The Nocturnal Brain

by Guy Leschziner

  As we all know, the more complex a system, the more likely it is to develop glitches. As I watch the computer engineers in our hospital wrestle with the nightmare of our IT systems whenever I have a technical issue, I realise that the days of switching the basic calculator of my school days off and on again when it stops working have truly passed. Our brains are infinitely more intricate than any man-made system, so it is perhaps surprising that such a complex system does not go awry more often than it does.

  The range of sleep disorders is vast. From those who sleep too much, to those who sleep too little, and those who sleep at the wrong time or in the wrong way – these different sleep disorders allow us insights into the workings of the brain; how the brain influences sleep, but also how sleep influences the brain.

  The functions and dysfunctions of the brain in wakefulness are myriad. In our daytime lives, we experience normal emotions, memories, cognition, everything that defines us as humans and individual conscious beings. And when these processes go wrong, we experience disorders, such as anxiety, depression, dementia, epilepsy, migraine, and so on. But while we think of our brains switching off at night, these patients illustrate that quite the opposite is true. The functions and dysfunctions of our nocturnal brains are as numerous and varied as those of the daytime, and influence every aspect of our waking lives too.

  However, while the progress we have made in understanding the relationship between our nocturnal and daytime lives has been tremendous, I can’t help but feel that we have only just scratched the surface. Many questions remain unanswered. Some of these questions are almost inconceivably big, such as the true function (or functions) of dreaming, or whether we really prevent Alzheimer’s disease by improving sleep. Others are less fundamental, but equally important to sufferers of a particular condition, like how precisely the immune system targets neurones in narcolepsy, what actually causes Kleine–Levin syndrome, or whether there is a cure for these conditions.

  But we live in an era of great hope. As the disciplines of genetics, neuroscience and technology move forward, techniques to study sleep advance at an astounding pace. Our ability to track sleep, not only movement, at home for prolonged periods of time will help. So will methods to identify and analyse the genetics of individuals in huge numbers. And novel techniques of studying and influencing the brain, like using magnetic fields or electrical stimulation, will offer us new insights. Parallel to all this, the development of technological solutions to the collection and analysis of ‘big data’, for example the medical data and sleep parameters for huge populations, will be crucial.

  And so I dream that many of these questions surrounding sleep will be answered in my lifetime. I look forward to the day when I sit in my clinic and, faced with a question from my patients, I no longer have to admit that I just don’t know.

  APPENDIX OF DIAGRAMS

  This hypnogram is a graphical representation of a typical night’s sleep for a young adult. We cycle, on average, four to five times through the various stages of sleep, entering into REM sleep usually some 60–90 minutes after sleep onset. With each successive cycle, less non-REM sleep is seen, with increasing periods of REM sleep as we progress through the night. Brief awakenings are common and, when arising from REM sleep, as in this hypnogram, may result in the recollection of dreams.

  Major anatomical divisions of the brain. The frontal lobe has a wide array of functions, including control, initiation of movement, and, in the prefrontal cortex, planning, decision-making and regulation of behaviour. In sleepwalking (Chapters 2 and 10), the prefrontal cortex often exhibits reduced activity, explaining impaired reasoning and planning. The parietal lobe is the site of sensory processing, and, in particular, the superior parietal lobule is the site of representation of one’s body in space (see Chapter 9).

  Cross-sectional cut of the brain. The cingulate cortex, hippocampus and amygdala all contribute to the limbic system, which mediates emotions, memories and arousal. Activation of this limbic system is fundamental to the ‘flight-fight-fright’ response, and plays an important role in sleepwalking (Chapters 2 and 10) and in some types of epilepsy (Chapter 8). Many of the important nuclei that regulate wake and sleep are located in the hypothalamus, pons and medulla.

