Unravelling the neurocognitive mechanisms underlying counterconditioning in humans
- Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Netherlands
- Cognitive Psychology, Ruhr University Bochum, Germany
- Department of Psychiatry and Neuropsychology, MHeNs, Maastricht University, Netherlands
- Department of Psychiatry and Behavioral Sciences, University of Texas at Austin, United States
Figures
Figure 1
Overview of the experimental design.
(A). Participants were assigned to the counterconditioning (CC) or extinction (Ext) group. On day 1, participants performed two blocks of acquisition of category-conditioned threat responses separated by a 30 s break, followed by CC or extinction. Day 2 consisted of a spontaneous recovery test, a reinstatement procedure and test, an item memory test and a valence-specific response characterization. Valence and arousal ratings for the different categories were taken before or after the tasks as indicated by ‘V+A Rating.’ All tasks were performed in an MRI scanner. (B) During acquisition, participants viewed trial-unique exemplars of objects and animals. Exemplars of one category (CS + animals or objects counterbalanced) were paired with a shock in 50% of trials. CS- trials were not reinforced. (C) Participants in the CC group could earn a monetary reward if they responded quickly enough to exemplars in the CS + category. (D) Participants in the Ext group underwent extinction. During the extinction task, recovery test,f and reinstatement test, neither CS + nor CS- exemplars were paired with a shock. (E) In the valence-specific response characterization task, participants viewed three different colored squares. One color was associated with shock (CS +S), one color with reward (CS +R), and one color served as CS-. The trial structure was otherwise identical to the acquisition and CC tasks. (F) In all Pavlovian tasks, trial onset was marked by presentation of a unique category exemplar. After a variable interval, a ring appeared, to which participants were instructed to respond as quickly as possible. Upon response, the ring shifted in color as response confirmation. In the acquisition task, shocks could occur 0.5–1.5 s after the response window had elapsed (indicated as ‘pre-shock’). The category exemplar and cue remained visible 1 s after potential shock administration (indicated as ‘post-shock’). During CC, participants received visual feedback for 2 s (+€0.50 approximately the fastest 70% of trials, +€0.00 on other trials). During the other tasks, participants viewed neutral feedback (three dots). Trials were separated by an 8–10 s intertrial interval, during which a fixation cross is displayed in the centre of the screen.
Figure 2
Differential PDRs during counterconditioning (CC)/extinction and explicit ratings of arousal and valence provided after the counterconditioning or extinction phase.
(A) Differential pupil dilation responses (PDRs) for the early (light red) and late (dark red) phase of counterconditioning (CC, solid bars) or extinction (EXT, open bars). Participants undergoing CC showed increased differential PDRs as compared to participants undergoing extinction (CS-type x Group interaction, N=36). (B) Arousal and (C) valence ratings displayed separately for participants assigned to the counterconditioning (CC, solid bars) and extinction (EXT, open bars) groups. Participants who had undergone CC gave stronger differential arousal scorings than participants who had undergone extinction (CS-type x Group interaction, N=46). In addition, participants who underwent CC showed flipped differential valence ratings: while valence differential valence ratings were negative after extinction, the direction reversed to positive differential ratings after CC (CS-type x Group interaction, N=46). Error bars represent ± standard error of the mean. *=p<0.05, **=p<0.01, ***=p<0.001, ≠ indicates that the bar is significantly different from 0.
Figure 3
Differential pupil dilation responses (PDRs) during the last two trials of counterconditioning or extinction and the first two trials of the spontaneous recovery test.
Differential PDRs show selective spontaneous recovery after extinction (Ext, open bars) but not after counterconditioning (CC, solid bars). During the first two trials of the spontaneous recovery test, differential PDRs are increased in the Ext group as compared to the CC group (CS-type x Group interaction, N=31). Insets show PDRs to the CS+ (red) and CS- (blue) during the last two trials of CC/Ext and the first two trials of the spontaneous recovery test. While the Ext group shows differential responding during the spontaneous recovery test (paired t-test, N=15), the CC group does not (paired t-test, N=16). Error bars represent ± standard error of the mean. *=p<0.05, #=p<0.05 one-tailed significance.
Figure 4
Stimulus-type specific activation differs between participants undergoing counterconditioning (CC) versus extinction.
