Biology subjects

Surges, R.

Publications and source records attributed to Surges, R..

14 recordsLinked to original sources

bioRxiv2026

Single-cell profiling reveals tumor grade-dependent immune remodeling in BRAFV600E-driven glioneuronal tumors

BRAFV600E is the key driver variant in epilepsy-associated glioneuronal tumors (GNTs). These tumors often share MAPK/PI3K hyperactivation, a generally benign biological course and rare occurrence of malignant variants. We aimed to characterize the poorly defined immune cell milieu of GNTs with distinct biological behavior. We mapped cellular heterogeneity of the tumor microenvironment (TME) using single-cell transcriptomics on murine models of low-grade (LG-GNT; BRAFV600E/AKTA) and high-grade (HG-GNT; BRAFV600E/AKTA/Trp53KO) tumors, generated via intraventricular in utero electroporation (IUE). Furthermore, ex vivo functional assays with CSF1R-mediated myeloid depletion were utilized to assess the role of identified signaling molecules on tumor viability. We observed a striking, grade-dependent immunological dichotomy: LG-GNT exhibited a permissive niche with prominent surveillance by T cells and pro-inflammatory microglia. In contrast, HG-GNT TME was characterized by a restricted T cell infiltration, massively dominated by myeloid cell infiltrates. Differential gene expression analysis identified Spp1 (osteopontin) as a key mediator of this immunosuppressive HG-GNT TME, exclusively expressed in microglia and border-associated macrophages (BAMs). Crucially, ex vivo functional assays demonstrated that recombinant SPP1 enhances tumor viability through a paracrine mechanism. These findings suggest fundamentally distinct immune activation (a) stimulated by aberrant MAPK/PI3K signaling in LG-GNT, versus (b) malignant tumor feature-driven, e.g. through necrosis in HG-GNT. In the latter, SPP1 signaling creates the immunosuppressive niche. Consequently, while modulating the pro-inflammatory niche may mitigate tumor-related epileptogenicity in LG-GNTs, targeting the SPP1-myeloid axis may restore anti-tumor immunity in HG-GNTs.

neuroscience↗

bioRxiv2026

Epileptogenesis dynamics driven by peritumoral circuit rewiring in gangliogliomas

Gangliogliomas (GGs) are emblematic low-grade epilepsy-associated tumors, yet the developmental mechanisms underlying their epileptogenicity remain unclear. Here, we investigated how tumor-network interactions evolve across postnatal maturation using an in-utero electroporated BRAFV600E-driven mouse model combining multiscale electrophysiology with histology, single-nucleus RNA sequencing, and complementary analyses in human GG tissue. We show that GGs induce early and evolutive modification of cortical organization and glioneuronal architecture. Despite glioneuronal preservation, seizure initiation shifted from distal cortical regions at postnatal stages to tumor-adjacent areas in adult networks. In both mouse and human, GG slices exhibited seizure activity localized to the peritumoral cortex. At the cellular level, neurons exhibited a developmental arrest of intrinsic electrophysiological maturation from postnatal to adult stages. Transcriptomic profiling identified stage-specific neuronal remodeling, with early alterations in inhibitory neurons and later changes affecting excitatory populations. Such developmental spatial seizure dynamics were associated with a pharmacological shift as NKCC1 inhibition with bumetanide selectively reduced seizure-like activity in neonatal but not mature tumor networks, indicating a restricted window of chloride-dependent epileptogenesis relevant to GABAergic maturation. Together, our results demonstrate that GG-associated epileptogenesis arises from developmentally regulated tumor-network interactions, highlighting distinct cellular and molecular mechanisms across maturation and revealing potential age-specific therapeutic targets.

neuroscience↗

bioRxiv2026

Bayesian heart-rate entropy identifies autonomic dynamics during seizure evolution: a reproducible pilot study

