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Scheffler, K.

Publications and source records attributed to Scheffler, K..

At least 37 records · Page 2Linked to original sources

Fornix fractional anisotropy mediates the association between Mediterranean diet adherence and memory four years later in older adults without dementia

Here, we investigated whether fractional anisotropy (FA) of hippocampus-relevant white-matter tracts mediates the association between baseline Mediterranean diet adherence (MeDiAd) and verbal episodic memory over four years. Participants were healthy older adults with and without subjective cognitive decline and patients with amnestic mild cognitive impairment from the DELCODE cohort study (n = 376; age: 71.47 {+/-} 6.09 years; 48.7% female). MeDiAd and diffusion data were obtained at baseline. Verbal episodic memory was assessed at baseline and four yearly follow-ups. The associations between baseline MeDiAd and white matter, and verbal episodic memorys mean and rate of change over four years were tested with latent growth curve modeling. Baseline MeDiAd was associated with verbal episodic memory four years later (95% confidence interval, CI [0.01, 0.32]) but not with its rate of change over this period. Baseline Fornix FA mediated - and, thus, explained - that association (95% CI [0.002, 0.09]). Fornix FA may be an appropriate response biomarker of Mediterranean diet interventions on verbal memory in older adults.

neuroscience↗

Somatic small-variant calling methods in Illumina DRAGEN™ Secondary Analysis

We present the DRAGEN somatic pipeline for calling small somatic variants from tumor samples, with or without paired normal samples. The DRAGEN somatic variant caller offers 1) a flexible architecture that can be used on a wide array of somatic use cases; 2) built-in noise models enabling robustness against various sources of noise artifacts (mapping, genome context, or sample specific); 3) performance of joint analysis of tumor and normal samples in the case of a tumor-normal workflow yielding improved accuracy; 4) benefits from FPGA acceleration for efficient run time. We demonstrate the speed and accuracy of the DRAGEN tumor-normal pipeline across a range of whole genome sequencing (WGS) datasets and compare against third party tools such as Mutect2/GATK4 [1] and Strelka2 [2]. DRAGEN secondary analysis outperforms all other tools with its ability to complete a 110x/40x T/N whole-genome analysis in less than two hours. It offers exceptional accuracy, with higher sensitivity and precision than third party tools. We also show that the DRAGEN T/N workflow supports analysis of liquid and late-stage solid tumors by tolerating tumor-in-normal (TiN) contamination.

bioinformatics↗

Memory systems integration in sleep complements rapid systems consolidation in wakefulness

Sleep benefits memory performance by fostering systems consolidation, a process that embeds memories into neocortical networks and renders them independent of the hippocampus. Recent evidence shows that memory rehearsal during wakefulness likewise initiates systems consolidation and rapidly engenders neocortical engrams. Here, we investigate the effect of sleep-dependent consolidation for memories that have undergone rapid systems consolidation during wakefulness. After sleep compared to wakefulness, we find better memory retention and higher functional brain activity during memory retrieval in the medial parietal cortex, which hosts memory representations after rehearsal, and in the striatum and thalamus. Increased striatal and thalamic contributions were correlated with higher retrieval performance. Furthermore, all three regions decreased their functional connectivity to the hippocampus specifically after sleep. These findings show that besides continuing of systems consolidation initiated during wakefulness, sleep also acts to integrate different memory systems. Thus, rehearsal-induced and sleep-dependent consolidation seem to be complementary in nature.

neuroscience↗

Age- and sex-dependent effects of DNA glycosylase Neil3 on amyloid pathology, adult neurogenesis, and memory in a mouse model of Alzheimer's disease

Oxidative stress generating DNA damage has been shown to be a key characteristic in Alzheimers disease (AD). However, how it affects the pathogenesis of AD is not yet fully understood. Neil3 is a DNA glycosylase initiating repair of oxidative DNA base lesions and with a distinct expression pattern in proliferating cells. In brain, its function has been linked to hippocampal-dependent memory and to induction of neurogenesis after stroke and in prion disease. Here, we generated a novel AD mouse model deficient for Neil3 to study the impact of impaired oxidative base lesion repair on the pathogenesis of AD. Our results demonstrate an age-dependent decrease in amyloid-{beta} (A{beta}) plaque deposition in female Neil3-deficient AD mice, whereas no significant difference was observed in male mice. Furthermore, male but not female Neil3-deficient AD mice show reduced neural stem cell proliferation in the adult hippocampus and impaired working memory compared to controls. These effects seem to be independent of DNA repair as both sexes show increased level of oxidative base lesions in the hippocampus upon loss of Neil3. Thus, our findings suggest an age- and sex-dependent role of Neil3 in the progression of AD by altering cerebral A{beta} accumulation and promoting adult hippocampal neurogenesis to maintain cognitive function.