(A) Whole-brain Group × CS-type interaction effects (N=46) revealed distinct stimulus-specific activation of regions, including the anterior cingulate, cuneus, nucleus accumbens, caudate, thalamus, and inferior frontal gyrus during the counterconditioning vs. extinction phase. Panel A displays group F-images (see Table 1 for directions) FWE-corrected at p<0.05, cluster-forming threshold p=0.001. (B) The right amygdala showed a Group × CS-type × Phase interaction (N=46) during the CC/extinction task, indicating that CC compared to extinction is associated with decreased activation of the amygdala. (C) The bilateral nucleus accumbens (NAcc) showed a Group × CS-type interaction (N=46) during the CC/extinction task, revealing increased NAcc activation in response to the CS + compared to the CS- in the CC but not in the extinction (Ext) group. Panel B and C display group F-images FWE-SVC at p<0.05, cluster-forming threshold p=0.001, along with post-hoc tests on mean parameter estimates from the complete ROI included in the analyses. **p<0.01, *p<0.05, ≠ indicates that the value is significantly different from 0.
Figure 5
ROI analyses during the counterconditioning (CC)/extinction task reveal distinct activity in the hippocampus and left ventromedial prefrontal cortex (vmPFC).
During the CC/extinction task, stimulus-specific activation of the hippocampus (C) and left vmPFC (D) changes differently between groups (N=46). **p<0.01, *p<0.05, ≠ indicates that the bar is significantly different from 0. Group F-images FWE-SVC at p<0.05, cluster-forming threshold p=0.001, along with post-hoc tests on mean parameter estimates from complete ROI included in the analyses.
Figure 6
Twenty-four-hour recognition memory results.
During acquisition and extinction on the first day of the experiment, participants viewed trial-unique exemplars from two semantic categories (objects, animals) that served as CS + and CS-. The next day, participants completed a surprise memory test for these items, mixed with an equal number of novel exemplars. Participants recognized relatively more items from the CS + category (main effect CS-type, N=45), and participants that underwent counterconditioning (CC) showed improved item recognition compared to participants in the extinction (Ext) group (CS-type x Group interaction, N=45). Error bars represent ± standard error of the mean. *=p<0.05.
Appendix 1—figure 1
Pupil dilation responses (PDRs), explicit arousal, and valence rating for the different CSs presented during the valence-specific response characterization task.
(A) PDRs to the shock reinforced (CS+S), reward reinforced (CS+R) and CS- stimuli, averaged across the task and all participants. PDRs were increased for the CS+S and CS+R as compared to the CS- (main effect CS-type, N=36) (B) Explicit ratings of arousal and (C) valence provided immediately after the task. Explicit ratings of arousal for the CS+S exceeded ratings for the CS-, and the CS+R was rated higher in arousal than the CS+S (main effect CS-type, N=47). Valence ratings (1=extremely negative, 10=extremely positive) for the CS+R were more positive than ratings for the CS-, while ratings for the CS+S were more negative than for the CS- and CS+R (main effect CS-type, N=47). Error bars represent ± standard error of the mean *=p<0.05, ***=p<0.001.
Appendix 1—figure 2
Differential pupil dilation responses (PDRs) during acquisition and explicit ratings of arousal and valence provided after acquisition.
(A) Differential PDRs for the early (light red) and late (dark red) phase of the acquisition task, (B) arousal and (C) valence ratings, displayed separately for participants assigned to the counterconditioning (CC, solid bars) and extinction (EXT, open bars) groups. Both groups showed comparable differential PDRs and arousal ratings during the acquisition task. Participants in both groups showed negative differential valence ratings (stronger negative valence for CS+ vs CS-), although this effect was stronger in the Ext group (CS-type x Group interaction, N=46). Error bars represent ± standard error of the mean. *p<0.05. ≠. Significantly different from 0.
Appendix 1—figure 3
Differential threat responses during acquisition revealed CS-specific activation of clusters encompassing a range of regions including the bilateral insula, thalamus, precuneus, anterior cingulate and midbrain.
Group F-image of the effect of CS type, thresholded at cluster-level FWE-corrected p<0.05, cluster-forming threshold p=0.001, displayed on the single-subject high-resolution T1 volume provided by the Montreal Neurological Institute (MNI).
