brain

Apigenin and the Shield Around the Brain

The Brain's Fragile Reliance on Constant Flow

The human brain, while making up only a small fraction of body weight, consumes a disproportionate share of the body's oxygen and glucose. It has almost no energy reserves of its own. When blood flow is interrupted, even briefly, a cascade of destruction begins within minutes. Ischemic stroke, caused by a blocked vessel, and hemorrhagic stroke, caused by a ruptured one, both unleash waves of damage that can permanently disable or kill. Beyond stroke, traumatic blows to the head trigger a similar storm of secondary injury that continues to harm brain tissue long after the initial impact. Finding ways to make the brain more resilient to these insults, to salvage the tissue that hovers between survival and death in the hours and days following injury, is a central goal of neuroscience. Among the natural compounds being investigated for this purpose, the plant flavonoid apigenin has shown a remarkable capacity to protect neural tissue through a combination of anti-excitotoxic, antioxidant, anti-inflammatory, and vascular-stabilizing actions.

Crossing the Barrier to Reach Vulnerable Cells

Any compound intended to protect the brain must first cross the blood-brain barrier, a tightly regulated border of cells that keeps most circulating molecules out of neural tissue. Apigenin possesses a chemical structure that allows it to pass through this barrier with relative ease compared to many other flavonoids. Once inside the brain, it distributes into regions that are especially vulnerable to stroke, such as the cerebral cortex and the hippocampus. This ability to reach the site of injury is the first reason apigenin has drawn attention from stroke researchers. In animal models of cerebral ischemia, apigenin administered after the onset of a stroke has been detected in brain tissue at meaningful concentrations, setting the stage for its protective effects.

Calming the Storm of Overexcitation

In the immediate aftermath of a stroke, neurons deprived of oxygen and glucose lose their ability to maintain proper electrical balance. They release vast quantities of glutamate, a neurotransmitter that, in excess, overstimulates neighboring neurons to the point of death. This process, called excitotoxicity, is one of the earliest and most destructive events in brain injury. Apigenin has been shown to dampen excitotoxicity by modulating receptors for glutamate and by enhancing the activity of GABA, the brain's primary calming neurotransmitter. It also helps neurons restore their calcium balance, preventing the catastrophic overload that triggers enzymes to chew apart cellular proteins and DNA. By quieting this electrical storm, apigenin preserves neurons that would otherwise be doomed in the first hours after injury.

Quenching the Oxidative Fire and Inflammatory Cascade

Once blood flow is restored to a deprived area, either naturally or through medical intervention, a second wave of injury occurs. Reperfusion floods the tissue with oxygen, which generates a burst of free radicals that overwhelm antioxidant defenses. Apigenin steps into this breach by activating the Nrf2 pathway, a master switch that turns on the cell's own arsenal of protective enzymes, including superoxide dismutase, catalase, and glutathione peroxidase. At the same time, it suppresses NF-kB, the central regulator of inflammation, reducing the production of cytokines, chemokines, and adhesion molecules that summon immune cells into the injured area. This dual action means that apigenin attacks both the oxidative and inflammatory arms of reperfusion injury simultaneously. In rodent stroke models, this translates to a smaller area of dead tissue, a larger halo of salvageable brain around the core, and better performance on tests of motor function and memory.

Preserving the Brain's Wiring and White Matter

A stroke does not only destroy the gray matter where neuronal cell bodies reside. It also damages the white matter, the bundles of insulated fibers that connect different brain regions. Damage to these tracts disrupts communication within the brain and is a major contributor to long-term disability. Apigenin has been found to protect oligodendrocytes, the cells that produce myelin, and to reduce the breakdown of myelin sheaths after ischemia. In models of chronic cerebral hypoperfusion, where a gradual reduction in blood flow mimics the vascular dementia seen in aging, apigenin preserved white matter integrity and reduced cognitive decline. This ability to defend the brain's connective wiring adds a dimension to its protection that extends beyond the rescue of individual neurons.

Defending the Blood-Brain Barrier from Collapse

The blood-brain barrier is not just a gate; it is a dynamic structure that can break down catastrophically after a stroke or head trauma. When it does, fluid and proteins leak into the brain, causing edema and exposing neurons to molecules they were never meant to encounter. Apigenin has been shown to reinforce the tight junctions between the endothelial cells that form the barrier. It reduces the activity of matrix metalloproteinases, enzymes that digest the structural supports of the barrier, and it suppresses the inflammatory signals that cause endothelial cells to retract from one another. In animal models of both ischemic stroke and cerebral hemorrhage, apigenin treatment reduced brain swelling, limited the leakage of blood components into tissue, and helped the barrier reseal itself more quickly.

