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Prof. Annabelle Singer on Gamma Sensory Flicker Therapy Tackling Alzheimer’s – Our Longevity Futures, with Chris Curwen | Ep. 9

14 June 2021

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Over the last 150 years, our life expectancy has grown, from 40 years in 1850 to over 90 years today in some countries. This can be attributed to advances in medical science, improvements in public health, and equitable access to healthcare, especially for maternal and infant care.

What will the future hold for our world? Will we be overwhelmed by a ‘silver tsunami’ of retirees with poor health, or will we use the latest research findings to rejuvenate the elderly and extend their lifespan?

Our Longevity Futures is a show where I, Chris Curwen, speak to scientists, engineers, entrepreneurs, doctors, politicians, and community activists who are giving the world the hope that we can all live longer and better, and improve our health.

In today’s episode of Our Longevity Futures, we are delighted to speak to Prof. Annabelle Singer. Annabelle is an Assistant Professor in the Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, where she runs the Singer Lab.

The central goal of Dr. Singer’s research program is to understand how neural activity produces memories and spurs the brain’s immune system. Her research integrates innovative behavioral, electrophysiological, and computational methods to identify and restore failures in neural activity that lead to memory impairment.

The Singer Lab’s latest publication, titled “A feasibility trial of gamma sensory flicker for patients with prodromal Alzheimer’s disease” is based on the positive impact gamma sensory flicker intervention has been shown to have on slowing the progress of Alzheimer’s disease, in animal models. Gamma sensory flicker is a therapeutic technique in which individuals are exposed to light and sound flickering at 40hz for a period of time.

In today’s talk with Annabelle, we discuss the origin of this unique therapeutic technique, its mechanism of action, and also the potential impact of gamma sensory flicker therapy.

A feasibility trial of gamma sensory flicker for patients with prodromal Alzheimer’s disease

Prof. Annabelle Singer models an experimental visor and earphones that play 40 Hertz light and sound. Source: Georgia Tech

Here are some of the highlights for my conversation with Annabelle:

Chris: So could you tell us, in Layman’s terms, what Gamma sensory flicker therapy is?

Annabelle: Yes. So it’s really quite simple. It is flickering lights and sounds that are at a very precise frequency, so 40 Hertz, which is in the gamma range. And we found in our animal studies that entrains neural activity in multiple brain regions. And then that has effects on immune cells and immune signals as well as reduces pathology in animal models of Alzheimer’s.

So the stimulation is totally non-invasive and it’s done for an hour a day every day. And this study, we did it for eight weeks.

Chris: Where did the idea of gamma sensory flicker therapy first come from?

Annabelle: Yes, absolutely. So it started by looking at deficits in neural activity, or neural activity that’s lacking in the animal models of the disease. And we found deficits in a pattern of activity we call replay, which is like when the brain replays prior experiences to remember them later.

And part of that activity is this gamma frequency or for the stimulation we’re doing 40 Hertz, but gamma in the brain is a wide range of frequencies. But what we found was missing was around 40 Hertz. And so that inspired us to stimulate at gamma and see what the effect would be. And in particular, some of those deficits we found were before we saw memory deficits in the mice.

So that made us wonder if this would affect pathology early in the disease, as opposed to affecting memory, which we know gamma plays a role in.

Chris: What do we know about the biochemical pathways that are stimulated by the 40 Hertz frequency, and why do they have a positive impact on Alzheimer’s progression?

Annabelle: Yeah. So we’re currently studying that: what is the biochemical signaling involved? We’ve found so far changes in immune signals, including phosphorylation of pathways that we know controls immune signaling, in particular cytokines, the cytokines are signals between cells that we know affect immune cells.

And then we know that immune cells change in response to this stimulation. And so the immune cells in particular, one cell type of interest or microglia, they are like the trash collectors of the brain, they move around and take up things, including pathogens like amyloid beta. So we think they’re playing a role in clearing out pathogens.

We also see changes in synapses, so those are the connections between neurons, and some of the biochemical pathways we’ve identified are important for synaptic plasticity or strengthening and weakening connections between neurons.

Chris: So if this frequency has an effect on Alzheimer’s, do other frequencies have other effects?