Appendix 1—figure 4
During the spontaneous recovery test, stimulus type-specific activation of the inferior temporal and frontal gyri differed between groups.
The inferior temporal gyrus (A) and inferior frontal gyrus (B) show increased CS+-specific activation in the counterconditioning (CC) group as compared to the extinction (Ext) group (main effect group, N=46). Group F images thresholded at FWE-corrected p<0.05, cluster-forming threshold p=0.001, displayed on the single-subject high-resolution T1 volume provided by the Montreal Neurological Institute (MNI) and parameters estimates from peak voxels.
Tables
Table 1
Whole-brain main effects of group (counterconditioning CC, extinction Ext), CS type (CS+, CS-), and phase (early, late) and interactions, during the counterconditioning/extinction task.
Cluster-forming threshold p=0.001, FWE-corrected at p<0.05, clusters were labeled using the Talairach Daemon atlas and the automated anatomic labeling (AAL) atlas for ROIs. For each cluster, the peak voxel coordinates (Montreal Neurological Institute, MNI space) and regions are reported, and additional regions contained within the cluster are added in italics. See Appendix 1—table 1 for main effects of CS-type.
| 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 | |
Appendix 1—table 1
Whole-brain main effects of group (counterconditioning CC, extinction Ext), CS type (CS+, CS-), and phase (early, late) and interactions, during the acquisition task.
Cluster-forming threshold p=0.001, FWE-corrected at p<0.05, clusters were labeled using the Talairach Daemon atlas and the automated anatomic labeling (AAL) atlas for ROIs. For each cluster, the peak voxel coordinates (Montreal Neurological Institute, MNI space) and regions are reported, and additional regions contained within the cluster are added in italics.
| Peak MNI coordinates | ||||||||
|---|---|---|---|---|---|---|---|---|
| Region | Cluster | x | y | z | Size (mm3) | pFWE (cluster) | Peak F-value | Direction |
| CS-type × phase | ||||||||
| Parahippocampal Gyrus L Insula L, Parahippocampal Gyrus Hippocampus L, Claustrum L, Lentiform Nucleus Putamen L, Uncus L, Postcentral Gyrus BA43 L | 1 | –18 | –10 | –16 | 6656 | 0.005 | 25.86 | Early CS+>Late CS+ |
| Parahippocampal Gyrus Amygdala R Inferior Frontal Gyrus R, Subcallosal Gyrus BA34R | 2 | 20 | -4 | –22 | 2116 | 0.033 | 25.34 | Early CS+>Late CS+ |
| Culmen L Declive L, Lingual Gyrus L | 3 | -8 | –54 | –16 | 1720 | 0.027 | 20.57 | Early CS+>Late CS+ |
| Parahippocampal Gyrus L Parahippocampal gyrus BA36L/BA30L, Culmen L | 4 | –20 | –42 | -2 | 5236 | 0.006 | 31.65 | Early CS+>Late CS+ |
| Medial Frontal Gyrus BA11 L Anterior Cingulate BA32L, Medial Frontal Gyrus BA10 R, BA11 R | 5 | -4 | 38 | –14 | 1104 | 0.046 | 17.23 | |
| Superior Temporal Gyrus L Middle Temporal Gyrus BA21/BA22 L | 6 | –52 | 10 | –14 | 3056 | 0.015 | 28.06 | |
