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The present eye-tracking study investigates whether individuals with different levels of contamination fear are more likely to focus their attention on disgusting stimuli to explore them or to pull their attention away to avoid them. Ninety-two nonclinical participants with varying degrees of contamination fear performed a dot probe task. Eye-tracking methodology was employed to record gaze patterns during the task. In each trial participants looked at two pictures (disgust-neutral, fear-neutral, or neutral-neutral). Participants were further asked about the contents of the picture and the confidence of their answer. The results show that reaction times were slower and fixations were longer and more frequent for disgust targets compared with fear and neutral targets, which was further amplified in individuals with high contamination fear. However, image details of disgusting pictures were remembered less correctly than details of fearful pictures. These findings confirm the idea that attention on disgusting stimuli is maintained. Further, the findings indicate that disgust is processed more superficially and might also be related to disgust-associated uncertainty and ambiguity. The results may help to understand the difficult-to-change nature of disgust, which could be relevant to habituation and extinction processes in exposure therapy. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Attention prioritizes stimuli previously associated with reward or punishment. The present study examined whether this attentional bias, widely considered to be involuntary and automatic, could be suppressed with sufficient motivation. Participants performed visual search for a shape-defined target. One color-singleton distractor predicted the possibility of receiving a reward and another an electric shock, with each outcome occurring infrequently. Participants were informed that the likelihood to earn a reward or avert punishment depended on fast and accurate performance, thus providing strong motivation to resist distraction by reward- and shock-related stimuli. Results revealed a reduction in the magnitude of attentional capture by reward- and threat-associated distractors, relative to neutral distractors, that persisted into extinction. In a second experiment, we replicated the suppression of value-modulated attentional capture in the absence of the shock condition, thus confirming that the suppression did not result from the presence of threat. Finally, in a third experiment, we replicated the typical pattern of attentional capture by reward cues using a more conventional procedure in which the motivation to suppress valent stimuli was low (the likelihood to be rewarded was high and not contingent on fast performance). This study demonstrates that signals for reward and threat can be actively suppressed with sufficient motivation. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Behavior change interventions that incentivize desired behavior are highly effective for improving personal health, but difficult to maintain long term. Relapse is common and examining the mechanisms that contribute to relapse in experimental settings can identify processes relevant to substance abuse treatment. We developed a laboratory task that parallels a recent operant model of relapse after incentivized choice reported in the rodent laboratory. In two experiments, undergraduate participants first learned to make an operant response (keyboard button; R1) to earn a reinforcer consisting of an image of a preferred snack food (O1). In a second phase (Phase 2), R1 was still reinforced, but a new response (R2) was introduced and reinforced with a different reinforcer (a coin; O2). In a test phase, contingent incentives for R2 were removed (extinction) and relapse of R1 was assessed. Experiment 1 found that the O2 contingency suppressed R1 during Phase 2, and R1 relapsed rapidly in the test. Neither effect was consistently related to O2 value. Experiment 2 examined whether noncontingent presentations of O1 or O2 during the test could weaken relapse. Here, we found that noncontingent reinforcers did little to reduce or slow the increase in R1 responding. The present experiments highlight a laboratory approach to studying variables that may influence relapse after incentivized treatment. We identify and discuss areas for development to address differences between the present results and prior observations from animal and clinical studies. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Background While effective, exposure therapy can be distressing, which creates problems with treatment acceptance. Can exposure be effectively delivered unconsciously-and thus without causing phobic people to experience distress? No study has tested this hypothesis in a sufficiently rigorous experiment that selected between mechanisms for reducing fear unconsciously. Methods We conducted a psychophysiological experiment of an unconscious exposure intervention to discern its mechanism of therapeutic action. We identified 98 highly spider-phobic participants with a validated fear questionnaire and a Behavioral Avoidance Test in which they gradually approached and exhibited impairment of a live tarantula, which was indicative of a DSM-5 diagnosis of specific phobia. These participants were randomized to viewing unconscious exposure to spiders, visible exposure to spiders, or unconscious exposure to flowers (control). In a novel psychophysiological design, concurrent changes in sympathetic arousal and subjective fear were monitored throughout exposure. Shortly thereafter, phobic participants approached the tarantula again in order to measure exposure-induced changes in real-life avoidance behavior and experienced fear. Results Unconscious exposure did not induce concurrent changes in sympathetic arousal or subjective fear, and subsequently reduced fear of the tarantula. Visible exposure to the same phobic stimuli, by contrast, induced significant arousal and fear, but did not affect fear of the tarantula. Levels of arousal during exposure moderated effects on fear of the tarantula: lower arousal during unconscious exposure, but not during conscious exposure, predicted greater fear reduction. Conclusions Unconscious exposure reduces fear by generating new implicit learning of nonaversive, stimulus-response associations that facilitate fear extinction in phobic persons.

Objective The impact of disrupted sleep on the effectiveness of prolonged exposure (PE) therapy for posttraumatic stress disorder (PTSD) is not well understood. Researchers have suggested that comorbid sleep disorders contribute to nonresponse by impairing therapeutic mechanisms such as emotional processing of trauma memories and extinction in cued fear conditioning. Several studies indicate daytime sleepiness, insomnia, and nightmares are correlated with PTSD symptom severity. However, a recent randomized controlled trial found that these sleep disorder symptoms did not affect PTSD symptom change over the course of massed PE (i.e., daily sessions across 2 weeks). Method The current study used an ecologically valid clinical sample to examine whether daytime sleepiness, insomnia, and nightmares interfere with the slope of symptom change in massed PE. Results Results indicate that all 3 sleep disorder symptoms correlate with PTSD symptom severity on the first day of treatment but were not associated with symptom change. Conclusions These findings are consistent with the expectation that the daily structure of massed PE may enhance treatment engagement in patients who are typically drowsy or not well-rested, thus facilitating fear extinction. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The endocannabinoid system is known to be involved in mechanisms relevant to PTSD aetiology and maintenance, though this understanding is mostly based on animal models of the disorder. Here we review how human paradigms can successfully translate animal findings to human subjects, with the view that substantially increased insight into the effect of endocannabinoid signalling on stress responding, emotional and intrusive memories, and fear extinction can be gained using modern paradigms and methods for assessing the state of the endocannabinoid system in PTSD.

