Cognition in males and females with autism: similarities and differences

The male bias in autism spectrum conditions (ASC) has led to females with ASC being under-researched. This lack of attention to females could hide variability due to sex that may explain some of the heterogeneity within ASC. In this study we investigate four key cognitive domains (mentalizing and emotion perception, executive function, perceptual attention to detail, and motor function) in ASC, to test for similarities and differences between males and females with and without ASC (n = 128 adults; n = 32 per group). In the mentalizing and facial emotion perception domain, males and females with ASC showed similar deficits compared to neurotypical controls. However, in attention to detail and dexterity involving executive function, although males with ASC showed poorer performance relative to neurotypical males, females with ASC performed comparably to neurotypical females. We conclude that performance in the social-cognitive domain is equally impaired in male and female adults with ASC. However, in specific non-social cognitive domains, performance within ASC depends on sex. This suggests that in specific domains, cognitive profiles in ASC are modulated by sex

Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women

Excitation-inhibition (E:I) imbalance is theorized as an important pathophysiological mechanism in autism. Autism affects males more frequently than females and sex-related mechanisms (e.g., X-linked genes, androgen hormones) can influence E:I balance. This suggests that E:I imbalance may affect autism differently in males versus females. With a combination of in-silico modeling and in-vivo chemogenetic manipulations in mice, we first show that a time-series metric estimated from fMRI BOLD signal, the Hurst exponent (H), can be an index for underlying change in the synaptic E:I ratio. In autism we find that H is reduced, indicating increased excitation, in the medial prefrontal cortex (MPFC) of autistic males but not females. Increasingly intact MPFC H is also associated with heightened ability to behaviorally camouflage social-communicative difficulties, but only in autistic females. This work suggests that H in BOLD can index synaptic E:I ratio and that E:I imbalance affects autistic males and females differently

Sex differences in frontal lobe connectivity in adults with autism spectrum conditions

Autism spectrum conditions (ASC) are more prevalent in males than females. The biological basis of this difference remains unclear. It has been postulated that one of the primary causes of ASC is a partial disconnection of the frontal lobe from higher-order association areas during development (that is, a frontal ‘disconnection syndrome’). Therefore, in the current study we investigated whether frontal connectivity differs between males and females with ASC. We recruited 98 adults with a confirmed highfunctioning ASC diagnosis (61 males: aged 18–41 years; 37 females: aged 18–37 years) and 115 neurotypical controls (61 males: aged 18–45 years; 54 females: aged 18–52 years). Current ASC symptoms were evaluated using the Autism Diagnostic Observation Schedule (ADOS). Diffusion tensor imaging was performed and fractional anisotropy (FA) maps were created. Mean FA values were determined for five frontal fiber bundles and two non-frontal fiber tracts. Between-group differences in mean tract FA, as well as sex-by-diagnosis interactions were assessed. Additional analyses including ADOS scores informed us on the influence of current ASC symptom severity on frontal connectivity. We found that males with ASC had higher scores of current symptom severity than females, and had significantly lower mean FA values for all but one tract compared to controls. No differences were found between females with or without ASC. Significant sex-by-diagnosis effects were limited to the frontal tracts. Taking current ASC symptom severity scores into account did not alter the findings, although the observed power for these analyses varied. We suggest these findings of frontal connectivity abnormalities in males with ASC, but not in females with ASC, have the potential to inform us on some of the sex differences reported in the behavioral phenotype of ASC.This work was supported by grant GO 400061 (to DGMM) from the UK Medical Research Council (http://www.mrc.ac.uk/index.htm). The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution. The National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care—East of England (CLAHRC-EoE) also supported the project. This paper represents independent research (part) funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. During the period of the study M-CL and AR were supported by the William Binks Autism Neuroscience Fellowship and Autism Research Trust, and M-CL was also supported by the O’Brien Scholars Program within the Child and Youth Mental Health Collaborative at the Centre for Addiction and Mental Health and The Hospital for Sick Children, Toronto. The Autism Research Trust supported SB-C, BC and ML

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

Unsupervised data-driven stratification of mentalizing heterogeneity in autism.

Individuals affected by autism spectrum conditions (ASC) are considerably heterogeneous. Novel approaches are needed to parse this heterogeneity to enhance precision in clinical and translational research. Applying a clustering approach taken from genomics and systems biology on two large independent cognitive datasets of adults with and without ASC (n = 694; n = 249), we find replicable evidence for 5 discrete ASC subgroups that are highly differentiated in item-level performance on an explicit mentalizing task tapping ability to read complex emotion and mental states from the eye region of the face (Reading the Mind in the Eyes Test; RMET). Three subgroups comprising 45-62% of ASC adults show evidence for large impairments (Cohen's d = -1.03 to -11.21), while other subgroups are effectively unimpaired. These findings delineate robust natural subdivisions within the ASC population that may allow for more individualized inferences and accelerate research towards precision medicine goals.This study was supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) East of England at Cambridgeshire and Peterborough NHS Foundation Trust. This study was also conducted in association with the European Autism Interventions—A Multicentre Study for Developing New Medications (EU-AIMS) consortium; EU-AIMS receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013), EFPIA companies, and Autism Speaks. This study was also supported by grants from the UK Medical Research Council (MRC) (G0600977), the Wellcome Trust (091774/Z/10/Z), and the Autism Research Trust (ART). M-CL and AR received support from the William Binks Autism Neuroscience Fellowship at the University of Cambridge. M-CL received support from the O’Brien Scholars Program within the Child and Youth Mental Health Collaborative at the Centre for Addiction and Mental Health and The Hospital for Sick Children, Toronto.This is the final version of the article. It first appeared from Nature Publishing Group via https://doi.org/10.1038/srep3533

