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Background: Autism spectrum disorder (ASD) is characterized by impaired social communication and interaction, and stereotyped, repetitive behaviour and sensory interests. To date, there is no effective medication that can improve social communication and interaction in ASD, and effect sizes of behaviour-based psychotherapy remain in the low to medium range. Consequently, there is a clear need for new treatment options. ASD is associated with altered activation and connectivity patterns in brain areas which process social information. Transcranial direct current stimulation (tDCS) is a technique that applies a weak electrical current to the brain in order to modulate neural excitability and alter connectivity. Combined with specific cognitive tasks, it allows to facilitate and consolidate the respective training effects. Therefore, application of tDCS in brain areas relevant to social cognition in combination with a specific cognitive training is a promising treatment approach for ASD., Methods: A phase-IIa pilot randomized, double-blind, sham-controlled, parallel-group clinical study is presented, which aims at investigating if 10 days of 20-min multi-channel tDCS stimulation of the bilateral tempo-parietal junction (TPJ) at 2.0 mA in combination with a computer-based cognitive training on perspective taking, intention and emotion understanding, can improve social cognitive abilities in children and adolescents with ASD. The main objectives are to describe the change in parent-rated social responsiveness from baseline (within 1 week before first stimulation) to post-intervention (within 7 days after last stimulation) and to monitor safety and tolerability of the intervention. Secondary objectives include the evaluation of change in parent-rated social responsiveness at follow-up (4 weeks after end of intervention), change in other ASD core symptoms and psychopathology, social cognitive abilities and neural functioning post-intervention and at follow-up in order to explore underlying neural and cognitive mechanisms., Discussion: If shown, positive results regarding change in parent-rated social cognition and favourable safety and tolerability of the intervention will confirm tDCS as a promising treatment for ASD core-symptoms. This may be a first step in establishing a new and cost-efficient intervention for individuals with ASD., Trial Registration: The trial is registered with the German Clinical Trials Register (DRKS), DRKS00014732 . Registered on 15 August 2018., Protocol Version: This study protocol refers to protocol version 1.2 from 24 May 2019.

Purpose: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit., Methods: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits., Results: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly., Conclusion: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.

Language-related change-detection processes are often investigated using syllables that are very simple in terms of phonological structure. However, phonological complexity is known to be challenging for young typically developing children and pathological populations. We investigated brain correlates of phonological processing and their age-related changes with a passive change-detection protocol including stimuli of varying phonological complexity, which allowed comparing responses to simple and complex phonological deviancies. Mismatch Negativity (MMN) and Late Discriminative Negativity (LDN) responses were recorded in both school-age children (n = 22) and adults (n = 24). MMN was similar for simple and complex phonological deviancy in both groups, whereas LDN appeared to be modulated by phonological complexity, albeit with different patterns according to age. In response to complex phonological change, children displayed a larger LDN response with a typical fronto-central scalp distribution, while adults showed an additional right-posterior activity but no larger amplitude than for simple change. Thus, LDN appears to be a good electrophysiological index of phonological complexity processing. This study validated the use of the LDN through this protocol for the investigation of phonological complexity processing throughout the development., (© 2020 Society for Psychophysiological Research.)

Background: Faces are crucial social stimuli, eliciting automatic processing associated with increased physiological arousal in observers. The level of arousal can be indexed by pupil diameter (the 'Event-Related Pupil Dilation', ERPD). However, many parameters could influence the arousal evoked by a face and its social saliency (e.g. virtual vs. real, neutral vs. emotional, static vs. dynamic). A few studies have shown an atypical ERPD in autism spectrum disorder (ASD) patients using several kinds of faces but no study has focused on identifying which parameter of the stimulus is the most interfering with face processing in ASD., Methods: In order to disentangle the influence of these parameters, we propose an original paradigm including stimuli along an ecological social saliency gradient: from static objects to virtual faces to dynamic emotional faces. This strategy was applied to 186 children (78 ASD and 108 typically developing (TD) children) in two pupillometric studies (22 ASD and 47 TD children in the study 1 and 56 ASD and 61 TD children in the study 2)., Results: Strikingly, the ERPD in ASD children is insensitive to any of the parameters tested: the ERPD was similar for objects, static faces or dynamic faces. On the opposite, the ERPD in TD children is sensitive to all the parameters tested: the humanoid, biological, dynamic and emotional quality of the stimuli. Moreover, ERPD had a good discriminative power between ASD and TD children: ASD had a larger ERPD than TD in response to virtual faces, while TD had a larger ERPD than ASD for dynamic faces., Conclusions: This novel approach evidences an abnormal physiological adjustment to socially relevant stimuli in ASD., (© 2019 Association for Child and Adolescent Mental Health.)

The new version of the International Classification of Diseases (ICD-11) mentions the existence of four different profiles in the verbal part of the Autism Spectrum Disorder (ASD), describing them as combinations of either spared or impaired functional language and intellectual abilities. The aim of the present study was to put ASD heterogeneity to the forefront by exploring whether clear profiles related to language and intellectual abilities emerge when investigation is extended to the entire spectrum, focusing on verbal children. Our study proposed a systematic investigation of both language (specifically, structural language abilities) and intellectual abilities (specifically, nonverbal cognitive abilities) in 51 6- to 12-year-old verbal children with ASD based on explicitly motivated measures. For structural language abilities, sentence repetition and nonword repetition tasks were selected; for nonverbal cognitive abilities, we chose Raven's Progressive Matrices, as well as Matrix Reasoning and Block Design from the Wechsler Scales. An integrative approach based on cluster analyses revealed five distinct profiles. Among these five profiles, all four logically possible combinations of structural language and nonverbal abilities mentioned in the ICD-11 were detected. Three profiles emerged among children with normal language abilities and two emerged among language-impaired children. Crucially, the existence of discrepant profiles of abilities suggests that children with ASD can display impaired language in presence of spared nonverbal intelligence or spared language in the presence of impaired nonverbal intelligence, reinforcing the hypothesis of the existence of a separate language module in the brain. Autism Res 2020, 13: 1155-1167. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The present work put Autism Spectrum Disorder heterogeneity to the forefront by exploring whether clear profiles related to language and cognitive abilities emerge when investigation is extended to the entire spectrum (focusing on verbal children). The use of explicitly motivated measures of both language and cognitive abilities and of an unsupervised machine learning approach, the cluster analysis, (a) confirmed the existence of all four logically possible profiles evoked in the new ICD-11, (b) evoked the existence of (at least) a fifth profile of language/cognitive abilities, and (c) reinforced the hypothesis of a language module in the brain., (© 2020 International Society for Autism Research, Wiley Periodicals, Inc.)

