Glutamatergic synapse in autism: a complex story for a complex disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose pathophysiological mechanisms are still unclear. Hypotheses suggest a role for glutamate dysfunctions in ASD development, but clinical studies investigating brain and peripheral glutamate levels showed heterogenous results leading to hypo- and hyper-glutamatergic hypotheses of ASD. Recently, studies proposed the implication of elevated mGluR5 densities in brain areas in the pathophysiology of ASD. Thus, our objective was to characterize glutamate dysfunctions in adult subjects with ASD by quantifying (1) glutamate levels in the cingulate cortex and periphery using proton magnetic resonance spectroscopy and metabolomics, and (2) mGluR5 brain density in this population and in a validated animal model of ASD (prenatal exposure to valproate) at developmental stages corresponding to childhood and adolescence in humans using positron emission tomography. No modifications in cingulate Glu levels were observed between individuals with ASD and controls further supporting the difficulty to evaluate modifications in excitatory transmission using spectroscopy in this population, and the complexity of its glutamate-related changes. Our imaging results showed an overall increased density in mGluR5 in adults with ASD, that was only observed mostly subcortically in adolescent male rats prenatally exposed to valproic acid, and not detected in the stage corresponding to childhood in the same animals. This suggest that clinical changes in mGluR5 density could reflect the adaptation of the glutamatergic dysfunctions occurring earlier rather than being key to the pathophysiology of ASD.

Emotional expression visual mismatch negativity in children.

Detection of changes in facial emotions is crucial to communicate and to rapidly process threats in the environment. This function develops throughout childhood via modulations of the earliest brain responses, such as the P100 and the N170 recorded using electroencephalography. Automatic brain signatures can be measured through expression-related visual mismatch negativity (vMMN), which reflects the processing of unattended changes. While increasing research has investigated vMMN processing in adults, few studies have been conducted on children. Here, a controlled paradigm previously validated was used to disentangle specific responses to emotional deviants (angry face) from that of neutral deviants. Latencies and amplitudes of P100 and N170 both decrease with age, confirming that sensory and face-specific activity is not yet mature in school-aged children. Automatic change detection-related activity is present in children, with a similar vMMN pattern in response to both emotional and neutral deviant stimuli to what previously observed in adults. However, vMMN processing is delayed in children compared to adults and no emotion-specific response is yet observed, suggesting nonmature automatic detection of salient emotional cues. To our knowledge, this is the first study investigating expression-related vMMN in school-aged children, and further investigations are needed to confirm these results.

High spatial frequency filtered primes hastens happy faces categorization in autistic adults.

Coarse information of a visual stimulus is conveyed by Low Spatial Frequencies (LSF) and is thought to be rapidly extracted to generate predictions. This may guide fast recognition with the subsequent integration of fine information, conveyed by High Spatial Frequencies (HSF). In autism, emotional face recognition is challenging, and might be related to alterations in LSF predictive processes. We analyzed the data of 27 autistic and 34 non autistic (NA) adults on an emotional Stroop task (i.e., emotional face with congruent or incongruent emotional word) with spatially filtered primes (HSF vs.LSF). We hypothesized that LSF primes would generate predictions leading to faster categorization of the target face compared to HSF primes, in the NA group but not in autism. Surprisingly, HSF primes led to faster categorization than LSF primes in both groups. Moreover, the advantage of HSF vs.LSF primes was stronger for angry than happy faces in NA, but was stronger for happy than angry faces in autistic participants. Drift diffusion modelling confirmed HSF advantage and showed a longer non-decision time (e.g., encoding) in autism. Despite LSF predictive impairments in autism was not corroborated, our analyses suggest low level processing specificities in autism.

Inflexibility in Autism Spectrum Disorder: Need for certainty and atypical emotion processing share the blame.

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.

Brain mechanisms involved in angry prosody change detection in school-age children and adults, revealed by electrophysiology.

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.

Scalp current density mapping in the analysis of mismatch negativity paradigms.

