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Rationale: Preclinical research suggests that pharmacologically elevating cannabinoid levels may attenuate fear memory expression and enhance fear extinction. Objectives: We studied the effects of cannabidiol (CBD) on fear memory expression and fear re-extinction in 69 patients with panic disorder with agoraphobia or with social anxiety disorder. Moderation by sex, diagnosis, and serotonergic antidepressant (AD) use was explored. Methods: A cued fear conditioning paradigm was applied before the first treatment session with 300 mg CBD/placebo augmented exposure therapy. Study medication was administered orally preceding 8 weekly sessions. Fear acquisition and suboptimal extinction took place prior to the first medication ingestion (T0). After the first medication ingestion (T1), we investigated effects on fear memory expression at retention and fear re-extinction. Subjective fear, shock expectancy, skin conductance, and startle responses to conditioned (CS+) and safety stimulus (CS−) were measured. Results: Across the sample, CBD reduced shock expectancy at retention under low and ambiguous threat of shock, but fear re-extinction at T1 was unaffected by CBD. However, in AD users, re-extinction of subjective fear was impaired in the CBD condition compared to placebo. In female AD users, CBD interfered with safety learning measured with fear-potentiated startle. Conclusions: The current findings provide no evidence for enhanced fear re-extinction by CBD. However, CBD acutely decreased threat expectation at retention, without affecting other indices of fear. More studies are needed to elucidate possible interactions with AD use and sex, as well as potential effects of CBD on threat expectancies.

Fear-related disorders, including post-traumatic stress disorder (PTSD), and anxiety disorders are pervasive psychiatric conditions marked by persistent fear, stemming from its dysregulated acquisition and extinction. The primary treatment for these disorders, exposure therapy (ET), relies heavily on fear extinction (FE) principles. Adolescence, a vulnerable period for developing psychiatric disorders, is characterized by neurobiological changes in the fear circuitry, leading to impaired FE and increased susceptibility to relapse following ET. Ketamine, known for relieving anxiety and reducing PTSD symptoms, influences fear-related learning processes and synaptic plasticity across the fear circuitry. Our study aimed to investigate the effects of ketamine (10 mg/kg) on FE in adolescent male C57 BL/6 mice at the behavioral and molecular levels. We analyzed the protein and gene expression of synaptic plasticity markers in the hippocampus (HPC) and prefrontal cortex (PFC) and sought to identify neural correlates associated with ketamine’s effects on adolescent extinction learning. Ketamine ameliorated FE in the adolescent males, likely affecting the consolidation and/or recall of extinction memory. Ketamine also increased the Akt and mTOR activity and the GluA1 and GluN2A levels in the HPC and upregulated BDNF exon IV mRNA expression in the HPC and PFC of the fear-extinguished mice. Furthermore, ketamine increased the c-Fos expression in specific brain regions, including the ventral HPC (vHPC) and the left infralimbic ventromedial PFC (IL vmPFC). Providing a comprehensive exploration of ketamine’s mechanisms in adolescent FE, our study suggests that ketamine’s effects on FE in adolescent males are associated with the activation of hippocampal Akt-mTOR-GluA1 signaling, with the vHPC and the left IL vmPFC as the proposed neural correlates.

Here, we used RNA capture-seq to identify a large population of lncRNAs that are expressed in the infralimbic prefrontal cortex of adult male mice in response to fear-related learning. Combining these data with cell-type-specific ATAC-seq on neurons that had been selectively activated by fear extinction learning, we find inducible 434 lncRNAs that are derived from enhancer regions in the vicinity of protein-coding genes. In particular, we discover an experience-induced lncRNA we call ADRAM (activity-dependent lncRNA associated with memory) that acts as both a scaffold and a combinatorial guide to recruit the brain-enriched chaperone protein 14-3-3 to the promoter of the memory-associated immediate-early gene Nr4a2 and is required fear extinction memory. This study expands the lexicon of experience-dependent lncRNA activity in the brain and highlights enhancer-derived RNAs (eRNAs) as key players in the epigenomic regulation of gene expression associated with the formation of fear extinction memory.

Stress represents a major risk factor for psychiatric disorders, including post-traumatic stress disorder (PTSD). Recently, we dissected the destabilizing effects of acute stress on the excitatory glutamate system in the prefrontal cortex (PFC). Here, we assessed the effects of single subanesthetic administration of ketamine (10 mg/kg) on glutamate transmission and dendritic arborization in the PFC of footshock (FS)-stressed rats, along with changes in depressive, anxious, and fear extinction behaviors. We found that ketamine, while inducing a mild increase of glutamate release in the PFC of naïve rats, blocked the acute stress-induced enhancement of glutamate release when administered 24 or 72 h before or 6 h after FS. Accordingly, the treatment with ketamine 6 h after FS also reduced the stress-dependent increase of spontaneous excitatory postsynaptic current (sEPSC) amplitude in prelimbic (PL)-PFC. At the same time, ketamine injection 6 h after FS was found to rescue apical dendritic retraction of pyramidal neurons induced by acute stress in PL-PFC and facilitated contextual fear extinction. These results show rapid effects of ketamine in animals subjected to acute FS, in line with previous studies suggesting a therapeutic action of the drug in PTSD models. Our data are consistent with a mechanism of ketamine involving re-establishment of synaptic homeostasis, through restoration of glutamate release, and structural remodeling of dendrites.

Here, we used RNA capture-seq to identify a large population of lncRNAs that are expressed in the infralimbic prefrontal cortex of adult male mice in response to fear-related learning. Combining these data with cell-type-specific ATAC-seq on neurons that had been selectively activated by fear extinction learning, we find inducible 434 lncRNAs that are derived from enhancer regions in the vicinity of protein-coding genes. In particular, we discover an experience-induced lncRNA we call ADRAM (activity-dependent lncRNA associated with memory) that acts as both a scaffold and a combinatorial guide to recruit the brain-enriched chaperone protein 14-3-3 to the promoter of the memory-associated immediate-early gene Nr4a2 and is required fear extinction memory. This study expands the lexicon of experience-dependent lncRNA activity in the brain and highlights enhancer-derived RNAs (eRNAs) as key players in the epigenomic regulation of gene expression associated with the formation of fear extinction memory.

The consequences of the COVID-19 pandemic have resulted in many disruptions to daily life, including an abrupt increase in social disconnection. As measures were put in place to combat the spread of COVID-19, people across the globe began living in states of limited social contact, fostering feelings of social isolation and loneliness. Previous literature suggests that these increases in social disconnection can have profound effects on both physical and mental health, perhaps especially in the case of fear disorders. The combination of feeling disconnected from others and the high level of daily threat experienced due to COVID-19 created conditions under which dysfunctional and persistent fears were especially likely to develop. Building on current understanding of the harmful effects of social disconnection on well-being in general as well as specific implications for fear, here we present findings from three preliminary investigations that are the first to directly examine the effects of loneliness on how fears are learned and maintained. The Results of this work show that loneliness impairs the process by which fears are extinguished, which is central to both the regulation of fear and treatment of fear disorders, and provide insight into potential avenues to mitigate such effects.

