40-HZ Therapy: Stimulating neural activity at Gamma frequency

A sudden flickering of light and a quick, stumbling buzz of noise could in fact have our answer to beating Alzheimer’s disease—with a recent study in lab mice offering insight as to how these sensory cues could work in an unconventional therapy for humans.

This noninvasive brain-stimulation technology makes use of a sort of audiovisual disco – 40-hertz stimuli occurring in rhythms, has been designed to bulk up the brain’s health by stimulating neural activity at a similar “gamma” frequency.

The patient gets their therapy from the comfort of their own home, putting on headsets and sitting by an illuminating display panel, and early clinical trials have shown it offers some promise for future research. In patients already suffering from different stages of Alzheimer’s disease, the therapy has been correlated with preservation of brain volume, a strengthened connectivity among neurons, improvement in mental functioning, and even having more restful sleep, among its other benefits.

A new medical device startup by the name of Cognito Therapeutics is presently evaluating this sensory therapy with a large randomized trial of test subjecs who have mild-to-moderate Alzheimer’s. Simultaneously, Cognito’s academic co-founders—the neuroscientist Li-Huei Tsai and Ed Boyden, a neuroengineer, both from the Massachusetts Institute of Technology (MIT)—continue their emphasis on how these 40-Hz sync can sessions induce positive changes in lab mice.

In their most recent paper, the MIT research team discovered that the rhythmic remedy is the key to removing beta-amyloid, a glue-like protein that clumps together in the brain of a patient with Alzheimer’s disease, creating the ‘plaque’ that builds over the brain’s various connections. The 40 Hz rhythm eliminates the plaque using a neural-cleansing cycle called glymphatic clearance.

So what does 40-Hz therapy do?

This 40-Hz therapy works by carrying more cerebrospinal fluid (CSF) to the brain. These neural juices then churn around, accumulating the beta-amyloid gunk as they do so, and then flow out of the brain via specialized waste-removal networks before they are finally eventually eliminated through excretory pathways of the body.

“It’s so important to understand how this works,” said Tsai, who is the director of MIT’s Picower Institute for Learning and Memory. “It really makes the therapy that much more compelling.”

Not everyone is patient to know about these types of mechanistic insights, much less wait for any definitive clinical data, before they’ve jumping on the 40-Hz bandwagon.

Indeed, there are tech companies that have already offered consumer-oriented devices as well as phone and tablet apps delivering gamma frequency stimulation by way of light and sound. Marketed as “general wellness,” you can obtain products like the EVY Light—a $2,000 priced light box marketed by OptoCeutics emitting a very subtle, almost imperceptible 40-Hz flicker, crafted to be easier on the human eye than intense strobe lights often used by other testing products—are targeted to people anxious about future cognitive decline. However, these technologies have yet to be clinically approved in the treatment or even prevention of neurodegenerative conditions.

Before they made their device available to purchase, OptoCeutics decided to run trials with small groups in order to ensure that their product is safe and could in fact produce synchronized brain rhythms in its users. There is currently a randomized follow-up trial taking place in Denmark to confirm that this therapy is able to relieve the various complications of Alzheimer’s.

These trial results could, however, take years before they fully materialize. The necessary regulatory approval alone could take much longer than that. “And if we really, truly want to know how this technology is going to impact people’s lives, we have to test it out in the real world,” says the OptoCeutics cofounder and CEO Mai Nguyen.

Considering the minimal risks involved with using the new technology, she says, her company opted to make their device immediately available. “The pros outweigh the cons at the moment,” Nguyen says.

The OptoCeutics platform, like every single 40-Hz therapy program either available or currently in development right now, can trace its inspiration to what was a landmark study conducted by Tsai and the MIT team back in 2016. In their work back then, these researchers demonstrated how a white flickering light broadcast at a 40-Hz frequency was able  to synchronize neural waves in those regions of the brain associated with reason, planning, and memory.

