No evidence that arousal affects reactivated memories.

Memory for inherently neutral elements of emotional events is often enhanced on delayed tests - an effect that has been attributed to noradrenergic arousal. Reactivation of a memory is thought to return its corresponding neural ensemble to a state that is similar to when it was originally experienced. Therefore, we hypothesized that neutral elements of memories, too, can be enhanced through reactivation concurrent with heightened arousal. Participants (n = 94) visited the lab for three sessions. During the first session, they encoded 120 neutral memories consisting of an object presented in unique context images. In session two, the 80 objects were reactivated by presenting their corresponding context images, 40 of which were immediately followed by an arousal-inducing shock. Finally, recognition memory for all objects was tested. It was found that memory for reactivated objects was enhanced, but even though the shocks elicited elevations in arousal as indexed by skin conductance, there was no difference between memory of objects reactivated with and without heightened arousal. We thus conclude that arousal, when isolated from other cognitive and affective variables that might impact memory, has no enhancing effect on reactivated memories.

Episodic memory enhancement versus impairment is determined by contextual similarity across events.

For over a century, stability of spatial context across related episodes has been considered a source of memory interference, impairing memory retrieval. However, contemporary memory integration theory generates a diametrically opposite prediction. Here, we aimed to resolve this discrepancy by manipulating local context similarity across temporally disparate but related episodes and testing the direction and underlying mechanisms of memory change. A series of experiments show that contextual stability produces memory integration and marked reciprocal strengthening. Variable context, conversely, seemed to result in competition such that new memories become enhanced at the expense of original memories. Interestingly, these patterns were virtually inverted in an additional experiment where context was reinstated during recall. These observations 1) identify contextual similarity across original and new memories as an important determinant in the volatility of memory, 2) present a challenge to classic and modern theories on episodic memory change, and 3) indicate that the sensitivity of context-induced memory changes to retrieval conditions may reconcile paradoxical predictions of interference and integration theory.

Robust BOLD Responses to Faces But Not to Conditioned Threat: Challenging the Amygdala's Reputation in Human Fear and Extinction Learning.

Most of our knowledge about human emotional memory comes from animal research. Based on this work, the amygdala is often labeled the brain's "fear center", but it is unclear to what degree neural circuitries underlying fear and extinction learning are conserved across species. Neuroimaging studies in humans yield conflicting findings, with many studies failing to show amygdala activation in response to learned threat. Such null findings are often treated as resulting from MRI-specific problems related to measuring deep brain structures. Here we test this assumption in a mega-analysis of three studies on fear acquisition (n = 98; 68 female) and extinction learning (n = 79; 53 female). The conditioning procedure involved the presentation of two pictures of faces and two pictures of houses: one of each pair was followed by an electric shock [a conditioned stimulus (CS+)], the other one was never followed by a shock (CS-), and participants were instructed to learn these contingencies. Results revealed widespread responses to the CS+ compared with the CS- in the fear network, including anterior insula, midcingulate cortex, thalamus, and bed nucleus of the stria terminalis, but not the amygdala, which actually responded stronger to the CS- Results were independent of spatial smoothing, and of individual differences in trait anxiety and conditioned pupil responses. In contrast, robust amygdala activation distinguished faces from houses, refuting the idea that a poor signal could account for the absence of effects. Moving forward, we suggest that, apart from imaging larger samples at higher resolution, alternative statistical approaches may be used to identify cross-species similarities in fear and extinction learning.SIGNIFICANCE STATEMENT The science of emotional memory provides the foundation of numerous theories on psychopathology, including stress and anxiety disorders. This field relies heavily on animal research, which suggests a central role of the amygdala in fear learning and memory. However, this finding is not strongly corroborated by neuroimaging evidence in humans, and null findings are too easily explained away by methodological limitations inherent to imaging deep brain structures. In a large nonclinical sample, we find widespread BOLD activation in response to learned fear, but not in the amygdala. A poor signal could not account for the absence of effects. While these findings do not disprove the involvement of the amygdala in human fear learning, they challenge its typical portrayals and illustrate the complexities of translational science.

