An Enduring Role for Hippocampal Pattern Completion in Addition to an Emergent Nonhippocampal Contribution to Holistic Episodic Retrieval after a 24†h Delay.

Episodic memory retrieval is associated with the holistic neocortical reinstatement of all event information, an effect driven by hippocampal pattern completion. However, whether holistic reinstatement occurs, and whether hippocampal pattern completion continues to drive reinstatement, after a period of consolidation is unclear. Theories of systems consolidation predict either a time-variant or time-invariant role of the hippocampus in the holistic retrieval of episodic events. Here, we assessed whether episodic events continue to be reinstated holistically and whether hippocampal pattern completion continues to facilitate holistic reinstatement following a period of consolidation. Female and male human participants learned "events" that comprised multiple overlapping pairs of event elements (e.g., person-location, object-location, location-person). Importantly, encoding occurred either immediately before or 24 h before retrieval. Using fMRI during the retrieval of events, we show evidence for holistic reinstatement, as well as a correlation between reinstatement and hippocampal pattern completion, regardless of whether retrieval occurred immediately or 24 h after encoding. Thus, hippocampal pattern completion continues to contribute to holistic reinstatement after a delay. However, our results also revealed that some holistic reinstatement can occur without evidence for a corresponding signature of hippocampal pattern completion after a delay (but not immediately after encoding). We therefore show that hippocampal pattern completion, in addition to a nonhippocampal process, has a role in holistic reinstatement following a period of consolidation. Our results point to a consolidation process where the hippocampus and neocortex may work in an additive, rather than compensatory, manner to support episodic memory retrieval.

Theta and alpha oscillations in human hippocampus and medial parietal cortex support the formation of location-based representations.

Our ability to navigate in a new environment depends on learning new locations. Mental representations of locations are quickly accessible during navigation and allow us to know where we are regardless of our current viewpoint. Recent functional magnetic resonance imaging (fMRI) research using pattern classification has shown that these location-based representations emerge in the retrosplenial cortex and parahippocampal gyrus, regions theorized to be critically involved in spatial navigation. However, little is currently known about the oscillatory dynamics that support the formation of location-based representations. We used magnetoencephalogram (MEG) recordings to investigate region-specific oscillatory activity in a task where participants could form location-based representations. Participants viewed videos showing that two perceptually distinct scenes (180° apart) belonged to the same location. This "overlap" video allowed participants to bind the two distinct scenes together into a more coherent location-based representation. Participants also viewed control "non-overlap" videos where two distinct scenes from two different locations were shown, where no location-based representation could be formed. In a post-video behavioral task, participants successfully matched the two viewpoints shown in the overlap videos, but not the non-overlap videos, indicating they successfully learned the locations in the overlap condition. Comparing oscillatory activity between the overlap and non-overlap videos, we found greater theta and alpha/beta power during the overlap relative to non-overlap videos, specifically at time-points when we expected scene integration to occur. These oscillations localized to regions in the medial parietal cortex (precuneus and retrosplenial cortex) and the medial temporal lobe, including the hippocampus. Therefore, we find that theta and alpha/beta oscillations in the hippocampus and medial parietal cortex are likely involved in the formation of location-based representations.

A registered report testing the effect of sleep on Deese-Roediger-McDermott false memory: greater lure and veridical recall but fewer intrusions after sleep.

Human memory is known to be supported by sleep. However, less is known about the effect of sleep on false memory, where people incorrectly remember events that never occurred. In the laboratory, false memories are often induced via the Deese-Roediger-McDermott (DRM) paradigm where participants are presented with wordlists comprising semantically related words such as nurse, hospital and sick (studied words). Subsequently, participants are likely to falsely remember that a related lure word such as doctor was presented. Multiple studies have examined whether these false memories are influenced by sleep, with contradictory results. A recent meta-analysis suggests that sleep may increase DRM false memory when short lists are used. We tested this in a registered report (N = 488) with a 2 (Interval: Immediate versus 12 h delay) × 2 (Test Time: 9:00 versus 21:00) between-participant DRM experiment, using short DRM lists (N = 8 words/list) and free recall as the memory test. We found an unexpected time-of-day effect such that completing free recall in the evening led to more intrusions (neither studied nor lure words). Above and beyond this time-of-day effect, the Sleep participants produced fewer intrusions than their Wake counterparts. When this was statistically controlled for, the Sleep participants falsely produced more critical lures. They also correctly recalled more studied words (regardless of intrusions). Exploratory analysis showed that these findings cannot be attributed to differences in output bias, as indexed by the number of total responses. Our overall results cannot be fully captured by existing sleep-specific theories of false memory, but help to define the role of sleep in two more general theories (Fuzzy-Trace and Activation/Monitoring theories) and suggest that sleep may benefit gist abstraction/spreading activation on one hand and memory suppression/source monitoring on the other.

