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Cited by 349Cerebrospinal fluid and hydrocephalusSleep and Wakefulness ResearchTraumatic Brain Injury and Neurovascular Disturbances

The DOI matches its Crossref record; 129 of the 129 references it cites were found in a registry or an index; 69 of the 102 sources its claims cite were checked for support.

Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep

Open access
Hauglund, Natalie L., Andersen, Mie, Tokarska, Klaudia, Radovanovic, Tessa, Kjaerby, Celia, Sørensen, Frederikke L., Bojarowska, Zuzanna, Untiet, Verena, Ballestero, Sheyla B., Kolmos, Mie G., Weikop, Pia, Hirase, Hajime, Nedergaard, Maiken·2025·Cell
DOI 10.1016/j.cell.2024.11.027PMC PMC12340670
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Abstract

As the brain transitions from wakefulness to sleep, processing of external information diminishes while restorative processes, such as glymphatic removal of waste products, are activated. Yet, it is not known what drives brain clearance during sleep. We here employed an array of technologies and identified tightly synchronized oscillations in norepinephrine, cerebral blood volume, and cerebrospinal fluid (CSF) as the strongest predictors of glymphatic clearance during NREM sleep. Optogenetic stimulation of the locus coeruleus induced anti-correlated changes in vasomotion and CSF signal. Furthermore, stimulation of arterial oscillations enhanced CSF inflow, demonstrating that vasomotion acts as a pump driving CSF into the brain. On the contrary, the sleep aid zolpidem suppressed norepinephrine oscillations and glymphatic flow, highlighting the critical role of norepinephrine-driven vascular dynamics in brain clearance. Thus, the micro-architectural organization of NREM sleep, driven by norepinephrine fluctuations and vascular dynamics, is a key determinant for glymphatic clearance.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

Norepinephrine (NE) oscillations from the locus coeruleus drive slow vasomotion, and these arterial constriction–dilation cycles act as a pump for cerebrospinal fluid (CSF) influx and glymphatic clearance during NREM sleep. The sleep aid zolpidem suppresses NE oscillations and reduces glymphatic tracer influx despite increasing sleep.

Key findings

  • NE and blood albumin signals were anti-correlated across wake, NREM, and REM; blood albumin lagged NE by 0.29±0.6 s in wakefulness and 0.69±0.3 s in NREM sleep. NE oscillation trough-to-peak amplitude was higher in NREM sleep than wakefulness or REM sleep, and NE–blood correlation variability was lower in NREM (SD 0.06) than wake/REM (SD 0.13).
  • Optogenetic locus coeruleus stimulation increased NE and decreased blood albumin in a stimulation-frequency-dependent manner; panadrenergic blockade (PPA) abolished the blood decrease. LC inhibition decreased NE and increased blood albumin. The NE-insensitive GRABNEmut peak during NREM infraslow oscillation was 7.2% of the GRABNE2m peak.
  • CSF tracer was anti-correlated with blood albumin and highest on average in NREM sleep and lowest in REM sleep. LC stimulation increased CSF tracer in a frequency-dependent manner, and this increase was abolished by PPA. NE, blood, and CSF showed phase-locked infraslow oscillations at 0.01–0.02 Hz in NREM sleep (REM: 0.02–0.03 Hz; wake: below ~0.005 Hz).
  • Direct optogenetic stimulation of vascular smooth muscle cells increased vascular oscillation frequency (from 50 s to 10 s period) and enhanced CSF tracer penetration in the stimulated hemisphere in hippocampus and dorsal cortex, but not in ventral surface far from stimulation. Glymphatic clearance correlated negatively with micro-arousal frequency, not with total NREM time, REM time, wake time, NREM delta/theta/sigma/beta power, or wake bouts >20 s. Zolpidem (5 mg/kg) reduced NE oscillation magnitude, decreased baseline prefrontal NE by approximately 50%, increased micro-arousals not associated with NE peaks by ~70%, and lowered glymphatic tracer influx.

Methods

  • Freely behaving mice (wildtype C57BL/6, TH-Cre, Sm22-Cre:Ai32-ChR2 and controls) were used with EEG/EMG, fiber-optic cannula, cisterna magna catheter, and chronic liver-secreted fluorescent albumin labeling. “Flow fiber photometry” combined GRABNE2m NE biosensor, blood albumin, and CSF tracers (3 kDa TMR or FITC dextran) to track NE, vascular, and CSF dynamics across wake, NREM, and REM sleep without head fixation or anesthesia.
  • Optogenetic manipulations targeted locus coeruleus (ChR2 or ArchT) or vascular smooth muscle cells (Sm22-Cre:Ai32-ChR2); pharmacological blockade used prazosin, propranolol, and atipamezole (PPA). Miniscope imaging measured artery/vein diameter and NE; SPECT/CT with intrastriatal [99mTc]-DTPA quantified glymphatic clearance; microdialysis measured prefrontal NE; zolpidem was tested at 5 mg/kg.
  • Analyses included sleep scoring, cross-correlations, power spectral density, time-locking to EEG sigma peaks and micro-arousals, correlation of clearance/influx with sleep parameters, and standard parametric/nonparametric statistics with outlier removal.

Limitations

  • The paper states that hemoglobin absorption may alter the CSF tracer trace during REM sleep, so the study focused on NREM sleep; it also states that REM sleep’s contribution to glymphatic function could not be detected and remains unresolved.
  • The paper states that human confirmation is needed and that it is difficult to know whether zolpidem suppresses NE dynamics in human subjects; it also notes that anesthesia differs from natural sleep and was avoided here.
  • Evident from the text: the causal evidence is mainly from mouse optogenetics and correlational sleep/clearance analyses, with local optogenetic stimulation effects and no direct human glymphatic clearance measurement.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.cell.2024.11.027

Cites

129 of 129 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

69 of 102 cited sources checked · 23 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Multiple 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.”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [10] Zhou Y, Cai J, Zhang W, Impairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human. Ann Neurol. 2020; 87(3): 357– 369. doi: 10.1002/ana.25670 31916277 source
    • cites [16] Eide PK, Vinje V, Pripp AH, Mardal K-A, Ringstad G. Sleep deprivation impairs molecular clearance from the human brain. Brain. 2021; 144(3): 863– 874. doi: 10.1093/brain/awaa443 33829232 source

      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 measured
    • cites [105] Eide PK, Vatnehol SAS, Emblem KE, Ringstad G. Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes. Sci Rep. 2018; 8(1): 7194. doi: 10.1038/s41598-018-25666-4 29740121 PMC5940793 source

      The Introduction says a previous human MRI study showed glymphatic contrast enhancement, and the Discussion reports this study’s in-vivo evidence of tracer drainage to cervical lymph nodes alongside glymphatic enhancement. Those findings support evidence for a human glymphatic system, but the paper calls them evidence rather than proof and notes that aspects of glymphatic circulation remain controversial (Discussion; page unavailable). (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [106] Demiral ŞB, Tomasi D, Sarlls J, Apparent diffusion coefficient changes in human brain during sleep – Does it inform on the existence of a glymphatic system? Neuroimage. 2019; 185: 263– 273. doi: 10.1016/j.neuroimage.2018.10.043 30342236 PMC6289767 source

      The Introduction says it is currently unknown whether a glymphatic system as described in rodents exists in the human brain. The Discussion describes the human findings as preliminary and not conclusive, and other clinical studies as providing indirect evidence—not proof. (LLM, conf=0.89)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [107] Yang G, Deng N, Liu Y, Gu Y, Yao X. Evaluation of Glymphatic System Using Diffusion MR Technique in T2DM Cases. Front Hum Neurosci. 2020; 14: 1– 7. doi: 10.3389/fnhum.2020.00300 32922272 PMC7456821 source

      The Introduction describes the glymphatic system as a discovered brain system, and the Discussion refers to earlier human tracer studies. But the paper’s own human study uses diffusion MRI as an indirect measure of presumed glymphatic activity; its Discussion says the findings ‘may indicate’ damage to the system. It does not establish that multiple studies have proven the system’s existence in humans. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    NREM sleep is characterized by regular oscillations in brain norepinephrine levels with a frequency of approximately 0.02 Hz.

