Biology subjects

Gellersen, H. M.

Publications and source records attributed to Gellersen, H. M..

8 recordsLinked to original sources

bioRxiv2026

Mesoscale medial temporal lobe connectivity patterns relate to tau pathology and memory in older adults

The medial temporal lobe (MTL) is crucial for episodic memory. Tau pathology is a hallmark of Alzheimer's disease (AD) and accumulates in layer-specific patterns in the MTL during aging. It is, however, unclear whether early AD pathology relates to mesoscale network signatures distinct from non-pathological aging. To address this gap, we acquired 7 Tesla submillimeter-resolution resting-state fMRI, plasma-based AD biomarkers, glial fibrillary acidic protein (GFAP) levels, APOE genotype, regional [18F]PI-2620 tau PET burden, and longitudinal episodic memory data in 75 cognitively unimpaired older adults. Older age was associated with lower perirhinal-hippocampal connectivity and lower network segregation, whereas higher plasma-based AD pathology was associated with higher perirhinal-hippocampal connectivity. Furthermore, temporal-lobe tau burden was related to altered connectivity patterns in tau-vulnerable MTL subfields and layers, dependent on GFAP levels. Retrosplenial tau burden was associated with higher hippocampal-retrosplenial connectivity consistent with tau spread along canonical hippocampal output pathways. Finally, higher connectivity within the hippocampus attenuated the negative association between temporal-lobe tau burden and memory performance but predicted unfavorable memory trajectories. Our findings show differential associations of age and AD pathology with mesoscale MTL-connectivity patterns. Importantly, increased hippocampal connectivity may support memory function in the short term while contributing to subsequent memory decline.

neuroscience↗

bioRxiv2026

Dynamic shifts between pattern separation and reinstatement in human CA3 and dentate gyrus

Distinguishing similar memories is thought to require hippocampal pattern separation, the orthogonalization of overlapping neural representations. Here, high-resolution 7-Tesla fMRI during one-shot encoding of similar target-lure pairs demonstrated that pattern separation and reinstatement are modulated by stimulus domain, similarity, and hippocampal long-axis position. Univariate novelty responses during successful object and scene discrimination were found across medial temporal lobe cortex and hippocampal subfields. Multivariate neural pattern similarity was reduced for correctly rejected low-similarity lures across domains throughout all medial temporal regions, consistent with pattern separation. Increasing target-lure similarity resulted in more hippocampal than cortical pattern separation. An exception were high-similarity scene lures which elicited greater hippocampal pattern similarity, indicating reinstatement. In dentate gyrus and CA3, reduced pattern similarity predicted better object, increased similarity better scene memory, depending on hippocampal long-axis position. Pattern separation and reinstatement are therefore not fixed computational properties of specific subregions but shift dynamically during fast episodic learning.

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bioRxiv2025

Informational Complexity as a Neural Marker of Cognitive Reserve

In Alzheimers disease (AD), a mismatch between neurological damage and cognitive functioning often is attributed to individual differences in cognitive reserve. Understanding the neural mechanism of cognitive reserve could help assessing the therapeutic effectiveness of interventions in AD. To address this, here, 38 elderly participants performed a sustained attention task during high-density EEG while awake and during drowsiness. Operationally, the degree to which performance was impaired under drowsiness signalled the extent of cognitive reserve, with less impairment indicating a higher level of cognitive reserve. Investigating performance variations during the active management of neural challenges offers a novel approach to studying cognitive reserve, capturing dynamics that mirror everyday cognitive demand. We related cognitive reserve to various measures, including informational complexity using the Lempel-Ziv (LZSUM) algorithm. We found a significant interaction effect between arousal and performance, where LZSUM values increased in high performers when drowsy but decreased in low performers. This effect was most pronounced in the frontal and central areas. Our findings suggest LZSUM to be indicative of a compensatory mechanism and thus show potential for LZSUM as a neural marker in assessing cognitive reserve. However, we found no consistent relationship between performance and structural brain measures, and proxies of cognitive reserve. Critically, our findings present a counterexample to the prevailing view that informational complexity purely reflects conscious level. Further research, such as a study with the same paradigm in patients with mild cognitive impairment (MCI) and AD, may lead to additional insights of whether we are truly measuring cognitive reserve.

