From cognitive maps to spatial schemas.

A schema refers to a structured body of prior knowledge that captures common patterns across related experiences. Schemas have been studied separately in the realms of episodic memory and spatial navigation across different species and have been grounded in theories of memory consolidation, but there has been little attempt to integrate our understanding across domains, particularly in humans. We propose that experiences during navigation with many similarly structured environments give rise to the formation of spatial schemas (for example, the expected layout of modern cities) that share properties with but are distinct from cognitive maps (for example, the memory of a modern city) and event schemas (such as expected events in a modern city) at both cognitive and neural levels. We describe earlier theoretical frameworks and empirical findings relevant to spatial schemas, along with more targeted investigations of spatial schemas in human and non-human animals. Consideration of architecture and urban analytics, including the influence of scale and regionalization, on different properties of spatial schemas may provide a powerful approach to advance our understanding of spatial schemas.

Organization of pRF size along the AP axis of the hippocampus and adjacent medial temporal cortex is related to specialization for scenes versus faces.

The hippocampus is largely recognized for its integral contributions to memory processing. By contrast, its role in perceptual processing remains less clear. Hippocampal properties vary along the anterior-posterior (AP) axis. Based on past research suggesting a gradient in the scale of features processed along the AP extent of the hippocampus, the representations have been proposed to vary as a function of granularity along this axis. One way to quantify such granularity is with population receptive field (pRF) size measured during visual processing, which has so far received little attention. In this study, we compare the pRF sizes within the hippocampus to its activation for images of scenes versus faces. We also measure these functional properties in surrounding medial temporal lobe (MTL) structures. Consistent with past research, we find pRFs to be larger in the anterior than in the posterior hippocampus. Critically, our analysis of surrounding MTL regions, the perirhinal cortex, entorhinal cortex, and parahippocampal cortex shows a similar correlation between scene sensitivity and larger pRF size. These findings provide conclusive evidence for a tight relationship between the pRF size and the sensitivity to image content in the hippocampus and adjacent medial temporal cortex.

Single voxel autocorrelation uncovers gradients of temporal dynamics in the hippocampus and entorhinal cortex during rest and navigation.

During navigation, information at multiple scales needs to be integrated. Single-unit recordings in rodents suggest that gradients of temporal dynamics in the hippocampus and entorhinal cortex support this integration. In humans, gradients of representation are observed, such that granularity of information represented increases along the long axis of the hippocampus. The neural underpinnings of this gradient in humans, however, are still unknown. Current research is limited by coarse fMRI analysis techniques that obscure the activity of individual voxels, preventing investigation of how moment-to-moment changes in brain signal are organized and how they are related to behavior. Here, we measured the signal stability of single voxels over time to uncover previously unappreciated gradients of temporal dynamics in the hippocampus and entorhinal cortex. Using our novel, single voxel autocorrelation technique, we show a medial-lateral hippocampal gradient, as well as a continuous autocorrelation gradient along the anterolateral-posteromedial entorhinal extent. Importantly, we show that autocorrelation in the anterior-medial hippocampus was modulated by navigational difficulty, providing the first evidence that changes in signal stability in single voxels are relevant for behavior. This work opens the door for future research on how temporal gradients within these structures support the integration of information for goal-directed behavior.

Transcranial magnetic stimulation to the angular gyrus modulates the temporal dynamics of the hippocampus and entorhinal cortex.

