MORE ABOUT THIS BOOK
We think of sleep as a tranquil act, when our minds are stilled and our brains are quiet. The act of sleeping is a passive one, and is associated with a blissful unconsciousness and the delight of waking refreshed. The only awareness we might have of something happening in the night are the fragments of a dream. That is, at least, for most of us. But for many of the patients in my sleep clinic, their nights are anything but this. Rather, a night in the sleep laboratory, where I admit my patients to study their nocturnal behaviour, is punctuated by shouts, jerks, snores, twitches or even more dramatic goings-on, and the torture of poor or even no sleep at all.
The normal expectation of waking up feeling ready for the day ahead is rarely found among my patients, or indeed their partners. Their nights are tormented by a range of conditions, such as terrifying nocturnal hallucinations, sleep paralysis, acting out their dreams or debilitating insomnia. The array of activities in sleep reflects the spectrum of human behaviour in our waking lives. Sometimes these medical problems have a biological explanation, at other times a psychological one, and the focus of the clinical work that I and my colleagues do is to unravel the causes for their sleep disorders and attempt to find a treatment or cure.
For the past few years, I have seen hundreds of patients per year with sleep disorders, causing insomnia, profound excessive daytime sleepiness or bizarre and frightening experiences at night. My path to this work has been accidental. In keeping with most doctors of my generation, my exposure to the world of sleep during my medical degree was pretty much non-existent. I cannot recall a single moment of teaching that focused on sleep until well into my clinical training as a neurologist, almost a decade after I graduated. It was only by chance, when I opted for an intercalated degree in neuroscience as a nineteen-year-old, that I was asked to write an essay on the function of sleep. As a naive but intellectually curious teenager, I had assumed, like most people, that the function of sleep was to stop you feeling sleepy, and that assumption was born out of personal experience. I went to bed when sleepy, and when I woke up, that sleepiness had left me.
However, in preparation for that essay, I came across a paper co-authored by Francis Crick, one of the discoverers of the structure of DNA. Crick had in later life become increasingly fascinated by consciousness and neuroscience, in part driven by a sabbatical at the Salk Institute in San Diego, a world-leading centre in neuroscience research. In that paper, Crick and his colleague speculated as to the function of dreaming, which at that time was thought to exclusively happen during a stage of sleep known as rapid eye movement (REM) sleep. They argued that the function of dreaming, rather than representing a Freudian ‘royal road to the unconscious’, was a form of housekeeping for the brain. Dreaming, they postulated, acts to prune out connections between cells in the brain that have developed during the day, and constitutes a type of ‘reverse learning’ to get rid of useless information. The validity of this hypothesis remains controversial, but reading this paper was a light-bulb moment for an ignorant but interested medical student. The realisation that sleep not only had a purpose other than making you feel less sleepy, but was also a complex set of brain states, not simply a state of unconsciousness between going to bed and waking up, had a profound effect. It sparked my interest in sleep and its disorders, and has led me into this fascinating and often bizarre clinical realm of sleep medicine.
In this twilight world, glitches in the human brain result in striking and poorly understood conditions. All the more so as, in contrast to chest pain, headaches, skin rashes and more usual medical symptoms, these problems most often arise without any awareness, at a time when people’s brains and minds are detached from their internal and external world.
In the pages that follow, I will introduce you to some of my patients who have been willing to share their stories. The tales of these individuals are dramatic, terrifying, illuminating, poignant and sometimes amusing. You will see how their disorders affect the lives of those around them, their relationships with partners and children, as well as their own.
So why is it that I’m writing about these patients? And, more importantly, why should you read about them? Many of the stories that follow are about patients with extreme sleep disorders, at the very limits of the spectrum of human experience, and it is by studying these extremes that we can learn about the less severe end of the spectrum; by understanding how these patients are affected by their sleep disorders, we come to know a little about how we ourselves are affected by our sleep. Many of these conditions are not rare, either: chronic insomnia affects one in ten adults; sleep apnoea about one in fifteen; and restless legs syndrome (RLS) about one in twenty. It is almost certain that anyone reading this book will either suffer from one or more of these disorders themselves or know someone close to them who does.
* * *
Doctors love stories; we love telling them and we love hearing them. We teach, learn and entertain each other with stories. In medical parlance, what a patient tells you in their own words is the history, the story, of their problem. As medical students and junior doctors, we acquire the skills to extract this history. Our medical journals and conferences are full of case histories, and it is precisely through the sharing of these stories that we circulate expertise and further our knowledge base.
I am a neurologist first and foremost, and the skills that I have learned through my neurological training are equally applicable in the practice of sleep medicine. As registrars (the equivalent of senior residents in the US) at the National Hospital for Neurology, Queen Square, in central London, we were exposed to a rite of passage: the venerated Gowers Round on a Thursday afternoon. Largely for teaching purposes, but also to provide some entertainment, this session takes place in a large lecture theatre with steep stalls. From the second row, where the neurology registrars sat, it felt a little like being in one of the amphitheatres of Rome — and we were about to be fed to the lions. The craftiest registrars among us would find a patient that urgently needed assessment on the wards so that they could creep into the rear of the auditorium late, along with the hordes of junior doctors, medical students and visiting neurologists from abroad. The most devious would arrange for a colleague to page them early in the proceedings so they could make a show of leaving to deal with ‘an emergency’ before sneaking in at the back of the lecture theatre later on.
The audience would await the sporting event with gleeful anticipation, while the registrars could only hope to survive the ordeal with a shred of dignity left intact. I have heard stories of colleagues vomiting in nervousness every Thursday lunchtime, others taking a beta-blocker pill to calm their anxiety prior to entering. For a painful ninety minutes, three cases would be presented. Usually the patients would be wheeled in at the front and the consultant chairing Gowers that day would grill the registrars on the cases, often exposing gaping holes in our knowledge under the glare of the 200 people sitting behind us.
After a particularly humiliating session, you would feel 400 eyes burning into the back of your head, as you wished that the earth would open up and swallow you whole. Some of my colleagues still talk about their most painful experiences twenty years later, such is the impact. (Even writing about it now I feel a slight flush, a delicate churning in the stomach …) As excruciating as these rounds were, they provided a fantastic opportunity to learn and to see conditions that you might never have heard of before, the knowledge perhaps reinforced by the sheer terror of the lesson. (I myself shall remember Triple-A syndrome and its association with neurological problems until my dying days, even though I have never heard it even mentioned since.)