neuroscience↗

bioRxiv2023

Converging on consistent functional connectomics

Functional interactions between brain regions can be viewed as a network, empowering neuroscientists to leverage network science to investigate distributed brain function. However, obtaining a brain network from functional neuroimaging data involves multiple steps of data manipulation, which can drastically affect the organisation and validity of the estimated brain network and its properties. Here, we provide a systematic evaluation of 576 unique data-processing pipelines for functional connectomics from resting-state functional MRI, obtained from all possible recombinations of popular choices for brain atlas type and size, connectivity definition and selection, and global signal regression. We use the portrait divergence, an information-theoretic measure of differences in network topology across scales, to quantify the influence of analytic choices on the overall organisation of the derived functional connectome. We evaluate each pipeline across an entire battery of criteria, seeking pipelines that (i) minimise spurious test-retest discrepancies of network topology, while simultaneously (ii) mitigating motion confounds, and being sensitive to both (iii) inter-subject differences and (iv) experimental effects of interest, as demonstrated by propofol-induced general anaesthesia. Our findings reveal vast and systematic variability across pipelines suitability for functional connectomics. Choice of the wrong data-processing pipeline can lead to results that are not only misleading, but systematically so, distorting the functional connectome more drastically than the passage of several months. We also found that the majority of pipelines failed to meet at least one of our criteria. However, we identified 8 candidates satisfying all criteria across each of four independent datasets spanning minutes, weeks, and months, ensuring the generalisability of our recommendations. Our results also generalise to alternative acquisition parameters and preprocessing and denoising choices. By providing the community with a full breakdown of each pipelines performance across this multi-dataset, multi-criteria, multi-scale and multi-step approach, we establish a comprehensive set of benchmarks to inform future best practices in functional connectomics.

neuroscience↗

bioRxiv2022

Reduced memory precision in older age is associated with functional and structural differences in the angular gyrus

Decreased fidelity of mnemonic representations plays a critical role in age-related episodic memory deficits, yet the brain mechanisms underlying such reductions remain unclear. Using functional and structural neuroimaging, we examined how changes in two key nodes of the posterior-medial network, the hippocampus and the angular gyrus, might underpin loss of memory precision in older age. Healthy young and older adults completed a memory task that involved reconstructing object features on a continuous scale. Investigation of BOLD activity during retrieval revealed an age-related reduction in activity reflecting successful recovery of object features in the hippocampus, whereas trial-wise modulation of BOLD signal by graded memory precision was diminished in the angular gyrus. Grey matter volume of the angular gyrus further predicted individual differences in memory precision in older age, beyond likelihood of successful retrieval. These findings provide converging evidence for a role of functional and structural integrity of the angular gyrus in constraining the fidelity of episodic remembering in older age, yielding new insights into parietal contributions to age-related episodic memory decline.

neuroscience↗

bioRxiv2022

Medial temporal lobe structure, mnemonic and perceptual discrimination in healthy older adults and those at risk for mild cognitive impairment

Cognitive tests sensitive to the integrity of the medial temporal lobe (MTL), such as mnemonic discrimination of perceptually similar stimuli, may be useful early markers of risk for cognitive decline in older populations. Perceptual discrimination of stimuli with overlapping features also relies on MTL, but remains relatively unexplored in this context. We assessed mnemonic discrimination in two test formats (Forced Choice, Yes/No) and perceptual discrimination of objects and scenes in 111 community-dwelling older adults at different risk status for cognitive impairment based on neuropsychological screening. We also investigated associations between performance and MTL subregion volume and thickness. The at-risk group exhibited reduced entorhinal thickness and impaired perceptual and mnemonic discrimination. Perceptual discrimination impairment partially explained group differences in mnemonic discrimination and correlated with entorhinal thickness. Executive dysfunction accounted for Yes/No deficits in at-risk adults, demonstrating the importance of test format for the interpretation of memory decline. These results suggest that perceptual discrimination tasks may be useful tools for detecting incipient cognitive impairment related to reduced MTL integrity in non-clinical populations.

