Tag: tau

Experimental Blood Test Could Flag Alzheimer’s

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New studies show that elevated levels of a form of tau called p-tau217 can accurately distinguish Alzheimer’s disease from other forms of dementia, and perhaps even predict it.

by Kerry Grens

Three studies presented at the Alzheimer’s Association International Conference this week describe the performance of blood tests used to diagnose, and even predict, Alzheimer’s disease using circulating levels of a form of tau protein called p-tau217. The largest assessment of this approach, which included 1,402 participants, showed that circulating p-tau217 levels worked just as well at detecting Alzheimer’s as standard PET scans and tests of cerebrospinal fluid.

“This blood test very, very accurately predicts who’s got Alzheimer’s disease in their brain, including people who seem to be normal,” Michael Weiner, an Alzheimer’s disease researcher at the University of California, San Francisco, who was not involved in the study, tells The New York Times. “It’s not a cure, it’s not a treatment, but you can’t treat the disease without being able to diagnose it. And accurate, low-cost diagnosis is really exciting, so it’s a breakthrough.”

A blood test could help identify people on track to develop Alzheimer’s early on—and perhaps get them enrolled in drug trials aimed at finding an effective treatment for the disease. Scientists have pursued a number of potential circulating biomarkers, such as amyloid-β, to find those that can reliably diagnose Alzheimer’s disease or predict its development, but to date none have come to market.

High levels of tau or its phosphorylated form, p-tau, have emerged as promising biomarker candidates because they may indicate the presence of damaging structures known as neurofibrillary tangles in the brain.

The large study on one type of p-tau, p-tau217, published in JAMA July 28 to coincide with the presentation at the meeting, was a collection of three experiments using a blood test developed by Eli Lilly (some of the coauthors work for the company). In one assessment of several hundred Swedes, the test accurately distinguished patients who had Alzheimer’s from those with other forms of dementia with 89–98 percent accuracy. “That’s pretty good. We’ve never seen that” precision before, Maria Carrillo, the Alzheimer’s Association’s chief science officer, tells the Associated Press.

In another assessment of the Eli Lilly test, which included hundreds of related individuals, some of whom have a gene that causes Alzheimer’s, p-tau217 levels in the blood aligned with the genetics, even decades before cognitive impairment is likely to begin.

Another study presented at the conference found a p-tau217 blood test could accurately distinguish Alzheimer’s patients from those with frontotemporal lobar degeneration, according to a conference press release. And a third presentation of a study by Suzanne Schindler of Washington University in St. Louis and her colleagues reported that circulating p-tau217 was superior to another form that’s been studied as a potential biomarker, p-tau181, as a proxy for amyloid accumulation in the brain.

“I personally find it very reassuring that these different groups are using different types of assays and getting the same result,” Schindler tells the Times. “It looks real. It looks like 217 has tremendous promise as a blood test for Alzheimer’s disease, and it is likely to correspond with the symptoms.”

Speaking to The Guardian, Clive Ballard, who studies age-related disease at the University of Exeter Medical School and who was not involved in these projects, says, “further validation in people from more routine clinical settings are still needed, and a lot of work will be needed to achieve standardisation of the test across laboratories—so it could still be at least five years before we see an accurate blood biomarker test for dementia in the clinic.”

https://www.the-scientist.com/news-opinion/experimental-blood-test-could-flag-alzheimers-67779?utm_campaign=TS_DAILY%20NEWSLETTER_2020&utm_medium=email&_hsmi=92321648&_hsenc=p2ANqtz-8ayk91AfO8kNKldfK3kfssyQf2GRuKPsOimQKjhl3hz5Ap-KFfFI0molaN5LwimzBJw9JHyX8TCowcon5V50G5hr5ErA&utm_content=92321648&utm_source=hs_email

Experimental PET scan detects abnormal tau protein in brains of living former NFL players

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CTE is a neurodegenerative disease that has been associated with a history of repetitive head impacts, including those that may or may not be associated with concussion symptoms in American football players. The image is in the public domain.

