In Alzheimer's research, scientists reveal brain rhythm role

October 23, 2019

Science Daily/Picower Institute at MIT

In the years since her lab discovered that exposing Alzheimer's disease model mice to light flickering at the frequency of a key brain rhythm could stem the disorder's pathology, MIT neuroscientist Li-Huei Tsai and her team at The Picower Institute for Learning and Memory have been working to understand what the phenomenon may mean both for fighting the disease and understanding of how the brain works.

Two papers earlier this year in Cell and in Neuron replicated and substantially extended the initial findings reported in Nature in 2016 and clinical trials with human volunteers recently began. In a special lecture at the Society for Neuroscience Annual Meeting in Chicago Oct. 22, Tsai will share the latest research updates on what she's found -- and the new questions she is asking -- about using light and sound to strengthen the brain' s 40Hz "gamma" rhythm, a technique she calls "GENUS," for Gamma Entrainment Using Sensory stimuli.

"We are eager to learn as much as we can about GENUS for two main reasons," said Tsai, Picower Professor of Neuroscience in the Department of Brain and Cognitive Sciences and a founder of MIT's Aging Brain Initiative. "We hope our findings in mice will translate to helping people with Alzheimer's disease, though it's certainly too soon to tell and many things that have worked in mice have not worked in people. But there also may be exciting implications for fundamental neuroscience in understanding why stimulating a specific rhythm via light or sound can cause profound changes in multiple types of cells in the brain."

Gamma and Alzheimer's disease

In 2016, Tsai and colleagues showed that Alzheimer's disease model mice exposed to a light flickering at 40 Hz for an hour a day for a week had significantly less buildup of amyloid and tau proteins in the visual cortex, the brain region that processes sight, than experimental control mice did. Amyloid plaques and tangles of phosphorylated tau are both considered telltale hallmarks of Alzheimer's disease.

But the study raised new questions: Could GENUS prevent memory loss? Could it prevent the loss of neurons? Does it reach other areas of the brain? And could other senses be stimulated for beneficial effect?

The new studies addressed those questions. In March, the team reported that sound stimulation reduced amyloid and tau not only in the auditory cortex, but also in the hippocampus, a crucial region for learning and memory. GENUS-exposed mice also performed significantly better on memory tests than unstimulated controls. Simultaneous light and sound, meanwhile, reduced amyloid across the cortex, including the prefrontal cortex, a locus of cognition.

In May, another study reported similar advances from exposing Alzheimer's model mice to light for 3 or 6 weeks. Coordinated increases in gamma rhythm power were evident across the brains of GENUS-exposed mice. Memory improved compared to controls. More neurons survived and they maintained more circuit connections, called synapses. In her talk, Tsai will share data showing that longer-term GENUS light exposure also reduced amyloid and tau across the cortex.

Encouraged by the results, the lab has begun human trials. At SfN Tsai will present some initial data, indicating that GENUS safely increases gamma rhythm power and synchrony across the brain in healthy people.

Gamma "signatures" in the brain

Tsai's team has also been working to understand the mechanisms underlying the changes they see. The research has revealed that brain rhythms appear to exert a great deal of influence over the activity of multiple cell types in the brain.

Neuroscientists have known about rhythms for more than a century, but they have only recently begun to acknowledge that they might affect how the brain works. Gamma is associated with brain functions like sensory processing, working memory and spatial navigation, but scientists have long debated whether they are consequential or mere byproducts.

But Tsai will describe how her studies show that increasing gamma power and synchrony with sensory stimulation causes changes in neurons, brain immune cells called microglia, and the brain's vasculature. These changes may be "signatures" of gamma's significance, she says.

Increasing gamma power causes neurons to reduce processing of amyloid precursor protein and changes endosomal physiology as well, the team has found. In Alzheimer's model mice, neuronal gene expression related to synaptic function and biochemical transport within cells is reduced, but with GENUS exposure, gene expression related to those functions improves.

Microglia similarly experience major changes after GENUS exposure, all three studies have found. Gene expression becomes less inflammatory and more consistent with capturing and disposing of amyloid. Indeed, they hunt amyloid more effectively, the data show, and they secrete less of an inflammatory marker.

The March study with audio stimulation showed that amid GENUS exposure, blood vessels in the brain expand and more amyloid co-locates with a protein that draws amyloid to the vessels. The results suggest increased gamma power may help drive a mechanism for clearing amyloid out of the brain.

