[The BSE2 scale : A new clinical tool for the diagnostic of ASD within NDDs]. / L'échelle ECA2 : un nouvel outil clinique pour le diagnostic du TSA au sein des TND.

OBJECTIVES: The behavioral summarized evaluation scales, the BSE and its revised version the BSE-R, were developed and validated in the 1980-1990s. The BSE-R is still used daily by clinical teams in France and foreign countries, and it is recommended by the French Health Authority (2018). Having taken into account knowledge improvement in neurodevelopment and autism spectrum disorder (ASD) and the importance of observation by relatives in ecological context, the second version of the BSE was developed. This paper presents the construction and the validation study of the second version of the behavioral summarized evaluation scale, the BSE2 and the BSE2-P rated by parents. METHODS: Construct validity of the BSE2 scale has been studied in a population of 244 children and adolescents with ASD according to DSM-5 criteria, aged from 30 months to 18 years. Discriminant validity has been analyzed using a population of 86 patients of the same age, with neurodevelopmental disorder (NDD) without comorbidity of ASD. RESULTS: BSE2 comprises 30 items and is a two-dimensional scale as was BSE-R. Both dimensions, labelled "Interaction" (11 items) and "Modulation" (11 items), accounted for 41.7 % of the total variance. They describe autism severity and are in accordance with the two DSM-5 dimensions. Internal consistency (0.927 and 0.850 respectively) and inter-rater reliability (0.932 and 0.897 respectively) are good or excellent for both dimensions. Sensibility and specificity (0.758 and 0.767 respectively) range BSE2 among the tools with good psychometric properties. The parent version, BSE2-P, dedicated to ecological context is easily rated by parents. CONCLUSIONS: BSE2 scale for children and adolescents is a clinical tool with good psychometric properties. Its two-dimensional structure is in accordance with DSM-5 criteria. This scale covers all spectrum of ASD clinical forms in both children and adolescents. It can be used to identify ASD in complex neurodevelopmental disorders with several comorbidities and can help to distinguish autism symptomatology from other neurodevelopmental diagnoses. Furthermore, this scale allows to expand the rating context, involving parents to define and adjust the individualized therapeutic project. Thus the BSE2 is a valuable clinical tool for practitioners for both diagnosis and follow-up.

GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disability.

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.

Brain correlates of automatic visual change detection.

A number of studies support the presence of visual automatic detection of change, but little is known about the brain generators involved in such processing and about the modulation of brain activity according to the salience of the stimulus. The study presented here was designed to locate the brain activity elicited by unattended visual deviant and novel stimuli using fMRI. Seventeen adult participants were presented with a passive visual oddball sequence while performing a concurrent visual task. Variations in BOLD signal were observed in the modality-specific sensory cortex, but also in non-specific areas involved in preattentional processing of changing events. A degree-of-deviance effect was observed, since novel stimuli elicited more activity in the sensory occipital regions and at the medial frontal site than small changes. These findings could be compared to those obtained in the auditory modality and might suggest a "general" change detection process operating in several sensory modalities.

[Repetitive and restricted behaviours (RRB) in autism: clinical evaluation]. / Comportements répétés et restreints (C2R) dans les troubles autistiques: évaluation clinique.

INTRODUCTION: Restricted and repetitive behaviours (RRB) represent a common problem throughout the autistic spectrum. They comprise a wide range of behavioural manifestations that persist over time and resist therapeutics. Furthermore, degrees of heterogeneity have been reported in the clinical expression of autistic syndrome, particularly in the restricted and repetitive aspects. Advances are needed in the understanding of this complex and heterogeneous clinical dimension of autism to improve efficacy of therapeutics. LITERATURE FINDINGS: Most clinical studies have subdivided RRB into "lower-level" sensory-motor behaviours and "higher-level" behaviours, which are more complex and characteristic features of autism. However, none of these studies have taken into account all the forms of RRB. To date, there is no specific and thorough tool to evaluate this dimension of autism. From the analysis of the literature, we proposed a list of 43 behaviours covering the full range of repetitive, restricted and stereotyped activities observed in autism. AIM OF THE STUDY: The aim of the present study was to test the relevance of these 43 RRB in a family context. CLINICAL SETTINGS: The participants were 14 children with an autism spectrum disorder, aged from six to 16 years. Circumscribed interests were the most commonly reported RRB, and motor stereotypies, aggressive and body-focused behaviours were the least expressed behaviours. RESULTS: Multivariate statistical analysis identified three groups of children with different behavioural profiles and three clusters of RRB, i.e. repetitive motor behaviours, repetitive sensory-vocal behaviours and restricted ideational behaviours. DISCUSSION: Although these preliminary results need to be validated in a wider population, the list of 43 RRB allowed us to describe accurately this symptomatology of autism and to confirm the heterogeneity of this dimension of autistic disorders. The identification of clinical subgroups, possibly underlain by different psychopathological or physiopathological factors would help research and contribute to the development of specific new therapeutic strategies which are still needed to improve quality of life of patients with autistic disorder and their families.

Emotional prosody in congenital amusia: Impaired and spared processes.

