Cognito Therapeutics, a neurotechnology company led by MIT researchers, made headlines earlier this year when it announced a $73 million investment in Phase 3 clinical trials for its lead therapy for Alzheimer’s disease. Recognized as a “Breakthrough Technology” by the FDA, the team of researchers and engineers have designed a headset that provides simultaneous light and sound stimulation at 40 Hz. Promising results from early animal studies and clinical trials showed that this technology was able to restore the abnormal gamma brainwave activity often seen in the early stages of Alzheimer’s disease.
However, recent attempts to replicate these findings have been inconsistent, raising questions about its underlying mechanism of action. While behavioral animal studies are helpful in understanding whether an intervention works, how it works can only be determined by closely examining the brain at the cellular and molecular levels. Often, this is done by using a microscope to examine the brains of mouse models exposed to stimulation and comparing them with a control mouse group. Such mouse models contain specific genetic mutations associated with hereditary Alzheimer’s disease. If 40 Hz light and sound stimulation is a viable treatment for Alzheimer’s disease, we would expect to see a reduction in beta-amyloid plaques and tau neurofibrillary tangles, which are hallmarks of the disease.
To their surprise, a preliminary study conducted by Iacciano et. al found that 40 Hz auditory and visual stimulation not only reduced the accumulation of beta-amyloid plaques in the brain, but also modified the activity of microglial brain cells. Microglia are the first and primary immune defense system of the central nervous system. When they come in contact with beta-amyloid protein, microglia respond by activating a robust inflammatory cascade to clear the debris and restore nerve tissues. While this immune response is necessary to respond to acute nerve damage such as infection, chronic inflammation can also injure healthy cells.
Studies have shown that as beta-amyloid plaques accumulate in Alzheimer’s, microglia become overactive and produce an excessive inflammatory response. It has been proposed that strong activation of microglia may be a major driver of widespread neurodegeneration in advanced stages of the disease.
Reducing inflammation in the brain has increasingly been implicated as a potential therapeutic target for treating Alzheimer’s disease. Now, evidence seems to suggest that using auditory and visual stimulation to manipulate electrical activity may be able to do this. A recent study from the Georgia Institute of Technology found that 40 Hz stimulation selectively increases inflammatory pathways.
The investigators began this study by exposing rats to one of four experimental conditions: 40 Hz flickering light for one hour, random interval light flickering at 40 Hz or 20 Hz, or continuous light. After stimulation, rats were sacrificed and their brains were frozen for further analysis. Across all mouse groups, there were no differences in anxiety-induced behaviors, confirming that different visual stimulation conditions did not affect animal behavior.
Garza et. al found that mice exposed to 40 Hz light flicker stimulation displayed increased phosphorylation, or activation, within the NF-κB inflammatory pathway. This pathway is crucially involved in the production of cytokine proteins, which help control inflammation. Specifically, 40 Hz light flicker stimulation was found to increase the expression of anti-inflammatory cytokines, such as interleukin-6 and interleukin-7. In addition to its role in inflammation, the NF-κB pathway has also been involved in learning and long-term memory. Together, these findings suggest that stimulation at this frequency may provide neuroprotective effects for those in the early stages of Alzheimer’s disease.
Do other frequencies provide similar benefits? Garza et. al were surprised to find that different frequencies recruited different types of cytokines through activation of the NB-κB pathway. However, compared to 20 Hz light flicker, 40 Hz stimulation produced the greatest cytokine response. This is consistent with previous studies suggesting that 40 Hz stimulation provides the greatest clinical benefit with very little risk of adverse events.
Alzheimer’s disease has been closely linked to inflammation in the brain. The emergence of electrical brain activity as a potential therapeutic target has uncovered new insights into how Alzheimer’s develops and progresses. Despite this, several questions remain unanswered: What are the long term effects of 40 Hz stimulation? Can the benefits be sustained over a long period of time, or does the brain desensitize to stimulation over time? Highly anticipated results from current clinical trials and animal studies may soon answer these questions.