Sleep

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Shedding light on our nocturnal activity

A function still shrouded in mystery, but with a decisive impact on our health: We spend nearly a third of our lives asleep. Memory and learning, metabolism, immunity… although many hypotheses have yet to be confirmed, while others will inevitably emerge, it is perfectly evident that sleep is crucial for numerous biological functions. It presents a major challenge: the incidence of sleep disorders, which affect a large part of the population, has increased in recent decades. It raises questions in terms of future changes in our health.

Challenges facing research: Because sleep has an influence on health and the risk of accidents, it is essential to understand the factors which specifically determine sleep quality and duration. Faster progress is being made due to the rapid expansion in neurosciences, further highlighting the importance of a good night's sleep.

  • A good night's sleep consists of at least 3 to 5 cycles of 90 minutes on average
  • In France 1 person in 3 has a sleep disorder
  • Cardiovascular diseases; obesity and diabetes; cancer; accidents; poor sleep increases their risk
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Report drawn up in collaboration with Pierre-Hervé Luppi, Physiopathology of Sleep Cycle Neuronal Networks Team Leader, Centre de Recherche en Neurosciences de Lyon (Inserm Unit 1028)

Loupe comprendre Understanding sleep

On average the French get 1h30 less sleep thant 50 years ago
45% of those aged 25-45 feel that they do not get enough sleep
13% of those aged 25-45 feel that sleeping is a waste of time

Sleep corresponds to a reduced state of consciousness which separates two periods of wakefulness. It is characterized by loss of vigilance, reduced muscle tone, and partially preserved sensory perception.

NREM, deep, paradoxical (or REM), sleep is multifaceted

Briefly, sleep corresponds to a succession of 3 to 6 successive cycles, each lasting 60 to 120 minutes. A cycle consists of alternating NREM and REM sleep, each corresponding to different brain activity evidenced by electroencephalography (EEG): on the tracing, the electrical waves passing through the brain, indicating neuronal activity, have a different appearance according to the sleep phase. During the wakefulness phase, for example, they are short and frequent.

NREM sleep is characterized by slow-wave sleep. It comprises several stages: after a transitional phase (N1) lasting a few minutes, between wakefulness and sleep, the light sleep phase (N2) begins. This is followed by a phase of increasingly deep sleep (N3) which lasts for several dozen minutes. During this period, the EEG reveals the presence of large amplitude and low frequency waves. Functional imaging indicates lower oxygen consumption and, therefore, slower brain metabolism. Muscle tone is also decreased but still present to some degree, thus explaining sleep-walking episodes (see below).

Paradoxical (REM) sleep corresponds to a period in which brain activity is similar to the wakefulness phase. It is also referred to as the REM (Rapid Eye Movement) phase due to being characterized by frequent rapid eye movements (beneath closed eyelids). Conversely, muscle tone is totally suppressed during this phase, except for limited movement of the extremities. At the same time, blood pressure and respiratory rate undergo frequent fluctuations. REM sleep is, moreover, conducive to dreaming: it is the phase in which the most intense dreams occur, and which are remembered once awake. Dreaming may also occur during the light NREM phase, but is less intense and correspond less to dreamlike representations of facts or actions than abstract ideas.

As the night progresses restorative deep-slow wave gives way to light slow-wave sleep
As the night progresses restorative deep-slow wave gives way to light slow-wave sleep © Inserm/Pinci, Alexandra

The sleep rhythm is never fixed

The sleep rhythm primarily varies in a given night: briefly, the first cycles mainly consist of deep NREM sleep, whereas REM takes precedence in the later part of the night. If the previous night's sleep was poor, NREM sleep will be deeper the next night.

Sleep also varies as the years go by: NREM sleep is deeper during growth, up to the age of approximately 20 years. As we grow older, this type of sleep declines and gives way to lighter NREM sleep, thus explaining the increase in sleep disorders in later years. At the same time, REM sleep is longer in the first years of life. This phase decreases in length in adulthood.

