Ten years following the initial experiments by researchers at The Picower Institute for Learning and Memory at MIT, investigating whether brain sensory stimulation at the 40Hz “gamma” frequency rhythms could serve as a treatment for Alzheimer’s disease in mice, a mounting body of evidence has emerged from laboratories worldwide supporting the notion that it can enhance brain health in both humans and animals. A new open-access review article in PLOS Biology outlines the current state of research and highlights key fundamental and clinical inquiries at the forefront of noninvasive gamma stimulation today.
“Throughout our observations, numerous others in the field have released findings that are remarkably consistent,” notes Li-Huei Tsai, Picower professor of neuroscience at MIT, director of MIT’s Aging Brain Initiative, and senior author of the newly published review alongside postdoc Jung Park. “Research has utilized various methods to induce gamma, including sensory stimulation, transcranial alternating current stimulation, and transcranial magnetic stimulation, but the essential factor is administering stimulation at 40 hertz. All studies report positive effects.”
A decade of exploration at MIT
Commencing with a publication in Nature in 2016, a consortium led by Tsai has yielded multiple studies demonstrating that 40Hz stimulation through light, sound, a combination of both, or tactile vibrations lessens the indicators of Alzheimer’s pathology such as amyloid and tau proteins, halts neuronal death, reduces synapse loss, and supports memory and cognitive functions in various Alzheimer’s mouse models. The collaboration’s exploration into the mechanisms responsible for these advantages has so far revealed specific cellular and molecular reactions across various brain cell types, including neurons, microglia, astrocytes, oligodendrocytes, and the brain’s vascular structures. For instance, last year, the lab reported in Nature that 40Hz auditory and visual stimulation prompted interneurons in mice to enhance the release of the peptide VIP, which increased the clearance of amyloid from brain tissue through the brain’s glymphatic “plumbing” system.
Meanwhile, both at MIT and at the MIT spinoff firm Cognito Therapeutics, phase II clinical trials have indicated that individuals with Alzheimer’s who were subjected to 40Hz light and sound experienced considerable slowing of brain shrinkage and improvements in certain cognitive assessments compared to untreated controls. Cognito, which has also observed significant preservation of the brain’s “white matter” in participants, has been undertaking a crucial, nationwide phase III clinical trial of sensory gamma stimulation for over a year.
“Neuroscientists frequently bemoan that it is an excellent era for AD [Alzheimer’s disease] if you are a mouse,” Park and Tsai articulated in the review. “Thus, our ultimate aim is to translate GENUS discoveries into a safe, accessible, and noninvasive therapy for patients with AD.” The MIT group often refers to 40Hz stimulation as “GENUS” for Gamma Entrainment Using Sensory Stimulation.
An expanding field
As Tsai’s collaboration, which comprises MIT colleagues Edward Boyden and Emery N. Brown, has published its findings, several additional laboratories have produced studies contributing to the evidence that diverse methods of noninvasive gamma sensory stimulation can address Alzheimer’s pathology. Among the numerous examples referenced in the new review, in 2024 a research team in China independently validated that 40Hz sensory stimulation augments glymphatic fluid circulation in mice. In another instance, a team based at Harvard Medical School in 2022 demonstrated that 40Hz gamma stimulation using Transcranial Alternating Current Stimulation significantly diminished the accumulation of tau in three out of four human participants. Moreover, in another investigation encompassing over 100 individuals, researchers in Scotland in 2023 utilized audio and visual gamma stimulation (at 37.5Hz) to enhance memory recall.
Unresolved inquiries
Amidst the increasing volume of publications describing preclinical studies involving mice and clinical trials with humans, unresolved inquiries persist, Tsai and Park concede. The MIT team and others continue to explore the cellular and molecular mechanisms that underpin GENUS’s effects. Tsai mentions that her lab is investigating additional neuropeptide and neuromodulatory systems to gain a deeper understanding of the sequence of events that connect sensory stimulation to the observed cellular reactions. Meanwhile, the specifics of how certain cells, like microglia, respond to gamma stimulation and its influence on pathology remains ambiguous, Tsai adds.
Despite the ongoing national phase III clinical trial, it remains crucial to investigate these essential mechanisms, asserts Tsai, as new insights into the effects of noninvasive gamma stimulation on the brain could enhance and broaden its therapeutic applicability.
“The more we comprehend the mechanisms, the better ideas we will develop regarding how to further refine the treatment,” says Tsai. “And the more we understand its action and the circuits it impacts, the clearer we will be on what other neurological disorders beyond Alzheimer’s disease could benefit from this.”
Indeed, the review highlights studies at MIT and additional institutions that provide at least some support that GENUS may help with Parkinson’s disease, stroke, anxiety, epilepsy, and cognitive side effects arising from chemotherapy as well as conditions that diminish myelin, such as multiple sclerosis. Tsai’s lab has also been investigating whether it can assist individuals with Down syndrome.
The unresolved inquiries may shape the next decade of GENUS research.