Extent of magnitude representation deficit and relationship with arithmetic skills in children with 22q11.2DS.

BACKGROUND: Previous studies have produced conflicting results concerning the extent of magnitude representation deficit and its relationship with arithmetic achievement in children with 22q11.2 deletion syndrome. More specifically, it remains unclear whether deficits are restricted to visuospatial content or are more general and whether they could explain arithmetical impairment. METHODS: Fifteen 5- to 12-year-old children with 22q11.2 deletion syndrome and 23 age-matched healthy controls performed a non-symbolic magnitude comparison task. Depending on the trial, participants had to compare stimuli with high or low visuospatial load (visuospatial stimuli or temporal sequence of visual stimuli). The participants also completed a battery of arithmetic skills (ZAREKI-R) and a battery of global cognitive functioning (WISC-V or WPPSI-IV), from which working memory and visuospatial indices were derived. RESULTS: Children with 22q11.2DS responded as fast as healthy controls did but received fewer correct responses, irrespective of visuospatial load. In addition, their performance in the non-symbolic magnitude comparison task did not correlate with the ZAREKI total score, while the working memory index did. CONCLUSION: Children with 22q11.2DS might suffer from a global magnitude representation deficit rather than a specific deficit due to visuospatial load. However, this deficit alone does not seem to be related to arithmetic achievement. Working memory might be a better concern of interest in favoring arithmetic skills in patients with 22q11.2 deletion syndrome. TRIAL REGISTRATION: Clinicaltrials, NCT04373226 . Registered 16 September 2020.

Current and future applications of light-sheet imaging for identifying molecular and developmental processes in autism spectrum disorders.

Autism spectrum disorder (ASD) is identified by a set of neurodevelopmental divergences that typically affect the social communication domain. ASD is also characterized by heterogeneous cognitive impairments and is associated with cooccurring physical and medical conditions. As behaviors emerge as the brain matures, it is particularly essential to identify any gaps in neurodevelopmental trajectories during early perinatal life. Here, we introduce the potential of light-sheet imaging for studying developmental biology and cross-scale interactions among genetic, cellular, molecular and macroscale levels of circuitry and connectivity. We first report the core principles of light-sheet imaging and the recent progress in studying brain development in preclinical animal models and human organoids. We also present studies using light-sheet imaging to understand the development and function of other organs, such as the skin and gastrointestinal tract. We also provide information on the potential of light-sheet imaging in preclinical drug development. Finally, we speculate on the translational benefits of light-sheet imaging for studying individual brain-body interactions in advancing ASD research and creating personalized interventions.

Maternal immune activation during pregnancy is associated with more difficulties in socio-adaptive behaviors in autism spectrum disorder.

Autism spectrum disorder (ASD) are neurodevelopmental conditions characterised by deficits in social communication and interaction and repetitive behaviours. Maternal immune activation (MIA) during the mid-pregnancy is a known risk factor for ASD. Although reported in 15% of affected individuals, little is known about the specificity of their clinical profiles. Adaptive skills represent a holistic approach to a person's competencies and reflect specifically in ASD, their strengths and difficulties. In this study, we hypothesised that ASD individual with a history of MIA (MIA+) could be more severely socio-adaptively impaired than those without MIA during pregnancy (MIA-). To answer this question, we considered two independent cohorts of individuals with ASD (PARIS study and FACE ASD) screened for pregnancy history, and used supervised and unsupervised machine learning algorithms. We included 295 mother-child dyads with 14% of them with MIA+. We found that ASD-MIA+ individuals displayed more severe maladaptive behaviors, specifically in their socialization abilities. MIA+ directly influenced individual's socio-adaptive skills, independent of other covariates, including ASD severity. Interestingly, MIA+ affect persistently the socio-adaptive behavioral trajectories of individuals with ASD. The current study has a retrospective design with possible recall bias regarding the MIA event and, even if pooled from two cohorts, has a relatively small population. In addition, we were limited by the number of covariables available potentially impacted socio-adaptive behaviors. Larger prospective study with additional dimensions related to ASD is needed to confirm our results. Specific pathophysiological pathways may explain these clinical peculiarities of ASD- MIA+ individuals, and may open the way to new perspectives in deciphering the phenotypic complexity of ASD and for the development of specific immunomodulatory strategies.

