Mapping of CSF transport using high spatiotemporal resolution dynamic contrast‐enhanced MRI in mice: Effect of anesthesia

Abstract

Purpose Dynamic contrast‐enhanced MRI (DCE‐MRI) represents the only available approach for glymphatic cerebrospinal fluid (CSF) flow 3D mapping in the brain of living animals and humans. The purpose of this study was to develop a novel DCE‐MRI protocol for mapping of the glymphatic system transport with improved spatiotemporal resolution, and to validate the new protocol by comparing the transport in mice anesthetized with either isoflurane or ketamine/xylazine. Methods The contrast agent, gadobutrol, was administered into the CSF of the cisterna magna and its transport visualized continuously on a 9.4T preclinical scanner using 3D fast‐imaging with a steady‐state free‐precession sequence (3D‐FISP), which has a spatial resolution of 0.001 mm3 and a temporal resolution of 30 s. The MR signals were measured dynamically for 60 min in multiple volumes of interest covering the entire CSF space and brain parenchyma. Results The results confirm earlier findings that glymphatic CSF influx is higher under ketamine/xylazine than with isoflurane anesthesia. This was extended to account for new details about the distinct CSF efflux pathways under the two anesthetic regimens. Dynamic contrast MR shows that CSF clearance occurs mainly along the vagus nerve near the jugular vein under isoflurane and via the olfactory bulb under ketamine/xylazine. Conclusion The improved spatial and temporal sampling rates afforded by 3D‐FISP shed new light on the pharmacological modulation of CSF efflux paths. The present observations may have the potential to set a new standard for future experimental DCE‐MRI studies of the glymphatic system.

A network model of glymphatic flow under different experimentally-motivated parametric scenarios

“…Note that prior studies computed enhancement factors based on oscillatory (zero mean) flow ( 64, 65 ), whereas our calculations are based on steady (nonzero mean) flow, which we have previously argued is more effective for dispersive transport ( 19, 63 ). Although Taylor dispersion in pial PVSs is unlikely to account for the entirety of tracer transport observed in experiments, these estimates generally suggest that Intermediate scenario 1 with small precapillary PVSs (Γ precap = 0.07) is the only scenario with sleep/awake variations in volume flow rate large enough to explain tracer transport reported in several experiments ( 5, 51, 52, 61 ).…”

Quantitative analysis of macroscopic solute transport in the murine brain

“…In particular, Xie et al showed K-X to mimic natural sleep with respect to glymphatic activity [ 10 ]. Stanton et al recently confirmed that contrast transport pathways differ between isoflurane and K-X anesthetic regimes [ 71 ]. Specifically, parenchymal penetration is poorer using isoflurane due to rapid efflux of contrast agent into the spinal canal and along cranial nerve sheaths.…”

Cerebrospinal fluid outflow through skull channels instructs cranial hematopoiesis

“…We hypothesized that these numerous links between the skull marrow and the dura enable not only cell traffic towards the meninges ( 4 ) but also bidirectional crosstalk. We therefore implemented a 2-photon intravital microscopy (IVM) and ex vivo imaging pipeline to visualize CSF distribution after fluorescent tracer injection into the cisterna magna ( 9, 10 ). Intracisternal injection of 70 kD FITC-labeled ovalbumin was combined with intravenous labeling of the blood pool using 70 kD Texas red-labeled dextran.…”