Biology subjects

Wolbers, T.

Publications and source records attributed to Wolbers, T..

18 recordsLinked to original sources

bioRxiv2026

Temporal instability weakens entorhinal grid-like coding in older adults

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.

neuroscience↗

bioRxiv2026

Entorhinal grid coding as a functional link between tau accumulation and episodic memory in human aging

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.

neuroscience↗

bioRxiv2026

Path Integration and Spatial Updating Recruit Distinct Cognitive-Neural Mechanisms in Humans

Path integration and spatial updating refer to the integration of self-motion information during navigation to update ones start location and the positions of other locations, respectively. Even though path integration has been described as a fundamental process whose output may serve as a building block for other navigational computations like spatial updating, the exact relationship between path integration and spatial updating is unknown. Here we addressed this question with an eye-tracking behavioral experiment and a subsequent fMRI study. Despite experiencing identical self-motion cues, participants showed differential eye fixation patterns and responded more quickly during spatial updating than during path integration, casting doubt on the fundamental role of path integration. Neuroimaging results showed that the precuneus and the dorsal premotor cortex were more activated during spatial updating, but the precuneus had stronger functional connectivity with the thalamus and the frontal cortex during path integration. Further supporting this dissociation, the two tasks invoked distinct brain-wide inter-regional functional networks. Together, the combined findings of both experiments suggest that spatial updating and path integration are dissociable navigation processes supported by distinct behavioral and neural mechanisms, rather than one process operating on the basis of the other.

neuroscience↗

bioRxiv2025

How human aging disrupts the head direction network: evidence from VR experiments and mechanistic models

Navigational deficits during aging can severely limit mobility and reduce quality of life. While research on the underlying neural mechanisms has primarily focused on medial temporal lobe dysfunction, the head-direction (HD) system--a core component of the mammalian navigation circuit--remains largely unexplored in the context of aging. We established an immersive virtual reality paradigm that provides direct behavioral read-outs of HD signals. In addition, we developed a biologically inspired HD model, which accommodates noise sources that simulate age-related neural changes. Compared to younger adults, older participants exhibited larger angular errors, and a brief delay increased their heading uncertainty. In addition, our novel ring-attractor architecture shows that synaptic noise and small-scale neuronal loss replicate the magnitude and dynamics of the age-related deficits observed behaviorally. Together, these behavioral and computational findings provide the first evidence that aging compromises the fidelity and stability of the HD system. By pinpointing noise accumulation and neuron attrition as mechanistic contributors, our study significantly advances the understanding of spatial navigation deficits in old age, and it highlights novel targets for interventions aimed at preserving navigational abilities and quality of life.

neuroscience↗

bioRxiv2025

Altered coding of environmental boundaries in human aging: an fMRI study

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 behaviour 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.

neuroscience↗

bioRxiv2025

A Unique Role for the Hippocampus in Cue Integration During Human Spatial Navigation

It is a central question in cognitive neuroscience how the brain integrates diverse sensory inputs to improve cognitive performance. This study investigated this question in the domain of human spatial navigation using high-field fMRI, a novel navigation task, and desktop virtual reality. Participants learned and retrieved spatial locations using landmarks alone (landmark condition), visual self-motion cues alone (i.e., optic flow; self-motion condition), or both cues together (combination condition). Behaviorally, participants benefited from cue integration. fMRI analyses revealed a cue integration effect in the hippocampus, which displayed positional coding only in the combination condition, and only in participants who showed behavioral evidence of cue integration. Notably, the posterior hippocampus exhibited stronger positional coding in the combination condition than in both single-cue conditions. Additionally, positional coding in the hippocampus predominantly reflected actual, rather than self-reported, locations, suggesting relatively early involvement in the cue integration process. These findings suggest that the hippocampus supports precise memory-guided navigation by integrating different spatial cues, a function beyond simple spatial representation. More broadly, this work helps reconcile the longstanding debate regarding the hippocampuss role in spatial navigation versus episodic and relational memory, facilitating a unified understanding of hippocampal function.

neuroscience↗

bioRxiv2025

Path integration impairments reveal early cognitive changes in Subjective Cognitive Decline

Path integration, the ability to track ones position using self-motion cues, is critically dependent on the grid cell network in the entorhinal cortex, a region vulnerable to early Alzheimers disease pathology. In this study, we examined path integration performance in individuals with subjective cognitive decline (SCD), a group at increased risk for Alzheimers 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 Alzheimers disease-related cognitive changes. TeaserVirtual reality, modelling, and plasma biomarkers reveal path integration deficits in pre-symptomatic Alzheimers vs normal aging.

