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Through advances in both basic and clinical scientific research, Pavlovian fear conditioning and extinction have become an exemplary translational model for understanding and treating anxiety disorders. Discoveries in associative and neurobiological mechanisms underlying extinction have informed techniques for optimizing exposure therapy that enhance the formation of inhibitory associations and their consolidation and retrieval over time and context. Strategies that enhance formation include maximizing prediction-error correction by violating expectancies, deepened extinction, occasional reinforced extinction, attentional control and removal of safety signals/behaviours. Strategies that enhance consolidation include pharmacological agonists of NMDA (i.e. d-cycloserine) and mental rehearsal. Strategies that enhance retrieval include multiple contexts, retrieval cues, and pharmacological blockade of contextual encoding. Stimulus variability and positive affect are posited to influence the formation and the retrieval of inhibitory associations. Inhibitory regulation through affect labelling is considered a complement to extinction. The translational value of extinction will be increased by more investigation of elements central to extinction itself, such as extinction generalization, and interactions with other learning processes, such as instrumental avoidance reward learning, and with other clinically relevant cognitive–emotional processes, such as self-efficacy, threat appraisal and emotion regulation, will add translational value. Moreover, framing fear extinction and related processes within a developmental context will increase their clinical relevance. This article is part of a discussion meeting issue ‘Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.

Return of fear after successful exposure therapy for a phobia is a common clinical challenge. A previous study on mice demonstrated that the persistent attenuation of remote fear memories can be achieved by combining histone deacetylase inhibitors (HDACis) with fear-memory retrieval prior to extinction training. To evaluate the translational potential of this approach, we conducted a randomized, double-blind, placebo-controlled trial. Forty-eight individuals with DSM-IV spider phobia received either HDACi valproic acid (VPA, 500 mg) or a placebo prior to the retrieval of fear memory, followed by exposure therapy in virtual reality. No significant group difference was found in terms of behavioral change on the behavioral approach test at 3 months follow-up and baseline (primary outcome). However, the VPA group displayed significantly reduced fear in two self-report questionnaires related to spider phobia (Fear of Spiders Questionnaire; Spider Phobia Beliefs Questionnaire) as compared to the placebo group. No group differences were observed for psychophysiological indicators of fear. The favorable impact of a single administration of VPA in combination with fear-memory retrieval prior to exposure therapy suggests that it might be an effective way to enhance symptom improvement at the subjective level in the treatment of phobias. Further studies need to investigate the conditions under which an improvement on the psychophysiological and behavioral levels can be achieved as well.

Rationale To improve outcomes for patients undergoing extinction-based therapies (e.g., exposure therapy) for anxiety disorders such as post-traumatic stress disorder (PTSD), there has been interest in identifying pharmaceutical compounds that might facilitate fear extinction learning and recall. Oxytocin (OT) is a mammalian neuropeptide that modulates activation of fear extinction-based neural circuits and fear responses. Little is known, however, about the effects of OT treatment on conditioned fear responding and extinction in humans. Objectives The purpose of the present study was to assess the effects of OT in a fear-potentiated startle task of fear conditioning and extinction. Methods A double-blind, placebo-controlled study of 44 healthy human participants was conducted. Participants underwent a conditioned fear acquisition procedure, after which they were randomized to treatment group and delivered OT (24 IU) or placebo via intranasal (IN) spray. Forty-five minutes after treatment, participants underwent extinction training. Twenty-four hours later, subjects were tested for extinction recall. Results Relative to placebo, the OT group showed increased fear-potentiated startle responding during the earliest stage of extinction training relative to placebo; however, all treatment groups showed the same level of reduced responding by the end of extinction training. Twenty-four hours later, the OT group showed significantly higher recall of extinction relative to placebo. Conclusions The current study provides preliminary evidence that OT may facilitate fear extinction recall in humans. These results support further study of OT as a potential adjunctive treatment for extinction-based therapies in fear-related disorders.

