Brain Mechanisms of Attention Orienting Following Frustration: Associations With Irritability and Age in Youths

Abstract

Objective: Childhood irritability is a common, impairing problem with changing age-related manifestations that predict long-term adverse outcomes. However, more investigation of overall and age-specific neural correlates is needed. Because youths with irritability exhibit exaggerated responses to frustrating stimuli, the authors used a frustration functional MRI (fMRI) paradigm to examine associations between irritability and neural activation and tested the moderating effect of age.

Method: The authors studied a transdiagnostic sample of 195 youths with varying levels of irritability (disruptive mood dysregulation disorder, N=52; anxiety disorder, N=42; attention deficit hyperactivity disorder, N=40; and healthy volunteers, N=61). Irritability was measured by parent and child reports on the Affective Reactivity Index. The fMRI paradigm was a cued-attention task differentiating neural activity in response to frustration (rigged feedback) from activity during attention orienting in the trial following frustration.

Results: Whole-brain activation analyses revealed associations with irritability during attention orienting following frustration. Irritability was positively associated with frontal-striatal activation, specifically in the dorsolateral prefrontal cortex, inferior frontal gyrus, and caudate. Age moderated the association between irritability and activation in some frontal and posterior regions (the anterior cingulate cortex, medial frontal gyrus, cuneus, precuneus, and superior parietal lobule [F=19.04-28.51, df=1, 189, partial eta squared=0.09-0.13]). Specifically, higher irritability was more strongly related to increased activation in younger youths compared with older youths.

Conclusions: Following frustration, levels of irritability correlated with activity in neural systems mediating attention orienting, top-down regulation of emotions, and motor execution. Although most associations were independent of age, dysfunction in the anterior cingulate cortex and posterior regions was more pronounced in young children with irritability.

Trial registration: ClinicalTrials.gov NCT00006177 NCT00018057 NCT00025935.

Keywords: Age; Attention Orienting; Frustrative Non-Reward; Irritability; fMRI.

Figures

Figure 1 legend:

Trial Structure during Frustration Runs of the Affective Posner 2 Task Note. ITI = inter-trial interval; ISI = inter-stimulus interval. In frustration runs, 60% of correct responses were followed by rigged feedback (“TOO SLOW”), and 40% of correct responses were followed by positive feedback (“YOU WIN”). All incorrect responses were followed by negative feedback (“WRONG”). Imaging analyses focused on the “N+1 trial” (red square) and the “feedback” (blue square) portions of the task. Neural responses for the “N+1 trial” were modeled from the onset of the two boxes for 2 seconds; neural responses for the feedback portion were modeled for the whole duration of the feedback stimulus (2000 ms). Significant associations with irritability emerged from the “N+1 trial” i.e., the attentional event following rigged vs. positive feedback (red square).

Figure 2 legend:

Age Moderating the Association between Irritability and Activation in Medial Prefrontal Cortex/Anterior Cingulate Cortex during Attention Orienting Following Rigged vs. Positive feedback A. Left medial prefrontal cortex extending to the anterior cingulate cortex from the whole-brain N+1 trial activation analysis. During the attentional portion of the trial, activation after receiving rigged vs. positive feedback varied with irritability (i.e., Affective Reactivity Index, ARI, scores) and age. B. Associations among ARI, age, and brain activation (all variables were continuous). The BOLD % signal change for this cluster was extracted for each condition (the N+1 trial after rigged and after positive feedback) for each subject. These values were entered in the same ANCOVA model (controlling for symptoms of anxiety and attention-deficit/hyperactivity disorder and motion) as in the main analysis, and predicted % signal changes were generated. The differences between the predicted % signal changes after rigged vs. positive feedback were plotted. The 3-D graph shows that, after receiving rigged vs. positive feedback, younger youth with high irritability exhibited increased activation. C. Partial regression plots (controlling for symptoms of anxiety and attention-deficit/hyperactivity disorder and motion) by age tertiles (n=65 for each age group) depict individual data points and the association between ARI (mean-centered) and the % signal change difference between trials occurring after rigged vs. after positive feedback. Age was treated as a continuous variable in the analyses. The age tertiles here were used for visualization only. Higher irritability was more strongly related to increased activation on this contrast in early childhood (age 8–11.5 years) than in early adolescence (age 11.5–14 years); irritability was not related to activation in late adolescence (age 14–18 years). Note that these correlations may be inflated given that they were computed based on extracted signal change from voxels that survived whole-brain correction (40).

Figure 3 legend:

Association between Irritability and Dorsolateral Prefrontal Cortex (dlPFC) Activation during Attention Orienting Following Rigged vs. Positive feedback A. dlPFC from the whole-brain N+1 trial activation analysis. During the attentional portion of the trial, activation after receiving rigged vs. positive feedback varied with irritability (i.e., Affective Reactivity Index, ARI, scores). B. Partial regression plots (controlling for symptoms of anxiety and attention-deficit/hyperactivity disorder and motion) depicted individual data points and the association between ARI (mean-centered) and the % signal change difference between trials occurring after rigged vs. positive feedback. Higher irritability was related to more activation on this contrast. Note that these correlations may be inflated given that they were computed based on extracted signal change from voxels that survived whole-brain correction (40).