Hippocampal contributions to novel spatial learning are both age-related and age-invariant.

Older adults show declines in spatial memory, although the extent of these alterations is not uniform across the healthy older population. Here, we investigate the stability of neural representations for the same and different spatial environments in a sample of younger and older adults using high-resolution functional MRI of the medial temporal lobes. Older adults showed, on average, lower neural pattern similarity for retrieving the same environment and more variable neural patterns compared to young adults. We also found a positive association between spatial distance discrimination and the distinctiveness of neural patterns between environments. Our analyses suggested that one source for this association was the extent of informational connectivity to CA1 from other subfields, which was dependent on age, while another source was the fidelity of signals within CA1 itself, which was independent of age. Together, our findings suggest both age-dependent and independent neural contributions to spatial memory performance.

A contextual binding theory of episodic memory: systems consolidation reconsidered.

Episodic memory reflects the ability to recollect the temporal and spatial context of past experiences. Episodic memories depend on the hippocampus but have been proposed to undergo rapid forgetting unless consolidated during offline periods such as sleep to neocortical areas for long-term storage. Here, we propose an alternative to this standard systems consolidation theory (SSCT) - a contextual binding account - in which the hippocampus binds item-related and context-related information. We compare these accounts in light of behavioural, lesion, neuroimaging and sleep studies of episodic memory and contend that forgetting is largely due to contextual interference, episodic memory remains dependent on the hippocampus across time, contextual drift produces post-encoding activity and sleep benefits memory by reducing contextual interference.

Machine learning classifiers for electrode selection in the design of closed-loop neuromodulation devices for episodic memory improvement.

Successful neuromodulation approaches to alter episodic memory require closed-loop stimulation predicated on the effective classification of brain states. The practical implementation of such strategies requires prior decisions regarding electrode implantation locations. Using a data-driven approach, we employ support vector machine (SVM) classifiers to identify high-yield brain targets on a large data set of 75 human intracranial electroencephalogram subjects performing the free recall (FR) task. Further, we address whether the conserved brain regions provide effective classification in an alternate (associative) memory paradigm along with FR, as well as testing unsupervised classification methods that may be a useful adjunct to clinical device implementation. Finally, we use random forest models to classify functional brain states, differentiating encoding versus retrieval versus non-memory behavior such as rest and mathematical processing. We then test how regions that exhibit good classification for the likelihood of recall success in the SVM models overlap with regions that differentiate functional brain states in the random forest models. Finally, we lay out how these data may be used in the design of neuromodulation devices.

Evidence of Impaired Remote Experience-near Semantic Memory in Medial Temporal Lobe Amnesia.

Neuropsychological research suggests that "experience-near" semantic memory, meaning knowledge attached to a spatiotemporal or event context, is commonly impaired in individuals who have medial temporal lobe amnesia. It is not known if this impairment extends to remotely acquired experience-near knowledge, which is a question relevant to understanding hippocampal/medial temporal lobe functioning. In the present study, we administered a novel semantic memory task designed to target knowledge associated with remote, "dormant" concepts, in addition to knowledge associated with active concepts, to four individuals with medial temporal lobe amnesia and eight matched controls. We found that the individuals with medial temporal lobe amnesia generated significantly fewer experience-near semantic memories for both remote concepts and active concepts. In comparison, the generation of abstract or "experience-far" knowledge was largely spared in the individuals with medial temporal lobe amnesia, regardless of whether the targets for retrieval were remote or active concepts. We interpret these findings as evidence that the medial temporal lobes may have a sustained role in the retrieval of semantic memories associated with spatiotemporal and event contexts, which are cognitive features often ascribed to episodic memory. These results align with recent theoretical models proposing that the hippocampus/medial temporal lobes support cognitive processes that are involved in, but not exclusive to, episodic memory.

Combination and competition between path integration and landmark navigation in the estimation of heading direction.