Anxiety disorders are among the most prevalent mental disorders. Present treatments such as cognitive behavior therapy and pharmacological treatments show only moderate success, which emphasizes the importance for the development of new treatment protocols. Non-invasive brain stimulation methods such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been probed as therapeutic option for anxiety disorders in recent years. Mechanistic information about their mode of action, and most efficient protocols is however limited. Here the fear extinction model can serve as a model of exposure therapies for studying therapeutic mechanisms, and development of appropriate intervention protocols. We systematically reviewed 30 research articles that investigated the impact of rTMS and tDCS on fear memory and extinction in animal models and humans, in clinical and healthy populations. The results of these studies suggest that tDCS and rTMS can be efficient methods to modulate fear memory and extinction. Furthermore, excitability-enhancing stimulation applied over the vmPFC showed the strongest potential to enhance fear extinction. We further discuss factors that determine the efficacy of rTMS and tDCS in the context of the fear extinction model and provide future directions to optimize parameters and protocols of stimulation for research and treatment.

RationaleA 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.MethodsIn 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.ResultsIn 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.ConclusionThe 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.

Recent research on changing fears has examined targeting reconsolidation. During reconsolidation, stored information is rendered labile after being retrieved. Pharmacological manipulations at this stage result in an inability to retrieve the memories at later times, suggesting that they are erased or persistently inhibited. Unfortunately, the use of these pharmacological manipulations in humans can be problematic. Here we introduce a non-invasive technique to target the reconsolidation of fear memories in humans. We provide evidence that old fear memories can be updated with non-fearful information provided during the reconsolidation window. As a consequence, fear responses are no longer expressed, an effect that lasted at least a year and was selective only to reactivated memories without affecting others. These findings demonstrate the adaptive role of reconsolidation as a window of opportunity to rewrite emotional memories, and suggest a non-invasive technique that can be used safely in humans to prevent the return of fear. An appointment with fear Reconsolidation is a natural mechanism in human memory: the reconsolidation phase allows new information available at the time of retrieval to be incorporated into an old memory. Although pharmacological blockade of reconsolidation has been used to prevent the return of fear in animal models, many of these manipulations involve compounds that are toxic to humans. Elizabeth Phelps and co-workers now report a non-invasive technique of rewriting fear memories that avoids the use of drugs. The procedure is based on an established technique in which memories of traumatic events are 'extinguished' by repeated exposure to traumatic reminders in a safe environment. This works up to a point, but memories are masked rather than eliminated and can return, for example with the passage of time or due to stress. The new advance lies in timing: if the 'safe' information is introduced during the reconsolidation window of old fear memories, the fear does not return. This work suggests that post-traumatic stress disorder and other anxiety conditions might be responsive to new types of non-invasive therapy. During reconsolidation of memories, stored information is rendered labile after being retrieved and can be manipulated. Previous studies have used pharmacological intervention to disrupt retrieved memories; here, however, a non-invasive, behavioural technique is used to target the reconsolidation of fear memories in humans. Non-fearful information provided during the reconsolidation window appears to update old fear memories, causing a lack of expression of fear responses.

The nonapeptide, oxytocin (OT), known for its role in social bonding and attachment formation, has demonstrated anxiolytic properties in animal models and human studies. However, its role in the regulation of fear responses appears more complex, brain site-specific, sex-specific, and dependent on a prior stress history. Studies have shown that OT neurons in the hypothalamus are activated during cued and contextual fear conditioning and during fear recall, highlighting the recruitment of endogenous oxytocin system in fear learning. OT is released into the extended amygdala, which contains the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), both critical for the regulation of fear and anxiety-like behaviors. Behavioral studies report that OT in the CeA reduces contextual fear responses; whereas in the BNST, OT receptor (OTR) neurotransmission facilitates cued fear and reduces fear responses to un-signaled, diffuse threats. These ostensibly contrasting behavioral effects support growing evidence that OT works to promote fear discrimination by reducing contextual fear or fear of diffuse threats, yet strengthening fear responses to imminent and predictable threats. Recent studies from the basolateral nucleus of the amygdala (BLA) support this notion and show that activation of OTR in the BLA facilitates fear discrimination by increasing fear responses to discrete cues. Also, OTR transmission in the CeA has been shown to mediate a switch from passive freezing to active escape behaviors in confrontation with an imminent, yet escapable threat but reduce reactivity to distant threats. Therefore, OT appears to increase the salience of relevant threat-signaling cues yet reduce fear responses to un-signaled, distant, or diffuse threats. Lastly, OTR signaling has been shown to underlie emotional discrimination between conspecifics during time of distress, social transmission of fear, and social buffering of fear. As OT has been shown to enhance salience of both positive and negative social experiences, it can also serve as a warning system against potential threats in social networks. Here, we extend the social salience hypothesis by proposing that OT enhances the salience of relevant environmental cues also in non-social contexts, and as such promotes active defensive behaviors.