Sleep disorders are among the most common comorbidities in children with Autism Spectrum Disorder (ASD), and subjectively defined sleep disturbances have been related to ASD symptom severity. However, no study has investigated the differential impact of objectively measured sleep and circadian rhythm disturbances on behavioral difficulties in this population. Fifty-two children with ASD aged 3-10 years underwent assessments of sleep and circadian rest-activity rhythms objectively with actigraphy and subjectively with the Children's Sleep Habits Questionnaire. Behavioral difficulties were assessed using the ABC-C. Group comparison analyses were used to compare sleep and circadian rhythm parameters of children with higher and lower behavioral difficulties and dominance analysis to rank predictors and address multicollinearity. Children with high irritability had a shorter continuous sleep period compared to those with lower irritability (-60 min, p = 0.04), as well as those with high stereotypic behaviors compared to children with less stereotypies (-75 min, p = 0.006). Objective circadian and sleep disturbances accounted together for, respectively, 17%, 18% and 36% of the variance in social withdrawal, irritability and stereotypic behaviors. The identification of both sleep and circadian rhythm disturbances as explanatory factors for behavioral difficulties warrants their inclusion in the existing behavioral management strategies for children with ASD.

Purpose: Eye pathology could be related to atypical visual behaviours and impaired social communication through visual cues in children with autism spectrum disorder (ASD). The main purpose of this prospective study was to assess ophthalmological disorders in children with ASD and to investigate the relationships with intellectual disability (ID) and ASD severity., Methods: In this prospective study, comprehensive ophthalmological and oculomotor examinations were performed. ASD severity and verbal and performance intelligence quotients were determined using adapted scales. These clinical data were compared between groups of children based on the presence or absence of ophthalmological disorders and the achievement or not of visual acuity (VA) testing by using non-parametric statistical tests., Results: Amongst a sample of 51 children, ophthalmological disorders were found in 39% of cases, with 35% having significant refractive errors and 10% presenting with strabismus. Children with ASD and ophthalmological disorders had significantly lower verbal (29.8 ± 14.7 compared with 44.3 ± 21.5; p = 0.010) and performance quotients (57.8 ± 18.3 compared with 67.59 ± 20; p = 0.049) but no significant result was found between the presence of ophthalmological disorders and ASD severity, level of communication and social contact, or modulating behaviour when changes occur. Children who did not achieve monocular VA testing (39%) had significantly lower verbal (25.1 ± 9.7 compared with 46.1 ± 20.9; p < 0.001) and performance quotients (52.7 ± 17 compared with 69.8 ± 18.8; p = 0.001), also presented higher social interaction impairment (p = 0.002), and expressed more important behavioural signs (p = 0.007)., Conclusions: Ophthalmological disorders are frequently found in children with ASD, especially in those with ID. Ophthalmologists and child psychiatrists should pay attention to perform ophthalmological examination in children with ASD since eye disorders might remain undetected. A comprehensive examination by a paediatric ophthalmologist would help to improve the individual clinical description and the global intervention., Trial Registration: Clinical trial registration number: NCT02444117.

Introduction: Prevalence of postpartum depression (PPD) ranges from 10 to 15 % of parturients. The impact of the PPD is major on the maternal bond and the health of both mother and child. Its physiopathological mechanisms appear to differ from other types of depression. Today, pharmacotherapy is based on nonspecific treatment, and recent therapeutic advances in this field require a comprehensive approach of the implication of the GABAergic system in the development of PPD. Neurosteroid levels during pregnancy and after parturition and the GABA-A-r modulation are thought to be involved in PPD., Objective: To evaluate if the GABAergic approach is relevant in postpartum depression management., Methods: We conducted a systematic review of literature based on the MEDLINE database with the following Medical Subject Headings (MeSH): "postpartum depression", "GABA", "ganaxolone", "brexanolone", "allopregnanolone", prior to September 2019. We selected articles in English: preclinical and clinical studies, literature review, observational and therapeutic studies., Results: Preclinical models (mouse and rat) show changes in GABAergic inhibition in the peripartum period and correlation between allopregnanolone and GABA-A-r plasticity. This plasticity in the peripartum period maintains levels of inhibition adapted despite increased neurosteroid levels. KO models for the GABA-A-r δ subunit develop depression and anxiety symptoms in the postpartum period, and a change in the expression of the gene coding for the GABA-R alpha-4 subunit was found. Artificial inhibition of progesterone metabolism during post-partum increased depression symptoms. GABAergic fluctuation seems to be interrelated with other systems such as those of oxytocins. A synthetic neurosteroid (SGE-516) was tested on mouse models of PPD, KO for δ-GABA-A-r or KCC2, and showed decreased depressive symptoms and better mothering. Clinical studies confirm neurosteroid fluctuation and changes in the GABAergic system during the peripartum period. Allopregnanolone is the neurosteroid the most studied in PPD, and it is elevated in the brain during the pregnancy. Studies disagree on the presence of significant differences in allopregnanolone plasma levels during pregnancy or postpartum between women with PPD or not. Women with a history of PPD have greater susceptibility to neurosteroid withdrawal. Imagery and genetical data also show a link between allopregnanolone and PPD. The GABA-A-r may not recover in time following a reduced number during pregnancy, and this mismatch between neurosteroid levels and their receptor may trigger PPD. Several randomized controlled trials investigated brexanolone administrated IV, a synthetic formulation of allopregnanolone, and demonstrated a rapid and well tolerated reduction in depressive symptoms. In March 2019 brexanolone obtained FDA approval in PPD indication under the name Zulresso. However, there are differences in the time of beginning of PPD, which could constitute different subgroups of this disease, and which physiopathology could respond to different mechanisms. Prenatal depression does not respond to a GABAergic approach, but women without any risk factor or previous mood disorder developing PPD in the weeks following childbirth could be particularly responsive to this kind of treatment., Conclusion: Disability to modulate GABA-A-r expression during pregnancy and restore its previous state after parturition appears to trigger PPD. The GABAergic system is a promising pharmacotherapy target. From preclinical to clinical studies for about twenty years the GABAergic system has been incriminated and targeted in this challenging mental disease., (Copyright © 2019 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Autism Spectrum Disorder (ASD) is currently diagnosed by the joint presence of social impairments and restrictive, repetitive patterns of behaviors. While the co-occurrence of these two categories of symptoms is at the core of the pathology, most studies investigated only one dimension to understand underlying physiopathology. In this study, we analyzed brain hemodynamic responses in neurotypical adults (CTRL) and adults with autism spectrum disorder during an oddball paradigm allowing to explore brain responses to vocal changes with different levels of saliency (deviancy or novelty) and different emotional content (neutral, angry). Change detection relies on activation of the supratemporal gyrus and insula and on deactivation of the lingual area. The activity of these brain areas involved in the processing of deviancy with vocal stimuli was modulated by saliency and emotion. No group difference between CTRL and ASD was reported for vocal stimuli processing or for deviancy/novelty processing, regardless of emotional content. Findings highlight that brain processing of voices and of neutral/ emotional vocal changes is typical in adults with ASD. Yet, at the behavioral level, persons with ASD still experience difficulties with those cues. This might indicate impairments at latter processing stages or simply show that alterations present in childhood might have repercussions at adult age., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

