The "Reading the Mind in the Eyes" test (Eyes test) is an advanced test of theory of mind. Typical sex difference has been reported (i.e., female advantage). Individuals with autism show more ...difficulty than do typically developing individuals, yet it remains unclear how this is modulated by sex, as females with autism have been under-represented. Here in a large, non-male-biased sample we test for the effects of sex, diagnosis, and their interaction. The Eyes test (revised version) was administered online to 395 adults with autism (178 males, 217 females) and 320 control adults (152 males, 168 females). Two-way ANOVA showed a significant sex-by-diagnosis interaction in total correct score (F(1,711) = 5.090, p = 0.024, ηp2 = 0.007) arising from a significant sex difference between control males and females (p < 0.001, Cohen's d = 0.47), and an absence of a sex difference between males and females with autism (p = 0.907, d = 0.01); significant case-control differences were observed across sexes, with effect sizes of d = 0.35 in males and d = 0.69 in females. Group-difference patterns fit with the extreme-male-brain (EMB) theory predictions. Eyes test-Empathy Quotient and Eyes test-Autism Spectrum Quotient correlations were significant only in females with autism (r = 0.35, r = -0.32, respectively), but not in the other 3 groups. Support vector machine (SVM) classification based on response pattern across all 36 items classified autism diagnosis with a relatively higher accuracy for females (72.2%) than males (65.8%). Nevertheless, an SVM model trained within one sex generalized equally well when applied to the other sex. Performance on the Eyes test is a sex-independent phenotypic characteristic of adults with autism, reflecting sex-common social difficulties, and provides support for the EMB theory predictions for both males and females. Performance of females with autism differed from same-sex controls more than did that of males with autism. Females with autism also showed stronger coherence between self-reported dispositional traits and Eyes test performance than all other groups.
Autism spectrum conditions (ASC) affect more males than females in the general population. However, within ASC it is unclear if there are phenotypic sex differences. Testing for similarities and ...differences between the sexes is important not only for clinical assessment but also has implications for theories of typical sex differences and of autism. Using cognitive and behavioral measures, we investigated similarities and differences between the sexes in age- and IQ-matched adults with ASC (high-functioning autism or Asperger syndrome). Of the 83 (45 males and 38 females) participants, 62 (33 males and 29 females) met Autism Diagnostic Interview-Revised (ADI-R) cut-off criteria for autism in childhood and were included in all subsequent analyses. The severity of childhood core autism symptoms did not differ between the sexes. Males and females also did not differ in self-reported empathy, systemizing, anxiety, depression, and obsessive-compulsive traits/symptoms or mentalizing performance. However, adult females with ASC showed more lifetime sensory symptoms (p = 0.036), fewer current socio-communication difficulties (p = 0.001), and more self-reported autistic traits (p = 0.012) than males. In addition, females with ASC who also had developmental language delay had lower current performance IQ than those without developmental language delay (p<0.001), a pattern not seen in males. The absence of typical sex differences in empathizing-systemizing profiles within the autism spectrum confirms a prediction from the extreme male brain theory. Behavioral sex differences within ASC may also reflect different developmental mechanisms between males and females with ASC. We discuss the importance of the superficially better socio-communication ability in adult females with ASC in terms of why females with ASC may more often go under-recognized, and receive their diagnosis later, than males.
Abstract
Sex differences in the human brain are of interest for many reasons: for example, there are sex differences in the observed prevalence of psychiatric disorders and in some psychological ...traits that brain differences might help to explain. We report the largest single-sample study of structural and functional sex differences in the human brain (2750 female, 2466 male participants; mean age 61.7 years, range 44-77 years). Males had higher raw volumes, raw surface areas, and white matter fractional anisotropy; females had higher raw cortical thickness and higher white matter tract complexity. There was considerable distributional overlap between the sexes. Subregional differences were not fully attributable to differences in total volume, total surface area, mean cortical thickness, or height. There was generally greater male variance across the raw structural measures. Functional connectome organization showed stronger connectivity for males in unimodal sensorimotor cortices, and stronger connectivity for females in the default mode network. This large-scale study provides a foundation for attempts to understand the causes and consequences of sex differences in adult brain structure and function.
This review examines the role of hormones in the development of social and nonsocial cognition and the brain. Research findings from human studies designed to elucidate the effects of both prenatal ...and postnatal exposure to hormones in children and young adults are summarized. Effects are found to be both time and dose dependent, with exposure to abnormal hormone levels having a limited impact outside the “critical window” in development. Particular attention is given to the role of prenatal hormone exposure, which appears to be vital for early organization of the brain. In later life, measurements of circulating hormone levels and the administration of testosterone and oxytocin are found to predict behavior, but the effect is thought to be one of “activation” or “fine-tuning” of the early organization of the brain. Possible directions for valuable future research are discussed.
