Biology subjects

Voss, J.

Publications and source records attributed to Voss, J..

8 recordsLinked to original sources

bioRxiv2026

Real-time detection of N2 and N3 sleep from scalp and intracranial EEG

Sleep rhythms such as slow oscillations and spindles arise predominantly during N2 and N3 sleep (N2+N3). Closed-loop stimulation targeting these rhythms is a promising strategy to enhance memory. Such stimulation requires online sleep stage classification. Conventional staging labels completed 30-s epochs using past and future data and cannot support online staging. We developed a causal tracker that, every 2 s, estimates the current stage from the preceding 10 s of scalp or intracranial EEG. We also evaluated a simulated rule that permits stimulation after three consecutive estimates indicating N2+N3 sleep. In six adults with drug-resistant epilepsy with simultaneous scalp EEG and stereo-EEG, real-time N2+N3 discrimination remained close to offline scoring of the same recordings (scalp AUC 0.953 versus 0.958). Thalamic channels alone reached AUC 0.934 and exceeded mesial temporal channels in every patient, and scalp plus thalamus performed best (0.967). The scalp tracker, retrained in 28 healthy adults, reached 0.976. When patients transitioned into N2+N3 sleep with stimulation initially disabled, the rule permitted stimulation within 5 min in 63-73% of transitions, with a median delay of 42-64 s among those detected. After leaving N2+N3, stimulation was disabled after a median of 19-22 s. The rule also switched on incorrectly 1.4-1.8 times per hour outside N2+N3 and remained active during 28-31% of REM in patients, compared with 2% in healthy adults. These findings show that both scalp and thalamic EEG can support real-time N2+N3 detection and inform when stimulation is permitted. Translationally, implanted thalamic leads, increasingly used for neuromodulation in epilepsy, could support sleep-stage-dependent stimulation without scalp EEG, while scalp EEG might be used for noninvasive neuromodulation. Closed-loop systems should be evaluated not only by sleep-stage classification accuracy but also by how reliably and promptly they enable and disable stimulation.

neuroscience↗

bioRxiv2026

Thalamic Nuclei Differentially Coordinate Propagation of Cortical Slow Oscillations

Sleep slow oscillations (SOs) vary in the spatial extent of their cortical propagation, ranging from widespread Global events to spatially restricted Frontal events. These distinctions could have functional consequences for memory consolidation. It remains unknown whether individual thalamic nuclei are differentially engaged across SO propagation types, and whether thalamic activity before SO onset predicts subsequent propagation. We analyzed simultaneous scalp EEG and thalamic stereo-EEG from 24 full-night recordings in 6 epilepsy patients, sampling 11 thalamic nuclei and enabling direct characterization of nucleus-specific thalamocortical interactions during naturally occurring sleep slow oscillations. Cortical SOs were classified by propagation type and thalamocortical coupling was characterized via peri-event histograms, phase-locking analysis, waveform morphology comparisons, and pre-onset spectral and cross-frequency coupling features. All well-sampled thalamic nuclei showed broad temporal co-occurrence with prefrontal SOs, yet occupied distinct phase positions within the cortical SO cycle. Medial pulvinar (PuM) showed the strongest phase locking across subjects, with significant preference for the ascending post-trough phase. Among the examined nuclei, Frontal SOs were associated with significant phase locking in PuM, whereas Global SOs preferentially synchronized the centromedian nucleus near the cortical down-state trough. Thalamic waveform morphology differed systematically with propagation extent, with opposing effects between pulvinar and intralaminar nuclei. Pre-onset PuM activity showed suppressed alpha, sigma, and beta power and delta-phase cross-frequency coupling before Global SOs (all p < 0.05). The human thalamus engages NREM sleep SOs through nucleus-specific, propagation-sensitive dynamics rather than as a functionally uniform structure. Pre-onset PuM activity contains predictive signatures of cortical SO propagation extent. This finding has implications for closed-loop neuromodulation targeting specific SO states, although replication in larger cohorts is needed.

neuroscience↗

bioRxiv2026

Slow Oscillations Gate Interictal Spikes Across the Human Thalamocortical-Epileptogenic Network

