Memory editing from science fiction to clinical practice.

Science fiction notions of altering problematic memories are starting to become reality as techniques emerge through which unique memories can be edited. Here we review memory-editing research with a focus on improving the treatment of psychopathology. Studies highlight two windows of memory vulnerability: initial storage, or consolidation; and re-storage after retrieval, or reconsolidation. Techniques have been identified that can modify memories at each stage, but translating these methods from animal models to humans has been challenging and implementation into clinical therapies has produced inconsistent benefits. The science of memory editing is more complicated and nuanced than fiction, but its rapid development holds promise for future applications.

Temporally and anatomically specific contributions of the human amygdala to threat and safety learning.

Neural plasticity in subareas of the rodent amygdala is widely known to be essential for Pavlovian threat conditioning and safety learning. However, less consistent results have been observed in human neuroimaging studies. Here, we identify and test three important factors that may contribute to these discrepancies: the temporal profile of amygdala response in threat conditioning, the anatomical specificity of amygdala responses during threat conditioning and safety learning, and insufficient power to identify these responses. We combined data across multiple studies using a well-validated human threat conditioning paradigm to examine amygdala involvement during threat conditioning and safety learning. In 601 humans, we show that two amygdala subregions tracked the conditioned stimulus with aversive shock during early conditioning while only one demonstrated delayed responding to a stimulus not paired with shock. Our findings identify cross-species similarities in temporal- and anatomical-specific amygdala contributions to threat and safety learning, affirm human amygdala involvement in associative learning and highlight important factors for future associative learning research in humans.

Overestimating the intensity of negative feelings in autobiographical memory: evidence from the 9/11 attack and COVID-19 pandemic.

When recalling autobiographical events, people not only retrieve event details but also the feelings they experienced. The current study examined whether people are able to consistently recall the intensity of past feelings associated with two consequential and negatively valenced events, i.e. the 9/11 attack (N = 769) and the COVID-19 pandemic (N = 726). By comparing experienced and recalled intensities of negative feelings, we discovered that people systematically recall a higher intensity of negative feelings than initially reported - overestimating the intensity of past negative emotional experiences. The COVID-19 dataset also revealed that individuals who experienced greater improvement in emotional well-being displayed smaller biases in recalling their feelings. Across both datasets, the intensity of remembered feelings was correlated with initial feelings and current feelings, but the impact of the current feelings was stronger in the COVID-19 dataset than in the 9/11 dataset. Our results demonstrate that when recalling negative autobiographical events, people tend to overestimate the intensity of prior negative emotional experiences with their degree of bias influenced by current feelings and well-being.

Pupil Size Encodes Uncertainty during Exploration.

Exploration is an important part of decision making and is crucial to maximizing long-term rewards. Past work has shown that people use different forms of uncertainty to guide exploration. In this study, we investigate the role of the pupil-linked arousal system in uncertainty-guided exploration. We measured participants' (n = 48) pupil dilation while they performed a two-armed bandit task. Consistent with previous work, we found that people adopted a hybrid of directed, random, and undirected exploration, which are sensitive to relative uncertainty, total uncertainty, and value difference between options, respectively. We also found a positive correlation between pupil size and total uncertainty. Furthermore, augmenting the choice model with subject-specific total uncertainty estimates decoded from the pupil size improved predictions of held-out choices, suggesting that people used the uncertainty estimate encoded in pupil size to decide which option to explore. Together, the data shed light on the computations underlying uncertainty-driven exploration. Under the assumption that pupil size reflects locus coeruleus-norepinephrine neuromodulatory activity, these results also extend the theory of the locus coeruleus-norepinephrine function in exploration, highlighting its selective role in driving uncertainty-guided random exploration.

Hippocampus Guides Adaptive Learning during Dynamic Social Interactions.

