Multi-sensory Gamma Stimulation Ameliorates Alzheimer's-Associated Pathology and Improves Cognition
Anthony J Martorell, Abigail L Paulson, Ho-Jun Suk, Fatema Abdurrob, Gabrielle T Drummond, Webster Guan, Jennie Z Young, David Nam-Woo Kim, Oleg Kritskiy, Scarlett J Barker, Vamsi Mangena, Stephanie M Prince, Emery N Brown, Kwanghun Chung, Edward S Boyden, Annabelle C Singer, Li-Huei Tsai, Anthony J Martorell, Abigail L Paulson, Ho-Jun Suk, Fatema Abdurrob, Gabrielle T Drummond, Webster Guan, Jennie Z Young, David Nam-Woo Kim, Oleg Kritskiy, Scarlett J Barker, Vamsi Mangena, Stephanie M Prince, Emery N Brown, Kwanghun Chung, Edward S Boyden, Annabelle C Singer, Li-Huei Tsai
Abstract
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.
Keywords: Alzheimer’s disease; acoustic stimulation; amyloid; astrocytes; cognition; gamma rhythms; memory; microglia; photic stimulation; vasculature.
Conflict of interest statement
Conflict of Interest
L.-H.T. and E.S.B are co-Scientific Founders and serve on the scientific advisory board of Cognito Therapeutics and A.C.S. owns shares of Cognito Therapeutics Inc.
Copyright © 2019 Elsevier Inc. All rights reserved.
Figures
![Figure 1.. 40 Hz auditory stimulation modulates…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6774262/bin/nihms-1538841-f0001.jpg)
![Figure 2.. Auditory GENUS improves recognition and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6774262/bin/nihms-1538841-f0002.jpg)
![Figure 3.. Auditory GENUS reduces amyloid load…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6774262/bin/nihms-1538841-f0003.jpg)
Figure 4.. Auditory GENUS induces glial response…
Figure 4.. Auditory GENUS induces glial response in AC and CA1 in 5XFAD mice
Figure 5.. Auditory GENUS increases amyloid-vasculature associations.
Figure 5.. Auditory GENUS increases amyloid-vasculature associations.
A. Immunohistochemistry with lectin stain (DL-1174, green) in…
Figure 6.. Combined auditory and visual GENUS…
Figure 6.. Combined auditory and visual GENUS induces a clustering phenotype response by microglia
A.…
Figure 7.. Combined auditory and visual GENUS…
Figure 7.. Combined auditory and visual GENUS reduces amyloid load in the mPFC and neocortex
- A stimulating approach.Yates D. Yates D. Nat Rev Neurosci. 2019 May;20(5):249. doi: 10.1038/s41583-019-0167-8. Nat Rev Neurosci. 2019. PMID: 30940918 No abstract available.
- Improving cognition.Stower H. Stower H. Nat Med. 2019 May;25(5):710. doi: 10.1038/s41591-019-0454-y. Nat Med. 2019. PMID: 31068706 No abstract available.
- Gamma frequency entrainment attenuates amyloid load and modifies microglia.Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, Adaikkan C, Canter RG, Rueda R, Brown EN, Boyden ES, Tsai LH. Iaccarino HF, et al. Nature. 2016 Dec 7;540(7632):230-235. doi: 10.1038/nature20587. Nature. 2016. PMID: 27929004 Free PMC article.
- Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology.Spangenberg EE, Lee RJ, Najafi AR, Rice RA, Elmore MR, Blurton-Jones M, West BL, Green KN. Spangenberg EE, et al. Brain. 2016 Apr;139(Pt 4):1265-81. doi: 10.1093/brain/aww016. Epub 2016 Feb 26. Brain. 2016. PMID: 26921617 Free PMC article.
- Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection.Adaikkan C, Middleton SJ, Marco A, Pao PC, Mathys H, Kim DN, Gao F, Young JZ, Suk HJ, Boyden ES, McHugh TJ, Tsai LH. Adaikkan C, et al. Neuron. 2019 Jun 5;102(5):929-943.e8. doi: 10.1016/j.neuron.2019.04.011. Epub 2019 May 7. Neuron. 2019. PMID: 31076275 Free PMC article.
- Effects of CX3CR1 and Fractalkine Chemokines in Amyloid Beta Clearance and p-Tau Accumulation in Alzheimer's Disease (AD) Rodent Models: Is Fractalkine a Systemic Biomarker for AD?Merino JJ, Muñetón-Gómez V, Alvárez MI, Toledano-Díaz A. Merino JJ, et al. Curr Alzheimer Res. 2016;13(4):403-12. doi: 10.2174/1567205013666151116125714. Curr Alzheimer Res. 2016. PMID: 26567742 Review.