    “NREM sleep is characterized by regular oscillations in brain norepinephrine (NE) levels with a frequency in the range of ~0.02 Hz32–34.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [32] Osorio-Forero A, Cardis R, Vantomme G, Noradrenergic circuit control of non-REM sleep substates. Curr Biol. 2021; 31(22): 5009– 5023. doi: 10.1016/j.cub.2021.09.041 34648731 source

      The section “Thalamic NA levels during NREMS are high and fluctuate on infraslow time intervals” (p. 6) reports recurrent fluctuations in norepinephrine levels measured in the thalamus of sleeping mice. The Results (p. 4) place the associated sigma-power cycle at about 50 seconds, or 0.02 Hz. The evidence supports the approximate timescale, but the claim presents it as a general feature of brain norepinephrine during NREM sleep rather than a finding measured in mouse thalamus. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [33] Kjaerby C, Andersen M, Hauglund N, Memory-enhancing properties of sleep depend on the oscillatory amplitude of norepinephrine. Nat Neurosci. 2022; 25(8): 1059– 1070. doi: 10.1038/s41593-022-01102-9 35798980 PMC9817483 source

      The Results section (‘Increased NE descent amplitude primes awakenings over micro-arousals’; page unavailable) reports infraslow norepinephrine oscillations during NREM sleep, supporting the main point. It gives a frequency of 0.034 ± 0.004 Hz, however, rather than approximately 0.02 Hz. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [34] Antila H, Kwak I, Choi A, A noradrenergic-hypothalamic neural substrate for stress-induced sleep disturbances. Proc Natl Acad Sci. 2022; 119(45): 1– 12. doi: 10.1073/pnas.2123528119 PMC9659376 36331996 source

      The Results section, “The Activity of LC-NE Neurons Rhythmically Fluctuates during NREMs” (page unavailable), reports rhythmic LC noradrenergic-neuron activity in sleeping mice peaking at 0.017 ± 0.005 Hz, approximately 0.02 Hz. A separate Results section measures norepinephrine levels in the preoptic area during NREM sleep, but does not establish that the levels themselves oscillate at that frequency throughout the brain. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Findingown data

    Panadrenergic inhibition with prazosin, propranolol and atipamezole blocked the locus coeruleus-induced decrease in blood albumin signal.

    “Panadrenergic inhibition (i.p. administration of the α1-adrenergic receptor antagonist prazosin, the broad β-adrenergic receptor antagonist propranolol, and the α2-adrenergic antagonist atipamezole, PPA13,14) blocked the LC-induced decrease in blood albumin signal (Figure 1H).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [13] Hussain R, Tithof J, Wang W, Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema. Nature. 2023; 623(7989): 992– 1000. doi: 10.1038/s41586-023-06737-7 37968397 PMC11216305 source
    • cites [14] Xie L, Kang H, Xu Q, Sleep Drives Metabolite Clearance from the Adult Brain. Science (80-). 2013; 342(6156): 373– 377. doi: 10.1126/science.1241224 PMC3880190 24136970 source

      The passage on adrenergic signaling (section labeled Abstract; page unavailable) reports using a cocktail of adrenergic receptor antagonists, supporting the general description of panadrenergic inhibition. It does not name prazosin, propranolol, or atipamezole; its antagonists were delivered intracisternally or applied to the cortex, not injected intraperitoneally. The LC-induced blood-albumin result is presented as the citing paper’s own Figure 1H result, rather than a finding attributed to this source. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    Glymphatic fluid transport is enhanced during sleep.

    “Glymphatic fluid transport is enhanced during sleep14–19.”
    Quote in the paperSubstantial claim4 of 6 sources checked
    • cites [14] Xie L, Kang H, Xu Q, Sleep Drives Metabolite Clearance from the Adult Brain. Science (80-). 2013; 342(6156): 373– 377. doi: 10.1126/science.1241224 PMC3880190 24136970 source
    • cites [15] Hauglund NL, Pavan C, Nedergaard M. Cleaning the sleeping brain – the potential restorative function of the glymphatic system. Curr Opin Physiol. 2020; 15: 1– 6. doi: 10.1016/j.cophys.2019.10.020 source
    • cites [16] Eide PK, Vinje V, Pripp AH, Mardal K-A, Ringstad G. Sleep deprivation impairs molecular clearance from the human brain. Brain. 2021; 144(3): 863– 874. doi: 10.1093/brain/awaa443 33829232 source

      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 measured
    • cites [17] Fultz NE, Bonmassar G, Setsompop K, Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science (80-). 2019; 366(6465): 628– 631. doi: 10.1126/science.aax5440 PMC7309589 31672896 source

      The paper reports stronger CSF inflow oscillations during human NREM sleep than during wakefulness (Results, page unavailable) and notes prior findings of increased interstitial fluid volume and waste clearance during sleep (Introduction, page unavailable). It does not directly measure glymphatic transport, so the claim is more specific than this paper’s finding. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [18] Shokri-Kojori E, Wang G-J, Wiers CE, β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc Natl Acad Sci. 2018; 115(17): 4483– 4488. doi: 10.1073/pnas.1721694115 29632177 PMC5924922 source
    • cites [19] Miyakoshi LM, Stæger FF, Li Q, The state of brain activity modulates cerebrospinal fluid transport. Prog Neurobiol. 2023; 229(June): 102512. doi: 10.1016/j.pneurobio.2023.102512 37482196 source
  • Premisecitation

    Optogenetically stimulated vasoconstriction in anesthetized Sm22-Cre:Ai32-ChR2 mice directly enhances cerebrospinal fluid tracer influx.

    “We previously showed that optogenetically stimulated vasoconstriction in anesthetized transgenic mice expressing channelrhodopsin-2 in vascular smooth muscle cells (Sm22-Cre:Ai32-ChR2) directly enhances CSF tracer influx43.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [43] Holstein-Rønsbo S, Gan Y, Giannetto MJ, Glymphatic influx and clearance are accelerated by neurovascular coupling. Nat Neurosci. 2023; 26(6): 1042– 1053. doi: 10.1038/s41593-023-01327-2 37264158 PMC10500159 source
  • Probably not a substantial claim. 24
  • It may state two separate claims as one. 45

  • Probably not a substantial claim.

