Biology subjects

Madsen, J.

Publications and source records attributed to Madsen, J..

At least 19 recordsLinked to original sources

bioRxiv2026

During natural vision, semantic novelty modulates fixation-related processing in primate cortex

We sample visual scenes with short gaze fixations separated by saccades. While low-level integration is known, semantic integration of foveal vision across fixations remains unclear. We hypothesized that the brain responds to changes in semantic information from one fixation to the next, and therefore postulated a neural signal associated with semantic novelty for each saccade. Novelty was measured from different layers of a deep network on foveal vision. Only semantic, and not low- or mid-level, novelty modulated frontal and occipital fixation-related potentials in male and female human scalp EEG during natural viewing of full-length movies (3.4x106 saccades). Intracranial recordings in male and female humans (9.0x104 saccades) and female non-human primates (Macaca mulatta; 3.3x104 saccades) revealed broadband high-frequency activity modulations in scene-specific ventral visual and frontal brain areas only for semantic novelty. This modulation was stronger for movies than static images, and frontal modulation occurred early alongside occipital modulation, suggesting top-down effects. This modulation of fixation-related activity with novelty suggests that foveal representations are integrated across fixations to construct scene representations during natural viewing in primates.

neuroscience↗

bioRxiv2026

What drives intersubject correlation of EEG during auditory narratives?

When participants are engaged with auditory narratives, physiological and neural signals exhibit temporal correlations between subjects. The intersubject correlation (ISC) increases when attention is directed to the stories, suggesting that shared neural and bodily dynamics arise from a similar processing of the narratives. Identifying the factors that drive these common responses is clinically relevant for interpreting EEG ISC exhibited in unresponsive patients. In this study, we investigated whether the ISC of the EEG elicited by auditory narratives is driven by low-level acoustic (envelope, spectrogram) and/or higher-level linguistic information (word onset, word surprisal) in two groups of healthy participants during passive, attentive and distracted listening. We use temporal response functions (TRFs) for acoustic, and linguistic features to assess the contribution of each feature to the ISC, measured using correlated component analysis (CorrCA). TRFs derived for acoustic features explained a larger fraction of variance in the EEG than linguistic features and were the main contributors to the ISC. The attention-related increase in ISC was driven by all features. Importantly, word surprisal had an effect on ISC only during active story engagement, with timing and scalp distribution consistent with language processing. Notably, the linear responses captured by TRFs only explained a small amount of the overall ISC, suggesting that ISC is largely driven by nonlinear responses to the narratives. We propose that the combined use of ISC and TRFs has the potential to provide meaningful markers of language processing in patients with disorders of consciousness, and we suggest practical recommendations for their implementation.

neuroscience↗

bioRxiv2026

Benchmarking computational decontamination of ambient RNA

Gene expression profiling of single cells using single-cell and single-nucleus RNA sequencing (sxRNA-seq) enables researchers to characterize cellular heterogeneity and unraveling complex biological processes at unprecedented resolution. However, sxRNA-seq faces challenges due to the presence of ambient RNA, extraneous RNA molecules not originating from the cells of interest. Sample preparation is a major source of ambient RNA, where harsh conditions can lead to cell lysis and the release of intracellular RNA. This inescapable inclusion of ambient RNA can cause erroneous results and hinder downstream analyses. To address this issue, various methodologies have been developed to identify, quantify, and remove ambient RNA. Here, we rigorously evaluate 7 state-of-the-art methodologies for ambient RNA removal using simulated datasets, species-mixing experiments of varying complexities, and genotype-mixing experiments. We find that no single method performs the best across all datasets and metrics, but CellBender, DecontX and SoupX generally perform well.

bioinformatics↗

bioRxiv2025

Brain-body dynamics is asymmetric and stable across cognitive states

The human body displays slow, spontaneous fluctuations in brain activity, autonomic physiology, and small incidental movements. It is unknown whether these co-fluctuations reflect a stable endogenous brain-body dynamic, or whether this dynamic varies with cognitive state. We addressed this question using a dynamical systems approach to analyze simultaneously recorded neural activity (EEG), autonomic physiology, and behavior while participants listened to spoken narratives or were at rest. We found that cognitive state did not substantially alter the endogenous dynamic. Acoustic and linguistic features predicted neural activity, which in turn affected physiological responses. Only low-level sound fluctuations exerted direct effects on autonomic signals. Peripheral physiology and behavior exerted stronger influences on EEG than the reverse. These findings suggest that slow co-fluctuations are the result of a stablebrain-body dynamic with strong bottom-up feedback, and that the narrative entrains this dynamic by engaging cognition.

