Acute Stress Effects on Statistical Learning and Episodic Memory.

Stress is widely considered to negatively impact hippocampal function, thus impairing episodic memory. However, the hippocampus is not merely the seat of episodic memory. Rather, it also (via distinct circuitry) supports statistical learning. On the basis of rodent work suggesting that stress may impair the hippocampal pathway involved in episodic memory while sparing or enhancing the pathway involved in statistical learning, we developed a behavioral experiment to investigate the effects of acute stress on both episodic memory and statistical learning in humans. Participants were randomly assigned to one of three conditions: stress (socially evaluated cold pressor) immediately before learning, stress ∼15 min before learning, or no stress. In the learning task, participants viewed a series of trial-unique scenes (allowing for episodic encoding of each image) in which certain scene categories reliably followed one another (allowing for statistical learning of associations between paired categories). Memory was assessed 24 hr later to isolate stress effects on encoding/learning rather than retrieval. We found modest support for our hypothesis that acute stress can amplify statistical learning: Only participants stressed ∼15 min in advance exhibited reliable evidence of learning across multiple measures. Furthermore, stress-induced cortisol levels predicted statistical learning retention 24 hr later. In contrast, episodic memory did not differ by stress condition, although we did find preliminary evidence that acute stress promoted memory for statistically predictable information and attenuated competition between statistical and episodic encoding. Together, these findings provide initial insights into how stress may differentially modulate learning processes within the hippocampus.

Integrating and fragmenting memories under stress and alcohol.

Stress can powerfully influence the way we form memories, particularly the extent to which they are integrated or situated within an underlying spatiotemporal and broader knowledge architecture. These different representations in turn have significant consequences for the way we use these memories to guide later behavior. Puzzlingly, although stress has historically been argued to promote fragmentation, leading to disjoint memory representations, more recent work suggests that stress can also facilitate memory binding and integration. Understanding the circumstances under which stress fosters integration will be key to resolving this discrepancy and unpacking the mechanisms by which stress can shape later behavior. Here, we examine memory integration at multiple levels: linking together the content of an individual experience, threading associations between related but distinct events, and binding an experience into a pre-existing schema or sense of causal structure. We discuss neural and cognitive mechanisms underlying each form of integration as well as findings regarding how stress, aversive learning, and negative affect can modulate each. In this analysis, we uncover that stress can indeed promote each level of integration. We also show how memory integration may apply to understanding effects of alcohol, highlighting extant clinical and preclinical findings and opportunities for further investigation. Finally, we consider the implications of integration and fragmentation for later memory-guided behavior, and the importance of understanding which type of memory representation is potentiated in order to design appropriate interventions.

Multiple Memory Subsystems: Reconsidering Memory in the Mind and Brain.

The multiple-memory-systems framework-that distinct types of memory are supported by distinct brain systems-has guided learning and memory research for decades. However, recent work challenges the one-to-one mapping between brain structures and memory types central to this taxonomy, with key memory-related structures supporting multiple functions across substructures. Here we integrate cross-species findings in the hippocampus, striatum, and amygdala to propose an updated framework of multiple memory subsystems (MMSS). We provide evidence for two organizational principles of the MMSS theory: First, opposing memory representations are colocated in the same brain structures; second, parallel memory representations are supported by distinct structures. We discuss why this burgeoning framework has the potential to provide a useful revision of classic theories of long-term memory, what evidence is needed to further validate the framework, and how this novel perspective on memory organization may guide future research.

Acute Stress Enhances Memory and Preference for Smoking-Related Associations in Smokers.