Transcranial magnetic stimulation (TMS) delivered to the angular gyrus (AG) affects hippocampal function and associated behaviors (Thakral PP, Madore KP, Kalinowski SE, Schacter DL. Modulation of hippocampal brain networks produces changes in episodic simulation and divergent thinking. 2020a. Proc Natl Acad Sci U S A. 117:12729-12740). Here, we examine if functional magnetic resonance imaging (fMRI)-guided TMS disrupts the gradient organization of temporal signal properties, known as the temporal organization, in the hippocampus (HPC) and entorhinal cortex (ERC). For each of 2 TMS sessions, TMS was applied to either a control site (vertex) or to a left AG target region (N = 18; 14 females). Behavioral measures were then administered, and resting-state scans were acquired. Temporal dynamics were measured by tracking change in the fMRI signal (i) "within" single voxels over time, termed single-voxel autocorrelation and (ii) "between" different voxels over time, termed intervoxel similarity. TMS reduced AG connectivity with the hippocampal target and induced more rapid shifting of activity in single voxels between successive time points, lowering the single-voxel autocorrelation, within the left anteromedial HPC and posteromedial ERC. Intervoxel similarity was only marginally affected by TMS. Our findings suggest that hippocampal-targeted TMS disrupts the functional properties of the target site along the anterior/posterior axis. Further studies should examine the consequences of altering the temporal dynamics of these medial temporal areas to the successful processing of episodic information under task demand.

Differential involvement of the anterior and posterior hippocampus, parahippocampus, and retrosplenial cortex in making precise judgments of spatial distance and object size for remotely acquired memories of environments and objects.

The hippocampus is known to support processing of precise spatial information in recently learned environments. It is less clear, but crucial for theories of systems consolidation, to know whether it also supports processing of precise spatial information in familiar environments learned long ago and whether such precision extends to objects and numbers. In this fMRI study, we asked participants to make progressively more refined spatial distance judgments among well-known Toronto landmarks (whether landmark A is closer to landmark B or C) to examine hippocampal involvement. We also tested whether the hippocampus was similarly engaged in estimating magnitude regarding sizes of familiar animals and numbers. We found that the hippocampus was only engaged in spatial judgment. Activation was greater and lasted longer in the posterior than anterior hippocampus, which instead showed greater modulation as discrimination between spatial distances became more fine grained. These findings suggest that the anterior and posterior hippocampus have different functions which are influenced differently by estimation of differential distance. Similarly, parahippocampal-place-area and retrosplenial cortex were involved only in the spatial condition. By contrast, activation of the intraparietal sulcus was modulated by precision in all conditions. Therefore, our study supports the idea that the hippocampus and related structures are implicated in retrieving and operating even on remote spatial memories whenever precision is required, as posted by some theories of systems consolidation.

Early mobile app training proficiency predicts how well memory-impaired individuals learn to use digital memory aids in the real world.

Functional memory impairment following acquired brain injury can lead to decreased independence. External memory aids such as smartphones can be highly effective compensation tools, but cognitive deficits may create barriers to implementation in daily life. The present study examined predictors of real-world use of mobile calendar applications for memory compensation in an acquired brain injury sample. A retrospective chart review was completed from an outpatient rehabilitation program, extending 15 years into the past, yielding data from 34 eligible participants. All participants demonstrated skill learning of the calendar function in their digital device and subsequently completed the generalization phase of training, which is focused on real-world implementation (measured through prospective memory tasks). The results showed that the length of time required for skill learning of mobile calendars (event entry or responding to alerts) was not predictive of the duration of generalization training. Initial training performance for responding to alerts, but not event entry, was a significant predictor of the duration of generalization training needed to complete the program. A secondary analysis with a subset of the data revealed that individuals with additional executive deficits took significantly longer to complete generalization training compared to those with a more focal memory impairment.

Mobile app learning in memory intervention for acquired brain injury: Neuropsychological associations of training duration.

Memory impairment is a common consequence of acquired brain injury, often leading to functional difficulties day-to-day and decreased independence. Memory Link is a theory-driven training programme for individuals with moderate-to-severe memory dysfunction, which enables the acquisition of digital device skills for functional compensation. The present study examined how neuropsychological functioning and initial training performance contribute to training duration in our outpatient memory rehabilitation programme. A retrospective chart review was conducted, extending 12 years into the past, yielding data from 37 eligible participants. All participants demonstrated skill learning of the calendar function in their digital device to the criterion point. The results showed that performance on neuropsychological tests of explicit memory (e.g., CVLT-II, BVMT-R), processing speed (e.g., Digit Symbol Coding, Trail Making sequencing), executive functioning (e.g., Trail Making switching), and perceptual ability (i.e., Block Design) were significantly associated with training duration to learn the core steps of calendar use. Furthermore, linear regression revealed that initial training performance was a significant predictor of training duration. Lastly, profile of cognitive impairment, with regard to severity of memory functioning and the presence of additional deficits, was found to be a significant factor contributing to how many training trials were required to learn application skills.

