Vers de bonnes pratiques en recherche participative.

The Groupe de réflexion avec les associations de malades (GRAM)—a joint scientist/association think tank at the French National Institute of Health and Medical Research (INSERM)—has reflected, on the basis of internal surveys and the experiences of its members, on focus points concerning good practice to help partners involved in participatory research projects. In this article, we list these focus points and highlight the need to afford partners opportunities for dialogue, in order to give good chances of success to participatory research projects, in both the interest of associations and researchers.

Neurodevelopmental disorders (NDD) without boundaries: research and interventions beyond classifications.

On June 2022, the 2nd Webinar "Neurodevelopmental Disorders (NDD) without boundaries took place at the Imagine Institute in Paris and was broadcasted live and in replay. The aim of this webinar is to address NDD in a dimensional rather than in a categorical approach. Several speakers were invited to present their researches on the subject. Classifications in NDD were discussed: irritability in NDD, involvement of the immune system in neurodevelopment, nutrition and gut microbiota modulate brain inflammation and neurodevelopment, co-occurring conditions in autistic adolescents and adults without intellectual disability. Classifications in psychiatric disorders were asked: mapping the effect of genes on cognition and autism risk, epigenetics and symptomatic trajectory in neurodevelopmental disorders, the autism-schizophrenia continuum in two examples: minor neurological signs and EEG microstates, the cerebellum in schizophrenia and autism: from imaging to intervention perspectives. Both genetic and environmental factors, along with clinical and imaging features, argue toward a continnum between NDD but also with adult psychiatric presentations. This new paradigm could modify the therapeutic strategy, with the development of large-spectrum treatments or new psychotherapies addressing co-occuring symptoms. The complexity and the heterogeneity of NDD apply well to the next scientific and political challenges: developing international convergence to push back the frontiers of our knowledge. This article is a summary of the 2nd webinar "Neurodevelopmental Disorders (NDD) without boundaries: research and interventions beyond classifications" sponsored by the French National Academy of Medicine, the autism and neurodevelopmental disorders scientific interest group (GIS), the International Research Network Dev-O-Psy and the French Institute of Psychiatry (GDR3557). Oral presentations are available as a replay on the following website (in French): https://autisme-neurodev.org/evenements/2022/04/12/tnd-sans-frontieres-la-recherche-et-les-interventions-au-dela-des-classifications/ .

A comparative study of cognitive and socio-emotional development in children with Rubinstein-Taybi syndrome and children with Autism Spectrum Disorder associated with a severe intellectual disability, and in young typically developing children with matched developmental ages.

BACKGROUND: Cognitive and socio-emotional profiles of children with CREBBP-related Rubinstein-Taybi syndrome (RSTS 1), children with Autism Spectrum Disorder (ASD) with severe intellectual disability and developmental ages (DA) under 24 months, and typically developing (TD) children with similar DA were compared. PARTICIPANTS: Thirty-one children with RSTS 1 (mean chronological age, CA = 59,8 months; 33-87) and thirty children with ASD, matched on CA and DA and developmental quotients (DQ), were compared to thirty TD children (CA ranged from 12 to 24 months). METHODS: Cognitive and socio-emotional developmental levels, DA and DQ were assessed with appropriated tests. RESULTS: More socio-emotional developmental similarities were observed between TD and RSTS 1 than between TD and ASD children. Clinical groups displayed similar developmental delays in cognitive (self-image, symbolic play, means-ends, and object permanence) and socio-emotional domains (language and imitation). Children with RSTS 1 exhibited higher developmental levels in behavior regulation, joint attention, affective relations, emotional expression domains, and a lower developmental level in spatial relations domain. CONCLUSIONS: Common interventions centered on symbolic play, self-image, language, and imitation for both clinical groups, and differentiated interventions centered on spatial abilities for RSTS 1 children and on social abilities for ASD could be used by caregivers were suggested.