How do we evaluate whether someone will make a good friend or collaborative peer? A hallmark of human cognition is the ability to make adaptive decisions based on information garnered from limited prior experiences. Using an interactive social task measuring adaptive choice (deciding who to reengage or avoid) in male and female participants, we find the hippocampus supports value-based social choices following single-shot learning. These adaptive choices elicited a suppression signal in the hippocampus, revealing sensitivity for the subjective perception of a person and how well they treat you during choice. The extent to which the hippocampus was suppressed was associated with flexibly interacting with prior generous individuals and avoiding selfish individuals. Further, we found that hippocampal signals during decision-making were related to subsequent memory for a person and the offer they made before. Consistent with the hippocampus leveraging previously executed choices to solidify a reliable neural signature for future adaptive behavior, we also observed a later hippocampal enhancement. These findings highlight the hippocampus playing a multifaceted role in socially adaptive learning.SIGNIFICANCE STATEMENT Adaptively navigating social interactions requires an integration of prior experiences with information gleaned from the current environment. While most research has focused on striatal-based feedback learning, open questions remain regarding the role of hippocampal-based episodic memory systems. Here, we show that during social decisions based on prior experience, hippocampal suppression signals were sensitive to adaptive choice, while hippocampal enhancements was related to subsequent memory for the original social interaction. These findings highlight the hippocampus playing a multifaceted role in socially adaptive learning.

Emotion and decision making: multiple modulatory neural circuits.

Although the prevalent view of emotion and decision making is derived from the notion that there are dual systems of emotion and reason, a modulatory relationship more accurately reflects the current research in affective neuroscience and neuroeconomics. Studies show two potential mechanisms for affect's modulation of the computation of subjective value and decisions. Incidental affective states may carry over to the assessment of subjective value and the decision, and emotional reactions to the choice may be incorporated into the value calculation. In addition, this modulatory relationship is reciprocal: Changing emotion can change choices. This research suggests that the neural mechanisms mediating the relation between affect and choice vary depending on which affective component is engaged and which decision variables are assessed. We suggest that a detailed and nuanced understanding of emotion and decision making requires characterizing the multiple modulatory neural circuits underlying the different means by which emotion and affect can influence choices.

Survival of the salient: Aversive learning rescues otherwise forgettable memories via neural reactivation and post-encoding hippocampal connectivity.

The effects of aversive events on memory are complex and go beyond the simple enhancement of threatening information. Negative experiences can also rescue related but otherwise forgettable details encoded close in time. Here, we used functional magnetic resonance imaging (fMRI) in healthy young adults to examine the brain mechanisms that support this retrograde memory effect. In a two-phase incidental encoding paradigm, participants viewed different pictures of tools and animals before and during Pavlovian fear conditioning. During Phase 1, these images were intermixed with neutral scenes, which provided a unique 'context tag' for this specific phase of encoding. A few minutes later, during Phase 2, new pictures from one category were paired with a mild shock (threat-conditioned stimulus; CS+), while pictures from the other category were not shocked. FMRI analyses revealed that, across-participants, individuals who showed aversive learning-related retroactive memory benefits for Phase 1 CS+ items were also more likely to exhibit three brain effects: first, greater spontaneous reinstatement of the Phase 1 context when participants viewed conceptually-related CS+ items in Phase 2; second, greater successful encoding-related VTA/SN and LC activation for Phase 2 CS+ items; and third, learning-dependent increases in post-encoding hippocampal functional coupling with CS+ category-selective cortex. These biases in hippocampal-cortical connectivity also mediated the relationship between VTA/SN aversive encoding effects and across-participant variability in the retroactive memory benefit. Collectively, our findings suggest that both online and offline brain mechanisms may enable threatening events to preserve memories that acquire new significance in the future.

Elemental and configural threat learning bias extinction generalization.

Emotional experiences often contain a multitude of details that may be represented in memory as individual elements or integrated into a single representation. How details associated with a negative emotional event are represented in memory can have important implications for extinction strategies designed to reduce emotional responses. For example, is extinguishing one cue associated with an aversive outcome sufficient to reduce learned behavior to other cues present at the time of learning that were not directly extinguished? Here, we used a between-subjects multi-day threat conditioning and extinction task to assess whether participants generalize extinction from one cue to unextinguished cues. On Day 1, one group of participants learned that a compound conditioned stimulus, composed of a tone and colored square, predicted an uncomfortable shock to the wrist (Compound group). A second group learned that the tone and square separately predicted shock (Separate group). On Day 2, participants in both groups were exposed to the tone in the absence of shocks (cue extinction). On Day 3, we tested whether extinction generalized from the extinguished to the unextinguished cue, as well as to a compound composed of both cues. Results showed that configural and elemental learning had unique and opposite effects on extinction generalization. Subjects who initially learned that a compound cue predicted shock successfully generalized extinction learning from the tone to the square, but exhibited threat relapse to the compound cue. In contrast, subjects who initially learned that each cue individually predicted shock did not generalize extinction learning from the tone to the square, but threat responses to the compound were low. These results highlight the importance of whether details of an aversive event are represented as integrated or separated memories, as these representations affect the success or limits of extinction generalization.

