GABA and Glx predict EEG responses of visual sensitivity in autism.

The mechanisms underlying atypical sensory processing in autism remain to be elucidated, but research points toward a role of the glutamatergic/GABAergic balance. To investigate the potential relationships between visual sensitivity and its molecular correlates in autism, we combined data from electroencephalography (EEG) and magnetic resonance spectroscopy (MRS) studies. Twenty autistic adults and sixteen neurotypical adults (NT) participated in both an EEG study assessing visual sensitivity (Sapey-Triomphe et al., Autism Research, 2023) and in an MRS study measuring Glx and GABA+ concentrations in the occipital cortex (Sapey-Triomphe et al., Molecular Autism, 2021). These studies revealed no group differences in neural detection thresholds or in Glx/GABA levels in the occipital cortex. Neural detection thresholds for contrast and spatial frequency (SF) were determined using fast periodic visual stimulations and neural frequency tagging. In the present study, Glx/GABA+ concentrations in the occipital cortex and neural detection thresholds did not differ between groups. Interestingly, lower Glx/GABA+ ratios were associated with lower contrast detection thresholds and higher SF detection thresholds. These correlations were also significant within the neurotypical and autistic groups. This report suggests that the Glx/GABA balance regulates visual detection thresholds across individuals. In both autistic and NTs, lower Glx/GABA ratios in the occipital cortex allow for better detection of visual inputs at the neural level. This study sheds light on the neurochemical underpinnings of visual sensitivity in autism and warrants further investigation.

Disentangling sensory precision and prior expectation of change in autism during tactile discrimination.

Predictive coding theories suggest that core symptoms in autism spectrum disorders (ASD) may stem from atypical mechanisms of perceptual inference (i.e., inferring the hidden causes of sensations). Specifically, there would be an imbalance in the precision or weight ascribed to sensory inputs relative to prior expectations. Using three tactile behavioral tasks and computational modeling, we specifically targeted the implicit dynamics of sensory adaptation and perceptual learning in ASD. Participants were neurotypical and autistic adults without intellectual disability. In Experiment I, tactile detection thresholds and adaptation effects were measured to assess sensory precision. Experiments II and III relied on two-alternative forced choice tasks designed to elicit a time-order effect, where prior knowledge biases perceptual decisions. Our results suggest a subtler explanation than a simple imbalance in the prior/sensory weights, having to do with the dynamic nature of perception, that is the adjustment of precision weights to context. Compared to neurotypicals, autistic adults showed no difference in average performance and sensory sensitivity. Both groups managed to implicitly learn and adjust a prior that biased their perception. However, depending on the context, autistic participants showed no, normal or slower adaptation, a phenomenon that computational modeling of trial-to-trial responses helped us to associate with a higher expectation for sameness in ASD, and to dissociate from another observed robust difference in terms of response bias. These results point to atypical perceptual learning rather than altered perceptual inference per se, calling for further empirical and computational studies to refine the current predictive coding theories of ASD.

Intact predictive processing in autistic adults: evidence from statistical learning.

Impairment in predictive processes gained a lot of attention in recent years as an explanation for autistic symptoms. However, empirical evidence does not always underpin this framework. Thus, it is unclear what aspects of predictive processing are affected in autism spectrum disorder. In this study, we tested autistic adults on a task in which participants acquire probability-based regularities (that is, a statistical learning task). Twenty neurotypical and 22 autistic adults learned a probabilistic, temporally distributed regularity for about 40 min. Using frequentist and Bayesian methods, we found that autistic adults performed comparably to neurotypical adults, and the dynamics of learning did not differ between groups either. Thus, our study provides evidence for intact statistical learning in autistic adults. Furthermore, we discuss potential ways this result can extend the scope of the predictive processing framework, noting that atypical processing might not always mean a deficit in performance.

A multilevel investigation of sensory sensitivity and responsivity in autistic adults.

