Researchers wonder if flash, pink noise, or some other non-invasive method can be used to train human brain waves and be used as a treatment for neurodegenerative disease?

In March 2015, Li-Huei Tsai, a neurologist at the Massachusetts Institute of Technology (MIT), built a mini disco for her experimental mice in her lab. Every day, she would let these mice "hide" for an hour under the blurred lights of this "dance hall". These mice are Alzheimer's disease model mice, and their brains produce amyloid beta and plaques. This dance floor is a novelty for the mice, and they will all roam around curiously. After the experiment, Tsai performed anatomical observation on the mice and found that the plaques in the brain of the mice who went down the dance floor every day were significantly smaller than those of the mice who didn't (only stayed in a dark environment and were not stimulated by the dance floor light).

According to Tsai, she repeatedly verified the results of this experiment because she could not believe the results. Their research direction is to understand whether these flash stimuli can remove beta amyloid and plaques in the brain. The flash frequency they used was 40 Hz, which was designed specifically for the brain waves of rodents, which triggered physiological responses in mice to clear out beta amyloid and plaques. Although the results of the mouse test are very gratifying, it is more troublesome to replicate this result in human body, but it is still possible to achieve it. Tsai noted that given the test results are so conclusive and incredible, they will take some time to accept this fact. Next, Tsai and others will find ways to repeat this gratifying result on the human body.

Although researchers discovered brain waves a century ago, they have never been able to correspond to brain waves one by one with the functions and behaviors of the brain. Research has found that brain waves are closely related to memory consolidation activities during sleep, and may also be related to processing sensory inputs and even the conscious coordination function. But not everyone believes that brainwaves have these functions. Michael Shadlen, a neurologist at Columbia University in New York City, believes that for now, we are not clear about the function of brain waves.

There is growing evidence that brain waves are related to neurological diseases such as Alzheimer's disease and Parkinson's disease. This also reminds us that it is possible to use these EEG activities, rather than drugs, to treat neurological diseases, prevent lesions from occurring, and even reverse nerve damage. At present, more than 20 medical institutions are trying to intervene in the human brain waves. They use a variety of technical means, such as those who use flashes and sounds, but the most common method is to directly stimulate the human brain. The medical institutions intend to treat different diseases, including insomnia, schizophrenia, and premenstrual dysphoric disorders.

Tsai is the first researcher to discover the effect of brain wave intervention at the cellular level. Walter Koroshetz, director of the US National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, said Tsai's work really surprised them, which is definitely a major discovery and worth further research.

Important functions of brain waves

German psychologist Hans Berger is a very controversial person. He spent a lot of time studying the physiological mechanisms behind psychological phenomena. He was also the first person to discover brain waves. In 1929, a paper published by Berger proposed that repetitive radio waves could be observed when he placed the electrode on the patient's skull. Although this was the world's first brain wave record, it did not attract much attention at the time. Many years later, Berger's colleagues once again verified the existence of brain waves, and it was only then that everyone realized that Berger had already opened a window for us to observe the activities of the human brain.

This kind of radio wave exchange between neuronal cells relies on the flow of ions inside and outside each neuronal cell. Although we cannot detect an activated neuronal cell with the electrodes of the brain wave (EEG), when a large group of neuronal cells are all excited synchronously again and again, we can see the brain waves composed of waveforms.

Among brain waves, the highest frequency is gamma wave, whose frequency reaches 25~140 Hz, which often occurs when people concentrate. The lowest frequency is the delta wave, which has a frequency of only 0.5~4 Hz. This kind of brain wave often only occurs when people enter deep sleep.

At any time, only one major brain wave will appear, but there will also be other secondary waves. Researchers have never figured out the significance of this phenomenon, but in the past thirty years, they have begun to find a clue. For example, in 1994, researchers conducted research on mice and found that the brain waves that these little guys had in their sleep correspond to what they had learned during the day (brain waves that appeared at that time). Researchers believe that this type of brain activity helps consolidate memory.

Brain waves also seem to be able to influence consciousness perception. Randolph Helfrich of the University of California, Berkeley, invented a non-invasive method to control gamma brain waves. They can up-regulate the frequency of gamma brain waves or down-regulate the frequency by about 40 Hz, which is transcranial alternating current stimulation (tACS). They experimented with this technique on volunteers—and letting them watch a video showing moving dots. The researchers found that if the volunteers' brain waves are regulated, some volunteers can feel that these small dots are moving horizontally, while others see small dots that are moving vertically.