MMN oddball paradigms are frequently used to assess auditory (dys)functions in clinical populations, or the influence of various factors (such as drugs and alcohol) on auditory processing. A widely used procedure is to compare the MMN responses between two groups of subjects (e.g. patients vs controls), or between experimental conditions in the same group. To correctly interpret these comparisons, it is important to take into account the multiple brain generators that produce the MMN response. To disentangle the different components of the MMN, we describe the advantages of scalp current density (SCD)-or surface Laplacian-computation for ERP analysis. We provide a short conceptual and mathematical description of SCDs, describe their properties, and illustrate with examples from published studies how they can benefit MMN analysis. We conclude with practical tips on how to correctly use and interpret SCDs in this context.

Sex modulation of faces prediction error in the autistic brain.

Recent research suggests that autistic females may have superior socio-cognitive abilities compared to autistic males, potentially contributing to underdiagnosis in females. However, it remains unclear whether these differences arise from distinct neurophysiological functioning in autistic males and females. This study addresses this question by presenting 41 autistic and 48 non-autistic adults with a spatially filtered faces oddball paradigm. Analysis of event-related potentials from scalp electroencephalography reveal a neurophysiological profile in autistic females that fell between those of autistic males and non-autistic females, highlighting sex differences in autism from the initial stages of face processing. This finding underscores the urgent need to explore neurophysiological sex differences in autism and encourages efforts toward a better comprehension of compensation mechanism and a clearer definition of what is meant by camouflaging.

My voice or yours? An electrophysiological study.

This study examined the neural processes underlying own voice discrimination using electrophysiological methods. Event-related potentials were recorded while healthy subjects (n = 17) heard passively three oddball sequences composed of recordings of the French vowel/a/pronounced either by the participant her/himself or by two unknown persons. The results indicated that, although the mismatch negativity (MMN) displayed similar peak latency and amplitude in both conditions, the subsequent P3a clearly distinguished the two conditions since its amplitude was significantly smaller for own voice discrimination than for that of unknown voices. Moreover, the own voice discriminative response was associated with an early pre-MMN response. This early response involved a left inferior frontal component, the activity of which lasted throughout the time course of the discriminative response, which included both MMN and P3a.

FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation.

X-linked mental retardation (XLMR) is an inherited condition that causes failure to develop cognitive abilities, owing to mutations in a gene on the X chromosome. The latest XLMR update lists up to 136 conditions leading to 'syndromic', or 'specific', mental retardation (MRXS) and 66 entries leading to 'nonspecific' mental retardation (MRX). For 9 of the 66 MRX entries, the causative gene has been identified. Our recent discovery of the contiguous gene deletion syndrome ATS-MR (previously known as Alport syndrome, mental retardation, midface hypoplasia, elliptocytosis, OMIM #300194), characterized by Alport syndrome (ATS) and mental retardation (MR), indicated Xq22.3 as a region containing one mental retardation gene. Comparing the extent of deletion between individuals with ATS-MR and individuals with ATS alone allowed us to define a critical region for mental retardation of approximately 380 kb, containing four genes. Here we report the identification of two point mutations, one missense and one splice-site change, in the gene FACL4 in two families with nonspecific mental retardation. Analysis of enzymatic activity in lymphoblastoid cell lines from affected individuals of both families revealed low levels compared with normal cells, indicating that both mutations are null mutations. All carrier females with either point mutations or genomic deletions in FACL4 showed a completely skewed X-inactivation, suggesting that the gene influences survival advantage. FACL4 is the first gene shown to be involved in nonspecific mental retardation and fatty-acid metabolism.

Habituation, Adaptation and Prediction Processes in Neurodevelopmental Disorders: A Comprehensive Review.

