1. Benítez-Burraco A, Progovac L. Language evolution: examining the link between cross-modality and aggression through the lens of disorders. Philosophical transactions of the Royal Society of London Series B, Biological sciences. 2021; 376(1824): 20200188.

We demonstrate how two linguistic phenomena, figurative language (implicating cross-modality) and derogatory language (implicating aggression), both demand a precise degree of (dis)inhibition in the same cortico-subcortical brain circuits, in particular cortico-striatal networks, whose connectivity has been significantly enhanced in recent evolution. We examine four cognitive disorders/conditions that exhibit abnormal patterns of (dis)inhibition in these networks: schizophrenia (SZ), autism spectrum disorder (ASD), synaesthesia and Tourette’s syndrome (TS), with the goal of understanding why the two phenomena altered reactive aggression and altered cross-modality cluster together in these disorders. Our proposal is that enhanced cross-modality (necessary to support language, in particular metaphoricity) was a result, partly a side-effect, of self-domestication (SD). SD targeted the taming of reactive aggression, but reactive impulses are controlled by the same cortico-subcortical networks that are implicated in cross-modality. We further add that this biological process of SD did not act alone, but was engaged in an intense feedback loop with the cultural emergence of early forms of language/grammar, whose high degree of raw metaphoricity and verbal aggression also contributed to increased brain connectivity and cortical control. Consequently, in conjunction with linguistic expressions serving as approximations/’fossils’ of the earliest stages of language, these cognitive disorders/conditions serve as confident proxies of brain changes in language evolution, helping us reconstruct certain crucial aspects of early prehistoric languages and cognition, as well as shed new light on the nature of the disorders. This article is part of the theme issue ‘Reconstructing prehistoric languages’.

Lien vers le texte intégral (Open Access ou abonnement)

2. Brand JS, Lawlor DA, Larsson H, Montgomery S. Association Between Hypertensive Disorders of Pregnancy and Neurodevelopmental Outcomes Among Offspring. JAMA pediatrics. 2021; 175(6): 577-85.

IMPORTANCE: Hypertensive disorders of pregnancy (HDP) have been associated with poorer neurodevelopmental outcomes in offspring, but the role of familial confounding in these associations is unclear. OBJECTIVE: To investigate associations of maternal HDP with risks in offspring of autism spectrum disorders (ASDs), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID), as well as variation in overall cognitive performance in offspring. DESIGN, SETTING, AND PARTICIPANTS: This Swedish register-based study used data from a birth cohort divided into 1 085 024 individuals born between 1987 and 1996 and followed up until December 31, 2014, and 285 901 men born between 1982 and 1992 who attended assessments for military conscription, including a cognitive function test. Statistical analysis was performed from April 1, 2019, to June 1, 2020. EXPOSURES: Diagnoses of HDP, which were provided by the Medical Birth Register. MAIN OUTCOMES AND MEASURES: Diagnoses of ASDs, ADHD, and ID were extracted from the National Patient Register. Cognitive function was assessed using written tests and summarized as a single 9-point score. Whole-cohort and within-sibship analyses were performed; the latter accounted for unmeasured familial confounding factors shared by siblings. RESULTS: The study included 1 085 024 individuals (556 912 male participants [51.3%]) born between 1987 and 1996 and 285 901 men born between 1982 and 1992 who attended assessments for military conscription. The prevalence of maternal HDP was 4.0% in the 1987-1996 birth cohort (n = 42 980) and 5.1% in the military conscription cohort (n = 14 515). A total of 15 858 participants received a diagnosis of ASD, 36 852 received a diagnosis of ADHD, and 8454 received a diagnosis of ID. The mean (SD) cognitive score among the men in the conscription cohort was 5.1 (1.9). In whole-cohort analyses with multivariable adjustment, HDP were associated with offspring ASDs (hazard ratio [HR], 1.22; 95% CI, 1.13-1.31), ADHD (HR, 1.10; 95% CI, 1.05-1.16), and ID (HR, 1.39; 95% CI, 1.27-1.53). Analyses comparing siblings discordant for HDP were less statistically powered but indicated estimates of similar magnitude for ASDs (HR, 1.19; 95% CI, 1.00-1.42) and possibly ADHD (HR, 1.09; 95% CI, 0.95-1.24), but not for ID (HR, 1.04; 95% CI, 0.83-1.29). Hypertensive disorders of pregnancy were associated with somewhat lower cognitive scores in whole-cohort analysis (mean difference comparing offspring exposed with those unexposed, -0.10; 95% CI, -0.13 to -0.07), but in within-sibship analysis, the association was null (mean difference, 0.00; 95% CI, -0.09 to 0.08). CONCLUSIONS AND RELEVANCE: The study results suggest that HDP are associated with small increased risks of ASDs and possibly ADHD in offspring, whereas associations with ID and cognitive performance are likely confounded by shared familial (environmental or genetic) factors.