neuroscience↗

bioRxiv2025

rTCT: Rodent Triangle Completion Task to facilitate translational study of path integration

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 Alzheimers 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 Alzheimers 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.

neuroscience↗

bioRxiv2023

Path integration selectively predicts midlife risk of Alzheimer's disease

The entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimers disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration, we predicted that path integration impairment would represent the first behavioural change in adults at-risk of AD. Using immersive virtual reality, we found that midlife path integration impairments predicted both hereditary and physiological AD risk, with no corresponding impairment on tests of episodic memory or other spatial behaviours. Impairments related to poorer angular estimation and were associated with hexadirectional grid-like fMRI signal in the posterior-medial EC. These results indicate that altered path integration may represent the transition point from at-risk state to disease onset in AD, prior to impairment in other cognitive domains.

neuroscience↗

bioRxiv2022

The 3D Structural Architecture of the Human Hand Area is Non-Topographic

The functional topography of the human primary somatosensory cortex (S1) hand area is a widely studied model system to understand sensory organization and plasticity. It is so far unclear whether or not the underlying 3D structural architecture also shows a topographic organization. We used 7T MRI data to quantify layer-specific myelin, iron and mineralization in relation to population receptive field maps of individual finger representations in Brodman area 3b (BA 3b) of human S1 in female and male younger adults. This 3D description allowed us to identify a characteristic profile of layer-specific myelin and iron deposition in the BA 3b hand area, but revealed an absence of structural differences, an absence of low-myelin borders, and high similarity of 3D microstructure profiles between individual fingers. However, structural differences and borders were detected between the hand and face areas. We conclude that the 3D structural architecture of the human hand area is non-topographic, unlike in some monkey species, which suggests a high degree of flexibility for functional finger organization and a new perspective on human topographic plasticity. Significance StatementUsing ultra-high field MRI, we provide the first comprehensive in vivo description of the 3D structural architecture of the human BA 3b hand area in relation to functional population receptive field (pRF) maps. High similarity of precise finger-specific 3D profiles, together with an absence of structural differences and an absence of low-myelin borders between individual fingers, reveal the 3D structural architecture of the human hand area to be non-topographic. This suggests reduced structural limitations to cortical plasticity and reorganization, and allows for shared representational features across fingers.

neuroscience↗

bioRxiv2022

Coexistence of Cue-specific and Cue-independent Spatial Representations for Landmarks and Self-motion Cues in Human Retrosplenial Cortex

Landmark-based and self-motion-based navigation are two fundamental forms of spatial navigation, which involve distinct cognitive mechanisms. A critical question is whether these two navigation modes invoke common or distinct spatial representations for a given environment in the brain. While a number of electrophysiological studies in non-human animals have investigated this question but yielded inconsistent results, it still awaits rigorous investigation in humans. In the current study, we combined ultra-high field fMRI at 7T and desktop virtual reality with state-of-the-art fMRI data analysis techniques. Using a novel linear track navigation task, we dissociated the use of landmarks and self-motion cues, so that participants used different spatial cues to encode and retrieve the same set of spatial locations. Focusing on the retrosplenial cortex (RSC) and the hippocampus, we observed that RSC contained both cue-specific and cue-independent spatial representations, which were driven by objective location (where the participant was actually located) and subjective location (the participants self-reported location), respectively. The hippocampus showed strong functional coupling with RSC and exhibited a similar spatial coding scheme, but with reduced effect sizes. Taken together, the current study demonstrated for the first time concurrent cue-specific and cue-independent spatial representations in RSC in the same spatial context, suggesting that this area might transform cue-specific spatial inputs into coherent cue-independent spatial representations to guide navigation behavior.

