Age, not autism, influences multisensory integration of speech stimuli among adults in a McGurk/MacDonald paradigm.

Differences between autistic and non-autistic individuals in perception of the temporal relationships between sights and sounds are theorized to underlie difficulties in integrating relevant sensory information. These, in turn, are thought to contribute to problems with speech perception and higher level social behaviour. However, the literature establishing this connection often involves limited sample sizes and focuses almost entirely on children. To determine whether these differences persist into adulthood, we compared 496 autistic and 373 non-autistic adults (aged 17 to 75 years). Participants completed an online version of the McGurk/MacDonald paradigm, a multisensory illusion indicative of the ability to integrate audiovisual speech stimuli. Audiovisual asynchrony was manipulated, and participants responded both to the syllable they perceived (revealing their susceptibility to the illusion) and to whether or not the audio and video were synchronized (allowing insight into temporal processing). In contrast with prior research with smaller, younger samples, we detected no evidence of impaired temporal or multisensory processing in autistic adults. Instead, we found that in both groups, multisensory integration correlated strongly with age. This contradicts prior presumptions that differences in multisensory perception persist and even increase in magnitude over the lifespan of autistic individuals. It also suggests that the compensatory role multisensory integration may play as the individual senses decline with age is intact. These findings challenge existing theories and provide an optimistic perspective on autistic development. They also underline the importance of expanding autism research to better reflect the age range of the autistic population.

Gamma aminobutyric acid production by commercially available probiotic strains.

AIMS: Certain bacteria can produce gamma aminobutyric acid (GABA) from glutamate in the human intestinal tract, leading to the possibility of altering GABA levels through diet. To this end, we assessed the ability of seven commercially available probiotic supplements to produce GABA. METHOD AND RESULTS: Probiotic strains were compared for GABA production in pure culture. The bacteria were inoculated at a concentration of 107 CFU ml-1 in 10 ml MRS supplemented with monosodium glutamate (1% w/v), both with and without oligofructose-enriched inulin (OFI) (1% w/v). Two strains with the highest production of GABA were further assessed for 48 h in pH-controlled anaerobic batch cultures inoculated with faecal bacteria. Liquid chromatography-mass spectrometry (LC-MS) was used for quantification of GABA and microbiota composition was determined through 16S rRNA gene sequencing. Levilactobacillus brevis LB01 (CGMCC 16921) and Lactiplantibacillus plantarum 299v (DSM 9843) were the most efficient producers of GABA. High GABA levels (28.32 mmol l-1 ± 0.29) were produced by the probiotic strain L. brevis LB01 at pH 5.4-5.6. This was significantly higher than the levels of GABA produced by L. plantarum (4.8 mmol l-1 ± 6.8) and a negative control (2.9 mM ± 3.1). The addition of OFI did not further stimulate GABA production under the conditions tested. The ability of these strains to produce GABA in-vitro was further evaluated in a faecal microbiota environment. Once again, L.brevis LB01 produced the highest levels of GABA (40.24 mmol l-1 ± 20.98). CONCLUSIONS: L. brevis LB01 was found to be the most efficient probiotic strain, of those tested, for GABA production.

Research Review: The relationship between social anxiety and social cognition in children and adolescents: a systematic review and meta-analysis.

BACKGROUND: Childhood Social Anxiety Disorder (SAD) is common and impairing. The recommended treatment is a disorder specific form of cognitive behavioural therapy (CBT) that includes social skills training and, whilst they appear to be more effective than more general treatments, it is not clear whether social skills training is the critical component involved in improved outcomes, particularly given that evidence for the relationship between social anxiety and social skills deficits in children is inconsistent. This may be partly due to an overlap in their observable features, and because the nature of the association may vary in different contexts (e.g. according to child age). An alternative approach is to examine the association between social anxiety and the social cognitive capacities that underpin social skills. This paper aims to examine the association between social anxiety and social cognition in children and adolescents, and examine conceptual and methodological moderators of this relationship. METHODS: Papers published between 1980 and 2019 were screened systematically. Fifty studies were identified from which an effect size could be calculated for the relationship between social anxiety and social cognition, including 15,411 children and adolescents. RESULTS: An overall significant, but moderate effect (r = -.15) was identified, where increased social anxiety was associated with lower social cognitive ability. Moderation analyses revealed specific associations within studies examining social anxiety among participants with and without ASD who were older than 7 years old, and studies assessing the relationship between social anxiety and specific aspects of Theory of Mind (ToM). No significant association was identified between social anxiety and emotion recognition. CONCLUSIONS: Significant associations between social anxiety and social cognitive abilities appear to be accounted for by elevated social anxiety among children with ASD, and those with difficulties in specific aspects of ToM but not broader social skills, such as emotion recognition. This reinforces the importance of accurately identifying and treating social anxiety within ASD populations. In addition, treatments for social anxiety among neurotypical populations may benefit from targeting particular aspects of ToM rather than emotion recognition and other broad social skills.