Chromosomal rearrangement in the 22q11.2 region: a critical locus for sociability and attentional skills.

Rearrangements of 22q11.2 region, most often deletions and duplications, are responsible for multiple congenital disorders. These rearrangements are involved in syndromes that share some phenotypic similarities. To date, 22q11.2 triplication remains very rare, with few cases described in the literature. Here, we report for the first time the clinical, neurocognitive, social cognition and psychiatric properties of a 6-year-old child with 22q11.2 triplication, in comparison with a patient with 22q11.2 duplication and 16 cases of patients with 22q11.2 deletion. Chromosomal region 22q11.2 seems to be a critical locus for sociability and attentional skills and rearrangements could be interpreted as a predisposing factor for the development of psychotic symptoms (22q11.2 deletion), a protective factor (22q11.2 duplication) or a tendency factor for hypersociability (22q11.2 triplication).

A new scale for the screening of childhood early psychotic symptoms.

This study aimed to develop a new scale, the Early Psychotic Symptoms screening scale (EPSy), to assess the prodromes of psychotic symptoms in children aged 4 to 13 years. Two versions were proposed: one to assess the child's current behavior and one to assess the child's behavior when he/she was 2 years old. The second aim of this study was to investigate the presence of these symptoms at the age of 2 years and their evolution up to the child's current age. The analysis of EPSy identified three main factors, namely mistrust/paranoia, perceptual aberrations/hallucinations and disorganized symptoms. It has good psychometric properties. Data also shows that, independently of the participant's age, the total score on the 2-years-old version predicts the total score on the current-age version, and this is also the case for each individual factor. Finally, it is of clinical interest since it makes it possible to describe symptomatology both at age 2 and at the child's present age depending on the group to which the children are assigned (control children, psychotic children, non-psychotic children).

A new neurodevelopmental disorder linked to heterozygous variants in UNC79.

PURPOSE: The "NALCN channelosome" is an ion channel complex that consists of multiple proteins, including NALCN, UNC79, UNC80, and FAM155A. Only a small number of individuals with a neurodevelopmental syndrome have been reported with disease causing variants in NALCN and UNC80. However, no pathogenic UNC79 variants have been reported, and in vivo function of UNC79 in humans is largely unknown. METHODS: We used international gene-matching efforts to identify patients harboring ultrarare heterozygous loss-of-function UNC79 variants and no other putative responsible genes. We used genetic manipulations in Drosophila and mice to test potential causal relationships between UNC79 variants and the pathology. RESULTS: We found 6 unrelated and affected patients with UNC79 variants. Five patients presented with overlapping neurodevelopmental features, including mild to moderate intellectual disability and a mild developmental delay, whereas a single patient reportedly had normal cognitive and motor development but was diagnosed with epilepsy and autistic features. All displayed behavioral issues and 4 patients had epilepsy. Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a heterozygous loss-of-function variant have a developmental delay in body weight compared with wild type. In addition, they have impaired ability in learning and memory. CONCLUSION: Our results demonstrate that heterozygous loss-of-function UNC79 variants are associated with neurologic pathologies.

An optimized iDISCO+ protocol for tissue clearing and 3D analysis of oxytocin and vasopressin cell network in the developing mouse brain.

Here, we present an optimized iDISCO+ protocol combining tissue clearing and light sheet microscopy to map the postnatal development of oxytocin and vasopressin neurons in mouse hypothalamus. We describe tissue preparation, immunostaining, clearing, and imaging. We then detail how to process the 3D cell dataset to analyze cell network using a point-based recording procedure that accurately maps neurons in the Allen brain atlas. This protocol can be applied to any neuronal population, in different brain regions and at different developmental stages. For complete details on the use and execution of this protocol, please refer to Soumier et al. (2021).1.

