Lack of Focalization of Distant Connectivity with Attentional Engagement in ASD Children

Background: Atypical functional connectivity (FC) particularly between long-distant regions, is posited to be a key pathology in Autism Spectrum Disorder (ASD). FC is measured by temporal correlations across regions during functional magnetic resonance imaging (fMRI). While many studies highlight long-distant underconnectivity in ASD, overconnectivity has also been observed (Müller et al., 2011). The mixed findings cannot be reconciled in the present literature as studies differ on multiple factors including methodological, subject characteristics, and task states (resting, cognitive task).

Objectives: FC may be atypical in ASD children, not only with respect to overall strength, but also in a failure to change in response to cognitive state.  This has never been examined in ASD.  Thus, we examined both local and long-distant intrinsic FC in two cognitive states (resting vs. sustained attention) in the same ASD and control children, using a data-driven voxelwise approach (Sepulcre et al., 2010).   Further, we examined whether the state-related change in FC predicted attentional function in everyday life measured by ADHD Rating Scale (DuPaul et al., 1998).

Methods: 15 9-13 year old ASD and 16 age, gender and IQ matched control children underwent fMRI (3mm isotropic resolution, TR 2000ms, TE 30 ms, flip angle 90°, FOV 192x192 mm) during rest and an attention task(Zink et al.,2003). Images were motion corrected by scrubbing (Power et al., 2011), slicetime corrected, normalized and resliced to 4mm, smoothed with 4mm FWHM, low pass filtered(<0.08Hz) and physiological noise removed. Time course of each voxel was correlated to every other voxel and thresholded at p=.001 FDR corrected (r > .32).  FC maps were computed by averaging, for each voxel, the r-to-Z Fisher transformed values for voxels inside (local) and outside (distant) of 14 mm radius.  Group (ASD, Control) X state (rest, task) interaction was examined for local and distant FC at p<.001, 5 voxels (p < .05 Monte Carlo corrected) covarying out age and motion.

Results: No interaction was observed for local FC.  Changes in distant FC in frontal [left superior orbital frontal gyrus, Supplementary Motor Area (SMA), left Middle Frontal Gyrus (MFG - covering BA 10,6,8,9,44) and parietal (right paracentral lobule, right angular gyrus, left Temporal-Parietal Junction(TPJ)] lobes in response to sustained attentional engagement differed between ASD and control children such that distant FC strength was reduced (became more focal) in control children but increased (became more diffuse) in ASD children. Increased task-related distant FC may be maladaptive as the amount of increase in left superior orbital frontal gyrus, left MFG(BA 8,9,10,44), and SMA regions predicted inattention in everyday life in ASD children.

Conclusions: Group differences in FC of frontal and parietal cortex to the rest of the brain depended upon cognitive state.  During the task, focalization of FC in control children may reflect selective engagement of task relevant networks whereas more diffuse FC in ASD children may reflect indiscriminate network engagement, perhaps leading to worse attentional function.