neuroscience↗

Integration of visual motion and pursuit signals in areas V3A and V6+ across cortical depth using 9.4T fMRI

Neural mechanisms underlying a stable perception of the world during pursuit eye movements are not fully understood. Both, perceptual stability as well as perception of real (i.e. objective) motion are the product of integration between motion signals on the retina and efference copies of eye movements. Human areas V3A and V6 have previously been shown to have strong objective ( real) motion responses. Here we used high-resolution laminar fMRI at ultra-high magnetic field (9.4T) in human subjects to examine motion integration across cortical depths in these areas. We found an increased preference for objective motion in areas V3A and V6+ i.e. V6 and possibly V6A towards the upper layers. When laminar responses were detrended to remove the upper-layer bias present in all responses, we found a unique, condition-specific laminar profile in V6+, showing reduced mid-layer responses for retinal motion only. The results provide evidence for differential, motion-type dependent laminar processing in area V6+. Mechanistically, the mid-layer dip suggests a special contribution of retinal motion to integration, either in the form of a subtractive (inhibitory) mid-layer input, or in the form of feedback into extragranular or infragranular layers. The results show that differential laminar signals can be measured in high-level motion areas in the human occipitoparietal cortex, opening the prospect of new mechanistic insights using non-invasive brain imaging. Significance StatementVisual stability and our ability to differentiate between self-induced and real motion are central to our visual sense. Both require the integration of two signals - retinal motion and copies of muscle commands used for eye movements (efference copies). A reasonable assumption is that either the efference copy or the result of integration will be conveyed to high-level visual regions along with visual retinal input, possibly differentially across cortical depth as the input sources differ. Our ultra-high field recordings present the first laminar evidence of differential signal processing of retinal and objective motion signals in area V6+, and present a first window into a mechanistic understanding of visual high-level motion processing.

neuroscience↗

Anatomically-based skeleton kinetics and pose estimation in freely-moving rodents

Forming a complete picture of the relationship between neural activity and body kinetics requires quantification of skeletal joint biomechanics during behavior. However, without detailed knowledge of the underlying skeletal motion, inferring joint kinetics from surface tracking approaches is difficult, especially for animals where the relationship between surface anatomy and skeleton changes during motion. Here we developed a videography-based method enabling detailed three-dimensional kinetic quantification of an anatomically defined skeleton in untethered freely-behaving animals. This skeleton-based model has been constrained by anatomical principles and joint motion limits and provided skeletal pose estimates for a range of rodent sizes, even when limbs were occluded. Model-inferred joint kinetics for both gait and gap-crossing behaviors were verified by direct measurement of limb placement, showing that complex decision-making behaviors can be accurately reconstructed at the level of skeletal kinetics using our anatomically constrained model.

neuroscience↗

Particle interactions and their effect on magnetic particle imaging and spectroscopy

Tracer and thus signal stability is crucial for an accurate diagnosis via magnetic particle imaging (MPI). However, MPI-tracer nanoparticles frequently agglomerate during their in vivo applications leading to particle interactions. Here, we investigate the influence of such magnetic coupling phenomena on the MPI signal. We prepared and characterized Zn0.4Fe2.6O4 nanoparticles and controlled their interparticle distance by variying SiO2 coating thickness. The silica shell affected the magnetic properties indicating stronger particle interactions for a smaller interparticle distance. The SiO2-coated Zn0.4Fe2.6O4 outperformed the bare sample in magnetic particle spectroscopy (MPS) in terms of signal/noise, however, the shell thickness itself only weakly influenced the MPS signal. To investigate the importance of magnetic coupling effects in more detail, we benchmarked the MPS signal of the bare and SiO2-coated Zn-ferrites against commercially available PVP-coated Fe3O4 nanoparticles in water and PBS. PBS is known to destabilize nanoparticles mimicking an agglomeration in vivo. The bare and coated Zn-ferrites showed excellent signal stability, despite their agglomeration in PBS. We attribute this to their aggregated morphology formed during their flame-synthesis. On the other hand, the MPS signal of commercial PVP-coated Fe3O4 strongly decreased in PBS compared to water, indicating strongly changed particle interactions. The relevance of this effect was further investigated in a mammalian cell model. For PVP-coated Fe3O4, we could detect a strong discrepancy between the particle concentration obtained from the MPS signal and the actual concentration determined via ICP-MS. The same trend was observed during their MPI analysis; while SiO2-coated Zn-ferrites could be precisely located in water and PBS, PVP-coated Fe3O4 could not be detected in PBS at all. This drastically limits the sensitivity and also general applicability of MPI using such standard commercial tracers and highlights the advantages of our flame-made Zn-ferrites concerning signal stability and ultimately diagnostic accuracy.

