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The results of this experiment revealed that PTSD patients showed greater differential responses to the two CS, while non-PTSD patients did not. The same research group previously ran a similar experiment,[5] which highlighted that high symptom sub-threshold PTSD individuals showed higher HR to both CSs compared with the low symptom group. Furthermore, Orr et al[3] show that cardiac acceleration to the CS+ is present only in PTSD patients and not in non-PTSD participants, creating further discrepancies. [Extracted from the article]

Background: Alcohol use disorder (AUD) is a significant public health problem. A better understanding of the psychosocial factors contributing to AUD is important for developing public health policy. The purpose of this study was to identify social mechanisms involved in AUD and, more specifically, to determine whether vicarious learning deficits are related to the disorder. A secondary objective was to evaluate the role of empathy in social fear conditioning. Methods: Patients with severe AUD (n = 30) and healthy participants (n = 30) performed a social fear learning (SFL) task. The task assesses how an association between a stimulus and an aversive consequence is acquired through social means. Specifically, participants observed a person receiving an electric shock (unconditioned stimulus; US) that was associated (conditioned stimulus; CS+) or not (CS−) with a neutral CS. The skin conductance response was used to measure the effect of learning. Results: Individuals with severe AUD showed a deficit in SFL, indicating that they had difficulty learning from another's negative experience. Patients also evaluated the emotional experience as less unpleasant than healthy participants. Conclusions: This study is the first to show that patients with severe AUD have social learning deficits. The findings suggest that these individuals do not learn from another's negative experience. At a fundamental level, the findings demonstrate the importance of understanding the role of social mechanisms in AUD. At a clinical level, the study highlights the potential for using social learning enhancement to prevent relapse in individuals with severe AUD. [ABSTRACT FROM AUTHOR]

Background: The association between anxious mood and aberrant fear learning mechanisms has not been fully elucidated. Studying how fear conditioning and extinction constructs relate to anxiety symptoms and reactivity to stressful and benign moments in everyday life provides a powerful addition to experimental paradigms. Method: Fifty-one young adults completed laboratory-based differential conditioning and extinction tasks with (CS +) and without (CS-) an aversive unconditional stimulus (US). Electrodermal skin conductance responses were measured during each phase, followed by ecological momentary assessment (EMA) tapping anxiety and stressors six times daily for seven days (2, 142 moments). Results: Conditioned electrodermal reactivity to the CS + and overgeneralisation to the CS- were associated with greater change in anxiety (measured via EMA), across non-stressful situations, remaining the same across stressful situations. Likewise, during extinction when the CS + is now safe, more electrodermal reactivity to the CS + was associated with more anxiety change across non-stressful situations and remained the same across stressful situations. Also, during extinction when threat is absent, more electrodermal reactivity at the late stage of the CS- was associated with less momentary anxiety change in response to stressful situations; more electrodermal activity at the late stage of the CS + was associated with more anxiety change across non-stressful situations and remained the same across stressful situations. Conclusions: Sampling 'in vivo' emotion and stress experiences, study findings revealed links between conditioned electrodermal reactivity and overgeneralisation to safe stimuli and heightened anxious reactivity during non-stressful (i.e. safe) moments in daily life, coupled with less change in response to actual stressors. [ABSTRACT FROM AUTHOR]

Fear generalization is a crucial mechanism underlying maladaptive behavior, but factors influencing this process are not fully understood. We investigated the effects of cue training and context on fear generalization and how cognitive rules influence responses to different conditions. We also examined the role of stimulus intensity in fear generalization to provide insight into fear generalization mechanisms. Participants (n = 104) completed a fear emotion task with two stages: acquisition and generalization testing. Subjective fear expectancy ratings were used as outcome measures. Participants who received single threat cue training exhibited stronger fear generalization responses than those who received discrimination training with threat and safe cues. Participants who received discrimination training and used linear rules had the strongest fear response to the largest stimulus. Therefore, a safe cue may mitigate fear generalization but could increase fear responses to more intense stimuli. Altering context did not change the fear generalization response because fear generalization is mainly governed by the association between the conditioned stimulus and the unconditioned fear stimulus. The present study emphasizes the multifaceted nature of fear generalization and the importance of examining multiple factors to understand this phenomenon. These findings elucidate fear learning and provide insights needed for effective interventions for maladaptive behavior. [ABSTRACT FROM AUTHOR]

Fear and anxiety are crucial for adaptive responding in life‐threatening situations. Whereas fear is a phasic response to an acute threat accompanied by selective attention, anxiety is characterized by a sustained feeling of apprehension and hypervigilance during situations of potential threat. In the current literature, fear and anxiety are usually considered mutually exclusive, with partially separated neural underpinnings. However, there is accumulating evidence that challenges this distinction between fear and anxiety, and simultaneous activation of fear and anxiety networks has been reported. Therefore, the current study experimentally tested potential interactions between fear and anxiety. Fifty‐two healthy participants completed a differential fear conditioning paradigm followed by a test phase in which the conditioned stimuli were presented in front of threatening or neutral contextual images. To capture defense system activation, we recorded subjective (threat, US‐expectancy), physiological (skin conductance, heart rate) and visuocortical (steady‐state visual evoked potentials) responses to the conditioned stimuli as a function of contextual threat. Results demonstrated successful fear conditioning in all measures. In addition, threat and US‐expectancy ratings, cardiac deceleration, and visuocortical activity were enhanced for fear cues presented in threatening compared with neutral contexts. These results are in line with an additive or interactive rather than an exclusive model of fear and anxiety, indicating facilitated defensive behavior to imminent danger in situations of potential threat. Our research adds a new perspective on a potential interaction between fear and anxiety. We provide first evidence for enhanced defensive (fear) responses in potentially threatening (anxiety) contexts as indexed by multiple measures of defensive responding (perceived threat, HR, and EEG), suggesting that anxiety may facilitate fear responses rather than both emotional states being mutually exclusive. [ABSTRACT FROM AUTHOR]

Gestational hypothyroidism is a prevalent disorder in pregnant women and also impairs fetal development with relevant outcomes. One of the outcomes of greatest interest has been rodent fear- and anxiety-like behavior. However, the relationship between maternal hypothyroidism and onset of conditioned fear-related responses in offspring remains controversial. Here, we used a well-validated methimazole-induced gestational hypothyroidism to investigate the behavioral consequences in offspring. Dams were treated with methimazole at 0.02% in drinking water up to gestational Day 9. Maternal body weights and maternal behavior were evaluated, and the puppies ware analyzed for weight gain and physical/behavioral development and assigned for the open field and fear conditioning test. Methimazole-induced gestational hypothyroid- ism induced loss in maternal and litter weight, increases in maternal behavior, and impairs in offspring developmental landmarks in both male and female rodents. Only male offspring enhanced responsiveness to conditioned fear-like behavior in adulthood. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is characterized by loss of dystrophin in muscle, however patients also have variable degree of intellectual disability and neurobehavioural co-morbidities. In contrast to muscle, in which a single full-length dystrophin isoform (Dp427) is produced, multiple isoforms are produced in the brain, and their deficiency accounts for the variability of CNS manifestations, with increased risk of comorbidities in patients carrying mutations affecting the 3′ end of the gene, which disrupt expression of shorter Dp140 and Dp71 isoforms. A mouse model (mdx mouse) lacks Dp427 in muscle and CNS and exhibits exaggerated startle responses to threat, linked to the deficiency of dystrophin in limbic structures such as the amygdala, which normalize with postnatal brain dystrophin-restoration therapies. A pathological startle response is not a recognized feature of DMD, and its characterization has implications for improved clinical management and translational research. To investigate startle responses in DMD, we used a novel fear-conditioning task in an observational study of 56 males aged 7–12 years (31 affected boys, mean age 9.7 ± 1.8 years; 25 controls, mean age 9.6 ± 1.4 years). Trials of two neutral visual stimuli were presented to participants: one 'safe' cue presented alone; one 'threat' cue paired with an aversive noise to enable conditioning of physiological startle responses (skin conductance response and heart rate). Retention of conditioned physiological responses was subsequently tested by presenting both cues without the aversive noise in an 'Extinction' phase. Primary outcomes were the initial unconditioned skin conductance and change in heart rate responses to the aversive 'threat' and acquisition and retention of conditioned responses after conditioning. Secondary and exploratory outcomes were neuropsychological measures and genotype associations. The mean unconditioned skin conductance response was greater in the DMD group than controls [mean difference 3.0 µS (1.0, 5.1); P = 0.004], associated with a significant threat-induced bradycardia only in the patient group [mean difference –8.7 bpm (–16.9, –0.51); P = 0.04]. Participants with DMD found the task more aversive than controls, with increased early termination rates during the Extinction phase (26% of DMD group versus 0% of controls; P = 0.007). This study provides the first evidence that boys with DMD show similar increased unconditioned startle responses to threat to the mdx mouse, which in the mouse respond to brain dystrophin restoration. Our study provides new insights into the neurobiology underlying the complex neuropsychiatric co-morbidities in DMD and defines an objective measure of this CNS phenotype, which will be valuable for future CNS-targeted dystrophin-restoration studies. [ABSTRACT FROM AUTHOR]

