Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep

In the paper

“NE is known to be a potent vasoconstrictor36,37.”

What the sources say

• Supported

  In “Relationship between noradrenaline concentration and fluorescence” (page not provided), the paper reports that noradrenaline produced maximal constriction of isolated arteries at concentrations well below those needed for detectable fluorescence. This supports the cited statement that norepinephrine is a potent vasoconstrictor. (LLM, conf=0.88)

  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
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“The glymphatic system uses the perivascular spaces as low-resistance routes for fast influx of CSF into deep brain regions1.”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

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

  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 sourceExperimental — accuracy not yet measured
• Partly supported

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

  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 sourceExperimental — accuracy not yet measured
• Not checked yetcites [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

In the paper

“The glymphatic system is a highly organized, brain-wide network for cerebrospinal fluid (CSF) transport that exports protein waste, including amyloid and tau1–3.”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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
• Supported

  The Introduction describes perivascular, AQP4-facilitated transport from brain interstitial fluid into CSF and reports that AQP4 deficiency reduces amyloid-β clearance. The Results and discussion calls the glymphatic system a brain-wide pathway for eliminating extracellular substances and reports that it clears extracellular tau from the brain to CSF. These passages support the cited description, although the paper attributes the amyloid finding to earlier studies. (LLM, conf=0.90)

  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

In the paper

“glymphatic flow is enhanced by optogenetic stimulation of excitatory neurons in hippocampus across a broad range of frequencies89”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“Since it is difficult to control when rodents enter natural sleep, anesthesia is commonly used as a proxy for sleep1,24,99,100.”

What the sources say

• ?Could not verify

  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)

  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 sourceExperimental — accuracy not yet measured
• ?Could not verify

  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)

  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 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“glymphatic flow is partly active in quiet wakefulness, whereas active wakefulness potently suppresses CSF inflow88.”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“Common to both studies was the finding that neural synchrony drive glymphatic clearance.”

What the sources say

• Supported

  The Discussion states that coordinated neuronal firing generates rhythmic ionic waves that facilitate CSF perfusion and metabolic-waste removal. It also reports that rhythmic neuronal oscillations organize brain clearance, supporting the paraphrase that neural synchrony drives glymphatic clearance. (LLM, conf=0.93)

  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
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“similar observations have been done in response to sensory gamma stimulation (40 Hz, visual or auditory)90.”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• Not checked yetcites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“Prescription of zolpidem is currently not recommended for individuals older than 65 by the American Geriatric Society93,94.”

What the sources say

• ?Could not verify

  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)

  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 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

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

  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 sourceExperimental — accuracy not yet measured

In the paper

“zolpidem has previously been shown to increase the risk of reversible dementia and has also been linked to neuropsychiatric adverse events92.”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“measurements of CSF dynamics have proven more difficult and have mostly been restricted to experiments in awake and anesthetized mice24.”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“astrocyte endfeet may act as valves that promote CSF flow through the perivascular spaces and prevent backflow86,87.”

What the sources say

• Not checked yetcites [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
• Supported

  The Introduction proposes that astrocyte endfeet act as valves and explains that reduced permeability during artery constriction inhibits reflux from the extracellular space. The Discussion says the modeled valve action promotes directed net flow in perivascular spaces. The claim’s tentative wording matches the paper’s proposed mechanism. (LLM, conf=0.94)

  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

In the paper

“chronic sleep fragmentation impairs both slow vasomotion and glymphatic function77.”

What the sources say

• Supported

  The Abstract reports that chronic sleep fragmentation reduced glymphatic function and suppressed slow vasomotion in young wildtype mice. The Discussion likewise reports reduced CSF transport and dampened slow vasomotion after 30 days of sleep fragmentation. (LLM, conf=0.94)

  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

In the paper

“a hallmark of aging and neurodegenerative diseases is the impairment of functional hyperemia, i.e., vasodilation in response to neural activity83.”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“Most prior studies looking at vascular dynamics have used two-photon imaging in head-fixed mice31,47,98”

What the sources say

• Supported

  The Methods sections describe two-photon imaging of blood vessels in mice trained to be head-fixed. This paper is therefore an example of the study type cited in the sentence; it does not itself establish how many prior studies used that approach. (LLM, conf=0.90)

  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
• Supported

  The Results describe this study as using two-photon microscopy to measure vascular dynamics in un-anesthetized, head-fixed mice. The Materials and methods section confirms that the mice were head-fixed while pial and penetrating arterioles were imaged. This source therefore serves as an example of the type of prior study cited, rather than independently establishing that most prior studies used the approach. (LLM, conf=0.88)

  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
• Supported

  The In vivo two-photon microscopy section describes imaging capillary blood flow in head-fixed mice using a two-photon microscope. Figure 1 likewise identifies a head-fixed mouse setup for vascular imaging. This paper therefore supports the citation as an example of the method described. (LLM, conf=0.91)

  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

In the paper

“flow fiber photometry enables recordings from deep brain tissues and combined monitoring of blood and CSF dynamics using virally-delivered biosensors45,101–104.”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• Supported

  Citation 17 is attached to the observation of CSF flow during sleep, not to the separate statement about autonomic arousals, which cites 42. The supplied passages report a 0.05 Hz CSF oscillation during human NREM sleep and describe fMRI measurement with the imaging boundary at the fourth ventricle. (LLM, conf=0.93)

  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
• Supported

  Citation 42 is attached to the temporal association with autonomic arousals, not the 0.05 Hz frequency, which the sentence cites separately. The Results (page unavailable) report CSF inflow events alongside autonomic arousals during sleep, and the Discussion describes an autonomic contribution to CSF pulsations near the fourth ventricle. The relationship is time-lagged rather than simultaneous. (LLM, conf=0.88)

  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

In the paper

“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).”

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“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).”

In the paper

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

In the paper

“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.”

In the paper

“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).”

In the paper

“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).”

In the paper

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

In the paper

“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).”

In the paper

“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.”

In the paper

“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).”

In the paper

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

In the paper

“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).”

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“Most prior studies have concluded that vasomotion reflects intrinsic activity of vascular smooth muscle cells78,79.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

“it is difficult to decipher whether zolpidem also suppresses NE dynamics in human subjects.”

In the paper

“Anesthesia potently suppresses NE release and vasomotion71–73”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• Not checked yetcites [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

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

In the paper

“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.”

In the paper

“Zolpidem (Ambien) is a high-affinity positive modulator of GABAA receptors, that enhances GABAergic transmission by binding to the alpha1 subunit91.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“these drugs are associated with considerable adverse effects and an increased risk of early mortality97.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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).”

In the paper

“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.”

In the paper

“The limits of detection (at signal-to-noise-ratio 3) for NE, concentrations were 12 fmol/10 μl.”

In the paper

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

In the paper

“our observations that directly links NE release to slow vasomotion and CSF flow.”

In the paper

“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.”