Sex Differences in Autism: A Resting-State fMRI Investigation of the Intrinsic Neural Circuitry in Males and Females

Background:  Sex is increasingly recognized as a source of heterogeneity in psychiatric neuropathophysiology. Disorders related to social functioning such as autism spectrum disorders (ASD) differ considerably in prevalence and severity between males and females. Little is known however on the neural systems underlying these sex-differential expressions.

Objectives:  In light of the dysconnection model of autism linking ASD to altered brain connectivity within specific circuits, the current study aimed to examine whether (i) ASD-related alterations in intrinsic functional connectivity are similar or different in males and females with ASD; and/or (ii) whether alterations in functional connectivity fit predictions of the ‘extreme male brain’ theory, i.e., by reflecting neural masculinization in males and/or females with ASD.

Methods:  Sex-specific differences in intrinsic functional connectivity were analyzed using a large, multicenter resting-state fMRI dataset, comprising 42 males/ 42 females with ASD and 75 male/ 75 female typical controls (TC), included in the Autism Brain Imaging Data Exchange (ABIDE) repository.

Three indices of functional circuitry were examined, including (i) investigations of the functional circuitry of the posterior superior temporal sulcus, a key ‘hub’ in social information processing networks; (ii) exploration of the functional circuitry of the posterior cingulate cortex, a core region of the default network; and (iii) an investigation of region-to-region functional connectivity within a whole-brain parcellated network, comprising 200 regions-of-interest.

Results:  Males and females showed a differential neural expression of ASD, characterized by strikingly consistent patterns of hypo-connectivity in males with ASD (blue connections in figure A), and hyper-connectivity in females with ASD (red connections in figure A). This pattern was found for all the examined connectivity indices (figure shows this pattern for region-to-region functional connectivity within the whole-brain parcellated network). Further, females with ASD generally displayed higher connectivity compared to males with ASD (blue connections in figure B), whereas typical females generally displayed lower connectivity compared to typical males (red connections in figure B). Patterns of hyper-connectivity in females with ASD therefore reflected a shift towards the (high) connectivity levels seen in typical males (neural masculinization), whereas patterns of hypo-connectivity observed in males with ASD reflected a shift towards the (low) typical feminine connectivity patterns (neural feminization) (red interaction pattern in figure C).

Conclusions:  In summary, our data support the notion that ASD reflects a disorder of sexual differentiation rather than a disorder characterized by masculinization in both genders. Future work is needed to identify the underlying factors such as sex hormonal alterations that relate to and/or drive the observed neural effects and to elucidate the mechanisms by which these sex-specific neural expressions modulate the presentation of the ASD neurophenotype.