05. All analyses reported were statistically corrected for multiple comparisons across the whole brain at the cluster level, Bioactive Compound Library order unless otherwise noted. Results Within-group effects: TD controls We first examined the effects of observing negative facial expressions with direct and averted gaze separately in comparison to null events for each group. When TD subjects viewed negative expressions with direct gazes (Fig. 1A), they recruited a network of regions associated with visual and face processing (e.g., occipital cortex and bilateral fusiform gyri). Also in response to direct gaze, they showed activation in frontal regions, Inhibitors,research,lifescience,medical including bilateral VLPFC extending into ventral inferior frontal gyrus on the left and premotor

cortex, as well as in subcortical regions including bilateral Inhibitors,research,lifescience,medical amygdalae, left caudate head, and the pulvinar nucleus of the thalamus (Table 2). Table 2 Peaks of activation while viewing faces with gaze-direct and gaze-averted negative expressions Figure 1 Negative direct. (A) TD group: BOLD signal changes while viewing negative-direct gaze (vs. null events) in Inhibitors,research,lifescience,medical bilateral visual-association cortices, bilateral VLPFC (BA 47), and right premotor cortex (BA 6). (B) ASD group: BOLD signal changes in bilateral … In contrast, when TD children viewed these identical expressions in faces with averted gaze, we observed a striking difference in regional activation. While visual Inhibitors,research,lifescience,medical regions and fusiform

gyri were almost identically activated, none of the areas active in gaze-direct conditions in frontal and prefrontal cortices, or in subcortical areas such as the amygdalae and caudate showed a statistically significant response relative to null events. A direct comparison of brain activity in response to gaze-direct versus gaze-averted negative emotion faces in the TD group (Fig. 2A) revealed left VLPFC (BA 47; x, y, z = −46, 28, −4; Z = 3.33), medial temporal gyrus (BA 37/21; x, y, z = 44, v60, 4; Z = 3.49), and fusiform gyrus (BA 37; x,

y, z = −42, −50, −12; Z = 3.66) to be reliably more responsive to viewing direct as opposed to averted gaze Inhibitors,research,lifescience,medical (P < 0.05, corrected for multiple comparisons at the cluster level). Figure 2 Negative direct–negative averted. (A) TD group: BOLD signal changes while viewing negative-direct versus negative-averted gaze in left VLPFC (x, y, z = −46, 28, −4, BA 47; 128 voxels). (B) ASD TCL group: BOLD signal changes while viewing … Within-group effects: Children with ASD When children with ASD viewed negative expressions with direct gazes (Fig. 1B and Table 2), as with the TD children, they too showed significant and extensive activation of occipital and fusiform cortices. These gaze-direct faces, however, elicited no significant signal changes in the inferior frontal or subcortical regions observed in the TD group, with activation limited to visual-association cortices (P < 0.05, corrected for multiple comparisons at the cluster level). An exploratory threshold (P < 0.