Circadian modulation of aperiodic background and oscillatory activity as a biomarker of seizure burden in Lennox-Gastaut syndrome.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a severe childhood onset epilepsy marked by drug-resistant seizures and generalized electroencephalographic abnormalities. Because patient-reported seizures are often unreliable, objective biomarkers are needed. This study investigates circadian modulation of aperiodic and oscillatory brain activity as a potential monitoring biomarker of seizure burden in LGS. METHODS: We analyzed baseline intracranial recordings from 19 patients with LGS implanted bilaterally with responsive neurostimulation (RNS) targeting the centromedian-parafascicular thalamic complex (CM-Pf) and premotor frontal cortex in an ongoing clinical trial (ClinicalTrials.gov: NCT05339126). Aperiodic (nonoscillatory) and periodic (oscillatory) components were extracted from scheduled recordings without epileptiform activity or stimulation. Circadian modulation was defined as the difference between daytime and nighttime measures of these components. Seizure burden was quantified as the percentage of days with at least one reported seizure, pre- and postimplantation, validated by an objective device-based measure (average daily detections). RESULTS: Higher seizure burden was associated with reduced diurnal modulation of both aperiodic and oscillatory activity. This relationship was anatomically specific, appearing as a significant negative correlation only in contacts within an LGS network "hotspot" in caudal middle frontal gyrus previously identified in LGS, and a positive correlation in thalamic contacts outside the CM-Pf. SIGNIFICANCE: These results suggest that abnormal circadian rhythmicity may provide a candidate monitoring biomarker of disease severity in LGS that localizes to a previously defined LGS network and may extend beyond the traditional CM-Pf target.