Stress represents a major risk factor for psychiatric disorders, including post-traumatic stress disorder (PTSD). Recently, we dissected the destabilizing effects of acute stress on the excitatory glutamate system in the prefrontal cortex (PFC). Here, we assessed the effects of single subanesthetic administration of ketamine (10 mg/kg) on glutamate transmission and dendritic arborization in the PFC of footshock (FS)-stressed rats, along with changes in depressive, anxious, and fear extinction behaviors. We found that ketamine, while inducing a mild increase of glutamate release in the PFC of naïve rats, blocked the acute stress-induced enhancement of glutamate release when administered 24 or 72 h before or 6 h after FS. Accordingly, the treatment with ketamine 6 h after FS also reduced the stress-dependent increase of spontaneous excitatory postsynaptic current (sEPSC) amplitude in prelimbic (PL)-PFC. At the same time, ketamine injection 6 h after FS was found to rescue apical dendritic retraction of pyramidal neurons induced by acute stress in PL-PFC and facilitated contextual fear extinction. These results show rapid effects of ketamine in animals subjected to acute FS, in line with previous studies suggesting a therapeutic action of the drug in PTSD models. Our data are consistent with a mechanism of ketamine involving re-establishment of synaptic homeostasis, through restoration of glutamate release, and structural remodeling of dendrites.

Recent meta-analyses indicated differences in fear acquisition and extinction between patients with anxiety-related disorders and comparison subjects. However, these effects are small and may hold for only a subsample of patients. To investigate individual trajectories in fear acquisition and extinction across patients with anxiety-related disorders (N = 104; before treatment) and comparison subjects (N = 93), data from a previous study (Duits et al., 2017) were re-analyzed using data-driven latent class growth analyses. In this explorative study, subjective fear ratings, shock expectancy ratings and startle responses were used as outcome measures. Fear and expectancy ratings, but not startle data, yielded distinct fear conditioning trajectories across participants. Patients were, compared to controls, overrepresented in two distinct dysfunctional fear conditioning trajectories: impaired safety learning and poor fear extinction to danger cues. The profiling of individual patterns allowed to determine that whereas a subset of patients showed trajectories of dysfunctional fear conditioning, a significant proportion of patients (≥50 %) did not. The strength of trajectory analyses as opposed to group analyses is that it allows the identification of individuals with dysfunctional fear conditioning. Results suggested that dysfunctional fear learning may also be associated with poor treatment outcome, but further research in larger samples is needed to address this question.

Arbeit an der Bibliothek noch nicht eingelangt - Daten nicht geprüft, Innsbruck, Univ., Masterarb., 2021

Reminders of loved ones have long been avoided during extinction-based treatments because of their assumed status as safety signals, which, by inhibiting fear in the moment, impair the long-term outcomes of fear extinction. Yet, recent work has demonstrated that in contrast to standard safety signals, social support reminders actually enhance fear extinction and lead to lasting reduction of fear, suggesting that they may have beneficial effects during exposure therapy that have before-now been overlooked. Here, we argue for a revision of the assumption that social support is detrimental to fear extinction processes and propose that future work should focus on the potential of social support reminders to improve treatment outcomes in those with anxiety disorders.

Background: Transcranial direct current stimulation (tDCS) has previously been shown to improve fear extinction learning and retention when administered prior to or during extinction learning. This study investigates whether tDCS immediately following extinction learning improves efficacy of extinction memory retention. Methods: 30 participants completed a 2-day fear learning and extinction paradigm, where they acquired fear of a stimulus conditioned to an aversive electric shock on day 1. Extinction learning occurred on day 1, with tDCS or sham tDCS administered immediately following the learning phase. Participants returned for a second day test of extinction memory recall. Skin conductance was measured as the primary outcome. Results/Conclusions: Participants in the tDCS group showed impaired fear extinction retention on day 2, marked by significant generalisation of fear to the safety stimulus. This contrasts with earlier studies showing improved extinction retention when stimulation occurred during encoding of extinction learning, compared to immediate consolidation as in our study. These findings may have important implications for the use of tDCS during exposure therapy for anxiety and trauma disorders.

Early life stress is a known antecedent to anxiety- and fear-related disorders. It may disrupt the ability to regulate fear and act to trigger the development of an anxiety- or fear-related disorder. Hence, in this thesis, I examined the link between early life stress and fear regulation across development. To do this, I used Pavlovian fear extinction as a model of fear regulation to assess the effects of infancy and peri-adolescent stress in rats. In Chapter 2, I examined whether a chronic infancy stressor altered fear extinction in juvenile rats. This series of experiments utilized the limited bedding and nesting model of chronic infancy stress. I found that chronic infancy stress resulted in the precocious emergence of relapse-prone fear in male juvenile rats. However, chronic infancy stress had little effect on extinction behavior in female juvenile rats, as they exhibited relapse-prone fear regardless of stress condition. In Chapter 3, I investigated whether chronic peri-adolescent stress altered fear extinction in adolescence and adulthood. This series of experiments utilized social isolation as a model of chronic peri-adolescent stress. Peri-adolescent stress had a sex-specific effect on fear extinction. In males, peri-adolescent stress resulted in impairments in extinction recall in adolescent and adult male rats. However, in females, peri-adolescent stress had no effect on fear extinction behavior. In Chapter 4, I explored the interplay between peri-adolescent stress and physical activity on fear extinction in adolescence. Peri-adolescent stress, as modelled by social isolation, impaired extinction recall in male adolescents, but this effect was prevented by increased physical activity. Extinction recall in female adolescents was again unaffected by peri-adolescent stress. Surprisingly, increased physical activity was disruptive to extinction recall in peri-adolescent stressed females. Pharmacological suppression of cellular proliferation in peri-adolescent

Reminders of loved ones have long been avoided during extinction-based treatments because of their assumed status as safety signals, which, by inhibiting fear in the moment, impair the long-term outcomes of fear extinction. Yet, recent work has demonstrated that in contrast to standard safety signals, social support reminders actually enhance fear extinction and lead to lasting reduction of fear, suggesting that they may have beneficial effects during exposure therapy that have before-now been overlooked. Here, we argue for a revision of the assumption that social support is detrimental to fear extinction processes and propose that future work should focus on the potential of social support reminders to improve treatment outcomes in those with anxiety disorders.

Insomnia is one of the most common health issues, with occasional symptoms affecting up to 50% of the general population. Lack of sleep is associated with many negative health effects. A new evolutionary hypothesis has been proposed to explain the mechanism behind insomnia symptoms. The evolutionary-emotional hypothesis proposes that while acute insomnia might be advantageous from an evolutionary perspective, chronic insomnia is maladaptive and may follow from a failure or delay of fear extinction. The aim of the current thesis was to investigate which neural mechanisms might be at work if one is to consider the evolutionaryemotional hypothesis about the causes of insomnia plausible and to review studies from cognitive neuroscience to discover what support there might be for the hypothesis. Studies have found heightened activation in fear-related brain areas in insomnia patients. Delayed fear extinction and altered emotion regulation circuitry, among other things, were also observed for insomnia patients. However, few experimental studies on the effect of fear extinction on sleep in insomnia patients have been conducted. At this time, some emerging evidence lends support for the evolutionary-emotional hypothesis of insomnia, but more studies that directly assess fear conditioning and fear extinction processes in insomnia patients are needed to assess the explanatory power of the theory.

