Amygdala-prefrontal cortex functional connectivity during threat-induced anxiety and goal distraction

Abstract

Background: Anxiety produced by environmental threats can impair goal-directed processing and is associated with a range of psychiatric disorders, particularly when aversive events occur unpredictably. The prefrontal cortex (PFC) is thought to implement controls that minimize performance disruptions from threat-induced anxiety and goal distraction by modulating activity in regions involved in threat detection, such as the amygdala. The inferior frontal gyrus (IFG), orbitofrontal cortex (OFC), and ventromedial PFC (vmPFC) have been linked to the regulation of anxiety during threat exposure. We developed a paradigm to determine if threat-induced anxiety would enhance functional connectivity between the amygdala and IFG, OFC, and vmPFC.

Methods: Healthy adults performed a computer-gaming style task involving capturing prey and evading predators to optimize monetary rewards while exposed to the threat of unpredictable shock. Psychophysiological recording (n = 26) and functional magnetic resonance imaging scanning (n = 17) were collected during the task in separate cohorts. Task-specific changes in functional connectivity with the amygdala were examined using psychophysiological interaction analysis.

Results: Threat exposure resulted in greater arousal measured by increased skin conductance but did not influence performance (i.e., monetary losses or rewards). Greater functional connectivity between the right amygdala and bilateral IFG, OFC, vmPFC, anterior cingulate cortex, and frontopolar cortex was associated with threat exposure.

Conclusions: Exposure to unpredictable threat modulates amygdala-PFC functional connectivity that may help maintain performance when experiencing anxiety induced by threat. Our paradigm is well-suited to explore the neural underpinnings of the anxiety response to unpredictable threat in patients with various anxiety disorders.

Keywords: Amygdala; Functional connectivity; Inferior frontal gyrus; Orbitofrontal cortex; Psychophysiological interaction; Ventromedial prefrontal cortex.

Figure 1

Schematic of experimental trial for predator-prey task. (A) The nonthreat and threat conditions were separated by 12-second rest periods. (B, C) The nonthreat and threat conditions were explicitly conveyed via 2-second visual cues before each 30-second maze period. (D) The dual task was identical in both conditions: to maximize points by manipulating the movement of the avatar to capture prey (green squares), resulting in point gains, and to avoid capture by the predator (purple square), resulting in point losses. (E, F) Participants used a joystick to navigate an avatar (black square) through a two-dimensional maze. In the nonthreat condition, the blue background indicated no shocks would be administered at any time. In the threat condition, the red background indicated participants may receive a shock at any time. (G) Shock was randomly delivered on a subset of threat trials. To eliminate the confound of shock effects, only threat trials with no shock delivery were included in the threat versus nonthreat comparisons.

Figure 2

Voxel-wise results: Main effect of shock occurrences. Shock activation map (z > 1.96, p < .0125 cluster corrected) on the volume rendering (left column) and inflated cortical surface for the following post-stimulus onset time points (tp): (A) tp 1: onset to 2 seconds; (B) tp 2: 2 to 4 seconds; (C) tp 3: 4 to 6 seconds; and (D) tp 4: 6 to 8 seconds. ACC, anterior cingulate cortex; amyg, amygdala; IFG, inferior frontal gyrus; L, left; OFC, orbitofrontal cortex; PCC, posterior cingulate cortex; R, right.

Figure 3

Voxel-wise results: Threat versus nonthreat contrast. The results for the threat versus nonthreat contrast are shown. Activation (z > 1.96, p < .05 cluster corrected) in the left amygdala (amyg) is shown on the volume rending (top row). Displayed on the lateral view of the inflated cortical surface (bottom row), there was activation in orbitofrontal prefrontal cortex (OFC) and inferior frontal gyrus (i.e., pars orbitalis). L, left; R, right.

Figure 4

Voxel-wise results: Right amygdala psychophysiological interaction (PPI) analysis. Increased connectivity (z > 1.96, p < .05 cluster corrected) with the right (R) amygdala seed (inset) during the threat versus nonthreat was observed in the following a priori regions: bilateral inferior frontal gyrus (IFG), bilateral orbitofrontal cortex, and medial prefrontal cortex (PFC) with local maxima in ventromedial PFC, anterior cingulate cortex, and frontopolar cortex. Other PPI activation was observed in the left (L) anterior insula, left middle frontal gyrus, left lateral temporal lobe, cuneus, and left precuneus.

Figure 5

Correlations of functional connectivity and performance by condition. Individual differences analyses were conducted to investigate associations of functional connectivity strength and performance separately in the threat and nonthreat conditions. Scatter plots show the relationship between performance, measured as the average rate of prey captures (y-axis), with functional connectivity, quantified as the average right amygdala psychophysiological interaction beta coefficient (x-axis), for the medial prefrontal cortex (mPFC) and ventromedial prefrontal cortex (vmPFC) assessed during threat (red diamonds) and nonthreat (blue squares). (A) The correlation in the mFC for the threat condition (R² = .37) was stronger than the correlation for the nonthreat condition (R² = .003), based on the modified Pearson-Filon (ZPF) statistic = 2.11, p = .035. (B) The correlation in the vmFC for the threat condition (R² = .41) was stronger than the correlation for the nonthreat condition (R² = .05), based on the modified Pearson-Filon (ZPF) statistic = 2.82, p = .005.