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Upon reactivation, consolidated memories can enter a temporary labile state and require restabilisation, known as reconsolidation. Interventions during this reconsolidation period can disrupt the reactivated memory. However, it is unclear whether different kinds of memory that depend on distinct brain regions all undergo reconsolidation. Evidence for reconsolidation originates from studies assessing amygdala-dependent memories using cue-conditioning paradigms in rodents, which were subsequently replicated in humans. Whilst studies providing evidence for reconsolidation of hippocampus-dependent memories in rodents have predominantly used context conditioning paradigms, studies in humans have used completely different paradigms such as tests for wordlists or stories. Here our objective was to bridge this paradigm gap between rodent and human studies probing reconsolidation of hippocampus-dependent memories. We modified a recently developed immersive Virtual Reality paradigm to test in humans whether contextual threat-conditioned memories can be disrupted by a reminder-extinction procedure that putatively targets reconsolidation. In contrast to our hypothesis, we found comparable recovery of contextual conditioned threat responses, and comparable retention of subjective measures of threat memory, episodic memory and exploration behaviour between the reminder-extinction and standard extinction groups. Our result provide no evidence that a reminder before extinction can prevent the return of context conditioned threat memories in humans.

Contains fulltext : 177119.pdf (Publisher’s version ) (Open Access) Despite a wealth of knowledge on how humans and nonhuman animals learn to associate meaningful events with cues in the environment, far less is known about how humans learn to associate these events with the environment itself. Progress on understanding spatiotemporal contextual processes in humans has been slow in large measure by the methodological constraint of generating and manipulating immersive spatial environments in well-controlled laboratory settings. Fortunately, immersive Virtual Reality (iVR) technology has improved appreciably and affords a relatively straightforward methodology to investigate the role of context on learning, memory, and emotion while maintaining experimental control. Here, we review context conditioning literature in humans and describe challenges to study contextual learning in humans. We then provide details for a novel context threat (fear) conditioning paradigm in humans using a commercially available VR headset and a cross-platform game engine. This paradigm resulted in the acquisition of subjective threat, threat-conditioned defensive responses, and explicit threat memory. We make the paradigm publicly available and describe obstacles and solutions to optimize future studies of context conditioning using iVR. As computer technology advances to replicate the sensation of realistic environments, there are increasing opportunities to bridge the translational gap between rodent and human research on how context modulates cognition, which may ultimately lead to more optimal treatment strategies for anxiety- and stress-related disorders.

The ability to adaptively regulate responses to the proximity of potential danger is critical to survival and imbalance in this system may contribute to psychopathology. The bed nucleus of the stria terminalis (BNST) is implicated in defensive responding during uncertain threat anticipation whereas the amygdala may drive responding upon more acute danger. This functional dissociation between the BNST and amygdala is however controversial, and human evidence scarce. Here we used data from two independent functional magnetic resonance imaging studies [n= 108 males andn= 70 (45 females)] to probe how coordination between the BNST and amygdala may regulate responses during shock anticipation and actual shock confrontation. In a subset of participants from Sample 2 (n= 48) we demonstrate that anticipation and confrontation evoke bradycardic and tachycardic responses, respectively. Further, we show that in each sample when going from shock anticipation to the moment of shock confrontation neural activity shifted from a region anatomically consistent with the BNST toward the amygdala. Comparisons of functional connectivity during threat processing showed overlapping yet also consistently divergent functional connectivity profiles for the BNST and amygdala. Finally, childhood maltreatment levels predicted amygdala, but not BNST, hyperactivity during shock anticipation. Our results support an evolutionary conserved, defensive distance-dependent dynamic balance between BNST and amygdala activity. Shifts in this balance may enable shifts in defensive reactions via the demonstrated differential functional connectivity. Our results indicate that early life stress may tip the neural balance toward acute threat responding and via that route predispose for affective disorder.SIGNIFICANCE STATEMENTPreviously proposed differential contributions of the BNST and amygdala to fear and anxiety have been recently debated. Despite the significance of understanding their contributions to defensive reactions, there is a paucity of human studies that directly compared these regions on activity and connectivity during threat processing. We show strong evidence for a dissociable role of the BNST and amygdala in threat processing by demonstrating in two large participant samples that they show a distinct temporal signature of threat responding as well as a discriminable pattern of functional connections and differential sensitivity to early life threat.