Differential Influence of Ventromedial Prefrontal Cortex Lesions on Neural Representations of Schema and Semantic Category Knowledge.

Prior knowledge, such as schemas or semantic categories, influences our interpretation of stimulus information. For this to transpire, prior knowledge must first be reinstated and then instantiated by being applied to incoming stimuli. Previous neuropsychological models implicate the ventromedial prefrontal cortex (vmPFC) in mediating these functions for schemas and the anterior/lateral temporal lobes and related structures for categories. vmPFC, however, may also affect processing of semantic category information. Here, the putative differential role of the vmPFC in the reinstatement and instantiation of schemas and semantic categories was examined by probing network-level oscillatory dynamics. Patients with vmPFC damage (n = 11) and healthy controls (n = 13) were instructed to classify words according to a given schema or category, while electroencephalography was recorded. As reinstatement is a preparatory process, we focused on oscillations occurring 500 msec prior to stimulus presentation. As instantiation occurs at stimulus presentation, we focused on oscillations occurring between stimulus presentation and 1000 msec poststimulus. We found that reinstatement was associated with prestimulus, theta and alpha desynchrony between vmPFC and the posterior parietal cortex for schemas, and between lateral temporal lobe and inferotemporal cortex for categories. Damage to the vmPFC influenced both schemas and categories, but patients with damage to the subcallosal vmPFC showed schema-specific deficits. Instantiation showed similar oscillatory patterns in the poststimulus time frame, but in the alpha and beta frequency bands. Taken together, these findings highlight distinct but partially overlapping neural mechanisms implicated in schema- and category-mediated processing.

Reminders activate the prefrontal-medial temporal cortex and attenuate forgetting of event memory.

Replicas of an aspect of an experienced event can serve as effective reminders, yet little is known about the neural basis of such reminding effects. Here we examined the neural activity underlying the memory-enhancing effect of reminders 1 week after encoding of naturalistic film clip events. We used fMRI to determine differences in network activity associated with recently reactivated memories relative to comparably aged, non-reactivated memories. Reminders were effective in facilitating overall retrieval of memory for film clips, in an all-or-none fashion. Prefrontal cortex and hippocampus were activated during both reminders and retrieval. Peak activation in ventro-lateral prefrontal cortex (vPFC) preceded peak activation in the right hippocampus during the reminders. For film clips that were successfully retrieved after 7 days, pre-retrieval reminders did not enhance the quality of the retrieved memory or the number of details retrieved, nor did they more strongly engage regions of the recollection network than did successful retrieval of a non-reminded film clip. These results suggest that reminders prior to retrieval are an effective means of boosting retrieval of otherwise inaccessible episodic events, and that the inability to recall certain events after a delay of a week largely reflects a retrieval deficit, rather than a storage deficit for this information. The results extend other evidence that vPFC drives activation of the hippocampus to facilitate memory retrieval and scene construction, and show that this facilitation also occurs when reminder cues precede successful retrieval attempts. The time course of vPFC-hippocampal activity during the reminder suggests that reminders may first engage schematic information meditated by vPFC followed by a recollection process mediated by the hippocampus.

Reminders reinstate context-specificity to generalized remote memories in rats: relation to activity in the hippocampus and aCC.

Conditioned fear memories that are context-specific shortly after conditioning generalize over time. We exposed rats to a context reminder 30 d after conditioning, which served to reinstate context-specificity, and investigated how this reminder alters retrieval-induced activity in the hippocampus and anterior cingulate cortex (aCC) relative to a no reminder condition. c-Fos expression in dorsal CA1 was observed following retrieval in the original context, but not in a novel context, whether or not the memory was reactivated, suggesting that dCA1 retains the context-specific representation. c-Fos was highly expressed in aCC following remote memory testing in both contexts, regardless of reminder condition, indicating that aCC develops generalized representations that are insensitive to memory reactivation.