Uncertainty is a core component of threat and associated learning processes. One methodological factor impacting uncertainty in threat learning paradigms is the threat reinforcement rate, which refers to the proportion of times a cue is reinforced with an aversive stimulus. This study tested the effect of partial vs continuous threat reinforcement on threat / safety discrimination learning, as indexed by skin conductance response (SCR). Using a within-participants design, fifty-nine participants completed a task in which three colored shapes were paired with electric shock at reinforcement schedules of 100% (CS+), 50% (CS+) and 0% (CS-). In addition, the study examined the relationship between the Intolerance of Uncertainty scale (IU) and two subscales - inhibitory and prospective IU - with threat discrimination learning. The data show heightened SCR in the continuous vs partial reinforcement condition to all stimuli, but limited evidence of enhanced discrimination learning. Furthermore, no association was observed between total IU score and threat-safety discrimination. However, using a two-factor model of IU, findings showed higher inhibitory IU and higher prospective IU were associated with diminished and heightened threat discrimination, respectively. These results contribute to a fast-growing literature exploring how the uncertainty inherent to predictors of threat, individual differences in sensitivity to uncertainty, and interactions between these two factors, can shape the acquisition of threat memory. [ABSTRACT FROM AUTHOR]

This study develops a fear-potentiated startle paradigm (FPS) and a machine learning approach to accurately predict PTSD symptoms using electrogram data. A three-phase fear-potentiated startle paradigm was designed to assess the conditioning, generalization, and extinction of fear. Electrooculogram and electrocardiogram signals were collected during the FPS. A total of 1107 Chinese firefighters participated in the study. The Chinese version PCL-C was administered to all subjects. A cutoff of 38 or higher is used to indicate PTSD symptoms. Electrogram features were extracted and selected to build a machine learning model to classify individuals. The machine learning model was 5-fold cross validated. The importance of the selected features was calculated. Classification performance metrics were evaluated for the machine learning model. The machine learning model can identify firefighters with a PCL-C score of 38 or above with sensitivity and specificity both above 0.85 when 5-fold cross validated on a 1107-person sample. The area under the receiver operating characteristic curve of the model is 0.93. Features related to fear generalization are found to be the most important. The proposed fear-potentiated startle paradigm and machine learning approach can accurately predict PTSD symptoms in Chinese firefighters, which can improve the screening and diagnosis of PTSD. [ABSTRACT FROM AUTHOR]

Anxiety can sometimes inhibit and sometimes potentiate sexual arousal. We examined whether an anxiety manipulation in a classical fear-conditioning paradigm impacts self-reported sexual arousal in men and women. University students (62 men, 61 women) underwent differential fear conditioning to erotic images; half the images were sometimes (60%) paired with a shock (CS+) and half were never paired with a shock (CS–). For each trial, participants rated their sexual arousal and anxiety in response to the image; skin conductance response (SCR) and zygomatic and corrugator activity were recorded. During acquisition, self-reported sexual arousal was lower to CS+ than CS− (inhibiting effect), but in men only. During extinction, self-reported sexual arousal was lower to CS+ than CS− for both genders. Some differences produced by CS+ and CS− were observed for SCR and zygomatic and corrugator activation at different points during acquisition and extinction, but the effects were unrelated to ratings of anxiety or sexual arousal. The negative impact of anxiety on sexual arousal appears to be resistant to extinction, and small gender differences were observed. Future studies should include direct measures of physiological sexual arousal. The relationship between sexual arousal and anxiety appears to be complex and should be further investigated. [ABSTRACT FROM AUTHOR]

Objective: We sought to determine whether acute delta 9‐tetrahyrdrocannabidol (THC) administration would facilitate fear extinction in young occasional cannabis users, given that animal models indicate THC facilitates extinction learning, and recent studies indicate THC administration may also enhance threat memory extinction in humans. Methods: On each of the 2 days, 24+ hour THC‐deprived participants were conditioned to fear visual stimuli in a delay conditioning and extinction paradigm. Both CS+ and CS− were faces of negative emotional valence, with the CS+ paired with mild electric shock. Throughout both conditioning and extinction paradigms, EEG was measured to quantify event‐related potentials for these learning processes. Following conditioning, individuals, in a randomized and counter‐balanced order, smoked either an active THC cigarette (26.25 mg/2.7% THC) or a placebo marijuana cigarette (0.002% THC) on 1 day and the opposite cigarette on the second day. After smoking, CS+ and CS− were presented without shock, resulting in extinction of conditioned fear. Results: Relative to placebo, THC facilitated extinction of the conditioned response to the CS+, as reflected by reductions in late positive potential amplitude during extinction learning. Conclusions: The results indicate that acute THC administration may facilitate extinction of the conditioned fear response in humans. [ABSTRACT FROM AUTHOR]

Despite its increasing recognition and extensive research, there is no unifying hypothesis on the pathophysiology of the postural tachycardia syndrome. In this cross-sectional study, we examined the role of fear conditioning and its association with tachycardia and cerebral hypoperfusion on standing in 28 patients with postural tachycardia syndrome (31 ± 12 years old, 25 females) and 21 matched controls. We found that patients had higher somatic vigilance (P = 0.0167) and more anxiety (P < 0.0001). They also had a more pronounced anticipatory tachycardia right before assuming the upright position in a tilt-table test (P = 0.015), a physiological indicator of fear conditioning to orthostasis. While standing, patients had faster heart rate (P < 0.001), higher plasma catecholamine levels (P = 0.020), lower end-tidal CO2 (P = 0.005) and reduced middle cerebral artery blood flow velocity (P = 0.002). Multi-linear logistic regression modelling showed that both epinephrine secretion and excessive somatic vigilance predicted the magnitude of the tachycardia and the hyperventilation. These findings suggest that the postural tachycardia syndrome is a functional disorder in which standing may acquire a frightful quality, so that even when experienced alone it may elicit a fearful conditioned response. Heightened somatic anxiety is associated with and may predispose to a fear-conditioned hyperadrenergic state when standing. Our results have therapeutic implications. [ABSTRACT FROM AUTHOR]

