EXPRESS: Measuring solute clearance across brain states: methods and the sleep–brain–drain debate

BACKGROUND: The glymphatic hypothesis posits that cerebrospinal fluid and interstitial fluid bulk-flow clears brain waste, with increased waste transport during sleep. Recent studies reporting the opposite have generated substantial controversy. Three issues underlie the controversy surrounding this hypothesis and are the subject of this reviewMethods:We critically reviewed these three issues. First, we identified heterogeneity in the methods used to quantify brain "clearance" and evaluated their validity, recalculating rate constants from published data where these were not originally reported. Second, we examined uncertainty regarding the physical forces driving fluid and solute movement, and how assumptions about advection influence model specification. Third, we critiqued the dichotomization of brain state into "sleep" and "wakefulness". RESULTS: Clearance rates reported by competing groups fall within a similar range, yet the conclusions drawn about the influence of sleep are diametrically opposed. No gold-standard approach exists either for measuring clearance or for defining and inducing brain states. CONCLUSION: These conflicting results cannot be adjudicated: the debate persists not because the rates differ but because no shared standard exists to determine whether the opposing state-associations are real. Methodological standardization is a precondition for a reproducible account of how brain solute clearance is regulated.