Biology subjects

Stein, T.

Publications and source records attributed to Stein, T..

16 recordsLinked to original sources

bioRxiv2026

Posterior but not frontal neural signatures of subjective visibility in report-independent EEG decoding

A central question in consciousness research is whether perceptual awareness arises predominantly from activity in posterior sensory regions or from later frontal processes associated with access and report. Empirical tests of these alternatives are challenging because most paradigms rely on explicit perceptual reports, introducing motor and decisional confounds. Here, we used an electroencephalography design combining two independent tasks to isolate neural signatures of subjective visibility while minimizing report-related activity. Participants viewed lateralized gratings in a backward-masking task and rated their subjective visibility, while in a separate no-report task they viewed unmasked gratings without reporting. Classifiers were trained on stimulus location in the no-report task and tested on masked trials sorted by subjective visibility in the masking task. This cross-decoding approach isolates stimulus-specific neural representations that generalize across tasks and are therefore independent of reporting and decision processes. Decoding revealed a reliable difference between subjectively visible and invisible stimuli in an early time window from 130 to 170 milliseconds, driven by posterior sensors over occipital, temporal, and parietal regions. No corresponding effects were observed over frontal sensors. These results indicate that subjective awareness is associated with early, posterior neural representations, whereas frontal activity observed in report-based paradigms likely reflects post-perceptual processing rather than awareness per se.

neuroscience↗

bioRxiv2026

Running Style and Stability During Uphill Running Are Largely Preserved with Increasing Shoe Sole Thickness

Advanced footwear technology (AFT) shoes incorporate increased sole thickness and compliant midsole materials that may alter running biomechanics. While these effects have been widely studied during level running, little is known about how sole thickness influences running style and stability during uphill running. This study examined the effects of two AFT shoes differing in sole thickness (35 mm-AFT35; 50 mm-AFT50) and a traditional control shoe (27 mm-CON27) on running style and stability during uphill running. Seventeen experienced male runners performed treadmill running at a 10% incline at 6.5 and 10 km/h in three shoe conditions. Running style was assessed using duty factor, normalized step frequency, center-of-mass oscillation, vertical and leg stiffness, and lower-limb joint kinematics. Running stability was evaluated using local dynamic stability via the maximum Lyapunov exponent and detrended fluctuation analysis of stride time. Duty factor and normalized step frequency did not differ between shoes. However, AFT shoes showed greater center-of-mass oscillation (p = 0.004), lower vertical stiffness (p = 0.022) compared to CON27. Joint kinematics revealed significant shoe effects at the ankle (p = 0.001), particularly increased dorsiflexion and eversion in AFT conditions. Running stability showed only minor changes. Local dynamic stability differed at the trunk (p = 0.027), with reduced stability in AFT50 compared with CON27 (p = 0.006), while global stability remained unchanged. No shoe x speed interactions were observed for any variable. Overall, uphill running style and stability remained largely preserved across shoe conditions, suggesting that sole thickness alone had limited influence.

bioengineering↗

bioRxiv2026

Effects of expectation, attention, and NMDA receptor blockade on feedforward and feedback processing

Perception is increasingly viewed as an inferential process wherein sensory inputs are integrated with prior expectations. We employed time-resolved decoding on electroencephalography (EEG) data (n = 30 male participants) to investigate how expectations modulate sensory processing across varying levels of stimulus complexity, and tested the effect of attention and NMDA receptor blockade. We designed a visual stimulus containing features of different complexity whose processing relies on distinct neural mechanisms: local contrast, collinearity, and the Kanizsa illusion, involving primarily feedforward, lateral, and feedback processes, respectively. EEG decoding revealed that expectations modulated lateral and feedback processing (better decoding for unexpected stimuli) but not feedforward processing. These expectation effects were confined to attended (task-relevant) features and were not observed for task-irrelevant features. The NMDA receptor antagonist memantine selectively enhanced decoding of the Kanizsa illusion, implicating NMDA-mediated feedback mechanisms in perceptual inference, but it did not modulate the effects of expectation or attention. These findings highlight the differential impact of expectations across different stages of sensory processing and reveal a distinct role of NMDA receptor-mediated feedback mechanisms. Significance statementPerception integrates sensory inputs with prior expectations. Using EEG decoding, we examined how expectations shape sensory processing at different levels of complexity and tested the effects of attention and NMDA receptor blockade. Our visual stimuli were designed to capture EEG markers of feedforward, lateral, and feedback mechanisms. Expectations influenced lateral and feedback processing (better decoding for unexpected stimuli) but not feedforward processing, and these effects were selective to task-relevant stimulus features. Memantine, an NMDA receptor antagonist, selectively improved decoding of the Kanizsa illusion, implicating NMDA-mediated feedback in perceptual inference, but it did not shape expectation or attention effects.