Lastly, the necessary quantity and quality of sleep vary considerably from one person to another. The environment, lifestyle and pace of life contribute to the ability to sleep well and to truly recover during a night's sleep. Genetics apparently help differentiate between early risers and night owls, or long sleepers from short sleepers. Short sleepers apparently have very short phases of light sleep. However, irrespective of the duration of sleep each person requires, the duration of deep sleep is said to be relatively constant, while light sleep and REM sleep vary in duration.

How is sleep studied?

The reference examination is polysomnography. This generates a hypnogram, i.e., a graph showing several parameters, obtained using electrodes placed on the skull and different parts of the body: brain activity (by EEG), muscle activity (electromyogram), and eye movements (electrooculogram). These data enable the different sleep phases to be monitored and identified. At the same time, heart rate, respiratory rate, and leg movements are also recorded so as to characterize certain disorders or nocturnal diseases.

Other approaches are used to explore sleep disorders: a sleep diary allows individuals to record their sleep and wakefulness habits, their waking and sleeping patterns, to describe any existing insomnia more effectively. Actigraphy, which records body movements via a wristband, is also able to characterize alternating periods of wakefulness and sleep during the day more effectively. Furthermore, multiple sleep latency tests (MSLT) are indicated in the exploration of narcolepsy and maintenance of wakefulness tests (MWT) are indicated to evaluate daytime drowsiness and propensity to sleep.

Lastly, medical imaging (MRI, CT scan) techniques, and particularly functional imaging  (PET scan, functional MRI, magnetoencephalography) techniques, offer scientists the means of accurately studying the characteristics and role of each sleep phase, while identifying the brain structures involved.

Falling asleep: a complex phenomenon

Sleep does not only occur as a result of fatigue. Lifestyle, substance use (alcohol, stimulants, etc.), the immediate environment (light, noise, etc.) may affect a person's ability to fall asleep. However, from a biological perspective, this phase also requires a combination of several factors:

  • homeostatic processes, which increase the need for sleep as the wakefulness period is prolonged
  • circadian processes, which aim to synchronize the body with sleep over an alternating day-night period

Homeostatic processes, the regulator of NREM sleep

Sleep regulation primarily depends on certain factors produced during the day (interleukin-1, prostaglandin D2, somatoliberin, etc.), pressure on which is said to gradually promote the onset of sleep. Among these, adenosine is said to play a central role. Produced during the wakefulness period, accumulation thereof is said to promote sleep. It is said to gradually inhibit brain function until sleep is triggered. Adenosine is then gradually eliminated during the night. Under experimental conditions, as sleep deficit increases, adenosine level also increases and deep NREM sleep waves become more intense: this is supposedly a mechanism which allows the brain to catch up.

The circadian system, the regulator of the biological clock

Physiologically, the circadian rhythm is specific to each individual: with a rhythmicity close to 24 hours, in reality it varies by a few dozen minutes from one individual to another. Several factors are therefore involved in fine-tuning this system, including:

  • Melanopsin ganglion cells
    The body's day-night cycle depends on melanopsin-containing retinal ganglion cells. In practice, we now know that these only play a partial role in sleep induction. Studies conducted on subjects isolated from sunlight for several consecutive days show that alternating wake-sleep cycles similar to those usually experienced nonetheless persist. Triggering sleep is therefore an endogenous phenomenon which persists in the absence of light. Melanopsin ganglion cells mainly play a role in transmitting information on alternating day-night rhythms to brain structures involved in other functions. Nevertheless, using screens or LED lights, with high levels of blue light, late at night, stimulates these cells and disrupts sleep.
     
  • Melatonin
    Sleep induction is also hormonally dependent on melatonin. Commonly known as the sleep hormone, melatonin is produced in darkness, at the beginning of the night, by the pineal gland (or epiphysis), located behind the hypothalamus. Conversely, its synthesis is inhibited when retinal cells detect light. When it is released at the beginning of the night, it promotes the induction of sleep. Melatonin production becomes less and less effective with the aging process. This is explained by numerous age-related sleep disorders.
     
