Imaging genetics of frontostriatal function in autism spectrum disorders

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by abnormalities in three primary domains: language and communication, social interactions, and the presence of repetitive behaviors and restricted interests. While it is generally accepted that autism is a brain disorder, there remains no consensus on which brain regions are consistently affected or how they relate to the key features of autism. The frontostriatal system may play an important role in the development of many of the symptoms of autism across all three domains. Known sequelae of striatal abnormalities include: impaired implicit learning, abnormal responses to reward, and motor abnormalities such as repetitive and stereotypic behaviors. In the first of two functional magnetic resonance imaging (fMRI) studies, the neural correlates of implicit language learning in typically developing (TD) children and children with ASD were examined. To examine learning effects, signal increases were modeled across exposure to each speech stream. For speech streams that were most language-like (i.e., had the greatest statistical regularity and prosodic cues), TD children showed significantly greater signal increases over time (taken to index implicit learning) in left-lateralized parietal cortices and striatum than children with ASD. Additionally, the signal increases in parietal cortex were significantly correlated with the degree of impairments in communication in the ASD children. The second fMRI study (Study 2) investigated the role of reward processing during an implicit learning task in children with ASD. Results indicate that ASD children showed significantly decreased ventral striatum (VS) response to social rewards, but not monetary rewards, than TD children. Finally, children from Study 2 were genotyped on a candidate gene, CNTNAP2, chosen for a prior association to ASD and plausible role in frontostriatal function, to investigate the effect of genotype on the functional phenotype. CNTNAP2 Non-risk allele carriers reduced activity in the medial prefrontal cortex during reward processing, whereas Risk allele carriers slightly increased activity in this region. Additionally, we found that the risk allele contributed to greater local and less long-range connectivity, consistent with the abnormalities observed in autism. Together, these studies provide evidence for abnormal frontostriatal function in ASD, and support CNTNAP2 as a risk gene for abnormal brain connectivity.