Atypical sensory processing is a core symptom of autism spectrum disorders (ASD). We aimed at better characterizing visual sensitivity and responsivity in ASD at the self-reported, behavioral and neural levels, and at describing the relationships between these levels. We refer to sensory sensitivity as the ability to detect sensory stimuli and to sensory responsivity as an affective response to sensory stimuli. Participants were 25 neurotypical and 24 autistic adults. At the self-reported level, autistic participants had higher scores of sensory sensitivity and responsivity than neurotypicals. The behavioral and neural tasks involved contrast-reversing gratings which became progressively (in)visible as their contrast or spatial frequency evolved. At the behavioral level, autistic participants had higher detection and responsivity thresholds when gratings varied in spatial frequency, but their thresholds did not differ from neurotypicals when gratings varied in contrast. At the neural level, we used fast periodic visual stimulations and electroencephalography to implicitly assess detection thresholds for contrast and spatial frequency, and did not reveal any group difference. Higher self-reported responsivity was associated with higher behavioral responsivity, more intolerance of uncertainty and anxiety, in particular in ASD. At the self-reported level, higher sensitivity was associated with more responsivity in both groups, contrary to the behavioral level where these relationships were not found. These heterogeneous results suggest that sensitivity and responsivity per se are not simply increased in ASD, but may be modulated by other factors such as environmental predictability. Multi-level approaches can shed light on the mechanisms underlying sensory issues in ASD.

Neural correlates of hierarchical predictive processes in autistic adults.

Bayesian theories of autism spectrum disorders (ASD) suggest that atypical predictive mechanisms could underlie the autistic symptomatology, but little is known about their neural correlates. Twenty-six neurotypical (NT) and 26 autistic adults participated in an fMRI study where they performed an associative learning task in a volatile environment. By inverting a model of perceptual inference, we characterized the neural correlates of hierarchically structured predictions and prediction errors in ASD. Behaviorally, the predictive abilities of autistic adults were intact. Neurally, predictions were encoded hierarchically in both NT and ASD participants and biased their percepts. High-level predictions were following activity levels in a set of regions more closely in ASD than NT. Prediction errors yielded activation in shared regions in NT and ASD, but group differences were found in the anterior cingulate cortex and putamen. This study sheds light on the neural specificities of ASD that might underlie atypical predictive processing.

Associative learning under uncertainty in adults with autism: Intact learning of the cue-outcome contingency, but slower updating of priors.

LAY ABSTRACT: We have an internal representation of the world that guides our behavior, helps us predicting what comes next and therefore, reducing uncertainty. For instance, after hearing the noise of a door opening, we usually expect to see a person appearing, whose features differ depending on the context. In this example of associative learning, predictions need to be adjusted if there is a change in the environment (e.g. different person depending on the location). Recent theories suggest that the symptoms encountered in autism could be due to an atypical learning of predictions or to a decreased influence of these expectations on perception. Here, we conducted an experiment assessing whether adults with autism could learn and adjust their predictions in a changing environment. Throughout a behavioral task, participants learned to associate a sound with a visual outcome, but this association could sometimes reverse. Results showed that autistic adults could learn to make predictions that fitted the main sound-vision association, but were slower to adapt their expectations when there was an unannounced change in the environment. We also observed that both adults with and without autism tended to be biased by their expectations, as they reported seeing what they expected to see rather than what was actually shown. Altogether, our results indicate that autistic adults can learn predictions but are more inflexible to adjust these predictions in a changing environment. These results help refining recent theories of autism (called "predictive coding" theories), which intend to identify the core mechanisms underlying the autistic symptomatology.

Prediction learning in adults with autism and its molecular correlates.