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bioRxiv2021

Searching for Consistent Brain Network Topologies Across the Garden of (Shortest) Forking Paths

The functional interactions between regions of the human brain can be viewed as a network, empowering neuroscientists to leverage tools such as graph theory to obtain insight about brain function. However, obtaining a brain network from functional neuroimaging data inevitably involves multiple steps of data manipulation, which can affect the organisation (topology) of the resulting network and its properties. Test-retest reliability is a gold standard for both basic research and clinical use: a suitable data-processing pipeline for brain networks should recover the same network topology across repeated scan sessions of the same individual. Analyzing resting-state functional Magnetic Resonance Imaging (rs-fMRI) recordings from two test-retest studies across short (45 minutes), medium (2-4 weeks) and long term delays (5-16 months), we investigated the reliability of network topologies constructed by applying 576 unique pipelines to the same fMRI data, obtained from considering combinations of atlas type and size, edge definition and thresholding, and use of global signal regression. We adopted the portrait divergence, an information-theoretic criterion to measure differences in network topology across all scales, enabling us to quantify the influence of different pipelines on the overall organisation of the resulting network. Remarkably, our findings reveal that the choice of pipeline plays a fundamental role in determining how reproducible an individuals brain network topology will be across different scans: there is large and systematic variability across pipelines, such that an inappropriate choice of pipeline can distort the resulting network more than an interval of several months between scans. Across datasets and time-spans, we also identify specific combinations of data-processing steps that consistently yield networks with reproducible topology, enabling us to make recommendations about best practices to ensure high-quality brain networks.

neuroscience↗

bioRxiv2020

Memory precision of object-location binding is unimpaired in APOE ε4-carriers with spatial navigation deficits

Research suggests that tests of memory fidelity, feature binding and spatial navigation are promising for early detection of subtle behavioural changes related to Alzheimers disease (AD). In the absence of longitudinal data, one way of testing the early detection potential of cognitive tasks is through the comparison of individuals at different genetic risk for AD. Most studies have done so using samples aged 70 years or older. Here, we tested whether memory fidelity of long-term object-location binding may be a sensitive marker even among cognitively healthy individuals in their mid-60s by comparing participants at low and higher risk based on presence of the {varepsilon}4-allele of the apolipoprotein gene (n=26 {varepsilon}3{varepsilon}3, n=20 {varepsilon}3{varepsilon}4 carriers). We used a continuous report paradigm in a visual memory task that required participants to recreate the spatial position of objects in a scene. We employed mixture modelling to estimate the two distinct memory processes that underpin the trial-by-trial variation in localisation errors: retrieval success which indexes the proportion of trials where participants recalled any information about an objects position and the precision with which participants retrieved this information. Prior work has shown that these memory paradigms that separate retrieval success from precision are capable of detecting subtle differences in mnemonic fidelity even when retrieval success could not. Nonetheless, a Bayesian analysis found good evidence that {varepsilon}3{varepsilon}4 carriers did not remember fewer object locations (F(1, 42)=.450, p=.506, BF01 =3.02), nor was their precision for the spatial position of objects reduced compared to {varepsilon}3{varepsilon}3 carriers (F(1, 42)=.12, p=.726, BF01 =3.19). Because the participants in the sample presented here were a subset of a study on APOE effects on spatial navigation in the Sea Hero Quest game (Coughlan et al., 2019. PNAS, 116(9)), we obtained these data to contrast APOE effects on the two tasks within the same sample (n=33). Despite the smaller sample size, wayfinding deficits among {varepsilon}3{varepsilon}4 could be replicated (F(1, 33) =5.60, p=.024, BF10 =3.44). Object-location memory metrics and spatial navigation scores were not correlated (all r<.25, p>.1, 0<BF10 <3). These findings show spared object-location binding in the presence of a detrimental APOE {varepsilon}4 effect on spatial navigation. This suggests that the sensitivity of memory fidelity and binding tasks may not extend to individuals with one {varepsilon}4-allele in their early to mid-60s. The results provide further support to prior proposals that spatial navigation may be a sensitive marker for the earliest AD-dependent cognitive changes, even before episodic memory.

neuroscience↗