Multi-sensory Gamma Stimulation Ameliorates Alzheimer’s-Associated Pathology and Improves Cognition
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We previously reported that inducing gamma oscillations with a non-invasive light flicker (gamma entrainment using sensory stimulus or GENUS) impacted pathology in the visual cortex of Alzheimer's disease mouse models. Here, we designed auditory tone stimulation that drove gamma frequency neural activity in auditory cortex (AC) and hippocampal CA1. Seven days of auditory GENUS improved spatial and recognition memory and reduced amyloid in AC and hippocampus of 5XFAD mice. Changes in activation responses were evident in microglia, astrocytes, and vasculature. Auditory GENUS also reduced phosphorylated tau in the P301S tauopathy model. Furthermore, combined auditory and visual GENUS, but not either alone, produced microglial-clustering responses, and decreased amyloid in medial prefrontal cortex. Whole brain analysis using SHIELD revealed widespread reduction of amyloid plaques throughout neocortex after multi-sensory GENUS. Thus, GENUS can be achieved through multiple sensory modalities with wide-ranging effects across multiple brain areas to improve cognitive function.
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Gamma oscillations using transcranial alternating current stimulation (tACS) at 40 Hz increased blood perfusion in bilateral temporal lobes in mild to moderate AD patients based on an arterial spin labeling study using MRI.
“Gamma oscillations using transcranial alternating current stimulation (tACS) at 40 Hz increased blood perfusion in bilateral temporal lobes in mild to moderate AD patients based on an arterial spin labeling study using MRI ([70]; NCT03290326, and NCT 03412604).”
From Current therapeutics for Alzheimer’s disease and clinical trials (2024) · cites this paper as [70]
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“Research in mice has shown that 40-Hz gamma entrainment with audiovisual stimulation can reduce phosphorylated tau and amyloid in mice [45–47].”
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“Recently, 40-Hz gamma-rhythmic sensory stimuli (flicker and acoustic stimulation) have been used to improve cognitive function, providing an important advancement in the nonpharmacological treatment of cognitive impairment [29,31].”
BackgroundGamma oscillations and episodic memory
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40 Hz light flickering facilitates the glymphatic flow via adenosine signaling in mice
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“In fact, GENUS reduces β -amyloid deposit and reverses cognitive de fi cits in AD mouse models 12,13 , reduces ventricular dilation and hippocampal atrophy, and improves memory performance in mild AD patients 15 .”
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“Martorell [6] extended this work by using an auditory 40 Hz stimulus for one hour per day for seven days.”
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“(10 Hz or 40 Hz) using binaural auditory beats [58], pulsed light at alpha or gamma frequencies elicited a positive effect on the brain in mouse models of AD [59, 60].”
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“Given previous work showing the importance of theta and gamma waves for cognitive processes and the development of AD pathology, 79 it would be interesting for future studies to investigate the role of these bands in tau spread.”
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40 Hz light flickering promotes sleep through cortical adenosine signaling
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“The electrical properties of neurons can change in neurodegeneration (Llinás, 2014; Martorell et al., 2019; Adaikkan and Tsai, 2020), and alterations in neuronal oscillations, identified by different frequencies, occur in neurodegenerative disorders.”
Audible sound-controlled spatiotemporal patterns in out-of-equilibrium systems
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“…finding suggests that while both LPS and 40 Hz flicker may up- regulate some similar cytokines, they may be leading to different downstream mechanisms that explain why LPS is known to be neurotoxic, while 40 Hz flicker is known to be neuroprotective (Iaccarino et al., 2016; Martorell et al., 2019).”
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“In turn, sensory-evoked gamma oscillations elicit morphological and/or gene and protein expression responses in microglia in diverse mouse models of neurodegeneration, including 5XFAD, APP/PS1, Tau P301S, and CK-p25 mice [130, 155, 156].”
