Role of Human Ventromedial Prefrontal Cortex in Learning and Recall of Enhanced Extinction

Abstract

Standard fear extinction relies on the ventromedial prefrontal cortex (vmPFC) to form a new memory given the omission of threat. Using fMRI in humans, we investigated whether replacing threat with novel neutral outcomes (instead of just omitting threat) facilitates extinction by engaging the vmPFC more effectively than standard extinction. Computational modeling of associability (indexing surprise strength and dynamically modulating learning rates) characterized skin conductance responses and vmPFC activity during novelty-facilitated but not standard extinction. Subjects who showed faster within-session updating of associability during novelty-facilitated extinction also expressed better extinction retention the next day, as expressed through skin conductance responses. Finally, separable patterns of connectivity between the amygdala and ventral versus dorsal mPFC characterized retrieval of novelty-facilitated versus standard extinction memories, respectively. These results indicate that replacing threat with novel outcomes stimulates vmPFC involvement on extinction trials, leading to a more durable long-term extinction memory.SIGNIFICANCE STATEMENT Psychiatric disorders characterized be excessive fear are a major public health concern. Popular clinical treatments, such as exposure therapy, are informed by principles of Pavlovian extinction. Thus, there is motivation to optimize extinction strategies in the laboratory so as to ultimately develop more effective clinical treatments. Here, we used functional neuroimaging in humans and found that replacing (rather than just omitting) expected aversive events with novel and neutral outcomes engages the ventromedial prefrontal cortex during extinction learning. Enhanced extinction also diminished activity in threat-related networks (e.g., the insula, thalamus) during immediate extinction and a 24 h extinction retention test. This is new evidence for how behavioral protocols designed to enhance extinction affects neurocircuitry underlying the learning and retention of extinction memories.

Keywords: Pavlovian conditioning; extinction; fMRI; inhibitory learning; ventromedial prefrontal cortex.

Copyright © 2019 the authors.

Figures

Figure 1.

Experimental design and behavioral results. A, Two groups underwent threat conditioning with a picture of a face (CS+) paired with wrist shock on a partial CS-US pairing schedule, and a second picture (CS−) not paired with shock. Conditioning was followed immediately by either EXT, in which the shock was omitted on CS+ trials, or NFE, in which the shock was replaced by a tone at the end of each CS+ trial. Subjects returned 24 h later, and the CSs were presented in the absence of any shocks or tones. B, Conditioned SCRs replicate prior findings (Dunsmoor et al., 2015a), showing faster extinction and comparatively diminished SCRs 24 h later in the NFE group compared with the EXT group. C, Best-fit associability trace for CS+ trials illustrate accelerated updating during NFE compared with EXT. D, The weighting parameter (η) that governs the rate of associability updating was elevated during NFE compared with EXT. E, Individual differences in the associability weighting parameter during NFE was correlated with recovery of conditioned SCRs the next day, such that subjects who assigned more weight to the prediction error on NFE trials showed better retention of extinction 24 h later. Error bars indicate ± SEM. ***p < 0.001. **p < 0.01. *p < 0.05.

Figure 2.

Whole-brain ANOVA and associability-modulated vmPFC activity during extinction. The group × CS type interaction of extinction revealed activations in vmPFC, superior frontal gyrus, dACC, and insula. A, Parameter estimates extracted from these regions characterized the interaction as deactivations to CS+ versus CS− in vmPFC and superior frontal gyrus during both conditioning and extinction in the EXT group but a switch in CS+ versus CS− activity during extinction in the NFE group. dACC and left insula exhibited heightened CS+ versus CS− differential activity during condition and extinction in the EXT group but diminished CS+ versus CS− activity during extinction in the NFE group. B, NFE exhibited stronger associability-modulated engagement of the vmPFC than EXT. This region of the vmPFC corresponds to an area of the sgACC considered homologous to the rodent infralimbic cortex. p.e., Parameter estimates, arbitrary units. Error bars indicate ± SEM. ***p < 0.001 (one-sample t test). *p < 0.05 (one-sample t test).

Figure 3.

Whole-brain ANOVA and functional connectivity at 24 h test. A, The group × CS type interaction revealed activity in the vmPFC, including a region in the sgACC. Parameter estimates extracted from the vmPFC/sgACC characterized the interaction as strong CS+ deactivations 24 h after EXT compared with NFE. B, The main effect of CS type revealed activation in left amygdala. C, Task-based functional connectivity analysis using the vmPFC/sgACC as a seed region showed stronger correlations between the vmPFC and amygdala 24 h after NFE compared with EXT. D, A complementary exploratory analysis using the left amygdala as a seed region showed dissociable patterns of connectivity between groups, with the NFE group exhibiting stronger connectivity with the vmPFC (mirroring the prior analysis) and the EXT group exhibiting stronger connectivity with the dACC 24 h later. p.e., Parameter estimates, arbitrary units. Error bars indicate ± SEM. **p < 0.01.