Emotional learning selectively and retroactively strengthens memories for related events.

Neurobiological models of long-term memory propose a mechanism by which initially weak memories are strengthened through subsequent activation that engages common neural pathways minutes to hours later. This synaptic tag-and-capture model has been hypothesized to explain how inconsequential information is selectively consolidated following salient experiences. Behavioural evidence for tag-and-capture is provided by rodent studies in which weak early memories are strengthened by future behavioural training. Whether a process of behavioural tagging occurs in humans to transform weak episodic memories into stable long-term memories is unknown. Here we show, in humans, that information is selectively consolidated if conceptually related information, putatively represented in a common neural substrate, is made salient through an emotional learning experience. Memory for neutral objects was selectively enhanced if other objects from the same category were paired with shock. Retroactive enhancements as a result of emotional learning were observed following a period of consolidation, but were not observed in an immediate memory test or for items strongly encoded before fear conditioning. These findings provide new evidence for a generalized retroactive memory enhancement, whereby inconsequential information can be retroactively credited as relevant, and therefore selectively remembered, if conceptually related information acquires salience in the future.

Stimulus generalization as a mechanism for learning to trust.

How do humans learn to trust unfamiliar others? Decisions in the absence of direct knowledge rely on our ability to generalize from past experiences and are often shaped by the degree of similarity between prior experience and novel situations. Here, we leverage a stimulus generalization framework to examine how perceptual similarity between known individuals and unfamiliar strangers shapes social learning. In a behavioral study, subjects play an iterative trust game with three partners who exhibit highly trustworthy, somewhat trustworthy, or highly untrustworthy behavior. After learning who can be trusted, subjects select new partners for a second game. Unbeknownst to subjects, each potential new partner was parametrically morphed with one of the three original players. Results reveal that subjects prefer to play with strangers who implicitly resemble the original player they previously learned was trustworthy and avoid playing with strangers resembling the untrustworthy player. These decisions to trust or distrust strangers formed a generalization gradient that converged toward baseline as perceptual similarity to the original player diminished. In a second imaging experiment we replicate these behavioral gradients and leverage multivariate pattern similarity analyses to reveal that a tuning profile of activation patterns in the amygdala selectively captures increasing perceptions of untrustworthiness. We additionally observe that within the caudate adaptive choices to trust rely on neural activation patterns similar to those elicited when learning about unrelated, but perceptually familiar, individuals. Together, these findings suggest an associative learning mechanism efficiently deploys moral information encoded from past experiences to guide future choice.

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.

Stress promotes generalization of older but not recent threat memories.

Stress broadly affects the ability to regulate emotions and may contribute to generalization of threat-related behaviors to harmless stimuli. Behavioral generalization also tends to increase over time as memory precision for recent events gives way to more gist-like representations. Thus, acute stress coupled with a delay in time from a negative experience may be a strong predictor of the transition from normal to generalized fear expression. Here, we investigated the effect of a single-episode acute stressor on generalization of aversive learning when stress is administered either immediately after an aversive learning event or following a delay. In a between-subjects design, healthy adult volunteers underwent threat (fear) conditioning using a tone-conditioned stimulus paired with an electric shock to the wrist and another tone not paired with shock. Behavioral generalization was tested to a range of novel tones either on the same day (experiment 1) or 24 h later (experiment 2) and was preceded by either an acute stress induction or a control task. Anticipatory sympathetic arousal [i.e., skin conductance responses (SCRs)] and explicit measures of shock expectancy served as dependent measures. Stress administered shortly after threat conditioning did not affect behavioral generalization. In contrast, stress administered following a delay led to heightened arousal and increased generalization of SCRs and explicit measures of shock expectancy. These findings show that acute stress increases generalization of older but not recent threat memories and have clinical relevance to understanding overgeneralization characteristics of anxiety and stress-related disorders.

Stress attenuates the flexible updating of aversive value.

