Biology subjects

Seth, A.

Publications and source records attributed to Seth, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Loss of Farnesoid X Receptor Signaling Promotes Choroidal Neovascularization in Mice

Choroidal neovascularization (CNV) is a defining feature of neovascular age-related macular degeneration (nAMD). Although anti-vascular endothelial growth factor (VEGF) therapies suppress neovascular activity, incomplete responses, recurrent leakage, and subretinal fibrosis remain important clinical challenges. The farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor with anti-inflammatory, anti-fibrotic, and anti-angiogenic functions in other tissues, but its role in CNV is unknown. Analysis of publicly available human transcriptomic data (GSE135092) showed FXR expression in the retinal pigment epithelium (RPE)/choroid and significant downregulation in AMD-affected macular RPE/choroid. To define the role of FXR in CNV, laser photocoagulation was performed in wild-type (WT) and FXR-deficient (FXR-KO) mice, with disease progression assessed by in vivo imaging, histology, ex vivo choroidal sprouting, and endothelial cell assays. FXR expression in the RPE/choroid was reduced 14 days after laser injury. Compared with WT mice, FXR-KO mice developed larger CNV lesions, more extensive hyperfluorescence on fluorescein angiography, and increased lesion area during disease progression. FXR deficiency also impaired resolution of fibrotic remodeling. In WT mice, alpha-SMA peaked at day 14 and declined by day 21, whereas collagen I remained low throughout; in FXR-KO mice, both collagen I and alpha-SMA were significantly elevated relative to WT and remained significantly higher than WT at day 21. Consistent with these findings, FXR-deficient choroidal explants exhibited increased vascular sprouting, and FXR-KO endothelial cells formed more extensive capillary-like networks. Together, these findings identify FXR as an endogenous regulator of pathological angiogenesis, vascular leakage, mesenchymal activation, and fibrotic remodeling during CNV and provide a rationale for investigating FXR-directed strategies for nAMD.

biochemistry↗

bioRxiv2026

Defining Quality Control Standards for Single-Cell Proteomics by Inter-Laboratory Benchmarking

Single-cell proteomics can quantify thousands of proteins from individual mammalian cells, yet the absence of community-wide quality control limits biological interpretability. Here, the HUPO Single Cell Initiative presents the first inter-laboratory single-cell proteomics benchmarking study across seven laboratories using standardized 384-well plates acquired on Orbitrap Astral and timsTOF Ultra2 instruments. Centralized analysis across six DIA software tools revealed that software choice impacts identification depth and quantitative accuracy more than instrument vendor. Multi-layered quality control enabled the detection of cell-leakage during sorting, LC misconfiguration, column degradation and site-specific pipetting failures. Inter-lab quantitative correlations were strongest between instruments of the same vendor relative to cross-platform comparisons. Sequential correction for plate identity and well position recovered clean cell-type separation for confident downstream differential expression analysis. This study provides a data-driven quality control framework spanning plate design to batch correction for reproducible single-cell proteomics across laboratories and platforms.

biochemistry↗

bioRxiv2026

Co-contraction index improves estimates of knee joint contact forces: A musculoskeletal modelling study

Healthy individuals are hypothesized to adopt muscle coordination strategies that minimize energy expenditure. However, under pathological conditions, these patterns often change, as patients adopt alternative strategies to enhance stability. In musculoskeletal modeling, such changes in muscle coordination are often not accounted for when estimating internal quantities such as knee joint contact forces. To address this, we adapted the objective function of a muscle redundancy solver to inform muscle activations from electromyography measurements, minimizing errors in both muscle activations and co-contraction levels. The resulting estimates of knee joint contact force were compared with in vivo measurements across three activities. The co-contraction index-informed approach achieved the lowest root-mean-square-error of 0.31 body weight, averaged across all subjects and activities, improving the results of the minimum activation solver by 7% body weight. Notably, root-mean-squared-error increased with the level of co-contraction with the minimum activation approach ({beta} = 1.55, 95% confidence interval [0.79, 2.30]), whereas the co-contraction index-informed approach remained less sensitive ({beta} = 0.78, 95% confidence interval [0.14, 1.43]). These findings suggest that objective functions based on minimum muscle activation may be insufficient to accurately estimate knee joint forces in individuals with altered muscle coordination. Incorporating co-contraction information is therefore essential to capture subject-specific adaptations.

