Anticipatory prefrontal cortex activity underlies stress-induced changes in Pavlovian fear conditioning

Abstract

Excessive stress exposure often leads to emotional dysfunction, characterized by disruptions in healthy emotional learning, expression, and regulation processes. A prefrontal cortex (PFC)-amygdala circuit appears to underlie these important emotional processes. However, limited human neuroimaging research has investigated whether these brain regions underlie the altered emotional function that develops with stress. Therefore, the present study used functional magnetic resonance imaging (fMRI) to investigate stress-induced changes in PFC-amygdala function during Pavlovian fear conditioning. Participants completed a variant of the Montreal Imaging Stress Task (MIST) followed (25 min later) by a Pavlovian fear conditioning task during fMRI. Self-reported stress to the MIST was used to identify three stress-reactivity groups (Low, Medium, and High). Psychophysiological, behavioral, and fMRI signal responses were compared between the three stress-reactivity groups during fear conditioning. Fear learning, indexed via participant expectation of the unconditioned stimulus during conditioning, increased with stress reactivity. Further, the High stress-reactivity group demonstrated greater autonomic arousal (i.e., skin conductance response, SCR) to both conditioned and unconditioned stimuli compared to the Low and Medium stress-reactivity groups. Finally, the High stress group did not regulate the emotional response to threat. More specifically, the High stress-reactivity group did not show a negative relationship between conditioned and unconditioned SCRs. Stress-induced changes in these emotional processes paralleled changes in dorsolateral, dorsomedial, and ventromedial PFC function. These findings demonstrate that acute stress facilitates fear learning, enhances autonomic arousal, and impairs emotion regulation, and suggests these stress-induced changes in emotional function are mediated by the PFC.

Figure 1

Differential (Stress - Control) self-reported stress and heart rate (HR) during the MIST for Low, Medium, and High stress-reactivity groups. a) Increases in self-reported stress from Low to Medium to High demonstrated increased stress reactivity across groups. b) HR was measured as a manipulation check and demonstrated that the differential HR (Stress - Control) increased across Low to High stress-reactivity groups. Asterisk indicates a significant difference (p < 0.05; corrected).

Figure 2

Differential responses to stimulus events (CS+ vs CS− or CS+UCS vs UCS alone) separated by stress-reactivity groups (Low, Medium, High) for each behavioral and psychophysiological measure (UCS expectancy, SCR). a) The High group (but not Low and Medium) reported greater UCS expectancy to the CS+ than CS−. b) All groups reported greater UCS expectancy prior to UCSs that were predictable (CS+UCS) compared to UCSs that were unpredictable (UCS alone). c) Average SCRs to the CSs (CS+ and CS−) were greater for the High than Medium and Low stress-reactivity groups. Medium and Low groups did not differ. d) Average SCRs to the UCSs (CS+UCS and UCS alone) were greater for the High than Medium and Low groups. Medium and Low groups did not differ. Asterisk indicates a significant difference (p < 0.05; corrected).

Figure 3

The relationship between SCRs to the CS+ and CS+UCS. Dashed lines reflect the correlation between the CR and UCR in each panel. Panel a) shows the negative CR and UCR relationship for all participants, collapsed across stress-reactivity groups (Low, Medium, High). Panels b–c) show the negative CR and UCR relationship in Low and Medium stress-reactivity groups. Panel d) shows no relationship between the CR and UCR in the High stress-reactivity group.

Figure 4

Clusters of significant activation for the interaction between stimulus type (CS+ vs CS) and stress-reactivity groups (High, Medium, Low). Differential neural responses to CS+ and CS− varied across stress-reactivity groups in the dlPFC and dmPFC (a–d). As stress reactivity increased, responses to CS+ showed a corresponding increase. Alternatively, as stress reactivity increased, responses to CS− demonstrated a corresponding decrease.

Figure 5

Relationship between CR and UCR activity. Regardless of group, CRs in a) the right dlPFC and b) the left superior dmPFC were inversely related to UCRs in the amygdala.

Figure 6

Relationship between CR and UCR activity that varied with stress-reactivity group. CRs in the right superior dlPFC were inversely related to UCRs in a similar right dlPFC region for the Low and Medium group. Only the High group showed no relationship between CRs in the right superior dlPFC and UCRs in the right dlPFC region.

Figure 7

Relationship between the CR and UCR that varied with stress-reactivity groups. CRs in the left dmPFC were inversely related to UCRs in the amygdala only for the Medium stress-reactivity group. The Low and High stress-reactivity groups showed no relationship between CRs to the CS+ in the left dmPFC and UCRs in the amygdala.