Extending the Window of Opportunity

The only widely approved drug for acute ischemic stroke, tissue plasminogen activator, must be given within a narrow window of a few hours, and many patients arrive too late to benefit. Researchers have explored whether apigenin might extend this therapeutic window by making brain tissue more resistant to injury. Some studies have shown that combining apigenin with delayed thrombolysis reduces the risk of hemorrhagic transformation, the dreaded complication in which restored blood flow causes a brain bleed. By protecting the microvasculature and calming inflammation, apigenin seems to create a more forgiving environment for reperfusion, raising the possibility that it could one day help more patients safely access clot-busting treatment.

Softening the Impact of Traumatic Brain Injury

In head trauma, the initial mechanical damage is followed by a prolonged period of secondary injury that shares many features with stroke, including excitotoxicity, oxidative stress, and neuroinflammation. Studies in animals subjected to controlled cortical impact have demonstrated that apigenin given after injury can reduce the volume of brain contusion, lessen swelling, and improve performance on cognitive tasks such as navigating a water maze. The compound appears to preserve synaptic proteins that are critical for learning and memory, and it reduces the activation of microglia, the brain's resident immune cells, which can shift from helpful to harmful when chronically stimulated. While these findings are preclinical, they hint at a role for apigenin in recovery from concussions and more severe brain trauma.

A Quiet Dietary Contributor to Neural Resilience

No one should view apigenin as a replacement for blood pressure control, smoking cessation, or the use of helmets and seatbelts. It is not an emergency treatment, and the doses used in animal studies are difficult to achieve through diet alone. Yet the same parsley on a plate, the same chamomile tea in the evening, the same celery crunching in a salad, deliver a steady, low-level exposure to this compound over a lifetime. The brain, with its constant demand for oxygen and its lifelong vulnerability, may benefit from this quiet, cumulative support. As researchers continue to study apigenin in the context of stroke, trauma, and vascular dementia, the compound serves as a compelling reminder that the dietary choices made every day can slowly shape the brain's capacity to withstand the storms that may one day come.

(Source : DeepSeek)

Laboratory and animal studies show neuroprotective actions for ashwagandha (Withania somnifera), and a handful of small human trials report modest cognitive benefits, but the clinical evidence is still preliminary and larger, longer studies are needed.

Researchers have studied ashwagandha for brain protection in two broad ways: first, by testing purified compounds from the plant (notably the withanolides such as withaferin A and related molecules) and second, by testing whole-root extracts in cells, animals and small human trials. In cell and animal experiments these compounds reduce oxidative stress and inflammation in brain tissue, help neurons resist toxic insults, and encourage processes that support neuron health such as neurite outgrowth and synaptic function. For example, several laboratory studies show that ashwagandha extracts can blunt the damage caused by beta-amyloid (a protein linked to Alzheimer’s disease), reduce markers of inflammation and cell death, and improve memory-related behavior in rodent models. These mechanistic and animal findings are summarized in recent reviews of the literature. (American Chemical Society)

How does it do that? The proposed mechanisms are familiar ones for a botanical with neuroprotective activity: antioxidant effects that lower harmful free radicals; anti-inflammatory actions that reduce damaging immune signaling in the brain; modulation of stress pathways (for example reducing excessive glucocorticoid/HPA-axis activation) that otherwise hurt neurons over time; and direct effects on protein handling and neuronal structure that can reduce toxic protein aggregation and support synapse formation. Specific chemicals from the plant — withanolides and sitoindosides — have been shown in lab work to engage these pathways, although which compound (or combination) matters for which effect is still being mapped out. (American Chemical Society)

What about human evidence? A handful of randomized, placebo-controlled trials have tested standardized root extracts in people. Some studies in stressed adults and in people with mild cognitive impairment report improved memory, attention and processing speed after several weeks to a few months of supplementation, and these trials generally reported good tolerability. However, the trials are small, used different extract preparations and doses, and often measured subjective or short-term endpoints — so while the results are encouraging, they do not yet prove that ashwagandha prevents or reverses major neurodegenerative diseases in people. Larger, longer and better-standardized clinical trials are underway or have been registered. (PubMed)

In plain terms: think of ashwagandha as a botanical that contains molecules able to protect nerve cells in laboratory settings and to nudge human cognition modestly in some small trials. That biological plausibility (antioxidant, anti-inflammatory, anti-amyloid and neurotrophic effects) makes it a promising candidate for further study, but the current human evidence is not yet strong enough to treat it as a proven therapy for Alzheimer’s, Parkinson’s or other major brain diseases. If you’re considering it for memory or brain health, it’s sensible to discuss it with a clinician — especially because product quality, dose and interactions vary. (PMC)

(Source : ChatGPT) (Image : Grok)

Patients undergoing chemotherapy often experience cognitive effects such as memory impairment and difficulty concentrating — a condition commonly known as “chemo brain.”

