Atypical Rightward Lateralization of the Corpus Callosum Is Present in Males but Not Females with Autism

Background:

Rightward cerebral lateralization has been suggested to be involved in the neuropathology of autism spectrum conditions. In particular, corpus callosum volume is related to functional and structural brain asymmetries and due to its topographic organization might show lateralized morphology itself. Atypical patterns of cerebral lateralization might therefore be part of the pathophysiology of autism. Here we test if this is true in both males and females with autism, and whether this is true in siblings of people with autism.

Objectives:

To investigate whether rightward cerebral lateralization is (a) more common in adolescents with autism compared to their unaffected siblings and typically developing controls, (b) correlated with clinical measures of symptom severity and (c) different in males and females with autism. We predicted, that in view of the “left hemisphere dysfunction” theory, in autism stronger rightward lateralization would be associated with more severe psychological deficits. We had no predictions in relation to sex as this was an exploratory study. Finally, if atypical lateralization is part of the “broader autism phenotype” it should also be present in the siblings of people with autism.

Methods:

Participants comprised adolescents with autism (males=35; females=17), their unaffected siblings (males=12; females=28) and typically developing controls (males=20; females=20) aged 12-18 years. We assessed functional asymmetry in terms of handedness using the Edinburgh Handedness Inventory and neuroanatomical lateralization in terms of corpus callosum asymmetry through manual tracing. Symptom severity was assessed using subdomains of the ADI-R and ADOS-G.

Results:

Male adolescents with autism showed stronger rightward lateralization in the posterior and anterior midbody the more left-handed they were, compared to controls. There were no significant differences in females with autism. In both sexes, symptom severity was related to rightward asymmetry in several subregions (splenium, isthmus, posterior midbody and rostral body). However the same directional associations occurred with different symptoms in the two sexes (males: repetitive and stereotyped behaviours (ADOS D), abnormalities in reciprocal social interaction (ADI A, ADOS B); females: communication problems (ADOS A), social interaction difficulties (ADOS B), abnormal play & imagination (ADOS C)). We did not find similar results in sibling pairs.

Conclusions:

Atypical rightward lateralization is present in males but not females with autism. This sex difference within autism might account for established sex differences within prevalence and clinical phenotype and suggest the need for sex-specific diagnostic criteria. The dependence of atypical rightward lateralization on hand-preference highlights the link between function and anatomy. Siblings showed no similar pattern suggesting that atypical lateralization is a marker of autism per se, rather than the broader autism phenotype. Within groups, rightward lateralization has clinical relevance in both sexes. Future research should focus on the meaning of handedness and corpus callosum morphometry as a potential marker of clinical subgroups.