Unravelling the neurocognitive mechanisms underlying counterconditioning in humans

Trauma-related disorders are prevalent and highly detrimental to the individual’s quality of life (Kessler et al., 2005). To treat these disorders, patients undergo exposure therapy in a safe therapeutic environment, causing threat responses to fade away (Scheveneels et al., 2016). Although exposure therapy may be successful initially, relapse often occurs and is the most prevalent remaining challenge in optimizing treatment efficacy. Research suggests that exposure therapy creates a safety memory that competes for expression with the original threat memory (Bouton, 2004, Myers and Davis, 2002), suggesting that relapse may occur because of relatively weak learning and retention of the safety memory. Therefore, identifying mechanisms that can be used to strengthen safety learning is a key step in advancing treatment for trauma-related disorders. A promising approach to strengthen safety learning is to create a new, positive association with the event that was previously linked to an aversive outcome. However, while there are indications that establishing positive associations can prevent relapse, the underlying mechanisms are poorly understood (for a review, see Keller et al., 2020).

To study threat responses in a controlled setting, aversive Pavlovian conditioning is typically used. A neutral stimulus (conditioned stimulus, CS; e.g. a picture) is coupled with a biologically aversive unconditioned stimulus (US; e.g. an electrical shock), after which the CS alone also elicits a conditioned threat response. Conditioned threat responses to the CS can be attenuated using extinction, during which the CS is repeatedly presented in absence of the US. However, early theories have suggested that threat responses may more easily be inhibited by engaging appetitive systems (Dickinson and Pearce, 1977; Rescorla and Solomon, 1967). Indeed, experiments provide evidence that coupling a CS to a positive US after threat conditioning, a process known as aversive-to-appetitive CC, may be superior to regular extinction. Specifically, CC compared to regular extinction was associated with a faster attenuation of learned threat responses (Dickinson and Pearce, 1977; Pearce and Dickinson, 1975), stronger decreases in threat expectancy (Kang et al., 2018, Newall et al., 2017), and more positive valence ratings of the CS (Luck and Lipp, 2018; van Dis et al., 2019; Jozefowiez et al., 2020) immediately post-CC.

Tests for spontaneous recovery, reinstatement, and renewal can subsequently be used to evaluate the return of threat responses over time, after unsignaled presentation of the US, or in a novel context, respectively (Bouton, 2004, Bouton, 2002). Thereby, one can investigate whether CC persistently attenuates threat responses. While early rodent studies showed that CC may be prone to the same relapse as extinction (Bouton and Peck, 1992, Brooks et al., 1995), recent neurobiological work in rodents showed that CC can enhance the activation of an amygdala-striatal pathway, which is also recruited during extinction – albeit to a lesser degree – and that CC compared to regular extinction can reduce the return of threat responses (Correia et al., 2016). Recent studies suggest that CC may diminish the return of threat responses in humans as well. Specifically, it was shown that CC, compared to regular extinction, reduced renewal of previously learned food-allergy associations when presented in a novel context one day later (Keller et al., 2023). Counterconditioning compared to regular extinction was also associated with reduced recovery of arousal and shock expectancy the following day (Kang et al., 2018, Keller et al., 2022), as well as reduced reinstatement (Kang et al., 2018).

Extinction learning appears to be mediated by activation of the ventromedial prefrontal cortex (vmPFC), which inhibits the expression of threat responses by suppressing amygdala activity (Quirk et al., 2000; Morgan et al., 1993; Quirk et al., 2003; Phelps et al., 2004). When extinction is enhanced by replacing aversive with novel, neutral outcomes, the vmPFC was found to be engaged more effectively than during standard extinction (Dunsmoor et al., 2019). When extinction is enhanced by replacing aversive outcomes with a reward (counterconditioning), evidence in rodents suggests stronger engagement of the ventral striatum, a region known to be involved in the anticipation and receipt of reward (Diekhof et al., 2012). However, human studies only provide indirect evidence for such a mechanism since involvement of the ventral striatum could only be shown during spontaneous recovery (Keller et al., 2022) or during reinstatement (Bulganin et al., 2014), but not during CC itself. Although it was observed that brain areas of the fear network are reduced during CC versus regular extinction in humans (Keller et al., 2022), it is unclear how this difference is achieved. Therefore, although evidence suggests that CC is more effective than regular extinction in preventing the return of threat responses, the neural mechanisms are not well understood yet. It remains unclear whether CC is a form of enhanced extinction that is mediated by enhanced engagement of extinction networks, including the vmPFC, or whether it is driven by engagement of reward networks.

To investigate the qualitative differences between CC versus regular extinction further, category conditioning can be used, a procedure in which conditioned threat responses are learnt by coupling a US to conceptually linked exemplars that together form a category (e.g. pictures of animals) (Dunsmoor et al., 2012). It allows for the typical measures of threat conditioning but also provides the opportunity to probe episodic memory for the CS category exemplars (Dunsmoor and Kroes, 2019). Specifically, retrieval of a picture probes the retrieval of specific episodic elements, whereas retrieval of the category-threat association (fear retrieval) takes place at a conceptual level and may be semantic in nature. When episodic memory was probed 24 hr after CC and extinction, it was shown that memory for CS + stimuli that had undergone CC was stronger than memory for CS + stimuli that had undergone regular extinction (Keller and Dunsmoor, 2020). This suggests that compared to regular extinction, CC can enhance episodic memory consolidation and potentially provide stronger retrieval competition against a threat memory.

