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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.

In human evolution, social group living and Pavlovian fear conditioning have evolved as adaptive mechanisms promoting survival and reproductive success. The evolutionarily conserved hypothalamic peptide oxytocin is a key modulator of human sociality, but its effects on fear conditioning are still elusive. In the present randomized controlled study involving 97 healthy male subjects, we therefore employed functional magnetic resonance imaging and simultaneous skin conductance response (SCR) measures to characterize the modulatory influence of intranasal oxytocin (24 IU) on Pavlovian fear conditioning. We found that the peptide strengthened conditioning on both the behavioral and neural levels. Specifically, subjects exhibited faster task-related responses and enhanced SCRs to fear-associated stimuli in the late phase of conditioning, which was paralleled by heightened activity in cingulate cortex subregions in the absence of changes in amygdala function. This speaks against amygdalocentric views of oxytocin having pure anxiolytic-like effects. Instead, it suggests that the peptide enables extremely rapid and flexible adaptation to fear signals in social contexts, which may confer clear evolutionary advantages but could also elevate vulnerability for the pathological sequelae of interpersonal trauma.

Some people hear voices that others do not, but only some of those people seek treatment. Using a Pavlovian learning task, we induced conditioned hallucinations in four groups of people who differed orthogonally in their voice-hearing and treatment-seeking statuses. People who hear voices were significantly more susceptible to the effect. Using functional neuroimaging and computational modeling of perception, we identified processes that differentiated voice-hearers from non–voice-hearers and treatment-seekers from non–treatment-seekers and characterized a brain circuit that mediated the conditioned hallucinations. These data demonstrate the profound and sometimes pathological impact of top-down cognitive processes on perception and may represent an objective means to discern people with a need for treatment from those without.

Dopamine neurons in the ventral tegmental area are thought to signal reward prediction error. The authors show that these neurons respond with striking homogeneity during classical conditioning. All dopamine neurons appear to calculate reward prediction error similarly, enabling robust and consistent broadcasting of this signal throughout the brain. Dopamine neurons are thought to signal reward prediction error, or the difference between actual and predicted reward. How dopamine neurons jointly encode this information, however, remains unclear. One possibility is that different neurons specialize in different aspects of prediction error; another is that each neuron calculates prediction error in the same way. We recorded from optogenetically identified dopamine neurons in the lateral ventral tegmental area (VTA) while mice performed classical conditioning tasks. Our tasks allowed us to determine the full prediction error functions of dopamine neurons and compare them to each other. We found marked homogeneity among individual dopamine neurons: their responses to both unexpected and expected rewards followed the same function, just scaled up or down. As a result, we were able to describe both individual and population responses using just two parameters. Such uniformity ensures robust information coding, allowing each dopamine neuron to contribute fully to the prediction error signal.

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.

Research on avoidance conditioning began in the late 1930s as a way to use laboratory experiments to better understand uncontrollable fear and anxiety. Avoidance was initially conceived of as a two-factor learning process in which fear is first acquired through Pavlovian aversive conditioning (so-called fear conditioning), and then behaviors that reduce the fear aroused by the Pavlovian conditioned stimulus are reinforced through instrumental conditioning. Over the years, criticisms of both the avoidance paradigm and the two-factor fear theory arose. By the mid-1980s, avoidance had fallen out of favor as an experimental model relevant to fear and anxiety. However, recent progress in understanding the neural basis of Pavlovian conditioning has stimulated a new wave of research on avoidance. This new work has fostered new insights into contributions of not only Pavlovian and instrumental learning but also habit learning, to avoidance, and has suggested that the reinforcing event underlying the instrumental phase should be conceived in terms of cellular and molecular events in specific circuits rather than in terms of vague notions of fear reduction. In our approach, defensive reactions (freezing), actions (avoidance) and habits (habitual avoidance) are viewed as being controlled by unique circuits that operate nonconsciously in the control of behavior, and that are distinct from the circuits that give rise to conscious feelings of fear and anxiety. These refinements, we suggest, overcome older criticisms, justifying the value of the new wave of research on avoidance, and offering a fresh perspective on the clinical implications of this work.

d-cycloserine (DCS), a partial NMDA-receptor agonist, seems to be a promising enhancer for exposure therapy in anxiety disorders. It has been tested successfully in animal models of fear extinction, where DCS enhanced extinction learning. Applied in clinical studies, results of DCS-augmented exposure therapy remain ambiguous, calling for a deeper understanding of the underlying mechanisms of DCS and its exact effect on extinction learning and return of fear (ROF) in humans. In the present study, we investigated the effect of DCS-augmented extinction learning on behavioral, psychophysiological, and neural indices of ROF during a 24-h delayed recall test. Thirty-seven participants entered a randomized, placebo-controlled, double-blind, 3-day fear conditioning and delayed extinction fMRI design. One hour before extinction training, participants received an oral dose of 50 mg of DCS or a placebo. Behavioral arousal ratings revealed a generalized ROF during extinction recall in the placebo but not DCS group. Furthermore, participants receiving DCS compared to placebo showed attenuated differential BOLD responses in left posterior hippocampus and amygdala from extinction learning to extinction recall, due to increased hippocampal recruitment in placebo and trendwise decreased amygdala responding in DCS subjects. Our finding that DCS reduces ROF in arousal ratings and neural structures subserving defensive reactions support a role for NMDA receptors in extinction memory consolidation and encourage further translational research.