Abstract: Psychological trauma is typically accompanied by physical pain, and posttraumatic stress disorder (PTSD) often cooccurs with chronic pain. Clinical reports suggest that pain after trauma may be part of re-experiencing symptomatology. Classical conditioning can underlie visual re-experiencing because intrusions can occur as conditioned responses (CRs) to trauma-related cues. If individuals also experience pain to cues previously paired with, but not inflicting nociceptive stimulation anymore (ie, conditioned stimuli, CS), conditioning could also explain re-experiencing of pain. Sixty-five participants underwent classical conditioning, where painful electrocutaneous stimulation and aversive film clips served as unconditioned stimuli (US) in a 2 (pain/no pain) × 2 (aversive/neutral film) design. Conditioned stimuli were neutral pictures depicting contextual details from the films. One day later, participants were re-exposed to CS during a memory-triggering task (MTT). We assessed pain-CRs by self-report and an fMRI-based marker of nociceptive pain, the neurological pain signature (NPS), and recorded spontaneous daily-life pain intrusions with an e-diary. During conditioning, pain-signaling CS elicited more self-reported pain and NPS responses than no-pain-signaling CS. Possibly because the aversive film masked differences in participants' responses to pain-signaling CS vs no pain-signaling CS, pain-CRs during acquisition were most evident within the neutral film condition. When participants were re-exposed to CS during MTT, self-reported pain-CRs during the neutral film condition and, although more uncertain, NPS-CRs during the aversive film condition persisted. Of importance, participants with stronger pain-CRs showed a greater probability and severity of experiencing spontaneous pain intrusions during daily life. Our data support that spatiotemporally associating innocuous cues with pain (CS) endows these cues to elicit conditioned pain responses in the absence of noxious stimulation. In this way pain can emerge as a CR with emotional and sensory components. Classical conditioning presents a possible mechanism explaining pain intrusions and, more broadly, pain experienced without a nociceptive input. [ABSTRACT FROM AUTHOR]

Aim: To investigate the current condition and degree of fear of disease progression and associated factors in patients with mild or common type COVID‐19. Background: At the end of 2019, COVID‐19 spread from Wuhan in Hubei Province throughout China. Confirmed cases and deaths have since been reported in many countries around the world. However, fear of progression in these patients has been poorly explored. Methods: During February 2020, we recruited 114 patients with mild or common type COVID‐19 admitted to a Fangcang shelter hospital. We assessed patients' degree of fear using the simplified Fear of Progression Questionnaire (Chinese version). Multiple regression analysis was applied to explore potential factors. Results: The fear of disease progression scores of patients with mild or common COVID‐19 was at the low‐to‐moderate level. Current unemployment, disease duration of 28 days or more and not having a spouse diagnosed with COVID‐19 were factors potentially associated with fear of progression. Conclusion: With a high prevalence of fear of disease progression in patients with COVID‐19, the risk of psychological effects from the pandemic is significant and fear of progression is one of the manifestations. The need for psychological support services for patients should be included in all pandemic and disaster planning. Summary statement: What is already known about this topic? Fear of progression is a common bio‐socio‐psychological consequence that widespread in cancer patients as well as chronic diseases.Very few studies focus on fear of progression in patients with major infectious disease, not to mention coronavirus disease (COVID‐19). What this paper adds? The present study surveys fear of progression in patients with mild or common type COVID‐19 and revealed a low‐to‐moderate level overall.Being unemployed, having no spouse diagnosed with COVID‐19, and a disease duration of 28 days or more are potential factors associated to patients' fear of the disease progression. The implications of this paper: The COVID‐19 outbreak has been declared as a public health emergency of international concern. Mental health problems such as fear of disease progression might need more attention beyond medical treatment.Future mental health nursing practice and research need to focus on those potential factors or patients with specific characteristics. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate age-related differences in fear learning and generalization in healthy children and adolescents (n = 133), aged 8–17 years, using an aversive discriminative fear conditioning and generalization paradigm adapted from Lau et al. (2008). In the current task, participants underwent 24 trials of discriminative conditioning of two female faces with neutral facial expressions, with (CS+) or without (CS−) a 95-dB loud female scream, presented simultaneously with a fearful facial expression (US). The discriminative conditioning was followed by 72 generalization trials (12 CS+, 12 GS1, 12 GS2, 12 GS3, 12 GS4, and 12 CS−): four generalization stimuli depicting gradual morphs from CS+ to CS− in 20%-steps were created for the generalization phases. We hypothesized that generalization in children and adolescents is negatively correlated with age. The subjective ratings of valence, arousal, and US expectancy (the probability of an aversive noise following each stimulus), as well as skin conductance responses (SCRs) were measured. Repeated-measures ANOVAs on ratings and SCR amplitudes were calculated with the within-subject factors stimulus type (CS+, CS−, GS1-4) and phase (Pre-Acquisition, Acquisition 1, Acquisition 2, Generalization 1, Generalization 2). To analyze the modulatory role of age, we additionally calculated ANCOVAs considering age as covariate. Results indicated that (1) subjective and physiological responses were generally lower with increasing age irrespective to the stimulus quality, and (2) stimulus discrimination improved with increasing age paralleled by reduced overgeneralization in older individuals. Longitudinal follow-up studies are required to analyze fear generalization with regard to brain maturational aspects and clarify whether overgeneralization of conditioned fear promotes the development of anxiety disorders or vice versa. [ABSTRACT FROM AUTHOR]

Conditioned fear can substantially reduce the likelihood that an individual will engage in reward‐related behavior––a phenomenon coined conditioned suppression. Despite the unmistakable relevance of conditioned suppression for excessive fears and their adverse consequences, the phenomenon has primarily been observed in animal models and is not yet well understood. Here, we aimed to develop a conditioned suppression paradigm that enables a robust quantification of the effect of Pavlovian fear on subsequent reward‐related behavior in humans and assess its potential relation to physiological measures of fear. In phase 1, an instrumental response was incentivized with monetary rewards. In phase 2, one of two conditioned stimuli (CS+) was reinforced with an aversive unconditioned stimulus (US, i.e., electric stimulus). During Pavlovian fear learning we assessed differential skin conductance (SCR) and fear‐ potentiated startle responses (FPS). Lastly, we tested the effect of the fear conditioned CS+ on the response rate of the instrumental response in a transfer phase. Despite strong Pavlovian fear conditioning, as indicated by large effect sizes in differential SCR and FPS, we did not find any evidence for conditioned suppression: that is, there was no significant reduction of instrumental responding in the presence of the CS+ compared to a new control stimulus. This lack of conditioned suppression is in line with previous studies that reported difficulties inducing conditioned suppression and points toward a general challenge in investigating conditioned suppression in humans. Implications and directions for future research on the highly relevant behavioral effects of fear and anxiety are discussed. In humans, little is known about the effect of fear conditioned cues on formally unrelated instrumental behavior, so called aversive Pavlovian‐to‐Instrumental (PIT). Here, we aimed to investigate one form of aversive PIT, conditioned suppression, but found no evidence for suppression after fear conditioning or for a link between physiological measures of fear and conditioned suppression. We complement previous research indicating that conditioned suppression is not a robust effect after Pavlovian fear conditioning in humans. [ABSTRACT FROM AUTHOR]

Fear conditioning represents the prevailing model by which organisms acquire novel threat contingencies. However, little work has been devoted to linking laboratory measures of fear conditioning to the development of real-world threat responses. To fill this gap, the present study explored whether individual differences in a laboratory-based fear conditioning measure could predict levels of COVID-19-related anxiety and avoidance assessed during the first month of the pandemic. Forty-eight undergraduate students who had previously participated in two fear conditioning experiments prior to COVID-19 completed a survey assessing COVID-19 anxiety and avoidance. The fear conditioning experiment involved learning to discriminate between a shape contingently associated with mild electric shock (CS+) and two other shapes that were not (CS-). Increased subjective anxiety to our laboratory CS+ prior to the pandemic predicted heightened COVID-19 anxiety. Follow-up analyses revealed that participants with high COVID-19 anxiety exhibited increased anxiety to CS+ during the final experimental block relative to participants with low COVID-19 anxiety. Findings from this exploratory study tentatively implicate fear conditioning in the development of real-world fear responses and underscore the importance of investigating laboratory fear conditioning as a predictor of anxiety responses to real-world threats. [ABSTRACT FROM AUTHOR]