- Review: experimental manipulations of microglia in mouse models of Alzheimer's pathology: activation reduces amyloid but hastens tau pathology.Lee DC, Rizer J, Hunt JB, Selenica ML, Gordon MN, Morgan D. Lee DC, et al. Neuropathol Appl Neurobiol. 2013 Feb;39(1):69-85. doi: 10.1111/nan.12002. Neuropathol Appl Neurobiol. 2013. PMID: 23171029 Free PMC article. Review.
- Maresin1 Ameliorates Sepsis-Induced Microglial Neuritis Induced through Blocking TLR4-NF-κ B-NLRP3 Signaling Pathway.Wu H, Wang Y, Fu H, Ji L, Li N, Zhang D, Su L, Hu Z. Wu H, et al. J Pers Med. 2023 Mar 16;13(3):534. doi: 10.3390/jpm13030534. J Pers Med. 2023. PMID: 36983716 Free PMC article.
- Influence of Binaural Beats Stimulation of Gamma Frequency over Memory Performance and EEG Spectral Density.Borges LR, Arantes APBB, Naves ELM. Borges LR, et al. Healthcare (Basel). 2023 Mar 9;11(6):801. doi: 10.3390/healthcare11060801. Healthcare (Basel). 2023. PMID: 36981458 Free PMC article.
- Alzheimer's disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression.Meftah S, Gan J. Meftah S, et al. Front Synaptic Neurosci. 2023 Mar 9;15:1129036. doi: 10.3389/fnsyn.2023.1129036. eCollection 2023. Front Synaptic Neurosci. 2023. PMID: 36970154 Free PMC article. Review.
- Electroclinical characteristics of photosensitive epilepsy: A retrospective study of 31 Chinese children and literature review.Zhang B, Chen T, Hao X, Xin M, Liang J. Zhang B, et al. Front Pediatr. 2023 Mar 9;11:994817. doi: 10.3389/fped.2023.994817. eCollection 2023. Front Pediatr. 2023. PMID: 36969295 Free PMC article.
- How to entrain a selected neuronal rhythm but not others: open-loop dithered brain stimulation for selective entrainment.Duchet B, Sermon JJ, Weerasinghe G, Denison T, Bogacz R. Duchet B, et al. J Neural Eng. 2023 Mar 7;20(2):10.1088/1741-2552/acbc4a. doi: 10.1088/1741-2552/acbc4a. J Neural Eng. 2023. PMID: 36880684 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Acoustic Stimulation / methods*
- Alzheimer Disease / pathology
- Alzheimer Disease / therapy*
- Amyloid / metabolism
- Amyloid beta-Peptides / metabolism
- Animals
- Auditory Perception / physiology
- Brain / metabolism
- Cognition / physiology*
- Disease Models, Animal
- Gamma Rhythm / physiology
- Hippocampus / metabolism
- Male
- Mice
- Mice, Inbred C57BL
- Microglia / metabolism
- Plaque, Amyloid / metabolism
- Amyloid
- Amyloid beta-Peptides
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
NCBI Literature Resources
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![Figure 4.. Auditory GENUS induces glial response…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6774262/bin/nihms-1538841-f0004.jpg)
![Figure 5.. Auditory GENUS increases amyloid-vasculature associations.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6774262/bin/nihms-1538841-f0005.jpg)
Figure 6.. Combined auditory and visual GENUS…
Figure 6.. Combined auditory and visual GENUS induces a clustering phenotype response by microglia
A.…
Figure 7.. Combined auditory and visual GENUS…
Figure 7.. Combined auditory and visual GENUS reduces amyloid load in the mPFC and neocortex
- A stimulating approach.Yates D. Yates D. Nat Rev Neurosci. 2019 May;20(5):249. doi: 10.1038/s41583-019-0167-8. Nat Rev Neurosci. 2019. PMID: 30940918 No abstract available.
- Improving cognition.Stower H. Stower H. Nat Med. 2019 May;25(5):710. doi: 10.1038/s41591-019-0454-y. Nat Med. 2019. PMID: 31068706 No abstract available.
- Gamma frequency entrainment attenuates amyloid load and modifies microglia.Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, Adaikkan C, Canter RG, Rueda R, Brown EN, Boyden ES, Tsai LH. Iaccarino HF, et al. Nature. 2016 Dec 7;540(7632):230-235. doi: 10.1038/nature20587. Nature. 2016. PMID: 27929004 Free PMC article.
- Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology.Spangenberg EE, Lee RJ, Najafi AR, Rice RA, Elmore MR, Blurton-Jones M, West BL, Green KN. Spangenberg EE, et al. Brain. 2016 Apr;139(Pt 4):1265-81. doi: 10.1093/brain/aww016. Epub 2016 Feb 26. Brain. 2016. PMID: 26921617 Free PMC article.
- Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection.Adaikkan C, Middleton SJ, Marco A, Pao PC, Mathys H, Kim DN, Gao F, Young JZ, Suk HJ, Boyden ES, McHugh TJ, Tsai LH. Adaikkan C, et al. Neuron. 2019 Jun 5;102(5):929-943.e8. doi: 10.1016/j.neuron.2019.04.011. Epub 2019 May 7. Neuron. 2019. PMID: 31076275 Free PMC article.
- Effects of CX3CR1 and Fractalkine Chemokines in Amyloid Beta Clearance and p-Tau Accumulation in Alzheimer's Disease (AD) Rodent Models: Is Fractalkine a Systemic Biomarker for AD?Merino JJ, Muñetón-Gómez V, Alvárez MI, Toledano-Díaz A. Merino JJ, et al. Curr Alzheimer Res. 2016;13(4):403-12. doi: 10.2174/1567205013666151116125714. Curr Alzheimer Res. 2016. PMID: 26567742 Review.
- Review: experimental manipulations of microglia in mouse models of Alzheimer's pathology: activation reduces amyloid but hastens tau pathology.Lee DC, Rizer J, Hunt JB, Selenica ML, Gordon MN, Morgan D. Lee DC, et al. Neuropathol Appl Neurobiol. 2013 Feb;39(1):69-85. doi: 10.1111/nan.12002. Neuropathol Appl Neurobiol. 2013. PMID: 23171029 Free PMC article. Review.
- Maresin1 Ameliorates Sepsis-Induced Microglial Neuritis Induced through Blocking TLR4-NF-κ B-NLRP3 Signaling Pathway.Wu H, Wang Y, Fu H, Ji L, Li N, Zhang D, Su L, Hu Z. Wu H, et al. J Pers Med. 2023 Mar 16;13(3):534. doi: 10.3390/jpm13030534. J Pers Med. 2023. PMID: 36983716 Free PMC article.
- Influence of Binaural Beats Stimulation of Gamma Frequency over Memory Performance and EEG Spectral Density.Borges LR, Arantes APBB, Naves ELM. Borges LR, et al. Healthcare (Basel). 2023 Mar 9;11(6):801. doi: 10.3390/healthcare11060801. Healthcare (Basel). 2023. PMID: 36981458 Free PMC article.
- Alzheimer's disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression.Meftah S, Gan J. Meftah S, et al. Front Synaptic Neurosci. 2023 Mar 9;15:1129036. doi: 10.3389/fnsyn.2023.1129036. eCollection 2023. Front Synaptic Neurosci. 2023. PMID: 36970154 Free PMC article. Review.
- Electroclinical characteristics of photosensitive epilepsy: A retrospective study of 31 Chinese children and literature review.Zhang B, Chen T, Hao X, Xin M, Liang J. Zhang B, et al. Front Pediatr. 2023 Mar 9;11:994817. doi: 10.3389/fped.2023.994817. eCollection 2023. Front Pediatr. 2023. PMID: 36969295 Free PMC article.
- How to entrain a selected neuronal rhythm but not others: open-loop dithered brain stimulation for selective entrainment.Duchet B, Sermon JJ, Weerasinghe G, Denison T, Bogacz R. Duchet B, et al. J Neural Eng. 2023 Mar 7;20(2):10.1088/1741-2552/acbc4a. doi: 10.1088/1741-2552/acbc4a. J Neural Eng. 2023. PMID: 36880684 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Acoustic Stimulation / methods*
- Alzheimer Disease / pathology
- Alzheimer Disease / therapy*
- Amyloid / metabolism
- Amyloid beta-Peptides / metabolism
- Animals
- Auditory Perception / physiology
- Brain / metabolism
- Cognition / physiology*
- Disease Models, Animal
- Gamma Rhythm / physiology
- Hippocampus / metabolism
- Male
- Mice
- Mice, Inbred C57BL
- Microglia / metabolism
- Plaque, Amyloid / metabolism
- Amyloid
- Amyloid beta-Peptides
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
![Figure 6.. Combined auditory and visual GENUS…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6774262/bin/nihms-1538841-f0006.jpg)
Figure 7.. Combined auditory and visual GENUS…
Figure 7.. Combined auditory and visual GENUS reduces amyloid load in the mPFC and neocortex
![Figure 7.. Combined auditory and visual GENUS…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6774262/bin/nihms-1538841-f0007.jpg)
Source: PubMed