Traumatic events can engender persistent excessive fear responses to trauma reminders that may return even after successful treatment. Extinction, the laboratory analog of behavior therapy, does not erase conditioned fear memories but generates competing, fear-inhibitory “extinction memories” that, however, are tied to the context in which extinction occurred. Accordingly, a dominance of fear over extinction memory expression—and, thus, return of fear—is often observed if extinguished fear stimuli are encountered outside the extinction (therapy) context. We show that postextinction administration of the dopamine precursor l -dopa makes extinction memories context-independent, thus strongly reducing the return of fear in both mice and humans. Reduced fear is accompanied by decreased amygdala and enhanced ventromedial prefrontal cortex activation in both species. In humans, ventromedial prefrontal cortex activity is predicted by enhanced resting-state functional coupling of the area with the dopaminergic midbrain during the postextinction consolidation phase. Our data suggest that dopamine-dependent boosting of extinction memory consolidation is a promising avenue to improving anxiety therapy.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder associated with memories of traumatic experiences. Conditioned fear memory, a representative model of traumatic memories, is observed across species from lower to higher animals, including humans. Numerous studies have investigated the mechanisms of conditioned fear memory and have led to the identification of the underlying processes involved in fear memory regulation, including cellular and systems consolidation of fear conditioning, destabilization/reconsolidation and extinction after fear memory retrieval, and forgetting of fear memory. These studies suggested that mechanisms for fear memory regulation are shared by humans and other higher animals. Additionally, rodent studies have identified the mechanisms of fear memory at the molecular, cellular, and circuit levels. Findings from these studies in rodents have been applied to facilitate the development and improvement of PTSD intervention. For instance, reconsolidation and extinction of fear memories have been applied for PTSD treatment to improve prolonged exposure (PE) therapy, an effective psychotherapy for PTSD. Combination of medications weakening retrieved traumatic memory (e.g., by facilitating both destabilization and extinction) with PE therapy may contribute to improvement of PTSD. Interestingly, a recent study in mice identified forgetting of fear memory as another potential therapeutic target for PTSD. A better understanding of the mechanisms involved in fear memory processes is likely to facilitate the development of better treatments for PTSD. This review describes fear memory processes and their mechanisms and discusses the pros and cons of applying how this knowledge can be applied in the development of interventions for PTSD.

COVID-19 is a major source of fear, stress, and anxiety as well as a major factor impacting the health and wellbeing of people worldwide. The present study builds on the recently developed “Fear of COVID-19 Scale” (Ahorsu et al., In International Journal of Mental Health and Addiction, https://doi.org/10.1007/s11469-020-00270-8 , 2020). The sample comprised of 850 participants, male and female young adults from Russia and Belarus. The majority of survey participants are university students and graduates. Females, students, and others from Russia report higher levels of COVID-19-related fear than those from Belarus. Respondents from Russia and Belarus report less fear than people from Iran who were surveyed earlier. The scale used for the present survey evidenced a good Cronbach’s Alpha measure of internal consistency or reliability (0.809). Clearly, further research is needed across locations and over time about the nature and extent of fear caused by COVID 19. Overall, the FCV-19S appears to be a valuable and brief instrument that may provide useful information for intervention and policy purposes to migrate fear and problem behavior linked to infectious disease outbreaks.