Maiken Nedergaard
During wakefulness, neuromodulators operate largely independently to support behavior and cognition. By contrast, sleep reorganizes their activity into a coordinated brain rhythm. During sleep, the major neuromodulators-norepinephrine, acetylcholine, serotonin, and dopamine-exhibit synchronized fluctuations with a periodicity of ~50 seconds. These oscillations appear as recurrent bursts of fast (10 to 30 hertz) electroencephalography activity and are phase-coupled to cerebrospinal fluid flow. Neuromodulators are vasoactive agents and drive slow vasomotion, which provide the mechanical force that supports glymphatic clearance of metabolic waste. Disruption of neuromodulator signaling, as seen in psychiatric disorders, cardiovascular disease, aging, or with commonly prescribed drugs, impairs clearance of neurotoxic proteins, including amyloid-β and tau. Failure of this evolutionarily conserved brain rhythm may therefore represent a previously unrecognized mechanistic pathway linking diverse disorders with sleep disturbances to increased dementia risk.