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databases (Pubmed, Scopus and Web of Science) as well as through searching cited literature and contacting authors for unpublished data. 122 studies involving 32,547 participants were included in a meta-analysis, and the remaining studies are included in a descriptive review.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.

False memories for ending of events.

Memories are not perfect recordings of the past and can be subject to systematic biases. Memory distortions are often caused by our experience of what typically happens in a given situation. However, it is unclear whether memory for events is biased by the knowledge that events usually have a predictable structure (a beginning, middle, and an end). Using video clips of everyday situations, we tested how interrupting events at unexpected time points affects memory of how those events ended. In four free recall experiments (1, 2, 4, and 5), we found that interrupting clips just before a salient piece of action was completed, resulted in the false recall of details about how the clip might have ended. We refer to this as "event extension." On the other hand, interrupting clips just after one scene had ended and a new scene started, resulted in omissions of details about the true ending of the clip (Experiments 4 and 5). We found that these effects were present, albeit attenuated, when testing memory shortly after watching the video clips compared to a week later (Experiments 5a and 5b). The event extension effect was not present when memory was tested with a recognition paradigm (Experiment 3). Overall, we conclude that when people watch videos that violate their expectations of typical event structure, they show a bias to later recall the videos as if they had ended at a predictable event boundary, exhibiting event extension or the omission of details depending on where the original video was interrupted. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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.

The Importance of Semantic Network Brain Regions in Integrating Prior Knowledge with an Ongoing Dialogue.

To understand a dialogue, we need to know the topics that are being discussed. This enables us to integrate our knowledge of what was said previously to interpret the current dialogue. This study involved a large-scale behavioral experiment conducted online and a separate fMRI experiment, both testing human participants. In both, we selectively manipulated knowledge about the narrative content of dialogues presented in short videos. The clips were scenes from situation comedies that were split into two parts. The speech in the part 1 clips could either be presented normally or spectrally rotated to render it unintelligible. The part 2 clips that concluded the scenes were always presented normally. The behavioral experiment showed that knowledge of the preceding narrative boosted memory for the part 2 clips as well as increased the intersubject semantic similarity of recalled descriptions of the dialogues. The fMRI experiment replicated the finding that prior knowledge improved memory for the conclusions of the dialogues. Furthermore, prior knowledge strengthened temporal intersubject correlations in brain regions including the left angular gyrus and inferior frontal gyrus. Together, these findings show that (1) prior knowledge constrains the interpretation of a dialogue to be more similar across individuals; and (2), consistent with this, the activation of brain regions involved in semantic control processing is also more similar between individuals who share the same prior knowledge. Processing in these regions likely supports the activation and integration of prior knowledge, which helps people to better understand and remember dialogues as they unfold.

The Neural Representation of Events Is Dominated by Elements that Are Most Reliably Present.

An episodic memory is specific to an event that occurred at a particular time and place. However, the elements that constitute the event-the location, the people present, and their actions and goals-might be shared with numerous other similar events. Does the brain preferentially represent certain elements of a remembered event? If so, which elements dominate its neural representation: those that are shared across similar events, or the novel elements that define a specific event? We addressed these questions by using a novel experimental paradigm combined with fMRI. Multiple events were created involving conversations between two individuals using the format of a television chat show. Chat show "hosts" occurred repeatedly across multiple events, whereas the "guests" were unique to only one event. Before learning the conversations, participants were scanned while viewing images or names of the (famous) individuals to be used in the study to obtain person-specific activity patterns. After learning all the conversations over a week, participants were scanned for a second time while they recalled each event multiple times. We found that during recall, person-specific activity patterns within the posterior midline network were reinstated for the hosts of the shows but not the guests, and that reinstatement of the hosts was significantly stronger than the reinstatement of the guests. These findings demonstrate that it is the more generic, familiar, and predictable elements of an event that dominate its neural representation compared with the more idiosyncratic, event-defining, elements.

Activation of Person Knowledge in Medial Prefrontal Cortex during the Encoding of New Lifelike Events.

Our knowledge about people can help us predict how they will behave in particular situations and interpret their actions. In this study, we investigated the cognitive and neural effects of person knowledge on the encoding and retrieval of novel life-like events. Healthy human participants learnt about two characters over a week by watching 6 episodes of one of two situation comedies, which were both centered on a young couple. In the scanner, they watched and then silently recalled 20 new scenes from both shows that were all set in unfamiliar locations: 10 from their trained show and 10 from the untrained show. After scanning, participants' recognition memory was better for scenes from the trained show. The functional magnetic resonance imaging (fMRI) patterns of brain activity when watching the videos were reinstated during recall, but this effect was not modulated by training. However, person knowledge boosted the similarity in fMRI patterns of activity in the medial prefrontal cortex (MPFC) when watching the new events involving familiar characters. Our findings identify a role for the MPFC in the representation of schematic person knowledge during the encoding of novel, lifelike events.

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.

The brain regions supporting schema-related processing of people's identities.