bioengineering↗

bioRxiv2026

UP-REGULATION OF SYNAPTOBREVIN-2 TO DELAY AGE-RELATED COGNITIVE IMPAIRMENT

The slowing of executive function and memory impairment are the leading hallmarks of cognitive decline with age. The exact cause of this change is unknown and is the focus of aging research. Expression levels of Vesicle Associated Membrane Protein 2 (VAMP2)/Synaptobrevin-2 (syb2) are decreased with age. Here we report results from a novel transgenic mouse model (TgV2) that overexpresses syb2. We hypothesized that overexpression of syb2 improves synaptic function during aging, thus it delays dementia. Aged TgV2 mice, which maintained syb2 levels, performed better in spatial memory tests than 2-year-old WT control mice, which had lost half of syb2 due aging. In hippocampal CA1 synapses of aged TgV2 mice, long-term potentiation was increased. These effects of maintained syb2 levels were beneficial for both males and females providing improved synaptic plasticity. These results indicate that overexpression of syb2 supports cognitive function throughout the aging process and better resist age-related synaptic dysfunction.

neuroscience↗

bioRxiv2026

MSK-Morph: An automated framework to systematically morph landmark-defined musculoskeletal models into subject-specific bone geometries

Musculoskeletal models are widely used to study human movement, investigate musculoskeletal disorders and evaluate athletic performance. The accuracy of these models depends primarily on representing subject-specific musculoskeletal geometry, which determines joint definitions and muscle paths. Subject-specific models can be derived from medical imaging, however the task remains labour-intensive with numerous subjective decisions, which limits their reproducibility and use in large-scale studies. Automated methods that preserve anatomical model topology while adapting models to individual bone geometries are therefore needed. Here, we develop and demonstrate a landmark-based morphing framework, MSK-Morph, to systematically transform template musculoskeletal models into subject-specific models based on bone geometry derived from medical imaging. MSK-Morph introduces an anatomical landmark-defined musculoskeletal model that embeds segment and joint definitions, and muscle paths, and uses them to systematically and reproducibly morph the model to target bone geometries. MSK-Morph automatically updates the joint definitions and muscle paths to reflect inter-individual skeletal variation while maintaining the structural topology of the original model. MSK-Morph produces landmark-defined musculoskeletal models that remain compatible with existing simulation workflows. By enabling rapid generation of models with subject-specific skeletal geometry, this framework facilitates large-scale musculoskeletal modelling and the development of more diverse generic model libraries.

bioengineering↗

bioRxiv2026

RNA exosome-mediated RNA surveillance governs developmental timing in the human cerebellum

Defects in RNA metabolism are a defining feature of neurodevelopmental disease, yet how RNA decay pathways contribute to human brain development remains poorly understood. Mutations in ubiquitously expressed RNA surveillance factors often cause highly tissue-selective disease, highlighting a central paradox in human biology. The RNA exosome is a conserved ribonuclease complex traditionally viewed as a housekeeping machine for RNA turnover, yet recessive mutations in genes encoding structural subunits of the complex disproportionately cause neurological disease, suggesting an instructive role in nervous system development. Here, we show that the RNA exosome regulates the temporal progression of gene expression programs during human cerebellar differentiation. Using CRISPR-engineered human cerebellar organoids modeling EXOSC3 variants, we find that RNA exosome dysfunction does not broadly alter transcript abundance, but instead disrupts transitions between developmental states. Mutant organoids exhibit incomplete and mis-timed resolution of early transcriptional programs, altered lineage specificity, and impaired coordination of maturation-associated gene expression programs, with pronounced effects in neuronal lineages, particularly Purkinje cells and rhombic lip-derivatives. These defects are accompanied by disorganized laminar architecture and reduced coordination of neuronal activity, despite preserved intrinsic excitability. Together, our findings establish RNA surveillance as a key regulator of developmental timing, lineage fidelity, and neurodevelopmental disease.