MIT researchers have now shown that a noninvasive treatment that stimulates gamma frequency brain waves may hold promise for treating chemo brain. In a study of mice, they found that daily exposure to light and sound with a frequency of 40 hertz protected brain cells from chemotherapy-induced damage. The treatment also helped to prevent memory loss and impairment of other cognitive functions.
This treatment, which was originally developed as a way to treat Alzheimer’s disease, appears to have widespread effects that could help with a variety of neurological disorders, the researchers say.
“The treatment can reduce DNA damage, reduce inflammation, and increase the number of oligodendrocytes, which are the cells that produce myelin surrounding the axons,” says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and the Picower Professor in the MIT Department of Brain and Cognitive Sciences. “We also found that this treatment improved learning and memory, and enhanced executive function in the animals.” Tsai is the senior author of the new study, which appears today in Science Translational Medicine. The paper’s lead author is TaeHyun Kim, an MIT postdoc.

Protective brain waves

Several years ago, Tsai and her colleagues began exploring the use of light flickering at 40 hertz (cycles per second) as a way to improve the cognitive symptoms of Alzheimer’s disease. Previous work had suggested that Alzheimer’s patients have impaired gamma oscillations — brain waves that range from 25 to 80 hertz (cycles per second) and are believed to contribute to brain functions such as attention, perception, and memory. Tsai’s studies in mice have found that exposure to light flickering at 40 hertz or sounds with a pitch of 40 hertz can stimulate gamma waves in the brain, which has many protective effects, including preventing the formation of amyloid beta plaques. Using light and sound together provides even more significant protection. The treatment also appears promising in humans: Phase 1 clinical trials in people with early-stage Alzheimer’s disease have found the treatment is safe and does offer some neurological and behavioral benefits. In the new study, the researchers set out to see whether this treatment could also counteract the cognitive effects of chemotherapy treatment. Research has shown that these drugs can induce inflammation in the brain, as well as other detrimental effects such as loss of white matter — the networks of nerve fibers that help different parts of the brain communicate with each other. Chemotherapy drugs also promote loss of myelin, the protective fatty coating that allows neurons to propagate electrical signals. Many of these effects are also seen in the brains of people with Alzheimer’s.

“Chemo brain caught our attention because it is extremely common, and there is quite a lot of research on what the brain is like following chemotherapy treatment,” Tsai says. “From our previous work, we know that this gamma sensory stimulation has anti-inflammatory effects, so we decided to use the chemo brain model to test whether sensory gamma stimulation can be beneficial.”

As an experimental model, the researchers used mice that were given cisplatin, a chemotherapy drug often used to treat testicular, ovarian, and other cancers. The mice were given cisplatin for five days, then taken off of it for five days, then on again for five days. One group received chemotherapy only, while another group was also given 40-hertz light and sound therapy every day.

After three weeks, mice that received cisplatin but not gamma therapy showed many of the expected effects of chemotherapy: brain volume shrinkage, DNA damage, demyelination, and inflammation. These mice also had reduced populations of oligodendrocytes, the brain cells responsible for producing myelin.
However, mice that received gamma therapy along with cisplatin treatment showed significant reductions in all of those symptoms. The gamma therapy also had beneficial effects on behavior: Mice that received the therapy performed much better on tests designed to measure memory and executive function.

“A fundamental mechanism”

Using single-cell RNA sequencing, the researchers analyzed the gene expression changes that occurred in mice that received the gamma treatment. They found that in those mice, inflammation-linked genes and genes that trigger cell death were suppressed, especially in oligodendrocytes, the cells responsible for producing myelin. In mice that received gamma treatment along with cisplatin, some of the beneficial effects could still be seen up to four months later. However, the gamma treatment was much less effective if it was started three months after the chemotherapy ended. The researchers also showed that the gamma treatment improved the signs of chemo brain in mice that received a different chemotherapy drug, methotrexate, which is used to treat breast, lung, and other types of cancer.

“I think this is a very fundamental mechanism to improve myelination and to promote the integrity of oligodendrocytes. It seems that it’s not specific to the agent that induces demyelination, be it chemotherapy or another source of demyelination,” Tsai says.