Insomnia is one of the most common health issues, with occasional symptoms affecting up to 50% of the general population. Lack of sleep is associated with many negative health effects. A new evolutionary hypothesis has been proposed to explain the mechanism behind insomnia symptoms. The evolutionary-emotional hypothesis proposes that while acute insomnia might be advantageous from an evolutionary perspective, chronic insomnia is maladaptive and may follow from a failure or delay of fear extinction. The aim of the current thesis was to investigate which neural mechanisms might be at work if one is to consider the evolutionaryemotional hypothesis about the causes of insomnia plausible and to review studies from cognitive neuroscience to discover what support there might be for the hypothesis. Studies have found heightened activation in fear-related brain areas in insomnia patients. Delayed fear extinction and altered emotion regulation circuitry, among other things, were also observed for insomnia patients. However, few experimental studies on the effect of fear extinction on sleep in insomnia patients have been conducted. At this time, some emerging evidence lends support for the evolutionary-emotional hypothesis of insomnia, but more studies that directly assess fear conditioning and fear extinction processes in insomnia patients are needed to assess the explanatory power of the theory.

We review findings and propose a model explaining why womens adaptation to traumatic stress might be different than mens, including the role of cycling hormones and sleep differences in the development of post-traumatic stress and other stress-related disorders. Women are diagnosed with stress-related mental health disorders at a higher frequency than men. Most mental health disorders involve sleep disturbances, which may contribute to these disorders. The mechanisms by which sleep contributes to the development of mental health disorders in women have not been addressed in basic research. Sleep features such as spindle density and rapid eye movement (REM) sleep theta power are important for the role of sleep in emotion and cognition. The effect of hormonal cycles on these and other critical sleep features is only beginning to be understood. We explore what sleep factors could confer resilience to mental health disorders and how they might be altered by hormonal cycles in women. We target a specific system at the nexus of arousal control, stress response, and memory consolidation processes that has not been explored at all in women or across the hormonal cycle in animal studies: the locus coeruleus noradrenergic (LC-NE) system.

submitted by Anna Sibylle Hofmann, Arbeit gesperrt, University of Innsbruck, Diplomarbeit, 2020, (VLID)5483662

Systematic exposure to feared stimuli is an integral component of cognitive behavioral-based therapies and is often regarded as the ‘gold-standard’ psychotherapeutic strategy for anxiety-related disorders. While many individuals respond to exposure-based treatments, a significant proportion experience a return of fear after treatment has concluded (e.g., Loerinc et al., 2015) – with others failing to respond to treatment all together (e.g., Taylor, Abramowitz, & McKay, 2012). Over the past several decades, associative learning theory has continued to evolve and has given rise to significant paradigm shifts in our fundamental understanding of fear learning (e.g., Rescorla & Wagner, 1972). These theoretical updates have provided explanations as to why anxious individuals often fail to adequately extinguish fear during exposure and have provided modernized learning principles which may be translated to practice to enhance exposure-based outcomes (e.g., Craske, Liao, Brown, & Vervliet, 2012; Craske, Treanor, Conway, Zbozinek, & Vervliet, 2014; Sewart & Craske, 2019). In addition, our new understanding of these processes also give rise to additional questions regarding potential unidentified, aberrant fear learning processes in anxious individuals which may also interfere with treatment response. This dissertation will include three papers that aim to both enhance our understanding of fear conditioning phenomenology in humans and translate fear learning principles to optimize exposure-based treatments. Study 1 seeks to establish within-session expectancy violation as a more robust predictor of treatment response to exposure therapy when compared with within-session fear habituation. Study 2 seeks to investigate who benefits the most from a pharmacological augmentation exposure therapy that is to proposed to decontextualize extinction learning. Study 3 seeks to further investigate how perceptual similarity impacts return of fear for complex stimuli in

Stressful or traumatic events can be risk factors for anxiety or trauma- and stressor-related disorders. In this regard, it has been shown that stress affects aversive learning and memory processes. In rodents, stress exposure 10 days prior to fear acquisition impairs fear extinction. However, in humans the effect of distal stress on fear conditioning is sparse. Therefore, we examined the influence of distal stress on fear memory in humans in two studies. In Study 1, participants underwent either socially evaluated cold-pressor test (SECPT) or sham procedure 10 days or 40 min before a fear conditioning paradigm (four groups, N = 78). In Study 2, context effects were examined by conducting SECPT and sham procedures 10 days prior conditioning either in the later fear conditioning context or in another context (three groups, N = 69). During acquisition phase, one geometrical shape (cond

This thesis investigated the impact of female reproductive experience on fear regulation. The first three experimental chapters examined fear extinction, the laboratory basis of exposure therapy for anxiety disorders, in female rats. In the first Experimental series (Chapter 2), I found that fear extinction was NMDAR-dependent in nulliparous (virgin), but not primiparous (reproductively experienced) rats. Contrastingly, fear conditioning appeared to be NMDAR-dependent in both nulliparous and primiparous rats. It also emerged that primiparous rats exhibited higher levels of freezing during extinction training, extinction recall, and conditioning recall compared to nulliparous rats.The next Experimental series (Chapter 3) investigated the effect of d-cycloserine and estradiol on fear extinction in nulliparous and primiparous rats. Both drugs were effective in enhancing extinction recall among nulliparous rats, but not primiparous rats. In Chapter 3, I also found that the expression of genes coding for the NMDAR subunits, NR2A and NR2B, and the classical estrogen receptors, ERα and ERβ, may be upregulated in the hippocampus following reproductive experience.In Chapter 4, I used a hierarchical multiple regression analysis to identify and compare hormonal and behavioural predictors of fear extinction between nulliparous and primiparous rats. This analysis revealed both overlapping (e.g., extinction rate and late extinction) and dissociable (e.g., estrous phase) predictors of fear extinction between these groups of rats. Moreover, follow-up analyses demonstrated that primiparous rats exhibited extinction recall levels that were between that of nulliparous rats extinguished during metestrus and nulliparous rats extinguished during proestrus.Finally, in Chapter 5, I sought to translate the findings of my animal studies to clinical settings by examining how treatment outcomes compare between men and women of varying reproductive status receiving internet-based cognitive beha

