The effects of study task on prestimulus subsequent memory effects in the hippocampus

Functional magnetic resonance imaging (fMRI) was employed to examine the effects of a study task manipulation on pre‐stimulus activity in the hippocampus predictive of later successful recollection. Eighteen young participants were scanned while making either animacy or syllable judgments on visually presented study words. Cues presented before each word denoted which judgment should be made. Following the study phase, a surprise recognition memory test was administered in which each test item had to be endorsed as “Remembered,” “Known,” or “New.” As expected, “deep” animacy judgments led to better memory for study items than did “shallow” syllable judgments. In both study tasks, pre‐stimulus subsequent recollection effects were evident in the interval between the cue and the study item in bilateral anterior hippocampus. However, the direction of the effects differed according to the study task: whereas pre‐stimulus hippocampal activity on animacy trials was greater for later recollected items than items judged old on the basis of familiarity (replicating prior findings), these effects reversed for syllable trials. We propose that the direction of pre‐stimulus hippocampal subsequent memory effects depends on whether an optimal pre‐stimulus task set facilitates study processing that is conducive or unconducive to the formation of contextually rich episodic memories. © 2015 Wiley Periodicals, Inc.     

Blocking of irrelevant memories by posterior alpha activity boosts memory encoding

In our daily lives, we are confronted with a large amount of information. Because only a small fraction can be encoded in long‐term memory, the brain must rely on powerful mechanisms to filter out irrelevant information. To understand the neuronal mechanisms underlying the gating of information into long‐term memory, we employed a paradigm where the encoding was directed by a “Remember” or a “No‐Remember” cue. We found that posterior alpha activity increased prior to the “No‐Remember” stimuli, whereas it decreased prior to the “Remember” stimuli. The sources were localized in the parietal cortex included in the dorsal attention network. Subjects with a larger cue‐modulation of the alpha activity had better memory for the to‐be‐remembered items. Interestingly, alpha activity reflecting successful inhibition following the “No‐Remember” cue was observed in the frontal midline structures suggesting preparatory inhibition was mediated by anterior parts of the dorsal attention network. During the presentation of the memory items, there was more gamma activity for the “Remember” compared to the “No‐Remember” items in the same regions. Importantly, the anticipatory alpha power during cue predicted the gamma power during item. Our findings suggest that top‐down controlled alpha activity reflects attentional inhibition of sensory processing in the dorsal attention network, which then finally gates information to long‐term memory. This gating is achieved by inhibiting the processing of visual information reflected by neuronal synchronization in the gamma band. In conclusion, the functional architecture revealed by region‐specific changes in the alpha activity reflects attentional modulation which has consequences for long‐term memory encoding. Hum Brain Mapp 35:3972–3987, 2013. © 2013 Wiley Periodicals, Inc.     

Peri-encoding predictors of memory encoding and consolidation

We review reports of brain activations that occur immediately prior to the onset or following the offset of to-be-remembered information and can predict subsequent mnemonic success. Memory-predictive pre-encoding processes, occurring from fractions of a second to minutes prior to event onset, are mainly associated with activations in the medial temporal lobe (MTL), amygdala and midbrain, and with enhanced theta oscillations. These activations may be considered as the neural correlates of one or more cognitive operations, including contextual processing, attention, and the engagement of distinct computational modes associated with prior encoding or retrieval. Post-encoding activations that correlate with subsequent memory performance are mainly observed in the MTL, sensory cortices and frontal regions. These activations may reflect binding of elements of the encoded information and initiation of memory consolidation. In all, the findings reviewed here illustrate the importance of brain states in the immediate peri-encoding time windows in determining encoding success. Understanding these brain states and their specific effects on memory may lead to optimization of the encoding of desired memories and mitigation of undesired ones.     

