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State-of-the-art and future directions for extinction as a translational model for fear and anxiety
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'.
Journal Article
Orion and the Dark
Orion is so scared of the dark, Dark decides to pay him a visit! Orion is scared of a lot of things, but most of all he's scared of the dark. So one night Dark decides to take Orion on an adventure.
Book
The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample
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.
Journal Article
Re-encountering the phobic cue within days after a reconsolidation intervention is crucial to observe a lasting fear reduction in spider phobia
Memory reconsolidation interventions offer an exciting alternative to exposure treatment because they may target fear memories directly, thereby preventing relapse. A previous reconsolidation intervention for spider fear abruptly reduced avoidance behaviour, whereas changes in self-reported fear followed later. In this pre-registered placebo-controlled study, we first aimed to conceptually replicate these effects in spider phobia. Second, we investigated whether re-encountering the phobic cue after the reconsolidation intervention is necessary for changes in self-reported fear to occur. Third, we tested whether the window to trigger such changes is time limited. Individuals with spider phobia (
N
= 69) were randomized into three groups and underwent a memory reactivation procedure with a tarantula, followed immediately by propranolol (reconsolidation intervention) or placebo. One reconsolidation intervention group and the placebo group re-encountered spiders two days after treatment in behavioural approach tasks, whereas another reconsolidation intervention group re-encountered spiders after four weeks. Changes in spider avoidance behaviour and self-reported fear were followed for one year. In the short term, the reconsolidation intervention was not more effective than placebo: both conditions benefited from the intervention. In the long term, the reconsolidation intervention was more effective than placebo, but only when the phobic stimulus was re-encountered within days after treatment. Specifically, we found less tarantula avoidance behaviour and self-reported fear over the course of one year when spiders were re-encountered two days after the reconsolidation intervention, but not when the behavioural test was conducted four weeks after the intervention. These findings challenge the idea that a reconsolidation-inspired intervention alone is sufficient to treat clinical fears: Experiencing the behavioural change during the re-encounter within days after the reconsolidation window has closed seems crucial to observe a lasting fear reduction.
Journal Article
Effects of the histone deacetylase inhibitor valproic acid in combination with fear-memory retrieval before exposure therapy for spider phobia: A randomized controlled trial
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.
Journal Article
A Systematic Review on the Effect of Transcranial Direct Current and Magnetic Stimulation on Fear Memory and Extinction
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.
Journal Article