Cross-paradigm integration shows a common neural basis for aversive and appetitive conditioning.

Sharing imaging data and comparing them across different psychological tasks is becoming increasingly possible as the open science movement advances. Such cross-paradigm integration has the potential to identify commonalities in findings that neighboring areas of study thought to be paradigm-specific. However, even the integration of research from closely related paradigms, such as aversive and appetitive classical conditioning is rare - even though qualitative comparisons already hint at how similar the 'fear network' and 'reward network' may be. We aimed to validate these theories by taking a multivariate approach to assess commonalities across paradigms empirically. Specifically, we quantified the similarity of an aversive conditioning pattern derived from meta-analysis to appetitive conditioning fMRI data. We tested pattern expression in three independent appetitive conditioning studies with 29, 76 and 38 participants each. During fMRI scanning, participants in each cohorts performed an appetitive conditioning task in which a CS+ was repeatedly rewarded with money and a CS- was never rewarded. The aversive pattern was highly similar to appetitive CS+ > CS- contrast maps across samples and variations of the appetitive conditioning paradigms. Moreover, the pattern distinguished the CS+ from the CS- with above-chance accuracy in every sample. These findings provide robust empirical evidence for an underlying neural system common to appetitive and aversive learning. We believe that this approach provides a way to empirically integrate the steadily growing body of fMRI findings across paradigms.

Amygdala and nucleus accumbens involvement in appetitive extinction.

Extinction of appetitive conditioning is regarded as an important model for the treatment of psychiatric disorders like addiction. However, very few studies have investigated its neural correlates. Therefore, we investigated neural correlates of appetitive extinction in a large human sample including all genders (N = 76, 40 females) to replicate and extend results from a previous study. During differential appetitive conditioning, one stimulus (CS+) was paired with the chance to win a monetary reward, whereas another stimulus (CS-) was not. During appetitive extinction on the next day, neither the CS+ nor the CS- were reinforced. After successful acquisition of appetitive conditioning, the extinction phase elicited significant reductions of valence and arousal ratings toward the CS+ and a significant reduction in skin conductance responses to the CS+ from early to late extinction. On a neural level, early extinction showed significant differential (CS+ - CS-) activation in dACC and hippocampus, whereas involvement of the vACC and caudate nucleus did not replicate. The differential activation of amygdala and nucleus accumbens during late extinction was replicated, with the amygdala displaying significantly higher differential activation during the late phase of extinction as compared to the early phase of extinction. We show discernible signals for reward learning and extinction in subregions of amygdala and nucleus accumbens after extinction learning. This successful replication underlines the role of nucleus accumbens and amygdala in neural models of appetitive extinction in humans that was previously only based on animal findings.

Multiple extinction contexts modulate the neural correlates of context-dependent extinction learning and retrieval.

Exposure therapy is a successful treatment for patients with anxiety and fear-related disorders. Extinction of conditioned fear comprises one important mechanism underlying the effects of exposure therapy. Yet, relapses frequently occur in the long-term, probably related to difficulties in generalizing the extinction of conditioned fear to new contexts, leading to renewal of conditioned fear. Extinction training in multiple extinction contexts depicts a promising opportunity to reduce this renewal of conditioned fear. However, the underlying neural correlates are unknown yet. In this functional magnetic resonance imaging study, 49 healthy men participated in a fear conditioning paradigm with fear acquisition training in context A on a first day, extinction training in a single context (B1) or in four different contexts (B1-B4) one day later, and fear and extinction recall and reinstatement in context B1 and a novel context C on a third day one week later. Multiple extinction contexts led to a stronger differential activation decrease in the hippocampus during extinction learning compared to a single extinction context. One week later, the multiple context group compared with the single context group showed reduced differential amygdala activation during fear renewal in the novel context C compared with the extinction context B1. Furthermore, multiple extinction contexts diminished amygdala activation during a subsequent reinstatement test in context B1. However, there were no significant differences in differential conditioned SCRs. These results indicate that the use of multiple extinction contexts during extinction training leads to reduced conditioned responses in the amygdala-hippocampus complex.

Attributed social context and emotional content recruit frontal and limbic brain regions during virtual feedback processing.