Ensembles of human MTL neurons “jump back in time” in response to a repeated stimulus

Episodic memory, which depends critically on the integrity of the medial temporal lobe (MTL), has been described as “mental time travel” in which the rememberer “jumps back in time.” The neural mechanism underlying this ability remains elusive. Mathematical and computational models of performance in episodic memory tasks provide a specific hypothesis regarding the computation that supports such a jump back in time. The models suggest that a representation of temporal context, a representation that changes gradually over macroscopic periods of time, is the cue for episodic recall. According to these models, a jump back in time corresponds to a stimulus recovering a prior state of temporal context. In vivo single‐neuron recordings were taken from the human MTL while epilepsy patients distinguished novel from repeated images in a continuous recognition memory task. The firing pattern of the ensemble of MTL neurons showed robust temporal autocorrelation over macroscopic periods of time during performance of the memory task. The gradually‐changing part of the ensemble state was causally affected by the visual stimulus being presented. Critically, repetition of a stimulus caused the ensemble to elicit a pattern of activity that resembled the pattern of activity present before the initial presentation of the stimulus. These findings confirm a direct prediction of this class of temporal context models and may be a signature of the mechanism that underlies the experience of episodic memory as mental time travel. © 2012 Wiley Periodicals, Inc.     

The medial temporal lobes distinguish between within‐item and item‐context relations during autobiographical memory retrieval

During autobiographical memory retrieval, the medial temporal lobes (MTL) relate together multiple event elements, including object (within‐item relations) and context (item‐context relations) information, to create a cohesive memory. There is consistent support for a functional specialization within the MTL according to these relational processes, much of which comes from recognition memory experiments. In this study, we compared brain activation patterns associated with retrieving within‐item relations (i.e., associating conceptual and sensory‐perceptual object features) and item‐context relations (i.e., spatial relations among objects) with respect to naturalistic autobiographical retrieval. We developed a novel paradigm that cued participants to retrieve information about past autobiographical events, non‐episodic within‐item relations, and non‐episodic item‐context relations with the perceptuomotor aspects of retrieval equated across these conditions. We used multivariate analysis techniques to extract common and distinct patterns of activity among these conditions within the MTL and across the whole brain, both in terms of spatial and temporal patterns of activity. The anterior MTL (perirhinal cortex and anterior hippocampus) was preferentially recruited for generating within‐item relations later in retrieval whereas the posterior MTL (posterior parahippocampal cortex and posterior hippocampus) was preferentially recruited for generating item‐context relations across the retrieval phase. These findings provide novel evidence for functional specialization within the MTL with respect to naturalistic memory retrieval. © 2015 Wiley Periodicals, Inc.     

Repetition suppression in the medial temporal lobe and midbrain is altered by event overlap

Repeated encounters with the same event typically lead to decreased activation in the medial temporal lobe (MTL) and dopaminergic midbrain, a phenomenon known as repetition suppression. In contrast, encountering an event that overlaps with prior experience leads to increased response in the same regions. Such increased responding is thought to reflect an associative novelty signal that promotes memory updating to resolve differences between current events and stored memories. Here, we married these ideas to test whether event overlap significantly modulates MTL and midbrain responses—even when events are repeated and expected—to promote memory updating through integration. While undergoing high‐resolution functional MRI, participants were repeatedly presented with objects pairs, some of which overlapped with other, intervening pairs and some of which contained elements unique from other pairs. MTL and midbrain regions showed widespread repetition suppression for nonoverlapping pairs containing unique elements; however, the degree of repetition suppression was altered for overlapping pairs. Entorhinal cortex, perirhinal cortex (PRc), midbrain, and PRc—midbrain connectivity showed repetition‐related increases across overlapping pairs. Notably, increased PRc activation for overlapping pairs tracked individual differences in the ability to reason about the relationships among pairs—our behavioral measure of memory integration. Within the hippocampus, activation increases across overlapping pairs were unique to CA₁, consistent with its hypothesized comparator function. These findings demonstrate that event overlap engages MTL and midbrain functions traditionally implicated in novelty processing, even when overlapping events themselves are repeated. Our findings further suggest that the MTL—midbrain response to event overlap may promote integration of new content into existing memories, leading to the formation of relational memory networks that span experiences. Moreover, the results inform theories about the division of labor within MTL, demonstrating that the role of PRc in episodic encoding extends beyond familiarity processing and item‐level recognition. © 2016 Wiley Periodicals, Inc.     