    Premisecitation

    Norepinephrine is a potent vasoconstrictor.

    “NE is known to be a potent vasoconstrictor36,37.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [36] Avakian O V, Gillespie JS. Uptake of noradrenaline by adrenergic nerves, smooth muscle and connective tissue in isolated perfused arteries and its correlation with the vasoconstrictor response. Br J Pharmacol Chemother. 1968; 32(1): 168– 184. doi: 10.1111/j.1476-5381.1968.tb00441.x 5640169 PMC1570308 source
    • cites [37] Korte N, James G, You H, Noradrenaline released from locus coeruleus axons contracts cerebral capillary pericytes via α 2 adrenergic receptors. J Cereb Blood Flow Metab. 2023; 43(7): 1142– 1152. doi: 10.1177/0271678X231152549 36688515 PMC10291462 source

      The Results report that noradrenaline constricted cerebral capillaries near pericytes, and the Discussion says it evokes contractile tone in cerebral arterioles and capillaries (page numbers unavailable). This supports its vasoconstrictor action, but the paper does not establish the broader claim that it is a potent vasoconstrictor generally. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The glymphatic system uses perivascular spaces as low-resistance routes for fast influx of cerebrospinal fluid into deep brain regions.

    “The glymphatic system uses the perivascular spaces as low-resistance routes for fast influx of CSF into deep brain regions1.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [1] Iliff JJ, Wang M, Liao Y, A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid. Sci Transl Med. 2012; 4(147): 1– 11. doi: 10.1126/scitranslmed.3003748 PMC3551275 22896675 source

      The Results sections on paravascular CSF influx report rapid flow along spaces surrounding arteries into the brain, including the basal ganglia and thalamus. But the paper describes AQP4-mediated movement between paravascular spaces and the interstitium—not the influx spaces themselves—as a low-resistance pathway; it also uses that description for venous efflux. The low-resistance characterization of the influx route is therefore not supported. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Most if not all anesthetic regimens suppress or eliminate characteristic features of natural sleep, such as oscillatory norepinephrine release, micro-arousals, vasomotion and REM sleep, rendering anesthesia unsuited to dissect the drivers of glymphatic flow in natural sleep.

    “However, most if not all anesthetic regimens suppress or eliminate the characteristic features of natural sleep, such as oscillatory release of NE, micro-arousals, vasomotion and REM sleep, which renders anesthesia unsuited to dissect the drivers of glymphatic flow in natural sleep38–41.”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [38] Colantuoni A, Bertuglia S, Intaglietta M. Effects of anesthesia on the spontaneous activity of the microvasculature. Int J Microcirc Clin Exp. 1984; 3(1): 13– 28. 6480227
    • cites [39] Akata T, Kodama K, Takahashi S. Volatile anaesthetic actions on norepinephrine-induced contraction of small splanchnic resistance arteries. Can J Anaesth. 1995; 42(11): 1040– 1050. doi: 10.1007/BF03011080 8590495 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [40] Akeju O, Brown EN. Neural oscillations demonstrate that general anesthesia and sedative states are neurophysiologically distinct from sleep. Curr Opin Neurobiol. 2017; 44: 178– 185. doi: 10.1016/j.conb.2017.04.011 28544930 PMC5520989 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [41] Tort-Colet N, Capone C, Sanchez-Vives MV., Mattia M. Attractor competition enriches cortical dynamics during awakening from anesthesia. Cell Rep. 2021; 35(12): 109270. doi: 10.1016/j.celrep.2021.109270 34161772

  • Probably not a substantial claim.

    Premisecitation

    The glymphatic system is a highly organized, brain-wide network for cerebrospinal fluid transport that exports protein waste, including amyloid and tau.

    “The glymphatic system is a highly organized, brain-wide network for cerebrospinal fluid (CSF) transport that exports protein waste, including amyloid and tau1–3.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [1] Iliff JJ, Wang M, Liao Y, A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid. Sci Transl Med. 2012; 4(147): 1– 11. doi: 10.1126/scitranslmed.3003748 PMC3551275 22896675 source

      The Discussion (page not supplied) describes a brain-wide glymphatic pathway for CSF transport and interstitial-solute clearance in mice. The Results section on AQP4 (page not supplied) supports clearance of soluble amyloid β, but our copy does not establish tau clearance; a search for “tau” found no relevant passage. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [2] Iliff JJ, Chen MJ, Plog BA, Impairment of Glymphatic Pathway Function Promotes Tau Pathology after Traumatic Brain Injury. J Neurosci. 2014; 34(49): 16180– 16193. doi: 10.1523/JNEUROSCI.3020-14.2014 25471560 PMC4252540 source
    • cites [3] Ishida K, Yamada K, Nishiyama R, Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration. J Exp Med. 2022; 219(3): 1– 9. doi: 10.1084/jem.20211275 PMC8932543 35212707 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Glymphatic flow is enhanced by optogenetic stimulation of excitatory neurons in hippocampus across a broad range of frequencies.

    “glymphatic flow is enhanced by optogenetic stimulation of excitatory neurons in hippocampus across a broad range of frequencies89”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [89] Jiang-Xie L-F, Drieu A, Bhasiin K, Quintero D, Smirnov I, Kipnis J. Neuronal dynamics direct cerebrospinal fluid perfusion and brain clearance. Nature. 2024; 627(8002): 157– 164. doi: 10.1038/s41586-024-07108-6 38418877 PMC12054998 source

      The “Synthesized waves enhance CSF-to-ISF perfusion” section reports increased tracer infiltration in the hippocampus after optogenetic stimulation at 1 Hz and 8 Hz. The Methods identify a CaMKIIa-ChRmine vector used for activation. The claim overstates the frequency evidence: the paper tests two stimulation frequencies, not a broad range. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim.

    Premisecitation

    Anesthesia is commonly used as a proxy for sleep because it is difficult to control when rodents enter natural sleep.

    “Since it is difficult to control when rodents enter natural sleep, anesthesia is commonly used as a proxy for sleep1,24,99,100.”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [1] Iliff JJ, Wang M, Liao Y, A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid. Sci Transl Med. 2012; 4(147): 1– 11. doi: 10.1126/scitranslmed.3003748 PMC3551275 22896675 source

      Materials and Methods > Anesthesia says the mice were anesthetized for all experiments, and Results > In vivo imaging describes imaging anesthetized mice (page numbers unavailable). Neither passage says anesthesia was used as a proxy for sleep, that this is common practice, or that controlling the onset of natural sleep is difficult. Searches for those terms found no passage addressing the claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [24] Mestre H, Tithof J, Du T, Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat Commun. 2018; 9(1): 4878. doi: 10.1038/s41467-018-07318-3 30451853 PMC6242982 source

      The Methods (Animals and surgical preparation; page unavailable) say the mice were anesthetized with ketamine/xylazine. Our copy does not say anesthesia was used as a proxy for sleep, that this is common practice, or that difficulty controlling natural sleep is the reason. Searches for those terms and for sleep found no passage addressing the claim. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [99] Lee H, Xie L, Yu M, The Effect of Body Posture on Brain Glymphatic Transport. J Neurosci. 2015; 35(31): 11034– 11044. doi: 10.1523/JNEUROSCI.1625-15.2015 26245965 PMC4524974 source
    • cites [100] Plog BA, Mestre H, Olveda GE, Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain. JCI Insight. 2018; 3(23): 1– 15. doi: 10.1172/jci.insight.126138 PMC6328017 30518698 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Glymphatic flow is partly active in quiet wakefulness, whereas active wakefulness potently suppresses CSF inflow.

