Sleep deprivation exhibits age-dependent effect on infra-slow global brain activity

Infra-slow (< 0.1 Hz) global brain activity, quantified by the global mean BOLD (gBOLD) signal in resting-state fMRI, is elevated during sleep and closely associated with cerebrospinal fluid (CSF) dynamics, a key mechanism for the brain waste clearance implicated in neurodegenerative disorders such as Alzheimer’s disease (AD). However, the effect of sleep deprivation on gBOLD activity and its interaction with aging remain poorly understood. Using a rigorously controlled in-laboratory total sleep deprivation (TSD) protocol, we demonstrate that TSD significantly increases both the amplitude of the gBOLD signal and its coupling with CSF flow, suggesting a compensatory mechanism that may enhance glymphatic clearance following acute sleep loss. Notably, these TSD-induced enhancements exhibit robust age dependency, with diminished responses in individuals at midlife (40-50 yrs). The absence of this compensatory mechanism in these midlife participants may exacerbate age-related impairments in neurotoxic clearance and increase dementia susceptibility, thereby offering mechanistic insights into the nexus between sleep disruption, aging, and neurodegeneration.