Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder

Abstract

Background: A clinical characteristic of posttraumatic stress disorder (PTSD) is persistently elevated fear responses to stimuli associated with the traumatic event. The objective herein is to determine whether extinction of fear responses is impaired in PTSD and whether such impairment is related to dysfunctional activation of brain regions known to be involved in fear extinction, viz., amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC), and dorsal anterior cingulate cortex (dACC).

Methods: Sixteen individuals diagnosed with PTSD and 15 trauma-exposed non-PTSD control subjects underwent a 2-day fear conditioning and extinction protocol in a 3-T functional magnetic resonance imaging scanner. Conditioning and extinction training were conducted on day 1. Extinction recall (or extinction memory) test was conducted on day 2 (extinguished conditioned stimuli presented in the absence of shock). Skin conductance response (SCR) was scored throughout the experiment as an index of the conditioned response.

Results: The SCR data revealed no significant differences between groups during acquisition and extinction of conditioned fear on day 1. On day 2, however, PTSD subjects showed impaired recall of extinction memory. Analysis of functional magnetic resonance imaging data showed greater amygdala activation in the PTSD group during day 1 extinction learning. During extinction recall, lesser activation in hippocampus and vmPFC and greater activation in dACC were observed in the PTSD group. The magnitude of extinction memory across all subjects was correlated with activation of hippocampus and vmPFC during extinction recall testing.

Conclusions: These findings support the hypothesis that fear extinction is impaired in PTSD. They further suggest that dysfunctional activation in brain structures that mediate fear extinction learning, and especially its recall, underlie this impairment.

Figure 1

Schematic of experimental protocol. A. Pictures showing the visual contexts used in the experiment, within which conditioned stimuli were presented. In this example, pictures of an office and a conference room represent conditioning and extinction contexts respectively, whereas the blue light represents the CS+ that was paired with the shock and later extinguished. Extinction recall was conducted on day 2. B. Schematic representation of the different phases of the experiment. The numbers of each stimulus type presented during the conditioning, extinction learning, and extinction recall are indicated. Gray shading represents the extinction context. Habituation phase is not shown.

Figure 2

Responses during late extinction learning (last 12 of 16 trials). A. SCRs to the conditioned stimulus that was previously paired with shock (CS+, dark shading) vs. the conditioned stimulus that was never paired with shock (CS-, light shading) in PTSD (red) vs. TENC (black) subjects. B. Group × Stimulus interaction in vmPFC and amygdala, Talairach coordinates: x= −15, y=34, z= −21 for vmPFC and x= 25, y= −6, z= −24 for amygdala. Image is masked to show only the activation in this hypothesized brain region. Threshold for displaying the images is set at p = 0.01. C. Percent signal change extracted from the amygdala and vmPFC functional region of interest shown in B.

Figure 3

Responses during early extinction recall (first four trials). A. SCRs to the stimulus that was previously extinguished on day 1 (CS+E, dark shading) vs. the CS that was not extinguished on day 1 (CS+U, light shading) in PTSD (red) vs. TENC (black) subjects. * p < 0.05. B. Group × Stimulus interactions. Talairach coordinates: L-vmPFC: x= −10, y= 43, z= −11; R-vmPFC: x= 2, y= 45, z= −12; hippocampus, x= 32, y= −9, z= −27; dACC: x= −2, y= 37, z= 18. All images were masked to only show activations/deactivations in hypothesized brain regions. Threshold for displaying the images is set at p = 0.01. C. Percent signal change extracted from the functional regions of interest shown in B.

Figure 4

Regression plots between % extinction retention and % BOLD signal change during extinction recall extracted from the functional regions of interest shown in Figure 2, collapsed across groups. All p values listed in the figures are below the Bonferroni correction threshold.