Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension

Abstract

Flow of cerebrospinal fluid (CSF) through perivascular spaces (PVSs) in the brain is important for clearance of metabolic waste. Arterial pulsations are thought to drive flow, but this has never been quantitatively shown. We used particle tracking to quantify CSF flow velocities in PVSs of live mice. CSF flow is pulsatile and driven primarily by the cardiac cycle. The speed of the arterial wall matches that of the CSF, suggesting arterial wall motion is the principal driving mechanism, via a process known as perivascular pumping. Increasing blood pressure leaves the artery diameter unchanged but changes the pulsations of the arterial wall, increasing backflow and thereby reducing net flow in the PVS. Perfusion-fixation alters the normal flow direction and causes a 10-fold reduction in PVS size. We conclude that particle tracking velocimetry enables the study of CSF flow in unprecedented detail and that studying the PVS in vivo avoids fixation artifacts.

Intracranial pressure elevation alters CSF clearance pathways

“…The maximal recorded PVS velocity (not including model 6) was computed to be 5.66 µm/s in model 4. In the experimental studies, several investigators used an infusion rate of 2 µL/min in rodents [30,31,46], which was shown to increase ICP by 2.5 mmHg [31], a substantial increase, but less than in our model of a human with an infusion rate of 1.5 mL/min. In addition, Bedussi et al [5], used a much lower infusion rate of 0.34 µL/min, only resulting in a pressure rise of 0.1 mmHg.…”

“…Mestre et al [46] demonstrate PVS collapse after fixation. This observation entails that a gap size of 100 nm at the precapillary level, as used by Faghih and Sharp [19] and measured after fixation, may be an underestimation.…”

“…However, other studies suggest flow within the paravascular spaces at the level of capillaries [65,25]. Furthermore, it has been argued that fixation, which was used by Bedussi et al [5], shrinks the PVS [46]. As such, the resistance of the PVS at the capillary level should be further investigated and compared to the high resistance to flow through the ECS of the brain parenchyma [29,62,54].…”

“…The main bulk of evidence for the glymphatic pathway has been established via in-vivo rodent experiments. In these experiments, tracers are typically infused in the CSF in rodents at a rate of 0.34-2 µL/min, with a resulting pressure increase of 0.1-2.5 mmHg [31,5,46]. Thus, such tracer experiments may in fact be viewed as infusion tests.…”

Spatiotemporal Distribution of Agrin after Intrathecal Injection and Its Protective Role in Cerebral Ischemia/Reperfusion Injury

“…However, there is still some controversy about the “glymphatic” function . The perivascular spaces (PVS), as the main component of glymphatic system, carry CSF through the brain, sweeping away metabolic waste . After being directly administrated into the CSF compartment, molecular imaging probes or contrast agents could move along the flow of CSF, and transport from the subarachnoid space entering the brain parenchyma via the PVS .…”