We talk to Dr Annabelle Singer about pioneering Alzheimer’s research and the surprising impact that flickering lights at specific frequencies can have on mice.
Finding a treatment for Alzheimer’s disease, the most common cause of dementia, is one of the key challenges for modern science, and a research team in the US might have made a significant breakthrough.
The team’s paper, Gamma frequency entrainment attenuates amyloid load and modifies microglia, was published at the end of 2016 in Nature. It explains how they were able to reduce levels of the beta-amyloid proteins that are a hallmark of Alzheimer’s by stimulating neural oscillations – that is, brain waves.
Brain waves come in many types, among them gamma waves. These oscillate at around 20 to 50hz (20 to 50 times a second) and are associated with high-level cognitive functions, such as memory and perception.
Disruptions to gamma waves have been observed in various neurological disorders, including schizophrenia, as well as Alzheimer’s, but the research team took the unusual approach of considering the interference to the waves to be more than just symptomatic.
Dr Annabelle Singer, Assistant Professor in the Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, is one of the leading members of the team, and she completed this work while a postdoctoral fellow at the Massachusetts Institute of Technology, where the rest of the team resides.
Dr Singer explains the team’s strategy: “Typically people have thought of Alzheimer’s disease as progressing in one direction: from molecular pathology, such as an excess build-up of proteins, to dysfunctional brain waves to memory impairment. So it was novel to ask if dysfunctional brain waves themselves lead to changes in protein build-up.”
This protein build-up is the cause of the gradual accumulation of the plaque that is thought to disrupt the connections between neurons and eventually impair the normal function of the brain. Most current medication targets the amyloid protein in a bid to prevent the plaque from growing and so maintain the ability of neurons to work as part of the overall network.
The team analysed not just the connections between neurons, but also how the neurons work together, and they took the view that the disruption to the gamma waves was akin to a systems failure. If they could correct the misfiring gamma waves, could they somehow correct the failure?
They worked with mice that had a genetic form of Alzheimer’s that had yet to develop into the full-blown disease. The nature of the research also meant they had to come up with some smart investigative techniques: how were they to stimulate the gamma waves and record the results?
“We used two different methods to the drive gamma brain waves,” says Dr Singer. “First we used optogenetics, a technique that allows us to drive neural firing with light. A virus delivered light-sensitive proteins to PV interneurons in the hippocampus, and we then implanted a fibre that delivered blue light to turn those neurons on with millisecond precision. Second we used light flicker: we built a circuit to turn lights off and on also with millisecond precision.
We then put the mice in an enclosure that was dark except for these flickering lights. The advantage of this paradigm is that it is totally non-invasive.” Recording neural activity in mice is a challenge, so to record the brain waves, the group used an unusual method where mice were running through a virtual reality environment, or when their brains were being stimulated by something like an ultra-fast strobe light.
“We had to restrict their head movements while we were recording and assessing their brain waves,” says Dr Singer.
The team was surprised at what they found. So surprised they had to repeat the test several times to confirm what they were seeing. There was no mistake: stimulating the gamma waves drastically cut the levels of amyloids in the brains of the mice. In fact, a light flickering at 40hz for one hour reduced them by as much as 50%.
The suggestion is that disruptions to gamma waves in the brain is not just a consequence of Alzheimer’s disease, but may actually promote it. So what is happening with the gamma waves? Why might they play such a key role in the disease? The team went back to the mice and used 3D imaging to get a clearer picture of what was going on in the rodent’s brains after the gamma waves had been stimulated.
“We discovered that driving this particular type of brain wave at a very specific frequency recruits microglia,” says Dr Singer. “Microglia are like the trash collectors of the brain, so when they were stimulated by the gamma waves, they did a better job of taking up and getting rid of proteins that make plaques.” This could be a vital discovery in the fight against Alzheimer’s, though it raises further questions – what causes the disruption of the gamma waves, and how do the waves recruit the microglia?
Buoyed by their findings, Dr Singer and her colleagues hope to get approval from the US Food and Drug Administration to conduct human trials.
“We have licensed the technology to a company that is working towards this. But human trials are a major undertaking with lots of logistics, so that in itself will be a challenge. Otherwise, the main challenge is that we don’t have a great way of detecting early Alzheimer’s in humans. Ideally, patients would be recruited early in the course of the disease and it would be prevented from ever fully developing. “I think there is real potential for this approach,” says Dr Singer, “to either become a therapy or to inform other new approaches based on the same idea of stimulating brain waves. It is such a radically different approach that it is both very promising and hard to predict how well it will translate to humans.”
ALL ABOUT ANNABELLE
✔ Earned a PhD in neuroscience from University of California, San Francisco in 2010
✔ Joined the Coulter Department of Biomedical Engineering at Georgia Tech and Emory School of Medicine to continue to decode memory in health and disease
✔ Previously discovered how the hippocampus broadcasts information about future options to the rest of the brain by replaying previous activity to correctly navigate a maze
✔ Developed new tools to record and manipulate neural activity in animal models of diseases
✔ Research featured in top journals, such as Nature and Neuron and in popular press like BBC and Time.