To investigate the neural mechanisms that distinguish CC from regular extinction and to establish whether CC is indeed associated with a memory that is qualitatively different from the safety memory established during regular extinction, we performed a two-day fMRI study comparing CC versus regular extinction in a between-subjects design (Figure 1A). Participants underwent category conditioning and subsequently either aversive-to-appetitive CC (CC group) or regular extinction (Ext group; Figure 1B–C). During the CC task, participants in the CC group obtained monetary rewards depending on how quickly they responded to a cue superimposed on novel category exemplars from the CS +category, a procedure similar to the monetary incentive delay (MID) task (Knutson et al., 2000). To maximize task similarity between tasks and groups, the cued-response element was kept consistent in all tasks (acquisition, CC/extinction, spontaneous recovery, reinstatement), but response-time contingent monetary rewards were only present during the CC task (Figure 1F). To assess the potential of CC versus regular extinction in persistently attenuating the expression of threat response, we tested retrieval of the threat memory and reinstatement of threat responses one day later (Figure 1D). Episodic memory for exemplars of the CS categories that were presented during threat conditioning and CC/extinction was assessed by means of a surprise memory test. To characterize pupil dilation responses (PDRs) and skin conductance responses (SCRs) during the anticipation of shock- and reward-reinforcement independently from prior conditioning, a separate valence-specific response characterization task was included at the end of the experiment (Figure 1E).

Figure 1

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In line with previous results (Kang et al., 2018, Keller et al., 2022), we hypothesized that CC compared to extinction would lead to a more persistent attenuation of threat responses. As indicated above, this could be mediated by two possible neural mechanisms: either through enhanced engagement of extinction networks, reflected by increased engagement of the vmPFC, or through a shift towards reward networks, reflected by activation of the ventral striatum. Based on previous results (Keller and Dunsmoor, 2020), we expected stronger episodic memory for CS exemplars presented during CC, whereas regular extinction would not show such a strengthening effect.

In the valence-specific response characterization task (Figure 1E), we observed that both threat and reward-anticipation induced strong arousal-related PDRs and SCRs (see Appendix 1). However, PDRs allowed for a better differentiation of the two compared to the CS- (Appendix 1—figure 1A). Therefore, we focused on PDRs in all analyses and refer to Appendix 1 for details on the analysis of SCRs. During the acquisition task, both groups showed comparable and successful acquisition of differential conditioned threat responses (PDR means ± SD: CC CS+=1.085 ± 0.030, CC CS-=1.054 ± 0.033, Ext CS+=1.084 ± 0.050, Ext CS-=1.050 ± 0.035; for PDR, SCR, and fMRI results see Appendix 1).

Extinction and aversive-to-appetitive counterconditioning

After threat acquisition, participants in the CC group underwent CC, while participants in the Ext group underwent regular extinction (see Figure 1A for design overview). Across both groups and phases (early vs. late), we observed retention of conditioned differential PDRs CS-type (CS+, CS-) × Phase (Early, Late) × Group (CC, Ext) rmANOVA, main effect CS-type: F(1,34)=15.393, p<0.001, η²=0.312, Figure 2A, as well as a decrease in PDRs over the course of the task (main effect phase: F(1,34)=10.121, p=0.003, η²=0.229). These findings are in contrast to our expectation of a CS-type × Phase × Group interaction. Specifically, we expected differential PDRs to become extinguished in the Ext group, while being sustained in the CC group, potentially due to increased reward anticipation. Extinction in the Ext group, however, already occurred during the early phase (paired t-test, early CS+ vs CS-, p=0.233), and differential responses did not change towards the late phase (p=0.979). As a result, we found distinct differential conditioned PDRs throughout the CC/extinction task between groups (CS-type × Group interaction: F(1,34)=6.053, p=0.019, η²=0.151), with participants undergoing CC showing stronger PDRs to CS+ vs CS- category exemplars (paired t-test average CS+ vs CS-, t(20)=3.602, p=0.002, CS+: 1.07±0.04, CS-: 1.04±0.04), whereas differential PDRs were extinguished in participants undergoing extinction (paired t-test average CS+ vs CS-, p=0.246, CS+: 1.05±0.04, CS-: 1.04±0.04). Results of the valence-specific response characterization task showed that differential PDRs can also be indicative of anticipation of reward (Appendix 1—figure 1A). Thus, while PDRs in the Ext group indicated that differential conditioned threat responses were successfully extinguished, differential PDRs persisted in the CC group, likely reflecting reward anticipation. Differential SCRs persisted during the late phase of both CC and extinction but were no longer detectable in the last two trials and were comparable between groups (see Appendix 1).

