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Study reveals ways in which 40Hz sensory stimulation may preserve brain’s “white matter”

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Early-stage trials in Alzheimer’s disease patients and studies in mouse models of the disease have suggested positive impacts on pathology and symptoms from exposure to light and sound presented at the “gamma” band frequency of 40 hertz (Hz). A new study zeroes in on how 40Hz sensory stimulation helps to sustain an essential process in which the signal-sending branches of neurons, called axons, are wrapped in a fatty insulation called myelin. Often called the brain’s “white matter,” myelin protects axons and insures better electrical signal transmission in brain circuits.

“Previous publications from our lab have mainly focused on neuronal protection,” says Li-Huei Tsai , Picower Professor in The Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences at MIT and senior author of the new open-access study in Nature Communications . Tsai also leads MIT’s Aging Brain Initiative. “But this study shows that it’s not just the gray matter, but also the white matter that’s protected by this method.”

This year Cognito Therapeutics, the spinoff company that licensed MIT’s sensory stimulation technology, published phase II human trial results in the Journal of Alzheimer’s Disease indicating that 40Hz light and sound stimulation significantly slowed the loss of myelin in volunteers with Alzheimer’s. Also this year, Tsai’s lab published a study showing that gamma sensory stimulation helped mice withstand neurological effects of chemotherapy medicines, including by preserving myelin. In the new study, members of Tsai’s lab led by former postdoc Daniela Rodrigues Amorim used a common mouse model of myelin loss — a diet with the chemical cuprizone — to explore how sensory stimulation preserves myelination.

Amorim and Tsai’s team found that 40Hz light and sound not only preserved myelination in the brains of cuprizone-exposed mice, it also appeared to protect oligodendrocytes (the cells that myelinate neural axons), sustain the electrical performance of neurons, and preserve a key marker of axon structural integrity. When the team looked into the molecular underpinnings of these benefits, they found clear signs of specific mechanisms including preservation of neural circuit connections called synapses; a reduction in a cause of oligodendrocyte death called “ferroptosis;” reduced inflammation; and an increase in the ability of microglia brain cells to clean up myelin damage so that new myelin could be restored.

“Gamma stimulation promotes a healthy environment,” says Amorim, who is now a Marie Curie Fellow at the University of Galway in Ireland. “There are several ways we are seeing different effects.”

The findings suggest that gamma sensory stimulation may help not only Alzheimer’s disease patients but also people battling other diseases involving myelin loss, such as multiple sclerosis, the authors wrote in the study.

Maintaining myelin

To conduct the study, Tsai and Amorim’s team fed some male mice a diet with cuprizone and gave other male mice a normal diet for six weeks. Halfway into that period, when cuprizone is known to begin causing its most acute effects on myelination, they exposed some mice from each group to gamma sensory stimulation for the remaining three weeks. In this way they had four groups: completely unaffected mice, mice that received no cuprizone but did get gamma stimulation, mice that received cuprizone and constant (but not 40Hz) light and sound as a control, and mice that received cuprizone and also gamma stimulation.

After the six weeks elapsed, the scientists measured signs of myelination throughout the brains of the mice in each group. Mice that weren’t fed cuprizone maintained healthy levels, as expected. Mice that were fed cuprizone and didn’t receive 40Hz gamma sensory stimulation showed drastic levels of myelin loss. Cuprizone-fed mice that received 40Hz stimulation retained significantly more myelin, rivaling the health of mice never fed cuprizone by some, but not all, measures.

The researchers also looked at numbers of oligodendrocytes to see if they survived better with sensory stimulation. Several measures revealed that in mice fed cuprizone, oligodendrocytes in the corpus callosum region of the brain (a key point for the transit of neural signals because it connects the brain’s hemispheres) were markedly reduced. But in mice fed cuprizone and also treated with gamma stimulation, the number of cells were much closer to healthy levels.

