bioRxiv Science⌕ Search

bioRxiv · 10.1101/2025.04.23.650361

Forecasting Seizure Duration from Neural Connectivity Patterns in a Neural Mass Model

Abstract

Understanding seizure duration is crucial for predicting seizure evolution and developing targeted therapeutic strategies. This study investigates how changes in neural connectivity patterns estimated in a Neural Mass Model (NMM) relate to seizure duration and whether these parameters can be used to forecast seizure duration. We applied a biologically plausible NMM to intracranial EEG recordings from a Tetanus Toxin rat model of epilepsy. Model parameters, representing synaptic connectivity strengths between excitatory and inhibitory neuronal populations across different cortical layers, were estimated using the Unscented Kalman Filter. A Random Forest classifier was trained to predict seizure duration (short vs. long) based on these connectivity parameters. We assessed the classification performance using the receiver operating characteristic (ROC) curve and area under the curve (AUC). Our findings reveal that stronger excitatory-to-excitatory connectivity before seizure onset was associated with longer seizure durations. In contrast, inhibitory-to-inhibitory and excitatory-to-inhibitory connectivity strengths decreased before long seizures. The Random Forest classifier achieved an AUC of 0.91 when using both preictal (1 minute before seizure onset) and early ictal (first 5 seconds of the seizures) parameters, demonstrating excellent predictive power. Classification using only preictal parameters resulted in an AUC of 0.70. Our study highlights the critical role of preictal neural connectivity in determining seizure duration. The findings suggest that network excitability and inhibitory control before seizure onset influence how long seizures persist. These insights provide a foundation for personalized, time-based therapeutic interventions and seizure management strategies, ultimately improving the quality of life of patients with epilepsy.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Zarei Eskikand, P., Cook, M., Burkitt, A. N., Grayden, D. B.. 2025-04-26. Forecasting Seizure Duration from Neural Connectivity Patterns in a Neural Mass Model. https://doi.org/10.1101/2025.04.23.650361

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

SilencioM: silencing connected interfering oligonucleotides against MAPT as a potential disease modifying therapeutic for tauopathies

Tauopathies are a diverse group of neurodegenerative diseases whose pathogenesis involves brain accumulation of misfolded, pathological tau (Microtubule Associated Protein Tau, MAPT). More than twenty tauopathies have been identified thus far that collectively impact millions of people worldwide, of which the most common is Alzheimer's disease (AD). Despite substantial efforts to develop drugs for tauopathies, no effective treatments currently exist, highlighting the urgent need for therapeutics to combat these prevalent and ruinous neurodegenerative diseases. Strategies that target tau are likely to have the greatest impact since tau is the proximal cause of their pathogenesis. Small interfering RNAs (siRNAs) have emerged as a powerful class of precision therapeutics that silence disease-causing genes through RNA interference with favorable safety profiles. Delivery challenges are rapidly being addressed, and siRNA-based approaches are poised to transform the therapeutic landscape of neurological diseases. In this study, we describe SilencioM (Silencing connected interfering oligonucleotides against MAPT) and show its efficacy in markedly reducing tau pathology after a single intracerebroventricular injection in PS19 mice, a mouse model of severe tauopathy. SilencioM targets human, primate, rat and mouse ortholog genes; thus, the same compound can proceed from efficacy studies to Investigational New Drug Application (IND)-enabling studies. SilencioM is simple to manufacture and is administered without encapsulation in lipid nanoparticles and without requirements for lipophilic conjugation, making it a promising candidate for further development as a novel therapeutic for tauopathies, including AD.

pathology↗

SilencioMA: A single compound that targets both MAPT and APP as a potential disease modifying therapeutic for Alzheimer's Disease

Alzheimer's Disease (AD) is the most common age-related neurodegenerative disease and the leading cause of dementia worldwide. AD pathogenesis involves aggregation of amyloid-beta (A{beta}), produced from amyloidogenic proteolytic processing of Amyloid Precursor Protein (APP), and accumulation of misfolded, pathological tau (Microtubule Associated Protein Tau, MAPT). Current efforts focus on developing disease modifying therapeutics (DMTs) against single targets: A{beta} or tau. However, DMTs that concurrently target both tau and A{beta} are likely to have the greatest impact since they target both culprits of AD pathogenesis. Here we describe the development of SilencioMA, a single compound that targets both MAPT and APP messenger RNAs (mRNAs) based on silencing connected interfering oligonucleotides against MAPT and APP. Cerebrospinal fluid (CSF) administration of SilencioMA reduces A{beta} and tau and pathology after a single intracerebroventricular injection in 5XFAD/PS19 mice, an animal model of severe amyloidosis and tauopathy. SilencioMA does not rely on lipid nanoparticles or lipophilic conjugates for CSF administration. At the same time its modular design permits conjugation of ligands that facilitate transcytosis through the blood brain barrier, allowing systemic administration. Our findings provide proof-of-concept for a strategy that targets the dual A{beta} and tau pathologies of AD, and establishes a compelling foundation for further development of SilencioMA as a next-generation DMT for AD.

pathology↗

TREM2-stimulated, PDGF-dependent macrophage-fibroblast crosstalk induces beneficial plaque remodeling in clonal hematopoiesis

Background: In Jak2V617F clonal hematopoiesis, inflammatory signaling suppresses macrophage TREM2 and promotes features of plaque instability, while therapeutic TREM2 agonism reverses plaque instability by increasing fibroblasts and fibrous cap formation. We tested whether macrophage-derived PDGFB and stromal cell PDGFR? signaling mediate this response. Methods: Low allele burden (LAB) Jak2V617F atherosclerosis models were combined with inducible Pdgfb deletion in CX3CR1-lineage monocytes/macrophages or Pdgfra deletion in Col1a2-lineage fibroblast-enriched stromal cells. Mice were treated with the TREM2 agonist 4D9. Plaque composition, macrophage-fibroblast interactions, and aortic stromal cell populations were analyzed. Human WT and JAK2V617F iPSC-derived macrophages were used for validation. Results: TREM2 activation with 4D9 increased macrophage PDGFB production and promoted fibrous cap formation in LAB Jak2V617F atherosclerosis. Deletion of Pdgfb in CX3CR1-lineage cells markedly attenuated the 4D9-mediated increase in fibrous cap area and lesional PDGFR?+ cells, establishing macrophage-derived PDGFB as a key signal for the stromal response. Consistently, Col1a2-lineage Pdgfra deletion abolished the 4D9-induced fibrous cap response without significantly altering lesion or necrotic core area. Single cell RNA-seq identified increased Fmod+ and CD26/Dpp4+ fibroblast populations associated with 4D9 treatment. Fmod+ fibroblasts represented an abundant matrix-associated population, whereas CD26+ fibroblasts showed greatest enrichment, prominent extracellular matrix, collagen organization, and matrix-remodeling programs that were enhanced by 4D9 and attenuated by Pdgfra deletion. The stromal response was also associated with reduced macrophage migration-related programs and predicted chemokine communication from CD26+ fibroblasts to macrophages which was verified by macrophage migration studies. Moreover, stromal Pdgfra deletion increased lesional CCR2+ and CCR5+ macrophages. Conclusions: In a CH model of inflammatory atherosclerosis, TREM2 activation promotes a macrophage PDGFB-stromal PDGFR? pathway that expands Fmod+ and CD26+ fibroblast populations and increases fibrous cap matrix formation. CD26+ fibroblasts impair macrophage chemotaxis in a DPP4-dependent manner, suggesting reciprocal macrophage-fibroblast communication that coordinates matrix remodeling and inflammatory cell trafficking in the plaque.

pathology↗