INTRODUCTION: Nicotine dependence follows a chronic course that is characterized by repeated relapse, often driven by acute stress and rewarding memories of smoking retrieved from related contexts. These two triggers can also interact, with stress influencing retrieval of contextual memories. However, the roles of these processes in nicotine dependence remain unknown. AIMS AND METHODS: We investigated how acute stress biases memory for smoking-associated contexts among smokers (N = 65) using a novel laboratory paradigm. On day 1, participants formed associations between visual stimuli of items (either neutral or related to smoking) and places (background scenes). On day 2 (24 hours later), participants were exposed to an acute laboratory-based stressor (socially evaluated cold pressor test; N = 32) or a matched control condition (N = 33) prior to being tested on their memory recognition and preferences for each item and place. We distinguished the accuracy of memory into specific (ie, precisely correct) or gist (ie, lure items with similar content) categories. RESULTS: Results demonstrated that the stressor significantly induced physiological and subjective perceived stress responses, and that stressed smokers exhibited a memory bias in favor of smoking-related items. In addition, the stressed group displayed greater preference for both smoking-related items and places that had been paired with the smoking-related items. We also found suggestive evidence that stronger smoking-related memory biases were associated with more severe nicotine dependence (ie, years of smoking). CONCLUSIONS: These results highlight the role of stress in biasing smokers toward remembering contexts associated with smoking, and amplifying their preference for these contexts. IMPLICATIONS: The current study elucidates the role of acute stress in promoting memory biases favoring smoking-related associations among smokers. The results suggest that the retrieval of smoking-biased associative memory could be a crucial factor in stress-related nicotine seeking. This may lead to a potential intervention targeting the extinction of smoking-related context memories as a preventive strategy for stress-induced relapse.

Network state dynamics underpin craving in a transdiagnostic population.

Emerging fMRI brain dynamic methods present a unique opportunity to capture how brain region interactions across time give rise to evolving affective and motivational states. As the unfolding experience and regulation of affective states affect psychopathology and well-being, it is important to elucidate their underlying time-varying brain responses. Here, we developed a novel framework to identify network states specific to an affective state of interest and examine how their instantaneous engagement contributed to its experience. This framework investigated network state dynamics underlying craving, a clinically meaningful and changeable state. In a transdiagnostic sample of healthy controls and individuals diagnosed with or at risk for craving-related disorders (N=252), we utilized connectome-based predictive modeling (CPM) to identify craving-predictive edges. An edge-centric timeseries approach was leveraged to quantify the instantaneous engagement of the craving-positive and craving-negative networks during independent scan runs. Individuals with higher craving persisted longer in a craving-positive network state while dwelling less in a craving-negative network state. We replicated the latter results externally in an independent group of healthy controls and individuals with alcohol use disorder exposed to different stimuli during the scan (N=173). The associations between craving and network state dynamics can still be consistently observed even when craving-predictive edges were instead identified in the replication dataset. These robust findings suggest that variations in craving-specific network state recruitment underpin individual differences in craving. Our framework additionally presents a new avenue to explore how the moment-to-moment engagement of behaviorally meaningful network states supports our changing affective experiences.

Hippocampal Mechanisms Support Cortisol-Induced Memory Enhancements.

Stress can powerfully influence episodic memory, often enhancing memory encoding for emotionally salient information. These stress-induced memory enhancements stand at odds with demonstrations that stress and the stress-related hormone cortisol can negatively affect the hippocampus, a brain region important for episodic memory encoding. To resolve this apparent conflict and determine whether and how the hippocampus supports memory encoding under cortisol, we combined behavioral assays of associative memory, high-resolution fMRI, and pharmacological manipulation of cortisol in a within-participant, double-blinded procedure (in both sexes). Behaviorally, hydrocortisone promoted the encoding of subjectively arousing, positive associative memories. Neurally, hydrocortisone led to enhanced functional connectivity between hippocampal subregions, which predicted subsequent memory enhancements for emotional associations. Cortisol also modified the relationship between hippocampal representations and associative memory: whereas hippocampal signatures of distinctiveness predicted memory under placebo, relative integration predicted memory under cortisol. Together, these data provide novel evidence that the human hippocampus contains the necessary machinery to support emotional associative memory enhancements under cortisol.SIGNIFICANCE STATEMENT Our daily lives are filled with stressful events, which powerfully shape the way we form episodic memories. For example, stress and stress-related hormones can enhance our memory for emotional events. However, the mechanisms underlying these memory benefits are unclear. In the current study, we combined functional neuroimaging, behavioral tests of memory, and double-blind, placebo-controlled hydrocortisone administration to uncover the effects of the stress-related hormone cortisol on the function of the human hippocampus, a brain region important for episodic memory. We identified novel ways in which cortisol can enhance hippocampal function to promote emotional memories, highlighting the adaptive role of cortisol in shaping memory formation.

