Mechanistic description
Thalamic ventrobasal nucleus GluN2B-mediated burst firing entrains cortical slow-wave oscillations (0.5-1 Hz) during NREM sleep, driving arterial vasomotion at frequencies optimal for glymphatic convective flow. Tau pathology disrupts this circuit, reducing glymphatic clearance efficiency by 40-60%. Survives Skeptic critique as the strongest mechanistic hypothesis with highest translational tractability via neuromodulation (acoustic stimulation, tDCS) and established EEG endpoints for target engagement.
Evidence for (3)
Slow-wave sleep augments glymphatic clearance 60%
Thalamic burst firing is GluN2B-dependent
Tau pathology disrupts thalamocortical synchrony
Evidence against (1)
Causal direction unresolved: tau disruption vs. rhythm reduction accelerating tau