Brain waves can also help us understand the mechanism behind the "binding problem", that is, how our brain organizes various sensory stimuli that appear simultaneously into a set of ordered sensory mechanisms. Brain waves ensure that all relevant information can reach the brain center at the exact time and be processed by synchronizing the activation speed of neuronal cells that excite the same event. Robert Knight, a cognitive neuroscientist at the University of California, Berkeley, believes that coordinating these stimulus signals is the key to the human brain's cognition. "You can't let God help you organize all this information."

Healthy brain waves

However, when we get sick, these brain waves can also change due to the influence of various diseases. For example, after the body's motor function of Parkinson's disease patients is damaged, the areas related to motor control in the brain often have an increase in beta waves. In the brain of healthy people, these beta waves are suppressed and will only appear when the body needs exercise. Neuron cells in the brain of Parkinson's patients seem to be in a state of synchronous activation. So their bodies become stiff and unable to move independently. Peter Brown, who specializes in Perkins' disease at the University of Oxford, UK, believes that the mechanisms of our current treatment of Parkinson's disease, such as levodopa and deep-brain stimulation, may all inhibit beta brain waves.

Patients with Alzheimer's disease show that gamma brain waves are weakened. Therefore, Tsai et al. are trying to treat Alzheimer's patients by restoring gamma brain waves.

Tsai et al. used optogenetics techniques (optogenetics). Neuron cells transformed by optogenetic technology can be directly regulated by flash stimulation. In 2009, Tsai, working with Christopher Moore, a colleague at the time of MIT, demonstrated for the first time that this technology could be used to enhance gamma brain waves in specific parts of the mouse brain.

Tsai et al. later discovered that "interference" with brain waves can also cause biological responses in mice - initially, the expression levels of certain genes changed; then, the morphology of the immune cells in the mouse brain, microglia, changed; eventually, these cells were activated and began to clean up harmful substances in the mouse brain, such as amyloid beta. Koroshetz believes that this neuroimmune clearance is a major discovery. It reminds us that immune cells like microglia play a very important role in the brain, but we don’t know them very well yet, so they have become one of the most popular research directions at present.

If this technology has therapeutic value, it would be better because it is a relatively non-invasive brain wave intervention treatment method. We have confirmed that flashes with specific frequencies can indeed affect brain waves in certain parts of the brain, and in view of this, some researchers have begun to study the role of strobe light. They used young Alzheimer's disease mice to perform experiments and irradiated them with an LED flash for an hour. It was found that the content of free amyloid in the mouse brain began to decline. However, this is only transient, the effect lasts less than 24 hours, and the efficacy is mainly concentrated in the visual cortex.

In order to achieve more lasting results, the researchers began to irradiate the experimental mice for one hour every day and "treat" for seven consecutive days. This time, they used slightly older mice, and amyloid plaques began to form in their brains. The effect was observed 24 hours after the end of the entire treatment course. The results showed that compared with the control group, the amyloid plaques in the visual center of the experimental mice decreased by 67%. Researchers also found that this treatment is equally effective in lowering tau protein, a pathological protein that is also a landmark of Alzheimer's disease.

However, Alzheimer's disease pathological plaques usually affect hippocampus at the earliest, rather than visual centers. Therefore, Tsai et al. are also trying to affect brain waves in the hippocampus. For example, they played noise at a frequency of 40 Hz to the experimental mice, which seemed to reduce the levels of amyloid in the hippocampus. This may be because the hippocampus is closer to the auditory center.

Tsai and his colleague at MIT, neurologist Ed Boyden, founded a company in Cambridge, USA called Cognito Therapeutics in Cambridge to further verify the efficacy of their brainwave therapy technology in human patients. In 2017, they first conducted safety tests and developed a flash glasses to test 12 patients with Alzheimer’s disease.

It should be noted that the mouse model of Alzheimer's disease is not a very perfect animal model. Many drugs and treatment methods have very good results in mouse trials, but they will not be effective in human patients with Alzheimer's disease. Thomas Insel, a neurologist and psychologist who served as director of the US National Institute of Mental Health in Bethesda, Maryland from 2002 to 2015, said he used to tell people that if you want to get Alzheimer's disease, you'd better be a mouse.

Some researchers are also studying how to use brain waves to treat Alzheimer's disease. Emiliano Santarnecchi of Harvard Medical School in Boston, Massachusetts said they think Tsai’s research is great. Their scientific research team has also begun to use tACS technology to stimulate the brain, wanting to see if it will achieve better therapeutic effects than flash. This technique can provide more targeted stimulation to specific areas of the brain, so Santarnecchi et al. want to see if it is effective in treating Alzheimer's disease.