neuroscience↗

bioRxiv2025

Overlap and Differences of Autism and ADHD: Digital Phenotyping of Movement and Communication During Development

Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) frequently co-occur with overlapping traits. We investigated whether automated behavioral analysis during a clinician-child interview can identify distinct, objective features of the two conditions. Analyzing audio-video recordings of 2,529 youths (ages 5-22) in a broad community sample, multivariate models revealed that language difficulties often attributed to ADHD are primarily explained by age, cognitive ability, or co-occurring ASD. Increased motor activity specifically marked hyperactive-impulsive ADHD, but not ASD or inattentive ADHD. ASD was uniquely characterized by divergent narrative production and idiosyncratic responses, alongside a distinct vocal profile of higher pitch and dysphonia, despite structurally intact language. While these digital behavioral measures correlate with most diagnostic categories and age, the joint analysis effectively separates the effects of ASD from ADHD. These findings show that scalable digital assessment from recorded clinical interviews can disentangle overlapping ASD and ADHD diagnoses into domain-specific behavioral signatures.

bioengineering↗

bioRxiv2025

Disentangling covariate effects on single cell-resolved epigenomes with DeepDive

Understanding the effects of individual biological factors from single cell-resolved epigenomic data is hindered by multicollinearity, particularly in human cohorts. We introduce DeepDive, a novel deep learning framework designed to systematically disentangle known and unknown sources of variation in single-nucleus ATAC-seq data. DeepDive accurately reconstructs chromatin accessibility, outperforms state-of-the-art methods with incomplete covariate information, and robustly recovers true biological signals from even highly entangled covariates, unlocking counter-factual, what-if, analyses. Applying DeepDive to pancreatic islet cells, we perform counter-factual analyses to prioritize covariates associated with a type 2 diabetes-linked beta cell subtype and nominate transcription regulators. DeepDive offers a powerful and unbiased tool for mechanistic discovery in complex human disease cohorts.

bioinformatics↗

bioRxiv2025

Crystal structures of human SP-D complexed with synthetic oligosaccharides suggest a role for phosphorylated inner core LPS saccharides in host-pathogen interactions

The innate immune protein human surfactant protein D (SP-D) recognises pathogens in the lungs via binding to carbohydrate surface structures. SP-D has been shown to target gram-negative bacterial lipopolysaccharide via calcium-dependent binding, preferentially to the inner core heptose (HepI). To further investigate this recognition, we have determined the high-resolution crystal structures of a trimeric recombinant fragment of human SP-D complexed with synthetic di- and trisaccharides, HepI-Kdo, HepIII-HepII-HepI, and HepII-HepI phosphorylated at either HepI or HepII, inner core motifs common to the lipopolysaccharide of many gram-negative bacteria. In contrast to acid-hydrolysed lipopolysaccharide used in several previous studies, these synthetic saccharides allow presentation of both the innermost Kdo in its natural pyranose form and heptose phosphorylation. The structures confirm the flexibility of SP-D to adopt an alternative binding mode when the preferred epitope is not available, reveal a preference for recognition of the reducing terminal heptose (HepI) via the glyceryl group, indicate that a single Kdo attached to HepI does not have a significant role in ligand recognition, and provide evidence that recognition of phosphorylated inner core diheptosyl ligands varies dependent on whether HepI or HepII is phosphorylated. The disaccharide with HepII O4 phosphorylation binds via the preferred HepI glyceryl-hydroxyls, while HepI O4 phosphorylation reveals HepII binding via the pyranose ring O3 and O4 hydroxyls. The ability of the HepII O4 phosphate to prevent preferred HepI recognition suggests a role for heptose phosphorylation in shielding the bacterial LPS inner core from immune recognition.

immunology↗

bioRxiv2025

State and trait measures of attention predict performance in video-based learning