Commentary: 'Camouflaging' in autistic people - reflection on Fombonne (2020).

Fombonne's (2020) editorial is a thought-provoking appraisal of the literature on 'camouflaging', whereby some autistic people mask or compensate for their autistic characteristics as an attempt to fit in and to cope with disabilities under neurotypical social norms. Fombonne (2020) highlights three issues of contention: (a) construct validity and measurement of camouflaging; (b) camouflaging as a reason for late autism diagnosis in adolescence/adulthood; and (c) camouflaging as a feature of the 'female autism phenotype'. Here, we argue that (a) establishing construct validity and measurement of different aspects of camouflaging is warranted; (b) subjective experiences are important for the differential diagnosis of autism in adolescence/adulthood; and (c) camouflaging is not necessarily a feature of autism in female individuals - nevertheless, taking into account sex and gender influences in development is crucial to understand behavioural manifestations of autism. Future research and clinical directions should involve clarification of associated constructs and measurements, demography, mechanisms, impact (including harms and benefits) and tailored support.

Enhancement of indirect functional connections with shortest path length in the adult autistic brain.

Autism is a neurodevelopmental condition characterized by atypical brain functional organization. Here we investigated the intrinsic indirect (semi-metric) connectivity of the functional connectome associated with autism. Resting-state functional magnetic resonance imaging scans were acquired from 65 neurotypical adults (33 males/32 females) and 61 autistic adults (30 males/31 females). From functional connectivity networks, semi-metric percentages (SMPs) were calculated to assess the proportion of indirect shortest functional pathways at global, hemisphere, network, and node levels. Group comparisons were then conducted to ascertain differences between autism and neurotypical control groups. Finally, the strength and length of edges were examined to explore the patterns of semi-metric connections associated with autism. Compared with neurotypical controls, autistic adults displayed significantly higher SMP at all spatial scales, similar to prior observations in adolescents. Differences were primarily in weaker, longer-distance edges in the majority between networks. However, no significant diagnosis-by-sex interaction effects were observed on global SMP. These findings suggest increased indirect functional connectivity in the autistic brain is persistent from adolescence to adulthood and is indicative of reduced functional network integration.

Reduced reward-related neural response to mimicry in individuals with autism.

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.

Thinking about others and the future: Neural correlates of perspective taking relate to preferences for delayed rewards.

We infer the thoughts and feelings of others by taking their perspectives. Similar processes could be used to understand how we will be affected by future events, by allowing us to take the perspective of our future self. In this paper, we test this idea using a previously presented framework for guiding predictions. The framework proposes that a shared neural mechanism is involved in controlling egocentric bias, both while shifting our perspective away from self and towards others, and while shifting our perspective from immediate to future perspectives. To test this framework, 36 adults performed an intertemporal choice task. They were then scanned using 3T functional magnetic resonance imaging while completing a false-belief "localizer" task, which requires egocentric bias control. A positive correlation was observed between the right temporoparietal junction (rTPJ) response during the false-belief task, and preferences for delayed rewards in intertemporal choices. A subset of participants performed the intertemporal choice task again in the scanner, which revealed that the response of the same rTPJ cluster, individually localized during the false-belief task, was higher during delayed over immediate reward choices. In addition, functional connectivity between the rTPJ and ventromedial prefrontal cortex was found to differ between immediate and delayed choices. The current results indicate an overlap in processes of egocentric bias control and those that determine preferences in intertemporal choices, offering a social cognitive explanation for why rewards are devalued with delay in temporal discounting.

Empathy modulates the temporal structure of social attention.