While the fear of total humiliation in the Gowers Round sharpens the mind, it is hearing the complex stories of these patients that is its most valuable aspect. It is the patient history that physicians in general and neurologists in particular fixate upon, and the same can be said in sleep medicine. By far the most useful information when making or ‘formulating’ a diagnosis is the history, not the examination or the results of blood tests or scans. A man’s recollection of some twitching in the left hand just before he fell and injured his head, suggesting a seizure arising in the right motor area of the brain, which leads to the diagnosis of a brain tumour; a young woman who reports visual loss spreading slowly over minutes across the visual field, confirming the visual aura of migraine — the spread of abnormal electrical activity associated with migraine head-aches across the visual cortex — rather than an eye problem; the episode of dizziness several years previously that suggests that the woman sitting in front of you with a tingly hand may have multiple sclerosis rather than nerve impingement in the wrist; or the family history of imbalance, implying that the man with heavy alcohol use might have coordination difficulties due to a genetic disorder rather than as a result of his excessive drinking. The best neurologists I have worked with are the ones who have the patience and the ruthless determination to extract the full history, like a forensic FBI interrogator.
Such is the focus on the use of case histories for teaching that the case presentation is the standard way in which doctors are trained and their expertise is maintained. It enables us to ‘experience’ rare cases that we may at some point see in the future — hence the Gowers Round and its variations that exist in hospitals throughout the world.
During an admission into hospital, most patients are frustrated by the repetitive ‘taking’ of their history by medical students, tiers of junior doctors, generalists, specialty teams and consultants. The history is regurgitated and pored over again and again, and various aspects are repeatedly explored further. The impact of the condition on various aspects of one’s life are surveyed but, as a rule, this facet of our patients’ stories is something we do less well in the melee of a busy out-patient clinic, with the number of patients waiting outside our door ever increasing, under the irritated stares of people who have been waiting way beyond their appointment times. Our understanding of their relationship with their condition, how it affects their social or family life, and the minutiae of their complaints that are irrelevant to moving forward in the management of their illness are bystander casualties to efficiency. In reality, we simply try to extract all the necessary information to make a firm diagnosis and to formulate a treatment plan in the minimum possible time, so that we can move on to the next person.
As a schoolboy, I vividly remember picking up a copy of Oliver Sacks’s book, The Man Who Mistook His Wife for a Hat. As I read these stories of a mariner unable to form new memories, of a man who could not recognise his own leg, of the woman who heard music as a result of epileptic seizures, I was gripped. But it was the context in which he put these symptoms, the impact on the lives of the human beings in front of him, that led to a deeper understanding of the nature of these conditions and how they affect us. And it was reading these stories that inspired my interest in neuroscience, and no doubt many of my colleagues too.
* * *
Neurologists are obsessed by ‘lesions’, the medical term for damage or injury. Whenever we assess a patient, we ask ourselves where the lesion is. We put together the symptoms and signs to ‘localise the lesion’, to identify its location in the nervous system. The damage may be due to a stroke, an injury, or a tumour. It may be visible to the naked eye or evident on a scan. It may be microscopic, only detectable after a biopsy or post-mortem. Or it might be transient, a ‘lesion’ that results from the temporary dysfunction of a small part of the nervous system due to an electrical aberration. But it is not just numbness of the arm or paralysis of the face that can be understood in terms of a lesion. Many of the sleep disorders that you will hear about in the following chapters are also a direct result of lesions.
Perhaps the most famous lesion of all in the world of neurology affected the brain of a man called Phineas Gage. Born in Grafton County, New Hampshire, Gage began working with explosives in his youth, perhaps on farms or nearby quarries. His introduction to blasting powder turned out to be very unfortunate for him, but very fortunate for modern neurology. At around 4.30 p.m. on 13 September 1848, near Cavendish, Vermont, while managing a work gang blasting rock to build a local railroad, the 25-year-old Gage was tamping explosive into a hole with a tamping iron, a long metal pole designed to pack explosive tightly. As he pushed it down, it must have sparked against the rock, igniting the explosive in the hole. The tamping iron flew out of the hole like a spear, whereupon it impaled Gage, entering the left side of his face, passing behind his left eye and smashing through the front of his brain and the top of his skull. The javelin-like rod landed some distance away, ‘smeared in blood and brain’. Extraordinarily, after a brief convulsion, he sat up and was taken to the local doctor in an oxcart. According to this doctor’s gruesome account,
I first noticed the wound upon the head before I alighted from my carriage, the pulsations of the brain being very distinct. The top of the head appeared somewhat like an inverted funnel, as if some wedge-shaped body had passed from below upward. Mr Gage, during the time I was examining this wound, was relating the manner in which he was injured to the bystanders. I did not believe Mr Gage’s statement at that time, but thought he was deceived. Mr Gage persisted in saying that the bar went through his head. Mr G. got up and vomited; the effort of vomiting pressed out about half a teacupful of the brain, which fell upon the floor.
Gage’s survival, especially in the mid-nineteenth century, was truly remarkable. But even more so was the change that occurred in him after the accident. After a long convalescence, complicated by delirium, infection and coma, he finally made it to his parents’ home some ten weeks later. It was not the same man who returned, however.
The details are scant, but prior to his accident he was described as hardworking, diligent and popular. His employers praised him as ‘the most efficient and capable foreman in their employ’. After that dreadful accident, though, Harlow, one of his physicians, wrote,
The equilibrium or balance, so to speak, between his intellectual faculties and animal propensities, seems to have been destroyed. He is fitful, irreverent, indulging at times in the grossest profanity (which was not previously his custom), manifesting but little deference for his fellows, impatient of restraint or advice when it conflicts with his desires, at times pertinaciously obstinate, yet capricious and vacillating, devising many plans of future operations, which are no sooner arranged than they are abandoned in turn for others appearing more feasible. A child in his intellectual capacity and manifestations, he has the animal passions of a strong man. Previous to his injury, although untrained in the schools, he possessed a well-balanced mind, and was looked upon by those who knew him as a shrewd, smart business man, very energetic and persistent in executing all his plans of operation. In this regard his mind was radically changed, so decidedly that his friends and acquaintances said he was ‘no longer Gage’.
