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Alzheimer's disease (AD) is characterized by significant memory loss and toxic protein deposits (amyloid and tau) in the brain. The investigators' lab found a non-invasive way to remove these toxic proteins from the brain in AD mouse models. Remarkably, treated mice also have improved memory on behavioral testing. The investigators aim to translate this non-invasive method, which uses light and sound to stimulate the brain, to be used in mild Alzheimer's patients. 40 participants with mild Alzheimer's disease will be recruited, and the investigators will assess their brain waves with electroencephalogram (EEG) before, during, and after light and sound stimulation for safety, feasibility, and to optimize the stimulation device for use in the mild AD population.
It is known that Alzheimer's disease (AD) patients have significant disruptions in brain waves, especially the gamma frequency (~30 - 100 Hz) waves. Recently, the investigators' lab found that gamma entrainment using light and sound stimulation, which the investigators call GENUS, improves memory and decreases toxic accumulation of amyloid and tau in AD mouse models. This study aims to translate these findings in the mouse models to be used in mild Alzheimer's patients. The investigators will recruit 40 patients diagnosed with mild AD who will be randomly assigned to two study arms. Cognitive and mental health evaluations as well as memory tests will be performed on all subjects. All subjects will also be exposed to the GENUS device, which can deliver light and sound waves at different frequencies. The GENUS device is composed of a panel with light-emitting diode (LED) illumination and speakers for auditory stimulation. Each of the 2 groups will have different combinations of light and sound settings. The investigators will use electroencephalography (EEG) to check for how the participant's brain waves respond to the stimulation, and use questionnaires to evaluate for safety and tolerability.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Exposure to active stimulation for 30 - 60 min | Experimental | Subjects in this arm will receive 30 - 60 minutes of active stimulation |
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| Exposure to control stimulation for 30 - 60 min | Sham Comparator | Subjects in this arm will receive 30 - 60 minutes of control stimulation |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| GENUS device (Active Settings) | Device | Participants in the experimental group will use the GENUS device configured to active settings for 30 - 60 minutes. |
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| Measure | Description | Time Frame |
|---|---|---|
| Feasibility of gamma frequency stimulation | Feasibility of gamma frequency stimulation in subjects with mild AD will be assessed by analyzing the EEG data from each subject for a sign of change in gamma frequency waves and determining the percent of subjects who show this change. | Immediately after the completion of the stimulation |
| Tolerability of gamma frequency stimulation | Tolerability of gamma frequency stimulation will be assessed by using a questionnaire asking for the subjects' overall experience with the stimulation. | Immediately after the completion of the stimulation |
| Safety of gamma frequency stimulation | Safety of gamma frequency stimulation will be assessed by using a questionnaire asking for any adverse effects of the stimulation. | Immediately after the completion of the stimulation |
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| Measure | Description | Time Frame |
|---|---|---|
| Changes in working memory after gamma frequency stimulation | Exploratory measure to check if there is any change in n-back test performance, between baseline and immediately after the completion of the stimulation. The n-back test involves a sequence of stimuli (e.g., letters, numbers), presented one at a time, and a subject is asked to indicate when the current stimulus is the same as the stimulus presented n times earlier in the sequence. The performance metrics will include the "hit" rate (number of correct responses out of total number of target stimuli; ranging from 0 to 1), "false alarm" rate (number of incorrect responses out of total number of non-target stimuli; ranging from 0 to 1), and response time. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Li-Huei Tsai, PhD | Massachusetts Institute of Technology | Principal Investigator |
| Edward S Boyden, PhD | Massachusetts Institute of Technology | Principal Investigator |
| Diane Chan, MD, PhD | Massachusetts Institute of Technology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Massachusetts Institute of Technology | Cambridge | Massachusetts | 02139 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27929004 | Background | 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. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016 Dec 7;540(7632):230-235. doi: 10.1038/nature20587. | |
| 30879788 | Background |
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| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| D060825 | Cognitive Dysfunction |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D014467 | Ultraviolet Therapy |
| ID | Term |
|---|---|
| D010789 | Phototherapy |
| D013812 | Therapeutics |
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|
| GENUS device (Sham Settings) | Device | Participants in the control group will use the GENUS device configured to sham settings for 30 - 60 minutes. |
|
|
| Baseline and immediately after the completion of the stimulation |
| Martorell AJ, Paulson AL, Suk HJ, Abdurrob F, Drummond GT, Guan W, Young JZ, Kim DN, Kritskiy O, Barker SJ, Mangena V, Prince SM, Brown EN, Chung K, Boyden ES, Singer AC, Tsai LH. Multi-sensory Gamma Stimulation Ameliorates Alzheimer's-Associated Pathology and Improves Cognition. Cell. 2019 Apr 4;177(2):256-271.e22. doi: 10.1016/j.cell.2019.02.014. Epub 2019 Mar 14. |
| 31076275 | Background | Adaikkan C, Middleton SJ, Marco A, Pao PC, Mathys H, Kim DN, Gao F, Young JZ, Suk HJ, Boyden ES, McHugh TJ, Tsai LH. Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection. Neuron. 2019 Jun 5;102(5):929-943.e8. doi: 10.1016/j.neuron.2019.04.011. Epub 2019 May 7. |
| 36454969 | Derived | Chan D, Suk HJ, Jackson BL, Milman NP, Stark D, Klerman EB, Kitchener E, Fernandez Avalos VS, de Weck G, Banerjee A, Beach SD, Blanchard J, Stearns C, Boes AD, Uitermarkt B, Gander P, Howard M 3rd, Sternberg EJ, Nieto-Castanon A, Anteraper S, Whitfield-Gabrieli S, Brown EN, Boyden ES, Dickerson BC, Tsai LH. Gamma frequency sensory stimulation in mild probable Alzheimer's dementia patients: Results of feasibility and pilot studies. PLoS One. 2022 Dec 1;17(12):e0278412. doi: 10.1371/journal.pone.0278412. eCollection 2022. |
| D024801 |
| Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D003072 | Cognition Disorders |