Habituation, the simplest form of learning preserved across species and evolution, is characterized by a response decrease as a stimulus is repeated. This adaptive function has been shown to be altered in some psychiatric and neurodevelopmental disorders such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD) or schizophrenia. At the brain level, habituation is characterized by a decrease in neural activity as a stimulation is repeated, referred to as neural adaptation. This phenomenon influences the ability to make predictions and to detect change, two processes altered in some neurodevelopmental and psychiatric disorders. In this comprehensive review, the objectives are to characterize habituation, neural adaptation, and prediction throughout typical development and in neurodevelopmental disorders; and to evaluate their implication in symptomatology, specifically in sensitivity to change or need for sameness. A summary of the different approaches to investigate adaptation will be proposed, in which we report the contribution of animal studies as well as electrophysiological studies in humans to understanding of underlying neuronal mechanisms.

Glutamate levels of the right and left anterior cingulate cortex in autistics adults.

BACKGROUND: The neurobiology of Autism Spectrum Disorder (ASD) is still unknown. Alteration in glutamate metabolism might translate into an imbalance of the excitation/inhibition equilibrium of cortical networks that in turn are related to autistic symptoms, but previous studies using voxel located in bilateral anterior cingulate cortex (ACC) failed to show abnormalities in total glutamate level. Due to the functional differences in the right and left ACC, we sought to determine whether a difference between right and left ACC glutamate levels could be found when comparing ASD patients and control subjects. METHODS: Using single-voxel proton magnetic resonance spectroscopy (1H-MRS), we analyzed the glutamate + glutamine (Glx) concentrations in the left and right ACC of 19 ASD patients with normal IQs and 25 matched control subjects. RESULTS: No overall group differences in Glx were shown, in the left ACC (p = 0.24) or in the right ACC (p = 0.11). CONCLUSIONS: No significant alterations in Glx levels were detected in the left and right ACC in high-functioning autistic adults. In the excitatory/inhibitory imbalance framework, our data reinforce the critical need to analyze the GABAergic pathway, for better understanding of basic neuropathology in autism.

Neural repetition suppression to vocal and non-vocal sounds.

Adaptation to the sensory environment is essential in everyday life, to anticipate future events and quickly detect and respond to changes; and to distinguish vocal variations in congeners, for communication. The aim of the current study was to explore the effects of the nature (vocal/non-vocal) of the information to be encoded, on the establishment of auditory regularities. In electrophysiology, neural adaptation is measured by the 'Repetition Positivity' (RP), which refers to an increase in positive potential, with the increasing number of repetitions of a same stimulus. The RP results from the combined variation of several ERP components; the P1, the first positivity (∼100 ms) may reflect the onset of repetition effects. We recorded auditory evoked potentials during a roving paradigm in which trains of 4, 8 or 16 repetitions of the same stimulus were presented. Sequences of vocal and non-vocal complex stimuli were delivered, to study the influence of the type of stimulation on the characteristics of the brain responses. The P1 to each train length, and the RP responses were recorded between 90 and 200 ms, reflecting adaptation for both vocal and non-vocal stimuli. RP was not different between vocal and non-vocal sequences (in latency, amplitude and spatial organization) and was found to be similar to that found in previous studies using pure tones, suggesting that the repetition suppression phenomena is somehow independent of the nature of the stimulus. However, results showed faster stabilization of the P1 amplitude for non-vocal stimuli than for vocal stimuli, which require more repetitions. This revealed different dynamics for the establishment of regularity encoding for non-vocal and vocal stimuli, indicating that the richness of vocal sounds may require further processing before full neural adaptation occurs.

Flexibility in autism during unpredictable shifts of socio-emotional stimuli: Investigation of group and sex differences.