neuroscience↗

bioRxiv2024

Changes in Muscle Synergy Structure and Activation Patterns Underlie Force Field Adaptation, Retention, and Generalization

1Humans can adapt their motor commands in response to errors when they perform reaching movements in new dynamic conditions, a process called motor adaptation. They acquire knowledge about the new dynamics, which they can use when they are re-exposed and, limitedly, generalize to untrained reaching directions. While force field adaptation, retention, and generalization have been thoroughly investigated at a kinematic and kinetic task level, the underlying coordination at a muscular level remains unclear. Many studies propose that the central nervous system uses low- dimensional control, i.e., coordinates muscles in functional groups: so-called muscle synergies. Accordingly, we hypothesized that changes in muscle synergy structure and activation patterns represent the acquired knowledge underlying force field adaptation, retention, and generalization. To test this, 36 male humans practiced reaching to a single target in a viscous force field and were tested for retention and generalization to new directions, while we simultaneously measured muscle activity from 13 upper-body muscles. We found that muscle synergies used for unperturbed reaching cannot explain the muscle patterns when adapted. Instead, muscle synergies specific to this adapted state were necessary, alongside a novel four-phasic pattern of muscle synergy activation. Furthermore, these structural changes and patterns were also evident during retention and generalization. Our results suggest that reaching in an environment with altered dynamics requires structural changes to muscle synergies compared to unperturbed reaching, and that these changes facilitate retention and generalization. These findings provide new insights into how the central nervous system coordinates the muscles underlying motor adaptation, retention, and generalization. 2 Significance StatementHumans can adapt their reaching movements to new dynamic conditions. They acquire knowledge about the new dynamics and can use it not only when re-exposed to these conditions but also, in part, to generalize unpracticed reaching directions. While adaptation, retention, and generalization in a force field with new dynamics have been thoroughly investigated at a kinematic and kinetic task level, coordination of the underlying muscles remains elusive. Our results show how muscle synergies - functional groupings of co-activated muscles - underlie adaptation, retention, and generalization. In particular, we observed structural changes in the muscle synergies after adaptation compared to unperturbed reaching. These changes facilitate retention and spatial generalization. Thus, muscle synergies provide new insights into human motor adaptation.

neuroscience↗

bioRxiv2024

The effects of running shoe stack height on running style and stability during level running at different running speeds

The footwear market contains a wide variety of running shoe solutions aiming at optimizing performance and minimizing injuries. Stack height is one of the most highly discussed design features of running shoes, but its effects are not yet well understood. This study investigated the effects of different shoes differing mainly in their stack heights (High: 50 mm, Medium: 35 mm & Low: 27 mm) on running style and stability during treadmill running at 10 and 15 km/h. A total of 17 healthy experienced runners participated in this study. The kinematic data were recorded with a 3D motion capturing system. The running style was investigated by a dual-axis framework with duty factor (DF) and leg length normalized to step frequency (SFnorm). Additionally, the ratio of landing to take-off duration, the lower body joint angle time series in the sagittal and frontal planes, the vertical center of mass oscillation (COMosc), and the stiffness parameters (kver & kleg) were compared for different conditions. The stability was analyzed using linear (i.e. discrete frontal ankle parameters) and nonlinear methods (i.e. Maximum Lyapunov Exponent for local dynamic stability of head, trunk, hip, and foot, and detrended fluctuation analysis of stride time). High resulted in longer ground contact relative to stride time (DF) compared to Low. The higher the stack height, the higher was the COMosc. Furthermore, High led to a longer foot eversion during stance compared to Medium. In addition, the local dynamic stability of the hip decreased with High in comparison with Low. The higher stack heights ([≥] 35 mm) led to a lower SFnorm at 15 km/h but not at 10 km/h. The remaining shoe effects were independent of the running speed. Findings showed that changes in stack height can affect running style. Furthermore, the highest stack height resulted in changes related with instabilities (i.e., longer foot eversion and lower hip dynamic stability) which may be a critical issue in terms of injuries and performance. However, this study did not include joint load analysis or running performance measures such as VO2. Future studies may benefit from the combination of analysis approaches to better understand stack height effects on running injuries and performance.