Lien vers le texte intégral (Open Access ou abonnement)

3. Contestabile A, Casarotto G, Girard B, Tzanoulinou S, Bellone C. Deconstructing the contribution of sensory cues in social approach. The European journal of neuroscience. 2021; 53(9): 3199-211.

Social interaction is a complex and highly conserved behavior that safeguards survival and reproductive success. Although considerable progress has been made regarding our understanding of same-sex conspecific and non-aggressive interactions, questions regarding the precise contribution of sensory cues in social approach and their specific neurobiological correlates remain open. Here, by designing a series of experiments with diverse social and object stimuli manipulations in custom-made enclosures, we first sought to deconstruct key elements of social preference as assessed by the three-chamber task. Our results highlight the importance of social olfactory cues in approach behavior. Subsequently, we interrogated whether a social odor would activate dopaminergic neurons of the Ventral Tegmental Area in the same way as a juvenile conspecific would. Employing in vivo recordings in freely behaving mice, we observed an increase of the firing only during the transition toward the juvenile mouse and not during the transition toward the object impregnated with social odor, suggesting that these two experiences are distinct and can be differentiated at the neuronal level. Moreover, using a four-choice task, we further showed that mice prefer to explore complex social stimuli compared to isolated sensory cues. Our findings offer insights toward understanding how different sensory modalities contribute to the neurobiological basis of social behavior which can be essential when studying social deficits observed in autism-, depression-, anxiety-, or schizophrenia-related mouse models.

Lien vers le texte intégral (Open Access ou abonnement)

4. Cuddapah VA, Dubbs HA, Adang L, Kugler SL, McCormick EM, Zolkipli-Cunningham Z, Ortiz-González XR, McCormack S, Zackai E, Licht DJ, Falk MJ, Marsh ED. Understanding the phenotypic spectrum of ASXL-related disease: Ten cases and a review of the literature. American journal of medical genetics Part A. 2021; 185(6): 1700-11.

Over the past decade, pathogenic variants in all members of the ASXL family of genes, ASXL1, ASXL2, and ASXL3, have been found to lead to clinically distinct but overlapping syndromes. Bohring-Opitz syndrome (BOPS) was first described as a clinical syndrome and later found to be associated with pathogenic variants in ASXL1. This syndrome is characterized by developmental delay, microcephaly, characteristic facies, hypotonia, and feeding difficulties. Subsequently, pathogenic variants in ASXL2 were found to lead to Shashi-Pena syndrome (SHAPNS) and in ASXL3 to lead to Bainbridge-Ropers syndrome (BRPS). While SHAPNS and BRPS share many core features with BOPS, there also seem to be emerging clear differences. Here, we present five cases of BOPS, one case of SHAPNS, and four cases of BRPS. By adding our cohort to the limited number of previously published patients, we review the overlapping features of ASXL-related diseases that bind them together, while focusing on the characteristics that make each neurodevelopmental syndrome unique. This will assist in diagnosis of these overlapping conditions and allow clinicians to more comprehensively counsel affected families.

Lien vers le texte intégral (Open Access ou abonnement)

5. Delehanty AD, Wetherby AM. Rate of Communicative Gestures and Developmental Outcomes in Toddlers With and Without Autism Spectrum Disorder During a Home Observation. American journal of speech-language pathology. 2021; 30(2): 649-62.

Purpose Most toddlers with autism spectrum disorder and other developmental delays receive early intervention at home and may not participate in a clinic-based communication evaluation. However, there is limited research that has prospectively examined communication in very young children with and without autism in a home-based setting. This study used granular observational coding to document the communicative acts performed by toddlers with autism, developmental delay, and typical development in the home environment. Method Children were selected from the archival database of the FIRST WORDS Project (N = 211). At approximately 20 months of age, each child participated in everyday activities with a caregiver during an hour-long, video-recorded, naturalistic home observation. Inventories of unique gestures, rates per minute, and proportions of types of communicative acts and communicative functions were coded and compared using a one-way analysis of variance. Concurrent and prospective relationships between rate of communication and measures of social communication, language development, and autism symptoms were examined. Results A total of 40,738 communicative acts were coded. Children with autism, developmental delay, and typical development used eight, nine, and 12 unique gestures on average, respectively. Children with autism used deictic gestures, vocalizations, and communicative acts for behavior regulation at significantly lower rates than the other groups. Statistically significant correlations were observed between rate of communication and several outcome measures. Conclusion Observation of social communication in the natural environment may improve early identification of children with autism and communication delays, complement clinic-based assessments, and provide useful information about a child’s social communication profile and the family’s preferred activities and intervention priorities. Supplemental Material https://doi.org/10.23641/asha.14204522.