A 1-Day Training Course to Disseminate the BREF Psychoeducational Program to Caregivers and Promote Network Establishment between Psychiatry Departments and Family Associations.

OBJECTIVE: Although international guidelines state that psychoeducation to caregivers should be provided systematically, it remains insufficiently available in psychiatry. This study reports the development and evaluation of an original training course aimed to provide participants with the knowledge and skills to implement "BREF," a psychoeducational program for caregivers. METHODS: The BREF program training course, a free, 1-day course incorporating peer role-play was developed. In addition to psychiatrists, nurses, and psychologists, caregivers were involved as preceptors. Participants were mental health professionals and volunteer caregivers. Participants to the first 28 sessions of the course (n=467) completed a post-course questionnaire (n=341) and a cross-sectional questionnaire (n=56). Quantitative data on satisfaction, learning, and behavior changes following the course were collected equating to levels 1, 2, and 3 of Kirkpatrick's model. RESULTS: After the course, high levels of satisfaction and commitment were observed with 100% of responders recommending the course and 81% intending to implement the BREF program. Confidence mean score to implement BREF was 7.9/10 (±1.4) with no significant effect of course session. At cross-sectional evaluation, 73% of responders reported improvements in skills related to providing psychoeducation to caregivers, 64% stated that the BREF program was implemented/under implementation, and 66% stated that their department had connected with a family association. CONCLUSIONS: Training course sessions alone can increase psychoeducational programs for caregivers and network establishment. The BREF program training course demonstrates a high level of participant satisfaction and is a promising method to disseminate psychoeducation to caregivers, thus addressing a major shortage in mental health organization.

Human type I IFN deficiency does not impair B cell response to SARS-CoV-2 mRNA vaccination.

Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)-specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines.

Gender differences in psychosocial function and self-reported health status in late-diagnosed autistic adults: results from the FACE-ASD national cohort.

BACKGROUND: While adult outcome in autism spectrum disorder (ASD) is generally measured using socially valued roles, it could also be understood in terms of aspects related to health status - an approach that could inform on potential gender differences. METHODS: We investigated gender differences in two aspects of outcome related to health-status, i.e. general functioning and self-perceived health status, and co-occurring health conditions in a large multi-center sample of autistic adults. Three hundred and eighty-three participants were consecutively recruited from the FondaMental Advanced Centers of Expertise for ASD cohort (a French network of seven expert centers) between 2013 and 2020. Evaluation included a medical interview, standardized scales for autism diagnosis, clinical and functional outcomes, self-perceived health status and verbal ability. Psychosocial function was measured using the Global Assessment of Functioning scale. RESULTS: While autistic women in this study were more likely than men to have socially valued roles, female gender was associated with poorer physical and mental health (e.g. a 7-fold risk for having three or more co-occurring physical health conditions) and a poorer self-perceived health status. Psychosocial function was negatively associated with depression and impairment in social communication. Half of the sample had multiple co-occurring health conditions but more than 70% reported that their visit at the Expert Center was their first contact with mental health services. CONCLUSIONS: To improve objective and subjective aspects of health outcome, gender differences and a wide range of co-occurring health conditions should be taken into account when designing healthcare provision for autistic adults.

The Time Course of Information Processing During Eye Direction Perception.