molecular biology↗

bioRxiv2026

Liver Disease Reveals KIF12 as a Critical Regulator of Mitochondria, Lysosome and Cilia Localization

Pathogenic variants in kinesin family member 12 (KIF12) cause pediatric liver disease, yet the cellular mechanisms underlying this phenotype remain unknown. Here we show that KIF12 expression in the healthy human liver is primarily detected in biliary epithelial cells, as revealed by single cell RNA-sequencing data. To investigate its role in biliary pathology, we introduced a homozygous KIF12 p.Arg219* mutation into induced pluripotent stem cells (iPSCs), which were differentiated into 2D cholangiocyte-like cells (iCCs) and 3D biliary organoids. Pioneering single-molecule fluorescence microscopy in live iCCs, we observed wildtype KIF12 co-localizing with microtubules, consistent with its predicted role as a microtubule-associated motor protein. Our data reveals that KIF12 dysfunction causes abnormal perinuclear clustering of mitochondria and lysosomes, and mislocalization of primary cilia in cholangiocytes. Restoration of wildtype KIF12 expression in mutant KIF12 iCCs rescued organelle positioning and normalized GGT activity. This study uncovers a novel link between KIF12 dysfunction and organelle dynamics in human cholangiocytes, extending our understanding of kinesin roles beyond their established functions in neuronal systems. Our findings provide new insights into the pathogenesis of KIF12-related cholestatic liver disease and lay the groundwork for developing targeted genetic therapies.

genetics↗

bioRxiv2025

Surface-by-temperature interactions shape the relationship between viral free-living survival and reproduction

Environmental factors play a critical role in viral persistence, yet the combined effects of temperature and surface chemistry on viral fitness are not fully understood. We examined bacteriophages T4 and{varphi} X174 across copper, stainless steel, and polypropylene plastic surfaces at 4{degrees}C and 37{degrees}C to assess how these variables influence survival and reproduction. Both phages exhibited marked differences in survival across surfaces: copper at 37{degrees}C caused rapid inactivation, and cooler conditions promoted persistence. Reproductive capacity varied independently of survival, indicating that viral stability and replication are partially decoupled traits shaped by environmental context. Linear modeling and correlation analyses confirmed significant, non-additive interactions between surface type and temperature. These findings suggest that abiotic factors can act synergistically to determine viral fitness outside the host. More broadly, they refine our understanding of the mechanisms that govern the environmental ecology of viruses and the canonical relationship between survival and transmission.

ecology↗

bioRxiv2025

Fine-Tuning of Label-Free Single-Cell Proteomics Workflows

Mass spectrometry-based single-cell proteomics emerges as the most promising method for studying cellular heterogeneity at the global proteome level with unprecedented depth and coverage. Its widespread application remains limited due to robustness, reproducibility, and throughput requirements, still difficult to meet as analyzing large cohorts of single cells is necessary to ensure statistical confidence. In this context, we have conducted method optimizations at three levels. First, we benchmarked three distinct workflows compatible with the nanoElute2 platform using different sample collection/preparation plate supports (EVO96 oil-free, LF48 oil-based and LF48 oil-free, a streamlined automated sample resuspension and direct injection protocol). Then, we compared the optimized EVO96 workflow on nanoElute2 with EVOSEP-based separations operating at two analytical throughputs (80 and 120 samples per day). Subsequently, we evaluated digestion efficiency using a range of enzyme/protein ratios (1:1; 10:1; 20:1; 50:1) to maximize peptide recovery. Finally, the chromatographic setup was refined to determine the best compromise between throughput and robustness. Altogether, these optimizations allowed to establish a robust workflow quantifying up to 5,000 proteins in 10min gradient time per single Hela cell at a 55 samples-per-day throughput.

