Annabelle Singer, PhD, Assistant Professor of Biomedical Engineering at Georgia Tech, speaks about a new device that could help those patients fighting Alzheimer’s.
Can you tell us about the flicker device, what it is and what it does?
SINGER: The flicker device presents patients with flickering lights and sound. The lights are like a strobe light but faster. The sound is a tone that turns on and off rapidly. They present sound and lights at 40 hertz or 40 times per second, which in animals we’ve shown changes the molecular pathology of Alzheimer’s to reduce amyloid beta, the protein that produces plaques. This stimulation also transforms microglia, or the primary immune cells to the brain, which are like trash collectors that take out the trash in the brain.
What’s the science behind it? How does that help with cognition?
SINGER: We’re still figuring out some of the basic science. What we know so far is that we use the sounds and lights to drive this gamma activity, around 40 Hz, which is turning on a cascade of biochemical signals that are important for immune function. That immune function is helping to clear out these pathogens, like amyloid beta. There are other beneficial effects, as well. We see things like a reduction in phosphorylated tau, which is another pathology in Alzheimer’s disease. And, we see changes in the vasculature or blood vessels, as well. Most of this work has been done in mice where we have also seen improvement in memory behavior. The mice do better after a week of this stimulation for an hour a day. They do better in things where they must recognize an object they’ve seen before or find a platform in a pool, for example. We think that it’s improving their memory. Whether that will translate to humans is to be determined.
How are people treated who are prone to seizures regarding the flickering lights?
SINGER: You probably have heard the warnings that if you have a seizure disorder or have had seizures in the past, you shouldn’t be exposed to strobe light? A strobe light is very different than this in the sense that the strobe light is much slower. What we call photo induced seizures are rare and even rarer with faster frequencies like the 40 hertz stimulation we’re using. So, we don’t expect most people to have a seizure in response to this kind of stimulation. We are carefully monitoring our human subjects. If they were to have an adverse reaction like that, we would exclude them from the study and immediately stop the stimulation.
Can you talk about the studies you’ve done in mice and how that led to this point in humans?
SINGER: It really started with looking at gamma activity in mice that are genetically programmed to develop a lot of the pathology of Alzheimer’s. We found recording electrical activity in those mice from a brain region important for memory, the hippocampus, the activity that’s normally there was lacking. It made us wonder what would happen if we stimulated gamma to boost this activity that was missing. When we stimulated, that’s when we found we could reduce amyloid beta as well as transform microglia, the immune cells of the brain. And, that was the beginning. That initial stimulation was invasive so not something we could try in humans. We knew from previous work that if you flicker lights or sounds at a particular frequency, you entrain or drive that frequency in visual and auditory brain regions. All of that was really the beginning that this specific frequency of stimulation could be beneficial. Then we wanted to know if we could do it in deeper brain regions, not just the sensory areas. We started playing around with sound and light stimulation and found we could use sound alone or sound and light to train deeper brain regions like the hippocampus and the prefrontal cortex, which is important for memory but also what we call executive functions, all sorts of higher cognitive functions like multitasking. That’s what finally led me to say we’re ready to try this in humans. I came to Allan Levey and Jim Lah and said we’ve done this work in mice, do you think we could try it in humans? I was expecting them to say, oh, you need to do five to 10 more years of mouse studies before we’re ready for that. But instead, they said yes, let’s do it, let’s try it. The stimulation is non-invasive and we didn’t expect safety issues or adverse effects. So, they were open to giving it a try. This first study that we’re doing is small to figure out things like safety, tolerance, and how well patients do with the stimulation. But we’re also looking at some of the biological effects to give us an idea of whether it’s working and what we would do for our next larger study.
Do you have any ideas of what you would do for the larger study?
SINGER: Safety, tolerance, and adherence, meaning how well patients stick to the therapy, have been looking good with the data we have so far. That was really our first question. If those were good, that opens the door to trying it with a larger group of people. So, a next study would be larger and longer and probably a year of stimulation an hour a day, or more.
What do you think that would mean for the quality of life for somebody who was just diagnosed with early Alzheimer’s?
SINGER: What we’re imagining is this is something you could use at various stages of the disease, even preventatively, before any cognitive symptoms show up. It could be something that when you reach a certain age, you just start doing it before you even are concerned about impairment. And then for somebody who is a little further along, maybe they have what we call MCI, mild cognitive impairment, or early Alzheimer’s. They would potentially use it to stave off the progression of the disease. Whether or not it’s going to work with those benefits, we don’t know yet.
Would it be beneficial for someone who’s in late stage Alzheimer’s?
SINGER: That’s a great question. Based on the mouse studies, we can reduce plaques in animals that are further along in the mouse version of the disease. So that gives me hope that it would be helpful for people in later stages of the disease. It really depends a lot on what kind of stage you’re at and what’s reversible versus what’s not reversible. There are aspects of the disease that we think are highly reversible. For example, synapse loss happens, that’s loss in the connections between neurons that are crucial for transmitting information. This is one of the things that best correlate with cognitive decline. We think its really part of what’s going on in the earlier stages of the disease, but it continues as the disease progresses. Synapse loss can be reversed. Cell death that happens later in the disease, we don’t think that’s reversible.
Is there anything else you feel people should know?
SINGER: We’re now studying different ways to stimulate with this sensory stimulation, different frequencies, and different durations. We’re finding different types of stimulation have different effects in the mice, which makes me want to encourage people to be careful about how they use stimulation because 40 hertz is a very specific frequency. You need to present it with millisecond precision. So, be careful about finding something online or something somebody told you about.
Is it only that particular frequency when these patients have the device on, or are there levels they can adjust to?
SINGER: They can adjust levels. The adjustments the patients can make are in terms of the volume and the brightness for comfort level. In mice, we have tried different frequencies. There’s probably a range around 40 hertz, but we don’t know exactly what it is. And, something like 20 hertz has different effects. They’re not beneficial effects, like reducing amyloid or transforming microglia. We don’t see that at 20 hertz.
Finally, are you taking other measurements, besides safety?
SINGER: Yes, the primary outcomes are safety, tolerance, and adherence. But we’re looking at several different measures in these patients. We’re looking at amyloid levels, phosphorylated tau levels, immune signals in the cerebral spinal fluid, and EEG for whether they’re entraining. We’re looking at that now and collecting the last bits of data. The data we get from that study will really help us understand where we can expect to see changes and areas where there are no changes. We won’t be able to say for sure simply because it was too small and too short of a study. So, we’ll need to do another bigger study to confirm anything we find from this study.
END OF INTERVIEW
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