Spared Brain Function During Mentalizing and Self-Representation in Females with Autism Spectrum Conditions

Background:  

Females with autism spectrum conditions (ASC) remain an important yet understudied population. Recent work suggests that females may be a sub-group within autism and possess different underlying mechanisms from their male counterparts (Schwarz et al., 2010, Mol Psychiatry). If females represent a sub-group within autism, it will be important to identify where females diverge from males at various levels of analysis and what mechanisms may be responsible for such sex-specific patterns. Finally, work on females will also have methodological impact in informing the extent to which heterogeneity is introduced by including mixed samples of males and females.

Objectives:  

Here we investigate whether males and females with ASC show different patterns of response at the neural systems level. Our past work has shown marked hypoactivation of ventromedial prefrontal cortex (vMPFC) and right temporo-parietal junction (RTPJ) for self-representation and mentalizing respectively, in males with ASC (Lombardo et al., 2010, Brain; Lombardo et al., 2011, Neuroimage). In this study, we aimed to assess whether similar or different patterns are seen in matched samples of females with and without ASC.

Methods:  

Twenty-nine males adults with ASC and 29 age- and IQ-matched females with ASC (all ADI-R confirmed) were compared to IQ- and age-matched typically-developing Controls (males n = 33; females n = 29). All participants were scanned with fMRI at 3T while making mentalizing or physical judgments about themselves or a familiar but non-close other (the British Queen). Regions of interest (ROI) were defined independently via a quantitative meta-analysis of mentalizing studies (Lombardo et al., 2011, Neuroimage) and included regions well-established for their role in mentalizing and self-representation; vMPFC, RTPJ, left temporo-parietal junction (LTPJ), posterior cingulate/precuneus (PCC), and dorsomedial prefrontal cortex (dMPFC). Main-effects (Mentalizing>Physical; Self>Other) and interaction contrasts were computed for each individual and were each input into a 2x2 factorial ANOVA (sex and diagnosis as factors) for each ROI. 

Results:  

Replicating past work in males (Lombardo et al., 2010, Brain; Lombardo et al., 2011, Neuroimage), PCC, LTPJ, and dMPFC showed no main-effect of diagnosis across any contrast as well as no main-effect of sex or a sex*diagnosis interaction. However, vMPFC and RTPJ showed a significant sex*diagnosis interaction. In both vMPFC and RTPJ, the hypoactivation present in males with ASC was not apparent in females with ASC. Females with ASC showed a trend for an opposite pattern of increased activation compared to female Controls.

Conclusions:  

Females with ASC show spared function of vMPFC and RTPJ during high-level self-referential and mentalizing processes. These observations are congruent with prior work (Lai et al., 2011, PLoS One) that this sample of high-functioning females adults with ASC presented less severe current symptoms on the ADOS, yet self-reported more autistic traits. This work suggests potential implications for females as a sub-group. Stratification of samples by sex in future studies will be important in reducing heterogeneity and may aid in detecting sex-specific biological and cognitive mechanisms at work in autism (Schwarz et al., 2010, Mol Psychiatry; Lai et al., 2011, PLoS One).