The reach of reactivation: Effects of consciously triggered versus unconsciously triggered reactivation of associative memory.

Consolidating memories for long-term storage depends on reactivation. Reactivation occurs both consciously, during wakefulness, and unconsciously, during wakefulness and sleep. While considerable work has examined conscious awake and unconscious sleep reactivation, in this study, we directly compare the consequences of conscious and unconscious reactivation during wakefulness. Forty-one participants learned associations consisting of adjective-object-position triads. Objects were clustered into distinct semantic groups (e.g., fruits, vehicles) such that we could examine consequences of reactivation on semantically related memories. After an intensive learning protocol, we systematically reactivated some of the triads by presenting the adjective as a cue. Reactivation was done so that it was consciously experienced for some triads, and only unconsciously processed for others. Memory for spatial positions, the most distal part of the association, was affected by reactivation in a consciousness-dependent and memory-strength-dependent manner. Conscious reactivation resulted in weakening of semantically related memories that were strong initially, resonating with prior findings of retrieval-induced forgetting. Unconscious reactivation, on the other hand, selectively benefited weak reactivated memories, as previously shown for reactivation during sleep. Semantically linked memories were not impaired, but rather were integrated with the reactivated memory. These results taken together demonstrate that conscious and unconscious reactivation have qualitatively different consequences. Results support a consciousness-dependent inhibition account, whereby unconscious reactivation entails less inhibition than conscious reactivation, thus allowing more liberal spread of activation. Findings set the stage for additional exploration into the role of conscious experience in memory storage and structuring.

Identifying causal subsequent memory effects.

Over 40 y of accumulated research has detailed associations between neuroimaging signals measured during a memory encoding task and later memory performance, across a variety of brain regions, measurement tools, statistical approaches, and behavioral tasks. But the interpretation of these subsequent memory effects (SMEs) remains unclear: if the identified signals reflect cognitive and neural mechanisms of memory encoding, then the underlying neural activity must be causally related to future memory. However, almost all previous SME analyses do not control for potential confounders of this causal interpretation, such as serial position and item effects. We collect a large fMRI dataset and use an experimental design and analysis approach that allows us to statistically adjust for nearly all known exogenous confounding variables. We find that, using standard approaches without adjustment, we replicate several univariate and multivariate subsequent memory effects and are able to predict memory performance across people. However, we are unable to identify any signal that reliably predicts subsequent memory after adjusting for confounding variables, bringing into doubt the causal status of these effects. We apply the same approach to subjects' judgments of learning collected following an encoding period and show that these behavioral measures of mnemonic status do predict memory after adjustments, suggesting that it is possible to measure signals near the time of encoding that reflect causal mechanisms but that existing neuroimaging measures, at least in our data, may not have the precision and specificity to do so.

Event Integration and Temporal Differentiation: How Hierarchical Knowledge Emerges in Hippocampal Subfields through Learning.

Everyday life is composed of events organized by changes in contexts, with each event containing an unfolding sequence of occurrences. A major challenge facing our memory systems is how to integrate sequential occurrences within events while also maintaining their details and avoiding over-integration across different contexts. We asked if and how distinct hippocampal subfields come to hierarchically and, in parallel, represent both event context and subevent occurrences with learning. Female and male human participants viewed sequential events defined as sequences of objects superimposed on shared color frames while undergoing high-resolution fMRI. Importantly, these events were repeated to induce learning. Event segmentation, as indexed by increased reaction times at event boundaries, was observed in all repetitions. Temporal memory decisions were quicker for items from the same event compared to across different events, indicating that events shaped memory. With learning, hippocampal CA3 multivoxel activation patterns clustered to reflect the event context, with more clustering correlated with behavioral facilitation during event transitions. In contrast, in the dentate gyrus (DG), temporally proximal items that belonged to the same event became associated with more differentiated neural patterns. A computational model explained these results by dynamic inhibition in the DG. Additional similarity measures support the notion that CA3 clustered representations reflect shared voxel populations, while DG's distinct item representations reflect different voxel populations. These findings suggest an interplay between temporal differentiation in the DG and attractor dynamics in CA3. They advance our understanding of how knowledge is structured through integration and separation across time and context.