Most of our knowledge about human emotional memory comes from animal research. Based on this work, the amygdala is often labeled the brain's “fear center”, but it is unclear to what degree neural circuitries underlying fear and extinction learning are conserved across species. Neuroimaging studies in humans yield conflicting findings, with many studies failing to show amygdala activation in response to learned threat. Such null findings are often treated as resulting from MRI-specific problems related to measuring deep brain structures. Here we test this assumption in a mega-analysis of three studies on fear acquisition (n= 98; 68 female) and extinction learning (n= 79; 53 female). The conditioning procedure involved the presentation of two pictures of faces and two pictures of houses: one of each pair was followed by an electric shock [a conditioned stimulus (CS+)], the other one was never followed by a shock (CS–), and participants were instructed to learn these contingencies. Results revealed widespread responses to the CS+compared with the CS–in the fear network, including anterior insula, midcingulate cortex, thalamus, and bed nucleus of the stria terminalis, but not the amygdala, which actually responded stronger to the CS–. Results were independent of spatial smoothing, and of individual differences in trait anxiety and conditioned pupil responses. In contrast, robust amygdala activation distinguished faces from houses, refuting the idea that a poor signal could account for the absence of effects. Moving forward, we suggest that, apart from imaging larger samples at higher resolution, alternative statistical approaches may be used to identify cross-species similarities in fear and extinction learning.SIGNIFICANCE STATEMENTThe science of emotional memory provides the foundation of numerous theories on psychopathology, including stress and anxiety disorders. This field relies heavily on animal research, which suggests a central role of the amygdala in fear learning and memory. However, this finding is not strongly corroborated by neuroimaging evidence in humans, and null findings are too easily explained away by methodological limitations inherent to imaging deep brain structures. In a large nonclinical sample, we find widespread BOLD activation in response to learned fear, but not in the amygdala. A poor signal could not account for the absence of effects. While these findings do not disprove the involvement of the amygdala in human fear learning, they challenge its typical portrayals and illustrate the complexities of translational science.

Schizotypy can be defined as a combination of traits qualitatively similar to those found in schizophrenia, but milder in their expression, that can be found in clinical and non-clinical populations. In this research, we explore, to our knowledge, for the first time, whether schizotypal personality traits may affect the acquisition of conditioned fear by social means only. Apart from being an essential capacity to ensure learning in safe environments, social fear learning shares important characteristics with direct fear acquisition, which also makes it a great candidate for developing successful extinction procedures. Undergraduate students (n = 72) performed a task of social fear learning. In this task, participants watched a video of a person that simulated to receive electric shocks (unconditioned stimulus; US) paired with a coloured square (conditioned stimulus plus; CS+), while another coloured square was never paired (conditioned stimulus minus; CS−) with the shock. After that, they were presented with a similar sequence of coloured screens. Their Skin Conductance Responses (SCRs) were registered during the whole process. Once they finished, they completed the Schizotypal Personality Questionnaire (SPQ). Our results revealed that participants with a low score in the Cognitive-Perceptual factor of the SPQ exhibited higher SCRs when they saw the US than when they saw the CS− (all ps ps > 0.05), a pattern that has been similarly found in schizophrenia. During the final trials of the test phase, participants with the highest scores in the Disorganized factor were the only ones that maintained a higher SCR towards the CS+ than towards the CS− (p = 0.006), which could be associated with an impairment in their extinction processes.

Previous studies have shown that activating the attachment system attenuates fear learning. This study aimed to explore whether attachment priming can also impact on fear extinction processes, which underpin the management of anxiety disorders. In this study, 81 participants underwent a standard fear conditioning and extinction protocol on day 1 and returned 24 h later for an extinction recall and reinstatement test. Half the participants were primed to imagine their closest attachment figure prior to undergoing extinction training, while the other half were instructed to imagine a positive situation. Fear-potentiated startle and subjective expectancies of shock were measured as the primary indicators of fear. Attachment priming led to less relapse during the reinstatement test at the physiological but not subjective levels. These findings have translational potential to imply that activating awareness of attachment figures might augment long-term safety memories acquired in existing treatments to reduce relapse of fear.

Background Emerging human studies demonstrate that theta oscillations in the dorsal anterior cingulate cortex are enhanced during fear recall (enhanced fear expression) and reduced during successful extinction recall (reduced fear expression). Although evidence suggests sex differences in fear recall and extinction recall, there are currently no human studies examining the oscillatory foundations of these memory processes separately in men and women. Methods Because previous studies suggest that estradiol partially mediates these sex differences, we examined 20 men (low estradiol and low progesterone), 20 women using oral contraceptives (low estradiol and low progesterone), and 20 free-cycling women during midcycle (high estradiol and low progesterone). We used a fear-conditioning procedure, allowing us to separately assess fear recall and extinction recall 24 hours after fear and extinction learning. Skin conductance responses and electroencephalography were recorded during fear recall and extinction recall, and prefrontal oscillations were source localized. Results We found elevated fear expression during fear recall and impaired extinction recall, as indicated by increased peripheral arousal (skin conductance responses) and fronto-central theta oscillations, source localized in the dorsal anterior cingulate cortex and dorsomedial prefrontal cortex. Importantly, peripheral arousal and dorsal anterior cingulate cortex theta oscillations were stronger in men and women on oral contraceptives than in women from the midcycle group. Conclusions Our data show that neural oscillatory and peripheral correlates of heightened fear expression during fear recall and (impaired) extinction recall do not simply differ between sexes but depend on hormonal fluctuations within women.

Anxiety and stress-related disorders are more prevalent in women and associated with negative emotional memory consolidation as well as impaired fear extinction recall. Recent research has identified a role of gonadal steroid hormones in influencing emotional memories and fear extinction, however most individual studies have small samples and employed various protocols. A systematic review and meta-analysis were conducted on studies that examined sex hormones (estrogen, progesterone, testosterone, allopregnanolone, dehydroepiandrosterone) on four aspects of memory, namely, intentional recall (k = 13), recognition memory (k = 7), intrusive memories (k = 9), and extinction recall (k = 11). The meta-analysis on natural cycling women revealed that progesterone level was positively associated with negative recall and negative intrusive memories, and this effect on intentional recall was enhanced under stress induction. Estradiol level was positively associated with extinction recall. This study reveals an important role of progesterone and estradiol in influencing emotional memory consolidation. It highlights the need to control for these hormonal effects and examine progesterone and estradiol concurrently across all menstrual phases in future emotional memory paradigms.

Previous research in extinction indicates no difference in US expectancies for aversive and non-aversive unconditioned stimuli (USs). In this study, we bridged these topics by examining how concurrent perceptual and conceptual cues influence conditioned generalisation of generalised anxiety disorder (GAD) patients by using non-aversive USs. The study included two consecutive phases: acquisition and generalisation. In the acquisition phase, we used blue and purple images as the perceptually conditioned stimuli, images of animals and household items as the conceptually conditioned stimuli, and non-aversive images as unconditioned stimuli (US). In the generalisation phase, we used images containing both conceptual and perceptual cues (e.g. blue animals) as the generalisation stimuli. Participants rated the US expectancy for all images. We found that compared with the control group, the patients exhibited generalisation in response to stimuli that included conditional conceptual cues. These results reveal novel evidence of generalisation in GAD and may have implications for considering the concept-based information in extinction treatment.

