Sleep is of the brain, by the brain and for the brain

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For decades it was assumed that brain activity was greatly reduced orabsent during sleep. Subjective experience of the loss of consciousnessand the lack of memory of mental activity during sleep appeared tosupport this conclusion. Even such great scientists as Charles Sher-rington1 and Ivan Pavlov2 backed this idea.

This assumption was overturned when the regular cyclic alterationof rapid eye movement (REM) and non-REM (NREM) sleep phaseswas discovered in the 1950s and 60s (ref. 3). The discovery of REMsleep and its correlation with vivid hallucinatory dreaming was evi-dence that the brain was highly active during sleep4. Soon after this dis-covery it was noticed that sensory inputs and motor outputs weresimultaneously blocked when the brain was activated during REMsleep, putting it ‘off-line’.

It was a great surprise to discover that the vigorous brain activationof REM sleep occurred at regular 90-minute intervals and occupied upto 20% of sleep. This fact alone invalidated the belief that sleep wascaused by and associated with a cessation of brain activity. Other factssupported the idea that the brain was continuously active during sleep.The early cerebral blood flow studies of Kety5 and later Sokolovshowed only a 20% reduction in cerebral blood flow during sleep.Because blood flow is correlated with neuronal activity it should nothave been a surprise to find that almost as many neurons increasedtheir firing rate at sleep onset as their activity decreased6. Even duringNREM sleep, when consciousness may be totally obliterated, the brainremains significantly active.

The descriptive study of sleep, so richly productive during the earlyyears of the sleep laboratory era, has been complemented in the pastdecade by the application of brain imaging7–9 and quantitative electro-encephalogram (EEG) mapping10. Imaging techniques showed thatthe regional activation of the brain is very different in the two EEG-activated states, REM sleep and waking, and both are different fromthe NREM phase of sleep (when the EEG shows high-voltage slowwaves instead of low-voltage fast activity). Quantitative EEG studiesalso revealed regional differences in brain electrical activity10,11.

These new data indicate that the brain is relatively quiescent duringslow-wave sleep (when the EEG is dominated by sleep spindles andhigh-voltage slow waves). But it must be emphasized that such globaldeactivation is only relative. Although consciousness is dulled, the brainis still roughly 80% activated and thus capable of robust and elaborate

information processing. Thus, the EEG spindles and slow waves repre-sent changes in the excitability of cortical and thalamic circuitry andshould be regarded not simply as ‘noise’, which subjective experienceleads us to assume, but as signals used by the brain for its own func-tional purposes12.

Mechanisms and functions of sleepAll in all, these findings support two radical ideas. One is that sleep isan actively regulated process, not simply the passive result of dimin-ished waking. The other is that sleep should be regarded as a reorgani-zation of neuronal activity rather than a cessation of activity. Withrespect to the first idea, it soon became apparent that although mam-malian sleep occurs during the rest phase of the circadian rhythm, it isproduced by brain processes in the hypothalamus and brainstem. It isin this context that Saper’s recent description of a sleep switch is bestunderstood and appreciated (see the review in this issue by Saper,Scammell and Lu, p. 1257).

Almost all mammals that have been studied show the NREM–REMcyclic alternation, which suggests not only a shared mechanism acrossspecies but a universal functional significance that must be far richerthan the mere energy saving that the subjective experience-based theories thought adequate. The discovery of the continuous and elab-orately modulated nature of sleep made it imperative to seek moreactive functional consequences, such as the homeostatic control ofenergy and the reinforcement of learning, that have recently beenfound. This is the context for thinking about Stickgold’s descriptionsof procedural learning enhancement during sleep (see the review inthis issue by Stickgold, p. 1272).

The resurgence of interest in sleep and learning was sparked byrobust evidence for sleep’s promotion of consolidation and improve-ment in learned motor skill performance in terrestrial mammals.Some animals can learn despite having little and/or poor sleep, butthis does does not mean that demonstrated sleep–learning links areirrelevant artefacts. The general principle could be that a species usessleep for learning if it can afford to do so. The more vexing problemof understanding how sleep does (or does not) benefit narrativememory will be solved only by more assiduous and strategic study.Then, and only then, can we speak of sleep as beneficial to memorywhere memory is defined as the conscious recollection of learned

1Department of Psychiatry, Harvard Medical School, 74 Fenwood Road, 401 Park Drive,, 2nd Floor East, Boston, Massachusetts 02115, USA.

Sleep is of the brain, by the brain and for the brainJ. Allan Hobson1

Sleep is a widespread biological phenomenon, and its scientific study is proceeding at multiple levels at thesame time. Marked progress is being made in answering three fundamental questions: what is sleep, what areits mechanisms and what are its functions? The most salient answers to these questions have resulted fromapplying new techniques from basic and applied neuroscience research. The study of sleep is also sheddinglight on our understanding of consciousness, which undergoes alteration in parallel with sleep-inducedchanges in the brain.

