Vladislava Segen

SUMMARY: Entorhinal grid cell representations are thought to support spatial navigation and episodic memory, functions that decline with age. Their putative fMRI correlate, the hexadirectional signal, varies markedly among older adults, but the source of this variability is unknown. Using virtual navigation and fMRI in 85 older adults, we tested whether signal strength was related to the stability of hexadirectional signals. Hexadirectional orientation stability, the cross-run reproducibility of direction-specific activity patterns, was associated with hexadirectional signal strength in the posterior-medial-entorhinal-cortex (pmEC). In left-pmEC, higher orientation stability also predicted better object-location memory. In contrast, age and local structural measures did not account for individual differences in either measure. Finally, retrosplenial absolute-orientation stability was associated with left-pmEC orientation stability, and a mediation analysis supported an indirect association with hexadirectional signals through pmEC orientation stability. Together, these findings suggest that weaker entorhinal hexadirectional signal in aging may reflect unstable, rather than absent, entorhinal grid-cell-like representations.

Episodic memory decline is a common feature of cognitively normal aging, but its extent varies markedly across individuals. Although entorhinal tau pathology is thought to be a key contributor to episodic memory impairment, the neural mechanisms linking early tau accumulation to memory differences remain unclear. Grid-cell computations in the entorhinal cortex, which provide scaffolds for organizing experiences into episodic memories, offer one candidate mechanism. Here, we combined virtual-reality functional MRI, multivariate analysis, tau PET, and delayed word-list recall in cognitively normal older adults to test whether tau-related alterations in entorhinal coding are associated with worse episodic memory. Weaker left entorhinal grid-cell-like signal was associated with poorer memory performance, and individuals with higher left entorhinal tau burden showed weaker grid-cell-like signal. This association was specific to the canonical six-fold signal and was not explained by entorhinal volume, mean diffusivity, or intracortical myelination. A cross-sectional Bayesian mediation analysis further demonstrated that bilateral medial temporal tau burden is related to memory indirectly through left entorhinal grid-cell-like signal. Together, these findings provide evidence that entorhinal grid codes may constitute a functional pathway linking tau accumulation to memory variability in normal aging.

Path integration is navigation in the absence of environmental landmarks and is a primary cognitive mechanism underlying spatial memory. Path integration performance is primarily assessed in humans using the Triangle Completion Task (TCT). In humans, TCT has shown promise for the early diagnosis of Alzheimer's disease. In rodents, however, path integration is assessed using a wide variety of tasks, but none of which currently provide a homologue for the TCT. As rodents are routinely used as preclinical models, homologous path integration tasks that result in comparable performance metrics between species are important. In the present study, we developed and tested a novel rodent version of the triangle completion task to enhance cross‐species comparability of path integration performance. Rats were able to comprehend and perform the task. A group of Alzheimer's disease model rats (TgF344‐AD) exhibited similar path integration performance to their wild‐type littermates. This work establishes a novel rodent homologue of the triangle completion task, facilitating enhanced reverse translational study of human path integration.

Aging is associated with changes in spatial memory and navigation, yet the mechanisms underlying these changes are not yet fully understood. Environmental boundaries are among the most salient and reliable spatial cues, supporting both spatial memory and orientation. Here, we investigated how aging affects the use and the neural representation of boundary information during a virtual object location memory task. Healthy young and older adults navigated a square virtual environment while undergoing functional magnetic resonance imaging, allowing us to assess moment‐to‐moment encoding of distance to environmental boundaries in the entorhinal cortex and subiculum. Behaviorally, both age groups showed more accurate memory for objects located near boundaries, but this effect was amplified in older adults, whose spatial precision declined more steeply with increasing distance from boundaries. Older adults also exhibited a stronger bias to recall objects closer to boundaries. Analysis of navigation behavior revealed that older adults followed boundary‐oriented paths regardless of target location, whereas young adults flexibly adapted their navigation based on spatial context. Neurally, older adults—but not young adults—showed significant blood‐oxygen‐level‐dependent modulation by boundary distance in the entorhinal cortex and subiculum, with activity decreasing as participants moved farther from boundaries. This effect was most pronounced in low‐performing older adults and was associated with stronger behavioral boundary bias, suggesting a maladaptive reliance on proximity‐based cues. Together, our results provide converging behavioral and neural evidence that aging alters the use and representation of boundary information, with downstream effects on spatial memory. Altered boundary processing may represent a key mechanism contributing to age‐related declines in spatial cognition.