Congenital amusia is a lifelong deficit of music processing, in particular of pitch processing. Most research investigating this neurodevelopmental disorder has focused on music perception, but pitch also has a critical role for intentional and emotional prosody in speech. Two previous studies investigating amusics' emotional prosody recognition have shown either some deficit or no deficit (compared to controls). However, these previous studies have used only long sentence stimuli, which allow for limited control over acoustic content. Here, we tested amusic individuals for emotional prosody perception in sentences and vowels. For each type of material, participants performed an emotion categorization task, followed by intensity ratings of the recognized emotion. Compared to controls, amusic individuals had similar recognition of emotion in sentences, but poorer performance in vowels, especially when distinguishing sad and neutral stimuli. These lower performances in amusics were linked with difficulties in processing pitch and spectro-temporal parameters of the vowel stimuli. For emotion intensity, neither sentence nor vowel ratings differed between participant groups, suggesting preserved implicit processing of emotional prosody in amusia. These findings can be integrated into previous data showing preserved implicit processing of pitch and emotion in amusia alongside deficits in explicit recognition tasks. They are thus further supporting the hypothesis of impaired conscious analysis of pitch and timbre in this neurodevelopmental disorder.

Assessment of auditory discrimination in hearing-impaired patients.

Hearing loss can impair auditory discrimination, especially in noisy environments, requiring greater listening effort, which can impact socio-occupational life. To assess the impact of hearing loss in noisy environments, clinicians may use subjective or objective methods. Subjective methods, such as speech audiometry in noise, are used in clinical practice to assess reported discomfort. Objective methods, such as cortical auditory evoked potentials (CAEPs), are mainly used in research. Subjective methods mainly comprise speech audiometry in noise, in which the signal-to-noise ratio can be varied so as to determine the individual speech recognition threshold, with and without hearing rehabilitation, the aim being to highlight any improvement in auditory performance. Frequency discrimination analysis is also possible. Objective methods assess auditory discrimination without the patient's active participation. One technique used for patients with auditory rehabilitation is the study of auditory responses by CAEPs. This electrophysiological examination studies cortical auditory rehabilitation oddball paradigms, enabling wave recordings such as mismatch negativity, P300 or N400, and analysis of neurophysiological markers according to auditory performance. The present article reviews all these methods, in order to better understand and evaluate the impact of hearing loss in everyday life.

Emotional prosodic change detection in autism Spectrum disorder: an electrophysiological investigation in children and adults.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by atypical behaviors in social environments and in reaction to changing events. While this dyad of symptoms is at the core of the pathology along with atypical sensory behaviors, most studies have investigated only one dimension. A focus on the sameness dimension has shown that intolerance to change is related to an atypical pre-attentional detection of irregularity. In the present study, we addressed the same process in response to emotional change in order to evaluate the interplay between alterations of change detection and socio-emotional processing in children and adults with autism. METHODS: Brain responses to neutral and emotional prosodic deviancies (mismatch negativity (MMN) and P3a, reflecting change detection and orientation of attention toward change, respectively) were recorded in children and adults with autism and in controls. Comparison of neutral and emotional conditions allowed distinguishing between general deviancy and emotional deviancy effects. Moreover, brain responses to the same neutral and emotional stimuli were recorded when they were not deviants to evaluate the sensory processing of these vocal stimuli. RESULTS: In controls, change detection was modulated by prosody: in children, this was characterized by a lateralization of emotional MMN to the right hemisphere, and in adults, by an earlier MMN for emotional deviancy than for neutral deviancy. In ASD, an overall atypical change detection was observed with an earlier MMN and a larger P3a compared to controls suggesting an unusual pre-attentional orientation toward any changes in the auditory environment. Moreover, in children with autism, deviancy detection depicted reduced MMN amplitude. In addition in children with autism, contrary to adults with autism, no modulation of the MMN by prosody was present and sensory processing of both neutral and emotional vocal stimuli appeared atypical. CONCLUSIONS: Overall, change detection remains altered in people with autism. However, differences between children and adults with ASD evidence a trend toward normalization of vocal processing and of the automatic detection of emotion deviancy with age.

Evaluating Sex and Age Differences in ADI-R and ADOS Scores in a Large European Multi-site Sample of Individuals with Autism Spectrum Disorder.

Research on sex-related differences in Autism Spectrum Disorder (ASD) has been impeded by small samples. We pooled 28 datasets from 18 sites across nine European countries to examine sex differences in the ASD phenotype on the ADI-R (376 females, 1763 males) and ADOS (233 females, 1187 males). On the ADI-R, early childhood restricted and repetitive behaviours were lower in females than males, alongside comparable levels of social interaction and communication difficulties in females and males. Current ADI-R and ADOS scores showed no sex differences for ASD severity. There were lower socio-communicative symptoms in older compared to younger individuals. This large European ASD sample adds to the literature on sex and age variations of ASD symptomatology.

Bioclinical profiles of autism and other developmental disorders using a multivariate statistical approach.