Epileptic seizures are accompanied by profound alterations in autonomic regulation, yet the physiological information encoded in cardiac dynamics remains incompletely understood. Bayesian heart-rate (HR) entropy has recently been proposed as a probabilistic measure of cardiac dynamics, but whether it captures clinically meaningful aspects of seizure physiology--such as behavioral awareness or seizure evolution--has not been established. We estimated Bayesian HR entropy from electrocardiographic recordings acquired during video-electroencephalographic monitoring using the BayesianAtHeart framework. Entropy-derived measures were integrated with quality-controlled clinical metadata to generate a frozen seizure-level analysis dataset, from which all subsequent analyses were performed. Associations between seizure-average Bayesian HR entropy and clinical variables were evaluated using linear mixed-effects models accounting for repeated seizures within patients, and time-resolved entropy trajectories were analyzed descriptively. Following ECG quality control, Bayesian HR entropy was successfully estimated for 51 of 67 seizures from 10 patients; the remaining 16 seizures were excluded because ECG quality was insufficient. Forty-eight seizures with complete awareness classification comprised the primary analysis cohort. Bayesian HR entropy was not associated with ictal awareness across seizure-average analyses, mixed-effects models, or time-resolved entropy trajectories. Instead, seizure duration emerged as the strongest clinical correlate of Bayesian HR entropy, with longer seizures exhibiting progressively lower Bayesian HR entropy. Time-resolved analyses indicated that this association reflected a gradual decline in entropy during seizure evolution rather than lower Bayesian HR entropy at seizure onset. Post hoc sensitivity analyses showed that this association was not attributable to selection bias or to the number of beat-to-beat intervals available to the entropy estimator, and that duration, rather than stable between-patient differences, was the dominant source of entropy variance. Entropy was not generally reduced during seizures relative to a pre-ictal baseline; instead, the variability of the entropy trajectory declined progressively with seizure duration, more strongly than its mean. These findings suggest that Bayesian HR entropy primarily reflects the evolving organization of autonomic regulation during seizures rather than behavioral awareness. Beyond identifying seizure duration as the strongest correlate of Bayesian HR entropy in this cohort, this study establishes a fully reproducible computational framework for Bayesian HR entropy analysis that provides a foundation for future prospective investigations of autonomic dynamics in epilepsy.

neuroscience↗

bioRxiv2026

Human medial temporal lobe neurons link future reward coding with intertemporal choice and impulsivity

The ability to delay gratification emerges early in life and is linked to long-term health and economic success. Conversely, high impulsivity, marked by a preference for immediate rewards, can be associated with psychiatric disorders. Although processes underlying human delay discounting have been studied at behavioural and macroscopic neural levels, they remain elusive at the single-neuron level. Specifically, it remains unknown how human neurons encode extended reward delays, predict intertemporal choices, and how these processes vary with impulsivity. Here, we record single-neuron activity in the human medial temporal lobe (MTL) to explore decision and delay coding. We identify neurons that predict upcoming decisions in the amygdala and hippocampus. Neurons in the entorhinal cortex and hippocampus encode reward delays, with particularly hippocampal population activity coding prospective temporal periods. Importantly, neuronal activity in impulsive individuals shows diminished prospective temporal coding and predicts decisions only shortly before choices are reported. Our findings reveal how distinct MTL regions contribute to intertemporal decisions and provide insight into the neuronal signatures underlying impulsivity.