Figure 2

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Valence and arousal ratings provide further support for the extinction of differential responses in the Ext group and positive, reward-induced arousal for CS+ items in the CC group (Figure 2B–C). Differential valence ratings for the CS +and CS- differed between groups after the CC/extinction task (CS-type (CS+, CS-) × Group (CC, Ext) rmANOVA, CS-type × Group interaction: F(1,44)=12.054, p=0.001, η²=0.215). Participants in the CC group rated CS + stimuli more positive than CS- stimuli (t(21)=3.469, p=0.002, CS+: 7.5±0.30, CS-: 5.41±0.38), while participants in the Ext group gave both categories similar valence ratings (p=0.245, CS+: 5.63±0.32, CS-: 6.21±0.28). Since there were group-dependent differences in valence ratings after acquisition (the CS- category was rated more positively by the Ext compared to the CC group, see Appendix 1), we ran an additional analysis, adding differential valence ratings after fear acquisition as a covariate. Results suggested that the group difference in differential valence ratings after CC/extinction remained (main effect Group: F(1,43)=7.364, p=0.010, η²=0.146). Differential arousal ratings for the CS+ and CS- also differed between groups CS-type (CS+, CS-) × Group (CC, Ext) rmANOVA, CS-type × Group interaction: (F(1,44)=20.862, p<0.001, η²=0.322). Participants in the CC group reported higher arousal levels for the CS+ category than for the CS- category (t(21)=6.370, p<0.001, CS+: 6.64±0.20, CS-: 3.45±0.38) while participants in the Ext group gave similar arousal ratings for the CS+ and CS- categories (p=0.290, CS+: 4.21±0.43, CS-: 3.80±0.40). Taken together, more positive valence and higher arousal ratings for the CS+ in the CC group as compared to the Ext group further support the interpretation of increased differential PDRs reflecting arousal induced by reward anticipation.

CC prevents differential spontaneous recovery

To investigate whether CC prevented the spontaneous recovery of differential conditioned threat responses one day later (see Figure 1A for design overview), we compared PDRs in the last two trials of the CC/extinction task and the first two trials of the spontaneous recovery test in a CS-type (CS+, CS-) × Group (CC, Ext) × Phase (last two trials of CC/extinction, first two trials of the spontaneous recovery test) rmANOVA [16 participants were excluded due to (partially) missing data, leaving 15 participants in both groups (total N=30)]. We expected the Ext group to show an increase in PDRs from the extinction task to the spontaneous recovery task, while we expected PDRs for the CC group to remain stable or decrease. Critically, differential spontaneous recovery of PDRs differed between groups (Group × CS-type × Phase interaction: F(1,28)=6.329, p<0.018, η²=0.184, Figure 3). While the CC group showed a decrease in differential PDRs from CC to spontaneous recovery (t(14)=-1.807, p=0.046, one-tailed, CC: 0.34±0.2, spontaneous recovery: –0.01±0.18), the Ext group showed an increase in differential PDRs (t(14)=1.850, p=0.043, one-tailed significance, extinction: 0.11±0.01, spontaneous recovery: 0.04±0.02). To conclude, while we observed differential spontaneous recovery in the Ext group, we did not find evidence for differential spontaneous recovery in the CC group, suggesting that CC attenuated the recovery of threat responses compared to regular extinction.

Figure 3

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However, since participants undergoing CC showed persistent differential PDRs during the last two trials of the CC phase (likely due to reward anticipation), while participants undergoing extinction did not, we additionally explored whether there was differential responding during the first two trials of the spontaneous recovery test. During the first two trials of the spontaneous recovery test, participants in the CC group showed decreased differential PDRs as compared to the Ext group (CS-type (CS+, CS-) x Group (CC, Ext) rmANOVA, CS-type × Group interaction: F(1,29)=3.901, p=0.029, one-tailed, η²=0.119). Further exploration within the groups confirmed that participants in the CC group did not show retention of differential responses (paired t-test, CS+ and CS- responses during the first two trials of the spontaneous recovery test, p=0.219, one-tailed), while the Ext group did show increased responses to the CS+ as compared to the CS- (t(14)=1.958, p=0.035, one-tailed). Thus, both the differential spontaneous recovery of PDRs between sessions and differential responding within the first two trials of the spontaneous recovery test suggested that CC prevented spontaneous recovery of differential responses compared to extinction. SCRs did not show differential recovery and were comparable between groups (see Appendix 1).

CC also appeared to have lasting beneficial effects on valence ratings compared to extinction. At the start of the second testing day, differential valence ratings continued to differ between groups (CS-type (CS+, CS-) × Group (CC, Ext) rmANOVA, CS-type × Group interaction: F(_1,44)=5.160, p=0.028, η²=0.105). While participants in the CC group gave similar valence ratings to both categories (p=0.179, CS+: 6.3±0.34, CS-: 5.4±0.35), participants in the Ext group gave more negative valence ratings to the CS + category than to the CS- category (t(23)=-1.964, p=0.031 one-tailed test, CS+: 5.5±0.30, CS-: 6.3±0.24), also illustrative of relapse of threat associations. Since the CC group received no rewards during the spontaneous recovery task and was aware of this, it was expected that the effect of reward anticipation on PDRs would be weakened in the CC group. So while PDRs did not differ between CS+ and CS- in the CC group because no rewards were given, CS + and CS- items were still rated of similar valence. In comparison, the Ext group rated the CS+ significantly more negative and threat responses to the CS + returned.