We evaluated event-based prospective memory (EBPM) in adolescents with Autism, varying the load of the to-be-performed intentions. We included measures of inhibition, working memory and binding. Results showed that increasing the retrospective memory load reduced performance in controls. In Autism, adolescents were impaired in the low load condition with normal performance for the ongoing task, with the reverse pattern in the high load condition. EBPM may be impacted in Autism due to difficulty to process ongoing and EBPM tasks simultaneously possibly because of restricted inhibitory control.

Although ASD (Autism Spectrum Disorder) diagnosis requires the co-occurrence of socio-emotional deficits and inflexible behaviors, the interaction between these two domains remains unexplored. We used an emotional Wisconsin Card Sorting Test adapted to fMRI to explore this question. ASD and control participants matched a central card (a face) with one of four surrounding cards according to one of three rules: frame color, facial identity or expression. Feedback informed participants on whether to change or maintain the current sorting rule. For each rule, we modeled feedback onsets to change, switch (confirming the newly found rule) and maintenance events. "Bias error", which measures participants' willingness to switch, was larger in ASD participants for the emotional sorting rule. Brain activity to change events showed no group differences. In response to switch events significantly larger activity was observed for ASD participants in bilateral Inferior Parietal Sulci. Inflexibility in ASD appears characterized by the unwillingness to switch toward processing socio-emotional information, rather than a major disruption in cognitive flexibility. However, a larger activity to switch events in ASD highlights the need for a higher level of certainty before setting into a stable processing stage, which may be particularly detrimental in the highly changeable socio-emotional environment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Extreme prematurity is known as a risk factor for autism spectrum disorder (ASD). However, the association between prematurity and ASD, for children born moderately and late preterm (MLPT) and those born early term (ET), is less established. This retrospective study aimed to characterize the phenotypic characteristics (i.e. behavioral profile and cognitive abilities) of 254 children with ASD, between 3 and 15 years of age, born MLPT (19 children), ET (60 children) and full term (175 children). MLPT and ET births do not modify ASD symptomatology, but modify cognitive development. The results highlight that incomplete gestation, i.e., MLPT or ET, has a negative impact on both verbal and nonverbal cognitive abilities, in children with neurodevelopmental vulnerability.

Introduction: Psychomotor impairments in Autism Spectrum Disorders (ASD) have frequently been described in scientific literature. Such deficits impact upon the development of social motor function and interfere with the ability to adjust to everyday life. The inclusion of sensory-motor signs in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) confirms their importance in the diagnosis of ASD. Previous literature has shown the presence precocity of these signs, sometimes before the alteration of the social communication. To our knowledge, there are no existing clinical tools to measure sensory-psychomotor deficit, specifically in ASD. The current paper presents the construction and validation of a new scale, designed to evaluate sensory-psychomotor signs in Autism: 'the Sensory-psychomotor Particularities Scale in Autism' (SPSA)., Method: The scale is composed of 160 items describing common sensory-psychomotor signs in autism. These items are grouped into 20 variables: touch, nociception, vestibular sensitivity, proprioceptive sensitivity, vision, auditory, multimodality, tone, posture, balance, global coordination, manual dexterity, body schema, bodily self-consciousness, relational adjustment, emotional expression, use of objects, space, time and tonico-emotional regulation. For each item, the psychomotor therapist evaluated sensori-psychomotor signs according to a five-level Likert scale (0="the sign is never expressed by the person", 1="weakly expressed", 2="moderately expressed", 3="severely expressed" and 4="the sign is very characteristic of the person and very severely expressed"). This is completed by a family interview in order to assess the impact of these signs on everyday situations. The study included 111 children with autism. The presence of neurological and genetic diseases was exclusion criteria. For each child, a global developmental evaluation was carried out by an expert clinical team specializing in ASD. Standardized clinical tools were used: Autism Diagnostic Observation Schedule (ADOS), Childhood Autism Rating Scale (CARS), Behavior Summarized Evaluation scale (BSE-R), Repeated and Restricted Behavior scale (RRB), Movement Assessment Battery for Children (M-ABC), Motor Development Rating scale (MDR), Sensory Profile (SP). Developmental quotients (DQ) were evaluated using various tests depending on age and ability., Results: Factor analysis produced three clinically relevant factors: F1: "sensory-emotional synchronization", F2: "multisensory integration" and F3: "motor skills": each containing a similar quantity of items. They account for roughly equal percentages of variance (18.9%, 18.0%, 16.8%, respectively). The factorial structure does not change if the 26 children with comorbid developmental coordination disorder are removed. The three factors show good internal consistency and excellent inter-rater reliability. F1 is comprised of 6 items: touch, nociception, proprioceptive sensitivity, vision, emotional expression and tonico-emotional regulation. This factor is significantly associated with items of the Sensory Profile (touch processing, poor registration, sensory seeking). F2 is comprised of 5 items: multimodality, bodily self-consciousness, relational adjustment, use of objects and space. This factor is associated with ADOS, BSE-R and RRB scores, and the item "touch processing" of the Sensory Profile. F3 is comprised of 4 items: tone, posture, global coordination, manual dexterity. This factor is associated with the M-ABC, the MDR and the item "low endurance" of the Sensory Profile., Conclusion: The SPSA is a relevant clinical tool to assess the severity of sensory-psychomotor clinical signs in order to describe the individual profiles of children with ASD. It represents a critical step in advancing knowledge of the complex and heterogeneous pattern of psychomotor development in autism. It could make a valuable contribution to the field, both in research and clinical practice., (Copyright © 2019 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Managing an autistic child.General practitioners and pediatricians are on the front line not only to detect atypical developmental trajectories in children but also to guide functional evaluation to facilitate early interventions. They have to inform parents and to guide them toward specialized professionals where further multidisciplinary evaluation will be conducted to define an individualized early intervention program. It is admitted that early intervention is a factor of better prognosis in autism. To help starting early intervention, general practitioners have to be aware of the recent knowledge in clinical aspects of social and communication abilities development but also in the different evaluations and therapeutic interventions which are recommended. General practitioners and pediatricians will keep up following the child evolution as part of the childcare team with parents and specialized professionals., Competing Interests: F. Bonnet-Brilhault déclare n’avoir aucun lien avec l’industrie.