Perceptual Generalization of Alcohol-Related Value Characterizes Risky Drinkers.

Generalizing from past experiences to novel situations is critical for adaptive behavior, whereas overgeneralization can promote maladaptive responses (e.g., context-inappropriate fear in anxiety). Here, we propose that overgeneralizing alcohol-related associations characterizes risky drinking. We conducted two online experiments assessing generalization of alcohol-related gains (Study 1) and losses (Study 2) among individuals who engaged in light or risky patterns of drinking (Study 1: N = 88, 24-44 years old; Study 2: N = 87, 21-44 years old). After learning to associate cards with alcohol and non-alcohol-related outcomes, participants chose whether to play with cards varying in perceptual similarity to those shown during conditioning. Finally, participants completed a surprise recognition memory test for all outcomes. Although both groups showed comparable conditioning, we found that risky drinkers overgeneralized alcohol-related gains and losses. Risky drinkers also showed a bias toward recognizing alcohol-related images. These results indicate a novel role for overgeneralization of alcohol-related gains and losses as a mechanism associated with risky drinking.

Binge drinking is associated with higher cortisol and lower hippocampal and prefrontal gray matter volume: Prospective association with future alcohol intake.

Background: Cortisol is a significant driver of the biological stress response that is potently activated by acute alcohol intake and increased with binge drinking. Binge drinking is associated with negative social and health consequences and risk of developing alcohol use disorder (AUD). Both cortisol levels and AUD are also associated with changes in hippocampal and prefrontal regions. However, no previous research has assessed structural gray matter volume (GMV) and cortisol concurrently to examine BD effects on hippocampal and prefrontal GMV and cortisol, and their prospective relationship to future alcohol intake. Methods: Individuals who reported binge drinking (BD: N = 55) and demographically matched non-binge moderate drinkers (MD: N = 58) were enrolled and scanned using high-resolution structural MRI. Whole brain voxel-based morphometry was used to quantify regional GMV. In a second phase, 65% of the sample volunteered to participate in prospective daily assessment of alcohol intake for 30 days post-scanning. Results: Relative to MD, BD showed significantly higher cortisol and smaller GMV in regions including hippocampus, dorsal lateral prefrontal cortex (dlPFC), prefrontal and supplementary motor, primary sensory and posterior parietal cortex (FWE, p < 0.05). GMV in bilateral dlPFC and motor cortices were negatively associated with cortisol levels, and smaller GMV in multiple PFC regions was associated with more subsequent drinking days in BD. Conclusion: These findings indicate neuroendocrine and structural dysregulation associated with BD relative to MD. Notably, BD-associated lower GMV regions were those involved in stress, memory and cognitive control, with lower GMV in cognitive control and motor regions also predicting higher levels of future alcohol intake in BD.

Hippocampal mechanisms support cortisol-induced memory enhancements.

Stress can powerfully influence episodic memory, often enhancing memory encoding for emotionally salient information. These stress-induced memory enhancements stand at odds with demonstrations that stress and the stress-related hormone cortisol can negatively affect the hippocampus, a brain region important for episodic memory encoding. To resolve this apparent conflict and determine whether and how the hippocampus supports memory encoding under cortisol, we combined behavioral assays of associative memory, high-resolution functional magnetic resonance imaging (fMRI), and pharmacological manipulation of cortisol in a within-participant, double-blinded procedure. Hydrocortisone led to enhanced functional connectivity between hippocampal subregions, which predicted subsequent memory enhancements for emotional information. Cortisol also modified the relationship between hippocampal representations and memory: whereas hippocampal signatures of distinctiveness predicted memory under placebo, relative integration predicted memory under cortisol. Together, these data provide novel evidence that the human hippocampus contains the necessary machinery to support emotional memory enhancements under stress.

High-Risk Drinkers Engage Distinct Stress-Predictive Brain Networks.