Posttraumatic stress disorder can be viewed as a disorder of fear dysregulation. An abundance of research suggests that the prefrontal cortex is central to fear processing—that is, how fears are acquired and strategies to regulate or diminish fear responses. The current review covers foundational research on threat or fear acquisition and extinction in nonhuman animals, healthy humans, and patients with posttraumatic stress disorder, through the lens of the involvement of the prefrontal cortex in these processes. Research harnessing advances in technology to further probe the role of the prefrontal cortex in these processes, such as the use of optogenetics in rodents and brain stimulation in humans, will be highlighted, as well other fear regulation approaches that are relevant to the treatment of posttraumatic stress disorder and involve the prefrontal cortex, namely cognitive regulation and avoidance/active coping. Despite the large body of translational research, many questions remain unanswered and posttraumatic stress disorder remains difficult to treat. We conclude by outlining future research directions related to the role of the prefrontal cortex in fear processing and implications for the treatment of posttraumatic stress disorder.

Fear extinction is not permanent but is instead more vulnerable than the original fear memory, as traditionally shown by the return of fear phenomena. Because of this, techniques to mitigate the return of fear are needed in the clinical treatment of related psychological conditions. One promising strategy is the occasional reinforced extinction treatment, introducing a gradual and sparse number of conditioned stimulus–unconditioned stimulus (CS-US) pairings within the extinction treatment. We present the results of three experiments in which we used a threat conditioning procedure in humans. Our main aim was to evaluate whether occasional reinforced extinction could reduce two different forms of relapse: spontaneous recovery (Experiments 1 and 2) and reinstatement (Experiment 3). Contrary to our predictions and previous literature, the results indicate that an occasional reinforcement treatment did not mitigate relapse compared with standard extinction. From a theoretical standpoint, these results are more consistent with the idea that extinction entails the acquisition of new knowledge than with the idea that there are conditions in which extinction leads to a weakening of the original fear memory. These findings also question the generality of the potential benefits of using occasional reinforced extinction in clinical settings.

Fluctuations of endogenous estrogen modulates fear extinction, but the influence of exogenous estradiol is less studied. Moreover, little focus has been placed on the impact of estradiol on broad network connectivity beyond the fear extinction circuit. Here, we examined the effect of acute exogenous estradiol administration on fear extinction-induced brain activation, whole-brain functional connectivity (FC) during the fear extinction task and post-extinction resting-state. Ninety healthy women (57 using oral contraceptives [OC], 33 naturally cycling [NC]) were fear conditioned on day 1. They ingested an estradiol or placebo pill prior to extinction learning on day 2 (double-blind design). Extinction memory was assessed on day 3. Task-based functional MRI data were ascertained on days 2 and 3 and resting-state data were collected post-extinction on day 2 and pre-recall on day 3. Estradiol administration significantly modulated the neural signature associated with fear extinction learning and memory, consistent with prior studies. Importantly, estradiol administration induced significant changes in FC within multiple networks, including the default mode and somatomotor networks during extinction learning, post-extinction, and during extinction memory recall. Exploratory analyses revealed that estradiol impacted ventromedial prefrontal cortex (vmPFC) activation and FC differently in the NC and OC women. The data implicate a more diffused and significant effect of acute estradiol administration on multiple networks. Such an effect might be beneficial to modulating attention and conscious processes in addition to engaging neural processes associated with emotional learning and memory consolidation.

Background Neurocircuitry models of posttraumatic stress disorder (PTSD) suggest specific alterations in brain structures linked with fear conditioning and extinction. Most models assume a unitary pattern of neurocircuitry dysfunction in PTSD and little attention has focused on defining unique profiles of neurocircuitry engagement (i.e., biotypes), despite known clinical heterogeneity in PTSD. Here, we aim to address this gap using a data-driven approach to characterize unique neurocircuitry profiles among women with PTSD. Methods Seventy-six women with PTSD related to assaultive violence exposure competed a task during fMRI that alternated between fear conditioning, where a geometric shape predicted the occurrence of an electric shock, and fear extinction, where the geometric shape no longer predicted electric shock. A multivariate clustering analysis was applied to neurocircuitry patterns constrained within an a priori mask of structures linked with emotion processing. Resulting biotypes were compared on clinical measures of neurocognition, trauma exposure, general mental health symptoms, and PTSD symptoms and on psychophysiological responding during the task. Results The clustering analysis identified three biotypes (BT), differentiated by patterns of engagement within salience, default mode, and visual processing networks. BT1 was characterized by higher working memory, fewer general mental health symptoms, and low childhood sexual abuse, and lower PTSD symptom severity. BT2 was characterized by lower verbal IQ but better extinction learning as defined by psychophysiology and threat expectancy. BT3 was characterized by low childhood sexual abuse, anxious arousal, and re-experiencing symptoms. Conclusion: This data demonstrates unique profiles of neurocircuitry engagement in PTSD, each associated with different clinical characteristics, and suggests further research defining distinct biotypes of PTSD. Clinicaltrials.gov , https://clinicaltrials.gov/ct2/home , NCT02560389.

Recovery-from-extinction effects in which a conditioned response returns after extinction have been shown in mammals, birds and fish. Thus, these effects appear to be conserved among vertebrates; however, they have yet to be investigated in amphibians. Using prey catching conditioning in the fire-bellied toad (Bombina orientalis), we tested if renewal and reinstatement occurred after extinction when subjects were respectively re-exposed to the context or reinforcer used during conditioning. For renewal, a different context was used during extinction and thus renewal tests assessed if external contextual cues associated during conditioning stimulated prey catching performance. For reinstatement, the reinforcer withheld during extinction was simply delivered again prior to a test assessing if internal cues associated with recent prey consumption stimulated prey catching performance. Conditioning followed a fixed ratio 5 schedule of reinforcement, where five attempts to capture a cricket stimulus displayed on a computer screen were reinforced by delivery of a single live cricket. Performance was measured as the time to reach five prey catching attempts. A significant improvement in prey catching performance during conditioning followed by deterioration with extinction was seen in the experiments. Upon return to the context used for conditioning after extinction, toads showed a renewal effect whereby they displayed faster performance during testing compared to the end of extinction. Conversely, toads showed no reinstatement effect because pre-feeding of a cricket did not influence performance during the test that followed extinction. Reinstatement could have been lost in amphibian phylogeny due to secondary simplification of the nervous system.

Background A nonsynonymous single nucleotide polymorphism in the neuropeptide S receptor 1 (NPSR1) gene (rs324981) results in isoleucine-to-asparagine substitution at amino acid 107. In humans, the ancestral variant (NPSR1 I107) is associated with increased anxiety sensitivity and risk of panic disorder, while the human-specific variant (NPSR1 N107) is considered protective against excessive anxiety. In rodents, neurobiological constituents of the NPS system have been analyzed in detail and their anxiolytic-like effects have been endorsed. However, their implication for anxiety and related disorders in humans remains unclear, as rodents carry only the ancestral NPSR1 I107 variant. Methods We hypothesized that phenotypic correlates of NPSR1 variants manifest in fear-related circuits in the amygdala. We used CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9)-mediated gene editing to generate a “humanized” mouse strain, in which individuals express either NPSR1 I107 or NPSR1 N107. Results Stimulation of NPSR1 evoked excitatory responses in principal neurons of the anterior basal amygdala with significant differences in magnitude between genotypes, resulting in synaptic disinhibition of putative extinction neurons in the posterior basal amygdala in mice expressing the human-specific hypofunctional N107 but not the ancestral I107 variant. N107 mice displayed improved extinction of conditioned fear, which was phenocopied after pharmacological antagonism of NPSR1 in the anterior basal amygdala of I107 mice. Differences in fear extinction between male and female mice were related to an interaction of Npsr1 genotype and salience of fear training. Conclusions The NPS system regulates extinction circuits in the amygdala depending on the Npsr1 genotype, contributing to sex-specific differences in fear extinction and high anxiety sensitivity of individuals bearing the ancestral NPSR1 I107 variant.