Gaze directed at the observer (direct gaze) is a highly salient social signal. Despite the existence of a preferential orientation toward direct gaze, none of the studies carried out so far seem to have explicitly studied the time course of information processing during gaze direction judgment. In an eye direction judgment task, participants were presented with a sketch of a face. A temporal asynchrony was introduced between the presentation of the eyes and that of the rest of the face. Indeed, the face could be presented before the eyes, the eyes could be presented before the face, or the face and the eyes could be presented simultaneously. In a second time, the face direction was also manipulated. The results suggest that the time course of information processing during eye direction judgment follows a continuum that makes it possible to perceive the eyes first and then to use the facial context to judge the direction of gaze. Furthermore, the congruency between the direction of gaze and that of the face confirms this observation. Although these results are discussed in the light of existing theories about the mechanisms underlying gaze processing, our data provide new information suggesting that, despite their power to capture attention, the eyes probably have to stand out from a more general spatial configuration (i.e., the face) in order for their direction to be adequately processed.

Actionable Predictive Factors of Homelessness in a Psychiatric Population: Results from the REHABase Cohort Using a Machine Learning Approach.

BACKGROUND: There is a lack of knowledge regarding the actionable key predictive factors of homelessness in psychiatric populations. Therefore, we used a machine learning model to explore the REHABase database (for rehabilitation database-n = 3416), which is a cohort of users referred to French psychosocial rehabilitation centers in France. METHODS: First, we analyzed whether the different risk factors previously associated with homelessness in mental health were also significant risk factors in the REHABase. In the second step, we used unbiased classification and regression trees to determine the key predictors of homelessness. Post hoc analyses were performed to examine the importance of the predictors and to explore the impact of cognitive factors among the participants. RESULTS:  First, risk factors that were previously found to be associated with homelessness were also significant risk factors in the REHABase. Among all the variables studied with a machine learning approach, the most robust variable in terms of predictive value was the nature of the psychotropic medication (sex/sex relative mean predictor importance: 22.8, σ = 3.4). Post hoc analyses revealed that first-generation antipsychotics (15.61%; p < 0.05 FDR corrected), loxapine (16.57%; p < 0.05 FWER corrected) and hypnotics (17.56%; p < 0.05 FWER corrected) were significantly associated with homelessness. Antidepressant medication was associated with a protective effect against housing deprivation (9.21%; p < 0.05 FWER corrected). CONCLUSIONS: Psychotropic medication was found to be an important predictor of homelessness in our REHABase cohort, particularly loxapine and hypnotics. On the other hand, the putative protective effect of antidepressants confirms the need for systematic screening of depression and anxiety in the homeless population.

Dissociation of early and late face-related processes in autism spectrum disorder and Williams syndrome.

BACKGROUND: Williams syndrome (WS) and Autism Spectrum Disorders (ASD) are neurodevelopmental conditions associated with atypical but opposite face-to-face interactions patterns: WS patients overly stare at others, ASD individuals escape eye contact. Whether these behaviors result from dissociable visual processes within the occipito-temporal pathways is unknown. Using high-density electroencephalography, multivariate signal processing algorithms and a protocol designed to identify and extract evoked activities sensitive to facial cues, we investigated how WS (N = 14), ASD (N = 14) and neurotypical subjects (N = 14) decode the information content of a face stimulus. RESULTS: We found two neural components in neurotypical participants, both strongest when the eye region was projected onto the subject's fovea, simulating a direct eye contact situation, and weakest over more distant regions, reaching a minimum when the focused region was outside the stimulus face. The first component peaks at 170 ms, an early signal known to be implicated in low-level face features. The second is identified later, 260 ms post-stimulus onset and is implicated in decoding salient face social cues. Remarkably, both components were found distinctly impaired and preserved in WS and ASD. In WS, we could weakly decode the 170 ms signal based on our regressor relative to facial features, probably due to their relatively poor ability to process faces' morphology, while the late 260 ms component was highly significant. The reverse pattern was observed in ASD participants who showed neurotypical like early 170 ms evoked activity but impaired late evoked 260 ms signal. CONCLUSIONS: Our study reveals a dissociation between WS and ASD patients and points at different neural origins for their social impairments.

Differential fate between oxytocin and vasopressin cells in the developing mouse brain.