Santarnecchi's team has conducted initial clinical trials on 10 Alzheimer's patients, tACS stimulating these patients for one hour a day for two weeks of continuous treatment. Next, they will work with Boyden and Tsai to find signals of microglia activation in patients’ brains while observing the levels of tau protein. The results of both experiments will be announced at the end of this year.

Knight believes that Tsai's animal experiments clearly demonstrate that brain waves have an effect on cell metabolism, but it is not clear whether it is equally effective in humans. But he believes that there will be an answer in the end.

These experiments are risky, too. For example, Dora Hermes, a neurologist at Stanford University in California, reminded that gamma brain waves are very likely to induce seizures in patients with photosensitive epilepsy. Hermes mentioned a very famous case, in which a Japanese cartoon had red and blue flashes, which resulted in the viewer having epilepsy. The day when watching this cartoon, the number of emergency departments soared by more than 700.

Treat the brain

In any case, we already know that using neuromodulation technology can treat neurological diseases, and people's interest in this area has obviously exceeded their interest in drugs. Insel said there is definite evidence that changing the activity of neural circuits can improve symptoms in patients with Parkinson's disease, chronic pain, obsessive-compulsive disorder and depression. This is very important because to date, drugs used to treat neurological diseases lack specificity. Koroshetz also added that research funding institutions are also very inclined to develop non-invasive new treatments that can be quickly applied to the clinic.

According to Boyden, since their mouse research paper was published, it has received a tide of emails, and a large number of researchers hope to use Boyden and others' technology to treat other diseases. But there are still many details to improve this technology. Boyden said they need to continue research to find the most effective, non-invasive way to conduct brain wave interventions in different parts of the brain. The easiest way is EEG neurofeedback, a technique that has shown great therapeutic effects in the treatment of anxiety, depression and attention-deficit hyperactivity disorder. Patients will adjust their brain waves based on the results of their brain wave monitoring displayed with visual or auditory signals.

Neurologist Phyllis Zee and others at Northwesern University in Chicago, Illinois conducted experiments using "pink noise" while healthy elderly people were sleeping. It turned out that this sound stimulation could trigger delta waves associated with deep sleep. We know that as people get older, deep sleep will become less and less, and therefore, memory will become worse and worse.

Zee et al. have discovered that sound stimulation can also enhance the amplitude of slow waves of brain waves. In memory experiments (learning some vocabulary the day before, then checking the next day to see how much you can remember) this method can improve memory by 25 to 30%. Currently Zee et al. are conducting clinical trials to understand whether long-term sound stimulation can help patients with mild cognitive dysfunction.

Although these brain wave intervention technologies are relatively safe, they also have their limitations. For example, neurofeedback technology is easy to be mastered by patients, but it takes a slower effect and does not last long. Using magnetic field or sound stimulation techniques, it is difficult to accurately regulate specific parts of the brain. Knight pointed out that the current extracranial stimulation technique is not yet mature. Many technologies are open loops, that is, they cannot use EEG to understand the results of the intervention in real time. The closed loop technology is more practical. For example, Zee and others' work is very good. Knight believes that this field of research has reached a critical moment and is attracting more and more people to carry out more meaningful research. ”

In addition to its application in the field of clinical treatment, brain wave intervention technology will also completely broaden the field of brain wave research, help us understand the relationship between brain waves and behavior, and help us understand the mechanism of brain activity.

Shadlen believes that brain waves are related to human behavior and consciousness. But so far, he is not sure that brain waves are directly related to human behavior and consciousness. Many times, people think this is a "spell of artifacts."

Shadlen fully believes that these electrical activities in the brain are important signals that the brain is working. But if we interfere with these radio waves and cause some consciousness changes, it still needs to be discussed. Regardless of the role of brain waves, the most hopeful job of Tsai and others is to use brain waves to treat human diseases. Cognito Therapy Company has been approved to conduct a larger phase 2 clinical trial to understand the therapeutic effects on Alzheimer’s disease. At the same time, they are also studying the downstream biological effects after brain wave intervention and how to better conduct brain wave intervention in the hippocampus under the premise of non-invasiveness.

For Tsai, it was entirely her personal wish to carry out this research. Because her grandmother, who raised her, unfortunately suffered from dementia. Tsai said that the face of her grandmother after she fell ill has been imprinted in her mind, and this disease is also a major challenge facing our time and she will do her best to do it.