| Lingual Gyrus BA18/BA19 R | 7 | -6 | –68 | -2 | 2584 | 0.018 | 35.21 | |
| Insula R Inferior Parietal Lobule R, Superior Temporal Gyrus BA22 R, Postcentral Gyrus BA3 R, Superior Temporal Gyrus BA22 R, Precentral Gyrus BA4/BA6, Inferior Parietal Lobule BA40, Middle Temporal Gyrus, Superior Temporal Gyrus BA42 | 8 | 38 | -6 | 18 | 24488 | 0.001 | 27.62 | |
| Parahippocampal Gyrus R | 9 | 24 | –36 | -4 | 1432 | 0.035 | 22.26 | |
| Inferior Frontal Gyrus BA45 R | 10 | 52 | 14 | 14 | 1392 | 0.036 | 21.37 | |
| Precentral Gyrus L | 11 | –60 | -8 | 32 | 5640 | 0.006 | 22.09 | |
| Inferior Parietal Lobule BA40L Postcentral gyrus BA2L | 12 | –56 | –36 | 42 | 1104 | 0.046 | 20.42 | |
| Precuneus L Postcentral gyrus L, Cingulate gyrus L | 13 | –14 | –42 | 54 | 1496 | 0.034 | 19.85 | |
| Precuneus R Paracentral Lobule Ba7 R, Precuneus R, Cingulate gyrus R, Superior Parietal Lobule BA7 R | 14 | 20 | –52 | 54 | 5528 | 0.006 | 24.86 | |
| Medial Frontal gyrus L (23) Medial frontal gyrus BA6LR, Paracentral Lobule L | 15 | -6 | –20 | 64 | 1840 | 0.025 | 21.47 | |
| CS-type | ||||||||
| Postcentral Gyrus L Inferior Parietal Lobule LR, Insula LR, Postcentral Gyrus R, Cingulate Gyrus LR, Thalamus LR, Caudate LR, Inferior- Middle- and Superior Frontal Gyrus LR, Posterior Cingulate R, Precentral Gyrus LR, Precuneus L, Delice R, Culmen R, Cuneus L, Superior Temporal Gyrus LR, Anterior Cingulate LR, Parahippocampal Gyrus BA27 R, Lentiform Nucleus LR | 1 | –50 | –20 | 16 | 425400 | <0.001 | 195.37 | CS +>CS- |
| Posterior Cingulate BA31 L Precuneus M | 2 | -4 | –56 | 24 | 2816 | 0.021 | 26.17 | CS +<CS- |
| Corpus Callosum M Corpus Callosum R | 3 | 0 | 0 | 22 | 1296 | 0.049 | 35.45 | |
| Angular Gyrus R Angular Gyrus BA39 R, Precuneus R | 4 | 56 | –66 | 30 | 2432 | 0.024 | 31.42 | |
| Angular Gyrus BA39L | 5 | –54 | –68 | 30 | 5584 | 0.010 | 36.02 | |
| Superior Frontal Gyrus BA9L Superior Frontal Gyrus BA8L, Middle Frontal Gyrus BA6L | 6 | –18 | 40 | 42 | 7200 | 0.007 | 33.18 | |
| Phase | ||||||||
| Superior Temporal Gyrus LR, Inferior Parietal Lobule R, Middle Temporal Gyrus LR, Inferior- Middle- and Superior Frontal Gyrus LR, Caudate LR, Middle Occipital Gyrus LR, Cingulate Gyrus LR, Anterior Cingulate LR, Declive LR, Precuneus LR, Insula LR, Culmen LR, Superior Temporal Gyrus LR, Lingual Gyrus LR, Fusiform Gyrus LR, Angular Gyrus R, Claustrum LR, Thalamus LR, Parahippocampal Gyrus LR, Cuneus LR | 1 | –64 | –38 | 12 | 784632 | <0.001 | 77.44 | Early >Late |
Appendix 1—table 2
Whole-brain main effect of CS-type during the counterconditioning (CC)/extinction task.
Cluster-forming threshold p=0.001, FWE-corrected at p<0.05, clusters were labeled using the Talairach Daemon atlas and the automated anatomic labeling (AAL) atlas for ROIs. For each cluster, the peak voxel coordinates (Montreal Neurological Institute, MNI space) and regions are reported, and additional regions contained within the cluster are added in italics.