    “glymphatic flow is partly active in quiet wakefulness, whereas active wakefulness potently suppresses CSF inflow88.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [88] von Holstein-Rathlou S, Petersen NC, Nedergaard M. Voluntary running enhances glymphatic influx in awake behaving, young mice. Neurosci Lett. 2018; 662(September 2017): 253– 258. doi: 10.1016/j.neulet.2017.10.035 29079431 PMC5696653 source

      The Results (‘Regional fluorescence intensity differs’; page unavailable) show CSF tracer uptake in awake mice. The Results (‘Wheel running impairs tracer influx’; page unavailable) report that acute running suppressed influx relative to awake behaving, exercised mice. The paper does not establish that the comparator was in quiet wakefulness or that active wakefulness generally suppresses inflow; it tests running specifically. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Neural synchrony drives glymphatic clearance.

    “Common to both studies was the finding that neural synchrony drive glymphatic clearance.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [89] Jiang-Xie L-F, Drieu A, Bhasiin K, Quintero D, Smirnov I, Kipnis J. Neuronal dynamics direct cerebrospinal fluid perfusion and brain clearance. Nature. 2024; 627(8002): 157– 164. doi: 10.1038/s41586-024-07108-6 38418877 PMC12054998 source
    • cites [90] Murdock MH, Yang CY, Sun N, Multisensory gamma stimulation promotes glymphatic clearance of amyloid. Nature. 2024; 627(8002): 149– 156. doi: 10.1038/s41586-024-07132-6 38418876 PMC10917684 source

      The Abstract reports that multisensory 40 Hz stimulation promoted glymphatic fluid movement in a mouse model of Alzheimer’s disease. The Discussion links gamma rhythms to neuronal synchrony but says they “may be relevant” to clearance and that brain rhythms “contribute” to its regulation. Thus, the paper supports a role for stimulated neural rhythms, not the unqualified claim that neural synchrony itself drives glymphatic clearance. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Glymphatic flow is enhanced by sensory gamma stimulation (40 Hz, visual or auditory).

    “similar observations have been done in response to sensory gamma stimulation (40 Hz, visual or auditory)90.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [90] Murdock MH, Yang CY, Sun N, Multisensory gamma stimulation promotes glymphatic clearance of amyloid. Nature. 2024; 627(8002): 149– 156. doi: 10.1038/s41586-024-07132-6 38418876 PMC10917684 source

      The ‘Gamma stimulation promotes glymphatic clearance’ section reports increased CSF influx and ISF efflux after 40 Hz stimulation in 5XFAD mice. The intervention was multisensory—combined light and sound—so the paper does not establish the claimed effect for visual or auditory stimulation individually. Page numbers were not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Other studies reported divergent observations with regard to the effects of zolpidem on EEG sigma power, micro-arousals and consolidation of memory.

    “Other studies reported divergent observations with regard to the effects of zolpidem on EEG sigma power, micro-arousals and consolidation of memory67,68,95,96.”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [67] Kopp C, Rudolph U, Tobler I. Sleep EEG changes after zolpidem in mice. Neuroreport. 2004; 15(14): 2299– 2302. doi: 10.1097/00001756-200410050-00031 15371753 source
    • cites [68] Uygun DS, Ye Z, Zecharia AY, Bottom-Up versus Top-Down Induction of Sleep by Zolpidem Acting on Histaminergic and Neocortex Neurons. J Neurosci. 2016; 36(44): 11171– 11184. doi: 10.1523/JNEUROSCI.3714-15.2016 27807161 PMC5148237 source

      The Results section, “Zolpidem does not induce sleep in γ2I77 lox mice” (page unavailable), reports reduced NREM EEG power at 5–16 Hz in one mouse group but no change in another, supporting divergent observations in a range that includes sigma frequencies. The cited paper does not report effects on micro-arousals or memory consolidation; its discussion of the number of awakenings is not a measure of micro-arousals. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [95] Leong CWY, Leow JWS, Grunstein RR, A systematic scoping review of the effects of central nervous system active drugs on sleep spindles and sleep-dependent memory consolidation. Sleep Med Rev. 2022; 62: 101605. doi: 10.1016/j.smrv.2022.101605 35313262
    • cites [96] Zhang J, Yetton B, Whitehurst LN, Naji M, Mednick SC. The effect of zolpidem on memory consolidation over a night of sleep. Sleep. 2020; 43(11). doi: 10.1093/sleep/zsaa084 PMC8064806 32330272 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Prescription of zolpidem is currently not recommended for individuals older than 65 by the American Geriatric Society.

    “Prescription of zolpidem is currently not recommended for individuals older than 65 by the American Geriatric Society93,94.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [93] Shih H-I, Lin C-C, Tu Y-F, An Increased Risk of Reversible Dementia May Occur After Zolpidem Derivative Use in the Elderly Population. Medicine (Baltimore). 2015; 94(17): e809. doi: 10.1097/MD.0000000000000809 25929937 PMC4603066 source

      The Discussion describes risks of zolpidem use in older adults, and the conclusion calls for careful evaluation and follow-up. Neither passage states an American Geriatrics Society recommendation against prescribing it to people over 65; searches for that recommendation and the Beers criteria found no such statement in our copy. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [94] Merel SE, Paauw DS. Common Drug Side Effects and Drug-Drug Interactions in Elderly Adults in Primary Care. J Am Geriatr Soc. 2017; 65(7): 1578– 1585. doi: 10.1111/jgs.14870 28326532 source

  • It may state two separate claims as one.

    Interpretationcitation

    Establishing the connection between vascular dynamics and CSF inflow provides the mechanistic link between vascular pathology and glymphatic stagnation that may explain the increased risk of Alzheimer's disease in patients suffering from cardiovascular diseases.

    “establishing the connection between vascular dynamics and CSF inflow is important because it provides the mechanistic link between vascular pathology and glymphatic stagnation that may explain the increased risk of Alzheimer’s disease in patients suffering from cardiovascular diseases84,85.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [84] Lennon MJ, Makkar SR, Crawford JD, Sachdev PS. Midlife Hypertension and Alzheimer’s Disease: A Systematic Review and Meta-Analysis. J Alzheimer’s Dis. 2019; 71(1): 307– 316. doi: 10.3233/JAD-190474 31381518 source
    • cites [85] Abdulrahman H, van Dalen JW, den Brok M, Latimer CS, Larson EB, Richard E. Hypertension and Alzheimer’s disease pathology at autopsy: A systematic review. Alzheimer’s Dement. 2022; 18(11): 2308– 2326. doi: 10.1002/alz.12707 35758526 PMC9796086 source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Zolpidem has previously been shown to increase the risk of reversible dementia and has also been linked to neuropsychiatric adverse events.