Humans are able to cognitively regulate emotions by changing their thoughts. Neuroimaging studies show correlations between dorsolateral prefrontal cortex (dlPFC) activity and cognitive regulation of emotions. Here our objective was to investigate whether dlPFC damage is associated with impaired cognitive regulation of emotion. We therefore tested the ability of patients with dlPFC lesions (N = 6) and matched control participants (N = 19) to utilize a laboratory version of cognitive regulation training (CRT) to regulate subjective fear and autonomic threat responses following Pavlovian threat conditioning. We found that patients with dlPFC lesions were able to acquire conditioned threat but seemed impaired in their ability to utilize CRT to cognitively regulate subjective fear to a threatening stimulus. Despite inclusion of a limited number of lesion patients, our results suggest that the dlPFC is important for the cognitive regulation of subjective fear.

It can be challenging to explain why certain mundane details circumstantial to an emotional event are nonetheless remembered long after the experience. Here, we examined how attention selectively shapes memory for neutral objects that happen to coincide with either an unexpected or anticipated emotional event. Pictures of neutral objects were presented for 2 s and terminated with either a high-intensity shock, a low-intensity shock, or no shock. Recognition memory was tested 24 -hs later in a surprise test. Results showed no effect of shock intensity on memory for attended objects when shocks were unpredictable (Experiment 1). Similarly, there was no effect of shock intensity for attended objects when shock delivery was signaled before the object appeared (Experiment 2). There was a reduction in memory for unattended objects paired with an anticipated high-intensity shock (Experiment 3). Finally, subjects recognized slightly more attended objects paired with a high-intensity shock if shock intensity was signaled one second after the object was encoded (Experiment 4). We conclude that simply pairing objects with high-intensity shocks is insufficient to drive episodic memory enhancements for neutral information. But anticipation of an impending source of arousal can induce bidirectional effects: attending to an impending emotional event interferes with encoding of neutral information, but encoding an object just prior to anticipation of an emotional event can sometimes benefit memory. Overall, these results highlight a complex interplay between arousal, attention, and anticipation on emotion-induced memory for neutral information.

Administering the anesthetic propofol after a brief reminder reduces retrieval of established emotional memory 24 hours later., The adjustment of maladaptive thoughts and behaviors associated with emotional memories is central to treating psychiatric disorders. Recent research, predominantly with laboratory animals, indicates that memories can become temporarily sensitive to modification following reactivation, before undergoing reconsolidation. A method to selectively impair reconsolidation of specific emotional or traumatic memories in humans could translate to an effective treatment for conditions such as posttraumatic stress disorder. We tested whether deep sedation could impair emotional memory reconsolidation in 50 human participants. Administering the intravenous anesthetic propofol following memory reactivation disrupted memory for the reactivated, but not for a non-reactivated, slideshow story. Propofol impaired memory for the reactivated story after 24 hours, but not immediately after propofol recovery. Critically, memory impairment occurred selectively for the emotionally negative phase of the reactivated story. One dose of propofol following memory reactivation selectively impaired subsequent emotional episodic memory retrieval in a time-dependent manner, consistent with reconsolidation impairment.

The ability to generalize from and distinguish between aversive memories and novel experiences is critical to survival. Previous research has revealed mechanisms underlying generalization of threat-conditioned defensive responses, but little is known about generalization of episodic memory for threatening events. Here we tested if aversive learning influences generalization of episodic memory for threatening events in human adults. Subjects underwent Pavlovian threat-conditioning in which objects from one category were paired with a shock and objects from a different category were unpaired. The next day, subjects underwent a recognition memory test that included old, highly similar, and entirely novel items from the shock-paired and shock-unpaired object categories. Results showed that items highly similar to those from the object category previously paired with shock were mistaken for old items more often than items from the shock-unpaired category. This finding indicates that threat learning promotes generalization of episodic memory, and is consistent with the idea that threat generalization is an active process that may be adaptive for avoiding a myriad of potential threats following an emotional experience. Enhanced generalization of aversive episodic memories may be maladaptive, however, when old threat memories are inappropriately reactivated in harmless situations, exemplified in a number of stress- and anxiety-related disorders. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