BACKGROUND: According to Bayesian hypotheses, individuals with Autism Spectrum Disorder (ASD) have difficulties making accurate predictions about their environment. In particular, the mechanisms by which they assign precision to predictions or sensory inputs would be suboptimal in ASD. These mechanisms are thought to be mostly mediated by glutamate and GABA. Here, we aimed to shed light on prediction learning in ASD and on its neurobiological correlates. METHODS: Twenty-six neurotypical and 26 autistic adults participated in an associative learning task where they had to learn a probabilistic association between a tone and the rotation direction of two dots, in a volatile context. They also took part in magnetic resonance spectroscopy (MRS) measurements to quantify Glx (glutamate and glutamine), GABA + and glutathione in a low-level perceptual region (occipital cortex) and in a higher-level region involved in prediction learning (inferior frontal gyrus). RESULTS: Neurotypical and autistic adults had their percepts biased by their expectations, and this bias was smaller for individuals with a more atypical sensory sensitivity. Both groups were able to learn the association and to update their beliefs after a change in contingency. Interestingly, the percentage of correct predictions was correlated with the Glx/GABA + ratio in the occipital cortex (positive correlation) and in the right inferior frontal gyrus (negative correlation). In this region, MRS results also showed an increased concentration of Glx in the ASD group compared to the neurotypical group. LIMITATIONS: We used a quite restrictive approach to select the MR spectra showing a good fit, which led to the exclusion of some MRS datasets and therefore to the reduction of the sample size for certain metabolites/regions. CONCLUSIONS: Autistic adults appeared to have intact abilities to make predictions in this task, in contrast with the Bayesian hypotheses of ASD. Yet, higher ratios of Glx/GABA + in a frontal region were associated with decreased predictive abilities, and ASD individuals tended to have more Glx in this region. This neurobiological difference might contribute to suboptimal predictive mechanisms in ASD in certain contexts.

Structural and contextual priors affect visual search in children with and without autism.

Bayesian predictive coding theories of autism spectrum disorder propose that impaired acquisition or a broader shape of prior probability distributions lies at the core of the condition. However, we still know very little about how probability distributions are learned and encoded by children, let alone children with autism. Here, we take advantage of a recently developed distribution learning paradigm to characterize how children with and without autism acquire information about probability distributions. Twenty-four autistic and 25-matched neurotypical children searched for an odd-one-out target among a set of distractor lines with orientations sampled from a Gaussian distribution repeated across multiple trials to allow for learning of the parameters (mean and variance) of the distribution. We could measure the width (variance) of the participant's encoded distribution by introducing a target-distractor role-reversal while varying the similarity between target and previous distractor mean. Both groups performed similarly on the visual search task and learned the distractor distribution to a similar extent. However, the variance learned was much broader than the one presented, consistent with less informative priors in children irrespective of autism diagnosis. These findings have important implications for Bayesian accounts of perception throughout development, and Bayesian accounts of autism specifically. LAY SUMMARY: Recent theories about the underlying cognitive mechanisms of autism propose that the way autistic individuals estimate variability or uncertainty in their perceptual environment may differ from how typical individuals do so. Children had to search an oddly tilted line in a set of lines pointing in different directions, and based on their response times we examined how they learned about the variability in a set of objects. We found that autistic children learn variability as well as typical children, but both groups learn with less precision than typical adults do on the same task.

Priors Bias Perceptual Decisions in Autism, But Are Less Flexibly Adjusted to the Context.

According to the predictive coding framework, percepts emerge from combinations of sensory input and prior knowledge, whose relative contributions depend on their reliability. Recent predictive coding theories suggest that Autism Spectrum Disorder (ASD) could be characterized by an atypical weighting of priors. Here, we assessed whether individuals with ASD can flexibly adjust the weight (precision) of the prior to the context. Thirty-one neurotypical adults (NT) and 26 adults with ASD participated in a visual discrimination task designed to elicit a time-order effect (TOE). The TOE reflects the integration of priors with sensory estimates. We used two experimental contexts: a narrow stimulus range (Narrow condition) and a broader range (Broad condition) in order to induce a prior with a higher and lower precision, respectively. Both groups learned a prior that biased their perception, as shown with the TOE. As expected, the NT group had a larger TOE in the Narrow condition than in the Broad condition, revealing a contextual adjustment of the prior precision. In contrast, ASD participants were more inflexible: the extent of the TOE was not modulated by the context. In addition, the accuracy increased when the stimulus range decreased in both group, which may be interpreted as a contextual adjustment of the sensory precision. To conclude, adults with and without ASD implicitly learned a prior mean, but ASD participants failed to flexibly adjust the prior precision to the context. This increased inflexibility in ASD could account for many symptoms, such as their intolerance of uncertainty. LAY SUMMARY: Based on our experience, we have expectations about our environment. Theories suggest that the symptoms encountered in autism could be due to atypical expectations, leading to an impression of an unpredictable world. Using a visual discrimination task, we showed that adults with and without autism were biased by their expectations. Yet, the extent to which expectations biased perception did not depend on the context in autism. This higher inflexibility found in autism may explain symptoms such as resistance to change.