Because of its widespread effects, Tsai’s lab is also testing gamma treatment in mouse models of other neurological diseases, including Parkinson’s disease and multiple sclerosis. Cognito Therapeutics, a company founded by Tsai and MIT Professor Edward Boyden, has finished a phase 2 trial of gamma therapy in Alzheimer’s patients, and plans to begin a phase 3 trial this year. “My lab’s major focus now, in terms of clinical application, is Alzheimer’s; but hopefully we can test this approach for a few other indications, too,” Tsai says. The research was funded by the JPB Foundation, the Ko Hahn Seed Fund, and the National Institutes of Health.

(Source : MITNews)

Forty hertz (40 Hz) is a rhythm — a pulse that repeats 40 times every second. When the brain or body is exposed to a 40 Hz rhythm (by gentle sound, light, touch, or weak electrical stimulation), a few things can happen that may help the body and overall health.

First, 40 Hz can make you feel more alert and focused for a short time. That’s because it nudges certain brain circuits that help attention and short-term memory, so people often notice they can concentrate a bit better right after stimulation. Second, in many animal studies 40 Hz seems to wake up the brain’s cleanup cells (microglia) so they move more and clear away waste and sticky protein clumps. By helping clear waste, this could protect brain cells from slow damage over time — which is why scientists are excited about possible benefits for brain aging, although in people the evidence is still very limited. Third, 40 Hz can change chemical signals in the brain (small messenger molecules and genes) that reduce long-term inflammation and promote repair; because the brain talks to the rest of the body through nerves and hormones, these shifts can sometimes lower inflammation outside the brain too. Fourth, rhythm-based stimulation can influence the autonomic nervous system (the body’s “automatic” control for heart, digestion, breathing), which may help with stress, heart-rate patterns, and digestion for some people.

Those are the hopeful benefits: short boosts in attention, possible support for brain cleanup and reduced inflammation, and secondary improvements in stress and bodily functions through nerve and hormone pathways. Important to know: most strong results are from animal or lab work; human studies are small and preliminary. Also, some methods (very loud sounds, flashing lights) can be unsafe for people with hearing issues or photosensitive epilepsy. In short, 40 Hz is promising for brief mental boosts and potential brain-protective effects, but it’s not a proven medical treatment yet — it’s best seen as an interesting tool that might complement good sleep, exercise, and medical care, not replace them.

When I say “the brain talks to the rest of the body through nerves and hormones,” I mean there are two main communication systems the brain uses: fast electrical wiring (nerves) and slower chemical mail (hormones). A 40 Hz rhythm changes how groups of brain cells fire together, and those changes ripple out through these two channels.

Nerve signals are like electrical telephone wires. Certain brain cells send rapid bursts down long nerve fibers to organs — for example, the vagus nerve carries instructions from the brain to the heart, lungs, gut and immune tissues. If 40 Hz stimulation makes those brain cells fire in a new pattern, the signal traveling down the nerve changes too. That can shift heart rate, digestion, and the activity of immune cells sitting near those organs almost immediately.

Hormones work more like postal delivery. The brain can tell glands (like the adrenal glands) to release hormones into the blood. Those hormones spread through the whole body and change how distant cells behave — raising or lowering inflammation, changing energy use, or altering stress responses. A change in brain activity at 40 Hz can alter the brain’s hormonal commands, so the body’s overall chemical environment shifts over minutes to hours.

There’s also a third route that sits between nerves and hormones: immune signaling. Brain activity can change the balance of chemical messengers called cytokines inside the brain, and some of these messages affect immune cells nearby or trigger signals that travel out to the body. Conversely, nerves like the vagus can tell immune tissues to calm down or ramp up. So by changing brain rhythms, you can modify this neuro-immune conversation and indirectly change immune activity in the body.

Finally, the timing matters. A coordinated 40 Hz pattern forces many neurons to act together instead of firing at random. That coordinated firing is more effective at sending clear instructions down nerves, prompting glands, and organizing immune-related signals. In short: 40 Hz changes the brain’s activity pattern, and because the brain controls organs and the immune system through nerves, hormones and immune messengers, those brain changes can produce measurable effects throughout the body.

Here’s a clearer picture of what “indirectly change immune activity in the body” can mean, in plain language.

When brain activity shifts (for example because of 40 Hz stimulation), that change can travel out of the skull in three main ways and each one can alter immune behavior elsewhere in the body. The fastest route is nerves: the brain sends electric signals down big nerves like the vagus. Those nerve signals tell organs and immune tissues to calm down or ramp up. For example, vagus nerve activity can trigger a “cholinergic anti-inflammatory” response that tells immune cells to make fewer inflammatory messengers, so levels of things like TNF or IL-6 can fall within minutes to hours.