Electrophysiological tests among neural axons in the corpus callosum showed that gamma sensory stimulation was associated with improved electrical performance in cuprizone-fed mice who received gamma stimulation compared to cuprizone-fed mice left untreated by 40Hz stimulation. And when researchers looked in the anterior cingulate cortex region of the brain, they saw that MAP2, a protein that signals the structural integrity of axons, was much better preserved in mice that received cuprizone and gamma stimulation compared to cuprizone-fed mice who did not.

A key goal of the study was to identify possible ways in which 40Hz sensory stimulation may protect myelin.

To find out, the researchers conducted a sweeping assessment of protein expression in each mouse group and identified which proteins were differentially expressed based on cuprizone diet and exposure to gamma frequency stimulation. The analysis revealed distinct sets of effects between the cuprizone mice exposed to control stimulation and cuprizone-plus-gamma mice.

A highlight of one set of effects was the increase in MAP2 in gamma-treated cuprizone-fed mice. A highlight of another set was that cuprizone mice who received control stimulation showed a substantial deficit in expression of proteins associated with synapses. The gamma-treated cuprizone-fed mice did not show any significant loss, mirroring results in a 2019 Alzheimer’s 40Hz study that showed synaptic preservation. This result is important, the researchers wrote, because neural circuit activity, which depends on maintaining synapses, is associated with preserving myelin. They confirmed the protein expression results by looking directly at brain tissues.

Another set of protein expression results hinted at another important mechanism: ferroptosis. This phenomenon, in which errant metabolism of iron leads to a lethal buildup of reactive oxygen species in cells, is a known problem for oligodendrocytes in the cuprizone mouse model. Among the signs was an increase in cuprizone-fed, control stimulation mice in expression of the protein HMGB1, which is a marker of ferroptosis-associated damage that triggers an inflammatory response. Gamma stimulation, however, reduced levels of HMGB1.

Looking more deeply at the cellular and molecular response to cuprizone demyelination and the effects of gamma stimulation, the team assessed gene expression using single-cell RNA sequencing technology. They found that astrocytes and microglia became very inflammatory in cuprizone-control mice but gamma stimulation calmed that response. Fewer cells became inflammatory and direct observations of tissue showed that microglia became more proficient at clearing away myelin debris, a key step in effecting repairs.

The team also learned more about how oligodendrocytes in cuprizone-fed mice exposed to 40Hz sensory stimulation managed to survive better. Expression of protective proteins such as HSP70 increased and as did expression of GPX4, a master regulator of processes that constrain ferroptosis.

In addition to Amorim and Tsai, the paper’s other authors are Lorenzo Bozzelli, TaeHyun Kim, Liwang Liu, Oliver Gibson, Cheng-Yi Yang, Mitch Murdock, Fabiola Galiana-Meléndez, Brooke Schatz, Alexis Davison, Md Rezaul Islam, Dong Shin Park, Ravikiran M. Raju, Fatema Abdurrob, Alissa J. Nelson, Jian Min Ren, Vicky Yang and Matthew P. Stokes.

Fundacion Bancaria la Caixa, The JPB Foundation, The Picower Institute for Learning and Memory, the Carol and Gene Ludwig Family Foundation, Lester A. Gimpelson, Eduardo Eurnekian, The Dolby Family, Kathy and Miguel Octavio, the Marc Haas Foundation, Ben Lenail and Laurie Yoler, and the U.S. National Institutes of Health provided funding for the study.

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Older Adults Do Not Benefit From Moderate Drinking, Large Study Finds

Virtually any amount increased the risk for cancer, and there were no heart benefits, the researchers reported.

By Roni Caryn Rabin

Even light drinking was associated with an increase in cancer deaths among older adults in Britain, researchers reported on Monday in a large study. But the risk was accentuated primarily in those who had existing health problems or who lived in low-income areas.

The study, which tracked 135,103 adults aged 60 and older for 12 years, also punctures the long-held belief that light or moderate alcohol consumption is good for the heart.

The researchers found no reduction in heart disease deaths among light or moderate drinkers, regardless of this health or socioeconomic status, when compared with occasional drinkers.

The study defined light drinking as a mean alcohol intake of up to 20 grams a day for men and up to 10 grams daily for women. (In the United States, a standard drink is 14 grams of alcohol .)

