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
Electrostimulation can improve working memory in people
As memories fade, can we supercharge them back to life?
April 12, 2019
Science Daily/Boston University
In a groundbreaking study published in Nature Neuroscience, Rob Reinhart, an assistant professor of psychological and brain sciences at Boston University and BU doctoral researcher John Nguyen, demonstrate that electrostimulation can improve the working memory of people in their 70s so that their performance on memory tasks is indistinguishable from that of 20-year-olds.
Reinhart and Nguyen's research targets working memory -- the part of the mind where consciousness lives, the part that is active whenever we make decisions, reason, and recall our grocery lists. Working memory starts to decline in our late 20s and early 30s, Reinhart explains, as certain areas of the brain gradually become disconnected and uncoordinated. By the time we reach our 60s and 70s, these neural circuits have deteriorated enough that many of us experience noticeable cognitive difficulties, even in the absence of dementias like Alzheimer's disease.
But the duo has discovered something incredible: by using electrical currents to noninvasively stimulate brain areas that have lost their rhythm, we can drastically improve working memory performance.
During the study, which was supported by a National Institutes of Health grant, they asked a group of people in their 20s and a group in their 60s and 70s to perform a series of memory tasks that required them to view an image, and then, after a brief pause, to identify whether a second image was slightly different from the original.
At baseline, the young adults were much more accurate at this, significantly outperforming the older group. However, when the older adults received 25 minutes of mild stimulation delivered through scalp electrodes and personalized to their individual brain circuits, the difference between the two groups vanished. Even more encouraging? That memory boost lasted at least to the end of the 50-minute time window after stimulation -- the point at which the experiment ended.
To understand why this technique is so effective, we need to take a look at the two mechanisms that allow working memory to function properly: coupling and synchronization.
Coupling occurs when different types of brain rhythms coordinate with one another, and it helps us process and store working memories. Slow, low-frequency rhythms -- theta rhythms -- dance in the front of your brain, acting like the conductors of an orchestra. They reach back to faster, high-frequency rhythms called gamma rhythms, which are generated in the region of the brain that processes the world around us.
Just as a musical orchestra contains flutes, oboes, violins -- so too, the gamma rhythms that reside within your brain each contribute something unique to the electricity-based orchestra that creates your memories. One gamma rhythm might process the color of an object you're holding in your mind, for instance, while another captures its shape, another its orientation, and another its sound.
But when the conductors fumble with their batons -- when the theta rhythms lose the ability to connect with those gamma rhythms to monitor them, maintain them, and instruct them -- the melodies within the brain begin to disintegrate and our memories lose their sharpness.
Meanwhile, synchronization -- when theta rhythms from different areas of the brain synchronize with one another -- allows separate brain areas to communicate with one another. This process serves as the glue for a memory, combining individual sensory details to create one coherent recollection. As we age, our theta rhythms become less synchronized and the fabric of our memories starts to fray.
Reinhart and Nguyen's work suggests that by using electrical stimulation, we can reestablish these pathways that tend to go awry as we age, improving our ability to recall our experiences by restoring the flow of information within the brain. And it's not just older adults that stand to benefit from this technique: it shows promise for younger people as well.
In the study, 14 of the young-adult participants performed poorly on the memory tasks despite their age -- so he called them back to stimulate their brains too.
"We showed that the poor performers who were much younger, in their 20s, could also benefit from the same exact kind of stimulation," Reinhart says. "We could boost their working memory even though they weren't in their 60s or 70s."
Coupling and synchronization, he adds, exist on a continuum: "It's not like there are people who don't couple versus people who couple."
On one end of the spectrum, someone with an incredible memory may be excellent at both synchronizing and coupling, whereas somebody with Alzheimer's disease would probably struggle significantly with both. Others lie between these two extremes -- for instance, you might be a weak coupler but a strong synchronizer, or vice versa.
And when we use this stimulation to alter neural symphonies, we aren't just making a minor tweak, Reinhart emphasizes. "It's behaviorally relevant. Now, [people are] performing tasks differently, they're remembering things better, they're perceiving better, they're learning faster. It is really extraordinary."
Looking ahead, he foresees a variety of future applications for his work.
"It's opening up a whole new avenue of potential research and treatment options," he says, "and we're super excited about it."
Reinhart would like to investigate electrostimulation's effects on individual brain cells by applying it to animal models, and he's curious about how repeated doses of stimulation might further enhance brain circuits in humans. Most of all, though, he hopes his discovery will one day lead to a treatment for the millions of people around the world living with cognitive impairments -- particularly those with Alzheimer's disease.
https://www.sciencedaily.com/releases/2019/04/190412130954.htm