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Table 1 Accounts of the enhanced plasticity hypothesis and extreme male brain theory to explain sex–related features in the autism spectrum

From: Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism

  Sex-related autistic features Enhanced plasticity hypothesis Extreme male brain theory
Sex ratio For every female, four to ten males are identified with autism. Males have a lower threshold than females for developing an enhanced plastic reaction to the same biological event. This reaction targets perceptual or language-related cerebral regions, resulting in autistic strength and social neglect. Autism reflects ‘extreme expression of the (…) attributes of the male brain'; males require fewer biological changes than females to exhibit autism; strong empathy skills protect women against autistic social deficits.
IQ/sex ratio relationship The excess of males increases with IQ. Severe mutations leading to low IQ mask any sex-differences. In high functioning AS, mutations are less deleterious, preserving normal, sexually dimorphic plasticity. Females with syndromic autism are easier to identify than those with high IQ autism because the social competence of women compensates for autistic social features.
Social & communication phenotype AS males show more social and communication impairments than AS females. Social symptoms result from the neglect of socially-guided behaviors caused by the domination of perceptual (AS individuals with SOD) or language (AS individuals without SOD)-guided behaviors, which are in turn favored by strong experience-dependent plasticity in males. Social symptoms result from strong expression of the non-autistic male social behavioral phenotype, which is less driven toward the social domain than that of females.
RRBI phenotype AS males show more RRBI than females. Enhanced perceptual-functioning accounts for perception-based RRBI. Some high-level RRBI are rule-based behaviors accounted for by extreme systematizing, a male strength.
Perceptual regions are more likely to be targeted by the enhanced plastic reaction in males than in females.
Non hormone-related genetic findings Many genes involved in autism are related to synaptic plasticity, and some show sexually-dimorphic expression.
- Deleterious and DN CNV/ SNV are more frequent in autistic females than males.
Synaptic plasticity is expressed through different mechanisms in males and females throughout life. The ‘genetic protective effect’ in females contributes to the small sex-ratio in low-IQ autism. Genetic differences unrelated to hormonal effects are not accounted for by the EMB model.
Causative mutations are more likely to affect or trigger a plastic reaction in males than in females, because of the lower threshold of plasticity in males.
AS females and low-IQ males, but not high-IQ AS have a high incidence of DN LGD mutations. Deleterious mutations disrupt plasticity resulting in a similar phenotype, mostly composed of ‘negative’ signs, in low IQ males and females.
Hormone-related genetic findings A dozen sex-steroid pathway genes are associated with AS. Sex steroids modulate plasticity mechanisms resulting from non-steroid related plasticity genes and thus can also be associated with autism. Genetic alteration of the sex-steroid pathway modifies fetal androgens levels, causing hyper-masculinization of the autistic brain.
Brain structure Autism-related differences overlap with sexually dimorphic structures. Autism-related differences overlap with the most variable regions of the non-autistic brain. Differences in structure may reflect previous differences in plasticity mechanisms. Altered brain structure in AS results from hyper-masculinization.
Brain connectivity Connectivity patterns in AS resemble particularities of the brain network of non-autistic males. Connectivity reflects the way networks were organized by plasticity mechanisms mainly during development. Loci of enhanced connectivity are determined by loci of enhanced variability in humans. Connectivity pattern in autism results from hyper-masculinization of the brain networks.
Brain function Autism-related differences overlap with sexually dimorphic patterns of activation. Enhanced experience-dependent plasticity in associative perceptual (or language) regions, accounts for enhanced activity in autism. Given that these regions are among the most variable and plastic areas and underlie some of the most recent functions in evolution, they are likely to show group differences in activity like male/female or AS/non-AS dimorphisms. Altered activations sometimes show the pattern females > males > AS or AS > males > females, reflecting hyper-masculinization of brain functions.
Cognition Autistic strengths and non-autistic male strengths overlap. This overlap is limited to some visuospatial tasks. Autistic strengths extend beyond male strengths, and manifest as enhanced perceptual functioning, even in domains where no clear male advantage is reported (for example, pitch). AS individuals strongly express male cognitive strengths and weaknesses.
Scores in psychological tests show the following patterns:
Systemizing/Autism Quotients: AS > males > females
Empathy Quotient: SQ/EQ/AQ tests are not sensitive enough to distinguish male/female differences from autism/control differences.
Females > males > AS
Behavioral phenotype Autistic males present more social negative symptoms and positive repetitive symptoms. Differences in male and female autistic phenotype result from sex differences in the target of the plastic reaction. Phenotypic gender differences reflect the masculinization of autistic behavior.
  1. In some domains, the two hypotheses are not mutually exclusive and represent complementary views. References: the current review, [7] and [217]. AS: Autism Spectrum; CNV: Copy Number Variant; DN: De Novo; EMB: Extreme Male Brain; IQ: Intelligence Quotient; LGD: Likely Gene Disruptive; RRBI: Repetitive, Restrictive Behaviors and Interests; SNV Single Nucleotide Variant, SOD: Speech Onset Delay.