Stressful or traumatic events can be risk factors for anxiety or trauma- and stressor-related disorders. In this regard, it has been shown that stress affects aversive learning and memory processes. In rodents, stress exposure 10 days prior to fear acquisition impairs fear extinction. However, in humans the effect of distal stress on fear conditioning is sparse. Therefore, we examined the influence of distal stress on fear memory in humans in two studies. In Study 1, participants underwent either socially evaluated cold-pressor test (SECPT) or sham procedure 10 days or 40 min before a fear conditioning paradigm (four groups, N = 78). In Study 2, context effects were examined by conducting SECPT and sham procedures 10 days prior conditioning either in the later fear conditioning context or in another context (three groups, N = 69). During acquisition phase, one geometrical shape (conditioned stimulus, CS+) was paired with painful electric shocks (unconditioned stimulus, US), but never a second shape (CS−). Extinction phase was identical to acquisition, but without US delivery. Importantly, for Study 1 these phases were conducted on one day, while for Study 2 on two separated days. Successful fear acquisition was indicated by aversive ratings and startle potentiation to CS+ versus CS− in both studies. Interestingly, participants stressed 10 days earlier showed impaired extinction on the implicit level (startle potentiation to CS+ vs. CS−) in Study 1 and only in the acquisition context on the explicit level (aversive ratings for CS+ vs. CS−) in Study 2. In sum, distal stress may strengthen later acquired fear memories and thereby impair fear extinction. This finding could have clinical implications, showing that prior stress exposure sensitizes later aversive processing and impairs therapy.

Recent research indicates that there is mixed success in using exposure therapies on patients with post-traumatic stress disorder (PTSD). Our study argues that there are two major reasons for this: The first is that there are nonassociative aspects of PTSD, such as hyperactive amygdala activity, that cannot be attenuated using the exposure therapy; The second is that exposure therapy is conceptualized from the theoretical framework of Pavlovian fear extinction, which we know is heavily context dependent. Thus, reducing fear response in a therapist's office does not guarantee reduced response in other situations. This study also discusses work relating to the role of the hippocampus in context encoding, and how these findings can be beneficial for improving exposure therapies.

The present thesis examined the sex differences in fear learning in the developing rat. Traditionally, it has been widely assumed that pre-pubertal sex differences are negligible in developmental studies. However, epidemiological studies and sexual dimorphism in the brain prior to puberty, indicate that sex differences in fear learning may emerge early in life. In chapter 2, I assessed renewal, reinstatement and spontaneous recovery of extinguished fear (i.e. relapse of extinguished fear) in juvenile male and female rats. I found that P18 females showed all three fear relapse behaviors while P18 males did not. This finding implied that P18 female rats were able to form the contextual memories while P18 males could not. However, whether the ability to form a context-shock association contributes to fear extinction in juvenile rats, has not been explicitly tested. Therefore in chapter 3a and 3b, I directly compared renewal with context fear, using identical fear conditioning parameters in the developing rats. In chapter 3a, I found that P18 male rats did not show renewal while P25 male rats did. P18 and P25 male rats displayed comparable contextual freezing immediately after conditioning and after 24 hours delay. In chapter 3b, both P18 and P25 female rats displayed renewal. I also found that P18 female rats displayed a developmental deficit in context fear learning compared to P25 female rats. Together, findings from chapter 2, 3a and 3b strongly suggested that the emergence of context memory may be sex-dependent, where context-specific extinction emerges earlier in females while context fear learning emerges first in males. Given the critical role of the hippocampus in context-dependent learning, I thought the sex differences in the hippocampal function may underlie the observed sex differences in fear learning. In chapter 4, I examined the role of dHPC and vHPC in fear extinction in P18 male and female rats. I showed that temporary inactivation of the dHPC prior to

Systematic exposure to feared stimuli is an integral component of cognitive behavioral-based therapies and is often regarded as the ‘gold-standard’ psychotherapeutic strategy for anxiety-related disorders. While many individuals respond to exposure-based treatments, a significant proportion experience a return of fear after treatment has concluded (e.g., Loerinc et al., 2015) – with others failing to respond to treatment all together (e.g., Taylor, Abramowitz, & McKay, 2012). Over the past several decades, associative learning theory has continued to evolve and has given rise to significant paradigm shifts in our fundamental understanding of fear learning (e.g., Rescorla & Wagner, 1972). These theoretical updates have provided explanations as to why anxious individuals often fail to adequately extinguish fear during exposure and have provided modernized learning principles which may be translated to practice to enhance exposure-based outcomes (e.g., Craske, Liao, Brown, & Vervliet, 2012; Craske, Treanor, Conway, Zbozinek, & Vervliet, 2014; Sewart & Craske, 2019). In addition, our new understanding of these processes also give rise to additional questions regarding potential unidentified, aberrant fear learning processes in anxious individuals which may also interfere with treatment response. This dissertation will include three papers that aim to both enhance our understanding of fear conditioning phenomenology in humans and translate fear learning principles to optimize exposure-based treatments. Study 1 seeks to establish within-session expectancy violation as a more robust predictor of treatment response to exposure therapy when compared with within-session fear habituation. Study 2 seeks to investigate who benefits the most from a pharmacological augmentation exposure therapy that is to proposed to decontextualize extinction learning. Study 3 seeks to further investigate how perceptual similarity impacts return of fear for complex stimuli in

Recent research indicates that there is mixed success in using exposure therapies on patients with post-traumatic stress disorder (PTSD). Our study argues that there are two major reasons for this: The first is that there are nonassociative aspects of PTSD, such as hyperactive amygdala activity, that cannot be attenuated using the exposure therapy; The second is that exposure therapy is conceptualized from the theoretical framework of Pavlovian fear extinction, which we know is heavily context dependent. Thus, reducing fear response in a therapist's office does not guarantee reduced response in other situations. This study also discusses work relating to the role of the hippocampus in context encoding, and how these findings can be beneficial for improving exposure therapies.

Extinction learning is assumed to represent a core mechanism underlying exposure therapy. Empirical evaluations of this assumption, however, are largely lacking. The current study investigated whether neural activations and self-report outcomes during extinction learning and extinction recall could specifically predict exposure therapy response in specific phobia. In this double-blind randomized controlled trial, individuals with spider phobia (N = 45; female/male = 41/4) were on group basis randomly allocated to exposure therapy (n = 25; female/male = 24/1) or progressive muscle relaxation (PMR; n = 20; female/male = 17/3). Intervention effects were measured with the Fears of Spiders questionnaire. Participants also underwent a three-day fear conditioning, extinction learning, and extinction recall paradigm during functional magnetic resonance imaging at baseline. Extinction outcomes were self-reported fear and threat expectancy, and neural responses during conditioned stimulus processing and during extinction-related prediction errors (US omissions) in regions of interest (ventromedial prefrontal cortex (vmPFC) and nucleus accumbens). Results showed that exposure therapy resulted in stronger symptom reductions than PMR (Cohen's d = 0.90). Exposure therapy response was specifically predicted by prediction-error related vmPFC activation during early extinction. There were also indications vmPFC activations during conditioned safety stimulus processing at early extinction predicted therapy outcome. Neural activations during extinction recall and self-report data did however not predict therapy outcome. These findings indicate that exposure therapy may rely on neural extinction learning processes. Prediction errors are thought to drive the extinction learning process, and prediction error-related vmPFC activation specifically predicted therapy outcome. The extent to which vmPFC processes safety signals may additionally be predictive of exposure therapy response, bu