In communication, who is communicating can be just as important as what is said. However, sender identity in virtual communication is often inferred rather than perceived. Therefore, the present research investigates the brain structures activated by sender identity attributions and evaluative feedback processing during virtual communication. In a functional magnetic resonance imaging (fMRI) study, 32 participants were told that they would receive personality feedback, either sent from another human participant or from a randomly acting computer. In reality, both conditions contained random but counterbalanced feedback, automatically delivered by approving or denying negative, neutral, or positive adjectives. Although physically identical, feedback attributed to the "human" sender activated multiple regions within a "social brain" network, including the superior frontal, medial prefrontal, and orbitofrontal cortex, anterior and posterior parts of the cingulate cortex, and the bilateral insula. Regardless of attributed sender, positive feedback increased responses in the striatum and bilateral amygdalae, while negative compared to neutral feedback elicited stronger insula and somatosensory responses. These results reveal the recruitment of an extensive mentalizing and social brain network by mere sender attributions and the activation of brain structures related to reward and punishment by verbal feedback, demonstrating its embodied processing.

The relationship between neuroticism and appetitive conditioning.

Appetitive conditioning is considered a central mechanism for the vulnerability to psychiatric disorders. However, the investigation of individual differences that are related to altered appetitive learning has been almost neglected so far. The aim of this study was to investigate the link between neuroticism and appetitive conditioning processes. 79 subjects participated in a differential conditioning procedure in which a conditioned stimulus (CS+) was paired with a reward (money) after a fast behavioral response, while a second conditioned stimulus (CS-) was never followed by a reward, irrespective of the behavioral response. As a main result, neuroticism correlated negatively with the underlying neural processes of appetitive conditioning in females, but not in males. In detail, higher levels of neuroticism were associated with decreased neural responses in the left (p = .001) and right amygdala (p = .011), left (p = .063) and right (p = .019) nucleus accumbens, and left (p = .002) and right (p = .021) orbitofrontal cortex (all results are family-wise-error-corrected). The present results support previous findings, which also showed an inverse sex-specific effect in the context of neuroticism and emotional processing in females. In addition, the findings suggest that neuroticism is not solely linked to increased amygdala sensitivity during the processing of negative stimuli but also to decreased neural responses when processing rewarding stimuli. Possible explanations for the sex differences and implications are discussed.

Altered reward learning and hippocampal connectivity following psychosocial stress.

Acute stress has a profound influence on learning, as has been demonstrated in verbal learning or fear conditioning. However, its effect on appetitive conditioning is still unclear. Fear conditioning research suggests the possibility of overgeneralization of conditioning to the CS- under acute stress due to its effect on prefrontal and hippocampal processing. In this study, participants (N = 56 males) were subjected to the Trier Social Stress Test or a placebo version. After that, all participants underwent an appetitive conditioning paradigm in the fMRI, in which one neutral cue (CS+) was repeatedly paired with reward, while another (CS-) was not. Importantly, the stress-group revealed overgeneralization of conditioning to the CS- on the behavioral level. On the neural level, stressed participants showed increased connectivity between the hippocampus and amygdala, vACC, and OFC, which maintain specificity of conditioning and also showed reduced differential activation. The results indicate overgeneralization of appetitive conditioning promoted by maladaptive balancing of pattern separation and pattern completion in the hippocampus under acute stress and are discussed with respect to clinical implications.

Neural correlates of subjective CS/UCS association in appetitive conditioning.

Explicit knowledge of conditioned stimulus (CS)/unconditioned stimulus (UCS) associations is proposed as important factor in classical conditioning. However, while previous studies have focused on its roles in fear conditioning, it has been neglected in the context of appetitive conditioning. The present functional magnetic resonance study aimed to investigate neural activation and functional connectivity linked to subjective CS/UCS association in appetitive conditioning. In total, 85 subjects participated in an appetitive acquisition procedure in which a neutral stimulus (CS+) was paired with a monetary reward, while another neutral stimulus (CS-) was never paired with the reward. Directly afterwards, subjective CS/UCS association was assessed by measuring the extent to which the CS+ was thought to be associated with the UCS compared to the CS-. Close relationships were established between subjective CS/UCS association and activations in the primary visual cortex (V1) during the early phase of conditioning and in the striatum during the late conditioning phase. In addition, we observed inverse relationships between subjective CS/UCS association and both V1/ventromedial prefrontal cortex (vmPFC) and striatal/vmPFC connectivity. The results suggest the involvement of decoupling vmPFC connectivity in reward learning in general and the roles of attentional processes in the formation of the subjective CS/UCS association during the early phase and reward prediction during the late phase of appetitive conditioning.

