Why We Sleep

by Matthew Walker

  If this were not wicked enough, there is an extra layer of malevolence to the condition that truly devastates the patient’s quality of life. Cataplectic attacks are not random, but are triggered by moderate or strong emotions, positive or negative. Tell a funny joke to a narcoleptic patient, and they may literally collapse in front of you. Walk into a room and surprise a patient, perhaps while they are chopping food with a sharp knife, and they will collapse perilously. Even standing in a nice warm shower can be enough of a pleasurable experience to cause a patient’s legs to buckle and have a potentially dangerous fall caused by the cataplectic muscle loss.

  Now extrapolate this, and consider the dangers of driving a car and being startled by a loud horn. Or playing an enjoyable game with your children, or having them jump on you and tickle you, or feeling strong, tear-welling joy at one of their musical school recitals. In a narcoleptic patient with cataplexy, any one of these may cause the sufferer to collapse into the immobilized prison of his or her own body. Consider, then, how difficult it is to have a loving, pleasurable sexual relationship with a narcoleptic partner. The list becomes endless, with predictable and heart-wrenching outcomes.

  Unless patients are willing to accept these crumpling attacks, which is really no option of any kind, all hope of living an emotionally fulfilling life must be abandoned. A narcoleptic patient is banished to a monotonic existence of emotional neutrality. They must forfeit any semblance of succulent emotions that we are all nourished by on a moment-to-moment basis. It is the dietary equivalent of eating the same tepid bowl of unflavorful porridge day after day. You can well imagine the loss of appetite for such a life.

  If you saw a patient collapse under the influence of cataplexy, you would be convinced that they had fallen completely unconscious or into a powerful sleep. This is untrue. Patients are awake and continue to perceive the outside world around them. Instead, what the strong emotion has triggered is the total (or sometimes partial) body paralysis of REM sleep without the sleep of the REM state itself. Cataplexy is therefore an abnormal functioning of the REM-sleep circuitry within the brain, wherein one of its features—muscle atonia—is inappropriately deployed while the individual is awake and behaving, rather than asleep and dreaming.

  We can of course explain this to an adult patient, lowering their anxiety during the event through comprehension of what is happening, and help them rein in or avoid emotional highs and lows to reduce cataplectic occurrences. However, this is much more difficult in a ten-year-old youngster. How can you explain such a villainous symptom and disorder to a child with narcolepsy? And how do you prevent a child from enjoying the normal roller coaster of emotional existence that is a natural and integral part of a growing life and developing brain? Which is to say, how do you prevent a child from being a child? There are no easy answers to these questions.

  We are, however, beginning to discover the neurological basis of narcolepsy and, in conjunction, more about healthy sleep itself. In chapter 3, I described the parts of the brain involved in the maintenance of normal wakefulness: the alerting, activating regions of the brain stem and the sensory gate of the thalamus that sits on top, a setup that looks almost like a scoop of ice cream (thalamus) on a cone (brain stem). As the brain stem powers down at night, it removes its stimulating influence to the sensory gate of the thalamus. With the closing of the sensory gate, we stop perceiving the outside world, and thus we fall asleep.

  What I did not tell you, however, was how the brain stem knows that it’s time to turn off the lights, so to speak, and power down wakefulness to begin sleep. Something has to switch the activating influence of the brain stem off, and in doing so, allow sleep to be switched on. That switch—the sleep-wake switch—is located just below the thalamus in the center of the brain, in a region called the hypothalamus. It is the same neighborhood that houses the twenty-four-hour master biological clock, perhaps unsurprisingly.

  The sleep-wake switch within the hypothalamus has a direct line of communication to the power station regions of the brain stem. Like an electrical light switch, it can flip the power on (wake) or off (sleep). To do this, the sleep-wake switch in the hypothalamus releases a neurotransmitter called orexin. You can think of orexin as the chemical finger that flips the switch to the “on,” wakefulness, position. When orexin is released down onto your brain stem, the switch has been unambiguously flipped, powering up the wakefulness-generating centers of the brain stem. Once activated by the switch, the brain stem pushes open the sensory gate of the thalamus, allowing the perceptual world to flood into your brain, transitioning you to full, stable wakefulness.