biochemistry↗

bioRxiv2025

High-throughput Single-Cell Proteomics and Transcriptomics from the Same Cells with a Nanoliter-Scale Spin-Transfer Approach

Single-cell multiomic platforms provide a comprehensive snapshot of cellular states and cell types by offering critical insights into the spatiotemporal regulation of biomolecular networks at a systems level, thereby defining the basis of multicellularity. Here, we introduce nanoSPINS, an advanced platform that enables high-throughput profiling and integrative analysis of the transcriptome and proteome from the same single cells using RNA sequencing and isobaric labeling LC-MS-based proteomics, respectively. NanoSPINS can efficiently transfer mRNA-containing droplets across two microarrays via a centrifugation-based approach, while proteins are retained on the initial platform. Benchmarking of nanoSPINS on two cell lines demonstrates its ability to generate global proteomic and transcriptomic profiles that align well with previously established methodologies/platforms. The incorporation of isobaric TMTpro labeling into this single-cell multiomics platform significantly enhances the throughput of single-cell proteomic analyses. Through the high-throughput quantification of the proteome and transcriptome, nanoSPINS not only facilitates the identification of molecular features at both mRNA and protein level but also provides larger sample sizes for improved statistical power in clustering and differential abundance. Given the broad applicability of single-cell multiomics in biological research and clinical settings, we believe nanoSPINS represents a powerful platform for the characterization of heterogeneous cell populations.

systems biology↗

bioRxiv2025

The energetic cost of human standing balance and gait initiation over a range of natural postures

Humans typically select movements that minimize energetic cost, a principle most clearly observed during locomotion. Whether such optimization of energy expenditure also governs standing balance remains unclear because its energetic cost has not been systematically quantified across a range of natural postures. Moreover, because standing is often the resting state from which most walking begins, the optimization of posture may also reflect the energetic demands of initiating gait. In this study, we use a combination of indirect calorimetry and musculoskeletal simulations to characterize the energetic cost of standing and gait initiation across natural standing postures and investigate whether humans optimize energy expenditure under these conditions. In Experiment 1 (N = 13), we measured metabolic cost at preferred and six different prescribed whole-body orientations. Energy expenditure was lowest at a slight anterior orientation (1.15{degrees}) and increased monotonically with whole-body angle, rising twice as fast posteriorly compared to anteriorly. This asymmetry challenges the common modeling simplification that effort is symmetric and linear or quadratic with lean angle. Furthermore, participants preferred body orientations (1.50 {+/-} 0.73{degrees}) with similar energy expenditure to the minimum-cost orientation but with significantly more postural variability, suggesting that strict postural regulation was not necessary for energy-optimal control. In Experiment 2 (N = 20), participants initiated forward and backward walking from preferred or prescribed lean orientations. Participants did not alter their standing posture before expected gait initiations in the forward or backward direction, consistent with musculoskeletal simulations showing that leaning further in the anticipated direction did not significantly improve gait initiation time or energetic costs. Together, these findings suggest that postural strategies optimize energy efficiency when permitted by the demands of movement readiness. Our study quantifies the energetic cost landscape that governs human postural control, challenges widely used inverted pendulum estimations of this cost, and offers an empirical foundation for developing more accurate simulations of posture and energy expenditure. Author summaryHumans are thought to move in ways that save energy. This idea is well supported for walking, but it is not known whether we do the same during quiet standing. Furthermore, because standing is our idle state from which we initiate movement, we may optimize our posture to ease these transitions. In this study, we investigated whether humans stand in postures that minimize energy expenditure. First, we measured and simulated how the cost of posture changes over a range of natural whole-body orientations and determined that humans tend to choose postures close to the orientation with the lowest cost. Leaning backward incurs an additional energetic cost at twice the rate of forward-leaning postures. Second, we investigated whether expecting to walk in the forward or backward direction affects our preferred posture. Surprisingly, participants did not change their posture in preparation for the known direction of walking. Simulations demonstrated that the energetic benefit of doing so was small. Overall, our findings show that maintaining a slight forward lean results in optimal energy expenditure during standing and gait initiation. However, commonly used assumptions of how energy expenditure varies with lean angle do not match the measured cost distribution and those predicted by musculoskeletal simulation.