Source memory in the real world: a neuropsychological study of flashbulb memory

A flashbulb memory (FM) is a vivid, enduring memory for how one learned about a surprising, shocking event. It thus involves memory for the source of event information, as opposed to memory for the event itself. Which brain regions are involved in FM, however, is uncertain. Although medial temporal lobe/diencephalic (MTL/D) damage impairs content or item memory, frontal lobe (FL) damage has been associated with impaired source memory. One would therefore expect that FM should depend on the FLs, although two recent reports do not support this idea. In the current study, we examined memory for the events of September 11th, and memory for the source of that information, in MTL/D patients, FL patients, and healthy subjects. Only the MTL/D patients were impaired in long-term memory for the event itself, measured after a 6 month retention interval. The FL patients, on the other hand, showed a selective deficit in source memory, although their memory for the target event was unimpaired. MTL/D and FL structures appear to play different roles in memory for flashbulb events.     

Early signal from the hippocampus for memory encoding

The mediotemporal lobe (MTL), including the hippocampus, is involved in all stages of episodic memory including memory encoding, consolidation, and retrieval. However, the exact timing of the hippocampus' involvement immediately after stimulus encounter remains unclear. In this study, we used high‐density 156‐channel electroencephalography to study the processing of entirely new stimuli, which had to be encoded, in comparison to highly overlearned stimuli. Sixteen healthy subjects performed a continuous recognition task with meaningful pictures repeated up to four consecutive times. Waveform and topographic cluster analyses of event‐related potentials revealed that new items, in comparison to repetitions, were processed significantly differently at 220–300 ms. Source estimation localized activation for processing new stimuli in the right MTL. Our study demonstrates the occurrence of a transient signal from the MTL in response to new information already at 200–300 ms poststimulus onset, which presumably reflects encoding as an initial step toward memory consolidation.     

The content of hippocampal “replay”

One of the most striking features of the hippocampal network is its ability to self‐generate neuronal sequences representing temporally compressed, spatially coherent paths. These brief events, often termed “replay” in the scientific literature, are largely confined to non‐exploratory states such as sleep or quiet rest. Early studies examining the content of replay noted a strong correlation between the encoded spatial information and the animal's prior behavior; thus, replay was initially hypothesized to play a role in memory formation and/or systems‐level consolidation via “off‐line” reactivation of previous experiences. However, recent findings indicate that replay may also serve as a memory retrieval mechanism to guide future behavior or may be an incidental reflection of pre‐existing network assemblies. Here, I will review what is known regarding the content of replay events and their correlation with past and future actions, and I will discuss how this knowledge might inform or constrain models which seek to explain the circuit‐level mechanisms underlying these events and their role in mnemonic processes.     

The role of hippocampal subfield volume and fornix microstructure in episodic memory across the lifespan

Advancing age is associated with both declines in episodic memory and degradation of medial temporal lobe (MTL) structure. The contribution of MTL to episodic memory is complex and depends upon the interplay among hippocampal subfields and surrounding structures that participate in anatomical connectivity to the cortex through inputs (parahippocampal and entorhinal cortices) and outputs (fornix). However, the differential contributions of MTL system components in mediating age effects on memory remain unclear. In a sample of 177 healthy individuals aged 20–94 we collected high‐resolution T1‐weighted, ultrahigh‐resolution T2/PD, and diffusion tensor imaging (DTI) MRI sequences on a 3T Phillips Achieva scanner. Hippocampal subfield and entorhinal cortex (ERC) volumes were measured from T2/PD scans using a combination of manual tracings and training of a semiautomated pipeline. Parahippocampal gyrus volume was estimated using Freesurfer and DTI scans were used to obtain diffusion metrics from tractography of the fornix. Item and associative episodic memory constructs were formed from multiple tests. Competing structural equation models estimating differential association among these structural variables were specified and tested to investigate whether and how fornix diffusion and volume of parahippocampal gyrus, ERC, and hippocampal subfields mediate age effects on associative and/or item memory. The most parsimonious, best‐fitting model included an anatomically based path through the MTL as well as a single hippocampal construct which combined all subfields. Results indicated that fornix microstructure independently mediated the effect of age on associative memory, but not item memory. Additionally, all regions and estimated paths (including fornix) combined to significantly mediate the age‐associative memory relationship. These findings suggest that preservation of fornix connectivity and MTL structure with aging is important for maintenance of associative memory performance across the lifespan.     