Altered Appetitive Conditioning and Neural Connectivity in Subjects With Compulsive Sexual Behavior.

INTRODUCTION: There has been growing interest in a better understanding of the etiology of compulsive sexual behavior (CSB). It is assumed that facilitated appetitive conditioning might be an important mechanism for the development and maintenance of CSB, but no study thus far has investigated these processes. AIM: To explore group differences in neural activity associated with appetitive conditioning and connectivity in subjects with CSB and a healthy control group. METHODS: Two groups (20 subjects with CSB and 20 controls) were exposed to an appetitive conditioning paradigm during a functional magnetic resonance imaging experiment, in which a neutral stimulus (CS+) predicted visual sexual stimuli and a second stimulus (CS-) did not. MAIN OUTCOME MEASURES: Blood oxygen level-dependent responses and psychophysiologic interaction. RESULTS: As a main result, we found increased amygdala activity during appetitive conditioning for the CS+ vs the CS- and decreased coupling between the ventral striatum and prefrontal cortex in the CSB vs control group. CONCLUSION: The findings show that neural correlates of appetitive conditioning and neural connectivity are altered in patients with CSB. The increased amygdala activation might reflect facilitated conditioning processes in patients with CSB. In addition, the observed decreased coupling could be interpreted as a marker for impaired emotion regulation success in this group.

Impact of COMT Val158Met-polymorphism on appetitive conditioning and amygdala/prefrontal effective connectivity.

Appetitive conditioning is an important mechanism for the development, maintenance, and treatment of psychiatric disorders like substance abuse. Therefore, it is important to identify genetic variations, which impact appetitive conditioning. It has been suggested that the Val(158) Met-polymorphism in the Catechol-O-Methyl-Transferase (COMT) is associated with the alteration of neural processes of appetitive conditioning due to the central role of the dopaminergic system in reward processing. However, no study has so far investigated the relationship between variations in the COMT Val(158) Met-polymorphism and appetitive conditioning. In this fMRI study, an appetitive conditioning paradigm was applied, in which one neutral stimulus (CS+) predicted appetitive stimuli (UCS) while a second neutral stimulus (CS-) was never paired with the UCS. As a main result, we observed a significant association between the COMT Val(158) Met-genotype and appetitive conditioning: skin conductance responses (SCRs) revealed a significant difference between CS+ and CS- in Val/Val-allele carriers but not in the other genotype groups. Val/Val-allele carriers showed increased hemodynamic responses in the amygdala compared with the Met/Met-allele group in the contrast CS+ > CS-. In addition, psychophysiological-interaction analysis revealed increased effective amygdala/ventromedial prefrontal cortex connectivity in Met/Met-allele carriers. The increased amygdala activity points to facilitated appetitive conditioning in Val/Val-allele carriers while the amygdala/prefrontal connectivity results could be regarded as a marker for altered emotion regulation during conditioning, which potentially impacts appetitive learning sensitivity. The SCRs finding indicates a stronger conditioned response in the Val/Val-allele group and dovetails with the neural differences between the groups. These findings contribute to the current research on COMT in emotional processing.

Behavioral pattern separation is associated with neural and electrodermal correlates of context-dependent fear conditioning.

Hippocampus-dependent pattern separation is considered as a relevant factor for context discrimination and might therefore impact the contextual modulation of conditioned fear. However, the association between pattern separation and context-dependent fear conditioning has not been investigated so far. In the current study, 72 healthy female students completed the Mnemonic Similarity Task, a measure of behavioral pattern separation, in addition to a context-dependent fear conditioning paradigm during functional magnetic resonance imaging. The paradigm included fear acquisition in context A and extinction training in context B on a first day, as well as retrieval testing of the fear and extinction memories in the safe context B (extinction recall) and a novel context C (fear renewal) one day later. Main outcome measures comprised skin conductance responses (SCRs) and blood oxygen level-dependent responses in brain regions of the fear and extinction circuit. Regarding retrieval testing, pattern separation did not correlate with extinction recall, but with stronger dorsal anterior cingulate cortex activation and conditioned SCRs (trend) during fear renewal, indicating a stronger retrieval of the fear memory trace. Our findings suggest that behavioral pattern separation ability seems to be important for context-dependent fear modulation, which is impaired in patients with posttraumatic stress disorder.

Individual cortisol response to acute stress influences neural processing of sexual cues.

