Optimizing responsive neurostimulation targeting based on interictal high‐frequency oscillations and phase–amplitude coupling

Objective This study was undertaken to determine whether interictal high‐frequency oscillations (HFOs) and phase–amplitude coupling (PAC) can serve as spatial biomarkers on intracranial electroencephalography (iEEG) to guide responsive neurostimulation (RNS) targeting. Methods We conducted a retrospective study of patients with drug‐resistant epilepsy who underwent iEEG monitoring and subsequent RNS implantation. Eligible participants had ≥60 min of slow‐wave sleep iEEG data and ≥6 months of post‐RNS follow‐up. Patients with simultaneous or subsequent resective surgery or exclusively thalamic RNS electrodes were excluded. Interictal HFOs and delta–HFO PAC (via modulation index [MI]) were calculated using open‐source tools (PyHFO, PACTv0.31). Weighted median distances from each iEEG electrode to the nearest RNS electrode were computed, adjusted by the proportion of HFO and MI. The primary outcome was ≥50% seizure reduction (good outcome group [G]) vs. <50% reduction (poor outcome group [P]) at the last follow‐up. Predictive performance was evaluated using receiver operating characteristic (ROC) analysis with leave‐one‐out cross‐validation. Results Eighteen patients (median follow‐up = 36 months in group G, 33 months in group P; median age = 14.5 years, range = 6–28) met the inclusion criteria, with 10 achieving good outcomes. Weighted median distances from RNS electrodes to peak HFO and MI sites were significantly shorter in group G than in group P (rank‐biserial correlation = .30–.45, p < .0001). ROC analysis indicated that distances within 20–30 mm between stimulation sites and peak biomarker locations were optimal (area under the curve > .70 for both HFOs and PAC), outperforming seizure onset zone (SOZ)‐based targeting. Exploratory analysis showed favorable outcomes for patients with thalamic electrodes stimulating areas of elevated HFO or MI. Significance RNS electrode placement guided by interictal HFOs and delta–HFO PAC distribution may offer a feasible, effective alternative to conventional SOZ‐based approaches. These findings have immediate clinical relevance due to validated open‐source analytical tools, facilitating widespread implementation and prospective validation across multiple institutions.