Dieuwke Sevenster

Prediction error governs pharmacologically induced amnesia for learned fear

Overwriting Human Memory A consolidated fear memory can enter a transient labile phase upon its reactivation. Pharmacological blockade of the subsequent protein synthesis-dependent restabilization produces a memory deficit. Sevenster et al. (p. 830) found that prediction error (a discrepancy between actual and expected events) is a necessary condition for reconsolidation of a fear memory in human subjects. Retrieval cued by a negative prediction error, for example, like a conditioned stimulus presented in the absence of the unconditioned stimulus, resulted in labilization and subsequent reconsolidation was blocked by the drug propranolol. However, if there was no prediction error because the conditioned stimulus and the aversive unconditioned stimulus were presented simultaneously, the memory did not enter a labile state and its reconsolidation could not be blocked. Human fear memory labilization can be assessed noninvasively, independent of whether reconsolidation occurs. Although reconsolidation opens up new avenues to erase excessive fear memory, subtle boundary conditions put constraints on retrieval-induced plasticity. Reconsolidation may only take place when memory reactivation involves an experience that engages new learning (prediction error). Thus far, it has not been possible to determine the optimal degree of novelty required for destabilizing the memory. The occurrence of prediction error could only be inferred from the observation of a reconsolidation process itself. Here, we provide a noninvasive index of memory destabilization that is independent from the occurrence of reconsolidation. Using this index, we show in humans that prediction error is (i) a necessary condition for reconsolidation of associative fear memory and (ii) determined by the interaction between original learning and retrieval. Insight into the process of memory updating is crucial for understanding the optimal and boundary conditions on reconsolidation and provides a clear guide for the development of reconsolidation-based treatments.

Retrieval per se is not sufficient to trigger reconsolidation of human fear memory

Ample evidence suggests that consolidated memories, upon their retrieval, enter a labile state, in which they might be susceptible to change. It has been proposed that memory labilization allows for the integration of relevant information in the established memory trace (memory updating). Memory labilization and reconsolidation do not necessarily occur when a memory is being reactivated, but only when there is something to be learned during memory retrieval (prediction error). Thus, updating of a fear memory trace should not occur under retrieval conditions in which the outcome is fully predictable (no prediction error). Here, we addressed this issue, using a human differential fear conditioning procedure, by eliminating the very possibility of reinforcement of the reminder cue. A previously established fear memory (picture-shock pairings) was reactivated with shock-electrodes attached (Propranolol group, n=18) or unattached (Propranolol No-Shock Expectation group, n=19). We additionally tested a placebo-control group with the shock-electrodes attached (Placebo group, n=18). Reconsolidation was not triggered when nothing could be learned during the reminder trial, as noradrenergic blockade did not affect expression of the fear memory 24h later in the Propranolol No-Shock Expectation group. Only when the outcome of the retrieval cue was not fully predictable, propranolol, contrary to placebo, reduced the startle fear response and prevented the return of fear (reinstatement) the following day. In line with previous studies, skin conductance response and shock expectancies were not affected by propranolol. Remarkably, a double dissociation emerged between the emotional (startle response) and more cognitive expression (expectancies, SCR) of the fear memory. Our findings have important implications for reconsolidation blockade as treatment strategy for emotional disorders. First, fear reducing procedures that target the emotional component of fear memory do not necessarily affect the cognitive component and vice versa. Second, mere retrieval of the fear memory is not sufficient to induce its labilization and reconsolidation.

Prediction error demarcates the transition from retrieval, to reconsolidation, to new learning

Although disrupting reconsolidation is promising in targeting emotional memories, the conditions under which memory becomes labile are still unclear. The current study showed that post-retrieval changes in expectancy as an index for prediction error may serve as a read-out for the underlying processes engaged by memory reactivation. Minor environmental changes define whether retrieval induces memory reconsolidation or the initiation of a new memory trace even before fear extinction can be observed.