Autobiographical descriptions and clinician observations suggest that some individuals with autism, particularly females, ‘camouflage’ their social communication difficulties, which may require ...considerable cognitive effort and lead to increased stress, anxiety and depression. Using data from 60 age- and IQ-matched men and women with autism (without intellectual disability), we operationalized camouflaging in adults with autism for the first time as the quantitative discrepancy between the person’s ‘external’ behavioural presentation in social–interpersonal contexts (measured by the Autism Diagnostic Observation Schedule) and the person’s ‘internal’ status (dispositional traits measured by the Autism Spectrum Quotient and social cognitive capability measured by the ‘Reading the Mind in the Eyes’ Test). We found that the operationalized camouflaging measure was not significantly correlated with age or IQ. On average, women with autism had higher camouflaging scores than men with autism (Cohen’s d = 0.98), with substantial variability in both groups. Greater camouflaging was associated with more depressive symptoms in men and better signal-detection sensitivity in women with autism. The neuroanatomical association with camouflaging score was largely sex/gender-dependent and significant only in women: from reverse inference, the most correlated cognitive terms were about emotion and memory. The underlying constructs, measurement, mechanisms, consequences and heterogeneity of camouflaging in autism warrant further investigation.
Over the last 25years, “mindblindness” (deficits in representing mental states) has been one of the primary explanations behind the hallmark social-communication difficulties in autism spectrum ...conditions (ASC). However, highlighting neural systems responsible for mindblindness and their relation to variation in social impairments has remained elusive. In this study we show that one of the neural systems responsible for mindblindness in ASC and its relation to social impairments is the right temporo-parietal junction (RTPJ). Twenty-nine adult males with ASC and 33 age and IQ-matched Controls were scanned with fMRI while making reflective mentalizing or physical judgments about themselves or another person. Regions of interest within mentalizing circuitry were examined for between-group differences in activation during mentalizing about self and other and correlations with social symptom severity. RTPJ was the only mentalizing region that responded atypically in ASC. In Controls, RTPJ was selectively more responsive to mentalizing than physical judgments. This selectivity for mentalizing was not apparent in ASC and generalized across both self and other. Selectivity of RTPJ for mentalizing was also associated with the degree of reciprocal social impairment in ASC. These results lend support to the idea that RTPJ is one important neural system behind mindblindness in ASC. Understanding the contribution of RTPJ in conjunction with other neural systems responsible for other component processes involved in social cognition will be illuminating in fully explaining the hallmark social-communication difficulties of autism.
► RTPJ is not selectively responsive to mental state information in autism. ► Lack of RTPJ mentalizing selectivity in autism generalizes across self and other. ► RTPJ mentalizing selectivity is related to variation in social impairment in autism.
Postmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism spectrum disorder (ASD), with a putative link to aberrant mTOR-dependent synaptic ...pruning. ASD is also characterized by atypical macroscale functional connectivity as measured with resting-state fMRI (rsfMRI). These observations raise the question of whether excess of synapses causes aberrant functional connectivity in ASD. Using rsfMRI, electrophysiology and in silico modelling in Tsc2 haploinsufficient mice, we show that mTOR-dependent increased spine density is associated with ASD -like stereotypies and cortico-striatal hyperconnectivity. These deficits are completely rescued by pharmacological inhibition of mTOR. Notably, we further demonstrate that children with idiopathic ASD exhibit analogous cortical-striatal hyperconnectivity, and document that this connectivity fingerprint is enriched for ASD-dysregulated genes interacting with mTOR or Tsc2. Finally, we show that the identified transcriptomic signature is predominantly expressed in a subset of children with autism, thereby defining a segregable autism subtype. Our findings causally link mTOR-related synaptic pathology to large-scale network aberrations, revealing a unifying multi-scale framework that mechanistically reconciles developmental synaptopathy and functional hyperconnectivity in autism.
Individuals with autism spectrum conditions (ASC) have profound impairments in the interpersonal social domain, but it is unclear if individuals with ASC also have impairments in the intrapersonal ...self-referential domain. We aimed to evaluate across several well validated measures in both domains, whether both self-referential cognition and empathy are impaired in ASC and whether these two domains are related to each other.
Thirty adults aged 19-45, with Asperger Syndrome or high-functioning autism and 30 age, sex, and IQ matched controls participated in the self-reference effect (SRE) paradigm. In the SRE paradigm, participants judged adjectives in relation to the self, a similar close other, a dissimilar non-close other, or for linguistic content. Recognition memory was later tested. After the SRE paradigm, several other complimentary self-referential cognitive measures were taken. Alexithymia and private self-consciousness were measured via self-report. Self-focused attention was measured on the Self-Focus Sentence Completion task. Empathy was measured with 3 self-report instruments and 1 performance measure of mentalizing (Eyes test). Self-reported autistic traits were also measured with the Autism Spectrum Quotient (AQ). Although individuals with ASC showed a significant SRE in memory, this bias was decreased compared to controls. Individuals with ASC also showed reduced memory for the self and a similar close other and also had concurrent impairments on measures of alexithymia, self-focused attention, and on all 4 empathy measures. Individual differences in self-referential cognition predicted mentalizing ability and self-reported autistic traits. More alexithymia and less self memory was predictive of larger mentalizing impairments and AQ scores regardless of diagnosis. In ASC, more self-focused attention is associated with better mentalizing ability and lower AQ scores, while in controls, more self-focused attention is associated with decreased mentalizing ability and higher AQ scores. Increasing private self-consciousness also predicted better mentalizing ability, but only for individuals with ASC.
We conclude that individuals with ASC have broad impairments in both self-referential cognition and empathy. These two domains are also intrinsically linked and support predictions made by simulation theory. Our results also highlight a specific dysfunction in ASC within cortical midlines structures of the brain such as the medial prefrontal cortex.
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.
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