Individuals with low empathy often show reduced attention towards social stimuli. A limitation of this literature is the lack of empirical work that has explicitly characterized how this relationship manifests itself over time. We investigate this issue by analysing data from two large eye-tracking datasets (total n = 176). Via growth-curve analysis, we demonstrate that self-reported empathy (as measured by the empathy quotient-EQ) predicts the temporal evolution of gaze behaviour under conditions where social and non-social stimuli compete for attention. In both datasets, we found that EQ not only predicted a global increase in social attention, but predicted a different temporal profile of social attention. Specifically, we detected a reliable effect of empathy on gaze towards social images after prolonged viewing. An analysis of switch latencies revealed that low-EQ observers switched gaze away from an initially fixated social image more frequently and at earlier latencies than high-EQ observers. Our analyses demonstrate that modelling these temporal components of gaze signals may reveal useful behavioural phenotypes. The explanatory power of this approach may provide enhanced biomarkers for conditions marked by deficits in empathy-related processes.

The Effects of Maternal Mirroring on the Development of Infant Social Expressiveness: The Case of Infant Cleft Lip.

Parent-infant social interactions start early in development, with infants showing active communicative expressions by just two months. A key question is how this social capacity develops. Maternal mirroring of infant expressions is considered an important, intuitive, parenting response, but evidence is sparse in the first two months concerning the conditions under which mirroring occurs and its developmental sequelae, including in clinical samples where the infant's social expressiveness may be affected. We investigated these questions by comparing the development of mother-infant interactions between a sample where the infant had cleft lip and a normal, unaffected, comparison sample. We videotaped dyads in their homes five times from one to ten weeks and used a microanalytic coding scheme for maternal and infant behaviours, including infant social expressions, and maternal mirroring and marking responses. We also recorded maternal gaze to the infant, using eye-tracking glasses. Although infants with cleft lip did show communicative behaviours, the rate of their development was slower than in comparison infants. This group difference was mediated by a lower rate of mirroring of infant expressions by mothers of infants with cleft lip; this effect was, in turn, partly accounted for by reduced gaze to the infant's mouth, although the clarity of infant social expressions (indexed by cleft severity) and maternal self-blame regarding the cleft were also influential. Results indicate the robustness of parent-infant interactions but also their sensitivity to specific variations in interactants' appearance and behaviour. Parental mirroring appears critical in infant social development, likely supported by the mirror neuron system and underlying clinical and, possibly, cultural differences in infant behaviour. These findings suggest new avenues for clinical intervention.

Commentary: Critical considerations for studying low-functioning autism.

Jack and Pelphrey provide a systematic review of neuroimaging studies in understudied populations within the autistic spectrum, focussing specifically on those with minimal verbal ability, intellectual disability and developmental regression. Despite accounting for nearly a third of the autistic spectrum, the number of studies focussing on these populations is extremely low. This review highlights a critical need for further neuroimaging research on these populations, and provides practical suggestions for overcoming the challenges posed by it. In this commentary, I discuss some of the theoretical questions that arise from the review, on the conceptualisation of the autistic spectrum as well as on optimising experimental design and analysis.

Frontal networks in adults with autism spectrum disorder.

It has been postulated that autism spectrum disorder is underpinned by an 'atypical connectivity' involving higher-order association brain regions. To test this hypothesis in a large cohort of adults with autism spectrum disorder we compared the white matter networks of 61 adult males with autism spectrum disorder and 61 neurotypical controls, using two complementary approaches to diffusion tensor magnetic resonance imaging. First, we applied tract-based spatial statistics, a 'whole brain' non-hypothesis driven method, to identify differences in white matter networks in adults with autism spectrum disorder. Following this we used a tract-specific analysis, based on tractography, to carry out a more detailed analysis of individual tracts identified by tract-based spatial statistics. Finally, within the autism spectrum disorder group, we studied the relationship between diffusion measures and autistic symptom severity. Tract-based spatial statistics revealed that autism spectrum disorder was associated with significantly reduced fractional anisotropy in regions that included frontal lobe pathways. Tractography analysis of these specific pathways showed increased mean and perpendicular diffusivity, and reduced number of streamlines in the anterior and long segments of the arcuate fasciculus, cingulum and uncinate--predominantly in the left hemisphere. Abnormalities were also evident in the anterior portions of the corpus callosum connecting left and right frontal lobes. The degree of microstructural alteration of the arcuate and uncinate fasciculi was associated with severity of symptoms in language and social reciprocity in childhood. Our results indicated that autism spectrum disorder is a developmental condition associated with abnormal connectivity of the frontal lobes. Furthermore our findings showed that male adults with autism spectrum disorder have regional differences in brain anatomy, which correlate with specific aspects of autistic symptoms. Overall these results suggest that autism spectrum disorder is a condition linked to aberrant developmental trajectories of the frontal networks that persist in adult life.