Summary: PET imaging of former NFL players who exhibited cognitive decline and psychiatric symptoms linked to CTE showed higher levels of tau in areas of the brain associated with the neurodegenerative disease. Using an experimental positron emission tomography (PET) scan, researchers have found elevated amounts of abnormal tau protein in brain regions affected by chronic traumatic encephalopathy (CTE) in a small group of living former National Football League (NFL) players with cognitive, mood and behavior symptoms. The study was published online in the New England Journal of Medicine.

Source: Boston University School of Medicine

The researchers also found the more years of tackle football played (across all levels of play), the higher the tau protein levels detected by the PET scan. However, there was no relationship between the tau PET levels and cognitive test performance or severity of mood and behavior symptoms.

“The results of this study provide initial support for the flortaucipir PET scan to detect abnormal tau from CTE during life. However, we’re not there yet,” cautioned corresponding author Robert Stern, PhD, professor of neurology, neurosurgery and anatomy and neurobiology at Boston University School of Medicine (BUSM). “These results do not mean that we can now diagnose CTE during life or that this experimental test is ready for use in the clinic.”

CTE is a neurodegenerative disease that has been associated with a history of repetitive head impacts, including those that may or may not be associated with concussion symptoms in American football players. At this time, CTE can only be diagnosed after death by a neuropathological examination, with the hallmark findings of the build-up of an abnormal form of tau protein in a specific pattern in the brain. Like Alzheimer’s disease (AD), CTE has been suggested to be associated with a progressive loss of brain cells. In contrast to AD, the diagnosis of CTE is based in part on the pattern of tau deposition and a relative lack of amyloid plaques.

The study was conducted in Boston and Arizona by a multidisciplinary group of researchers from BUSM, Banner Alzheimer’s Institute, Mayo Clinic Arizona, Brigham and Women’s Hospital and Avid Radiopharmaceuticals. Experimental flortaucipir PET scans were used to assess tau deposition and FDA-approved florbetapir PET scans were used to assess amyloid plaque deposition in the brains of 26 living former NFL players with cognitive, mood, and behavior symptoms (ages 40-69) and a control group of 31 same-age men without symptoms or history of traumatic brain injury. Results showed that the tau PET levels were significantly higher in the former NFL group than in the controls, and the tau was seen in the areas of the brain which have been shown to be affected in post-mortem cases of neuropathologically diagnosed CTE.

Interestingly, the former player and control groups did not differ in their amyloid PET measurements. Indeed, only one former player had amyloid PET measurements comparable to those seen in Alzheimer’s disease.

“Our findings suggest that mild cognitive, emotional, and behavioral symptoms observed in athletes with a history of repetitive impacts are not attributable to AD, and they provide a foundation for additional research studies to advance the scientific understanding, diagnosis, treatment, and prevention of CTE in living persons, said co-author, Eric Reiman, MD, Executive Director of Banner Alzheimer’s Institute in Phoenix, Arizona. “More research is needed to draw firm conclusions, and contact sports athletes, their families, and other stakeholders are waiting.

With support from NIH, the authors are working with additional researchers to conduct a longitudinal study called the DIAGNOSE CTE Research Project in former NFL players, former college football players, and persons without a history of contact sports play to help address these and other important questions. Initial results of that study are expected in early 2020.

Experimental PET scan detects abnormal tau protein in brains of living former NFL players

Scientists have found a previously unknown mechanism in which the protein tau, which is implicated in Alzheimer’s disease, damages brain cells by interfering with their internal communications.

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The discovery sheds new light on the origins of this most common cause of dementia, a hallmark of which is the buildup of tangled tau protein filaments in the brain.

The finding could also lead to new treatments for Alzheimer’s and other diseases that progressively destroy brain tissue, conclude the researchers in a paper about their work that now features in the journal Neuron.

Scientists from Massachusetts General Hospital (MGH) in Charlestown and the Johns Hopkins School of Medicine in Baltimore, MD, led the study, which set out to investigate how tau protein might contribute to brain cell damage.

Alzheimer’s disease does not go away and gets worse over time. It is the sixth most common cause of death in adults in the United States, where an estimated 5.7 million people have the disease.

Exact causes of Alzheimer’s still unknown

Exactly what causes Alzheimer’s and other forms of dementia is still a mystery to science. Evidence suggests that a combination of environment, genes, and lifestyle is involved, with different factors having different amounts of influence in different people.

