Electrophysiological signatures of acute systemic lipopolysaccharide: potential implications for delirium science

Background: Novel preventive therapies are needed for postoperative delirium, which especially affects aged patients. A mouse model is presented that captures inflammation-associated cortical slow wave activity (SWA) observed in patients, allowing exploration of the mechanistic role of prostaglandin-adenosine signaling. Methods: EEG and cortical cytokine measurements (interleukin 6 [IL-6], monocyte chemoattractant protein-1 [MCP-1]) were obtained from adult and aged mice. Behavior, SWA, and functional connectivity (alpha-band weighted phase lag index) were assayed before and after systemic administration of lipopolysaccharide (LPS) +/- piroxicam (cyclooxygenase inhibitor) or caffeine (adenosine receptor antagonist). To avoid confounds from inflammation-driven changes in movement, which alter SWA and connectivity, electrophysiological recordings were classified as occurring during quiescence or movement, and propensity score matching used to match distributions of movement magnitude between baseline and LPS. Results: LPS produces increases in cortical cytokines and behavioral quiescence. In movement-matched data, LPS produces increases in SWA (likelihood-ratio test: χ2(4)=21.51, p=0.00057), but not connectivity (χ2(4)=6.39, p=0.17). Increases in SWA associate with IL6 (p<0.001) and MCP-1 (p=0.001) and are suppressed by piroxicam (p<0.001) and caffeine (p=0.046). Aged animals compared to adult show similar LPS-induced SWA during movement, but exaggerated cytokine response and increased SWA during quiescence. Conclusions: Cytokine-SWA correlations during wakefulness are consistent with observations in patients with delirium. Absence of connectivity effects after accounting for movement changes suggests decreased connectivity in patients is a biomarker of hypoactivity. Exaggerated effects in quiescent aged animals are consistent with increased hypoactive delirium in older patients. Prostaglandin-adenosine signaling may link inflammation to neural changes and hence delirium.