While participants in the CC group showed heightened differential arousal ratings immediately after CC as compared to ratings from participants who had undergone extinction (Figure 2B), participants in both groups gave comparable differential arousal ratings at the start of the second day immediately before the spontaneous recovery test (CS-type (CS+, CS-) × Group (CC, Ext) rmANOVA, main effect of CS-type: F(1,44)=10.932, p=0.002, η²=0.022, CS+: 4.8±0.28, CS-: 3.9±0.24). Likewise, response times to the CS + and CS- during the first two trials of the spontaneous recovery task were similar across both groups (all p’s>0.2). These findings may suggest that differential arousal evoked by the categories was similar in both groups immediately before and during the spontaneous recovery test.

The spontaneous recovery test was followed by a reinstatement procedure, consisting of three unsignaled shocks, and a reinstatement test. However, mean PDRs decreased from spontaneous recovery to reinstatement (t(30)=3.063, p=0.005, last two trials of spontaneous recovery: 1.04±0.01, first two trials of reinstatement: 1.01±0.01). Given that we did not observe successful reinstatement in either group, our reinstatement test was not informative on whether CC can lead to a more persistent attenuation of threat responses as compared to regular extinction. A full description of PDR and SCR results of the reinstatement test can be found in Appendix 1.

Distinct CS-type specific activation for extinction and appetitive counterconditioning

During the CC/extinction task, whole-brain analysis revealed that CS-type-specific activation changed differentially between the two groups in a large cluster encompassing multiple regions in the medial temporal lobe (Group × CS-type × Phase interaction, cluster size = 1760 mm³, p=0.034, whole-brain FWE-corrected, Figure 4B and Table 1). We further investigated the anatomical location of the cluster using our ROIs to probe for activity and found that the effect encompassed the amygdala. To further investigate the interaction effect in the amygdala, we extracted parameter estimates from the complete bilateral amygdalae (Automated Anatomic Labeling, AAL, atlas in the WFU PickAtlas toolbox in MN152 space) and performed post-hoc comparisons. In the early phase, CS-type specific responses differed between the groups (t(1,44)=2.173, p=0.035, CC: 0.18±0.08, Ext: –0.073±0.08). Specifically, the CC group showed increased amygdala activation to the CS+ as compared to the CS- (t(23)=2.210, p=0.037) while that was not the case in the Ext group (p=0.390). In the late phase, differential responses were comparable between the groups (p=0.503).

Figure 4

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Table 1

Peak MNI coordinate
Region	Cluster	x	y	z	Size (mm3)	pFWE (cluster)	Peak F-value	Direction
Group × CS-type × phase
Parahippocampal Gyrus BA34R Parahippocampal Gyrus Amygdala, Uncus BA34R	1	18	-8	–20	1760	0.034	23.40	CS +>CS- difference increases from early to late phase for CC, not for Ext
Group × CS-type
Lateral Geniculum Body LR, Caudate Head LR, Thalamus LR, Lentiform Nucleus LR	1	2	–26	–18	29920	<0.001	73.15	(CC CS +>CS-) > (Ext CS +>CS-)
Cuneus L Lingual Gyrus BA17/BA18 LR, Posterior Cingulate LR, Cuneus BA18R, Cuneus BA30L Declive R	2	-6	–96	2	23272	<0.001	43.50
Inferior Frontal Gyrus BA47L Insula BA13 L	3	–36	18	-6	4504	0.009	30.62
Extra-Nucleus R	4	30	26	2	3136	0.016	37.67
Superior Temporal Gyrus L Superior Temporal Gyrus BA41 L, Transverse Temporal Gyrus L	5	–60	–44	14	9088	0.002	43.56
Transverse Temporal Gyrus BA41 R Superior Temporal Gyrus R, Superior Temporal Gyrus BA42/BA22R	6	44	–22	12	7784	0.003	42.17
Anterior Cingulate BA32R Anterior Cingulate BA32L, Cingulate Gyrus R	7	6	30	26	8880	0.002	27.90
Precentral Gyrus L Inferior Frontal Gyrus L	8	–36	0	30	3624	0.014	30.10
Precentral Gyrus R Sub-Gyral R	9	40	2	32	4056	0.011	40.64
Precentral Gyrus BA6L Middle Frontal Gyrus BA6L	10	–44	-6	52	2184	0.028	24.34	(CC CS +>CS-) > (Ext CS +>CS-)
Angular Gyrus R Supramarginal Gyrus R	11	54	–60	36	1944	0.032	24.18
Group × Phase
No significant clusters
CS-type × Phase
No significant clusters
Group
No significant clusters
Phase
Inferior Frontal Gyrus R Inferior Frontal Gyrus BA45 R	1	30	26	8	4848	0.006	40.27	Early Phase >Late Phase
Insula L Superior Temporal Gyrus BA22, Precentral Gyrus L	2	–28	26	0	4368	0.007	38.41
Postcentral Gyrus L	3	–54	–24	22	1768	0.031	23.75

Whole-brain analysis further revealed a number of clusters showing distinct CS-specific activations between groups throughout the task, including the anterior cingulate, cuneus, nucleus accumbens, caudate, thalamus, and inferior frontal gyrus (Figure 4A, Table 1). The group and stimulus-specific activation of the NAcc was in line with a priori expectations for the CC phase (Figure 4C). To further explore this effect, averaged parameter estimates from the bilateral NAcc ROI (mask acquired from the IBASPM 71 atlas in the WFU PickAtlas toolbox in MNI152 space) were extracted. Across the bilateral NAcc, differential activation was increased in the CC as compared to the Ext group (t(44)=2.731, p=0.009, CC: 0.37±0.10, Ext: 0.04±0.06), with the CC showing increased NAcc activation to the CS +compared to the CS- (t(23)=6.194, p<0.001, CS+: 0.59±1.12, CS-: 0.16±0.09) whereas the Ext group did not (p=0.574).

