Chronic Sleep Deprivation as a Neuroinflammatory Trigger: Clinical Evidence and Theoretical Framework for the Peripheral-Central Amplification Loop

Background: Over 2.5 billion people worldwide are affected by chronic sleep deprivation, but there is no integrated theoretical framework explaining how it induces neuroinflammation. Current research is limited to single pathway analyses and does not explain the nature of sleep deprivation as a trigger for multi-system dysregulation. Methods: Systematic retrieval of adult clinical studies from 2015 to 2025, including participants with ≥24 hours of sleep deprivation, ≥2 inflammatory biomarkers, and cognitive assessment; data pooled on a logarithmic scale and converted to odds ratios, reporting 95% confidence intervals and τ²-based prediction intervals. Results: A total of 42 studies (n = 3,847) were included in the analysis. The cumulative sample size across these studies reached 53,847 participants.Chronic deprivation (defined as a minimum of three nights and less than five hours of sleep per night) was found to be significantly correlated with increased levels of IL-6 (2.42-fold increase, 95% CI 2.11–2.73, PI 1.35–4.10), TNF-α (1.89-fold increase, 1.67–2.11, PI 1.20–2.95), and CRP (1.76-fold increase, 1.59–1.93, PI 1.20–2.55). The peak of inflammation occurred on days 3–5, after which it transitioned to a self-sustaining state. The systemic immune-inflammatory index demonstrated a negative correlation with cognition (r = −0.61, P < 0.001). Furthermore, Hartung-Knapp adjustments and sensitivity analyses supported the robustness of the findings. Conclusions : Sleep deprivation establishes a self-sustaining loop via peripheral activation-blood-brain barrier disruption-glial response, consistent with PCAL. Three falsifiable predictions and a 72-hour intervention window are proposed, pointing towards combined circadian-sleep trials with ‘peripheral-central inflammatory phase convergence’ as primary endpoint.