Time for Memories.

The ability to store information about the past to dynamically predict and prepare for the future is among the most fundamental tasks the brain performs. To date, the problems of understanding how the brain stores and organizes information about the past (memory) and how the brain represents and processes temporal information for adaptive behavior have generally been studied as distinct cognitive functions. This Symposium explores the inherent link between memory and temporal cognition, as well as the potential shared neural mechanisms between them. We suggest that working memory and implicit timing are interconnected and may share overlapping neural mechanisms. Additionally, we explore how temporal structure is encoded in associative and episodic memory and, conversely, the influences of episodic memory on subsequent temporal anticipation and the perception of time. We suggest that neural sequences provide a general computational motif that contributes to timing and working memory, as well as the spatiotemporal coding and recall of episodes.

Goal Shifts Structure Memories and Prioritize Event-defining Information in Memory.

Every day, we encounter far more information than we could possibly remember. Thus, our memory systems must organize and prioritize the details from an experience that can adaptively guide the storage and retrieval of specific episodic events. Prior work has shown that shifts in internal goal states can function as event boundaries, chunking experiences into distinct and memorable episodes. In addition, at short delays, memory for contextual information at boundaries has been shown to be enhanced compared with items within each event. However, it remains unclear if these memory enhancements are limited to features that signal a meaningful transition between events. To determine how changes in dynamic goal states influence the organization and content of long-term memory, we designed a 2-day experiment in which participants viewed a series of black-and-white objects surrounded by a color border on a two-by-two grid. The location of the object on the grid determined which of two tasks participants performed on a given trial. To examine if distinct types of goal shifts modulate the effects of event segmentation, we changed the border color, the task, or both after every four items in a sequence. We found that goal shifts influenced the temporal memory in a manner consistent with the formation of distinct events. However, for subjective memory representations in particular, these effects differed by the type of event boundary. Furthermore, to examine if goal shifts lead to the prioritization of goal-relevant features in longer lasting memories, we tested the source memory for each object's color and grid location both immediately and after a 24-hr delay. On the immediate test, boundaries enhanced the memory for all concurrent source features compared with nonboundary items, but only if those boundaries involved a goal shift. In contrast, after a delay, the source memory was selectively enhanced for the feature relevant to the goal shift. These findings suggest that goals can adaptively structure memories by prioritizing contextual features that define a unique episode in memory.

Data-driven clustering of functional signals reveals gradients in processing both within the anterior hippocampus and across its long axis.

A particularly elusive puzzle concerning the hippocampus is how the structural differences along its long, anteroposterior axis might beget meaningful functional differences, particularly in terms of the granularity of information processing. One measure posits to quantify this granularity by calculating the average statistical independence of the BOLD signal across neighboring voxels, or inter-voxel similarity (IVS), and has shown the anterior hippocampus to process coarser-grained information than the posterior hippocampus. This measure, however, has yielded opposing results in studies of developmental and healthy aging samples, which also varied in fMRI acquisition parameters and hippocampal parcellation methods. In order to reconcile these findings, we measured IVS across two separate resting-state fMRI acquisitions and compared the results across many of the most widely used parcellation methods in a large young-adult sample of male and female humans (Acquisition 1, N = 233; Acquisition 2, N = 176). Finding conflicting results across acquisitions and parcellations, we reasoned that a data-driven approach to hippocampal parcellation is necessary. To this end, we implemented a group masked independent components analysis (mICA) to identify functional subunits of the hippocampus, most notably separating the anterior hippocampus into separate anterior-medial, anterior-lateral, and posteroanterior-lateral components. Measuring IVS across these components revealed a decrease in IVS along the medial-lateral axis of the anterior hippocampus but an increase from anterior to posterior. We conclude that inter-voxel similarity is deeply affected by parcellation, and that grounding one's parcellation in a functionally informed approach might allow for a more complex and reliable characterization of the hippocampus.SIGNIFICANCE STATEMENT:Processing information along hierarchical scales of granularity is critical for many of the feats of cognition considered most human. Recently, the changes in structure, cortical connectivity, and apparent functional properties across parcels of the hippocampal long axis have been hypothesized to underlie this hierarchical gradient in information processing. We show here, however, that the choice of parcellation method itself drastically affects one particular measure of granularity across the hippocampus, and that a functionally informed approach to parcellation reveals gradients both within the anterior hippocampus and in non-linear form across the long axis. These results point to the issue of parcellation as a critical one in the study of the hippocampus and reorient interpretation of existing results.