BACKGROUND: Excessive alcohol intake is a major public health problem and can be triggered by stress. Heavy drinking in patients with alcohol use disorder also alters neural, physiological, and emotional stress responses. However, it is unclear whether adaptations in stress-predictive brain networks can be an early marker of risky drinking behavior. METHODS: Risky social drinkers (regular bingers; n = 53) and light drinker control subjects (n = 51) aged 18 to 53 years completed a functional magnetic resonance imaging-based sustained stress protocol with repeated measures of subjective stress state, during which whole-brain functional connectivity was computed. This was followed by prospective daily ecological momentary assessment for 30 days. We used brain computational predictive modeling with cross-validation to identify unique brain connectivity predictors of stress in risky drinkers and determine the prospective utility of stress-brain networks for subsequent loss of control over drinking. RESULTS: Risky drinkers had anatomically and functionally distinct stress-predictive brain networks (showing stronger predictions from visual and motor networks) compared with light drinkers (default mode and frontoparietal networks). Stress-predictive brain networks defined for risky drinkers selectively predicted future real-world stress levels for risky drinkers and successfully predicted prospective future real-world loss of control over drinking across all participants. CONCLUSIONS: These results indicate adaptations in computationally derived stress-related brain circuitry among high-risk drinkers, suggesting potential targets for early preventive intervention and revealing the malleability of the neural processes that govern stress responses.

Polygenic scores for empathy associate with posttraumatic stress severity in response to certain traumatic events.

BACKGROUND: Posttraumatic stress disorder (PTSD) is triggered by environmental stressors. Empathy may predispose an individual to respond to life events differently if high empathizers are emotionally more sensitive to trauma. For the first time, we test this hypothesis using genetic information. METHODS: We applied polygenic scoring (PGS) to investigate the shared genetics linking empathy (measured using the Empathy Quotient (EQ), a self-report measure of empathy; N = 46,861) and PTSD symptom severity (measured using the 6-item PTSD Checklist 6-item (PCL-6)) in the UK Biobank (N = 126,219). Follow-up analyses were performed in the context of (1) experiencing any of 16 potential traumas, (2) the total number of traumas endorsed, and (3) the context of trauma. Autism, depression, generalized anxiety, and PCL-17 PGS were included as covariates to verify the specificity of the effect. RESULTS: EQPGS associated with PCL-6 (R 2  = 0.012%, P = 9.35 × 10-5). This effect remained significant after accounting for autism, depression, PTSD, and anxiety PGS but was observed only in those who endorsed experiencing at least one traumatic event. EQPGS showed the strongest effect on PCL-6 (ß = 2.32, s.e. = 0.762, P = 0.002) among those who endorsed childhood neglect/abuse (felt hated as a child). With respect to case status, the highest probability of PTSD was 17.93% and 10.04% for those who endorsed "feeling hated as a child" and those who did not, respectively (P diff = 0.011; Cohen's d = 1.951, 95%CI 1.70-2.20). CONCLUSIONS: A genetic predisposition to higher empathy, which may index greater emotional sensitivity, predisposes an individual to more severe PTSD symptoms, especially after early-life adversity.

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.

Hippocampal seed connectome-based modeling predicts the feeling of stress.

Although the feeling of stress is ubiquitous, the neural mechanisms underlying this affective experience remain unclear. Here, we investigate functional hippocampal connectivity throughout the brain during an acute stressor and use machine learning to demonstrate that these networks can specifically predict the subjective feeling of stress. During a stressor, hippocampal connectivity with a network including the hypothalamus (known to regulate physiological stress) predicts feeling more stressed, whereas connectivity with regions such as dorsolateral prefrontal cortex (associated with emotion regulation) predicts less stress. These networks do not predict a subjective state unrelated to stress, and a nonhippocampal network does not predict subjective stress. Hippocampal networks are consistent, specific to the construct of subjective stress, and broadly informative across measures of subjective stress. This approach provides opportunities for relating hypothesis-driven functional connectivity networks to clinically meaningful subjective states. Together, these results identify hippocampal networks that modulate the feeling of stress.

Memory biases in alcohol use disorder: enhanced memory for contexts associated with alcohol prospectively predicts alcohol use outcomes.