    “zolpidem has previously been shown to increase the risk of reversible dementia and has also been linked to neuropsychiatric adverse events92.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [92] Mittal N, Mittal R, Gupta MC. Zolpidem for Insomnia: A Double-Edged Sword. A Systematic Literature Review on Zolpidem-Induced Complex Sleep Behaviors. Indian J Psychol Med. Published online 2021. doi: 10.1177/0253717621992372 PMC8450729 34584301 source

      The Abstract’s discussion of key findings links zolpidem to neuropsychiatric adverse events, including hallucinations, delirium, and amnesia. It does not say zolpidem increases the risk of reversible dementia; the Discussion’s Limitations section mentions dementia only as a possible concomitant disorder. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Measurements of CSF dynamics have proven more difficult and have mostly been restricted to experiments in awake and anesthetized mice.

    “measurements of CSF dynamics have proven more difficult and have mostly been restricted to experiments in awake and anesthetized mice24.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [24] Mestre H, Tithof J, Du T, Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat Commun. 2018; 9(1): 4878. doi: 10.1038/s41467-018-07318-3 30451853 PMC6242982 source

      The Methods (Animals and surgical preparation; page unavailable) describe CSF-flow experiments in anesthetized mice, and the Results (Quantifying flow in perivascular spaces; page unavailable) describe how flow was measured. Our copy does not establish that measurements have mostly been restricted to mice, address measurements in awake mice, or explicitly characterize CSF-dynamics measurements as difficult. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Astrocyte endfeet may act as valves that promote CSF flow through the perivascular spaces and prevent backflow.

    “astrocyte endfeet may act as valves that promote CSF flow through the perivascular spaces and prevent backflow86,87.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [86] Bork PAR, Ladrón-de-Guevara A, Christensen AH, Jensen KH, Nedergaard M, Bohr T. Astrocyte endfeet may theoretically act as valves to convert pressure oscillations to glymphatic flow. J R Soc Interface. 2023; 20(204): 1– 5. doi: 10.1098/rsif.2023.0050 PMC10336390 37434503
    • cites [87] Gan Y, Holstein-Rønsbo S, Nedergaard M, Boster KAS, Thomas JH, Kelley DH. Perivascular pumping of cerebrospinal fluid in the brain with a valve mechanism. J R Soc Interface. 2023; 20(206): 1– 17. doi: 10.1098/rsif.2023.0288 PMC10509587 37727070 source

  • It may state two separate claims as one.

    Premisecitation

    Chronic sleep fragmentation impairs both slow vasomotion and glymphatic function.

    “chronic sleep fragmentation impairs both slow vasomotion and glymphatic function77.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [77] Deng S, Hu Y, Chen S, Chronic sleep fragmentation impairs brain interstitial clearance in young wildtype mice. J Cereb Blood Flow Metab. 2024;(130). doi: 10.1177/0271678X241230188 PMC11418708 38639025 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Impairment of functional hyperemia (vasodilation in response to neural activity) is a hallmark of aging and neurodegenerative diseases.

    “a hallmark of aging and neurodegenerative diseases is the impairment of functional hyperemia, i.e., vasodilation in response to neural activity83.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [83] Zimmerman B, Rypma B, Gratton G, Fabiani M. Age-related changes in cerebrovascular health and their effects on neural function and cognition: A comprehensive review. Psychophysiology. 2021; 58(7): e13796. doi: 10.1111/psyp.13796 33728712 PMC8244108 source

      The section on impaired vasculature (page unavailable) defines functional hyperemia as local vasodilation during neural activity and reports disrupted neurovascular coupling in both normal and pathologically aging humans. It does not establish the impairment as a hallmark of neurodegenerative diseases generally; that wording is broader and stronger than the passage supports. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Most prior studies looking at vascular dynamics have used two-photon imaging in head-fixed mice.

    “Most prior studies looking at vascular dynamics have used two-photon imaging in head-fixed mice31,47,98”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [31] Bojarskaite L, Vallet A, Bjørnstad DM, Sleep cycle-dependent vascular dynamics in male mice and the predicted effects on perivascular cerebrospinal fluid flow and solute transport. Nat Commun. 2023; 14(1): 953. doi: 10.1038/s41467-023-36643-5 36806170 PMC9941497 source
    • cites [47] Turner KL, Gheres KW, Proctor EA, Drew PJ. Neurovascular coupling and bilateral connectivity during nrem and rem sleep. Elife. 2020; 9: 1. doi: 10.7554/eLife.62071 PMC7758068 33118932 source
    • cites [98] Tsai C-J, Nagata T, Liu C-Y, Cerebral capillary blood flow upsurge during REM sleep is mediated by A2a receptors. Cell Rep. 2021; 36(7): 109558. doi: 10.1016/j.celrep.2021.109558 34407410 source

  • It may state two separate claims as one.

    Study design and conductcitation

    Flow fiber photometry enables recordings from deep brain tissues and combined monitoring of blood and CSF dynamics using virally-delivered biosensors.

    “flow fiber photometry enables recordings from deep brain tissues and combined monitoring of blood and CSF dynamics using virally-delivered biosensors45,101–104.”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [45] Feng J, Zhang C, Lischinsky JE, A Genetically Encoded Fluorescent Sensor for Rapid and Specific In Vivo Detection of Norepinephrine. Neuron. 2019; 102(4): 745– 761.e8. doi: 10.1016/j.neuron.2019.02.037 30922875 PMC6533151 source

      The STAR METHODS > METHOD DETAILS section describes fiber-photometry recordings from deep brain regions in mice after viral delivery of a fluorescent norepinephrine sensor. It does not report combined monitoring of blood and CSF dynamics; the recordings described are of brain fluorescence signals. Page numbers are not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [101] Jing M, Li Y, Zeng J, An optimized acetylcholine sensor for monitoring in vivo cholinergic activity. Nat Methods. 2020; 17(11): 1139– 1146. doi: 10.1038/s41592-020-0953-2 32989318 PMC7606762 source

      The Online Methods section, “Fiber photometry, EEG and EMG recordings in mice” (page not provided), describes fiber-photometry recordings in the basolateral amygdala and hippocampus using an AAV-delivered ACh sensor. It does not report combined monitoring of blood and CSF dynamics; its mention of hemodynamic change concerns correction of a recording artifact. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [102] Wan J, Peng W, Li X, A genetically encoded sensor for measuring serotonin dynamics. Nat Neurosci. 2021; 24(5): 746– 752. doi: 10.1038/s41593-021-00823-7 33821000 PMC8544647 source

      The Methods section, “Fiber-photometry recording in mice” (page unavailable), describes optical-fiber recordings from mouse brain regions using AAV-delivered serotonin sensors. The paper supports that part of the sentence, but our copy does not describe combined monitoring of blood and CSF dynamics. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [103] Zhu R, Zhang G, Jing M, Genetically encoded formaldehyde sensors inspired by a protein intra-helical crosslinking reaction. Nat Commun. 2021; 12(1): 581. doi: 10.1038/s41467-020-20754-4 33495458 PMC7835342 source

      The Results section, “Visualization of FA dynamics in mouse brain tissues by FAsors” (page unavailable), describes viral delivery of a fluorescent biosensor to the mouse hippocampus and imaging of formaldehyde responses in acute brain slices. It does not describe flow fiber photometry, recordings from deep brain tissue in vivo, or combined monitoring of blood and CSF dynamics. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [104] Wu Z, He K, Chen Y, A sensitive GRAB sensor for detecting extracellular ATP in vitro and in vivo. Neuron. 2022; 110(5): 770– 782. doi: 10.1016/j.neuron.2021.11.027 34942116 source

  • It may state two separate claims as one.