A second route is hormones. Brain activity controls hormone glands (the hypothalamus → pituitary → adrenal chain). If that control changes, the body releases different amounts of hormones such as cortisol. Cortisol circulates in the blood and tells many immune cells to slow their activity, change what proteins they make, and move less aggressively into tissues. Hormonal effects are slower than nerve effects (typically hours) but act broadly throughout the body.

The third route is immune signaling itself. The brain can change the mix of small chemical messengers (cytokines and chemokines) locally, and those signals either feed into the nerve/hormone systems or are carried to the blood and lymph where they shift immune cell behavior. That can change which genes are turned on inside immune cells, alter how sticky they are to blood vessels (so they enter tissues more or less), and change whether they produce inflammatory or anti-inflammatory substances. Over days this can lead to different numbers or types of immune cells sitting in tissues.

Put simply: these three pathways mean 40 Hz brain changes could make immune cells produce fewer inflammatory chemicals, move differently through the body, or behave in a calmer, “cleanup” mode rather than an aggressive, inflammatory one. The timing differs — nerve effects can be quick, hormones take longer, and gene-expression or cell-composition changes take the longest. Also, responses vary by person and context (stress, illness, medications).

Important caveat: most clear evidence for these chains of events comes from animal and lab studies; human results are preliminary. So while the mechanisms above are real biological routes, how strong or useful these changes are in people is still being worked out.

Because 40 Hz mainly changes brain activity, the kinds of body-wide immune problems it could plausibly help are those driven by too much inflammation — especially diseases where calming inflammatory signals makes a real clinical difference. In plain language, the strongest candidates are conditions like rheumatoid arthritis and inflammatory bowel disease, because we already have both animal data and early human work showing that changing brain activity (via nerves such as the vagus, or via sensory 40 Hz entrainment) can lower inflammatory chemicals in the body and calm immune cells. (PMC)

Here’s how that would work: 40 Hz stimulation can push the brain to send different patterns down major nerves (for example the vagus nerve), and that nerve pathway is known to trigger a “cholinergic anti-inflammatory” response that reduces key inflammatory messengers like TNF and IL-6. That same nerve/hormone route is why implanted or noninvasive vagus-nerve stimulation has been tested in rheumatoid arthritis and inflammatory bowel disease with some promising early results. (physoc.onlinelibrary.wiley.com)

Animal and lab studies that used sensory 40 Hz (light or sound) also reported lower inflammatory signals in brain tissue and shifts in cytokines that can travel into the blood or change how immune cells behave in the body. Those findings make it biologically plausible that 40 Hz could help other inflammatory problems too (for example some post-stroke inflammation or systemic inflammation related to aging), but evidence in people is still small. (PMC)

It’s important to be realistic: most of the strongest, mechanistic results come from animals or from studies of nerve stimulation rather than large, definitive clinical trials. That means 40 Hz approaches are promising for inflammatory diseases but not yet established medical treatments — more and bigger human trials are needed to prove benefit, find the best dosing, and check safety. If someone is considering trying 40 Hz (or a vagus-stimulation device) for an inflammatory disease, they should discuss it with their doctor and not stop proven medications. (PLOS)

(Source : ChatGPT)

When the MIT article says 40 Hz stimulation produces “changes in immune system activity,” it’s talking mainly about effects on the brain’s immune cells and the signals that control them — not a general immune-system overhaul. In animal and lab studies, driving the brain at the gamma frequency (about 40 cycles per second) makes microglia, the brain’s resident immune/cleanup cells, change their shape and behaviour so they become more likely to move toward, surround, and engulf (phagocytose) harmful material such as amyloid plaques. Those microglial changes were first reported in a key mouse study and are one of the clearest immune-type responses seen after 40 Hz stimulation. (Nature)

Along with the microglial activation, researchers have measured shifts in immune signaling molecules (cytokines and growth factors) in the brain after 40 Hz stimulation. Some cytokines that recruit or support microglia go up, and gene-expression patterns linked to immune activity change — in short, the local chemical “calls” that tell immune cells what to do are altered, which helps explain why microglia become more phagocytic and why protein clearance can increase. Studies also suggest 40 Hz stimulation can interact with clearance pathways (like glymphatic flow) and with neuronal release of peptides that further promote removal of pathological proteins. (PMC)

