Toward Unified Biomarkers for Focal Epilepsy

Accurately localizing the epileptogenic network (EpiNet) remains a major barrier to effective epilepsy treatment, largely due to limited mechanistic understanding. The EpiNet is a patient-specific brain network shaped by complex, overlapping pathology. While combining biomarkers can improve localization, it also generates high-dimensional feature data that increases the risk of overfitting and reduces interpretability. We hypothesized that the core epileptogenic dynamics could be captured in a low-dimensional latent space derived from empirical data, without the need to record seizures. From interictal stereo-EEG (SEEG) recordings in 64 patients (29 females), we extracted 260 neuronal features and reduced them to 10 latent components using singular value decomposition. A classifier trained on these 10 components was then simplified into a probabilistic EpiNet model requiring only two components as input. Individual position in this two-dimensional latent space correlated with previously reported classification accuracy (<i>r</i> ² = 0.5), supporting its functional relevance. In three independent patients, the probabilistic model captured time-varying epileptogenic dynamics during sleep-SEEG recordings, corroborated clinical assessments, and achieved peak classification accuracies of 0.63, 0.85, and 0.94. These predictions were independently validated by tensor component analysis. Together, these results provide evidence for a robust low-dimensional representation of epileptogenicity across brain states and pathological substrates. This approach simplifies interpretation, facilitates integration of additional biomarkers, and enables large-scale cohort analyses, establishing a proof of concept for a unified framework for epilepsy biomarkers.