Most cases of Alzheimer’s do not show symptoms until people are in their 60s and older. The risk of getting the disease rises rapidly with age after this.

Brain studies of people with the disease — together with postmortem analyses of brain tissue — have revealed much about how Alzheimer’s changes and harms the brain.

“Age-related changes” include: inflammation; shrinkage in some brain regions; creation of unstable, short-lived molecules known as free radicals; and disruption of cellular energy production.

The brain of a person with Alzheimer’s disease also has two distinguishing features: plaques of amyloid protein that form between cells, and tangles of tau protein that form inside cells. The recent study concerns the latter.

Changes to tau behavior

Brain cells, or neurons, have internal structures known as microtubules that support the cell and its function. They are highly active cell components that help carry substances from the body of the cell out to the parts that connect it to other cells.

In healthy brain cells, tau protein normally “binds to and stabilizes” the microtubules. Tau behaves differently, however, in Alzheimer’s disease.

Changes in brain chemistry make tau protein molecules come away from the microtubules and stick to each other instead.

Eventually, the detached tau molecules form long filaments, or neurofibrillary tangles, that disrupt the brain cell’s ability to communicate with other cells.

The new study introduces the possibility that, in Alzheimer’s disease, tau disrupts yet another mechanism that involves communication between the nucleus of the brain cell and its body.

Communication with cell nucleus

The cell nucleus communicates with the rest of the cell using structures called nuclear pores, which comprise more than 400 different proteins and control the movement of molecules.

Studies on the causes of amyotrophic lateral sclerosis, frontotemporal, and other types of dementia have suggested that flaws in these nuclear pores are involved somehow.

The recent study reveals that animal and human cells with Alzheimer’s disease have faulty nuclear pores, and that the fault is linked to tau accumulation in the brain cell.

“Under disease conditions,” explains co-senior study author Bradley T. Hyman, the director of the Alzheimer’s Unit at MGH, “it appears that tau interacts with the nuclear pore and changes its properties.”

He and his colleagues discovered that the presence of tau disrupts the orderly structure of nuclear pores containing the major structural protein Nup98. In Alzheimer’s disease cells, there were fewer of these pores and those that were there tended to be stuck to each other.

‘Mislocalized’ Nup98
They also observed another curious change involving Nup98 inside Alzheimer’s disease brain cells. In cells with aggregated tau, the Nup98 was “mislocalized” instead of staying in the nuclear pore.

They revealed that this feature was more exaggerated in brain tissue of people who had died with more extreme forms of Alzheimer’s disease.

Finally, when they added human tau to living cultures of rodent brain cells, the researchers found that it caused mislocalization of Nup98 in the cell body and disrupted the transport of molecules into the nucleus.

This was evidence of a “functional link” between the presence of tau protein and damage to the nuclear transport mechanism.

The authors note, however, that it is not clear whether the Nup98-tau interaction uncovered in the study just occurs because of disease or whether it is a normal mechanism that behaves in an extreme fashion under disease conditions.

They conclude:

“Taken together, our data provide an unconventional mechanism for tau-induced neurodegeneration.”

https://www.medicalnewstoday.com/articles/322991.php

New research shows a mechanism by which tau may be toxic in Alzheimer’s disease

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New evidence suggests a mechanism by which progressive accumulation of Tau protein in brain cells may lead to Alzheimer’s disease. Scientists studied more than 600 human brains and fruit fly models of Alzheimer’s disease and found the first evidence of a strong link between Tau protein within neurons and the activity of particular DNA sequences called transposable elements, which might trigger neurodegeneration. The study appears in the journal Cell Reports.

“One of the key characteristics of Alzheimer’s disease is the accumulation of Tau protein within brain cells, in combination with progressive cell death,” said corresponding author Dr. Joshua Shulman, associate professor of neurology, neuroscience and molecular and human genetics at Baylor College of Medicine and investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital. “In this study we provide novel insights into how accumulation of Tau protein may contribute to the development of Alzheimer’s disease.”