By doing so, this therapy decreased the overall buildup of beta-amyloid plaques and tau tangles—paramount symptoms of Alzheimer’s—within the brains of lab mice who had been engineered to mimic Alzheimer’s related conditions.


What could 40-Hz therapy do?

This new study and subsequent studies conducted by the MIT group have discovered that both auditory and visual stimuli processed by the brain at 40 Hz can promote a healthier cognitive state in the neurons of lab mice, even working to reverse some traits of neurological degeneration. In addition, this type of sensory experience has also worked to decrease the inflammation produced by microglia, which serve as the brain’s immune cells.

And this year, documented in Nature, the researchers have found a connection between the glymphatic system of the brain when it comes to mediating this treatment’s beta-amyloid-lowering effects. Furthermore, the researchers have pinpointed a significant peptide-signaling molecule used by the neurons to maintain CSF movement and greenlight glymphatic clearance.

In another independent study, also published in February by Nature, authored by the neuroimmunologist Jonathan Kipnisand colleagues at Washington University gives further detail on how rhythmic neuronal activity of the kind this 40-Hz therapy induces is often critical to how the brain moves fluids and how it performs self-cleaning like that which occurs during sleep.

“The results are very convincing,” according to Andrey Vyshedskiy, a neuroscientist at Boston University who is also one of the creators of the AlzLife, app that administers gamma-frequency stimulation along with a multitude of cognitive-training exercises. Together, Vyshedskiy believes, these “animal studies create a scientific foundation and a better understanding of what is changing in the brain.”

If subsequent clinical trials are able to confirm the ability of the 40-Hz stimuli to eliminate plaque buildup, maintain the brain’s structure, and slow down the onset of dementia, then this therapy may rise as both an affordable and user-friendly approach to managing the symptoms of Alzheimer’s—especially when it is compared against the alternative – what are monoclonal antibody treatments. These drugs that target amyloid in the brain are often costly, with some families spending tens of thousands of dollars every year just for the relief they can provide, but worse, they often have side effects that produce swelling or bleeding in the patient’s brain.

“This may be a preferred option for Alzheimer’s treatment,” according to Ralph Kern, who serves as Cognito’s chief medical officer. Results from the company’s pivotal trial are expected some time next year.

Cognito’s invention, known by the name Spectris, pairs a set of opaque glasses containing built-in, flashing LED lights with a set of headphones. One potential drawback to their design is their requirement for the user to keep in a stationary position while undergoing treatment sessions, cut off from any type of external entertainment like television watching or other distractions. Some could find this difficult, particularly those already in an advanced stage of the disease. In an optimistic sign however, the designer’s feasibility tests have suggested that this challenge is fairly doable, with more than 85 percent of the study’s participants routinely  using their device on a daily basis over the course of six-months as they partook in the study.

“Maybe it’s counterintuitive,” Kern suspects, “but there’s something very attractive about sitting calmly for an hour and having a treatment at home. And we find that people generally are comfortable doing that.”

In addition to their study on Alzheimer’s, Cognito also has plans to test their headset device on people who are living with Parkinson’s disease as well as multiple sclerosis. Annabelle Singer, a  neurobiologist at Georgia Tech who also serves on the company’s board of scientific advisors, also expects that their therapy will prove beneficial in treating other neurological conditions as well.

Consider, for example, a treatment-resistant epilepsy. When working with a small group of patients as they were evaluated for potential brain surgery, Singer and her team of researchers discovered tha thet 40-Hz sensory therapy showed promise in reducing the occurence of abnormal brainwave events that indicate an individual’s propensity for having seizures.

Autism, various forms of schizophrenia, strokes—a host of other brain disorders may potentially be remedied by leveraging the gamma frequencies in order to promote a synchronized neuronal activity in the brain.

“It certainly is having a beneficial activity on pathological activity that is known to affect cognition,” says Singer. “That’s indicative that this could be useful in a variety of contexts where that matters.”

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