“We did not find evidence of a beneficial association between low drinking and mortality,” said Dr. Rosario Ortolá, an assistant professor of preventive medicine and public health at Universidad Autónoma de Madrid and the lead author of the paper, which was published in JAMA Network Open.

On the other hand, she added, alcohol probably raises the risk of cancer “from the first drop.”

The findings add to a mounting body of evidence that is shifting the paradigm in alcohol research. Scientists are turning to new methodologies to analyze the risks and benefits of alcohol consumption in an attempt to correct what some believe were serious flaws in earlier research, which appeared to show that there were benefits to drinking.

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Weight-loss drugs like wegovy may help stave off some cancers.

Yuki Noguchi

Obesity, Cancer, and GLP1s

GLP-1 drugs, like Wegovy and Ozempic, may not be good only for diabetes and weight-loss. They are also showing promise for preventing some cancers. UCG/Universal Images Group/Getty Images hide caption

Drugs like Ozempic, Wegovy and Zepbound have transformed treatment for obesity and diabetes. Now researchers are excited about their potential impact on other conditions, including addiction and sleep apnea — and even cancer.

Scientists see this class of drugs, called GLP-1 agonists, as a breakthrough because of how they act on the brain to regulate the body’s hormones, slow digestion, and tamp down hunger. And in several recent studies, they show early promise in preventing many common cancers — including breast, colon, liver, and ovarian — known to be driven by obesity and excess weight.

“It's a hopeful story, which is, frankly, what people need,” says Arif Kamal, an oncologist specializing in breast cancer as well as chief patient officer at the American Cancer Society.

Though research on GLP-1 drugs is still in its relative infancy, so far studies fairly consistently show their benefit in staving off certain cancers. One research letter published in JAMA Oncology last year, for example, suggests GLP-1 drugs might reduce the risk of colon cancer , even among people who are not overweight. A more recent analysis in JAMA Network Open suggests GLP-1s provide far more protection against cancer for diabetic patients than insulin treatments.

Another recent study presented at the American Society of Clinical Oncologists meeting in June, showed both bariatric surgery and GLP-1 medications dramatically reduce the risk of the 13 obesity-related cancers . Among those who had bariatric surgery, that risk declined by 22% over 10 years compared to those who received no treatment. But among those taking GLP1 medications, risk dropped by a whopping 39%.

“And I think a 39% risk reduction is one of the most impactful risk reductions we've ever really seen,” says Kamal.

GLP-1 agonist drugs were originally developed to treat diabetes nearly two decades ago. Over the past decade, regulators started approving them as treatments for weight loss – first as liraglutide, sold under the brand Saxenda and, more recently, in the form of semaglutide or tirzepatide, under brands like Wegovy and Zepbound.

When it comes to cancer prevention, scientists are finding the link between obesity in cancer is complex and intertwined; the obesity-related cancers are heavily concentrated among organs involved in digestion and metabolism, like the liver and pancreas, for example, as well as among gynecologic cancers, including breast and uterus. Reproductive organs are highly sensitive to the hormone estrogen, which plays a role in allowing cells to grow rapidly during pregnancy, for example.

But Kamal says there’s also an especially close relationship between estrogen and cancer. “What we do know is that estrogen in particular — and possibly some other hormones, but estrogen for sure — drives the growth of many cancers,” he says. And fat cells increase production of estrogen.

That means women today are increasingly susceptible to cancer. Historically, men faced a much higher risk of developing cancers — in large part because they were more likely to engage in high-risk behaviors like smoking or drinking, Kamal says. But in recent years, the high prevalence of obesity among both men and women is closing that gender gap.

Obesity is also likely the most significant driver behind increasing cancer rates among younger adults , he says, just as tobacco was in generations past.

“Unhealthy weight is the smoking of our generation,” Kamal says.

That’s why indications that GLP-1 drugs may help slash that risk is so significant.

What’s more, that ASCO study suggests that GLP-1 drugs have a notable impact on cancer risk, even when patients don’t lose a lot of weight as a result of taking them. In other words, the medications seem to act on a number of the body’s mechanisms to reduce vulnerabilities to cancer.

