Le numéro de mars 2018 de l’European Journal of Neuroscience est consacré aux bases neurobiologiques de l’autisme.

The neurobiological bases of autism spectrum disorders

1. Noel JP, Stevenson RA, Wallace MT. Atypical Audiovisual Temporal Function in Autism and Schizophrenia : Similar Phenotype, Different Cause. Eur J Neurosci ;2018 (Mar 25)

Binding across sensory modalities yields substantial perceptual benefits, including enhanced speech intelligibility. The coincidence of sensory inputs across time is a fundamental cue for this integration process. Recent work has suggested that individuals with diagnoses of Schizophrenia (SZ) and Autism Spectrum Disorder (ASD) will characterize auditory and visual events as synchronous over larger temporal disparities than their neurotypical counterparts. Namely, these clinical populations possess an enlarged temporal binding window (TBW). Although SZ and ASD patients share aspects of their symptomatology, phenotypic similarities may result from distinctly etiologies. To examine similarities and variances in audiovisual temporal function in these two populations, individuals diagnosed with ASD (n=46 ; controls n=40) and SZ (n=16, controls=16) completed an audiovisual simultaneity judgment task. In addition to standard psychometric analyses, synchrony judgments were assessed using Bayesian causal inference modeling. This approach permits distinguishing between distinct causes of an enlarged TBW : an a priori bias to bind sensory information and poor fidelity in the sensory representation. Findings indicate that both ASD and SZ populations show deficits in multisensory temporal acuity. Importantly, results suggest that while the wider TBWs in ASD most prominently results from atypical priors, the wider TBWs in SZ results from a trend toward changes in prior and weaknesses in the sensory representations. Results are discussed in light of current ASD and SZ theories and highlight that different perceptual training paradigms focused on improving multisensory integration may be most effective in these two clinical populations and emphasize that similar phenotypes may emanate from distinct mechanistic causes. This article is protected by copyright. All rights reserved.

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2. Foxe JJ, Molholm S, Baudouin SJ, Wallace MT. Explorations and perspectives on the neurobiological bases of autism spectrum disorder. Eur J Neurosci ;2018 (Mar) ;47(6):488-496.

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3. Mundy P. A review of joint attention and social-cognitive brain systems in typical development and autism spectrum disorder. Eur J Neurosci ;2018 (Mar) ;47(6):497-514.

This article provides a review of the increasingly detailed imaging literature on the neurodevelopment of joint attention. Many findings from this literature support and inform the hypothesis that the neurodevelopment of joint attention contributes to the functional development of neural systems for human social cognition. Joint attention begins to develop by 5 months of age and is tantamount to the ability to adopt a common perspective with another person. It involves a whole-brain system with nodes in the : (a) dorsal and medial frontal cortex, (b) orbital frontal/insula cortex, (c) anterior/posterior cingulate cortex, (d) superior temporal cortex, (e) precuneus/parietal cortex, and (f) amygdala and striatum. This system integrates triadic information processing about (a) self-attention/action, (b) information about others’ attention/action during social interactions that involve, (c) coordinated attention as well as processing a common referent in space. The results of this new imaging literature have the potential to advance current models of social cognition and the social brain, which rarely consider the contribution of the cognitive neurodevelopment of joint attention. The new neuroscience of joint attention is also extremely valuable for clinical research on social-cognitive neurodevelopmental disorders. This is most clearly the case for autism spectrum disorder (ASD) because it is consistent with the hypothesis of substantial functional neurodevelopmental continuity between the preschool impairments of joint attention, and childhood theory of mind ability that characterizes the development of ASD.

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4. Aggernaes B. Autism : a transdiagnostic, dimensional, construct of reasoning ?. Eur J Neurosci ;2018 (Mar) ;47(6):515-533.

The concept of autism has changed across time, from the Bleulerian concept, which defined it as one of several symptoms of dementia praecox, to the present-day concept representing a pervasive development disorder. The present theoretical contribution to this special issue of EJN on autism introduces new theoretical ideas and discusses them in light of selected prior theories, clinical examples, and recent empirical evidence. The overall aim is to identify some present challenges of diagnostic practice and autism research and to suggest new pathways that may help direct future research. Future research must agree on the definitions of core concepts such as autism and psychosis. A possible redefinition of the concept of autism may be a condition in which the rationale of an individual’s behaviour differs qualitatively from that of the social environment due to characteristic cognitive impairments affecting reasoning. A broad concept of psychosis could focus on deviances in the experience of reality resulting from impairments of reasoning. In this light and consistent with recent empirical evidence, it may be appropriate to redefine dementia praecox as a developmental disorder of reasoning. A future challenge of autism research may be to develop theoretical models that can account for the impact of complex processes acting at the social level in addition to complex neurobiological and psychological processes. Such models could profit from a distinction among processes related to (i) basic susceptibility, (ii) adaptive processes and (iii) decompensating factors involved in the development of manifest illness.