    Premisecitation

    A slightly faster 0.05 Hz oscillation in CSF flow was observed in the 4th ventricle of human subjects while sleeping in an MR scanner and was temporally directly correlated with autonomic arousals.

    “a slightly faster 0.05 Hz oscillation in CSF flow was observed in the 4th ventricle of human subjects while sleeping in an MR scanner17 and was temporally directly correlated with autonomic arousals42.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [17] Fultz NE, Bonmassar G, Setsompop K, Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science (80-). 2019; 366(6465): 628– 631. doi: 10.1126/science.aax5440 PMC7309589 31672896 source
    • cites [42] Picchioni D, Özbay PS, Mandelkow H, Autonomic arousals contribute to brain fluid pulsations during sleep. Neuroimage. 2022; 249(November 2021): 118888. doi: 10.1016/j.neuroimage.2022.118888 35017126 PMC11395500 source

  • It may state two separate claims as one.

    Findingown data

    Artery diameter but not vein diameter was highly dynamic, and norepinephrine and artery diameter displayed the same state-dependent oscillatory patterns and negative correlation observed with fiber photometry.

    “The analysis showed that artery diameter but not vein diameter was highly dynamic and that NE and artery diameter displayed the same state-dependent oscillatory patterns and negative correlation that were observed with fiber photometry (Figure S1I–N).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    REM sleep displayed an oscillatory component with a faster frequency (0.02-0.03 Hz), while wakefulness displayed a much slower frequency peak below approximately 0.005 Hz.

    “REM sleep also displayed an oscillatory component but with a faster (0.02–0.03 Hz) frequency, while wakefulness displayed a much slower frequency peak below ~0.005 Hz.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Optogenetic inhibition of locus coeruleus activity by Arch-eGFP decreased the norepinephrine signal concurrently with increasing the blood albumin signal.

    “optogenetic inhibition of LC activity by expression of the light-driven proton pump Arch-eGFP in TH-Cre mice decreased the NE signal concurrently with increasing the blood albumin signal.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The cerebrospinal fluid tracer signal fluctuated dynamically in the opposite direction of the blood albumin signal, with a small lag in the blood albumin signal after the cerebrospinal fluid tracer signal (0.3±3 seconds in wakefulness, 0.6±0.4 seconds in NREM sleep and 0.5±2.3 seconds in REM sleep).

    “The CSF tracer signal fluctuated dynamically in the opposite direction of the blood albumin signal with a small lag in the blood albumin signal after the CSF tracer signal (0.3±3 seconds in wakefulness, 0.6±0.4 seconds in NREM sleep and 0.5±2.3 seconds in REM sleep) (Figure 2B–D).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The increase in cerebrospinal fluid was abolished in mice pre-treated with the panadrenergic receptor cocktail PPA, demonstrating that it is norepinephrine that mediates the cerebrospinal fluid dynamics via vasoconstriction.

    “The increase in CSF was abolished in mice pre-treated with the panadrenergic receptor cocktail, PPA, demonstrating that it is NE that mediates the CSF dynamics via vasoconstriction.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Upon locus coeruleus stimulation, an increase in norepinephrine and a decrease in blood albumin signal were consistently noted.

    “Upon LC stimulation, an increase in NE and a decrease in blood albumin signal were consistently noted (Figure 1H).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The blood albumin signal lagged after the norepinephrine signal by 0.29±0.6 seconds in wakefulness and by 0.69±0.3 seconds in NREM sleep, while a broader time dependency was observed in REM sleep.

    “The blood albumin signal lagged after the NE signal by 0.29±0.6 seconds in wakefulness and by 0.69±0.3 seconds in NREM sleep, while a broader time dependency was observed in REM sleep.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Norepinephrine, blood and cerebrospinal fluid signals all exhibited infraslow oscillations in the 0.01-0.02 Hz range during NREM sleep.

    “Power spectral density analysis of NE, blood and CSF signals normalized to the area under the curve showed that all three signals exhibited infraslow oscillations in the 0.01–0.02 Hz range during NREM sleep (Figure 3B).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The average cerebrospinal fluid tracer level was highest in NREM sleep and lowest in REM sleep.

    “The average CSF tracer level was highest in NREM sleep and lowest in REM sleep (Figure 2E).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Zolpidem reduced the latency to sleep, concurrently with potently interfering with the normal sleep architecture and suppressing glymphatic flow in mice.

    “our study clearly indicates that zolpidem reduced the latency to sleep, concurrently with potently interfering with the normal sleep architecture and suppressing glymphatic flow in mice.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Glymphatic influx exhibited a positive correlation with the frequency of micro-arousals, while not correlating with total time spent in NREM sleep, NREM delta power, theta power, sigma power or wake episodes >20 seconds.

    “Additionally, glymphatic influx exhibited a positive correlation with the frequency of micro-arousals, while not correlating with total time spent in NREM sleep, NREM delta power, theta power, sigma power or wake episodes > 20 seconds (Figure S4F).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Neither total time spent in NREM sleep, time spent awake, time spent in REM sleep, nor the number of REM bouts predicted tracer clearance.

    “Correlation of tracer clearance with basic parameters of sleep showed that neither total time spent in NREM sleep, time spent awake, time spent in REM sleep, nor the number of REM bouts predicted tracer clearance (Figure 5C and Figure S4B).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Zolpidem dampened the power of NE oscillations and reduced glymphatic CSF tracer inflow.

    “our analysis clearly showed that zolpidem dampened the power of the NE oscillations and reduced glymphatic CSF tracer inflow (Figure 6).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Administration of 5 mg/kg zolpidem in mice expressing GRABNE2m in the dorsal cortex resulted in a reduction in the magnitude of the infraslow EEG sigma power oscillation and sigma power amplitude along with a suppression of the infraslow norepinephrine oscillation magnitude in NREM sleep.

    “Administration of 5 mg/kg zolpidem in mice expressing GRABNE2m in the dorsal cortex resulted in a reduction in magnitude the infraslow EEG sigma power oscillation (Figure 6A–B) and sigma power amplitude (Figure S5C) along with a suppression of the infraslow NE oscillation magnitude in NREM sleep (figure 6C).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Time-locked analysis to the beginning of micro-arousals showed a sharp increase in norepinephrine, a sharp transient decrease in blood albumin, and a sharp transient increase in cerebrospinal fluid.

    “The analysis showed a distinct pattern with a sharp increase in NE levels, a sharp and transient decrease in blood albumin signal, and a sharp and transient increase in CSF signal.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Stimulation of vascular smooth muscle cells induced a decrease in blood albumin signal in both wakefulness and NREM sleep and in a similar range to natural micro-arousals.