Hippocampal theta activity during encoding promotes subsequent associative memory in humans.

Hippocampal theta oscillations have been implicated in associative memory in humans. However, findings from electrophysiological studies using scalp electroencephalography or magnetoencephalography, and those using intracranial electroencephalography are mixed. Here we asked 10 pre-surgical epilepsy patients undergoing intracranial electroencephalography recording, along with 21 participants undergoing magnetoencephalography recordings, to perform an associative memory task, and examined whether hippocampal theta activity during encoding was predictive of subsequent associative memory performance. Across the intracranial electroencephalography and magnetoencephalography studies, we observed that theta power in the hippocampus increased during encoding, and that this increase differed as a function of subsequent memory, with greater theta activity for pairs that were successfully retrieved in their entirety compared with those that were not remembered. This helps to clarify the role of theta oscillations in associative memory formation in humans, and further, demonstrates that findings in epilepsy patients undergoing intracranial electroencephalography recordings can be extended to healthy participants undergoing magnetoencephalography recordings.

Targeted memory reactivation during sleep can induce forgetting of overlapping memories.

Memory reactivation during sleep can shape new memories into a long-term form. Reactivation of memories can be induced via the delivery of auditory cues during sleep. Although this targeted memory reactivation (TMR) approach can strengthen newly acquired memories, research has tended to focus on single associative memories. It is less clear how TMR affects retention for overlapping associative memories. This is critical, given that repeated retrieval of overlapping associations during wake can lead to forgetting, a phenomenon known as retrieval-induced forgetting (RIF). We asked whether a similar pattern of forgetting occurs when TMR is used to cue reactivation of overlapping pairwise associations during sleep. Participants learned overlapping pairs-learned separately, interleaved with other unrelated pairs. During sleep, we cued a subset of overlapping pairs using TMR. While TMR increased retention for the first encoded pairs, memory decreased for the second encoded pairs. This pattern of retention was only present for pairs not tested prior to sleep. The results suggest that TMR can lead to forgetting, an effect similar to RIF during wake. However, this effect did not extend to memories that had been strengthened via retrieval prior to sleep. We therefore provide evidence for a reactivation-induced forgetting effect during sleep.

Schematic information influences memory and generalisation behaviour for schema-relevant and -irrelevant information.

Schemas modulate memory performance for schema-congruent and -incongruent information. However, it is assumed they do not influence behaviour for information irrelevant to themselves. We assessed memory and generalisation behaviour for information related to an underlying pattern, where a schema could be extracted (schema-relevant), and information that was unrelated and therefore irrelevant to the extracted schema (schema-irrelevant). Using precision measures of long-term memory, where participants learnt associations between words and locations around a circle, we assessed memory and generalisation for schema-relevant and -irrelevant information. Words belonged to two semantic categories: human-made and natural. For one category, word-locations were clustered around one point on the circle (clustered condition), while the other category had word-locations randomly distributed (non-clustered condition). The presence of an underlying pattern in the clustered condition allows for the extraction of a schema that can support both memory and generalisation. At test, participants were presented with old (memory) and new (generalisation) words, requiring them to identify a remembered location or make a best guess. The presence of the clustered pattern modulated memory and generalisation. In the clustered condition, participants placed old and new words in locations consistent with the underlying pattern. In contrast, for the non-clustered condition, participants were less likely to place old and new non-clustered words in locations consistent with the clustered condition. Therefore, we provide evidence that the presence of schematic information modulates memory and generalisation for schema-relevant and -irrelevant information. Our results highlight the need to carefully construct appropriate schema-irrelevant control conditions such that behaviour in these conditions is not modulated by the presence of a schema. Theoretically, models of schema processing need to account for how the presence of schematic information can have consequences for information that is irrelevant to itself.

Retrieval practice transfer effects for multielement event triplets.