  The sensory homunculus. Bodily sensations are processed by the primary sensory cortex, but the body is represented in a distorted way, with more sensitive body parts such as the face and hands represented by larger areas of cerebral cortex. The tongue, pharynx and intra-abdominal organs are represented in part of the sensory cortex overlying the insula, explaining some of the symptoms experienced in seizures arising from the insula (Chapter 8).

  The hypocretin-producing neurones located in the hypothalamus project very widely, acting on several nuclei that promote wakefulness and non-REM sleep. These include the tuberomammillary nucleus (TMN), laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT), dorsal raphe (DR), locus coeruleus (LC) and nucleus accumbens (NAc). Damage to the hypocretin neurones in narcolepsy (Chapters 6 and 13) results in destabilisation of these circuits, causing patients to flick in and out of sleep, especially REM sleep. This instability results in the hallmark features of this condition, such as sleep attacks, sleep paralysis, hallucinations and cataplexy.

  Cross-sectional view of the brain from the side, demonstrating the location of the cingulate cortex, part of the limbic system. The substantia nigra, the area of the brain that degenerates in Parkinson’s disease, sits in close proximity to the hypothalamus. Nuclei in the pons called the sublaterodorsal nucleus and precoeruleus are active in REM sleep, and project to the spinal cord, normally inducing paralysis in REM sleep. Damage to this circuitry results in the loss of paralysis in REM sleep seen in REM sleep behaviour disorder (Chapter 3).

  The suprachiasmatic nucleus (SCN) is the location of the ‘master clock’, which maintains the circadian rhythm (Chapter 1). Direct projections from the retina allow the SCN to be influenced by light, resulting in shifts in the circadian rhythm as a result of light exposure. The SCN mediates some of its effects by controlling the release of melatonin by the pineal gland.

  ACKNOWLEDGEMENTS

  First and foremost, this book would not exist without the help and kindness of the patients described, and their willingness to share their stories. They have been largely driven by their desire to highlight their experiences, and to help disseminate knowledge of their conditions, so that others experiencing similar problems might achieve a diagnosis and treatment more quickly. I am enormously grateful to them all. Equally, I have put together the amalgam of research in the field, presenting the hard and brilliant work of many researchers in the fields of sleep, neuroscience and clinical neurology. They are rapidly pushing at the boundaries of our understanding of sleep and the brain.

  This book has come into fruition entirely accidentally. I had never anticipated writing anything other than academic texts. It is entirely due to my agent, Luigi Bonomi, who emailed me out of the blue, having heard the BBC Radio 4 series, Mysteries of Sleep. He convinced me to give writing a try. Luigi also succeeded in convincing Iain MacGregor, my superb editor at Simon & Schuster, to commission the book, who showed amazing enthusiasm for the project from the start. Thanks must also go to my agents in the US and Europe, George Lucas at InkWell and Nicki Kennedy at ILA, and Michael Flamini, my US editor at St Martin’s Press.

  Some of the work in this book originated from Mysteries of Sleep, and that is largely down to my fantastic producer, Sally Abrahams, who taught me how to tell a story, and the team at BBC Radio 4, who allowed me to make the series in the first place: Hugh Levinson, Mohit Bakaya and Richard Vadon. I am also grateful to my colleagues who contributed either to the radio series or through discussions regarding the contents of this book: Adrian Williams, Brian Kent, Ivana Rosenzweig, David O’Regan, Alex Nesbitt, Paul Gringras, Michael Farquhar, Sofia Eriksson, Sean Higgins, Mike Koutroumanidis, Al Santhouse, Russell Foster, Michael Kopelman, Annett Schrag and Meir Kryger. Meir also showed me th
at it is possible to bridge the gap between a busy clinical workload, research and writing. Thanks must also go to Allan Hobson, at Harvard, who patiently talked me through his theories about REM sleep.

  My friends over the years have been bored rigid by my tales of neurology and sleep. Some have been further gluttons for punishment and have been volunteered to provide critical feedback – Jonathan Turner, Richard Ambrose and Rob Mills.