Path integration, the ability to track one’s position using self-motion cues, is critically dependent on the grid cell network in the entorhinal cortex, a region vulnerable to early Alzheimer’s disease pathology. In this study, we examined path integration performance in individuals with subjective cognitive decline (SCD), a group at increased risk for Alzheimer’s disease, and healthy controls using an immersive virtual reality task. We developed a Bayesian computational model to decompose path integration errors into distinct components. SCD participants exhibited significantly higher path integration error, primarily driven by increased memory leak, while other modeling-derived error sources, such as velocity gain, sensory, and reporting noise, remained comparable across groups. Our findings suggest that path integration deficits, specifically memory leak, may serve as an early marker of neurodegeneration in SCD and highlight the potential of self-motion–based navigation tasks for detecting presymptomatic Alzheimer’s disease–related cognitive changes.

In this study we introduce a new gaze-contingent visual foraging task in which participants searched through an environment by looking at trees displayed on a computer screen. If the looked-at tree contained a fruit item, the item became visible and was collected. In each trial, the participant’s task was to forage for a defined number of fruit items. In two experiments, fruit items were either randomly distributed about the trees (dispersed condition) or organised in one large patch (patchy condition). In the second experiment, we addressed the role of memory for foraging by including a condition that did not require memorising which trees had already been visited by changing their appearance (tree fading). Foraging performance was superior in the patchy as compared to the dispersed condition and benefited from tree-fading. In addition, with further analyses on search behaviour, these results suggest (1) that participants were sensitive to the distribution of resources, (2) that they adapted their search/foraging strategy accordingly, and (3) that foraging behaviour is in line with predictions derived from foraging theories, specifically area-restricted search, developed for large scale spatial foraging. We therefore argue that the visual search task presented shares characteristics and cognitive mechanisms involved in successful large-scale search and foraging behaviour and can therefore be successfully employed to study these mechanisms.

Path integration, the ability to track one’s position using self-motion cues, is critically dependent on the grid cell network in the entorhinal cortex, a region vulnerable to early Alzheimer’s disease pathology. In this study, we examined path integration performance in individuals with subjective cognitive decline (SCD), a group at increased risk for Alzheimer’s disease, and healthy controls using an immersive virtual reality task. We developed a Bayesian computational model to decompose path integration errors into distinct components. SCD participants exhibited significantly higher path integration error, primarily driven by increased memory leak, while other modelling-derived error sources, such as velocity gain, sensory and reporting noise, remained comparable across groups. Our findings suggest that path integration deficits, specifically memory leak, may serve as an early marker of neurodegeneration in SCD and highlight the potential of self-motion-based navigation tasks for detecting pre-symptomatic Alzheimer’s disease-related cognitive changes. Teaser Virtual reality, computational modelling, and biomarkers uncover path integration deficits, distinguishing pre-symptomatic Alzheimer’s from normal aging.

Path integration is navigation in the absence of environmental landmarks and is a primary cognitive mechanism underlying spatial memory. Path integration performance is primarily assessed in humans using the Triangle Completion Task (TCT). In humans, TCT has shown promise for the early diagnosis of Alzheimer’s disease. In rodents, however, path integration is assessed using a wide variety of tasks but none of which currently provide a homologue for the TCT. As rodents are routinely used as preclinical models, homologous path integration tasks that result in comparable performance metrics between species are important. In the present study we developed and tested a novel rodent version of the triangle completion task to enhance cross species comparability of path integration performance. Rats were able to comprehend and perform the task. A group of Alzheimer’s disease model rats (TgF344-AD) exhibited similar path integration performance to their wild-type littermates; however, analysis of behavioural structure suggests use of differing behavioural strategies. This work establishes a novel rodent homologue of the triangle completion task, facilitating enhanced reverse translational study of human path integration.

Spatial memory studies often employ static images depicting a scene, an array of objects, or environmental features from one perspective and then following a perspective-shift-prompt memory either of the scene or objects within the scene. The current study investigated a previously reported systematic bias in spatial memory where, following a perspective shift from encoding to recall, participants indicated the location of an object farther to the direction of the shift. In Experiment 1, we aimed to replicate this bias by asking participants to encode the location of an object in a virtual room and then indicate it from memory following a perspective shift induced by camera translation and rotation. In Experiment 2, we decoupled the influence of camera translations and rotations and examined whether adding additional objects to the virtual room would reduce the bias. Overall, our results indicate that camera translations result in greater systematic bias than camera rotations. We propose that the accurate representation of camera translations requires more demanding mental computations than camera rotations, leading to greater uncertainty regarding the location of an object in memory. This uncertainty causes people to rely on an egocentric anchor, thereby giving rise to the systematic bias in the direction of camera translation.