Evaluating Executive Functions As Endophenotypes of Autism Spectrum Disorders

Background: Autism spectrum disorders (ASD) are highly heritable, but insight in the etiology is still limited, mainly due to considerable heterogeneity between ASD individuals. This large heterogeneity stimulates the search for more ‘genetically informative phenotypes’ or ‘endophenotypes’ that allow us to delineate more homogeneous subgroups. Endophenotypes are phenotypes that are more proximal to the biological etiology of a clinical disorder than its signs and symptoms and influenced by one or more of the same genes that confer susceptibility to the condition. Some of the proposed criteria for good ASD endophenotypes are that they should co-occur with ASD and be expressed at a higher rate in unaffected first degree relatives of ASD probands than in the general population. Potentially interesting ASD endophenotypes are neurocognitive measures of executive functioning (EF). EF is an umbrella term for higher-order cognitive functions necessary for the regulation of thoughts and actions. We make a distinction between five domains: cognitive flexibility, inhibition, working memory, planning and generativity.

Objectives: The aim of our study is to assess which EF measures provide good endophenotype candidates for ASD.

Methods: We developed a battery of tasks measuring each EF domain as purely as possible, containing at least two tasks per domain. This battery was administered from children with ASD (n=62), their unaffected siblings (n=38) and parents (n=91), and typically developing (TD) children (n=63) and adults (n=61).

Results: Preliminary analyses comparing 48 ASD and 48 TD children matched for age, IQ and gender, show that ASD children have problems with cognitive flexibility, inhibition and working memory. Their difficulties with cognitive flexibility were expressed as more errors on switch compared to repeat trials in one flexibility task (p < 0.01) and a higher reaction time on switch compared to repeat trials on another task measuring flexibility (p = 0.04). The group differences in inhibition and working memory depended on the task. On one inhibition task ASD children made more inhibition errors (Go/No-Go task, p = 0.03), while on another inhibition task (flanker task) no significant group differences were found. Concerning their working memory capacities, we only observed group differences on the most difficult working memory task (p = 0.02), but not on the other task. So far, no group differences in planning and generativity were found, but not all generativity tasks have yet been analyzed.

Conclusions: We have found evidence that problems with cognitive flexibility, inhibition and working memory are potentially useful ASD endophenotypes, since they co-occur with the disorder. However, we still need to evaluate whether these features are also expressed at a higher rate in their siblings and parents than in the general population. In addition, cluster analyses will be applied to evaluate whether more homogeneous ASD subgroups can be delineated based on their EF performance. At the time of the conference the results of these additional analyses will also be available.