Task Selection is Critical for the Demonstration of Reciprocal Patterns of Sex Differences in Hand/Arm Motor Control and Near/Far Visual Processing

Women have been reported to perform better with hand rather than arm movements ( Sanders and Walsh, 2007 ) and with visual stimuli in near rather than far space ( Sanders, Sinclair and Walsh, 2007 ). Men performed better with the arm and in far space. These reciprocal patterns of sex differences appear as Muscle * Sex and Space * Sex interactions. We investigated these claims using target cancellation tasks in which task difficulty was manipulated by varying target size or the number of distracters. In Study 1 we did not find the Muscle * Sex or the Space * Sex interaction. We argue that ballistic movement was too simple to reveal the Muscle * Sex interaction. However, a trend for the Space * Sex interaction suggested task difficulty was set too high. Study 2 introduced easier levels of difficulty and the overall Space * Sex interaction narrowly failed to reach significance ( p = 0.051). In Study 3 the Space * Sex interaction was significant ( p = 0.001). A review of the present, and four previously published, studies indicates that task selection is critical if the Space * Sex interaction and its associated reciprocal within-sex differences are to be demonstrated without the obscuring effects of Space and Difficulty. These sex differences are compatible with predictions from the hunter-gatherer hypothesis. Implications for two-visual-system-models are considered

White-matter relaxation time and myelin water fraction differences in young adults with autism

Increasing evidence suggests that autism is associated with abnormal white-matter (WM) anatomy and impaired brain ‘connectivity’. While myelin plays a critical role in synchronized brain communication, its aetiological role in autistic symptoms has only been indirectly addressed by WM volumetric, relaxometry and diffusion tensor imaging studies. A potentially more specific measure of myelin content, termed myelin water fraction (MWF), could provide improved sensitivity to myelin alteration in autism. We performed a cross-sectional imaging study that compared 14 individuals with autism and 14 age- and IQ-matched controls. T 1 relaxation times (T 1), T 2 relaxation times (T 2) and MWF values were compared between autistic subjects, diagnosed using the Autism Diagnostic Interview – Revised (ADI-R), with current symptoms assessed using the Autism Diagnostic Observation Schedule (ADOS) and typical healthy controls. Correlations between T 1, T 2 and MWF values with clinical measures [ADI-R, ADOS, and the Autism Quotient (AQ)] were also assessed. Individuals with autism showed widespread WM T 1 and MWF differences compared to typical controls. Within autistic individuals, worse current social interaction skill as measured by the ADOS was related to reduced MWF although not T 1. No significant differences or correlations with symptoms were observed with respect to T 2. Autistic individuals have significantly lower global MWF and higher T 1, suggesting widespread alteration in tissue microstructure and biochemistry. Areas of difference, including thalamic projections, cerebellum and cingulum, have previously been implicated in the disorder; however, this is the first study to specifically indicate myelin alteration in these regions

Neural self-representation in autistic women and association with 'compensatory camouflaging'.

Prior work has revealed sex/gender-dependent autistic characteristics across behavioural and neural/biological domains. It remains unclear whether and how neural sex/gender differences are related to behavioural sex/gender differences in autism. Here, we examined whether atypical neural responses during mentalizing and self-representation are sex/gender-dependent in autistic adults and explored whether 'camouflaging' (acting as if behaviourally neurotypical) is associated with sex/gender-dependent neural responses. In total, N = 119 adults (33 typically developing males, 29 autistic males, 29 typically developing females and 28 autistic females) participated in a task-related functional magnetic resonance imaging paradigm to assess neural activation within right temporo-parietal junction and ventromedial prefrontal cortex during mentalizing and self-representation. Camouflaging in autism was quantified as the discrepancy between extrinsic behaviour in social-interpersonal contexts and intrinsic status. While autistic men showed hypoactive right temporo-parietal junction mentalizing and ventromedial prefrontal cortex self-representation responses compared to typically developing men, such neural responses in autistic women were not different from typically developing women. In autistic women only, increasing camouflaging was associated with heightened ventromedial prefrontal cortex self-representation response. There is a lack of impaired neural self-representation and mentalizing in autistic women compared to typically developing women. Camouflaging is heightened in autistic women and may relate to neural self-representation response. These results reveal brain-behaviour relations that help explain sex/gender-heterogeneity in social brain function in autism