neuroscience↗

bioRxiv2025

Bendless-mediated K63 ubiquitination modulates cellular signalling to regulate Drosophila hematopoiesis

Ubiquitination is a reversible modification whose traditional role has been associated with K48-linked poly-ubiquitination involved in proteasomal degradation. However, the role of K63-linked poly-ubiquitination has been explored in various cellular processes like DNA repair, endocytosis, innate immune response, kinase activation, etc. Since K63-linked poly-ubiquitination can regulate the stability, localization, and activity of its target molecules, its regulation and function in various developmental and disease contexts are being explored. Here, we investigate how K63 ubiquitination regulates Drosophila blood cell homeostasis. Ubc13 (UBE2N), an E2 conjugating enzyme, is highly expressed in Acute Myeloid Leukemia (AML), wherein it controls innate immune signalling for the survival of AML cells; however, its role during developmental hematopoiesis is less explored. In Drosophila, Bendless is the functional homolog of Ubc13, whose role in stem cell regulation and particularly hematopoiesis is unknown. Our results indicate that spatial genetic perturbation of Bendless and its associated molecules, namely Uev1a, Effete, and E3 ligase - Traf6, that mediate K63 ubiquitination are critical for maintaining hematopoietic progenitors and regulating their differentiation. We show that Bendless-mediated K63 ubiquitination controls the Wingless signalling pathway by regulating Dishevelled in the larval lymph gland (LG) thereby modulating hematopoietic progenitor maintenance and differentiation. Furthermore, an excess of K63 ubiquitination activates the JNK pathway in the LG, resulting in lamellocyte production. Genetic epistasis analysis shows that activation of the canonical Wingless pathway in the background of Bendless depletion or inactivation of the JNK pathway in Bendless over-expression conditions can restore physiological hematopoiesis. Our findings indicate that regulators of K63 ubiquitination, like Bendless, could act as molecular inter-nodes that are capable of signalling cross-regulation, especially where intricate signalling networks are involved. Our study provides important mechanistic insights into the signalling mechanisms regulated by K63 ubiquitination during stem cell homeostasis.

developmental biology↗

bioRxiv2025

Identification of a novel bicarbonate transporter critical for Leishmania virulence

Leishmania parasites survive and proliferate within the acidic phagolysosomes of host macrophages while maintaining a near-neutral cytosolic pH, a process essential for intracellular survival and virulence. Although our prior work implicated a bicarbonate-based buffering mechanism, the absence of any annotated bicarbonate transporter in the parasite genome has hindered its identification. Using an isotope ratio mass spectrometry-based assay, we first confirmed the presence of a functional bicarbonate transport system in the parasite. Guided by this, a noncanonical homology search identified an uncharacterized protein, hereafter designated LmSLC26A, with similarity to metazoan SLC26 family of multi-anion transporters. LmSLC26A localized to the parasite plasma membrane and, under acidic conditions, was found to associate with the membrane carbonic anhydrase LmCA2. Disruption of a single LmSLC26A allele significantly reduced bicarbonate uptake, leading to intracellular acidification that was reversible upon exogenous bicarbonate supplementation. LmSLC26A-deficient parasites exhibited sluggish growth, increased apoptosis, reduced production of virulence associated cAMP and impaired exosome release. Consequently, these mutant parasites showed diminished survival within host macrophages and markedly attenuated virulence in mice. Intriguingly, LmSLC26A harbours a unique histidine ecto-phosphatase domain, revealing an unprecedented functional coupling between bicarbonate transport and enzymatic activity. Together, these findings establish LmSLC26A as the first identified bicarbonate transporter not only in Leishmania but also across the broader trypanosomatid and protozoan lineages, and define bicarbonate transport as a critical determinant of pH homeostasis and pathogenicity in the parasite. Significance StatementLeishmania parasites proliferate within the acidic phagolysosomes of host macrophages, yet the mechanism by which they maintain intracellular pH homeostasis has remained incompletely understood. Here, we identify LmSLC26A as the first bicarbonate transporter discovered in Leishmania and, more broadly, in protozoan parasites and demonstrate its essential role in bicarbonate uptake and maintenance of cytosolic pH homeostasis. LmSLC26A-deficient parasites exhibited impaired growth, increased apoptosis, reduced virulence-associated cAMP production and exosome release, resulting in compromised intracellular survival and attenuated virulence in mice. Intriguingly, LmSLC26A harbours a unique histidine ecto-phosphatase domain, revealing a previously unrecognized functional coupling between bicarbonate transport and enzymatic activity. Collectively, these findings establish LmSLC26A as a central regulator of parasite physiology and virulence.