neuroscience↗

bioRxiv2021

Global and Local Head Direction Coding in the Human Brain

Orientation-specific head direction (HD) cells increase their firing rate to indicate ones facing direction in the environment. Rodent studies suggest HD cells in distinct areas of thalamus and retrosplenial cortex (RSC) code either for global (relative to the wider environment) or local (e.g., room-specific) reference frames. To investigate whether similar neuroanatomical dissociations exist in humans, we reanalysed functional magnetic resonance imaging data in which participants learned the orientation of unique images in separate local environments relative to distinct global landmarks (Shine, Valdes-Herrera, Hegarty, & Wolbers, 2016). The environment layout meant that we could establish two separate multivariate analysis models in which the HD on individual trials was coded relative either to global (North, South, East, West) or local (Front, Back, Right, Left) reference frames. Examining the data first in key regions of interest (ROI) for HD coding, we replicated our previous results and found that global HD was decodable in the thalamus and precuneus; the RSC, however, was sensitive only to local HD. Extending recent findings in both humans and rodents, V1 was sensitive to both HD reference frames. Additional small volume-corrected searchlight analyses supported the ROI results and indicated that the anatomical locus of the thalamic global HD coding was located in the medial thalamus, bordering the anterior thalamus, a region critical for global HD coding in rodents. Our findings elucidate further the putative neural basis of HD coding in humans, and suggest that distinct brain regions code for different frames of reference in HD. Significance statementHead direction (HD) cells provide a neural signal as to ones orientation in the environment. HD can be coded relative to global or local (e.g., room-specific) reference frames, with studies suggesting that distinct areas of thalamus and retrosplenial cortex (RSC) code for this information. We reanalysed fMRI data where human participants associated images with global HDs before undergoing scanning. The design enabled us to examine both global and local HD coding. Supporting previous findings, global HD was decodable in thalamus, however the RSC coded only for local HD. We found evidence also for both reference frames in V1. These findings elucidate the putative neural basis of HD coding in humans, with distinct brain regions coding for different HD reference frames.

neuroscience↗

bioRxiv2019

Increased hippocampal excitability and reduced modulation in relevant neural networks underlying age-related cognitive mapping deficits

Learning the spatial layout of a novel environment is associated with dynamic activity changes in the hippocampus and in medial parietal areas. With advancing age, the ability to learn spatial environments deteriorates substantially but the underlying neural mechanisms are unknown. Here, we report findings from a behavioral and a fMRI experiment where older and younger adults performed a spatial learning task in a photorealistic virtual environment. We modeled individual learning states using a Bayesian state-space model and found that activity in retrosplenial cortex/parieto-occipital sulcus and anterior hippocampus did not change systematically as a function learning in older compared to younger adults across repeated episodes in the environment. Moreover, effective connectivity analyses revealed that the age-related learning deficits are linked to an increase in hippocampal excitability. Together, these results provide important insights into how human aging affects computations in the brains navigation system, highlighting the critical role of the hippocampus.

neuroscience↗

bioRxiv2018

Sources of path integration error in young and aging humans

Path integration is a vital function in navigation: it enables the continuous tracking of ones position in space by integrating self-motion cues. Path integration abilities vary across individuals but tend to deteriorate in old age. The specific causes of path integration errors, however, remain poorly characterized. Here, we combined tests of path integration performance with a novel analysis based on the Langevin diffusion equation, which allowed us to decompose errors into distinct causes that can corrupt path integration computations. Across age groups, the dominant errors were due to noise and a bias in speed estimation. Noise-driven errors accumulated with travel distance not elapsed time, suggesting that the dominant noise originates in the velocity input rather than within the integrator. Age-related declines were traced primarily to a growth in this unbiased noise. Together, these findings shed light on the contributors to path integration error and the mechanisms underlying age-related navigational deficits.

neuroscience↗

bioRxiv2018

Evidence for allocentric boundary and goal direction information in the human entorhinal cortex and subiculum

In rodents, cells in the medial entorhinal cortex (EC) and subiculum code for the allocentric direction to environment boundaries, which is an important prerequisite for accurate positional coding. Although in humans boundary-related signals have been reported, there is no evidence that they contain allocentric direction information. Furthermore, it has not been possible to separate boundary versus goal direction signals in the EC/subiculum. To address these important questions, participants learned a virtual environment containing four unique boundaries, after which they underwent fMRI scanning where they made judgments about the allocentric direction of a cue object. Using multivariate decoding, we found information regarding allocentric boundary direction in posterior EC and subiculum, whereas in anterior EC and subiculum we could decode allocentric goal direction. These data provide the first evidence of allocentric boundary coding in humans, and are consistent with recent conceptualisations of a division of labour within the EC.

neuroscience↗

bioRxiv2018

The Human Hippocampus Contributes to Egocentric Coding of Distance to a Local Landmark