We are constantly interacting with our environment whilst we encode memories. However, how actions influence memory formation remains poorly understood. Goal-directed movement engages the locus coeruleus (LC), the main source of noradrenaline in the brain. Noradrenaline is also known to enhance episodic encoding, suggesting that action could improve memory via LC engagement. Here we demonstrate, across seven experiments, that action (Go-response) enhances episodic encoding for stimuli unrelated to the action itself, compared to action inhibition (NoGo). Functional magnetic resonance imaging, and pupil diameter as a proxy measure for LC-noradrenaline transmission, indicate increased encoding-related LC activity during action. A final experiment, replicated in two independent samples, confirmed a novel prediction derived from these data that emotionally aversive stimuli, which recruit the noradrenergic system, modulate the mnemonic advantage conferred by Go-responses relative to neutral stimuli. We therefore provide converging evidence that action boosts episodic memory encoding via a noradrenergic mechanism., Goal-directed movement is known to promote release of noradrenaline in the brain, and noradrenaline is known to enhance memory encoding. Here, the authors provide evidence that active movement, compared to action inhibition, boosts episodic memory encoding in humans via a noradrenergic mechanism.

Contains fulltext : 152028.pdf (Publisher’s version ) (Closed access) BACKGROUND: Fear learning in stressful situations is highly adaptive for survival by steering behavior in subsequent situations, but fear learning can become disproportionate in vulnerable individuals. Despite the potential clinical significance, the mechanism by which stress modulates fear learning is poorly understood. Memory theories state that stress can cause a shift away from more controlled processing depending on the hippocampus toward more reflexive processing supported by the amygdala and striatum. This shift may be mediated by activation of the mineralocorticoid receptor (MR) for cortisol. We investigated how stress shifts processes underlying cognitively demanding learning versus less demanding fear learning using a combined trace and delay fear conditioning paradigm. METHODS: In a pharmacological functional magnetic resonance imaging study, we tested 101 healthy men probing the effects of stress (socially evaluated cold pressor vs. control procedure) and MR-availability (400 mg spironolactone vs. placebo) in a randomized, placebo-controlled, full-factorial, between-subjects design. RESULTS: Effective stress induction and successful conditioning were confirmed by subjective, physiologic, and somatic data. In line with a stress-induced shift, stress enhanced later recall of delay compared with trace conditioning in the MR-available groups as indexed by skin conductance responses. During learning, this was accompanied by a stress-induced reduction of learning-related hippocampal activity for trace conditioning. The stress-induced shift in fear and neural processing was absent in the MR-blocked groups. CONCLUSIONS: Our results are in line with a stress-induced shift in fear learning, mediated by the MR, resulting in a dominance of cognitively less demanding amygdala-based learning, which might be particularly prominent in individuals with high MR sensitivity. 10 p.

Contains fulltext : 177015.pdf (Publisher’s version ) (Open Access) A reminder can temporarily renew flexibility of consolidated memories, referred to as reconsolidation. Pavlovian threat-conditioning studies suggest that a reminder can renew flexibility of threat responses but that episodic memories remain stable. In contrast, outside the threat-conditioning domain, studies testing memory for word lists or stories find that a reminder can renew flexibility of episodic memory. This discrepancy in findings leaves it unclear if episodic memories reconsolidate, or only Pavlovian responses. Here we unite the different approaches in the field and show that a reminder can retroactively strengthen episodic memory for Pavlovian threat-conditioned events, but that, in contrast to threat-conditioning studies with simple sensory stimuli, extinction after a reminder fails to prevent recovery of generalized threat responses. Our results indicate the episodic memories also reconsolidate, allowing strengthening of relevant memories. These findings also suggest that generalized threat responses and episodic memories are less susceptible to be modified by reminder-interventions procedures.