  • Clock genes
    The expression of fifteen or so clock genes (CLOCK, BMAL, Per, Cry, Reverb, etc.) is modulated according to the information received by the retinal cells, melatonin, and other synchronizing factors (physical activity, food intake, etc.). Expressed in the suprachiasmatic nuclei, these enable messages to be transmitted to several secondary clocks located in the brain, able to regulate sleep, along with numerous other functions the rhythm of which is controlled by the circadian cycle (cortisol, ACTH, growth hormone production, etc.). Under experimental conditions, the destruction of the suprachiasmatic nuclei in animals maintains alternating wakefulness and sleep patterns, but according to disorganized, irregular rhythms during the day. The internal clock is thus said to organize periods of wakefulness and sleep.

Sleep means health

In adolescents, insufficient sleep is correlated with reduce gray matter volume
AS Urrila et coll. Sci Rep, 2017
Less than 6h sleep per night increases the risk of type 2 diabetes vy 28%
FP Cappuccio et coll. Diabetes Care, 2010
Insufficient sleep  leads to a four-fold risk  of catching a cold
AA Prather et coll. Sleep, 2015

Sleep represents the optimum form of rest. It thus allows the body to recover, both physically and mentally. NREM sleep is said to play a specific role in this process since slow waves are more intense and higher when the quantity or quality of sleep has been poor the previous night. Sleep is also able to reduce the metabolism and preserve energy (homeostatic role). Hence, body temperature falls to around 36°C during the night.

At the end of the 19th century, the first sleep deprivation experiments conducted over more than three days notably reported impaired memory capacity and motor response time, hallucinations, and lower body temperature. Subsequent studies confirmed the role of sleep in concentration, learning, memorizing or orientation phenomena.

From the 1980s, it became increasingly evident that sleep was not only useful for memory and recovery. It is also said to play a particularly important role in health. Owing to research studying the impairment in the health of individuals suffering from sleep disorders, it was possible to highlight the fact that poor quality/quantity of sleep accentuates the risk of irritability and depressive symptoms, but also weight gain, hypertension, and infection. These data support the widely accepted idea that people suffering from fatigue are at greater risk of illness...

Sleep, brain maturation, and learning

Imaging data show that learning new tasks is associated, the following night, with an increase in the number of dendritic spines, protrusions which connect adjacent neurons and facilitate the transfer of information from one to the other. These mechanisms probably explain why a neonate needs twice as much sleep as an adult.

Sleep and metabolism

Sleep deprivation increases the appetite by modulating the hormones which regulate hunger (leptin, ghrelin, orexin). Increased food intake, combined with fatigue and daytime drowsiness, leads to lower energy expenditure during the wakefulness phases, hence a risk of weight gain. Furthermore, epidemiological data demonstrate a correlation between the average duration of sleep in a population and body mass index (BMI).

At the same time, the reduction in sleep duration disrupts the circadian rhythm which regulates the synthesis of certain hormones, such as cortisol or growth hormone, involved in glucose metabolism. This phenomenon is said to promote the onset of glucose intolerance and the gradual progression to type 2 diabetes, independently of weight gain itself. The role of sleep in other aspects of cardiovascular health has yet to be described and elucidated.

In French : Sleep and metabolism - interview - 3 min 59 - video from the POM Bio series (2013)

Sleep and immunity

In the 1970s, a number of studies suggested that factor S, derived from the bacterial wall, was able to regulate sleep. This theory has since been demolished, but led to research being stepped up in the relationship between sleep, infection, and immunity. While the findings are still incomplete, numerous experimental data have enabled the initial connections to be outlined: the production of certain mediators of immunity is thus said to follow a circadian rhythm. Sleep deprivation is said to alter the nature or number of immune cells, such as leukocytes or NK lymphocytes. Lastly, by activating pro-inflammatory immune mediators (interleukin-1, TNF alpha, etc.), certain episodes of bacterial or viral infection are said to promote the prolongation of sleep duration.

Dreaming, a phenomenon still shrouded in mystery

Numerous hypotheses have since emerged following Sigmund Freud's famous psychoanalytic theory, in which dreams were seen as an unconscious expression of repressed desires and feelings.

According to some hypotheses, dreams enable events, feelings or learning of new tasks to be memorized. This is demonstrated by the role of several cortical zones (including the frontal region) which play a role in speech, memory, decision-making, and movement. According to other hypotheses, dreams allow innate or acquired behaviors to be incorporated or revised by unconscious repetition while dreaming.