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“…prior studies of 5XFAD mice have found spatial and memory impairments (novel object location, novel object recognition, Morris water maze) at or before this age (Flanigan et al., 2014; Martorell et al., 2019; O’Leary et al., 2018; Oakley et Cell Rep. Author manuscript; available in PMC 2021 May 21.”
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“The tUS stimulation might have a later therapeutic effect on the functionality of the brain than auditory or visual stimulation [23, 24], as in our consecutive analysis, the spontaneous gamma power showed significant improvement on day 14, but not on day 7.”
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“In recent studies, enhancing gamma frequency oscillations via external stimuli reduced amyloid burden, possibly via increased microglia activity, and improved cognitive function in rodents (Laccarino et al., 2016; Martorell et al., 2019).”
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“108 In addition, digital technologies such as wearable sensors and mobile apps can monitor medication adherence to improve efficacy of clinical care and clinical trials.”
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An update on the use of gamma (multi)sensory stimulation for Alzheimer’s disease treatment
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Optimal flickering light stimulation for entraining gamma waves in the human brain
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Self-citationPhotobiomodulation for Neurodegenerative Diseases: A Scoping Review
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“They discovered that this combined stimulation could promote the clustering of microglial cells around A β plaques, leading to a widespread reduction in amyloid proteins and phosphorylated Tau proteins in multiple brain regions [89].”
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“in the gamma band, decrease levels of amyloid plaques [26], auditory and visual stimulation at low-gamma frequency (40Hz) ameliorate AD pathology and improve cognition in an AD mouse model [30].”
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Clinically-derived vagus nerve stimulation enhances cerebrospinal fluid penetrance
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Benefits in Alzheimer’s Disease of Sensory and Multisensory Stimulation
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Self-citation
- Authors
- 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., Mangena, V., Prince, S. M., Brown, E. N., Chung, K., Boyden, E. S., Singer, A. C., & Tsai, L.-H.
- Affiliations
- Massachusetts Institute of Technology (US)
- Georgia Institute of Technology (US)
- McGovern Institute for Brain Research (US)
- Harvard–MIT Division of Health Sciences and Technology (US)
- Harvard University (US)
- Broad Institute (US)
- Corresponding author
- Tsai, Li-Huei
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 177
- Issue
- 2
- Pages
- 256-271.e22
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6774262
- OpenAlex
- W2922175568
- Cited by
- 798
- References
- 55
- Citations by year
- 2026: 125 · 2025: 134 · 2024: 138 · 2023: 111 · 2022: 107 · 2021: 96 · 2020: 62 · 2019: 23
- FWCI
- 49.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- NIH (R01-NS109226, T32 NS007480-18, RF1-AG047661, U01-NS090473, U01MH117072, T32 GM007484, R01-EY023173, R01-GM104948, DP1-OD003646)
- Packard Award in Science and Engineering
- Friends and Alumni of Georgia Tech, Lane Family
- Fulton County Elder Health Science
- Wright Family
- Robert and Renee Belfer Family Foundation
- Halis Family Foundation
- JPB Foundation
- Burroughs Wellcome Fund
- Searle
- NARSAD
- NCSOFT
- Integrative Neuronal Systems
- MIT
- Henry E. Singleton
- William C. and Margaret H. Rousseau
- SITA Foundation
- Samsung
- MIT Aging Brain Initiative (to L.-H.T. and E.S.B.), John Doerr, Edward and Kay Poitras
- HHMI-Simons
- Open Philanthropy, Charles Hieken
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, gamma oscillations, auditory stimulation, genus, non-invasive brain stimulation, auditory cortex, hippocampal CA1, amyloid plaques, tau phosphorylation, 5xFAD mice, microglia, astrocytes, spatial memory, recognition memory, multisensory stimulation, cognitive enhancement
- MeSH terms
- Acoustic Stimulation, Alzheimer Disease, Amyloid, Animals, Auditory Perception, Brain, Cognition, Disease Models, Animal, Hippocampus, Male, Mice, Inbred C57BL, Amyloid beta-Peptides, Microglia, Mice, Plaque, Amyloid, Gamma Rhythm
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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.
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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