Neural dynamics supporting auditory long-term memory effects on target detection.

Auditory long-term memory has been shown to facilitate signal detection. However, the nature and timing of the cognitive processes supporting such benefits remain equivocal. We measured neuroelectric brain activity while young adults were presented with a contextual memory cue designed to assist with the detection of a faint pure tone target embedded in an audio clip of an everyday environmental scene (e.g., the soundtrack of a restaurant). During an initial familiarization task, participants heard such audio clips, half of which included a target sound (memory cue trials) at a specific time and location (left or right ear), as well as audio clips without a target (neutral trials). Following a 1-h or 24-h retention interval, the same audio clips were presented, but now all included a target. Participants were asked to press a button as soon as they heard the pure tone target. Overall, participants were faster and more accurate during memory than neutral cue trials. The auditory contextual memory effects on performance coincided with three temporally and spatially distinct neural modulations, which encompassed changes in the amplitude of event-related potential as well as changes in theta, alpha, beta and gamma power. Brain electrical source analyses revealed greater source activity in memory than neutral cue trials in the right superior temporal gyrus and left parietal cortex. Conversely, neutral trials were associated with greater source activity than memory cue trials in the left posterior medial temporal lobe. Target detection was associated with increased negativity (N2), and a late positive (P3b) wave at frontal and parietal sites, respectively. The effect of auditory contextual memory on brain activity preceding target onset showed little lateralization. Together, these results are consistent with contextual memory facilitating retrieval of target-context associations and deployment and management of auditory attentional resources to when the target occurred. The results also suggest that the auditory cortices, parietal cortex, and medial temporal lobe may be parts of a neural network enabling memory-guided attention during auditory scene analysis.

The contributions of spatial context and imagery to the recollection of single words.

A number of theories of hippocampal function have placed spatial context at the center of richly recollected memories, but the subjective and objective ways that spatial context underlies the recollection of single words has been largely overlooked and underexplained. In this study, we conducted three experiments to investigate the involvement of spatial context in the recollection of single words. In all three experiments, participants encoded single words with varying features such as location and color. The subjective experience of recollection was measured using remember/know judgments and participant self-report of the types of information they recollected about the words. Objectively, recollection was measured using source memory judgments for both spatial and non-spatial features associated with the words. Our results provide evidence that spatial context frequently accompanies the recollection of single, isolated words, reviving discussions on the role of the hippocampus in spatial and detailed recollection.

Recalling the firedog: Individual differences in associative memory for unitized and nonunitized associations among older adults.

Memory deficits in aging are characterized by impaired hippocampus-mediated relational binding-the formation of links between items in memory. By reducing reliance on relational binding, unitization of two items into one concept enhances associative recognition among older adults. Can a similar enhancement be obtained when probing memory with recall? This question has yet to be examined, because recall has been assumed to rely predominantly on relational binding. Inspired by recent evidence challenging this assumption, we investigated individual differences in older adults' recall of unitized and nonunitized associations. Compared with successfully aging individuals, older adults with mild memory deficits, typically mediated by the hippocampus, were impaired in recall of paired-associates in a task which relies on relational binding (study: "PLAY-TUNNEL"; test: PLAY-T?). In stark contrast, the two groups showed similar performance when items were unitized into a novel compound word (study: "LOVEGIGGLE"; test: LOVEG?). Thus, boosting nonrelational aspects of recall enhances associative memory among aging individuals with subtle memory impairments to comparable levels as successfully aging older adults.

Hippocampal and Retrosplenial Goal Distance Coding After Long-term Consolidation of a Real-World Environment.