  I am grateful to Guy’s and St Thomas’ NHS Trust, which has allowed us to develop a superb sleep centre (in my biased view unparalleled in the UK), staffed by a huge number of incredibly diligent, bright and capable individuals who work as a fantastic team. Also the excellent sleep team at London Bridge Hospital.

  Finally, it is important to recognise my family. My parents, who triggered and encouraged my interest in science and enabled the pursuit of my medical career, and my children, Maya and Ava, who put up with me retreating into the study to write in spare moments. Finally, and most importantly, my wife Kavita, whose encouragement and critique has shaped much of this book. She always told me I had a book inside me, and I ignored her for years. As ever, I should have listened to her.

  GLOSSARY

  Amygdala – an almond-shaped structure deep in the temporal lobe, part of the network that constitutes the limbic system. It has a fundamental role in emotional responses such as fear, aggression and anxiety, but also contributes to memory and decision-making

  Apnoea – a pause in breathing

  Autonomic nervous system – a part of the nervous system that mediates largely unconscious control of the internal organs and skin. The sympathetic system drives the ‘fright-fight-flight’ response, causing an increase in heart rate, sweating, pupil dilatation and diversion of blood away from the gut and skin to the muscles, heart and lungs. The parasympathetic system mediates the opposite response: that associated with being relaxed

  Cataplexy – a phenomenon found almost exclusively in narcolepsy. Strong emotions, particularly laughter, result in sudden loss of muscle strength, causing transient weakness in various body parts or even the whole body Cerebral cortex – the outer layer of the brain, also known as grey matter

  Chronotype – the tendency for an individual to fall asleep and wake up at a particular time, e.g. a ‘morning person’ or an ‘evening person’

  Cingulate – an area of the brain, the cortex of which plays an integral role in the limbic system, the network of the brain responsible for emotion, behaviour and motivation

  Circadian – a biological process recurring on a 24-hour cycle

  Delayed sleep phase syndrome (or disorder) – a shift of the internal body clock forward, resulting in sufferers only being able to go to sleep much later, and wanting to wake up much later, to such an extent that it has a negative impact on their waking lives

  Dementia with Lewy bodies – a degenerative condition of the brain, resulting in cognitive dysfunction and hallucinations. It has significant overlap with Parkinson’s disease, both in terms of symptoms and signs but also on a microscopic level

  EEG (electroencephalogram) – a technique utilised to study electrical activity of the brain. Different appearances on the electrical traces permit the differentiation of different stages of sleep, and abnormal brain activity caused by epilepsy or other neurological disorders

  Frontal lobe – the region of the brain closest to the forehead, above the eye sockets. Its functions include control of voluntary movement, planning, judgement, decision-making and emotional expression

  Homeostatic mechanism – one of the processes that regulates sleep. The longer you are awake, the stronger the drive to enter sleep

  Hypnagogic hallucinations – hallucinations, often in the form of an intruder in the room or an out-of-body experience, at the point of drifting off to sleep or waking (termed hypnopompic). They are thought to represent intrusion of dreamlike processes into wakefulness

  Hypocretin – the neurotransmitter that is lost in narcolepsy as a result of the death of or damage to the neurones producing this chemical

  Hypothalamus – a small area of the brain behind and between the eyes containing multiple nuclei important in the regulation of metabolic processes, hunger, sleep, circadian rhythms, thirst and body temperature

  Insula – an area of cerebral cortex that is covered by the parietal, frontal and temporal lobes. It acts as a junction between these parts of the brain and the limbic system

  Lesion – the term for an area of damage to tissue. In neurological terms, it defines a location in the nervous system that is diseased, damaged or in some way not functioning correctly

  Limbic system – a brain network comprising a set of structures including the hippocampus, amygdala, cingulate gyrus, thalamus, fundamental to the integration of memories, emotions and smells. It influences motivation, emotional experiences and behaviour