Contrast estimates in further a priori defined ROIs during the CC/extinction task were submitted to a Group (CC, Ext) × CS-type (CS+, CS-) × Phase (early, late) rmANOVA (Figure 5). The bilateral hippocampi (right hippocampus cluster size: 664 mm³, p=0.001, FWE-SVC, left hippocampus cluster size: 112 mm³, p=0.024, FWE-SVC) and the left vmPFC (mask defined as bilateral gyrus rectus and medial orbital gyri, cluster size = 160 mm³, p=0.013, FWE-SVC) showed differentially changing CS-type-specific activations between the groups (Group × CS-type × Phase interaction). While CS+-specific suppression of these regions appeared to increase during the CC task, this was not the case during the extinction task. Post-hoc comparisons on averaged parameter estimates in the bilateral hippocampi confirmed that stimulus-specific suppression increased during the course of the task in the CC group (t(23)=3.280, p=0.003, early CS+-CS-: 0.054±0.07, late: –0.150±0.07), but not in the Ext group (p=0.266). Post-hoc comparisons across the vmPFC ROI also revealed increased CS+-specific suppression in the CC group compared to the Ext group (t(44)=2.221, p=0.032, CC: –0.189±0.06, Ext: –0.070±0.10). While the extinction group showed increased CS+-specific activation from the early to the late phase of the extinction task (t(21)=2.235, p=0.036, early CS+: –0.149±0.08, late CS+: 0.040±0.09), the CC group did not (p=0.120). During the late phase, the CC group showed increased vmPFC deactivation to the CS+ compared to the CS- (t(23)=3.174, p=0.004, late CS+: –0.284±0.06, late CS-: –0.095±0.05), while the Ext group did not (p=0.503). Thus, across both the hippocampus and the vmPFC, CC induced increased stimulus-specific suppression.

Figure 5

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During the spontaneous recovery task, a priori defined regions of interest did not reveal any effects (see Appendix 1).

Counterconditioning retroactively enhances item recognition for conditioned exemplars

Following the reinstatement test, participants completed a surprise item recognition test approximately 24 hr after acquisition and the CC/extinction task. One outlier was excluded from this analysis (CS- false alarm rate = 0.91). Threat conditioning has previously been shown to enhance 24 hr item recognition for category exemplars presented during the acquisition phase (Dunsmoor et al., 2012). However, this enhancement for CS+ items did not extend to items presented during an extinction session separated from the acquisition phase by a short break (Dunsmoor et al., 2018). We, therefore, analyzed item recognition for the CS+ and CS- during acquisition and the CC/extinction phase separately to examine whether the groups differed in recognition memory performance (Figure 6).

Figure 6

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Corrected recognition scores (hits probability-false alarms probability) were subjected to a task (acquisition, CC/extinction task) × CS-type (CS+, CS-) × Group (CC, Ext) rmANOVA, including CS+-category (animals, tools) as covariate. Overall, participants showed better memory for items from the CS + category (main effect of CS-type: F(1,42)=10.615, p=0.002, η²=0.202) and participants who underwent CC showed better memory as compared to participants who underwent extinction (main effect of Group: F(1,42)=4.963, p=0.031, η²=0.106). Stimulus-type specific item recognition differed between the CC and Ext groups (CS-type × Group interaction: F(1,42)=4.535, p=0.039, η²=0.094). While participants in the CC group showed better recognition memory for the CS+ category compared to the CS- category (t(22)=2.531, p=0.019, means ± SD: CS+ 0.39 ± 0.17, CS- 0.31±0.10), this was not the case for participants in the Ext group (t(23)=0.889, p=0.384, means ± SD: CS+ 0.30±0.13, CS- 0.28±0.11). Although the effect of stimulus type was stronger for tools as CS+, this was not different between groups (see Appendix 1). Thus, across the acquisition and CC/extinction phase, participants who underwent CC showed a stronger enhancement of CS+ memory compared to the participants who underwent extinction.

