Thomas Wolbers

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.

Background: Craving is a diagnostic criterion and predictor of relapse in patients with alcohol dependence (AD) and is induced in cue exposure therapy (CET) to prepare patients for real-life risk situations. The benefits of virtual reality (VR) as an innovative tool within treatment for this highly prevalent disorder include increased practicability, standardization, and personalization of CET. Accurate measurement of craving is essential to develop effective virtual reality cue exposure (VR-CE) scenarios. Despite being relevant for diagnostics and therapy, the psychophysiological reaction to alcohol cues and its relationship to subjective craving has not been sufficiently examined. Objective: This study aimed to investigate the induction of subjective craving, its physiological correlates, and their relationship in patients with AD during an innovative VR-CE paradigm, including 2 alcohol-associated risk scenarios (bar and living room) and a neutral baseline scenario. Methods: Craving was analyzed by measuring physiological reactions (electrodermal activity, including nonspecific skin conductance responses [NS-SCR] and skin conductance level [SCL]; heart rate [variability] [HR(V)]; brightness-corrected pupil diameter [BCPD]; and respiration rate [RR]) and subjective craving (visual analog scale) in 61 patients with AD. Linear mixed-effects models were conducted to estimate the effects of VR-CE. Correlations between subjective and physiological craving parameters were analyzed using Spearman correlations. Results: Results showed that alcohol-associated VR scenarios had significant effects on subjective craving ( β values between 9.48, 95% CI 6.02‐12.95 and 15.93, 95% CI 12.47‐19.40, with moderate effect sizes between d =0.56 and d =0.72) and on NS-SCR frequency ( β values between 0.97, 95% CI 0.14‐1.80 and 3.06, 95% CI 2.23‐3.89, with small-to-large effect sizes between d =0.31 and d =0.91), BCPD ( β values between 0.03, 95% CI 0.01‐0.06 and 0.05, 95% CI 0.02‐0.07, with small effect sizes between d =0.21 and d =0.29), and RR ( β values between 0.67, 95% CI 0.06‐1.28 and 1.66, 95% CI 1.05‐2.26, with small effect sizes between d =0.22 and d =0.45), but not on SCL and HR(V). Correlation analyses showed significant but weak correlations between subjective craving and electrodermal activity (SCL: r =0.20, P =.04; NS-SCR frequency: r =0.21, P =.03). Conclusions: This study showed that subjective and physiological craving (NS-SCR, BCPD, and RR but not SCL and HR[V]) can be successfully induced by VR-CE in patients with AD. These outcomes add to research on the induction of craving using a wide range of psychophysiological and subjective parameters. Furthermore, this study expands the still-limited research on the relationship between subjective and psychophysiological craving in patients with AD. In the long term, this study informs the development of effective VR-CET, which could, by further building on psychophysiological parameters, lead to biofeedback VR-CET as an innovative treatment option for patients with AD.

Grid cells in the human entorhinal cortex (EC) play a critical role in spatial navigation and memory. The EC is also one of the first regions affected by ageing and Alzheimer’s disease. This pre-registered functional magnetic resonance imaging (fMRI) study aimed to detect grid-cell-like signals (GLS) in a passive virtual navigation task. Contrary to our hypotheses and previous findings, we did not observe significant GLS at a population level, even in younger participants. Further exploratory analyses investigated the impact of task-engagement, as inferred from object-location memory performance, and showed no relationship with GLS magnitude. We also examined potential influences of a confounding one-fold directional signal and various data-processing choices but observed no consistent patterns. Our findings, consistent with recent null results from similar studies, suggest that passive navigation paradigms may be insufficient for reliably eliciting grid-like signals in human fMRI.

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.

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.

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.

INTRODUCTION: Entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration (PI)–based spatial behaviors, we predicted that PI impairment would represent the first behavioral change in adults at risk of AD.METHODS: We compared immersive virtual reality (VR) PI ability to other cognitive domains in 100 asymptomatic midlife adults stratified by hereditary and physiological AD risk factors. In some participants, behavioral data were compared to 7T magnetic resonance imaging (MRI) measures of brain structure and function.RESULTS: Midlife PI impairments predicted both hereditary and physiological AD risk, with no corresponding multi‐risk impairment in episodic memory or other spatial behaviors. Impairments associated with altered functional MRI signal in the posterior‐medial EC.DISCUSSION: Altered PI may represent the transition point from at‐risk state to disease manifestation in AD, prior to impairment in other cognitive domains.

Rationale: Animal studies suggest that the so-called “female” hormone estrogen enhances spatial navigation and memory. This contradicts the observation that males generally out-perform females in spatial navigation and tasks involving spatial memory. A closer look at the vast number of studies actually reveals that performance differences are not so clear. Objectives: To help clarify the unclear performance differences between men and women and the role of estrogen, we attempted to isolate organizational from activational effects of estrogen on spatial navigation and memory. Methods: In a double-blind, placebo-controlled study, we tested the effects of orally administered estradiol valerate (E2V) in healthy, young women in their low-hormone menstrual cycle phase, compared to healthy, young men. Participants performed several first-person, environmentally rich, 3-D computer games inspired by spatial navigation and memory paradigms in animal research. Results: We found navigation behavior suggesting that sex effects dominated any E2 effects with men performing better with allocentric strategies and women with egocentric strategies. Increased E2 levels did not lead to general improvements in spatial ability in either sex but to behavioral changes reflecting navigation flexibility. Conclusion: Estrogen-driven differences in spatial cognition might be better characterized on a spectrum of navigation flexibility rather than by categorical performance measures or skills.