Fast Ripple-Delta Coupling as Early Biomarker for Post-Traumatic Epileptogenesis in Repetitive Brain Injury

Traumatic brain injury (TBI) can induce post-traumatic epilepsy (PTE), but early biomarkers for epileptogenesis are lacking. We used a repetitive diffuse TBI (rdTBI) model in mice with continuous video-EEG monitoring up to 4½ months post-injury to investigate electrographic biomarkers before and during post-traumatic seizure development. 25% of mice developed post-traumatic seizures with highly variable latency (5-126 days post-injury). Most significantly, we identified fast ripple-delta DOWN state coupling as an early biomarker that was detectable at 4 days post-TBI and appeared before seizure onset in all seizure-experiencing mice. This EEG signature distinguished seizure-experiencing from seizure-free TBI mice with high specificity. Power spectrum analysis revealed elevated delta and theta power, reduced physiological fast oscillations (alpha, beta, gamma) and increased pathological high-frequency oscillations (fast ripples) in seizure-experiencing animals, indicating network hyperexcitability. Spike analysis showed that while TBI itself increased cortical excitability, seizure onset triggered a dramatic further escalation in interictal activity. These electrographic signatures were remarkably consistent across all seizure-experiencing animals regardless of single or recurrent seizure pattern. Our results demonstrate that fast ripple-delta coupling represents a promising early biomarker detectable at 4 days post-TBI, before seizure onset, offering potential for early identification of post-traumatic seizure susceptibility. Importantly, this biomarker identified all seizure-prone animals regardless of whether they developed single or recurrent seizures, suggesting shared underlying mechanisms and clinical relevance for any post-traumatic seizure occurrence. These findings emphasize the utility of temporal EEG analysis for detecting early electrographic changes in post-traumatic epileptogenesis and may inform future intervention strategies.