Lien vers le texte intégral (Open Access ou abonnement)

6. Fukushi D, Inaba M, Katoh K, Suzuki Y, Enokido Y, Nomura N, Tokita Y, Hayashi S, Mizuno S, Yamada K, Wakamatsu N. R3HDM1 haploinsufficiency is associated with mild intellectual disability. American journal of medical genetics Part A. 2021; 185(6): 1776-86.

R3HDM1 (R3H domain containing 1) is an uncharacterized RNA-binding protein that is highly expressed in the human cerebral cortex. We report the first case of a 12-year-old Japanese male with haploinsufficiency of R3HDM1. He presented with mild intellectual disability (ID) and developmental delay. He had a pericentric inversion of 46,XY,inv(2)(p16.1q21.3)dn with breakpoints in intron 19 of R3HDM1 (2q21.3) and the intergenic region (2p16.1). The R3HDM1 levels in his lymphoblastoid cells were reduced to approximately half that of the healthy controls. However, the expression of MIR128-1, in intron 18 of R3HDM1, was not affected via the pericentric inversion. Knockdown of R3HDM1 in mouse embryonic hippocampal neurons suppressed dendritic growth and branching. Notably, the Database of Genomic Variants reported the case of a healthy control with a 488-kb deletion that included both R3HDM1 and MIR128-1. miR-128 has been reported to inhibit dendritic growth and branching in mouse brain neurons, which directly opposes the novel functions of R3HDM1. These findings suggest that deleting both R3HDM1 and MIR128-1 alleviates the symptoms of the disease caused by loss-of-function mutations in R3HDM1 only. Thus, haploinsufficiency of R3HDM1 in the patient may be the cause of the mild ID due to the genetic imbalance between R3HDM1 and MIR128-1.

Lien vers le texte intégral (Open Access ou abonnement)

7. Garza-Mayén G, Ulloa-Avilés V, Villarroel CE, Navarrete-Meneses P, Lieberman-Hernández E, Abreu-González M, Márquez-Quiroz L, Azotla-Vilchis C, Cifuentes-Goches JC, Del Castillo-Ruiz V, Durán-McKinster C, Pérez-Vera P, Salas-Labadía C. UPD(14)mat and UPD(14)mat in concomitance with mosaic small supernumerary marker chromosome 14 in two new patients with Temple syndrome. European journal of medical genetics. 2021; 64(5): 104199.

Temple syndrome (TS14) can be originated by maternal uniparental disomy (UPD(14)mat), paternal deletion, or epimutation, leading to disturbances in 14q32.2 imprinted region. The most frequent phenotypic manifestations are prenatal and postnatal growth failure, hypotonia, developmental delay, small hands/feet, precocious puberty, and truncal obesity. However, the diagnosis can be challenging due to the clinical overlap with other imprinting disorders such as Silver-Russell or Prader-Willi syndromes. Although rare, TS14 has been also reported in patients with concomitant UPD(14)mat and mosaic trisomy 14. In the present report, the clinical and genetic profiles of two new patients with TS14 are described. SNParray and MS-MLPA, allowed the determination of segmental UPD(14)mat and the hypomethylation of MEG3 gene. Additionally, in one of our patients we also observed by cytogenetics a small supernumerary marker chromosome that led to partial trisomy 14 in mosaic. Only few patients with concomitant UPD(14)mat and mosaic partial trisomy 14 have been reported. Our patients share cardinal TS14 phenotypic features that are associated to the genetic abnormalities detected; however, we also observed some clinical features such as fatty liver disease that had not previously been reported as part of this syndrome. The detailed clinical, cytogenetical and molecular description of these two new patients, contributes to a more accurately delineation of this syndrome.

Lien vers le texte intégral (Open Access ou abonnement)

8. Hall SS, Riley MJ, Weston RN, Lepage JF, Hong DS, Jo B, Hallmayer J, Reiss AL. Effects of X Chromosome Monosomy and Genomic Imprinting on Observational Markers of Social Anxiety in Prepubertal Girls with Turner Syndrome. Journal of autism and developmental disorders. 2022; 52(1): 16-27.

Previous studies have suggested that girls with Turner syndrome (TS) exhibit symptoms of social anxiety during interactions with others. However, few studies have quantified these behaviors during naturalistic face-to-face social encounters. In this study, we coded observational markers of social anxiety in prepubertal girls with TS and age-matched controls during a 10-min social encounter with an unfamiliar examiner. Results showed that girls with TS exhibited significantly higher levels of gaze avoidance compared to controls. Impairments in social gaze were particularly increased in girls with a maternally retained X chromosome (Xm), suggesting a genomic imprinting effect. These data indicate that social gaze avoidance may be a critical behavioral marker for identifying early social dysfunction in young girls with TS.

Lien vers le texte intégral (Open Access ou abonnement)

9. Hayashi W, Hanawa Y, Yuriko I, Aoyagi K, Saga N, Nakamura D, Iwanami A. ASD symptoms in adults with ADHD: a preliminary study using the ADOS-2. European archives of psychiatry and clinical neuroscience. 2022; 272(2): 217-32.