Reward Enhances Memory via Age-Varying Online and Offline Neural Mechanisms across Development.

Reward motivation enhances memory through interactions between mesolimbic, hippocampal, and cortical systems, both during and after encoding. Developmental changes in these distributed neural circuits may lead to age-related differences in reward-motivated memory and the underlying neural mechanisms. Converging evidence from cross-species studies suggests that subcortical dopamine signaling is increased during adolescence, which may lead to stronger memory representations of rewarding, relative to mundane, events and changes in the contributions of underlying subcortical and cortical brain mechanisms across age. Here, we used fMRI to examine how reward motivation influences the "online" encoding and "offline" postencoding brain mechanisms that support long-term associative memory from childhood to adulthood in human participants of both sexes. We found that reward motivation led to both age-invariant enhancements and nonlinear age-related differences in associative memory after 24 h. Furthermore, reward-related memory benefits were linked to age-varying neural mechanisms. During encoding, interactions between the prefrontal cortex (PFC) and ventral tegmental area (VTA) were associated with better high-reward memory to a greater degree with increasing age. Preencoding to postencoding changes in functional connectivity between the anterior hippocampus and VTA were also associated with better high-reward memory, but more so at younger ages. Our findings suggest that there may be developmental differences in the contributions of offline subcortical and online cortical brain mechanisms supporting reward-motivated memory.SIGNIFICANCE STATEMENT A substantial body of research has examined the neural mechanisms through which reward influences memory formation in adults. However, despite extensive evidence that both reward processing and associative memory undergo dynamic change across development, few studies have examined age-related changes in these processes. We found both age-invariant and nonlinear age-related differences in reward-motivated memory. Moreover, our findings point to developmental differences in the processes through which reward modulates the prioritization of information in long-term memory, with greater early reliance on offline subcortical consolidation mechanisms and increased contribution of systems-level online encoding circuitry with increasing age. These results highlight dynamic developmental changes in the cognitive and neural mechanisms through which motivationally salient information is prioritized in memory from childhood to adulthood.

Cross-Modal Facilitation of Episodic Memory by Sequential Action Execution.

Throughout our lives, the actions we produce are often highly familiar and repetitive (e.g., commuting to work). However, layered upon these routine actions are novel, episodic experiences. Substantial research has shown that prior knowledge can facilitate learning of conceptually related new information. But despite the central role our behavior plays in real-world experience, it remains unclear how engagement in a familiar sequence of actions influences memory for unrelated, nonmotor information coincident with those actions. To investigate this, we had healthy young adults encode novel items while simultaneously following a sequence of actions (key presses) that was either predictable and well-learned or random. Across three experiments (N = 80 each), we found that temporal order memory, but not item memory, was significantly enhanced for novel items encoded while participants executed predictable compared with random action sequences. These results suggest that engaging in familiar behaviors during novel learning scaffolds within-event temporal memory, an essential feature of episodic experiences.

Mnemonic Content and Hippocampal Patterns Shape Judgments of Time.

Our experience of time can feel dilated or compressed, rather than reflecting true "clock time." Although many contextual factors influence the subjective perception of time, it is unclear how memory accessibility plays a role in constructing our experience of and memory for time. Here, we used a combination of behavioral and functional MRI measures in healthy young adults (N = 147) to ask the question of how memory is incorporated into temporal duration judgments. Behaviorally, we found that event boundaries, which have been shown to disrupt ongoing memory integration processes, result in the temporal compression of duration judgments. Additionally, using a multivoxel pattern similarity analysis of functional MRI data, we found that greater temporal pattern change in the left hippocampus within individual trials was associated with longer duration judgments. Together, these data suggest that mnemonic processes play a role in constructing representations of time.

Neurophysiology of Remembering.