Background and aims: Problematic pornography use can be conceptualized as an impulse control disorder or alternatively as a behavioral addiction. Stress is an important trigger in addiction, but less is known about the neural effect of stress in problematic pornography use. Therefore, we aimed at investigating the effect of stress during the anticipation and viewing of sexually explicit material while considering person characteristics related to potentially being at risk for developing problematic pornography use. Methods: In an fMRI study (n = 157 men, age: mean = 25.46, SD = 4.11) we used a sexual incentive delay task. A social stress test was used to induce stress in half of the participants. Salivary cortisol was repeatedly measured and person characteristics were considered moderating the effects of cortisol response. Results: We found no group differences in the neural responses during the anticipation phase, but a higher reactivity to sexual stimuli in the dACC in the stress group. Acute stress activated a pronounced cortisol response, which positively correlated with neural activations in the reward system (NAcc, dACC) to sexual cues. Further, the individual time spent on pornography use moderated the effect of cortisol in some regions of the reward system (dACC, mOFC). Discussion and conclusions: Our results suggest that acute stress related increases in cortisol can enhance the incentive value of cues announcing sexual stimuli. This might explain why acute stress is considered a trigger of pornography use and relapse and why individual stress response might be a risk factor for developing a problematic pornography use.

Sexual incentive delay in the scanner: Sexual cue and reward processing, and links to problematic porn consumption and sexual motivation.

BACKGROUND AND AIMS: The use of pornography, while unproblematic for the majority, can grow into addiction-like behavior which in its extreme form is labeled as compulsive sexual behavioral disorder in the ICD-11 (WHO, 2018). The aim of this study was to investigate the addiction-specific reactivity to cues in order to better understand underlying mechanisms in the development of this disorder. METHODS: We have used an optimized Sexual Incentive Delay Task to study brain activity in reward associated brain areas during an anticipation phase (with cues predicting pornographic videos, control videos or no videos) and a corresponding delivery phase in healthy men. Correlations to indicators of problematic pornography use, the time spent on pornography use, and trait sexual motivation were analyzed. RESULTS: The results of 74 men showed that reward-related brain areas (amygdala, dorsal cingulate cortex, orbitofrontal cortex, nucleus accumbens, thalamus, putamen, caudate nucleus, and insula) were significantly more activated by both the pornographic videos and the pornographic cues than by control videos and control cues, respectively. However, we found no relationship between these activations and indicators of problematic pornography use, time spent on pornography use, or with trait sexual motivation. DISCUSSION AND CONCLUSIONS: The activity in reward-related brain areas to both visual sexual stimuli as well as cues indicates that optimization of the Sexual Incentive Delay Task was successful. Presumably, associations between reward-related brain activity and indicators for problematic or pathological pornography use might only occur in samples with increased levels and not in a rather healthy sample used in the present study.

Subjective reward value of visual sexual stimuli is coded in human striatum and orbitofrontal cortex.

Human neuroimaging research suggests the existence of one core network for the subjective valuation of rewards, including the striatum and orbitofrontal cortex. However, there is little research on the neural representation of subjective reward values of visual sexual stimuli (VSS) and on the role of these subjective valuations in the development of related addictive behaviors. Here, we investigate how neural reactivity to VSS is connected to individual preference using functional magnetic resonance imaging (fMRI). During the fMRI scan, 72 men viewed different VSS film clips. Ratings regarding valence and sexual arousal were collected and used as parametric modulators in the fMRI analysis. Subjects also filled out questionnaires on self-reported symptoms of problematic pornography use (PPU). Firstly, we found that neural reactivity towards VSS clips in the nucleus accumbens, caudate nucleus and orbitofrontal cortex was positively correlated with individual ratings of the respective VSS in all subjects. Second, the strength of the association between neural activity and sexual arousal ratings was positively correlated with self-reported symptoms of PPU. The first result suggests a precise appraisal of VSS according to individual preferences in established reward valuation regions. Secondly, stronger neural differentiation based on preference in participants with more PPU symptoms indicates an increased importance of VSS/preference fit in these individuals. This heightened correspondence between individual liking and neural activity may facilitate PPU development by increased signaling of incentive salience, thus boosting motivation to seek out and respond to these preferred stimuli.

Relationship of sensation seeking with the neural correlates of appetitive conditioning.

