From threat to fear: the neural organization of defensive fear systems in humans

Abstract

Postencounter and circa-strike defensive contexts represent two adaptive responses to potential and imminent danger. In the context of a predator, the postencounter reflects the initial detection of the potential threat, whereas the circa-strike is associated with direct predatory attack. We used functional magnetic resonance imaging to investigate the neural organization of anticipation and avoidance of artificial predators with high or low probability of capturing the subject across analogous postencounter and circa-strike contexts of threat. Consistent with defense systems models, postencounter threat elicited activity in forebrain areas, including subgenual anterior cingulate cortex (sgACC), hippocampus, and amygdala. Conversely, active avoidance during circa-strike threat increased activity in mid-dorsal ACC and midbrain areas. During the circa-strike condition, subjects showed increased coupling between the midbrain and mid-dorsal ACC and decreased coupling with the sgACC, amygdala, and hippocampus. Greater activity was observed in the right pregenual ACC for high compared with low probability of capture during circa-strike threat. This region showed decreased coupling with the amygdala, insula, and ventromedial prefrontal cortex. Finally, we found that locomotor errors correlated with subjective reports of panic for the high compared with low probability of capture during the circa-strike threat, and these panic-related locomotor errors were correlated with midbrain activity. These findings support models suggesting that higher forebrain areas are involved in early-threat responses, including the assignment and control of fear, whereas imminent danger results in fast, likely "hard-wired," defensive reactions mediated by the midbrain.

Figure 1.

Schematic representation of the paradigm and subjective scores for task relating to anxiety, panic, and panic-related locomotor errors. The experiment commenced with the pre-encounter state (A), in which a maze appeared surrounded by a gray box. The subject's goal was to navigate a triangle toward flashing squares. Next, the subject moved with equal probability to the SC (B), which was signaled by a green box around the maze and indicated that the subjects would avoid any interaction with the artificial predators, or to the postencounter phases, which were divided into two subphases: PE_HI (C) or PE_HI (D) signaling that the subject had a probability of moving to the circa-strike phases in which the CS_HI (E) and the CS_LO (F) began to chase the subjects blue triangle. The CS_HI predator captured subjects on 87.5% of the trials (G), and the CS_LO predator captured the subjects on 12.5% of the trials (H). When the subjects were caught, a 2 s wait occurred before either one or three shocks were administered to the dorsum of the right hand with 50% probability. Subjective scores for (I) self-reported anxiety for all fear states. J, The correlation between self-reported panic sensations and locomotor errors (r = 0.35; p < 0.05). *p < 0.05. ns, Not significant.

Figure 2.

Theoretical model of defense avoidance, SCLs, and fMRI results. A, McNaughton and Corr's defense avoidance model (McNaughton and Corr, 2004). B, Mean-normalized SCLs for the pre-encounter and postencounter and circa-strike contexts. C, BOLD signal for the interaction between circa-strike (shown in orange) and postencounter contexts (shown in purple); parameter estimates for activity in the sgACC (0, 26, −12; p < 0.005svc) (D), right amygdala (24, −8, −24; p < 0.0005svc) (E), hypothalamus (−2, 2, −12; p < 0.002svc) (F), and midbrain (8, −26, −8; p < 0.0005 (G); family wise error corrected for whole brain (FWEcorr).

Figure 3.

PPIs from the midbrain seed. A, Positive connectivity with the dACC and lateral midbrain. B, Midbrain seed (seed location, 8, −26, −8). C, Negative PPIs with the sgACC, pgACC, PCC, insula, amygdala, ventral striatum (VS), and hippocampus. Blue arrow indicates negative connectivity. Red arrow indicates positive coupling.

Figure 4.

Direct comparison between CS_HI − CS_LO conditions and panic-related locomotor errors. A, Render showing right pgACC activity (20, 44, 6; p < 0.024svc) and parameter estimates for the CS_IS − CS_ES comparison. B, PPI analysis showing decreased coupling, most notably the left amygdala (−20, 2, −24; p < 0.05svc). The gray arrows denote negative coupling. C, How panic-related motors errors were quantified. Red arrows equate to bumps in the wall (i.e., locomotor errors). Green arrows indicate smooth uninterrupted movements through the maze. D, correlations between midbrain activity and panic-related locomotor errors (0, −28, −8; p < 0.05svc).