A de novo frameshift pathogenic variant in TBR1 identified in autism without intellectual disability.

BACKGROUND: In order to be able to provide accurate genetic counseling to patients with Autism Spectrum Disorder (ASD), it is crucial to identify correlations between heterogeneous phenotypes and genetic alterations. Among the hundreds of de novo pathogenic variants reported in ASD, single-nucleotide variations and small insertions/deletions were reported in TBR1. This gene encodes a transcription factor that plays a key role in brain development. Pathogenic variants in TBR1 are often associated with severe forms of ASD, including intellectual disability and language impairment. METHODS: Adults diagnosed with ASD but without intellectual disability (diagnosis of Asperger syndrome, according to the DSM-IV) took part in a genetic consultation encompassing metabolic assessments, a molecular karyotype and the screening of a panel of 268 genes involved in intellectual disability, ASD and epilepsy. In addition, the patient reported here went through a neuropsychological assessment, structural magnetic resonance imaging and magnetic resonance spectroscopy measurements. RESULTS: Here, we report the case of a young adult male who presents with a typical form of ASD. Importantly, this patient presents with no intellectual disability or language impairment, despite a de novo heterozygous frameshift pathogenic variant in TBR1, leading to an early premature termination codon (c.26del, p.(Pro9Leufs*12)). CONCLUSION: Based on this case report, we discuss the role of TBR1 in general brain development, language development, intellectual disability and other symptoms of ASD. Providing a detailed clinical description of the individuals with such pathogenic variants should help to understand the genotype-phenotype relationships in ASD.

Ventral stream hierarchy underlying perceptual organization in adolescents with autism.

Object recognition relies on a hierarchically organized ventral visual stream, with both bottom-up and top-down processes. Here, we aimed at investigating the neural underpinnings of perceptual organization along the ventral visual stream in Autism Spectrum Disorders (ASD), and at determining whether this would be associated with decreased top-down processing in ASD. Nineteen typically developing (TD) adolescents and sixteen adolescents with ASD participated in an fMRI study where they had to detect visual objects. Five conditions displayed Gabor patterns (defined by texture and/or contour) with increasing levels of perceptual organization. In each condition, both groups showed similar abilities. In line with the expected cortical hierarchy, brain activity patterns revealed a progressive involvement of regions, from low-level occipital regions to higher-level frontal regions, when stimuli became more and more organized. The brain patterns were generally similar in both groups, but the ASD group showed greater activation than TD participants in the middle occipital gyrus and lateral occipital complex when perceiving fully organized everyday objects. Effective connectivity analyses suggested that top-down functional connections between the lower levels of the cortical hierarchy were less influenced by the meaning carried by the stimuli in the ASD group than in the TD group. We hypothesize that adolescents with ASD may have been less influenced by top-down processing when perceiving recognizable objects.

Sensory sensitivity in autism mostly depends on contextual predictions.

A signal detection theory was elaborated in order to account for three types of sensory sensitivity (subjective, behavioral and neural) in neurotypical individuals and in autism. Here, we argue that the predictive coding framework could better account for the atypical pattern of sensory sensitivity in autism. We review the idea that sensory sensitivity should be considered as mostly depending on contextual predictions and that these account for the heterogeneous pattern of neural responses.

Tactile hypersensitivity and GABA concentration in the sensorimotor cortex of adults with autism.