Item does not contain fulltext Although humans live in societies that regularly demand engaging with multiple people simultaneously, little is known about social learning in group settings. In two experiments, we combined a Pavlovian learning framework with dyadic economic games to test whether blocking mechanisms support value-based social learning in the gain (altruistic dictators) and loss (greedy robbers) domains. Subjects first learned about an altruistic dictator, who subsequently made altruistic splits collectively with a partner. Results revealed that because the presence of the dictator already predicted the outcome, subjects did not learn to associate value with the partner. This social blocking effect was not observed in the loss domain: A kind robber's partner, who could steal all the subjects' money but stole little, acquired highly positive value-which biased subjects' subsequent behavior. These findings reveal how Pavlovian mechanisms support efficient social learning, while also demonstrating that violations of social expectations can attenuate how readily these mechanisms are recruited.

Item does not contain fulltext Research in nonhuman animals reveals threat-sensitive generalization of defensive behavior that favors widespread generalization when threat intensity is high and limited generalization (i.e., specificity) when threat intensity is low. Here, we used Pavlovian fear conditioning to systematically investigate whether threat intensity widens behavioral generalization gradients to stimuli that decreasingly resemble a learned threat cue. Using a between-subjects design, volunteers underwent fear conditioning with a tone paired with either a high-intensity or low-intensity aversive stimulus prior to a test of fear generalization to novel tones. Results showed no effect of threat intensity on initial acquisition of conditioned fear. However, volunteers who underwent fear conditioning with a high-intensity aversive stimulus exhibited widespread generalization of autonomic arousal (skin conductance responses) as compared to volunteers who received a low-intensity aversive stimulus. These results show a transition from normal (selective) to overgeneralized fear as threat intensity increases, and have implications for understanding overgeneralization characteristic of trauma- and stress-related disorders. (PsycINFO Database Record

Contains fulltext : 177645.pdf (Publisher’s version ) (Closed access) It is well documented that emotionally arousing experiences are better remembered than mundane events. This is thought to occur through hippocampus-amygdala crosstalk during encoding, consolidation, and retrieval. Here we investigated whether emotional events (context) also cause a memory benefit for simultaneously encoded non-arousing contents and whether this effect persists after a delay via recruitment of a similar hippocampus-amygdala network. Participants studied neutral pictures (content) encoded together with either an arousing or a neutral sound (that served as context) in two study sessions three days apart. Memory was tested in a functional magnetic resonance scanner directly after the second study session. Pictures recognised with high confidence were more often thought to have been associated with an arousing than with a neutral context, irrespective of the veridical source memory. If the retrieved context was arousing, an area in the hippocampus adjacent to the amygdala exhibited heightened activation and this area increased functional connectivity with the parahippocampal gyrus, an area known to process pictures of scenes. These findings suggest that memories can be shaped by the retrieval act. Memory structures may be recruited to a higher degree when an arousing context is retrieved, and this may give rise to confident judgments of recognition for neutral pictures even after a delay. 13 p.

Contains fulltext : 157652.pdf (Publisher’s version ) (Closed access) Combining beta-blockers with exposure therapy has been advocated to reduce fear, yet experimental studies combining beta-blockers with memory reactivation have had contradictory results. We explored how beta-blockade might affect the course of safety learning and the subsequent return of fear in a double-blind placebo-controlled functional magnetic resonance imaging study in humans (N=46). A single dose of propranolol before extinction learning caused a loss of conditioned fear responses, and prevented the subsequent return of fear and decreased explicit memory for the fearful events in the absence of drug. Fear-related neural responses were persistently attenuated in the dorsal medial prefrontal cortex (dmPFC), increased in the hippocampus 24 h later, and correlated with individual behavioral indices of fear. Prediction error-related responses in the ventral striatum persisted during beta-blockade. We suggest that this pattern of results is most consistent with a model where beta-blockade can prevent the return of fear by (i) reducing retrieval of fear memory, via the dmPFC and (ii) increasing contextual safety learning, via the hippocampus. Our findings suggest that retrieval of fear memory and contextual safety learning form potential mnemonic target mechanisms to optimize exposure-based therapy with beta-blockers. 10 p.