It seems that what had once been a pleasant, social man had been replaced with a belligerent, swearing and unpleasant character: ‘He was gross, profane, coarse, and vulgar, to such a degree that his society was intolerable to decent people.’ The story of Gage took on a life of its own, and was no doubt exaggerated and overblown with repetitive telling. In reality, it appears that in later life he was left less affected. But his was certainly one of the most famous historical cases of localisation, illustrating that different parts of the brain have different functions. Damage to the frontal lobes, whether through tumour, types of dementia or tamping iron, is known to cause personality change, and suggests that the frontal lobes have a fundamental role in our social behaviour and planning.
Correlating lesions to symptoms or signs, therefore, allows us to understand how our brains function, how they are organised and how our lives are determined by them. These lesions may be accidental or caused by disease. In animal experiments, they may be created by design. In clinical practice, we endeavour to characterise the location of the lesion in the nervous system. We attempt to form a unifying diagnosis, a single underlying cause to explain all the symptoms and examination findings.
In the world of sleep, however, this principle of Occam’s razor — that the simplest explanation, a single diagnosis, should be sought to explain everything — does not always apply. Of course, in the neurology clinic, the explanation for a patient’s migraine may be influenced by their stress levels or whether they have drunk alcohol, but for the most part this does not alter the diagnosis. In contrast, however, as anyone will testify, sleep is the absolute confluence of factors biological, social, environmental and psychological. Clearly anxiety may cause the tingling in your hands, and noise may worsen your migraine, but the link between your snoring, your work shift pattern, your noisy bedroom, your anxiety and your experience of sleep is so much more direct; these factors so much more fundamental to the difference between feeling rested and alert or exhausted beyond belief. Understanding all these aspects of your life is crucial to the evaluation of your sleep. But exploring all these facets can be a challenge in a thirty-minute consultation, especially when you are taking notes, struggling with the computer and dictating a letter at the same time.
Yet many of the sleep disorders that you will read about in the following chapters, like other neurological disorders, represent lesions of the nervous system — largely microscopic, transient or genetically determined, but lesions nonetheless. They are nature’s experiments, giving us a window of opportunity to understand ourselves and help us identify how glitches in the brain’s control of sleep can result in this huge array of phenomena. We will see how lesions of the brain result in uncontrollable sleep attacks, vivid dreams, hallucinations, sleep paralysis and collapses during the day. How abnormalities in the brainstem cause us to act out our dreams, and how genetic factors influence our ability to walk, eat, have sex or even ride a motorbike in our sleep. How chemical abnormalities in the nervous system can give rise to odd and distressing sensations at night. How our genes influence our body clock. And how seizures arising in our sleep can generate terrifying nocturnal experiences. Thus these phenomena can tell us about how our brains regulate our sleep, and how various aspects of our sleep are controlled.
Other patients in this book will illustrate how psychological or biological factors can influence sleep, causing debilitating insomnia, for instance, or sleep apnoea, where your breathing disrupts your sleep. One story in particular will demonstrate how a partner can have a huge impact on one’s sleep. But even in these cases, when the cause is not related to damage in the nervous system, sleep itself is lesioned, disrupted or altered in some way. Through these case studies we also gain insight into the role of normal sleep in maintaining the brain — memory, mood, vigilance — through the impact of sleep deprivation or interference. These individuals provide windows into our understanding of the importance of sleep in the maintenance of physical, psychological and neurological health.
* * *
I am eager to introduce you to my patients and their stories, but before I do so, please forgive me a brief but important digression. To appreciate abnormal sleep, it is helpful to understand normal sleep. As we pass through life, our sleep changes, both in quantity and in quality. A newborn will sleep for two-thirds of the day, but by the time we are adults, we tend to sleep between roughly six and a half and eight and a half hours a night. Sleep is not a static state, however, and there are actually multiple stages involved.
As we first drift off, we enter into Stage 1 sleep, also known as drowsiness. The brain exhibits a quietening of normal waking electrical activity and the eyes slowly roll from side to side. As sleep progresses, we enter into Stage 2 sleep — light sleep — when the brain activity slows further. When we record the brainwaves during this stage, features called sleep spindles and K-complexes — transient alterations in the background brainwave rhythm not evident in wakefulness — become visible. By the time we reach Stage 3 sleep — deep sleep — usually within about thirty minutes or so of drifting off, the brainwaves slow considerably but increase in size. This stage is therefore sometimes referred to as ‘slow-wave’ sleep. Stages 1 to 3 are considered non-rapid eye movement (non-REM) sleep, and it is only after sixty to seventy-five minutes or so that we enter into rapid eye movement (REM) sleep.
As we will see, in REM sleep, the eyes dart back and forth rapidly, the brainwaves look to be highly active — a little like being awake — and it is in this stage of sleep that we most obviously dream. As adults, over the course of the night we cycle through these various stages of sleep, usually four or five times, with the majority of deep, Stage 3 sleep in the first half of the night, and the majority of REM sleep in the second half.
As we age, the proportions of these various stages of sleep change. As newborns, we spend about half of our sleep in REM sleep, while in adults this ranges from 15—25 per cent, gradually falling as we approach old age. The proportion of Stage 3 sleep also changes, being roughly 15—25 per cent in adulthood, but dropping a little in the elderly, usually replaced by Stage 1 and 2 sleep. As we get older, the amount of wakefulness at night (very brief awakenings) increases too. As I will go on to show you, a complex system of brain nuclei, brain circuits and neurotransmitters regulate this biological process, controlling the initiation and termination of sleep, as well as the switch between non-REM and REM sleep.
There are two further processes that are important to grasp, since these mechanisms control the drive to sleep. The first is the homeostatic mechanism.
As anyone will know, the longer you have been awake, the stronger your drive to sleep. With prolonged wakefulness, levels of certain neurotransmitters that promote sleep build up, increasing sleepiness and thus promoting sleep onset. But the second potent force is that of the circadian clock, as we will go on to see.
Within us sits a timekeeper, an internal clock that co-ordinates our neurological and bodily functions with the external world. As we approach the dead of night, this clock exerts its strongest influence, compelling us to sleep, and in the daytime makes us feel more alert.
For the most part, these two mechanisms, the circadian and homeostatic, work in sync to ensure we sleep an appropriate amount at night and feel wide awake during the day. At least, they do when they are both working properly.
* * *
What I describe in the subsequent pages are patients I have seen over the years in the Sleep Disorders Centre, Guy’s Hospital, and at London Bridge Hospital. I have been incredibly fortunate to know some of these people for many years and to have gained an insight into their conditions and their lives. For others, I have had opportunities to delve into their world more deeply, to meet them and their families in their homes, outside the constraints of the clinic, where time is less restricted and our discussions more leisurely. They have all consented and collaborated in the descriptions of their cases, ensuring accuracy and veracity. The only details changed are names where marked with an asterisk.