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.

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.

A relative indifference to the human voice is a characteristic of Autism Spectrum Disorder (ASD). Yet, studies of voice perception in ASD provided contradictory results: one study described an absence of preferential response to voices in ASD while another reported a larger activation to vocal sounds than environmental sounds, as seen in typically developed (TD) adults. In children with ASD, an absence of preferential response to vocal sounds was attributed to an atypical response to environmental sounds. To have a better understanding of these contradictions, we re-analyzed the data from sixteen children with ASD and sixteen age-matched TD children to evaluate both inter- and intra-subject variability. Intra-subject variability was estimated with a single-trial analysis of electroencephalographic data, through a measure of inter-trial consistency, which is the proportion of trials showing a positive activity in response to vocal and non-vocal sounds. Results demonstrate a larger inter-subject variability in response to non-vocal sounds, driven by a subset of children with ASD (7/16) who do not show the expected negative Tb peak in response to non-vocal sounds around 200 ms after the start of the stimulation due to a reduced inter-trial consistency. A logistic regression model with age and clinical parameters allowed demonstrating that not a single parameter discriminated the subgroups of ASD participants. Yet, the electrophysiologically-based groups differed on a linear combination of parameters. Children with ASD showing a reduced inter-trial consistency were younger and characterized by lower verbal developmental quotient and less attempt to communicate by voice. This data suggests that a lack of specialization for processing social signal may stem from an atypical processing of environmental sounds, linked to the development of general communication abilities. Discrepancy reported in the literature may arise from that heterogeneity and it may be inadequate to divide children with ASD based only on intellectual quotient or language abilities. This analysis could be a useful tool in providing complementary information for the functional diagnostic of ASD and evaluating verbal communication impairment.

Background : Cranio-facial anomalies frequently occur in neurodevelopmental disorders because both face and brain are derived from neuroectoderm. The identification of differences in the facial phenotype of children with Autism Spectrum Disorders (ASD) may reflect alterations in embryologic brain development in children with ASD. Methods : we evaluated 33 caucasian children with ASD using a 2D computerized photogrammetry. Anthropometric euclidean measurements and landmarks located on the soft tissue of the face and head, were based on five cranio-facial indexes. Relationships between anthropometric z-scores and participant characteristics (i.e., age, Global IQ, severity of autistic symptoms measured using the CARS checklist) were assessed. Results : Cephalic index z-score differed significantly from 0 in our ASD group ( p = 0.019). Moreover, a significant negative correlation was found between Facial Index z-score and CARS score ( p = 0.003); conversely, a positive correlation was found between Interchantal Index z-score and CARS score ( p = 0.028). Conclusion : our measurements shows a dolichocephalic head shape which is not correlated with autism severity. Importantly, two craniofacial markers were significantly correlated with autism severity: increased orbital hyperthelorism and decrease of height of the facial midline. These data support previous findings of craniofacial anomalies in autism spectrum disorder suggesting an "ASD facial phenotype" that could be used to improve ASD diagnoses.

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)'.

LIMK2 is involved in neuronal functions by regulating actin dynamics. Different isoforms of LIMK2 are described in databanks. LIMK2a and LIMK2b are the most characterized. A few pieces of evidence suggest that LIMK2 isoforms might not have overlapping functions. In this study, we focused our attention on a less studied human LIMK2 isoform, LIMK2-1. Compared to the other LIMK2 isoforms, LIMK2-1 contains a supplementary C-terminal phosphatase 1 inhibitory domain (PP1i). We found out that this isoform was hominidae-specific and showed that it was expressed in human fetal brain and faintly in adult brain. Its coding sequence was sequenced in 173 patients with sporadic non-syndromic intellectual disability (ID), and we observed an association of a rare missense variant in the PP1i domain (rs151191437, p.S668P) with ID. Our results also suggest an implication of LIMK2-1 in neurite outgrowth and neurons arborization which appears to be affected by the p.S668P variation. Therefore our results suggest that LIMK2-1 plays a role in the developing brain, and that a rare variation of this isoform is a susceptibility factor in ID., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

This retrospective study aimed to specify the critical period for atypical brain development in individuals with autism spectrum disorder (ASD) using prenatal and postnatal head growth parameters. The sample consisted of 80 Caucasian, unrelated, idiopathic patients with ASD born after 1995. Fetal ultrasound parameters (head circumference [HC], abdominal circumference, and femur length) were obtained during the second and third trimesters of gestation. HC at birth and postnatal parameters at 12 and 24 months of age were also collected. Head overgrowth, assessed by HC, was highlighted during the second (20-26 weeks of amenorrhea) and third (28-36 weeks of amenorrhea) trimesters. Normal growth of body fetal parameters indicated that head overgrowth was not because of overall body overgrowth. Moreover, postnatal results replicated previously and reported head overgrowth. A critical time window for atypical brain development in autism is hypothesized to begin from the 22nd week of amenorrhea. This period is critical for cortical lamination and glial activation. A pathophysiological cascade is suggested with interactions between candidate genes and environmental factors. Autism Research 2018, 11: 1635-1642. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: It is now widely acknowledged in the scientific community, that autism is a neurodevelopmental disorder. Recent evidence from animal and pathological studies has implicated the in utero period. However, the precise time of onset of abnormal brain development remains unknown. This retrospective study reports novel findings, identifying an atypical head growth trajectory in children with autism, during the in utero period (after the 22nd week of amenorrhea). In the same children, postnatal head overgrowth was also observed. Late gestation is identified as a critical period for atypical brain development underlying autism symptoms., (© 2018 International Society for Autism Research, Wiley Periodicals, Inc.)

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.