Schematic knowledge about people helps us to understand their behaviour in novel situations. The ventromedial prefrontal cortex (vmPFC) and hippocampus play important, yet poorly understood, roles in schema-based processing. Here, we manipulated schematic knowledge by familiarizing participants over the course of a week to the two lead characters of one of two TV shows. Then during MRI scanning, they viewed pictures of all four characters and performed a recognition memory test afterwards. Memory was also tested for short videos. Schematic knowledge boosted performance on both memory tests. Whole-brain analyses revealed knowledge related activation increases in the vmPFC and retrosplenial cortex while a similar effect was identified in a hippocampal region-of-interest. Representational similarity analyses identified person-specific patterns of activity in the vmPFC but not hippocampus, but no effect of familiarization. Our findings suggest complementary roles for the vmPFC and hippocampus in processing schematic knowledge that was acquired in a naturalistic manner.

Predicting memory formation over multiple study episodes.

Repeated study typically improves episodic memory performance. Two different types of explanations of this phenomenon have been put forward: (1) reactivating the same representations strengthens and stabilizes memories, or (2) greater encoding variability benefits memory by promoting richer traces. The present experiment directly compared these predictions in a design with multiple repeated study episodes, allowing to dissociate memory for studied items and their context of study. Participants repeatedly encoded names of famous people four times, either in the same task, or in different tasks. During the test phase, an old/new judgment task was used to assess item memory, followed by a source memory judgment about the encoding task. Consistent with predictions from the encoding variability view, encoding stimulus in different contexts resulted in higher item memory. In contrast, consistent with the reactivation view, source memory performance was higher when participants encoded stimuli in the same task repeatedly. Taken together, our findings indicate that encoding variability benefits episodic memory, by increasing the number of items that are recalled. These benefits are however at the expenses of source recollection and memory for details, which are decreased, likely due to interference and generalization across contexts.

Effects of amnesia on processing in the hippocampus and default mode network during a naturalistic memory task: A case study.

Despite their severely impaired episodic memory, individuals with amnesia are able to comprehend ongoing events. Online representations of a current event are thought to be supported by a network of regions centred on the posterior midline cortex (PMC). By contrast, episodic memory is widely believed to be supported by interactions between the hippocampus and these cortical regions. In this MRI study, we investigated the encoding and retrieval of real life-like events (video clips) in a patient with severe amnesia likely resulting from a stroke to the right (and possibly the left) thalamus, and a group of 20 age-matched controls. Structural MRI revealed grey matter reductions in left hippocampus and left thalamus in comparison to controls. We first characterised the regions activated in the controls while they watched and retrieved the videos. There were no differences in activation between the patient and controls in any of the regions. We then identified a widespread network of brain regions, including the hippocampus, that were functionally connected with the PMC in controls. However, in the patient there was a specific reduction in functional connectivity between the PMC and a region of left hippocampus when both watching and attempting to retrieve the videos. A follow up analysis of the control group revealed that, when watching the videos, the functional connectivity between these two regions was correlated with memory performance. Taken together, these findings support the view that the interactions between the PMC and the hippocampus enable the encoding and retrieval of naturalistic events.

The processing of color preference in the brain.

Decades of research has established that humans have preferences for some colors (e.g., blue) and a dislike of others (e.g., dark chartreuse), with preference varying systematically with variation in hue (e.g., Hurlbert and Owen, 2015). Here, we used functional MRI to investigate why humans have likes and dislikes for simple patches of color, and to understand the neural basis of preference, aesthetics and value judgements more generally. We looked for correlations of a behavioural measure of color preference with the blood oxygen level-dependent (BOLD) response when participants performed an irrelevant orientation judgement task on colored squares. A whole brain analysis found a significant correlation between BOLD activity and color preference in the posterior midline cortex (PMC), centred on the precuneus but extending into the adjacent posterior cingulate and cuneus. These results demonstrate that brain activity is modulated by color preference, even when such preferences are irrelevant to the ongoing task the participants are engaged. They also suggest that color preferences automatically influence our processing of the visual world. Interestingly, the effect in the PMC overlaps with regions identified in neuroimaging studies of preference and value judgements of other types of stimuli. Therefore, our findings extends this literature to show that the PMC is related to automatic encoding of subjective value even for basic visual features such as color.

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.

Multiscale Integration of Contextual Information During a Naturalistic Task.

Everyday experience requires rapid and automatic integration of incoming stimuli with previously stored knowledge. Prior knowledge can help to construct a general "situation model" of the event, as well as aid comprehension of an ongoing narrative. Using fMRI in healthy adult humans, we investigated processing of videos whose locations and characters were always familiar but whose narratives were either a continuation or noncontinuation of an earlier video (high context (HC) or low context (LC), respectively). Responses in parahippocampal gyrus and retrosplenial cortex were composed of an initial transient, locked to the video onsets, followed by a period of lower amplitude activation that was greater in the LC condition. This may reflect rapid processing of core components of situation models such as location and characters and more gradual incorporation of their narrative themes. By contrast, activity increases in left hemisphere middle temporal gyrus (MTG), angular gyrus, and inferior frontal gyrus were maintained throughout the videos and were higher for HC versus LC videos. Further, activity in the left MTG peaked earlier in the HC condition. We suggest that these regions support representations of the specific interlinked concepts necessary to comprehend an ongoing narrative, which are already established for the HC videos.