Investigating the balance between goal-directed and habitual control in experimental and real-life settings.

Do people differ in their propensity to form habits? The current study related individual differences in habitual performance on the slips-of-action task to habit formation in real life. To this end, we developed a novel key-cover procedure that controls for the amount of repetition and motivation within a naturalistic setting. Participants received a key cover for the key to their home, which after several weeks was switched with a key cover that was previously attached to a dummy key. Participants recorded effort, time, attention, and mistakes in the key-selection process. Results were in line with established properties of habits, as attention decreased in the learning phase, yet effort, time, and mistakes increased after the key-cover switch. Performance on the slips-of-action task correlated negatively with changes in attention in the real-life key-cover task. This negative correlation may reflect that flexible behavioral adjustment requires more attention in people with a relatively weak goal-directed system.

Manipulating affective state influences conditioned appetitive responses.

Affective states influence how individuals process information and behave. Some theories predict emotional congruency effects (e.g. preferential processing of negative information in negative affective states). Emotional congruency should theoretically obstruct the learning of reward associations (appetitive learning) and their ability to guide behaviour under negative mood. Two studies tested the effects of the induction of a negative affective state on appetitive Pavlovian learning, in which neutral stimuli were associated with chocolate (Experiment 1) or alcohol (Experiment 2) rewards. In both experiments, participants showed enhanced approach tendencies towards predictors of reward after a negative relative to a positive performance feedback manipulation. This increase was related to a reduction in positive affect in Experiment 1 only. No effects of the manipulation on conditioned reward expectancies, craving, or consumption were observed. Overall, our findings support the idea of counter-regulation, rather than emotional congruency effects. Negative affective states might therefore serve as a vulnerability factor for addiction, through increasing conditioned approach tendencies.

Breaking boundaries: optimizing reconsolidation-based interventions for strong and old memories.

Recent research has demonstrated that consolidated memories can enter a temporary labile state after reactivation, requiring restabilization in order to persist. This process, known as reconsolidation, potentially allows for the modification and disruption of memory. Much interest in reconsolidation stems from the possibility that maladaptive memory traces-a core feature of several psychiatric conditions-could be tackled by disrupting their reconsolidation. However, research has indicated a range of supposed boundary conditions on the induction of reconsolidation. Stronger memories, often resulting from exposure to stressful conditions, or older memories, appear to be relatively resistant to undergoing reconsolidation. This may be taken as a potential stumbling block for reconsolidation-based interventions: in clinical practice, old and strong maladaptive memories are the norm rather than the exception. Yet, boundary conditions have been derived from limited experimental evidence, are not unique to reconsolidation-based interventions, and do not seem to be absolute. In this paper, we review a range of experimental studies that have aimed to disrupt old memories, or memories that were strengthened by stress manipulations, through reconsolidation. Such research highlights several techniques that could be used to optimize reconsolidation-based approaches and overcome putative boundary conditions. We supplement this review of experimental literature with a case study of a reconsolidation-based treatment of a strong and decades-old phobia for mice, further suggesting that age and strength of memory may not be insurmountable barriers. Translating findings from basic science, to human experiments, to clinical applications and back again, can potentially unlock powerful new treatments for the many people who suffer daily from anxiety disorders.

Tackling maladaptive memories through reconsolidation: From neural to clinical science.