bioengineering↗

REViewer: Haplotype-resolved visualization of read alignments in and around tandem repeats

BackgroundExpansions of short tandem repeats are the cause of many neurogenetic disorders including familial amyotrophic lateral sclerosis, Huntington disease, and many others. Multiple methods have been recently developed that can identify repeat expansions in whole genome or exome sequencing data. Despite the widely-recognized need for visual assessment of variant calls in clinical settings, current computational tools lack the ability to produce such visualizations for repeat expansions. Expanded repeats are difficult to visualize because they correspond to large insertions relative to the reference genome and involve many misaligning and ambiguously aligning reads. ResultsWe implemented REViewer, a computational method for visualization of sequencing data in genomic regions containing long repeat expansions. To generate a read pileup, REViewer reconstructs local haplotype sequences and distributes reads to these haplotypes in a way that is most consistent with the fragment lengths and evenness of read coverage. To create appropriate training materials for onboarding new users, we performed a concordance study involving 12 scientists involved in STR research. We used the results of this study to create a user guide that describes the basic principles of using REViewer as well as a guide to the typical features of read pileups that correspond to low confidence repeat genotype calls. Additionally, we demonstrated that REViewer can be used to annotate clinically-relevant repeat interruptions by comparing visual assessment results of 44 FMR1 repeat alleles with the results of triplet repeat primed PCR. For 38 of these alleles, the results of visual assessment were consistent with triplet repeat primed PCR. ConclusionsRead pileup plots generated by REViewer offer an intuitive way to visualize sequencing data in regions containing long repeat expansions. Laboratories can use REViewer to assess the quality of repeat genotype calls as well as to visually detect interruptions or other imperfections in the repeat sequence and the surrounding flanking regions.

bioinformatics↗

Lifelong musical activity is associated with multi-domain cognitive and brain benefits in older adults

1AO_SCPLOWBSTRACTC_SCPLOWRegular musical activity as a highly-stimulating lifestyle activity is proposed to be protective against age-related cognitive decline and Alzheimers disease (AD). This study investigated associations between lifelong regular musical instrument playing, late-life cognitive abilities and brain morphology in older adults. We show that musical activity over the life course is associated with better global cognition, working memory, executive functions, language, and visuospatial abilities accounting for reserve proxies. Playing music is not significantly associated with gray matter volume in regions most affected by aging and AD. Selectively in the musically active participants, multi-domain cognitive abilities were enhanced with preserved gray matter volume in frontal and temporal regions. Our correlational findings suggest that playing a musical instrument may improve the recruitment of existing brain resources to facilitate late-life cognitive capacities. We propose that engaging in regular musical activity could serve as a low-threshold multimodal enrichment strategy that may promote cognitive resilience in advanced age.

neuroscience↗

Sensitivity and resolution improvement for in-vivo magnetic resonance current density imaging (MRCDI) of the human brain

PurposeMagnetic resonance current density imaging (MRCDI) combines MR brain imaging with the injection of time-varying weak currents (1-2 mA) to assess the current flow pattern in the brain. However, the utility of MRCDI is still hampered by low measurement sensitivity and poor image quality. MethodsWe recently introduced a multi-gradient-echo-based MRCDI approach that has the hitherto best documented efficiency. We now advanced our MRCDI approach in three directions and performed phantom and in-vivo human brain experiments for validation: First, we verified the importance of enhanced spoiling and optimize it for imaging of the human brain. Second, we improved the sensitivity and spatial resolution by using acquisition weighting. Third, we added navigators as a quality control measure for tracking physiological noise. Combining these advancements, we tested our optimized MRCDI method by using 1 mA transcranial electrical stimulation (TES) currents injected via two different electrode montages in five subjects. ResultsFor a session duration of 4:20 min, the new MRCDI method was able to detect magnetic field changes caused by the TES current flow at a sensitivity level of 84 pT, representing in a twofold increase relative to our original method. Comparing both methods to current flow simulations based on personalized head models demonstrated a consistent increase in the coefficient of determination of {Delta}R2=0.12 for the current-induced magnetic fields and {Delta}R2=0.22 for the current flow reconstructions. Interestingly, some of the simulations still clearly deviated from the measurements despite of the strongly improved measurement quality. This suggests that MRCDI can reveal useful information for the improvement of head models used for current flow simulations. ConclusionThe advanced method strongly improves the sensitivity and robustness of MRCDI and is an important step from proof-of-concept studies towards a broader application of MRCDI in clinical and basic neuroscience research.