bioengineering↗

bioRxiv2024

Reverse-breaking CFS (rev-bCFS): Disentangling conscious and unconscious effects by measuring suppression and dominance times during continuous flash suppression

Breaking continuous flash suppression (bCFS) is a widely used experimental paradigm that exploits detection tasks to measure the time an initially invisible stimulus requires to escape interocular suppression and access awareness. One pretty contentious and unresolved issue is whether differences in detection times reflect unconscious or conscious processing. To answer this question, here we introduce a novel approach (i.e., reverse-bCFS [rev-bCFS]) that measures the time an initially visible stimulus requires to be suppressed from awareness. Results from two experiments using face stimuli indicate that rev-bCFS can capture conscious effects, which indicates that contrasting standard bCFS with rev-bCFS can isolate unconscious processing occurring specifically during bCFS. For example, while face inversion impacted both bCFS and rev-bCFS, effects were larger in bCFS, suggesting a distinct contribution of unconscious processing to the advantage of upright over inverted faces in accessing awareness. Combining standard bCFS and rev-bCFS may offer a fruitful approach able to disentangle conscious and unconscious effects occurring during interocular suppression.

neuroscience↗

bioRxiv2024

NMDA receptor antagonist memantine selectively affects recurrent processing during perceptual inference

Perceptual inference requires the integration of visual features through recurrent processing, the dynamic exchange of information between higher and lower level cortical regions. While animal research has demonstrated a crucial role of NMDA receptors in recurrent processing, establishing a causal link between NMDA receptors and recurrent processing in humans has remained challenging. Here, we report two pharmacological studies with randomized, double-blind, crossover designs in which we administered the NMDA antagonist memantine, while collecting human electroencephalography (EEG). We trained and tested EEG classifiers to reflect the processing of specific stimulus features with increasing levels of complexity, namely differences in stimulus contrast, collinearity between local line elements, and illusory surfaces of a Kanizsa triangle. In two experiments involving different participants and visual tasks, we found that memantine selectively improved decoding of the Kanizsa illusion, known to depend on recurrent processing, while leaving decoding of contrast and collinearity largely unaffected. Interestingly, the results from an attentional blink (experiment 1) and task-relevance manipulation (experiment 2) showed that memantine was only effective when the stimulus was attended and consciously accessed. These findings suggest that NMDA inhibition through memantine enhances recurrent processing, especially for attended objects, and thereby provide a crucial step toward bridging animal and human research, shedding light on the neural mechanisms underpinning perceptual inference and conscious perception. This research was supported by a grant from the H2020 European Research Council (ERC STG 715605, SVG).

neuroscience↗

bioRxiv2024

Criterion placement threatens the construct validity of neural measures of consciousness

How consciousness arises from brain activity has been a topic of intense scientific research for decades. But how does one identify the neural basis of something that is intrinsically personal and subjective? A hallmark approach has been to ask observers to judge stimuli as seen (conscious) and unseen (unconscious) and use post hoc sorting of neural measurements based these judgments. Unfortunately, cognitive and response biases are known to strongly affect how observers place their criterion for judging stimuli as seen vs. unseen, thereby confounding neural measures of consciousness. Surprisingly however, the effect of conservative and liberal criterion placement on neural measures of unconscious and conscious processing has never been explicitly investigated. Here we use simulations and electrophysiological brain measurements to show that conservative criterion placement has an unintuitive consequence: rather than selectively providing a cautious estimate of conscious processing, it inflates effect sizes in neural measures of both conscious and unconscious processing, while liberal criterion placement does the reverse. After showing this in simulation, we performed decoding analyses on two electroencephalography studies that employ common subjective indicators of conscious awareness, in which we experimentally manipulated the response criterion. The results confirm that the predicted confounding effects of criterion placement on neural measures of unconscious and conscious processing occur in empirical data, while further showing that the most widely used subjective scale, the Perceptual Awareness Scale (PAS), does not guard against criterion confounds. Follow-up simulations explicate how the experimental context determines whether the relative confounding effect of criterion placement is larger in neural measures of either conscious or unconscious processing. We conclude that criterion placement threatens the construct validity of neural measures of conscious and unconscious processing.