neuroscience↗

bioRxiv2026

Sleep ripples drive single-neuron reactivation for human memory consolidation

Sleep transforms fragile experiences into lasting memories, but the neuronal basis of this process in humans has remained elusive. In rodents, hippocampal ripples orchestrate the replay of place cell sequences, establishing a cellular mechanism for consolidation - though with limited generalizability to human memory. In humans, neuroimaging has revealed large-scale offline reactivation, but these coarse signals leave open whether individual neurons are reactivated and how ripples might mediate this process. Here, we bridge this gap by directly recording 1,466 medial temporal lobe (MTL) neurons and intracranial electroencephalography during learning, post-learning wakefulness, and sleep. We show that ripples robustly drive neuronal firing, with sleep ripples eliciting stronger activation than wake ripples. Critically, neurons tuned to items that were later remembered fired more strongly during ripples than those coding for forgotten items, and this memory-linked reactivation was selectively observed during sleep. Finally, ripple-associated neuronal MTL bursts were detectable across widespread cortical activity, pointing to a mechanism for systems-level consolidation. Together, these findings provide the first direct evidence that ripple-driven single-neuron reactivation supports human episodic memory consolidation and reveal why sleep -- compared to wakefulness -- offers a privileged window for stabilizing memories.

neuroscience↗

bioRxiv2026

Targeting epilepsy with photopharmacology in human brain tissue

Photo-activatable drugs (PDs) are rapidly emerging as precision therapeutics across biomedical research, yet their potential in epilepsy treatment has remained understudied. Given that 30% of epilepsies are medically refractory, and anti-seizure medications often cause multi-organ side-effects, PDs could break new ground. Here, we evaluate light-switchable ion-channel blockers QAQ and CQAQ, and a newly developed caged propofol (CaP), in murine brain slices, and postsurgical brain tissue from patients with epilepsy or brain tumors. In mice, we show that QAQ/CQAQ reversibly suppress neuronal firing, while photo-activated CaP prolonged inhibitory post-synaptic currents and enhanced leak current. While QAQ caused identical effects in human tissue, CQAQ unexpectedly increased firing. Activated CaP robustly suppressed epileptiform activity across species. This work establishes CaP as a tool for neuroscience and disease-related studies. Our results highlight the necessity for early human model testing in biomedical research, and showcase photopharmacology as a potential powerful approach to control human epilepsy.

pharmacology and toxicology↗

bioRxiv2026

Sequential coupling of sleep oscillations enables concept-neuron reactivation and supports information flow across the human hippocampal-cortical circuit

Effective memory consolidation during sleep is thought to rely on the transfer of reactivated memory traces from the hippocampus to the cortex. However, the mechanisms supporting this essential dialogue across brain areas remain poorly understood. Here, we recorded single-neuron activity (n = 1097) in the medial temporal lobe (MTL) of 10 epilepsy patients across 21 nights of sleep. Before sleep, patients engaged in a memory task with stimuli eliciting concept-neuron responses. During non-rapid eye movement (NREM) sleep, neuronal firing locked to sharp wave-ripples (SWR) revealed a directed flow of information from the hippocampus to cortical targets. Notably, within SWR-driven activity, experience-dependent concept neurons exhibited elevated co-activation both within and across MTL regions, indicating selective reactivation of behaviorally relevant information. Cross-regional co-activation of concept cells was markedly enhanced when hippocampal SWRs coincided with cortical slow oscillation-spindle complexes, suggesting an active role of the cortex in shaping interregional communication. These findings provide evidence that SWRs in humans selectively reactivate experience-related neural ensembles across the hippocampal-cortical network, while synergistic interactions with cortical slow oscillation-spindle events might facilitate effective memory consolidation.

neuroscience↗

bioRxiv2025

Attention modulates hippocampal sharp-wave ripples in humans

Hippocampal sharp-wave ripples (SWRs) are high-frequency events critical for memory consolidation, typically studied during sleep and quiet wakefulness. Emerging evidence suggests that SWRs also occur during active behavior, yet their role in awake cognition remains unclear. Here, we demonstrate that changes in sustained attention modulate both the occurrence of SWRs and their temporal alignment to ongoing hippocampal oscillations. Using intracranial EEG recordings from epilepsy patients performing a sustained attention to response task (SART), we first identified attentional states based on behavioral variability and subjective reports. Next, we observed that SWRs were more frequent during high-attention periods, despite the absence of memory demands. Importantly, SWRs during low-attention periods showed higher phase synchrony with low-frequency oscillations (theta to lower beta) indicating increased endogenous coordination of SWRs under low attentional focus. These findings show that SWRs are dynamically regulated by attentional engagement, supporting a broader role for ripples in active cognitive processing.