These patients illustrate the fundamental importance of sleep to our lives. And, as neurologist Oliver Sacks so aptly put it: ‘In examining disease, we gain wisdom about anatomy and physiology and biology. In examining the person with disease, we gain wisdom about life.’
GREENWICH MEAN TIME
If you have ever been on a long-haul flight crossing time zones, the feeling of jet lag will be all too familiar. You know something is amiss: you feel sluggish and detached from your environment; the bright sunshine of your destination is discordant with your yearning to be tucked up in bed. There is the nausea of needing to stay awake when every fibre in your body craves sleep, or the incongruity of being wide awake at 2 a.m. while the world around you slumbers, and all you can think about is breakfast. Thankfully, your body soon adjusts, and within a few days you are back in tune with life around you. But imagine if that was how you felt all the time, that it was the reality of your daily life, and there was no hope of recovery.
I first meet Vincent, and his mother Dahlia, at Guy’s Hospital. He is sixteen years old, and this particular clinic is specifically for teenagers transitioning from the sleep services in the children’s hospital to the adult world. Typically, this clinic is full of children with narcolepsy or severe sleepwalking. But Vincent is not typical in this regard — or, indeed, any other. He is a shy and reserved teenager, not particularly tall but stocky and well-built. I learn that this is testament to his enthusiasm for boxing. Dahlia, in contrast, is bubbly and very talkative. Originally from South America, she speaks English fluently but with a strong accent and at a machine-gun pace. For the most part, Vincent sits there quietly as Dahlia tells me the story of the past few years, only interrupting when his frustration bubbles over. When he does talk, he is slow and hesitant; he occasionally finds it difficult to find his words.
Between them, they paint a picture of Vincent’s life.
Vincent first became aware of some difficulties with sleep at around the age of nine or ten, but it was really only at the age of thirteen that his problems became much more evident. Dahlia thinks it started after Vincent had two operations on his hip, the second to remove metal plates inserted during the first procedure.
‘Well, it was kind of gradual. At first I didn’t really know what was happening,’ Vincent tells me. He was initially finding it harder and harder to fall asleep, drifting off at three or four in the morning. ‘The first time I properly realised it was a problem was when I was always trying to go to sleep, and then I started seeing the sun rise every time.’
It quickly got to the point where Vincent would be wanting to fall asleep at eleven in the morning and wake up at nine in the evening. Unsurprisingly, his schooling quickly began to suffer. ‘I really missed a lot of school. At first I didn’t want to tell anybody that I was having trouble sleeping, because they would just think that I’m lazy. So I just told them I was unwell a lot.’
For Dahlia, this time in their lives still stings. ‘I started to notice when I was trying to wake him up to go to school that I could not wake him for love nor money. I would shake him, but just not be able to get him up. I was so confused because he had never been late for primary school. Never! I thought I was being judged as a mother. Possibly Vincent thought he was being judged as a student too. I got into so much trouble with his school. I was fined for Vincent’s poor attendance!’
Vincent also recalls feeling judged: ‘The school, my dad and friends found it hard to understand.’ Some people, including his father, from whom Dahlia is separated, raised the likelihood that it was simply a case of a typical teenager oversleeping, or that it was psychosomatic. In fact, I think Vincent’s father still considers this to be the case. On one occasion, I spoke to Dahlia on the telephone and I could hear him in the background, arguing with her that there was no medical issue.
Dahlia knew that there was more to it than teenage sleep patterns, however, and as Vincent’s school attendance dropped further, she sought medical advice. Dahlia recalls taking Vincent to see their family doctor. ‘We went maybe about seven or eight times, a few months apart, just to say Vincent has a problem with sleep. [We got] the usual recommendations — give him a hot milky drink before bedtime, no screens at night — all of that. Lavender oil…’ she scoffs.
The problem nevertheless persisted, and eventually Vincent was referred to a paediatrician. It was at this point, some two years after he had realised he had a problem, that Vincent finally received a diagnosis: Vincent’s internal body clock seemed to be set at the wrong time. Rather than being attuned to the world around him, he was told by doctors that his own body clock was running several hours later than everyone else’s. He was diagnosed with delayed sleep phase syndrome.
* * *
We are all children of the sun. We are enthralled by it, and enslaved by it; we march to the beat of the sun’s drum. Our sleep patterns are defined by the 24-hour rhythm of the rotation of the earth and our exposure to the sun’s light. This makes total sense: to be awake and foraging for food when it is light and we can see prey and predators, and to sleep when it is dark and we are vulnerable to predation, seems crucial to our survival. It is not only our sleep that is defined by this rhythm, however.
Type ‘circadian rhythm’ — from the Latin for ‘about a day’ and the name for this 24-hour cycle — into PubMed, the most widely used search engine in the life sciences and medicine, and it will return over 70,000 hits — papers with titles ranging from ‘Biological clocks and rhythms of anger and aggression’ and ‘Circadian regulation of kidney function’ to ‘Biological clocks: their relevance to immune-allergic disease’. Our 24-hour rhythm influences our brain, our gut, our kidneys, our liver and our hormones — every cell in our bodies. In fact, remove a cell, place it in a Petri dish, and it will demonstrate a 24-hour rhythm in some form or other. Indeed, 40 per cent of our genes that encode proteins are under the regulation of this circadian rhythm.
It is not simply a matter of exposure to light, though. The sun is not the metronome that keeps this rhythm going — at least not any more. Put humans in dim light, without any exposure to the rising and setting of the sun, and the rhythm will continue.
In the 1930s, Nathaniel Kleitman, one of the founding fathers of modern sleep science, experimented on himself and others in the depths of Mammoth Cave, Kentucky, the longest known cave system in the world. Deep underground, without light and without fluctuations in temperature and humidity, he tried to impose a 28-hour cycle, but found he could not. Even in the absence of the external cue of the sun’s light, body temperature, sleep and other physiological parameters retain this 24-hour rhythm, implying that somewhere within us is a clock that keeps time.
