Prefrontal Executive Control Rescues Risk for Anxiety Associated with High Threat and Low Reward Brain Function

Abstract

Compared with neural biomarkers of risk for mental illness, little is known about biomarkers of resilience. We explore if greater executive control-related prefrontal activity may function as a resilience biomarker by "rescuing" risk associated with higher threat-related amygdala and lower reward-related ventral striatum activity. Functional MRI was used to assay baseline threat-related amygdala, reward-related ventral striatum, and executive control-related prefrontal activity in 120 young adult volunteers. Participants provided self-reported mood and anxiety ratings at baseline and follow-up. A moderation model revealed a significant three-way interaction wherein higher amygdala and lower ventral striatum activity predicted increases in anxiety in those with average or low but not high prefrontal activity. This effect was specific to anxiety, with the neural biomarkers explaining ~10% of the variance in change over time, above and beyond baseline symptoms, sex, age, IQ, presence or absence of DMS-IV diagnosis, and both early and recent stress. Our findings are consistent with the importance of top-down executive control in adaptive regulation of negative emotions, and highlight a unique combination of neural biomarkers that may identify at-risk individuals for whom the adoption of strategies to improve executive control of negative emotions may prove particularly beneficial.

Figure 1.

Task-specific brain activity. The 3 fMRI tasks each led to robust activity in a priori regions of interest: threat-related activity in the left (–22, –6, –18) and right amygdala (28, –4, –20) for the contrast of fearful and angry faces > shapes (left), reward-related activity in the left (–12, 8, –8) and right ventral striatum (12, 10, –8) for the contrast of positive feedback > negative feedback (middle), and executive control-related activity in the left (–42, 2, 30) and right dorsolateral prefrontal cortex (44, 10, 30) for the contrast of computation in working memory > computation plus maintenance of information (right). All coordinates are reported in MNI space, and all activation clusters are from contrast-specific thresholds of P < 0.05, FWE-corrected.

Figure 2.

Neural biomarkers of change in anxiety. A significant three-way interaction between amygdala, VS, and dlPFC activity predicted change in anxiety over time (P = 0.0123, R²-change = 4.1%). Post hoc analyses of the two-way interactions revealed a significant interaction between reward-related VS activity and threat-related amygdala activity leading to changes in anxiety, at low dlPFC activity (bottom; b = –41.65, P < 0.001) or average dlPFC activity (middle; b = –25.15, P = 0.002), but not at high dlPFC activity (top; b = –8.64, P = 0.278).