Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an established treatment for patients with drug-refractory epilepsy (DRE), yet long-term therapeutic outcomes are highly variable and challenging to predict. This variability is compounded by the delayed and gradual effects of DBS, the difficulty of consistent seizure monitoring, and the absence of physiological biomarkers to inform treatment. In this study, we analyzed longitudinal intracranial recordings over a four-year observational period from a cohort of 22 patients with ANT-DBS. Our primary goal is the identification of neurophysiological signatures that could predict and track clinical DBS response. Our results show that DBS-responders and non-responders exhibit distinct ANT spectral trajectories over time, with responders showing a progressive increase in higher frequencies (β₁,γ) and decreased lower-frequency (δ,θ) activity, as compared to non-responders. Notably, these dynamic biomarkers, particularly high-to-low frequency ratios (e.g., β₁/θ), enabled the early discrimination of clinical outcomes. Additionally, we provide evidence of robust circadian and multidien rhythms in ANT local field potentials, with further analyses supporting the feasibility of adaptive stimulation protocols to improve therapeutic outcomes. Together, these findings propose ANT spectral dynamics in outpatient settings as a promising tool for early prediction of therapeutic efficacy and pave the way for biomarker-guided optimization of DBS therapy in epilepsy.

The authors have declared no competing interest.

This work was funded by a grant awarded to R.P. and L.I. from the Swiss National Science Foundation (SNF 197766). The authors report no competing interests.

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Local ethics committee (Kantonale Ethikkommission, KEK Zurich) gave ethical approval for this work

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