Research presented at Neuroscience 2019, hosted in Chicago this week, has shown promising pre-clinical data in mice that suggests altering the electrical oscillations of neuronal networks with external light and sound stimulation might have brain-boosting effects that reduce pathology related to Alzheimer’s disease (AD).
In a plenary talk, MIT Picower Institute for Learning and Memory Professor Li-Huei Tsai gave an overview of research which implicates aberrant brain rhythms as having a contributory role in the neurodegeneration that is a hallmark of AD pathology.
AD is the leading cause of dementia, a progressive neurodegenerative disease which leads to memory loss and is ultimately fatal. AD is estimated to affect nearly six million Americans, and efforts to find pharmacological therapies that can combat the disease have so far hit a dead end (with one recent exception).
New research directions are providing hope that we can fight AD, and the Tsai lab’s research is a prime example. In her study, Tsai showed that mouse models of AD exposed to certain environmental stimuli showed improvements in both histological and behavioural symptoms of AD.
The rhythm of the brain
Gamma rhythms are one of several types of electrical network activity in our brain. Speaking to Technology Networks, Professor Tsai explained the origin of gamma brain waves, “In our hands, it is very clear that if we silence GABAergic interneurons, the rhythms are no longer produced.” These rhythms, said Tsai, appear to decline early in the course of Alzheimer’s pathology, and her lab made it a research goal to find ways to boost gamma rhythms, given their importance to the type of functions that are impaired in AD. “Gamma rhythms are particularly associated with higher order functions, such as when animals are actively engaged in some sort of task related to working memory,” explains Tsai.
Tsai’s lab, in two separate publications published in Cell and Neuron, sought to target gamma rhythms both by auditory and visual stimulation. This stimulation was termed gamma entrainment using sensory stimuli, or GENUS.
In one study, mice genetically modified to develop human-like Alzheimer’s pathology were subjected to daily pulses of light at various frequencies. Mice exposed to light pulses at 40 Hz, which was shown in a previous study to induce gamma rhythms, showed reduced neurodegeneration and performed better in memory tasks as opposed to control mice not exposed to light pulses. A second study aimed to see if auditory stimulation with specific tones could produce similar results. Whilst auditory GENUS had similar results to the visual stimulation, when Tsai’s researchers used both in concert, additional benefits to immune cells in the brain were seen.
A safer way to treat Alzheimer’s?
Many promising results in mouse models of neurodegenerative disease have failed to translate to human studies, and Tsai said her team were keen to get started with clinical trials. The advantage of GENUS is that the technique not only simple to administer, but initial trials in healthy volunteers suggest it is free of negative side effects.
Thrillingly, the lab has already announced recruitment for a clinical trial involving GENUS for AD patients. Given the failure of many high-profile pharmacological interventions for AD, does Tsai think that non-invasive methods like GENUS and transcranial magnetic stimulation (TMS) will become more popular? “I think it is absolutely the way to go. Because it's so safe,” said Tsai. “And I think it doesn't cost that much compared to drugs developed in the pharmaceutical industry. I think the non-invasive sensory stimulation is particularly attractive because say with TMS, this patient will probably have to go to the hospital every day to receive stimulation. But with light, all you need is a simple light panel and speaker, everybody can do it at home.”
Despite the promising progress of Tsai’s research, one rather large question remains. We have a good grasp of the molecular changes that GENUS produces. Tsai’s talk showed that these were widespread; improved brain vasculature, reduced brain inflammation and changes to synaptic connections. But why would changes to electrical activity have these effects? Tsai said that this is the focus of the lab’s current research, alongside efforts to stimulate gamma rhythms using other senses.
“We are discovering all the different cell types that respond to gamma rhythms: microglia, neurons, cells in the vasculature,” said Tsai. “Gamma rhythms produce all these fascinating changes in the cells’ behavior. And the changes converge to reduce pathology in this condition, but the fundamental question we still don't understand is “How do these different cells sense gamma rhythms?””
Could people without AD boost their brain with a light and sound show? Tsai said that their current data suggests that young, healthy mice were not affected by the gamma rhythms. But research is advancing at a rapid pace. Given the scale of AD’s effect on society, it needs to. “We just published our first paper in 2016,” said Tsai. “I would say the field has already moved very fast. But human testing always takes time. For the FDA to say whether this thing is really effective or not, they usually want to see you test hundreds, if not thousands of patients, so it takes time.”