Autism spectrum disorders (ASD) affect approximately 1 in 150 children nationwide (Centers for Disease Control and Prevention, 2009), but recent Department of Defense data suggest that this number is higher in military families (1/88). Progress in identifying causal mechanisms has been slowed by genetic/etiological diversity within ASD. As a result, genetic association studies of thousands of individuals with ASD have yielded few replicated findings. In the context of this diversity, identifying biologically defined subgroups of individuals with ASD is a crucial strategy for advancing studies of ASD, individualizing treatments, evaluating effects of novel treatments, and developing laboratory-based approaches for early detection. The approach proposed in this application for teasing apart this variability is to identify and characterize heritable biological traits present in both individuals with ASD and their unaffected family members. Family studies using this type of strategy have been instrumental in identifying genes and discrete pathological mechanisms in several common medical illnesses such as asthma and epilepsy, but progress in this line of work in ASD remains very limited to date.
The challenge for work in this area is to identify and validate the best measures for resolving heterogeneity. Reliability of measurement and heritability are important, and biological measures closer to gene expression effects and less influenced by environmental effects are desirable. Multiple family studies have identified atypical psychological characteristics in first-degree relatives of individuals with ASD (i.e., ASD relatives) that represent milder forms of the core clinical features. These include communication and social style dimensions. Few studies have examined biological characteristics in family members that are known to be heritable. We recently completed a study of unaffected ASD relatives that identified a profile of sensorimotor and neurocognitive abnormalities during eye movement testing that was strikingly similar to that which we have previously reported in ASD patients (Mosconi et al., in press). These data indicate alterations in three specific brain circuits involving the cerebellum, left hemisphere fronto-temporal cortex, and prefrontal cortex. In the proposed project, we aim for the first time to examine within family associations these specific brain circuitry abnormalities by studying both individuals with ASD and their unaffected relatives. Second, we will study the integrity of these three brain circuitries in ASD using both manual and oculomotor tasks as a strategy for both replicating and cross-validating our prior findings within distinct but overlapping brain systems. Further, by examining both oculomotor and manual motor brain circuitry, these studies will provide novel insight into atypical sensorimotor functioning in affected individuals and assess the familiality of these impairments.
Fifty probands with ASD and their unaffected parents (50 mother/father pairs) and 75 age- and IQ-matched healthy controls (50 matched to the 100 parents, 25 matched to the 50 probands) will be recruited. Participants will perform three types of sensorimotor tasks: (1) ballistic tasks in which they respond to abrupt changes in the environment, such as making a rapid eye movement or rapid grip flexion; (2) tracking tasks in which they follow a slowly moving target with their eyes or sustain a constant grip force; and (3) response suppression tasks in which they inhibit reflexive eye movements or manual responses. By extending our preliminary study of family members to parent-child trios and performing parallel eye movement and manual motor studies, the proposed research is both innovative and has the potential to be highly informative regarding alterations in discrete brain pathways that cause sensorimotor deficits in ASD and may be heritable. These studies are an important step aimed to establish the kind of biological measures that are urgently needed to resolve the diversity of causal pathways in ASD in order to speed gene discovery and treatment development.