| Peak MNI coordinate | ||||||||
|---|---|---|---|---|---|---|---|---|
| Region | Cluster | x | y | z | Size (mm3) | pFWE (cluster) | Peak F-value | Direction |
| CS-type | ||||||||
| Caudate Head L Thalamus LR, Caudate Head R, Substantia Nigra LR | 1 | –10 | 10 | -2 | 25136 | 0.001 | 60.98 | CS +>CS- |
| Insula R Inferior Frontal Gyrus R, Precentral Gyrus BA44 R, Inferior Frontal Gyrus BA45 R | 3 | 28 | 26 | 0 | 22800 | 0.001 | 89.75 | |
| Inferior Frontal Gyrus L Insula BA13 L | 4 | –32 | 28 | 0 | 7808 | 0.004 | 52.01 | |
| Lingual Gyrus L Inferior Occipital Gyrus L, Cuneus L, Middle Occipital Gyrus L | 5 | –24 | –80 | –12 | 5696 | 0.006 | 32.81 | |
| Superior Temporal Gyrus R Transverse Temporal Gyrus R | 6 | 50 | –18 | 6 | 3744 | 0.012 | 30.65 | |
| Lingual Gyrus R Cuneus R | 7 | 8 | –94 | 6 | 3688 | 0.012 | 27.81 | |
| Superior Temporal Gyrus L Transverse Temporal Gyrus L | 8 | –44 | –24 | 8 | 3864 | 0.011 | 44.50 | |
| Anterior Cingulate BA32 R Medial Frontal Gyrus BA8 R, Anterior Cingulate LR, Cingulate Gyrus BA32 R | 9 | 4 | 38 | 20 | 7064 | 0.004 | 26.61 | |
| Superior Temporal Gyrus R Supramarginal Gyrus R, Inferior Parietal Lobule BA40R | 10 | 64 | –34 | 14 | 3720 | 0.012 | 25.88 | |
| Superior Temporal Gyrus L | 11 | –60 | –46 | 16 | 2504 | 0.023 | 36.62 | |
| Cingulate Gyrus L Posterior Cingulate BA23R, Posterior Cingulate L | 13 | -6 | –20 | 30 | 3928 | 0.011 | 38.33 | |
| Angular Gyrus L Middle Temporal Gyrus L, Angular Gyrus BA39 L | 12 | –44 | –64 | 32 | 4104 | 0.010 | 23.58 | CS->CS + |
| Inferior Temporal Gyrus BA21 L, Middle Temporal Gyrus BA21 L | 2 | –64 | –10 | –22 | 1696 | 0.039 | 27.05 | |
| Angular Gyrus R Supramarginal Gyrus R | 14 | 44 | –66 | 34 | 1392 | 0.050 | 18.35 | |
| Postcentral Gyrus BA40R Precentral Gyrus Ba4/BA3 R | 15 | 34 | –40 | 58 | 1704 | 0.038 | 19.84 | |
| Middle Frontal Gyrus BA8/BA6 L | 16 | –24 | 16 | 48 | 4576 | 0.008 | 34.03 | |
Appendix 1—table 3
Peak voxel coordinates and statistics of activations during the spontaneous recovery phase in the counterconditioning (CC) group.
Clusters were labeled using the automated anatomic labeling (AAL) atlas. For each cluster, the peak voxel coordinates and regions are reported, and additional regions contained within the cluster are added in italics. Clusters are whole-brain FWE-corrected at p<0.05.
| Peak MNI coordinate | ||||||||
|---|---|---|---|---|---|---|---|---|
| Region | Cluster | x | y | z | Size (mm3) | pFWE (cluster) | Peak T-value | Direction |
| CS-type | ||||||||
| Thalamus R Parahippocampal Gyrus R | 1 | 10 | –22 | -4 | 2160 | <0.001 | 6.70 | CS +>CS- |
| Inferior temporal Gyrus R Fusiform gyrus R | 2 | 46 | –52 | -2 | 4856 | <0.001 | 6.56 | |
| Inferior frontal gyrus, triangular R | 3 | 58 | 26 | 26 | 4992 | <0.001 | 5.93 | |
| Superior parietal lobe R Angular Gyrus R | 4 | 26 | –60 | 50 | 2048 | <0.001 | 5.36 | |
| Inferior frontal gyrus, orbital part L | 5 | 50 | 26 | -6 | 1120 | 0.019 | 5.31 | |
| Fusiform gyrus L Lingual gyrus | 6 | –38 | –80 | –18 | 1176 | 0.015 | 5.18 | |
| Caudate R | 7 | 6 | 0 | 10 | 1952 | <0.001 | 4.87 | |
| Middle Frontal gyrus R | 8 | 37 | 0 | 44 | 992 | 0.03 | 4.86 | |
| Superior parietal lobule L Angular gyrus L | 9 | –32 | –58 | 58 | 1480 | 0.004 | 4.53 | |
Additional files
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Unravelling the neurocognitive mechanisms underlying counterconditioning in humans
eLife 13:RP101518.
https://doi.org/10.7554/eLife.101518.3