It also seems that this clock is common to all life on this planet. Bacteria, single-cell organisms, plants, flies, fish and whales — they all have this endogenous clock. For some life-forms, the need for this clock is clear. But why should bacteria need to know what time it is, or indeed plants? Plants certainly need to know when the sun is shining, to know when to open their leaves and photosynthesise, but this does not need to be guided by an internal clock; simply detecting light would be enough. And why should fish living in cave systems, blind and not exposed to the light of the sun for thousands of generations, hold on to this clock? The fact that they do implies that this circadian rhythm is hardwired into the very essence of life, that since the existence of the last ‘universal common ancestor’, the very origin of all lifeforms on the planet, there has been an evolutionary pressure and natural selection acting to maintain this endogenous clock.
At the most simple end of life as we know it, bacteria and algae, it is difficult to know what this pressure might have been, however. It has been proposed that the origins may lie in a desire to avoid cell replication, which involves the copying of genes, during times of exposure to ultraviolet radiation, known to produce mutations. A more widely accepted hypothesis is that these rhythms evolved to control the production of genes that pre-empt and counteract daily fluctuations in oxygen levels and the damage that oxygen does. The circadian rhythm may in fact date back to the Great Oxygenation Event, approximately 2.45 billion years ago. This time period is defined by the evolution of bacteria called cyanobacteria, believed to have been the first microbes to achieve photosynthesis — the conversion of carbon dioxide to oxygen using energy from the sun’s rays. At that time, atmospheric oxygen levels were low, and any free oxygen quickly became chemically bound to other substances. But the sudden rise in free atmospheric oxygen caused by cyanobacteria is thought to have provoked one of the largest mass extinctions in the history of the world, killing off most organisms for whom oxygen was highly toxic. Surviving organisms needed to develop mechanisms to protect themselves from the dangerous effects of free oxygen. It is thought that this need for protection resulted in the evolution of proteins called redox proteins, which mop up the toxic by-products of chemical reactions involving oxygen. The theory suggests that by predicting sunlight, and knowing when oxygen levels are going to rise, organisms can protect themselves from toxic damage, by generating these proteins at an appropriate time of day. But the truth is the origins of the circadian rhythm remain a mystery.
Any clock needs to be adjustable or reset, like a horologist tinkering with the pendulum of a grandfather clock to keep it running on time. The circadian rhythm, particularly for more complex organisms, needs to be tweaked according to the changing patterns of our seasons. Over the past few decades, our understanding of how this occurs has advanced. We are now aware of the influence of environmental cues or influences that gently nudge our circadian rhythms forward or back. These are termed Zeitgebers — ‘givers of time’ in German. Left to its own devices, the human circadian rhythm is set to 24.2 hours, and without Zeitgebers we would eventually find our internal clock drifting relative to the world around us. Our internal clock is sensitive to temperature, physical activity and eating, but by far the most potent Zeitgeber is light — particularly light at the blue end of the spectrum, like sunlight. While our circadian clock has proved itself independent of the sun, therefore, it is still its greatest influence.
The Royal Observatory, Greenwich, only a few minutes’ train ride from the Sleep Disorders Centre, Guy’s Hospital, sits atop a hill overlooking a large loop in the River Thames. From the thirtieth floor of the hospital, I can see the hill rising slowly towards south-east London, but cannot quite make out the building between the forest of ugly 1960s towers and new skyscrapers. On the roof of the observatory, a large metal mast with a weather vane on its tip juts into the typically grey London sky. On this mast, a large red ball, several feet in diameter, is impaled. Every day, at 12.55 p.m. Greenwich Mean Time in the winter, British Summer Time in the summer, the ball rises halfway up; then, at 12.58 p.m., ascends to the top. At 1 p.m. exactly, the time ball drops down the mast. In the present day, the area around the observatory is dominated by the skyscrapers of Canary Wharf, the main financial district of London, looming over the city from across the river. In the mid-nineteenth century, however, the Thames below would have been chock-full of sailing ships, ferrying the lifeblood of trade through the British Empire. Hundreds of telescopes would have been focused on the time ball of the observatory, waiting for the ball to drop. This would be the sailors’ opportunity to reset the chronometer on board each ship to Greenwich Mean Time, crucial for the calculation of longitude on their journeys to the East Indies and beyond.
Like the chronometers on these ships, there are multiple clocks within the human body, but the seat of the master clock — the large red ball of the Royal Observatory — in humans, and indeed all vertebrates, is a tiny area of the brain called the suprachiasmatic nucleus. This tiny area, comprising a paltry few thousand neurones, sits in the hypothalamus, immediately above the optic chiasm, where the optic nerves carrying information from the eyes merge. This tiny nub of tissue is the control room for all circadian rhythms throughout the body, and destruction of the suprachiasmatic nucleus results in the loss of this rhythmicity.
Within the neurones of the suprachiasmatic nucleus, a complex dance occurs on a daily basis, with several genes with names like CLOCK and Period interacting with each other, feeding back to each other, conducting the ticking of our clock. But light, as a Zeitgeber, sways this dance, tweaking it forward or back. In the retina, at the back of the eye, in addition to the rod and cone cells responsible for converting light into vision, are cells known as retinal ganglion cells. A few of these cells have no contribution at all to vision. Their purpose is instead to conduct signals to the suprachiasmatic nucleus, through a direct projection called the retinohypothalamic tract. And it is through this pathway that light influences the rhythm in the suprachiasmatic nucleus, affecting the phase, the relationship of the 24-hour rhythm to the outside world, and the amplitude, the strength with which this rhythm runs. For people without any vision, the control of the circadian rhythm can be problematic, as we will see later.
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The paediatrician’s diagnosis in Vincent of delayed sleep phase syndrome is a common one. For those with this condition, their circadian rhythm runs behind that of the outside world. While most people want to go to sleep between 10 p.m. and midnight and wake between 6 and 8 a.m., people with delayed sleep phase syndrome may want to sleep at 3 a.m., sometimes as late as 7 a.m., and wake up seven or eight hours later. If they get this amount of sleep, then they feel fine. Unfortunately, life often gets in the way of sleep, and within the constraints of modern society, holding down a job or getting an education is difficult, if not impossible, on this sleep schedule.
To some extent, having a tendency to want to wake up early and go to bed early, or wake up late and go to bed late, is normal. There is a broad spectrum of chronotypes — a person’s preference to go to sleep and wake up at a particular time. At the extremes of ‘morningness’ or ‘eveningness’ are those individuals known as ‘morning larks’ or ‘evening owls’. People with delayed sleep phase syndrome can be considered extremes of the extreme, ‘evening owls’ whose circadian rhythm is so delayed that it has negative consequences on their life.