Successful navigation requires the ability to compute one's location and heading from incoming multisensory information. Previous work has shown that this multisensory input comes in two forms: body-based idiothetic cues, from one's own rotations and translations, and visual allothetic cues, from the environment (usually visual landmarks). However, exactly how these two streams of information are integrated is unclear, with some models suggesting the body-based idiothetic and visual allothetic cues are combined, while others suggest they compete. In this paper we investigated the integration of body-based idiothetic and visual allothetic cues in the computation of heading using virtual reality. In our experiment, participants performed a series of body turns of up to 360 degrees in the dark with only a brief flash (300ms) of visual feedback en route. Because the environment was virtual, we had full control over the visual feedback and were able to vary the offset between this feedback and the true heading angle. By measuring the effect of the feedback offset on the angle participants turned, we were able to determine the extent to which they incorporated visual feedback as a function of the offset error. By further modeling this behavior we were able to quantify the computations people used. While there were considerable individual differences in performance on our task, with some participants mostly ignoring the visual feedback and others relying on it almost entirely, our modeling results suggest that almost all participants used the same strategy in which idiothetic and allothetic cues are combined when the mismatch between them is small, but compete when the mismatch is large. These findings suggest that participants update their estimate of heading using a hybrid strategy that mixes the combination and competition of cues.

Combining egoformative and alloformative cues in a novel tabletop navigation task.

Previous work has shown how different interfaces (i.e., route navigation, maps, or a combination of the two) influence spatial knowledge and recollection. To test for the existence of intermediate representations along an egocentric-to-allocentric continuum, we developed a novel task, tabletop navigation, to provide a mixture of cues that inform the emergence of egocentric and allocentric representations or strategies. In this novel tabletop task, participants navigated a remote-controlled avatar through a tabletop scale model of the virtual city. Participants learned virtual cities from either navigating routes, studying maps, or our new tabletop navigation task. We interleaved these learning tasks with either an in situ pointing task (the scene- and orientation-dependent pointing [SOP] task) or imagined judgements of relative direction (JRD) pointing. In Experiment 1, performance on each memory task was similar across learning tasks and performance on the route and map learning tasks correlated with more precise spatial recall on both the JRD and SOP tasks. Tabletop learning performance correlated with SOP performance only, suggesting a reliance on egocentric strategies, although increased utilization of the affordances of the tabletop task were related to JRD performance. In Experiment 2, using a modified criterion map learning task, participants who learned using maps provided more precise responses on the JRD compared to route or tabletop learning. Together, these findings provide mixed evidence for both optimization and egocentric predominance after learning from the novel tabletop navigation task.

An Important Step toward Understanding the Role of Body-based Cues on Human Spatial Memory for Large-Scale Environments.

Moving our body through space is fundamental to human navigation; however, technical and physical limitations have hindered our ability to study the role of these body-based cues experimentally. We recently designed an experiment using novel immersive virtual-reality technology, which allowed us to tightly control the availability of body-based cues to determine how these cues influence human spatial memory [Huffman, D. J., & Ekstrom, A. D. A modality-independent network underlies the retrieval of large-scale spatial environments in the human brain. Neuron, 104, 611-622, 2019]. Our analysis of behavior and fMRI data revealed a similar pattern of results across a range of body-based cues conditions, thus suggesting that participants likely relied primarily on vision to form and retrieve abstract, holistic representations of the large-scale environments in our experiment. We ended our paper by discussing a number of caveats and future directions for research on the role of body-based cues in human spatial memory. Here, we reiterate and expand on this discussion, and we use a commentary in this issue by A. Steel, C. E. Robertson, and J. S. Taube (Current promises and limitations of combined virtual reality and functional magnetic resonance imaging research in humans: A commentary on Huffman and Ekstrom (2019). Journal of Cognitive Neuroscience, 2020) as a helpful discussion point regarding some of the questions that we think will be the most interesting in the coming years. We highlight the exciting possibility of taking a more naturalistic approach to study the behavior, cognition, and neuroscience of navigation. Moreover, we share the hope that researchers who study navigation in humans and nonhuman animals will synergize to provide more rapid advancements in our understanding of cognition and the brain.

