LPS-induced systemic inflammation disrupts brain activity in a region- and vigilance-state specific manner

Sepsis-associated encephalopathy (SAE) is a common complication of sepsis and the systemic inflammatory response syndrome that leads to lasting consequences in survivors. It manifests as early EEG changes that are region-, time- and state-specific, possibly reflecting distinct mechanisms of injury. Here, we investigated the effects of 5 mg/kg lipopolysaccharide (LPS) on hippocampal and cortical sleep-wake states, oscillatory and non-oscillatory neuronal activity, as well as on within- and between-state dynamics using state-space analysis. LPS induced rapid-onset severe temporal and spatial vigilance state fragmentation, which preceded all other spectral changes by ∼90 min. Thereafter, LPS led to specific destabilization and increased delta oscillatory activity in wakefulness, but not NREM sleep, although state transitions remained largely normal. Instead, reduced NREM delta power resulted from aperiodic spectrum changes. LPS specifically reduced higher frequency hippocampal gamma oscillations (60-80 Hz peak) in wakefulness, but not cortical high gamma or lower frequency gamma oscillations. These results suggest that disruption of sleep-wake patterns could serve as an early indicator of sepsis and associated encephalopathy, independent of spectral changes. Moreover, treatment aimed at stabilizing vigilance states in early stages of sepsis might prove to be a novel option preventing the development of further pathological neurophysiology, as well as limiting inflammation-related brain damage.