Biology subjects

Kudlacek, J.

Publications and source records attributed to Kudlacek, J..

5 recordsLinked to original sources

bioRxiv2026

High-frequency oscillations reveal progressive recruitment of remote cortex into the epileptic network in a mouse model of focal cortical dysplasia type II

Interictal epileptiform discharges (IEDs) and pathological high-frequency oscillations (HFOs) are established biomarkers of epileptogenic tissue, but how their spatiotemporal evolution reflects epileptic network reorganization in neocortical epilepsy remains unclear. We investigated longitudinal IED and HFO dynamics throughout epileptogenesis and chronic epilepsy in a mouse model of focal cortical dysplasia type II (FCD II). Long-term bilateral cortical recordings were obtained before and after spontaneous seizure onset. IEDs and HFOs (gamma, ripples, and fast ripples) were quantified in the dysplastic lesion and contralateral cortex during pre-epileptic, early, and late epileptic stages. The dysplastic lesion remained the principal seizure onset zone throughout disease progression and showed stable HFO activity after epilepsy onset. In contrast, the contralateral cortex exhibited progressive increases in IEDs and HFOs, demonstrating continuous recruitment into the epileptic network. Fast ripples were the earliest marker of this process, emerging within the first week after the first seizure and preceding increases in ripples, gamma, and IEDs. Propagation analysis showed that this contralateral increase was driven by independently generated HFOs rather than propagation from the lesion, indicating emergence of autonomous epileptogenic activity outside the primary focus. Spatiotemporal HFO analysis thus captures dynamic epileptic network remodeling beyond epileptogenic lesion. Fast ripples may serve as an early signature of network expansion and epileptogenicity emerging outside the primary lesion. Widespread structural and connectivity abnormalities extending beyond the lesion, combined with intense recurrent epileptic activity, may underlie the high endogenous epileptogenicity of FCD II, enabling small dysplastic lesions to recruit extensive neuronal networks across both hemispheres.

neuroscience↗

bioRxiv2026

Dasatinib-Quercetin May Reduce Senescence Markers, Without Senolysis or Seizure Modification, in a Mouse Model of Focal Cortical Dysplasia

Mounting evidence from surgical type II focal cortical dysplasia (FCD) tissues and mouse models have recently shown that dysmorphic neurons carrying MTOR mutations (DNs) in FCD exhibit hallmarks of cellular senescence. Building on pioneering work from the Baulac group identifying cellular senescence as a feature of mTOR-pathway FCD, a recent study by Ribierre et al. (2024) [1] proposed oral dasatinib and quercetin (DQ) as a therapy that partially decreases the load of mutant, senescent neurons and thus reduces seizure occurrence in FCD mice. Using a different mouse strain and a different gain-of-function mutation in MTOR, our data confirm the presence of senescence hallmarks in FCD mice, but do not support one of the conclusions of Ribierre et al.--that DQ acts as a senolytic in an FCD mouse model--and we propose an alternative interpretation. We longitudinally tracked individual cell fate using two-photon microscopy and complemented these data with EEG monitoring and immunohistochemistry. Immunohistochemical analyses were performed within the same sections using multiple markers, allowing direct identification of mutant neurons and assessment of senescence-associated labeling. While we observed a detectable reduction in a senescence-associated marker, consistent with a senomorphic effect, it did not translate into a change in seizure phenotype, despite treatment timing and dosing matching those in the original study. For detailed materials and methods, see Extended Methods.

neuroscience↗

bioRxiv2025

SEIZURE OCCURRENCE IN FCD TYPE II IS PREDICTED BY LESION POSITION AND LINKED TO CYTOARCHITECTURAL ALTERATIONS

Focal cortical dysplasia (FCD) is a common malformation of cortical development and a major cause of early-onset, drug-resistant epilepsy. FCD type II is defined by abnormal lamination, altered cellular composition, and pathological cells, notably dysmorphic neurons (DNs) and balloon cells. DNs are thought to drive epileptogenicity through both cell-autonomous and non-cell-autonomous mechanisms, the latter including not only aberrant connectivity but also indirect modulation of excitability in local cell populations. We performed a multiscale structural and morphological analysis to elucidate the basis of FCD epileptogenicity and the impact of somatic mTOR mutations during brain development. Using a mouse model of FCD type II, we show that lesions in frontal and motor cortical regions are the strongest predictors of spontaneous seizure occurrence. This localization-dependent epileptogenicity offers an experimental explanation for the higher clinical epileptogenicity of frontal FCDs and suggests that posterior lesions may remain silent--an open question in human pathology. In our model, FCD tissue displayed considerable expansion, with cortical thickness up to [~]20% in seizure-bearing animals. This expansion coincided with an overall [~]40% reduction in neuronal density, consistent with tissue hypertrophy. DN density did not differ between seizure and non-seizure animals, challenging the notion that higher DN load directly predicts epileptogenesis. At the microscopic level, we describe DN axonal pathologies, including giant varicosities. In the cortex, these appeared as vesicle-filled boutons, whereas along callosal axons they were frequent but largely empty. Bouton density was markedly reduced in FCD cortex. Together, these findings leave the net synaptic effect of dysmorphic neurons unresolved, challenging the assumption that axonal hypertrophy translates into increased excitatory drive. While morphological abnormalities in FCD type II are well documented, their functional consequences remain incompletely understood. Here, we used macro- and microscopic structural features of FCDII to assess seizure susceptibility, providing new insights into epileptogenesis.