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5. Bozzi Y, Provenzano G, Casarosa S. Neurobiological bases of autism-epilepsy comorbidity : a focus on excitation/inhibition imbalance. Eur J Neurosci ;2018 (Mar) ;47(6):534-548.

Autism spectrum disorders (ASD) and epilepsy are common neurological diseases of childhood, with an estimated incidence of approximately 0.5-1% of the worldwide population. Several genetic, neuroimaging and neuropathological studies clearly showed that both ASD and epilepsy have developmental origins and a substantial degree of heritability. Most importantly, ASD and epilepsy frequently coexist in the same individual, suggesting a common neurodevelopmental basis for these disorders. Genome-wide association studies recently allowed for the identification of a substantial number of genes involved in ASD and epilepsy, some of which are mutated in syndromes presenting both ASD and epilepsy clinical features. At the cellular level, both preclinical and clinical studies indicate that the different genetic causes of ASD and epilepsy may converge to perturb the excitation/inhibition (E/I) balance, due to the dysfunction of excitatory and inhibitory circuits in various brain regions. Metabolic and immune dysfunctions, as well as environmental causes also contribute to ASD pathogenesis. Thus, an E/I imbalance resulting from neurodevelopmental deficits of multiple origins might represent a common pathogenic mechanism for both diseases. Here, we will review the most significant studies supporting these hypotheses. A deeper understanding of the molecular and cellular determinants of autism-epilepsy comorbidity will pave the way to the development of novel therapeutic strategies.

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6. Freedman EG, Foxe JJ. Eye movements, sensorimotor adaptation and cerebellar-dependent learning in autism : toward potential biomarkers and subphenotypes. Eur J Neurosci ;2018 (Mar) ;47(6):549-555.

Because of the wide range of symptoms expressed in individuals with autism spectrum disorder (ASD) and their idiosyncratic severity, it is unlikely that a single remedial approach will be universally effective. Resolution of this dilemma requires identifying subgroups within the autism spectrum, based on symptom set and severity, on an underlying neuro-structural difference, and on specific behavioral dysfunction. This will provide critical insight into the disorder and may lead to better diagnoses, and more targeted remediation in these subphenotypes of people with ASD. In this review, we discuss findings that appear to link the structure of the cerebellar vermis and plasticity of the saccadic eye-movement system in people with an autism spectrum disorder (ASD). Differences in cerebellar vermis structure in ASD could critically impact visuo-sensorimotor development in early infancy, which may in turn manifest as the visual orienting, communication and social interaction differences often seen in this population. It may be possible to distinguish a subpopulation of children with vermal hypoplasia, to establish whether this group manifests more severe deficits in visual orienting and in adaptation to persistent visual errors, and to establish whether this putative subphenotype of ASD is associated with a specific and distinct clinical symptom profile.

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7. Kim SH, Grammer J, Benrey N, Morrison F, Lord C. Stimulus processing and error monitoring in more-able kindergarteners with autism spectrum disorder : a short review and a preliminary Event-Related Potentials study. Eur J Neurosci ;2018 (Mar) ;47(6):556-567.

Deficits in executive functions (EF) in individuals with autism spectrum disorder (ASD) have been identified. However, there is limited evidence about patterns of deficits in EF-related skills, especially at the neurobiological level, in young children with ASD and little is known about how these skills are related to other domains of functioning and symptom severity. In this study, we provide a focused review of EF-related Event-Related Potentials (ERP) studies in children with ASD, accompanied by preliminary data for neurophysiological correlates of EF on a child-friendly Go/No-go task. We focus our preliminary investigation on ERPs associated with stimulus processing (N2, P3) and error monitoring [error/correct-related negativity (ERN, CRN), error positivity (Pe)] in 5-year-old kindergarteners with ASD and typical controls matched on age, gender and task accuracy. Children with ASD showed significantly greater amplitudes of ERN/CRN compared to matched controls, suggesting heightened response monitoring. The ASD group also showed less distinct inhibitory P3 compared to the TD group, potentially suggesting atypical stimulus processing. In children with ASD, higher autism symptom severity was correlated with larger P3. Better behavioral performance on an EF-related task was correlated with smaller CRN. Our study is the first investigation to demonstrate the presence of N2, P3, ERN/CRN and Pe in kindergartners with ASD. The potential links between ERP patterns and behavioral and clinical features in more-able children with ASD highlight the need for further exploration into the functional mechanisms of these atypical neural activities and for more focused behavioral interventions targeting cognitive control and response monitoring.