Path integration in large-scale space and with novel geometries: Comparing vector addition and encoding-error models.

Path integration is thought to rely on vestibular and proprioceptive cues yet most studies in humans involve primarily visual input, providing limited insight into their respective contributions. We developed a paradigm involving walking in an omnidirectional treadmill in which participants were guided on two sides of a triangle and then found their back way to origin. In Experiment 1, we tested a range of different triangle types while keeping the distance of the unguided side constant to determine the influence of spatial geometry. Participants overshot the angle they needed to turn and undershot the distance they needed to walk, with no consistent effect of triangle type. In Experiment 2, we manipulated distance while keeping angle constant to determine how path integration operated over both shorter and longer distances. Participants underestimated the distance they needed to walk to the origin, with error increasing as a function of the walked distance. To attempt to account for our findings, we developed configural-based computational models involving vector addition, the second of which included terms for the influence of past trials on the current one. We compared against a previously developed configural model of human path integration, the Encoding-Error model. We found that the vector addition models captured the tendency of participants to under-encode guided sides of the triangles and an influence of past trials on current trials. Together, our findings expand our understanding of body-based contributions to human path integration, further suggesting the value of vector addition models in understanding these important components of human navigation.

Landmarks: A solution for spatial navigation and memory experiments in virtual reality.

Research into the behavioral and neural correlates of spatial cognition and navigation has benefited greatly from recent advances in virtual reality (VR) technology. Devices such as head-mounted displays (HMDs) and omnidirectional treadmills provide research participants with access to a more complete range of body-based cues, which facilitate the naturalistic study of learning and memory in three-dimensional (3D) spaces. One limitation to using these technologies for research applications is that they almost ubiquitously require integration with video game development platforms, also known as game engines. While powerful, game engines do not provide an intrinsic framework for experimental design and require at least a working proficiency with the software and any associated programming languages or integrated development environments (IDEs). Here, we present a new asset package, called Landmarks, for designing and building 3D navigation experiments in the Unity game engine. Landmarks combines the ease of building drag-and-drop experiments using no code, with the flexibility of allowing users to modify existing aspects, create new content, and even contribute their work to the open-source repository via GitHub, if they so choose. Landmarks is actively maintained and is supplemented by a wiki with resources for users including links, tutorials, videos, and more. We compare several alternatives to Landmarks for building navigation experiments and 3D experiments more generally, provide an overview of the package and its structure in the context of the Unity game engine, and discuss benefits relating to the ongoing and future development of Landmarks.

Grid coding, spatial representation, and navigation: Should we assume an isomorphism?

Grid cells provide a compelling example of a link between cellular activity and an abstract and difficult to define concept like space. Accordingly, a representational perspective on grid coding argues that neural grid coding underlies a fundamentally spatial metric. Recently, some theoretical proposals have suggested extending such a framework to nonspatial cognition as well, such as category learning. Here, we provide a critique of the frequently employed assumption of an isomorphism between patterns of neural activity (e.g., grid cells), mental representation, and behavior (e.g., navigation). Specifically, we question the strict isomorphism between these three levels and suggest that human spatial navigation is perhaps best characterized by a wide variety of both metric and nonmetric strategies. We offer an alternative perspective on how grid coding might relate to human spatial navigation, arguing that grid coding is part of a much larger conglomeration of neural activity patterns that dynamically tune to accomplish specific behavioral outputs.

Verbal cues flexibly transform spatial representations in human memory.