neuroscience↗

bioRxiv2025

Interictal activity fluctuations follow rather than precede seizures on multiple time scales in a mouse model of focal cortical dysplasia

The unpredictability of seizure occurrence is a major debilitating factor for people with epilepsy. A seizure forecasting system would greatly improve their quality of life. Successful seizure forecasting necessitates a comprehensive understanding of the factors influencing seizure timing at multiple temporal scales. In this study, we investigated multiscale properties of interictal epileptiform discharges (IEDs) and seizure parameters in a highly realistic mouse model of focal cortical dysplasia-related epilepsy. We analyzed the properties evolution at four timescales, ranging from epilepsy progression and seizure clusters to circadian and peri-ictal changes. We discovered that the FCD-related epilepsy syndrome was progressive in terms of interictal activity rate and seizure characteristics. Sixty percent of seizures occurred in clusters. During the clusters, the seizure duration, seizure power, and IED rate were increasing. Circadian rhythm influenced seizure occurrence with the peak seizure probability at 4 p.m. under a standard 12/12 light dark cycle with lights-on at 6 a.m. Peri-ictal analysis revealed no significant change in IED rate preceding individual seizures; however, a consistent two-peak pattern of IED elevation was observed following seizures. Specifically, an initial peak in IED rate emerged 5-10 minutes post-seizure, returning to baseline within two hours, followed by a secondary peak 6-12 hours later, which again subsided to baseline levels in 24-48 hours. This pattern could be fitted with a sum of three exponentials. Using the three-exponential pattern, we simulated IED rate fluctuations in each animal. The smoothed simulated IED rates showed good agreement with the smoothed real recorded IED rates, suggesting that the cumulative effect of post-ictal IED patterns can account for long-term fluctuations in IED rate. Our results indicate that, in our model of FCD-related epilepsy, consistent IED rate fluctuations follow rather than precede individual seizures. Therefore, fluctuations in IED rate can be viewed as a reflection of cyclic seizure occurrence. This implies that either IED rate fluctuations or accurate seizure records may be equally valuable for seizure risk forecasting. HighlightsO_LIFCD-related epilepsy model displays a progressive nature and fluctuations between high and low seizure risk. C_LIO_LISeizures occur with higher probability in the day time which corresponds to sleep-related seizures commonly occurring in human patients with FCD. C_LIO_LIIED rate increases significantly after seizures, indicating a postictal effect rather than a preictal one, with the post-ictal phase displaying a two-peak pattern of fast and slow IED rate increase. C_LIO_LILong-term changes in the IED rate could be attributed to the time-dependent cumulative effect of the two-peak seizure-related increase in IED rate. C_LI

neuroscience↗

bioRxiv2025

Ion Dynamics Underlying the Seizure Delay Effect of Low-Frequency Electrical Stimulation

The biological mechanisms underlying the spontaneous and recurrent transition to seizures in the epileptic brain are still poorly understood. As a result, seizures remain uncontrolled in a substantial proportion of patients. Brain stimulation is an emerging and promising method to treat various brain disorders, including drug-refractory epilepsy. Selected stimulation protocols previously demonstrated therapeutic efficacy in reducing the seizure rate. The stimulation efficacy critically depends on chosen stimulation parameters, such as the time point, amplitude, and frequency of stimulation. This study aims to explore the neurobiological impact of 1Hz stimulation and provide the mechanistic explanation behind its seizure-delaying effects. We study this effect using a computational model, a modified version of the Epileptor-2 model, in close comparison with such stimulation effects on spontaneous seizures recorded in vitro in a high-potassium model of ictogenesis in rat hippocampal slices. In particular, we investigate the mechanisms and dynamics of spontaneous seizure emergence, the seizure-delaying effect of the stimulation, and the optimal stimulation parameters to achieve the maximal anti-seizure effect. We show that the modified Epileptor-2 model replicates key experimental observations, and captures seizure dynamics and the anti-seizure effects of low-frequency electrical stimulation (LFES) observed in hippocampal slices. We identify the critical thresholds in the model for seizure onset and determine the optimal stimulation parameters - timing, amplitude, and duration - that exceed specific thresholds to delay seizures without triggering premature seizures. Our study highlights the central role of sodium-potassium pump dynamics in terminating seizures and mediating the LFES effect. Author SummaryThis study investigates the mechanisms by which low-frequency electrical stimulation can suppress epileptic seizures. Epilepsy patients often do not respond to pharmacological treatment, necessitating alternative approaches, such as brain stimulation. Using a combination of computational modeling and in vitro experiments on rat hippocampal slices, we examine how periodic stimulation at 1 Hz influences seizure occurrence. Our results show that carefully timed low-frequency stimulation can delay seizure onset by modulating neuronal excitability, largely through the action of the Na-K-pump that maintains ion homeostasis. We employ a modified version of the Epileptor 2 model to reproduce the protective effects seen experimentally. By systematically varying stimulation parameters, we identify conditions that effectively delay seizures, helping to explain the antagonistic effects of stimulation observed by previous studies. Overall, this work advances our understanding of how low-frequency electrical stimulation interacts with intrinsic neuronal mechanisms to prevent seizures, thus offering a potential target for more effective neuromodulation strategies in drug-resistant epilepsy.

neuroscience↗