Early Intervention in Severe Autism: Positive Outcome Using Exchange and Development Therapy.

Early intervention programs positively affect key behaviors for children with autism spectrum disorder (ASD). However, most of these programs do not target children with severe autistic symptomatology associated with intellectual disability (ID). This study aimed to investigate the psychological and clinical outcomes of children with severe autism and ID enrolled in the Tailored and Inclusive Program for Autism-Tours (TIPA-T). The first step of the TIPA-T is the Exchange and Development Therapy (EDT): an individual neurofunctional intervention consisting of one-to-one exchanges between a child and a therapist taking place in a pared-down environment. It aims to rehabilitate psychophysiological abilities at the roots of social communication through structured sequences of "social play." Cognitive and socio-emotional skills and general development were evaluated with the Social Cognitive Evaluation Battery scale and the Brunet-Lézine Scale-Revised, respectively, before and after 9 months of intervention in 32 children with ASD and ID. Autistic symptomatology was evaluated with the Behavior Summarized Evaluation-Revised scale at five time-points in a subset of 14 children, both in individual and group settings. Statistically significant post-intervention improvements were found in cognitive and socio-emotional skills. All but one child showed improvements in at least one social domain, and 78% of children gained one level in at least four social domains. Twenty-nine children improved in cognitive domains, with 66% of children improving in at least three cognitive domains. Autistic symptomatology evaluated in one-to-one settings significantly decreased with therapy; this reduction was observed in more than 85% of children. In group settings, autistic symptomatology also decreased in more than 60% of children. Global developmental age significantly increased by 3.8 months. The TIPA-T, including EDT in particular, improves socio-emotional skills of most children with ASD and reduces autistic symptomatology, yet with heterogeneous outcomes profiles, in line with the strong heterogeneity of profiles observed in ASD. At the group level, this study highlights the benefits of the TIPA-T for children with severe autism and associated ID. Assessment of autistic core symptoms showed an improvement of social interaction, both in one-to-one and group evaluations, demonstrating the generalizability of the skills learned during the EDT.

Heterogeneities in Cognitive and Socio-Emotional Development in Children With Autism Spectrum Disorder and Severe Intellectual Disability as a Comorbidity.

Introduction: Intellectual disability (ID) is frequently associated as a comorbidity in autism spectrum disorders (ASD). This study investigated a) how similar the heterogeneity in the cognitive and socio-emotional developmental profiles was for children with ASD and ID, b) the difference between the subjects' profiles and those of typically developing children (TD) matched for developmental levels, c) the skills existing with the lowest and highest developmental levels, and d) the relationship between developmental profiles in ASD and the severity of autism, ID, and the overall developmental level. Participants: The sample was comprised of 119 children (101 boys and 18 girls) who ranged in chronological age (CA) from 21 months to 14 years (M = 5 years 2 months; SD = 2 years 6 months) with developmental levels lower than 24 months. They came from three countries (France = 40, Brazil = 40, and Algeria = 39). The control group was comprised of 40 TD children from these same countries who ranged in CA from 4 to 24 months (M = 1 year 3 months; SD = 5 months). The ASD diagnosis was carried out according to International Statistical Classification of Diseases and Related Health Problems-10th Edition (ICD-10), Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR), Diagnostic and Statistical Manual of Mental Disorders-5th ed (DSM-5) criteria and the Childhood Autism Rating Scale (CARS). Measures: Children were tested using the Social Cognitive Evaluation Battery (SCEB; Adrien, 2007) by trained psychologists from public and private institutions specialized in the diagnosis of autism and interventions in this field. The SCEB explores 16 functional abilities, in both cognitive and socio-emotional areas, and allows the calculation of domain and area developmental levels and heterogeneity indices for the global, cognitive, and socio-emotional areas. Results: Children with ASD developmental profiles show very high heterogeneity as opposed to TD children. Regardless of the country of origin, there are similarities between the heterogeneous cognitive and socio-emotional developmental profiles of the children with ASD, whose profiles are characterized by lower developmental levels of language and vocal imitation skills, and a relationship between these developmental heterogeneities and the degree of severity of autistic symptomatology, intellectual disability, and overall development level. The implications of this study are presented for clinical assessment and intervention purposes in ASD and ID.