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8. Giuliano A, Saviozzi I, Brambilla P, Muratori F, Retico A, Calderoni S. The effect of age, sex and clinical features on the volume of Corpus Callosum in pre-schoolers with Autism Spectrum Disorder : a case-control study. Eur J Neurosci ;2018 (Mar) ;47(6):568-578.

A growing body of literature has identified volume alterations of the corpus callosum (CC) in subjects with autism spectrum disorders (ASD). However, to date very few investigations have been conducted on pre-school-age ASD children. This study aims to compare the volume of CC and its sub-regions between pre-schoolers with ASD and controls (CON) and to examine their relationship to demographic and clinical variables (sex, age, non-verbal IQ -NVIQ-, expressive non-echolalic language, emotional and behavioural problems, and autism severity). The volume of CC of 40 pre-schoolers with ASD (20 males and 20 females ; mean age : 49 +/- 12 months ; mean NVIQ : 73 +/- 22) and 40 sex-, age-, and NVIQ-matched CON subjects (20 M and 20 F ; mean age : 49 +/- 14 months ; mean NVIQ : 73 +/- 23) were quantified applying the FreeSurfer automated parcellation software on Magnetic Resonance images. No significant volumetric differences in CC total volume and in its sub-regions between ASD and CON were found using total brain volume as a covariate. Analogously, absence of CC volumetric differences was evident when boys and girls with ASD were compared with their matched controls. The CC total volume of younger ASD male subjects was found significantly larger with respect to matched CON, which is consistent with the atypical growth trajectory widely reported in these young children. The CC total volume was negatively correlated with autism severity, whereas no association between CC volume and other clinical variables was detected. If replicated, the indirect relationship between CC volume and autism severity suggests the involvement of CC in core ASD symptoms.

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9. Datko M, Pineda JA, Muller RA. Positive effects of neurofeedback on autism symptoms correlate with brain activation during imitation and observation. Eur J Neurosci ;2018 (Mar) ;47(6):579-591.

Autism has been characterized by atypical task-related brain activation and functional connections, coinciding with deficits in sociocommunicative abilities. However, evidence of the brain’s experience-dependent plasticity suggests that abnormal activity patterns may be reversed with treatment. In particular, neurofeedback training (NFT), an intervention based on operant conditioning resulting in self-regulation of brain electrical oscillations, has shown increasing promise in addressing abnormalities in brain function and behavior. We examined the effects of >/= 20 h of sensorimotor mu-rhythm-based NFT in children with high-functioning autism spectrum disorders (ASD) and a matched control group of typically developing children (ages 8-17). During a functional magnetic resonance imaging imitation and observation task, the ASD group showed increased activation in regions of the human mirror neuron system following the NFT, as part of a significant interaction between group (ASD vs. controls) and training (pre- vs. post-training). These changes were positively correlated with behavioral improvements in the ASD participants, indicating that mu-rhythm NFT may be beneficial to individuals with ASD.

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10. Gu X, Zhou TJ, Anagnostou E, Soorya L, Kolevzon A, Hof PR, Fan J. Heightened brain response to pain anticipation in high-functioning adults with autism spectrum disorder. Eur J Neurosci ;2018 (Mar) ;47(6):592-601.

Autism spectrum disorder (ASD) is marked by both socio-communicative difficulties and abnormalities in sensory processing. Much of the work on sensory deficits in ASD has focused on tactile sensations and the perceptual aspects of somatosensation, such as encoding of stimulus intensity and location. Although aberrant pain processing has often been noted in clinical observations of patients with ASD, it remains largely uninvestigated. Importantly, the neural mechanism underlying higher order cognitive aspects of pain processing such as pain anticipation also remains unknown. Here we examined both pain perception and anticipation in high-functioning adults with ASD and matched healthy controls (HC) using an anticipatory pain paradigm in combination with functional magnetic resonance imaging (fMRI) and concurrent skin conductance response (SCR) recording. Participants were asked to choose a level of electrical stimulation that would feel moderately painful to them. Compared to HC group, ASD group chose a lower level of stimulation prior to fMRI. However, ASD participants showed greater activation in both rostral and dorsal anterior cingulate cortex during the anticipation of stimulation, but not during stimulation delivery. There was no significant group difference in insular activation during either pain anticipation or perception. However, activity in the left anterior insula correlated with SCR during pain anticipation. Taken together, these results suggest that ASD is marked with aberrantly higher level of sensitivity to upcoming aversive stimuli, which may reflect abnormal attentional orientation to nociceptive signals and a failure in interoceptive inference.

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11. Haigh SM. Variable sensory perception in autism. Eur J Neurosci ;2018 (Mar) ;47(6):602-609.