Role of the medial temporal lobes in relational memory: neuropsychological evidence from a cued recognition paradigm

In this study, we examined the role of the hippocampus in relational memory by comparing item recognition performance in amnesic patients with medial temporal lobe (MTL) damage and their matched controls. Specifically, we investigated the contribution of associative memory to item recognition using a cued recognition paradigm. Control subjects studied cue-target pairs once, whereas amnesic patients studied cue-target pairs six times. Following study, subjects made recognition judgments about targets that were presented either alone (no cue), with the originally presented cue (same cue), or with a cue that had been presented with a different target (recombined cue). Controls had higher recognition scores in the same cue than in the recombined cue condition, indicating that they benefited from the associative information provided by the same cue. By contrast, amnesic patients did not. This was true even for a subgroup of patients whose recognition performance in the no cue condition was matched to that of the controls. These data provide further support for the idea that the hippocampus plays a critical role in relational memory, even when associative information need not be retrieved intentionally.     

A High‐resolution study of hippocampal and medial temporal lobe correlates of spatial context and prospective overlapping route memory

When navigating our world we often first plan or retrieve an ideal route to our goal, avoiding alternative paths that lead to other destinations. The medial temporal lobe (MTL) has been implicated in processing contextual information, sequence memory, and uniquely retrieving routes that overlap or “cross paths.” However, the identity of subregions of the hippocampus and neighboring cortex that support these functions in humans remains unclear. The present study used high‐resolution functional magnetic resonance imaging (hr‐fMRI) in humans to test whether the CA3/DG hippocampal subfield and parahippocampal cortex are important for processing spatial context and route retrieval, and whether the CA1 subfield facilitates prospective planning of mazes that must be distinguished from alternative overlapping routes. During hr‐fMRI scanning, participants navigated virtual mazes that were well‐learned from prior training while also learning new mazes. Some routes learned during scanning shared hallways with those learned during pre‐scan training, requiring participants to select between alternative paths. Critically, each maze began with a distinct spatial contextual Cue period. Our analysis targeted activity from the Cue period, during which participants identified the current navigational episode, facilitating retrieval of upcoming route components and distinguishing mazes that overlap. Results demonstrated that multiple MTL regions were predominantly active for the contextual Cue period of the task, with specific regions of CA3/DG, parahippocampal cortex, and perirhinal cortex being consistently recruited across trials for Cue periods of both novel and familiar mazes. During early trials of the task, both CA3/DG and CA1 were more active for overlapping than non‐overlapping Cue periods. Trial‐by‐trial Cue period responses in CA1 tracked subsequent overlapping maze performance across runs. Together, our findings provide novel insight into the contributions of MTL subfields to processing spatial context and route retrieval, and support a prominent role for CA1 in distinguishing overlapping episodes during navigational “look‐ahead” periods. © 2014 Wiley Periodicals, Inc.     

A Comparison of 'Errorless' and 'Trial-and-error' Learning Methods for Teaching Individuals with Acquired Memory Deficits

We present nine experiments, in three study phases, which test the hypothesis that learning methods which prevent the making of errors (“errorless learning”) will lead to greater learning than “trial-and-error” learning methods amongst individuals who are memory impaired as a result of acquired brain injury. Results suggest that tasks and situations which facilitate retrieval of implicit memory for the learned material (such as learning names with a first letter cue) will benefit from errorless learning methods, whilst those that require the explicit recall of novel associations (such as learning routes or programming an electronic organiser) will not benefit from errorless learning. The more severely amnesic patients benefit to a greater extent from errorless learning methods than those who are less severely memory impaired, but this may only apply when the interval between learning and recall is relatively short.     