Behavioral neuroscience has greatly informed how we understand the formation, persistence, and plasticity of memory. Research has demonstrated that memory reactivation can induce a labile period, during which previously consolidated memories are sensitive to change, and in need of restabilization. This process is known as reconsolidation. Such findings have advanced not only our basic understanding of memory processes, but also hint at the prospect of harnessing these insights for the development of a new generation of treatments for disorders of emotional memory. However, even in simple experimental models, the conditions for inducing memory reconsolidation are complex: memory labilization appears to result from the interplay of learning history, reactivation, and also individual differences, posing difficulties for the translation of basic experimental research into effective clinical interventions. In this paper, we review a selection of influential animal and human research on memory reconsolidation to illustrate key insights these studies afford. We then consider how these findings can inform the development of new treatment approaches, with a particular focus on the transition of memory from reactivation, to reconsolidation, to new memory formation, as well as highlighting possible limitations of experimental models. If the challenges of translational research can be overcome, and if reconsolidation-based procedures become a viable treatment option, then they would be one of the first mental health treatments to be directly derived from basic neuroscience research. This would surely be a triumph for the scientific study of mind and brain.

Memory Reconsolidation Interference as an Emerging Treatment for Emotional Disorders: Strengths, Limitations, Challenges, and Opportunities.

Experimental research on emotional memory reconsolidation interference, or the induction of amnesia for previously established emotional memory, has a long tradition, but the potential of that research for the development of novel interventions to treat psychological disorders has been recognized only recently. Here we provide an overview of basic research and clinical studies on emotional memory reconsolidation interference. We point out specific advantages of interventions based on memory reconsolidation interference over traditional treatment for emotional disorders. We also explain how findings from basic research suggest limitations and challenges to clinical translation that may help to understand why clinical trials have met with mixed success so far and how their success can be increased. In closing, we preview new intervention approaches beyond the induction of amnesia that the phenomenon of memory reconsolidation may afford for alleviating the burden imposed by emotional memories and comment on theoretical controversies regarding the nature of memory reconsolidation.

Fearing shades of grey: individual differences in fear responding towards generalisation stimuli.

Individual differences in fear generalisation have been proposed to play a role in the aetiology and/or maintenance of anxiety disorders, but few data are available to directly support that claim. The research that is available has focused mostly on generalisation of peripheral and central physiological fear responses. Far less is known about the generalisation of avoidance, the behavioural component of fear. In two experiments, we evaluated how neuroticism, a known vulnerability factor for anxiety, modulates an array of fear responses, including avoidance tendencies, towards generalisation stimuli (GS). Participants underwent differential fear conditioning, in which one conditioned stimulus (CS+) was repeatedly paired with an aversive outcome (shock; unconditioned stimulus, US), whereas another was not (CS-). Fear generalisation was observed across measures in Experiment 1 (US expectancy and evaluative ratings) and Experiment 2 (US expectancy, evaluative ratings, skin conductance, startle responses, safety behaviours), with overall highest responding to the CS+, lowest to the CS- and intermediate responding to the GSs. Neuroticism had very little impact on fear generalisation (but did affect GS recognition rates in Experiment 1), in line with the idea that fear generalisation is largely an adaptive process.

A Bayesian hierarchical diffusion model decomposition of performance in Approach-Avoidance Tasks.

Common methods for analysing response time (RT) tasks, frequently used across different disciplines of psychology, suffer from a number of limitations such as the failure to directly measure the underlying latent processes of interest and the inability to take into account the uncertainty associated with each individual's point estimate of performance. Here, we discuss a Bayesian hierarchical diffusion model and apply it to RT data. This model allows researchers to decompose performance into meaningful psychological processes and to account optimally for individual differences and commonalities, even with relatively sparse data. We highlight the advantages of the Bayesian hierarchical diffusion model decomposition by applying it to performance on Approach-Avoidance Tasks, widely used in the emotion and psychopathology literature. Model fits for two experimental data-sets demonstrate that the model performs well. The Bayesian hierarchical diffusion model overcomes important limitations of current analysis procedures and provides deeper insight in latent psychological processes of interest.

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.

Can neutral episodic memories become emotional? Evidence from facial expressions and subjective feelings.