Autism is associated with sensory and cognitive abnormalities. Individuals with autism generally show normal or superior early sensory processing abilities compared to healthy controls, but deficits in complex sensory processing. In the current opinion paper, it will be argued that sensory abnormalities impact cognition by limiting the amount of signal that can be used to interpret and interact with environment. There is a growing body of literature showing that individuals with autism exhibit greater trial-to-trial variability in behavioural and cortical sensory responses. If multiple sensory signals that are highly variable are added together to process more complex sensory stimuli, then this might destabilise later perception and impair cognition. Methods to improve sensory processing have shown improvements in more general cognition. Studies that specifically investigate differences in sensory trial-to-trial variability in autism, and the potential changes in variability before and after treatment, could ascertain if trial-to-trial variability is a good mechanism to target for treatment in autism.

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12. Hsu CT, Neufeld J, Chakrabarti B. Reduced reward-related neural response to mimicry in individuals with autism. Eur J Neurosci ;2018 (Mar) ;47(6):610-618.

Mimicry is a facilitator of social bonds in humans, from infancy. This facilitation is made possible through changing the reward value of social stimuli ; for example, we like and affiliate more with people who mimic us. Autism spectrum disorders (ASD) are marked by difficulties in forming social bonds. In this study, we investigate whether the reward-related neural response to being mimicked is altered in individuals with ASD, using a simple conditioning paradigm. Multiple studies in humans and nonhuman primates have established a crucial role for the ventral striatal (VS) region in responding to rewards. In this study, adults with ASD and matched controls first underwent a conditioning task outside the scanner, where they were mimicked by one face and ‘anti-mimicked’ by another. In the second part, participants passively viewed the conditioned faces in a 3T MRI scanner using a multi-echo sequence. The differential neural response towards mimicking vs. anti-mimicking faces in the VS was tested for group differences as well as an association with self-reported autistic traits. Multiple regression analysis revealed lower left VS response to mimicry (mimicking > anti-mimicking faces) in the ASD group compared to controls. The VS response to mimicry was negatively correlated with autistic traits across the whole sample. Our results suggest that for individuals with ASD and high autistic traits, being mimicked is associated with lower reward-related neural response. This result points to a potential mechanism underlying the difficulties reported by many of individuals with ASD in building social rapport.

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13. Subbaraju V, Sundaram S, Narasimhan S. Identification of lateralized compensatory neural activities within the social brain due to autism spectrum disorder in adolescent males. Eur J Neurosci ;2018 (Mar) ;47(6):631-642.

Socio-behavioral impairments are important characteristics of autism spectrum disorders (ASD) and MRI-based studies are pursued to identify a neurobiological basis behind these conditions. This paper presents an MRI-based study undertaken to (i) identify the differences in brain activities due to ASD, (ii) verify whether such differences exist within the ‘social brain’ circuit which is hypothesized to be responsible for social functions, and (iii) uncover potential compensatory mechanisms within the identified differences in brain activities. In this study, a whole-brain voxel-wise analysis is performed using resting-state fMRI data from 598 adolescent males, that is openly available from the ABIDE consortium. A new method is developed, which can (i) extract the discriminative brain activities, that provide high separability between the blood oxygenation time-series signals from ASD and neurotypical populations, (ii) select the activities that are relevant to ASD by evaluating the correlation between the separability and traditional severity scores, and (iii) map the spatial pattern of regions responsible for generating the discriminative activities. The results show that the most discriminative brain activities occur within a subset of the social brain that is involved with affective aspects of social processing, thereby supporting the idea of the social brain and also its fractionalization in ASD. Further, it has also been found that the diminished activities in the posterior cingulate area are potentially compensated by enhanced activities in the ventromedial prefrontal and anterior temporal areas within the social brain. Hemispherical lateralization is also observed on such compensatory activities.

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14. Dickinson A, DiStefano C, Senturk D, Jeste SS. Peak alpha frequency is a neural marker of cognitive function across the autism spectrum. Eur J Neurosci ;2018 (Mar) ;47(6):643-651.

Cognitive function varies substantially and serves as a key predictor of outcome and response to intervention in autism spectrum disorder (ASD), yet we know little about the neurobiological mechanisms that underlie cognitive function in children with ASD. The dynamics of neuronal oscillations in the alpha range (6-12 Hz) are associated with cognition in typical development. Peak alpha frequency is also highly sensitive to developmental changes in neural networks, which underlie cognitive function, and therefore, it holds promise as a developmentally sensitive neural marker of cognitive function in ASD. Here, we measured peak alpha band frequency under a task-free condition in a heterogeneous sample of children with ASD (N = 59) and age-matched typically developing (TD) children (N = 38). At a group level, peak alpha frequency was decreased in ASD compared to TD children. Moreover, within the ASD group, peak alpha frequency correlated strongly with non-verbal cognition. As peak alpha frequency reflects the integrity of neural networks, our results suggest that deviations in network development may underlie cognitive function in individuals with ASD. By shedding light on the neurobiological correlates of cognitive function in ASD, our findings lay the groundwork for considering peak alpha frequency as a useful biomarker of cognitive function within this population which, in turn, will facilitate investigations of early markers of cognitive impairment and predictors of outcome in high risk infants.