Attention-deficit/hyperactivity disorder (ADHD) has long been regarded as disparate and mutually exclusive to autism spectrum disorder (ASD) in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-III-R and DSM-IV. However, this idea has become obsolete due to a growing body of evidence suggesting numerous phenotypic and genetic similarities between ADHD and ASD. ASD symptoms or autistic traits in individuals with ADHD have been examined; however, most studies were conducted on children and relied on self- or parent- reports. ASD symptoms assessed with more direct, objective measures, such as the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) in adults with ADHD, remain understudied. In the present study, we used the ADOS-2 to evaluate ASD symptoms in adults with ADHD who were not clinically diagnosed with ASD. Fifty-six adults (mean age 33.9 years, 35 males, intelligence quotient ≥ 85), who were diagnosed with ADHD based on the DSM-5 criteria, completed Module 4 of the ADOS-2. Autism Spectrum Quotient (AQ), Conners’ Adult ADHD Rating Scale (CAARS), and Wechsler Adult Intelligence Scale (WAIS)-III were also administered to assess self-rated ASD symptoms, ADHD symptoms, and intelligence, respectively. Overall, 23.3% of participants met the ASD diagnostic classification on the ADOS-2. Social reciprocal interaction scores tended to be higher, while restricted and repetitive behavior scores were low. The scoring patterns and possible overlapping and differing phenotypic characteristics of ADHD and ASD are discussed.

Lien vers le texte intégral (Open Access ou abonnement)

10. Hodge MA, Boulton KA, Sutherland R, Barnett D, Bennett B, Chan E, Cramsie J, Drevensek S, Eapen V, Ganesalingam K, Masi A, Ong N, Williamsz M, Guastella AJ, Silove N. Predictors of adaptive functioning in preschool aged children with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research. 2021; 14(7): 1444-55.

Difficulties in adaptive functioning are common in autism spectrum disorder (ASD) and contribute to negative outcomes across the lifespan. Research indicates that cognitive ability is related to degree of adaptive functioning impairments, particularly in young children with ASD. However, the extent to which other factors, such as socioeconomic status (SES) and ASD symptom severity, predict impairments in adaptive functioning remains unclear. The goal of this study was to determine the extent to which SES, ASD symptom severity, and cognitive ability contribute to variability in domain-specific and global components of adaptive functioning in preschool-aged children with ASD. Participants were 99 preschool-aged children (2-6 years) with ASD who attended a tertiary diagnostic service. Results demonstrate that cognitive ability accounted for a significant proportion of variance in domain-specific and global components of adaptive functioning, with higher cognitive ability predicting better adaptive functioning. Results also demonstrate that SES accounted for some variability in domain-specific communication skills and global adaptive functioning when compared to basic demographic factors alone (age and gender). By contrast, ASD symptom severity did not predict variability in domain-specific or global components of adaptive functioning. These findings provide support for a relationship between cognitive ability and adaptive functioning in preschool-aged children with ASD and help to explain specific contributions of verbal and nonverbal ability to adaptive functioning; from this, we can better understand which children are likely to show the greatest degree of impairments across components of adaptive functioning early in development. LAY SUMMARY: People with autism often have difficulties with everyday communication, daily living, and social skills, which are also called adaptive functioning skills. This study investigated factors that might be related to these difficulties in preschoolers with autism. We found that better cognitive ability, but not autism symptoms, were associated with better adaptive functioning. This suggests that interventions for young children with autism should take into account cognitive ability to better understand which children are likely to have difficulties with adaptive functioning.

Lien vers le texte intégral (Open Access ou abonnement)

11. Iannuzzi D, Hall M, Oreskovic NM, Aryee E, Broder-Fingert S, Perrin JM, Kuhlthau KA. Emergency Department Utilization of Adolescents and Young Adults with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2022; 52(2): 617-22.

This study examined emergency department (ED) utilization by adolescents and young adults, 12-30 years of age (AYA) with autism spectrum disorder (ASD) using the 2016 Healthcare Cost and Utilization Project/National Emergency Department Sample (HCUP/NEDS). We investigated the principal reason for an ED visit, presence of an ambulatory care sensitive condition (ACSC), and likelihood of hospital admission following ED encounter in ASD and Non-ASD cohorts. The ASD cohort had a higher proportion of ED visits for ACSC diagnoses as compared to the Non-ASD cohort. In addition, the likelihood of admission following an ED visit in the ASD cohort was 3.7 times greater than in the Non-ASD cohort.

Lien vers le texte intégral (Open Access ou abonnement)

12. Jedrzejewska A, Dewey J. Camouflaging in Autistic and Non-autistic Adolescents in the Modern Context of Social Media. Journal of autism and developmental disorders. 2022; 52(2): 630-46.

