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Research Unveils Benefits of 40Hz Sensory Stimulation in Myelin Preservation

Recent studies in both Alzheimer’s patients and mouse models have shown that sensory stimulation at a frequency of 40 Hz, involving light and sound, has promising effects on pathological changes and symptoms associated with the disease. A new study investigates the role of this gamma frequency sensory input in preserving myelin, the fatty insulation surrounding neuronal axons. Myelin, often referred to as the brain’s “white matter,” plays a vital role in facilitating efficient electrical signal transmission within neural circuits.

“Our previous work has largely centered on neuron protection,” remarked Li-Huei Tsai, Picower Professor at MIT’s Picower Institute for Learning and Memory, and senior author of this new study published in Nature Communications. “However, this research underscores the importance of protecting not just gray matter but also white matter.”

Cognito Therapeutics, a company that has adopted MIT’s sensory stimulation technologies, recently shared results from a phase II clinical trial in the Journal of Alzheimer’s Disease. The findings indicate that 40 Hz light and sound stimulation significantly mitigated myelin loss among Alzheimer’s volunteers. Additionally, Tsai’s lab demonstrated earlier this year that gamma sensory stimulation helped preserve myelin in mice undergoing chemotherapy, highlighting its protective capacity. In the latest investigation, Tsai’s team, led by former postdoctoral researcher Daniela Rodrigues Amorim, utilized a common mouse model that induces myelin damage via the toxic substance cuprizone to assess how sensory stimulation aids myelination.

The researchers discovered that 40 Hz stimulation not only helped maintain myelin levels in cuprizone-exposed mice but also appeared to support the health of oligodendrocytes—the cells responsible for wrapping myelin around axons. Furthermore, the stimulation enhanced neuronal electric performance and preserved crucial structural markers of axons. Delving deeper, the study identified several protective mechanisms, including the preservation of synaptic connections, reduction of oligodendrocyte cell death due to ferroptosis, lowered inflammation, and enhanced microglial activity that aids in the clearing and repair of damaged myelin.

“Gamma stimulation fosters a beneficial environment for neuronal health,” noted Amorim, who is now a Marie Curie Fellow at the University of Galway in Ireland. “We are observing diverse positive effects.”

The implications of these findings extend beyond Alzheimer’s disease, suggesting that gamma sensory stimulation could also benefit individuals suffering from other disorders characterized by myelin degradation, such as multiple sclerosis.

Experimental Design and Results

In conducting the study, Tsai and Amorim’s team divided male mice into groups, giving some a cuprizone-laced diet while others received regular food over a six-week period. At the three-week mark, the researchers introduced gamma sensory stimulation to select mice from each dietary group. This setup established four distinct cohorts: (1) mice without cuprizone, (2) mice with normal diets receiving gamma stimulation, (3) cuprizone-fed mice given control stimulation, and (4) cuprizone-fed mice subjected to gamma stimulation.

Post-experiment assessments revealed that the control group of mice maintained healthy myelin levels. Conversely, cuprizone-fed mice lacking gamma stimulation exhibited significant myelin loss. In contrast, those receiving 40 Hz stimulation showed retention of myelin levels that approached those observed in the healthy control mice under various measures.

The research also assessed oligodendrocyte populations within the corpus callosum—the brain’s crucial structure for inter-hemispheric signaling. Results indicated a substantial reduction in oligodendrocytes among cuprizone-fed mice not receiving gamma stimulation, while those treated with gamma input had cell counts nearer to normal.

Electrophysiological evaluations of the neural axons in cuprizone-affected mice demonstrated that gamma stimulation was linked to better electrical functioning compared to untreated mice. Additionally, within the anterior cingulate cortex—the region associated with emotional processing—MAP2 levels, a marker of axonal integrity, were significantly higher in mice receiving both cuprizone and gamma stimulation versus their control counterparts.

Understanding Molecular Mechanisms

The research aimed to clarify the underlying mechanisms through which 40 Hz sensory stimulation may bolster myelin preservation. To this end, the team conducted comprehensive protein expression analyses across all groups to identify discrepancies tied to diet and stimulation.

Key findings included an uptick in MAP2 levels among gamma-treated mice, while cuprizone mice experiencing control stimulation displayed notable deficits in proteins associated with synaptic integrity—a crucial component for neural circuit function and myelin conservation. This observation aligns with earlier research that similarly linked gamma stimulation to synaptic preservation, highlighting its potential clinical relevance.

Moreover, the study uncovered signs related to ferroptosis within the cuprizone cohort receiving control stimulation, specifically increases in HMGB1 protein—an indicator of ferroptosis-related damage. In contrast, gamma stimulation notably reduced HMGB1 levels, suggesting a protective effect against this form of cell death.

Further analysis using single-cell RNA sequencing technology showed that while inflammatory responses escalated in the brains of cuprizone-fed mice without gamma stimulation, those subjected to 40 Hz input exhibited a calming effect on inflammation. This resulted in improved microglial activity for cleaning-up myelin debris, an essential step for healing.

Additionally, gamma stimulation bolstered the expression of protective proteins in oligodendrocytes—both HSP70 and GPX4—which are key regulators in preventing ferroptosis.

This collaborative research involved contributions from various notable authors at MIT and was supported by several funding sources, including Fundacion Bancaria la Caixa, The JPB Foundation, and the National Institutes of Health, among others.

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