Patients undergoing chemotherapy often experience cognitive effects, such as memory impairment and difficulty concentrating – a condition often referred to as the "chemobrain".
Researchers at the Massachusetts Institute of Technology have now shown that a non-invasive method that stimulates gamma-frequency brain waves may be promising for chemo-brain. In a study of mice, they found that daily exposure to light and sound at a frequency of 40 hertz protected brain cells from chemotherapy-induced damage. It also helps prevent memory loss and other cognitive impairments.
Originally developed as a method for Alzheimer's disease, the researchers say, this appears to have a wide range of effects that can help with various neurological disorders.
This reduces DNA damage, reduces inflammation, and increases the number of oligodendrocytes, which are cells that produce myelin around axons," said Li-Huei Tsai, director of the Picaul Institute for Learning and Memory at MIT and a Picaul professor in the Department of Brain and Cognitive Sciences at MIT. "We also found that this method improved the learning and memory of the animals and enhanced their executive function. ”
Cai is the senior author of the new study, which was published today in the journal Science Translational Medicine. The first author of this ** is Taehyun Kim, a postdoctoral fellow at the Massachusetts Institute of Technology.
Protective brain waves
A few years ago, Cai and her colleagues began exploring the use of 40 hertz (cycles per second) of flashing light to improve cognitive symptoms of Alzheimer's disease. Previous studies have shown impaired gamma oscillations in people with Alzheimer's, which are brain waves that range between 25 and 80 hertz (cycles per second) and are believed to be associated with brain functions such as attention, perception, and memory.
Tsai's research in mice found that exposure to 40 hertz of flashing light or 40 hertz of sound stimulated gamma waves in the brain, which had many protective effects, including preventing the formation of amyloid plaques. The combination of light and sound can provide more effective protection. This ** also seems promising in humans: Phase 1 clinical trials in patients with early-stage Alzheimer's disease have found that this ** is safe and does have some neurological and behavioral benefits.
In the new study, researchers set out to investigate whether this kind of ** could also counteract the cognitive effects of digestive therapy. Studies have shown that these drugs can cause inflammation in the brain, as well as other harmful effects, such as the loss of white matter, a network of nerve fibers that help different parts of the brain communicate with each other. Chemotherapy drugs also promote the loss of myelin, a protective fat coating that allows neurons to transmit electrical signals. Many of these effects can also be seen in the brains of Alzheimer's patients.
Chemobrain caught our attention because it was so common and there was quite a bit of research on what the brain looked like after chemotherapy," Cai said. "From our previous work, we knew that this gamma sensory stimulation had anti-inflammatory effects, so we decided to use a chemobrain model to test whether sensory gamma stimulation was beneficial. ”
As an experimental model, the researchers used mice given cisplatin, a chemotherapy drug often used for ovarian and other cancers. Mice are given cisplatin for 5 days, then discontinued for 5 days, and then discontinued for another 5 days. One group received chemotherapy only, while the other group also received 40 Hz of light and sound** per day.
After three weeks, mice that received cisplatin instead of gamma** showed many of the effects expected by chemotherapy: reduced brain volume, DNA damage, demyelination, and inflammation. The mice also had a reduced number of oligodendrocytes, brain cells responsible for producing myelin.
However, mice receiving gamma** and cisplatin experienced significant reductions in all of these symptoms. Gamma also had a beneficial effect on behavior: mice that received ** performed better on tests designed to measure memory and executive function.
"A basic mechanism".
Using single-cell RNA sequencing, the researchers analyzed gene expression changes in mice that received gamma**. They found that in these mice, genes associated with inflammation and genes that trigger cell death were suppressed, especially in oligodendrocytes, which are responsible for producing myelin.
In mice receiving gamma ** and cisplatin**, some beneficial effects can still be seen after 4 months. However, if started three months after the end of chemotherapy, gamma** is much less effective.
The researchers also showed that gamma** improved chemobrain symptoms in mice that received another chemotherapy drug, methotrexate**. Methotrexate is used for breast, lung, and other types of cancer.
I think this is a very fundamental mechanism for improving myelination and promoting oligodendrocyte integrity. It seems that this is not limited to drugs that induce demyelination, whether chemotherapy or other demyelinating drugs, Cai said.
Because of its wide-ranging effects, Cai's lab has also tested gamma** in mouse models of other neurological disorders, including Parkinson's disease and multiple sclerosis. Cognito Therapeutics, founded by Tsai Kang-ying and MIT professor Edward Boyden, has completed a Phase 2 trial of gamma in Alzheimer's disease patients and plans to begin a Phase 3 trial this year.
In terms of clinical applications, my lab is now primarily focused on Alzheimer's disease; But hopefully we can test this approach on some other signs as well," Cai said.
This research was funded by the JPB**, Ko Hahn Seeds**, and the National Institutes of Health.