Posts Tagged ‘Helen Thomson’

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.”


By Helen Thomson

What would you do if you had 60 days of extra free time a year? Ask Abby Ross, a retired psychologist from Miami, Florida, a “short-sleeper”. She needs only four hours sleep a night, so has a lot of spare time to fill while the rest of the world is in the land of nod.

“It’s wonderful to have so many hours in my day – I feel like I can live two lives,” she says.

Short-sleepers like Ross never feel lethargic, nor do they ever sleep in. They wake early – normally around four or five o’clock – raring to get on with their day. Margaret Thatcher may have been one – she famously said she needed just four hours a night, whereas Mariah Carey claims she needs 15.

What makes some people fantastically efficient sleepers, while others spend half their day snoozing? And can we change our sleeping pattern to make it more efficient?

In 2009, a woman came into Ying-Hui Fu’s lab at the University of California, San Francisco, complaining that she always woke up too early. At first, Fu thought the woman was an extreme morning lark – a person who goes to bed early and wakes early. However, the woman explained that she actually went to bed around midnight and woke at 4am feeling completely alert. It was the same for several members of her family, she said.

Fu and her colleagues compared the genome of different family members. They discovered a tiny mutation in a gene called DEC2 that was present in those who were short-sleepers, but not in members of the family who had normal length sleep, nor in 250 unrelated volunteers.

When the team bred mice to express this same mutation, the rodents also slept less but performed just as well as regular mice when given physical and cognitive tasks.

Getting too little sleep normally has a significant impact on health, quality of life and life expectancy. It can cause depression, weight gain and put you at greater risk of stroke and diabetes. “Sleep is so important, if you sleep well you can avoid many diseases, even dementia,” says Fu. “If you deprive someone of just two hours sleep a day, their cognitive functions become significantly impaired almost immediately.”

But why sleep is so important is still a bit of a mystery. The general consensus is that the brain needs sleep to do some housekeeping and general maintenance, since it doesn’t get much downtime during the day. While we sleep, the brain can repair cellular damage, remove toxins that accumulate during the day, boost flagging energy supplies and lay down memories.

“Clearly people with the DEC2 mutation can do the same cleaning up process in a shorter period of time – they are just more efficient than the rest of us at sleeping,” says Fu. “But how are they doing that? That’s the key question.”

Since discovering the DEC2 mutation, a lot of people have come forward claiming to only sleep a few hours a day, says Fu. Most of these had insomnia, she says. “We’re not focusing on those people who have sleeping issues that make them sleep less, we wanted to focus on people who sleep for a few hours and feel great.”

A positive outlook is common among all of the short-sleepers that Fu has studied. “Anecdotally,” she says, “they are all very energetic, very optimistic. It’s very common for them to feel like they want to cram as much into life as they can, but we’re not sure how or whether this is related to their mutations.”

Ross would seem to fit that mould. “I always feel great when I wake up,” she says. She has been living on four to five hours sleep every day for as long as she can remember.

“Those hours in the morning – around five o’clock – are just fabulous. It’s so peaceful and quiet and you can get so much done. I wish more shops were open at that time, but I can shop online, or I can read – oh there’s so much to read in this world! Or I can go out and exercise before anyone else is up, or talk to people in other time zones.”

Her short sleeping patterns allowed her to complete university in two and a half years, as well as affording her time to learn lots of new skills. For example, just three weeks after giving birth to her first son, Ross decided to use one of her early mornings to attempt to run around the block. It took her 10 minutes. The following day she did it again, running a little further. She slowly increased the time she ran, finally completing not one, but 37 marathons – one a month over three years – plus several ultramarathons. “I can get up and do my exercise before anyone else is up and then it’s done, out of the way,” she says.

As a child, Ross remembers spending very early mornings with her dad, another short-sleeper. “Our early mornings gave us such a special time together,” she says. Now, if she ever oversleeps – which she says has only ever happened a handful of times, her husband thinks she’s dead. “I just don’t lay in, I’d feel terrible if I did,” she says.

Fu has subsequently sequenced the genomes of several other families who fit the criteria of short-sleepers. They’re only just beginning to understand the gene mutations that lead to this talent, but in principle, she says, it might one day be possible to enable short sleeping in others.

Until then, are there any shortcuts to a more efficient night’s sleep for the rest of us? Neil Stanley, an independent sleep consultant, says yes: “The most effective way to improve your sleep is to fix your wake-up time in the morning.”

Stanley says that when your body gets used to the time it needs to wake up, it can use the time it has to sleep as efficiently as possible. “Studies show that your body prepares to wake up one and a half hours prior to actually waking up. Your body craves regularity, so if you chop and change your sleep pattern, your body hasn’t got a clue when it should prepare to wake up or not.”

You could also do yourself a favour by ignoring society’s views on sleep, he says. “There’s this social view that short sleeping is a good thing and should be encouraged – we’re always hauling out the example of Margaret Thatcher and top CEOs who don’t need much sleep. In fact, the amount of sleep you need is genetically determined as much as your height or shoe size. Some people need very little sleep, others need 11 or 12 hours to feel their best.”

Stanley says that a lot of people with sleep issues actually don’t have any problem sleeping, instead they have an expectation that they need to sleep for a certain amount of time. “If we could all figure out what kind of sleeper we are, and live our life accordingly, that would make a huge difference to our quality of life,” he says.