neuroscience↗

bioRxiv2023

Isolating feedforward, lateral, and feedback mechanisms underlying perceptual and attentional impairments of conscious access

This study investigates failures in conscious access resulting from either weak sensory input (perceptual impairments) or unattended input (attentional impairments). Participants viewed a Kanizsa stimulus with or without an illusory triangle within a rapid serial visual presentation of distractor stimuli. We designed a novel Kanizsa stimulus that contained additional ancillary features of different complexity (local contrast and collinearity) that were independently manipulated. Perceptual performance on the Kanizsa stimulus (presence vs. absence of an illusion) was equated between the perceptual (masking) and attentional (attentional blink) manipulation to circumvent common confounds related to conditional differences in task performance. We trained and tested classifiers on electroencephalogram (EEG) data to reflect the processing of specific stimulus features, with increasing levels of complexity. We show that late stages of processing ([~]200-250 ms), reflecting the integration of complex stimulus features (collinearity, illusory triangle), were impaired by masking but spared by the attentional blink. In contrast, decoding of local contrast (the spatial arrangement of stimulus features) was observed early in time ([~]80 ms) and was left largely unaffected by either manipulation. These results replicate previous work showing that feedforward processing is largely preserved under both perceptual and attentional impairments. Crucially however, under matched levels of performance, only attentional impairments left the processing of more complex visual features relatively intact, likely related to spared lateral and local feedback processes during inattention. These findings reveal distinct neural mechanisms associated with perceptual and attentional impairments and thus contribute to a comprehensive understanding of distinct neural stages leading to conscious access.

neuroscience↗

bioRxiv2023

Clusterin can mediate apoptosis-induced molecular mechanisms in immune thrombocytopenia

Abnormalities in the apoptosis pathway are possible risk factors for various autoimmune diseases including immune thrombocytopenia (ITP). ITP is an autoimmune bleeding disorder characterized by a low platelet count and mostly mild but in rare occasions life threatening bleeding symptoms. Platelets and megakaryocytes (MKs) may be seen as the major targets of the pathogenic immune responses in ITP. A mechanistic understanding of the ITP pathogenesis is still lacking. Our data indicate that mechanisms associated with impaired clusterin-mediated apoptosis might play a role in ITP platelet pathophysiology and platelet production by MKs. We could demonstrate by apoptosis proteomic profiling significantly increased expression levels of some apoptotic genes such as clusterin (CLU), pro-caspase 3, catalase, TRAILR1/DR4, Bax, Bad and Bcl-2 compared to healthy controls in platelet-rich plasma (PRP) from 10 ITP patients. We could validate by both RT-qPCR and Western blotting that CLU, a stress-activated chaperone, is significantly increased in both newly diagnosed and chronic ITP. We used the human megakaryoblastic cell line MEG-01, treated for 4h with plasma from acute and chronic ITP patients and healthy controls. We performed chemical treatments in plasma treated MEG-01 by using pan-caspase inhibitors (Z-VAD-FMK), apoptosis inducer ABT-737, Rotenone and Rapamycin. We determined the expression at mRNA levels of apoptosis pathway regulatory genes Bax, caspase-3, -8, -9 as well as CLU, GRP78 and GRP94 by qRT-PCR. We could demonstrate significantly downregulation of mRNA expression levels of these apoptotic markers in ITP plasma treated and CLU siRNA transfected MEG-01 cells. Our results indicate a possible impairment of apoptosis pathway via upregulation of CLU and Bax in platelets and in their producers MKs that can lead to platelet destruction in ITP disease.