neuroscience↗

bioRxiv2025

Semantic Tuning of Single Neurons in the Human Medial Temporal Lobe

The Medial Temporal Lobe (MTL) is key to human cognition, supporting memory, emotional processing, navigation, and semantic coding. Rare direct human MTL recordings revealed concept cells, which were proposed as episodic memory building blocks due to their context- and modality-invariant response. However, there is a long-standing debate whether concept cells encode information in a discrete, all-or-none fashion, or as a graded, continuous function of semantic dimensions. To resolve this, we developed a closed-loop protocol that analyzes neuronal spiking in real time and adaptively presents new stimuli based on semantic similarity to response-eliciting previous ones. We found that human concept cells show graded responses, following semantic tuning curves. Furthermore, the tuning width and steepness of MTL neurons vary, with the hippocampus exhibiting the steepest tuning. Regional analysis of these tuning curves yields region-specific categorical response profiles (e.g., food responses in the amygdala). Finally, we show that at the population level, MTL activity is best captured by continuous semantic vector models, which outperform categorical and network-based metrics. Together, these findings establish that concept cells exhibit semantic tuning curves, providing new mechanistic insights into the neural organization of semantic information in the human brain.

neuroscience↗

bioRxiv2025

Gamma - Theta - Spike Coupling Coordinates Sequential Memory in Human MTL

It has been suggested that hierarchical synchronization of theta and gamma oscillations coordinates neural activity during sequence memory. Yet, the role of gamma oscillations and their interaction with theta and single-unit activity (SUA) has not been directly examined in humans. We analysed simultaneous micro wire recordings of single-unit activity (N = 1417) and local field potentials (N = 917 channels) from the medial temporal lobe (MTL) of epilepsy patients performing a visual multi-item sequence memory task. During encoding, both spiking activity and gamma power contained item-specific information and were temporally coupled. During memory maintenance, stimulus-specific gamma was characterized by recurring bursts during which spiking was tightly synchronized and both, gamma and spiking, were preferentially aligned to similar theta phases predictive of sequential stimulus position. These findings demonstrate that theta-gamma-spike interactions support a phase-based multiplexed code for sequential memories in the human MTL.

neuroscience↗

bioRxiv2024

Region-specific spreading depolarization drives aberrant post-ictal behavior

Confusion, aphasia, and unaware wandering are prominent post-ictal symptoms regularly observed in temporal lobe epilepsy (TLE)1. Despite the potentially life-threatening nature of the immediate post-ictal state2, its neurobiological underpinnings remain understudied3. We provide evidence in mice and humans that seizure-associated focal spreading depolarization (sSD) is a pathoclinical key factor in epilepsy. Using two-photon or widefield imaging (hippocampus, neocortex), field potential and single unit recordings, and behavioral assessment in mice, we first studied seizures during viral encephalitis, and subsequently established an optogenetic approach to dissociate hippocampal seizures and SD. We find region-specific occurrence of sSD that displays distinct spatial trajectories to preceding seizures, and show that seizure-related and isolated hippocampal SD prompt post-ictal wandering. This clinically relevant locomotor phenotype occurred in the absence of hippocampal SD progression to the neocortex. Finally, we confirm sSD existence in human epilepsy, in a patient cohort with refractory focal epilepsy, via Behnke-Fried electrode recordings. In this cohort, sSD displayed a similar temporomesial propensity as in mice. This work uncovers sSD as a previously underrecognized pathoclinical entity underlying postictal behavioral abnormalities in epilepsy. Our results carry wide-reaching ramifications for epilepsy research and neurology, and challenge current EEG-standards.