    “Stimulation of the vascular smooth muscle cells induced a decrease in blood albumin signal in both wakefulness and NREM sleep (Figure S3A) and in a similar range to natural micro-arousals (Figure 4C).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The hippocampus and the dorsal cortex both exhibited significantly higher tracer penetration in the stimulated hemisphere.

    “the hippocampus and the dorsal cortex both exhibited significantly higher tracer penetration in the stimulated hemisphere (Figure 4I–J).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Clearance was not correlated with NREM delta power (1-4 Hz), theta power (4-8 Hz), sigma power (8-15 Hz) or beta power (13-20 Hz).

    “Clearance was also not correlated with NREM delta power (1–4 Hz), theta power (4–8 Hz), sigma power (8–15 Hz) or beta power (13–20 Hz).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingreasoning

    mCherry, GRAB-mut fluorescence, and background fluorescence before tracer injection exhibited lower intensity during REM sleep.

    “mCherry, GRAB-mut fluorescence and background fluorescence before tracer injection was found to exhibit lower intensity during REM sleep”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Locus coeruleus-induced norepinephrine oscillations are the key mechanism of slow vasomotion and thereby of glymphatic solute clearance during natural sleep.

    “The observations identify locus coeruleus (LC)-induced NE oscillations as the key mechanism of slow vasomotion and thereby of glymphatic solute clearance during natural sleep.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Both optogenetic activation and inhibition of the locus coeruleus control the dynamics of the cerebral vasculature.

    “Thus, both optogenetic activation and inhibition of the LC control the dynamics of the cerebral vasculature.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductnone given

    Flow fiber photometry is the first methodology that allows simultaneous longitudinal tracking of cerebrospinal fluid and blood dynamics while avoiding anesthesia.

    “We utilized ‘Flow fiber photometry’ – a technique that combines fiber photometry with blood and CSF tracers and is the first methodology that allows simultaneous longitudinal tracking of the CSF and blood dynamics, while avoiding the use of anesthesia.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Cerebrospinal fluid and cerebral blood volume exhibit anti-correlated and state-dependent fluctuations that are controlled by norepinephrine released by the locus coeruleus.

    “Thus, CSF and cerebral blood volume exhibit anti-correlated and state-dependent fluctuations that are controlled by NE released by the LC.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    Infraslow vasomotion represents an alternative driver of glymphatic flow.

    “Magnetic resonance encephalography (MREG) mapping of pulsation in the human brain showed already in 2016 that infraslow vasomotion represents an alternative driver of glymphatic flow75”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Kiviniemi V, Wang X, Korhonen V, Ultra-fast magnetic resonance encephalography of physiological brain activity – Glymphatic pulsation mechanisms? J Cereb Blood Flow Metab. 2016; 36(6): 1033– 1045. doi: 10.1177/0271678X15622047 26690495 PMC4908626 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Most prior studies have concluded that vasomotion reflects intrinsic activity of vascular smooth muscle cells.

    “Most prior studies have concluded that vasomotion reflects intrinsic activity of vascular smooth muscle cells78,79.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [78] Vasomotion Intaglietta M. and flowmotion: physiological mechanisms and clinical evidence. Vasc Med Rev. 1990; vmr-1(2): 101– 112. doi: 10.1177/1358836X9000100202 source
    • cites [79] Aalkjær C, Boedtkjer D, Matchkov V. Vasomotion – what is currently thought? Acta Physiol. 2011; 202(3): 253– 269. doi: 10.1111/j.1748-1716.2011.02320.x 21518271 source

  • It may state two separate claims as one.

    Interpretationreasoning

    Vascular volume changes is the pump forcing CSF transport in both the 4th ventricle and within the cortical tissue.

    “Thus, vascular volume changes is the pump forcing CSF transport in both the 4th ventricle and within the cortical tissue.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Cerebrospinal fluid flow is promoted by norepinephrine oscillations, i.e. vasoconstriction, but does not require the presence of micro-arousals.

    “This point towards the conclusion that CSF flow is promoted by NE oscillations, i.e. vasoconstriction, but do not require the presence of micro-arousals.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Locus coeruleus-mediated norepinephrine release drives slow vasomotion, which in turn promotes glymphatic clearance.

    “In summary, our results point to a mechanism where LC-mediated NE release drives slow vasomotion, which in turn promotes glymphatic clearance (Figure 7).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    It is difficult to decipher whether zolpidem also suppresses NE dynamics in human subjects.

    “it is difficult to decipher whether zolpidem also suppresses NE dynamics in human subjects.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Anesthesia potently suppresses norepinephrine release and vasomotion.

    “Anesthesia potently suppresses NE release and vasomotion71–73”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [71] Mefford IN, Garrick NA. Effects of xylazine on cerebrospinal fluid catecholamines in the rhesus monkey. Brain Res. 1989; 492(1–2): 377– 380. doi: 10.1016/0006-8993(89)90923-2 2568878 source
    • cites [72] Ambrisko TD, Hikasa Y. Neurohormonal and metabolic effects of medetomidine compared with xylazine in beagle dogs. Can J Vet Res. 2002; 66(1): 42– 49. 11858648 PMC226981
    • cites [73] Kanda T, Hikasa Y. Neurohormonal and metabolic effects of medetomidine compared with xylazine in healthy cats. Can J Vet Res. 2008; 72(3): 278– 286. 18505192 PMC2327246

  • It may state two separate claims as one.

    Interpretationown data

    The frequency of micro-arousals displayed a stronger correlation with glymphatic influx and clearance than all other measures of sleep analyzed, including total amount of NREM sleep and NREM delta power, suggesting that norepinephrine oscillations are the main determinant of glymphatic clearance in NREM sleep.

    “In summary, the frequency of micro-arousals displayed a stronger correlation with glymphatic influx and clearance than all other measures of sleep analyzed, including total amount of NREM sleep and NREM delta power, suggesting that NE oscillations is the main determinant of glymphatic clearance in NREM sleep.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Zolpidem dampens the infraslow norepinephrine dynamics of sleep, which suppresses cerebrospinal fluid tracer influx, despite increasing the duration of sleep.

    “Thus, zolpidem dampens the infraslow NE dynamics of sleep, which suppresses CSF tracer influx, despite increasing the duration of sleep.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Glymphatic influx is not correlated with statically high norepinephrine (wakefulness) or statically low norepinephrine (REM sleep), but depends on the dynamic norepinephrine release that occurs in NREM sleep for optimal flow.

    “Furthermore, the observations indicate that glymphatic influx is not correlated with statically high NE (wakefulness) or statically low NE (REM sleep), but depends on the dynamic NE release that occurs in NREM sleep for optimal flow.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Boosting of inhibitory transmission dramatically alters the microarchitecture of sleep, possibly by direct suppression of LC activity, and thereby the NE oscillations characteristic of NREM sleep.

    “A key difference between natural and pharmacologically supported sleep is that boosting of inhibitory transmission dramatically alters the microarchitecture of sleep, possibly by direct suppression of LC activity, and thereby the NE oscillations characteristic of NREM sleep.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Infraslow norepinephrine oscillations trigger slow vasomotion, which in turn is the primary driver of glymphatic flow in NREM sleep.