In a dynamic environment, sources of threat or safety can unexpectedly change, requiring the flexible updating of stimulus-outcome associations that promote adaptive behavior. However, aversive contexts in which we are required to update predictions of threat are often marked by stress. Acute stress is thought to reduce behavioral flexibility, yet its influence on the modulation of aversive value has not been well characterized. Given that stress exposure is a prominent risk factor for anxiety and trauma-related disorders marked by persistent, inflexible responses to threat, here we examined how acute stress affects the flexible updating of threat responses. Participants completed an aversive learning task, in which one stimulus was probabilistically associated with an electric shock, while the other stimulus signaled safety. A day later, participants underwent an acute stress or control manipulation before completing a reversal learning task during which the original stimulus-outcome contingencies switched. Skin conductance and neuroendocrine responses provided indices of sympathetic arousal and stress responses, respectively. Despite equivalent initial learning, stressed participants showed marked impairments in reversal learning relative to controls. Additionally, reversal learning deficits across participants were related to heightened levels of alpha-amylase, a marker of noradrenergic activity. Finally, fitting arousal data to a computational reinforcement learning model revealed that stress-induced reversal learning deficits emerged from stress-specific changes in the weight assigned to prediction error signals, disrupting the adaptive adjustment of learning rates. Our findings provide insight into how stress renders individuals less sensitive to changes in aversive reinforcement and have implications for understanding clinical conditions marked by stress-related psychopathology.

The Functional Roles of the Amygdala and Prefrontal Cortex in Processing Uncertainty.

Decisions under uncertainty distinguish between those made under risk (known probabilities) and those made under ambiguity (unknown probabilities). Despite widespread interest in decisions under uncertainty and the successful documentation that these distinct psychological constructs profoundly-and differentially-impact behavior, research has not been able to systematically converge on which brain regions are functionally involved in processing risk and ambiguity. We merge a lesion approach with computational modeling and simultaneous measurement of the arousal response to investigate the impact the medial prefrontal cortex (mPFC), lateral prefrontal cortex (lPFC), and amygdala have on decisions under uncertainty. Results reveal that the lPFC acts as a unitary system for processing uncertainty: Lesions to this region disrupted the relationship between arousal and choice, broadly increasing both risk and ambiguity seeking. In contrast, the mPFC and amygdala appeared to play no role in processing risk, and the mPFC only had a tenuous relationship with ambiguous uncertainty. Together, these findings reveal that only the lPFC plays a global role in processing the highly aversive nature of uncertainty.

Functional MRI-based lie detection: scientific and societal challenges.

Functional MRI (fMRI)-based lie detection has been marketed as a tool for enhancing personnel selection, strengthening national security and protecting personal reputations, and at least three US courts have been asked to admit the results of lie detection scans as evidence during trials. How well does fMRI-based lie detection perform, and how should the courts, and society more generally, respond? Here, we address various questions ­ some of which are based on a meta-analysis of published studies ­ concerning the scientific state of the art in fMRI-based lie detection and its legal status, and discuss broader ethical and societal implications. We close with three general policy recommendations.

Prepared stimuli enhance aversive learning without weakening the impact of verbal instructions.

Fear-relevant stimuli such as snakes and spiders are thought to capture attention due to evolutionary significance. Classical conditioning experiments indicate that these stimuli accelerate learning, while instructed extinction experiments suggest they may be less responsive to instructions. We manipulated stimulus type during instructed aversive reversal learning and used quantitative modeling to simultaneously test both hypotheses. Skin conductance reversed immediately upon instruction in both groups. However, fear-relevant stimuli enhanced dynamic learning, as measured by higher learning rates in participants conditioned with images of snakes and spiders. Results are consistent with findings that dissociable neural pathways underlie feedback-driven and instructed aversive learning.

Active Avoidance: Neural Mechanisms and Attenuation of Pavlovian Conditioned Responding.