Neuroimaging has revealed robust interactions between the prefrontal cortex and the hippocampus when people stop memory retrieval. Efforts to stop retrieval can arise when people encounter reminders to unpleasant thoughts they prefer not to think about. Retrieval stopping suppresses hippocampal and amygdala activity, especially when cues elicit aversive memory intrusions, via a broad inhibitory control capacity enabling prepotent response suppression. Repeated retrieval stopping reduces intrusions of unpleasant memories and diminishes their affective tone, outcomes resembling those achieved by the extinction of conditioned emotional responses. Despite this resemblance, the role of inhibitory fronto-hippocampal interactions and retrieval stopping broadly in extinction has received little attention. Here we integrate human and animal research on extinction and retrieval stopping. We argue that reconceptualising extinction to integrate mnemonic inhibitory control with learning would yield a greater understanding of extinction’s relevance to mental health. We hypothesize that fear extinction spontaneously engages retrieval stopping across species, and that controlled suppression of hippocampal and amygdala activity by the prefrontal cortex reduces fearful thoughts. Moreover, we argue that retrieval stopping recruits extinction circuitry to achieve affect regulation, linking extinction to how humans cope with intrusive thoughts. We discuss novel hypotheses derived from this theoretical synthesis.

Relapse to drug use during abstinence is a defining feature of addiction. During the last several decades, this clinical scenario has been studied at the preclinical level using classic relapse/reinstatement models in which drug seeking is assessed after experimenter-imposed home-cage forced abstinence or extinction of the drug-reinforced responding in the self-administration chambers. To date, however, results from studies using rat relapse/reinstatement models have yet to result in Food and Drug Administration-approved medications for relapse prevention. The reasons for this state of affairs are complex and multifaceted, but one potential reason is that, in humans, abstinence is often self-imposed or voluntary and occurs either because the negative consequences of drug use outweigh the drug's rewarding effects or because of the availability of nondrug alternative rewards that are chosen over the drug. Based on these considerations, we and others have recently developed rat models of relapse after voluntary abstinence, achieved either by introducing adverse consequences to drug taking (punishment) or seeking (electric barrier) or by providing mutually exclusive choices between the self-administered drug and nondrug rewards (palatable food or social interaction). In this review, we provide an overview of these translationally relevant relapse models and discuss recent neuropharmacological findings from studies using these models. We also discuss sex as a biological variable, future directions, and clinical implications of results from relapse studies using voluntary abstinence models. Our main conclusion is that the neuropharmacological mechanisms controlling relapse to drug seeking after voluntary abstinence are often different from the mechanisms controlling relapse after home-cage forced abstinence or reinstatement after extinction. SIGNIFICANCE STATEMENT: This review describes recently developed rat models of relapse after voluntary abstinence, achieved either by introducing adverse consequences to drug taking or seeking or by providing mutually exclusive choices between the self-administered drug and nondrug rewards. This review discusses recent neuropharmacological findings from studies using these models and discusses future directions and clinical implications.

Nocebo hyperalgesia is a pervasive problem that significantly adds to the burden of pain. Conditioning is a key mechanism of nocebo hyperalgesia and recent evidence indicates that, once established, nocebo hyperalgesia is resistant to extinction. This means that preventive strategies are critical. We therefore tested whether two novel strategies – overshadowing (Experiment 1) and pre-exposure (Experiment 2) – could inhibit conditioned nocebo hyperalgesia. Overshadowing involves introducing additional cues during conditioning that should compete with and overshadow learning about the target nocebo cue. Pre-exposure involves pre-exposing the target nocebo cue in the absence of pain, which should diminish its ability to become associated with pain later. In both studies, healthy volunteers (N = 141) received exposure to a series of electrocutaneous pain stimuli with and without a sham electrode ‘activated’, which they were led to believe was a genuine hyperalgesic treatment. Nocebo conditioning was achieved by pairing sham activation with high pain prior to testing at equivalent pain intensity. In both studies, standard nocebo conditioning led to clear nocebo hyperalgesia relative to natural history controls. In Experiment 1, there was no evidence that overshadowing attenuated nocebo hyperalgesia. Importantly, however, Experiment 2 found that pre-exposure successfully attenuated nocebo hyperalgesia with post hoc analysis suggesting that this effect was dose-dependent. These findings provide novel evidence that pre-exposure, but not overshadowing, could be a cheap and effective way for mitigating the substantial harm caused by conditioned nocebo hyperalgesia in clinical settings. Perspective Nocebo hyperalgesia causes substantial patient burden with few preventive options available. Our study found novel evidence that pre-exposing treatment cues without pain, but not overshadowing them with other cues, has the capacity to inhibit conditioned nocebo hyperalgesia. Pre-exposure may therefore be an effective preventive strategy to combat nocebo hyperalgesia.

Anorexia nervosa is characterized by anxiety-driven behaviors, such as food avoidance and distressing persistent thoughts about weight gain and body image. The present study used a classical fear conditioning procedure to test the processes of fear acquisition and generalization, extinction, and renewal in patients with anorexia nervosa and healthy controls. An app-based fear conditioning procedure was administered remotely to 64 patients and 60 healthy controls, over two sessions. A human female scream served as the unconditioned stimulus (US) and two neutral shapes were used as either the paired conditioned stimulus (danger cue; CS+) or the unpaired conditioned stimulus (safe cue; CS-). Patients with anorexia nervosa reported greater threat expectancy in response to the danger cue during the extinction and renewal phases and overall higher levels of negative affect throughout the task, compared with controls. Future research is warranted to replicate these findings and highlight the role that anxiety plays in explaining fear conditioning responses in patients with anorexia nervosa. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

BACKGROUND: Based on findings from adults with Obsessive-Compulsive Disorder (OCD), this study examined alterations in resting-state functional connectivity (rs-fc) between the basolateral amygdala (BLA) and the ventromedial prefrontal cortex (vmPFC) in children and adolescents with OCD. We also assessed whether such BLA-vmPFC connectivity changed with or predicted response to Exposure and Response Prevention (E/RP), the first-line treatment for pediatric OCD, given the involvement of these regions in fear processing, regulation, and extinction learning—a probable mechanism of action of E/RP. METHODS: Resting state functional magnetic resonance imaging scans were acquired from 25 unmedicated, treatment-naïve pediatric patients with OCD (12.8 ± 2.9 years) and 23 age- and sex-matched healthy controls (HCs; 11.0 ± 3.3 years). Patients completed a 12–16-week E/RP intervention for OCD. Participants were rescanned after the 12–16-week period. ANCOVAs tested group differences in baseline rs-fc. Cross-lagged panel models examined relationships between BLA-vmPFC rs-fc and OCD symptoms pre- and post-treatment. All tests were adjusted for participants’ age, sex, and head motion. RESULTS: Right BLA-vmPFC rs-fc was significantly reduced (more negative) in patients with OCD relative to HCs at baseline, and increased following treatment. In patients, more positive (less negative) right BLA-vmPFC rs-fc pre-treatment predicted greater OCD symptoms reduction post-treatment. Changes in BLA-vmPFC rs-fc was unassociated with change in OCD symptoms pre- to post-treatment. CONCLUSIONS: These results provide further evidence of the BLA-vmPFC pathway as a potential target for novel treatments or prevention strategies aimed at facilitating adaptive learning and fear extinction in children with OCD or subclinical OCD symptoms.