Positive Effect of Visual Cuing in Episodic Memory and Episodic Future Thinking in Adolescents With Autism Spectrum Disorder.

Cognitive studies generally report impaired autobiographical memory in individuals with autism spectrum disorder (ASD), but mostly using verbal paradigms. In the present study, we therefore investigated the properties of both past and future autobiographical productions using visual cues in 16 boys with ASD and 16 typically developing (TD) participants aged between 10 and 18 years. We focused on sensory properties, emotional properties, and recollection, probing past and future productions for both near and distant time periods. Results showed that the ASD group performed more poorly than controls on free recall for recent periods, but performed like them when provided with visual cues. In addition, the ASD group reported fewer sensory details than controls and exhibited difficulties in the experience of recollection for the most remote events. These data suggest a combination of consolidation and binding deficits. Finally, our findings reveal the relevance of using visual cues to probe autobiographical memory, with possible perspectives for memory rehabilitation.

Author Correction: 22q13 deletion syndrome: communication disorder or autism? Evidence from a specific clinical and neurophysiological phenotype.

Since the online publication of the above article, the authors have noted errors with the author list. The author names were listed as '(last name)(first name)' instead of '(first name)(last name)'.

[Autism, a neuro-developmental disorder]. / L'autisme, un trouble du neurodéveloppement.

Autism, a neuro-developmental disorder.Autism, now called autism spectrum disorder, is part of the specific chapter entitled "neurodevelopmental disorders" in France as well as in the international manuals for the classification of diseases, DSM and CIM. French national commitments and actions that are now starting to consider autism in both areas of health and disability, from alert to diagnosis, towards the implementation of lifespan coordinated personnalized medical and social practices.

L'autisme, un trouble du neurodéveloppement. L'autisme, que l'on appelle désormais « trouble du spectre de l'autisme ¼, est inscrit au chapitre « troubles du neurodéveloppement ¼ en France comme dans les manuels internationaux de classification des maladies, Manuel diagnostique et statistique des troubles mentaux et Classification internationale des maladies. Les engagements nationaux et les actions qui commencent à se déployer positionnent l'autisme dans le champ de la santé et du handicap, du repérage au diagnostic et à la mise en oeuvre de pratiques médicales, paramédicales, médico-sociales personnalisées et coordonnées de la petite enfance à l'âge adulte.

22q13 deletion syndrome: communication disorder or autism? Evidence from a specific clinical and neurophysiological phenotype.

Phelan-McDermid syndrome is related to terminal 22q13 deletions of various sizes affecting the SHANK3 gene. In this neurodevelopmental disorder, behavioural symptoms of autism spectrum disorder (ASD) are reported in half of cases. Extensive clinical and neurophysiological characterization is lacking to understand the genotype-phenotype correlation. Eighteen patients (8 males, mean age 12.7 years, SD = 9.2) with known 22q13 deletions were fully explored with determination of deletion size, along with behavioural, language and cognitive standardized assessments. Neurophysiological indices previously reported to be altered in autism (i.e., eye tracking in a social/non-social task and auditory evoked potential mismatch) were also recorded. Thirty-nine percent met ASD clinical criteria, exceeding cut-off scores on both ADI-R (Autism Diagnosis Interview based on the period spanning 4-5 years of age) and ADOS-2 (Autism Diagnosis Observation Schedule for the current period). All patients had intellectual disability and language disability. Deletion size was significantly correlated with expressive and receptive language disability but not with ASD standardized assessment scores. Developmental Quotient tended to be lower in patients with the largest deletions. Using Eye Tracking, smaller pupil size, which is typically described in ASD, was not observed in these patients. Furthermore, atypical shortened latency of mismatch negativity response previously reported in ASD was not observed, whereas the N250 pattern, related to language, was affected. Language disability combined with cognitive deficits may lead to autistic behavioural symptoms, but with different neurophysiological networks compared to typical autism. These results highlight the indication for early speech therapy rather than intensive autism programme to treat these patients.

