Sleep: suspending the computer?
We spend approximately a third of our lives sleeping. This number may seem like a luxury that few, if anyone (at Caltech) can afford. But regardless of the precise number, we dedicate significant portion of our lives to doing something that we basically do not understand. Sleeping is not clearly controled by our volition. Even in circumstances where it is extremely dangerous to fall asleep, for example, while driving, people do fall asleep. Why do we need to sleep? What are the evolutionary advantages because of which sleep arose? What are the functions of sleep today for humans?
The prevalent view of sleep (even today) is that of a resting state. After thinking and working for a whole day, the brain needs to take some time to save energy and be ready for the following day. In modern day terminology, it would correspond to suspending the computer when you are not using it or shutting it down at night.
In greek mythology, Hypnos (Somnus in the roman literature), god of sleep was the brother of Thanatos (god of Death). His sons were the 'bringers of dreams': Morpheus (people), Icelus (animals) and Phantasus (inanimate things). According to many religions, it is god's will to decide whether we will wake up after sleep or continue "sleeping". In 1834, in one of the few books on sleep of the time, it is stated that sleep is an intermediate state between wakefulness and death (Robert MacNish, The philosophy of Sleep, 1834.)
This view of sleep has changed radically over the past 50 years due to multidisciplinary research on the psychological, electrophysiological, behavioural and functional aspects of sleep.
Sleep onset
What causes sleep to start? A number of different theories have been proposed.
A reduction of stimulation causes sleep.
According to this view, a reduction in the sensory stimulation to the brain is responsible for the onset of the sleep state. A series of clever lession experiments (see below) argue strongly against this view of sleep onset.
"Vascular Theories".
Blood goes away from the brain to accumulate in the digestive tract, causing the brain to sleep. Some scientists held the opposite view: blood pressure accumulates in the brain, causing the brain to sleep.
"Hypnotoxin Theory".
A "fatigue" product (or a toxin that we need to get rid of) accumulates in the brain causing sleep. This idea was very fashionable at the turn of the century and was discarded afterwards. However, a more refined modern version of this idea may not be altogether wrong.
1907 Legendre and Pieron, "Conditioned Media Experiment". Cerebro-spinal fluid from sleep-deprived dogs can induce sleep in non sleep-deprived dogs.
1920 Nathaniel Kleitman, a simple and yet beautiful observation. After one-night sleep deprivation, people are more tired in the middle of the night than the following morning. This argues against a continual build-up of a neurotoxin or fatigue product.
Recent evidence actually supports the notion that the accumulation of certain neurotransmitters (e.g. adenosine) at a precise time and location is correlated with sleep. More experiments need to be done to establish a causal link.
A first window into the brain: Electroencephalogram
1875 Richard Caton connected a voltmeter to the surface of a rabbit brain and measured electrical potentials.
1928 Hans Berger recorded an electrical signal from the human scalp. He developed the EEG (electroencephalogram) as we know it today. For the first time, sleep could be monitored without disturbing the subject. It is not trivial to tell whether someone is sleeping or not! Many scientists were skeptical about these inital results, particularly given how easy it is to obtain electrical artifacts. Berger then showed that when subjects closed their eyes, a particular band in the frequency spectrum (8-12 Hz, later called alpha waves) was enhanced.
1930s Nathaniel Kleitman characterized the EEG patterns throughout sleep. Sleep was characterized by high amplitude and low frequency waves while the awake state showed low amplitude waves of higher frequencies. The brain was clearly active during sleep. The idea of sleep as shutting down the brain gave way to the idea of a synchronized and slowly oscilating activity during sleep.
Lesion experiments
1918 A "natural experiment": influenza epidemic. A particularly virulent strain of Influenza killed neurons in the brains of the patients, producing the encephalitis lethargic syndrome. Patients were unable to remain awake. Von Economo suggested that:
1) There are localized cells that regulate and control the sleep/wake transition.
2) Furthermore, these cells may be concentrated in an area of the brain called the brainstem.
1930s Frederic Bremer, working in cats, provided the strongest evidence against the "deafferentation theory of sleep" (i.e. that sleep arises the default state when there is no sensory stimulation). Sleep is not merely the absence of waking. He performed two crucial lesion experiments, based on the ideas derived from the encephalitis lethargic patients from 1918.
"cerveau isolé" (isolated forebrain). He also did a cut in the upper part of the brain stem. EEG indicates continuum deep-sleep character. And the cats were continually drowsy and sleepy (hypersomnolent cats).
"encéphale isolé" (isolated forebrain and hindbrain). He did a cut in the lower part of the medulla, just above the spinal cord. EEG indicates sleep/wake cycles, even with an enhancement in wakefulness (hypervigilant cats)
Bremer suggested that there is an active control of sleep, between the levels of the two transections.
1949 Moruzzi and Magoun implanted electrodes in the brainstem and electrically stimulated the formation while recording the EEG. They observed activation in the EEG (small voltage signals with high frequency) and behavioural arousal. Chronic lessions in these nuclei induced slow waves in the EEG and immobility.
What about dreams?
TopDreams were historically discarded from scientific exploration. They were fleeting moments interrupting the night."... The soul would leave the body temporarily during dreams and permanently at night ...".