It’s important to stress nuance: these immune changes are best documented in mice and in cell experiments, and the pattern of changes is complex — sometimes some inflammatory markers rise briefly (which can be part of a healthy cleanup response) while longer-term measures of chronic inflammation fall or tissue pathology improves. Human trials so far are small and preliminary, so we don’t yet know how reliably these immune effects translate to people or whether they are always beneficial. In short, “changes in immune system activity” means measurable shifts in microglial behaviour and immune signaling in the brain that tend to promote clearance of pathological proteins in animal models — but the full picture and clinical relevance for humans remain under active study. (alz-journals.onlinelibrary.wiley.com)

In plain terms, saying 40 Hz causes “cellular and molecular changes” means it makes certain brain cells act differently and shifts the chemical signals those cells use to talk to each other. One clear effect is on microglia — the brain’s cleanup crew. After repeated 40 Hz stimulation they change shape, become more active, move toward problem areas (like sticky protein clumps) and “eat” or clear away debris more than before.

At the chemical level, 40 Hz can change which genes are turned on or off in brain tissue and it alters levels of signaling molecules (the cytokines and growth factors) that tell microglia and other cells how to behave. Those changing signals help explain why microglia switch into a cleanup mode. Certain fast-firing brain cells also change how they fire and release signals, and that altered neuronal activity appears to coordinate with the immune response and with the brain’s fluid-clearance systems (think of it like improving the brain’s plumbing so waste is carried away more efficiently).

Researchers have also seen changes in the systems that tag unwanted material for removal, so the balance shifts toward a short, helpful cleanup instead of long-lasting harmful inflammation. Most of these findings come from animal and lab studies; human evidence is still limited, so we don’t yet know how big or lasting these effects are in people.

(Source : ChatGPT)

Researchers survey a broadening landscape of studies showing what’s known, and what remains to be found, about the therapeutic potential of noninvasive sensory, electrical, or magnetic stimulation of gamma brain rhythms.

A surprising MIT study published in Nature at the end of 2016 helped to spur interest in the possibility that light flickering at the frequency of a particular gamma-band brain rhythm could produce meaningful therapeutic effects for people with Alzheimer’s disease. In a new review paper in the Journal of Internal Medicine, the lab that led those studies takes stock of what a growing number of scientists worldwide have been finding out since then in dozens of clinical and lab benchtop studies.

Brain rhythms (also called brain “waves” or “oscillations”) arise from the synchronized network activity of brain cells and circuits as they coordinate to enable brain functions such as perception or cognition. Lower-range gamma-frequency rhythms, those around 40 cycles a second, or hertz (Hz), are particularly important for memory processes, and MIT’s research has shown that they are also associated with specific changes at the cellular and molecular level. The 2016 study and many others since then have produced evidence, initially in animals and more recently in humans, that various noninvasive means of enhancing the power and synchrony of 40Hz gamma rhythms helps to reduce Alzheimer’s pathology and its consequences.

“What started in 2016 with optogenetic and visual stimulation in mice has expanded to a multitude of stimulation paradigms, a wide range of human clinical studies with promising results, and is narrowing in on the mechanisms underlying this phenomenon,” write the authors including Li-Huei Tsai, Picower Professor in The Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences at MIT.

Though the number of studies and methods has increased and the data have typically suggested beneficial clinical effects, the article’s authors also clearly caution that the clinical evidence remains preliminary and that animal studies intended to discern how the approach works have been instructive, but not definitive.

“Research into the clinical potential of these interventions is still in its nascent stages,” the researchers, led by MIT postdoc Cristina Blanco-Duque, write in introducing the review. “The precise mechanisms underpinning the beneficial effects of gamma stimulation in Alzheimer’s disease are not yet fully elucidated, but preclinical studies have provided relevant insights.”

Preliminarily promising

The authors list and summarize results from 16 clinical studies published over the last several years. These employ gamma-frequency sensory stimulation (e.g., exposure to light, sound, tactile vibration, or a combination); transcranial alternating current stimulation (tACS), in which a brain region is stimulated via scalp electrodes; or transcranial magnetic stimulation (TMS), in which electric currents are induced in a brain region using magnetic fields. The studies also vary in their sample size, design, duration, and in what effects they assessed. Some of the sensory studies using light have tested different colors and different exact frequencies. And while some studies show that sensory stimulation appears to affect multiple regions in the brain, tACS and TMS are more regionally focused (though those brain regions still connect and interact with others).

Given the variances, the clinical studies taken together offer a blend of uneven but encouraging evidence, the authors write. Across clinical studies involving patients with Alzheimer’s disease, sensory stimulation has proven safe and well-tolerated. Multiple sensory studies have measured increases in gamma power and brain network connectivity. Sensory studies have also reported improvements in memory and/or cognition, as well as sleep. Some have yielded apparent physiological benefits such as reduction of brain atrophy, in one case, and changes in immune system activity in another. So far, sensory studies have not shown reductions in Alzheimer’s hallmark proteins, amyloid or tau.