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15. Fitzgerald J, Leemans A, Kehoe E, O’Hanlon E, Gallagher L, McGrath J. Abnormal fronto-parietal white matter organisation in the superior longitudinal fasciculus branches in autism spectrum disorders. Eur J Neurosci ;2018 (Mar) ;47(6):652-661.

Core features of autism spectrum disorder (ASD) may be underpinned by disrupted functional and structural neural connectivity. Abnormal fronto-parietal functional connectivity has been widely reported in the literature ; this may be underpinned by disrupted microstructural organisation of white matter. The superior longitudinal fasciculus (SLF) is a major fronto-parietal white matter tract, the structure of which has been little studied in ASD. The fronto-parietal projections of this tract (SLF I, II and III) are thought to play an important role in a number of cognitive functions including attention and visuospatial processing. To date, the isolation of the fronto-parietal branches of the SLF has been hampered by limitations of traditional tractography approaches. Constrained spherical deconvolution (CSD)-based tractography is an advanced approach that allows valid isolation of the fronto-parietal branches of the SLF. Diffusion MRI data were acquired from 45 participants with ASD and 45 age- and IQ-matched controls. The SLF I, II and III branches were isolated using CSD-based tractography in ExploreDTI. Significantly greater fractional anisotropy (FA) was observed in the right SLF II relative to controls. The ASD group also showed greater linear diffusion coefficient in the left SLF I and the right SLF II. In the SLF II, the ASD group had significantly greater right lateralisation of FA in comparison with the control group. The clinical and functional implications of increased FA in white matter are poorly understood ; however, it is possible that this increased white matter organisation in the SLF in ASD may contribute to relative processing advantages in the condition.

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16. Huang D, Yu L, Wang X, Fan Y, Wang S, Zhang Y. Distinct patterns of discrimination and orienting for temporal processing of speech and nonspeech in Chinese children with autism : an event-related potential study. Eur J Neurosci ;2018 (Mar) ;47(6):662-668.

Although many studies have reported domain-general impaired duration perception for speech and nonspeech sounds in children with autism, it remained unclear whether this phenomenon is universally applicable regardless of language background. In some languages such as Finnish and Japanese, vowel duration serves a phonemic role that can signify semantic distinction, and in others (e.g., Mandarin Chinese), vowel duration does not carry this phonemic function. The present event-related potential study investigated neural sensitivity to duration contrasts in speech and nonspeech contexts in Mandarin-speaking children with autism and a control group of age-matched typically developing (TD) children. A passive oddball paradigm was adopted to elicit the mismatch negativity (MMN) and involuntary orienting response (P3a) for change detection. A pure tone condition and a vowel condition were used. The MMN results showed that the autism group had diminished response amplitude and delayed latency in the pure tone condition compared to the TD group, whereas no group difference was found in the vowel condition. The P3a results showed no significant between-group MMN difference in the pure tone condition. In the vowel condition, the autism group had smaller P3a than the TD group. Together, the distinct patterns of discrimination and orienting responses for duration contrasts in pure tones and vowels are consistent with the ‘allophonic perception’ theory for autism, which may reflect a compromised perceptual weighting system for speech learning.

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17. Donaldson PH, Kirkovski M, Rinehart NJ, Enticott PG. Autism-relevant traits interact with temporoparietal junction stimulation effects on social cognition : a high-definition transcranial direct current stimulation and electroencephalography study. Eur J Neurosci ;2018 (Mar) ;47(6):669-681.