Poor academic performance is often linked to attention deficits, but it remains unclear whether these reflect enduring traits or momentary lapses in focus. In this study, we examined how state and trait-level attention relate to learning from short educational videos. Across four experiments (N = 152), participants completed standardized assessments of inattention, hyperactivity, working memory capacity, and GPA. They then viewed 3-6-minute educational videos while electroencephalography (EEG) tracked neural responses, followed by quizzes assessing short-term retention. Neural synchrony during video viewing, a measure of attentional state, strongly predicted test performance (p < 0.001). In contrast, trait inattention did not predict retention (p > 0.05), although it was negatively associated with GPA. Attentional state was positively associated with working memory capacity but not with trait inattention. These findings suggest that students with attentional difficulties can still learn effectively from short, engaging content, emphasizing the importance of instructional format in supporting diverse learners.

neuroscience↗

bioRxiv2025

The Brain, Body, and Behavior Dataset (BBBD): Multimodal Recordings during Educational Videos

When humans engage with video, their brain and body interact in response to sensory input. To investigate these interactions, we recorded and are releasing a dataset from N=178 participants across five experiments featuring short online educational videos. This dataset comprises approximately 110 hours of multimodal data including electrocardiogram (ECG), heart rate, respiration, breathing rate, pupil size, electrooculogram (EOG), gaze position, saccades, blinks, fixations, head movement, and electroencephalogram (EEG). Participants viewed 3-6 videos (mean total duration: 28{+/-}5 min) to test attentional states (attentive vs. distracted), memory retention (multiple-choice questions), learning scenarios (incidental vs. intentional), and an intervention (monetary incentive). Demographic data, ADHD self-report (ASRS), and working memory assessments (digit span) were collected. Basic statistics and noteworthy effects: increased alpha power in a distracted condition, broadband EEG power increases from posterior to anterior scalp, increased blink-rate, and decreased saccade-rate in distracted and intervention conditions. All modalities are time-aligned with stimuli and standardized using BIDS, making the dataset valuable for researchers investigating attention, memory, and learning in naturalistic settings.

neuroscience↗

bioRxiv2024

Optimizing Coarse-Grained Models for Large-Scale Membrane Protein Simulation

Coarse-grained (CG) models have been developed for studying membrane proteins at physiologically relevant scales. Such methods, including popular CG lipid models, exhibit stability and efficiency at moderate scales, but they can become impractical or even unusable beyond a critical size due to various technical issues. Here, we report that these scale-dependent issues can arise from progressively slower relaxation dynamics and become confounded by unforeseen instabilities observed only at larger scales. To address these issues, we systemically optimized a 4-site solvent-free CG lipid model that is suitable for conducting micron-scale molecular dynamics simulations of membrane proteins under various membrane properties. We applied this lipid model to explore the long-range membrane deformation induced by a large mechanosensitive ion channel, PIEZO. We show that the optimized CG models are powerful in elucidating the structural and dynamic interplay between PIEZO and the membrane. Furthermore, we anticipate that our methodological insights can prove useful for resolving issues stemming from scale-dependent limitations of similar CG methodologies.

biophysics↗

bioRxiv2023

Literate programming for iterative design-build-test-learn cycles in bioengineering

Synthetic biology dictates the data-driven engineering of biocatalysis, cellular functions, and organism behavior. Integral to synthetic biology is the aspiration to efficiently find, access, interoperate, and reuse high-quality data on genotype-phenotype relationships of native and engineered biosystems under FAIR principles, and from this facilitate forward-engineering strategies. However, biology is complex at the regulatory level, and noisy at the operational level, thus necessitating systematic and diligent data handling at all levels of the design, build, and test phases in order to maximize learning in the iterative design-build-test-learn engineering cycle. To enable user-friendly simulation, organization, and guidance for the engineering of complex biosystems, we have developed an open-source python-based computer-aided design and analysis platform operating under a literate programming user-interface hosted on Github. The platform is called teemi and is fully compliant with FAIR principles. In this study we apply teemi for i) designing and simulating bioengineering, ii) integrating and analyzing multivariate datasets, and iii) machine-learning for predictive engineering of a metabolic pathway designs for production of a key precursor to medicinal alkaloids. The teemi platform is publicly available at PyPi and GitHub.