  Localisation – part of the diagnostic process focused on identifying the location of a lesion within the nervous system

  Lucid dreaming – the maintenance of a degree of consciousness or conscious control during dreaming

  Narcolepsy – a neurological disorder that results in the inability to regulate sleep and dreaming, thought to be caused by the destruction of brain cells producing hypocretin, a neurotransmitter fundamental to the control of sleep, in the hypothalamus. It results in excessive sleepiness, hypnagogic hallucinations, sleep paralysis and cataplexy (see Chapters 6 and 13)

  Non-REM parasomnias – conditions causing abnormal behaviours such as sleepwalking, night terrors, sleep-talking, or sleep-eating, all arising from non-REM sleep, particularly Stage 3 sleep

  Non-REM sleep – comprises Stage 1, Stage 2 and Stage 3 sleep

  Non-24-hour rhythm disorder – a syndrome defined by the circadian clock running on a rhythm that is outside the normal 24-hour interval, usually longer. Also known as free-running disorder

  Parasomnia – any abnormal behaviour arising from sleep

  Parietal lobe – the area of the brain principally involved in sensation, representation of the physical world around us, and our own bodies within the world

  Parkinson’s disease – a common disorder of brain degeneration, principally affecting movement, resulting in tremor, difficulty walking, stiffness and slowing

  Pineal gland – a small, cone-shaped structure a few millimetres in diameter that secretes melatonin. It is located deep within the brain, behind one of the fluid cavities known as the third ventricle, as it is itself bathed in cerebrospinal fluid

  Prefrontal cortex – an area of cerebral cortex in the frontal lobe, implicated in the making of decisions, planning of actions, social behaviour and expression of personality

  REM (rapid eye movement) sleep – the stage of sleep most associated with dreaming, characterised by rapid movements of the eyes from side to side, paralysis of almost all muscles, but an active brain state

  REM sleep behaviour disorder – loss of paralysis of muscles in REM sleep, resulting in the acting out of dreams

  Retinal ganglion cells – light-detecting cells in the retina that have no function in vision. They detect blue light in particular and project directly to the suprachiasmatic nucleus via the retinohypothalamic tract, feeding information about environmental light to the master clock in the suprachiasmatic nucleus

  Sexsomnia – a form of non-REM parasomnia resulting in behaviour of a sexual nature

  Sleep apnoea – the recurrent pausing of breathing in sleep, usually related to partial or complete obstruction of the airway as it becomes more floppy in sleep

  Sleepwalking – a form of non-REM parasomnia. Behaviours arising from Stage 3 non-REM sleep, consisting of getting out of bed, performing complex tasks and interacting with the environment, usually with no or very limited recall

  Slow wave sleep – see Stage 3 sleep

  Stage 1 sleep – the lightest stage of sleep, also known as drowsiness. It is defined by slow, rolling eye movements and a quietening of electrical activity of the brain when measure
d on the EEG

  Stage 2 sleep – intermediate sleep, defined by signature patterns of the EEG, known as sleep spindles and K-complexes

  Stage 3 sleep – the deepest stage of sleep, also known as slow wave sleep, thought to be most important for restoration of function and recovery. The brainwaves become much slower and larger and in this stage of sleep it is the most difficult to rouse someone

  Suprachiasmatic nucleus – the tiny area of the hypothalamus that represents the master clock of the body, maintaining the circadian rhythm

  Temporal lobe – a region of the brain responsible for language function, hearing and auditory processing. The inner aspect of the temporal lobe contains the hippocampus and amygdala, and is therefore also involved in emotional processing and memory

  Zeitgeber – a factor external to the master clock in the suprachiasmatic nucleus that influences the circadian rhythm, such as light and melatonin

  FURTHER READING

  It is impossible to include all references without adding a further 100 pages to this book. Below is a list of key publications related to the chapters, largely review articles. Where the cases have been published in the medical literature, these references have also been included.

  Chapter 1: Greenwich Mean Time