To study the relationships between clinical and biological data that are necessary for physiopathological analysis in the field of developmental disorders, we developed a quantified grouping system, based on four developmental assessment parameters. Parallel with this clinical research, we developed electrophysiological procedures adapted to the pathology of autism. In this paper, we report the utilization of an original multivariate descriptive statistical approach (correspondence analysis followed by cluster analysis) that allowed us to identify different bioclinical profiles using these clinical and electrophysiological data conjointly. These profiles are believed to be evidence for different underlying cerebral dysfunctions. This procedure proved effective in identifying two main bioclinical dimensions in a population of 145 developmentally disordered children. These dimensions reflect the association of intellectual impairment and centroparietal electrophysiological reactivity on the one hand, and autistic behavior and temporal electrophysiological reactivity on the other. This study, performed on a large population of children using objective methods of data analysis, provides validation of numerous multidisciplinary studies of autism and other developmental disorders carried out on small samples of children.

Maturation of frontal and temporal components of mismatch negativity (MMN) in children.

The mismatch negativity (MMN) response of auditory ERPs in adults appears to result from several overlapping components involving both frontal and temporal brain areas. Our aim was to test whether a similar configuration could be observed in children, and to examine the maturation rates of the different components. MMN (standard tones: 1000 Hz, deviants: 1100 Hz) was recorded from 28 scalp electrodes in 24 healthy children aged from 5 to 10 and in eight adults for comparison. Scalp current density analysis revealed both temporal and frontal components in children of all ages as well as in adults. Moreover the amplitudes of the temporal components were significantly greater in children than in adults, whereas the frontal components were similar at all ages. The results strongly suggest that MMN is mediated by at least two separate neural systems, and that the frontal system matures earlier than the sensory-specific system.

Effect of acute zinc deficiency on insulin receptor binding in rat adipocytes.

Considerable data have been reported on the relationship between insulin resistance and zinc deficiency. In this study, insulin receptor binding was measured in isolated rat adipocytes. Two assays were carried out at 37 degrees C (binding and internalization) and 16 degrees C (binding) using 125I insulin 0.05-20 nM. A decreased insulin receptor binding was observed in zinc-deficient rat adipocytes, but we could not make any distinction between the specific zinc depletion effects and the effects of the caloric restriction induced by zinc deficiency.

Electrophysiological evidence of atypical visual change detection in adults with autism.

Although atypical change detection processes have been highlighted in the auditory modality in autism spectrum disorder (ASD), little is known about these processes in the visual modality. The aim of the present study was therefore to investigate visual change detection in adults with ASD, taking into account the salience of change, in order to determine whether this ability is affected in this disorder. Thirteen adults with ASD and 13 controls were presented with a passive visual three stimuli oddball paradigm. The findings revealed atypical visual change processing in ASD. Whereas controls displayed a vMMN in response to deviant and a novelty P3 in response to novel stimuli, patients with ASD displayed a novelty P3 in response to both deviant and novel stimuli. These results thus suggested atypical orientation of attention toward unattended minor changes in ASD that might contribute to the intolerance of change.

fMRI investigation of visual change detection in adults with autism.

People with autism spectrum disorders (ASD) may show unusual reactions to unexpected changes that appear in their environment. Although several studies have highlighted atypical auditory change processing in ASD, little is known in this disorder about the brain processes involved in visual automatic change detection. The present fMRI study was designed to localize brain activity elicited by unexpected visual changing stimuli in adults with ASD compared to controls. Twelve patients with ASD and 17 healthy adults participated in the experiment in which subjects were presented with a visual oddball sequence while performing a concurrent target detection task. Combined results across participants highlight the involvement of both occipital (BA 18/19) and frontal (BA 6/8) regions during visual change detection. However, adults with ASD display greater activity in the bilateral occipital cortex and in the anterior cingulate cortex (ACC) associated with smaller activation in the superior and middle frontal gyri than controls. A psychophysiological interaction (PPI) analysis was performed with ACC as the seed region and revealed greater functionally connectivity to sensory regions in ASD than in controls, but less connectivity to prefrontal and orbito-frontal cortices. Thus, compared to controls, larger sensory activation associated with reduced frontal activation was seen in ASD during automatic visual change detection. Atypical psychophysiological interactions between frontal and occipital regions were also found, congruent with the idea of atypical connectivity between these regions in ASD. The atypical involvement of the ACC in visual change detection can be related to abnormalities previously observed in the auditory modality, thus supporting the hypothesis of an altered general mechanism of change detection in patients with ASD that would underlie their unusual reaction to change.

Functional morphological imaging of autism spectrum disorders: current position and theories proposed.

Autism is a pervasive disorder of childhood development. Polymorphous clinical profiles combining various degrees of communication and social interaction with restricted and stereotyped behaviour are grouped under the heading of 'autism spectrum disorders' (ASD). Many teams are trying to pick out the underlying cerebral abnormalities in order to understand the neuronal networks involved in relationships with others. Here we review the morphological, spectroscopic and functional abnormalities in the amygdala-hippocampal circuit, the caudate nuclei, the cerebellum, and the frontotemporal regions, which have been described in subjects with ASD. White matter abnormalities have also been described in diffusion tensor imaging, leading to suspected damage to the subjacent neural networks, such as mirror neurones or the social brain.