Recent research indicates the hippocampus may code the distance to the goal during navigation of newly learned environments. It is unclear however, whether this also pertains to highly familiar environments where extensive systems-level consolidation is thought to have transformed mnemonic representations. Here we recorded fMRI while University College London and Imperial College London students navigated virtual simulations of their own familiar campus (>2 years of exposure) and the other campus learned days before scanning. Posterior hippocampal activity tracked the distance to the goal in the newly learned campus, as well as in familiar environments when the future route contained many turns. By contrast retrosplenial cortex only tracked the distance to the goal in the familiar campus. All of these responses were abolished when participants were guided to their goal by external cues. These results open new avenues of research on navigation and consolidation of spatial information and underscore the notion that the hippocampus continues to play a role in navigation when detailed processing of the environment is needed for navigation.

The Primacy of Spatial Context in the Neural Representation of Events.

Some theories of episodic memory hypothesize that spatial context plays a fundamental role in episodic memory, acting as a scaffold on which episodes are constructed. A prediction based on this hypothesis is that spatial context should play a primary role in the neural representation of an event. To test this hypothesis in humans, male and female participants imagined events, composed of familiar locations, people, and objects, during an fMRI scan. We used multivoxel pattern analysis to determine the neural areas in which events could be discriminated based on each feature. We found that events could be discriminated according to their location in areas throughout the autobiographical memory network, including the parahippocampal cortex and posterior hippocampus, retrosplenial cortex, posterior cingulate cortex, precuneus, and medial prefrontal cortex. Events were also discriminable based on person and object features, but in fewer regions. Comparing classifier performance in regions involved in memory for scenes and events demonstrated that the location of an event was more accurately classified than the person or object involved. These results support theories that suggest that spatial context is a prominent defining feature of episodic memory.SIGNIFICANCE STATEMENT Remembered and imagined events are complex, consisting of many elements, including people, objects, and locations. In this study, we sought to determine how these types of elements differentially contribute to how the brain represents an event. Participants imagined events consisting of familiar locations, people, and objects (e.g., kitchen, mom, umbrella) while their brain activity was recorded with fMRI. We found that the neural patterns of activity in brain regions associated with spatial and episodic memory could distinguish events based on their location, and to some extent, based on the people and objects involved. These results suggest that the spatial context of an event plays an important role in how an event is represented in the brain.

Coherence and congruency mediate medial temporal and medial prefrontal activity during event construction.

The precise roles of the hippocampus (HPC) and medial prefrontal cortex (mPFC) in initially constructing imagined events remains unclear. HPC activity during imagination may be modulated by mnemonic load, given its role in working memory for complex materials, and/or by the semantic relatedness (i.e. congruency) between items and their context. MPFC activation may track with congruency or mnemonic load, given the role of ventral mPFC in schema processing and the dorsal mPFC in working memory for social information. Sixteen healthy adults (M age = 22.3) underwent an event construction task, wherein participants were provided with a context and item words and imagined an event, forming as many inter-item associations as possible among the items. The stimuli varied by set size and by normatively-defined congruence (normative congruency) to explore their effects on HPC and mPFC activity and functional connectivity. We observed HPC connectivity during event construction in general, whereas dorsal mPFC connectivity occurred during imagining only at higher set sizes. Moreover, anterior hippocampal activity correlated positively with increasing coherence between items during imagining, suggesting that the anterior HPC is sensitive to the relational demands of constructing a novel event. Parahippocampal, hippocampal, temporal pole, and mPFC activity tracked only with individual differences in subjective ratings of congruency of imagined events, which may contribute to construction by retrieving existing schema-related information. Collectively, these findings provide new insights into the factors that modulate HPC and mPFC activity when constructing mental simulations.

Overlap between hippocampal pre-encoding and encoding patterns supports episodic memory.

It is well-established that whether the information will be remembered or not depends on the extent to which the learning context is reinstated during post-encoding rest and/or at retrieval. It has yet to be determined, however, if the fundamental importance of contextual reinstatement to memory extends to periods of spontaneous neurocognitive activity prior to learning. We thus asked whether memory performance can be predicted by the extent to which spontaneous pre-encoding neural patterns resemble patterns elicited during encoding. Individuals studied and retrieved lists of words while undergoing fMRI-scanning. Multivoxel hippocampal patterns during resting periods prior to encoding resembled hippocampal patterns at encoding most strongly for items that were subsequently remembered. Furthermore, across subjects, the magnitude of similarity correlated with a behavioral measure of episodic recall. The results indicate that the neural context before learning is an important determinant of memory.