The temporoparietal junction (TPJ) is implicated in mental and emotional state attribution, processes associated with autism-relevant traits. Transcranial direct current stimulation (tDCS) to the TPJ can influence social-cognitive performance. However, associations with electrophysiology and autism-relevant traits remain relatively unexamined. This study had two aims : first, exploring links between Autism-Spectrum Quotient (AQ) scores and social-cognitive performance ; second, examining interactions between AQ scores and high-definition-tDCS (HD-tDCS) applied to the right TPJ in terms of mental/emotional state attribution and neurophysiological outcomes. Fifty-three participants completed mental/emotional state attribution tasks before and after HD-tDCS. Pre-stimulation mental state attribution accuracy was reduced in participants with higher AQ Switching scores. Cathodal stimulation was associated with reduced emotion attribution performance in participants with higher AQ Switching and AQ Social scores (the latter at trend-level). Anodal stimulation more frequently interacted with AQ Social scores in terms of neurophysiology, in particular regarding reduced delta power in the left compared to right TPJ, and trend-level positive interactions with P100 and P300 latencies during the emotion recognition task. Elements of attention/switching (AQ Switching) may subserve or underpin elements of social cognition (AQ Social), and cathodal and anodal stimulation may have differing effects depending on trait levels in these domains. This study makes an important and original contribution in terms of increasing understanding of how such trait-level variation might interact with the effects of tDCS and also extending previous studies with regard to understanding potential roles of the rTPJ in both attention and social cognition and how autism-relevant traits might influence TPJ function.

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18. Lodhia V, Hautus MJ, Johnson BW, Brock J. Atypical brain responses to auditory spatial cues in adults with autism spectrum disorder. Eur J Neurosci ;2018 (Mar) ;47(6):682-689.

The auditory processing atypicalities experienced by many individuals on the autism spectrum disorder might be understood in terms of difficulties parsing the sound energy arriving at the ears into discrete auditory ‘objects’. Here, we asked whether autistic adults are able to make use of two important spatial cues to auditory object formation – the relative timing and amplitude of sound energy at the left and right ears. Using electroencephalography, we measured the brain responses of 15 autistic adults and 15 age- and verbal-IQ-matched control participants as they listened to dichotic pitch stimuli – white noise stimuli in which interaural timing or amplitude differences applied to a narrow frequency band of noise typically lead to the perception of a pitch sound that is spatially segregated from the noise. Responses were contrasted with those to stimuli in which timing and amplitude cues were removed. Consistent with our previous studies, autistic adults failed to show a significant object-related negativity (ORN) for timing-based pitch, although their ORN was not significantly smaller than that of the control group. Autistic participants did show an ORN to amplitude cues, indicating that they do not experience a general impairment in auditory object formation. However, their P400 response – thought to indicate the later attention-dependent aspects of auditory object formation – was missing. These findings provide further evidence of atypical auditory object processing in autism with potential implications for understanding the perceptual and communication difficulties associated with the condition.

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19. Pappaianni E, Siugzdaite R, Vettori S, Venuti P, Job R, Grecucci A. Three shades of grey : detecting brain abnormalities in children with autism using source-, voxel- and surface-based morphometry. Eur J Neurosci ;2018 (Mar) ;47(6):690-700.

Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interactions, communication and stereotyped behaviour. Recent evidence from neuroimaging supports the hypothesis that ASD deficits in adults may be related to abnormalities in a specific frontal-temporal network [Autism-specific Structural Network (ASN)]. To see whether these results extend to younger children and to better characterize these abnormalities, we applied three morphometric methods on brain grey matter (GM) of children with and without ASD. We selected 39 sMRI images of male children with ASD and 42 typically developing (TD) from the Autism Brain Imaging Data Exchange database. We used source-based morphometry (SoBM), a whole-brain multivariate approach to identify GM networks, voxel-based morphometry (VBM), a voxel-wise comparison of the local GM concentration and surface-based morphometry (SuBM) for the estimation of the cortical parameters. SoBM showed a bilateral frontal-parietal-temporal network different between groups, including the inferior-middle temporal gyrus, the inferior parietal lobule and the postcentral gyrus ; VBM returned differences only in the right temporal lobe ; SuBM returned a thinning in the right inferior temporal lobe thinner in ASD, a higher gyrification in the right superior parietal lobule in TD and in the middle frontal gyrus in ASD. For the first time, we investigated the brain abnormalities in children with ASD using three morphometric techniques. The results were relatively consistent between methods, stressing the role of an Autism-specific Structural Network in ASD individuals. We also make methodological speculations on the relevance of using multivariate and whole-brain neuroimaging analysis to capture ASD complexity.

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20. Martella G, Meringolo M, Trobiani L, De Jaco A, Pisani A, Bonsi P. The neurobiological bases of autism spectrum disorders : the R451C-neuroligin 3 mutation hampers the expression of long-term synaptic depression in the dorsal striatum. Eur J Neurosci ;2018 (Mar) ;47(6):701-708.