LAY ABSTRACT: Flexibility difficulties in autism might be particularly common in complex situations, when shifts (i.e. the switch of attentional resources or strategy according to the situation) are unpredictable, implicit (i.e. not guided by explicit rules) and the stimuli are complex. We analyzed the data of 101 autistic and 145 non-autistic adults, without intellectual deficiency, on two flexibility tasks performed online. The first task involved unpredictable and non-explicit shifts of complex socio-emotional stimuli, whereas the second task involved predictable and explicit shifts of character stimuli. Considering the discrepancies between laboratory results and the real-life flexibility-related challenges faced by autistic individuals, we need to determine which factor could be of particular importance in flexibility difficulties. We point out that the switch cost (i.e. the difference between shift and non-shift condition) was larger for autistic than for non-autistic participants on the complex flexibility task with unpredictable and non-explicit shifts of socio-emotional stimuli, whereas this was not the case when shifts were predictable, explicit and involved less complex stimuli. We also highlight sex differences, suggesting that autistic females have better social skills than autistic males and that they also have a specific cognitive profile, which could contribute to social camouflaging. The findings of this work help us understand which factors could influence flexibility difficulties in autism and are important for designing future studies. They also add to the literature on sex differences in autism which underpin better social skills, executive function, and camouflaging in autistic females.

The Predictive Role of Low Spatial Frequencies in Automatic Face Processing: A Visual Mismatch Negativity Investigation.

Visual processing is thought to function in a coarse-to-fine manner. Low spatial frequencies (LSF), conveying coarse information, would be processed early to generate predictions. These LSF-based predictions would facilitate the further integration of high spatial frequencies (HSF), conveying fine details. The predictive role of LSF might be crucial in automatic face processing, where high performance could be explained by an accurate selection of clues in early processing. In the present study, we used a visual Mismatch Negativity (vMMN) paradigm by presenting an unfiltered face as standard stimulus, and the same face filtered in LSF or HSF as deviant, to investigate the predictive role of LSF vs. HSF during automatic face processing. If LSF are critical for predictions, we hypothesize that LSF deviants would elicit less prediction error (i.e., reduced mismatch responses) than HSF deviants. Results show that both LSF and HSF deviants elicited a mismatch response compared with their equivalent in an equiprobable sequence. However, in line with our hypothesis, LSF deviants evoke significantly reduced mismatch responses compared to HSF deviants, particularly at later stages. The difference in mismatch between HSF and LSF conditions involves posterior areas and right fusiform gyrus. Overall, our findings suggest a predictive role of LSF during automatic face processing and a critical involvement of HSF in the fusiform during the conscious detection of changes in faces.

Relationship between Behavioral and Objective Measures of Sound Intensity in Normal-Hearing Listeners and Hearing-Aid Users: A Pilot Study.

Background: For hearing-impaired individuals, hearing aids are clinically fit according to subjective measures of threshold and loudness. The goal of this study was to evaluate objective measures of loudness perception that might benefit hearing aid fitting. Method: Seventeen adult hearing aid users and 17 normal-hearing adults participated in the study. Outcome measures including categorical loudness scaling, cortical auditory evoked potentials (CAEPs), and pupillometry. Stimuli were 1-kHz tone bursts presented at 40, 60, and 80 dBA. Results: Categorical loudness scaling showed that loudness significantly increased with intensity for all participants (p < 0.05). For CAEPs, high intensity was associated with greater P1, N1, and P2 peak amplitude for all listeners (p < 0.05); a significant but small effect of hearing aid amplification was observed. For all participants, pupillometry showed significant effects of high intensity on pupil dilation (p < 0.05); there was no significant effect of hearing aid amplification. A Focused Principal Component analysis revealed significant correlations between subjective loudness and some of the objective measures. Conclusion: The present data suggest that intensity had a significant impact on loudness perception, CAEPs, and pupil response. The correlations suggest that pupillometry and/or CAEPs may be useful in determining comfortable amplification for hearing aids.

Emotional visual mismatch negativity: a joint investigation of social and non-social dimensions in adults with autism.

