Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia

by | CIRS, Functional & Integrative Medicine

https://advances.sciencemag.org/content/5/2/eaav5447

Comment; So much to learn, so many ways in which we can learn to help the brain to heal. This may be beneficial for traumatic brain injury, toxic enceophalopathy due to mold exposures, Lyme and a variety of other conditions.

  1. Lauren M. Hablitz1, 
  2. Hanna S. Vinitsky1, 
  3. Qian Sun1, 
  4. Frederik Filip Stæger2, 
  5. Björn Sigurdsson2, 
  6. Kristian N. Mortensen2, 
  7. Tuomas O. Lilius2,3 and 
  8. Maiken Nedergaard1,2,*

 See all authors and affiliationsScience Advances  27 Feb 2019:
Vol. 5, no. 2, eaav5447
DOI: 10.1126/sciadv.aav5447

Abstract

The glymphatic system is responsible for brain-wide delivery of nutrients and clearance of waste via influx of cerebrospinal fluid (CSF) alongside perivascular spaces and through the brain. Glymphatic system activity increases during sleep or ketamine/xylazine (K/X) anesthesia, yet the mechanism(s) facilitating CSF influx are poorly understood. Here, we correlated influx of a CSF tracer into the brain with electroencephalogram (EEG) power, heart rate, blood pressure, and respiratory rate in wild-type mice under six different anesthesia regimens. We found that glymphatic CSF tracer influx was highest under K/X followed by isoflurane (ISO) supplemented with dexmedetomidine and pentobarbital. Mice anesthetized with α-chloralose, Avertin, or ISO exhibited low CSF tracer influx. This is the first study to show that glymphatic influx correlates positively with cortical delta power in EEG recordings and negatively with beta power and heart rate.

INTRODUCTION

Cerebrospinal fluid (CSF) can move along perivascular spaces in the brain and spinal cord to distribute nutrients and clear waste (1, 2). These processes are supported by the water channel aquaporin 4 (AQP4), which is present at high density on the vascular end feet of astrocytes (2–4). CSF tracer influx to the brain is higher in animals in the sleeping than in the awake condition (5). Previous studies of glymphatic function have shown that anesthesia with ketamine/xylazine (K/X) emulates sleep in that fluorescent CSF tracer influx and that the rate of radiolabeled Aβ efflux from the brain is comparable to findings in naturally sleeping animals (6). Although it remains largely unknown whether anesthetics other than K/X influence fluid movement from the CSF compartment into the brain, one experimental magnetic resonance imaging study showed that anesthesia with isoflurane (ISO) combined with the α2-agonist dexmedetomidine (dex) facilitated glymphatic transport of a contrast agent compared to ISO alone (7). The scarcity of information concerning the physiological mechanisms behind CSF transport has emerged as a limitation for current models and may contribute to controversy about the importance of AQP4 as a driver for fluid flow in the glymphatic system (3, 8).

Slow cortical network oscillations (delta waves) may contribute to the efficiency of fluid influx into the brain parenchyma and clearance of waste from the brain (5, 9). Delta waves are increased in naturally sleeping animals, potentially due to long-term homeostatic changes in the neuromodulatory, metabolic, and neurochemical environment (10) and broad synaptic scaling (11). Some types of sedatives, such as the α2-adrenergic agonists xylazine and dex, induce a sharp increase in electroencephalogram (EEG) delta power, whereas anesthesia with the volatile anesthetic, ISO, or the injectable γ-aminobutyric acid type A (GABAA) agonist pentobarbital maintain more high-frequency components (7, 12). In addition to neuronal network oscillations, cardiopulmonary parameters such as blood pressure, heart rate, and respiratory rate can also regulate glymphatic influx, and these parameters are themselves modified by different anesthetics in drug- and dose-specific manners (13, 14). Thus, anesthesia may be used to manipulate both EEG spectra and cardiopulmonary function and differentially regulate glymphatic influx. To test this hypothesis, we systematically compared glymphatic influx in mice under anesthesia with six anesthetic regimens. Groups of mice were anesthetized with K/X, pentobarbital, Avertin (2,2,2-tribromoethanol), α-chloralose, ISO supplemented with dex, and ISO alone. To establish how neural activity in conjunction with altered cardiopulmonary function controlled glymphatic influx, we recorded EEG and cardiopulmonary parameters in a separate cohort of mice under the same anesthetic conditions. Our analysis demonstrates that glymphatic influx occurs in direct proportion to the power of cortical delta wave activity, in inverse proportion to heart rate, and was most pronounced under K/X anesthesia.

Dr. Raymond Oenbrink
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