Although scientists have studied for years what happens when Tau forms aggregates inside neurons, it still is not clear why brain cells ultimately die. One thing that scientists have noticed is that neurons affected by Tau accumulation also appear to have genomic instability.

“Genomic instability refers to an increased tendency to have alterations in the genetic material, DNA, such as mutations or other impairments. This means that the genome is not functioning correctly. Genomic instability is known to be a major driving force behind other diseases such as cancer,” Shulman said. “Our study focused on a new possible causal connection between Tau accumulation within neurons and the resulting genomic instability in Alzheimer’s disease.”

Enter transposable elements
Previous studies of brain tissues from patients with other neurologic diseases and of animal models have suggested that the neurons not only present with genomic instability, but also with activation of transposable elements.

“Transposable elements are short pieces of DNA that do not seem to contribute to the production of proteins that make cells function. They behave in a way similar to viruses; they can make copies of themselves that are inserted within the genome and this can create mutations that lead to disease,” Shulman said. “Although most transposable elements are dormant or dysfunctional, some may become active in human brains late in life or in disease. That’s what led us to look specifically at Alzheimer’s disease and the possible association between Tau accumulation and activated transposable elements.”

Shulman and his colleagues began their investigations by studying more than 600 human brains from a population study run by co-author Dr. David Bennett at Rush University Medical Center in Chicago. This population study follows participants throughout their lives and at death, allowing the researchers to examine their brains in detail postmortem. One of the evaluations is the amount of Tau accumulation across many brain regions. In addition, co-author Dr. Philip De Jager at the Broad Institute and Columbia University comprehensively profiled gene expression in the same brains.

“With this large amount of data, we looked to identify signatures of active transposable elements, but this was not easy,” Shulman said. “We therefore reached out to Dr. Zhandong Liu, a co-author in this study, and together we developed a new software tool to detect signatures of active transposable elements from postmortem human brains. Then we conducted a statistical analysis in which we compared the amount of active transposable elements signatures with the amount of Tau accumulation, brain by brain.” Liu also is assistant professor of pediatrics – neurology at Baylor and a member of the Dan L Duncan Comprehensive Cancer Center.

The researchers found a strong link between the amount of Tau accumulation in neurons and detectable activity of transposable elements.

“We identified individual transposable elements that were active when Tau aggregates were present. Surprisingly, we also found evidence that the activation of transposable elements was quite broad across the genome,” Shulman said.

Other research has shown that Tau may disrupt the tightly packed architecture of the genome. It is believed that tightly packed DNA limits gene activation, while opening up the DNA may promote it. Keeping the DNA tightly packed may be an important mechanism to suppress the activity of transposable elements that lead to disease.

“The fact that Tau aggregates can affect that architecture of the genome may be one possible mechanism by which transposable elements are activated in Alzheimer’s disease,” Shulman said. “However, our studies in human brains only establish an association between Tau accumulation and activation of transposable elements. To determine whether Tau accumulation could in fact cause transposable element activation, we conducted studies with a fruit fly model of Alzheimer’s disease.”

In this fruit fly model of the disease, the researchers found that triggering Tau changes similar to those observed in human brains resulted in the activation of fruit fly transposable elements, strongly suggesting that Tau aggregates that disrupt the architecture of the genome can potentially mediate the activation of transposable elements and ultimately cause neurodegeneration.

“We think our experiments reveal new and potentially important insights relevant for understanding Alzheimer’s disease mechanisms,” Shulman said. “There is still a lot of work to be done, but by presenting our results we hope we can stimulate others in the research community to help work on this problem.”

https://www.bcm.edu/news/neurology/research-links-tau-aggregates-cell-death

How flashing lights and pink noise might banish Alzheimer’s, improve memory and more

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Illustration by Paweł Jońca

by Helen Thomson

In March 2015, Li-Huei Tsai set up a tiny disco for some of the mice in her laboratory. For an hour each day, she placed them in a box lit only by a flickering strobe. The mice — which had been engineered to produce plaques of the peptide amyloid-β in the brain, a hallmark of Alzheimer’s disease — crawled about curiously. When Tsai later dissected them, those that had been to the mini dance parties had significantly lower levels of plaque than mice that had spent the same time in the dark.