As with many features of our sleep, it appears that what chronotype we are is to some extent determined by our genes. Studies in twins or in families suggest that up to 50 per cent of our chronotype is under genetic control, and variants in the genes that regulate our circadian rhythm have been associated with both extreme ‘eveningness’ and extreme ‘morningness’. In a familial form of what’s known as ‘advanced sleep phase syndrome’, in which sufferers want to go to bed early in the evening and wake up extremely early in the morning, much rarer than delayed sleep phase syndrome, a mutation in one particular circadian gene, called ‘PER’, has been identified. Furthermore, mutations in another one of these circadian genes, called ‘DEC2’, seem to increase the amount of time we spend awake and reduce the amount of sleep required. For most people, however, it is not these few mutations that influence their wake/sleep pattern, but likely the cumulative effect of multiple milder variants in all of these genes.
Moreover, it appears that shifts in our chronotype also occur as the brain matures. Teenage circadian rhythms will typically shift later in the day, before then shifting back in adulthood. I can see this happening in my older daughter. Prising her out of bed in the morning is becoming increasingly difficult — as is getting her to go to sleep at a reasonable time at night. Undoubtedly this shift in the body clock seen in teenagers is compounded by the use of electronic gadgetry late in the evening. Being glued to your tablet, laptop or smartphone while in bed, as many teenagers are, provides a potent source of light to act as a Zeitgeber and makes this delay worse. This is a real problem. The consequence being that many teenagers, still needing to get up early to go to school, are sleep-deprived, and sleep deprivation is correlated with poorer performance at school as well as behavioural issues and anxiety. Individuals with delayed sleep phase syndrome, however, seem to be particularly sensitive to light exposure and its effects on the circadian rhythm. A burst of light in the evening seems to have a much greater delaying effect on the circadian clock in susceptible individuals than on average.
So, maybe the answer to Vincent’s problem is as simple as cutting out the use of electronic devices at night. Or even wearing sunglasses in the evening to stop as much light as possible, especially blue light, from hitting his retinal ganglion cells. There is only one problem with this solution: Vincent does not actually have delayed sleep phase syndrome. What he has is much rarer.
If you listen carefully to his story, it is readily apparent, because Vincent does not want to go to bed at the same time every night (or day for that matter).
‘Essentially my sleeping pattern shifts constantly, so my body wants to go to sleep an hour later every day,’ Vincent says. ‘So basically if I go to bed at 10 p.m. one day, I’ll be naturally inclined to go to bed at 11 p.m. the next day, and so on.’
For Vincent, this constant shifting in his internal body clock means that bedtime, and by extension waking time, progresses by an hour a day. For a few days of every month, therefore, Vincent is synchronised with the world around him, but he soon shifts out of phase. ‘For a week or so, I will be in social hours, but for the rest of the time, to different extents, I am out of sync.’ At its worst, Vincent is essentially nocturnal and tells me that he can sometimes want to go to sleep at 11 a.m. and wake up at 9 or 10 p.m.
The impact of this shifting pattern is enormous. The result is that Vincent is often incredibly sleep-deprived. For most of the cycle that he shifts through, he finds it difficult to fall asleep at an appropriate time, but is forcing himself to get up in order to go to school. Some days, it is the equivalent of being rudely awakened at 2 or 3 a.m. and then being expected to pay attention in class at 4 or 5 a.m. Essentially, he is almost constantly jet-lagged.
Vincent says: ‘When I’m in school, it can be very difficult to concentrate. One teacher noticed that my reading is particularly slow, and that it affects my processing skills. Sometimes it is almost impossible to stay awake and concentrate, so I could fall asleep during lessons.’
On one of the occasions we meet, it is about 5 p.m., but Vincent is in a phase when he wants to go to bed at 2 or 3 p.m. and wake up at midnight or 1 a.m. For Vincent, his brain is telling him he should be deeply asleep, and according to his body clock it is about 1 or 2 a.m. He struggles to string a sentence together, pausing constantly to find words, trying to get his thoughts in order. It reminds me of times as a junior doctor when I was on call for 24-hour shifts. I would be bleeped in the middle of the night and really have to pull myself together to give a sensible medical opinion. Vincent stumbles over his words: ‘I just feel I’m behind the rest of the world right now. When I’m in sync with the world, I feel pretty good, because then I am able to be the best version of myself, the most articulate version of myself. Whereas right now, I’m not particularly.’
Dahlia’s description of him when he is in sync and out of sync is striking:
When Vincent is on a phase when he wants to sleep all day, when he is awake he is not himself. He looks tired, his responses are delayed, and he is mentally exhausted. Oh, when he is in sync with the world, when he normally wakes up at 6.30 or 7 in the morning, he’s bright, he’s like everyone else. He is passionate about his studies, he engages personally a lot more. He engages better with the world basically.
Unsurprisingly, Vincent’s schooling has suffered terribly. ‘It was getting very difficult to get in [to school] every day because I was constantly late, and teachers weren’t being very understanding about the sleep disorder,’ Vincent tells me. ‘So after a while, I just dropped out because it was getting too difficult. It wasn’t very sustainable.’
Dahlia is clearly bitter at Vincent’s experience at school, and while she does not blame his teachers, she feels that there has been a lack of understanding and flexibility on their part regarding Vincent’s medical issues.
It was not just Vincent’s schooling that suffered; his social life was devastated too.
Dahlia says, ‘I had to turn his friends away sometimes. When they came to visit him at, say, 7 p.m. to play PlayStation or something, Vincent would have been asleep since 5 p.m. So I had to say to his friends, “Oh, guess what, he’s asleep!” But it is very strange for them, because a teenager never sleeps at 7 p.m.,’ she laughs with a slightly bitter undertone.
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Dahlia’s determination to get to the bottom of Vincent’s condition finally resulted in a referral to one of my sleep colleagues in the children’s hospital. The history that Vincent and his mother give is absolutely typical of a condition called non-24-hour rhythm disorder, and this was confirmed using actigraphy — prolonged tracking of Vincent’s sleep patterns using a wearable device, a medical version of some of the wrist activity trackers now widely available. Essentially, Vincent’s circadian clock is running at twenty-five hours, rather than twenty-four. Somehow, Vincent’s suprachiasmatic nucleus has become immune to or detached from the Zeitgebers — the external influences that normally nudge the clock to remain synchronised with the outside world.