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ory of that same day’s experience (ref. 14), new data indicate that anequally large incorporation of recollected memory antedates itsexpression in dreams by as much as six days. While awaiting system-atic replication, this finding should caution us about the uncriticalacceptance of any theoretical formation about dreaming that is notbased on evidence. A case in point is the finding that whatever the timelag to incorporation of some recent events in dreams, most dream con-tent has no identifiable experiential antecedent15. Nielsen’s studies pur-sue the implications of some of these findings (see the review in thisissue, p. 1286).

Sleep and consciousnessPerhaps the most far-reaching of the complications of modern sleepscience concerns the riddle of the basis of consciousness, a theme notaddressed by any of the articles in this Insight.

A moment’s reflection supports the idea that consciousness is statedependent. For centuries we made judgements about sleep and thebrain that were wrong because we assumed, mistakenly, that con-sciousness ceased at sleep onset and resumed only when we woke. Theoccasional recall of dreams should have ruined that theory but greatminds, including that of Sigmund Freud, incorrectly assumed thatdreaming only occurred during the process of awakening.

Although it is true that consciousness is dulled during deep NREMsleep, it is qualitatively altered in parallel with the reorganization ofbrain activity that occurs at sleep onset when dreamlike mental activ-ity is fleeting. This takes place during the lighter stages of NREM sleep,when dreaming may be more sustained and, most markedly, duringREM sleep when dreaming assumes its most florid character. Becausememory is so severely affected by sleep it has been difficult to get reli-able and valid descriptions of mental activity during sleep, but it is nowclear that consciousness undergoes alteration in parallel with sleepchanges in the brain.

The net effect of this conclusion is to strengthen the consciousstate hypothesis, which asserts that consciousness changes its inten-sity and character in a stereotypical way as the brain changes stateduring the sleep-wake cycle. One approach to the scientific study ofconsciousness is to simultaneously track changes in the brain and

material. Memory, so defined, depends upon learning but is notequivalent to it.

The variation in sleep between species and during their lifespansuggests, further, that sleep may have many functions. And those func-tions may not only vary but be absent in some animals. The same func-tions may also be achieved during periods of waking. But thisflexibility is not evidence of functionlessness. In other words, to saythat sleep is variable does not, of course, mean that sleep is not vital tothose species that do sleep. It only means that relatively sleeplessspecies have some other way of adapting to life’s demands. Such plas-ticity is evidence of a pluralistic and, we assume, adaptive set of brainmechanisms and functions associated with sleep. This is the idea thatinspires and underpins Siegel’s phylogenetic work (see the review bySiegel, p. 1264).

The study of sleep phylogeny has a long history. It soon becameclear that sleep, as we know it in higher mammals, tends to be corre-lated with relatively large brains and with homeothermy. The search-ing studies of Allison & Cichetti13 demonstrated that adaptations todiverse ecological niches also played a major role in determining theamount, temporal distribution and depth of sleep. The general rulewas that large, carnivorous surface-dwelling animals, such as lions,slept long and deep whenever they were not foraging or mating. Bycontrast, smaller, herbivorous species such as rabbits tend to be nestdwellers and sleep relatively little. They have frequent awakenings andspend more time foraging and eating. They needed to be vigilant todefend themselves from predators. The commonsense conclusionfrom this work is that an animal sleeps if it can afford to.

Additional evidence of variability comes from the studies of humansleep that have uncovered a vast and complex set of sleep disorders. Ifone considers sleep to be an actively regulated process, it is under-standable that some people get too little, others too much and others thewrong kind of sleep. The functional consequence of these disorders issimilarly variable. Mahowald and Schenks’s review (see p. 1279 in thisissue) of these sleep disorders emphasizes some of the many possibledissociations of sleep and wake components that can afflict us.

What effect has the new science of sleep had on dream theory?Contrary to Freud’s assertion that dreaming was stimulated by mem-

Wake NREM sleep REM sleep

Behaviour

Awake

Polygraph

EMG

EEG

EOG

Sensation andperception

Thought

Movement

VividExternally generated

VividInternally generated

Dull or absent

Illogical, bizarreLogical perseverativeLogical progressive

Continuous voluntary Episodic involuntaryCommanded butinhibited

Stages

REMI

II

III

IV

Figure 1 | Behavioural states in humans. Statesof waking, NREM sleep and REM sleep havebehavioural, polygraphic and psychologicalmanifestations. In the row labelled behaviour,changes in position (detectable by time-lapsephotography or video) can occur duringwaking and in concert with phase changes ofthe sleep cycle. Two different mechanismsaccount for sleep imobility. The first isdisfacilitation (during stages I–IV of NREMsleep). The second is inhibition (during REMsleep). During dreams, we imagine that wemove, but we do not. Sample tracings of threevariables used to distinguish the state areshown: an electromyogram (EMG), anelectroencephalogram (EEG) and and electro-oculogram (EOG). The EMG tracings arehighest during waking, intermediate duringNREM sleep and lowest during REM sleep.The EEG and EOG are both activated duringwaking and inactivated during NREM sleep.Each sample shown is approximately 20seconds long. The three bottom rows describeother subjective and objective state variables.Modified from ref. 19.