Tsai, a neuroscientist at Massachusetts Institute of Technology (MIT) in Cambridge, says she checked the result; then checked it again. “For the longest time, I didn’t believe it,” she says. Her team had managed to clear amyloid from part of the brain with a flickering light. The strobe was tuned to 40 hertz and was designed to manipulate the rodents’ brainwaves, triggering a host of biological effects that eliminated the plaque-forming proteins. Although promising findings in mouse models of Alzheimer’s disease have been notoriously difficult to replicate in humans, the experiment offered some tantalizing possibilities. “The result was so mind-boggling and so robust, it took a while for the idea to sink in, but we knew we needed to work out a way of trying out the same thing in humans,” Tsai says.

Scientists identified the waves of electrical activity that constantly ripple through the brain almost 100 years ago, but they have struggled to assign these oscillations a definitive role in behaviour or brain function. Studies have strongly linked brainwaves to memory consolidation during sleep, and implicated them in processing sensory inputs and even coordinating consciousness. Yet not everyone is convinced that brainwaves are all that meaningful. “Right now we really don’t know what they do,” says Michael Shadlen, a neuroscientist at Columbia University in New York City.

Now, a growing body of evidence, including Tsai’s findings, hint at a meaningful connection to neurological disorders such as Alzheimer’s and Parkinson’s diseases. The work offers the possibility of forestalling or even reversing the damage caused by such conditions without using a drug. More than two dozen clinical trials are aiming to modulate brainwaves in some way — some with flickering lights or rhythmic sounds, but most through the direct application of electrical currents to the brain or scalp. They aim to treat everything from insomnia to schizophrenia and premenstrual dysphoric disorder.

Tsai’s study was the first glimpse of a cellular response to brainwave manipulation. “Her results were a really big surprise,” says Walter Koroshetz, director of the US National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. “It’s a novel observation that would be really interesting to pursue.”


A powerful wave

Brainwaves were first noticed by German psychiatrist Hans Berger. In 1929, he published a paper describing the repeating waves of current he observed when he placed electrodes on people’s scalps. It was the world’s first electroencephalogram (EEG) recording — but nobody took much notice. Berger was a controversial figure who had spent much of his career trying to identify the physiological basis of psychic phenomena. It was only after his colleagues began to confirm the results several years later that Berger’s invention was recognized as a window into brain activity.

Neurons communicate using electrical impulses created by the flow of ions into and out of each cell. Although a single firing neuron cannot be picked up through the electrodes of an EEG, when a group of neurons fires again and again in synchrony, it shows up as oscillating electrical ripples that sweep through the brain.

Those of the highest frequency are gamma waves, which range from 25 to 140 hertz. People often show a lot of this kind of activity when they are at peak concentration. At the other end of the scale are delta waves, which have the lowest frequency — around 0.5 to 4 hertz. These tend to occur in deep sleep (see ‘Rhythms of the mind’).

At any point in time, one type of brainwave tends to dominate, although other bands are always present to some extent. Scientists have long wondered what purpose, if any, this hum of activity serves, and some clues have emerged over the past three decades. For instance, in 1994, discoveries in mice indicated that the distinct patterns of oscillatory activity during sleep mirrored those during a previous learning exercise. Scientists suggested that these waves could be helping to solidify memories.

Brainwaves also seem to influence conscious perception. Randolph Helfrich at the University of California, Berkeley, and his colleagues devised a way to enhance or reduce gamma oscillations of around 40 hertz using a non-invasive technique called transcranial alternating current stimulation (tACS). By tweaking these oscillations, they were able to influence whether a person perceived a video of moving dots as travelling vertically or horizontally.

The oscillations also provide a potential mechanism for how the brain creates a coherent experience from the chaotic symphony of stimuli hitting the senses at any one time, a puzzle known as the ‘binding problem’. By synchronizing the firing rates of neurons responding to the same event, brainwaves might ensure that the all of the relevant information relating to one object arrives at the correct area of the brain at exactly the right time. Coordinating these signals is the key to perception, says Robert Knight, a cognitive neuroscientist at the University of California, Berkeley, “You can’t just pray that they will self-organize.”