Oxytocin (OXT) and arginine vasopressin (AVP), two neuropeptides involved in socio-emotional behaviors have been anatomically defined in the adult brain. Yet their spatial organization during postnatal development is not clearly defined. We built a developmental atlas using 3D imaging of cleared immunolabeled tissue over four early postnatal (P) stages, from birth (P0, P3, P7, P14) to young adulthood (≥P56). Our atlas-based mapping revealed that the number of OXT neurons doubles according to unique temporal dynamics in selective hypothalamic regions, namely, the periventricular and paraventricular nuclei, and in a novel location we named the antero-lateral preoptic. In the paraventricular nucleus, single-cell densities and fluorescence analysis demonstrated selective expansion of OXT cells in the antero-ventral division, whereas the postero-dorsal division contained cells present at birth. No changes were observed for AVP neurons. Our findings show the coexisting of innate and plastic OXT/AVP brain circuits probably triggered by environmental adaptation of the social brain.

Emotional modulation of episodic memory in children and adolescents with Williams-Beuren syndrome.

Children and adolescents with Williams-Beuren syndrome (WBS) have been described as having specific memory abilities and emotional reactivity. Although it is well established in the literature that emotion can enhance memory, no such studies have been undertaken in individuals with WBS. In three experiments, the present study tested whether the negative or positive emotional valence of stimuli can influence verbal, visual and visuo-spatial memory by specifically evaluating two memory components: item and associative memory. Sixteen 8- to 18-year-old individuals with WBS performed the first two experiments and, among them, twelve participated in the third. They were compared to equivalent groups of typically developing control children. Participants completed intentional-encoding tasks followed by immediate item recognition, associative recall or item recall tasks. Event-related potential measures during encoding and recognition of pictures were also added in the third experiment. Results demonstrated, for the first time, effects of emotions on visual item memory and visuo-spatial associative memory in individuals with WBS, that were similar to those observed in typically developing children. By combining behavioral and neural measures, our study provides new knowledge of the interaction between emotion and memory in WBS individuals, which seems to be unaffected by their atypical development.

Eye Direction Detection and Perception as Premises of a Social Brain: A Narrative Review of Behavioral and Neural Data.

The eyes and the gaze are important stimuli for social interaction in humans. Impaired recognition of facial identity, facial emotions, and inference of the intentions of others may result from difficulties in extracting information relevant to the eye region, mainly the direction of gaze. Therefore, a review of these data is of interest. Behavioral data demonstrating the importance of the eye region and how humans respond to gaze direction are reviewed narratively, and several theoretical models on how visual information on gaze is processed are discussed to propose a unified hypothesis. Several issues that have not yet been investigated are identified. The authors tentatively suggest experiments that might help progress research in this area. The neural aspects are subsequently reviewed to best describe the low-level and higher-level visual information processing stages in the targeted subcortical and cortical areas. A specific neural network is proposed on the basis of the literature. Various gray areas, such as the temporality of the processing of visual information, the question of salience priority, and the coordination between the two hemispheres, remain unclear and require further investigations. Finally, disordered gaze direction detection mechanisms and their consequences on social cognition and behavior are discussed as key deficiencies in several conditions, such as autism spectrum disorder, 22q11.2 deletion, schizophrenia, and social anxiety disorder. This narrative review provides significant additional data showing that the detection and perception of someone's gaze is an essential part of the development of our social brain.

Emotional Modulation of Episodic Memory in School-Age Children and Adults: An Event-Related Potential Study.