The hippocampus is preferentially associated with memory for spatial context

Abstract The existence of a functional-anatomic dissociation for retrieving item versus contextual information within subregions of the medial temporal lobe (MTL) is currently under debate. We used a spatial source memory paradigm during event-related functional magnetic resonance imaging to investigate this issue. At study, abstract shapes were presented to the left or right of fixation. During test, old and new shapes were presented at fixation. Participants responded whether each shape had been previously presented on the "left," the "right," or was "new." Activity associated with contextual memory (i.e., source memory) was isolated by contrasting accurate versus inaccurate memory for spatial location. Item-memory-related activity was isolated by contrasting accurate item recognition without contextual memory with forgotten items. Source memory was associated with activity in the hippocampus and parahippocampal cortex. Although item memory was not associated with unique MTL activity at our original threshold, a region-of-interest (ROI) analysis revealed item-memory-related activity in the perirhinal cortex. Furthermore, a functional-anatomic dissociation within the parietal cortex for retrieving item and contextual information was not found in any of three ROIs. These results support the hypothesis that specific subregions in the MTL are associated with item memory and memory for context.     

Episodic memory: Neuronal codes for what,where, and when

Episodic memory is defined as the ability to recall events in a spatiotemporal context. Formation of such memories is critically dependent on the hippocampal formation and its inputs from the entorhinal cortex. To be able to support the formation of episodic memories, entorhinal cortex and hippocampal formation should contain a neuronal code that follows several requirements. First, the code should include information about position of the agent (“where”), sequence of events (“when”), and the content of the experience itself (“what”). Second, the code should arise instantly thereby being able to support memory formation of one‐shot experiences. For successful encoding and to avoid interference between memories during recall, variations in location, time, or in content of experience should result in unique ensemble activity. Finally, the code should capture several different resolutions of experience so that the necessary details relevant for future memory‐based predictions will be stored. We review how neuronal codes in entorhinal cortex and hippocampus follow these requirements and argue that during formation of episodic memories entorhinal cortex provides hippocampus with instant information about ongoing experience. Such information originates from (a) spatially modulated neurons in medial entorhinal cortex, including grid cells, which provide a stable and universal positional metric of the environment; (b) a continuously varying signal in lateral entorhinal cortex providing a code for the temporal progression of events; and (c) entorhinal neurons coding the content of experiences exemplified by object‐coding and odor‐selective neurons. During formation of episodic memories, information from these systems are thought to be encoded as unique sequential ensemble activity in hippocampus, thereby encoding associations between the content of an event and its spatial and temporal contexts. Upon exposure to parts of the encoded stimuli, activity in these ensembles can be reinstated, leading to reactivation of the encoded activity pattern and memory recollection.     

Memory for relations in the short term and the long term after medial temporal lobe damage

A central idea about the organization of declarative memory and the function of the hippocampus is that the hippocampus provides for the coding of relationships between items. A question arises whether this idea refers to the process of forming long‐term memory or whether, as some studies have suggested, memory for relations might depend on the hippocampus even at short retention intervals and even when the task falls within the province of short‐term (working) memory. The latter formulation appears to place the operation of relational memory into conflict with the idea that working memory is independent of medial temporal lobe (MTL) structures. In this report, the concepts of relational memory and working memory are discussed in the light of a simple demonstration experiment. Patients with MTL lesions successfully learned and recalled two word pairs when tested directly after learning but failed altogether when tested after a delay. The results do not contradict the idea that the hippocampus has a fundamental role in relational memory. However, there is a need for further elaboration and specification of the idea in order to explain why patients with MTL lesions can establish relational memory in the short term but not in long‐term memory. © 2017 Wiley Periodicals, Inc.     

Selective and shared contributions of the hippocampus and perirhinal cortex to episodic item and associative encoding