Exposure-based treatment for anxiety disorders is effective for many patients, but relapse is not uncommon. One predictor of the return of fear is the negative valence of fear-relevant stimuli. The aim of the current experiments was to examine whether counterconditioning with positive film clips reduces this negative stimulus valence as well as the return of fear, compared to standard extinction training and to an extinction training with non-contingent exposure to the positive film clips. Participants were 87 students in Experiment 1 (three-day paradigm), and 90 students in Experiment 2 (one-day paradigm). They first underwent a differential acquisition phase, in which one of three pictures was paired with an electric shock. They were then randomly allocated to one of the three intervention groups. Afterwards, they underwent a test phase in which pictures were presented without shock (to measure spontaneous recovery of fear), which was followed by unsignaled shocks to induce reinstatement of extinguished fear. Outcome variables were self-reported stimulus valence, shock expectancy, skin conductance, and fear-potentiated startle. In both experiments, counterconditioning decreased negative stimulus valence, relative to the other interventions, but it did not reduce spontaneous fear recovery or fear reinstatement. Overall, our findings do not support the notion that counterconditioning reduces return of fear.

Fear generalisation refers to the spread of fear to novel situations. Recent evidence has suggested that over-generalisation of fear is a pathogenic marker of anxiety disorders. Given that trait anxiety has been widely accepted as a vulnerability factor for developing an anxiety disorder, the current thesis aimed to examine whether trait anxious individuals show over-generalisation of fear like their clinical counterparts. Using a continuous perceptual dimension, the first experiment (Chapter 5) identified various generalisation gradients, which aligned logically with participants’ reported rules. Trait anxious individuals showed over-generalisation of fear to the novel test stimuli, but this pattern was only observed among those who failed to identify a clear rule. The following experiments (Chapter 6) further examined fear generalisation to objects that were conceptually related to the threat cues. Trait anxious individuals did not show more fear to novel exemplars that had clear categorical membership and therefore clear threat value. However, they showed more fear to novel exemplars that could be classified in both threat and safe categories, that is, exemplars with ambiguous threat value. The results supported the notion of threat appraisal bias under ambiguous threat among trait anxious individuals. The experiments in Chapter 7 examined the effect of trait anxiety on the generalisation of extinction learning along a blue-green stimulus dimension. Participants who received a generalisation stimulus (GS) in extinction showed an increase in conditioned fear to the original conditioned stimulus (CS) or to another novel GS in test. Conversely, this pattern was not found in those who received standard extinction with the CS. No trait anxiety effect was observed in the generalisation of extinction learning, however, trait anxious individuals showed slower fear extinction to the CS, but not to a GS. In summary, the present work suggests that over-generalisation of fea

This dissertation is a three-paper investigation of ways to improve treatment outcomes for anxiety disorders. Study 1 investigates whether training implicit approach or avoidance to feared stimuli augments or impedes fear extinction. We also investigate whether baseline explicit avoidance predicts extinction performance or future avoidance behavior. Extinction performance is used as a proxy for exposure therapy. Results revealed no effect of training implicit approach or avoidance on extinction performance nor future behavioral avoidance. Baseline explicit avoidance did not predict extinction performance, whereas it did predict future behavioral avoidance. Findings suggest that explicit avoidance may not affect fear extinction in an unambiguous fear-conditioning paradigm, but that it may affect future tendency to approach feared stimuli.Study 2 investigates behavioral avoidance as a moderator of treatment outcome for two behavioral therapies for social anxiety disorder. Individuals who were highly behaviorally avoidant on a public speaking task had better long-term treatment outcomes following cognitive behavioral therapy (CBT) than acceptance and commitment therapy. From a deficit correction model, individuals who are more behaviorally avoidant may benefit from a treatment that more systematically targets that avoidance. A version of this work has been published in the Journal of Behavior Therapy and Experimental Psychiatry (2017).Study 3 investigates interoceptive and in vivo avoidance as moderators of treatment outcome for two different CBTs for panic disorder. Individuals who displayed more in vivo avoidance at baseline had better outcome following CBT with interoceptive exposures than CBT with interoceptive and in vivo exposures. This suggests that avoidant individuals benefit more from a therapy that targets their primary interoceptive concerns as opposed to one that expands to in vivo avoidance.Taken together, these studies aim to improve treatment outcomes i

Translational neuroscience bridges insights from specific mechanisms in rodents to complex functions in humans and is key to advance our general understanding of central nervous function. A prime example of translational research is the study of cross-species mechanisms that underlie responding to learned threats, by employing Pavlovian fear conditioning protocols in rodents and humans. Hitherto, evidence for (and critique of) these cross-species comparisons in fear conditioning research was based on theoretical viewpoints. Here, we provide a perspective to substantiate these theoretical concepts with empirical considerations of cross-species methodology. This meta-research perspective is expected to foster cross-species comparability and reproducibility to ultimately facilitate successful transfer of results from basic science into clinical applications.

Fear generalisation refers to the spread of fear to novel situations. Recent evidence has suggested that over-generalisation of fear is a pathogenic marker of anxiety disorders. Given that trait anxiety has been widely accepted as a vulnerability factor for developing an anxiety disorder, the current thesis aimed to examine whether trait anxious individuals show over-generalisation of fear like their clinical counterparts. Using a continuous perceptual dimension, the first experiment (Chapter 5) identified various generalisation gradients, which aligned logically with participants’ reported rules. Trait anxious individuals showed over-generalisation of fear to the novel test stimuli, but this pattern was only observed among those who failed to identify a clear rule. The following experiments (Chapter 6) further examined fear generalisation to objects that were conceptually related to the threat cues. Trait anxious individuals did not show more fear to novel exemplars that had clear categorical membership and therefore clear threat value. However, they showed more fear to novel exemplars that could be classified in both threat and safe categories, that is, exemplars with ambiguous threat value. The results supported the notion of threat appraisal bias under ambiguous threat among trait anxious individuals. The experiments in Chapter 7 examined the effect of trait anxiety on the generalisation of extinction learning along a blue-green stimulus dimension. Participants who received a generalisation stimulus (GS) in extinction showed an increase in conditioned fear to the original conditioned stimulus (CS) or to another novel GS in test. Conversely, this pattern was not found in those who received standard extinction with the CS. No trait anxiety effect was observed in the generalisation of extinction learning, however, trait anxious individuals showed slower fear extinction to the CS, but not to a GS. In summary, the present work suggests that over-generalisation of fea

In chronic pain, pain-related fear seems to overgeneralize to safe stimuli, thus contributing to excessive fear and avoidance behavior. Evidence shows that pain-related fear can be acquired and generalized based on conceptual knowledge. Using a fear conditioning paradigm, we investigated whether this concept-based pain-related fear could also be extinguished. During acquisition, exemplars of one action category (conditioned stimuli; CSs) were followed by pain (CS+; e.g. opening boxes), whereas exemplars of another action category were not (CS-; e.g. closing boxes). Participants reported more pain-related fear and expectancy towards exemplars of the CS+ category compared with those of the CS- category. During generalization, fear and expectancy spread to novel exemplars (generalization stimuli; GSs) of the CS+ category (GS+), but not to those of the CS- category (GS-). During extinction, exemplars of both categories were presented in the absence of pain. At the end of extinction, participants no longer reported elevated fear or expectancy towards CS+ exemplars compared to CS- exemplars. These findings were not replicated in either the eye-blink startle, or skin conductance measures. This is the first study to demonstrate extinction of concept-based pain-related fear, thus providing evidence for the potential of extinction-based techniques in the treatment of conceptual pain-related fear.PERSPECTIVE: This study demonstrates the acquisition, generalization, and extinction of concept-based pain-related fear in healthy participants. These are the first results to show that concept-based pain-related fear can be extinguished, suggesting that conceptual relationships between fear-inducing stimuli may also be important to take into account in clinical practice.