Retrieval practice (RP) leads to improved retention relative to re-exposure and is considered a robust phenomenon when the final test conditions are identical to RP conditions. However, the extent to which RP 'transfers' to related material is less clear. Here, we tested for RP transfer effects under conditions known to induce integration of associated material at encoding, which may make transfer more likely. Participants learned multielement triplets (locations, animals and objects) and one pairwise association from each triplet was tested through RP, re-exposed, or not re-exposed (control). Two days later participants completed a final test of all pairwise associations. We found no evidence for an RP effect compared to re-exposure, but both tested/re-exposed pairs were better remembered than the not re-exposed control condition. We also found that transfer occurred from both tested to untested and re-exposed to not re-exposed pairs. Our results highlight that RP and re-exposure can boost retention for directly tested/re-exposed event pairs and associated but untested/not re-exposed event pairs, suggesting re-exposure of integrated information can be of pedagogical value. The results also question the boundary conditions for an increase in retention for RP relative to re-exposure, highlighting the need for a better theoretical understanding of RP effects.

The Formation and Retrieval of Holistic Event Memories Across Development.

Event memories consist of associations between their constituent elements, leading to their holistic retrieval via the process of pattern completion. This holistic retrieval can occur, under specific conditions, when each within-event association is encoded in a separate temporal context: adults are able to integrate the information into a single coherent representation. In this study, we sought to replicate the holistic retrieval of simultaneously encoded event elements in children, and examine whether children can similarly integrate across separated encoding contexts. Children (aged 6-7 years; 9-10 years) and adults encoded two series of three-element "events" consisting of an animal, object, and location. In the simultaneous condition, they encountered all three event elements at once; in the separated condition, they encountered each pairwise association separately (animal-object, animal-location, object-location). After encoding, they were tested on the retrieval of each within-event association using a 4-alternative-forced-choice task. We inferred the presence of holistic retrieval using a measure of retrieval dependency-the statistical dependency between retrieval of within-event associations. Memory for the pairs improved across ages, but there were no developmental differences in retrieval dependency. In the simultaneous encoding condition, all three age groups showed retrieval dependency. However, counter to previous studies, retrieval dependency was not observed in any age group following separated encoding. The results from the simultaneous encoding condition support the idea that pattern completion processes are developed by early childhood. The absence of retrieval dependency in adults following separated encoding prevent conclusions regarding the developmental trajectory of mnemonic integration.

Forgetting across a hierarchy of episodic representations.

Rich episodic experiences are represented in a hierarchical manner across a diverse network of brain regions, and as such, the way in which episodes are forgotten is likely to be similarly diverse. Using novel experimental approaches and statistical modelling, recent research has suggested that item-based representations, such as ones related to the colour and shape of an object, fragment over time, whereas higher-order event-based representations may be forgotten in a more 'holistic' uniform manner. We propose a framework that reconciles these findings, where complex episodes are represented in a hierarchical manner, from individual items, to small-scale events, to large-scale episodic narratives. Each level in the hierarchy is represented in distinct brain regions, from the perirhinal cortex, to posterior hippocampus, to anterior hippocampus and ventromedial prefrontal cortex. Critically, forgetting may be underpinned by different mechanisms at each level in the hierarchy, leading to different patterns of behaviour.

Tracking the Emergence of Location-based Spatial Representations in Human Scene-Selective Cortex.

Scene-selective regions of the human brain form allocentric representations of locations in our environment. These representations are independent of heading direction and allow us to know where we are regardless of our direction of travel. However, we know little about how these location-based representations are formed. Using fMRI representational similarity analysis and linear mixed models, we tracked the emergence of location-based representations in scene-selective brain regions. We estimated patterns of activity for two distinct scenes, taken before and after participants learnt they were from the same location. During a learning phase, we presented participants with two types of panoramic videos: (1) an overlap video condition displaying two distinct scenes (0° and 180°) from the same location and (2) a no-overlap video displaying two distinct scenes from different locations (which served as a control condition). In the parahippocampal cortex (PHC) and retrosplenial cortex (RSC), representations of scenes from the same location became more similar to each other only after they had been shown in the overlap condition, suggesting the emergence of viewpoint-independent location-based representations. Whereas these representations emerged in the PHC regardless of task performance, RSC representations only emerged for locations where participants could behaviorally identify the two scenes as belonging to the same location. The results suggest that we can track the emergence of location-based representations in the PHC and RSC in a single fMRI experiment. Further, they support computational models that propose the RSC plays a key role in transforming viewpoint-independent representations into behaviorally relevant representations of specific viewpoints.

Make or break it: boundary conditions for integrating multiple elements in episodic memory.