Circadian rhythms have received increasing attention within the context of mental disorders. Evening chronotype has been associated with enhanced risk to develop anxiety and post-traumatic stress disorder (PTSD). The classical fear conditioning paradigm is a powerful tool to reveal key mechanisms of anxiety and PTSD. We used this paradigm to study the neurocognitive basis of the association between chronotype and fear responses in healthy humans. 20 participants with evening chronotype and 20 controls (i.e., intermediate chronotype) completed a 2-day Pavlovian fear learning and extinction virtual reality task. Participants received fear conditioning, and extinction learning on day 1. Extinction memory recall was tested on day 2. To address interactions between chronotype and time of day of the fear conditioning, and extinction performance, half of the participants were tested in the morning, and the other half in the evening. Skin conductance response (SCR) and subjective fear ratings were measured as primary outcomes. Chronotype was established via the morningness-eveningness questionnaire (MEQ). We found an overall higher SCR for fear acquisition in participants with the evening chronotype profile, compared to controls. Moreover, the higher the MEQ scores -indicative of less eveningness - the lower the SCR was. No effects of chronotype were found for extinction and extinction recall. The higher vulnerability of the evening chronotype for anxiety and related disorders may thus be explained by enhanced fear acquisition of this group. [ABSTRACT FROM AUTHOR]

Conceptual generalisation occurs when conditional responses generalise to novel stimuli from the same category. Past research demonstrates that physiological fear responses generalise across categories, however, conceptual generalisation of stimulus valence evaluations during fear conditioning has not been examined. We investigated whether conceptual generalisation, as indexed by electrodermal responses and stimulus evaluations, would occur, and differ after training with single or multiple conditional stimuli (CSs). Stimuli from two of four categories (vegetables, farm animals, clothing, and office supplies) were used as the CS+ (followed by an electric stimulus) or CS- (presented alone). Generalisation was assessed by presenting novel stimuli from the CS categories after acquisition, extinction, and reinstatement. One category exemplar was used as the CS+ and CS- in the single group, whereas three exemplars were used as the CS+ and CS- in the multiple group. Electrodermal responses generalised in acquisition and extinction but did not differ between groups. In the multiple group, CS evaluations generalised in acquisition and extinction, whereas generalisation was not evident in the single group. Training with multiple CSs also resulted in the extinction of stimulus valence. The current findings have implications for future research examining the generalisation of valence and for exposure-based treatments of anxiety. [ABSTRACT FROM AUTHOR]

Return of fear may be prevented by post‐retrieval extinction (PRE), a procedure consisting of presenting a stimulus that was present during conditioning (retrieval cue) prior to extinction training. However, recent evidence suggests that there might be circumstances under which PRE is not effective to prevent the return of fear (boundary conditions), but some of these conditions remain unknown. We explored if rehearsing the CS, US or CS‐US contingency during the interval between the retrieval cue and extinction training might change the effects of PRE. One day after differential fear conditioning, healthy human participants (n = 83) underwent either standard extinction (control condition, n = 31) or two different PRE procedures, one in which participants rehearsed the CS‐US contingency during the interval between the retrieval cue and extinction (rehearsal condition, n = 25), or another in which they underwent a verbal fluency task directing their attention away from the experimental contingencies during this interval (nonrehearsal condition, n = 27). Return of fear in a reinstatement test was observed in both control and rehearsal conditions, whereas in the nonrehearsal condition there was a generalized increase in response to the CS+ and CS−. Differential response in the rehearsal condition had values slightly smaller than the control group with no significant differences from both control and nonrehearsal conditions. These results suggest that the overt behavior of participants during the interval between a retrieval cue and extinction training might change the effects of PRE in healthy human participants, but further manipulations of these variables are needed to confirm these findings. Studies show that fear memories can be erased with post‐retrieval extinction (PRE), but replication failures indicate the existence of boundary conditions limiting these effects. Our experiment suggests that rehearsing the CS‐US contingency after the presentation of a retrieval cue might be one of these boundary conditions and interfere with the effects of PRE. [ABSTRACT FROM AUTHOR]

Thus, we suggested that pain-CRs are instances of perceived pain and altered nociception, which arise in the absence of painful stimulation that caused the activation of peripheral nociceptors. Pain-CRs were qualitatively similar to pain directly resulting from nociceptive stimulation: pain-CRs were consciously perceived and verbally expressed by individuals in our study and transiently also yielded a physiological sensory component as suggested by neurologic pain signature responses. We thus argued that they have similarity with nociplastic pain.[[9]] Both, on the verbal and the central level, we found that these pain-CRs can have the same features as peripherally induced pain. [Extracted from the article]

Disgust can be acquired via evaluative conditioning; a process by which a neutral stimulus (conditioned stimulus; CS) comes to be evaluated as disgusting due to its pairing with an inherently disgusting stimulus (unconditioned stimulus; US). Research has shown that conditioned disgust responses are resistant to extinction which may have implications for disorders (i.e., contamination-based obsessive-compulsive disorder, specific phobias, and post-traumatic stress disorder) in which heightened disgust has been implicated. Importantly, extinction is the primary mechanism by which exposure therapies are thought to achieve symptom reduction for these disorders. Exposure therapies were originally modeled on fear extinction, whereas disgust extinction was largely overlooked until recently. Accordingly, differences in the degree to which learned disgust and fear can be attenuated via extinction learning remains unclear. The present investigation was a meta-analysis directly comparing the degree of extinction of conditioned disgust (n = 14) and conditioned fear (n = 14) in laboratory paradigms. Extinction was operationalized as the standardized mean difference (SMD) in evaluative ratings between the CS+ (the CS paired with the US) and CS- (the unpaired CS) after extinction training. Results of a subgroup analysis indicated that disgust (SMD = 0.52) was significantly more resistant to extinction than fear (SMD = 0.37). Additionally, a series of meta-regression analyses indicated that extinction was not influenced by important study characteristics (e.g., sex, age, number of conditioning and extinction trials). The findings suggest that extinction-based approaches may be less effective at attenuating learned disgust and research is needed to better optimize treatments for disgust-related disorders. • Meta-analysis comparing extinction of conditioned disgust and fear in laboratory paradigms. • Disgust significantly more resistant to extinction than fear. • Degree of extinction not influenced by study characteristics. [ABSTRACT FROM AUTHOR]

Across social species, the presence of another individual can reduce stress reactions to adverse stimuli, a phenomenon known as social buffering. The present study investigated whether social buffering influences the expression and extinction of learned fear in adolescence, a developmental period of diminished fear inhibition and increased social interaction. Quality of maternal care and degree of social investigation were examined as factors that may influence social buffering. In adolescence, male rats were fear conditioned and then given extinction training either in the presence of a same-age rat or alone. Animals were then tested alone for extinction retention. In two experiments, the presence of a conspecific robustly reduced conditioned fear responses during extinction training. Interestingly, a persistent social buffering effect was observed when the extinction and conditioning contexts had prominent differences in features (Experiment 1), but not when these contexts were relatively similar (Experiment 2). Neither quality of maternal care nor degree of social investigation predicted the effects of social buffering. These findings suggest that social buffering robustly dampens fear responses during adolescence when a peer is present and this suppression can persist, in some instances, even when the peer is absent. [Display omitted] • Social buffering during adolescence reduced learned fear responses at extinction. • In some cases, this effect persisted. • Social buffering did not influence renewal. • Maternal care and social investigation did not predict social buffering. [ABSTRACT FROM AUTHOR]

