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.

The Hippocampus Generalizes across Memories that Share Item and Context Information.

Episodic memory is known to rely on the hippocampus, but how the hippocampus organizes different episodes to permit their subsequent retrieval remains controversial. One major area of debate hinges on a discrepancy between two hypothesized roles of the hippocampus: differentiating between similar events to reduce interference and assigning similar representations to events that share overlapping items and contextual information. Here, we used multivariate analyses of activity patterns measured with fMRI to characterize how the hippocampus distinguishes between memories based on similarity at the level of items and/or context. Hippocampal activity patterns discriminated between events that shared either item or context information but generalized across events that shared similar item-context associations. The current findings provide evidence that, whereas the hippocampus can reduce mnemonic interference by separating events that generalize along a single attribute dimension, overlapping hippocampal codes may support memory for events with overlapping item-context relations. This lends new insights into the way the hippocampus may balance multiple mnemonic operations in adaptively guiding behavior.

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.

Older adults can use memory for distinctive objects, but not distinctive scenes, to rescue associative memory deficits.

Associative memory deficits in aging are frequently characterized by false recognition of novel stimulus associations, particularly when stimuli are similar. Introducing distinctive stimuli, therefore, can help guide item differentiation in memory and can further our understanding of how age-related brain changes impact behavior. How older adults use different types of distinctive information to distinguish overlapping events in memory and to avoid false associative recognition is still unknown. To test this, we manipulated the distinctiveness of items from two stimulus categories, scenes and objects, across three conditions: (1) distinct scenes paired with similar objects, (2) similar scenes paired with distinct objects, and (3) similar scenes paired with similar objects. Young and older adults studied scene-object pairs and then made both remember/know judgments toward single items as well as associative memory judgments to old and novel scene-object pairs ("Were these paired together?"). Older adults showed intact single item recognition of scenes and objects, regardless of whether those objects and scenes were similar or distinct. In contrast, relative to younger adults, older adults showed elevated false recognition for scene-object pairs, even when the scenes were distinct. These age-related associative memory deficits, however, disappeared if the pair contained an object that was visually distinct. In line with neural evidence that hippocampal functioning and scene processing decline with age, these results suggest that older adults can rely on memory for distinct objects, but not for distinct scenes, to distinguish between memories with overlapping features.

The hippocampus and orbitofrontal cortex jointly represent task structure during memory-guided decision making.

The hippocampus, well known for its role in episodic memory, might also be an important brain region for extracting structure from our experiences in order to guide future decisions. Recent evidence in rodents suggests that the hippocampus supports decision making by representing task structure in cooperation with the orbitofrontal cortex (OFC). Here, we examine how the human hippocampus and OFC represent task structure during an associative learning task that required learning of both context-determined and context-invariant probabilistic associations. We find that after learning, hippocampal and lateral OFC representations differentiated between context-determined and context-invariant task structures. The degree of this differentiation within the hippocampus and lateral OFC is highly correlated. These results advance our understanding of the hippocampus and suggest that the hippocampus and OFC support goal-directed behavior by representing information that guides the selection of appropriate decision strategies.