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Ten years after researchers at The Picower Institute for Learning and Memory at MIT initiated studies on the efficacy of stimulating the brain’s 40Hz “gamma” frequency rhythms as a potential treatment for Alzheimer’s disease in mouse models, there is a burgeoning body of evidence suggesting its benefits extend to human applications as well. A recent review published in PLOS Biology evaluates the current landscape of research and highlights critical questions in the realm of non-invasive gamma stimulation.
“Through our observations, we noticed a strong alignment in findings from others in the field,” remarked Li-Huei Tsai, Picower Professor at MIT, director of MIT’s Aging Brain Initiative, and the senior author of this review along with postdoc Jung Park. “Researchers have employed various techniques to induce gamma waves—ranging from sensory stimulation to transcranial magnetic and alternating current stimulation—but what consistently matters is maintaining that 40 Hz frequency. The benefits across these methodologies are evident.”
A decade of exploration at MIT
Beginning with a pivotal study published in Nature in 2016, a collaborative effort led by Tsai has yielded numerous findings that link 40Hz stimulation through light, sound, or tactile means to the reduction of Alzheimer’s disease indicators such as amyloid and tau proteins. These studies also demonstrate that gamma stimulation not only hinders neuronal death but also protects against synapse loss, thereby preserving memory and cognitive functions in various Alzheimer’s mouse models. Their research has uncovered specific cellular and molecular responses in diverse brain cell types, from neurons to the vascular systems within the brain. Notably, a study published last year in Nature unveiled that 40Hz sensory stimulation prompted interneurons in mice to release the neuropeptide VIP, enhancing the clearance of amyloid via the brain’s glymphatic system.
Additionally, both at MIT and its spinoff, Cognito Therapeutics, phase II clinical trials have demonstrated that Alzheimer’s patients who underwent 40Hz light and sound interventions experienced notable reductions in brain atrophy and enhancements in cognitive performance relative to untreated individuals. Cognito Therapeutics has also reported significant preservation of the brain’s white matter among participants and is currently conducting a larger, nationwide phase III clinical trial examining sensory gamma stimulation.
“Neuroscientists often express that it’s a particularly rewarding time to study Alzheimer’s in mouse models,” noted Park and Tsai in their review. “Thus, our ultimate objective is to translate our GENUS findings—Gamma Entrainment Using Sensory Stimulation—into a safe, accessible, and effective treatment for individuals with Alzheimer’s.”
A burgeoning field
As findings from Tsai’s team, which includes colleagues Edward Boyden and Emery N. Brown, continue to emerge, a number of other research groups have contributed additional evidence supporting the role of non-invasive gamma sensory stimulation in addressing Alzheimer’s pathology. For instance, a study from China in 2024 reaffirmed that 40Hz sensory stimulation enhances glymphatic fluid movement in mice. Furthermore, research out of Harvard Medical School in 2022 illustrated that Transcranial Alternating Current Stimulation at 40Hz significantly mitigated tau accumulation in three out of four human test subjects. Another study involving over 100 participants from Scotland in 2023 indicated that audio and visual gamma stimulation at 37.5 Hz could bolster memory recall.
Open questions
Despite the increasing volume of publications detailing preliminary studies in mice and clinical trials involving humans, several questions remain unanswered, as Tsai and Park have noted. The MIT team and other researchers continue to investigate the cellular and molecular mechanisms underpinning the effects of GENUS. Tsai’s lab is exploring additional neuropeptides and neuromodulatory networks to deepen their understanding of how sensory stimulation correlates with cellular reactions. The response of microglia to gamma stimulation and its implications for pathology, in particular, require further exploration.
Even with a national phase III trial currently in progress, gaining insights into these fundamental mechanisms remains a priority, Tsai emphasized, as they could enhance and broaden the therapeutic applications of non-invasive gamma stimulation.
“The more we comprehend the underlying mechanisms, the better we can devise strategies to optimize treatments,” Tsai stated. “A deeper understanding of its actions and the neural circuits it influences could unveil benefits beyond Alzheimer’s, potentially addressing other neurological disorders.” The review suggests preliminary evidence that GENUS might aid conditions such as Parkinson’s disease, stroke, anxiety, epilepsy, and cognitive impairments related to chemotherapy or demyelinating diseases like multiple sclerosis. Tsai’s team is also investigating its potential benefits for individuals with Down syndrome.
These unresolved questions may shape the next stage of GENUS research over the coming years.
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