Stimuli in our environment are not always associated with an outcome. Some of these stimuli, depending on how they are presented, may gain inhibitory value or simply be ignored. If experienced in the presence of other cues predictive of appetitive or aversive outcomes, they typically gain inhibitory value and become predictive cues indicating the absence of appetitive or aversive outcomes. In this case, these cues are referred to as conditioned inhibitors. Here, male and female Long Evans rats underwent cue discrimination training where a reward cue was paired with sucrose, a fear cue with footshock, and an inhibitor cue resulted in neither sucrose or footshock. During a subsequent summation test for conditioned inhibition of fear and reward, the inhibitor cue was presented concurrently with the reward and fear cues without any outcome, intermixed with trials of reinforced reward and fear trials. Males showed significant conditioned inhibition of freezing, while females did not, which was not dependent on estrous. Both males and females showed significant conditioned inhibition of reward. During a retardation of fear acquisition test, the inhibitor was paired with footshock and both males and females showed delayed acquisition of fear. During a retardation of reward acquisition test, the inhibitor was paired with sucrose, and females showed delayed acquisition of reward, while males did not. In summary, males and females showed significant reward-fear-inhibitor cue discrimination, conditioned inhibition of reward, and retardation of fear acquisition. The main sex difference, which was not estrous-dependent, was the lack of conditioned inhibition of freezing in females. These data imply that while the inhibitor cue gained some inhibitory value in the females, the strength of this inhibitory value may not have been great enough to effectively downregulate freezing elicited by the fear cue. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

The brainstem dorsal periaqueductal gray (dPAG) has been widely recognized as being a vital node orchestrating the responses to innate threats. Intriguingly, recent evidence also shows that the dPAG mediates defensive responses to fear conditioned contexts. However, it is unknown whether the dPAG displays independent or shared patterns of activation during exposure to innate and conditioned threats. It is also unclear how dPAG ensembles encode and predict diverse defensive behaviors. To address this question, we used miniaturized microscopes to obtain recordings of the same dPAG ensembles during exposure to a live predator and a fear conditioned context in male mice. dPAG ensembles encoded not only distance to threat, but also relevant features, such as predator speed and angular offset between mouse and threat. Furthermore, dPAG cells accurately encoded numerous defensive behaviors, including freezing, stretch-attend postures, and escape. Encoding of behaviors and of distance to threat occurred independently in dPAG cells. dPAG cells also displayed a shared representation to encode these behaviors and distance to threat across innate and conditioned threats. Last, we also show that escape could be predicted by dPAG activity several seconds in advance. Thus, dPAG activity dynamically tracks key kinematic and behavioral variables during exposure to threats, and exhibits similar patterns of activation during defensive behaviors elicited by innate or conditioned threats. These data indicate that a common pathway may be recruited by the dPAG during exposure to a wide variety of threat modalities. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Fear extinction alone does not erase the original fear memory. Interventions that enhance extinction can be beneficial for the treatment of fear-related disorders. Repetitive transcranial magnetic stimulation has been shown to improve memory performance. The present study examined the effects of intermittent theta-burst stimulation (iTBS) on fear extinction and the return of fear memory in humans. Methods: Ninety-one young healthy volunteers underwent 3 experiments using a randomized controlled experimental design. Participants first acquired fear conditioning, after which they received 30 Hz iTBS before and after extinction training. The iTBS was applied to 1 of 2 targets: the left dorsolateral prefrontal cortex (dlPFC) and the vertex (control). Fear responses were measured 24 hours later and 1 month later. Results: During the spontaneous recovery and reinstatement tests, iTBS of the left dlPFC before and after extinction significantly reduced fear response, whereas iTBS of the vertex had no effect on fear memory performance. This combined approach had a relatively long-lasting effect (i.e., at least 1 month). Limitations: We did not explore the effect of iTBS of the dlPFC on the expression of fear without extinction training. The neural mechanisms of iTBS with fear extinction to inhibit the fear response are unclear. Our results are preliminary and should be interpreted with caution. Conclusion: The present results showed that 30 Hz iTBS of the left dlPFC enhanced retention of fear extinction. Our study introduces a new intervention for fear memory and suggests that the left dlPFC may be a treatment target for fear-related disorders. [ABSTRACT FROM AUTHOR]

Background and Purpose: Women are twice as likely as men to develop post‐traumatic stress disorder (PTSD) making the search for biological mechanisms underlying these gender disparities especially crucial. One of the hallmark symptoms of PTSD is an alteration in the ability to extinguish fear responses to trauma‐associated cues. In male rodents, the endocannabinoid system can modulate fear extinction and has been suggested as a therapeutic target for PTSD. However, whether and how the endocannabinoid system may modulate fear expression and extinction in females remains unknown. Experimental Approach To answer this question, we pharmacologically manipulated endocannabinoid signalling in male and female rats prior to extinction of auditory conditioned fear and measured both passive (freezing) and active (darting) conditioned responses. Key Results: Surprisingly, we found that acute systemic inhibition of the endocannabinoid anandamide (AEA) or 2‐arachidonoyl glycerol (2‐AG) hydrolysis did not significantly alter fear expression or extinction in males. However, the same manipulations in females produced diverging effects. Increased AEA signalling at vanilloid TRPV1 receptors impaired fear memory extinction. In contrast, inhibition of 2‐AG hydrolysis promoted active over passive fear responses acutely via activation of cannabinoid1 (CB1) receptors. Measurement of AEA and 2‐AG levels after extinction training revealed sex‐ and brain region‐specific changes. Conclusion and Implications: We provide the first evidence that AEA and 2‐AG signalling affect fear expression and extinction in females in opposite directions. These findings are relevant to future research on sex differences in mechanisms of fear extinction and may help develop sex‐specific therapeutics to treat trauma‐related disorders. [ABSTRACT FROM AUTHOR]

Fear of heights is evolutionarily important for survival, yet it is unclear how and which brain regions process such height threats. Given the importance of the basolateral amygdala (BLA) in mediating both learned and innate fear, we investigated how BLA neurons may respond to high-place exposure in freely behaving male mice. We found that a discrete set of BLA neurons exhibited robust firing increases when the mouse was either exploring or placed on a high place, accompanied by increased heart rate and freezing. Importantly, these high-place fear neurons were only activated under height threats, but not looming, acoustic startle, predatory odor, or mild anxiogenic conditions. Furthermore, after a fear-conditioning procedure, these high-place fear neurons developed conditioned responses to the context, but not the cue, indicating a convergence in processing of dangerous/risky contextual information. Our results provide insights into the neuronal representation of the fear of heights and may have implications for the treatment of excessive fear disorders. [ABSTRACT FROM AUTHOR]

Adolescence is a peak time for the onset of psychiatric disorders, with anxiety disorders being the most common and affecting as many as 30% of youths. A core feature of anxiety disorders is difficulty regulating fear, with evidence suggesting deficits in extinction learning and corresponding alterations in frontolimbic circuitry. Despite marked changes in this neural circuitry and extinction learning throughout development, interventions for anxious youths are largely based on principles of extinction learning studied in adulthood. Safety signal learning, based on conditioned inhibition of fear in the presence of a cue that indicates safety, has been shown to effectively reduce anxiety-like behavior in animal models and attenuate fear responses in healthy adults. Cross-species evidence suggests that safety signal learning involves connections between the ventral hippocampus and the prelimbic cortex in rodents or the dorsal anterior cingulate cortex in humans. Particularly because this pathway follows a different developmental trajectory than fronto-amygdala circuitry involved in traditional extinction learning, safety cues may provide a novel approach to reducing fear in youths. In this review, the authors leverage a translational framework to bring together findings from studies in animal models and humans and to bridge the gap between research on basic neuroscience and clinical treatment. The authors consider the potential application of safety signal learning for optimizing interventions for anxious youths by targeting the biological state of the developing brain. Based on the existing cross-species literature on safety signal learning, they propose that the judicious use of safety cues may be an effective and neurodevelopmentally optimized approach to enhancing treatment outcomes for youths with anxiety disorders. [ABSTRACT FROM AUTHOR]