By linking the past with the future, our memories define our sense of identity. Because human memory engages the conscious realm, its examination has historically been approached from language and introspection and proceeded largely along separate parallel paths in humans and other animals. Here, we first highlight the achievements and limitations of this mind-based approach and make the case for a new brain-based understanding of declarative memory with a focus on hippocampal physiology. Next, we discuss the interleaved nature and common physiological mechanisms of navigation in real and mental spacetime. We suggest that a distinguishing feature of memory types is whether they subserve actions for single or multiple uses. Finally, in contrast to the persisting view of the mind as a highly plastic blank slate ready for the world to make its imprint, we hypothesize that neuronal networks are endowed with a reservoir of neural trajectories, and the challenge faced by the brain is how to select and match preexisting neuronal trajectories with events in the world.

Neural Evidence for Representational Persistence Within Events.

How does the brain process continuous experiences so they can be remembered? Evidence suggests that people perceive their experience as a series of distinct and meaningful events. Information encountered within the same event shows greater temporal integration into memory as well as enhanced neural representational similarity. Although these data support the theory that the brain builds and maintains a mental model of the current event that represents recently encountered stimulus information, this hypothesis has not been directly tested. We used fMRI in humans (N = 21, 13 female) to test whether within-event neural similarity indicates the persistence of stimulus representations in a mental model. Participants viewed trial-unique visual images that were grouped into events. We calculated neural pattern similarity across time in the category-selective visual cortex to measure stimulus persistence. Pattern similarity was enhanced within, compared with between, events in the object-sensitive left lateral occipital (LO) cortex. This was specific to situations when objects could persist within a mental model, suggesting modulation of neural activity based on the features and structure of the event. Left LO object persistence was correlated with activity in a medial prefrontal cortex (mPFC) region linked to representing mental models within events. mFPC activity also correlated with pattern similarity in the hippocampus but more generally across stimulus categories. Critically, left LO similarity was related to estimates of temporal proximity in memory. The data suggest that temporal neural stability reflects stimulus persistence in mental models and highlight the importance of within-event representational stability in the transformation of experience to memory.SIGNIFICANCE STATEMENT How does the brain process continuous experiences so they can be remembered? One idea is that information persists in mental models during stable events, facilitating the organization of events in memory. Using fMRI pattern similarity analysis, we found enhanced similarity within, compared with between, events in the object-sensitive LO but only when objects could persist within a mental model. mPFC activity correlated with left LO similarity when objects persisted within an event; in contrast, mPFC activity correlated with hippocampal similarity across stimulus categories. Left LO persistence was also related to the remembered temporal proximity of stimuli. The data suggest the brain dynamically maintains stimulus information in mental models during events, supporting the transformation of experience into memory.

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.

Age-Related Increases in Posterior Hippocampal Granularity Are Associated with Remote Detailed Episodic Memory in Development.

Episodic memory is critical to human functioning. In adults, episodic memory involves a distributed neural circuit in which the hippocampus plays a central role. As episodic memory abilities continue to develop across childhood and into adolescence, studying episodic memory maturation can provide insight into the development and construction of these hippocampal networks, and ultimately clues to their function in adulthood. While past developmental studies have shown that the hippocampus helps to support memory in middle childhood and adolescence, the extent to which ongoing maturation within the hippocampus contributes to developmental change in episodic memory abilities remains unclear. In contrast, slower maturing regions, such as the PFC, have been suggested to be the neurobiological locus of memory improvements into adolescence. However, it is also possible that the methods used to detect hippocampal development during middle childhood and adolescence are not sensitive enough. Here, we examine how temporal covariance (or differentiation) in voxel representations within anterior and posterior hippocampus change with age to support the development of detailed recollection in male and female developing humans. We find age-related increases in the distinctiveness of temporal activation profiles in the posterior, but not anterior, hippocampus. Second, we show that this measure of granularity, when present during postencoding rest periods, correlates with the recall of detailed memories of preceding stimuli several weeks postencoding, suggesting that granularity may promote memory stabilization.SIGNIFICANCE STATEMENT Studying hippocampal maturation can provide insight into episodic memory development, as well as clues to episodic functioning in adulthood. Past work has shown evidence both for and against hippocampal contributions to age-related improvements in memory performance, but has relied heavily on univariate approaches (averaging activity across hippocampal voxels), which may not be sensitive to nuanced developmental change. Here we use a novel approach, examining time signatures in individual hippocampal voxels to reveal regionally specific (anterior vs posterior hippocampus) differences in the distinctiveness (granularity) of temporal activation profiles across development. Importantly, posterior hippocampus granularity during windows of putative memory stabilization was associated with long-term memory specificity. This suggests that the posterior hippocampus gradually builds the capacity to support detailed episodic recall.