Introduction: Post-traumatic stress disorder (PTSD), a mental disorder, is associated with anxiety, depression, and social awkwardness resulting from past traumatic episodes like natural disasters, accidents, terrorist attacks, war, rape, and sexual violence. It affects primarily the amygdala, cortex, and hippocampus where neurochemical changes result in altered behavior. PTSD patients display impaired fear extinction, and past events keep haunting them. The topic presents relevant sections like PTSD pharmacotherapy, associated challenges, and the novel targets and drugs for future research and therapy.Areas covered: The authors discuss the current pharmacotherapy like SSRIs, NDRIs, SNRIs, anticonvulsants, antidepressants, and benzodiazepines, used to attenuate the associated symptoms. However, the primary focus being the novel and potential targets which can be explored better to understand possible future research and advanced therapy in PTSD. For the same, an account of both preclinical and clinical studies has been covered.Expert opinion: Excessive adverse effects, limited efficacy, and lower patient compliance are some of the major challenges with conventional drugs. Moreover, they correct only fewer symptoms without halting the disease progression. Several agents are investigated in different preclinical and clinical phases, which can potentially overcome the pitfalls and limitations associated with conventional therapies.

The midcingulate cortex (MCC) is associated with cognition and emotion regulation. Structural and correlational functional evidence suggests that rather than being homogenous, the MCC may have dissociable functions that can be mapped onto distinct subregions. In this study, we use the marmoset monkey to causally investigate the contributions of two proposed subregions of the MCC: the anterior and posterior midcingulate cortices (aMCC and pMCC) to behavioral and cardiovascular correlates of threat processing relevant to anxiety disorders. Transient inactivation of the aMCC decreased anxiety-like responses to a postencounter distal threat, namely an unfamiliar human intruder, while inactivation of the pMCC showed a mild but opposing effect. Furthermore, although inactivation of neither MCC subregions had any effect on basal cardiovascular activity, aMCC inactivation blunted the expression of both cardiovascular and behavioral conditioned responses to a predictable proximal threat (a rubber snake) during the extinction in a Pavlovian conditioning task, with pMCC inactivation having again an opposing effect, but primarily on the behavioral response. These findings suggest that the MCC is indeed functionally heterogeneous with regards to its role in threat processing, with aMCC providing a marked facilitative contribution to the expression of the emotional response to both proximal and distal threat.

Effects of statistical learning (SL) of distractor location have been shown to persist when the probabilities of distractor occurrence are equalized across different locations in a so-called extinction phase. Here, we asked whether lingering effects of SL are still observed when a true extinction phase, during which the distractor is completely omitted, is implemented. The results showed that, once established, the effects of SL of distractor location do survive the true extinction phase, indicating that the pattern of suppression in the saliency map is encoded in a form of long-lasting memory. Quite unexpectedly, we also found that the amount of filtering implemented at a given location is not only dictated by the specific rate of distractor occurrence at that location, as previously found, but also by the global distractor probability. We therefore suggest that the visual attention system could be more or less (implicitly) prone to suppression as a function of how often the distractor is encountered overall, and that this suppressive bias affects the degree of suppression at the specific distractor-probability location. Finally, our results showed that the effects of SL of distractor location can appear much more rapidly than has been previously documented, requiring a few trials to become manifest. Hence, SL of distractor location appears to have an asymmetrical rate of learning during acquisition and extinction, while the amount of suppression exerted at a specific distractor location is modulated by distractor contextual probabilistic information.

Anxiety and trauma-related disorders, such as post-traumatic stress disorder (PTSD), are debilitating mental illnesses with great personal and socioeconomic costs. Examining memory formation and relevant behavioural responding associated with aversive stimuli may improve our understanding of the neurobiology underlying fear memory processing and PTSD treatment. The neurocircuitry underpinning learned fear and its inhibition through extinction is complex, involving synergistic interactions between different neurotransmitter systems in inter-connected brain areas. Endocannabinoid and noradrenergic transmission have both been implicated separately in fear memory processing and PTSD but potential interactions between these systems in relation to fear extinction have received little attention to date. Their receptors are expressed together in brain areas crucial for fear extinction, which is enhanced by both cannabinoid and noradrenergic receptor activation in these areas. Moreover, cannabinoid signalling modulates the activity of locus coeruleus noradrenaline neurons and the release of noradrenaline in the medial prefrontal cortex, a brain area that is crucial for fear extinction. Interestingly, endocannabinoid-noradrenergic system interactions have been shown to regulate the encoding and retrieval of fear memory. Thus noradrenergic regulation of fear extinction may also be driven indirectly in part via cannabinoid receptor signalling. In this perspective paper, we collate the available relevant literature and propose a synergistic role for the endocannabinoid and noradrenergic systems in regulating fear extinction, the study of which may further our understanding of the neurobiological substrates of PTSD and its treatment.

Anxiety and fear-related disorders peak in prevalence during adolescence, a window of rapid behavioral development and neural remodeling. However, understanding of the development of threat responding and the underlying neural circuits remains limited. Preclinical models of threat conditioning and extinction have provided an unparalleled glimpse into the developing brain. In this review we discuss mouse and rat studies on the development of threat response regulation with a focus on the adolescent period. Evidence of non-linear patterns of threat responding during adolescence and the continued development of the underlying circuitry is highly indicative of an adolescent sensitive period for threat response regulation. While we highlight literature in support of this unique developmental window, we also emphasize the need for causal studies to clarify the parameters defining such a sensitive period. In doing so, we explore how stress and biological sex impact the development and expression of threat response regulation during adolescence and beyond. Ultimately, a deeper understanding of how these factors interact with and impact developmental trajectories of learning and memory will inform treatment and prevention strategies for pediatric anxiety disorders.