Maladaptive emotional memories are a transdiagnostic feature of mental health problems. Therefore, understanding whether and how emotional memories can change might help to prevent and treat mental disorders. We tested whether neutral memories of naturalistic events can retroactively acquire positive or negative affect, in a preregistered three-day Modification of Valence in Episodes (MOVIE) paradigm. On Day 1, participants (N = 41) encoded memories of neutral movie scenes, representing lifelike naturalistic experiences. On Day 2, they retrieved each episode before viewing a happy, sad, or neutral scene from the same movie (yielding a within-subjects design with a neutral-negative, neutral-positive, and neutral-neutral condition). On Day 3, participants again retrieved each memory from Day 1. We assessed the affective tone of episodes through facial expressions of positive and negative affect (using facial electromyography, fEMG) and through self-reported feelings. Positive updating of neutral episodes led to increased expressions of positive affect, whereas negative updating led to increased self-reported negative feelings. These results suggest that complex neutral episodic memories can retroactively acquire an affective tone, but the effects were modest and inconsistent across affect readouts. Future research should investigate alternative approaches to updating emotional memories that produce more profound changes in the valence of memories.

Bayesian evaluation of diverging theories of episodic and affective memory distortions in dysphoria.

People suffering from dysphoria retrieve autobiographical memories distorted in content and affect, which may contribute to the aetiology and maintenance of depression. However, key memory difficulties in dysphoria remain elusive because theories disagree how memories of different valence are altered. Here, we assessed the psychophysiological expression of affect and retrieved episodic detail while participants with dysphoria (but without a diagnosed mental illness) and participants without dysphoria relived positive, negative, and neutral memories. We show that participants with dysphoria retrieve positive memories with diminished episodic detail and negative memories with enhanced detail, compared to participants without dysphoria. This is in line with negativity bias but not overgeneral memory bias theories. According to confirmatory analyses, participants with dysphoria also express diminished positive affect and enhanced negative affect when retrieving happy memories, but exploratory analyses suggest that this increase in negative affect may not be robust. Further confirmatory analyses showed that affective responses to memories are not related to episodic detail and already present during the experience of new emotional events. Our results indicate that affective memory distortions may not emerge from mnemonic processes but from general distortions in positive affect, which challenges assumptions of memory theories and therapeutics. Protocol registration: The Stage 1 protocol for this Registered Report was accepted in principle on the 18rd of March 2021. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.14605374.v1 .

Cortical and Subcortical Brain Alterations in Specific Phobia and Its Animal and Blood-Injection-Injury Subtypes: A Mega-Analysis From the ENIGMA Anxiety Working Group.

OBJECTIVE: Specific phobia is a common anxiety disorder, but the literature on associated brain structure alterations exhibits substantial gaps. The ENIGMA Anxiety Working Group examined brain structure differences between individuals with specific phobias and healthy control subjects as well as between the animal and blood-injection-injury (BII) subtypes of specific phobia. Additionally, the authors investigated associations of brain structure with symptom severity and age (youths vs. adults). METHODS: Data sets from 31 original studies were combined to create a final sample with 1,452 participants with phobia and 2,991 healthy participants (62.7% female; ages 5-90). Imaging processing and quality control were performed using established ENIGMA protocols. Subcortical volumes as well as cortical surface area and thickness were examined in a preregistered analysis. RESULTS: Compared with the healthy control group, the phobia group showed mostly smaller subcortical volumes, mixed surface differences, and larger cortical thickness across a substantial number of regions. The phobia subgroups also showed differences, including, as hypothesized, larger medial orbitofrontal cortex thickness in BII phobia (N=182) compared with animal phobia (N=739). All findings were driven by adult participants; no significant results were observed in children and adolescents. CONCLUSIONS: Brain alterations associated with specific phobia exceeded those of other anxiety disorders in comparable analyses in extent and effect size and were not limited to reductions in brain structure. Moreover, phenomenological differences between phobia subgroups were reflected in diverging neural underpinnings, including brain areas related to fear processing and higher cognitive processes. The findings implicate brain structure alterations in specific phobia, although subcortical alterations in particular may also relate to broader internalizing psychopathology.

