Sleep deprivation impairs molecular clearance from the human brain
Open accessAbstract
It remains an enigma why human beings spend one-third of their life asleep. Experimental data suggest that sleep is required for clearance of waste products from brain metabolism. This has, however, never been verified in humans. The primary aim of the present study was to examine in vivo whether one night of total sleep deprivation affects molecular clearance from the human brain. Secondarily, we examined whether clearance was affected by subsequent sleep. Multiphase MRI with standardized T1 sequences was performed up to 48 h after intrathecal administration of the contrast agent gadobutrol (0.5 ml of 1 mmol/ml), which served as a tracer molecule. Using FreeSurfer software, we quantified tracer enrichment within 85 brain regions as percentage change from baseline of normalized T1 signals. The cerebral tracer enrichment was compared between two cohorts of individuals; one cohort (n = 7) underwent total sleep deprivation from Day 1 to Day 2 (sleep deprivation group) while an age and gender-matched control group (n = 17; sleep group) was allowed free sleep from Day 1 to Day 2. From Day 2 to 3 all individuals were allowed free sleep. The tracer enriched the brains of the two groups similarly. Sleep deprivation was the sole intervention. One night of sleep deprivation impaired clearance of the tracer substance from most brain regions, including the cerebral cortex, white matter and limbic structures, as demonstrated on the morning of Day 2 after intervention (sleep deprivation/sleep). Moreover, the impaired cerebral clearance in the sleep deprivation group was not compensated by subsequent sleep from Day 2 to 3. The present results provide in vivo evidence that one night of total sleep deprivation impairs molecular clearance from the human brain, and that humans do not catch up on lost sleep.
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Glymphatic fluid transport is enhanced during sleep.
“Glymphatic fluid transport is enhanced during sleep14–19.”
From Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep (2025) · cites this paper as [16]
The Results report reduced molecular tracer clearance from brain tissue after sleep deprivation, and the Discussion describes sleep-dependent clearance as part of the glymphatic concept. But the Discussion says the observations only may support that concept and that MRI cannot establish the tracer’s exact route; it does not establish that glymphatic fluid transport itself is enhanced during sleep. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe results provide further support to prior studies that identified sleep as a key driver of glymphatic flow in the rodent and human brain.
“The results presented here provide further support to prior studies that identified sleep as a key driver of glymphatic flow in the rodent and human brain14,16,19,63.”
From Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep (2025) · cites this paper as [16]
The Results report higher brain-tissue tracer levels after sleep deprivation, consistent with reduced molecular clearance in humans. The Discussion says these sleep-dependent observations may support the glymphatic concept, but cautions that MRI cannot establish the tracer’s exact route. Thus the paper supports a link between sleep and clearance, not the stronger claim that its results establish sleep as a driver of glymphatic flow. (LLM, conf=0.83)
Experimental — accuracy not yet measuredMultiple studies have proven the existence of a glymphatic system in humans.
“Multiple studies have proven the existence of a glymphatic system in humans10,16,105–107.”
From Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep (2025) · cites this paper as [16]
The Discussion cites multiple human tracer studies as support for the glymphatic concept. It also says the mechanisms remain debated and that MRI cannot establish the tracer’s exact route through brain tissue. Those qualifications do not support the claim that the system’s existence in humans has been proven. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAlmost all experiments that have been interpreted as showing that sleep or anesthesia change brain clearance have involved introducing markers into the CSF, which then move into the brain parenchyma, confounding quantification of clearance.
“Indeed, almost all the experiments that have been interpreted as showing that sleep or anesthesia change brain clearance have involved introducing markers into the CSF, which then move into the brain parenchyma14,26–30. Under these circumstances, entry, exit and redistribution of the marker are all occurring simultaneously, greatly confounding any quantification of clearance.”
From Brain clearance is reduced during sleep and anesthesia (2024) · cites this paper as [27]
The Discussion says this study added a tracer to CSF that subsequently entered the brain’s extravascular compartment, and identifies limitations of using that tracer to assess clearance. It does not establish that almost all sleep- or anesthesia-related clearance experiments used this approach, nor does it state that entry, exit, and redistribution simultaneously confound clearance quantification. (LLM, conf=0.84)
Experimental — accuracy not yet measured
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Sorted by citations
Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep
Hauglund, N. L., Andersen, M., Tokarska, K., Radovanovic, T., Kjaerby, C., Sørensen, F. L., Bojarowska, Z., Untiet, V., Ballestero, S. B., Kolmos, M. G., et al. (2025) · Cell · doi:10.1016/j.cell.2024.11.027 · Cited by 349 · see citing works
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A curious concept of CNS clearance
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- Authors
- Eide, P. K., Vinje, V., Pripp, A. H., Mardal, K.-A., & Ringstad, G.
- Affiliations
- Oslo University Hospital (NO)
- Simula Research Laboratory (NO)
- Center for Biomedical Computing, Simula Research Laboratory, Lysaker, Norway
- Corresponding author
- Eide, Per Kristian
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-03-01
- Volume
- 144
- Issue
- 3
- Pages
- 863-874
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W3145545686
- Cited by
- 403
- References
- 14
- Citations by year
- 2026: 91 · 2025: 102 · 2024: 86 · 2023: 68 · 2022: 35 · 2021: 20 · 2020: 1
- FWCI
- 14.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Department of Neurosurgery
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
- Keywords
- sleep deprivation, brain waste clearance, gadobutrol, T1-weighted imaging, sleep recovery, sleep homeostasis, brain metabolism, cerebral cortex, white matter, limbic structures
- MeSH terms
- Adult, Brain, Contrast Media, Female, Humans, Magnetic Resonance Imaging, Male, Organometallic Compounds, Sleep, Sleep Deprivation
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