Fear conditioning and extinction (FCE) are vital processes in adaptive emotion regulation and disrupted in anxiety disorders. Despite substantial comorbidity between alcohol dependence (ALC) and anxiety disorders and reports of altered negative emotion processing in ALC, neural correlates of FCE in this clinical population remain unknown. Here, we used a 2-day fear learning paradigm in 43 healthy participants and 43 individuals with ALC at the National Institutes of Health. Main outcomes of this multimodal study included structural and functional brain magnetic resonance imaging, clinical measures, as well as skin conductance responses (SCRs) to confirm differential conditioning. Successful FCE was demonstrated across participants by differential SCRs in the conditioning phase and no difference in SCRs to the conditioned stimuli in the extinction phase. The ALC group showed significantly reduced blood oxygenation level-dependent responses in the right amygdala during conditioning (Cohen's d = .89, P(FWE) = .037) and in the left amygdala during fear renewal (Cohen's d = .68, P(FWE) = .039). Right amygdala activation during conditioning was significantly correlated with ALC severity (r = .39, P(Bonferroni) = .009), depressive symptoms (r = .37, P(Bonferroni) = .015), trait anxiety (r = .41, P(Bonferroni) = .006), and perceived stress (r = .45, P(Bonferroni) = .002). Our data suggest that individuals with ALC have dysregulated fear learning, in particular, dysregulated neural activation patterns, in the amygdala. Furthermore, amygdala activation during fear conditioning was associated with ALC-related clinical measures. The FCE paradigm may be a promising tool to investigate structures involved in negative affect regulation, which might inform the development of novel treatment approaches for ALC. [ABSTRACT FROM AUTHOR]

There is now ample evidence that the strength and underlying mechanisms of memory formation can be drastically altered by prior experience. However, the prior work using rodent models on this topic has used only males as subjects, and as a result, we do know whether or not the effects of prior experience on subsequent learning are similar in both sexes. As a first step towards addressing this shortcoming, rats of both sexes were given auditory fear conditioning, or fear conditioning with unsignaled shocks, followed an hour or a day later by a single pairing of light and shock. Fear memory for each experience was assessed by measuring freezing behavior to the auditory cue and fear-potentiated startle to the light. Results showed that males trained with auditory fear conditioning showed facilitated learning to the subsequent visual fear conditioning session when the two training sessions were separated by one hour or one day. Females showed evidence of facilitation in rats given auditory conditioning when they were spaced by an hour but not when they were spaced by one day. Contextual fear conditioning did not support the facilitation of subsequent learning under any conditions. These results indicate that the mechanism by which prior fear conditioning facilitates subsequent learning differs between sexes, and they set the stage for mechanistic studies to understand the neurobiological basis of this sex difference. [ABSTRACT FROM AUTHOR]

Aim: Fear conditioning tests are intended to elucidate a subject's ability to associate a conditioned stimulus with an aversive, unconditioned stimulus, such as footshock. Among these tests, a paradigm related to precise cortical functions would be increasingly important in drug screening for disorders such as schizophrenia and dementia. Therefore, we established a new fear conditioning paradigm using a visual cue in mice. In addition, the validity of the test was evaluated using a genetically engineered mouse, heterozygous deficient in Mdga1 (Mdga1+/‐), which is related to schizophrenia. Results: Mice were given footshocks associated with a visual cue of moving gratings at training in 25‐minute sessions. The mice showed the conditioned response of freezing behavior to the visual stimulus at testing 24 hours after the footshocks. In the test for validation, the Mdga1+/‐ deficient mice showed significantly less freezing than wild‐type mice. Conclusion: The visually cued fear conditioning paradigm with moving gratings has been established, which is experimentally useful to evaluate animal cortical functions. The validity of the test was confirmed for Mdga1‐deficient mice with possible deficiency in cortical functions. [ABSTRACT FROM AUTHOR]

Background: Depression in elderly patients is common and characterized by anxiety symptoms and cognitive impairment. To our knowledge, no studies have yet investigated the process of fear extinction in these patients. We investigated fear extinction with a paradigm consisting of habituation, acquisition and extinction.Methods: We included three age matched (mean age: 75.7 years) groups: Late Life Depression (LLD, n = 33), Mild Cognitive Impairment (MCI, n = 39), healthy controls (HC, n = 39). All participants were diagnosed with a standardized procedure including clinical examination, CERAD cognitive test battery, as well as magnetic resonance imaging. Participants underwent a fear conditioning paradigm consisting of habituation, acquisition, and extinction. During acquisition, a neutral face (conditioned stimulus, CS+) was paired with an electrical unconditioned stimulus, whereas another face (safety stimulus, CS-) was unpaired. Conditioned responses were measured by US-expectancy and valence ratings.Results: Compared to HC, both patient groups showed a significantly lower, differential (CS+ vs. CS-) fear acquisition across all measurements. Patients with cognitive impairment showed a significantly slower extinction, which is characterized by higher US-expectancy and reduced positive valence for CS+. Fear extinction was significantly less differential (CS+ vs. CS-) in patients with LLD.Limitations: Due to the cross-sectional design we cannot distinguish whether the observed differences in fear extinction are state or trait markers in the LLD patients.Conclusions: In this study, we demonstrate that fear extinction is impaired in elderly patients with depression. These results can have influence on treatment strategies. [ABSTRACT FROM AUTHOR]

Through pharmacological manipulation of the serotonergic (5-Hydroxytryptamin, 5-HT) system, combined with behavioral analysis, we tested the hypothesis that fear responses to predictable and unpredictable threat are regulated through stimulation of 5-HT receptors (5-HT-R) in the anterodorsal section of the bed nucleus of the stria terminalis (adBNST). Local adBNST application of 5-HT1A-R antagonist WAY100635 and 5-HT1B-R antagonist NAS-181 before fear retrieval enhanced freezing, 24 h after predictable fear conditioning. In contrast, increased fear responses to unpredictable threat were blocked by 5-HT1A-R agonist Buspirone (given before conditioning or retrieval) and 5-HT1B-R agonist CP-94253 (applied before training). Prolonged fear responses were also blocked by local application of the 5-HT2A-R antagonist R-96544 before fear retrieval, and conversely, local application of the 5-HT2A-R agonist NBOH-2C-CN hydrochloride before fear retrieval enhanced freezing 24 h after predictable conditioning, indicating augmented fear responses. Activation of inhibitory 5-HT1A- or 5-HT1B-Rs and the blockade of the excitatory 5-HT2A-R before unpredictable fear conditioning significantly reduced freezing during retrieval. The results from this study suggest that modulation of inhibitory 5-HT1A/1B-R and/or excitatory 5-HT2A-R activity in the adBNST may represent potential targets for the development of new treatment strategies in anxiety disorders. In addition, this study supports the validity and reliability of the mouse model of modulated fear to predictable and unpredictable threats to study mechanisms of fear and anxiety in combination with pharmacological manipulations. [ABSTRACT FROM AUTHOR]

Experimental data suggest that associative learning can influence defensive avoidance behavior and pain perception in humans. However, whether voluntary movements can become conditioned stimuli (CSs) and influence pain responses is yet to be evaluated. Forty healthy volunteers participated in this study. Electrocutaneous stimuli applied to the shoulder at pain threshold level (US) and at pain tolerance level (US) were determined before a movement-conditioning paradigm. First, reaching movements to visual cues shown on one side of a computer screen were associated with the US (CS+ movements) on 80% of trials, whereas reaching movements to visual stimuli shown on the other side were never associated with the nociceptive-US (CS- movements). Next, participants underwent a test phase in which movements to visual cues on both sides were paired with the US on 50% of trials. During the test phase, participants were asked to evaluate whether the movement was painful (yes/no) and to rate pain intensity after each trial. Movement onset and duration as well as skin conductance responses were collected. The US stimuli were more likely to be perceived as painful and were also rated as more painful during CS+ movements. Movement onset latency and skin conductance responses were significantly higher in anticipation of the CS+ movement as compared to the CS- movement. These findings suggest that pain can be conditioned to voluntary movements. [ABSTRACT FROM AUTHOR]

