Scientists eager to explain brain rhythm boost's broad impact in Alzheimer's models
December 11, 2019
Science Daily/Picower Institute at MIT
Neuroscientists lay out the the few knowns and many unknowns that must be understood to determine why sensory stimuluation of 40Hz brain rhythms have broad effects, particularly in Alzheimer's models.
The sweeping extent to which increasing 40Hz "gamma" rhythm power in the brain can affect the pathology and symptoms of Alzheimer's disease in mouse models has been surprising, even to the MIT neuroscientists who've pioneered the idea. So surprising, in fact, they can't yet explain why it happens.
In three papers, including two this year in Cell and Neuron, they've demonstrated that exposing mice to light flickering or sound buzzing at 40Hz, a method dubbed "GENUS" for Gamma Entrainment Using Sensory stimuli, strengthens the rhythm across the brain and changes the gene expression and activity of multiple brain cell types. Pathological amyloid and tau protein buildups decline, neurons and their circuit connections are protected from degeneration and learning and memory endure significantly better than in disease model mice who do not receive GENUS.
In a new review article in Trends in Neurosciences two researchers leading those efforts lay out the few knowns and many unknowns that must be understood to determine how the widespread effects take place. It's a challenge they relish because the answers could both break new scientific ground and help them improve how GENUS could become a therapeutic or preventative approach for people.
"While we know it affects pathology in mice, we want to understand how because that will help us understand and refine potential treatment," said lead author Chinnakkaruppan Adaikkan, a postdoc in the lab of senior author Li-Huei Tsai, Picower Professor of Neuroscience and director of The Picower Institute for Learning and Memory.
Adaikkan has been interested in understanding how neural activity produces brain rhythms since his doctoral research. At MIT, he is channeling that passion into understanding how sensory stimulation can entrain oscillations.
"That's what drives me to come to the lab every day to study these mechanisms," Adaikkan said. "When we got the data from the first mouse where we recorded from the visual cortex, the hippocampus and the prefrontal cortex we were surprised to see that visual stimulation entrains in these brain regions. That was very exciting but we have a very long way to go to understand how this happens."
The new paper raises that question and many others for the field. What cells underlie the brain's response to GENUS? How do gamma rhythms engage non-neuronal cells such as astrocytes and microglia? How does it propagate beyond the brain regions responsible for perception? How extensively can enhancing gamma affect cognition? Does long-term stimulation affect brain circuit connections and how they change?
Cell roles
Studies of how groups of neurons engage in coherent oscillations of electrical activity have yielded two models to explain gamma rhythms. Both involve an interplay between excitatory and inhibitory neurons but differ on which type leads the interaction, Adaikkan and Tsai wrote. In his work, Adaikkan is attempting to dissect the roles of specific neuron types in GENUS and how closely those patterns mirror other sources of gamma, such as that invoked by cognitive tasks.
GENUS affects more than neurons. Tsai's lab has found that microglia change their gene expression, their physical form, their protein-consuming behavior and their inflammatory response depending on the Alzheimer's model involved. Work from another group showed that blocking vesicle release in astrocytes can hinder gamma power in mice and Tsai's group found that auditory GENUS recruits an increase reactive astrocytes, which are more inclined to consume pathological proteins.
The new paper offers three hypotheses about how such "glial" cells are involved: They might contribute directly to gamma entrainment by regulating the flow of ions that carry electrical charge; even if they don't contribute to rhythms, their ionic sensitivity may still make them responsive to gamma changes; they might instead be affected by changes in levels of neurotransmitters as a result of gamma.
Moreover, different glia may also become involved because of their proximity to electrical couplings between neurons called synapses, or because of how their activity is otherwise governed by neural activity.
The broader brain
That GENUS extends to the hippocampus, which is key for memory, and the prefrontal cortex, which is key for cognition, is likely a factor in how it preserves brain function. But again there are competing models for how increased gamma could facilitate multi-regional communication. In one, the authors write, coherence at the same frequency optimizes communication, while in the other model, one region's gamma activity directly drives activity in regions downstream. New experiments that directly manipulate inter-regional circuits, they argue, could help resolve which model better explains gamma entrainment's effects.
Finally, the effects of GENUS on brain function and behavior also aren't fully explained. The Tsai lab's has shown significant effects on spatial memory and some effects on other forms of memory, depending on the stimulation method. Other studies have shown that stimulating brain rhythms by other means, such as via genetic or optogenetic manipulations in mice, or via transcranial stimulation in humans, can also improve functions such as working memory. Adaikkan is interested in closing a gap between those studies and the Tsai lab's work: Most studies measure cognitive performance during stimulation, while the Tsai lab has done so after the conclusion of repeated stimulation. He said he'd like to also test how mice perform while GENUS is actively underway.
"Our lab is excited to tackle these many hypotheses and to see how the field tackles many more," Tsai said. "GENUS has created many intriguing new questions for neuroscience."
https://www.sciencedaily.com/releases/2019/12/191211115624.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
Brain wave device enhances memory function
October 22, 2018
Science Daily/University of California - Davis
The entrainment of theta brain waves with a commercially available device not only enhances theta wave activity, but also boosts memory performance, according to new research.
Electrical activity in the brain causes different types of brain waves that can be measured on the outside of the head. Theta waves occur at about five to six cycles per second, often associated with a brain that is actively monitoring something -- such as the brain of a rat navigating a maze.
In an earlier study, Charan Ranganath, professor of psychology, and colleagues at the Center for Neuroscience found that high levels of theta wave activity immediately before a memory task predicted better performance.
"Entrainment" devices use a combination of sound and lights to stimulate brain wave activity. The idea is that oscillating patterns in sensory inputs will be reflected in brain activity. The devices are marketed to address a range of problems such as anxiety, sleep issues, "low mood" and learning. However, there is very little published scientific evidence to support these claims.
Brooke Roberts, a postdoctoral researcher in Ranganath's lab, obtained a theta wave entrainment device and decided to test it. She had 50 volunteers either use the device for 36 minutes, or listen to 36 minutes of white noise, then do a simple memory test.
Improved memory performance
The subjects who had used the device showed both improved memory performance and enhanced theta wave activity, she found.
Roberts showed her results to Ranganath, who was intrigued but cautious and suggested new controls. They repeated the experiment with another 40 volunteers, but this time the control group received beta wave stimulations. Beta waves are a different type of brain wave pattern, occurring at about 12 to 30 cycles per second, associated with normal waking consciousness.
Once again, theta wave entrainment enhanced theta wave activity and memory performance.
Ranganath's lab also conducted a separate study using electrical stimulation to enhance theta waves. However, this actually had the opposite effect, disrupting theta wave activity, and temporarily weakened memory function.
Ranganath said he's surprised the devices work as well as they appear to do.
"What's surprising is that the device had a lasting effect on theta activity and memory performance for over half an hour after it was switched off," he said.
There is debate among neuroscientists over the function and role of these brain waves. Some researchers argue that they are simply a product of normal brain function with no particular role. Ranganath, however, thinks that they may play a role in coordinating brain regions.
"The neurons are more excitable at the peak of the wave, so when the waves of two brain regions are in sync with each other, they can talk to each other," he said.
Other authors on the paper are Alex Clarke, now at the University of Cambridge and Anglia Ruskin University, U.K.; and Richard Addante, now at California State University San Bernardino. Roberts is now a research scientist at QUASAR Inc., San Diego. The work was supported by a Guggenheim Fellowship and a Vannevar Bush Fellowship from the Office of Naval Research.
https://www.sciencedaily.com/releases/2018/10/181022172959.htm