Atypical Brain Mechanisms of Prediction According to Uncertainty in Autism.

Resistance to change is often reported in autism and may arise from an inability to predict events in uncertain contexts. Using EEG recorded in 12 adults with autism and age-matched controls performing a visual target detection task, we characterized the influence of a certain context (targets preceded by a predictive sequence of three distinct stimuli) or an uncertain context (random targets) on behavior and electrophysiological markers of predictive processing. During an uncertain context, adults with autism were faster than controls to detect targets. They also had an enhancement in CNV amplitude preceding all random stimuli-indexing enhanced preparatory mechanisms, and an earlier N2 to targets-reflecting faster information processing-compared to controls. During a certain context, both controls and adults with autism presented an increase in P3 amplitude to predictive stimuli-indexing information encoding of the predictive sequence, an enhancement in CNV amplitude preceding predictable targets-corresponding to the deployment of preparatory mechanisms, and an earlier P3 to predictable targets-reflecting efficient prediction building and implementation. These results suggest an efficient extraction of predictive information to generate predictions in both controls and adults with autism during a certain context. However, adults with autism displayed a failure to decrease mu power during motor preparation accompanied by a reduced benefit in reaction times to predictable targets. The data reveal that patients with autism over-anticipate stimuli occurring in an uncertain context, in accord with their sense of being overwhelmed by incoming information. These results suggest that adults with autism cannot flexibly modulate cortical activity according to changing levels of uncertainty.

Eye Movement Monitoring and Maturation of Human Face Exploration.

OBJECTIVE: The aim of this study was to characterize ocular exploration of neutral and emotional faces in the typical development of a child. SUBJECTS AND METHOD: In this eye-tracking study, visual exploration of faces (with neutral or emotional expressions: happiness or sadness) was characterized in a population of 52 children (24 girls and 28 boys from 4 to 15 years of age) and 44 adults (22 women and 22 men from 18 to 35 years of age). The time spent on the eyes, nose and mouth of the faces was measured. RESULTS: All participants spent more time on the eyes (13%) rather than the nose and mouth (6%). The youngest participants spent less time exploring the eyes than the older participants, suggesting the progressive establishment of interest in these informative regions of the face during maturation. This process seemed to occur later in females (7-9 years) than males (4-6 years). CONCLUSION: These results confirm the importance of the eye area and the capacity of this region to capture attention. In addition, this study shows that the exploration of this region increases with age and is lower among girls aged 4-6 years compared with boys of the same age.

Mutation screening of the ubiquitin ligase gene RNF135 in French patients with autism.

Many genes are now thought to confer susceptibility to autism. Despite the fact that this neuropsychiatric disease appears to be related to several different causes, common cellular and molecular pathways have emerged and point to synaptic dysfunction or cellular growth. Several studies have indicated the importance of the ubiquitin pathway in synaptic function and the aetiology of autism. Here, we focused on the ring finger protein 135 (RNF135) gene, encoding an E3 ubiquitin ligase expressed in the cortex and cerebellum, and located in the NF1 gene locus in 17q11.2, a region linked to autism. We carried out a genetic analysis of the coding sequence of RFN135 in a French cohort of patients with autism and observed a significantly increased frequency of genotypes carrying the rare allele of the rs111902263 (p.R115K) missense variant in patients (P=0.0019, odds ratio: 4.23, 95% confidence interval: 1.87-9.57). Particularly, three unrelated patients showed a homozygous genotype for K115, a situation not observed in the 1812 control individuals. Further cellular and molecular studies are required to elucidate the role of this gene and the variant K115 in brain development and neuronal function.

