40Hz Gamma Stimulation: Opening New Avenues for Brain Health
DINGLIHUAIn recent years, global research into brain health has deepened, with mounting evidence suggesting that 40Hz gamma stimulation exerts a positive and significant impact on brain function, particularly demonstrating substantial potential in combating neurological disorders.
Over the past decade, laboratories worldwide have conducted extensive research on 40Hz gamma stimulation. Since scientists at MIT's Picower Institute for Learning and Memory first pioneered experiments exploring the use of 40Hz gamma-frequency sensory stimulation to treat Alzheimer's disease in mice, a wealth of research findings has emerged. These studies have progressively confirmed that this approach to modulating brain neural oscillatory rhythms may not only be effective in animals but could also herald new possibilities for human brain health, such as slowing cognitive decline. [1]
A new review article recently published in PLOS Biology comprehensively synthesizes the current state of research. [2] MIT's Professor Li-Huei Tsai and Postdoctoral Fellow Jung Park note that findings from many different laboratories are highly consistent. Researchers have employed various methods to induce gamma waves—such as sensory stimulation, transcranial alternating current stimulation, or transcranial magnetic stimulation—but the core element remains delivering 40Hz stimulation, and beneficial effects have been consistently observed.
Since 2016, when the collaborative team led by Li-Huei Tsai published their groundbreaking paper in Nature, a series of in-depth investigations have followed. They discovered that 40Hz stimulation delivered through light, sound, a combination of both, or tactile vibration yielded significant effects in multiple mouse models of Alzheimer's disease. This stimulation reduced Alzheimer's pathologies, such as the accumulation of amyloid and tau proteins, prevented neuronal death, decreased synaptic loss, and preserved memory and cognitive function in the mice. [3]
The team has also conducted thorough investigations into the underlying mechanisms driving these benefits. Specific cellular and molecular responses have been identified across various brain cell types, including neurons, microglia, astrocytes, oligodendrocytes, and cerebrovascular cells. For instance, a report from the lab in Nature last year showed that 40Hz auditory and visual stimulation induced interneurons in mice to increase the release of the peptide VIP, which in turn promoted the brain's glymphatic "plumbing" system to clear amyloid from brain tissue.
On the clinical research front, MIT and its spin-off company, Cognito Therapeutics, have also achieved positive results. A Phase II clinical study demonstrated that compared to an untreated control group, Alzheimer's patients receiving 40Hz light and sound stimulation exhibited significantly slower rates of brain atrophy, improvements in certain cognitive measures, and notable preservation of the brain's "white matter." [4] Currently, Cognito is conducting a pivotal nationwide Phase III clinical study evaluating the effects of sensory gamma stimulation, which has been ongoing for over a year.
The MIT team refers to 40Hz stimulation as "GENUS," which stands for Gamma ENtrainment Using Sensory stimulation. Following the publication of their findings, many other laboratories have initiated follow-up studies. Numerous studies have further provided evidence that various non-invasive gamma sensory stimulation methods can counteract Alzheimer's pathology.
Despite ongoing progress, Tsai and Park acknowledge that several questions remain unanswered. Currently, both the MIT team and other groups are continuing to explore the cellular and molecular mechanisms underlying the GENUS effect. For example, exactly how cells like microglia respond to gamma stimulation and how this response influences pathological mechanisms is still not fully understood.
However, even as a nationwide Phase III clinical trial is underway, investigating these fundamental mechanisms remains critically important. Gaining new insights into how non-invasive gamma stimulation affects the brain will help refine and expand its therapeutic potential. As Tsai states, "The more we understand about the mechanism, the more we can come up with good ideas to further optimize the therapy. And the more we understand about how it works and which circuits it affects, the more we can learn what other neurological conditions, besides Alzheimer's disease, could benefit from this treatment."
In fact, the review already notes that studies from MIT and other institutions provide at least preliminary evidence suggesting GENUS may be helpful in conditions such as Parkinson's disease, stroke, anxiety, epilepsy, cognitive side effects of chemotherapy, and diseases involving myelin loss like multiple sclerosis. Tsai's lab is also investigating its potential for treating Down syndrome.
These unresolved questions undoubtedly chart the course for the next decade of GENUS research. As investigations continue to deepen, there is reason to hope that 40Hz gamma stimulation will bring benefits to more patients with neurological disorders, opening a new chapter for brain health.
[1] Picower Professor Li-Huei Tsai, Review: Evidence expanding that 40Hz gamma stimulation promotes brain health. THE PICOWER INSTITUTE, March 3, 2025.
https://picower.mit.edu/news/review-evidence-expanding-40hz-gamma-stimulation-promotes-brain-health
[2] Jung M. Park,Li-Huei Tsai, Innovations in noninvasive sensory stimulation treatments to combat Alzheimer’s disease. PLoS Biol, 23(2): e3003046.
https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003046
[3] Hunter F. Iaccarino, Annabelle C. Singer, et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature, 540, pages230–235 (2016).
https://www.nature.com/articles/nature20587
[4] Picower Institute at MIT, Study reveals ways in which 40Hz sensory stimulation may preserve brain’s ‘white matter.’ Nature Communications, 15, Article number: 6744 (2024)
https://www.eurekalert.org/news-releases/1053964