Previous research has linked sensation seeking with a heightened risk for drug abuse and other risk-taking behavior. As appetitive conditioning presents a model for the etiology and maintenance of addictive behavior, investigating sensation seeking in a classical conditioning paradigm might elucidate possible pathways toward addiction within this model. Furthermore, the theoretical concept underlying sensation seeking proposes a negative relationship between reward processing and sensation seeking in only moderately arousing situations, which has been neglected by previous research. This study aimed to investigate this inverse relationship in moderately stimulating situations entailing reward processing using functional magnetic resonance imaging. Subjects (N = 38) participated in a classical conditioning paradigm in which a neutral stimulus (CS+) was repeatedly paired with a monetary reward, while another neutral stimulus (CS-) was not. Imaging results revealed a negative relationship between sensation seeking and neural responses in the insula, amygdala and nucleus accumbens during the early phase and in the dorsal anterior cingulate cortex during the late phase of conditioning. These findings suggest reduced reward learning and consequently diminished processing of outcome expectancy in appetitive conditioning in subjects with high sensation seeking scores. The results are discussed with respect to clinical implications.

Increased neural reactivity to emotional pictures in men with high hair testosterone concentrations.

Testosterone has been linked to alterations in the activity of emotion neurocircuitry including amygdala, orbitofrontal cortex (OFC) and insula and diminished functional amygdala/prefrontal coupling. Such associations have only ever been studied using acute measures of testosterone, thus little is known about respective relationships with long-term testosterone secretion. Here, we examine associations between hair testosterone concentration (HTC), an index of long-term cumulative testosterone levels and neural reactivity during an emotional passive viewing task using functional magnetic resonance imaging (fMRI). Forty-six men viewed negative, positive and neutral pictures in the MRI. HTCs were assessed from 2 cm hair segments. The emotional paradigm elicited neural activation in the amygdala, insula and OFC. HTCs were associated with increased reactivity to negative pictures in the insula and increased reactivity to positive pictures in the OFC. We show an association of long-term testosterone levels with increased emotional reactivity in the brain. These results suggest a heightened emotional vigilance in individuals with high trait testosterone levels.

No Sex Difference Found: Cues of Sexual Stimuli Activate the Reward System in both Sexes.

Sexually explicit material (SEM) is increasingly used in western societies. One reason for this high usage might be the rewarding property of SEM demonstrated in many brain imaging studies showing an activation of the reward system during the presentation of SEM. It is not yet well understood why women use SEM to a remarkably lesser extent than men. Maybe men react stronger to stimuli - so called SEM cues -, which signal the presentation of SEM and are therefore more vulnerable to use SEM than women. Therefore, the present study aimed at investigating the sex specific neural correlates towards SEM and SEM cues. We were further interested in whether person characteristics as trait sexual motivation, extent of SEM use in the last month, and age at onset of goal-oriented SEM use affect the neural responses to SEM and SEM cues. The trials of the fMRI experiment consisted of an expectation phase with SEM or neutral cues and a presentation phase with SEM or neutral stimuli, respectively. Analyses showed that the reward circuitry was activated by SEM, but also by SEM cues. There were some sex differences in hemodynamic responses to SEM during the presentation phase, but not during the expectation phase to SEM cues in any of the regions of interest. The influence of the investigated person characteristics was only small if existent. The results suggest that sex specific cue processing cannot explain sex differences in the use of SEM.

Failure to Replicate the Association Between Fractional Anisotropy and the Serotonin Transporter Gene (5-HTTLPR, rs25531).

Recent work underlines the importance of alterations in white matter (e.g., measured by fractional anisotropy (FA)) as a neural vulnerability marker for psychiatric disorders. In this context, the uncinate fasciculus (UF), which connects the limbic system with prefrontal areas, has repeatedly been linked to psychiatric disorders, fear processing, and anxiety-related traits. Individual differences in FA may partly be genetically determined. Variation in the promoter region of the serotonin transporter gene (serotonin transporter-linked polymorphic region [5-HTTLPR]) is a particularly promising candidate in this context, which has been linked to psychiatric disorders as well as to limbic and prefrontal reactivity. However, findings on the association between the 5-HTTLPR and FA within the UF-tract have been heterogeneous. The present study investigated this relationship and extended previous work by considering different genetic classification approaches as well as sex effects in a human sample (n = 114). All participants were genotyped for the 5-HTTLPR and the rs25531 polymorphism. As a main result, we did not find any significant relationship between the 5-HTTLPR and FA in the UF-tract although power analyses showed an adequate power. In addition, genotype effects were neither found when different classification approaches were used nor when analyses were carried out in males or females only. The present findings suggest that the association of the 5-HTTLPR and FA seems to be a more labile phenomenon than previously assumed. Possible explanations and limitations are discussed.