Clinical studies stimulating 40Hz rhythms using tACS, ranging in sample size from only one to as many as 60, are the most numerous so far, and many have shown similar benefits. Most report benefits to cognition, executive function, and/or memory (depending sometimes on the brain region stimulated), and some have assessed that benefits endure even after treatment concludes. Some have shown effects on measures of tau and amyloid, blood flow, neuromodulatory chemical activity, or immune activity. Finally, a 40Hz stimulation clinical study using TMS in 37 patients found improvements in cognition, prevention of brain atrophy, and increased brain connectivity.

“The most important test for gamma stimulation is without a doubt whether it is safe and beneficial for patients,” the authors write. “So far, results from several small trials on sensory gamma stimulation suggest that it is safe, evokes rhythmic EEG brain responses, and there are promising signs for AD [Alzheimer's disease] symptoms and pathology. Similarly, studies on transcranial stimulation report the potential to benefit memory and global cognitive function even beyond the end of treatment.”

Studying underlying mechanisms

In parallel, dozens more studies have shown significant benefits in mice including reductions in amyloid and tau, preservation of brain tissue, and improvements in memory. But animal studies also have offered researchers a window into the cellular and molecular mechanisms by which gamma stimulation might have these effects.

Before MIT’s original studies in 2016 and 2019, researchers had not attributed molecular changes in brain cells to changes in brain rhythms, but those and other studies have now shown that they affect not only the molecular state of neurons, but also the brain’s microglia immune cells, astrocyte cells that play key roles in regulating circulation, and indeed the brain’s vasculature system. A hypothesis of Tsai’s lab right now is that sensory gamma stimulation might promote the clearance of amyloid and tau via increased circulatory activity of brain fluids.

A hotly debated aspect of gamma stimulation is how it affects the electrical activity of neurons, and how pervasively. Studies indicate that inhibitory “interneurons” are especially affected, though, offering a clue about how increased gamma activity, and its physiological effects, might propagate.

“The field has generated tantalizing leads on how gamma stimulation may translate into beneficial effects on the cellular and molecular level,” the authors write.

Gamma going forward

As the authors make clear that more definitive clinical studies are needed, they note that at the moment, there are now 15 new clinical studies of gamma stimulation underway. Among these is a phase 3 clinical trial by the company Cognito Therapeutics, which has licensed MIT’s technology. That study plans to enroll hundreds of participants.

Meanwhile, some recent or new clinical and preclinical studies have begun looking at whether gamma stimulation may be applicable to neurological disorders other than Alzheimer’s, including stroke or Down syndrome. In experiments with mouse models, for example, an MIT team has been testing gamma stimulation’s potential to help with cognitive effects of chemotherapy, or “chemobrain.”

“Larger clinical studies are required to ascertain the long-term benefits of gamma stimulation,” the authors conclude. “In animal models the focus should be on delineating the mechanism of gamma stimulation and providing further proof of principle studies on what other applications gamma stimulation may have.”

In addition to Tsai and Blanco-Duque, the paper’s other authors are Diane Chan, Martin Kahn, and Mitch Murdock.

(Source : MITNews)

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.

(Source : MITNews)

A decade after scientists in The Picower Institute for Learning and Memory at MIT first began testing whether sensory stimulation of the brain’s 40Hz “gamma” frequency rhythms could treat Alzheimer’s disease in mice, a growing evidence base supporting the idea that it can improve brain health — in humans as well as animals — has emerged from the work of labs all over the world. A new open-access review article in PLOS Biology describes the state of research so far and presents some of the fundamental and clinical questions at the forefront of the noninvasive gamma stimulation now.

“As we’ve made all our observations, many other people in the field have published results that are very consistent,” says Li-Huei Tsai, Picower professor of neuroscience at MIT, director of MIT’s Aging Brain Initiative, and senior author of the new review, with postdoc Jung Park. “People have used many different ways to induce gamma including sensory stimulation, transcranial alternating current stimulation, or transcranial magnetic stimulation, but the key is delivering stimulation at 40 hertz. They all see beneficial effects.”