On the other hand, certain hypotheses maintain that dreams are merely an activity related to waking: they are, in reality, the expression of a sudden reactivation of the consciousness which has a disorganized perception of the unconscious brain activity occurring in the night. Unless dreams are ultimately merely a random brain activity, with no particular organization or purpose? For the time being, neuroscience is better able to put forward these hypotheses than to confirm them.

In French : Why does the brain remember our dreams? Video press release - 3 min 31 - 2014

Sleep disorders, the scourge of modern societies...

Chronic insomnia: 16% of the population is affected
At least 5% of adults suffer from sleep apnea
8% have restless legs syndrome

Insomnia

There are several forms of insomnia: some occur occasionally, but others are chronic in nature. Certain forms are characterized by difficulty falling asleep, and others by waking at night or non-restorative sleep. These also differ in terms of their trigger factors: internal somatic or cognitive factors, or external factors which disrupt sleep induction or maintenance (lifestyle, light, using screens or practicing sports late at night, taking certain medications, etc.).

Hypersomnia and narcolepsy

Hypersomnia is characterized by an excessive need to sleep and episodes of excessive drowsiness during the day, despite normal or increased amounts of sleep. This symptom affects more than 5% of the adult population. Among the different types of hypersomnia, narcolepsy, still known as "maladie de Gélineau" in French, is a rare sleep disorder which affects 0.026% of the population, and is mainly triggered in adolescents and young adults. This severe disorder, which more than likely has an auto-immune origin, manifests as sudden, overwhelming drowsiness during the day. It is also associated with hallucinations (waking dreams) and cataplexy attacks in which sudden muscle weakness occurs.

Circadian rhythm disorders

These disorders occur following disruption of the biological clock. Individuals who go to sleep late at night experience a delayed sleep phase, while those suffering from advanced sleep phase disorder have difficulty staying awake after 19:00. Episodic disorders may exist, for example, related to a time zone differences. However, others are specific, such as non-24-hour sleep-wake disorder, affecting blind individuals who do not perceive alternating wake-sleep cycles. These individuals generally have a circadian rhythm of close to 25 hours, instead of the usual 24 hours. In all cases, these disorders are related to the disruption in chronobiology and may, consequently, give rise to diverse somatic repercussions.

Obstructive sleep apnea

Sleep apnea is a respiratory disorder the incidence of which increases with age, excessive weight and, particularly, obesity. During the night, brief apnea (lasting a few milliseconds to a few seconds) occurs due to obstruction of the throat by the tongue and loosening of pharyngeal muscles. This ultimately exacerbates the cardiovascular risk and, due to the resulting repeated, momentary awakening, causes fatigue and daytime drowsiness.

Parasomnias

Parasomnias correspond to group of abnormal phenomena which occur during the deep NREM sleep phase or during REM sleep.

During deep NREM sleep, the most common parasomnias are sleepwalking, bruxism (teeth grinding), somniloquy (sleep-talking), night terrors (common in children, between sleep-walking and sleep-talking) or enuresis (bed-wetting). During REM sleep, this entails violent movements (rapid eye movement sleep behavior disorder, RBD), inarticulate noises made by the sleeper (catathrenia) or unconscious sexual behavior (sexsomnia).

Parasomnias sometimes have a genetic element, but are usually promoted by external factors which disrupt normal sleep patterns (sleep phase intensity, duration and structure): neurodegenerative disease, stress, fever, certain medications, etc. Sexsomnia is, for example, said to be promoted by dopamine treatment in Parkinson's patients.

Restless leg syndrome

Restless leg syndrome (RLS or Willis-Ekbom disease) is characterized by an irrepressible urge to move the legs, associated with (or caused by) unpleasant sensations in the lower limbs: sometimes described as "fidgets".  These symptoms, which usually manifest during periods of rest or inactivity, intensify during the evening and at night. They disrupt sleep and, in the most severe cases, considerably disturb sleep (disorganization and fragmentation of sleep).

The mechanism for the disease has not yet been elucidated, but more than likely involves dysfunction of the dopaminergic system.  Certain forms of RLS are said to be secondary to end-stage chronic kidney disease, pregnancy, iron deficiency or use of certain medications (antihistamines, antipsychotics, antidepressants, etc.). Several predisposing genes, the expression of which modifies dopamine transmission, have also been identified.

