How Sleep Drives the Brain to Flush Away Damaging and Disease-Causing Metabolites

How Sleep Drives the Brain to Flush Away Damaging and Disease-Causing Metabolites

The brain removes metabolites most efficiently during sleep. This is according to a study published in Science that explained the restorative function of sleep and the potential link between lack of sleep and neurodegenerative diseases and disorders1.


The brain does not have a normal lymphatic system like much of the body. While lymph vessels remove proteins from peripheral tissues to the circulatory system, the brain needs another system, known as the glymphatic system. It involves a peri-vascular cerebrospinal fluid (CSF) transport system that interchanges with interstitial fluid (ISF) to remove interstitial proteins, including the amyloid-beta (Ab)2.


Previous rodent studies showed that the ISF Ab concentration increases during periods of wakefulness, suggesting being awake is associated with Ab production3. However, this research hypothesized that sleep facilitates Ab clearance and that glymphatic clearance is regulated by the sleep-wake cycle1. The researchers monitored the CSF influx into the cortex via in vivo two-photon imaging and recorded the brain activity of the mice via electrocorticography (ECoG) and electromyography (EMG) in three different stages of wakefulness: awake, asleep, and anesthetised1.


The Findings of the Research


  • The CSF influx was reduced by ~95% during the awake state compared to the sleeping state.
  • The real-time iontophoretic tetramethyl-ammonium method recorded a 60 percent increase in interstitial space volume in the cortex of natural sleeping and ketamine/xylazine anesthetized mice. The greater amount of interstitial space in the brain during sleep may facilitate the clearance of metabolites.
  • The clearance of the radiolabelled 125I- Aβ was two-fold faster in sleeping and anesthetized mice.
  • When the adrenergic signaling was inhibited in the awake mice, the glymphatic CSF influx and interstitial space volume increased, producing similar results to those of sleeping and anesthetized mice.
  • The sleep-wake state modulates the interstitial space volume and thus changes the rate of glymphatic clearance of metabolism by-products.


Therefore, this research suggested that sleep has a restorative effect by enhancing the clearance of degradation products that accumulated in the brain during wakefulness1.


The Benefits of Sleep to the Human Brain


The human brain utilizes 20 to 25 percent of the body’s total energy and generates potentially toxic protein waste and biological debris4. This is according to a recent human study reported by Demiral SB et al.5, which used an MRI to measure brain structure and water diffusivity in the brain during sleep and awake conditions in 50 healthy individuals. The researchers identified that the CSF volume increased significantly during sleep, although there were no differences in grey matter and white matter volume. This preliminary finding suggested the possibility of the existence of a glymphatic system in the human brain, which is consistent with findings in rodent brains5.


Although there is no conclusive research that proves the human brain has a glymphatic system, studies have shown a relationship between sleep and Aβ levels in the brain. Shokri-Kojori et al.6 demonstrated that acute deprivation of sleep increased the level of Aβ in human brains, especially in the right hippocampus and thalamus. The researchers also pointed out that the increment of Aβ levels was associated with a worsening of mood after sleep deprivation but was not related to genetic risk6.


Another study by Spira AP et al.7 reported that shorter sleep duration and poor sleep quality were associated with an increased level of Aβ deposition among community-dwelling older adults. Holth JK et al.8 also demonstrated an increase of tau in both sleep-deprived humans and rodents. Furthermore, ISF/CSF tau levels were regulated by the sleep-wake cycle8.


The deposition of toxins and waste products, such as Aβ and tau, in the brain is associated with neurodegenerative diseases. A better understanding of the human glymphatic system and its link with sleep may lead to potential therapeutics for neurodegenerative diseases. Regardless, optimal sleep is restorative and should be part of a healthy lifestyle.



  1. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O’Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science. 2013;342 (6156):373-7.
  2. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012;4(147):147ra111.
  3. Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009;326(5955):1005-7.
  4. Nedergaard, M., Goldman, S.A. Brain drain. Sci. Am. 2016;314:44–49.
  5. Demiral ŞB, Tomasi D, Sarlls J, Lee H, Wiers CE, Zehra A, Srivastava T, Ke K, Shokri-Kojori E, Freeman CR, Lindgren 2, Ramirez V, Miller G, Bandettini P, Horovitz S, Wang GJ, Benveniste H, Volkow ND. Apparent diffusion coefficient changes in human brain during sleep – Does it inform on the existence of a glymphatic system? NeuroImage. 2019;185:263–273.
  6. Shokri-Kojori E, Wang GJ, Wiers CE, Demiral SB, Guo M, Kim SW, Lindgren E, Ramirez V, Zehra A, Freeman C, Miller G, Manza P, Srivastava T, De Santi S, Tomasi D, Benveniste H, Volkow ND. β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc Natl Acad Sci U S A. 2018;115(17):4483-4488.
  7. Spira AP, Gamaldo AA, An Y, Wu MN, Simonsick EM, Bilgel M, Zhou Y, Wong DF, Ferrucci L, Resnick SM. Self-reported sleep and β-amyloid deposition in community-dwelling older adults. JAMA Neurol. 2013;70(12):1537-43.
  8. Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, Finn MB, Manis M, Geerling JC, Fuller PM, Lucey BP, Holtzman DM. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. 2019;363(6429):880-884.