“We think the protective effects of GLP-1s are probably multifactorial,” says Cindy Lin, resident physician at Case Western Reserve and co-author of the June ASCO study. “Part of it is weight [loss], but other factors may be contributing as well — better glycemic controls, anti-inflammatory effects.”

More research is necessary and inevitable — especially studies looking at the newer weight-loss formulations of GLP-1 medications, says Benjamin Liu, another resident physician at Case Western and co-author of the ASCO study.

He says he’s encouraged by the data so far. “It's very exciting to have, especially since it's more of a noninvasive strategy compared to bariatric surgery, and a lot more patients will be open to it.”

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Massive biomolecular shifts occur in our 40s and 60s, Stanford Medicine researchers find

Time marches on predictably, but biological aging is anything but constant, according to a new Stanford Medicine study.

August 14, 2024 - By Rachel Tompa

We undergo two periods of rapid change, averaging around age 44 and age 60, according to a Stanford Medicine study. Ratana21 /Shutterstock.com

If it’s ever felt like everything in your body is breaking down at once, that might not be your imagination. A new Stanford Medicine study shows that many of our molecules and microorganisms dramatically rise or fall in number during our 40s and 60s.

Researchers assessed many thousands of different molecules in people from age 25 to 75, as well as their microbiomes — the bacteria, viruses and fungi that live inside us and on our skin — and found that the abundance of most molecules and microbes do not shift in a gradual, chronological fashion. Rather, we undergo two periods of rapid change during our life span, averaging around age 44 and age 60. A paper describing these findings was published in the journal Nature Aging Aug. 14.

“We’re not just changing gradually over time; there are some really dramatic changes,” said Michael Snyder , PhD, professor of genetics and the study’s senior author. “It turns out the mid-40s is a time of dramatic change, as is the early 60s. And that’s true no matter what class of molecules you look at.”

Xiaotao Shen, PhD, a former Stanford Medicine postdoctoral scholar, was the first author of the study. Shen is now an assistant professor at Nanyang Technological University Singapore.

These big changes likely impact our health — the number of molecules related to cardiovascular disease showed significant changes at both time points, and those related to immune function changed in people in their early 60s.

Abrupt changes in number

Snyder, the Stanford W. Ascherman, MD, FACS Professor in Genetics, and his colleagues were inspired to look at the rate of molecular and microbial shifts by the observation that the risk of developing many age-linked diseases does not rise incrementally along with years. For example, risks for Alzheimer’s disease and cardiovascular disease rise sharply in older age, compared with a gradual increase in risk for those under 60.

The researchers used data from 108 people they’ve been following to better understand the biology of aging. Past insights from this same group of study volunteers include the discovery of four distinct “ ageotypes ,” showing that people’s kidneys, livers, metabolism and immune system age at different rates in different people.

Michael Snyder

The new study analyzed participants who donated blood and other biological samples every few months over the span of several years; the scientists tracked many different kinds of molecules in these samples, including RNA, proteins and metabolites, as well as shifts in the participants’ microbiomes. The researchers tracked age-related changes in more than 135,000 different molecules and microbes, for a total of nearly 250 billion distinct data points.

They found that thousands of molecules and microbes undergo shifts in their abundance, either increasing or decreasing — around 81% of all the molecules they studied showed non-linear fluctuations in number, meaning that they changed more at certain ages than other times. When they looked for clusters of molecules with the largest changes in amount, they found these transformations occurred the most in two time periods: when people were in their mid-40s, and when they were in their early 60s.

Although much research has focused on how different molecules increase or decrease as we age and how biological age may differ from chronological age, very few have looked at the rate of biological aging. That so many dramatic changes happen in the early 60s is perhaps not surprising, Snyder said, as many age-related disease risks and other age-related phenomena are known to increase at that point in life.

The large cluster of changes in the mid-40s was somewhat surprising to the scientists. At first, they assumed that menopause or perimenopause was driving large changes in the women in their study, skewing the whole group. But when they broke out the study group by sex, they found the shift was happening in men in their mid-40s, too.

