Neuroendophenotype Discovery Using An fMRI Social Battery Task

Thursday, May 17, 2012
Sheraton Hall (Sheraton Centre Toronto)
9:00 AM
A. A. Ahmed, Yale Child Study Center, Yale University, New Haven, CT
Background: Copy number variants (CNVs) have been strongly associated with autism spectrum disorder (ASD), and pathway analysis has revealed that these genetic variations overlap genes coding for proteins involved in synaptic plasticity. However, the biological mechanisms by which these CNVs impact brain function at a systems level is unknown. Imaging genetics seeks correlations between genetic and neuroimaging data. Functional magnetic resonance imaging (fMRI) has identified neural correlates of key social cognitive deficits in ASD, specifically, activations differing from neurotypical individuals in posterior superior temporal sulcus (pSTS), amygdala, and fusiform gyrus. Finding genes that influence these brain-based phenotypes would thus help define functionally relevant disease mechanisms for ASD.

Objectives: Imaging genetics studies require carefully chosen stimuli to promote the discovery of meaningful genetic associations. To this end, we developed a social battery task that engages brain regions known to be involved with the social cognitive deficits underlying ASD. We empirically evaluated the components of the task that give rise to disorder-relevant brain phenotypes. We will also use metrics that characterize individual differences between subjects, as well as test-retest reliability. The goal of the present study was to evaluate the feasibility of our current paradigm and assess whether it produces usable and meaningful imaging data. Upon completion, the task can be used to correlate brain phenotypes with genetic variation.

Methods: To date, 11 school-aged children with ASD (n = 4, mean age = 11.18 years) and typically developing controls (n = 7, mean age = 9.18 years) have been recruited to the Yale Child Study Center. They were shown a 4’26’’ imaging paradigm containing two components: (1) a point-light display of biological motion and scrambled motion, and (2) a series of fearful faces and houses. These data were analyzed using regions-of-interest (ROIs) created with an activation likelihood estimation meta-analysis. The data extracted from these ROIs were then subjected to an event-related averaging analysis. Our initial analysis focused on identifying trends that replicate previously reported findings.

Results: We report event-related activations in the right pSTS and fusiform gyrus in response to biological motion and fearful faces, respectively. Typically developing controls show increased activation to biological motion compared to probands, with peak signal changes of +0.46% in controls and +0.24% in probands during the stimulus period. Control subjects show right hemisphere lateralization in the fusiform gyrus to fearful faces, while probands do not. Both probands and typical individuals show minimal activation to fearful faces in the amygdala.

Conclusions: Our initial study demonstrates the feasibility of a brief imaging battery to produce significant event-related activations in a population of typically developing children and children with ASD. The waveforms produced are consistent with known response properties of target brain regions to these stimuli. Ongoing collection of data will allow us to continue developing these stimuli by assessing multiple versions of these stimuli in typical adults. We will analyze activations at two time-points using test-retest reliability, and draw correlations with individual differences as measured by the autism quotient and the social responsiveness scale.

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