Patients with anxiety disorders often experience a relapse in symptoms after exposure therapy. Similarly, threat responses acquired during Pavlovian threat conditioning often return after extinction learning. Accordingly, there is a need for alternative methods to persistently reduce threat responding. Studies in rodents have suggested that exercising behavioral control over an aversive stimulus can persistently diminish threat responses, and that these effects are mediated by the amygdala, ventromedial prefrontal cortex, and striatum. In this fMRI study, we attempted to translate these findings to humans. Subjects first underwent threat conditioning. We then contrasted two forms of safety learning: active avoidance, in which participants could prevent the shock through an action, and yoked extinction, with shock presentation matched to the active condition, but without instrumental control. The following day, we assessed subjects' threat responses (measured by skin conductance) to the conditioned stimuli without shock. Subjects next underwent threat conditioning with novel stimuli. Yoked extinction subjects showed an increase in conditioned response to stimuli from the previous day, but the active avoidance group did not. Additionally, active avoidance subjects showed reduced conditioned responding during novel threat conditioning, but the extinction group did not. We observed between-group differences in striatal BOLD responses to shock omission in Avoidance/Extinction. These findings suggest a differential role for the striatum in human active avoidance versus extinction learning, and indicate that active avoidance may be more effective than extinction in persistently diminishing threat responses.SIGNIFICANCE STATEMENT Extinguished threat responses often reemerge with time, highlighting the importance of identifying more enduring means of attenuation. We compared the effects of active avoidance learning and yoked extinction on threat responses in humans and contrasted the neural circuitry engaged by these two processes. Subjects who learned to prevent a shock through an action maintained low threat responses after safety learning and showed attenuated threat conditioning with novel stimuli, in contrast to those who underwent yoked extinction. The results suggest that experiences of active control over threat engage the striatum and promote a shift from expression of innate defensive responses toward more adaptive behavioral responses to threatening stimuli.

Chronic and Acute Stress Promote Overexploitation in Serial Decision Making.

Many decisions that humans make resemble foraging problems in which a currently available, known option must be weighed against an unknown alternative option. In such foraging decisions, the quality of the overall environment can be used as a proxy for estimating the value of future unknown options against which current prospects are compared. We hypothesized that such foraging-like decisions would be characteristically sensitive to stress, a physiological response that tracks biologically relevant changes in environmental context. Specifically, we hypothesized that stress would lead to more exploitative foraging behavior. To test this, we investigated how acute and chronic stress, as measured by changes in cortisol in response to an acute stress manipulation and subjective scores on a questionnaire assessing recent chronic stress, relate to performance in a virtual sequential foraging task. We found that both types of stress bias human decision makers toward overexploiting current options relative to an optimal policy. These findings suggest a possible computational role of stress in decision making in which stress biases judgments of environmental quality.SIGNIFICANCE STATEMENT Many of the most biologically relevant decisions that we make are foraging-like decisions about whether to stay with a current option or search the environment for a potentially better one. In the current study, we found that both acute physiological and chronic subjective stress are associated with greater overexploitation or staying at current options for longer than is optimal. These results suggest a domain-general way in which stress might bias foraging decisions through changing one's appraisal of the overall quality of the environment. These novel findings not only have implications for understanding how this important class of foraging decisions might be biologically implemented, but also for understanding the computational role of stress in behavior and cognition more broadly.

Persistence of Amygdala-Hippocampal Connectivity and Multi-Voxel Correlation Structures During Awake Rest After Fear Learning Predicts Long-Term Expression of Fear.

After encoding, memories undergo a process of consolidation that determines long-term retention. For conditioned fear, animal models postulate that consolidation involves reactivations of neuronal assemblies supporting fear learning during postlearning "offline" periods. However, no human studies to date have investigated such processes, particularly in relation to long-term expression of fear. We tested 24 participants using functional MRI on 2 consecutive days in a fear conditioning paradigm involving 1 habituation block, 2 acquisition blocks, and 2 extinction blocks on day 1, and 2 re-extinction blocks on day 2. Conditioning blocks were preceded and followed by 4.5-min rest blocks. Strength of spontaneous recovery of fear on day 2 served as a measure of long-term expression of fear. Amygdala connectivity primarily with hippocampus increased progressively during postacquisition and postextinction rest on day 1. Intraregional multi-voxel correlation structures within amygdala and hippocampus sampled during a block of differential fear conditioning furthermore persisted after fear learning. Critically, both these main findings were stronger in participants who exhibited spontaneous recovery 24 h later. Our findings indicate that neural circuits activated during fear conditioning exhibit persistent postlearning activity that may be functionally relevant in promoting consolidation of the fear memory.