Role of Human Ventromedial Prefrontal Cortex in Learning and Recall of Enhanced Extinction.

Standard fear extinction relies on the ventromedial prefrontal cortex (vmPFC) to form a new memory given the omission of threat. Using fMRI in humans, we investigated whether replacing threat with novel neutral outcomes (instead of just omitting threat) facilitates extinction by engaging the vmPFC more effectively than standard extinction. Computational modeling of associability (indexing surprise strength and dynamically modulating learning rates) characterized skin conductance responses and vmPFC activity during novelty-facilitated but not standard extinction. Subjects who showed faster within-session updating of associability during novelty-facilitated extinction also expressed better extinction retention the next day, as expressed through skin conductance responses. Finally, separable patterns of connectivity between the amygdala and ventral versus dorsal mPFC characterized retrieval of novelty-facilitated versus standard extinction memories, respectively. These results indicate that replacing threat with novel outcomes stimulates vmPFC involvement on extinction trials, leading to a more durable long-term extinction memory.SIGNIFICANCE STATEMENT Psychiatric disorders characterized be excessive fear are a major public health concern. Popular clinical treatments, such as exposure therapy, are informed by principles of Pavlovian extinction. Thus, there is motivation to optimize extinction strategies in the laboratory so as to ultimately develop more effective clinical treatments. Here, we used functional neuroimaging in humans and found that replacing (rather than just omitting) expected aversive events with novel and neutral outcomes engages the ventromedial prefrontal cortex during extinction learning. Enhanced extinction also diminished activity in threat-related networks (e.g., the insula, thalamus) during immediate extinction and a 24 h extinction retention test. This is new evidence for how behavioral protocols designed to enhance extinction affects neurocircuitry underlying the learning and retention of extinction memories.

Roles of the Amygdala and Basal Forebrain in Defense: a Reply to Luyck Et al. and Implications for Defensive Action.

The commentary by Luyck and colleagues on our paper provides many stimulating viewpoints and interpretations of our original study on dissociable responses in the amygdala and bed nucleus of the stria terminalis in threat processing. Here, we reply to some of the points raised and while agreeing with most of the comments also provide some alternative viewpoints. We end by putting forward a research agenda for how to further investigate the roles of these regions in threat processing, with an emphasis on studying their roles in defensive action.

How Human Amygdala and Bed Nucleus of the Stria Terminalis May Drive Distinct Defensive Responses.

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 and n = 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 STATEMENT Previously 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.

Associative Learning of Social Value in Dynamic Groups.

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.

Retrieved emotional context influences hippocampal involvement during recognition of neutral memories.

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.

Initial investigation of the effects of an experimentally learned schema on spatial associative memory in humans.

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.

Food can lift mood by affecting mood-regulating neurocircuits via a serotonergic mechanism.

It is commonly assumed that food can affect mood. One prevalent notion is that food containing tryptophan increases serotonin levels in the brain and alters neural processing in mood-regulating neurocircuits. However, tryptophan competes with other long-neutral-amino-acids (LNAA) for transport across the blood-brain-barrier, a limitation that can be mitigated by increasing the tryptophan/LNAA ratio. We therefore tested in a double-blind, placebo-controlled crossover study (N=32) whether a drink with a favourable tryptophan/LNAA ratio improves mood and modulates specific brain processes as assessed by functional magnetic resonance imaging (fMRI). We show that one serving of this drink increases the tryptophan/LNAA ratio in blood plasma, lifts mood in healthy young women and alters task-specific and resting-state processing in brain regions implicated in mood regulation. Specifically, Test-drink consumption reduced neural responses of the dorsal caudate nucleus during reward anticipation, increased neural responses in the dorsal cingulate cortex during fear processing, and increased ventromedial prefrontal-lateral prefrontal connectivity under resting-state conditions. Our results suggest that increasing tryptophan/LNAA ratios can lift mood by affecting mood-regulating neurocircuits.

An fMRI investigation of posttraumatic flashbacks.