Event memories are characterized by the holistic retrieval of their constituent elements. Studies show that memory for individual event elements (e.g. person, object and location) are statistically related to each other, and that the same associative memory structure can be formed by learning all pairwise associations across separated encoding contexts (person-object, person-location, object-location). Counter to previous studies that have shown no differences in holistic retrieval between simultaneously and separately encoded event elements, adults did not show evidence of holistic retrieval from separately encoded event elements when using a similar paradigm adapted for children (Experiment 1). We conducted a further five online experiments to explore the conditions under which holistic retrieval emerges following separated encoding of within-event associations, testing for influences of trial length (Experiment 2), the number of events learned (Experiment 3a) and stimulus presentation format (Experiments 3b, 4a, 4b). Presentation of written words was optimal for integrating elements across encoding trials, whereas the addition of spoken words disrupted integration across separately presented associations. The use of picture stimuli also produced effect sizes smaller than those of previously published research. We discuss the ways in which memory integration processes may be disrupted by these differences in presentation format. The findings have practical implications for the utility of this paradigm across research and learning contexts.

Dissociating memory accessibility and precision in forgetting.

Forgetting involves the loss of information over time; however, we know little about what form this information loss takes. Do memories become less precise over time, or do they instead become less accessible? Here we assessed memory for word-location associations across four days, testing whether forgetting involves losses in precision versus accessibility and whether such losses are modulated by learning a generalizable pattern. We show that forgetting involves losses in memory accessibility with no changes in memory precision. When participants learned a set of related word-location associations that conformed to a general pattern, we saw a strong trade-off; accessibility was enhanced, whereas precision was reduced. However, this trade-off did not appear to be modulated by time or confer a long-term increase in the total amount of information maintained in memory. Our results place theoretical constraints on how models of forgetting and generalization account for time-dependent memory processes. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 4 June 2019. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.c.4368464.v1 .

United we fall: All-or-none forgetting of complex episodic events.

Do complex event representations fragment over time, or are they instead forgotten in an all-or-none manner? For example, if we met a friend in a café and they gave us a present, do we forget the constituent elements of this event (location, person, and object) independently, or would the whole event be forgotten? Research suggests that item-based memories are forgotten in a fragmented manner. However, we do not know how more complex episodic, event-based memories are forgotten. We assessed both retrieval accuracy and dependency-the statistical association between the retrieval successes of different elements from the same event-for complex events. Across 4 experiments, we show that retrieval dependency is found both immediately after learning and following a 12-hr and 1-week delay. Further, the amount of retrieval dependency after a delay is greater than that predicted by a model of independent forgetting. This dependency was only seen for coherent "closed-loops," where all pairwise associations between locations, people, and objects were encoded. When "open-loops" were learned, where only 2 out of the 3 possible associations were encoded, no dependency was seen immediately after learning or after a delay. Finally, we also provide evidence for higher retention rates for closed-loops than for open-loops. Therefore, closed-loops do not fragment as a function of forgetting and are retained for longer than are open-loops. Our findings suggest that coherent episodic events are not only retrieved, but also forgotten, in an all-or-none manner. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Development of Holistic Episodic Recollection.

Episodic memory binds the diverse elements of an event into a coherent representation. This coherence allows for the reconstruction of different aspects of an experience when triggered by a cue related to a past event-a process of pattern completion. Previous work has shown that such holistic recollection is evident in young adults, as revealed by dependency in retrieval success for various associations from the same event. In addition, episodic memory shows clear quantitative increases during early childhood. However, the ontogeny of holistic recollection is uncharted. Using dependency analyses, we found here that 4-year-olds (n = 32), 6-year-olds (n = 30), and young adults (n = 31) all retrieved complex events in a holistic manner; specifically, retrieval accuracy for one aspect of an event predicted accuracy for other aspects of the same event. However, the degree of holistic retrieval increased from the age 4 to adulthood. Thus, extended refinement of multiway binding may be one aspect of episodic memory development.

Holistic Recollection via Pattern Completion Involves Hippocampal Subfield CA3.

