The effect of apolipoprotein E genotype on spatial processing in humans: A meta-analysis and systematic review.

The ε4 allele of the apolipoprotein E (APOE4) gene is an established risk factor for Alzheimer's disease but its impact on cognition in healthy adults across the lifespan is unclear. One cognitive domain that is affected early in the course of Alzheimer's disease is spatial cognition, yet the evidence for APOE-related changes in spatial cognition is mixed. In this meta-analysis we assessed the impact of carrying the APOE4 allele on five subdomains of spatial cognition across the lifespan. We included studies of healthy human participants where an APOE4-carrier group (heterozygous or homozygous) could be compared to a homozygous group of APOE3-carriers. We identified 156 studies in total from three databases (Pubmed, Scopus and Web of Science) as well as through searching cited literature and contacting authors for unpublished data. 122 studies involving 32,547 participants were included in a meta-analysis, and the remaining studies are included in a descriptive review. APOE4 carriers scored significantly lower than APOE3 carriers (θˆ = -.08 [-.14, -.02]) on tests of spatial long-term memory; this effect was very small and was not modulated by age. On other subdomains of spatial cognition (spatial construction, spatial working memory, spatial reasoning, navigation) there were no effects of genotype. Overall, our results demonstrate that the APOE4 allele exerts little influence on spatial cognitive abilities in healthy adults.

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.

Hippocampal and medial prefrontal cortices encode structural task representations following progressive and interleaved training schedules.

Memory generalisations may be underpinned by either encoding- or retrieval-based generalisation mechanisms and different training schedules may bias some learners to favour one of these mechanisms over the other. We used a transitive inference task to investigate whether generalisation is influenced by progressive vs randomly interleaved training, and overnight consolidation. On consecutive days, participants learnt pairwise discriminations from two transitive hierarchies before being tested during fMRI. Inference performance was consistently better following progressive training, and for pairs further apart in the transitive hierarchy. BOLD pattern similarity correlated with hierarchical distances in the left hippocampus (HIP) and medial prefrontal cortex (MPFC) following both training schedules. These results are consistent with the use of structural representations that directly encode hierarchical relationships between task features. However, such effects were only observed in the MPFC for recently learnt relationships. Furthermore, the MPFC appeared to maintain structural representations in participants who performed at chance on the inference task. We conclude that humans preferentially employ encoding-based mechanisms to store map-like relational codes that can be used for memory generalisation. These codes are expressed in the HIP and MPFC following both progressive and interleaved training but are not sufficient for accurate inference.

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.

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.

Minocycline differentially modulates human spatial memory systems.

Microglia play a critical role in many processes fundamental to learning and memory in health and are implicated in Alzheimer's pathogenesis. Minocycline, a centrally-penetrant tetracycline antibiotic, inhibits microglial activation and enhances long-term potentiation, synaptic plasticity, neurogenesis and hippocampal-dependent spatial memory in rodents, leading to clinical trials in human neurodegenerative diseases. However, the effects of minocycline on human memory have not previously been investigated. Utilising a double-blind, randomised crossover study design, we recruited 20 healthy male participants (mean 24.6 ± 5.0 years) who were each tested in two experimental sessions: once after 3 days of Minocycline 150 mg (twice daily), and once 3 days of placebo (identical administration). During each session, all completed an fMRI task designed to tap boundary- and landmark-based navigation (thought to rely on hippocampal and striatal learning mechanisms respectively). Given the rodent literature, we hypothesised that minocycline would selectively modulate hippocampal learning. In line with this, minocycline biased use of boundary- compared to landmark-based information (t980 = 3.140, p = 0.002). However, though this marginally improved performance for boundary-based objects (t980 = 1.972, p = 0.049), it was outweighed by impaired landmark-based navigation (t980 = 6.374, p < 0.001) resulting in an overall performance decrease (t980 = 3.295, p = 0.001). Furthermore, against expectations, minocycline significantly reduced activity during memory encoding in the right caudate (t977 = 2.992, p = 0.003) and five other cortical regions, with no significant effect in the hippocampus. In summary, minocycline impaired human spatial memory performance, likely through disruption of striatal processing resulting in greater biasing towards reliance on boundary-based navigation.

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 .

Cross-Situational Learning Is Supported by Propose-but-Verify Hypothesis Testing.

