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.

Fetal testosterone influences sexually dimorphic gray matter in the human brain.

In nonhuman species, testosterone is known to have permanent organizing effects early in life that predict later expression of sex differences in brain and behavior. However, in humans, it is still unknown whether such mechanisms have organizing effects on neural sexual dimorphism. In human males, we show that variation in fetal testosterone (FT) predicts later local gray matter volume of specific brain regions in a direction that is congruent with sexual dimorphism observed in a large independent sample of age-matched males and females from the NIH Pediatric MRI Data Repository. Right temporoparietal junction/posterior superior temporal sulcus (RTPJ/pSTS), planum temporale/parietal operculum (PT/PO), and posterior lateral orbitofrontal cortex (plOFC) had local gray matter volume that was both sexually dimorphic and predicted in a congruent direction by FT. That is, gray matter volume in RTPJ/pSTS was greater for males compared to females and was positively predicted by FT. Conversely, gray matter volume in PT/PO and plOFC was greater in females compared to males and was negatively predicted by FT. Subregions of both amygdala and hypothalamus were also sexually dimorphic in the direction of Male > Female, but were not predicted by FT. However, FT positively predicted gray matter volume of a non-sexually dimorphic subregion of the amygdala. These results bridge a long-standing gap between human and nonhuman species by showing that FT acts as an organizing mechanism for the development of regional sexual dimorphism in the human brain.

Effects of fetal testosterone on visuospatial ability.

This study investigated whether fetal testosterone (FT) measured from second trimester amniotic fluid was related to specific aspects of visuospatial ability, in children aged 7-10 years (35 boys, 29 girls). A series of tasks were used: the children's Embedded Figures Test (EFT) (a test of attention to detail), a ball targeting task (measuring hand-eye coordination), and a computerized mental rotation task (measuring rotational ability). FT was a significant predictor for EFT scores in both boys and girls, with boys also showing a clear advantage for this task. No significant sex differences were observed in targeting. Boys scored higher than girls on mental rotation. However, no significant relationships were observed between FT and targeting or mental rotation. Girls' performance on the mental rotation and targeting tasks was significantly related to age, indicating that these tasks may have been too difficult for the younger children. These results indicate that FT has a significant role in some aspects of cognitive development but that further work is needed to understand its effect on the different aspects of visuospatial ability.

Fetal testosterone predicts sexually differentiated childhood behavior in girls and in boys.

Mammals, including humans, show sex differences in juvenile play behavior. In rodents and nonhuman primates, these behavioral sex differences result, in part, from sex differences in androgens during early development. Girls exposed to high levels of androgen prenatally, because of the genetic disorder congenital adrenal hyperplasia, show increased male-typical play, suggesting similar hormonal influences on human development, at least in females. Here, we report that fetal testosterone measured from amniotic fluid relates positively to male-typical scores on a standardized questionnaire measure of sex-typical play in both boys and girls. These results show, for the first time, a link between fetal testosterone and the development of sex-typical play in children from the general population, and are the first data linking high levels of prenatal testosterone to increased male-typical play behavior in boys.

Fetal testosterone and autistic traits: a response to three fascinating commentaries.

This article is an author response to three previous commentaries on 'Fetal testosterone and autistic traits' (Auyeung et al., 2009).

Fetal testosterone and autistic traits.

Studies of amniotic testosterone in humans suggest that fetal testosterone (fT) is related to specific (but not all) sexually dimorphic aspects of cognition and behaviour. It has also been suggested that autism may be an extreme manifestation of some male-typical traits, both in terms of cognition and neuroanatomy. In this paper, we examine the possibility of a link between autistic traits and fT levels measured in amniotic fluid during routine amniocentesis. Two instruments measuring number of autistic traits (the Childhood Autism Spectrum Test (CAST) and the Child Autism Spectrum Quotient (AQ-Child)) were completed by these women about their children (N=235), ages 6-10 years. Intelligence Quotient (IQ) was measured in a subset of these children (N=74). fT levels were positively associated with higher scores on the CAST and AQ-Child. This relationship was seen within sex as well as when the sexes were combined, suggesting this is an effect of fT rather than of sex per se. No relationships were found between overall IQ and the predictor variables, or between IQ and CAST or AQ-Child. These findings are consistent with the hypothesis that prenatal androgen exposure is related to children exhibiting more autistic traits. These results need to be followed up in a much larger sample to test if clinical cases of ASC have elevated fT.

