scores were tested with three repetitions of each emotion/gaze combination, which did not produce any modulations. In Experiment 2, another group of TD individuals with low and high AQ scores were tested with eight repetitions, resulting in a « happy advantage » and a « direct gaze advantage », but no interactions. In Experiment 3, individuals with high-functioning autism (HFA) and a matched TD group were tested using eight repetitions. The HFA group revealed no emotion or gaze effects, while the matched TD group showed both a happy and a direct gaze advantage, and again no interaction. The results suggest that in autistic individuals the memory for facial expressions is intact, but is not modulated by the person’s expression type and gaze direction. We discuss whether anomalous implicit learning of facial cues could have contributed to these findings, its relevance for social intuition, and its possible contribution to social deficits in autism. LAY SUMMARY: It has often been found that memory for someone’s face (facial identity) is less good in autism. However, it is not yet known whether memory for someone’s facial expression is also less good in autism. In this study, the memory for expressions of joy and anger was investigated in typically-developed (TD) individuals who possessed either few or many autistic-like traits (Experiments 1 and 2), and in individuals with high-functioning autism (Experiment 3). The gaze direction was also varied (directed either toward, or away from, the observer). We found that TD individuals best remembered expressions of joy, and remembered expressions of both joy and anger better when the gaze was directed at them. These effects did not depend on the extent to which they possessed autistic-like traits. Autistic participants remembered the facial expression of a previously encountered person as good as TD participants did. However, in contrast to the TD participants, the memory of autistic participants was not influenced by the expression type and gaze direction of the previously encountered persons. We discuss whether this may lead to difficulties in the development of social intuition, which in turn could give rise to difficulties in social interaction that are characteristic for autism.

Lien vers le texte intégral (Open Access ou abonnement)

8. Mira-Bontenbal H, Tan B, Gontan C, Goossens S, Boers RG, Boers JB, Dupont C, van Royen ME, WFJ IJ, French P, Bedalov A, Gribnau J. Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells. Stem cell reports. 2022; 17(3): 693-706.

Rett syndrome may be treated by reactivating the silent copy of Mecp2 from the inactive X chromosome in female cells. Most studies that model Mecp2 reactivation have used mouse fibroblasts rather than neural cells, which would be critical for phenotypic reversal, and rely on fluorescent reporters that lack adequate sensitivity. Here, we present a mouse model based on a dual bioluminescent and fluorescent reporter to assess the level of reactivation of Mecp2 and the inactive X chromosome by treating neural stem cells with 5-azacytidine and Xist knockdown. We show that reactivation of Mecp2 and other X-linked genes correlates with CpG density, with distance from escapees, and, very strongly, with the presence of short interspersed nuclear elements. In addition, X-linked genes reactivated in neural stem cells overlap substantially with early reactivating genes by induced pluripotent stem cell reprogramming of fibroblasts or neuronal progenitors, indicating that X chromosome reactivation follows similar paths regardless of the technique or cell type used.

Lien vers le texte intégral (Open Access ou abonnement)

9. Neul JL, Percy AK, Benke TA, Berry-Kravis EM, Glaze DG, Peters SU, Jones NE, Youakim JM. Design and outcome measures of LAVENDER, a phase 3 study of trofinetide for Rett syndrome. Contemporary clinical trials. 2022; 114: 106704.

INTRODUCTION: Rett syndrome (RTT) is a debilitating neurodevelopmental disorder with no approved treatments. Trofinetide is a synthetic analog of glycine-proline-glutamate, the N-terminal tripeptide of insulin-like growth factor 1. In a phase 2, placebo-controlled trial in 82 females with RTT aged 5-15 years, a significant (p ≤ 0.042) improvement over placebo was observed with the highest trofinetide dose (200 mg/kg twice daily [BID]) on three measures: Rett Syndrome Behaviour Questionnaire (RSBQ), Clinical Global Impression-Improvement (CGI-I), and RTT-Clinician Domain Specific Concerns-Visual Analog Scale (RTT-DSC-VAS). Trofinetide was well tolerated at all doses (50, 100, and 200 mg/kg BID). A phase 3 trial utilizing disease-specific and novel scales was designed to investigate the efficacy and safety of trofinetide in girls and women with RTT. METHODS: This 12-week, double-blind, randomized, placebo-controlled study (LAVENDER; NCT04181723) will evaluate trofinetide in 187 females, aged 5-20 years, with RTT. Co-primary endpoints are the RSBQ and CGI-I scales. Clinical domains of the CGI-I include communication, ambulation, hand use, seizures, attentiveness, and social (eye contact) and autonomic (breathing) aspects. Secondary endpoints will leverage four novel RTT-specific clinician ratings (derived from the RTT-DSC-VAS) of hand function, ambulation, ability to communicate, and verbal communication, and existing scales, to evaluate other core symptoms of RTT, quality of life and caregiver burden. A 40-week, open-label extension study will follow. DISCUSSION: This study was designed using disease-specific scales optimized to demonstrate changes in core symptoms of RTT and may provide the first phase 3 data demonstrating drug efficacy in individuals with RTT. TRIAL REGISTRATION: Clinicaltrials.govNCT04181723.

