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Cognito TX co-founders on Nature: Multisensory Gamma stimulation promotes glymphatic clearance of amyloid

Feb. 28, 2024 Cognito TX scientific co-founders Drs. Li-Huei Tsai and Ed Boyden and their research team at MIT Picower Institute for Learning and Memory have published a Nature article today that reveals a key mechanism behind the beneficial effects of 40 Hz gamma stimulation. Using a mouse model of Alzheimer's (AD) disease, the authors found that multisensory gamma stimulation promotes glymphatic clearance of amyloid proteins, a hallmark of AD pathology. The brain’s glymphatic system is a pathway that facilitates waste clearance.

Previous studies have shown that sensory gamma stimulation promotes 40 Hz neural activity in multiple brain regions including the prefrontal cortex, and that the stimulation attenuates Alzheimer's disease-related pathology, ameliorates neurodegeneration, and morphologically transforms astrocytes and microglia in models of Alzheimer's disease. However, the cellular processes by which such stimulation attenuates amyloid load in the brain remains unresolved.

In the newly published research work, Cognito TX co-founders Drs. Tsai and Boyden and their research team found multisensory Gamma stimulation promotes glymphatic clearance of amyloid. The study was carried out following 1 h of multisensory 40 Hz stimulation, compared with the brain at no stimulation, 8 Hz stimulation and 80 Hz stimulation. They found out cerebral spinal fluid (CSF) influx into the cortex increased with gamma stimulation at 40 Hz. Meanwhile, they found ISF efflux--a pathway through which soluble amyloid is thought to be cleared from the brain--increased in the 40 Hz group.

The authors further revealed that upon 40 Hz stimulation, a group of neurons, called “interneurons,” experienced an uptick in the production of several peptides. It is well established that neuropeptides are released in a frequency-dependent manner. In this case, a particular peptide, VIP, seemed to be mediating the glymphatic clearance of amyloid: when the researchers chemically shut down the VIP neurons and then exposed the mice to 40 Hz stimulation, there was no longer an increase in arterial pulsatility or amyloid clearance. This leads to the mechanism of the gamma stimulation: Brain rhythm governs CSF dynamics via arterial pulsatility and peptide signaling. In particular, 40 Hz stimulation activates glymphatic pathways to promote amyloid clearance.

Interestingly, 40 Hz stimulation promoted the influx of CSF into the cortex and the efflux of ISF. Multisensory gamma stimulation increased arterial pulsatility in a VIP interneuron-dependent manner, highlighting an interconnected relationship between glial, neuronal, and vascular cells in the regulation of CSF dynamics.

What's Next

While an important mechanism, glymphatic clearance of amyloid as a result of 40 Hz stimulation may not be the only mechanism that matters in AD. It is worth noting that the clearance effects occurred only after 1 h of stimulation in mice, but human clinical studies have required weeks or months to see sustained effects on cognition. More research is needed to determine whether this is a result of a lifespan mismatch between humans and mice, or whether the 40 Hz stimulation needs to be fine tuned for humans.

Further research that identifies factors linking brain rhythms and vasoactive clearance may enhance the therapeutic potential of recruiting glymphatic transport for the treatment of other neurodegenerative disorders in which the accumulation of pathogenic extracellular proteins play a key role, such as Parkinson's.


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