Fetal programming effects of testosterone on the reward system and behavioral approach tendencies in humans.

BACKGROUND: Sex differences are present in many neuropsychiatric conditions that affect emotion and approach-avoidance behavior. One potential mechanism underlying such observations is testosterone in early development. Although much is known about the effects of testosterone in adolescence and adulthood, little is known in humans about how testosterone in fetal development influences later neural sensitivity to valenced facial cues and approach-avoidance behavioral tendencies. METHODS: With functional magnetic resonance imaging we scanned 25 8-11-year-old children while viewing happy, fear, neutral, or scrambled faces. Fetal testosterone (FT) was measured via amniotic fluid sampled between 13 and 20 weeks gestation. Behavioral approach-avoidance tendencies were measured via parental report on the Sensitivity to Punishment and Sensitivity to Rewards questionnaire. RESULTS: Increasing FT predicted enhanced selectivity for positive compared with negatively valenced facial cues in reward-related regions such as caudate, putamen, and nucleus accumbens but not the amygdala. Statistical mediation analyses showed that increasing FT predicts increased behavioral approach tendencies by biasing caudate, putamen, and nucleus accumbens but not amygdala to be more responsive to positive compared with negatively valenced cues. In contrast, FT was not predictive of behavioral avoidance tendencies, either through direct or neurally mediated paths. CONCLUSIONS: This work suggests that testosterone in humans acts as a fetal programming mechanism on the reward system and influences behavioral approach tendencies later in life. As a mechanism influencing atypical development, FT might be important across a range of neuropsychiatric conditions that asymmetrically affect the sexes, the reward system, emotion processing, and approach behavior.

Enhancing emotion recognition in children with autism spectrum conditions: an intervention using animated vehicles with real emotional faces.

This study evaluated The Transporters, an animated series designed to enhance emotion comprehension in children with autism spectrum conditions (ASC). n = 20 children with ASC (aged 4-7) watched The Transporters everyday for 4 weeks. Participants were tested before and after intervention on emotional vocabulary and emotion recognition at three levels of generalization. Two matched control groups of children (ASC group, n = 18 and typically developing group, n = 18) were also assessed twice without any intervention. The intervention group improved significantly more than the clinical control group on all task levels, performing comparably to typical controls at Time 2. We conclude that using The Transporters significantly improves emotion recognition in children with ASC. Future research should evaluate the series' effectiveness with lower-functioning individuals.

Organizational effects of fetal testosterone on human corpus callosum size and asymmetry.

Previous theory and research in animals has identified the critical role that fetal testosterone (FT) plays in organizing sexually dimorphic brain development. However, to date there are no studies in humans directly testing the organizational effects of FT on structural brain development. In the current study we investigated the effects of FT on corpus callosum size and asymmetry. High-resolution structural magnetic resonance images (MRI) of the brain were obtained on 28 8-11-year-old boys whose exposure to FT had been previously measured in utero via amniocentesis conducted during the second trimester. Although there was no relationship between FT and midsaggital corpus callosum size, increasing FT was significantly related to increasing rightward asymmetry (e.g., Right>Left) of a posterior subsection of the callosum, the isthmus, that projects mainly to parietal and superior temporal areas. This potential organizational effect of FT on rightward callosal asymmetry may be working through enhancing the neuroprotective effects of FT and result in an asymmetric distribution of callosal axons. We suggest that this possible organizational effect of FT on callosal asymmetry may also play a role in shaping sexual dimorphism in functional and structural brain development, cognition, and behavior.

Can emotion recognition be taught to children with autism spectrum conditions?

