In a university lab in 2018, our group of researchers set out to understand how the brain responds to flickering light. Our research was driven by a larger goal: to combat Alzheimer's disease, one of the most significant neurodegenerative disorders.

Over the past decade, promising studies have demonstrated the potential of stimulating the brain with 40 Hz light pulses to potentially treat Alzheimer's. Research on mice in the 2010s revealed significant reductions in amyloid and tau proteins, key markers of the disease. Inspired by these findings, our team of Danish and American researchers and engineers formed OptoCeutics, convinced that a better stimulation solution could be developed. We developed a novel technology coined Invisible Spectral Flicker (ISF), which aims to minimize the sensation of flicker associated with regular flickering light while still delivering 40~Hz stimulation to the brain.

What is flicker?

To put it simply, flicker is the visual sensation that occurs when a light source changes. It can be changes to either the brightness or to the color, thus distinguishing between:

• Luminance flicker: A rapid change in brightness, e.g. between on and off.
• Chromatic flicker: Alternating between two different colors, such as red and blue.

A key term here is "flicker fusion" or "critical flicker fusion frequency (CFF)"—the frequency at which flicker becomes so fast that it is imperceptible to the human eye. When alternating colors, the light can even appear as one blended color, a mix of the two sources.

While dependent on multiple factors, luminance flicker fusion typically occurs above 60 Hz, meaning that the light sources need to alternate faster than 60 times per second for the human eye not to detect flicker. However, for chromatic flicker colors, this threshold can be as low as 25 Hz. This is the basis for the ISF technology, which uses two distinct light sources flickering at 40 Hz that fuse together to produce a more pleasant white light that is perceived with minimal sensation of flicker. 

But if perceived with minimal sensation of flicker, does it still produce a brain response?

The short answer is yes, as previous research has already demonstrated. However, while clinical studies were already ongoing, we sought to explore a different direction — how the brain reacts to various types of flicker and how people perceive them. We found gaps in the literature concerning how factors like brightness, color, and whether the viewer needs to look directly at the light influence the brain's response.

Our study aims to address some of these questions. We tested four types of light: luminance flicker, chromatic flicker, ISF, and a non-flickering control light, each presented at three different brightness levels. Another key question we wanted to explore was whether looking directly at the light is necessary to trigger a brain response. To investigate this, we performed measurements with participants not looking directly at the light, specifically using ISF.

We used electroencephalography (EEG) to measure the brain's response to the various light stimulations. EEG provides an easy way to capture the brain’s immediate reaction as electric potentials generated by firing neurons. We conducted the study with 20 participants, adhering to the best statistical practices, including repetition, randomization, and blinding — all though blinding is always challenging, given that it’s hard to mask flickering light. Additionally, we asked participants to rate the comfort and perceived flicker of the different lights.

Key Findings from the Study

The main findings aligned with our expectations: Light that appears more flickering also generates a stronger brain response. However, we confirmed that it is possible to design a 40 Hz visual stimulation that is more comfortable and still able to evoke a response. This was even the case at lower brightness levels and when the subjects were not looking directly at the light. Together, these findings suggest that there may be a trade-off between comfort at brain response.

1. Comfort, Perception, and Brain Response: Both luminance and chromatic flicker produced a higher brain response than ISF. However, ISF outperformed both of them in terms of comfort and perceived flicker.
2. Stimulation Brightness: Lower brightness did not have a statistically significant effect on brain response or perceived flicker, but it did significantly improve comfort. We also observed a trend toward a lower brain response with reduced brightness.
3. Peripheral Stimulation: When using ISF from peripheral angles (i.e., participants not looking directly at the light), there was a slight decrease in the 40 Hz steady-state visually evoked potential (SSVEP) response. Nonetheless, a significant brain response was still observed even when participants weren’t looking directly at the light.

Now what?

Companies like Optoceutics, Cognito Therapeutics, and others are continuing to invest in research to explore how 40 Hz visual stimulation can be used to combat neurodegenerative disorders. It is still unclear how the differences in acute 40 Hz response to various types of stimulation translate to differences in clinical benefits. However, it is evident that increased comfort can be achieved while maintaining a 40 Hz brain response. This may ultimately be preferred over conventional luminance flicker if treatment adherence is improved. Our aim is to help guide the development of future light therapies, ultimately providing the best possible solutions for patients in need.

Read more: 

To delve more into the topic of 40 Hz gamma stimulation we invite readers to check out the following research:

• A recent News Feature by Nature exploring and discussing the field of light stimulation: Can flashing lights stall Alzheimer’s? What the science shows
• One of the earliest mice studies showing the potential of using 40 Hz visual stimulation as a therapeutics solution for Alzheimer's Disease. DOI: 10.1038/nature20587 
• The first study demonstrating that a brain response can be elicited using ISF stimulation: Agger M. et. al. 2022, DOI: 10.3233/JAD-220081
• A study showing that 40 Hz light stimuli alternating between two colors generate a higher brain response if either component is blue or red than if they are composed of only mid-spectrum colors. Interestingly, this appears to be more important than the two colors being spectrally different:  Henney M. A. et. al. 2024 DOI: 10.1038/s41598-024-52679-z 
• A study reviewing the scientific literature behind the choice of 40 Hz, starting with evidence from the 1960s. The researchers also conducted an experiment showing no strong preference for 40 Hz compared to other frequencies in the range of 36-44 Hz:  Henney M. A. et. al. DOI: 0.21203/rs.3.rs-4453298/v1 
• Results of the OVERTURE study, one of the largest completed clinical trials on 40 Hz stimulation in Alzheimer’s patients, showing promising effects: Megerian J. et. al. (2022) DOI: 10.1212/WNL.98.18_supplement.1936  
• A clinical study suggesting similar positive effects of ISF stimulation on Alzheimer’s patients:  Agger M. et al. 2023, DOI: 10.3233/JAD-221238.