This dissertation is a three-paper investigation of ways to improve treatment outcomes for anxiety disorders. Study 1 investigates whether training implicit approach or avoidance to feared stimuli augments or impedes fear extinction. We also investigate whether baseline explicit avoidance predicts extinction performance or future avoidance behavior. Extinction performance is used as a proxy for exposure therapy. Results revealed no effect of training implicit approach or avoidance on extinction performance nor future behavioral avoidance. Baseline explicit avoidance did not predict extinction performance, whereas it did predict future behavioral avoidance. Findings suggest that explicit avoidance may not affect fear extinction in an unambiguous fear-conditioning paradigm, but that it may affect future tendency to approach feared stimuli.Study 2 investigates behavioral avoidance as a moderator of treatment outcome for two behavioral therapies for social anxiety disorder. Individuals who were highly behaviorally avoidant on a public speaking task had better long-term treatment outcomes following cognitive behavioral therapy (CBT) than acceptance and commitment therapy. From a deficit correction model, individuals who are more behaviorally avoidant may benefit from a treatment that more systematically targets that avoidance. A version of this work has been published in the Journal of Behavior Therapy and Experimental Psychiatry (2017).Study 3 investigates interoceptive and in vivo avoidance as moderators of treatment outcome for two different CBTs for panic disorder. Individuals who displayed more in vivo avoidance at baseline had better outcome following CBT with interoceptive exposures than CBT with interoceptive and in vivo exposures. This suggests that avoidant individuals benefit more from a therapy that targets their primary interoceptive concerns as opposed to one that expands to in vivo avoidance.Taken together, these studies aim to improve treatment outcomes i

Background: Exposure is the gold standard treatment for phobic anxiety and is thought to represent the clinical application of extinction learning. Reward sensitivity might however also represent a predictive factor for exposure therapy outcome, as this therapy promotes positive experiences and involves positive comments by the therapist. We hypothesized that high reward sensitivity, as expressed by elevated reward expectancy and reward value, can be associated with better outcome to exposure therapy specifically.Methods: Forty-four participants with a specific phobia for spiders were included in the current study. Participants were randomly assigned to exposure therapy (n = 25) or progressive muscle relaxation (PMR) (n = 19). Treatment outcome was defined as pre- versus post-therapy phobia symptoms. Before treatment, functional brain responses and behavioral responses (i.e. reaction time and accuracy) during reward anticipation and consumption were assessed with the Monetary Incentive Delay task (MID). Behavioral and neural responses in regions of interest (i.e. nucleus accumbens, ventromedial prefrontal cortex and the ventral tegmental area) as well as across the whole-brain were subsequently regressed on treatment outcomes.Results: Exposure therapy was more effective in reducing phobia symptoms than PMR. Longer reaction times to reward cues and lower activation in the left posterior cingulate cortex during reward consumption were selectively associated with symptoms reductions following exposure therapy but not following PMR. Only within the exposure therapy group, greater symptom reduction was related to increased activation in the ventrolateral prefrontal cortex during reward anticipation, and decreased activation in the medial prefrontal cortex during reward consumption.Conclusion: Results indicate that individual differences in reward sensitivity can specifically predict exposure therapy outcome. Although activation in regions of inter

In chronic pain, pain-related fear seems to overgeneralize to safe stimuli, thus contributing to excessive fear and avoidance behavior. Evidence shows that pain-related fear can be acquired and generalized based on conceptual knowledge. Using a fear conditioning paradigm, we investigated whether this concept-based pain-related fear could also be extinguished. During acquisition, exemplars of one action category (conditioned stimuli; CSs) were followed by pain (CS+; e.g. opening boxes), whereas exemplars of another action category were not (CS-; e.g. closing boxes). Participants reported more pain-related fear and expectancy towards exemplars of the CS+ category compared with those of the CS- category. During generalization, fear and expectancy spread to novel exemplars (generalization stimuli; GSs) of the CS+ category (GS+), but not to those of the CS- category (GS-). During extinction, exemplars of both categories were presented in the absence of pain. At the end of extinction, participants no longer reported elevated fear or expectancy towards CS+ exemplars compared to CS- exemplars. These findings were not replicated in either the eye-blink startle, or skin conductance measures. This is the first study to demonstrate extinction of concept-based pain-related fear, thus providing evidence for the potential of extinction-based techniques in the treatment of conceptual pain-related fear.PERSPECTIVE: This study demonstrates the acquisition, generalization, and extinction of concept-based pain-related fear in healthy participants. These are the first results to show that concept-based pain-related fear can be extinguished, suggesting that conceptual relationships between fear-inducing stimuli may also be important to take into account in clinical practice.

Fear extinction is the well-known process of fear reduction through repeated re-exposure to a feared stimulus without the aversive outcome. The last two decades have witnessed a surge of interest in extinction learning. First, extinction learning is observed across species, and especially research on rodents has made great strides in characterising the physical substrate underlying extinction learning. Second, extinction learning is considered of great clinical significance since it constitutes a crucial component of exposure treatment. While effective in reducing fear responding in the short term, extinction learning can lose its grip, resulting in a return of fear (i.e., laboratory model for relapse of anxiety symptoms in patients). Optimization of extinction learning is, therefore, the subject of intense investigation. It is thought that the success of extinction learning is, at least partly, determined by the mismatch between what is expected and what actually happens (prediction error). However, while much of our knowledge about the neural circuitry of extinction learning and factors that contribute to successful extinction learning comes from animal models, translating these findings to humans has been challenging for a number of reasons. Here, we present an overview of what is known about the animal circuitry underlying extinction of fear, and the role of prediction error. In addition, we conducted a systematic literature search to evaluate the degree to which state-of-the-art neuroimaging methods have contributed to translating these findings to humans. Results show substantial overlap between networks in animals and humans at a macroscale, but current imaging techniques preclude comparisons at a smaller scale, especially in sub-cortical areas that are functionally heterogeneous. Moreover, human neuroimaging shows the involvement of numerous areas that are not typically studied in animals. Results obtained in research aimed to map the extinction circuit a

Although the presence of social-support figures (e.g., close friends and family members) is known to increase feelings of safety, reduce threat responses, and improve health, the route by which these effects occur is not well understood. One explanation is that social-support figures are members of a powerful category of safety signals—prepared safety stimuli. Here, we review research demonstrating that social-support figures act as prepared safety stimuli and explore the impact that these unique safety stimuli have on fear-learning processes. According to recent work, the presence of social-support figures both reduces fear acquisition and enhances fear extinction, ultimately decreasing perceptions of threat. These findings shed light on the route by which social support buffers against threat and illustrate the unique properties of prepared safety stimuli and how they might be used to improve mental and physical health outcomes.

