Systematically investigating the role of context on effect replicability in reinstatement of fear in humans

Context is crucial in guiding behavior in an ever changing world and contextual information plays a crucial role in associative learning processes. For instance, the return of fear (RoF) after reinstatement (i.e, re-exposure the unconditioned stimulus (US) after successful fear extinction) is context dependent and is suggested to occur only when either extinction and test, or extinction and reinstatement context are identical, not when US re-exposure (i.e., reinstatement) occurs in a context different from extinction and test. Human adaptions of reinstatement paradigms have resulted in mixed findings: CS specific as well as unspecific RoF or unexpected “reinstated” conditioned responding in no reinstatement US control groups. Here, we systematically investigate the role of context on reinstatement-induced RoF in a human differential fear conditioning paradigm using subjective and psychophysiological measures in a large sample (N=212) including reinstatement and control groups. Overall, response patterns in reinstatement-groups mirrored results from single-cue rodent work. Yet, only generalized, not differential RoF was observed. Remarkably, depending on outcome measure RoF was also observed under identical experimental context conditions without US-re-exposure, underlining effects of contextual change beyond the reinstatement-US and challenging reinstatement research in human subjects and what we think we know about the mechanisms behind the reinstatement-phenomenon.

Explaining the effectiveness of fear extinction through latent-cause inference

Acquiring fear responses to predictors of aversive outcomes is crucial for survival. At the same time, it is important to be able to modify such associations when they are maladaptive, for instance in treating anxiety and trauma-related disorders. Standard extinction procedures can reduce fear temporarily, but with sufficient delay or with reminders of the aversive experience, fear often returns. The latent-cause inference framework explains the return of fear by presuming that animals learn a rich model of the environment, in which the standard extinction procedure triggers the inference of a new latent cause, preventing the extinguishing of the original aversive associations. This computational framework had previously inspired an alternative extinction paradigm -- gradual extinction -- which indeed was shown to be more effective in reducing fear. However, the original framework was not sufficient to explain the pattern of results seen in the experiments. Here, we propose a formal model to explain the effectiveness of gradual extinction, in contrast to the ineffectiveness of standard extinction and a gradual reverse control procedure. We demonstrate through quantitative simulation that our model can explain qualitative behavioral differences across different extinction procedures as seen in the empirical study. We verify the necessity of several key assumptions added to the latent-cause framework, which suggest potential general principles of animal learning and provide novel predictions for future experiments.

EXPRESS: Limitations of occasional reinforced extinction to alleviate spontaneous recovery and reinstatement effects: Evidence for a trial signalling mechanism

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

Scopolamine blocks context-dependent reinstatement of fear responses in rats

Return of fear poses a problem for extinction-based therapies of clinical anxiety. Experimental research has discovered several pathways to return of fear, one of which is known as reinstatement. Here, we evaluated in rats the potential of scopolamine, a non-selective muscarinic receptor antagonist that is also safe for use in humans, to prevent the reinstatement of extinguished fear. We conducted three experiments with a total sample of 96 female rats. All rats went through a fear acquisition session (tone-shock pairings, CS-US), followed by two extinction sessions (CS only) and a post-extinction fear memory test. Twenty-four hours later, rats were placed in the same or a different context from extinction and received two unsignaled foot shock (US) presentations. On the following day, CS-evoked freezing returned when the reinstating USs had occurred in the same context compared to a different context (context-dependent reinstatement, Experiment 1). Systemic administration of scopolamine before or after the reinstating USs blocked the return of CS-evoked freezing on the following day (Experiments 2 and 3). Our findings suggest that administering scopolamine around the time of an aversive experience could prevent relapse of extinguished fears in humans.

Stimulus-Based Extinction Generalization: Neural Correlates and Modulation by Cortisol

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

Impact of the expectation on memory reconsolidation using a post retrieval extinction paradigm

ObjectiveThe present study examined if the expectation for learning enhances reconsolidation of conditioned fear memories using the post-retrieval extinction paradigm in an undergraduate sample (n = 48).MethodsThe study took place over three consecutive days. The expectation for learning was manipulated through oral instructions prior to memory reactivation. On day one, participants underwent differential fear conditioning to two spider images (CS+ and CS-). On day two, participants were assigned to either a reactivation with expectation for learning group, a reactivation with no expectation for learning group, or a no reactivation group. On day three, return of fear in response to the CS+ spider image was measured following reinstatement (i.e., four shocks). Fear potentiated startle (FPS) and skin conductance response (SCR) were taken as measures of fear.ResultsThe study found evidence that the expectation for learning may enhanced reconsolidation with FPS as a measure of fear as it was only the expectation for learning group in which FPS to the CS+ remained stable following reinstatement, however this effect was small and non-robust. In contrast, no evidence of reconsolidation was observed for SCR, as all participants exhibited a return of fear following reinstatement.ImplicationsThese findings suggest that a verbal manipulation of the expectation for learning may not be salient enough to induce reconsolidation as measured by SCR but may be sufficient as measured by FPS. Additionally, given in the inconsistent findings between SCR and FPS, the study’s results bring into question whether the post-retrieval extinction paradigm is appropriate to investigate reconsolidation using both physiological measures concurrently.