Camouflaging is described as a set of strategies used to prevent others from noticing one’s social difficulties. Research indicates heightened levels of camouflaging behaviours in the adult autistic population. To extend understanding of camouflaging in adolescents, this mixed-methods study explored camouflaging behaviours in offline and online contexts with 40 autistic and 158 non-autistic adolescents. At the quantitative phase, participants completed measures of camouflaging behaviours (online vs offline) and measures of social media use. Following this, six autistic adolescents participated in semi-structured interviews. Findings indicate that in the offline context, autistic adolescents camouflage more than non-autistic adolescents. Online, autistic participants camouflage less than they do offline, and females camouflage more than males. Implications for research and theory are discussed.

Lien vers le texte intégral (Open Access ou abonnement)

13. Lin M, Xue H, Wang Y, Huang H, Fu M, Guo N, Xu L. [Value of copy number variation analysis and chromosomal karyotyping for the diagnosis of children with intellectual disability/developmental delay]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2021; 38(3): 228-31.

OBJECTIVE: To assess the value of copy number variations (CNVs) and chromosomal karyotyping analysis for patients with intellectual disability/developmental delay (ID/DD). METHODS: Chromosomal karyotype analysis was applied to 530 children diagnosed with ID/DD. Single nucleotide polymorphism array (SNP-array) was further applied for 120 children with unknown etiology. RESULTS: Among the 530 children with ID/DD, 104 (19.62%) were detected with chromosomal abnormalities. For the 120 children analyzed by SNP-array, 44 (36.67%) were detected with CNVs, among which 20 were predicted as pathogenic, 6 as likely pathogenic, 10 as variants of unknown significance, 7 as likely benign,and 1 as loss of heterozygosity. CONCLUSION: SNP-array can facilitate delineation of the etiology of patients with ID/DD, which may provide a basis for their prognosis, consultation and clinical intervention.

Lien vers le texte intégral (Open Access ou abonnement)

14. Moeinian P, Alizadeh R, Hakim Shooshtari M, Mozdarani H, Yousefi Laksari F, Taherizadeh F, Mortazavi Z, Akouchekian M. Assessment of Peripheral Blood Lymphocytes in Parents of Autistic Children by Cytokinesis Block Micronucleus Assay. Neuromolecular medicine. 2021; 23(4): 466-70.

Autism spectrum disorders are neurodevelopmental complex diseases with causative de-novo and inherited genetic factors. They include a range of cognitive and behavioral conditions such as pervasive developmental disorder, Asperger’s syndrome, and autism. Cytokinesis-block micronucleus assay, as a cytogenetic study has been considered as one of the indicators of chromosomal damage in peripheral blood. This study aimed to investigate the frequency of micronucleus (MN) in peripheral blood lymphocytes of parents with autistic children. The study was case-control and the cases were parents of autistic children referring to the psychiatric department of the Ali-Asghar Hospital of Tehran. The total number of samples was 60 cases and 30 controls. The results showed that autistic children’s parents had a significant increase in MN frequency in binucleated lymphocytes. Further researches are suggested to analyze the environmental and genetic reasons for MN increase in autistic children parents.

Lien vers le texte intégral (Open Access ou abonnement)

15. Parker TC, Crowley MJ, Naples AJ, Rolison MJ, Wu J, Trapani JA, McPartland JC. The N170 event-related potential reflects delayed neural response to faces when visual attention is directed to the eyes in youths with ASD. Autism research : official journal of the International Society for Autism Research. 2021; 14(7): 1347-56.

Atypical neural response to faces is thought to contribute to social deficits in autism spectrum disorder (ASD). Compared to typically developing (TD) controls, individuals with ASD exhibit delayed brain responses to upright faces at a face-sensitive event-related potential (ERP), the N170. Given observed differences in patterns of visual attention to faces, it is not known whether slowed neural processing may simply reflect atypical looking to faces. The present study manipulated visual attention to facial features to examine whether directed attention to the eyes normalizes N170 latency in ASD. ERPs were recorded in 30 children and adolescents with ASD as well as 26 TD children and adolescents. Results replicated prior findings of shorter N170 latency to the eye region of the face in TD individuals. In contrast, those with ASD did not demonstrate modulation of N170 latency by point of regard to the face. Group differences in latency were most pronounced when attention was directed to the eyes. Results suggest that well-replicated findings of N170 delays in ASD do not simply reflect atypical patterns of visual engagement with experimental stimuli. These findings add to a body of evidence indicating that N170 delays are a promising marker of atypical neural response to social information in ASD. LAY SUMMARY: This study looks at how children’s and adolescents’ brains respond when looking at different parts of a face. Typically developing children and adolescents processed eyes faster than other parts of the face, whereas this pattern was not seen in ASD. Children and adolescents with ASD processed eyes more slowly than typically developing children. These findings suggest that observed inefficiencies in face processing in ASD are not simply reflective of failure to attend to the eyes.