Urinary p-cresol is elevated in young French children with autism spectrum disorder: a replication study.

The aromatic compound p-cresol (4-methylphenol) has been found elevated in the urines of Italian autistic children up to 8 years of age. The present study aims at replicating these initial findings in an ethnically distinct sample and at extending them by measuring also the three components of urinary p-cresol, namely p-cresylsulfate, p-cresylglucuronate and free p-cresol. Total urinary p-cresol, p-cresylsulfate and p-cresylglucuronate were significantly elevated in 33 French autism spectrum disorder (ASD) cases compared with 33 sex- and age-matched controls (p < 0.05). This increase was limited to ASD children aged ≤8 years (p < 0.01), and not older (p = 0.17). Urinary levels of p-cresol and p-cresylsulfate were associated with stereotypic, compulsive/repetitive behaviors (p < 0.05), although not with overall autism severity. These results confirm the elevation of urinary p-cresol in a sizable set of small autistic children and spur interest into biomarker roles for p-cresol and p-cresylsulfate in autism.

Event-related potential and eye tracking evidence of the developmental dynamics of face processing.

Although the wide neural network and specific processes related to faces have been revealed, the process by which face-processing ability develops remains unclear. An interest in faces appears early in infancy, and developmental findings to date have suggested a long maturation process of the mechanisms involved in face processing. These developmental changes may be supported by the acquisition of more efficient strategies to process faces (theory of expertise) and by the maturation of the face neural network identified in adults. This study aimed to clarify the link between event-related potential (ERP) development in response to faces and the behavioral changes in the way faces are scanned throughout childhood. Twenty-six young children (4-10 years of age) were included in two experimental paradigms, the first exploring ERPs during face processing, the second investigating the visual exploration of faces using an eye-tracking system. The results confirmed significant age-related changes in visual ERPs (P1, N170 and P2). Moreover, an increased interest in the eye region and an attentional shift from the mouth to the eyes were also revealed. The proportion of early fixations on the eye region was correlated with N170 and P2 characteristics, highlighting a link between the development of ERPs and gaze behavior. We suggest that these overall developmental dynamics may be sustained by a gradual, experience-dependent specialization in face processing (i.e. acquisition of face expertise), which produces a more automatic and efficient network associated with effortless identification of faces, and allows the emergence of human-specific social and communication skills.

1H-13C NMR-based urine metabolic profiling in autism spectrum disorders.

Autism Spectrum Disorders (ASD) are a group of developmental disorders caused by environmental and genetic factors. Diagnosis is based on behavioral and developmental signs detected before 3 years of age with no reliable biological marker. The purpose of this study was to evaluate the potential use of a 2D NMR-based approach to express the global biochemical signature of autistic individuals compared to normal controls. This technique has greater spectral resolution than to 1D (1)H NMR spectroscopy, which is limited by overlapping signals. The urinary metabolic profiles of 30 autistic and 28 matched healthy children were obtained using a (1)H-(13)C NMR-based approach. The data acquired were processed by multivariate orthogonal partial least-squares discriminant analysis (OPLS-DA). Some discriminating metabolites were identified: ß-alanine, glycine, taurine and succinate concentrations were significatively higher, and creatine and 3-methylhistidine concentrations were lower in autistic children than in controls. We also noted differences in several other metabolites that were unidentified but characterized by a cross peak correlation in (1)H-(13)C HSQC. Statistical models of (1)H and (1)H-(13)C analyses were compared and only 2D spectra allowed the characterization of statistically relevant changes [R(2)Y(cum)=0.78 and Q(2)(cum)=0.60] in the low abundance metabolites. This method has the potential to contribute to the diagnosis of neurodevelopment disorders but needs to be validated on larger cohorts and on other developmental disorders to define its specificity.