“This suggests that while menopause or perimenopause may contribute to the changes observed in women in their mid-40s, there are likely other, more significant factors influencing these changes in both men and women. Identifying and studying these factors should be a priority for future research,” Shen said.

Changes may influence health and disease risk

In people in their 40s, significant changes were seen in the number of molecules related to alcohol, caffeine and lipid metabolism; cardiovascular disease; and skin and muscle. In those in their 60s, changes were related to carbohydrate and caffeine metabolism, immune regulation, kidney function, cardiovascular disease, and skin and muscle.

It’s possible some of these changes could be tied to lifestyle or behavioral factors that cluster at these age groups, rather than being driven by biological factors, Snyder said. For example, dysfunction in alcohol metabolism could result from an uptick in alcohol consumption in people’s mid-40s, often a stressful period of life.

The team plans to explore the drivers of these clusters of change. But whatever their causes, the existence of these clusters points to the need for people to pay attention to their health, especially in their 40s and 60s, the researchers said. That could look like increasing exercise to protect your heart and maintain muscle mass at both ages or decreasing alcohol consumption in your 40s as your ability to metabolize alcohol slows.

“I’m a big believer that we should try to adjust our lifestyles while we’re still healthy,” Snyder said.

The study was funded by the National Institutes of Health (grants U54DK102556, R01 DK110186-03, R01HG008164, NIH S10OD020141, UL1 TR001085 and P30DK116074) and the Stanford Data Science Initiative.

• Rachel Tompa Rachel Tompa is a freelance science writer.

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

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Research shows our bodies go through rapid changes in our 40s and our 60s

For many people, reaching their mid-40s may bring unpleasant signs the body isn’t working as well as it once did. Injuries seem to happen more frequently. Muscles may feel weaker.

A new study, published Wednesday in Nature Aging , shows what may be causing the physical decline. Researchers have found that molecules and microorganisms both inside and outside our bodies are going through dramatic changes, first at about age 44 and then again when we hit 60. Those alterations may be causing significant differences in cardiovascular health and immune function.

The findings come from Stanford scientists who analyzed blood and other biological samples of 108 volunteers ages 25 to 75, who continued to donate samples for several years. 

“While it’s obvious that you’re aging throughout your entire life, there are two big periods where things really shift,” said the study’s senior author, Michael Snyder, a professor of genetics and director of the Center for Genomics and Personalized Medicine at Stanford Medicine. For example, “there’s a big shift in the metabolism of lipids when people are in their 40s and in the metabolism of carbohydrates when people are in their 60s.”

Lipids are fatty substances, including LDL, HDL and triglycerides, that perform a host of functions in the body, but they can be harmful if they build up in the blood.

The scientists tracked many kinds of molecules in the samples, including RNA and proteins, as well as the participants’ microbiomes.

The metabolic changes the researchers discovered indicate not that people in their 40s are burning calories more slowly but rather that the body is breaking food down differently. The scientists aren’t sure exactly what impact those changes have on health.

Previous research showed that resting energy use, or metabolic rate , didn’t change from ages 20 to 60. The new study’s findings don't contradict that.

The changes in metabolism affect how the body reacts to alcohol or caffeine, although the health consequences aren’t yet clear. In the case of caffeine, it may result in higher sensitivity. 

It’s also not known yet whether the shifts could be linked to lifestyle or behavioral factors. For example, the changes in alcohol metabolism might be because people are drinking more in their mid-40s, Snyder said.

For now, Snyder suggests people in their 40s keep a close eye on their lipids, especially LDL cholesterol.

“If they start going up, people might want to think about taking statins if that’s what their doctor recommends,” he said. Moreover, “knowing there’s a shift in the molecules that affect muscles and skin, you might want to warm up more before exercising so you don’t hurt yourself.”

Until we know better what those changes mean, the best way to deal with them would be to eat healthy foods and to exercise regularly, Snyder said.

Dr. Josef Coresh, founding director of the Optimal Aging Institute at the NYU Grossman School of Medicine, compared the new findings to the invention of the microscope.