Voices transmit social signals through speech and/or prosody. Emotional prosody conveys key information about the emotional state of a speaker and is thus a crucial cue that one has to detect in order to develop efficient social communication. Previous studies in adults reported different brain responses to emotional than to neutral prosodic deviancy. The aim of this study was to characterize such specific emotional deviancy effects in school-age children. The mismatch negativity (MMN) and P3a evoked potentials, reflecting automatic change detection and automatic attention orienting, respectively, were obtained for neutral and emotional angry deviants in both school-age children (n = 26) and adults (n = 14). Shorter latencies were found for emotional than for neutral preattentional responses in both groups. However, whereas this effect was observed on the MMN in adults, it appeared in an early discriminative negativity preceding the MMN in children. A smaller P3a amplitude was observed for the emotional than for the neutral deviants at all ages. Overall, the brain responses involved in specific emotional change processing are already present during childhood, but responses have not yet reached an adult pattern. We suggest that these processing differences might contribute to the known improvement of emotional prosody perception between childhood and adulthood.

Background: Children with autism spectrum disorder (ASD) require neurological evaluation to detect sensory-motor impairment. This will improve understanding of brain function in children with ASD, in terms of minor neurological dysfunctions (MNDs)., Methods: We compared 32 ASD children without intellectual disability (IQ ≥ 70) with 32 healthy controls. A standardized and age-specific neurological examination according to Touwen was used to detect the presence of MNDs. Particular attention was paid to severity and type of MNDs., Results: Children with ASD had significantly higher rates of MNDs compared to controls (96.9% versus 15.6%): 81.3% had simple MNDs ( p < 0.0001) and 15.6% had complex MNDs ( p = 0.053). The prevalence of MNDs in the ASD group was significantly higher ( p < 0.0001) than controls. With respect to specific types of MNDs, children with ASD showed a wide range of fine manipulative disability, sensory deficits and choreiform dyskinesia. We also found an excess of associated movements and anomalies in coordination and balance., Conclusions: Results replicate previous findings which found delays in sensory-motor behavior in ASD pointing towards a role for prenatal, natal and neonatal risk factors in the neurodevelopmental theory of autism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Autism and Autism Spectrum Disorder (ASD) cover a large variety of clinical profiles which share two main dimensions: social and communication impairment and repetitive behaviors or restricted interests, which are present during childhood. There is now no doubt that genetic factors are a major component in the etiology of autism but precise physiopathological pathways are still being investigated. Furthermore, developmental trajectories combined with compensatory mechanisms will lead to various clinical and neurophysiological profiles which together constitute this Autism Spectrum Disorder. To better understand the pathophysiology of autism, comprehension of key neurophysiological mechanisms and brain circuits underlying the different bioclinical profiles is thus crucial. To achieve this goal we propose a strategy which investigates different levels of information processing from sensory perception to complex cognitive processing, taking into account the complexity of the stimulus and whether it is social or non-social in nature. In order to identify different developmental trajectories and to take into account compensatory mechanisms, we further propose that such protocols should be carried out in individuals from childhood to adulthood representing a wide variety of clinical forms., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Mixed and inconsistent findings have been reported across languages concerning grammatical morphology in speakers with Autism Spectrum Disorders (ASD). Some researchers argue for a selective sparing of grammar whereas others claim to have identified grammatical deficits. The present study aimed to investigate this issue in 26 participants with ASD speaking European French who were matched on age, gender and SES to 26 participants with typical development (TD). The groups were compared regarding their productivity and accuracy of syntactic and agreement categories using the French MOR part-of-speech tagger available from the CHILDES. The groups significantly differed in productivity with respect to nouns, adjectives, determiners, prepositions and gender markers. Error analysis revealed that ASD speakers exhibited a disrupted behaviour in grammatical morphology. They made gender, tense and preposition errors and they omitted determiners and pronouns in nominal and verbal contexts. ASD speakers may have a reduced sensitivity to perceiving and processing the distributional structure of syntactic categories when producing grammatical morphemes and agreement categories. The theoretical and cross-linguistic implications of these findings are discussed.

Background: Individuals with autism spectrum disorder (ASD) show a relative indifference to the human voice. Accordingly, and contrarily to their typically developed peers, adults with autism do not show a preferential response to voices in the superior temporal sulcus; this lack of voice-specific response was previously linked to atypical processing of voices. In electroencephalography, a slow event-related potential (ERP) called the fronto-temporal positivity to voice (FTPV) is larger for vocal than for non-vocal sounds, resulting in a voice-sensitive response over right fronto-temporal sites. Here, we investigated the neurophysiological correlates of voice perception in children with and without ASD., Methods: Sixteen children with autism and 16 age-matched typically developing children heard vocal (speech and non-speech) and non-vocal sounds while their electroencephalographic activity was recorded; overall IQ was smaller in the group of children with ASD. ERP amplitudes were compared using non-parametric statistical tests at each electrode and in successive 20-ms time windows. Within each group, differences between conditions were assessed using a non-parametric Quade test between 0 and 400 ms post-stimulus. Inter-group comparisons of ERP amplitudes were performed using non-paired Kruskal-Wallis tests between 140 and 180 ms post-stimulus., Results: Typically developing children showed the classical voice-sensitive response over right fronto-temporal electrodes, for both speech and non-speech vocal sounds. Children with ASD did not show a preferential response to vocal sounds. Inter-group analysis showed no difference in the processing of vocal sounds, both speech and non-speech, but significant differences in the processing of non-vocal sounds over right fronto-temporal sites., Conclusions: Our results demonstrate a lack of voice-preferential response in children with autism spectrum disorders. In contrast to observations in adults with ASD, the lack of voice-preferential response was attributed to an atypical response to non-vocal sounds, which was overall more similar to the event-related potentials evoked by vocal sounds in both groups. This result suggests atypical maturation processes in ASD impeding the specialization of temporal regions in voice processing.