  At night, the opposite happens. The sleep-wake switch stops releasing orexin onto the brain stem. The chemical finger has now flipped the switch to the “off” position, shutting down the rousing influence from the power station of the brain stem. The sensory business being conducted within the thalamus is closed down by a sealing of the sensory gate. We lose perceptual contact with the outside world, and now sleep. Lights off, lights on, lights off, lights on—this is the neurobiological job of the sleep-wake switch in the hypothalamus, controlled by orexin.

  Ask an engineer what the essential properties of a basic electrical switch are, and they will inform you of an imperative: the switch must be definitive. It must either be fully on or fully off—a binary state. It must not float in a wishy-washy manner between the “on” and “off” positions. Otherwise, the electrical system will not be stable or predictable. Unfortunately, this is exactly what happens to the sleep-wake switch in the disorder of narcolepsy, caused by marked abnormalities of orexin.

  Scientists have examined the brains of narcoleptic patients in painstaking detail after they have passed away. During these postmortem investigations, they discovered a loss of almost 90 percent of all the cells that produce orexin. Worse still, the welcome sites, or receptors, of orexin that cover the surface of the power station of the brain stem were significantly reduced in number in narcoleptic patients, relative to normal individuals.

  Because of this lack of orexin, made worse by the reduced number of receptor sites to receive what little orexin does drip down, the sleep-wake state of the narcoleptic brain is unstable, like a faulty flip-flop switch. Never definitively on or off, the brain of a narcoleptic patient wobbles precariously around a middle point, teeter-tottering between sleep and wakefulness.

  The orexin-deficient state of this sleep-wake system is the main cause of the first and primary symptom of narcolepsy, which is excessive daytime sleepiness and the surprise attacks of sleep that can happen at any moment. Without the strong finger of orexin pushing the sleep-wake switch all the way over into a definitive “on” position, narcoleptic patients cannot sustain resolute wakefulness throughout the day. For the same reasons, narcoleptic patients have terrible sleep at night, dipping into and out of slumber in choppy fashion. Like a faulty light switch that endlessly flickers on and off, day and night, so goes the erratic sleep and wake experience suffered by a narcoleptic patient across each and every twenty-four-hour period.

  Despite wonderful work by many of my colleagues, narcolepsy currently represents a failure of sleep research at the level of effective treatments. While we have effective interventions for other sleep disorders, such as insomnia and sleep apnea, we lag far behind the curve for treating narcolepsy. This is in part due to the rarity of the condition, making it unprofitable for drug companies to invest their research effort, which is often a driver of fast treatment progress in medicine.

  For the first symptom of narcolepsy—daytime sleep attacks—the only treatment used to be high doses of the wake-promoting drug amphetamine. But amphetamine is powerfully addictive. It is also a “dirty” drug, meaning that it is promiscuous and affects many different chemical systems in the brain and body, leading to terrible side effects. A newer, “cleaner” drug, called Provigil, is now used to help narcoleptic patients stay more stably awake during the day and has fewer downsides. Yet it is marginally effective.


  Antidepressants are often prescribed to help with the second and third symptoms of narcolepsy—sleep paralysis and cataplexy—as they suppress REM sleep, and it is REM-sleep paralysis that is integral to these two symptoms. Nevertheless, antidepressants simply lower the incidence of both; they do not eradicate them.

  Overall, the treatment outlook for narcoleptic patients is bleak at present, and there is no cure in sight. Much of the treatment fate of narcolepsy sufferers and their families resides in the slower-progressing hands of academic research, rather than the more rapid progression of big pharmaceutical companies. For now, patients simply must try to manage life with the disorder, living as best they can.