Humans possess a unique ability to communicate spatially-relevant information, yet the intersection between language and navigation remains largely unexplored. One possibility is that verbal cues accentuate heuristics useful for coding spatial layouts, yet this idea remains largely untested. We test the idea that verbal cues flexibly accentuate the coding of heuristics to remember spatial layouts via spatial boundaries or landmarks. The alternative hypothesis instead conceives of encoding during navigation as a step-wise process involving binding lower-level features, and thus subsequently formed spatial representations should not be modified by verbal cues. Across three experiments, we found that verbal cues significantly affected pointing error patterns at axes that were aligned with the verbally cued heuristic, suggesting that verbal cues influenced the heuristics employed to remember object positions. Further analyses suggested evidence for a hybrid model, in which boundaries were encoded more obligatorily than landmarks, but both were accessed flexibly with verbal instruction. These findings could not be accounted for by a tendency to spend more time facing the instructed component during navigation, ruling out an attentional-encoding mechanism. Our findings argue that verbal cues influence the heuristics employed to code environments, suggesting a mechanism for how humans use language to communicate navigationally-relevant information.

Space, time, and episodic memory: The hippocampus is all over the cognitive map.

In recent years, the field has reached an impasse between models suggesting that the hippocampus is fundamentally involved in spatial processing and models suggesting that the hippocampus automatically encodes all dimensions of experience in the service of memory. Here, we consider key conceptual issues that have impeded progress in our understanding of hippocampal function, and we review findings that establish the scope and limits of hippocampal involvement in navigation and memory. We argue that space and time serve as a primary scaffold to break up experiences into specific contexts, and to organize multimodal input that is to be associated within a context. However, the hippocampus is clearly capable of incorporating additional dimensions into the scaffold if they are determined to be relevant in the event-defined context. Conceiving of the hippocampal representation as constrained by immediate task demands-yet preferring axes that involve space and time-helps to reconcile an otherwise disparate set of findings on the core function of the hippocampus.

Close but no cigar: Spatial precision deficits following medial temporal lobe lesions provide novel insight into theoretical models of navigation and memory.

Increasing evidence suggests that the human hippocampus contributes to a range of different behaviors, including episodic memory, language, short-term memory, and navigation. A novel theoretical framework, the Precision and Binding Model, accounts for these phenomenon by describing a role for the hippocampus in high-resolution, complex binding. Other theories like Cognitive Map Theory, in contrast, predict a specific role for the hippocampus in allocentric navigation, while Declarative Memory Theory predicts a specific role in delay-dependent conscious memory. Navigation provides a unique venue for testing these predictions, with past results from research with humans providing inconsistent findings regarding the role of the human hippocampus in spatial navigation. Here, we tested five patients with lesions primarily restricted to the hippocampus and those extending out into the surrounding medial temporal lobe cortex on a virtual water maze task. Consistent with the Precision and Binding Model, we found partially intact allocentric memory in all patients, with impairments in the spatial precision of their searches for a hidden target. We found similar impairments at both immediate and delayed testing. Our findings are consistent with the Precision and Binding Model of hippocampal function, arguing for its role across domains in high-resolution, complex binding. SIGNIFICANCE STATEMENT: Remembering goal locations in one's environment is a critical skill for survival. How this information is represented in the brain is still not fully understood, but is believed to rely in some capacity on structures in the medial temporal lobe. Contradictory findings from studies of both humans and animals have been difficult to reconcile with regard to the role of the MTL, specifically the hippocampus. By assessing impairments observed during navigation to a goal in patients with medial temporal lobe damage we can better understand the role these structures play in such behavior. Utilizing virtual reality and novel analysis techniques, we have more precisely assessed the impact that medial temporal lobe damage has on spatial memory and navigation.

Rightward and leftward biases in temporal reproduction of objects represented in central and peripheral spaces.