Autism spectrum disorders (ASDs) comprise a heterogeneous group of disorders with a complex genetic etiology. Current theories on the pathogenesis of ASDs suggest that they might arise from an aberrant synaptic transmission affecting specific brain circuits and synapses. The striatum, which is part of the basal ganglia circuit, is one of the brain regions involved in ASDs. Mouse models of ASDs have provided evidence for an imbalance between excitatory and inhibitory neurotransmission. Here, we investigated the expression of long-term synaptic plasticity at corticostriatal glutamatergic synapses in the dorsal striatum of the R451C-NL3 phenotypic mouse model of autism. This mouse model carries the human R451C mutation in the neuroligin 3 (NL3) gene that has been associated with highly penetrant autism in a Swedish family. The R451C-NL3 mouse has been shown to exhibit autistic-like behaviors and alterations of synaptic transmission in different brain areas. However, excitatory glutamatergic transmission and its long-term plasticity have not been investigated in the dorsal striatum so far. Our results indicate that the expression of long-term synaptic depression (LTD) at corticostriatal glutamatergic synapses in the dorsal striatum is impaired by the R451C-NL3 mutation. A partial rescue of LTD was obtained by exogenous activation of cannabinoid CB1 receptors or enhancement of the endocannabinoid tone, suggesting that an altered cannabinoid drive might underlie the deficit of synaptic plasticity in the dorsal striatum of R451C-NL3 mice.

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21. Finch KH, Tager-Flusberg H, Nelson CA. Neural responses to linguistic stimuli in children with and without autism spectrum disorder. Eur J Neurosci ;2018 (Mar) ;47(6):709-719.

Atypical neural responses to language have been found in toddlers with autism spectrum disorder (ASD) and in their unaffected siblings. However, given that language difficulties are often seen in these children, it is difficult to interpret whether these neural differences are a result of the diagnosis of ASD or impairments in their language abilities. In this study, we recorded event-related potentials (ERPs) from four groups of 36-month-olds : low-risk control (LRC), high risk for ASD defined as having an older sibling with ASD (HRA) but who do not have ASD or milder autism-like symptoms (HRA-Typ), HRA children who do not have ASD but exhibit milder autism-like symptoms (HRA-Atyp) and HRA children diagnosed with ASD (ASD). Children listened to words expected to be acquired early (e.g. ball) and words expected to be acquired late (e.g. calf). ERPs were analysed over time windows sensitive to word processing as well as frontal and temporo-parietal sites over the left and right hemispheres. When controlling for language abilities, there were group differences within the temporo-parietal sites. Specifically, the HRA-Atyp group showed a different timed response to late words compared to the ASD and LRC groups. In addition, we found a relation between neural responses in the left frontal sites and ASD severity. Our results suggest that both language abilities and ASD diagnoses are important to consider when interpreting neural differences in lexical processing.

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22. Braukmann R, Lloyd-Fox S, Blasi A, Johnson MH, Bekkering H, Buitelaar JK, Hunnius S. Diminished socially selective neural processing in 5-month-old infants at high familial risk of autism. Eur J Neurosci ;2018 (Mar) ;47(6):720-728.

The social and communicative difficulties that characterize autism spectrum disorder (ASD) are considered the most striking feature of the disorder. Research has reported that individuals with ASD show abnormalities in the brain regions associated with the processing of social information. Importantly, a recent study using functional near-infrared spectroscopy (fNIRS) found the first evidence of atypicalities in the neural processing of social information in 4- to 6-month-old infants at high familial risk of ASD. These findings provide an important step in the search for early markers of ASD and highlight the potential for neuroimaging techniques to detect atypical patterns of neural activity prior to the manifestation of most behavioural symptoms. This study aimed to extend the findings of reduced neural sensitivity to social stimuli in an independent cohort. Twenty-nine 5-month-old infants (13 low-risk infants, 16 high-risk infants) were presented with social and non-social visual stimuli, similar to the previous experiment. Importantly, a non-social dynamic motion control condition was introduced allowing the comparison between social dynamic and non-social, static, as well as dynamic stimuli. We found that while low-risk infants showed activation to social stimuli in the right posterior temporal cortex, this activation was reduced in infants at high risk of ASD. Although the current sample size was relatively small, our results replicate and extend previous work and provide evidence for a social processing difference in infants at risk of autism. Future research will determine whether these differences relate to an eventual ASD diagnosis or may rather reflect the broader autism phenotype.

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23. Olivito G, Lupo M, Laghi F, Clausi S, Baiocco R, Cercignani M, Bozzali M, Leggio M. Lobular patterns of cerebellar resting-state connectivity in adults with Autism Spectrum Disorder. Eur J Neurosci ;2018 (Mar) ;47(6):729-735.