  Some of you may have had the same realization that several drug companies did when we learned about the role of orexin and the sleep-wake switch in narcolepsy: could we reverse-engineer the knowledge and, rather than enhance orexin to give narcoleptic patients more stable wakefulness during the day, try and shut it off at night, thereby offering a novel way of inducing sleep in insomnia patients? Pharmaceutical companies are indeed trying to develop compounds that can block orexin at night, forcing it to flip the switch to the “off” position, potentially inducing more naturalistic sleep than the problematic and sedating sleep drugs we currently have.

  Unfortunately, the first of these drugs, suvorexant (brand name Belsomra), has not proved to be the magic bullet many hoped. Patients in the FDA-mandated clinical trials fell asleep just six minutes faster than those taking a placebo. While future formulations may prove more efficacious, non-pharmacological methods for the treatment of insomnia, outlined in the next chapter, remain a far superior option for insomnia sufferers.

  FATAL FAMILIAL INSOMNIA

  Michael Corke became the man who could not sleep—and paid for it with his life. Before the insomnia took hold, Corke was a high-functioning, active individual, a devoted husband, and a teacher of music at a high school in New Lexon, just south of Chicago. At age forty he began having trouble sleeping. At first, Corke felt that his wife’s snoring was to blame. In response to this suggestion, Penny Corke decided to sleep on the couch for the next ten nights. Corke’s insomnia did not abate, and only became worse. After months of poor sleep, and realizing the cause lay elsewhere, Corke decided to seek medical help. None of the doctors who first examined Corke could identify the trigger of his insomnia, and some diagnosed him with sleep-unrelated disorders, such as multiple sclerosis.

  Corke’s insomnia eventually progressed to the point where he was completely unable to sleep. Not a wink. No mild sleep medications or even heavy sedatives could wrestle his brain from the grip of permanent wakefulness. Should you have observed Corke at this time, it would be clear how desperate he was for sleep. His eyes would make your own feel tired. His blinks were achingly slow, as if the eyelids wanted to stay shut, mid-blink, and not reopen for days. They telegraphed the most despairing hunger for sleep you could imagine.

  After eight straight weeks of no sleep, Corke’s mental faculties were quickly fading. This cognitive decline was matched in speed by the rapid deterioration of his body. So compromised were his motor skills that even coordinated walking became difficult. One evening Corke was to conduct a school orchestral performance. It took several painful (though heroic) minutes for him to complete the short walk through the orchestra and climb atop the conductor’s rostrum, all cane-assisted.

  As Corke approached the six-month mark of no sleep, he was bedridden and approaching death. Despite his young age, Corke’s neurological condition resembled that of an elderly individual in the end stages of dementia. He could not bathe or clothe himself. Hallucinations and delusions were rife. His ability to generate language was all but gone, and he was resigned to communicating through rudimentary head movements and rare inarticulate utterances whenever he could muster the energy. Several more months of no sleep and Corke’s body and mental faculties shut down completely. Soon after turning forty-two years old, Michael Corke died of a rare, genetically inherited disorder called fatal familial insomnia (FFI). There are no treatments for this disorder, and there are no cures. Every patient diagnosed with the disorder has died within ten months, some sooner. It is one of the most mysterious conditions in the annals of medicine, and it has taught us a shocking lesson: a lack of sleep will kill a human being.

  The underlying cause of FFI is increasingly well understood, and builds on much of what we have discussed regarding the normal mechanisms of sleep generation. The culprit is an anomaly of a gene called PrNP, which stands for prion protein. All of us have prion proteins in our brain, and they perform useful functions. However, a rogue version of the protein is triggered by this genetic defect, resulting in a mutated version that spreads like a virus.fn2 In this genetically crooked form, the protein begins targeting and destroying certain parts of the brain, resulting in a rapidly accelerating form of brain degeneration as the protein spreads.

  One region that this malfeasant protein attacks, and attacks comprehensively, is the thalamus—that sensory gate within the brain that must close shut for wakefulness to end and sleep to begin. When scientists performed postmortem examinations of the brains of early sufferers of FFI, they discovered a thalamus that was peppered with holes, almost like a block of Swiss cheese. The prion proteins had burrowed throughout the thalamus, utterly degrading its structural integrity. This was especially true of the outer layers of the thalamus, which form the sensory doors that should close shut each night.