To further investigate to what extent CC retroactively affected memory for items presented during the acquisition task, we examined item recognition during acquisition and the CC/extinction tasks separately. While threat conditioning increased memory for CS+ items presented during the acquisition task across both groups (main effect CS-type: F(1,42)=18.147, p=<0.001, η²=0.302), subsequent CC enhanced this effect (Group x CS-type interaction: F(1,42)=5.112, p=0.029, η²=0.109). Post-hoc tests revealed increased item memory for the CS+ category compared to the CS- category presented during acquisition in the CC group (t(22)=2.341, p=0.029, means ± SD: CS+ 0.40±0.21, CS- 0.31±0.12) but not in the Ext group (t(23)=0.818, p=0.422, means ± SD: CS+ 0.33±0.16, CS- 0.30±0.13). Again, although the effect of stimulus type was stronger for tools as CS+, this was not different between groups (see Appendix 1). As the acquisition task was identical between groups, it appears that CC, in comparison to extinction, retroactively enhanced memory for CS + items. For items presented during the CC/extinction task, overall item recognition was better in the CC group compared to the Ext group (main effect group: F(1,42)=8.706, p=0.005, η²=0.172, means ± SD: CC 0.35±0.12, Ext 0.26±0.09). Thus, compared to regular extinction, CC enhanced recognition of items presented during CC, but interestingly also strengthened the emotional memory enhancement of CS+ exemplars presented during acquisition, suggesting that immediate CC may alter consolidation of a prior threat learning episode.

Following previous work (Keller and Dunsmoor, 2020; Dunsmoor et al., 2018; Dunsmoor et al., 2015), we explored stimulus-type specific decreases in item recognition between tasks, as well as within-phase differences between item recognition for the CS+ and CS- within each group. As expected, a post-hoc paired samples t-test showed that participants in the Ext group remembered significantly more CS+ items from the acquisition phase as compared to the extinction phase (t(23)=2.238, p=0.036, means ± SD: acquisition 0.33±0.16, extinction 0.27±0.13). In contrast, participants who had undergone CC remembered CS+ items presented during acquisition and CC equally well (t(22)=0.390, p=0.701, means ± SD: acquisition 0.40±0.21, CC 0.38±0.16). Thus, while recognition memory for items encoded during the extinction task was substantially weaker than memory for items from the acquisition task, this was not the case for items presented during CC.

This study aimed to test whether CC compared to regular extinction can lead to a more persistent attenuation of threat responses, and to investigate whether this is mediated by neural mechanisms reflecting extinction-related enhanced engagement of the vmPFC or engagement of reward-focused networks. We found that CC prevented differential spontaneous recovery of PDRs compared to regular extinction, suggesting that CC reduces the recovery of threat responses. Notably, there are individual differences (some participants in both groups show the opposite pattern), which should be further investigated in future studies with larger sample sizes, as it is crucial to identify who will respond to treatments based on the principles of standard extinction or counterconditioning. Our fMRI results suggested that CC engages different neural mechanisms compared to extinction. Most notably, while the extinction group showed an increase in CS+-specific vmPFC activation during extinction, the CC group showed CS+-specific deactivation of the vmPFC that persisted throughout the late phase of CC. Furthermore, CC led to increased NAcc activation for the CS + compared to the CS-, whereas this was not the case for extinction. Lastly, phase- and stimulus-specific activation of the hippocampus and the amygdala differed between extinction and CC. Compared to extinction, CC led to increased activation of the amygdala in the early phase and increasing stimulus-specific deactivation of the hippocampus over the course of the early and late phases. In addition, CC retroactively enhanced item recognition for conditioned exemplars presented during acquisition and strengthened memory for conditioned exemplars presented during CC compared to extinction.

The mechanism underlying CC appears to be qualitatively different from the mechanism underlying regular extinction. Regular extinction, which has been interpreted as an implicit form of emotion regulation (Hartley and Phelps, 2010), is associated with activation of the vmPFC (Phelps et al., 2004, Milad et al., 2007), which is thought to inhibit the expression of threat responses by suppressing amygdala activity (Quirk et al., 2000; Morgan et al., 1993; Quirk et al., 2003; Phelps et al., 2004). In comparison to regular extinction, novelty-facilitated extinction, a form of enhanced extinction in which aversive events are replaced with novel neutral outcomes, has shown stronger CS+-specific vmPFC activation (Dunsmoor et al., 2019). If CC was similarly mediated by enhanced recruitment of extinction networks, we would have expected increased activation of the vmPFC, yet we observed a CS+-specific deactivation of the vmPFC during CC, disproving this hypothesis. Interestingly, deactivation of the vmPFC during CC was also found in studies investigating a form of counterconditioning induced by means of real-time fMRI decoded neurofeedback (Koizumi et al., 2017, Taschereau-Dumouchel et al., 2018). During neurofeedback CC, participants implicitly learned to obtain monetary rewards by generating a representation of the target CS + in the visual cortex (Koizumi et al., 2017). After neurofeedback CC, reductions in threat responses were stronger in participants showing stronger vmPFC deactivation, suggesting that vmPFC disengagement may be associated with fear reductions (Koizumi et al., 2017). Taken together, both our findings and previous neurofeedback studies suggest that, in contrast to enhanced extinction, CC disengages the vmPFC. Given that we replicate this finding using a different approach that includes direct exposure to the CS+, vmPFC disengagement may be a distinguishing characteristic of CC, which could indicate that CC, in contrast to regular extinction, does not involve an implicit regulation strategy. The observed pattern of activity, including vmPFC deactivation, further bears resemblance to activity patterns observed during goal-directed eye movements in an experimental model of eye-movement desensitization and reprocessing (EMDR), which has also been shown to improve extinction learning (de Voogd et al., 2018). A similar activity pattern and effect has also been found for working memory-like tasks, such as a game of Tetris (Holmes et al., 2009; James et al., 2015; Price et al., 2013). Given that the above-mentioned tasks associated with vmPFC deactivation share their strong engagement of working memory and/or endogenous attention mechanisms, thereby engaging the executive control network, deactivation of the vmPFC and hippocampus could be the result of a deactivated default mode network due to competition between activation of large scale brain networks (Qin et al., 2009; Seeley et al., 2007; Liang et al., 2016).