With approximately 67 million individuals affected worldwide, autism spectrum disorder (ASD) is the fastest growing neurodevelopmental disorder (United Nations, 2011), with a prevalence estimated to be 1/100. In France ASD affects approximately 600,000 individuals (from childhood to adulthood, half of whom are also mentally retarded), who thus have a major handicap in communication and in adapting to daily life, which leads autism to be recognized as a national public health priority. ASD is a neurodevelopmental disorder that affects several domains (i.e., socio-emotional, language, sensori-motor, executive functioning). These disorders are expressed early in life with an age of onset around 18 months. Despite evidence suggesting a strong genetic link with ASD, the genetic determinant remains unclear. The clinical picture is characterized by impairments in social interaction and communication and the presence of restrictive and repetitive behaviors (DSM-5, ICD-10). However, in addition to these two main dimensions there is significant comorbidity between ASD and other neurodevelopmental disorders such as attention deficit hyperactivity disorder or with genetic and medical conditions. One of the diagnostic features of ASD is its early emergence: symptoms must begin in early childhood for a diagnosis to be given. Due to brain plasticity, early interventions are essential to facilitate clinical improvement. Therefore, general practitioners and pediatricians are on the front line to detect early signs of ASD and to guide both medical explorations and early rehabilitation., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background/aims: New surgical techniques have recently been developed in order to compensate for visual impairment and to improve visual comfort for patients with presbyopia. However, the results are still variable, depending on the correction modality used and/or the patient. The main purpose of this study was to identify predictive electrophysiological markers of postcorrection visual comfort for patients with presbyopia., Methods: Thirteen patients with presbyopia (aged between 45 and 60 years) received successive randomised presbyopia compensation with contact lenses supplying monovision (one eye corrected for distance, the other for near vision) and simultaneous vision (progressive lenses). The period for each type of correction lasted for 3 weeks, with a 2-week break without any presbyopia compensation between the two test phases. Examinations were performed at entry (T0) and after each correction modality (Tmono and Tsimult). They included testing for near and distance visual acuity, stereoacuity, binocular contrast sensitivity and electrophysiological recordings (monocular and binocular visual evoked potentials)., Results: Follow-up showed no significant differences between the two compensation modalities for either clinical or electrophysiological criteria. However, a significant correlation was found between the difference in TNO score (monovision-simultaneous vision) and the P100 latency evoked by the binocular pattern at T0, suggesting that late P100 latency could be associated with a lesser degree of decrease in stereoacuity with monovision., Conclusions: While our findings do not permit decisions regarding the superiority of one type of compensation over another, these preliminary results support using the P100 latency evoked by binocular patterns as a predictor of postcompensation stereoacuity., Trial Registration Number: NCT02444130, Pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Detection of changes in facial emotional expressions is crucial to communicate and to rapidly and automatically process possible threats in the environment. Recent studies suggest that expression-related visual mismatch negativity (vMMN) reflects automatic processing of emotional changes. In the present study we used a controlled paradigm to investigate the specificity of emotional change-detection. In order to disentangle specific responses to emotional deviants from that of neutral deviants, we presented neutral expression as standard stimulus ( p = 0.80) and both angry and neutral expressions as deviants ( p = 0.10, each). In addition to an oddball sequence, an equiprobable sequence was presented, to control for refractoriness and low-level differences. Our results showed that in an early time window (100-200 ms), the controlled vMMN was greater than the oddball vMMN only for the angry deviant, suggesting the importance of controlling for refractoriness and stimulus physical features in emotion related studies. Within the controlled vMMN, angry and neutral deviants both elicited early and late peaks occurring at 140 and 310 ms, respectively, but only the emotional vMMN presented sustained amplitude after each peak. By directly comparing responses to emotional and neutral deviants, our study provides evidence of specific activity reflecting the automatic detection of emotional change. This differs from broader "visual" change processing, and suggests the involvement of two partially-distinct pre-attentional systems in the detection of changes in facial expressions.

Investigation into the earliest signs of autism in infants has become a significant sub-field of autism research. This work invokes specific ethical concerns such as use of 'at-risk' language, communicating study findings to parents and the future perspective of enrolled infants when they reach adulthood. This study aimed to ground this research field in an understanding of the perspectives of members of the autism community. Following focus groups to identify topics, an online survey was distributed to autistic adults, parents of children with autism and practitioners in health and education settings across 11 European countries. Survey respondents (n = 2317) were positively disposed towards early autism research, and there was significant overlap in their priorities for the field and preferred language to describe infant research participants. However, there were also differences including overall less favourable endorsement of early autism research by autistic adults relative to other groups and a dislike of the phrase 'at-risk' to describe infant participants, in all groups except healthcare practitioners. The findings overall indicate that the autism community in Europe is supportive of early autism research. Researchers should endeavour to maintain this by continuing to take community perspectives into account., (© The Author(s) 2016.)

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.

Phenotypic and genetic heterogeneity is predominant in autism spectrum disorders (ASD), for which the molecular and pathophysiological bases are still unclear. Significant comorbidity and genetic overlap between ASD and other neurodevelopmental disorders are also well established. However, little is understood regarding the frequent observation of a wide phenotypic spectrum associated with deleterious mutations affecting a single gene even within multiplex families. We performed a clinical, neurophysiological (in vivo electroencephalography-auditory-evoked related potentials) and genetic (whole-exome sequencing) follow-up analysis of two families with known deleterious NLGN4X gene mutations (either truncating or overexpressing) present in individuals with ASD and/or with intellectual disability (ID). Complete phenotypic evaluation of the pedigrees in the ASD individuals showed common specific autistic behavioural features and neurophysiological patterns (abnormal MisMatch Negativity in response to auditory change) that were absent in healthy parents as well as in family members with isolated ID. Whole-exome sequencing in ASD patients from each family identified a second rare inherited genetic variant, affecting either the GLRB or the ANK3 genes encoding NLGN4X interacting proteins expressed in inhibitory or in excitatory synapses, respectively. The GRLB and ANK3 mutations were absent in relatives with ID as well as in control databases. In summary, our findings provide evidence of a double-hit genetic model focused on excitatory/inhibitory synapses in ASD, that is not found in isolated ID, associated with an atypical in vivo neurophysiological pattern linked to predictive coding.

Little is known about use of early interventions for autism spectrum disorder in Europe. Parents of children with autism spectrum disorder aged 7 years or younger (N = 1680) were recruited through parent organisations in 18 European countries and completed an online survey about the interventions their child received. There was considerable variation in use of interventions, and in some countries more than 20% of children received no intervention at all. The most frequently reported interventions were speech and language therapy (64%) and behavioural, developmental and relationship-based interventions (55%). In some parts of Europe, use of behavioural, developmental and relationship-based interventions was associated with higher parental educational level and time passed since diagnosis, rather than with child characteristics. These findings highlight the need to monitor use of intervention for children with autism spectrum disorder in Europe in order to contrast inequalities., (© The Author(s) 2015.)

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., (© 2016 S. Karger AG, Basel.)