Mental schemas form associative knowledge structures that can promote the encoding and consolidation of new and related information. Schemas are facilitated by a distributed system that stores components separately, presumably in the form of inter-connected neocortical representations. During retrieval, these components need to be recombined into one representation, but where exactly such recombination takes place is unclear. Thus, we asked where different schema components are neuronally represented and converge during retrieval. Subjects acquired and retrieved two well-controlled, rule-based schema structures during fMRI on consecutive days. Schema retrieval was associated with midline, medial-temporal, and parietal processing. We identified the multi-voxel representations of different schema components, which converged within the angular gyrus during retrieval. Critically, convergence only happened after 24-hour-consolidation and during a transfer test where schema material was applied to novel but related trials. Therefore, the angular gyrus appears to recombine consolidated schema components into one memory representation. DOI: http://dx.doi.org/10.7554/eLife.09668.001, eLife digest To make sense of the world around us, we constantly try to work out the relationship of new information to other things that we already know, and sort our knowledge into pre-existing mental frameworks, or “schemas”. This makes learning new things that are related to a schema, as well as remembering this knowledge, easier. The process of making these mental connections is thought to involve an extensive brain network. Separate types of information are stored in different brain regions within this network, yet to link this information together, the brain must combine them into a single representation. Wagner et al. have now investigated which brain regions are involved in recombining separate information. Human volunteers were trained to interpret the positions or colors of pairs of circles with different rules. The combination of these separate types of information formed a mental schema that could be used as a “weather forecast”. The design of the experiment meant that measuring the brain activity of the volunteers during the task (using a technique called functional magnetic resonance imaging) allowed the brain regions involved in retrieving the different parts of such a schema to be distinguished. Twenty-four hours later volunteers returned to use the mental schemas that they had learned to predict the weather. Retrieving which weather conditions the circle pairs represented activated a network of regions in the volunteers’ brains. Further analysis revealed that some of these regions showed specific activity patterns in response to remembering information about only one element of the task (for example, only the rules or only the visual information). However, the different aspects of the task all appeared to be integrated by a brain region called the angular gyrus. This suggests that the angular gyrus is responsible for combining separate memory parts and pieces of information into a single representation. It is able to do so by connecting to brain regions that code for such specific aspects, although this only occurs 24 hours after the mental schemas have been established. Future studies could investigate the result of damage to the angular gyrus: different pieces of information might not be combined, or could result in an incorrect memory during retrieval. Finally, since the angular gyrus has been related to a wealth of different mental processes, it remains a challenge for future research to "converge" these findings and to understand the underlying computations. DOI: http://dx.doi.org/10.7554/eLife.09668.002

Memory enhancement for emotional events is dependent on amygdala activation and noradrenergic modulation during learning. A potential role for noradrenaline (NE) during retrieval of emotional memory is less well understood. Here, we report that administration of the β-adrenergic receptor antagonist propranolol at retrieval abolishes a declarative memory enhancement for emotional items. Critically, this effect persists at a subsequent 24 h memory test, in the absence of propranolol. Thus, these findings extend our current understanding of the role of NE in emotional memory to encompass effects at retrieval, and provide face validity to clinical interventions using β-adrenergic antagonists in conjunction with reactivation of unwanted memories in anxiety-related disorders.

Contains fulltext : 127646.pdf (Publisher’s version ) (Closed access) Despite accumulating evidence for a reconsolidation process in animals, support in humans, especially for episodic memory, is limited. Using a within-subjects manipulation, we found that a single application of electroconvulsive therapy following memory reactivation in patients with unipolar depression disrupted reactivated, but not non-reactivated, memories for an emotional episode in a time-dependent manner. Our results provide evidence for reconsolidation of emotional episodic memories in humans. 3 p.

Networks of interconnected neocortical representations of prior knowledge, “schemas,” facilitate memory for congruent information. This facilitation is thought to be mediated by augmented encoding and accelerated consolidation. However, it is less clear how schema affects retrieval. Rodent and human studies to date suggest that schema-related memories are differently retrieved. However, these studies differ substantially as most human studies implement pre-experimental world-knowledge as schemas and tested item or nonspatial associative memory, whereas animal studies have used intraexperimental schemas based on item-location associations within a complex spatial layout that, in humans, could engage more strategic retrieval processes. Here, we developed a paradigm conceptually linked to rodent studies to examine the effects of an experimentally learned spatial associative schema on learning and retrieval of new object-location associations and to investigate the neural mechanisms underlying schema-related retrieval. Extending previous findings, we show that retrieval of schema-defining associations is related to activity along anterior and posterior midline structures and angular gyrus. The existence of such spatial associative schema resulted in more accurate learning and retrieval of new, related associations, and increased time allocated to retrieve these associations. This retrieval was associated with right dorsolateral prefrontal and lateral parietal activity, as well as interactions between the right dorsolateral prefrontal cortex and medial and lateral parietal regions, and between the medial prefrontal cortex and posterior midline regions, supporting the hypothesis that retrieval of new, schema-related object-location associations in humans also involves augmented monitoring and systematic search processes.

