Is glymphatic clearance the secret to restorative sleep?

Abstract Despite the universal need for sleep across animal species, the biological mechanisms underlying the restorative aspects of sleep remain poorly understood. While sleep architecture is traditionally evaluated using EEG, multiple studies have shown a mismatch between EEG-defined parameters and subjective sleep quality. In particular, slow-wave activity – a hallmark of non-REM (NREM) sleep – does not consistently align with perceptions of sleep depth or subsequent well-being. This discrepancy suggests that core physiological processes beyond neuronal activity contribute to the restorative value of sleep. Recent discoveries have identified the glymphatic system as a brain-wide clearance pathway that facilitates the removal of metabolic waste during sleep. In rodents, glymphatic activity is driven by a complex interplay between norepinephrine oscillations, vascular dynamics, and cerebrospinal fluid (CSF) flow – particularly during NREM sleep. Human imaging studies have revealed parallel signatures, including large-scale CSF pulsations and inverse coupling between blood and CSF volumes during sleep. Disruption of these infraslow dynamics has been observed in conditions such as insomnia, chronic fatigue, and sleep misperception, suggesting a potential link between impaired glymphatic function and non-restorative sleep. This review synthesizes the current evidence for glymphatic clearance as a contributor to sleep’s restorative function, discusses emerging biomarkers, such as cyclic alternating patterns (CAP) and pupil-based proxies of noradrenergic tone, and highlights the need for improved methods to evaluate glymphatic function in humans. We propose that brain clearance may represent a key physiological determinant of restorative sleep and suggest future directions to test this hypothesis across health and disease.