In several new experiments, Tsai says, the lab is continuing to study these underlying mechanistic changes. Related conference posters from her lab at the conference describe some of that work. The results of these new experiments may both help improve the possibility of translating GENUS for clinical use and further demonstrate the importance of rhythms in affecting brain function.

https://www.sciencedaily.com/releases/2019/10/191023093435.htm

Brain wave stimulation may improve Alzheimer's symptoms

Noninvasive treatment improves memory and reduces amyloid plaques in mice

March 14, 2019

Science Daily/Massachusetts Institute of Technology

By exposing mice to a unique combination of light and sound, neuroscientists have shown they can improve cognitive and memory impairments similar to those seen in Alzheimer's patients.

This noninvasive treatment, which works by inducing brain waves known as gamma oscillations, also greatly reduced the number of amyloid plaques found in the brains of these mice. Plaques were cleared in large swaths of the brain, including areas critical for cognitive functions such as learning and memory.

"When we combine visual and auditory stimulation for a week, we see the engagement of the prefrontal cortex and a very dramatic reduction of amyloid," says Li-Huei Tsai, director of MIT's Picower Institute for Learning and Memory and the senior author of the study.

Further study will be needed, she says, to determine if this type of treatment will work in human patients. The researchers have already performed some preliminary safety tests of this type of stimulation in healthy human subjects.

MIT graduate student Anthony Martorell and Georgia Tech graduate student Abigail Paulson are the lead authors of the study, which appears in the March 14 issue of Cell.

Memory improvement

The brain's neurons generate electrical signals that synchronize to form brain waves in several different frequency ranges. Previous studies have suggested that Alzheimer's patients have impairments of their gamma-frequency oscillations, which range from 25 to 80 hertz (cycles per second) and are believed to contribute to brain functions such as attention, perception, and memory.

In 2016, Tsai and her colleagues first reported the beneficial effects of restoring gamma oscillations in the brains of mice that are genetically predisposed to develop Alzheimer's symptoms. In that study, the researchers used light flickering at 40 hertz, delivered for one hour a day. They found that this treatment reduced levels of beta amyloid plaques and another Alzheimer's-related pathogenic marker, phosphorylated tau protein. The treatment also stimulated the activity of debris-clearing immune cells known as microglia.

In that study, the improvements generated by flickering light were limited to the visual cortex. In their new study, the researchers set out to explore whether they could reach other brain regions, such as those needed for learning and memory, using sound stimuli. They found that exposure to one hour of 40-hertz tones per day, for seven days, dramatically reduced the amount of beta amyloid in the auditory cortex (which processes sound) as well as the hippocampus, a key memory site that is located near the auditory cortex.

"What we have demonstrated here is that we can use a totally different sensory modality to induce gamma oscillations in the brain. And secondly, this auditory-stimulation-induced gamma can reduce amyloid and Tau pathology in not just the sensory cortex but also in the hippocampus," says Tsai, who is a founding member of MIT's Aging Brain Initiative.

The researchers also tested the effect of auditory stimulation on the mice's cognitive abilities. They found that after one week of treatment, the mice performed much better when navigating a maze requiring them to remember key landmarks. They were also better able to recognize objects they had previously encountered.

They also found that auditory treatment induced changes in not only microglia, but also the blood vessels, possibly facilitating the clearance of amyloid.

Dramatic effect

The researchers then decided to try combining the visual and auditory stimulation, and to their surprise, they found that this dual treatment had an even greater effect than either one alone. Amyloid plaques were reduced throughout a much greater portion of the brain, including the prefrontal cortex, where higher cognitive functions take place. The microglia response was also much stronger.

"These microglia just pile on top of one another around the plaques," Tsai says. "It's very dramatic."

The researchers found that if they treated the mice for one week, then waited another week to perform the tests, many of the positive effects had faded, suggesting that the treatment would need to be given continually to maintain the benefits.

In an ongoing study, the researchers are now analyzing how gamma oscillations affect specific brain cell types, in hopes of discovering the molecular mechanisms behind the phenomena they have observed. Tsai says she also hopes to explore why the specific frequency they use, 40 hertz, has such a profound impact.

The combined visual and auditory treatment has already been tested in healthy volunteers, to assess its safety, and the researchers are now beginning to enroll patients with early-stage Alzheimer's to study its possible effects on the disease.

The research was funded, in part, by the Robert and Renee Belfer Family Foundation, the Halis Family Foundation, the JPB Foundation, the National Institutes of Health and the MIT Aging Brain Initiative. 

https://www.sciencedaily.com/releases/2019/03/190314111004.htm