Sensory hypersensitivity is frequently encountered in autism spectrum disorder (ASD). Gamma-aminobutyric acid (GABA) has been hypothesized to play a role in tactile hypersensitivity. The aim of the present study was twofold. First, as a study showed that children with ASD have decreased GABA concentrations in the sensorimotor cortex, we aimed at determining whether the GABA reduction remained in adults with ASD. For this purpose, we used magnetic resonance spectroscopy to measure GABA concentration in the sensorimotor cortex of neurotypical adults (n = 19) and ASD adults (n = 18). Second, we aimed at characterizing correlations between GABA concentration and tactile hypersensitivity in ASD. GABA concentration in the sensorimotor cortex of adults with ASD was lower than in neurotypical adults (decrease by 17%). Interestingly, GABA concentrations were positively correlated with self-reported tactile hypersensitivity in adults with ASD (r = 0.50, P = 0.01), but not in neurotypical adults. In addition, GABA concentrations were negatively correlated with the intra-individual variation during threshold measurement, both in neurotypical adults (r = -0.47, P = 0.04) and in adults with ASD (r = -0.59, P = 0.01). In other words, in both groups, the higher the GABA level, the more precise the tactile sensation. These results highlight the key role of GABA in tactile sensitivity, and suggest that atypical GABA modulation contributes to tactile hypersensitivity in ASD. We discuss the hypothesis that hypersensitivity in ASD could be due to suboptimal predictions about sensations. Autism Research 2019, 12: 562-575. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism spectrum disorder (ASD) often experience tactile hypersensitivity. Here, our goal was to highlight a link between tactile hypersensitivity and the concentration of gamma-aminobutyric acid (GABA) (an inhibitory neurotransmitter) in the brain of adults with ASD. Indeed, self-reported hypersensitivity correlated with reduced GABA levels in brain areas processing touch. Our study suggests that this neurotransmitter may play a key role in tactile hypersensitivity in autism.

Correction to: Adults with Autism Tend to Underestimate the Hidden Environmental Structure: Evidence from a Visual Associative Learning Task.

The original version of this article unfortunately contained a mistake in the article title.

Adults with Autism Tend to Underestimate the Hidden Environmental Structure: Evidence from a Visual Associative Learning Task.

The learning-style theory of Autism Spectrum Disorders (ASD) (Qian, Lipkin, Frontiers in Human Neuroscience 5:77, 2011) states that ASD individuals differ from neurotypics in the way they learn and store information about the environment and its structure. ASD would rather adopt a lookup-table strategy (LUT: memorizing each experience), while neurotypics would favor an interpolation style (INT: extracting regularities to generalize). In a series of visual behavioral tasks, we tested this hypothesis in 20 neurotypical and 20 ASD adults. ASD participants had difficulties using the INT style when instructions were hidden but not when instructions were revealed. Rather than an inability to use rules, ASD would be characterized by a disinclination to generalize and infer such rules.

The Glasgow Sensory Questionnaire: Validation of a French Language Version and Refinement of Sensory Profiles of People with High Autism-Spectrum Quotient.

Sensory sensitivity peculiarities represent an important characteristic of Autism Spectrum Disorders (ASD). We first validated a French language version of the Glasgow Sensory Questionnaire (GSQ) (Robertson and Simmons in J Autism Dev Disord 43(4):775-784, 2013). The GSQ score was strongly positively correlated with the Autism-Spectrum Quotient (AQ) (r = 0.81, p < 10-6, n = 245). We further examined sensory profiles of groups with high versus low AQ. The high AQ group scored higher at the GSQ than the low AQ group for every sensory modality. Moreover, the high AQ group showed greater consistency in their patterns of hypersensitivity and hyposensitivity between sensory modalities, and stronger correlations between hyper and hyposensitivity. Results are discussed in the context of theories accounting for atypical sensory perception in ASD.

Deciphering human motion to discriminate social interactions: a developmental neuroimaging study.

Non-verbal communication plays a major role in social interaction understanding. Using functional magnetic resonance imaging, we explored the development of the neural networks involved in social interaction recognition based on human motion in children (8-11), adolescents (13-17), and adults (20-41). Participants watched point-light videos depicting two actors interacting or moving independently and were asked whether these agents were interacting or not. All groups successfully performed the discrimination task, but children had a lower performance and longer response times than the older groups. In all three groups, the posterior parts of the superior temporal sulci and middle temporal gyri, the inferior frontal gyri and the anterior temporal lobes showed greater activation when observing social interactions. In addition, adolescents and adults recruited the caudate nucleus and some frontal regions that are part of the mirror system. Adults showed greater activations in parietal and frontal regions (part of them belonging to the social brain) than adolescents.An increased number of regions that are part of the mirror system network or the social brain, as well as the caudate nucleus, were recruited with age. In conclusion, a shared set of brain regions enabling the discrimination of social interactions from neutral movements through human motion is already present in 8-year-old children. Developmental processes such as refinements in the social brain and mirror system would help grasping subtle cues in non-verbal aspects of social interactions.