Following treatment of fear-related disorders, return of fear remains a common occurrence. Currently, the presence of safety signals during treatment procedures is considered harmful, yet recent findings have demonstrated that certain safety signals (social-support figures) lead to enhanced fear extinction and thus might reduce return of fear. Here, we tested the effect of social-support-figure (vs. stranger) images on fear extinction outcomes. We found that, for conditional fear stimuli paired with social-support-figure images during extinction, return of fear was inhibited both immediately after extinction and during a fear reinstatement test 24 hr later; however, return of fear occurred for conditional stimuli paired with images of strangers. These findings suggest that social-support stimuli have unique safety-signaling properties that might enhance fear extinction and improve treatment outcomes for individuals with fear-related disorders.

Preclinical studies have demonstrated that conditioned fear extinction is impaired in females with low endogenous levels of the sex hormone estradiol, due to menstrual fluctuations or hormonal contraceptive use. As fear extinction is a laboratory model of exposure therapy for anxiety and trauma disorders, here we assessed the hypothesis that treatment outcomes may be diminished when exposure therapy occurs during periods of low estradiol. 90 women with spider phobia (60 cycling and 30 using hormonal contraceptives) underwent a one session exposure treatment for spider phobia, following which, serum estradiol levels were assessed. A median split in estradiol level was used to divide cycling participants into two groups; lower and higher estradiol. Behavioral avoidance and self-reported fear of spiders were measured pre-treatment, post-treatment, and at a 12 week follow-up assessment. Women using hormonal contraceptives exhibited a significantly slower rate of improvement across treatment, greater behavioral avoidance at post-treatment and follow-up, and fewer self initiated post-treatment exposure tasks, relative to both groups of cycling women, who did not differ. No group differences in self-reported fear were evident. Correlational analyses revealed that across the whole sample, lower estradiol levels were associated with slower rates of improvement across treatment, and greater self reported fear and behavioral avoidance at post-treatment, but not follow-up. These results provide the first evidence of an association between endogenous estradiol, hormonal contraceptive use, and exposure therapy outcomes in spider phobic women. Hormonal profile may partly account for variability in responsiveness to psychological treatments for anxiety and trauma disorders in women.

Development is a time of rapid change that sets the pathway to adult functioning across all aspects of physical and mental health. Developmental studies can therefore offer insight into the unique needs of individuals at different stages of normal development as well as the etiology of various disease states. The aim of this overview is to provide an introduction to the practical implementation of developmental studies in rats and mice, with an emphasis on the study of learned fear. We first discuss how developmental factors may influence experimental outcomes for any study. This is followed by a discussion of methodological issues to consider when conducting studies of developing rodents, highlighting examples from the literature on learned fear. Throughout, we offer some recommendations to guide researchers on best practice in developmental studies. © 2018 by John Wiley & Sons, Inc.

BACKGROUND AND OBJECTIVES: It is assumed that fear responses can be altered by changing the contingency between a conditioned stimulus (CS) and an unconditioned stimulus (US), or by devaluing the present mental representation of the US. The aim of the present study was to compare the efficacy of contingency- and devaluation-based intervention techniques on the diminishment in - and return of fear. We hypothesized that extinction (EXT, contingency-based) would outperform devaluation-based techniques regarding contingency measures, but that devaluation-based techniques would be most effective in reducing the mental representation of the US. Additionally, we expected that incorporations of the US during devaluation would result in less reinstatement of the US averseness.METHODS: Healthy participants received a fear conditioning paradigm followed by one of three interventions: extinction (EXT, contingency-based), imagery rescripting (ImRs, devaluation-based) or eye movement desensitization and reprocessing (EMDR, devaluation-based). A reinstatement procedure and test followed the next day.RESULTS: EXT was indeed most successful in diminishing contingency-based US expectancies and skin conductance responses (SCRs), but all interventions were equally successful in reducing the averseness of the mental US representation. After reinstatement EXT showed lowest expectancies and SCRs; no differences were observed between the conditions concerning the mental US representation.LIMITATIONS: A partial reinforcement schedule was used, resulting in a vast amount of contingency unaware participants. Additionally, a non-clinical sample was used, which may limit the generalizability to clinical populations.CONCLUSION: EXT is most effective in reducing conditioned fear responses.

Although the presence of social-support figures (e.g., close friends and family members) is known to increase feelings of safety, reduce threat responses, and improve health, the route by which these effects occur is not well understood. One explanation is that social-support figures are members of a powerful category of safety signals—prepared safety stimuli. Here, we review research demonstrating that social-support figures act as prepared safety stimuli and explore the impact that these unique safety stimuli have on fear-learning processes. According to recent work, the presence of social-support figures both reduces fear acquisition and enhances fear extinction, ultimately decreasing perceptions of threat. These findings shed light on the route by which social support buffers against threat and illustrate the unique properties of prepared safety stimuli and how they might be used to improve mental and physical health outcomes.

Following treatment of fear-related disorders, return of fear remains a common occurrence. Currently, the presence of safety signals during treatment procedures is considered harmful, yet recent findings have demonstrated that certain safety signals (social-support figures) lead to enhanced fear extinction and thus might reduce return of fear. Here, we tested the effect of social-support-figure (vs. stranger) images on fear extinction outcomes. We found that, for conditional fear stimuli paired with social-support-figure images during extinction, return of fear was inhibited both immediately after extinction and during a fear reinstatement test 24 hr later; however, return of fear occurred for conditional stimuli paired with images of strangers. These findings suggest that social-support stimuli have unique safety-signaling properties that might enhance fear extinction and improve treatment outcomes for individuals with fear-related disorders.

PTSD has been associated consistently with abnormalities in fear acquisition and extinction learning and retention. Fear acquisition refers to learning to discriminate between threat and safety cues. Extinction learning reflects the formation of a new inhibitory-memory that competes with a previously learned threat-related memory. Adjudicating the competition between threat memory and the new inhibitory memory during extinction may rely, in part, on cognitive processes such as working memory (WM). Despite significant shared neural circuits and signaling pathways the relationship between WM, fear acquisition, and extinction is poorly understood. Here, we analyzed data from a large sample of healthy Marines who underwent an assessment battery including tests of fear acquisition, extinction learning, and WM (N-back). Fear potentiated startle (FPS), fear expectancy ratings, and self-reported anxiety served as the primary dependent variables. High WM ability (N = 192) was associated with greater CS + fear inhibition during the late block of extinction and greater US expectancy change during extinction learning compared to individuals with low WM ability (N = 204). WM ability was not associated with magnitude of fear conditioning/expression. Attention ability was unrelated to fear acquisition or extinction supporting specificity of WM associations with extinction. These results support the conclusion that individual differences in WM may contribute to regulating fear responses.