Atypically rightward cerebral asymmetry in male adults with autism stratifies individuals with and without language delay.

In humans, both language and fine motor skills are associated with left-hemisphere specialization, whereas visuospatial skills are associated with right-hemisphere specialization. Individuals with autism spectrum conditions (ASC) show a profile of deficits and strengths that involves these lateralized cognitive functions. Here we test the hypothesis that regions implicated in these functions are atypically rightward lateralized in individuals with ASC and, that such atypicality is associated with functional performance. Participants included 67 male, right-handed adults with ASC and 69 age- and IQ-matched neurotypical males. We assessed group differences in structural asymmetries in cortical regions of interest with voxel-based analysis of grey matter volumes, followed by correlational analyses with measures of language, motor and visuospatial skills. We found stronger rightward lateralization within the inferior parietal lobule and reduced leftward lateralization extending along the auditory cortex comprising the planum temporale, Heschl's gyrus, posterior supramarginal gyrus, and parietal operculum, which was more pronounced in ASC individuals with delayed language onset compared to those without. Planned correlational analyses showed that for individuals with ASC, reduced leftward asymmetry in the auditory region was associated with more childhood social reciprocity difficulties. We conclude that atypical cerebral structural asymmetry is a potential candidate neurophenotype of ASC.

Subgrouping the autism "spectrum": reflections on DSM-5.

DSM-5 has moved autism from the level of subgroups ("apples and oranges") to the prototypical level ("fruit"). But making progress in research, and ultimately improving clinical practice, will require identifying subgroups within the autism spectrum.

Commentary: Not just genes--reclaiming a role for environmental influences on aetiology and outcome in autism. A commentary on Mandy and Lai (2016).

Mandy and Lai (2015) do the field a service in 'reclaiming' the role of pre- and postnatal environmental influences on the aetiology and course of autism spectrum conditions (ASC). This follows several decades where now discredited theories about putative psychogenic and biological disease models held sway, not least in the public mind. We discuss issues that arise from their review; including the need to identify how large the environmental influences on ASC are likely to be; the specificity of these environmental influences to ASC as opposed to a broader range of neurodevelopmental conditions and outcomes; how best to study complex interactions between genetic and environmental influences; and the promise of novel insights into their mechanisms of action. The review highlights current research that aims to better our understanding of the role of environmental factors in the aetiology and course of ASC and, in the near future, may offer the potential for personalised medicine approaches to intervention based on these discoveries.

Neuroanatomy of Individual Differences in Language in Adult Males with Autism.

One potential source of heterogeneity within autism spectrum conditions (ASC) is language development and ability. In 80 high-functioning male adults with ASC, we tested if variations in developmental and current structural language are associated with current neuroanatomy. Groups with and without language delay differed behaviorally in early social reciprocity, current language, but not current autistic features. Language delay was associated with larger total gray matter (GM) volume, smaller relative volume at bilateral insula, ventral basal ganglia, and right superior, middle, and polar temporal structures, and larger relative volume at pons and medulla oblongata in adulthood. Despite this heterogeneity, those with and without language delay showed significant commonality in morphometric features when contrasted with matched neurotypical individuals (n = 57). In ASC, better current language was associated with increased GM volume in bilateral temporal pole, superior temporal regions, dorsolateral fronto-parietal and cerebellar structures, and increased white matter volume in distributed frontal and insular regions. Furthermore, current language-neuroanatomy correlation patterns were similar across subgroups with or without language delay. High-functioning adult males with ASC show neuroanatomical variations associated with both developmental and current language characteristics. This underscores the importance of including both developmental and current language as specifiers for ASC, to help clarify heterogeneity.

Are power calculations useful? A multicentre neuroimaging study.

There are now many reports of imaging experiments with small cohorts of typical participants that precede large-scale, often multicentre studies of psychiatric and neurological disorders. Data from these calibration experiments are sufficient to make estimates of statistical power and predictions of sample size and minimum observable effect sizes. In this technical note, we suggest how previously reported voxel-based power calculations can support decision making in the design, execution and analysis of cross-sectional multicentre imaging studies. The choice of MRI acquisition sequence, distribution of recruitment across acquisition centres, and changes to the registration method applied during data analysis are considered as examples. The consequences of modification are explored in quantitative terms by assessing the impact on sample size for a fixed effect size and detectable effect size for a fixed sample size. The calibration experiment dataset used for illustration was a precursor to the now complete Medical Research Council Autism Imaging Multicentre Study (MRC-AIMS). Validation of the voxel-based power calculations is made by comparing the predicted values from the calibration experiment with those observed in MRC-AIMS. The effect of non-linear mappings during image registration to a standard stereotactic space on the prediction is explored with reference to the amount of local deformation. In summary, power calculations offer a validated, quantitative means of making informed choices on important factors that influence the outcome of studies that consume significant resources.