Neuroanatomical Correlates of Recognizing Face Expressions in Mild Stages of Alzheimer's Disease.

Early Alzheimer's disease can involve social disinvestment, possibly as a consequence of impairment of nonverbal communication skills. This study explores whether patients with Alzheimer's disease at the mild cognitive impairment or mild dementia stage have impaired recognition of emotions in facial expressions, and describes neuroanatomical correlates of emotion processing impairment. As part of the ongoing PACO study (personality, Alzheimer's disease and behaviour), 39 patients with Alzheimer's disease at the mild cognitive impairment or mild dementia stage and 39 matched controls completed tests involving discrimination of four basic emotions-happiness, fear, anger, and disgust-on photographs of faces. In patients, automatic volumetry of 83 brain regions was performed on structural magnetic resonance images using MAPER (multi-atlas propagation with enhanced registration). From the literature, we identified for each of the four basic emotions one brain region thought to be primarily associated with the function of recognizing that emotion. We hypothesized that the volume of each of these regions would be correlated with subjects' performance in recognizing the associated emotion. Patients showed deficits of basic emotion recognition, and these impairments were correlated with the volumes of the expected regions of interest. Unexpectedly, most of these correlations were negative: better emotional facial recognition was associated with lower brain volume. In particular, recognition of fear was negatively correlated with the volume of amygdala, disgust with pallidum, and happiness with fusiform gyrus. Recognition impairment in mild stages of Alzheimer's disease for a given emotion was thus associated with less visible atrophy of functionally responsible brain structures within the patient group. Possible explanations for this counterintuitive result include neuroinflammation, regional ß-amyloid deposition, or transient overcompensation during early stages of Alzheimer's disease.

Degradation of emotion processing ability in corticobasal syndrome and Alzheimer's disease.

Disturbed emotion processing and difficulty with social interactions are present to variable degrees in dementia. They are characteristic features of frontotemporal dementia, whereas these deficits tend to be mild in Alzheimer's disease, reflecting the different patterns of neurodegeneration seen in these disorders. Corticobasal syndrome is an atypical parkinsonian disorder clinically and pathologically related to frontotemporal dementia. Corticobasal syndrome typically presents as a motor disturbance, although cognitive and behavioural changes are now recognized. Pathological changes are found in frontoparietal cortical regions and in the basal ganglia; regions that are heavily involved in emotion processing. Despite the overlap with frontotemporal dementia and the observed regions of brain atrophy, emotion processing has not been systematically explored in corticobasal syndrome. This study aimed to (i) comprehensively examine emotion processing in corticobasal syndrome in comparison to Alzheimer's disease, to determine whether emotion processing deficits exist in this syndrome, beyond those seen in Alzheimer's disease; and (ii) identify the neural correlates underlying emotion processing in corticobasal syndrome and Alzheimer's disease. Sixteen patients with corticobasal syndrome, 18 patients with Alzheimer's disease and 22 matched healthy control subjects were assessed on a comprehensive battery of face and emotion processing tasks. Behavioural analyses revealed deficits in both basic face processing and high-level emotion processing tasks in patients with corticobasal syndrome. Notably, the emotion processing disturbance persisted even after controlling for face processing deficits. In contrast, patients with Alzheimer's disease were impaired on high-level complex and cognitively demanding emotion recognition tasks (Ekman 60, The Awareness of Social Inference Test) only. Neuroimaging analyses using FreeSurfer revealed that emotion processing deficits in corticobasal syndrome were associated with basal ganglia volume loss as well as cortical thinning of the left paracentral gyrus/precuneus region. In Alzheimer's disease, however, emotion processing deficits were associated with atrophy in a different set of brain regions, including the right cingulate and the bilateral insulae, as well as the hippocampi, right amygdala and nucleus accumbens bilaterally. Our results demonstrate that patients with corticobasal syndrome experience widespread deficits in emotion processing, and these deficits are related to changes in brain regions known to be crucial for emotion processing. These findings have important clinical implications for the treatment and management of these patients.