Two experiments with humans determined whether reduced conditioning following pre-exposure to the conditioned stimulus could be explained by conditioned inhibition (Experiment 1 [E1]) or extinction of responding that the conditioned stimulus (CS) might elicit during pre-exposure (Experiment 2 [E2]). In a video game task (Nelson et al., 2014), participants learned to respond to lights that signaled attacking spaceships. In E1, a red light was either pre-exposed or not pre-exposed between groups prior to conditioning with a green light. Summation tests of red combined with green produced no evidence of conditioned inhibition. In E2, participants received either no pre-exposure to the light, exposure in the same context in which the conditioning would occur, or exposure in a different context. These conditions were factorially combined with whether the light and spaceship were similar (same color) or dissimilar (different colors). In the similar conditions, the light elicited weak responding during pre-exposure, which extinguished. Such extinction did not occur in the dissimilar conditions. Conditioning occurred more rapidly in the similar conditions than in the dissimilar ones, but both conditions showed an equivalent context-dependent pre-exposure effect. Pre-exposure reduced conditioning regardless of whether it reduced responding prior to conditioning. The data are consistent with animal research (Lubow et al., 1968) showing no relation between responding during pre-exposure and the effects of stimulus pre-exposure. Theories which account for the effects of stimulus pre-exposure are discussed, with the conclusion that the data are most consistent with the ideas presented by Wagner (1981). (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Deficits in associative and Pavlovian learning are thought to lie at the center of anxiety-related disorders. However, the majority of studies have been carried out in adult populations. The aim of this review was to critically examine the behavioral and neuroimaging literature on Pavlovian learning in pediatric anxiety disorders. We conclude that although there is evidence for deficits in Pavlovian processes (e.g., heightened reactivity to safety cues in anxious samples), the extant literature suffers from key methodological and theoretical issues. We conclude with theoretical and methodological recommendations for future research in order to further elucidate the role of Pavlovian learning in the etiology, maintenance, and treatment of pediatric anxiety disorders.

Previous literature supports the use of functional analyses to prescribe treatments for children with feeding disorders (Bachmeyer et al., 2009). Nevertheless, clinicians often train caregivers to use healthy contingencies, independent of whether those contingencies are function based. However, it is unclear whether including nonfunction-based contingencies differentially affects inappropriate mealtime behavior. In the current investigation, the caregivers of 3 children with feeding disorders provided escape from bites and drinks and attention following inappropriate mealtime behavior. Results of a functional analysis showed escape from bites or drinks, but not attention, reinforced inappropriate mealtime behavior. We then tested the effects of escape extinction when the feeder either provided or withheld attention following inappropriate mealtime behavior. Inappropriate mealtime behavior decreased and acceptance increased when the feeder implemented escape extinction independent of whether they provided or withheld attention. We discuss the implications of including nonfunction-based components in the treatment of pediatric feeding disorders.

Noncontingent reinforcement (NCR) involves the delivery of maintaining reinforcers on a time-dependent schedule and often includes extinction. However, arbitrary reinforcers may be equally efficacious during NCR without extinction for treating escape-maintained problem behavior. The purpose of this study was to extend previous research on NCR by evaluating the relative efficacy of NCR without extinction and comparing maintaining versus arbitrary reinforcers for 4 individuals with escape-maintained problem behavior. Two different NCR conditions, NCR using the maintaining reinforcer (escape) and NCR using an arbitrary reinforcer (an edible), were evaluated using multielement and reversal designs. Treatment effects varied across participants. Results for 2 participants showed a reduction in problem behavior during NCR without extinction with both the arbitrary and maintaining reinforcers. For 1 participant, results showed a reduction in problem behavior with both the arbitrary and maintaining reinforcers only when extinction was added to NCR. For the 4th participant, the maintaining reinforcer was effective during NCR without extinction, but the arbitrary reinforcer was ineffective.

Background: Trauma-based psychotherapy is a first line treatment for post-traumatic stress disorder (PTSD) but not all patients achieve long-term remission. Transcranial direct current stimulation (tDCS) received considerable attention as a neuromodulation method that may improve trauma-based psychotherapy. Objective: We explored the effects of repeated anodal tDCS over the prefrontal cortex (PFC) on fear extinction in mice as a preclinical model for trauma-based psychotherapy. Methods: We performed auditory fear conditioning with moderate or high shock intensity on C57BL6/J mice. Next, mice received anodal tDCS (0.2 mA, 20 min) or sham stimulation over the PFC twice daily for five consecutive days. Extinction training was performed by repeatedly exposing mice to the auditory cue the day after the last stimulation session. Early and late retention of extinction were evaluated one day and three weeks after extinction training respectively. Results: We observed no significant effect of tDCS on the acquisition or retention of fear extinction in mice subjected to fear conditioning with moderate intensity. However, when the intensity of fear con-ditioning was high, tDCS significantly lowered freezing during the acquisition of extinction, regardless of the extinction protocol. Moreover, when tDCS was combined with a strong extinction protocol, we also observed a significant improvement of early extinction recall. Finally, we found that tDCS reduced generalized fear induced by contextual cues when the intensity of conditioning is high and extinction training limited. Conclusions: Our data provide a rationale to further explore anodal tDCS over the PFC as potential support for trauma-based psychotherapy for PTSD. (c) 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

The current study taught 6 children with autism spectrum disorder (ASD) to increase passive compliance of wearing a facemask across sequentially increasing durations of time. A changing-criterion design embedded within a nonconcurrent multiple baseline design was used to evaluate the effectiveness of a resetting differential reinforcement of other behavior (DRO) without escape extinction procedure on passive compliance. Terminal probe sessions determined DRO fading intervals. Results showed that 2 participants acquired mastery level passive compliance (30 min) without fading during the initial baseline sessions. The remaining 4 participants acquired mastery level passive compliance following fading intervals within the DRO intervention. Participants' passive compliance generalized across 2 novel settings. This study replicates previous studies and extends empirical support for the use of DRO without escape extinction interventions for increasing passive compliance with medical devices in children with ASD.

Fear conditioning and generalization are well-known mechanisms in the pathogenesis of anxiety disorders. Extinction of conditioned fear responses is crucial for the psychotherapeutic treatment of these diseases. Anxious depression as a subtype of major depression shares characteristics with anxiety disorders. We therefore aimed to compare fear learning mechanisms in patients with anxious versus non-anxious depression. Fear learning mechanisms in patients with major depression (n = 79; for subgroup analyses n = 41 patients with anxious depression and n = 38 patients with non-anxious depression) were compared to 48 healthy participants. We used a well-established differential fear conditioning paradigm investigating acquisition, generalization, and extinction. Ratings of valence, arousal and probability of expected threat were assessed as well as skin conductance response as an objective psychophysiological measure. Patients with major depression showed impaired acquisition of conditioned fear. In addition, depressed patients showed impaired extinction of conditioned fear responses after successful fear conditioning. Generalization was not affected. However, there was no difference between patients with anxious and non-anxious depression. Results differed between objective and subjective measures. Our findings show altered fear acquisition and extinction in major depression as compared to healthy controls, but they do not favor differential fear learning and extinction mechanisms in the pathogenesis of anxious versus non-anxious depression. The results of impaired extinction warrant future studies addressing extinction learning elements in the treatment of depression.