Fear conditioning of SCR but not the startle reflex requires conscious discrimination of threat and safety

There is conflicting evidence as to whether awareness is required for conditioning of the skin conductance response (SCR). Recently, Schultz and Helmstetter (2010) reported SCR conditioning in contingency unaware participants by using difficult to discriminate stimuli. These findings are in stark contrast with other observations in human fear conditioning research, showing that SCR predominantly reflects contingency learning. Therefore, we repeated the study by Schultz and Helmstetter and additionally measured conditioning of the startle response, which seems to be less sensitive to declarative knowledge than SCR. While we solely observed SCR conditioning in participants who reported awareness of the contingencies (n = 16) and not in the unaware participants (n = 18), we observed startle conditioning irrespective of awareness. We conclude that SCR but not startle conditioning depends on conscious discriminative fear learning.

Instructed extinction differentially affects the emotional and cognitive expression of associative fear memory

Instructed extinction after fear conditioning is relatively effective in attenuating electrodermal responding. Testing the single-process account of fear learning, we examined whether this manipulation similarly affects the startle response. Skin conductance responses (SCRs), startle responses, and online unconditioned stimulus (US) expectancy ratings were measured during fear acquisition (Day 1), extinction, and reinstatement (Day 2). Before extinction onset, half of the subjects were instructed that the conditioned stimulus would not be followed by the US (Instructed Extinction) whereas the other subjects were not instructed (Normal Extinction). This simple instruction completely abolished both differential SCR and US expectancy ratings, but not the startle fear response. Although the manipulation facilitated extinction learning, it did not prevent the recovery of the startle response. The present findings are better explained by a dual- rather than a single-process account of fear learning.

Personality predicts individual variation in fear learning: a multilevel growth modeling approach

Although fear-learning research has tended to focus on typical responses, there is substantial individual variation in response to threat. Here, we investigated how personality is related to variability in associative fear learning. We used multilevel growth curve modeling to examine the unique and interactive effects of Stress Reaction (SR) and Harmavoidance (HA; Multidimensional Personality Questionnaire scales) and their corresponding higher-order factors on differential fear conditioning (n = 225) and extinction (n = 109; 24–48 hr later). Fear was indexed by fear potentiation of the eyeblink startle reflex. Our findings demonstrated weaker discrimination between threat and safety with high levels of SR. Subsequently, both retention of differential fear acquisition and extinction were weaker with high levels of SR and HA, thereby indicating maladaptive fear learning, whereas they were stronger with low levels of SR and high levels of HA, which suggests efficient fear learning. These findings illustrate how specific personality traits may operate to confer vulnerability or resilience for anxiety disorders.

Disrupting reconsolidation of fear memory in humans by a noradrenergic β-blocker

The basic design used in our human fear-conditioning studies on disrupting reconsolidation includes testing over different phases across three consecutive days. On day 1 - the fear acquisition phase, healthy participants are exposed to a series of picture presentations. One picture stimulus (CS1+) is repeatedly paired with an aversive electric stimulus (US), resulting in the acquisition of a fear association, whereas another picture stimulus (CS2-) is never followed by an US. On day 2 - the memory reactivation phase, the participants are re-exposed to the conditioned stimulus without the US (CS1-), which typically triggers a conditioned fear response. After the memory reactivation we administer an oral dose of 40 mg of propranolol HCl, a β-adrenergic receptor antagonist that indirectly targets the protein synthesis required for reconsolidation by inhibiting the noradrenaline-stimulated CREB phosphorylation. On day 3 - the test phase, the participants are again exposed to the unreinforced conditioned stimuli (CS1- and CS2-) in order to measure the fear-reducing effect of the manipulation. This retention test is followed by an extinction procedure and the presentation of situational triggers to test for the return of fear. Potentiation of the eye blink startle reflex is measured as an index for conditioned fear responding. Declarative knowledge of the fear association is measured through online US expectancy ratings during each CS presentation. In contrast to extinction learning, disrupting reconsolidation targets the original fear memory thereby preventing the return of fear. Although the clinical applications are still in their infancy, disrupting reconsolidation of fear memory seems to be a promising new technique with the prospect to persistently dampen the expression of fear memory in patients suffering from anxiety disorders and other psychiatric disorders.