Nathniel Kleitman was interested in hunger cyclical behaviour in infants. He was also interested in measuring eye movements during sleep as an indicator of sleep and because of the huge cortical representation of eye movements. They started with simple observation through the eyelids and then they designed the EOG, the electroculagram. EEG was taken a few minutes per hour. This was done to conserve paper (not because of ecological reasons but because there was no research grant to work on sleep).
1899 Freud, interpretation of dreams. Dreaming discharges "instinctual energy".
1953 Aseinsky and Kleitman. REM sleep. Irregular respiration, accelerated heart rate and rapid eye movements. A lightening of sleep.
1957 Dement and Kleitman.
Cyclical variations of EEG patterns occuring every ~ 90 min. Dreams were associated with REM sleep.
1958 Dement.
Active suppression of motor activity (except for eye movements and twitching) during REM. In animals, the EEG during REM was indistinguishable from the awake state. This contradicted the dogma of the time. No one believed in activated EEGs associated with sleep.
Modern sleep research
And this leads us right into the modern fascinating results of sleep research. Throughout the course we will discuss the results of recent experiments in:
Sleep deprivation (both in humans and in animals).
What happens when animals/humans are sleep deprived? Is it possible to specifically deprive subjects of dreams? What would happen in that case?
The relationship between sleep and memory.
Sleep disorders.
What happens in the brain while we sleep? Electrophysiological recordings in animals. Functional imaging experiments in humans.
Lucid dreaming.
Circadian rhythms and sleep. Evolution of sleep.
Molecular and cellular basis of sleep.Why study sleep?
Sleep constitutes a fascinating open field in biology
To begin with, understanding the function(s) of sleep constitutes a fascinating open question in biology. There have been many fascinating discoveries in biology in the last fifty years and still, sleep is a gross subject that we are just starting to comprehend. It is not a fancy far-fetched question that requires a lot of knowledge to even explain what the question is. Every person knows that we need to sleep a substantial fraction of our lives.
Studying sleep will substantially increase our general understanding of neuroscience
As in many other fields, an important increase in our understanding of neuroscience will be achieved by studying sleep. When biologists started working towards solving the problem of cancer, they probably did not envision that the field would open unexplored areas in our understanding of the cell cycle, of telomerases, of angiogenesis, of tissue formation, of mutations. In a similar fashion, the study of sleep will enlighten the general neuroscience community.
Sleep disorders
There are a number of practical issues that require our understanding of sleep.
To begin with, there are a number of sleep disorders (such as insomnia, narcolepsy, sleep apnea and others) that affect a significant proportion of the population. Some of these disorders are quite disabling. And falling asleep while driving is extremely dangerous.
Other potential applications of sleep research
More into the realms of science fiction, one could envision a number of practical applications of sleep research.
What is the minimum amount of sleep required?
Is it possible to work on a problem/ invent a song/write a book while sleeping?
Is it possible to target our dreams to particular topics?
Dream movies?
What is sleep for?
(Brief summary of suggestions from the International Symposium on 'The Function of Sleep'. Italy 1994)
The Body
Restoration.
Energy conservation.
Immune function.Safety
Lack of food.
More danger.
No movement (static objects are harder to detect for predators).
Huddling (to make a 'bigger animal' and save more energy).
The Brain
Conservation of resources.
Restoration.
Energy conservation
Development
Learning and memory
Techniques to study sleep
Lesions
Sleep deprivation
Sleep disorders
Functional imaging (fMRI/PET)
Electrophysiology
Pharmacology intervention
Molecular biology. Knock-out technology has been very successful in starting to elucidate genes/molecular circuits involved in specific behaviors. Sleep is far behind in these types of studies. But they are extremely promising (see for example Siegel, J. (1999). "Narcolepsy: A key role for hypocretins (orexins)." Cell 98(4): 409-412.
Evolution of sleep. Comparison of sleep across different species.
Unresolved issues: Hot topics for a Ph.D
There are numerous unresolved issues in sleep research. Throughout the class I will point out some of the many remaining mysteries of sleep. I would actually even claim that we are just at the very beginning of starting to learn the techniques and preliminary ideas about the mechanisms and roles of sleep. Some sub-fields are more advanced than others. There are many sub-fields that have not even been created yet (maybe you, the student/reader, will).
A comprehensive theory of sleep should be able to accommodate and explain, among others, the following observations (to be discusses in more detail in future classes):
Rats die after on average 17 days of total sleep deprivation.
For some marine animals (like dolphins) and birds involved in transatlantic flights, sleep would be very dangerous given the conditions in which they live. They have developed uni-hemispheric sleep.
How did sleep arise in evolution from simpler forms of circadian rhythms?
Cycles in the EEG signals throughout the night with a period of approximately 90 minutes. What are the brain mechanisms that yield the different stages of sleep? What are the functional roles of the different sleep stages?
Deficits in humans with prolonged sleep deprivation.
Brain activity during sleep.
Sleep disorders.
Similarities and differences in brain activation between the states of general anesthesia, comma and sleep.
Hibernating animals come out of hibernation in order to sleep.
Functions of sleep. Memory, thermoregulation, development, restoration.
References
This is a partial list. For a more complete list of references, please go to the Bibliography page.
Moorcroft, W. H. (1995). Comments on the symposium and an attempt at synthesis. Behavioural Brain Research 69: 207-210.
Hobson, J. (1995). Sleep. New York, Scientific American Library.
Horne, J. (1988). Why we sleep: The functions of sleep in humans and other mammals. Oxford, Oxford University Press.