Several studies have observed heightened Pavlovian fear conditioning in PTSD. However, it is unclear how fear conditioning in PTSD is related to risk factors for the disorder, such as anxiety sensitivity. Fifty-one combat-exposed veterans (20 with PTSD, 31 without PTSD) completed a differential fear conditioning task in which one colored rectangle (CS+) predicted a loud scream (US), whereas a different colored rectangle (CS-) predicted no US. Veterans with PTSD were characterized by greater anxiety to the CS+ but not the CS- during acquisition and extinction, and greater US expectancy during the CS+ but not the CS- at extinction. Also, veterans with PTSD had greater pupil dilation to both CSs at extinction, but not at acquisition. Anxiety sensitivity was correlated with anxiety and US expectancy in response to the CS+, but not the CS-, at both acquisition and extinction, and also with pupil diameter to both the CS+ and CS- at extinction. Nearly all of these relations held when covarying for PTSD symptoms and trait anxiety. These findings suggest that increased fear conditioning in PTSD may be related to elevated anxiety sensitivity.

The ventromedial and dorsolateral prefrontal cortex are two major prefrontal regions that usually interact in serving different cognitive functions. On the other hand, these regions are also involved in cognitive processing of emotions but their contribution to emotional processing is not well-studied. In the present study, we investigated the role of these regions in three dimensions (valence, arousal and dominance) of emotional processing of stimuli via ratings of visual stimuli performed by the study participants on these dimensions. Twenty- two healthy adult participants (mean age 25.21 ± 3.84 years) were recruited and received anodal and sham transcranial direct current stimulation (tDCS) (1.5 mA, 15 min) over the dorsolateral prefrontal cortex (dlPFC) and and ventromedial prefrontal cortex (vmPFC) in three separate sessions with an at least 72-h interval. During stimulation, participants underwent an emotional task in each stimulation condition. The task included 100 visual stimuli and participants were asked to rate them with respect to valence, arousal, and dominance. Results show a significant effect of stimulation condition on different aspects of emotional processing. Specifically, anodal tDCS over the dlPFC significantly reduced valence attribution for positive pictures. In contrast, anodal tDCS over the vmPFC significantly reduced arousal ratings. Dominance ratings were not affected by the intervention. Our results suggest that the dlPFC is involved in control and regulation of valence of emotional experiences, while the vmPFC might be involved in the extinction of arousal caused by emotional stimuli. Our findings implicate dimension-specific processing of emotions by different prefrontal areas which has implications for disorders characterized by emotional disturbances such as anxiety or mood disorders.

Glutamate is the main excitatory neurotransmitter in the brain and is of critical importance for the synaptic and circuit mechanisms that underlie opioid addiction. Opioid memories formed over the course of repeated drug use and withdrawal can become powerful stimuli that trigger craving and relapse, and glutamatergic neurotransmission is essential for the formation and maintenance of these memories. In this review, we discuss the mechanisms by which gluta-mate, dopamine, and opioid signaling interact to mediate the primary rewarding effects of opioids, and cover the glutamatergic systems and circuits that mediate the expression, extinc-tion, and reinstatement of opioid seeking over the course of opioid addiction.

Background While healthy individuals and patients with anxiety disorders easily generalize fear responses, extinction learning is more stimulus specific. Treatments aiming to generalize extinction learning are urgently needed, since they comprise the potential to overcome stimulus specificity and reduce relapses, particularly in the face of stressful events. Methods In the current 3-day functional magnetic resonance imaging fear conditioning paradigm, we aimed to create a generalized extinction memory trace in 60 healthy men and women by presenting multiple sizes of 1 conditioned stimulus during extinction training (CS+G; generalized), whereas the other conditioned stimulus was solely presented in its original size (CS+N; nongeneralized). Recall was tested on the third day after pharmacological administration of either the stress hormone cortisol or placebo. Results After successful fear acquisition, prolonged activation of the amygdala and insula and deactivation of the ventromedial prefrontal cortex for CS+G compared with CS+N during extinction learning indicated sustained fear to the generalization stimuli. In line with our hypotheses, reduced amygdala activation was observed after extinction generalization on the third day in the contrast CS+G minus CS+N, possibly reflecting an attenuated return of fear. Cortisol administration before recall, however, blocked this effect. Conclusions Taken together, the findings show that extinction generalization was associated with decreased activation of the fear network during recall after prolonged activation of the fear network during extinction learning. However, the generalization of the extinction memory did not counteract the detrimental effects of stress hormones on recall. Thus, stimulus-based extinction generalization may not be sufficient to reduce relapses after stressful experiences.

The present study examined resurgence of reinforced variability in college students, who completed a 3-phase computer-based variability task. In the first phase, baseline, points were delivered for drawing rectangles that sufficiently differed from previous rectangles in terms of a target dimension (size or location, counterbalanced) but were sufficiently similar in terms of the alternative dimension. In the second phase, alternative, points were only delivered for rectangles that were sufficiently different in terms of the alternative dimension, but repetitive in terms of the target dimension. In the third phase, extinction, no points were delivered. In baseline, participants made rectangles that were highly varied in terms of the target dimension and less varied in terms of the alternative dimension, and vice versa in the alternative phase. During extinction, levels of variability increased for the target dimension, providing evidence for resurgence of reinforced variability of a specific dimension of behavior. However, levels of variability also remained high for the alternative dimension, indicating that extinction-induced response variability may also have impacted the results. Although future research is needed to explore other explanations, the results of this study replicate prior research with pigeons and provide some support for the notion of variability as an operant.

Background Evidence suggests that extinction during memory reconsolidation diminishes the return of defensive responses. In order to translate these effects to the clinical setting, we tested whether retrieving a traumatic memory and delivering a brief two-sessions imaginal exposure intervention during its reconsolidation would produce stronger decreases in reactivity to these memories than standard imaginal exposure method. Methods Participants with Post-Traumatic Stress Disorder (PTSD) had either their traumatic (n = 21) or a neutral (n = 21) memory retrieved 1 hour before an imaginal exposure session for two consecutive days. One day before and one day after, participants were exposed to script-driven imagery of their traumatic event, during which skin conductance responses were measured and, immediately after, subjective responses were assessed by means of Visual Analogue Scales. Results Traumatic retrieval improved the physiological, but not the subjective effects of imaginal exposure intervention on over-reactivity to traumatic memories. Conclusions Our results suggest that delivering extinction-based treatments over the reconsolidation of traumatic memories may enhance its effects. These results suggest that this is a promising path toward the development of new therapeutic techniques.

Fear-generalization is a critical function for survival, in which an organism extracts information from a specific instantiation of a threat (e.g., the western diamondback rattlesnake in my front yard on Sunday) and learns to fear—and accordingly respond to—pertinent higher-order information (e.g., snakes live in my yard). Previous work investigating fear-conditioning in humans has used functional magnetic resonance imaging (fMRI) to demonstrate that activity-patterns of stimuli from an aversively-conditioned category (CS+) are more similar to each other than those of a neutral category (CS-). Here we designed a three-phase (i.e., baseline, conditioned, extinction) experiment using fMRI and multiple aversively-conditioned categories to ask whether we would find only similarity increases within the CS+ categories or also an increase in similarity between the CS+ categories. Using representational similarity analysis, we correlated a set of models to activity-patterns underlying several regions of interest and found that, following fear-conditioning, between-category and within-category similarity increased for the CS+ categories in the superior frontal gyrus (SFG) and the right temporal pole (rTP). Activity patterns in the object-selective lateral occipital cortex tended to prefer the semantic model, regardless of the experimental phase. These results advance prior pattern-based neuroimaging work by exploring the effect of aversively-conditioning multiple categories and indicate an extended role for the SFG and rTP in potentially linking discrete information or abstractly representing supracategorical information during fear-learning for the purpose of proper generalization.

