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Clinical Trial
, 41 (6), 1569-78

How Administration of the Beta-Blocker Propranolol Before Extinction Can Prevent the Return of Fear

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Clinical Trial

How Administration of the Beta-Blocker Propranolol Before Extinction Can Prevent the Return of Fear

Marijn C W Kroes et al. Neuropsychopharmacology.

Abstract

Combining beta-blockers with exposure therapy has been advocated to reduce fear, yet experimental studies combining beta-blockers with memory reactivation have had contradictory results. We explored how beta-blockade might affect the course of safety learning and the subsequent return of fear in a double-blind placebo-controlled functional magnetic resonance imaging study in humans (N=46). A single dose of propranolol before extinction learning caused a loss of conditioned fear responses, and prevented the subsequent return of fear and decreased explicit memory for the fearful events in the absence of drug. Fear-related neural responses were persistently attenuated in the dorsal medial prefrontal cortex (dmPFC), increased in the hippocampus 24 h later, and correlated with individual behavioral indices of fear. Prediction error-related responses in the ventral striatum persisted during beta-blockade. We suggest that this pattern of results is most consistent with a model where beta-blockade can prevent the return of fear by (i) reducing retrieval of fear memory, via the dmPFC and (ii) increasing contextual safety learning, via the hippocampus. Our findings suggest that retrieval of fear memory and contextual safety learning form potential mnemonic target mechanisms to optimize exposure-based therapy with beta-blockers.

Figures

Figure 1
Figure 1
Results: sympathetic fear responses and explicit memory for fearful events. A single dose of propranolol before extinction learning eliminated learned fear responses, resulted in a subsequent loss of fear, prevented the return of fear, and attenuated explicit memory of the fearful events one day later in the absence of drug. Placebo group (solid bars), propranolol group (open bars), CS+ (red), CS− (blue), error bars reflect SEM. Critical test scores per task are: Conditioning (panel 1): Late phase (trials 7–12) over both groups (paired-samples T-test t(45)=−2.356, p=0.023); Extinction (panel 2): Early phase (trials 1–6) placebo group (paired-samples T-test t(23)=5.127, p<0.001), propranolol group (t(21)=1.054, p=0.308), and Late phase (trials 7–12) placebo group (t(23)=1.147, p=0.263), propranolol group (t(21)=1.341, p=0.194), and no absolute group differences in responses to CS+ or CS− trials in the early nor in the late phase were revealed by independent-samples T-tests; early phase CS+ (t(44)=−1.138, p=0.261), early phase CS− (t(44)=0.493, p=0.624), late phase CS+ (t(44)=−0.813, p=0.420), and late phase CS− (t(44)=−1.065, p=0.293); Recall (panel 3): As the recall paradigm is principally a second extinction session, extinction learning can be expected to occur rapidly. To maximize sensitivity to detect spontaneous recovery effects, we therefore calculated for each CS type (CS+, CS−) the average skin conductance for the early phase (trials 1–4), middle phase (trials 5–8), and late phase (9–12). Early phase placebo group (paired T-test t(23)=5.127, p<0.001), propranolol group (t(21)=1.515, p=0.145)); Re-extinction (fourth panel): a reinstatement score was calculated as the difference between the first re-extinction trial and the last trial of the recall task for the CS+ and CS− for each participant. Note, reinstatement (4 unsignaled shocks) occurred between recall and re-extinction. Placebo group (paired T-test t(23)=2.005, p=0.057), propranolol group (t(20)=−1.371, p=0.186), independent-samples T-tests for CS+ (t(37.021)=2.991, p=0.004) and CS− (t(43)=0.232, p=0.818). Contingency questionnaire (Panel 5): At the end of day 3, participants who had received propranolol on day 2 underestimated the number of shocks they had received following CS+ presentations on day 1 (independent samples T-tests day 1 CS+ t(43)=−2.560, p=0.014, CS−t(43)=0.453, p=0.653). Dotted line represents the actual number of received shocks on day 1. CS, conditioned stimulus.
Figure 2
Figure 2
Blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) analyses revealed neural regions responsive during fear extinction, recall and re-extinction. Red: CS+>CS− (‘activation'); blue: CS−>CS+ (‘deactivation'). During extinction activation of the dorsal medial prefrontal cortex (dmPFC), bilateral insula, and midbrain was detected, and deactivation of the ventromedial prefrontal cortex (vmPFC). At recall, activation of the dmPFC and midbrain, and deactivation of the hippocampus and amygdala was evident. During the re-extinction task, we found activation of the bilateral insula and dmPFC. Bars indicate T-values of main effects, activation clusters are displayed overlaid on selective slices of a template brain, and thresholded at p<0.001 uncorrected. CS, conditioned stimulus.
Figure 3
Figure 3
Beta-blockade effects on blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI). Propranolol administration affected the neural network of extinction learning. Analyses on the extracted data from regions revealed by the main effects of task showed that during extinction learning propranolol eliminated differential conditioned responses in the dorsal medial prefrontal cortex (dmPFC) while increasing differential responses in the midbrain (paired t-tests CS+ vs CS− within the placebo group for dmPFC: t(23)=2.395, p=0.025, and midbrain: t(23)=1.509, p=0.145; and the propranolol group dmPFC: t(21)=−0.222, p=0.826, and midbrain: t(21)=2.163, p=0.042). During the recall task, the propranolol group showed differential conditioned responses in the hippocampus, an effect not observed in the placebo group (paired T-tests placebo group CS+ vs CS− early phase: t(23)=0.097, p=0.924, and late phase: t(23)=−2.039, p=0.053; propranolol group early phase: t(21)=−3.085, p=0.006, late phase: t(21)=−2.615, p=0.016). During the re-extinction task, the propranolol group showed reduced responses in the dmPFC (independent sample T-test averaging over all conditions: t(43)=2.091, p=0.042). Placebo group (solid bars), propranolol group (open bars), CS+ (red), CS− (blue), early=average over the first half of the trials, late=average over second half of the trials, and error bars reflect SEM. CS, conditioned stimulus.
Figure 4
Figure 4
Prediction error analyses results. Left: Analyses of prediction error-related neural signals revealed an area in the ventral striatum (small-volume correction (SVC) nucleus accumbens based on Adcock et al, 2006; Carter et al, 2009). MNI (Montreal Neurological Institute): −6, 8, 6. Z-value=4.93. Cluster size is the number of significant voxels at p<0.001; uncorrected: 58. Middle: Ventral–striatal prediction error-related activity was not modulated by beta-blockade (independent-samples T-test t(43)=1.022, P=0.313; placebo mean: 2.585, SEM, 0.672, propranolol mean: 1.432, SEM, 0.790). Right: Ventral striatal prediction error-related activity was associated with greater differential skin conductance response (SCR) during extinction (rs=0.396, P=0.007), but critically showed no correlation with spontaneous recovery (rs=0.039, P=0.801) or reinstatement of fear (rs=0.136, P=0.379). Bar indicates T-values of main effects. Activation clusters are displayed overlaid on selective slices of a template brain, and thresholded at p<0.001. Display view follows neurological convention, that is, right hemisphere is depicted on the right. Placebo group (solid bars), propranolol group (open bars), and error bars reflect SEM.

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