Lien vers le texte intégral (Open Access ou abonnement)

16. Petruccelli M, Ramella L, Schaefer AJ, Sheldrick RC, Carter AS, Eisenhower A, Broder-Fingert S, Mackie TI. A Taxonomy of Reported Harms in Pediatric Autism Spectrum Disorder Screening: Provider and Parent Perspectives. Journal of autism and developmental disorders. 2022; 52(2): 647-73.

The U.S. Preventive Services Task Force (USPSTF) report on screening for Autism Spectrum Disorder (ASD) highlighted the need for research that examines the harms potentially associated with screening so as to assess the overall net benefit of universal screening. In response, this study engages qualitative, semi-structured interviews to generate a taxonomy outlining potential harms reported by parents and providers (pediatricians and Early Intervention providers) with experience in screening young children for ASD. Potential harms emerged including: physical, psychological, social, logistical/financial, opportunity cost, attrition, and exacerbation of non-targeted disparities. Respondents reported harms being experienced by the toddlers, parents, and providers. The harms reported highlight opportunities for providers to offer resources that mitigate the potential for these unintended consequences.

Lien vers le texte intégral (Open Access ou abonnement)

17. Pijuan J, Ortigoza-Escobar JD, Ortiz J, Alcalá A, Calvo MJ, Cubells M, Hernando-Davalillo C, Palau F, Hoenicka J. PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder. Autism research : official journal of the International Society for Autism Research. 2021; 14(6): 1088-100.

Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype-phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy-number variant and whole-exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine-rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient’s fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. LAY SUMMARY: Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD.

Lien vers le texte intégral (Open Access ou abonnement)

18. Postema MC, Hoogman M, Ambrosino S, Asherson P, Banaschewski T, Bandeira CE, Baranov A, Bau CHD, Baumeister S, Baur-Streubel R, Bellgrove MA, Biederman J, Bralten J, Brandeis D, Brem S, Buitelaar JK, Busatto GF, Castellanos FX, Cercignani M, Chaim-Avancini TM, Chantiluke KC, Christakou A, Coghill D, Conzelmann A, Cubillo AI, Cupertino RB, de Zeeuw P, Doyle AE, Durston S, Earl EA, Epstein JN, Ethofer T, Fair DA, Fallgatter AJ, Faraone SV, Frodl T, Gabel MC, Gogberashvili T, Grevet EH, Haavik J, Harrison NA, Hartman CA, Heslenfeld DJ, Hoekstra PJ, Hohmann S, Høvik MF, Jernigan TL, Kardatzki B, Karkashadze G, Kelly C, Kohls G, Konrad K, Kuntsi J, Lazaro L, Lera-Miguel S, Lesch KP, Louza MR, Lundervold AJ, Malpas CB, Mattos P, McCarthy H, Namazova-Baranova L, Nicolau R, Nigg JT, Novotny SE, Oberwelland Weiss E, O’Gorman Tuura RL, Oosterlaan J, Oranje B, Paloyelis Y, Pauli P, Picon FA, Plessen KJ, Ramos-Quiroga JA, Reif A, Reneman L, Rosa PGP, Rubia K, Schrantee A, Schweren LJS, Seitz J, Shaw P, Silk TJ, Skokauskas N, Soliva Vila JC, Stevens MC, Sudre G, Tamm L, Tovar-Moll F, van Erp TGM, Vance A, Vilarroya O, Vives-Gilabert Y, von Polier GG, Walitza S, Yoncheva YN, Zanetti MV, Ziegler GC, Glahn DC, Jahanshad N, Medland SE, Thompson PM, Fisher SE, Franke B, Francks C. Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets. Journal of child psychology and psychiatry, and allied disciplines. 2021; 62(10): 1202-19.

OBJECTIVE: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. METHODS: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. RESULTS: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing. CONCLUSION: Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.

Lien vers le texte intégral (Open Access ou abonnement)

19. Pruccoli J, Solari A, Terenzi L, Malaspina E, Angotti M, Pignataro V, Gualandi P, Sacrato L, Cordelli DM, Franzoni E, Parmeggiani A. Autism spectrum disorder and anorexia nervosa: an Italian prospective study. Italian journal of pediatrics. 2021; 47(1): 59.