The basis for how we represent temporal intervals in memory remains unclear. One proposal, the mental time line theory (MTL), posits that our representation of temporal duration depends on a horizontal mental time line, thus suggesting that the representation of time has an underlying spatial component. Recent work suggests that the MTL is a learned strategy, prompting new questions of when and why MTL is used to represent temporal duration, and whether time is always represented spatially. The current study examines the hypothesis that the MTL may be a time processing strategy specific to centrally-located stimuli. In two experiments (visual eccentricity and prismatic adaptation procedures), we investigated the magnitude of the rightward bias, an index of the MTL, in central and peripheral space. When participants performed a supra-second temporal interval reproduction task, we observed a rightward bias only in central vision (within 3° visual angle), but not in the peripheral space (approximately 6-8° visual angle). Instead, in the periphery, we observed a leftward bias. The results suggest that the MTL may be a learned strategy specific to central space and that strategies for temporal interval estimation that do not depend on MTL may exist for stimuli perceived peripherally.

Temporal encoding strategies result in boosts to final free recall performance comparable to spatial ones.

The method of loci is a highly effective mnemonic that recruits existing salient memory for spatial locations and uses the information as a scaffold for remembering a list of items (Yates, 1966). One possible account for the effectiveness of the spatial method of loci comes from the perspective that it utilizes evolutionarily preserved mechanisms for spatial navigation within the hippocampus (Maguire et al. in Proceedings of the National Academy of Sciences, 97(8), 4398-4403, 2000; O'Keefe & Nadel, 1978; Rodriguez et al. in Brain Research Bulletin, 57(3), 499-503, 2002). Recently, though, neurons representing temporal information have also been described within the hippocampus (Eichenbaum in Nature Reviews Neuroscience, 15(11), 732-744, 2014; Itskov, Curto, Pastalkova, & Buzsáki in The Journal of Neuroscience, 31(8), 2828-2834, 2011; MacDonald, Lepage, Eden, & Eichenbaum in Neuron, 71(4), 737-749, 2011; Mankin et al. in Proceedings of the National Academy of Sciences, 109(47), 19462-19467, 2012; Meck, Church, & Matell in Behavioral Neuroscience, 127(5), 642, 2013), challenging the primacy of spatial-based functions to hippocampal processing. Given the presence of both spatial and temporal coding mechanisms within the hippocampus, we predicted that primarily temporal encoding strategies might also enhance memory. In two different experiments, we asked participants to learn lists of unrelated nouns using the (spatial) method of loci (i.e., the layout of their home as the organizing feature) or using two novel temporal methods (i.e., autobiographical memories or using the steps to making a sandwich). Participants' final free recall performance showed comparable boosts to the method of loci for both temporal encoding strategies, with all three scaffolding approaches demonstrating performance well above uninstructed free recall. Our findings suggest that primarily temporal representations can be used effectively to boost memory performance, comparable to spatial methods, with some caveats related to the relative ease with which participants appear to master the spatial versus temporal methods.

Specific responses of human hippocampal neurons are associated with better memory.

A population of human hippocampal neurons has shown responses to individual concepts (e.g., Jennifer Aniston) that generalize to different instances of the concept. However, recordings from the rodent hippocampus suggest an important function of these neurons is their ability to discriminate overlapping representations, or pattern separate, a process that may facilitate discrimination of similar events for successful memory. In the current study, we explored whether human hippocampal neurons can also demonstrate the ability to discriminate between overlapping representations and whether this selectivity could be directly related to memory performance. We show that among medial temporal lobe (MTL) neurons, certain populations of neurons are selective for a previously studied (target) image in that they show a significant decrease in firing rate to very similar (lure) images. We found that a greater proportion of these neurons can be found in the hippocampus compared with other MTL regions, and that memory for individual items is correlated to the degree of selectivity of hippocampal neurons responsive to those items. Moreover, a greater proportion of hippocampal neurons showed selective firing for target images in good compared with poor performers, with overall memory performance correlated with hippocampal selectivity. In contrast, selectivity in other MTL regions was not associated with memory performance. These findings show that a substantial proportion of human hippocampal neurons encode specific memories that support the discrimination of overlapping representations. These results also provide previously unidentified evidence consistent with a unique role of the human hippocampus in orthogonalization of representations in declarative memory.

A Tale of Two Temporal Coding Strategies: Common and Dissociable Brain Regions Involved in Recency versus Associative Temporal Order Retrieval Strategies.