Heart rate pattern and resting heart rate variability mediate individual differences in contextual anxiety and conditioned responses

Cardiac activity provides possible markers for the identification of those at risk for the development of anxiety disorders. Cardiac deceleration has been linked to impaired fear conditioning while low heart rate variability (HRV) has been associated with elevated contextual anxiety and enhanced startle potentiation to affective stimuli. In the current study we examined individual differences in conditioned responses as a function of cardiac activity. In addition to classifying participants as decelerators and accelerators, we examined baseline fear responding and conditioned responses in participants with low and high resting state heart rate variability. We complemented well-established physiological measures (startle response and skin conductance) and online distress and retrospective expectancy ratings of fear conditioning with measures of heart rate (HR). In contrast to accelerators, decelerators did not show any sign of startle fear conditioning, but demonstrated increased differential conditioning of online distress. Only marginal differences in contextual anxiety and conditioned fear responding were observed for low and high HRV individuals. These results may contribute to the identification of individuals who are at risk for the development of anxiety disorders.

A translational perspective on neural circuits of fear extinction: Current promises and challenges

&NA; Fear extinction is the well‐known process of fear reduction through repeated re‐exposure to a feared stimulus without the aversive outcome. The last two decades have witnessed a surge of interest in extinction learning. First, extinction learning is observed across species, and especially research on rodents has made great strides in characterising the physical substrate underlying extinction learning. Second, extinction learning is considered of great clinical significance since it constitutes a crucial component of exposure treatment. While effective in reducing fear responding in the short term, extinction learning can lose its grip, resulting in a return of fear (i.e., laboratory model for relapse of anxiety symptoms in patients). Optimization of extinction learning is, therefore, the subject of intense investigation. It is thought that the success of extinction learning is, at least partly, determined by the mismatch between what is expected and what actually happens (prediction error). However, while much of our knowledge about the neural circuitry of extinction learning and factors that contribute to successful extinction learning comes from animal models, translating these findings to humans has been challenging for a number of reasons. Here, we present an overview of what is known about the animal circuitry underlying extinction of fear, and the role of prediction error. In addition, we conducted a systematic literature search to evaluate the degree to which state‐of‐the‐art neuroimaging methods have contributed to translating these findings to humans. Results show substantial overlap between networks in animals and humans at a macroscale, but current imaging techniques preclude comparisons at a smaller scale, especially in sub‐cortical areas that are functionally heterogeneous. Moreover, human neuroimaging shows the involvement of numerous areas that are not typically studied in animals. Results obtained in research aimed to map the extinction circuit are largely dependent on the methods employed, not only across species, but also across human neuroimaging studies. Directions for future research are discussed.

A review on the effects of verbal instructions in human fear conditioning: Empirical findings, theoretical considerations, and future directions

Fear learning reflects the adaptive ability to learn to anticipate aversive events and to display preparatory fear reactions based on prior experiences. Usually, these learning experiences are modeled in the lab with pairings between a neutral conditioned stimulus (CS) and an aversive unconditioned stimulus (US) (i.e., fear conditioning via CS-US pairings). Nevertheless, for humans, fear learning can also be based on verbal instructions. In this review, we consider the role of verbal instructions in laboratory fear learning. Specifically, we consider both the effects of verbal instructions on fear responses in the absence of CS-US pairings as well as the way in which verbal instructions moderate fear established via CS-US pairings. We first focus on the available empirical findings about both types of effects. More specifically, we consider how these effects are moderated by elements of the fear conditioning procedure (i.e., the stimuli, the outcome measures, the relationship between the stimuli, the participants, and the broader context). Thereafter, we discuss how well different mental-process models of fear learning account for these empirical findings. Finally, we conclude the review with a discussion of open questions and opportunities for future research.