A brief treatment for veterans with PTSD: an open-label case-series study.

Introduction: Despite the positive outcomes observed in numerous individuals undergoing trauma-focused psychotherapy for PTSD, veterans with this condition experience notably diminished advantages from such therapeutic interventions in comparison to non-military populations. Methods: In a preliminary study we investigated the efficacy of an innovative treatment approach in a small sample of veterans (n = 7). Recognizing that accessing and targeting trauma memory in veterans with PTSD may be more challenging compared to other patient populations, we employed unique and personalized retrieval cues that engaged multiple senses and were connected to the context of their trauma. This was followed by a session focused on memory reconsolidation, which incorporated both psychological techniques (i.e., imagery rescripting) and a pharmacological component (i.e., 40 mg of propranolol). Results: The findings from this small-scale case series cautiously indicate that this brief intervention, typically consisting of only one or two treatment sessions, shows promise in producing significant effects on symptoms of PTSD, distress and quality of life.This is particularly noteworthy given the complex symptomatology experienced by the veterans in this study. Conclusion: To summarize, there are grounds for optimism regarding this brief treatment of combat-related PTSD. It appears that the potential for positive outcomes is far greater than commonly believed, as demonstrated by the encouraging results of this pilot study.

A paradigm shift in the treatment of emotional memory disorders: Lessons from basic science.

Experiments demonstrating post-reactivation amnesia for learned fear in animals have generated a novel and influential hypothesis on the plasticity of memory, usually referred to as memory reconsolidation. The clinical potential of pharmacologically disrupting the process of memory reconsolidation has sparked a wave of interest into whether this phenomenon can also be demonstrated in humans, and ultimately harnessed for therapeutic purposes. In this essay we outline how the work of Karim Nader and colleagues has moved the field forward from a focus on extinction learning to the prospect of disrupting memory reconsolidation. We then review some promising findings on the necessary conditions, as well as potential boundary conditions, of pharmacologically disrupting the process of memory reconsolidation obtained in our laboratory. Even though laboratory experiments in animals and humans suggest that we may be at the brink of a breakthrough in fundamentally changing emotional memories, the necessary and sufficient conditions for targeting and disrupting memory reconsolidation in clinical practice are largely unknown. There is likely no universally effective reactivation procedure for triggering the reconsolidation of clinically significant emotional memories, and the impact of subtle boundary conditions observed in basic experiments compounds this issue. Notwithstanding these challenges, the discovery of changing emotional memory through disrupting the process of memory reconsolidation has unquestionably invigorated the field.

Manipulating expectancy violations to strengthen the efficacy of human fear extinction.

Recent theoretical and clinical articles have emphasized a role for expectancy violations in improving the effectiveness of exposure therapy. Expectancy violations are critical to extinction learning and strengthening these violations has been suggested to improve the formation and retention of extinction memories, which should result in lasting symptom reductions after treatment. However, more detailed mechanistic insights in this process are needed to better inform clinical interventions. In two separate fear-conditioning experiments, we investigated whether stronger expectancy violations (Exp1) or fostering awareness of expectancy violations (Exp2) during extinction could reduce the subsequent return of fear. We measured fear potentiated startle (FPS) and skin conductance responses (SCR) as physiological indices of fear, and US expectancy ratings to assess our manipulations. While we successfully created stronger expectancy violations in Exp1, we found no evidence that these stronger violations reduced the return of fear at test. Interestingly, fostering awareness of violations (Exp2) reduced differential SCRs, but not FPS responses. These findings provide novel insights into the effect of US expectancies on fear extinction in the lab, but they also illustrate the complexity of capturing clinically relevant processes of change with fear-conditioning studies.

Emotional memory in the lab: Using the Trier Social Stress Test to induce a sensory-rich and personally meaningful episodic experience.