molecular biology↗

bioRxiv2022

Identification of circRNAs linked to Alzheimer's disease and related dementias

We conducted a circular-transcriptome-wide analysis and examined circRNA expression patterns associated with AD and clinical and neuropathological AD severity measures in human hippocampus and cortex brain regions. We validated prior studies of circRNA in AD cortex, and demonstrate novel patterns of expression in the AD hippocampus. We also examined circRNA expression across multiple types of dementia and show that circRNA expression differs by dementia subtype. We demonstrate robust circRNA expression in human neuronal precursor cells (NPCs). Then, using NPCs to study qPCR validated circRNA, we show that exposure to oligomeric tau elicits downregulation of circRNA similar to that observed in AD brain. These data identify circRNA that are changed with AD, and suggest that treating neuronal cells with oligomeric tau can recapitulate some of these changes.

molecular biology↗

bioRxiv2021

Competition between distinct ApoE alleles and mCRP for the endothelial receptor CD31 differentially regulates neurovascular inflammation and Alzheimer's disease pathology

BACKGROUNDC-reactive protein (CRP) in peripheral inflammation is associated with increased Alzheimers disease (AD) risk in Apolipoprotein E4 (ApoE4), but not ApoE3 or E2, humans. It remains unknown whether peripheral monomeric CRP (mCRP) induces AD pathogenesis through some receptor of blood-facing endothelia in the brain in an ApoE genotype dependent fashion. METHODSWe used human samples, ApoE knock-in and deficient mouse models, and primary brain endothelia. Different ApoE mice were intraperitoneally (i.p.) injected with mCRP. The characterizations by immunostaining, proximity ligation assay (PLA) and siRNA were conducted to identify the receptor for mCRP. Brain microvessel and endothelia were isolated for RNA sequencing to explore the molecular pathway. RESULTSWe demonstrate that CD31 (PECAM-1), a blood-facing endothelial receptor in brain, is a competitive target of both mCRP and ApoE protein. ApoE2 competes more strongly with mCRP for CD31 than ApoE4 does, and expressing ApoE4 or knocking out ApoE gene results in higher levels of mCRP-CD31 binding, leading to a decrease of CD31 expression but an increase in CD31 phosphorylation, along with greater cerebrovascular damage and AD pathology. This competitive binding mediates differential endothelial molecular responses depending on ApoE genotype, increasing cerebrovascular inflammation and mitochondria impairment in ApoE4 mice, while inducing vasculogenesis and protective changes in the presence of ApoE2. CONCLUSIONSOur study reveals a novel and dynamic endothelial ApoE-mCRP-CD31 pathway for AD pathogenesis during chronic inflammation and provides some insight into the opposing ApoE4-neurodegenerative and ApoE2-neuroprotective effects in AD. Clinical PerspectiveO_ST_ABSWHAT IS NEW?C_ST_ABSO_LICD31 is a competitive target of both mCRP and ApoE in brain endothelia in an ApoE-allele dependent pattern C_LIO_LImCRP increases CD31 phosphorylation in the brain endothelia and damages cerebrovasculature in ApoE4 carriers and AD brains C_LIO_LImCRP expression results in neuroprotective or neurodegenerative pathway activation in an ApoE-dependent manner C_LI WHAT ARE THE CLINICAL IMPLICATIONS?O_LIAlthough ApoE4 is a major genetic risk factor of AD, some ApoE4 carriers do not develop AD by the age of 90. C_LIO_LIElderly people often experience peripheral inflammatory attacks and develop chronic low-grade inflammation, which results in the formation and release of mCRP. Because CRP is routine clinical laboratory test, clinicians can use blood CRP level to predict AD risk in ApoE4 carriers. C_LIO_LIEvidence of Apoe4 genotype and chronic low-grade inflammation stages marked by elevated CRP levels should be targeted in personalized treatment and clinical trials for AD. C_LI

neuroscience↗

bioRxiv2020

Processing of subjectively and objectively invisible stimuli in human visual cortex

The study of unconscious processing requires a measure of conscious awareness. Awareness measures can be either subjective (based on participants report) or objective (based on perceptual performance). The preferred awareness measure depends on the theoretical position about consciousness, and may influence conclusions about the extent of unconscious processing and about the neural correlates of consciousness. We obtained fMRI measurements from 43 subjects while they viewed masked faces and houses that were either subjectively or objectively invisible. We show that neural representations of objectively invisible faces and houses are limited to visual (shape-related) object properties, while subjectively invisible stimuli are processed up to more abstract, categorical levels of representation. These results demonstrate that the hypothesized extent of unconscious information processing is determined by the measurement approach. Furthermore, our data show that subjective and objective approaches are associated with different neural correlates of consciousness and thus have implications for neural theories of consciousness.

neuroscience↗

bioRxiv2019

Plumbagin-induced oxidative stress leads to inhibition of Na+/K+-ATPase (NKA) in canine cancer cells.

