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(Image: Richard Wilkinson)

They say they haven’t slept a wink, but tests show they were asleep all night. Figuring out this bizarre insomnia could tell us more about waking brains too

CHRIS RENNIK walked into the sleep clinic with a familiar complaint: he couldn’t sleep, his nights were terrible, he was going nuts. Michael Bonnet duly checked Rennik into his clinic at Wright State University in Dayton, Ohio, to run the usual battery of tests. What he found surprised him – Rennik (not his real name) was in fact sleeping like a baby.

“Then somebody’s made a mistake,” Rennik said, “or there’s something here you don’t understand.” Rennik was right about that.

People like him are a puzzle for physicians. They are tortured by their inability to sleep, but if you dissect their sleeping patterns in the lab, what emerges is hour after hour of perfectly normal repose. “So which do you believe?” asks John Peever, a sleep researcher at the University of Toronto, Canada.

After many decades, that question is finally attracting some answers, thanks to a type of analysis usually favoured by physicists. This has begun to pin down the underlying biology of this mysterious condition, and has uncovered some fundamental problems with the way we define sleep. It may even offer a new approach to understanding other long-standing mysteries of consciousness.

Insomnia is not to be taken lightly. Depending on the definition, anywhere from 15 to worldwide has problems sleeping. It has recently .

The public health consequences are huge: people with long-term sleep problems run a higher risk of hypertension, diabetes, obesity, heart attack and strokes. As a result, billions of dollars are spent every year on medical care and medication for such conditions.

Despite all this we don’t know much about insomnia, or indeed sleep itself. It’s not for lack of trying – after all, doctors want to help their patients, and the pharmaceutical industry has a gazillion-dollar incentive. But the neurochemical system that regulates sleep must be one of the most complex systems in the brain, which is already the most complex known system in the universe. “What’s being turned on and off with sleep is extremely complicated,” says Bonnet. “It has no single centre, no single neurotransmitter, no system.”

Back in 1968, however, two pioneering sleep researchers, Allan Rechtschaffen and Anthony Kales, put together . To do so, they looked at the electrical output of the brain.

Using an electroencephalograph (EEG) – a machine that reads the output of the brain’s billions of neurons via electrodes placed on the skull – Rechtschaffen and Kales mapped specific stages of sleep to corresponding brain patterns, or waves. Alpha waves, for example, are indicators of relaxed wakefulness and normally only show up in the early stages of sleep. The predominance of slower, languid delta waves is a sign of deep, restorative slow wave sleep, when growth hormones are secreted to repair tissues (see diagram). And so sleep analysis was formalised into a system that, with some minor revisions, has remained largely unchanged.

According to these criteria, verifying insomnia should be straightforward for a doctor: a predominance of “awake” signals and a corresponding lack of delta waves. But in the late 1970s, sleep researchers began to document . One 39-year-old woman came to a sleep researcher claiming not to have slept properly in 13 years. But like Rennik, after the usual tests her nightly sleep tally came to a standard 6.9 hours of shut-eye.

These patients contradicting their sleep tests soon incurred an entire catalogue of epithets: , sleep hypochondriacs and subjective insomniacs. The condition itself has been called or sleep state misperception. Assuming it was largely a psychological problem, sleep researchers invested little time in further investigation. “Sleeping insomniacs” were prescribed pills and told to stop watching television in their bedrooms, for example. Such treatments were unreliable, and tended not to work in the long term. Mainly, people like Rennik just went without sleep; or rather, sleep failed to restore them.

To understand how a physics technique changed the story, you first need to know what happens when a person goes to a sleep lab.

Over the past few decades, Rechtschaffen and Kales’s original EEG analyses have been augmented with signals from elsewhere on the body that tell sleep researchers what goes wrong with sleep (see “Why you can’t sleep“). When Rennik arrived at Bonnet’s sleep clinic, he was fitted with sensors to record the electrical signals emitted by his sleeping brain and by his muscles. A dozen channels were lined up like an orchestra score. The result, called a polysomnograph, or PSG, scrolled out of the printer and piled up neatly on the floor.

It then fell to a technician to closely read every page. Sleep techs pore over these vast tracts of rune-like squiggles, marking them off in 30-second increments, called epochs. On the basis of which EEG waves predominate, they make judgement calls and assign each epoch to one of the familiar stages of sleep.

But staging sleep in this way takes many hours and generates a daunting pile of paperwork. One night’s printout of Rennik’s sleep stretched to 900 pages. Michael Perlis, psychologist and sleep researcher at the University of Pennsylvania, Philadelphia, had a mentor who archived her research PSGs in a West Virginia salt mine.

The obvious solution was to automate the scoring: write an algorithm that could do everything the technician does, but within minutes. However, that software simply copied what the techs were doing: assess wave forms, assign sleep stages. Of the few commercial software packages that have been tested against trained technicians, . “Watch someone sleep for 8 to 10 hours?” says Sairam Parthasarathy, a sleep researcher at the University of Arizona in Tucson. “You’d have to have pretty smart technology to do that.” That’s why the American Academy of Sleep Medicine still requires .

But whether Rennik’s sleep was scrutinised by human analyst or software, his results showed the same thing – a person progressing normally through the usual stages of slumber, sharply at odds with his own perception.

“The assumption was that the patient is wrong and the PSG is right,” says Perlis. But the sheer number of people like Rennik . “If anything, the patient is right,” he says. “If you perceive something, you’re not asleep, and the more you remember from the night’s sleep, the less you experience sleep.” Peever agrees. “I think the PSG is not giving you the full story.”