Healthy oscillations

But these oscillations can become disrupted in certain disorders. In Parkinson’s disease, for example, the brain generally starts to show an increase in beta waves in the motor regions as body movement becomes impaired. In a healthy brain, beta waves are suppressed just before a body movement. But in Parkinson’s disease, neurons seem to get stuck in a synchronized pattern of activity. This leads to rigidity and movement difficulties. Peter Brown, who studies Parkinson’s disease at the University of Oxford, UK, says that current treatments for the symptoms of the disease — deep-brain stimulation and the drug levodopa — might work by reducing beta waves.

People with Alzheimer’s disease show a reduction in gamma oscillations5. So Tsai and others wondered whether gamma-wave activity could be restored, and whether this would have any effect on the disease.

They started by using optogenetics, in which brain cells are engineered to respond directly to a flash of light. In 2009, Tsai’s team, in collaboration with Christopher Moore, also at MIT at the time, demonstrated for the first time that it is possible to use the technique to drive gamma oscillations in a specific part of the mouse brain6.

Tsai and her colleagues subsequently found that tinkering with the oscillations sets in motion a host of biological events. It initiates changes in gene expression that cause microglia — immune cells in the brain — to change shape. The cells essentially go into scavenger mode, enabling them to better dispose of harmful clutter in the brain, such as amyloid-β. Koroshetz says that the link to neuroimmunity is new and striking. “The role of immune cells like microglia in the brain is incredibly important and poorly understood, and is one of the hottest areas for research now,” he says.

If the technique was to have any therapeutic relevance, however, Tsai and her colleagues had to find a less-invasive way of manipulating brainwaves. Flashing lights at specific frequencies has been shown to influence oscillations in some parts of the brain, so the researchers turned to strobe lights. They started by exposing young mice with a propensity for amyloid build-up to flickering LED lights for one hour. This created a drop in free-floating amyloid, but it was temporary, lasting less than 24 hours, and restricted to the visual cortex.

To achieve a longer-lasting effect on animals with amyloid plaques, they repeated the experiment for an hour a day over the course of a week, this time using older mice in which plaques had begun to form. Twenty-four hours after the end of the experiment, these animals showed a 67% reduction in plaque in the visual cortex compared with controls. The team also found that the technique reduced tau protein, another hallmark of Alzheimer’s disease.

Alzheimer’s plaques tend to have their earliest negative impacts on the hippocampus, however, not the visual cortex. To elicit oscillations where they are needed, Tsai and her colleagues are investigating other techniques. Playing rodents a 40-hertz noise, for example, seems to cause a decrease in amyloid in the hippocampus — perhaps because the hippo-campus sits closer to the auditory cortex than to the visual cortex.

Tsai and her colleague Ed Boyden, a neuro-scientist at MIT, have now formed a company, Cognito Therapeutics in Cambridge, to test similar treatments in humans. Last year, they started a safety trial, which involves testing a flickering light device, worn like a pair of glasses, on 12 people with Alzheimer’s.

Caveats abound. The mouse model of Alzheimer’s disease is not a perfect reflection of the disorder, and many therapies that have shown promise in rodents have failed in humans. “I used to tell people — if you’re going to get Alzheimer’s, first become a mouse,” says Thomas Insel, a neuroscientist and psychiatrist who led the US National Institute of Mental Health in Bethesda, Maryland, from 2002 until 2015.

Others are also looking to test how manipulating brainwaves might help people with Alzheimer’s disease. “We thought Tsai’s study was outstanding,” says Emiliano Santarnecchi at Harvard Medical School in Boston, Massachusetts. His team had already been using tACS to stimulate the brain, and he wondered whether it might elicit stronger effects than a flashing strobe. “This kind of stimulation can target areas of the brain more specifically than sensory stimulation can — after seeing Tsai’s results, it was a no-brainer that we should try it in Alzheimer’s patients.”

His team has begun an early clinical trial in which ten people with Alzheimer’s disease receive tACS for one hour daily for two weeks. A second trial, in collaboration with Boyden and Tsai, will look for signals of activated microglia and levels of tau protein. Results are expected from both trials by the end of the year.