The CC procedure led to clear CS+-specific activation of the NAcc, which is in line with expectations for reward anticipation in tasks with a monetary incentive delay aspect (Knutson and Cooper, 2005). Activation of the ventral striatum has also been reported for active avoidance and may be generally associated with instrumental actions as opposed to passive delivery of an outcome (Boeke et al., 2017, Delgado et al., 2009). In line with studies on active avoidance, delivery of a reward contingent on instrumental actions has been shown to yield CC that is more resistant to renewal (Thomas et al., 2012). CS+-specific activation of the NAcc was not seen in participants undergoing extinction, suggesting that this activation is specific to CC. However, previous work in rodents revealed an amygdala-ventral striatum (NAcc) pathway that is activated during extinction training (Correia et al., 2016). The recruitment of this pathway was shown to be enhanced during CC and reduce the return of fear (Correia et al., 2016), suggesting that CC may, in fact, enhance activation of reward-related networks that are weakly activated by extinction. Indeed, fMRI studies in humans that modeled prediction error for omitted aversive outcomes during extinction training (i.e. outcomes ‘better-than-expected’) showed involvement of the NAcc (Raczka et al., 2011; Thiele et al., 2021; Esser et al., 2021). Possibly, activation of the NAcc during extinction is limited to early extinction trials generating prediction errors. Nevertheless, based on our findings, it appears that sustained CS+-specific activation of the NAcc is a distinct mechanism underlying CC but not extinction, which is potentially associated with instrumental actions. In comparison to more implicit forms of emotion regulation, as is the case in regular extinction, CC may thus be a more active coping strategy, which is more effective in persistently preventing the return of threat responses (Boeke et al., 2017).

A recent neuroimaging study suggests that the neural differences between regular extinction and CC may be maintained over time (Keller et al., 2022). In their within-subject study, two CS+ categories (animals, objects) were used during threat conditioning. Subsequently, one of the CS+ categories was used for regular extinction, whereas the other was used for CC. During CC, CS+ exemplars were paired with positively valenced pictures. During a spontaneous recovery task the following day, it was shown that involvement of the vmPFC (amygdala-vmPFC functional connectivity) was stronger for regular extinction compared to CC. In contrast, CS+-specific increases in functional connectivity between the amygdala and the ventral striatum (NAcc) were only observed in the CC condition during a spontaneous recovery task. Both findings are in line with the CC-associated vmPFC deactivation and NAcc activation that we observed and suggest that differences in the neural mechanisms of regular extinction and CC may be maintained during threat retrieval.

CC compared to regular extinction also strengthened item memory for the conditioned category. While both reward and threat conditioning can enhance item recognition for the CS + category (Dunsmoor et al., 2012; Patil et al., 2017), recognition of CS + exemplars presented during extinction was shown to drop compared to acquisition (Dunsmoor et al., 2018). In contrast to extinction, within-session CC was previously shown to enhance memory, suggesting that CC has a unique, strengthening effect on memory (Keller and Dunsmoor, 2020). In the current study, we replicate this finding, showing strengthened memory after CC compared to extinction. While enhanced recognition of items presented during CC could be mediated by attentional prioritization (Talmi et al., 2008), CC also retrospectively strengthened memory for items presented during acquisition, suggesting that CC may alter the consolidation of a prior threat conditioning episode. Retroactive enhancement of memory consolidation for related items has previously been shown for conceptually related neutral items presented prior to threat conditioning (Dunsmoor et al., 2015) and reward conditioning (Patil et al., 2017). At a neurobiological level, these findings have been related to the synaptic tagging-and-capture hypothesis postulating that memories for neutral events can be strengthened if they are followed by salient events, due to an initially short-lived synaptic ‘tag’ that allows later events to stabilize the memory (Dunsmoor et al., 2015, Ballarini et al., 2009, Frey and Morris, 1997). At a systems level, retroactive memory strengthening has been linked to reverse replay (Braun et al., 2018). Specifically, animal research indicates that rewards increase reverse replay (Ambrose et al., 2016; Foster and Wilson, 2006; Diba and Buzsáki, 2007), and reward-induced reverse replay occurs concurrently with firing of midbrain dopamine neurons (Gomperts et al., 2015). Interestingly, spontaneous replay is also involved in regular extinction, in which unexpected omission of the US drives spontaneous reactivation of activity patterns in the vmPFC. This spontaneous reactivation was shown to be predictive of extinction recall and could be amplified through pharmacological enhancement of dopaminergic activity (Gerlicher et al., 2018). Yet while physiological dopaminergic modulation during extinction may be limited to prediction error signals during the early phase (Raczka et al., 2011; Thiele et al., 2021; Esser et al., 2021), dopaminergic modulation may be sustained throughout the MID-based CC task applied in this study. While we did not measure dopaminergic activity directly, activation of the NAcc during reward anticipation is predictive of dopamine release within the NAcc (Weiland et al., 2017; Weiland et al., 2014; Schott et al., 2008; Buckholtz et al., 2010). Given the increased stimulus-specific activation of the NAcc in the CC group, it is likely that dopaminergic activity was enhanced during CC compared to regular extinction. The enhanced dopaminergic modulation could strengthen memories through replay (Ambrose et al., 2016, Singer and Frank, 2009), or may increase synaptic plasticity directly, potentially explaining enhanced item recognition after CC compared to regular extinction (Braun et al., 2018, Atherton et al., 2015, Brzosko et al., 2015). In line with these findings, research in humans shows that reward systematically modulates memory for neutral objects in a retroactive manner, with objects closest to the reward being prioritized (Braun et al., 2018). It could be that reward conditioning during CC similarly drives reward-driven reverse replay, enhancing episodic memory for conceptually related items presented during the preceding acquisition task.