In otherwise healthy individuals, non-24-hour rhythm disorder is really rather rare, but is much more common in people who are completely blind. It is easy to understand why. In the absence of any vision at all, that most important of influences on the circadian rhythm, light, is completely abolished as an input to the suprachiasmatic nucleus. The effects of other Zeitgebers, such as physical activity or eating, are magnified in its absence. The pathway from the retinal ganglion cells at the back of the eye via a dedicated bundle of fibres, the retinohypothalamic tract, is no longer intact. In fact, between half and two-thirds of patients who are unable to perceive any light have problems with sleep consistent with a circadian rhythm disorder. In one recent study, 40 per cent of totally blind individuals had a non-24-hour rhythm. In normally sighted individuals like Vincent, however, it is incredibly rare and poorly understood, though we do know that it typically starts in early teenagehood and is much more common in males.
We know that much of the influence of the intrinsic clock on the brain is mediated via a hormone called melatonin. This hormone is secreted by the pineal gland, a tiny pine-cone-shaped structure deep within the centre of the brain. René Descartes proposed this tiny area as the seat of the soul, though in reality its role is rather less glamorous, although still important. Under the influence of the suprachiasmatic nucleus, it churns out melatonin in a cyclical pattern.
For people with a normal sleep/wake cycle, melatonin levels rise in the early evening, stay elevated in the night and then drop back down a couple of hours before waking. The melatonin acts as a chemical signal to the rest of the brain that it is time to sleep, acting on melatonin receptors distributed very widely, not only in the brain, but also in multiple other tissues like the kidneys, gut, heart, lungs, skin and reproductive organs. So, by studying the rise and fall in melatonin levels in the blood, we can monitor someone’s circadian rhythm, and the length of their cycle. But it is not quite as simple as that, because we know that a burst of bright light in the evening can suppress and delay this rise in melatonin before sleep. So, environmental factors can significantly alter the rise and fall of this hormone.
In order to understand someone’s internal clock, they need to be kept in constant dim lighting conditions, bright enough to see but dark enough so as not to influence the pineal gland’s secretion of melatonin. Looking at this pattern of melatonin in sighted individuals with non-24-hour rhythm disorder confirms that the sleep patterns seem to be internally driven, with an average cycle length of 25.2 hours — much longer than the 24.2 hours most people have. So maybe it is just having a cycle length that is so far off from the norm that is at least part of the problem. The effect of light and other Zeitgebers may simply not be strong enough to correct for such a big discrepancy.
Or it may be that there is just an insensitivity to the effects of light. Perhaps the suprachiasmatic nucleus is blind to the signals that the retinal ganglion cells send, like in patients who cannot see. In Vincent’s case, his sleeping problems certainly get much worse in the winter months, and this might be directly associated with the lower intensity of light. A reduced effect of light on melatonin secretion has not been demonstrated in these patients, however, nor has a reduced sensitivity of the retinal ganglion cells ever been proven.
There seem to be some commonalities between people with non-24-hour rhythms and those with delayed sleep phase syndrome. In both, the natural rhythm is slightly longer than normal individuals, and analysis of the genes that define the circadian clock has shown variants in a gene called PER3 to be associated with both patterns of sleep. So maybe it is the case that, if your rhythm is slightly longer than twenty-four hours, you have a tendency to run later, but eventually your rhythm is stabilised by the effects of Zeitgebers, causing delayed sleep phase syndrome. But if you run very long, and the drift is too great for the Zeitgebers to correct for, or the Zeitgebers simply don’t work very well, then you end up free-running, like Vincent. This is still a hypothesis, and remains to be proven, but it is curious that there have been a few reports of non-24-hour rhythm disorder starting after the manipulation of sleep/wake patterns in patients with delayed sleep phase syndrome.
Chronotherapy involves delaying the bedtime by a certain number of hours every day in an effort to bring someone with delayed sleep phase syndrome back into sync. The rationale is that it is easier to stay awake for an additional few hours than to force your body to go to sleep earlier. By pushing your sleep pattern around the clock, you eventually get in line with everyone else. However, it seems that doing this can push the circadian clock to the limit, and in rare cases may result in the loss of control that one finds in non-24-hour rhythm disorder. In Vincent’s case, perhaps it was the hip operations and the recovery period that were the initial disrupters of his sleep cycle.
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Some of the effects of battling against your own body clock are readily apparent. The sleepiness or insomnia are obvious, as are the effects on cognitive ability, alertness and vigilance. The nurse at the workstation who briefly dozes off on their third night shift in a row is not a rare sight on the wards. It is not a reflection of laziness, but a direct function of their underlying circadian rhythm. The effects of the natural shift in the circadian rhythm in teenagers has even led some scientists and educationalists to propose that secondary school should start later in the day, to maximise the potential of pupils who are otherwise left sleep-deprived by waking earlier than their circadian rhythm dictates.
We are now beginning to understand that there are far-reaching and long-lasting implications of chronic disruption of the circadian clock, however. To comprehend the impact of this, studying the health of people who have been working shifts for long periods of time is a good place to start. For over twenty years now, we have been aware of some of the possible risks. A study in 1996 suggested higher levels of breast cancer in Norwegian radio and telegraph operators, and since then this finding has been reproduced several times. There is also evidence to point to an increased risk of colorectal and prostate cancers in shift-workers. The evidence is robust enough for the World Health Organization to add ‘circadian disruption’ to the list of probable carcinogens; and the Danish government to provide compensation to shift-workers with breast cancer. Moreover, it appears that shift work is also associated with gastrointestinal disorders, cardiovascular disease and diabetes.
So why should shift-workers have increased rates of certain cancers? One hypothesis is centred around the exposure to light at night. As we’ve discussed, light exposure at night suppresses the production of melatonin by the pineal gland, and it is argued that melatonin may have some anti-cancer activity above and beyond its role as a hormone — specifically, to absorb toxic by-products of oxygen metabolism that are thought to damage our DNA and predispose us to cancer. So, by regular exposure to light at night, perhaps we are lessening our resistance to cancer. This hypothesis is supported by the fact that people who are totally blind are less likely to develop breast cancer than normally sighted individuals, and in one experiment mutant mice predisposed to breast cancer were more likely to develop tumours when their circadian rhythms were disrupted. But there are lots of potential confounders.