bioinformatics↗

bioRxiv2023

Brain-body interaction during natural story listening

It is often said that the body and the mind are connected. Yet, direct evidence of a bidirectional link is elusive. We hypothesized a top-down effect of cognition on arousal, and predicted that auditory narratives will drive not only brain signals but also peripheral physiological signals. We find that auditory narratives entrained gaze variation, saccade initiation, pupil size, and heart rate. This is consistent with a top-down effect of cognition on autonomic function. We also hypothesized a bottom-up effect, whereby autonomic physiology affects arousal. Controlled breathing affected pupil size, and heart rate was entrained by controlled saccades. Additionally, fluctuations in heart rate preceded fluctuations of pupil size and brain signals. Gaze variation, pupil size and heart rate were all associated with anterior-central brain signals. Together this suggests bidirectional causal effects between peripheral autonomic function and central brain circuits involved in the control of arousal. HighlightsO_LIListening to narratives modulates eye movements. C_LIO_LIHeart rate fluctuations precede fluctuations in pupil size and anterior-central neural activity. C_LIO_LIBreathing modulates pupil size suggesting causal effect on central arousal. C_LIO_LIRhythmic saccades can entrain heart beats. C_LI eTOCWhen we listen to a story our body is integrally involved in the experience. We provide evidence for a bidirectional and causal link between body and mind by analyzing brain signals, pupil size, heart rate and eye movements, while subjects listen to narratives and during interventions that control autonomic signals.

neuroscience↗

bioRxiv2022

Kinetic models for PET displacement studies

The traditional design of PET target engagement studies is based on a baseline scan and one or more scans after drug administration. We here evaluate an alternative design in which the drug is administered during an on-going scan (i.e., a displacement study). This approach results both in lower radiation exposure and lower costs. Existing kinetic models assume steady state. This condition is not present during a drug displacement and consequently, our aim here was to develop kinetic models for analysing PET displacement data. We modified existing compartment models to accommodate a time-variant increase in occupancy following the pharmacological in-scan intervention. Since this implies the use of differential equations that cannot be solved analytically, we developed instead one approximate and one numerical solution. Through simulations, we show that if the occupancy is relatively high, it can be estimated without bias and with good accuracy. The models were applied to PET data from six pigs where [11C]UCB-J was displaced by intravenous brivaracetam. The dose-occupancy relationship estimated from these scans showed good agreement with occupancies calculated with Lassen plot applied to baseline-block scans of two pigs. In summary, the proposed models provide a framework to determine target occupancy from a single displacement scan.

neuroscience↗

bioRxiv2022

Naturalistic viewing: An open-access dataset using simultaneous EEG-fMRI

In this work, we present a dataset that combines functional magnetic imaging (fMRI) and electroencephalography (EEG) to use as a resource for understanding human brain function in these two imaging modalities. The dataset can also be used for optimizing preprocessing methods for simultaneously collected imaging data. The dataset includes simultaneously collected recordings from 22 individuals (ages: 23-51) across various visual and naturalistic stimuli. In addition, physiological, eye tracking, electrocardiography, and cognitive and behavioral data were collected along with this neuroimaging data. Visual tasks include a flickering checkerboard collected outside and inside the MRI scanner (EEG-only) and simultaneous EEG-fMRI recordings. Simultaneous recordings include rest, the visual paradigm Inscapes, and several short video movies representing naturalistic stimuli. Raw and preprocessed data are openly available to download. We present this dataset as part of an effort to provide open-access data to increase the opportunity for discoveries and understanding of the human brain and evaluate the correlation between electrical brain activity and blood oxygen level-dependent (BOLD) signals.

neuroscience↗

bioRxiv2022

Ketones facilitate transcriptional resolution of secondary DNA structures in premature aging