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.

Human hippocampal theta power indicates movement onset and distance travelled.

Theta frequency oscillations in the 6- to 10-Hz range dominate the rodent hippocampal local field potential during translational movement, suggesting that theta encodes self-motion. Increases in theta power have also been identified in the human hippocampus during both real and virtual movement but appear as transient bursts in distinct high- and low-frequency bands, and it is not yet clear how these bursts relate to the sustained oscillation observed in rodents. Here, we examine depth electrode recordings from the temporal lobe of 13 presurgical epilepsy patients performing a self-paced spatial memory task in a virtual environment. In contrast to previous studies, we focus on movement-onset periods that incorporate both initial acceleration and an immediately preceding stationary interval associated with prominent theta oscillations in the rodent hippocampal formation. We demonstrate that movement-onset periods are associated with a significant increase in both low (2-5 Hz)- and high (6-9 Hz)-frequency theta power in the human hippocampus. Similar increases in low- and high-frequency theta power are seen across lateral temporal lobe recording sites and persist throughout the remainder of movement in both regions. In addition, we show that movement-related theta power is greater both before and during longer paths, directly implicating human hippocampal theta in the encoding of translational movement. These findings strengthen the connection between studies of theta-band activity in rodents and humans and offer additional insight into the neural mechanisms of spatial navigation.

The role of the hippocampus in recognition memory.

Many theories of declarative memory propose that it is supported by partially separable processes underpinned by different brain structures. The hippocampus plays a critical role in binding together item and contextual information together and processing the relationships between individual items. By contrast, the processing of individual items and their later recognition can be supported by extrahippocampal regions of the medial temporal lobes (MTL), particularly when recognition is based on feelings of familiarity without the retrieval of any associated information. These theories are domain-general in that "items" might be words, faces, objects, scenes, etc. However, there is mixed evidence that item recognition does not require the hippocampus, or that familiarity-based recognition can be supported by extrahippocampal regions. By contrast, there is compelling evidence that in humans, hippocampal damage does not affect recognition memory for unfamiliar faces, whilst recognition memory for several other stimulus classes is impaired. I propose that regions outside of the hippocampus can support recognition of unfamiliar faces because they are perceived as discrete items and have no prior conceptual associations. Conversely, extrahippocampal processes are inadequate for recognition of items which (a) have been previously experienced, (b) are conceptually meaningful, or (c) are perceived as being comprised of individual elements. This account reconciles findings from primate and human studies of recognition memory. Furthermore, it suggests that while the hippocampus is critical for binding and relational processing, these processes are required for item recognition memory in most situations.

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.

Consolidation of Complex Events via Reinstatement in Posterior Cingulate Cortex.

It is well-established that active rehearsal increases the efficacy of memory consolidation. It is also known that complex events are interpreted with reference to prior knowledge. However, comparatively little attention has been given to the neural underpinnings of these effects. In healthy adults humans, we investigated the impact of effortful, active rehearsal on memory for events by showing people several short video clips and then asking them to recall these clips, either aloud (Experiment 1) or silently while in an MRI scanner (Experiment 2). In both experiments, actively rehearsed clips were remembered in far greater detail than unrehearsed clips when tested a week later. In Experiment 1, highly similar descriptions of events were produced across retrieval trials, suggesting a degree of semanticization of the memories had taken place. In Experiment 2, spatial patterns of BOLD signal in medial temporal and posterior midline regions were correlated when encoding and rehearsing the same video. Moreover, the strength of this correlation in the posterior cingulate predicted the amount of information subsequently recalled. This is likely to reflect a strengthening of the representation of the video's content. We argue that these representations combine both new episodic information and stored semantic knowledge (or "schemas"). We therefore suggest that posterior midline structures aid consolidation by reinstating and strengthening the associations between episodic details and more generic schematic information. This leads to the creation of coherent memory representations of lifelike, complex events that are resistant to forgetting, but somewhat inflexible and semantic-like in nature.

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.

Categorical encoding of color in the brain.

The areas of the brain that encode color categorically have not yet been reliably identified. Here, we used functional MRI adaptation to identify neuronal populations that represent color categories irrespective of metric differences in color. Two colors were successively presented within a block of trials. The two colors were either from the same or different categories (e.g., "blue 1 and blue 2" or "blue 1 and green 1"), and the size of the hue difference was varied. Participants performed a target detection task unrelated to the difference in color. In the middle frontal gyrus of both hemispheres and to a lesser extent, the cerebellum, blood-oxygen level-dependent response was greater for colors from different categories relative to colors from the same category. Importantly, activation in these regions was not modulated by the size of the hue difference, suggesting that neurons in these regions represent color categorically, regardless of metric color difference. Representational similarity analyses, which investigated the similarity of the pattern of activity across local groups of voxels, identified other regions of the brain (including the visual cortex), which responded to metric but not categorical color differences. Therefore, categorical and metric hue differences appear to be coded in qualitatively different ways and in different brain regions. These findings have implications for the long-standing debate on the origin and nature of color categories, and also further our understanding of how color is processed by the brain.