ObjectivePosttraumatic stress disorder (PTSD) is reliably associated with reduced brain volume relative to healthy controls, in areas similar to those found in depression. We investigated whether in a PTSD sample brain volumes in these areas were related to reporting specific symptoms of PTSD or to overall symptom severity.MethodStructural MRI scans were obtained from 28 participants diagnosed with PTSD according to DSM-IV-TR. Participants reported the extent of individual PTSD symptoms using the Posttraumatic Diagnostic Scale. Voxel-based morphometry applying the Dartel algorithm implemented within SPM5 was used to identify volumetric changes, related to PTSD total, symptom cluster, and individual symptom scores.ResultsBrain volume was unrelated to overall PTSD severity, but greater reexperiencing scores predicted reduced volumes in the middle temporal and inferior occipital cortices. Increased reports of flashbacks predicted reduced volume in the insula/parietal operculum and in the inferior temporal gyrus.ConclusionThe data illustrate the value of analyses at the symptom level within a patient population to supplement group comparisons of patients and healthy controls. Areas identified were consistent with a neurobiological account of flashbacks implicating specific abnormalities in the ventral visual stream.

Contains fulltext : 98370.pdf (Publisher’s version ) (Open Access) BACKGROUND: Posttraumatic stress disorder (PTSD) and major depression are reliably associated with reductions in brain volume in markedly similar areas. To our knowledge, no volumetric studies have directly contrasted these conditions. We investigated which, if any, grey matter reductions would be uniquely associated with each disorder. We also investigated more subtle independent effects: specifically, correlations between brain volume and self-report measures of psychopathology. METHODS: We obtained structural magnetic resonance imaging scans from participants with PTSD, major depression and healthy controls exposed to trauma. Participants completed standardized self-report measures of anxiety and depression. We used voxel-based morphometry, applying the DARTEL algorithm within SPM5 to identify associated volumetric changes. RESULTS: We enrolled 24 patients with PTSD, 29 with major depression and 29 controls in our study. The clinical groups had regions of markedly smaller volume compared with the control group, particularly in prefrontal areas, but did not differ from each other. Greater self-reported anxiety was inversely related to volume in several areas, particularly the inferior temporal cortex, among patients with PTSD, but was associated with some volume increases in patients with major depression. Greater self-reported depression showed similar but weaker effects, being inversely related to brain volume in patients with PTSD but positively related to volume in the cuneus and precuneus of those with major depression. LIMITATIONS: To maintain the representativeness of the sample, patients with PTSD were not excluded if they had typical comorbid conditions, such as depression. Patients were not all medication-free, but we controlled for group differences in antidepressant use in the analyses. CONCLUSION: We identified commonalities in areas of brain volume in patients with PTSD and those with major depression, suggesting that existing findings concerning reductions in prefrontal areas in particular may not be specific to PTSD but rather related to features of the disorder that are shared with other conditions, such as depression. More subtle differences between patients with PTSD and those with major depression were represented by distinct structural correlates of self-reported anxiety and depression.

A polymorphism in the human serotonin transporter (5-HTT) gene is implicated in susceptibility to anxiety and depression and in enhanced emotion-induced activation in the amygdala. A role for 5-HTT polymorphism in the emotional modulation of human episodic memory has yet to be demonstrated. Here, we demonstrate that whereas emotional memory for aversive events per se is not influenced by 5-HTT polymorphism, an emotion-induced retrograde amnesia is expressed solely in the presence of the short allele. The findings indicate a critical role for the serotonin system in emotion-mediated memory disruption.