Knight says that Tsai’s animal studies clearly show that oscillations have an effect on cellular metabolism — but whether the same effect will be seen in humans is another matter. “In the end, it’s data that will win out,” he says.

The studies may reveal risks, too. Gamma oscillations are the type most likely to induce seizures in people with photosensitive epilepsy, says Dora Hermes, a neuroscientist at Stanford University in California. She recalls a famous episode of a Japanese cartoon that featured flickering red and blue lights, which induced seizures in some viewers. “So many people watched that episode that there were almost 700 extra visits to the emergency department that day.”

A brain boost

Nevertheless, there is clearly a growing excitement around treating neurological diseases using neuromodulation, rather than pharmaceuticals. “There’s pretty good evidence that by changing neural-circuit activity we can get improvements in Parkinson’s, chronic pain, obsessive–compulsive disorder and depression,” says Insel. This is important, he says, because so far, pharmaceutical treatments for neurological disease have suffered from a lack of specificity. Koroshetz adds that funding institutes are eager for treatments that are innovative, non-invasive and quickly translatable to people.

Since publishing their mouse paper, Boyden says, he has had a deluge of requests from researchers wanting to use the same technique to treat other conditions. But there are a lot of details to work out. “We need to figure out what is the most effective, non-invasive way of manipulating oscillations in different parts of the brain,” he says. “Perhaps it is using light, but maybe it’s a smart pillow or a headband that could target these oscillations using electricity or sound.” One of the simplest methods that scientists have found is neurofeedback, which has shown some success in treating a range of conditions, including anxiety, depression and attention-deficit hyperactivity disorder. People who use this technique are taught to control their brainwaves by measuring them with an EEG and getting feedback in the form of visual or audio cues.

Phyllis Zee, a neurologist at Northwestern University in Chicago, Illinois, and her colleagues delivered pulses of ‘pink noise’ — audio frequencies that together sound a bit like a waterfall — to healthy older adults while they slept. They were particularly interested in eliciting the delta oscillations that characterize deep sleep. This aspect of sleep decreases with age, and is associated with a decreased ability to consolidate memories.

So far, her team has found that stimulation increased the amplitude of the slow waves, and was associated with a 25–30% improvement in recall of word pairs learnt the night before, compared with a fake treatment7. Her team is midway through a clinical trial to see whether longer-term acoustic stimulation might help people with mild cognitive impairment.

Although relatively safe, these kinds of technologies do have limitations. Neurofeedback is easy to learn, for instance, but it can take time to have an effect, and the results are often short-lived. In experiments that use magnetic or acoustic stimulation, it is difficult to know precisely what area of the brain is being affected. “The field of external brain stimulation is a little weak at the moment,” says Knight. Many approaches, he says, are open loop, meaning that they don’t track the effect of the modulation using an EEG. Closed loop, he says, would be more practical. Some experiments, such as Zee’s and those involving neuro-feedback, already do this. “I think the field is turning a corner,” Knight says. “It’s attracting some serious research.”

In addition to potentially leading to treatments, these studies could break open the field of neural oscillations in general, helping to link them more firmly to behaviour and how the brain works as a whole.

Shadlen says he is open to the idea that oscillations play a part in human behaviour and consciousness. But for now, he remains unconvinced that they are directly responsible for these phenomena — referring to the many roles people ascribe to them as “magical incantations”. He says he fully accepts that these brain rhythms are signatures of important brain processes, “but to posit the idea that synchronous spikes of activity are meaningful, that by suddenly wiggling inputs at a specific frequency, it suddenly elevates activity onto our conscious awareness? That requires more explanation.”

Whatever their role, Tsai mostly wants to discipline brainwaves and harness them against disease. Cognito Therapeutics has just received approval for a second, larger trial, which will look at whether the therapy has any effect on Alzheimer’s disease symptoms. Meanwhile, Tsai’s team is focusing on understanding more about the downstream biological effects and how to better target the hippocampus with non-invasive technologies.

For Tsai, the work is personal. Her grandmother, who raised her, was affected by dementia. “Her confused face made a deep imprint in my mind,” Tsai says. “This is the biggest challenge of our lifetime, and I will give it all I have.”

https://www.nature.com/articles/d41586-018-02391-6