Lien vers le texte intégral (Open Access ou abonnement)

10. Taylor SC, Smernoff ZL, Rajan M, Steeman S, Gehringer BN, Dow HC, Barzilay R, Rader DJ, Bucan M, Almasy L, Brodkin ES. Investigating the relationships between resilience, autism-related quantitative traits, and mental health outcomes among adults during the COVID-19 pandemic. Journal of psychiatric research. 2022; 148: 250-7.

Resilience is a dynamic process through which people adjust to adversity and buffer anxiety and depression. The COVID-19 global pandemic has introduced a shared source of adversity for people across the world, with detrimental implications for mental health. Despite the pronounced vulnerability of autistic adults to anxiety and depression during the COVID-19 pandemic, relationships among autism-related quantitative traits, resilience, and mental health outcomes have not been examined. As such, we aimed to describe the relationships between these traits in a sample enriched in autism spectrum-related quantitative traits during the COVID-19 pandemic. We also aimed to investigate the impact of demographic and social factors on these relationships. Across three independent samples of adults, we assessed resilience factors, autism-related quantitative traits, anxiety symptoms, and depression symptoms during the COVID-19 pandemic. One sample (recruited via the Autism Spectrum Program of Excellence, n = 201) was enriched for autism traits while the other two (recruited via Amazon Mechanical Turk, n = 624 and Facebook, n = 929) drew from the general population. We found resilience factors and quantitative autism-related traits to be inversely related, regardless of the resilience measure used. Additionally, we found that resilience factors moderate the relationship between autism-related quantitative traits and depression symptoms such that resilience appears to be protective. Across the neurodiversity spectrum, resilience factors may be targets to improve mental health outcomes. This approach may be especially important during the ongoing COVID-19 pandemic and in its aftermath.

Lien vers le texte intégral (Open Access ou abonnement)

11. Tseng A, Camchong J, Francis SM, Mueller BA, Lim KO, Conelea CA, Jacob S. Differential extrinsic brain network connectivity and social cognitive task-specific demands in Autism Spectrum Disorder (ASD). Journal of psychiatric research. 2022; 148: 230-9.

Few studies have used task-based functional connectivity (FC) magnetic resonance imaging to examine emotion-processing during the critical neurodevelopmental period of adolescence in Autism Spectrum Disorders (ASDs). Moreover, task designs with pervasive confounds (e.g., lack of appropriate controls) persist because they activate neural circuits of interest reliably. As an alternative approach to « subtracting » activity from putative control conditions, we propose examining FC across an entire task run. By pivoting our analysis and interpretation of existing paradigms, we may better understand neural response to non-focal instances of socially-relevant stimuli that approximate real-world experiences more closely. Hence, using two well-established affective tasks (face-viewing, face-matching) with diverging social-cognitive demands, we investigated extrinsic FC from amygdala (AMG) and fusiform gyrus (FG) seeds in typically-developing (TD; N = 17) and ASD (N = 17) male adolescents (10-18 yo) and clinical correlations (Social Communication Questionnaire; SCQ) of group FC differences. Participant data (4TD, 6ASD) with excessive head-motion were excluded from final analysis. Direct between-group comparisons revealed significant differences between groups for neural response but not task performance (accuracy, reaction time). During face-viewing, we found greater FC from AMG and FG seeds for ASD participants (ASD > TD) in regions involved in the Default Mode and Fronto-Parietal Task Control Networks. During face-matching, we found greater FC from AMG and FG seeds for TD participants (TD > ASD), in regions associated with the Salience, Dorsal Attention, and Somatosensory Networks. SCQ scores correlated positively with regions with group differences on the face-viewing task and negatively with regions identified for the face-matching task. Task-dependent group differences in FC despite comparable behavioral performance suggest that high-functioning ASD may wield compensatory strategies; clinically-correlated FC patterns may associate with differential task-demands, ecological validity, and context-dependent processing. Employing this novel approach may further the development of targeted therapeutic interventions informed by individual differences in the highly heterogeneous ASD population.

Lien vers le texte intégral (Open Access ou abonnement)