BackgroundSlow oscillations (SOs; 0.5-1.5 Hz), a hallmark of non-rapid eye movement (NREM) sleep, are associated with a marked amplification of interictal epileptiform spike (IIS) activity in focal epilepsy. However, the network-level organization of this effect across the thalamocortical-epileptogenic system, and whether IIS-permissive SOs can be predicted from pre-onset brain states, remain unclear. MethodsWe analyzed simultaneous scalp EEG and stereo-EEG (SEEG) recordings from 6 patients with drug-resistant focal epilepsy across 24 full-day recording days, sampling prefrontal cortex (PFC), thalamus, and seizure onset zone (SOZ). SO-IIS coupling was characterized across vigilance states using peri-event and phase-based analyses, with a gamma-based validation step to reduce contamination by IIS-related slow potentials. Pre-onset phase-amplitude coupling (PAC) was compared between IIS-permissive and non-permissive SOs. ResultsSO-IIS coupling was observed across all regions, with the strongest and most temporally precise pre-trough IIS clustering in the SOZ (peak 4.4% in NREM), exceeding PFC (1.7%) and thalamic coupling. Thalamic coupling was preserved across wakefulness and NREM and was significant in 7/11 nuclei, with nucleus-specific phase preferences. SO morphological features, particularly up-slope and peak-to-peak amplitude at PFC contacts, predicted IIS occurrence in the SOZ. Pre-onset PAC differed significantly between permissive and non-permissive SOs across regions. ConclusionsSO-IIS coupling is a distributed, network-level phenomenon with region- and state-specific characteristics, and pre-onset PAC provides a predictive signature of IIS-permissive brain states. These findings support the feasibility of developing personalized, closed-loop neuromodulatory strategies targeting SO-gated IIS suppression in focal epilepsy.

neuroscience↗

bioRxiv2026

Attenuated interferon signalling in alveolar epithelium limits resistance to Streptococcus pyogenes

The upper respiratory tract is a primary niche for Streptococcus pyogenes colonisation and disease. Lower respiratory tract infection (pneumonia) is the most common invasive S. pyogenes syndrome. Studies have not previously examined how epithelial cells, from the airway to the alveolus, respond to S. pyogenes infection. Here, we established a scalable human in vitro model by differentiating induced pluripotent stem cells (iPSCs) into mature pseudostratified airway epithelium or alveolar type 2 epithelial cells, cultured at air-liquid interface and infected with S. pyogenes (M1UK and M75 strains). Both strains attached to iPSC-derived lung epithelial cells, with significantly greater adherence to the airway epithelium by M75 compared to M1UK. Moreover, invasion by both S. pyogenes strains of alveolar epithelial cells was greater than for the airway epithelium. Dynamic S. pyogenes gene expression changes were evident between 6 and 24 hours after infection, which was influenced by the infected cell type; however, virulence genes were not significantly altered. While infection of the airway epithelium induced rapid and dynamic inflammatory signalling, the alveolar epithelium demonstrated augmented cell death and mounted a transcriptional pro-inflammatory and proliferative response that was uncoupled from cytokine secretion. The airway epithelium model exhibited consistently higher baseline type I interferon (IFN) signalling than the alveolar epithelium. Invasion by S. pyogenes and inflammation was significantly reduced in IFN-{beta}-treated alveolar epithelial cells. In summary, we have established the first model of S. pyogenes infection in physiologically relevant airway and alveolar epithelial cells. Our findings suggest that host responses to infection are influenced by lung compartment, the S. pyogenes strain type, and infection timepoint, highlighting context-specific pathways that could be leveraged therapeutically.

microbiology↗

bioRxiv2026

Predictability of Sleep Slow Oscillation Emergence and Spatial Extent from Pre-Onset Neural Dynamics