cell biology↗

bioRxiv2025

Modeling glenohumeral stability in musculoskeletal simulations: A validation study with in vivo contact forces

Common optimization approaches to solve the muscle redundancy problem in musculoskeletal simulations can predict shoulder contact forces that violate joint stability with lines of action outside the glenohumeral joint border. Approaches with simple joint stability constraints were previously introduced imposing an upper limit on the direction of the contact force to stay within a specified stability perimeter. Such approaches predicted higher rotator cuff muscle activation than without constraints, but the estimated joint contact forces were oriented along the specified perimeter, raising questions about validity. In this study, several glenohumeral stability formulations were investigated, and tested against in vivo measurements of glenohumeral contact forces from the Orthoload dataset on one participant data in three dumbbell tasks: lateral raise, posterior raise, and and anterior raise. The investigated formulations either imposed inequality constraints on the contact force direction to remain within a stability perimeter whose shape was varied, or added a penalty term as a criterion measure to the objective function that made the objective function costly for contact force directions to deviate from the glenoid cavity center. All stability formulations predicted contact force magnitudes that agreed relatively well to the in vivo measured forces except for the strictest formulation that constrained the joint contact force to be directed at the glenoid cavity center. Models that restricted the force direction to lie within a specified shape estimated force vectors that largely lay along the perimeters. Models that instead penalized force directions that deviated from the glenoid cavity center estimated relatively more accurate contact force directions within the glenoid cavity, though still not entirely in agreement with in vivo measurements. Our findings support the proposed penalty formulations as more reasonable and accurate than other investigated existing glenohumeral stability formulations. Author summaryIn musculoskeletal models, the glenohumeral joint is often simplified as a purely rotational joint with no translation, whereas the actual joint movement involves both rotation and some translation, requiring stabilizing forces to prevent dislocation. Models that compute muscle forces based on a minimal effort strategy without specifically addressing glenohumeral stability may underestimate co-activation of the stabilizing rotator cuff muscles, and inaccurately predict that the contact force between the humerus and the glenoid is directed outside the articular surface of the joint. In this study, we compared existing stability models and proposed a new approach that penalized joint contact force whose direction deviates from the glenoid cavity center. We integrated these approaches into a muscle redundancy solver and estimated muscle and joint forces using the thoracoscapular shoulder musculoskeletal model. We compared model estimates to in vivo measurements of joint contact forces. We found that the penalty formulation reproduced the contact force direction most accurately, and promoted greater muscle co-contraction. These findings support the proposed penalty approach as a benchmark for more accurate analysis of shoulder biomechanics using musculoskeletal simulations.