We know that sleep deprivation in itself causes changes to appetite and promotes weight gain, a risk factor for breast cancer. And maybe shift work makes it more likely for you to take up an unhealthy lifestyle like smoking or exercising less. Also, very recently, a study has shown that even after three days of simulated shift work, the circadian clocks in the brain and in other organs become misaligned. The researchers found that markers of the brain’s circadian clock in the suprachiasmatic nucleus remained relatively stable, but simultaneously there were dramatic changes in levels of the breakdown products of food. It could therefore be that this misalignment of brain rhythms and other 24-hour cycles in the body, usually tightly regulated, has fundamental consequences for how these products of food metabolism are processed, increasing our risk of diabetes, obesity and other medical issues. Furthermore, through this clash in the rhythms of various physiological processes in our bodies, our normal processes of cell replication and DNA repair may be impaired, giving rise to increased cancer risk. While the precise nature of the mechanisms underlying disrupted circadian rhythms and ill health remains poorly understood, certainly this association raises some very broad implications for us. Are we causing ourselves long-term harm through our exposure to light indoors and the use of electronic gadgets late into the night?
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When my paediatric colleague told Vincent and his mother what the diagnosis was, there were mixed emotions. Vincent recalls feeling quite overwhelmed. ‘It’s a difficult concept that it’s a chronic disorder, where no matter what happens you’ve got it for the rest of your life. That’s quite a hard thing to get into your head.’ But there was also a clear sense of relief. ‘Before that [the diagnosis], I couldn’t really be sure. Some people thought it might be psychosomatic.’
Dahlia tells me something very similar. She was expecting it. ‘In my heart I knew. But when the diagnosis came, it was a relief too, because at least you know Vincent was not making it up. Vincent is not lazy. He was doing his very best. But on the other hand of course it’s sad because it is something he has to cope with.’
The diagnosis has clearly had some benefits. Despite dropping out of school, Vincent has gone on to achieve excellent grades in his exams at secondary school. With a medical diagnosis in hand, he started at a school for children with special needs, and the flexibility has allowed him to achieve something close to his full potential. Vincent now attends a boxing academy, where he studies alongside training.
The diagnosis has also permitted treatment to commence.
For patients with delayed or advanced sleep phase syndrome, extreme ‘evening owls’ or ‘morning larks’ respectively, apart from trying to keep a strict sleeping regime, there are two major forms of treatment.
As well as being the chemical cue that the pineal gland churns out to signal the chiming of the circadian clock, melatonin also directly influences that clock. Melatonin feeds back on the suprachiasmatic nucleus as well, and so is in itself a Zeitgeber. By giving people melatonin, the clock can also be shifted forward or back.
The other option is to manipulate light. Exposing people to very bright light, in the form of a lightbox, can also cause a shift. These lightboxes simulate natural sunlight, and are very rich in blue light, which seems to have the biggest effect on the retinal ganglion cells.
The timing of melatonin and light in relation to the underlying circadian clock is crucial, however. Depending on when in the circadian cycle melatonin or light is delivered, it can have very opposite effects. Exposing someone to bright light for an hour in the hour or two before natural bedtime can delay their bedtime by up to two hours; expose them to the same bright light in the morning after waking, and the bedtime will shift forward by about thirty minutes. Similarly, give someone melatonin in the early evening and they will go to sleep earlier; taken in the morning it will push bedtime back. In practice, we rarely give morning melatonin as it also potentially makes people drowsy, though there is some evidence that even small doses can cause a shift in the circadian clock without causing significant drowsiness.
Of course, for Vincent and others like him, there is no fixed rhythm that we can tailor melatonin and light timings to. But we can use these treatments to anchor his circadian rhythm. By giving his suprachiasmatic nucleus a regular evening dose of melatonin, and his retinal ganglion cells a dose of daytime bright light, his circadian rhythm is cajoled into staying a little more in sync with the outside world. And this regime, while not perfect, has made a significant improvement. Vincent still drifts a bit, particularly in the winter months, but treatment has made a big difference to his life.
‘At the moment, I’m attending college and, so far, I am able to attend most of the time. And it’s going okay. But I don’t always feel 100 per cent.’ Vincent tells me that he is currently managing to sleep at about 11 p.m. and get up at 6.30 a.m., and this cycle is fairly static. He has only missed a couple of days of school in the past few weeks. Every so often, however, despite our strategy to keep his rhythm regular, it still drifts. ‘When my sleeping pattern goes off track and it’s hard to bring it back, I’ll stay awake for the next day and just not sleep at night. Then I’ll fall asleep at a normal time again. That helps get me back into a pattern a bit quicker than waiting for several weeks. But it doesn’t always work 100 per cent.’
I ask him about his boxing. ‘I can be pretty inconsistent with my performance. So sometimes I can be much slower, or my reactions aren’t quite so good [when I am out of sync]. I try to compensate by being faster and more powerful. But sometimes it’s hard.’
We chat about what he thinks his future holds, what career he sees before him. ‘I don’t know. It’s definitely going to be very difficult to fit in properly. There’s not too much choice. Maybe self-employment or something like that. Something where I’m able to work on my own.’
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For anyone who has done shift work, or is a regular traveller, Vincent’s experiences will ring true. The disruption of your circadian cycle is disconcerting. I recall the drives into hospital at 3 a.m. on a Monday morning as a registrar, being called in to see someone with a stroke, feeling groggy and slightly nauseated, not thinking totally clearly. And even though I was passing through the streets of central London, one of the busiest cities on earth, I distinctly remember the feeling of being largely on my own — a strong sense of isolation; that I was not at one with the world. While the rest of the city was almost entirely tucked up in bed, here I was transgressing into a time of day that I had no business being awake in.
Ultimately, we are social beings. Although our circadian rhythms originated from our bacterial ancestors and have evolved to keep us awake in the sunlight and asleep in the dark, what I find remarkable is the importance they play in synchronising us as a social group, enabling people to live with similar rhythms: to eat at the same time; work at the same time; play at the same time; sleep at the same time.
This circadian clock knits our lives together as a species and as a society. And when one loses this clock, it sets us apart from the world around us; disconnects us from our family, friends and colleagues.
In Vincent’s case, however, he cannot simply quit his job, or fly around the world a little less. For him, this is a constant and natural state of being. I am struck by the sense that it is this apartness without an end in sight, more than any other aspect of his condition, that is the most distressing. The loneliness of living one’s life on a different rhythm to everyone else.
Copyright © 2019 by Guy Leschziner.