“Flicker” treatment is a striking non-pharmaceutical approach aimed at slowing or reversing Alzheimer’s disease. It represents a reversal of EEG: not only recording brain waves, but reaching into the brain and cajoling cells to dance. One neuroscientist commentator called the process “almost too fantastic to believe.”

With flashing lights and buzzing sounds, researchers think they can get immune cells in the brain to gobble up more amyloid plaques, the characteristic clumps of protein seen in Alzheimer’s. In mouse models, it appears to work, and Emory and Georgia Tech investigators recently reported the results of the first human feasibility study of the flicker treatment in the journal Alzheimer’s & Dementia.

“So far, this is very preliminary, and we’re nowhere close to drawing conclusions about the clinical benefit of this treatment,” said neurologist James Lah, who supervised the Flicker study at Emory Brain Health Center. “But we now have some very good arguments for a larger, longer study with more people.”

The good news: most participants in the study could tolerate the lights and sounds, and almost all stuck with the eight-week regimen of experimental treatment. (Some even joined an optional extension.) In addition, researchers observed that brain cells were dancing to the tunes they piped in, at least in the short term, and saw signs of a reduction in markers of inflammation. Whether the approach can have a long-term effect on neurodegeneration in humans is still to be determined.

Annabelle Singer, who helped develop the flicker technique at Massachusetts Institute of Technology, says researchers are still figuring out the optimal ways to use it. Recent studies have been assessing how long and how often people should experience the lights and sounds, and more are underway.

“We need to collect all the information we have about how to measure someone’s progress,” says Singer, who is now an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory.

In the feasibility study, ten people diagnosed with mild cognitive impairment used goggles and headphones that provided light/sound stimulation at home for an hour every day. This video from Georgia Public Broadcasting’s Your Fantastic Mind series demonstrates what that was like.

“To me — It’s not painfully loud. And the lights are not as bright as you would think they are… I don’t find them to be annoying,” says retired psychotherapist Jackie Spierman in the video.

“Adherence was one of our major concerns,” Singer says. “When we sent the device home with the participants, would they use it? Would they use it for a couple of days, and that would be it? We were pleasantly surprised that this wasn’t the case.”

Moving fast with gamma waves

Flicker’s light and sound are tuned to a frequency of 40 Hertz, or 40 times per second, corresponding to gamma waves in the brain. On EEG (electroencephalography), gamma waves are the fastest type of brain wave; the other types, from slow to fast, are delta, theta, alpha and beta. Gamma waves are thought to be associated with concentration or memory formation, particularly in the hippocampus.

The observation that gamma waves become weaker in people with Alzheimer’s drove a team at MIT led by Li-Huei Tsai (Singer’s postdoctoral advisor) to test whether imposing them from outside could help. Initial tests in a mouse model of Alzheimer’s took place in 2015. After strong results in animals, a startup company called Cognito Therapeutics developed a wearable system for delivering lights and sound called GammaSense.

Cognito started three clinical trials in 2018, and the Flicker study was one of them. In the Flicker study, researchers were able to see an immediate response of gamma brain wave “entrainment” during sensory stimulation. However, when stimulation is turned off, they did not see an effect on participants’ gamma waves after four weeks, and after eight weeks gamma waves became slightly weaker. In the paper, the authors speculate that this was a homeostatic/pushback response against stimulation.

The researchers did detect some positive effects on functional connectivity – a imaging measure of how much different brain regions activate in synchrony and may be talking to each other. After eight weeks, they saw connections strengthened between two areas in the default mode network (baseline awake but relaxed circuits), which are weakened in Alzheimer’s.

In addition, Flicker participants also displayed a reduction in inflammatory cytokines in their cerebrospinal fluid. Good signs, but there were no clear changes in CSF measures of the pathogenic proteins of Alzheimer’s, beta-amyloid or Tau, which the authors did not expect to see with a relatively short study.

The results of a larger study called Overture, which lasted six months, were reported in April at the 2021 International Conference on Alzheimer’s and Parkinson’s. Results from Overture, which Emory was not involved in, were a mixed bag: no improvements in memory/cognition, but some improvement in daily functioning and mental status exam scores, as well as a reduction in brain atrophy. A few participants had complaints of tinnitus, dizziness or headaches.

“The important takeaway from both FLICKER and OVERTURE is that these studies further elucidate the mechanism of action of gamma frequency neuromodulation from changes in chemokine and cytokine expression to evidence of changes in neural networking and connectivity, even in these small cohorts,” Lah says in a Cognito statement. “The results are mechanistically relevant and deserve additional study.”

A third study called Etude was supposed to compare different regimens: one hour every day, every other day or twice per day, or 30 – 120 minutes twice per day. the results have not been reported yet. Cognito has announced that it is planning to begin a pivotal study for the flicker technique later this year. Singer says it’s still up in the air which outcomes would be best to track: reduction in amyloid markers? performance on cognitive tests? The current round of studies, which have not been fully analyzed, will help researchers figure out the best design. One issue is: what sort of comparable experience should be used as a control?

Ahead: comparison with direct brain stimulation

Scientists still have lots of other questions about the flicker technique, such as: which circuits in the brain are being affected the most strongly by the rhythms they impose? Can they fine-tune the frequency of stimulation? And is passive stimulation OK or should study participants engage in cognitive/memory tasks? Some early studies used an easel-like device to deliver flashing light, and the next version of the goggles won’t be fully enclosed, so people could do other things while they are getting sensory stimulation.

To examine some of these issues, Singer and one of her graduate students, together with neurosurgeon Robert Gross, are currently engaged in an ambitious study of brain stimulation, comparing sensory stimulation to direct stimulation with electricity.

This is more of a translational brain engineering study. It is NOT being performed in people with Alzheimer’s or mild cognitive impairment, but rather, it takes advantage of a rare opportunity to access the brain directly: intracranial monitoring for diagnosis of drug-resistant epilepsy. In such a format, investigators at Emory previously showed that they can enhance memory formation through direct electrical stimulation of the amygdala.

It makes sense that regions in the cortex that process sensory information would entrain to the external beat set by the flashing lights and sounds. But the goal is to have the benefits spread to other regions, such as the amygdala or the hippocampus, which is critical for memory formation. The study with epilepsy patients will allow researchers to monitor effects on the hippocampus and other midbrain regions – and apply what they learn to studies on Alzheimer’s and other disorders.