BackgroundRisk for posttraumatic stress disorder (PTSD) is thought to be mediated by gene × environment (G × E) interactions that affect core cognitive processes such as fear learning. The catechol-O-methyltransferase (COMT) val158met polymorphism has been associated with risk for PTSD and impaired fear inhibition. We used a large, relatively homogenous population to (1) replicate previous findings of poor fear inhibition in COMT Met/Met carriers with PTSD; (2) determine if COMT association with fear inhibition is moderated by childhood trauma (CT), an environmental risk factor for PTSD; and (3) determine if COMT is associated with altered fear processes after recent exposure to combat trauma.MethodsMale Marines and Navy Corpsmen of European-American ancestry were assessed prior to (n = 714) and 4-6 months after deployment to Afghanistan (n = 452). Acquisition and extinction of fear-potentiated startle, childhood and combat trauma history, and PTSD diagnosis were assessed at both time points.ResultsBefore deployment, Met/Met genotype was associated with fear inhibition deficits in participants with current PTSD; however, this association was dependent on CT exposure. After deployment, combat trauma was associated with a modest reduction in fear extinction in Met/Met compared with Val/Val carriers. There were no associations of COMT genotype with fear extinction within healthy and non-traumatized individuals.ConclusionsThese findings support the hypothesis that G × E interactions underlie associations of COMT val158met with fear inhibition deficits. These studies confirm that Met/Met carriers with PTSD have poor fear inhibition, and support further research in understanding how this polymorphism might impact response to extinction-based therapies.

BACKGROUND AND OBJECTIVES: It is assumed that fear responses can be altered by changing the contingency between a conditioned stimulus (CS) and an unconditioned stimulus (US), or by devaluing the present mental representation of the US. The aim of the present study was to compare the efficacy of contingency- and devaluation-based intervention techniques on the diminishment in - and return of fear. We hypothesized that extinction (EXT, contingency-based) would outperform devaluation-based techniques regarding contingency measures, but that devaluation-based techniques would be most effective in reducing the mental representation of the US. Additionally, we expected that incorporations of the US during devaluation would result in less reinstatement of the US averseness.METHODS: Healthy participants received a fear conditioning paradigm followed by one of three interventions: extinction (EXT, contingency-based), imagery rescripting (ImRs, devaluation-based) or eye movement desensitization and reprocessing (EMDR, devaluation-based). A reinstatement procedure and test followed the next day.RESULTS: EXT was indeed most successful in diminishing contingency-based US expectancies and skin conductance responses (SCRs), but all interventions were equally successful in reducing the averseness of the mental US representation. After reinstatement EXT showed lowest expectancies and SCRs; no differences were observed between the conditions concerning the mental US representation.LIMITATIONS: A partial reinforcement schedule was used, resulting in a vast amount of contingency unaware participants. Additionally, a non-clinical sample was used, which may limit the generalizability to clinical populations.CONCLUSION: EXT is most effective in reducing conditioned fear responses.

Explicit instructions regarding stimulus-threat associations increase acquisition and extinction of fear in healthy participants. The current study aimed to investigate the effect of contingency instructions on fear acquisition and extinction in patients with anxiety disorders. Patients with various anxiety disorders (N = 104) and healthy comparison participants (N = 93) participated in a differential fear conditioning task (within-subjects design). Approximately halfway through the acquisition phase, participants were instructed about the stimulus-threat association, and approximately halfway through the extinction phase, participants were informed that the unconditioned stimulus (US) would no longer be administered. Outcome measures were: fear-potentiated startle, skin conductance, fearfulness ratings, and US expectancy ratings. Patients demonstrated overall increased physiological and subjective fear responses during acquisition and extinction phases, relative to the comparison group. There were no major differences in fear acquisition and extinction between patients with different anxiety disorders. During acquisition, instructions led to increased discrimination of fear responses between a danger cue (conditioned stimulus [CS]+) and safety cue (CS-) in both patients and comparison participants. Moreover, instructions strengthened extinction of fear responses in the patient and comparison group. Patients and healthy comparison participants are better able to discriminate between danger and safety cues when they have been explicitly informed about cues that announce a threat situation. Considering the analogies between fear extinction procedures and exposure therapy, this suggests that specific instructions on stimulus-threat associations during exposure therapy might improve short-term treatment efficacy. The question remains for future studies whether instructions have a positive effect on extinction learning in the longer term. (PsycINFO Database Record

Memories are not set forever, but can be altered following reactivation, which renders memories malleable, before they are again stabilized through reconsolidation. Fear memories can be attenuated by using extinction during the malleable period. The present study adopts a novel form of extinction, using verbal instructions, in order to examine whether fear memory reconsolidation can be affected by an imaginal exposure. The extinction using verbal instructions, called imaginal extinction, consists of a recorded voice encouraging participants to imagine the scene in which fear was acquired, and to envision the stimuli before their inner eye. The voice signals stimuli appearance, and identical to standard (in vivo) extinction, participants discover that the conditioned stimulus no longer is followed by unconditioned stimulus (UCS). In this way, imaginal extinction translates clinically used imaginal exposure into the standard experimental fear conditioning paradigm. Fear was acquired by pairing pictorial stimuli with an electric shock UCS. Then, both standard and imaginal extinction were given following fear memory reactivation, either after 10 min, within the reconsolidation interval, or after 6 h, outside of the reconsolidation interval. In vivo and imaginal extinction produced comparable reductions in conditioned responses during extinction and importantly, both disrupted reconsolidation of conditioned fear and abolished stimulus discrimination between reinforced and non-reinforced cues. Thus, disrupted reconsolidation of fear conditioning can be achieved without in vivo stimulus presentation, through purely cognitive means, suggesting possible therapeutic applications.

In auditory fear conditioning, experimental subjects learn to associate an auditory conditioned stimulus (CS) with an aversive unconditioned stimulus. With sufficient training, animals fear conditioned to an auditory CS show fear response to the CS, but not to irrelevant auditory stimuli. Although long-term potentiation (LTP) in the lateral amygdala (LA) plays an essential role in auditory fear conditioning, it is unknown whether LTP is induced selectively in the neural pathways conveying specific CS information to the LA in discriminative fear learning. Here, we show that postsynaptically expressed LTP is induced selectively in the CS-specific auditory pathways to the LA in a mouse model of auditory discriminative fear conditioning. Moreover, optogenetically induced depotentiation of the CS-specific auditory pathways to the LA suppressed conditioned fear responses to the CS. Our results suggest that input-specific LTP in the LA contributes to fear memory specificity, enabling adaptive fear responses only to the relevant sensory cue. VIDEO ABSTRACT.