Annabelle: Yes. So far in the studies we’ve published, we really compared 40 Hertz to random. Meaning there is stimulation, but that frequency is not regular, it’s a randomised pattern. And then some other frequencies, like 20 Hertz and 80 Hertz. Most of the time, 40 Hertz looks different than all the other frequencies of stimulation. But in some cases we see differences between the other frequencies. And it depends a little bit on the assay we’re using and the way we’re stimulating and things like that.

So far I think, there are really clear differences between 40 Hertz and 20 Hertz. And there are clear differences between stimulation and no stimulation, as well as there are differences between random stimulation and the other frequency.

Whether those are all going to be useful in the future is to be determined. I think so, based on what I’ve seen so far and not all of it’s published, I think that there’s going to be useful stimulation frequencies outside the 40 Hertz.

Chris: We have recently had the news that for the first time in 20 years the FDA has granted approval for a drug that specifically targets Alzheimer’s, called aducanumab. It is a drug that targets amyloid, the protein that forms abnormal clumps in the brains of people with Alzheimer’s that can damage cells. Is this different from the mechanism by which flickering light and sound tackles the disease? If so, how is it different?

Annabelle: Yes, it’s definitely a different mechanism. As you’ve probably read in the news it’s that drug is somewhat controversial because the effects on amyloid are clear, but the effects on cognition are quite mixed. And overall there’s a debate in the field, whether clearing amyloid alone is going to be enough, as a treatment.

The reality is Alzheimer’s affects the brain at multiple levels: it affects amyloid, meaning there’s amyloid accumulation, there’s also tau hyper-phosphorylation that accumulates into tangles, there’s changes in inflammation, there’s changes in synapses. Synaptic loss is actually one of the best predictors of cognitive decline.
So what I think we need is a drug or treatment that targets multiple levels. It may even be that we need treatments that are personalised. Meaning one person might have. An inflammatory form of Alzheimer’s where really what needs to be treated as inflammation and somebody else might need a different kind of thing treatment.

So with all that said, we really need to think about the disease at this multilevel way. The stimulation that we’re talking about does have affects at multiple levels. It makes it somewhat complicated in that we don’t fully understand which level of change, or which level of effect is that important, but it does mean that we’re having this complicated multi stage effects. So we have effects on inflammation and immune signaling. We have effects on synapses and synaptic plasticity. We see effects on amyloid, as well as phosphorylated tau.

So while we still need to work through whether each one of those things matters for the improvement, for instance in mice, but also in humans, it’s at least promising that we’re having effects on multiple levels.

Chris: Could combining gamma sensory flicker therapy and aducanumab into a multi-intervention approach, possibly enhance their individual impacts?

Annabelle: Absolutely. I think first we need a better handle on how varied Alzheimer’s can be. Like, each person is different we know that already, but there might be sub types of Alzheimer’s that would benefit from different treatments. And it may be, there are some combinations that you would use with one individual versus some combinations you would use with another.

There may also be simple drug combinations that are just incredibly effective together. We see this for cancer, where cancer, we now know as a much more complicated animal than we thought of it as 40 years ago, and the treatments, we don’t have one treatment for cancer. We have many, and each patient gets a tailored approach.

I think we’re going to see something similar with Alzheimer’s in the long run.

Chris: Alzheimer’s interventions famously have extremely low translation rate from successful animal testing, to successful human trials and then regulatory approval. Are you confident that this unique type of therapy will successfully translate across to human studies, and if so, what is it that makes you confident in this?

Annabelle: Yes. So there absolutely is a low rate of success from animal studies to human studies, not just for Alzheimer’s, for many different treatments. That’s part of why we need to do the studies, and why we’ve pushed to get into humans as quickly as possible, because the faster we find out the better off we are.

That said, we don’t know. And we won’t know, I won’t give you a confident statement until we’ve seen results from a big, long trial, meaning hundreds of people over multiple years. That’s when we’ll know for sure.

In the meantime, the results we’ve seen so far are promising. The results we saw from our own study, I think are promising, where we see changes in immune signaling and changes in functional connectivity in brain networks.