The Emotional Enhancement of Memory (EEM) has been well-demonstrated in adults, but less is known about EEM in children. The present study tested the impact of emotional valence of pictures on episodic memory using behavioral and neurophysiological measures. Twenty-six 8- to 11-year-old children were tested and compared to 30 young adults. Both groups participated in pictures' intentional encoding tasks while event-related potentials (ERPs) were recorded, followed by immediate free recall tasks. Behavioral results revealed a general EEM in free recall performances in both groups, along with a negativity effect in children. ERP responses revealed a particular sensitivity to negative pictures in children with a late emotion effect at anterior clusters, as well as a greater successful encoding effect for emotional pictures compared to neutral ones. For adults, the emotion effect was more pronounced for positive pictures across all time windows from the centro-parietal to the frontal part, and localized in the left hemisphere. Positive pictures also elicited a greater successful encoding effect at anterior clusters in adults. By combining behavioral and neurophysiological measures to assess the EEM in children compared with adults, our study provides new knowledge concerning the interaction between emotional and memory processes during development.

Erotomania and phenotypic continuum in a family frameshift variant of AUTS2: a case report and review.

BACKGROUND: Pathogenic variants of the AUTS2 (Autism Susceptibility candidate 2) gene predispose to intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, facial dysmorphism and short stature. This phenotype is therefore associated with neurocognitive disturbances and social cognition, indicating potential functional maladjustment in the affected subjects, and a potentially significant impact on quality of life. Although many isolated cases have been reported in the literature, to date no families have been described. This case reports on a family (three generations) with a frameshift variant in the AUTS2 gene. CASE PRESENTATION: The proband is 13 years old with short stature, dysmorphic features, moderate intellectual disability and autism spectrum disorder. His mother is 49 years old and also has short stature and similar dysmorphic features. She does not have autism disorder but presents an erotomaniac delusion. Her cognitive performance is heterogeneous. The two aunts are also of short stature. The 50-year-old aunt has isolated social cognition disorders. The 45-year-old aunt has severe cognitive impairment and autism spectrum disorder. The molecular analysis of the three sisters and the proband shows the same AUTS2 heterozygous duplication leading to a frame shift expected to produce a premature stop codon, p.(Met593Tyrfs*85). Previously reported isolated cases revealed phenotypic and cognitive impairment variability. In this case report, these variabilities are present within the same family, presenting the same variant. CONCLUSIONS: The possibility of a phenotypic spectrum within the same family highlights the need for joint psychiatry and genetics research.

Sex Differences in Recovery-Related Outcomes and Needs for Psychiatric Rehabilitation in People With Schizophrenia Spectrum Disorder.

BACKGROUND: Female sex/gender has been associated with better longitudinal outcomes in schizophrenia spectrum disorders (SSDs). Few studies have investigated the relationships between female gender and recovery-related outcomes. Women's specific psychiatric rehabilitation needs remain largely unknown. OBJECTIVE: The objectives of the present study are to investigate sex differences in (1) objective and subjective aspects of recovery and (2) psychiatric rehabilitation needs in a multicenter non-selected psychiatric rehabilitation SSD sample. METHODS: 1,055 outpatients with SSD (DSM-5) were recruited from the French National Centers of Reference for Psychiatric Rehabilitation (REHABase) cohort between January 2016 and November 2019. Evaluation included standardized scales for quality of life, satisfaction with life, and well-being and a broad cognitive battery. Socially valued roles at enrollment were recorded. Functional recovery was measured using the Global Assessment of Functioning scale (GAF) and personal recovery with the Stages of Recovery Instrument (STORI). RESULTS: Female sex was the best predictor of having more than 2 socially valued roles in the multivariate analysis (P < .001; OR [95% CI] = 5.42 [2.34-13.06]). No sex differences were found for functional recovery or personal recovery. Female gender was positively associated with self-stigma (P = .036) and suicidal history (P < .001) and negatively correlated with quality of life (P = .004) and satisfaction with interpersonal relationships (P = .029), an area in which women reported more unmet needs (P = .004). CONCLUSIONS: The present study found that women had poorer subjective recovery-related outcomes and more unmet needs than men. It would therefore be beneficial to develop recovery-oriented interventions addressing women's specific needs and implement these in psychiatric rehabilitation services.