Numerous studies indicate the importance of the hippocampus to temporal order retrieval. However, behavioral studies suggest that there are different ways to retrieve temporal order information from encoded sequences, one involving an associative strategy (retrieving associations using neighboring items in a list) and another involving a recency strategy (determining which of two items came first). It remains unresolved, however, whether both strategies recruit the hippocampus or only associative strategies, consistent with the hippocampus's role in relational processing. To address this, we developed a paradigm in which we dissociated associative versus recency-based retrieval, involving the same stimulus presentation during retrieval. Associative retrieval involved an increase in RT (and decrease in performance) with greater distances between intervals, consistent with the need to retrieve intervening associations. Recency-based retrieval involved an increase in RT (and decrease in performance) with shorter distances between intervals, suggesting the use of a strength-based coding mechanism to retrieve information. We employed fMRI to determine the neural basis of the different strategies. Both strategies showed significant levels of hippocampal activation and connectivity that did not differ between tasks. In contrast, both univariate and connectivity pattern analyses revealed differences in extrahippocampal areas such as parietal and frontal cortices. A covariate analysis suggested that differences could not be explained by task difficulty alone. Together, these findings suggest that the hippocampus plays a role in both forms of temporal order retrieval, with neocortical networks mediating the different cognitive demands for associative versus recency-based temporal order retrieval.

Interacting networks of brain regions underlie human spatial navigation: a review and novel synthesis of the literature.

Navigation is an inherently dynamic and multimodal process, making isolation of the unique cognitive components underlying it challenging. The assumptions of much of the literature on human spatial navigation are that 1) spatial navigation involves modality independent, discrete metric representations (i.e., egocentric vs. allocentric), 2) such representations can be further distilled to elemental cognitive processes, and 3) these cognitive processes can be ascribed to unique brain regions. We argue that modality-independent spatial representations, instead of providing exact metrics about our surrounding environment, more often involve heuristics for estimating spatial topology useful to the current task at hand. We also argue that egocentric (body centered) and allocentric (world centered) representations are better conceptualized as involving a continuum rather than as discrete. We propose a neural model to accommodate these ideas, arguing that such representations also involve a continuum of network interactions centered on retrosplenial and posterior parietal cortex, respectively. Our model thus helps explain both behavioral and neural findings otherwise difficult to account for with classic models of spatial navigation and memory, providing a testable framework for novel experiments.

A network approach for modulating memory processes via direct and indirect brain stimulation: Toward a causal approach for the neural basis of memory.

Electrical stimulation of the brain is a unique tool to perturb endogenous neural signals, allowing us to evaluate the necessity of given neural processes to cognitive processing. An important issue, gaining increasing interest in the literature, is whether and how stimulation can be employed to selectively improve or disrupt declarative memory processes. Here, we provide a comprehensive review of both invasive and non-invasive stimulation studies aimed at modulating memory performance. The majority of past studies suggest that invasive stimulation of the hippocampus impairs memory performance; similarly, most non-invasive studies show that disrupting frontal or parietal regions also impairs memory performance, suggesting that these regions also play necessary roles in declarative memory. On the other hand, a handful of both invasive and non-invasive studies have also suggested modest improvements in memory performance following stimulation. These studies typically target brain regions connected to the hippocampus or other memory "hubs," which may affect endogenous activity in connected areas like the hippocampus, suggesting that to augment declarative memory, altering the broader endogenous memory network activity is critical. Together, studies reporting memory improvements/impairments are consistent with the idea that a network of distinct brain "hubs" may be crucial for successful memory encoding and retrieval rather than a single primary hub such as the hippocampus. Thus, it is important to consider neurostimulation from the network perspective, rather than from a purely localizationalist viewpoint. We conclude by proposing a novel approach to neurostimulation for declarative memory modulation that aims to facilitate interactions between multiple brain "nodes" underlying memory rather than considering individual brain regions in isolation.