A decade of discovery at MIT

Starting with a paper in Nature in 2016, a collaboration led by Tsai has produced a series of studies showing that 40Hz stimulation via light, sound, the two combined, or tactile vibration reduces hallmarks of Alzheimer’s pathology such as amyloid and tau proteins, prevents neuron death, decreases synapse loss, and sustains memory and cognition in various Alzheimer’s mouse models. The collaboration’s investigations of the underlying mechanisms that produce these benefits have so far identified specific cellular and molecular responses in many brain cell types including neurons, microglia, astrocytes, oligodendrocytes, and the brain’s blood vessels. Last year, for instance, the lab reported in Nature that 40Hz audio and visual stimulation induced interneurons in mice to increase release of the peptide VIP, prompting increased clearance of amyloid from brain tissue via the brain’s glymphatic “plumbing” system.

Meanwhile, at MIT and at the MIT spinoff company Cognito Therapeutics, phase II clinical studies have shown that people with Alzheimer’s exposed to 40Hz light and sound experienced a significant slowing of brain atrophy and improvements on some cognitive measures, compared to untreated controls. Cognito, which has also measured significant preservation of the brain’s “white matter” in volunteers, has been conducting a pivotal, nationwide phase III clinical trial of sensory gamma stimulation for more than a year.
“Neuroscientists often lament that it is a great time to have AD [Alzheimer’s disease] if you are a mouse,” Park and Tsai wrote in the review. “Our ultimate goal, therefore, is to translate GENUS discoveries into a safe, accessible, and noninvasive therapy for AD patients.” The MIT team often refers to 40Hz stimulation as “GENUS” for Gamma Entrainment Using Sensory Stimulation.

A growing field

As Tsai’s collaboration, which includes MIT colleagues Edward Boyden and Emery N. Brown, has published its results, many other labs have produced studies adding to the evidence that various methods of noninvasive gamma sensory stimulation can combat Alzheimer’s pathology. Among many examples cited in the new review, in 2024 a research team in China independently corroborated that 40Hz sensory stimulation increases glymphatic fluid flows in mice. In another example, a Harvard Medical School-based team in 2022 showed that 40Hz gamma stimulation using Transcranial Alternating Current Stimulation significantly reduced the burden of tau in three out of four human volunteers. And in another study involving more than 100 people, researchers in Scotland in 2023 used audio and visual gamma stimulation (at 37.5Hz) to improve memory recall.

Open questions

Amid the growing number of publications describing preclinical studies with mice and clinical trials with people, open questions remain, Tsai and Park acknowledge. The MIT team and others are still exploring the cellular and molecular mechanisms that underlie GENUS’s effects. Tsai says her lab is looking at other neuropeptide and neuromodulatory systems to better understand the cascade of events linking sensory stimulation to the observed cellular responses. Meanwhile, the nature of how some cells, such as microglia, respond to gamma stimulation and how that affects pathology remains unclear, Tsai adds. Even with a national phase III clinical trial underway, it is still important to investigate these fundamental mechanisms, Tsai says, because new insights into how noninvasive gamma stimulation affects the brain could improve and expand its therapeutic potential.

“The more we understand the mechanisms, the more we will have good ideas about how to further optimize the treatment,” Tsai says. “And the more we understand its action and the circuits it affects, the more we will know beyond Alzheimer’s disease what other neurological disorders will benefit from this.”
Indeed, the review points to studies at MIT and other institutions providing at least some evidence that GENUS might be able to help with Parkinson’s disease, stroke, anxiety, epilepsy, and the cognitive side effects of chemotherapy and conditions that reduce myelin, such as multiple sclerosis. Tsai’s lab has been studying whether it can help with Down syndrome as well.

The open questions may help define the next decade of GENUS research.

(Source : MITNews)

Effects of extremely low-frequency pulsed electromagnetic fields (ELF-PEMFs) on glioblastoma cells (U87) :

The impact of extremely low-frequency pulsed electromagnetic fields (ELF-PEMFs) at various frequencies and amplitudes was investigated on cell cycle, apoptosis and viability of the Glioblastoma Multiforme (GBM) cell line (U87), in vitro. The GBM is a malignant brain tumor with high mortality in humans and poorly responsive to the most common type of cancer treatments, such as surgery, chemotherapy and radiation therapy.

The data suggest that the proliferation and apoptosis of human GBM are influenced by exposure to ELF-PEMFs in different time-dependent frequencies and amplitudes. The fact that some of the ELF-PEMFs frequencies and amplitudes favor U87 cells proliferation indicates precaution for the use of medical devices related to the MFs on cancer patients. On the other hand, some other ELF-PEMFs frequencies and intensities arresting U87 cells growth could open the way to develop novel therapeutic approaches.

The authors wish to appreciate the financial support of the Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, 76175-113 Kerman, Iran. 

(Source : Tandonfline)