Neural correlates of appetitive extinction in humans.

Appetitive extinction receives attention as an important model for the treatment of psychiatric disorders. However, in humans, its underlying neural correlates remain unknown. To close this gap, we investigated appetitive acquisition and extinction with fMRI in a 2-day monetary incentive delay paradigm. During appetitive conditioning, one stimulus (CS+) was paired with monetary reward, while another stimulus (CS-) was never rewarded. Twenty-four hours later, subjects underwent extinction, in which neither CS was reinforced. Appetitive conditioning elicited stronger skin conductance responses to the CS+ as compared with the CS-. Regarding subjective ratings, the CS+ was rated more pleasant and arousing than the CS- after conditioning. Furthermore, fMRI-results (CS+ - CS-) showed activation of the reward circuitry including amygdala, midbrain and striatal areas. During extinction, conditioned responses were successfully extinguished. In the early phase of extinction, we found a significant activation of the caudate, the hippocampus, the dorsal and ventral anterior cingulate cortex (dACC and vACC). In the late phase, we found significant activation of the nucleus accumbens (NAcc) and the amygdala. Correlational analyses with subjective ratings linked extinction success to the vACC and the NAcc, while associating the dACC with reduced extinction. The results reveal neural correlates of appetitive extinction in humans and extend assumptions from models for human extinction learning.

Don't fear 'fear conditioning': Methodological considerations for the design and analysis of studies on human fear acquisition, extinction, and return of fear.

The so-called 'replicability crisis' has sparked methodological discussions in many areas of science in general, and in psychology in particular. This has led to recent endeavours to promote the transparency, rigour, and ultimately, replicability of research. Originating from this zeitgeist, the challenge to discuss critical issues on terminology, design, methods, and analysis considerations in fear conditioning research is taken up by this work, which involved representatives from fourteen of the major human fear conditioning laboratories in Europe. This compendium is intended to provide a basis for the development of a common procedural and terminology framework for the field of human fear conditioning. Whenever possible, we give general recommendations. When this is not feasible, we provide evidence-based guidance for methodological decisions on study design, outcome measures, and analyses. Importantly, this work is also intended to raise awareness and initiate discussions on crucial questions with respect to data collection, processing, statistical analyses, the impact of subtle procedural changes, and data reporting specifically tailored to the research on fear conditioning.

No evidence for blocking the return of fear by disrupting reconsolidation prior to extinction learning.

Fear extinction is a central model for the treatment of anxiety disorders. Initial research has reported that the single presentation of a conditioned stimulus prior to extinction learning can permanently block the return of fear. However, only few studies have explored this issue and could not always replicate the findings. The present study examined human fear extinction using a four-day design. On the first day, two neutral stimuli were paired with electrical stimulation (UCS), while a third stimulus (CS-) was not. Twenty-four hours later, one conditioned stimulus (CS+rem) and the CS- were reminded once, 10 min before extinction learning, while the other conditioned stimulus (CS+non-rem) was not presented prior to extinction learning. All stimuli were presented during extinction learning and during two re-extinction sessions (24 h and 6-months after extinction learning) without reinforcement. Blood oxygen level-dependent (BOLD) responses and skin conductance responses (SCRs) to both CS+ and the CS- were explored during acquisition, extinction, and in both re-extinction sessions. Regarding SCRs, the results showed that a single presentation of a conditioned stimulus did not block the return of fear during re-extinction: Fear recovery during re-extinction (24 h and 6-months after extinction learning) was observed for both CS+ compared with the CS- with no difference between CS+rem and CS+non-rem. Regarding BOLD-responses, no significant differences between CS+rem and CS+non-rem were found in region of interest (ROI)-analyses (amygdala, ventromedial prefrontal cortex) during extinction learning and both re-extinction sessions. Whole-brain analyses showed increased BOLD-responses to the CS+non-rem as compared to the CS+rem in several regions (e.g., middle frontal gyrus) during extinction learning and re-extinction (24 h after extinction learning). The present findings suggest that the effect of preventing the return of fear by disrupting reconsolidation seems to be a more labile phenomenon than previously assumed. Possible boundary conditions and implications are discussed.