Neural circuitry underlying the regulation of conditioned fear and its relation to extinction

Abstract

Recent efforts to translate basic research to the treatment of clinical disorders have led to a growing interest in exploring mechanisms for diminishing fear. This research has emphasized two approaches: extinction of conditioned fear, examined across species; and cognitive emotion regulation, unique to humans. Here, we sought to examine the similarities and differences in the neural mechanisms underlying these two paradigms for diminishing fear. Using an emotion regulation strategy, we examine the neural mechanisms of regulating conditioned fear using fMRI and compare the resulting activation pattern with that observed during classic extinction. Our results suggest that the lateral PFC regions engaged by cognitive emotion regulation strategies may influence the amygdala, diminishing fear through similar vmPFC connections that are thought to inhibit the amygdala during extinction. These findings further suggest that humans may have developed complex cognition that can aid in regulating emotional responses while utilizing phylogenetically shared mechanisms of extinction.

Figure 1. Description of Experimental Conditions and Behavioral Data

(A) Participants were exposed to two different types of trial (Attend, Regulate) that varied with respect to cognitive instruction and two types of stimuli (conditioned stimulus or CS+ and CS−) that were either paired or not paired with a potential aversive consequence (i.e., the unconditioned stimulus, shock). (B) Physiological responses, measured by skin conductance, to different trial types. Error bars reflect standard error (±SEM).

Figure 2. BOLD Signals in dlPFC during Regulation

(A) BOLD responses in dlPFC (in blue) are higher during Regulate compared to Attend CS+ trials. (B) Correlation between physiological measure of regulation success and BOLD levels in dlPFC reflecting differential response of Attend and Regulate CS+ trials.

Figure 3. Activation of the Subgenual Anterior Cingulate (BA 32) and Mean Beta Weights

The pattern of BOLD response in this vmPFC ROI resembles observations of similar regions of interest in previous extinction studies (Milad et al., 2005; Phelps et al., 2004). Error bars reflect standard error (±SEM).

Figure 4. Mean Beta Weights Reflecting BOLD Responses in the Left Amygdala for the Main Conditions

Error bars reflect standard error (±SEM).

Figure 5. Similarities between BOLD Responses in the vmPFC in Two Separate Fear Conditioning Experiments

The left panel displays mean beta weights in the vmPFC for CS+ trials during both early (red) and late (yellow) extinction of conditioned fear (data from Milad et al., 2005; Phelps et al., 2004). The right panel displays mean beta weights in the vmPFC ROI from the current experiment for both Attend (purple) and Regulate (light blue) CS+ trials. Error bars reflect standard error (±SEM).

Figure 6. Connectivity Analysis Using vmPFC Seed ROI Time Course as Predictor

Regions in the dlPFC (green circle) and amygdala (yellow circle) are found to correlate with the seed ROI.