    “In summary, correlation analysis, as well as optogenetic stimulation or inhibition of LC, or direct stimulation of vascular smooth muscle cells, as well as indirect manipulations of slow vasomotion (zolpidem) document that it is the infraslow NE oscillations that triggers slow vasomotion, which in turn is the primary driver of glymphatic flow in NREM sleep (Figure 7).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    The observed increase in micro-arousal and decrease in glymphatic influx support that it is infraslow norepinephrine oscillations, and not micro-arousals, that drive cerebrospinal fluid flow.

    “Additionally, the observed increase in micro-arousal and decrease in glymphatic influx support that it is infraslow NE oscillations, and not micro-arousals, that drive CSF flow.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Zolpidem is a high-affinity positive modulator of GABAA receptors that enhances GABAergic transmission by binding to the alpha1 subunit.

    “Zolpidem (Ambien) is a high-affinity positive modulator of GABAA receptors, that enhances GABAergic transmission by binding to the alpha1 subunit91.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Kralic JE, O’Buckley TK, Khisti RT, Hodge CW, Homanics GE, Morrow AL. GABAA receptor alpha-1 subunit deletion alters receptor subtype assembly, pharmacological and behavioral responses to benzodiazepines and zolpidem. Neuropharmacology. 2002; 43(4): 685– 694. doi: 10.1016/S0028-3908(02)00174-0 12367614 source

  • It may state two separate claims as one.

    Premisecitation

    These drugs are associated with considerable adverse effects and an increased risk of early mortality.

    “these drugs are associated with considerable adverse effects and an increased risk of early mortality97.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Lohela TJ, Lilius TO, Nedergaard M. The glymphatic system: implications for drugs for central nervous system diseases. Nat Rev Drug Discov. 2022; 21(10): 763– 779. doi: 10.1038/s41573-022-00500-9 35948785 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    In the glymphatic clearance study (Figure 5), mice that spent less than 75 minutes of the 5 hours between scans in sleep were omitted from the analysis.

    “For the glymphatic clearance study (Figure 5), mice that spent less than 75 minutes of the 5 hours (25% of the time) between scans in sleep were omitted from the analysis (1 mouse).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Mice with excessive noise on the EEG signal were excluded from EEG power analyses.

    “Mice with excessive noise on the EEG signal were excluded from EEG power analyses.”
    • Also stated in: § Statistical analysis · plain
      “For all analysis of EEG power, mice were omitted if EEG power analysis could not be performed due to too noisy signals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    The HPLC-EC assay for NE had a limit of detection of 12 fmol/10 μl at a signal-to-noise ratio of 3.

    “The limits of detection (at signal-to-noise-ratio 3) for NE, concentrations were 12 fmol/10 μl.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Zolpidem impaired the NE dynamics that characterize normal restorative sleep, resulting in reduced glymphatic flow.

    “the sleep aid zolpidem impaired the NE dynamics that characterize normal restorative sleep resulting in reduced glymphatic flow.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    NE release is directly linked to slow vasomotion and CSF flow.

    “our observations that directly links NE release to slow vasomotion and CSF flow.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    In the glymphatic influx study (Figure S4), mice that spent less than 20 of the 30 minutes circulation time in sleep were omitted from the analysis.

    “For the glymphatic influx study (Figure S4), mice that spent less than 20 of the 30 minutes circulation time in sleep were omitted from the analysis (2 mice) in order to obtain enough sleep data.”
    Quote in the paperNot a substantial claim
64 of 64

  • The paper relies on this without support.

    The brain relies on cerebrospinal fluid circulation through the tissue to remove waste proteins because it lacks lymphatic vessels.

    “Due to the lack of lymphatic vessels, the brain relies on CSF circulation through the tissue to remove waste proteins.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Pharmacologic treatments for insomnia are generally given reduced recommendations in clinical guidelines due to concerns about dependence and cognitive side effects.

    “While pharmacologic treatments for insomnia are generally given reduced recommendations in clinical guidelines due to concerns about dependence and cognitive side effects, 47 , 48 , 49 , 50 our findings suggest possible differences in associations with cognitive outcomes across hypnotics, and further investigation is warranted.”

    From Critical evaluation of real‐world evidence of repurposable medicines in the Alzheimer's disease drug development pipeline using a target trial emulation (2026) · cites this paper as [50]

    The Discussion section on zolpidem and glymphatic flow says the American Geriatric Society does not recommend zolpidem for people over 65 and mentions a reported risk of reversible dementia. It does not address dependence or establish that clinical guidelines generally give reduced recommendations to pharmacologic insomnia treatments as a class. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting zolpidem doses for the marble-burying test

    Minor

    The results describe pilot testing at 1 and 5 mg/kg, including the marble-burying test, and the marble-burying method gives those same doses. The drug-preparation method instead says the test used 5 and 10 mg/kg.

  • Baseline microdialysis sample count does not match sampling interval

    Minor

    Samples were obtained every 20 minutes, so a 20-minute baseline would yield one sample, not the stated two.

    Reported 2 · recomputed 1

  • Conflicting SPECT acquisition and reconstruction peak energies

    Minor

    The acquisition specifies a 1200 keV detection peak, whereas reconstruction specifies a photopeak window centered at 140 keV. These are conflicting energies for the stated SPECT photopeak.

3 of 3

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Kanda, 2008, Neurohormonal and metabolic effects of medetomidine compared with xylazine in healthy cats, Can. J. Vet. Res., 72, 278

Cited by

Sorted by citations

Related

Metadata

Authors
Hauglund, N. L., Andersen, M., Tokarska, K., Radovanovic, T., Kjaerby, C., Sørensen, F. L., Bojarowska, Z., Untiet, V., Ballestero, S. B., Kolmos, M. G., Weikop, P., Hirase, H., & Nedergaard, M.
Affiliations
University of Copenhagen (DK)
Corresponding author
Nedergaard, Maiken
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2025-02
Volume
188
Issue
3
Pages
606-622.e17
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2024.11.027
PMC
PMC12340670
OpenAlex
W4406155654
Semantic Scholar
3637e1fc04948670cb2efbfa832f77cd587ec9da
Cited by
349
References
118
Citations by year
2026: 229 · 2025: 119
FWCI
186.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
  • Simons Foundation (811237)
  • Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
  • Independent Research Fund Denmark (0134-00107B, 3101-00282B)
  • Lundbeck Foundation (114955, R386-2021-165)
  • NIH (U19NS128613, AT011439, R01A 012707)
  • EU Joint Programme – Neurodegenerative Disease Research
  • Cure Alzheimer's Fund
  • Novo Nordisk Foundation (NNFOC0058058, NNF23OC0082427, NNF20OC0066419)
  • Human Frontier Science Program (RGP0036)
  • Army Research Office (MURI W911NF1910280)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
  • Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
glymphatic system, norepinephrine, vasomotion, NREM sleep, cerebrospinal fluid flow, cerebral blood volume, locus coeruleus, optogenetic stimulation, zolpidem, brain waste clearance, sleep-dependent memory consolidation
MeSH terms
Zolpidem, Glymphatic System, Animals, Brain, Cerebrospinal Fluid, Cerebrovascular Circulation, Locus Coeruleus, Male, Mice, Inbred C57BL, Norepinephrine, Sleep, Mice, Optogenetics

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-11-07, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-07 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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