Unusual behaviors and brain activity to socio-emotional stimuli have been reported in Autism Spectrum Disorder (ASD). Atypical reactivity to change and intolerance of uncertainty are also present, but little is known on their possible impact on facial expression processing in autism. The visual mismatch negativity (vMMN) is an electrophysiological response automatically elicited by changing events such as deviant emotional faces presented among regular neutral faces. While vMMN has been found altered in ASD in response to low-level changes in simple stimuli, no study has investigated this response to visual social stimuli. Here two deviant expressions were presented, neutral and angry, embedded in a sequence of repetitive neutral stimuli. vMMN peak analyses were performed for latency and amplitude in early and late time windows. The ASD group presented smaller amplitude of the late vMMN to both neutral and emotional deviants compared to the typically developed adults (TD) group, and only the TD group presented a sustained activity related to emotional change (i.e., angry deviant). Source reconstruction of the vMMNs further revealed that any change processing elicited a reduced activity in ASD group compared to TD in the saliency network, while the specific processing emotional change elicited activity in the temporal region and in the insula. This study confirms atypical change processing in ASD and points to a specific difficulty in the processing of emotional changes, potentially playing a crucial role in social interaction deficits. Nevertheless, these results require to be further replicated with a greater sample size and generalized to other emotional expressions.

Does Phonological Complexity Provide a Good Index of Language Disorder in Children With Cochlear Implants?

Purpose Phonological complexity is known to be a good index of developmental language disorder (DLD) in normal-hearing children, who have major difficulties on some complex structures. Some deaf children with cochlear implants (CIs) present a profile that evokes DLD, with persistent linguistic difficulties despite good audiological and environmental conditions. However, teasing apart what is related to auditory deficit or to language disorder remains complex. Method We compared the performance of three groups of school-age children, 33 children with CI, 22 with DLD, and 24 with typical development, on a nonword repetition (NWR) task based on phonological complexity. Children with CI were studied regarding their linguistic profile, categorized in four subgroups ranging from excellent to very poor performance. Influence of syllable length and phonological structures on the results of all the children were explored. Results The NWR task correctly distinguished children with DLD from typically developing children, and also children with CI with the poorest linguistic performance from other children with CI. However, most complex phonological structures did not reliably identify children with CI displaying a profile similar to that of children with DLD because these structures were difficult for all of the children with CI. The simplest phonological structures were better at detecting persistent language difficulties in children with CI, as they were challenging only for the children with the poorest language outcomes. Conclusions The most complex phonological structures are not good indices of language disorder in children with CI. Phonological complexity represents a gradient of difficulty that affects normal-hearing and deaf children differently.

Visual attention in autism families: 'unaffected' sibs share atypical frontal activation.

BACKGROUND: In addition to their more clinically evident abnormalities of social cognition, people with autism spectrum conditions (ASC) manifest perturbations of attention and sensory perception which may offer insights into the underlying neural abnormalities. Similar autistic traits in ASC relatives without a diagnosis suggest a continuity between clinically affected and unaffected family members. METHODS: We applied fMRI in the context of a non-social task of visual attention in order to determine whether this continuity persists at the level of brain physiology. RESULTS: Both boys with ASC and clinically unaffected brothers of people with ASC were impaired at a visual divided-attention task demanding conjunction of attributes from rapidly and simultaneously presented, spatially disjoint stimuli and suppression of spatially intervening distractors. In addition, both groups in comparison to controls manifested atypical fronto-cerebellar activation as a function of distractor congruence, and the degree of this frontal atypicality correlated with psychometric measures of autistic traits in ASC and sibs. Despite these resemblances between the ASC and sib groups, an exploratory, hypothesis-generating analysis of correlations across brain regions revealed a decrease in overall functional correlation only in the ASC group and not in the sibs. CONCLUSIONS: These results establish a neurophysiological correlate of familial susceptibility to ASC, and suggest that whilst abnormal time courses of frontal activation may reflect processes permissive of autistic brain development, abnormal patterns of functional correlation across a wider array of brain regions may relate more closely to autism's determinants.

Brain responses to change in phonological structures of varying complexity in children and adults.

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.

Brain correlates of emotional prosodic change detection in autism spectrum disorder.

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.