There’s some other studies that haven’t been published in peer reviewed journals yet, but they’ve been presented at conferences that also show some promising results. So I think together multiple studies showing promising results. I’m intrigued. I’m heartened. But we do need to see the results of a big trial.

Chris: And what are some of the main challenges from actually converting this therapy across from an animal study, to a human study? For example, I imagine the visual and audio head set vary hugely.

Annabelle: Yes, absolutely. It is a huge challenge. There are so many questions. So first you asked about the device, so the device is a set of goggles that have lights in them that flicker at the frequency programmed to. And then it’s headphones, and people have to do it for an hour a day, which is a big commitment.

So it’s not a small ask of our participants. But even besides that part, there were so many questions going into the study because mice and humans are so different. So we did with mice, we did an hour a day for a week and we thought is that what we should be doing with humans? And we decided an hour a day was a reasonable place to start.

But we didn’t think a week would be enough. So we opted for four to eight weeks. But there’s a whole other question; should it be an hour, a day? Should it be half an hour, a day? Should it be two hours a day? And that’s will be a subject of further study. And then there’s a whole other question in terms of the assays involved, all the assays we use in mice don’t necessarily work in humans. So we have to try to find something that is reasonably equivalent, but usually in a human participant we have much less sensitivity in the assays that we have. And then additional challenges: Humans are much more variable than mice, right? So we have to try to account for that. For real-world variability, both in terms of whether or not they’re going to use the device, but also just in terms of their basic biology.

So there’s many challenges. And in terms of getting this particular study off the ground, it was really team effort between myself, who had done many animal studies going into it, and our clinical team at Emory, so led by James Law, but also with an enormous clinical staff who makes these studies happen.
And we met over and over again to hammer out all the details and go through every detail of the study, every detail of what we knew from mice, and debated each point that ended up being the study design.

Chris: How was the therapy tolerated by the participants?

Annabelle: It was a big concern for us. Would they find the therapy intolerable and just not do it? Or would they, even if it was tolerable, would they keep doing it? Because an hour, a day is a lot to us. We were pleasantly surprised. We found people, tolerated it at a high level and they can turn that sound and volume and the light intensity up and down. So we do a kind of assessment in the beginning and ask them what they can tolerate in terms of the brightness and the volume. And they tolerated it at very high levels. So that was our first surprise and they tolerated it and they were willing to do it.

And then our second surprise, pleasant surprise was that they adhered to the treatment that they were prescribed. So meaning they’re supposed to do it in an hour, a day, every day. And people did that. On average, they did 95% of their prescribed treatment sessions – I think the minimum was 88% – so they really did adhere to what we asked them to do.

We also ask them what the experience was like for them. And anecdotally, I’ll paraphrase what some people said, so some of our participants said something along the lines of “at first it was hard to find time to do it, but then it became me time.” So it, somehow once they got it into their schedule or into their routine, it seemed to take on positive, or at least not negative experience of their life.

Chris: Alzheimer’s disease is a currently incurable, degenerative condition, meaning that victims start off with mild symptoms, which, with time, progressively gets worse. What stage of Alzheimer’s were the patients in your study? What does the data, from the animal studies or elsewhere, show in the therapies effectiveness against late-stage Alzheimer’s?

Annabelle: So our participants were what we call prodromal Alzheimer’s. So that means they’re early in the disease, they have early memory impairment, but it’s not that severe. And they have signs of amyloid pathology, what we call biomarker positive amyloid and tau pathology. So they’re early in the disease, we selected that stage because right now the prevailing hypothesis is that we need to intervene early in the disease to make make headway basically.
So most therapies are really geared towards that early stage.

Once you get to the later stages of the disease it’s potentially harder to turn things around. So in the early stages of the disease, there’s things like amyloid accumulation, inflammation, and synaptic loss. All of those things are reversible, when you get to the later stages of the disease, that’s when you’re seeing neuron loss and that we don’t think is reversible.

So that’s the challenge at the later stages. In between there’s a long period in a lot of different stages. So we’ve looked at in our own hands, we’ve looked at, I would say early and mid stages of the disease, but in a mouse model it’s not really disease stages it’s a little different.

