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Multisensory gamma stimulation promotes glymphatic clearance of amyloid
Open accessAbstract
The glymphatic movement of fluid through the brain removes metabolic waste 1–4 . Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer’s disease 5–8 . Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer’s disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.
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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.”
From Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep (2025) · cites this paper as [90]
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 measuredNeural synchrony drives glymphatic clearance.
“Common to both studies was the finding that neural synchrony drive glymphatic clearance.”
From Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep (2025) · cites this paper as [90]
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)
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Citations
Cites
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“Given the importance of astrocytes to glymphatic function 3,10 , we interrogated astrocytic transcriptional responses to multisensory 40 Hz stimulation.”
BackgroundSleep Drives Metabolite Clearance from the Adult Brain
Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., O’Donnell, J., Christensen, D. J., Nicholson, C., Iliff, J. J., et al. (2013) · Science · doi:10.1126/science.1241224 · Cited by 5,411
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A molecular atlas of cell types and zonation in the brain vasculature
Vanlandewijck, M., He, L., Mäe, M. A., Andrae, J., Ando, K., Del Gaudio, F., Nahar, K., Lebouvier, T., Laviña, B., Gouveia, L., et al. (2018) · Nature · doi:10.1038/nature25739 · Cited by 1,892 · cited 1×
“We further annotated vascular cells as endothelial cells, pericytes, smooth muscle cells and fibroblasts 28 (Fig.”
BackgroundImpairment of paravascular clearance pathways in the aging brain
Kress, B. T., Iliff, J. J., Xia, M., Wang, M., Wei, H. S., Zeppenfeld, D., Xie, L., Kang, H., Xu, Q., Liew, J. A., et al. (2014) · Annals of Neurology · doi:10.1002/ana.24271 · Cited by 1,521 · cited 2×
“We used established methods to quantify AQP4 polarization 12,21 .”
BackgroundMethodGamma frequency entrainment attenuates amyloid load and modifies microglia
Iaccarino, H. F., Singer, A. C., Martorell, A. J., Rudenko, A., Gao, F., Gillingham, T. Z., Mathys, H., Seo, J., Kritskiy, O., Abdurrob, F., et al. (2016) · Nature · doi:10.1038/nature20587 · Cited by 1,328
Self-citationCerebral Arterial Pulsation Drives Paravascular CSF–Interstitial Fluid Exchange in the Murine Brain
Iliff, J. J., Wang, M., Zeppenfeld, D. M., Venkataraman, A., Plog, B. A., Liao, Y., Deane, R., & Nedergaard, M. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.1592-13.2013 · Cited by 1,319
Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep
Fultz, N. E., Bonmassar, G., Setsompop, K., Stickgold, R. A., Rosen, B. R., Polimeni, J. R., & Lewis, L. D. (2019) · Science · doi:10.1126/science.aax5440 · Cited by 1,197
Glymphatic failure as a final common pathway to dementia
Nedergaard, M., & Goldman, S. A. (2020) · Science · doi:10.1126/science.abb8739 · Cited by 1,145 · cited 2×
“The meningeal lymphatic drainage network, arterial-driven CSF movement and neuronal network dysfunction contribute to amyloid pathology in Alzheimer’s disease 14 .”
BackgroundMulti-sensory Gamma Stimulation Ameliorates Alzheimer’s-Associated Pathology and Improves Cognition
Martorell, A. J., Paulson, A. L., Suk, H.-J., Abdurrob, F., Drummond, G. T., Guan, W., Young, J. Z., Kim, D. N.-W., Kritskiy, O., Barker, S. J., et al. (2019) · Cell · doi:10.1016/j.cell.2019.02.014 · Cited by 798 · cited 5×
“4d–f), although we cannot rule out a possible behavioural effect of chronic TGN020 treatment 6 .”
BackgroundMethodInfluentialSelf-citationCircadian control of brain glymphatic and lymphatic fluid flow
Hablitz, L. M., Plá, V., Giannetto, M., Vinitsky, H. S., Stæger, F. F., Metcalfe, T., Nguyen, R., Benrais, A., & Nedergaard, M. (2020) · Nature Communications · doi:10.1038/s41467-020-18115-2 · Cited by 704 · cited 6×
“We used established methods to quantify AQP4 polarization 12,21 .”
BackgroundMethodInfluentialMeningeal lymphatics affect microglia responses and anti-Aβ immunotherapy
Da Mesquita, S., Papadopoulos, Z., Dykstra, T., Brase, L., Farias, F. G., Wall, M., Jiang, H., Kodira, C. D., de Lima, K. A., Herz, J., et al. (2021) · Nature · doi:10.1038/s41586-021-03489-0 · Cited by 431
Neuropeptide and small transmitter coexistence: Fundamental studies and relevance to mental illness
Hökfelt, T., Barde, S., Xu, Z.-Q. D., Kuteeva, E., Rüegg, J., Le Maitre, E., Risling, M., Kehr, J., Ihnatko, R., Theodorsson, E., et al. (2018) · Frontiers in Neural Circuits · doi:10.3389/fncir.2018.00106 · Cited by 139
Chen, W., Zheng, Q., Huang, Q., Ma, S., & Li, M. (2022) · eLife · doi:10.7554/elife.75636 · Cited by 89
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Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep
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Metadata
- Authors
- Murdock, M. H., Yang, C.-Y., Sun, N., Pao, P.-C., Blanco-Duque, C., Kahn, M. C., Kim, T., Lavoie, N. S., Victor, M. B., Islam, M. R., Galiana, F., Leary, N., Wang, S., Bubnys, A., Ma, E., Akay, L. A., Sneve, M., Qian, Y., Lai, C., McCarthy, M. M., Kopell, N., Kellis, M., Piatkevich, K. D., Boyden, E. S., & Tsai, L.-H.
- Affiliations
- Massachusetts Institute of Technology (US)
- Broad Institute (US)
- Howard Hughes Medical Institute (US)
- Westlake University (CN)
- Boston University (US)
- Corresponding author
- Tsai, Li-Huei
- ORCID
- Venue
- Nature
- Published
- 2024-02-28
- Volume
- 627
- Issue
- 8002
- Pages
- 149-156
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC10917684
- OpenAlex
- W4392242084
- Cited by
- 379
- References
- 15
- Citations by year
- 2026: 161 · 2025: 158 · 2024: 60
- FWCI
- 94.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Massachusetts Institute of Technology
- National Institutes of Health
- National Institute on Aging (R01AG069232)
- National Institute of Mental Health (R01MH122971, R01MH114031)
- National Institute on Drug Abuse (R01DA045549, R01DA029639)
- National Institute of Neurological Disorders and Stroke (R37NS051874, R01NS051874)
- National Center for Complementary and Integrative Health (R01AT011460)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- glymphatic system, amyloid clearance, 40 Hz stimulation, Alzheimer's disease, aquaporin-4, astrocyte endfeet, meningeal lymphatic vessels, vasoactive intestinal peptide, arterial pulsatility, 5xFAD mice, chemogenetic manipulation
- MeSH terms
- Glymphatic System, Alzheimer Disease, Amyloid, Animals, Astrocytes, Brain, Cerebral Cortex, Cerebrospinal Fluid, Disease Models, Animal, Electric Stimulation, Interneurons, Vasoactive Intestinal Peptide, Extracellular Fluid, Mice, Aquaporin 4, Gamma Rhythm
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