By Helen Thomson

“When the tide came in, these kids started swimming. But not like I had seen before. They were more underwater than above water, they had their eyes wide open – they were like little dolphins.”

Deep in the island archipelagos on the Andaman Sea, and along the west coast of Thailand live small tribes called the Moken people, also known as sea-nomads. Their children spend much of their day in the sea, diving for food. They are uniquely adapted to this job – because they can see underwater. And it turns out that with a little practice, their unique vision might be accessible to any young person.

In 1999, Anna Gislen at the University of Lund, in Sweden was investigating different aspects of vision, when a colleague suggested that she might be interested in studying the unique characteristics of the Moken tribe. “I’d been sitting in a dark lab for three months, so I thought, ‘yeah, why not go to Asia instead’,” says Gislen.

Gislen and her six-year old daughter travelled to Thailand and integrated themselves within the Moken communities, who mostly lived on houses sat upon poles. When the tide came in, the Moken children splashed around in the water, diving down to pick up food that lay metres below what Gislen or her daughter could see. “They had their eyes wide open, fishing for clams, shells and sea cucumbers, with no problem at all,” she says.

Gislen set up an experiment to test just how good the children’s underwater vision really was. The kids were excited about joining in, says Gislen, “they thought it was just a fun game.”

The kids had to dive underwater and place their heads onto a panel. From there they could see a card displaying either vertical or horizontal lines. Once they had stared at the card, they came back to the surface to report which direction the lines travelled. Each time they dived down, the lines would get thinner, making the task harder. It turned out that the Moken children were able to see twice as well as European children who performed the same experiment at a later date.

What was going on? To see clearly above land, you need to be able to refract light that enters the eye onto the retina. The retina sits at the back of the eye and contains specialised cells, which convert the light signals into electrical signals that the brain interprets as images.

Light is refracted when it enters the human eye because the outer cornea contains water, which makes it slightly denser than the air outside the eye. An internal lens refracts the light even further.

When the eye is immersed in water, which has about the same density as the cornea, we lose the refractive power of the cornea, which is why the image becomes severely blurred.

Gislen figured that in order for the Moken children to see clearly underwater, they must have either picked up some adaption that fundamentally changed the way their eyes worked, or they had learned to use their eyes differently under water.

She thought the first theory was unlikely, because a fundamental change to the eye would probably mean the kids wouldn’t be able to see well above water. A simple eye test proved this to be true – the Moken children could see just as well above water as European children of a similar age.

It had to be some kind of manipulation of the eye itself, thought Gislen. There are two ways in which you can theoretically improve your vision underwater. You can change the shape of the lens – which is called accommodation – or you can make the pupil smaller, thereby increasing the depth of field.

Their pupil size was easy to measure – and revealed that they can constrict their pupils to the maximum known limit of human performance. But this alone couldn’t fully explain the degree to which their sight improved. This led Gislen to believe that accommodation of the lens was also involved.

“We had to make a mathematical calculation to work out how much the lens was accommodating in order for them to see as far as they could,” says Gislen. This showed that the children had to be able to accommodate to a far greater degree than you would expect to see underwater.

“Normally when you go underwater, everything is so blurry that the eye doesn’t even try to accommodate, it’s not a normal reflex,” says Gislen. “But the Moken children are able to do both – they can make their pupils smaller and change their lens shape. Seals and dolphins have a similar adaptation.”

Gislen was able to test a few Moken adults in the same way. They showed no unusual underwater vision or accommodation – perhaps explaining why the adults in the tribe caught most of their food by spear fishing above the surface. “When we age, our lenses become less flexible, so it makes sense that the adults lose the ability to accommodate underwater,” says Gislen.

Gislen wondered whether the Moken children had a genetic anomaly to thank for their ability to see underwater or whether it was just down to practice. To find out, she asked a group of European children on holiday in Thailand, and a group of children in Sweden to take part in training sessions, in which they dived underwater and tried to work out the direction of lines on a card. After 11 sessions across one month, both groups had attained the same underwater acuity as the Moken children.

“It was different for each child, but at some point their vision would just suddenly improve,” says Gislen. “I asked them whether they were doing anything different and they said, ‘No, I can just see better now’.”

She did notice, however, that the European kids would experience red eyes, irritated by the salt in the water, whereas the Moken children appeared to have no such problem. “So perhaps there is some adaptation there that allows them to dive down 30 times without any irritation,” she says.

Gislen recently returned to Thailand to visit the Moken tribes, but things had changed dramatically. In 2004, a tsunami created by a giant earthquake within the Indian Ocean destroyed much of the Moken’s homeland. Since then, the Thai government has worked hard to move them onto the land, building homes that are further inland and employing members of the tribe to work in the National Park. “It’s difficult,” says Gislen. “You want to help keep people safe and give them the best parts of modern culture, but in doing so they lose their own culture.”

In unpublished work, Gislen tested the same kids that were in her original experiment. The Moken children, now in their late teens, were still able to see clearly underwater. She wasn’t able to test many adults as they were too shy, but she is certain that they would have lost the ability to see underwater as they got older. “The adult eye just isn’t capable of that amount of accommodation,” she says.

Unfortunately, the children in Gislen’s experiments may be the last of the tribe to possess the ability to see so clearly underwater. “They just don’t spend as much time in the sea anymore,” she says, “so I doubt that any of the children that grow up these days in the tribe have this extraordinary vision.”