neuroscience↗

Predicting intelligence from fMRI data of the human brain in a few minutes of scan time

In recent years, the prediction of individual behaviour from the fMRI-based functional connectome has become a major focus of research. The motivation behind this research is to find generalizable neuromarkers of cognitive functions. However, insufficient prediction accuracies and long scan time requirements are still unsolved issues. Here we propose a new machine learning algorithm for predicting intelligence scores of healthy human subjects from resting state (rsfMRI) or task-based fMRI (tfMRI). In a cohort of 390 unrelated test subjects of the Human Connectome Project, we found correlations between the observed and the predicted general intelligence of more than 50 percent in tfMRI, and of around 59 percent when results from two tasks are combined. Surprisingly, we found that the tfMRI data were significantly more predictive of intelligence than rsfMRI even though they were acquired at much shorter scan times (approximately 10 minutes versus 1 hour). Existing methods that we investigated in a benchmark comparison underperformed on tfMRI data and produced prediction accuracies well below our results. Our proposed algorithm differs from existing methods in that it achieves dimensionality reduction via ensemble learning and partial least squares regression rather than via brain parcellations or ICA decompositions. In addition, it introduces Ricci-Forman curvature as a novel type of edge weight.

neuroscience↗

NEIL1 and NEIL2 DNA glycosylases regulate anxiety and learning in a cooperative manner

Oxidative DNA damage in the brain has been implicated in neurodegeneration and cognitive decline. DNA glycosylases initiate base excision repair (BER), the main pathway for oxidative DNA base lesion repair. NEIL1 and NEIL3 DNA glycosylases alter cognition in mice, the role of NEIL2 remains unclear. Here, we investigate the impact of NEIL2 and its potential overlap with NEIL1 on behavior in single and double knock-out mouse models. Neil1-/-Neil2-/- mice displayed hyperactivity, reduced anxiety and improved learning. Hippocampal oxidative DNA base lesion levels were comparable between genotypes, no mutator phenotype was found. Impaired canonical repair was thus not the cause of altered behavior. Electrophysiology indicated reduced stratum oriens afferents in the hippocampal CA1 region in Neil1-/-Neil2-/-. Within CA1, NEIL1 and NEIL2 jointly regulated transcription in genes relevant for synaptic function. Thus, we postulate a cooperative function of NEIL1 and NEIL2 in genome regulation beyond canonical BER modulating memory formation and anxiety.

molecular biology↗

Jumping over Baselines with New Methods to Predict Activation Maps from Resting-state fMRI

Cognitive fMRI research primarily relies on task-averaged responses over many subjects to describe general principles of brain function. Nonetheless, there exists a large variability between subjects that is also reflected in spontaneous brain activity as measured by resting state fMRI (rsfMRI). Leveraging this fact, several recent studies have therefore aimed at predicting task activation from rsfMRI using various machine learning methods within a growing literature on connectome fingerprinting. In reviewing these results, we found lack of an evaluation against robust baselines that reliably supports a novelty of predictions for this task. On closer examination to reported methods, we found most underperform against trivial baseline model performances based on massive group averaging when whole-cortex prediction is considered. Here we present a modification to published methods that remedies this problem to large extent. Our proposed modification is based on a single-vertex approach that replaces commonly used brain parcellations. We further provide a summary of this model evaluation by characterizing empirical properties of where prediction for this task appears possible, explaining why some predictions largely fail for certain targets. Finally, with these empirical observations we investigate whether individual prediction scores explain individual behavioral differences in a task.

neuroscience↗

Timing the SARS-CoV-2 Index Case in Hubei Province

Understanding when SARS-CoV-2 emerged is critical to evaluating our current approach to monitoring novel zoonotic pathogens and understanding the failure of early containment and mitigation efforts for COVID-19. We employed a coalescent framework to combine retrospective molecular clock inference with forward epidemiological simulations to determine how long SARS-CoV-2 could have circulated prior to the time of the most recent common ancestor. Our results define the period between mid-October and mid-November 2019 as the plausible interval when the first case of SARS-CoV-2 emerged in Hubei province. By characterizing the likely dynamics of the virus before it was discovered, we show that over two-thirds of SARS-CoV-2-like zoonotic events would be self-limited, dying out without igniting a pandemic. Our findings highlight the shortcomings of zoonosis surveillance approaches for detecting highly contagious pathogens with moderate mortality rates.