  Due to this puncturing attack by the prion proteins, the sensory gate of the thalamus was effectively stuck in a permanent “open” position. Patients could never switch off their conscious perception of the outside world and, as a result, could never drift off into the merciful sleep that they so desperately needed. No amount of sleeping pills or other drugs could push the sensory gate closed. In addition, the signals sent from the brain down into the body that prepare us for sleep—the reduction of heart rate, blood pressure, and metabolism, and the lowering of core body temperature—all must pass through the thalamus on their way down the spinal cord, and are then mailed out to the different tissues and organs of the body. But those signals were thwarted by the damage to the thalamus, adding to the impossibility of sleep in the patients.

  Current treatment prospects are few. There has been some interest in an antibiotic called doxycycline, which seems to slow the rate of the rogue protein accumulation in other prion disorders, such as Creutzfeldt-Jakob disease, or so-called mad cow disease. Clinical trials for this potential therapy are now getting under way.

  Beyond the race for a treatment and cure, an ethical issue emerges in the context of the disease. Since FFI is genetically inherited, we have been able to retrospectively trace some of its legacy through generations. That genetic lineage runs all the way back into Europe, and specifically Italy, where a number of afflicted families live. Careful detective work has rolled the genetic timeline back further, to a Venetian doctor in the late eighteenth century who appeared to have a clear case of the disorder. Undoubtedly, the gene goes back even further than this individual. More important than tracing the disease’s past, however, is predicting its future. The genetic certainty raises a eugenically fraught question: If your family’s genes mean that you could one day be struck down by the fatal inability to sleep, would you want to be told your fate? Furthermore, if you know that fate and have not yet had children, would that change your decision to do so, knowing you are a gene carrier and that you have the potential to prevent a next-step transmission of the disease? There are no simple answers, certainly none that science can (or perhaps should) offer—an additionally cruel tendril of an already heinous condition.

  SLEEP DEPRIVATION VS. FOOD DEPRIVATION

  FFI is still the strongest evidence we have that a lack of sleep will kill a human being. Scientifically, however, it remains arguably inconclusive, as there may be other disease-related processes that could contribute to death, and they are hard to distinguish from those of a lack of sleep. There h
ave been individual case reports of humans dying as a result of prolonged total sleep deprivation, such as Jiang Xiaoshan. He was alleged to have stayed awake for eleven days straight to watch all the games of the 2012 European soccer championships, all the while working at his job each day. On day 12, Xiaoshan was found dead in his apartment by his mother from an apparent lack of sleep. Then there was the tragic death of a Bank of America intern, Moritz Erhardt, who suffered a life-ending epileptic seizure after acute sleep deprivation from the work overload that is so endemic and expected in that profession, especially from the juniors in such organizations. Nevertheless, these are simply case studies, and they are hard to validate and scientifically verify after the fact.

  Research studies in animals have, however, provided definitive evidence of the deadly nature of total sleep deprivation, free of any comorbid disease. The most dramatic, disturbing, and ethically provoking of these studies was published in 1983 by a research team at the University of Chicago. Their experimental question was simple: Is sleep necessary for life? By preventing rats from sleeping for weeks on end in a gruesome ordeal, they came up with an unequivocal answer: rats will die after fifteen days without sleep, on average.

  Two additional results quickly followed. First, death ensued as quickly from total sleep deprivation as it did from total food deprivation. Second, rats lost their lives almost as quickly from selective REM-sleep deprivation as they did following total sleep deprivation. A total absence of NREM sleep still proved fatal, it just took longer to inflict the same mortal consequence—forty-five days, on average.

  There was, however, an issue. Unlike starvation, where the cause of death is easily identified, the researchers could not determine why the rats had died following sleep’s absence, despite how quickly death had arrived. Some hints emerged from assessments made during the experiment, as well as the later postmortems.