BACKGROUND: Potential overlaps exist between psychopathological features of Anorexia Nervosa (AN) and Autism Spectrum Disorder (ASD). The impact of malnutrition on autistic traits in patients with AN should be considered. This study investigates possible associations among the psychopathology of Eating Disorders (EDs), ASD traits and BMI in a group of young patients with AN, using the EDI-3 (Eating Disorder Inventory-3) test and gold-standard measures for ASD. METHODS: Prospective study involving 23 inpatients admitted to an Italian Centre for paediatric ED. ASD traits and ED psychopathology were assessed administering the ADOS-2 (Autism Diagnostic Observation Schedule-2), AQ (Autism Quotient) and EDI-3 tests. Both present and past autistic traits were investigated using different versions of AQ. Correlations were adjusted for BMI, Obsessive Compulsive Disorder (OCD) comorbidity and concurrent antipsychotic treatments. RESULTS: An ASD diagnosis was possible in 22% of patients. Significant correlations were documented between ASD traits and ED psychopathology: AQ total-Interpersonal problems (IPC) (p = 0.041); AQ total-Global psychological maladjustment (GMPC) (p = 0.027); AQ social skills-Ineffectiveness (IC) (p = 0.018); AQ social skills-IPC (p = 0.019); AQ social skills-Affective problems (APC) (p = 0.025); AQ social skills-GMPC (p = 0.007); AQ attention switching-IPC (p = 0.020); ADOS-2 imagination-IC (p = 0.035). These correlations were independent of BMI, OCD and antipsychotic treatments. CONCLUSIONS: ASD traits presented high prevalence in a group of young inpatients with AN. These traits were significantly correlated to 4 specific EDI-3 subscales and independent of BMI. This is the first study to investigate the relationship between ASD traits as measured with gold-standard measures, EDI-3 scores, and BMI.

Lien vers le texte intégral (Open Access ou abonnement)

20. Sampaio F, Feldman I, Lavelle TA, Skokauskas N. The cost-effectiveness of treatments for attention deficit-hyperactivity disorder and autism spectrum disorder in children and adolescents: a systematic review. European child & adolescent psychiatry. 2021.

Economic evaluations can help decision makers identify what services for children with neurodevelopmental disorders provide best value-for-money. The aim of this paper is to review the best available economic evidence to support decision making for attention deficit-hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in children and adolescents. We conducted a systematic review of economic evaluations of ADHD and ASD interventions including studies published 2010-2020, identified through Econlit, Medline, PsychINFO, and ERIC databases. Only full economic evaluations comparing two or more options, considering both costs and consequences were included. The quality of the studies was assessed using the Drummond checklist. We identified ten studies of moderate-to-good quality on the cost-effectiveness of treatments for ADHD and two studies of good quality of interventions for ASD. The majority of ADHD studies evaluated pharmacotherapy (n = 8), and two investigated the economic value of psychosocial/behavioral interventions. Both economic evaluations for ASD investigated early and communication interventions. Included studies support the cost-effectiveness of behavioral parenting interventions for younger children with ADHD. Among pharmacotherapies for ADHD, different combinations of stimulant/non-stimulant medications for children were cost-effective at willingness-to-pay thresholds reported in the original papers. Early intervention for children with suspected ASD was cost-effective, but communication-focused therapy for preschool children with ASD was not. Prioritizing more studies in this area would allow decision makers to promote cost-effective and clinically effective interventions for this target group.

Lien vers le texte intégral (Open Access ou abonnement)

21. Tortelli C, Turi M, Burr DC, Binda P. Objective pupillometry shows that perceptual styles covary with autistic-like personality traits. eLife. 2021; 10.

We measured the modulation of pupil size (in constant lighting) elicited by observing transparent surfaces of black and white moving dots, perceived as a cylinder rotating about its vertical axis. The direction of rotation was swapped periodically by flipping stereo-depth of the two surfaces. Pupil size modulated in synchrony with the changes in front-surface color (dilating when black). The magnitude of pupillary modulation was larger for human participants with higher Autism-Spectrum Quotient (AQ), consistent with a local perceptual style, with attention focused on the front surface. The modulation with surface color, and its correlation with AQ, was equally strong when participants passively viewed the stimulus. No other indicator, including involuntary pursuit eye movements, covaried with AQ. These results reinforce our previous report with a similar bistable stimulus (Turi, Burr, & Binda, 2018), and go on to show that bistable illusory motion is not necessary for the effect, or its dependence on AQ.

Lien vers le texte intégral (Open Access ou abonnement)

22. van Oosterhout J, van der Linden K, Simons CJP, van Amelsvoort T, Marcelis M. Exploring the autism spectrum: Moderating effects of neuroticism on stress reactivity and on the association between social context and negative affect. Development and psychopathology. 2021: 1-10.

Neuroticism is associated with increased stress reactivity. In autism spectrum disorders (ASD), emotional stress reactivity is increased and there is some evidence for an increased negative affect (NA) when with less familiar people. The aim of this study was to compare adults with ASD and controls on levels of neuroticism and on interactions between neuroticism and appraised stress or social context in models of NA. This is a cross-sectional observational study comprising a group of 50 adults with ASD and 51 controls. Experience sampling method (ESM) reports were collected for 10 days to measure daily life stress, mood, and social context. Multilevel regression analyses revealed significantly higher neuroticism levels in ASD than in controls. Adults with ASD who scored high on neuroticism showed a significantly stronger association between activity/social stress and NA (i.e., higher stress reactivity) than those with low scores. Furthermore, the association between neuroticism and NA was stronger when adults with ASD were with less familiar people compared with being alone or with familiar people. No consistent corresponding significant interactions were found in the control group. In conclusion, in ASD, neuroticism moderates the association between appraised stress and NA as well as the association between social context and NA.