Memory for prior drinking experiences may powerfully drive later alcohol use in familiar drinking contexts, yet we know little about what patients with alcohol use disorder (AUD) remember of alcohol-related episodes. Although animal and theoretical models of addiction emphasize the importance of different memory systems for understanding maladaptive use, clinical research parsing what AUD patients remember from alcohol-related episodes is lacking. The current study applied a novel memory task in which moderate drinkers (N = 30) and treatment-seeking individuals with alcohol use disorder (AUD: N = 29) encoded associations between photographs of objects (alcoholic beverages and neutral items) and photographs of neutral scenes. At least 24 h later, two types of memory were assessed: item memory (object recognition) and associative memory (cued recognition of scenes associated with objects). To assess which memories predicted drinking, real-world behavior was assessed in patients with AUD at baseline and for 4 weeks following memory tests. Despite demographic differences, the results showed broadly impaired item memory in AUD compared with moderate drinkers (p < 0.001), but enhanced associative memory for scenes paired with alcohol (p = 0.015). These associative memory biases were especially pronounced for stimuli rated as more affectively salient. Furthermore, stronger but less detailed memory for alcohol-related associations (i.e., choosing the correct scene but the incorrect photograph) significantly predicted heavier baseline (p = 0.002) and higher subsequent (p = 0.01) drinking in patients with AUD. These findings reveal a novel alcohol-related memory bias in AUD, and uncover the importance of associative memory for understanding real-world heavy alcohol use.

Sex differences in neural stress responses and correlation with subjective stress and stress regulation.

Emotional stress responses, encompassing both stress reactivity and regulation, have been shown to differ between men and women, but the neural networks supporting these processes remain unclear. The current study used functional neuroimaging (fMRI) to investigate sex differences in neural responses during stress and the sex-specific relationships between these responses and emotional stress responses for men and women. A significant sex by condition interaction revealed that men showed greater stress responses in prefrontal cortex (PFC) regions, whereas women had stronger responses in limbic/striatal regions. Although men and women did not significantly differ in emotional stress reactivity or subjective reports of stress regulation, these responses were associated with distinct neural networks. Higher dorsomedial PFC responses were associated with lower stress reactivity in men, but higher stress reactivity in women. In contrast, while higher ventromedial PFC stress responses were associated with worse stress regulation in men (but better regulation in women), dynamic increases in vmPFC responses during stress were associated with lower stress reactivity in men. Finally, stress-induced hippocampal responses were more adaptive for women: for men, high and dynamically increasing responses in left hippocampus were associated with high stress reactivity, and dynamic increases in the left (but not right) hippocampus were associated with worse stress regulation. Together, these results reveal that men and women engage distinct neural networks during stress, and sex-specific neural stress responses facilitate optimal emotional stress responses.

Acute stress throughout the memory cycle: Diverging effects on associative and item memory.

Acute stress can modulate memory for individual parts of an event (items), but whether it similarly influences memory for associations between items remains unclear. We used a within-subjects design to explore the influence of acute stress on item and associative memory in humans. Participants associated negative words with neutral objects, rated their subjective arousal for each pair, and completed delayed item and paired associative recognition tasks. We found strikingly different patterns of acute stress effects on item and associative memory: for high-arousal pairs, preencoding stress enhanced associative memory, whereas postencoding stress enhanced item memory. Preretrieval stress consistently impaired both forms of memory. We found that the influence of stress-induced cortisol also varied, with a linear relationship between cortisol and item memory but a quadratic relationship between cortisol and associative memory. These findings reveal key differences in how stress, throughout the memory cycle, shapes our memories for items and associations. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Enhancing memory with stress: Progress, challenges, and opportunities.

Stress can strongly influence what we learn and remember, including by making memories stronger. Experiments probing stress effects on hippocampus-dependent memory in rodents have revealed modulatory factors and physiological mechanisms by which acute stress can enhance long-term memory. However, extending these findings and mechanisms to understand when stress will enhance declarative memory in humans faces important challenges. This review synthesizes human and rodent studies of stress and memory, examining translational gaps related to measurements of declarative memory and stress responses in humans. Human studies diverge from rodent research by assessing declarative memories that may not depend on the hippocampus and by measuring peripheral rather than central stress responses. This highlights opportunities for future research across species, including assessing stress effects on hippocampal-dependent memory processes in humans and relating peripheral stress responses to stress effects on the function of memory-related brain regions in rodents. Together, these investigations will facilitate the translation of stress effects on memory function from rodents to humans and inform interventions that can harness the positive effects of stress on long-term memory.