Spatial navigation can depend on path integration or environmental cues (e.g., landmarks), which are thought to be integrated in hippocampal and entorhinal circuits. This study investigates the anatomical basis of path integration and navigation based on a single local landmark using an individual differences approach, since people vary substantially in their ability to navigate with path integration cues and landmarks. In two experiments, we dissociated the use of path integration and a local landmark in the same navigation task, and investigated whether morphological variability in the hippocampus and entorhinal cortex could explain behavioral variability in young healthy humans. In Experiment 1, participants navigated in a fully immersive virtual reality environment, with body-based cues available for path integration. The participants first walked through a series of posts before attempting to walk back to the remembered location of the first post. We found that gray matter volume of the hippocampus positively predicted behavioral accuracy of retrieving the targets distance in relation to the local landmark. Hippocampus also positively predicted path integration performance in terms of walking-distance to the target location. Experiment 2 was conducted in a desktop virtual environment, with no body-based cues available. Optic flow served as path integration cues, and participants were tested on their memory of a learned target location along a linear track. Consistent with Experiment 1, the results showed that hippocampal volume positively predicted performance on the targets distance in relation to the local landmark. In contrast to Experiment 1, there was no correlation between hippocampal volume and path integration performance. Together, our two experiments provide novel and converging evidence that the hippocampus plays an important role in encoding egocentric distance to a single local landmark during navigation, and they suggest a stronger hippocampal involvement when path integration is based on body-based compared to optic flow cues.

neuroscience↗

bioRxiv2018

Memory Image Completion (MIC): Establishing a task to behaviorally assess pattern completion in humans

For memory retrieval, pattern completion is a crucial process that restores memories from partial or degraded cues. Neurocognitive aging models suggest that the aged memory system is biased toward pattern completion, resulting in a behavioral preference for retrieval over encoding of memories. While there are behavioral tasks to assess the encoding side of these memory differences, pattern completion has received less attention in the literature. Here, we built on our previously developed behavioral recognition memory paradigm - the Memory Image Completion task (MIC) - a task to specifically target pattern completion. First, we used the original design with concurrent eye-tracking in order to rule out perceptual confounds that could interact with recognition performance. Second, we developed parallel versions of the task to accommodate test settings in clinical environments or longitudinal studies. The results show that older adults have a deficit in pattern completion ability with a concurrent bias toward pattern completion - a replication of previously found effects. Importantly, eye-tracking data during encoding could not account for age-related performance differences. At retrieval, spatial viewing patterns for both age groups were more driven by stimulus identity than by response choice, but compared to young adults, older adults fixation patterns overlapped more between stimuli that they (wrongly) thought had the same identity. This supports the observation that when making errors older adults choose responses perceived as similar to the correct stimulus, which is interpreted as a bias toward pattern completion. Additionally, two shorter versions of the task yielded comparable results, and no general learning effects were observed for repeated testing. Together, we present evidence that the MIC is a reliable behavioral task that targets pattern completion, that is easily and repeatedly applicable, and that is made freely available online.

animal behavior and cognition↗

bioRxiv2017

The GridCAT: A toolbox for automated analysis of human grid cell codes in fMRI

Human fMRI studies examining the putative firing of grid cells (i.e., the grid code) suggest that this cellular mechanism supports not only spatial navigation, but also more abstract cognitive processes. This research area, however, remains relatively unexplored, perhaps us to the complexities of data analysis. To overcome this, we have developed the Matlab-based Grid Code Analysis Toolbox (GridCAT), providing a graphical user interface, and open-source code, for the analysis of fMRI data. The GridCAT performs all analyses, from estimation and fitting of the grid code in the general linear model, to the generation of grid code metrics and plots. Moreover, it is flexible in allowing the specification of bespoke analysis pipelines; example data are provided to demonstrate the GridCATs main functionality. We believe the GridCAT is essential to opening this research area to the imaging community, and helping to elucidate the role of human grid codes in higher-order cognitive processes.\n\nHighlightsO_LIThe putative firing of grid cells (i.e., the grid code) can be examined using fMRI\nC_LIO_LINecessary steps for grid code analysis are reviewed\nC_LIO_LIThe Matlab-based grid code analysis toolbox (GridCAT) is introduced\nC_LIO_LIAutomated grid code analysis can be conducted either via a graphical user interface or open-source code\nC_LIO_LIA detailed manual and an example dataset are provided\nC_LI

neuroscience↗