Reduced cognitive control of response inhibition by the anterior cingulate cortex in autism spectrum disorders

Abstract

Response inhibition, or the suppression of prepotent, but contextually inappropriate behaviors, is essential to adaptive, flexible responding. In autism spectrum disorders (ASD), difficulty inhibiting prepotent behaviors may contribute to restricted, repetitive behavior (RRB). Individuals with ASD consistently show deficient response inhibition while performing antisaccades, which require one to inhibit the prepotent response of looking towards a suddenly appearing stimulus (i.e., a prosaccade), and to substitute a gaze in the opposite direction. Here, we used fMRI to identify the neural correlates of this deficit. We focused on two regions that are critical for saccadic inhibition: the frontal eye field (FEF), the key cortical region for generating volitional saccades, and the dorsal anterior cingulate cortex (dACC), which is thought to exert top-down control on the FEF. We also compared ASD and control groups on the functional connectivity of the dACC and FEF during saccadic performance. In the context of an increased antisaccade error rate, ASD participants showed decreased functional connectivity of the FEF and dACC and decreased inhibition-related activation (based on the contrast of antisaccades and prosaccades) in both regions. Decreased dACC activation correlated with a higher error rate in both groups, consistent with a role in top-down control. Within the ASD group, increased FEF activation and dACC/FEF functional connectivity were associated with more severe RRB. These findings demonstrate functional abnormalities in a circuit critical for volitional ocular motor control in ASD that may contribute to deficient response inhibition and to RRB. More generally, our findings suggest reduced cognitive control over behavior by the dACC in ASD.

Figure 1

Saccadic paradigm with idealized eye position traces. Saccadic trials lasted 4000 ms and began with an instructional cue at the center of the screen. For half of the participants, orange concentric rings were the cue for a prosaccade trial (A) and a blue X was the cue for an antisaccade trial (B). These cues were reversed for the rest of the participants. The cue was flanked horizontally by two small green squares of 0.2° width that marked the potential locations of stimulus appearance, 10° left and right of center. These squares remained on the screen for the duration of each run. C: At 300 ms, the instructional cue was replaced by a green fixation ring at the center of the screen, of 0.4° diameter and luminance of 20 cd/m². After 1700 ms, the ring shifted to one of the two target locations, right or left, with equal probability. This was the stimulus to which the participant responded by either making a saccade to it (prosaccade) or to the square on the opposite side (antisaccade). The green ring remained in the peripheral location for 1000 ms and then returned to the center, where participants were also to return their gaze for 1000 ms before the start of the next trial. Fixation intervals were simply a continuation of the fixation display that constituted the final second of the previous saccadic trial.

Figure 2

Behavioral results for the control and ASD groups. A: Antisaccade error rate. B: Latency of correct antisaccades and correct prosaccades. Asterisks denote statistical significance of group difference at p≤.05.

Figure 3

Frontal eye field (FEF) and dorsal anterior cingulate (dACC) activation. A, B: Statistical maps of group differences in fMRI activation at 4 s for the antisaccade versus prosaccade contrast. Statistical maps are displayed on the inflated cortical surfaces of the template brain at p<0.05. Regions of greater activation in controls are depicted in warm colors; greater activation in ASD patients is depicted in blue. The regions of interest are outlined in yellow. The gray masks cover subcortical regions in which activity is displaced in a surface rendering. C, D: Hemodynamic response functions. All plots correspond to the vertex that showed the largest contrast effects within the respective ROI. The top row shows activation in antisaccade versus prosaccade trials. The middle and bottom rows show activation for the control and ASD groups, respectively, during antisaccade and prosaccade trials separately, each relative to the fixation condition. Asterisks denote significance levels of p≤.05 at individual time points.

Figure 4

Statistical map of regression of activation at 4 s for the antisaccade vs. prosaccade contrast against antisaccade error rate. The map shows the significant correlation in the combined group. The scatter plot shows activation in the vertex with the most significant correlation in the right dACC, which is outlined in yellow.

Figure 5

Statistical map of regression of activation at 4 s for the antisaccade vs. prosaccade contrast against antisaccade latency in the ASD group. Scatter plots show activation in the left and right dACC vertices with the most significant correlations.

Figure 6

Statistical map of regression of activation at 4 s for the antisaccade vs. prosaccade contrast against ADI-R scores of RRB in the ASD group. Red and blue regions indicate positive and negative correlation, respectively. Scatter plot shows activation in the vertex with the most significant correlation in the left FEF, which is outlined in yellow.

Figure 7

Functional connectivity analysis. A: Group differences in functional connectivity of the FEF. Red regions indicate stronger connectivity in controls. Green crosses indicate the location of the voxel that showed the strongest group difference for the respective seed region. B: Regression against RRB in participants with ASD. The x axis indicates ADI-R scores of RRB, and the y axis indicates z-scores averaged across all FEF voxels that showed significant group differences in functional connectivity with the left dACC seed.

Figure 8

The effect of medication on inhibition-related activation in participants with ASD. Each panel shows mean activation across all vertices in each of the four ROIs for the control and ASD groups. The control participants, none of whom were medicated, are indicated by open black circles. Within the ASD group, unmedicated participants are indicated by open red circles, and medicated participants are indicated by filled red circles. The dashed lines indicate group means (with all subjects included).