Autism spectrum disorder is a neurodevelopmental disorder characterized by core deficits in social functioning. Core autistics traits refer to poor social and imagination skills, poor attention-switching/strong focus of attention, exceptional attention to detail, as expressed by the autism-spectrum quotient. Over the years, the importance of the cerebellum in the aetiology of autism spectrum disorder has been acknowledged. Neuroimaging studies have provided a strong support to this view, showing both structural and functional connectivity alterations to affect the cerebellum in autism spectrum disorder. According to the underconnectivity theory, disrupted connectivity within cerebello-cerebral networks has been specifically implicated in the aetiology of autism spectrum disorder. However, inconsistent results have been generated across studies. In this study, an integrated approach has been used in a selected population of adults with autism spectrum disorder to analyse both cerebellar morphometry and functional connectivity. In individuals with autism spectrum disorder, a decreased cerebellar grey matter volume affected the right Crus II, a region showing extensive connections with cerebral areas related to social functions. This grey matter reduction correlates with the degree of autistic traits as measured by autism-spectrum quotient. Interestingly, altered functional connectivity was found between the reduced cerebellar Crus II and contralateral cerebral regions, such as frontal and temporal areas. Overall, the present data suggest that adults with autism spectrum disorder present with specific cerebellar structural alterations that may affect functional connectivity within cerebello-cerebral modules relevant to social processing and account for core autistics traits.

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24. Lloyd-Fox S, Blasi A, Pasco G, Gliga T, Jones EJH, Murphy DGM, Elwell CE, Charman T, Johnson MH. Cortical responses before 6 months of life associate with later autism. Eur J Neurosci ;2018 (Mar) ;47(6):736-749.

Autism spectrum disorder (ASD) is a common, highly heritable, developmental disorder and later-born siblings of diagnosed children are at higher risk of developing ASD than the general population. Although the emergence of behavioural symptoms of ASD in toddlerhood is well characterized, far less is known about development during the first months of life of infants at familial risk. In a prospective longitudinal study of infants at familial risk followed to 36 months, we measured functional near-infrared spectroscopy (fNIRS) brain responses to social videos of people (i.e. peek-a-boo) compared to non-social images (vehicles) and human vocalizations compared to non-vocal sounds. At 4-6 months, infants who went on to develop ASD at 3 years (N = 5) evidenced-reduced activation to visual social stimuli relative to low-risk infants (N = 16) across inferior frontal (IFG) and posterior temporal (pSTS-TPJ) regions of the cortex. Furthermore, these infants also showed reduced activation to vocal sounds and enhanced activation to non-vocal sounds within left lateralized temporal (aMTG-STG/pSTS-TPJ) regions compared with low-risk infants and high-risk infants who did not develop ASD (N = 15). The degree of activation to both the visual and auditory stimuli correlated with parent-reported ASD symptomology in toddlerhood. These preliminary findings are consistent with later atypical social brain responses seen in children and adults with ASD, and highlight the need for further work interrogating atypical processing in early infancy and how it may relate to later social interaction and communication difficulties characteristic of ASD.

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25. Rai-Bhogal R, Ahmad E, Li H, Crawford DA. Microarray analysis of gene expression in the cyclooxygenase knockout mice – a connection to autism spectrum disorder. Eur J Neurosci ;2018 (Mar) ;47(6):750-766.

The cellular and molecular events that take place during brain development play an important role in governing function of the mature brain. Lipid-signalling molecules such as prostaglandin E2 (PGE2 ) play an important role in healthy brain development. Abnormalities along the COX-PGE2 signalling pathway due to genetic or environmental causes have been linked to autism spectrum disorder (ASD). This study aims to evaluate the effect of altered COX-PGE2 signalling on development and function of the prenatal brain using male mice lacking cyclooxygenase-1 and cyclooxygenase-2 (COX-1(-/-) and COX-2(-/-) ) as potential model systems of ASD. Microarray analysis was used to determine global changes in gene expression during embryonic days 16 (E16) and 19 (E19). Gene Ontology : Biological Process (GO:BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were implemented to identify affected developmental genes and cellular processes. We found that in both knockouts the brain at E16 had nearly twice as many differentially expressed genes, and affected biological pathways containing various ASD-associated genes important in neuronal function. Interestingly, using GeneMANIA and Cytoscape we also show that the ASD-risk genes identified in both COX-1(-/-) and COX-2(-/-) models belong to protein-interaction networks important for brain development despite of different cellular localization of these enzymes. Lastly, we identified eight genes that belong to the Wnt signalling pathways exclusively in the COX-2(-/-) mice at E16. The level of PKA-phosphorylated beta-catenin (S552), a major activator of the Wnt pathway, was increased in this model, suggesting crosstalk between the COX-2-PGE2 and Wnt pathways during early brain development. Overall, these results provide further molecular insight into the contribution of the COX-PGE2 pathways to ASD and demonstrate that COX-1(-/-) and COX-2(-/-) animals might be suitable new model systems for studying the disorders.

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