bioengineering↗

bioRxiv2025

Psychedelics Align Brain Activity with Context

Psychedelics can profoundly alter consciousness by reorganising brain connectivity; however, their effects are context-sensitive. To understand how this reorganisation depends on context, we collected and comprehensively analysed the largest psychedelic neuroimaging dataset to date. Sixty-two adults were scanned with functional MRI and EEG during rest and naturalistic stimuli (meditation, music, and movie), before and after ingesting 19 mg of psilocybin (functional MRI {approx}80 min post-dose; EEG {approx}150 min post-dose). Half the participants ranked the experience among the most meaningful of their lives. Under psilocybin, functional MRI and EEG signals recorded during eyes-closed conditions became similar to those recorded during an eyes-open condition. Global functional connectivity increased in associative regions and decreased in sensory areas. Using machine learning to represent neural activity as low-dimensional trajectories, we found that psilocybin reorganised these into structured, context-sensitive patterns of brain activity that reflected both experimental condition and the quality of subjective experience, revealing an organisation that was missed by time-averaged connectivity measures. Under psilocybin, brain networks that ordinarily segregate internal and external processing coherently integrated and aligned neural dynamics with context. This context-alignment manifested as distinct and cohesive neural trajectories in participants reporting positively felt self- and boundary-dissolving effects, corresponding to the felt experience of being part of the environment, which we refer to as embeddedness--the subjective experience of being continuous with, rather than separate from, the surrounding environment. The strength of this context-alignment was associated with next-day mindset change, bridging the neural, experiential, and therapeutic dimensions of the psychedelic state. These findings show that the organisation of brain activity covaries with the experiential coherence of the psychedelic state, and provide a systems-level framework for how context-sensitive brain dynamics link neurobiology to subjective experience and behavioural change.

neuroscience↗

bioRxiv2025

Hemispherotomy: a cortical island of sleep-like activity in awake humans

Hemispherotomy is a neurosurgical procedure for treating refractory epilepsy, which entails disconnecting a significant portion of the cortex, potentially encompassing an entire hemisphere, from its cortical and subcortical connections. While this intervention prevents the spread of seizures, it raises important questions. Given the complete isolation from sensory-motor pathways, it remains unclear whether the disconnected cortex retains any form of inaccessible awareness. More broadly, the activity patterns that large portions of the deafferented cortex can sustain in awake humans remain poorly understood. We address these questions by exploring for the first time the electrophysiological state of the isolated cortex before and after surgery in ten awake pediatric patients. Post-surgery, the isolated cortex exhibited prominent slow oscillations (<2 Hz) and a broad-band shift in power spectral density from high to low frequencies. This resulted in a marked decrease of the spectral exponent, a validated consciousness marker, indicating broad-band slowing characteristic of unconscious states. When compared with a reference pediatric sample across the sleep-wake cycle, the spectral exponent of the contralateral cortex aligned with wakefulness, whereas that of the isolated cortex was consistent with deep NREM sleep. However, spindles did not emerge in the isolated cortex due to the lack of subcortical inputs, constituting a fundamental difference from physiological sleep. These findings demonstrate a unihemispheric sleep-like state during wakefulness, challenging the possibility that hemispherotomy might lead to inaccessible "islands of awareness." Moreover, the persistence of sleep-like patterns years after disconnection provides unique insights into the electrophysiological effects of disconnections in the human brain.

neuroscience↗

bioRxiv2024

Investigating the role of sensorimotor spatial dependencies in shaping conscious access to virtual 3D objects