Although the general role of the medial-temporal lobe (MTL) in episodic memory is well established, controversy surrounds the precise division of labor between distinct MTL subregions. The perirhinal cortex (PrC) has been hypothesized to support nonassociative item encoding that contributes to later familiarity, whereas the hippocampus supports associative encoding that selectively contributes to later recollection. However, because previous paradigms have predominantly used recollection of the item context as a measure of associative encoding, it remains unclear whether recollection of different kinds of episodic detail depends on the same or different MTL encoding operations. In our current functional magnetic resonance imaging study, we devised a subsequent memory paradigm that assessed successful item encoding in addition to the encoding of two distinct episodic details: an item-color and an item-context detail. Hippocampal encoding activation was selectively enhanced during trials leading to successful recovery of either an item-color or item-context association. Moreover, the magnitude of hippocampal activation correlated with the number, and not the kind, of associated details successfully bound, providing strong evidence for a role of the hippocampus in domain-general associative encoding. By contrast, PrC encoding activation correlated with both nonassociative item encoding as well as associative item-color binding, but not with item-context binding. This pattern suggests that the PrC contributions to memory encoding may be domain-specific and limited to the binding of items with presented item-related features. Critically, together with a separately conducted behavioral study, these data raise the possibility that PrC encoding operations -- in conjunction with hippocampal mechanisms -- contribute to later recollection of presented item details.     

What forgetting tells us about remembering: The influence of top–down control on hemispheric asymmetries in verbal memory

It has been suggested that left hemisphere (LH) advantages in verbal processing is due to superior top–down control of verbal information. It is not clear how top–down mechanisms affect the encoding and retrieval of verbal information from hemispheric memory and whether they only influence activation or also encompass the inhibition of verbal information. The directed forgetting method, in conjunction with divided visual field presentation, was used to examine the influence of top–down control mechanisms on hemispheric asymmetries in verbal memory. Participants were cued to remember or forget words. Cues were presented either simultaneously with targets or after a short delay. A recognition memory test using divided visual field presentation was then given. Response times (RTs) revealed effects of cue timing in the LH. With simultaneous cues, RTs were faster to “Remember” words compared to “Forget” words. With delayed cues, RTs for “Remember” and “Forget” words were equivalent. In the right hemisphere (RH), “Remember” words were consistently faster than “Forget” words, regardless of cue timing. These data provide evidence that top–down mechanisms influenced LH verbal memory retrieval more than RH verbal memory retrieval. Finally, there was little evidence to suggest the hemispheres differ in inhibitory processing.     

Spatial and stimulus‐type tuning in the LEC,MEC, POR,PrC, CA1, and CA3 during spontaneous item recognition memory

According to the “two streams” hypothesis, the lateral entorhinal (LEC) and the perirhinal (PrC) cortices process information related to items (a “what” stream), the postrhinal (POR) and the medial entorhinal cortices (MEC) process spatial information (a “where” stream), and both types of information are integrated in the hippocampus (HIP). However, within the framework of memory function, only the HIP is reliably shown to preferentially process spatial information, and the PrC items' features. In contrast, the role of the LEC and MEC in memory is virtually unexplored, and conflicting results emerge for the POR. Moreover, the specific contribution of the hippocampal subfields CA1 and CA3 to spatial and non‐spatial memory is not thoroughly understood. To investigate which of these areas is specifically tuned to spatial demands or stimulus identity (odor or object), we assessed the pattern of activation of these areas during recognition memory by detecting the immediate‐early gene Arc, commonly used as a marker of neuronal activation. We report that all MTL areas were recruited during the spatial and the non‐spatial tasks. However, the LEC, MEC, POR, and CA1 were activated to a comparable level in spatial and non‐spatial tasks, while the PrC was tuned to stimulus‐type, not spatial demands, and CA3 to spatial demands but not stimulus‐type. Results are discussed within the frame of a recent model suggesting that the MTL could be segregated in terms of memory processes, such as recollection and familiarity, rather than information content. © 2013 Wiley Periodicals, Inc.     

Process dissociation between contextual retrieval and item recognition

We employed a source memory task in an event related fMRI study to dissociate MTL processes associated with either contextual retrieval or item recognition. To introduce context during study, stimuli (photographs of buildings and natural landscapes) were transformed into one of four single-color-scales: red, blue, yellow, or green. In the subsequent old/new recognition memory test, all stimuli were presented as gray scale photographs, and old-responses were followed by a four-alternative source judgment referring to the color in which the stimulus was presented during study. Our results suggest a clear-cut process dissociation within the human MTL. While an activity increase accompanies successful retrieval of contextual information, an activity decrease provides a familiarity signal that is sufficient for successful item recognition.