Why are autism spectrum conditions more prevalent in males?

Autism Spectrum Conditions (ASC) are much more common in males, a bias that may offer clues to the etiology of this condition. Although the cause of this bias remains a mystery, we argue that it occurs because ASC is an extreme manifestation of the male brain. The extreme male brain (EMB) theory, first proposed in 1997, is an extension of the Empathizing-Systemizing (E-S) theory of typical sex differences that proposes that females on average have a stronger drive to empathize while males on average have a stronger drive to systemize. In this first major update since 2005, we describe some of the evidence relating to the EMB theory of ASC and consider how typical sex differences in brain structure may be relevant to ASC. One possible biological mechanism to account for the male bias is the effect of fetal testosterone (fT). We also consider alternative biological theories, the X and Y chromosome theories, and the reduced autosomal penetrance theory. None of these theories has yet been fully confirmed or refuted, though the weight of evidence in favor of the fT theory is growing from converging sources (longitudinal amniocentesis studies from pregnancy to age 10 years old, current hormone studies, and genetic association studies of SNPs in the sex steroid pathways). Ultimately, as these theories are not mutually exclusive and ASC is multi-factorial, they may help explain the male prevalence of ASC.

Biological sex affects the neurobiology of autism.

In autism, heterogeneity is the rule rather than the exception. One obvious source of heterogeneity is biological sex. Since autism was first recognized, males with autism have disproportionately skewed research. Females with autism have thus been relatively overlooked, and have generally been assumed to have the same underlying neurobiology as males with autism. Growing evidence, however, suggests that this is an oversimplification that risks obscuring the biological base of autism. This study seeks to answer two questions about how autism is modulated by biological sex at the level of the brain: (i) is the neuroanatomy of autism different in males and females? and (ii) does the neuroanatomy of autism fit predictions from the 'extreme male brain' theory of autism, in males and/or in females? Neuroanatomical features derived from voxel-based morphometry were compared in a sample of equal-sized high-functioning male and female adults with and without autism (n = 120, n = 30/group). The first question was investigated using a 2 × 2 factorial design, and by spatial overlap analyses of the neuroanatomy of autism in males and females. The second question was tested through spatial overlap analyses of specific patterns predicted by the extreme male brain theory. We found that the neuroanatomy of autism differed between adult males and females, evidenced by minimal spatial overlap (not different from that occurred under random condition) in both grey and white matter, and substantially large white matter regions showing significant sex × diagnosis interactions in the 2 × 2 factorial design. These suggest that autism manifests differently by biological sex. Furthermore, atypical brain areas in females with autism substantially and non-randomly (P < 0.001) overlapped with areas that were sexually dimorphic in neurotypical controls, in both grey and white matter, suggesting neural 'masculinization'. This was not seen in males with autism. How differences in neuroanatomy relate to the similarities in cognition between males and females with autism remains to be understood. Future research should stratify by biological sex to reduce heterogeneity and to provide greater insight into the neurobiology of autism.

The integration of head and body cues during the perception of social interactions.

Humans spend a large proportion of time participating in social interactions. The ability to accurately detect and respond to human interactions is vital for social functioning, from early childhood through to older adulthood. This detection ability arguably relies on integrating sensory information from the interactants. Within the visual modality, directional information from a person's eyes, head, and body are integrated to inform where another person is looking and who they are interacting with. To date, social cue integration research has focused largely on the perception of isolated individuals. Across two experiments, we investigated whether observers integrate body information with head information when determining whether two people are interacting, and manipulated frame of reference (one of the interactants facing observer vs. facing away from observer) and the eye-region visibility of the interactant. Results demonstrate that individuals integrate information from the body with head information when perceiving dyadic interactions, and that integration is influenced by the frame of reference and visibility of the eye-region. Interestingly, self-reported autistics traits were associated with a stronger influence of body information on interaction perception, but only when the eye-region was visible. This study investigated the recognition of dyadic interactions using whole-body stimuli while manipulating eye visibility and frame of reference, and provides crucial insights into social cue integration, as well as how autistic traits affect cue integration, during perception of social interactions.