The noradrenergic system plays a critical role in the 'consolidation' of emotional memory. If we are to target 'reconsolidation' in patients with anxiety disorders, the noradrenergic strengthening of fear memory should not impair the disruption of reconsolidation. In Experiment I, we addressed this issue using a differential fear conditioning procedure allowing selective reactivation of one of two fear associations. First, we strengthened fear memory by administering an α(2)-adrenergic receptor antagonist (ie, yohimbine HCl; double-blind placebo-controlled study) 30 min before acquisition (time for peak value yohimbine HCl <1 h). Next, the reconsolidation of one of the fear associations was manipulated by administering a β-adrenergic receptor antagonist (ie, propranolol HCl) 90 min before its selective reactivation (time for peak value propranolol HCl <2 h). In Experiment II, we administered propranolol HCl after reactivation of the memory to rule out a possible effect of the pharmacological manipulation on the memory retrieval itself. The excessive release of noradrenaline during memory formation not only delayed the process of extinction 48 h later, but also triggered broader fear generalization. Yet, the β-adrenergic receptor blocker during reconsolidation selectively 'neutralized' the fear-arousing aspects of the noradrenergic-strengthened memory and undermined the generalization of fear. We observed a similar reduction in fear responding when propranolol HCl was administered after reactivation of the memory. The present findings demonstrate the involvement of noradrenergic modulation in the formation as well as generalization of human fear memory. Given that the noradrenergic strengthening of fear memory impaired extinction learning but not the disruption of reconsolidation, our findings may have implications for the treatment of anxiety disorders.

Abstract The neurocognitive processes underlying Pavlovian conditioning in humans are still largely debated. The conventional view is that conditioned responses (CRs) emerge automatically as a function of the contingencies between a conditioned stimulus (CS) and an unconditioned stimulus (US). As such, the associative strength model asserts that the frequency or amplitude of CRs reflects the strength of the CS–US associations. Alternatively, the expectation model asserts that the presentation of the CS triggers conscious expectancy of the US, which is responsible for the production of CRs. The present study tested the hypothesis that there are dissociable brain networks related to the expectancy and associative strength theories using a single-cue fear conditioning paradigm with a pseudo-random intermittent reinforcement schedule during functional magnetic resonance imaging. Participants’ (n = 21) trial-by-trial expectations of receiving shock displayed a significant linear effect consistent with the expectation model. We also found a positive linear relationship between the expectancy model and activity in frontoparietal brain areas including the dorsolateral prefrontal cortex (PFC) and dorsomedial PFC. While an exploratory analysis found a linear relationship consistent with the associated strength model in the insula and early visual cortex, our primary results are consistent with the view that conscious expectancy contributes to CRs.

It has been demonstrated that secretion of several hormones can be classically conditioned, however, the underlying brain responses of such conditioning have never been investigated before. In this study we aimed to investigate how oxytocin administration and classically conditioned oxytocin influence brain responses. In total, 88 females were allocated to one of three groups: oxytocin administration, conditioned oxytocin, or placebo, and underwent an experiment consisting of three acquisition and three evocation days. Participants in the conditioned group received 24 IU of oxytocin together with a conditioned stimulus (CS) during three acquisition days and placebo with the CS on three evocation days. The oxytocin administration group received 24 IU of oxytocin and the placebo group received placebo during all days. On the last evocation day, fMRI scanning was performed for all participants during three tasks previously shown to be affected by oxytocin: presentation of emotional faces, crying baby sounds and heat pain. Region of interest analysis revealed that there was significantly lower activation in the right amygdala and in two clusters in the left superior temporal gyrus in the oxytocin administration group compared to the placebo group in response to observing fearful faces. The activation in the conditioned oxytocin group was in between the other two groups for these clusters but did not significantly differ from either group. No group differences were found in the other tasks. Preliminary evidence was found for brain activation of a conditioned oxytocin response; however, despite this trend in the expected direction, the conditioned group did not significantly differ from other groups. Future research should, therefore, investigate the optimal timing of conditioned endocrine responses and study whether the findings generalize to other hormones as well.