Children with autism spectrum conditions (ASC) have major difficulties in recognizing and responding to emotional and mental states in others' facial expressions. Such difficulties in empathy underlie their social-communication difficulties that form a core of the diagnosis. In this paper we ask whether aspects of empathy can be taught to young children with ASC. We review a study that evaluated The Transporters, an animated series designed to enhance emotion comprehension in children with ASC. Children with ASC (4-7 years old) watched The Transporters every day for four weeks. Participants were tested before and after intervention on emotional vocabulary and emotion recognition at three levels of generalization. The intervention group improved significantly more than a clinical control group on all task levels, performing comparably to typical controls at time 2. The discussion centres on how vehicles as mechanical systems may be one key reason why The Transporters caused the improved understanding and recognition of emotions in children with ASC. The implications for the design of autism-friendly interventions are also explored.

Eagle-eyed visual acuity: an experimental investigation of enhanced perception in autism.

BACKGROUND: Anecdotal accounts of sensory hypersensitivity in individuals with autism spectrum conditions (ASC) have been noted since the first reports of the condition. Over time, empirical evidence has supported the notion that those with ASC have superior visual abilities compared with control subjects. However, it remains unclear whether these abilities are specifically the result of differences in sensory thresholds (low-level processing), rather than higher-level cognitive processes. METHODS: This study investigates visual threshold in n = 15 individuals with ASC and n = 15 individuals without ASC, using a standardized optometric test, the Freiburg Visual Acuity and Contrast Test, to investigate basic low-level visual acuity. RESULTS: Individuals with ASC have significantly better visual acuity (20:7) compared with control subjects (20:13)-acuity so superior that it lies in the region reported for birds of prey. CONCLUSIONS: The results of this study suggest that inclusion of sensory hypersensitivity in the diagnostic criteria for ASC may be warranted and that basic standardized tests of sensory thresholds may inform causal theories of ASC.

Talent in autism: hyper-systemizing, hyper-attention to detail and sensory hypersensitivity.

We argue that hyper-systemizing predisposes individuals to show talent, and review evidence that hyper-systemizing is part of the cognitive style of people with autism spectrum conditions (ASC). We then clarify the hyper-systemizing theory, contrasting it to the weak central coherence (WCC) and executive dysfunction (ED) theories. The ED theory has difficulty explaining the existence of talent in ASC. While both hyper-systemizing and WCC theories postulate excellent attention to detail, by itself excellent attention to detail will not produce talent. By contrast, the hyper-systemizing theory argues that the excellent attention to detail is directed towards detecting 'if p, then q' rules (or [input-operation-output] reasoning). Such law-based pattern recognition systems can produce talent in systemizable domains. Finally, we argue that the excellent attention to detail in ASC is itself a consequence of sensory hypersensitivity. We review an experiment from our laboratory demonstrating sensory hypersensitivity detection thresholds in vision. We conclude that the origins of the association between autism and talent begin at the sensory level, include excellent attention to detail and end with hyper-systemizing.

IQ, fetal testosterone and individual variability in children's functional lateralization.

Previous event-related potential (ERP) studies have revealed that faces and words show a robust difference in the lateralization of their N170. The present study investigated the development of this differential lateralization in school-age boys. We assessed the potential role of fetal testosterone (FT) level as a factor biasing the prenatal development of lateralization, and the role of reading skill and Verbal IQ as factors predicting left lateralization for words in childhood. The adult pattern of differential N170 lateralization for faces and words was not present in a group of 26 school-age boys. This suggests that N170 lateralization only appears with years of experience with these stimulus categories or with late childhood maturation. FT level measured by amniocentesis did not account for a significant part of the individual variability in lateralization. Verbal IQ correlated with the degree of left lateralization of the N170 to words, but this effect was not specific to language abilities and language lateralization. A strong correlation was observed between the degree of left lateralization for words and the degree of left lateralization for faces, and both lateralization scores correlated with Verbal and Performance IQ. Possible explanations for these results are discussed along with ERP correlates of words and faces in school-age boys.