When we encounter a new word, there are often multiple objects that the word might refer to [1]. Nonetheless, because names for concrete nouns are constant, we are able to learn them across successive encounters [2, 3]. This form of "cross-situational" learning may result from either associative mechanisms that gradually accumulate evidence for each word-object association [4, 5] or rapid propose-but-verify (PbV) mechanisms where only one hypothesized referent is stored for each word, which is either subsequently verified or rejected [6, 7]. Using model-based representation similarity analyses of fMRI data acquired during learning, we find evidence for learning mediated by a PbV mechanism. This learning may be underpinned by rapid pattern-separation processes in the hippocampus. Our findings shed light on the psychological and neural processes that support word learning, suggesting that adults rely on their episodic memory to track a limited number of word-object associations.

Reinstatement of memory representations for lifelike events over the course of a week.

When we remember an event, the content of that memory is represented across the brain. Detailed memory retrieval is thought to involve the reinstatement of those representations. Functional MRI combined with representational similarity analyses (RSA) of spatial patterns of brain activity has revealed reinstatement of recently-experienced events throughout a core memory retrieval network. In the present study, participants were scanned while they watched, immediately retrieved and then retrieved after a week, 24 short videos. Following the delayed retrieval, they freely recalled all videos outside of the scanner. We observed widespread within- and between-subject reinstatement effects within a posterior midline core memory retrieval network during all phases of the experiment. Within precuneus, bilateral middle temporal gyrus and the left hippocampus, reinstatement effects between the retrieval phases correlated with memory performance. These findings extend previous studies that have only employed short retention periods or highly rehearsed materials, demonstrating that memory representations for unique events are reliably reinstated over longer timeframes that are meaningful in the context of real-world episodic memory.

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.

The role of the hippocampus in generalizing configural relationships.

The hippocampus has been implicated in integrating information across separate events in support of mnemonic generalizations. These generalizations may be underpinned by processes at both encoding (linking similar information across events) and retrieval ("on-the-fly" generalization). However, the relative contribution of the hippocampus to encoding- and retrieval-based generalizations is poorly understood. Using fMRI in humans, we investigated the hippocampal role in gradually learning a set of spatial discriminations and subsequently generalizing them in an acquired equivalence task. We found a highly significant correlation between individuals' performance on a generalization test and hippocampal activity during the test, providing evidence that hippocampal processes support on-the-fly generalizations at retrieval. Within the same hippocampal region there was also a correlation between activity during the final stage of learning (when all associations had been learnt but no generalization was required) and subsequent generalization performance. We suggest that the hippocampus spontaneously retrieves prior events that share overlapping features with the current event. This process may also support the creation of generalized representations during encoding. These findings are supportive of the view that the hippocampus contributes to both encoding- and retrieval-based generalization via the same basic mechanism; retrieval of similar events sharing common features. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.

The interference effect in arithmetic fact solving: An fMRI study.

Some multiplication facts share common digits with other, previously learned facts, and as a result, different problems are associated with different levels of interference. The detrimental effect of interference in arithmetic facts knowledge has been recently highlighted in behavioral studies, in children as well as in adults, both in typical and atypical development. The present study investigated the brain regions involved in the interference effect when solving multiplication problems. Twenty healthy adults carried out a multiplication task in an MRI scanner. The event-related design comprised problems whose interference level and problem size were manipulated in a 2×2 factorial design. After each trial, individuals were requested to indicate whether they solved the trial by retrieving the answer from long-term memory. This allowed us to examine which brain areas were sensitive to the interference effect and problem size effect as well as the retrieval strategy. The results highlighted two specific regions: the left angular gyrus was more activated for low interfering than for high interfering problems, and the right intraparietal sulcus was more activated for large problems than for small problems. In both regions, brain activity was not modulated by the other effect. These results suggest that the left angular gyrus is sensitive to the level of interference of the multiplication problems, whereas previously this region was thought to be more activated by small problems or by retrieval strategy. Here, in a design manipulating interference and problem size, while controlling for retrieval strategy, we showed that it rather reflects an automatic mapping between the problem and the answer stored in long-term memory. The right intraparietal sulcus was modulated by the problem size effect, which supports the idea that the problem size effect comes from the higher overlap between magnitude of the answers of large problems compared to small ones. Importantly, neither effects can be reduced to a strategy effect since they were present when analyzing only retrieval trials.