Early-stage trials in Alzheimer’s disease patients and studies in mouse models have hinted at the potential benefits of exposure to light and sound at the “gamma” frequency of 40 hertz (Hz). This frequency, often observed in healthy brain activity, has been linked to improvements in pathology and symptoms. Now, a new study from MIT focuses on how 40Hz sensory stimulation might work its magic by supporting the health of myelin, the fatty insulation that protects nerve fibers and ensures efficient signal transmission in the brain.
“Previous publications from our lab have mainly focused on neuronal protection,” says Li-Huei Tsai, Picower Professor in The Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences at MIT and senior author of the new open-access study in Nature Communications. Tsai also leads MIT’s Aging Brain Initiative. “But this study shows that it’s not just the gray matter, but also the white matter that’s protected by this method.”
This year has seen a surge in research supporting the potential of 40Hz sensory stimulation. Cognito Therapeutics, a spinoff company licensing MIT’s technology, published phase II human trial results in the Journal of Alzheimer’s Disease indicating that 40Hz light and sound stimulation significantly slowed myelin loss in Alzheimer’s volunteers. Additionally, Tsai’s lab published a study in Science Translational Medicine showing that gamma sensory stimulation helped mice combat the neurological side effects of chemotherapy, including myelin preservation.
Building on these findings, the new study, led by former postdoc Daniela Rodrigues Amorim, utilized a mouse model of myelin loss induced by a cuprizone-rich diet. The team discovered that 40Hz light and sound not only preserved myelination in these mice but also seemed to protect oligodendrocytes (the myelin-producing cells), maintain neuronal electrical performance, and preserve a key marker of axon structural integrity.
Delving into the molecular mechanisms, the researchers observed several key effects: preservation of synapses (neural connections), reduction in oligodendrocyte death caused by “ferroptosis,” decreased inflammation, and enhanced microglia (brain immune cells) activity in clearing myelin debris for repair.
“Gamma stimulation promotes a healthy environment,” says Amorim, now a Marie Curie Fellow at the University of Galway in Ireland. “There are several ways we are seeing different effects.”
The study’s findings suggest that gamma sensory stimulation could benefit not only individuals with Alzheimer’s disease but also those battling other conditions involving myelin loss, such as multiple sclerosis.
The study involved feeding some mice a cuprizone diet while others received a normal diet for six weeks. Halfway through, when cuprizone’s effects on myelination are most pronounced, some mice from each group were exposed to gamma sensory stimulation for the remaining three weeks. This resulted in four groups: healthy mice, mice receiving only gamma stimulation, mice receiving cuprizone and constant (non-40Hz) light and sound, and mice receiving cuprizone and gamma stimulation.
The results were striking. Mice fed cuprizone without 40Hz stimulation showed significant myelin loss. However, cuprizone-fed mice receiving 40Hz stimulation retained significantly more myelin, approaching the levels of healthy mice in some measures.
Further investigations revealed that gamma stimulation protected oligodendrocytes, improved the electrical performance of neurons in the corpus callosum (a brain region connecting the hemispheres), and preserved MAP2, a protein indicating axon structural integrity.
The researchers identified several mechanisms behind these protective effects. Protein analysis revealed increased MAP2 in gamma-treated cuprizone-fed mice and preserved synapses, crucial for neural circuit activity and myelin maintenance. Additionally, gamma stimulation reduced HMGB1, a marker of ferroptosis-associated damage and inflammation.
Single-cell RNA sequencing showed that gamma stimulation calmed the inflammatory response in astrocytes and microglia, making them more efficient at clearing myelin debris for repair. Oligodendrocytes in gamma-stimulated mice showed increased expression of protective proteins like HSP70 and GPX4, a regulator of processes that prevent ferroptosis.
This research, funded by various organizations including The JPB Foundation, the National Institutes of Health, and the Dolby Family, offers a promising avenue for developing new treatments for neurological disorders. While further research is needed, the potential of 40Hz sensory stimulation to preserve myelin and improve brain health is becoming increasingly clear.
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