According to sensorimotor accounts of perceptual experience, the subjective veridicality of an object (the sense of its presence) builds up gradually as one learns how changes in sensory inputs depend on bodily movements. To investigate how sensorimotor interactions shape visual experience, we designed a virtual-reality-based study that allowed us to manipulate the complexity of spatial dependencies governing interactions with unfamiliar 3D objects. Participants had to learn to manually control fully visible objects that could move in congruent, opposite, novel (orthogonal), or random directions in response to their movements. The sensorimotor control tasks occurred alternately with a continuous flash suppression (CFS) task evaluating the access of stationary objects to visual awareness, operationalised as the time taken for a 3D object to break the interocular suppression. We hypothesised that objects whose motion was experienced as depending on actions in a lawful, and thus encodable, manner (i.e., according to a congruent, opposite, or novel - but not random - dependency) would overcome suppression faster than objects moving randomly in response to actions (for which there is no world-related statistical structure to learn). However, while performance in the sensorimotor tasks consistently decreased along with the difficulty of the conditions (i.e., congruent > opposite > novel > random), the pre-registered analysis yielded no significant differences in breakthrough times of objects manipulated under different coupling rules. An exploratory analysis assessing whether the acquisition of sensorimotor mastery was associated with reduced breakthrough times also revealed no significant effects. Thus, our results suggest that ones knowledge of how an object responds to action does not play a salient role in determining conscious access to visual stimuli. This extends previous evidence for a general ineffectiveness of sensorimotor spatial manipulations in interocular suppression paradigms. Notably, in all conditions, object movement remained tightly coupled (i.e., contingent) to the participants actions - and given such stimuli have already been shown to break suppression faster than uncoupled/pre-recorded visual inputs - it is possible that sensorimotor contingency was a sufficiently salient factor to override any influences related to how identifiable specific spatial dependencies were. HighlightsLearning sensorimotor control over objects was examined in novel VR tasks. We varied the complexity of spatial dependencies between manual and visual rotations. Controllable objects were expected to enter visual awareness faster in b-CFS. No differences in breakthrough times for differently complex spatial coupling rules. Sensorimotor contingency outweighs spatial congruence in affecting visual awareness.

neuroscience↗

bioRxiv2024

Capturing the emergent dynamical structure in biophysical neural models

Complex neural systems can display structured emergent dynamics. Capturing this structure remains a significant scientific challenge. Using information theory, we apply Dynamical Independence (DI) to uncover the emergent dynamical structure in a minimal 5-node biophysical neural model, shaped by the interplay of two key aspects of brain organisation: integration and segregation. In our study, functional integration within the biophysical neural model is modulated by a global coupling parameter, while functional segregation is influenced by adding dynamical noise, which counteracts global coupling. DI defines a dimensionally-reduced macroscopic variable (e.g., a coarse-graining) as emergent to the extent that it behaves as an independent dynamical process, distinct from the micro-level dynamics. We measure dynamical dependence (a departure from dynamical independence) for macroscopic variables across spatial scales. Our results indicate that the degree of emergence of macroscopic variables is relatively minimised at balanced points of integration and segregation and maximised at the extremes. Additionally, our method identifies to which degree the macroscopic dynamics are localised across microlevel nodes, thereby elucidating the emergent dynamical structure through the relationship between microscopic and macroscopic processes. We find that deviation from a balanced point between integration and segregation results in a less localised, more distributed emergent dynamical structure as identified by DI. This finding suggests that a balance of functional integration and segregation is associated with lower levels of emergence (higher dynamical dependence), which may be crucial for sustaining coherent, localised emergent macroscopic dynamical structures. This work also provides a complete computational implementation for the identification of emergent neural dynamics that could be applied both in silico and in vivo. Author summaryUnderstanding how complex neural systems give rise to emergent macroscopic patterns is a central challenge in neuroscience. Emergence, where macroscopic structures appear from underlying microscopic interactions, plays a crucial role in brain function, yet identifying the specific dynamics involved remains elusive. Traditionally, methods have quantified the extent of emergence but have struggled to pinpoint the emergent dynamical structure itself. In this study, we develop and apply a method, based on a quantity called Dynamical Independence (DI), which simultaneously captures the extent of emergence and reveals the underlying dynamical structure in neurophysiological data. Using a minimal 5-node biophysical neural model, we explore how a balance between functional integration and segregation--two key organisational principles in the brain--affects emergent macroscopic dynamics. Our results show that a finely balanced system produces highly localised, coherent macroscopic structures, while extreme deviations lead to more distributed, less localised dynamics. This work provides a computational framework for identifying emergent dynamical structure in both theoretical models and potentially in empirical brain data, advancing our understanding of the brains complex organisation across higher-order scales.

neuroscience↗