An MIT study shows how 40 Hz sensory stimulation with light and sound helps sustain myelination, an essential process in the brain that insulates the signal-sending branches of neurons, called axons, with protective myelin sheaths. Often called the brain’s “white matter,” myelin ensures electrical signal transmission in brain circuits. Demyelination, characterized by the loss of the myelin sheath and the oligodendrocyte cells that form it, leads to impaired axonal function, resulting in brain atrophy and neurodegeneration. Green staining indicates myelination in these mouse brain cross sections. The brain that received 40 Hz light and sound stimulation (right) shows significantly more myelin in four brain regions (insets): the cortex (CTX), the anterior commissure (AC), the corpus callosum (CC), and the striatum (STR), than in mice that did not receive 40 Hz stimulation (left). Courtesy of Tsai Laboratory/MIT Picower Institute. Early-stage trials in Alzheimer’s disease patients and studies in mouse models of the disease have suggested that exposure to light and sound at the gamma band frequency of 40 Hz can have a positive impact on the pathology and symptoms from neurodegenerative disorders. “Gamma stimulation promotes a healthy environment,” said researcher Daniela Rodrigues Amorim. “There are several ways we are seeing different effects.” The researchers used the cuprizone mouse model of demyelination to investigate the ways in which gamma sensory stimulation may promote myelination and reduce neuroinflammation. They divided the mice into four groups: mice that were fed a normal diet; mice that received no cuprizone but did receive gamma stimulation; mice that received cuprizone and constant, but not 40 Hz, stimulation; and mice that received cuprizone and 40 Hz stimulation. The cuprizone-fed mice that received 40 Hz stimulation retained significantly more myelin, rivaling the myelin health of mice never fed cuprizone in some areas. The team also investigated whether oligodendrocyte cells had higher survival rates in mice exposed to 40 Hz sensory stimulation. The number of oligodendrocyte cells was much closer to healthy levels in mice fed cuprizone and treated with gamma stimulation than in cuprizone-fed mice not exposed to gamma stimulation. Electrophysiological testing of the neural axons showed that electrical performance improved in the cuprizone-fed mice that received gamma stimulation, compared to the cuprizone-fed mice not treated with 40 Hz stimulation. To further explore how 40 Hz sensory stimulation might protect myelin, the researchers evaluated the protein expression from all four mouse groups. An analysis of the mice’s brain tissue identified distinct differences in protein expression between the cuprizone-fed mice exposed to control stimulation and the cuprizone-fed mice that received gamma stimulation. To assess the number of immature and mature oligodendrocytes in the corpus callosum (CC) in mice fed cuprizone and given 40 Hz stimulation (right) compared to mice fed cuprizone and given constant stimulation as a control (left), the researchers measured the marker PDGFRa (green) and APCCC1 (red). The 40 Hz group exhibited a significantly higher number of each type of oligodendrocytes. Courtesy of Tsai Laboratory/MIT Picower Institute. The gamma-treated, cuprizone-fed mice showed an increase in microtubule-associated protein 2 (MAP2), a protein that helps preserve the functional integrity of myelin. Synaptic plasticity, also associated with the preservation of myelin, was better preserved in the mice exposed to 40 Hz stimulation. Exposure to gamma stimulation also helped to decrease oligodendrocyte cell death, which is linked to demyelination, by reducing ferroptosis. The team assessed gene expression in the mice using single-cell RNA sequencing technology and found that gamma stimulation had an anti-inflammatory effect in the brain. When exposed to 40 Hz light and sound, fewer cells became inflammatory. Direct observation of tissue showed that microglia became more proficient at clearing away myelin debris, a key step in repairing myelin, in the gamma-stimulated group. The results of the study suggest that 40 Hz sensory stimulation with light and sound could be therapeutic for numerous disorders that exhibit myelin degeneration, including multiple sclerosis and Alzheimer’s disease. The course of these neurological conditions comprises severe neurodegenerative processes, including neuroinflammation, profound myelin damage, and brain atrophy. Cognito Therapeutics, the spin-off company that licensed MIT’s sensory stimulation technology, published phase II human trial results in the Journal of Alzheimer’s Disease in early 2024, which indicated that 40 Hz light and sound stimulation significantly slowed the loss of myelin in volunteers with Alzheimer’s. In 2024, the lab of professor Li-Huei Tsai also published a study showing that gamma sensory stimulation helped mice withstand neurological effects of chemotherapy medicines, including by preserving myelin. “Previous publications from our lab have mainly focused on neuronal protection,” Tsai said. “But this study shows that it’s not just the gray matter, but also the white matter that’s protected by this method.” The research was published in Nature Communications (www.doi.org/10.1038/s41467-024-51003-7).