Flashbacks are a defining feature of posttraumatic stress disorder (PTSD), but there have been few studies of their neural basis. We tested predictions from a dual representation model of PTSD that, compared with ordinary episodic memories of the same traumatic event, flashbacks would be associated with activity in dorsal visual stream and related areas rather than in the medial temporal lobe. Participants with PTSD, with depression but not PTSD, and healthy controls were scanned during a recognition task with personally relevant stimuli. The contrast of flashbacks versus ordinary episodic trauma memories in PTSD was associated with increased activation in sensory and motor areas including the insula, precentral gyrus, supplementary motor area, and mid-occipital cortex. The same contrast was associated with decreased activation in the midbrain, parahippocampal gyrus, and precuneus/posterior cingulate cortex. The results were discussed in terms of theories of PTSD and dual-process models of recognition.

Negative cognitive schema modification as mediator of symptom improvement after electroconvulsive therapy in major depressive disorder.

BACKGROUND: Electroconvulsive therapy (ECT) is a potent option for treatment-resistant major depressive disorder (MDD). Cognitive models of depression posit that negative cognitions and underlying all-or-nothing negative schemas contribute to and perpetuate depressed mood. This study investigates whether ECT can modify negative schemas, potentially via memory reactivation, and whether such changes are related to MDD symptom improvement. METHOD: Seventy-two patients were randomized to either an emotional memory reactivation electroconvulsive therapy (EMR-ECT) or control memory reactivation electroconvulsive therapy (CMR-ECT) intervention prior to ECT-sessions in a randomized controlled trail. Emotional memories associated with patients' depression were reactivated before ECT-sessions. At baseline and after the ECT-course, negative schemas and depression severity were assessed using the Dysfunctional Attitude Scale (DAS) and Hamilton Depression Rating Scale HDRS. Mediation analyses were used to examine whether the effects of ECT on HDRS-scores were mediated by changes in DAS-scores or vice versa. RESULTS: Post-ECT DAS-scores were significantly lower compared to baseline. Post-ECT, the mean HDRS-score of the whole sample (15.10 ± 8.65 [SD]; n = 59) was lower compared to baseline (24.83 ± 5.91 [SD]). Multiple regression analysis showed no significant influence of memory reactivation on schema improvement. Path analysis showed that depression improvement was mediated by improvement of negative cognitive schemas. CONCLUSION: ECT is associated with improvement of negative schemas, which appears to mediate the improvement of depressive symptoms. An emotional memory intervention aimed to modify negative schemas showed no additional effect.

Beta-adrenergic blockade during memory retrieval in humans evokes a sustained reduction of declarative emotional memory enhancement.

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 beta-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 beta-adrenergic antagonists in conjunction with reactivation of unwanted memories in anxiety-related disorders.

Structural brain abnormalities common to posttraumatic stress disorder and depression.

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 reminder before extinction failed to prevent the return of conditioned threat responses irrespective of threat memory intensity in rats.

After retrieval, reactivated memories may destabilize and require restabilization processes to persist, referred to as reconsolidation. The reminder-extinction procedure has been proposed as a behavioral reconsolidation-based intervention to persistently attenuate threat-conditioned memories. After the presentation of a single reminder trial, the conditioned threat memory may enter a labile state, and extinction training during this window can prevent the return of conditioned threat responses. However, findings on this reminder-extinction procedure are mixed and its effectiveness may be subject to boundary conditions, including memory strength. Here, we systematically investigate whether more intense threat memories are less susceptible to disruption through a reminder-extinction procedure. Using a Pavlovian auditory threat conditioning procedure at three different shock intensities, rats acquired conditioned threat responses of variable "strength." Rats subsequently underwent either extinction preceded by a reminder or standard extinction. Although different shock intensities led to different strength threat memories, all groups showed reinstatement of conditioned threat responses irrespective of shock intensity or reminder condition. Hence, regardless of the intensity of the threat memory, the reminder procedure was ineffective in preventing the return of threat responses in rats. We thus find no evidence that threat memory intensity is a potential modulator of the effectiveness of the reminder-extinction procedure. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Investigating the efficacy of the reminder-extinction procedure to disrupt contextual threat memories in humans using immersive Virtual Reality.

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.

