Theranostics 2018; 8(3):710-722. doi:10.7150/thno.19154

Research Paper

General Anesthesia Inhibits the Activity of the “Glymphatic System”

Clement Gakuba1,2✉, Thomas Gaberel1,3, Suzanne Goursaud1,2, Jennifer Bourges1,2, Camille Di Palma1,3, Aurélien Quenault1, Sara Martinez de Lizarrondo1, Denis Vivien1,4, Maxime Gauberti1,5✉

1. Normandie Univ, UNICAEN, INSERM, INSERM UMR-S U1237, “Physiopathology and Imaging of Neurological Disorders" PhIND, 14000 Caen, France;
2. CHU Caen, Department of Anesthesiology and Critical Care Medicine, CHU Caen Côte de Nacre, 14000 Caen, France;
3. CHU Caen, Department of Neurosurgery, CHU Caen Côte de Nacre, 14000 Caen, France;
4. CHU Caen, Department of Cell Biology, CHU Caen Côte de Nacre, 14000 Caen, France;
5. CHU Caen, Department of Diagnostic Imaging and Interventional Radiology, CHU Caen Côte de Nacre, 14000 Caen, France.

Abstract

INTRODUCTION: According to the “glymphatic system” hypothesis, brain waste clearance is mediated by a continuous replacement of the interstitial milieu by a bulk flow of cerebrospinal fluid (CSF). Previous reports suggested that this cerebral CSF circulation is only active during general anesthesia or sleep, an effect mediated by the dilatation of the extracellular space. Given the controversies regarding the plausibility of this phenomenon and the limitations of currently available methods to image the glymphatic system, we developed original whole-brain in vivo imaging methods to investigate the effects of general anesthesia on the brain CSF circulation.

METHODS: We used magnetic resonance imaging (MRI) and near-infrared fluorescence imaging (NIRF) after injection of a paramagnetic contrast agent or a fluorescent dye in the cisterna magna, in order to investigate the impact of general anesthesia (isoflurane, ketamine or ketamine/xylazine) on the intracranial CSF circulation in mice.

RESULTS: In vivo imaging allowed us to image CSF flow in awake and anesthetized mice and confirmed the existence of a brain-wide CSF circulation. Contrary to what was initially thought, we demonstrated that the parenchymal CSF circulation is mainly active during wakefulness and significantly impaired during general anesthesia. This effect was especially significant when high doses of anesthetic agent were used (3% isoflurane). These results were consistent across the different anesthesia regimens and imaging modalities. Moreover, we failed to detect a significant change in the brain extracellular water volume using diffusion weighted imaging in awake and anesthetized mice.

CONCLUSION: The parenchymal diffusion of small molecular weight compounds from the CSF is active during wakefulness. General anesthesia has a negative impact on the intracranial CSF circulation, especially when using a high dose of anesthetic agent.

Keywords: glymphatic system, anesthesia, magnetic resonance imaging, Alzheimer, choroid plexus.

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How to cite this article:
Gakuba C, Gaberel T, Goursaud S, Bourges J, Di Palma C, Quenault A, de Lizarrondo SM, Vivien D, Gauberti M. General Anesthesia Inhibits the Activity of the “Glymphatic System”. Theranostics 2018; 8(3):710-722. doi:10.7150/thno.19154. Available from http://www.thno.org/v08p0710.htm