evolutionary biology↗

The prophase oocyte nucleus is a homeostatic G-actin buffer

Formation of healthy mammalian eggs from oocytes requires specialised F-actin structures. F-actin disruption produces aneuploid eggs, which are a leading cause of human embryo deaths, genetic disorders, and infertility. We found that oocytes regulate F-actin organisation and function by promptly transferring excess monomeric G-actin from the cytoplasm to the nucleus. Inside healthy oocyte nuclei, transferred monomers form dynamic F-actin structures, a conserved feature that significantly declines with maternal age. Monomer transfer must be controlled tightly. Blocked nuclear import of G-actin triggers assembly of a dense cytoplasmic F-actin network, while excess G-actin in the nucleus dramatically stabilises nuclear F-actin. Imbalances in either direction predispose oocytes to aneuploidy. The large oocyte nucleus is thus a homeostatic G-actin buffer that is used to maintain cytoplasmic F-actin form and function. One Sentence SummaryMammalian oocyte nuclei buffer cytosolic G-actin

cell biology↗

Single-vessel cerebral blood flow fMRI to map blood velocity by phase-contrast imaging

Current approaches to high-field fMRI provide two means to map hemodynamics at the level of single vessels in the brain. One is through changes in deoxyhemoglobin in venules, i.e., blood oxygenation level-dependent (BOLD) fMRI, while the second is through changes in arteriole diameter, i.e., cerebral blood volume (CBV) fMRI. Here we introduce cerebral blood flow (CBF)-fMRI, which uses high-resolution phase-contrast MRI to form velocity measurements of flow and demonstrate CBF-fMRI in single penetrating microvessels across rat parietal cortex. In contrast to the venule-dominated BOLD and arteriole-dominated CBV fMRI signal, the phase-contrast -based CBF signal changes are highly comparable from both arterioles and venules. Thus, we have developed a single-vessel fMRI platform to map the BOLD, CBV, and CBF from penetrating microvessels throughout the cortex. This high-resolution single-vessel fMRI mapping scheme not only enables the vessel-specific hemodynamic mapping in diseased animal models but also presents a translational potential to map vascular dementia in diseased or injured human brains with ultra-high field fMRI. SummaryWe established a high-resolution PC-based single-vessel velocity mapping method using the high field MRI. This PC-based micro-vessel velocity measurement enables the development of the single-vessel CBF-fMRI method. In particular, in contrast to the arteriole-dominated CBV and venule-dominated BOLD responses, the CBF-fMRI shows similar velocity changes in penetrating arterioles and venules in activated brain regions. Thus, we have built a noninvasive single-vessel fMRI mapping scheme for BOLD, CBV, and CBF hemodynamic parameter measurements in animals.

neuroscience↗

Depth relationships and measures of tissue thickness in dorsal midbrain

Dorsal human midbrain contains two nuclei with clear laminar organization, the superior and inferior colliculi. These nuclei extend in depth between the superficial dorsal surface of midbrain and a deep midbrain nucleus, the periaqueductal gray matter (PAG). The PAG, in turn, surrounds the cerebral aqueduct (CA). This study examined the use of two depth metrics to characterize depth and thickness relationships within dorsal midbrain using the superficial surface of midbrain and CA as references. The first utilized nearest-neighbor Euclidean distance from one reference surface, while the second used a level-set approach that combines signed distance from both reference surfaces. Both depth methods provided similar functional depth profiles generated by saccadic eye movements in a functional MRI task, confirming their efficacy for superficial functional activity. Next, the boundaries of the PAG were estimated using Euclidean distance together with elliptical fitting, indicating that the PAG can be readily characterized by a smooth surface surrounding PAG. Finally, we used the level-set approach to measure tissue depth between the superficial surface and the PAG, thus characterizing the variable thickness of the colliculi. Overall, this study demonstrates depth-mapping schemes for human midbrain that enables accurate segmentation of the PAG and consistent depth and thickness estimates of the superior and inferior colliculi.

neuroscience↗

ExpansionHunter: A sequence-graph based tool to analyze variation in short tandem repeat regions

We describe a novel computational method for genotyping repeats using sequence graphs. This method addresses the long-standing need to accurately genotype medically important loci containing repeats adjacent to other variants or imperfect DNA repeats such as polyalanine repeats. Here we introduce a new version of our repeat genotyping software, ExpansionHunter, that uses this method to perform targeted genotyping of a broad class of such loci.\n\nAvailability and implementationExpansionHunter is implemented in C++ and is available under the Apache License Version 2.0. The source code, documentation, and Linux/macOS binaries are available at https://github.com/Illumina/ExpansionHunter/.\n\nContactmeberle@illumina.com

bioinformatics↗