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with no clinical biomarker. The aims of this study were to characterize a metabolic signature of ASD and to evaluate multiplatform analytical methodologies in order to develop predictive tools for diagnosis and disease follow-up. Urine samples were analyzed using (1)H and (1)H-(13)C NMR-based approaches and LC-HRMS-based approaches (ESI+ and ESI- on HILIC and C18 chromatography columns). Data tables obtained from the six analytical modalities on a training set of 46 urine samples (22 autistic children and 24 controls) were processed by multivariate analysis (orthogonal partial least-squares discriminant analysis, OPLS-DA). The predictions from each of these OPLS-DA models were then evaluated using a prediction set of 16 samples (8 autistic children and 8 controls) and receiver operating characteristic curves. Thereafter, a data fusion block-scaling OPLS-DA model was generated from the 6 best models obtained for each modality. This fused OPLS-DA model showed an enhanced performance (R(2)Y(cum) = 0.88, Q(2)(cum) = 0.75) compared to each analytical modality model, as well as a better predictive capacity (AUC = 0.91, p-value = 0.006). Metabolites that are most significantly different between autistic and control children (p < 0.05) are indoxyl sulfate, N-α-acetyl-l-arginine, methyl guanidine, and phenylacetylglutamine. This multimodality approach has the potential to contribute to find robust biomarkers and characterize a metabolic phenotype of the ASD population.

Introduction: Teenagers and adults with intellectual disabilities are nowadays "over-handicapped", often due to lack of care in self-sufficiency and continued learning, two essential domains for living in a community. Their cognitive limits, particularly on the executive functions, could be an obstacle to their involvement in the daily life activities, through their difficulties to plan, anticipate, shift and maintain information in working memory. These high level mental functions can be taught with the CRT program (Cognitive Remediation Therapy - Wykes and Reader 2005) developed in other pathologies and providing an adaptation regarding the developmental level of the person., Methods: Firstly, it is essential to determine cognitive developmental levels of the teenager or the adult, using standard tools, such as Wechsler scales. Secondly, functional and/or adaptative levels have to be assessed using specific tools, such as the Vineland Adaptative Behavior Scale 2nd Edition (VABS-II, Sparrow et al., 2005) and the Functional Intervention Scale (EFI, Willaye et al., 2005). Finally, in order to clearly distinguish what are the preserved and impaired cognitive domains, standard tools assessing executive functions such as the Wisconsin Card Sorting Test, the Tower of London, Stroop Test and BADS are used if possible for the patient. The setting of cognitive remediation programs, previously developed for schizophrenic patients, requires adaptation for teenagers and adults with intellectual disabilities, taking into account the limitation of their cognitive abilities. In this paper, we will show that the CRT method for cognitive remediation is particularly relevant for subjects with intellectual disabilities. This method is hence focused on strategies and exercises to improve working memory, categorization and moreover executive functions. Of course this method might need adaptations, with examples based on simplification of the different tasks, notably for verbal materials, and with variations of the media used. These sessions will be part of a wider individualized caring project, allowing the person to transfer the cognitive acquisitions to his/her daily life., Conclusion: The use of cognitive programs adapted to people with intellectual disabilities can provide benefits in the development of autonomy and daily life activities, leading to a better quality of life and self-esteem., (Copyright © 2014 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

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.

There is growing evidence that auditory selective attention operates via distinct facilitatory and inhibitory mechanisms enabling selective enhancement and suppression of sound processing, respectively. The lateral prefrontal cortex (LPFC) plays a crucial role in the top-down control of selective attention. However, whether the LPFC controls facilitatory, inhibitory, or both attentional mechanisms is unclear. Facilitatory and inhibitory mechanisms were assessed, in patients with LPFC damage, by comparing event-related potentials (ERPs) to attended and ignored sounds with ERPs to these same sounds when attention was equally distributed to all sounds. In control subjects, we observed 2 late frontally distributed ERP components: a transient facilitatory component occurring from 150 to 250 ms after sound onset; and an inhibitory component onsetting at 250 ms. Only the facilitatory component was affected in patients with LPFC damage: this component was absent when attending to sounds delivered in the ear contralateral to the lesion, with the most prominent decreases observed over the damaged brain regions. These findings have 2 important implications: (i) they provide evidence for functionally distinct facilitatory and inhibitory mechanisms supporting late auditory selective attention; (ii) they show that the LPFC is involved in the control of the facilitatory mechanisms of auditory attention., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Adolescence is a key period for frontal cortex maturation necessary for the development of cognitive ability. Sustained attention and prediction are cognitive functions critical for optimizing sensory processing, and essential to efficiently adapt behaviors in an ever-changing world. The aim of the current study was to investigate the brain developmental trajectories of attentive and predictive processing through adolescence. We recorded EEG in 36 participants from the age of 12-24 years (three age groups: 12-14, 14-17, 18-24 years) to target development during early and late adolescence, and early adulthood. We chose a visual target detection task which loaded upon sustained attention, and we manipulated target predictability. Continued maturation of sustained attention after age 12 was evidenced by improved performance (hits, false alarms (FAs) and sensitivity) in a detection task, associated with a frontal shift in the scalp topographies of the Contingent Negative Variation (CNV) and P3 responses, with increasing age. No effect of age was observed on predictive processing, with all ages showing similar benefits in reaction time, increases in P3 amplitude (indexing predictive value encoding and memorization), increases in CNV amplitude (corresponding to prediction implementation) and reduction in target-P3 latency (reflecting successful prediction building and use), with increased predictive content. This suggests that adolescents extracted and used predictive information to generate predictions as well as adults. The present results show that predictive and attentive processing follow distinct brain developmental trajectories: prediction abilities seem mature by the age of 12 and sustained attention continues to improve after 12-years of age and is associated with maturational changes in the frontal cortices.