Episodic memories typically comprise multiple elements. A defining characteristic of episodic retrieval is holistic recollection, i.e., comprehensive recall of the elements a memorized event encompasses. A recent study implicated activity in the human hippocampus with holistic recollection of multi-element events based on cues (Horner et al., 2015). Here, we obtained ultra-high resolution functional neuroimaging data at 7 tesla in 30 younger adults (12 female) using the same paradigm. In accordance with anatomically inspired computational models and animal research, we found that metabolic activity in hippocampal subfield CA3 (but less pronounced in dentate gyrus) correlated with this form of mnemonic pattern completion across participants. Our study provides the first evidence in humans for a strong involvement of hippocampal subfield CA3 in holistic recollection via pattern completion.SIGNIFICANCE STATEMENT Memories of daily events usually involve multiple elements, although a single element can be sufficient to prompt recollection of the whole event. Such holistic recollection is thought to require reactivation of brain activity representing the full event from one event element ("pattern completion"). Computational and animal models suggest that mnemonic pattern completion is accomplished in a specific subregion of the hippocampus called CA3, but empirical evidence in humans was lacking. Here, we leverage the ultra-high resolution of 7 tesla neuroimaging to provide first evidence for a strong involvement of the human CA3 in holistic recollection of multi-element events via pattern completion.

Linked networks for learning and expressing location-specific threat.

Learning locations of danger within our environment is a vital adaptive ability whose neural bases are only partially understood. We examined fMRI brain activity while participants navigated a virtual environment in which flowers appeared and were "picked." Picking flowers in the danger zone (one-half of the environment) predicted an electric shock to the wrist (or "bee sting"); flowers in the safe zone never predicted shock; and household objects served as controls for neutral spatial memory. Participants demonstrated learning with shock expectancy ratings and skin conductance increases for flowers in the danger zone. Patterns of brain activity shifted between overlapping networks during different task stages. Learning about environmental threats, during flower approach in either zone, engaged the anterior hippocampus, amygdala, and ventromedial prefrontal cortex (vmPFC), with vmPFC-hippocampal functional connectivity increasing with experience. Threat appraisal, during approach in the danger zone, engaged the insula and dorsal anterior cingulate (dACC), with insula-hippocampal functional connectivity. During imminent threat, after picking a flower, this pattern was supplemented by activity in periaqueductal gray (PAG), insula-dACC coupling, and posterior hippocampal activity that increased with experience. We interpret these patterns in terms of multiple representations of spatial context (anterior hippocampus); specific locations (posterior hippocampus); stimuli (amygdala); value (vmPFC); threat, both visceral (insula) and cognitive (dACC); and defensive behaviors (PAG), interacting in different combinations to perform the functions required at each task stage. Our findings illuminate how we learn about location-specific threats and suggest how they might break down into overgeneralization or hypervigilance in anxiety disorders.

Negative emotional content disrupts the coherence of episodic memories.

Events are thought to be stored in episodic memory as coherent representations, in which the constituent elements are bound together so that a cue can trigger reexperience of all elements via pattern completion. Negative emotional content can strongly influence memory, but opposing theories predict strengthening or weakening of memory coherence. Across a series of experiments, participants imagined a number of person-location-object events with half of the events including a negative element (e.g., an injured person), and memory was tested across all within event associations. We show that the presence of a negative element reduces memory for associations between event elements, including between neutral elements encoded after a negative element. The presence of a negative element reduces the coherence with which a multimodal event is remembered. Our results, supported by a computational model, suggest that coherent retrieval from neutral events is supported by pattern completion, but that negative content weakens associative encoding which impairs this process. Our findings have important implications for understanding the way traumatic events are encoded and support therapeutic strategies aimed at restoring associations between negative content and its surrounding context. (PsycINFO Database Record

Theta Rhythm: Temporal Glue for Episodic Memory.

The low frequency theta rhythm is thought to promote the formation of long-term multimodal memories in the hippocampus by orchestrating input from multiple cortical sources. New research has demonstrated a causal association between the timing of experimentally induced theta rhythms and episodic memory formation in humans.

No effect of hippocampal lesions on stimulus-response bindings.

The hippocampus is believed to be important for rapid learning of arbitrary stimulus-response contingencies, or S-R bindings. In support of this, Schnyer et al. (2006) (Experiment 2) measured priming of reaction times (RTs) to categorise visual objects, and found that patients with medial temporal lobe damage, unlike healthy controls, failed to show evidence of reduced priming when response contingencies were reversed between initial and repeated categorisation of objects (a signature of S-R bindings). We ran a similar though extended object classification task on 6 patients who appear to have selective hippocampal lesions, together with 24 age-matched controls. Unlike Schnyer et al. (2006), we found that reversing response contingencies abolished priming in both controls and patients. Bayes Factors provided no reason to believe that response reversal had less effect on patients than controls. We therefore conclude that it is unlikely that the hippocampus is needed for S-R bindings.