A decade after scientists at The Picower Institute for Learning and Memory at MIT began exploring the potential of sensory stimulation at the brain’s 40Hz “gamma” frequency to treat Alzheimer’s disease (AD) in mice, growing evidence supports its benefits for brain health in both humans and animals. A recent review article in PLOS Biology highlights the significant progress in this field and examines the key questions surrounding non-invasive gamma stimulation.
The Genesis of Gamma Stimulation Research
The research into 40Hz gamma stimulation began with a pivotal study in Nature in 2016, led by Li-Huei Tsai, a Picower Professor at MIT and director of MIT’s Aging Brain Initiative. This research has since yielded a series of groundbreaking findings that demonstrate how 40Hz stimulation, delivered through light, sound, or tactile vibration, can reduce key Alzheimer’s markers like amyloid-beta and tau proteins, prevent neuron death, and improve cognitive function in various Alzheimer’s mouse models.
As Tsai notes, “People have used many different ways to induce gamma including sensory stimulation, transcranial alternating current stimulation, or transcranial magnetic stimulation, but the key is delivering stimulation at 40 Hz. They all see beneficial effects.” These results are now forming the foundation of a promising new avenue for AD treatment.
Mechanisms Behind the Benefits of 40Hz Stimulation
The MIT team’s studies have delved into the cellular and molecular mechanisms that underlie the beneficial effects of 40Hz stimulation. Their findings show that 40Hz sensory stimulation activates a variety of brain cells, including neurons, microglia, astrocytes, and oligodendrocytes, and enhances the function of brain blood vessels. A key discovery was made last year, when the team found that 40Hz stimulation led to increased release of the peptide vasoactive intestinal peptide (VIP) in mice, which in turn boosted the brain’s glymphatic system—a network responsible for clearing amyloid plaques from brain tissue.
These findings were significant, as they suggest that sensory gamma stimulation could help the brain clear harmful proteins that contribute to AD pathology. The studies also demonstrated that 40Hz stimulation helps preserve synaptic function and reduces the loss of brain cells, which are hallmarks of Alzheimer’s disease.
Progress in Clinical Trials
As the MIT team’s work has gained traction, other labs worldwide have replicated and expanded upon these findings. Notably, Cognito Therapeutics, a spinoff company from MIT, has been conducting phase II clinical studies. In these trials, individuals with Alzheimer’s who were exposed to 40Hz light and sound stimulation showed significant slowing of brain atrophy and improved cognitive performance compared to untreated controls. The company has now progressed to a phase III nationwide trial, which aims to further assess the therapeutic potential of 40Hz gamma stimulation.
In addition to these clinical studies, a 2024 study in China confirmed that 40Hz sensory stimulation enhanced glymphatic fluid flow in mice, further supporting the idea that gamma stimulation helps clear amyloid deposits from the brain. Moreover, a 2022 study at Harvard Medical School demonstrated that transcranial alternating current stimulation at 40Hz reduced tau protein burden in human volunteers, while a 2023 study in Scotland showed that 37.5Hz audio and visual stimulation could improve memory recall in over 100 participants.
Challenges and Open Questions
Despite the growing body of evidence supporting the benefits of non-invasive gamma stimulation, some questions remain. Tsai and her team continue to explore the cellular and molecular pathways that mediate the effects of 40Hz stimulation, particularly the role of neuropeptides and neuromodulatory systems. Furthermore, the exact response of microglia—immune cells in the brain—to gamma stimulation is not fully understood. Microglia play a crucial role in brain health and Alzheimer’s pathology, and better understanding their response to gamma stimulation could unlock further therapeutic potential.
Tsai and her collaborators emphasize that while clinical trials are already underway, it is essential to continue investigating the fundamental mechanisms that underlie gamma stimulation’s effects. These insights could refine the technique and make it even more effective in treating Alzheimer’s disease.
A Bright Future for Non-Invasive Gamma Stimulation
As the research on 40Hz gamma stimulation continues to evolve, it brings hope for a non-invasive, safe, and accessible therapy for Alzheimer’s patients. By harnessing the power of sensory stimulation to activate the brain’s natural processes for clearing amyloid plaques and protecting neurons, this approach has the potential to revolutionize Alzheimer’s treatment. The combination of clinical trials, preclinical studies, and basic neuroscience research will be critical in bringing this innovative therapy from the lab to widespread clinical use, potentially offering a new tool to fight the devastating effects of Alzheimer’s disease.
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