And then another person in Li-Huei Tsai’s lab, looked at a very aggressive mouse model of neurodegeneration and he gave slicker stimulation, I think, light flicker for weeks, maybe even months, and drastic improvement in this aggressive model. He started early, so it’s not exactly addressing if you started late, but it was, I thought, quite compelling that it could help even slow down aggressive forms of the disease.

Chris: What are two or three things you intrinsically believe are inevitable regarding the future of dementia and Alzheimer’s treatment, and for the future of healthcare in general?

Annabelle: So I think we’re going to, for Alzheimer’s, I think we will end up having a landscape, like I said earlier, more like cancer, where we have multiple treatments and we have multiple categorization, or kind of personalization of therapies.

So I think it’s going to be much more diverse. I don’t think there’s one therapy, that’s the thing for everyone. And I’m looking forward to that. I’m looking forward to there being a slew of options for patients and doctor to, to try out. And that’s one.

What I hope is on the horizon are ways to prevent the disease. So not just treating it in the earliest stages, but even before onset. So we would be able to identify people who are at risk of the disease based on a variety of factors, including family history, genetics, health history, et cetera, and that those people could get an intervention early. That I hope for, and I think is possible.

As far as the future of healthcare, and this is related to Alzheimer’s and neurodegenerative disease in general, I think we’re going to see a lot of innovative therapies that are focused on the immune system of the brain. I think there’s some in the pipeline. I think there’s a lot of science being done in this area. And I think there’s going to be quite a bit of innovation in this area.

Chris: What obstacles may prevent these things from happening?

Annabelle: There’s a ton of basic research that needs to be done. That’s number one and a lot of that’s in the works, still actively very, these are very active areas of research.

I think, number two would be, we really need to overhaul the way we do clinical trials. The current clinical trial system is a clinical trial that to prove a therapy is effective, it’s called a pivotal trial and it’s huge and it’s incredibly expensive and so you can’t really try many things.

A company, typically with a lot of funds, will try a few things, or maybe just one thing. And I think we need more diversity. So to get that, then we need a different kind of trial approach. I don’t know exactly what the solution is there, because you do want to be able to test on a lot of people over a long time, but I think that would be really beneficial in terms of getting more shots on goal.

Chris: What are your thoughts on the field of ageing research and how it impacts your work?

Annabelle: We definitely think about ageing and for a couple of reasons. And we now have studies going, or starting looking at healthy ageing. So it’s definitely an important question.

So one of the reasons we are interested in ageing is because it has an immune component. The part of the reason that we think people are more susceptible to disease, but also other things like cognitive loss, memory loss, over the course of ageing is because we think that there’s these immune changes going on as we age. eAnd if we could revitalise our brain’s immune system, we think that could be really beneficial. It would both be good for healthy ageing, but also be potentially protective against disease. So that’s something we’re looking at right now.

And we’re also interested in healthy ageing because, like you said, it’s a major risk factor for Alzheimer’s disease and if we want to develop preventative treatments that’s where we need to be thinking.

Chris: What’s the current roadmap for the gamma sensory flicker technology?

Annabelle: I think there’s a couple major directions. So one is furthering the human trials. And there’s a couple of us as I mentioned, our study has been published, there are some other studies there that are either in the works, or they’ve presented a conferences and we plan to get together as a group and talk about everything we’ve learned to try to really put it all together into a comprehensive picture that’ll guide us for the next studies, the next bigger, longer trials. So really the next step there is a larger, longer trial. That is on the sort of human clinical trial front.

There’s a really a lot though, basic science still to be done in terms of understanding mechanism. Like we know some of it, but there’s still quite a bit to understand in terms of mechanism of action. As well as applying this to other different diseases, because there are a long list of diseases that have a neuro-immune component. So if we have a kind of stimulation that controls neuro-immune function, it could potentially be applicable to many diseases.

And then another area is developing it, this, as I said, in terms of a preventative treatment that would protect against disease instead of treating disease after onset, those are our main areas of interest right now.

We really appreciate Annabelle taking the time out of her busy schedule to come and talk to us. It was a truly fascinating conversation in which we all learnt so much about this exciting new Alzheimer’s therapy. A massive thank you from Chris and everyone on the Gowing life team. You can keep up-to-date with all that Annabelle and her team at Singer labs are doing here.

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