There is currently no established intervention for Cockayne syndrome, a disease characterized by progressive early onset neurodegeneration with features of premature aging. Here, we tested if acetyl-CoA precursors, citrate and beta-hydroxybutyrate, could reduce features of Cockayne syndrome in three model systems. We identified the gene Helicase 89B as a homologue of CSB in drosophila and found that the ketone beta-hydroxybutyrate rescued features of premature aging in Hel89B deficient flies. In mammals, loss of the citrate carrier Indy exacerbated the phenotype of Csbm/m mice which was rescued by a ketogenic diet. The rescue effect appeared to be mediated through ketone stimulated histone acetylation and facilitation of transcriptional readthrough of secondary DNA structures. These findings link a ketogenic diet with transcriptional resolution of secondary structures and DNA repair.

physiology↗

bioRxiv2021

Similar cognitive processing synchronizes brains, hearts, and eyes

Neural, physiological and behavioral signals synchronize between human subjects in a variety of settings. Multiple hypotheses have been proposed to explain this interpersonal synchrony, but there is no clarity under which conditions it arises, for which signals, or whether there is a common underlying mechanism. We hypothesized that similar cognitive processing of a shared stimulus is the source of synchrony between subjects, measured here as inter-subject correlation. To test this we presented informative videos to participants in an attentive and distracted condition and subsequently measured information recall. Inter-subject correlation was observed for electro-encephalography, gaze position, pupil size and heart rate, but not respiration and head movements. The strength of correlation was co-modulated in the different signals, changed with attentional state, and predicted subsequent recall of information presented in the videos. There was robust within-subject coupling between brain, heart and eyes, but not respiration or head movements. The results suggest that inter-subject correlation is the result of similar cognitive processing and thus emerges only for those signals that exhibit a robust brain-body connection. While physiological and behavioral fluctuations may be driven by multiple features of the stimulus, correlation with other individuals is co-modulated by the level of attentional engagement with the stimulus.

neuroscience↗

bioRxiv2021

The timescale and magnitude of aperiodic activity decreases with cortical depth in humans, macaques and mice

Cortical dynamics obey a 1/f power law, exhibiting an exponential decay of spectral power with increasing frequency. The slope and offset of this 1/f decay reflect the timescale and magnitude of aperiodic neural activity, respectively. These properties are tightly linked to cellular and circuit mechanisms (e.g. excitation:inhibition balance and firing rates) as well as cognitive processes (e.g. perception, memory, and state). However, the physiology underlying the 1/f power law in cortical dynamics is not well understood. Here, we compared laminar recordings from human, macaque and mouse cortex to evaluate how 1/f aperiodic dynamics vary across cortical layers and species. We report that 1/f slope is steepest in superficial layers and flattest in deep layers in each species. Additionally, the magnitude of this 1/f decay is greatest in superficial cortex and decreases with depth. We could account for both of these findings with a simple model in which superficial cortical transmembrane currents had longer time constants and greater densities than those in deeper layers. Together, our results provide novel insight into the organization of cortical dynamics, suggesting that the amplitude and time constant of local currents control circuit processing as a function of laminar depth. This may represent a general mechanism to facilitate appropriate integration of fast sensory inputs (infragranular) with slow feedback-type inputs (supragranular) across cortical areas and species.

neuroscience↗

bioRxiv2020

Mass spectrometry imaging of phosphatidylcholine metabolism in lungs administered with therapeutic surfactants and isotopic tracers

Mass spectrometry imaging (MSI) visualises molecular distributions throughout tissues but is blind to dynamic metabolic processes. Here, MSI with high mass resolution together with multiple stable isotope labelling provided spatial analyses of phosphatidylcholine (PC) metabolism in mouse lungs. Dysregulated surfactant metabolism is central to many respiratory diseases. Metabolism and turnover of therapeutic pulmonary surfactants were imaged from distributions of intact and metabolic products of an added tracer, universally 13C-labelled dipalmitoyl PC (U[13C]DPPC). The parenchymal distributions of newly synthesised PC species were also imaged from incorporations of methyl-D9-choline. This dual labelling strategy demonstrated both lack of inhibition of endogenous PC synthesis by exogenous surfactant and location of acyl chain remodelling processes acting on the U[13C]DPPC-labelled surfactant, leading to formation of polyunsaturated PC lipids. This ability to visualise discrete metabolic events will greatly enhance our understanding of lipid metabolism in diverse tissues, and has potential application to both clinical and experimental studies.

biochemistry↗