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.

Mnemonic prediction errors promote detailed memories.

When our experience violates our predictions, it is adaptive to update our knowledge to promote a more accurate representation of the world and facilitate future predictions. Theoretical models propose that these mnemonic prediction errors should be encoded into a distinct memory trace to prevent interference with previous, conflicting memories. We investigated this proposal by repeatedly exposing participants to pairs of sequentially presented objects (A → B), thus evoking expectations. Then, we violated participants' expectations by replacing the second object in the pairs with a novel object (A → C). The following item memory test required participants to discriminate between identical old items and similar lures, thus testing detailed and distinctive item memory representations. In two experiments, mnemonic prediction errors enhanced item memory: Participants correctly identified more old items as old when those items violated expectations during learning, compared with items that did not violate expectations. This memory enhancement for C items was only observed when participants later showed intact memory for the related A → B pairs, suggesting that strong predictions are required to facilitate memory for violations. Following up on this, a third experiment reduced prediction strength prior to violation and subsequently eliminated the memory advantage of violations. Interestingly, mnemonic prediction errors did not increase gist-based mistakes of identifying old items as similar lures or identifying similar lures as old. Enhanced item memory in the absence of gist-based mistakes suggests that violations enhanced memory for items' details, which could be mediated via distinct memory traces. Together, these results advance our knowledge of how mnemonic prediction errors promote memory formation.

Time-dependent transformations of memory representations differ along the long axis of the hippocampus.

Research has shown that sleep is beneficial for the long-term retention of memories. According to theories of memory consolidation, memories are gradually reorganized, becoming supported by widespread, distributed cortical networks, particularly during postencoding periods of sleep. However, the effects of sleep on the organization of memories in the hippocampus itself remains less clear. In a 3-d study, participants encoded separate lists of word-image pairs differing in their opportunity for sleep-dependent consolidation. Pairs were initially studied either before or after an overnight sleep period, and were then restudied in a functional magnetic resonance imaging (fMRI) scan session. We used multivariate pattern similarity analyses to examine fine-grained effects of consolidation on memory representations in the hippocampus. We provide evidence for a dissociation along the long axis of the hippocampus that emerges with consolidation, such that representational patterns for object-word memories initially formed prior to sleep become differentiated in anterior hippocampus and more similar, or overlapping, in posterior hippocampus. Differentiation in anterior hippocampal representations correlated with subsequent behavioral performance. Furthermore, representational overlap in posterior hippocampus correlated with the duration of intervening slow wave sleep. Together, these results demonstrate that sleep-dependent consolidation promotes the reorganization of memory traces along the long axis of the hippocampus.

Sleep Spindles Promote the Restructuring of Memory Representations in Ventromedial Prefrontal Cortex through Enhanced Hippocampal-Cortical Functional Connectivity.