Pictogramme microscope Challenges facing research

Continuing the development of sleep investigation techniques

Knowledge on sleep has made considerable progress in recent years owing to new imaging and functional imaging techniques. However, new approaches are now enabling the transition from analysis of general brain activity (or by anatomical regions) to the analysis of mechanisms on a neuronal or neuron network scale.

Using electrodes implanted into the brains of animals, it is now possible to monitor the activity of active neuronal networks during different sleep phases. These types of data may also be obtained in patients suffering from severe epilepsy, in whom brain electrodes have been implanted for therapeutic purposes. Recording their brain activity enables valuable information to be obtained on humans, and the nature of the neurotransmitters involved to be identified.

Over the past few years, research in neuroscience has, moreover, been dramatically transformed: experimental techniques developed in animals now enable specific types of neurons or a small zone of the brain to be accurately handled. With optogenetics, the neurons/zone of interest are transfected with a gene coding for a photoactivatable protein. Light emitted by an optical fiber then makes it possible to activate or specifically inhibit these neurons, and thus to study their role or function. Chemogenetics is based on the same principle, but uses a chemical molecule capable of modulating the activity of neurons expressing receptors for this molecule.

Shedding light on the relationship between sleep and health

Not all of the secrets of sleep have yet been revealed: In terms of memorization, according to experimental data, the specific role of each sleep phase in this process is still difficult to determine. While NREM sleep appears to play a role in the memorization process, this should not downplay the role of REM sleep: this, in fact, represents the predominant sleep phase among neonates and young infants. Disrupting or suppressing this phase gives rise to brain architecture disorders in rats. Its growing role in certain memorization processes, particularly explicit or declarative memory, is now therefore supported by an increasing number of data.

At the same time, studies have highlighted a link between sleep disorders and impaired cognitive capacity, via an increased presence of senile plaques on imaging. The link between sleep and the ability to eliminate toxins from brain tissue has thus been demonstrated. However, a more in-depth understanding of the mechanisms involved is now necessary. This will notably make it possible to determine whether cognitive disorders are related to sleep disorders, or if the latter ultimately promote cognitive decline. In short, this is a chicken vs. the egg problem, which moreover is not unique: epidemiological data also suggest a link between sleep and depression:  do sleep disorders make people vulnerable to the risk of depression or does depression affect sleep quality? Likewise, epidemiological observations indicate an increased risk of hypertension, hypercholesterolemia, and cardiovascular events (stroke, coronary artery disease) among individuals with poor sleep quality. These observations are currently the subject of studies which will shed light on the mechanisms involved.

The link between sleep and immunity should also be clarified, along these lines. In addition to understanding the role of sleep in terms of susceptibility to infection, the mechanisms identified could shed light on the growing incidence of cancer among night workers: the high risk of breast cancer, prostate cancer or colon may not only be related to a less efficient immune system, but also to desynchronization of the circadian rhythm, which affects certain molecular signaling pathways.

Clarification of sleep and vigilance disorders

What is the incidence of sleep disorders? How and why is this changing? What impact does it have from an epidemiological or individual perspective? All of these questions form the basis of numerous scientific research projects which are closely examining all of the factors of daily life which have a decisive impact on sleep quality: personal, educational or professional pace of life, influence of diet, use of new technologies including light which disrupts our nights… These projects can provide useful information in terms of public health and individual health, but also information which will allow us to improve knowledge and prevention in terms of accidents (road, household, etc.) or in the field of occupational medicine. In the latter field, questions relating to night work or shift work -which affects working/sleeping hours - should be studied more closely.

In French : Sleepiness at the wheel: measures to combat it - documentary - 4 min 15 - 2011

Unchangeable determining factors involved in sleep are also among the most promising themes: genetic screening studies are able to identify genetic determinants involved in the diverse sleeper profiles. Precise analysis of specific sleep disorders, such as narcolepsy, or those associated with certain illnesses, such as Parkinson's disease, may offer interesting insight into certain neurohormonal or metabolic pathways representing essential pivotal factors for good sleep quality and quantity.