FIGURE 19.

Physiological drivers of the glymphatic system. Flow in the glymphatic system is established by different physiological processes driving intracerebral pressure gradients. Top left inset: anterograde cerebral spinal fluid (CSF) flow in perivascular spaces of leptomeningeal surface arteries is driven by perivascular pumping. The distension of the arterial wall caused by the cardiac impulse wave pumps CSF forward in a pulsatile fashion, where increased CSF flow velocity occurs in phase with the R component of the ECG (systole) (21). Bottom left inset: the respiratory cycle changes intrathoracic pressure, which affects central venous pressure and also the cardiac cycle (respiratory bradycardia). This in turn affects venous pressure in brain as well as intracranial pressure (ICP). Intraventricular CSF flow is thus highly dependent on the respiratory cycle, where inspiration leads to a drop in venous blood volume in brain, thus causing increased flow of CSF into the ventricular system. Forced inspiration can increase this CSF flow rate (498, 515). In the glymphatic system, the venous pressure changes caused by the respiratory cycle are believed to have earlier and greater effects on perivenous spaces than periarterial spaces (495). This might impose a pressure gradient facilitating extracellular fluid flow toward the venous compartment during each inspiration. Top right inset: increased brain extracellular volume is associated with increased glymphatic function that occurs during sleep. The 60% increase in extracellular space volume that typically occurs during nonrapid eye movement (NREM) sleep causes a drop in hydraulic resistance that promotes fluid flow through the parenchyma (1). ECS, extracellular space. Bottom right inset: changes in arterial and arteriolar diameter caused by autoregulation of smooth muscle cell tone have been associated both with intraventricular CSF flow and brain clearance. In the 4th ventricle, increased CSF inflow deeper into the ventricular system has an anticorrelation with the blood oxygen level-dependent (BOLD) signal on functional MRI. This suggests that loss of cerebral blood volume due to vasoconstriction following the hyperemia induced by global increases in neural activity during NREM sleep increases CSF flow (501). Brain fluid clearance in mice has also been associated with vasomotion, both in association with 0.1-Hz neuronal oscillations occurring during wakefulness and during evoked functional hyperemia (439). PVS, perivascular space.