Several limitations of the current study are worth considering. First, while the monetary incentive aspect during CC clearly induced positive valence, it also increased physiological arousal, making it difficult to isolate the individual effects of positive valence and reward-induced arousal. While the current results are in line with previous work in CC using low-arousal, positive-valence pictures (Keller and Dunsmoor, 2020), we cannot exclude the possibility that the current findings (in part) reflect differences in task engagement between participants due to active instead of passive reward delivery. However, it is questionable whether it is meaningful to tease individual effects of valence and arousal apart since arousal may facilitate reward processing. Indeed, striatal responses to obtained monetary rewards are dependent on salience and are increased when rewards are dependent on active responses compared to passive delivery (Zink et al., 2004). Second, although we included a reinstatement procedure in the experiment, neither the Ext nor the CC group showed differential reinstatement. It is worth noting, however, that reinstatement paradigms in humans may not reliably produce differential reinstatement after extinction (Haaker et al., 2014). Third, it is important to note that CC/extinction was carried out within minutes after the acquisition phase, and the effects of CC and extinction may differ when carried out after the acquisition memory has been consolidated (Chang and Maren, 2009; Devenport, 1998; Maren, 2014; Myers et al., 2006). Fourth, whole-brain analysis of the CS-specific activation during the spontaneous recovery test in the Ext group did not yield any clusters above threshold, while physiological results indicated spontaneous recovery of differential threat responses. Given that recovered threat responses are often quick to extinguish and fMRI analyses require averaging across multiple trials to achieve sufficient signal-to-noise ratio, threat-evoked neural activity may have been too brief to be detected. Lastly, there was an unequal sex distribution in our sample, and the sample size did not allow for the investigation of sex-dependent differences, which should be addressed in future studies.

In conclusion, our findings show that appetitive CC improves the retention of safety memory over standard extinction. Strikingly, in contrast to activation of the vmPFC during extinction, CC was associated with stimulus-specific deactivation of the vmPFC. These findings may inform the development of future treatments for fear- and anxiety disorders. While a large body of research focuses on enhancing regular extinction, this study indicates that another promising and potentially longer-lasting approach may be to engage reward circuits. Although further work is needed, a major advantage of CC-based interventions over extinction-based interventions may be that CC could be more tolerable as it may shift attention away from the experience of fear.

The raw, pseudonomized data, as well as the fMRI subject-level contrast files used for group-level analyses are available from the Radboud Data Repository at https://doi.org/10.34973/kves-ee90. The processed data, fMRI group-level output, SPSS mask to replicate the behavioral and physiological data analyses, and scripts to replicate the publication figures are openly available at https://osf.io/mvsq6.

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Author details

1. Lisa Wirz

   1. Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands
   2. Cognitive Psychology, Ruhr University Bochum, Bochum, Germany

   Contribution

   Formal analysis, Supervision, Validation, Investigation, Visualization, Writing – original draft, Writing – review and editing

   Contributed equally with

   Maxime C Houtekamer

   For correspondence

   lisa.wirz@donders.ru.nl

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2811-4080

2. Maxime C Houtekamer

   Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Methodology, Writing – original draft

   Contributed equally with

   Lisa Wirz

   Competing interests

   No competing interests declared

3. Jette de Vos

   Department of Psychiatry and Neuropsychology, MHeNs, Maastricht University, Maastricht, Netherlands

   Contribution

   Data curation, Formal analysis

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5966-8257

4. Joseph E Dunsmoor

   Department of Psychiatry and Behavioral Sciences, University of Texas at Austin, Austin, United States

   Contribution

   Conceptualization, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5448-6873

5. Judith Homberg

   Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands

   Contribution

   Conceptualization, Writing – review and editing

   Contributed equally with

   Marloes JAG Henckens

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7621-1010

6. Marloes JAG Henckens

   Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands

   Contribution

   Conceptualization, Writing – review and editing

   Contributed equally with

   Judith Homberg

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2375-1611

7. Erno Hermans

   Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands

   Contribution

   Conceptualization, Supervision, Writing – review and editing

   Competing interests

   No competing interests declared

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