The hippocampus is critical for value-based decisions guided by dissociative inference.

The hippocampus supports flexible decision-making through memory integration: bridging across episodes and inferring associations between stimuli that were never presented together ('associative inference'). A pre-requisite for memory integration is flexible representations of the relationships between stimuli within episodes (AB) but also of the constituent units (A,B). Here we investigated whether the hippocampus is required for parsing experienced episodes into their constituents to infer their re-combined within-episode associations ('dissociative inference'). In three experiments male rats were trained on an appetitive conditioning task using compound auditory stimuli (AB+, BA+, CD-, DC-). At test either the compound or individual stimuli were presented as well as new stimuli. Rats with hippocampal lesions acquired and retained the compound discriminations as well as controls. Single constituent stimuli (A, B, C, D) were presented for the first time at test, so the only value with which they could be associated was the one from the compound to which they belonged. Controls inferred constituent tones' corresponding values while hippocampal rats did not, treating them as merely familiar stimuli with no associated value. This finding held whether compound training occurred before or after hippocampal lesions, suggesting that hippocampus-dependent inferential processes more likely occur at retrieval. The findings extend recent discoveries about the role of the hippocampus in intrinsic value representation, demonstrating hippocampal contributions to allocating value from primary rewards to individual stimuli. Importantly, we discovered that dissociative inferences serve to restructure or reparse patterns of directly acquired associations when animals are faced with environmental changes and need to extract relevant information from a multiplex memory. The hippocampus is critical for this fundamental flexible use of associations.

Cognitive mapping style relates to posterior-anterior hippocampal volume ratio.

As London taxi drivers acquire "the knowledge" and develop a detailed cognitive map of London, their posterior hippocampi (pHPC) gradually increase in volume, reflecting an increasing pHPC/aHPC volume ratio. In the mnemonic domain, greater pHPC/aHPC volume ratios in young adults have been found to relate to better recollection ability, indicating that the balance between pHPC and aHPC volumes might be reflective of cross-domain individual differences. Here, we examined participants' self-reported use of cognitive map-based navigational strategies in relation to their pHPC/aHPC hippocampal volume ratio. We find that greater reported cognitive map use was related to significantly greater posterior, relative to anterior, hippocampal volume in two separate samples of young adults. Further, greater reported cognitive map usage correlated with better performance on a self-initiated navigation task. Together, these data help to advance our understanding of differences between aHPC and pHPC and the greater role of pHPC in spatial mapping.

The effect of prior knowledge on post-encoding brain connectivity and its relation to subsequent memory.

It is known that prior knowledge can facilitate memory acquisition. It is unclear, however, whether prior knowledge can affect post-encoding brain activity to facilitate memory consolidation. In this fMRI study, we asked participants to associate novel houses with famous/nonfamous faces and investigated how associative-encoding tasks with/without prior knowledge differentially affected post-encoding brain connectivity during rest. Besides memory advantages in the famous condition, we found that post-encoding hippocampal connectivity with the fusiform face area (FFA) and ventral-medial-prefrontal cortex (vmPFC) was stronger following encoding of associations with famous than non-famous faces. Importantly, post-encoding functional connectivity between the hippocampus (HPC) and FFA, and between the anterior temporal pole region (aTPL) and posterior perceptual regions (i.e., FFA and the parahippocampal place area), together predicted a large proportion of the variance in subsequent memory performance. This prediction was specific for face-house associative memory, not face/house item memory, and only in the famous condition where prior knowledge was involved. These results support the idea that when prior knowledge is involved, the HPC, vmPFC, and aTPL, which support prior episodic, social-evaluative/schematic, and semantic memories, respectively, continue to interact with each other and posterior perceptual brain regions during the post-encoding rest to facilitate off-line processing of the newly formed memory, and enhance memory consolidation.