Olfactory disorders constitute a potential marker of many diseases and are considered valuable clues to the diagnosis and evaluation of progression for many disorders. The most commonly used test for the evaluation of impairments of olfactory identification requires the active participation of the subject, who must select the correct name of the perceived odor from a list. An alternative method is required because speech may be impaired or not yet learned in many patients. As odor identification is known to be facilitated by searching for visual clues, we aimed to develop an objective, vision-based approach for the evaluation of odor identification. We used an eye tracking method to quantify pupillary and ocular responses during the simultaneous presentation of olfactory and visual stimuli, in 39 healthy participants aged from 19 to 77years. Odor presentation triggered an increase in pupil dilation and gaze focus on the picture corresponding to the odor presented. These results suggest that odorant stimuli increase recruitment of the sympathetic system (as demonstrated by the reactivity of the pupil) and draw attention to the visual clue. These results validate the objectivity of this method., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To investigate brain asymmetry of the temporal auditory evoked potentials (T-complex) in response to monaural stimulation in children compared to adults., Methods: Ten children (7 to 9 years) and ten young adults participated in the study. All were right-handed. The auditory stimuli used were tones (1100 Hz, 70 dB SPL, 50 ms duration) delivered monaurally (right, left ear) at four different levels of stimulus onset asynchrony (700-1100-1500-3000 ms). Latency and amplitude of responses were measured at left and right temporal sites according to the ear stimulated., Results: Peaks of the three successive deflections (Na-Ta-Tb) of the T-complex were greater in amplitude and better defined in children than in adults. Amplitude measurements in children indicated that Na culminates on the left hemisphere whatever the ear stimulated whereas Ta and Tb culminate on the right hemisphere but for left ear stimuli only. Peak latency displayed different patterns of asymmetry. Na and Ta displayed shorter latencies for contralateral stimulation. The original finding was that Tb peak latency was the shortest at the left temporal site for right ear stimulation in children. Amplitude increased and/or peak latency decreased with increasing SOA, however no interaction effect was found with recording site or with ear stimulated., Conclusion: Our main original result indicates a right ear-left hemisphere timing advantage for Tb peak in children. The Tb peak would therefore be a good candidate as an electrophysiological marker of ear advantage effects during dichotic stimulation and of functional inter-hemisphere interactions and connectivity in children., (Copyright © 2014. Published by Elsevier B.V.)

It is not clear whether self-stimuli are processed by the brain as highly familiar overlearned stimuli or as self-specific stimuli. This study examined the neural processes underlying discrimination of one's own voice (OV) compared with a familiar voice (FV) using electrophysiological methods. Event-related potentials were recorded while healthy subjects (n = 15) listened passively to oddball sequences composed of recordings of the French vowel /a/ pronounced either by the participant her/himself, or by a familiar person or an unknown person. The results indicated that, although mismatch negativity displayed similar peak latency and amplitude in both conditions, the amplitude of the subsequent P3a was significantly smaller in response to OV compared with a FV. This study therefore indicated that fewer pre-attentional processes are involved in the discrimination of one's OV than in the discrimination of FVs., (© The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

The euthymic phase of bipolar disorders may be associated with residual emotional and/or subsyndromal symptoms. The aim of this study was to compare subjective and physiologic emotional response to negative, neutral and positive emotion eliciting pictures between euthymic bipolar patients (n=26) and healthy controls (n=30). We evaluated emotional response using an emotional induction method with emotional pictures from the International Affective Picture System. We measured subjective emotional response with the Self-Assessment Manikin and physiological emotional response by measuring pupil size. No difference was found between euthymic bipolar patients and controls regarding subjective emotional response. However, upon viewing positive pictures, pupil dilation was significantly lower in euthymic bipolar patients compared to controls. This finding suggests that euthymic bipolar phase may be associated with reduced physiologic emotional response to positive valence, which is consistent with a more general negative emotional bias or can be understood as a residual emotional subsyndromal symptom., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Autism spectrum disorders (ASD) are neurodevelopmental diseases with complex genetic and environmental etiological factors. Although genetic causes play a significant part in the etiology of ASD, metabolic disturbances may also play a causal role or modulate the clinical features of ASD. The number of ASD studies involving metabolomics is increasing, and sometime with conflicting findings. We assessed the metabolomics profiling of urine samples to determine a comprehensive biochemical signature of ASD. Furthermore, to date no study has combined metabolic profiles obtained from different analytical techniques to distinguish patient with ASD from healthy individuals. We obtained (1)H-NMR spectra and 2D (1)H-(13)C HSQC NMR spectra from urine samples of patients with ASD or healthy controls. We analyzed these spectra by multivariate statistical data analysis. The OPLS-DA model obtained from (1)H NMR spectra showed a good discrimination between ASD samples and non-ASD samples (R(2)Y(cum) = 0.70 and Q(2) = 0.51). Combining the (1)H NMR spectra and the 2D (1)H-(13)C HSQC NMR spectra increased the overall quality and predictive value of the OPLS-DA model (R(2)Y(cum) = 0.84 and Q(2) = 0.71), leading to a better sensitivity and specificity. Urinary excretion of succinate, glutamate and 3-methyl-histidine differed significantly between ASD and non-ASD samples. Urinary screening of children with neurodevelopmental disorders by combining NMR spectroscopies (1D and 2D) in multivariate analysis is a better sensitive and a straightforward method that could help the diagnosis ASD.

Background: Auditory verbal hallucinations (AVH) in schizophrenia may arise because of aberrant speech perception. We used an electroencephalography method to examine the neural processes underlying speech perception in schizophrenic patients with hallucinations., Methods: Cortical event-related potentials (ERPs) were analyzed topographically (scalp potential and scalp current density (SCD) mapping) in response to the vowel /a/ using a passive paradigm in 26 patients with schizophrenia., Results: From the SCD distribution of the P1 peak, we showed that, whereas the hallucination score (PSYRATS) was negatively correlated with the amplitude of the frontal currents, the PANSS negative symptom score was negatively correlated with the amplitude of the temporal currents in patients with schizophrenia., Conclusions: These results provide evidence that AVH and negative symptoms are associated with abnormal early processing of speech. Whereas AVH are related to decreased early frontal activation, negative symptoms are associated with a reduced early temporal response., (Copyright © 2014 Elsevier B.V. All rights reserved.)

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., (© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

We describe the case of a 23-year-old woman with Gender Identity Disorder (GID) asking for a cross-sex hormonal treatment with sex reassignment surgery and who was recently diagnosed with Autism Spectrum Disorder (ASD). Gender identity clinics are now reporting an overrepresentation of individuals with ASD among GID patients. The prevalence of ASD is 10-fold higher among GID patients than in general population. However, few case reports or studies have explored the co-occurrence of ASD and GID. This co-occurrence is relevant for diagnostic and clinical management and also raises important theoretical issues.

Objective: To investigate cortical auditory evoked potentials (CAEPs) in pediatric hearing aid (HA) users, with and without language impairment., Design: CAEPs were measured in 11 pediatric HA users (age: 8-12 years) with moderate bilateral sensorineural hearing loss (HL); participants were classified according to language ability. CAEPs were also measured for a control group of 11 age-matched, normal-hearing (NH) children., Results: HL children without language impairment exhibited normal CAEPs. HL children with language impairment exhibited atypical temporal CAEPs, characterized by the absence of N1c; frontocentral responses displayed normal age-related patterns., Conclusion: Results suggest that abnormal temporal brain function may underlie language impairment in pediatric HA users with moderate sensorineural HL.