• Visceral pain-related learning establishes a robust aversive memory trace. • Re-exposure to visceral pain induces return of extinguished conditioned fear. • Acute inflammation does not impair the extinction of aversive gut memories. • Inflammation is not a vulnerability factor for increased return of fear. Impaired extinction of pain-related fear memories can lead to persistent or resurging fear of pain, contributing to the development and maintenance of chronic pain conditions. The mechanisms underlying maladaptive pain-related learning and memory processes remain incompletely understood, particularly in the context of interoceptive, visceral pain. Inflammation is known to interfere with learning and memory, but its effects on the extinction of pain-related fear memories have never been tested. In a randomized, double-blind, placebo-controlled study, we assessed the impact of experimental acute inflammation on the extinction and reinstatement of conditioned visceral pain-related fear. Forty healthy male volunteers underwent differential fear conditioning with visceral pain as clinically relevant unconditioned stimulus (US). Participants then received an intravenous injection of either 0.8 ng/kg lipopolysaccharide (LPS) as inflammatory stimulus or physiological saline as placebo, and extinction training was conducted at the peak of the inflammatory response. Extinction recall and reinstatement test were performed after overnight consolidation. Results showed that visceral pain represents an effective US, eliciting pronounced conditioned pain-related fear responses. Repeated unreinforced presentation of the pain-predictive cue during extinction training resulted in full extinction of the conditioned behavioral response. However, unexpected re-exposure to the US during reinstatement test resulted in return of fear. Despite pronounced LPS-induced effects on inflammatory markers, cortisol, and negative affect, we did not find evidence that acute inflammation resulted in altered fear extinction. The findings support the notion that visceral pain-related fear learning establishes a robust aversive memory trace that remains preserved during inhibitory learning, leaving a latent vulnerability for the return of fear. Inflammation during inhibitory learning did neither weaken nor further amplify this aversive memory trace, suggesting that it is rather resistant to acute inflammation-induced effects, at least in healthy individuals with no additional vulnerability factors. [ABSTRACT FROM AUTHOR]

Past research on backward conditioning in evaluative and fear conditioning yielded inconsistent results in that self‐report measures suggest that the conditional stimulus (CS) acquired the valence of the unconditional stimulus (US) in fear conditioning (assimilation effects), but the opposite valence in evaluative conditioning (contrast effects). Conversely, implicit measures of CS valence suggest assimilation effects in evaluative backward conditioning, whereas startle modulation indicates contrast effects in backward fear conditioning. The current study investigated whether US intensity could account for the dissociation on implicit measures between fear and evaluative conditioning. Self‐report measures of evaluative learning indicated assimilation effects for forward conditioning, whereas backward contrast effects were observed with intense USs only. Blink startle modulation indicated assimilation effects in forward conditioning and contrast effects in backward conditioning, regardless of US intensity. Experiment 2 included a neutral US in order to assess whether the offset of the positive US elicits an opponent emotional response that mirrors relief (disappointment), which is thought to mediate the reduction in startle seen during backward CSs in fear conditioning. This opponent emotional response was evident as startle magnitude during backward CSs increased linearly with increasing US pleasantness. Omission of the forward CSs led to an assimilation effect in self‐report measures. The current results extend our understanding of emotional learning to stimuli encountered after salient emotional events. Startle reflects the emotion prevailing after US offset, relief or disappointment, whereas self‐report measures seem more attuned to factors such as US predictability and intensity. "Relief learning" in backward fear conditioning occurs when a conditional stimulus presented after an aversive unconditional stimulus acquires positive valence as indexed by startle blink inhibition. In two experiments, we show that, mirroring "relief learning," startles during a conditional stimulus presented after a pleasant unconditional stimulus are potentiated, which suggests the acquisition of negative valence (disappointment). This demonstrates that opposing (positive or negative) emotional conditional responses can be acquired from backward conditioning with aversive or pleasant unconditional stimuli. [ABSTRACT FROM AUTHOR]

Background: Establishing neurobiological markers of posttraumatic stress disorder (PTSD) is essential to aid in diagnosis and treatment development. Fear processing deficits are central to PTSD, and their neural signatures may be used as such markers. Methods: Here, we conducted a meta-analysis of seven Pavlovian fear conditioning fMRI studies comparing 156 patients with PTSD and 148 trauma-exposed healthy controls (TEHC) using seed-based d-mapping, to contrast neural correlates of experimental phases, namely conditioning, extinction learning, and extinction recall. Results: Patients with PTSD, as compared to TEHCs, exhibited increased activation in the anterior hippocampus (extending to the amygdala) and medial prefrontal cortex during conditioning; in the anterior hippocampus-amygdala regions during extinction learning; and in the anterior hippocampus-amygdala and medial prefrontal areas during extinction recall. Yet, patients with PTSD have shown an overall decreased activation in the thalamus during all phases in this meta-analysis. Conclusion: Findings from this metanalysis suggest that PTSD is characterized by increased activation in areas related to salience and threat, and lower activation in the thalamus, a key relay hub between subcortical areas. If replicated, these fear network alterations may serve as objective diagnostic markers for PTSD, and potential targets for novel treatment development, including pharmacological and brain stimulation interventions. Future longitudinal studies are needed to examine whether these observed network alteration in PTSD are the cause or the consequence of PTSD. [ABSTRACT FROM AUTHOR]

Summary: Sleep disturbances and anxiety disorders exhibit high comorbidity levels, but it remains unclear whether sleep problems are causes or consequences of increased anxiety. To experimentally probe the aetiological role of sleep disturbances in anxiety, we investigated in healthy participants how total sleep deprivation influences fear expression in a conditioning paradigm. In a fear conditioning procedure, one face stimulus (conditioned stimulus [CS+]) was paired with electric shock, whereas another face stimulus was not (unpaired stimulus [CS−]). Fear expression was tested the next morning using the two face stimuli from the training phase and a generalization stimulus (i.e. a morph between the CS+ and CS− stimuli). Between fear conditioning and test, participants were either kept awake in the laboratory for 12 hr (n = 20) or had a night of sleep at home (n = 20). Irrespective of stimulus type, subjective threat expectancies, but not skin conductance responses, were enhanced after sleep deprivation, relative to regular sleep. These results suggest that sleep disturbances may play a role in anxiety disorders by increasing perceived threat. [ABSTRACT FROM AUTHOR]

Understanding how information about threats in the environment is shared and transmitted between individuals is crucial for explaining adaptive, survival-related behaviour in humans and other animals, and for developing treatments for phobias and other anxiety disorders. Research across species has shown that observing a conspecific’s, a ‘demonstrator’s,’ threat responses causes strong and persistent threat memories in the ‘observer’. Here, we examined if physiological synchrony between demonstrator and observer can serve to predict the strength of observationally acquired conditioned responses. We measured synchrony between demonstrators’ and observers’ phasic electrodermal signals during learning, which directly reflects autonomic nervous system activity. Prior interpersonal synchrony predicted the strength of the observer’s later skin conductance responses to threat predicting stimuli, in the absence of the demonstrator. Dynamic coupling between an observer’s and a demonstrator’s autonomic nervous system activity may reflect experience sharing processes facilitating the formation of observational threat associations. [ABSTRACT FROM AUTHOR]

Several studies have revealed that fear recovery is prevented when extinction training is conducted after retrieval of a fear memory. Postretrieval extinction training is related to modification of memory during reconsolidation. Providing new information during reconsolidation can modify the original memory. We propose that avoidance behavior is a relevant factor that prevents subjects from obtaining new safety information during reconsolidation. Postretrieval extinction training without avoidance behavior reduced the fear response to conditioned stimulus and prevented spontaneous recovery in the current study, which corresponded with previous studies. Under the condition of postretrieval extinction training with avoidance behavior, the fear response was not reduced as much as it was in the condition without avoidance. It is possible that avoidance behavior prevents receiving new safety information during postretrieval extinction training. [ABSTRACT FROM AUTHOR]

