Fast ripple-delta coupling as an early biomarker for post-traumatic epileptogenesis in repetitive brain injury.

Abstract

OBJECTIVE: Traumatic brain injury (TBI) can induce posttraumatic epilepsy (PTE), but early biomarkers for epileptogenesis are lacking. We aimed to investigate electrographic biomarkers before and during posttraumatic seizure development. METHODS: We used a repetitive diffuse TBI model in mice with continuous video-EEG monitoring up to 4½ months postinjury. RESULTS: Twenty-five percent of mice developed posttraumatic seizures (PTS) with highly variable latency (5-126 days postinjury). 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 interictal activity escalation. These electrographic signatures were remarkably consistent across all seizure-experiencing animals regardless of single or recurrent seizure pattern. SIGNIFICANCE: 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 PTS 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 PTS occurrence. These findings emphasize the utility of temporal EEG analysis for detecting early electrographic changes in posttraumatic epileptogenesis and may inform future intervention strategies. PLAIN LANGUAGE SUMMARY: Some people develop epilepsy after a traumatic brain injury, but it is currently impossible to predict who is at risk. Using mice, we found that a specific brain wave pattern, brief bursts of very fast electrical activity occurring during deep sleep, appeared within days after injury in animals that later developed seizures. This pattern was not seen in injured animals that remained seizure-free. Detecting this early warning sign could help identify at-risk individuals and enable earlier treatment to potentially prevent epilepsy.