“The beauty of this type of paper is the level of detail we can see in molecular changes,” said Coresh, a professor of medicine at the school. “But it will take time to sort out what individual changes mean and how we can tailor medications to those changes. We do know that the origins of many diseases happen in midlife when people are in their 40s, though the disease may occur decades later.”

The new study “is an important step forward,” said Dr. Lori Zeltser, a professor of pathology and cell biology at the Columbia University Vagelos College of Physicians and Surgeons. While we don’t know what the consequences of those metabolic changes are yet, “right now, we have to acknowledge that we metabolize food differently in our 40s, and that is something really new.”

The shifts the researchers found might help explain numerous age-related health changes, such as muscle loss, because “your body is breaking down food differently,” Zeltser said.

Linda Carroll is a regular health contributor to NBC News. She is coauthor of "The Concussion Crisis: Anatomy of a Silent Epidemic" and "Out of the Clouds: The Unlikely Horseman and the Unwanted Colt Who Conquered the Sport of Kings." 

Blind cavefish have extraordinary taste buds

Cavefish increase the number and location of taste buds — to the head and chin, say uc biologists.

Over thousands of years, cavefish evolved and lost their vision, earning the moniker “the blind cavefish,” but some cavefish also developed an inordinate number of taste buds on the head and chin. 

In a new study, now published in the Nature journal Communications Biology , scientists at the University of Cincinnati have determined when the taste buds start to appear in areas beyond the oral cavity. The study was supported by the National Science Foundation. 

To begin, blind cavefish evolved in cave ponds in northeastern Mexico. They are pale pink and nearly translucent compared to their silvery counterparts that live in surface rivers and streams. While cavefish have the faintest outline of eye sockets, the surface fish have enormous round eyes that give them a perpetually surprised expression.

Despite the many obvious physical differences, the two fish are considered the same species.  

Professor Joshua Gross peers through a microscope in his biology lab. Photo/Andrew Higley/UC Creative + Brand

“Regression, such as the loss of eyesight and pigmentation, is a well-studied phenomenon, but the biological bases of constructive features are less well understood,” says the article’s senior author  UC professor and biologist Joshua Gross , whose laboratory is dedicated to the study of evolution and development of cave-dwelling vertebrates.

“Knowing just how many doors this opened for future research involving taste bud and taste development was a truly rewarding aspect of this research; especially considering how long these fish live,” says co-author Daniel Berning who earned his master’s degree in biology at UC in 2022, while working on the study in Dr. Gross’ lab.

Cavefish have a keener sense of taste.

Joshua Gross Professor of biology

Although scientists in the 1960s discovered that certain populations of blind cavefish had extra taste buds — on the head and chin — there was no further study of the developmental or genetic processes that explain this unusual trait, says Gross.

To determine when the extra taste buds appear, Gross and his research team looked at the species Astyanax mexicanus, including two separate cavefish populations that dwell in the Pachón and Tinaja caves in northwestern Mexico, known to have the additional taste buds. 

The research team found that the number of taste buds is similar to the surface fish from birth through 5 months of age. The taste buds then start to increase in number and appear on the head and chin in smatterings, well into adulthood, at approximately 18 months.

Blind cavefish. Photo by Andrew Higley/UC Marketing + Brand.

Cavefish can live much longer than 18 months in nature and captivity, and the authors suspect even more taste buds continually accumulate as the fish get older.

The increase correlates with the time that the cavefish stop eating other live foods for sustenance and start to pursue other food sources, Gross says, such as bat guano. Equally fascinating, he says, is that the expansion may occur in other cave locations where there are no bat populations.   

With more taste buds, he says, the cavefish have a keener sense of taste, “which is likely an adaptive trait.”   

“It remains unclear what is the precise functional and adaptive relevance of this augmented taste system,” says Gross, which has led the team to begin new studies that focus on taste, by exposing the fish to different flavors such as sour, sweet and bitter. 

Read more about Dr. Gross' cavefish studies on the UC website:

  "How blind cavefish survive a low-oxygen environment." 

"How do blind cavefish find their way?"   

Featured image at top of cavefish by Andrew Higley/UC Marketing + Brand. 

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