The role of the ventromedial prefrontal cortex (vmPFC) in human pavlovian threat conditioning has been relegated largely to the extinction or reversal of previously acquired stimulus–outcome associations. However, recent neuroimaging evidence questions this view by also showing activity in the vmPFC during threat acquisition. Here we investigate the casual role of vmPFC in the acquisition of pavlovian threat conditioning by assessing skin conductance response (SCR) and declarative memory of stimulus–outcome contingencies during a differential pavlovian threat-conditioning paradigm in eight patients with a bilateral vmPFC lesion, 10 with a lesion outside PFC and 10 healthy participants (each group included both females and males). Results showed that patients with vmPFC lesion failed to produce a conditioned SCR during threat acquisition, despite no evidence of compromised SCR to unconditioned stimulus or compromised declarative memory for stimulus–outcome contingencies. These results suggest that the vmPFC plays a causal role in the acquisition of new learning and not just in the extinction or reversal of previously acquired learning, as previously thought. Given the role of the vmPFC in schema-related processing and latent structure learning, the vmPFC may be required to construct a detailed representation of the task, which is needed to produce a sustained conditioned physiological response in anticipation of the unconditioned stimulus during threat acquisition.SIGNIFICANCE STATEMENTPavlovian threat conditioning is an adaptive mechanism through which organisms learn to avoid potential threats, thus increasing their chances of survival. Understanding what brain regions contribute to such a process is crucial to understand the mechanisms underlying adaptive as well as maladaptive learning, and has the potential to inform the treatment of anxiety disorders. Importantly, the role of the ventromedial prefrontal cortex (vmPFC) in the acquisition of pavlovian threat conditioning has been relegated largely to the inhibition of previously acquired learning. Here, we show that the vmPFC actually plays a causal role in the acquisition of pavlovian threat conditioning.

Previous research has shown that instrumental training can encourage the formation of binary associations between the representations of the elements present at the time of learning, that is, between the discriminative stimulus and the instrumental response (the S-R association), between the stimulus and outcome (the S-O association), and between the response and outcome (the R-O association). Studies with rats have used transfer procedures to explore the effects of discriminative extinction (i.e., extinction that is carried out in the presence of the discriminative stimuli) on these three binary associations. Thus, a reduction in the response rate of the extinguished response (R) can be detected in situations involving a different discriminative stimulus that was associated with the same outcome, and to unextinguished responses controlled by the discriminative stimulus (S) and associated with the outcome (O). These transfer effects suggest that R-O and S-O associations remain active after extinction in nonhuman animals. We carried out an experiment to explore these postextinction transfer effects in humans using a within-subject design. Contrary to nonhuman reports, the S-O association was affected by discriminative extinction, suggesting differences in the associative structure of instrumental conditioning in human and nonhuman animals that should be considered by those therapeutic strategies based in nonhuman animal research aimed to reduce unhealthy instrumental behaviours in human beings. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Pavlovian fear conditioning is widely used to study mechanisms of fear learning, but high-throughput studies are hampered by the labor-intensive nature of examining participants in the lab. To circumvent this bottle-neck, fear conditioning tasks have been developed for remote delivery. Previous studies have examined remotely delivered fear conditioning protocols using expectancy and affective ratings. Here we replicate and extend these findings using an internet-delivered version of the Screaming Lady paradigm, evaluating the effects on negative affective ratings and response time to an auditory probe during stimulus presentation. In a sample of 80 adults, we observed clear evidence of both fear acquisition and extinction using affective ratings. Response times were faster when probed early, but not later, during presentation of stimuli paired with an aversive scream. The response time findings are at odds with previous lab-based studies showing slower as opposed to faster responses to threat-predicting cues. The findings underscore the feasibility of employing remotely delivered fear conditioning paradigms with affective ratings as outcome. Findings further highlight the need for research examining optimal parameters for concurrent response time measures or alternate non-verbal indicators of conditioned responses in Pavlovian conditioning protocols.

The endocannabinoid (eCB) system is one the most ubiquitous signaling systems of the brain and offers a rich pharmacology including multiple druggable targets. Preclinical research shows that eCB activity influences functional connectivity between the prefrontal cortex and amygdala and thereby influences an organisms ability to cope with threats and stressful experiences. Animal studies show that CB1 receptor activation within the amygdala is essential for extinction of fear memories. Failure to extinguish traumatic memories is a core symptom of posttraumatic stress disorder, suggesting that potentiating eCB signaling may have a therapeutic potential in this condition. However, it has been unknown whether animal findings in this domain translate to humans. Data to inform this critical question are now emerging and are the focus of this review. We first briefly summarize the biology of the eCB system and the animal studies that support its role in fear extinction and stress responding. We then discuss the pharmacological eCB-targeting strategies that may be exploited for therapeutic purposes: direct CB1 receptor activation, using Delta(9)-tetrahydrocannabinol or its synthetic analogs; or indirect potentiation, through inhibition of eCB-degrading enzymes, the anandamide-degrading enzyme fatty acid amide hydrolase; or the 2-AG (2-arachidonoyl glycerol)-degrading enzyme monoacylglycerol lipase. We then review recent human data on direct CB1 receptor activation via Delta(9)-tetrahydrocannabinol and anandamide potentiation through fatty acid amide hydrolase blockade. The available human data consistently support a translation of animal findings on fear memories and stress reactivity and suggest a potential therapeutic utility in humans. Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [2013-07434, 2019-01138]; Brain & Behavior Research FoundationNARSAD [27094]; National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R33MH111935, R01MH122867]

Patients are encouraged to produce vivid mental imagery during imaginal exposure, as it is assumed to promote fear reduction. Nevertheless, the link between fear reduction and imagery vividness is unclear. We investigated the impact of vividness on fear responses using an experimental analogue of imaginal exposure - imaginal extinction - in which conditioned fear, measured with skin conductance, is reduced through exposure to mental imagery of the conditioned stimulus. We examined (1) if task-specific vividness (high vs low) of the conditioned stimulus during imaginal extinction moderated the reduction of fear responses, and (2) if task-specific vividness influenced remaining fear responses 24 h later. Findings suggest that high vividness may be advantageous for fear reduction during imaginal extinction, but it may not influence fear responses in the longer term. A possible clinical implication is that high imagery vividness during imaginal exposure may not be vital for overall treatment outcome. As high vividness is associated with increased levels of distress, a future direction would be to explore whether similar fear reduction can be obtained with less vivid imaginal exposure and thereby make treatment tolerable for more patients