Background: The central serotonergic system originating from the dorsal raphe nucleus (DR) plays a critical role in anxiety and trauma-related disorders such as posttraumatic stress disorder. Although many studies have investigated the role of serotonin (5-HT) within pro-fear brain regions such as the amygdala, the majority of these studies have utilized non-selective pharmacological approaches or poorly understood lesioning techniques which limit their interpretation.Aim: Here we investigated the role of amygdala-projecting 5-HT neurons in the DR in innate anxiety and conditioned fear behaviors.Methods: To achieve this goal, we utilized (1) selective lesion of 5-HT neurons projecting to the amygdala with saporin toxin conjugated to anti-serotonin transporter (SERT) injected into the amygdala, and (2) optogenetic excitation of amygdala-projecting DR cell bodies with a combination of a retrogradely transported canine adenovirus-expressing Cre-recombinase injected into the amygdala and a Cre-dependent-channelrhodopsin injected into the DR.Results: While saporin treatment lesioned both local amygdalar 5-HT fibers and neurons in the DR as well as reduced conditioned fear behavior, optical activation of amygdala-projecting DR neurons enhanced anxious behavior and conditioned fear response.Conclusion: Collectively, these studies support the hypothesis that amygdala-projecting 5-HT neurons in the DR represent an anxiety and fear-on network. [ABSTRACT FROM AUTHOR]

Impaired learning and memory functioning are prime markers for Alzheimer's disease (AD). Although initial evidence points to impaired fear acquisition in later AD, no study has investigated fear conditioning in early stages and amnestic mild cognitive impairment (aMCI), a condition often preceding AD. The present study examined if fear conditioning gradually decays from healthy elderly to patients with aMCI, to patients with AD. Patients with AD (n = 43), patients with aMCI (n = 43), and matched healthy controls (n = 40) underwent a classical fear conditioning paradigm. During acquisition, a neutral face (conditioned stimulus, CS+) was paired with an electrical stimulus, whereas another face (unconditioned stimulus, CS−) was unpaired. Conditioned responses were measured by unconditioned stimulus expectancy, valence, and skin conductance. Compared to healthy controls, both patient groups showed less differential (CS+ vs. CS−) fear acquisition across all measures. Patients further displayed slowed extinction indexed by higher unconditioned stimulus expectancy and reduced positive valence for CS+, declining from aMCI to AD. Groups did not differ in responses during a preconditioning habituation phase and in unconditioned responding. Diminished differential fear acquisition and slowed extinction could represent prognostic markers for AD onset. • Fear conditioning in antidementia medication–free early Alzheimer's disease. • Acquisition deficits increase from healthy controls to early Alzheimer's disease. • Slowed extinction in early Alzheimer's disease compared with healthy controls. • Mild cognitive impairment as a transitional stage regarding conditioning deficits. • Fear conditioning deficits may be an early marker to predict Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Fear renewal is defined as return of the conditioned fear responses after extinction when a conditioned stimulus (CS) is given outside of the extinction context. Previously, we have suggested that extinction induces S-nitrosylation of GluA1 in the lateral amygdala (LA), and that the extinction-induced S-nitrosylation of GluA1 lowers the threshold of GluA1 phosphorylation (at Ser 831) which is required for fear renewal. This fits nicely with the fact that fear renewal is induced by weak stimuli. However, it has not been tested whether S-nitrosylation of GluA1 in the LA is indeed required for fear renewal. In the present study, we used three different chemicals to impede protein S-nitrosylation via distinct mechanisms. Fear renewal was inhibited by microinjection of 7-Nitroindazole (nNOS inhibitor), and ZL006 (a blocker of PSD-95-nNOS interaction) before fear renewal. Furthermore, fear renewal was also attenuated by microinjection of a strong antioxidant (N-acetyl cysteine), which scavenges reactive oxygen including nitric oxide, into the LA before each extinction training. These findings suggest that protein S-nitrosylation is required for fear renewal. • Inhibition of nNOS in the LA attenuated fear renewal. • Disruption of PSD-95-nNOS interaction in the LA inhibited fear renewal. • NO scavenging in the LA during extinction inhibited subsequent fear renewal. [ABSTRACT FROM AUTHOR]

The return of fear following extinction therapy is an important issue associated with the treatment of many fear-related disorders. Fear renewal is a suitable model, with which context-dependent modulation of the fear response can be examined. In this model, any context outside of an extinction context (e.g., novel or familiar contexts) could evoke relapse of the fear response. However, brain regions associated with context-dependent modulation are not fully understood. The posterior parietal cortex (PPC) is considered a center for integrating multisensory information and making decisions. To study its role in the contextual modulation of fear relapse, we reversibly inactivated the PPC in mice before they were exposed to various contexts after extinction training. When muscimol was infused into the PPC, fear renewal was impaired in a novel context, but not in a familiar context. Fear relapses were blocked during optogenetic inhibition of the PPC, only when animals were placed in a novel context. We propose that the neural activity of the PPC is necessary for the relapse of a precise response to an extinguished conditioned stimulus in a novel context. [ABSTRACT FROM AUTHOR]

Rationale: A promising strategy to prevent a return of fear after exposure-based therapy in anxiety disorders is to pharmacologically enhance the extinction memory consolidation presumed to occur after exposure. Accumulating evidence suggests that the effect of a number of pharmacological consolidation enhancers depends on a successful fear reduction during exposure. Here, we employed the dopamine precursor L-DOPA to clarify whether its documented potential to enhance extinction memory consolidation is dependent on successful fear extinction. Methods: In two double-blind, randomized and placebo-controlled experiments (experiment 1: N = 79, experiment 2: N = 32) comprising fear conditioning (day 1), extinction followed by administration of 150 mg L-DOPA or placebo (day 2) and a memory test (day 3) in healthy male adults, conditioned responses were assessed as differential skin conductance responses. We tested whether the effect of L-DOPA on conditioned responses at test depended on conditioned responses at the end of extinction in an experiment with a short (10 trials, experiment 1) and long (25 trials, experiment 2) extinction session. Results: In both experiments, the effect of L-DOPA was dependent on conditioned responses at the end of extinction. That is, post-extinction L-DOPA compared to placebo administration reduced conditioned responses at test only in participants showing a complete reduction of conditioned fear at the end of extinction. Conclusion: The results support the potential use of L-DOPA as a pharmacological adjunct to exposure treatment, but point towards a common boundary condition for pharmacological consolidation enhancers: a successful reduction of fear in the exposure session. [ABSTRACT FROM AUTHOR]

Background and Purpose: Women are overrepresented in post-traumatic stress disorder (PTSD), a mental disorder characterised by ineffective inhibition of fear. The use of male animals dominates preclinical studies, which may contribute to a lack of understanding as to why this disparity exists. Thus, the current study explores sex differences in three mouse models of fear inhibition.Experimental Approach: All experiments tested male and female C57Bl/6J mice. Experiment 1 employed two fear conditioning protocols, in which tones were paired with footshocks of differing intensity (moderate or intense). Fear recall and extinction were tested subsequently. In Experiment 2, safety learning was investigated. Tones were explicitly unpaired with footshocks during safety conditioning. Recall of safety learning was tested 24 hr later. Experiment 3 assessed a model of fear-safety discrimination. Cued stimuli were paired or never paired with footshocks during fear and safety conditioning, respectively. Discrimination between stimuli was assessed 24 hr later.Key Results: In fear extinction, males, compared to females, responded with greater fear in sessions most proximal to conditioning but subsequently showed a more rapid fear extinction over time. Sex differences were not observed during safety learning. During fear-safety discrimination, both males and females discriminated between stimuli; however, males revealed a greater level of freezing to stimuli.Conclusion and Implications: The current study provides evidence that sex differences influence fear but not safety-based behaviour in C57Bl/6J mice. These findings indicate that processing of fear, but not safety, may play a greater role in sex differences observed for PTSD.Linked Articles: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc. [ABSTRACT FROM AUTHOR]