The Na+/K+-ATPase (NKA) complex is the master regulator of membrane potential and a target for anti-cancer therapies. Here, we investigate the effect of drug-induced oxidative stress on NKA activity. The natural product, plumbagin increases oxygen radicals through inhibition of oxidative phosphorylation. As a result, plumbagin treatment results in decreased production of ATP and a rapid increase in intracellular oxygen radicals. We show that plumbagin induces apoptosis in canine cancer cells via oxidative stress. We use this model to test the effect of oxidative stress on NKA activity. Using whole-cell patch-clamp electrophysiology we demonstrate that short-term exposure (4 min) to plumbagin results in 48% decrease in outward current at +50 mV. Even when exogenous ATP was supplied to the cells, plumbagin treatment resulted in 46% inhibition outward current through NKA at +50 mV. In contrast, when the canine cancer cells were pre-treated with the oxygen radical scavenger, N-acetylcysteine, the NKA inhibitory activity of plumbagin was abrogated. These experiments demonstrate that the oxidative stress-causing agents such as plumbagin and its analogues, are a novel avenue to regulate NKA activity in tumors.

cancer biology↗

bioRxiv2018

Contextual interference effect is independent of retroactive inhibition but variable practice is not always beneficial

Positive effects of variable practice conditions on subsequent motor memory consolidation and generalization are widely accepted and described as the contextual interference effect (CIE). However, the general benefits of CIE are low and these benefits might even depend on decreased retest performances in the blocked-practicing control group, caused by retroactive inhibition. The aim of this study was to investigate if CIE represents a true learning phenomenon or possibly reflects confounding effects of retroactive inhibition. We tested 48 healthy human participants adapting their reaching movements to three different force field magnitudes. Subjects practiced the force fields in either a Blocked (B), Random (R), or Constant (C) schedule. In addition, subjects of the Blocked group performed either a retest schedule that did (Blocked-Matched; BM) or did not (Blocked-Unmatched; BU) control for retroactive inhibition. Results showed that retroactive inhibition did not affect the results of the BU group much and that the Random group showed a better consolidation performance compared to both Blocked groups. However, compared to the Constant group, the Random group showed only slight benefits in its memory consolidation of the mean performance across all force field magnitudes and no benefits in absolute performance values. This indicates that CIE reflects a true motor learning phenomenon, which is independent of retroactive inhibition. However, random practice is not always beneficial over constant practice.

neuroscience↗

bioRxiv2018

Variable training but not sleep improves consolidation of motor adaptation

How motor memory consolidates still remains elusive. Motor tasks consolidation were shown to depend on periods of sleep, whereas pure non-hippocampal dependent tasks, like motor adaptation, might not. Some research suggests that the mode of training might affect the sleep dependency of motor adaptation tasks. Here we investigated whether sleep differentially impacts memory consolidation dependent on the variability during training. Healthy men were trained with their dominant, right hand on a force field adaptation task and re-tested after an 11-h consolidation period either involving overnight sleep (Sleep) or daytime wakefulness (Wake). Retesting also included a transfer to the non-dominant hand. Half of the subjects in each group adapted to different force field magnitudes with low inter-trial variability (Sleep-Blocked; Wake-Blocked), the other half with high variability (Sleep-Random; Wake-Random). EEG was recorded during task execution and overnight polysomnography. Motor adaptation was comparable between Wake and Sleep groups, although performance changes over sleep correlated with sleep spindles nesting in slow wave upstates. Higher training variability improved retest, including transfer learning, and these improvements correlated with higher alpha power in contralateral parietal areas. Enhanced consolidation after training might foster the ability to correct ongoing movements by responsive feedback rather than their pre-execution prediction.

neuroscience↗