A myriad of clinical theories places emotional memory or mental representations at the root of mental disorders. Various cognitive-behavioural interventions are based on the assumption that targeting the underlying emotional memory is the working mechanism of treatment efficacy. To test the assumptions about the role of emotional memory in the development, maintenance, and treatment of mental disorders, we first need to establish ecologically valid paradigms that can induce emotional memory in the lab. For this, we used the Trier Social Stress Test (TSST), a standardized protocol to elicit social distress, paired with a neutral unfamiliar ambient odour, to create a sensory-rich and personally meaningful episodic experience. Seven days later, participants (N = 132) reactivated the memory of the TSST with the aid of auditory, olfactory, and visual retrieval cues, during which their heart rate and self-reported affective responses were collected. Although increases in heart rate were only observed during encoding, and not at retrieval, self-report ratings showed that cues which directly referred to the aversive experience evoked more negative valence, arousal, and feelings of lack of control during memory reactivation compared to control cues across sensory modalities. These findings are indicative of successful memory induction and corroborate the utility of ambient odours as retrieval aids. Moreover, the self-reported response to the reactivated emotional memory correlated with individual differences in indices of (social) anxiety and depression. Thereby, we provide preliminary evidence of the translational significance of this paradigm that offers potential for being a model to induce ecologically valid emotional memory in the lab.

Time-dependent emotional memory transformation: Divergent pathways of item memory and contextual dependency.

Emotional memory can persist strikingly long, but it is believed that not all its elements are protected against the fading effects of time. So far, studies of emotional episodic memory have mostly investigated retention up to 24h postencoding and revealed that central emotional features (items) are usually strengthened, while contextual binding of the event is reduced. However, even though it is known for neutral memories that central versus contextual elements evolve differently with longer passage of time, the time-dependent evolution of emotional memories remains unclear. Hypothetically, compared to neutral memories, emotional item memory becomes increasingly stronger, accompanied by accelerated decay of-already fragile-links with their original encoding contexts, resulting in progressive reductions in contextual dependency. Here, we tested these predictions in a large-scale study. Participants encoded emotional and neutral episodes, and were assessed 30 minutes (N = 40), 1 day (N = 40), 1 week (N = 39), or 2 weeks (N = 39) later on item memory, contextual dependency, and subjective quality of memory. The results show that, with the passage of time, emotional memories were indeed characterized by increasingly stronger item memory and weaker contextual dependency. Interestingly, analyses of the subjective quality of memories revealed that stronger memory for emotional items with time was expressed in familiarity, whereas increasingly smaller contextual dependency for emotional episodes was reflected in recollection. Together, these findings uncover the time-dependent transformation of emotional episodic memories, thereby shedding light on the ways healthy and maladaptive human memories may develop. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Context reexposure to bolster contextual dependency of emotional episodic memory.

Contextual overgeneralization of emotional memory is a core aspect of anxiety disorders. Identifying methods to enhance contextual dependency of emotional memory is therefore of significant clinical interest. Animal research points to a promising approach: reexposure to the context in which fear is acquired reduces generalization to other contexts. However, the exact conditions for this effect are unknown, complicating translation to effective interventions. Most notably, exposure to a context that resembles-but is not identical to-the learning context may diminish contextual dependency of memory by integration of additional contextual cues. Here, we therefore assessed in a large-scale study (N = 180) whether context reexposure enhances contextual dependency of emotional episodic memory whereas exposure to a similar context impairs it. We also tested whether relatively strong memory retrieval during context (re)exposure amplifies these effects. We replicated prior research showing that correct recognition depends on context and contextual dependency is lower for emotional than neutral memories. However, exposure to the encoding context or a similar context did not affect contextual dependency of memory, and retrieval strength did not interact with such effects. Thorough insight into factors underlying the effects of context (re)exposure on contextual dependency seems key to eventually attain a memory recontextualization intervention.