Rethinking insomnia

To reconcile the two conflicting realities, they needed algorithms written not to imitate sleep techs, but to dig deeper into the waves, spindles and spikes, to find out whether the EEG might hold information about sleep that Rechtschaffen and Kales had overlooked. “If you could find a signature that distinguishes these insomniacs, you could say maybe they really have something consistent about the way their brains function,” says Daniel Buysse at the University of Pittsburgh, Pennsylvania.

But where do you start? And what do you look for? How could any sleep tech identify, in 900 pages of scribbles, patterns that no one had ever described?

Physicists have always needed methods to help them search through vast amounts of data for hidden signals. One of these techniques, called spectral analysis, has helped researchers in fields from atmospheric science to astronomy and geophysics.

Sure enough, spectral analysis has picked up plenty of stuff not obvious to a human wading through the sleep score, says Perlis, which “helps explain why the patient experiences sleep in one way and we score it another”.

The first things it uncovered were subtle differences in the EEGs of sleeping insomniacs: alpha waves – signatures of wakefulness that are supposed to show up only in early sleep – were intruding into deep sleep. Alpha intrusions can often be identified even without spectral analysis. “It looks like a choppy wave on top of a crown-like wave,” says Perlis. But Andrew Krystal of Duke University in Durham, North Carolina, used spectral analysis to quantify just how much they were intruding.

Krystal’s non-sleepers not only had a greater proportion of these alpha disturbances, but the alpha waves were bigger and the delta waves were correspondingly smaller.

That wasn’t all. When Perlis and other researchers applied spectral analysis algorithms to the EEGs of their sleeping insomniacs, they found different patterns, (Sleep, vol 24, p 110). Normally, these are indicators of consciousness, alertness and even anxiety. Rechtschaffen and Kales advised sleep techs to ignore these. “If I see them,” says Bonnet, “they look like junk to me, like an artefact you might see from tense muscles.”

Like alpha waves, Perlis calls these beta and gamma waves “intrusions” into normal sleep: “It’s as if somebody is playing with the switch – boop, boop – flipping at a mad rate between wake and sleep,” he says. More studies confirmed the link between beta and gamma waves and pseudoinsomnia.

“It’s as if somebody is flipping a switch at a mad rate between wake and sleep”

In light of these findings, more and more sleep researchers have begun to seriously rethink pseudoinsomnia. That’s good news for people like Rennik. Bonnet trained him to recognise the difference between his perception of being awake and the EEG’s report that he was asleep. Bonnet had identified . With some practice, Rennik got better at knowing whether or not he was awake. He says his sleep problem has improved, that is, he still doesn’t sleep well but he understands it better. At the very least, no one is calling him a hypochondriac.

But future treatments could go further. Spectral analysis could help people who battle with a wide range of insomnia. It could even take treatment beyond psychology.

Buysse says that spectral analysis could finally uncover the elusive objective “signature” of the brain’s output during sleep, the way blood pressure is a signature of the output of the cardiovascular system. This “objective quantifiable correlate,” says Martin Scharf at the Cleveland Sleep Research Center in Ohio, would mean a solid, measurable, replicable number to quantify the symptoms of insomnia, which has been “one of the holy grails of sleep research”.

With this information, it would be possible to investigate whether these waves reveal an underlying biological difference in the brains of insomniacs.

Some researchers are trying to piece this together. The work is still in its early days, and like much of the basic science of sleep, is still unclear. But greater beta and gamma power – what Perlis calls a “gained-up system” – may mean that arousal levels are higher in the brain of a sleeping insomniac, says Richard Bootzin of the University of Arizona. In other words, their problem is not so much that they don’t sleep but that, asleep or not, their brains are never quite off. “It’s the major hypothesis of what insomnia’s about,” he says.

Researchers are beginning to turn to the “always-on” hypothesis to explain forms of chronic insomnia beyond Rennik’s group. Earlier this year, a study by Rachel Salas at Johns Hopkins University in Baltimore, Maryland, and her colleagues revealed .

Around the clock, awake or not, their subjects’ brains showed enhanced activity compared with normal sleepers. One surprising consequence was that they picked up simple new tasks more quickly than their well-rested counterparts.

Always alert

The source of the “always on” disturbance seems to be neurons in the motor cortex. This, Salas’s team speculated, could point to new treatments that target the source of the hyper-arousal. They suggested transcranial magnetic stimulation (TMS) to regulate the electrical output of the misbehaving neurons with targeted bursts of high-intensity magnetic pulses. Indeed, . But because it involves medical supervision and large medical equipment, TMS may be too cumbersome and expensive to be a viable treatment for the majority of people with insomnia.

A friendlier option is transcranial direct current stimulation (tDCS), which works with batteries instead of giant magnets. “We’ve thought a lot about how you might use brain stimulation to intervene in cases of insomnia,” says Michael Weisend, a neuroscientist at Wright State University who works with the US air force to treat insomnia in soldiers. “It should be possible to use it to modify sleep,” he says, in particular to dampen the gamma intrusions. But it will take a lot of research, he cautions, to find the exact locations where stimulation would be most effective.

Spectral analysis might even help us probe other mysteries of consciousness. For example, Krystal’s alpha intrusions seem to correlate with a host of problems that – like pseudoinsomnia – have previously been considered unrelated to sleep: chronic pain and chronic fatigue syndrome, depression, and post-traumatic stress disorder. Scharf and others have also found alpha disturbances in the sleep of people with fibromyalgia, which involves chronic pain throughout the body.

The wide range of these links would come as no surprise to Parthasarathy. “In so many ways,” he says, “sleep is connected to our well-being.” It consolidates memory, improves mood, and boosts cognitive and physical performance. Perhaps it’s fitting that the people no one believed have yielded a key to understanding the whole field.

Leader: “Wake up – we need to know more about insomnia“

This article appeared in print under the headline “Fast awake and wide asleep”