FIGURE 20.

Glymphatic activity and cerebrospinal fluid (CSF) egress during sleep and wakefulness. The glymphatic system is primarily active during deep sleep, when brain clearance more than doubles compared with wakefulness. This is likely due to an increase in extracellular volume fraction, which in rats is ∼14% during wakefulness but increases to 23% in a process dependent on the loss of noradrenergic signaling from the locus coeruleus (1). This could occur by a mechanism whereby perivascular space access is shut off during periods of high noradrenergic tonus, but then opens up for fluid influx during the low noradrenergic tonus of sleep. The rate of CSF egress from the subarachnoid space shows an inverse relationship with glymphatic activity, thus increasing during wakefulness and decreasing during sleep (523). Top row: the relationship between sleep and glymphatic activity. It is important to note that many details of the interconnection between the various stages of sleep and glymphatic flow remain to be determined. For example, the activity of the glymphatic system during rapid eye movement (REM) sleep is unknown. Bottom row: the critical importance of the extracellular volume fraction on glymphatic flow in the active state (left) and during inactivity [non-REM (NREM) sleep, right]. See sect. 12.10 for details on CSF egress. ISF, interstitial fluid.