Lien vers le texte intégral (Open Access ou abonnement)

23. Xiao L, Yan J, Feng D, Ye S, Yang T, Wei H, Li T, Sun W, Chen J. Critical Role of TLR4 on the Microglia Activation Induced by Maternal LPS Exposure Leading to ASD-Like Behavior of Offspring. Frontiers in cell and developmental biology. 2021; 9: 634837.

Objective: To investigate the role of TLR4 on the microglia activation in the pre-frontal cortex, which leads to autism-like behavior of the offspring induced by maternal lipopolysaccharide (LPS) exposure. Methods: Pregnant TLR4(-/-) (knockout, KO) and WT (wild type, WT) dams were intraperitoneally injected with LPS or PBS, respectively. The levels of TNFα, IL-1β, and IL-6 in the maternal serum and fetal brain were assessed with ELISA following LPS exposure. The gestation period, litter size and weight of the offspring were evaluated. Three-chamber sociability test, open field test and olfactory habituation/dishabituation test were used to assess the offspring’s autism-like behavior at 7 weeks of age. Western blotting was performed to examine the levels of TLR4, Phospho-NFκB p65, IKKα, IBA-1, iNOS, Arg-1, C3, CR3A, NMDAR2A, and Syn-1 expression in the pre-frontal cortex. The morphological changes in the microglia, the distribution and expression of TLR4 were observed by immunofluorescence staining. Golgi-Cox staining was conducted to evaluate the dendritic length and spine density of the neurons in 2-week-old offspring. Results: Maternal LPS stimulation increased serum TNFα and IL-6, as well as fetal brain TNFα in the WT mice. The litter size and the weight of the WT offspring were significantly reduced following maternal LPS treatment. LPS-treated WT offspring had lower social and self-exploration behavior, and greater anxiety and repetitive behaviors. The protein expression levels of TLR4 signaling pathways, including TLR4, Phospho-NFκB p65, IKKα, and IBA-1, iNOS expression were increased in the LPS-treated WT offspring, whereas Arg-1 was decreased. Maternal LPS treatment resulted in the significant reduction in the levels of the synaptic pruning-related proteins, C3 and CR3A. Moreover, the neuronal dendritic length and spine density, as well as the expression levels of the synaptic plasticity-related proteins, NMDAR2A and Syn-1 were reduced in the WT offspring; however, gestational LPS exposure had no effect on the TLR4(-/-) offspring. Conclusion: Activation of TLR4 signaling pathway following maternal LPS exposure induced the abnormal activation of microglia, which in turn was involved in excessive synaptic pruning to decrease synaptic plasticity in the offspring. This may be one of the reasons for the autism-like behavior in the offspring mice.

Lien vers le texte intégral (Open Access ou abonnement)

24. Yao S, Becker B, Kendrick KM. Reduced Inter-hemispheric Resting State Functional Connectivity and Its Association With Social Deficits in Autism. Frontiers in psychiatry. 2021; 12: 629870.

Autism spectrum disorder (ASD) is an early onset developmental disorder which persists throughout life and is increasing in prevalence over the last few decades. Given its early onset and variable cognitive and emotional functional impairments, it is generally challenging to assess ASD individuals using task-based behavioral and functional MRI paradigms. Consequently, resting state functional MRI (rs-fMRI) has become a key approach for examining ASD-associated neural alterations and revealed functional alterations in large-scale brain networks relative to typically developing (TD) individuals, particularly those involved in social-cognitive and affective processes. Recent progress suggests that alterations in inter-hemispheric resting state functional connectivity (rsFC) between regions in the 2 brain hemispheres, particularly homotopic ones, may be of great importance. Here we have reviewed neuroimaging studies examining inter-hemispheric rsFC abnormities in ASD and its associations with symptom severity. As an index of inter-hemispheric functional connectivity, we have additionally reviewed previous studies on corpus callosum (CC) volumetric and fiber changes in ASD. There are converging findings on reduced inter-hemispheric (including homotopic) rsFC in large-scale brain networks particularly in posterior hubs of the default mode network, reduced volumes in the anterior and posterior CC, and on decreased FA and increased MD or RD across CC subregions. Associations between the strength of inter-hemispheric rsFC and social impairments in ASD together with their classification performance in distinguishing ASD subjects from TD controls across ages suggest that the strength of inter-hemispheric rsFC may be a more promising biomarker for assisting in ASD diagnosis than abnormalities in either brain wide rsFC or brain structure.

Lien vers le texte intégral (Open Access ou abonnement)