Slow oscillations (SOs; [~]0.5-1.5 Hz) are a hallmark of non-rapid eye movement (NREM) sleep and are known to support memory consolidation and large-scale cortical communication. Although their instantaneous dynamics are well characterized, the neural processes that precede SO initiation--and whether they predict the spatial extent of the upcoming event--remain largely unknown, despite their potential utility for anticipatory closed-loop intervention. Using high-density EEG from 29 healthy adults, we examined neural activity in the 2-s interval preceding the SO trough. Analyses focused on distinct SO subtypes defined by their spatiotemporal properties: Global, Frontal, and Local. We specifically focused on Global and Frontal events, both of which originate frontally but differ in their propagation. We quantified instantaneous spectral power, time-frequency dynamics, phase-amplitude coupling (PAC), and amplitude-amplitude coupling. Across all analyses, theta-band power (4-8 Hz) emerged as the earliest and most robust predictor of SO initiation, remaining informative after restricting analyses to temporally isolated SOs to reduce potential residual-aftereffect confounds from preceding SOs. Theta power exhibited a sustained rise beginning nearly two seconds before the SO trough ([~]1.6 s before onset). Theta power increases were absent in surrogate epochs and reliably differentiated Global from Frontal SOs with moderate-to-strong effect sizes (Cohens d = 0.45-0.77), demonstrating the robustness of theta power as a physiological signature. Mechanistically, Global SOs were preceded by enhanced delta-theta PAC and broad low-frequency synchronization, whereas Frontal SOs were preceded by elevated theta/alpha-to-beta/low-gamma coupling, reflecting a state of locally enhanced coupling at frequencies higher than the SO range, which appears to restrict propagation. A simple logistic regression classifier using only pre-onset theta power achieved >95% accuracy in distinguishing SOs from surrogate events and differentiated Global from Frontal SOs with [~]83% multiclass accuracy, showing further sensitivity improvements when delta power was included. These findings demonstrate that isolated SOs are preceded by structured network dynamics that are tied to their spatial extent. Thus, theta activity can be used to predict SO occurrence and might be leveraged in closed-loop neuromodulation.

neuroscience↗

bioRxiv2025

Targeting intracranial electrical stimulation to network regions defined within individuals causes network-level effects

Intracranial electrical stimulation (ES) is routinely used therapeutically, diagnostically, and to provide causal evidence in neuroscience studies. However, our understanding of the brain network-level effects of ES remains limited. We applied precision functional mapping (PFM), based on functional magnetic resonance imaging (fMRI), to define large-scale networks within individual epilepsy patients. We show that single-pulse electrical stimulation (SPES) and high-frequency electrical stimulation (HFES) are more likely to evoke within-network responses and elicit network-related behavioral effects, respectively, when applied near to a PFM-defined network region. Network-level effects were more likely when stimulating sites in white matter, in close proximity to the targeted network, and within a region predominantly occupied by the targeted network. Further, network-specific modulation may be achievable by applying lower current intensities at these sites. Our findings support that modulation of specific networks is achievable by targeting ES to a functional anatomic "sweet spot" that can be identified using PFM.

neuroscience↗

bioRxiv2021

A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered a novel class of small molecule ketobenzothiazole TMPRSS2 inhibitors with significantly improved activity over existing irreversible inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an IC50 of 340 pM against recombinant full-length TMPRSS2 protein, an EC50 of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV SARS-CoV-2 chimeric virus, and an EC50 of 74 nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East Respiratory Syndrome Coronavirus (MERS-CoV) cell entry with an EC50 of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in mice with a half-life of 8.6 hours in plasma and 7.5 h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 treatment.

microbiology↗

bioRxiv2020

Cerebellar theta and beta noninvasive stimulation rhythms differentially influence episodic memory versus language

The cerebellum is thought to interact with distributed brain networks to support cognitive abilities such as episodic memory and language. Episodic memory and language networks have been associated with distinct endogenous oscillatory activity frequency bands: theta ([~]3-8 Hz) versus beta ([~]13-30 Hz), respectively. We sought to test whether it is possible to toggle cerebellar participation in episodic memory versus language by noninvasively stimulating with theta versus beta rhythmic transcranial magnetic stimulation. Cerebellar theta stimulation improved episodic memory encoding but did not influence neural signals of language processing, whereas beta stimulation of the same cerebellar location increased neural signals of language processing but did not influence episodic memory encoding. This constitutes evidence for double-dissociation of cerebellar contributions to language versus episodic memory based on stimulation frequency pattern, supporting the hypothesis that the cerebellum can be biased to support these distinct cognitive abilities at the command of network-specific rhythmic activity.

neuroscience↗