Effectiveness of Emotional Memory Reactivation vs Control Memory Reactivation Before Electroconvulsive Therapy in Adult Patients With Depressive Disorder: A Randomized Clinical Trial.

Importance: Although electroconvulsive therapy (ECT) is often effective, approximately half of patients with depression undergoing ECT do not benefit sufficiently, and relapse rates are high. ECT sessions have been shown to weaken reactivated memories. The effect of emotional memory retrieval on cognitive schemas remains unknown. Objective: To assess whether emotional memory retrieval just before patients receive ECT sessions weakens underlying cognitive schemas, improves ECT effectiveness, increases ECT response, and reduces relapse rates. Design, Setting, and Participants: In this multicenter randomized clinical trial conducted from 2014 to 2018 in the departments of psychiatry in 3 hospitals in the Netherlands, 72 participants were randomized 1:1 to 2 parallel groups to receive either emotional memory reactivation (EMR-ECT) or control memory reactivation (CMR-ECT) interventions before ECT sessions. The Hamilton Depression Rating Scale (HDRS [total score range: 0-52, with 0-7 indicating no depression and ≥24 indicating severe depression]) was used to measure symptoms of depression during and after ECT, with a 6-month follow-up period. Participants were between ages 18 and 70 years with a primary diagnosis of unipolar major depressive disorder (MDD) according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) and in whom ECT was indicated. Data analysis was performed from July to November 2019. Interventions: EMR-ECT or CMR-ECT interventions prior to ECT sessions. Main Outcomes and Measures: Depression scores and relapse rates within 6 months were assessed with the HDRS and analyzed using logistic and linear multiple regression analyses. Results: A total of 66 patients (mean [SD] age, 49.3 [12.3] years; 39 [59.1%] women) were randomized to the EMR-ECT group (n = 32) or the CMR-ECT group (n = 34). Regardless of the memory intervention, 42.4% (28 of 66) of patients responded (≥50% decrease of symptom severity on the HDRS). Of patients who responded, 39.3% (11 of 28) relapsed within 6 months. Remission rates (CMR-ECT group, 29.4% [10 of 34] vs EMR-ECT group, 25.0% [8 of 32]; P = .58), mean (SD) HDRS scores after the ECT course (CMR-ECT group, 14.6 [8.6] vs EMR-ECT group, 14.9 [8.8]; P = .88), total mean (SD) number of required ECT sessions for response (CMR-ECT group, 14.9 [7.9] vs EMR-ECT group, 15.6 [7.3]; P = .39), and relapse rates (CMR-ECT group, 46.7% [7 of 15] vs EMR-ECT group, 30.8% [4 of 13]; P = .33) were not significantly altered by the intervention. Conclusions and Relevance: Study findings suggest that the EMR-ECT intervention just before patient receipt of ECT for depression did not improve effectiveness, increase speed of response, or reduce relapse rates after the ECT course compared with patients receiving CMR-ECT. Trial Registration: Trialregister.nl Identifier: NL4289.

Emotion-induced retrograde amnesia is determined by a 5-HTT genetic polymorphism.

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.

Episodic memory and Pavlovian conditioning: ships passing in the night.

Research on emotional learning and memory is traditionally approached from one of two directions: episodic memory and classical conditioning. These approaches differ substantially in methodology and intellectual tradition. Here, we offer a new approach to the study of emotional memory in humans that involves integrating theoretical knowledge and experimental techniques from these seemingly distinct fields. Specifically, we describe how subtle modifications to traditional Pavlovian conditioning procedures have provided new insight into how emotional experiences are selectively prioritized in long-term episodic memory. We also speculate on future directions and undeveloped lines of research where some of the knowledge and principles of classical conditioning might advance our understanding of how emotion modifies episodic memory, and vice versa.

Threat learning promotes generalization of episodic memory.

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).

Propofol-induced deep sedation reduces emotional episodic memory reconsolidation in humans.

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.

Emotional enhancement of memory for neutral information: The complex interplay between arousal, attention, and anticipation.

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.

Patients with dorsolateral prefrontal cortex lesions are capable of discriminatory threat learning but appear impaired in cognitive regulation of subjective fear.

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.