neuroscience↗

bioRxiv2023

How coupled slow oscillations, spindles and ripples control neuronal processing and communication during human sleep

Learning and plasticity rely on fine-tuned regulation of neuronal circuits during offline periods. An unresolved puzzle is how the sleeping brain - in the absence of external stimulation or conscious effort - controls neuronal firing rates (FRs) and communication within and across circuits, supporting synaptic and systems consolidation. Using intracranial Electroencephalography (iEEG) combined with multiunit activity (MUA) recordings from the human hippocampus and surrounding medial temporal lobe (MTL) areas, we here show that governed by slow oscillation (SO) up-states, sleep spindles set a timeframe for ripples to occur. This sequential coupling leads to a stepwise increase in (i) neuronal FRs, (ii) short-latency cross-correlations among local neuronal assemblies and (iii) cross-regional MTL interactions. Triggered by SOs and spindles, ripples thus establish optimal conditions for spike-timing dependent plasticity and systems consolidation. These results unveil how the coordinated coupling of specific sleep rhythms orchestrates neuronal processing and communication during human sleep.

neuroscience↗

bioRxiv2022

A key role of the hippocampal P3 in the attentional blink

The attentional blink (AB) refers to an impaired identification of target stimuli (T2), which are presented shortly after a prior target (T1) within a rapid serial visual presentation (RSVP) stream. It has been suggested that the AB is related to a failed transfer of T2 into working memory and that hippocampus (HC) and entorhinal (EC) cortex are regions crucial for this transfer. Since the event-related P3 component has been linked to inhibitory processes, we hypothesized that the hippocampal P3 elicited by T1 may impact on T2 processing within HC and EC. To test this hypothesis, we reanalyzed microwire data from 21 patients, who performed an RSVP task, during intracranial recordings for epilepsy surgery assessment (Reber et al., 2017). We identified T1-related hippocampal P3 components in the local field potentials (LFPs) and determined the temporal onset of T2 processing in HC/EC based on single-unit response onset activity. In accordance with our hypothesis, T1-related single-trial P3 amplitudes at the onset of T2 processing were clearly larger for unseen compared to seen T2-stimuli. Moreover, increased T1-related single-trial P3 peak latencies were found for T2[unseen] versus T2[seen] trials in case of lags 1 to 3, which was in line with our predictions. In conclusion, our findings support inhibition models of the AB and indicate that the hippocampal P3 elicited by T1 plays a central role in the AB.

neuroscience↗

bioRxiv2020

Auditory beat stimulation modulates memory-related single-neuron activity in the human medial temporal lobe

Auditory beats are composed of two sine waves using nearby frequencies, which can either be applied as a superposed signal to both ears or to each ear separately. In the first case, the beat sensation results from hearing an amplitude-modulated signal (monaural beat). In the second case, it is generated by phase-sensitive neurons in the brain stem (binaural beat). We investigated the effects of monaural and binaural 5 Hz beat stimulation on neural activity and memory performance in neurosurgical patients performing an associative recognition task. Previously, we had reported that these beat stimulation conditions modulated memory performance in opposite directions. Here, we analyzed data from a patient subgroup, in which microwires were implanted in the amygdala, hippocampus, entorhinal cortex and parahippocampal cortex. We identified neurons responding with firing rate changes to binaural versus monaural 5 Hz beat stimulation. In these neurons, we correlated the differences in firing rates for binaural versus monaural beats to the memory-related differences for remembered versus forgotten items and associations. In the left hemisphere for these neurons, we detected statistically significant negative correlations between firing rate differences for binaural versus monaural beats and remembered versus forgotten items/associations. Importantly, such negative correlations were also observed between beat stimulation-related firing rate differences in the baseline window and memory-related firing rate differences in the poststimulus windows. In line with concepts of homeostatic plasticity, we interpret our findings as indicating that beat stimulation is linked to memory performance via shifting baseline firing levels.

neuroscience↗