Memory consolidation is hypothesized to involve the distribution and restructuring of memory representations across hippocampal and cortical regions. Theories suggest that, through extended hippocampal-cortical interactions, cortical ensembles come to represent more integrated, or overlapping, memory traces that prioritize commonalities across related memories. Sleep processes, particularly fast sleep spindles, are thought to support consolidation, but evidence for this relationship has been mostly limited to memory retention benefits. Whether fast spindles provide a mechanism for neural changes hypothesized to support consolidation, including the strengthening of hippocampal-cortical networks and integration across memory representations, remains unclear, as does the specificity of regions involved. Using functional connectivity analyses of human fMRI data (both sexes), we show that fast spindle density during overnight sleep is related to enhanced hippocampal-cortical functional connectivity the next day, when restudying information learned before sleep. Spindle density modulated connectivity in distinct hippocampal-cortical networks depending on the category of the consolidated stimuli. Specifically, spindle density correlated with functional connectivity between anterior hippocampus and ventromedial prefrontal cortex (vmPFC) for object-word pairs, and posterior hippocampus and posteromedial cortex for scene-word pairs. Using multivariate pattern analyses, we also show that fast spindle density during postlearning sleep is associated with greater pattern similarity, or representational overlap, across individual object-word memories in vmPFC the next day. Further, the relationship between fast spindle density and representational overlap in vmPFC was mediated by the degree of anterior hippocampal-vmPFC functional connectivity. Together, these results suggest that fast spindles support the network distribution of memory traces, potentially restructuring memory representations in vmPFC.SIGNIFICANCE STATEMENT How new experiences are transformed into long-term memories remains a fundamental question for neuroscience research. Theories suggest that memories are stabilized as they are reorganized in the brain, a process thought to be supported by sleep oscillations, particularly sleep spindles. Although sleep spindles have been associated with benefits in memory retention, it is not well understood how spindles modify neural memory traces. This study found that spindles during overnight sleep correlate with changes in neural memory traces, including enhanced functional connectivity in distinct hippocampal-cortical networks and increased pattern similarity among memories in the cortex. The results provide critical evidence that spindles during overnight sleep may act as a physiological mechanism for the restructuring of neural memory traces.

Effects of hippocampal interictal discharge timing, duration, and spatial extent on list learning.

Interictal epileptiform discharges (IEDs) can impair memory. The properties of IEDs most detrimental to memory, however, are undefined. We studied the impact of temporal and spatial characteristics of IEDs on list learning. Subjects completed a memory task during intracranial EEG recordings including hippocampal depth and temporal neocortical subdural electrodes. Subjects viewed a series of objects, and after a distracting task, recalled the objects from the list. The impacts of IED presence, duration, and propagation to neocortex during encoding of individual stimuli were assessed. The effects of IED total number and duration during maintenance and recall periods on delayed recall performance were also determined. The influence of IEDs during recall was further investigated by comparing the likelihood of IEDs preceding correctly recalled items vs. periods of no verbal response. Across 6 subjects, we analyzed 28 hippocampal and 139 lateral temporal contacts. Recall performance was poor, with a median of 17.2% correct responses (range 10.4-21.9%). Interictal epileptiform discharges during encoding, maintenance, and recall did not significantly impact task performance, and there was no significant difference between the likelihood of IEDs during correct recall vs. periods of no response. No significant effects of discharge duration during encoding, maintenance, or recall were observed. Interictal epileptiform discharges with spread to lateral temporal cortex during encoding did not adversely impact recall. A post hoc analysis refining model assumptions indicated a negative impact of IED count during the maintenance period, but otherwise confirmed the above results. Our findings suggest no major effect of hippocampal IEDs on list learning, but study limitations, such as baseline hippocampal dysfunction, should be considered. The impact of IEDs during the maintenance period may be a focus of future research.

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.

Time-resolved neural reinstatement and pattern separation during memory decisions in human hippocampus.

Mnemonic decision-making has long been hypothesized to rely on hippocampal dynamics that bias memory processing toward the formation of new memories or the retrieval of old ones. Successful memory encoding may be best optimized by pattern separation, whereby two highly similar experiences can be represented by underlying neural populations in an orthogonal manner. By contrast, successful memory retrieval is thought to be supported by a recovery of the same neural pattern laid down during encoding. Here we examined how hippocampal pattern completion and separation emerge over time during memory decisions. We measured electrocorticography activity in the human hippocampus and posterior occipitotemporal cortex (OTC) while participants performed continuous recognition of items that were new, repeated (old), or highly similar to a prior item (similar). During retrieval decisions of old items, both regions exhibited significant reinstatement of multivariate high-frequency activity (HFA) associated with encoding. Further, the extent of reinstatement of encoding patterns during retrieval was correlated with the strength (HFA power) of hippocampal encoding. Evidence for encoding pattern reinstatement was also seen in OTC on trials requiring fine-grained discrimination of similar items. By contrast, hippocampal activity showed evidence for pattern separation during these trials. Together, these results underscore the critical role of the hippocampus in supporting both reinstatement of overlapping information and separation of similar events.