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changes in the mind and then to map back and forth between the twodomains. How might brain activity mediate conscious experience?The direct study of subjective experience during sleep is an importantpart of the current flurry of excitement in the domain of conscious-ness research16. Subjective experience is so problematical that all butthe bravest scientists17 have been discouraged. And yet it must be rec-ognized that subjectivity cannot be studied at all unless pains aretaken to overcome the pitfalls of using first-person data. When largesamples are taken, and the level of analysis is coarse-grained and itsfocus formal, the subjective data correlate with brain data at high lev-els of statistical and functional significance. Two examples help tomake this point.

Normal subjects were asked to report their mental experienceduring periods of active wake, quiet wake, sleep onset, NREM sleepand REM sleep. The reports were scored for descriptions of halluci-natory perception and of thinking, and a reciprocal relation to brainstate was observed. Hallucinatory mental content is lowest duringactive waking and highest during REM sleep. The incidence of think-ing is reciprocally highest during quiet waking and lowest duringREM sleep18.

The implication of these findings is that the sleeping brain caneither generate its own perceptions or it can think about them. It can-not do both at the same time. Dreaming is therefore as hallucinatoryand thoughtless (or delusional) as so-called mental illness.

In the second study we tested this hypothesis. When psychoticschizophrenic patients were given the thematic apperception test(TAT), in which verbal descriptions of simple but ambiguous picturesare recorded and scored, when they were awake and asked to reporttheir dreams, they had equally high scores on a bizarreness scale(designed to pick up cognitive discontinuity and incongruity) for both.Age- and sex-matched normal control subjects have the same amountof dream bizarreness as the patients but are much less bizarre in theirwake-state projective test responses (S. Scarone, M. L. Manzone, O.Gambini and J. A. Hobson, unpublished data).

These findings support the hypothesis that REM sleep is a physio-logical brain state that produces a distinctive and psychosis-like men-tal content, whereas during normal waking such properties aresuppressed. Put another way, when awake the brain is normally free ofthe formal aspects of dream activity. Conversely, normal dreaming isjustifiably considered to be an entirely normal model of highly abnor-mal conditions of the human brain and mind. It is now clear that the

kind of consciousness that a person experiences is a function of thestate of the brain.

Sleep and dream research is a rare convergence point for the bio-logical and psychological sciences. Ongoing work in this area promisesto bridge areas of research from molecular and cell biology, throughneuronal populations, to behavioural and conscious states. It may evenprove helpful in solving the mind–body problem. ■

1. Sherrington, C. Man on his Nature (Doubleday, Garden City, New York, 1995).2. Pavlov, I. I. Conditioned Reflexes. An Investigation of the Physiological Activity of the Cerebral

Cortex (Dover, New York, 1960).3. Aserinsky, E. & Kleitman, N. Regularly occurring periods of eye motility and concomitant

phenomena during sleep. Science 118, 273–274 (1953).4. Dement, W. C. & Kleitman, N. The relation of eye movements, body motility, and external

stimuli to dream content. J. Exp. Psychol. 55, 543–553 (1957).5. Kety, S. S., Landau, W. M. , Freygang, W. H., Rowland, L. P. & Sokoloff, L. The local circulation

of the living brain; values in the unanesthetized and anesthetized cat. Trans. Am. Neurol.Assoc. 80, 125–129 (1955).

6. Hobson, J. A. Dreaming: An Introduction to the Science of Sleep (Oxford Univ. Press, New York,2002).

7. Maquet, P. et al. Functional neuroanatomy of human rapid-eye movement sleep anddreaming. Nature 383, 163–166 (1996).

8. Nofzinger, E. A., Mintun, M. A., Wiseman, M. B., Kupfer, D. J. & Moore, R. Y. Forebrainactivation in REM sleep: An FDG PET study. Brain Res. 770, 192–201 (1997).

9. Braun, A. R. et al. Regional cerebral blood flow throughout the sleep-wake cycle — an (H2O)-O-15 PET study. Brain 120, 1173–1197 (1997).

10. Achermann, P. & Borbély, A. A. Low frequency (<1 Hz) oscillations in the human sleepelectroencephalogram. Neuroscience 81, 213–222 (1997).

11. Huber, R., Ghilardi, M. F., Massimini, M. & Tononi, G. Local sleep and learning. Nature 430,78–81 (2004).

12. Steriade, M., Timofeev, I. & Grenier, F. Intracellular activity of various neocortical cell-classesduring the natural wake-sleep cycle. Soc. Neurosci. Abstr. 25, 1661 (1999).

13. Allison, T. & Cicchetti, D. V. Sleep in mammals. Ecological and constitutional correlates.Science 194, 732–734 (1976).

14. Freud, S. An Outline of Psychoanalysis (Hogarth Press, London, 1949).15. Fosse, M., Fosse, R., Hobson, J. A. & Stickgold, R. Dreaming and episodic memory: a

functional dissociation? J. Cogn Neurosci. 15, 1–9 (2003).16. Libet, B., Gleason, C. A., Wright, E. W. and Pearl, D. K. Time of conscious intention to act in

relation to onset of cerebral activity (readiness-potential). The unconscious initiation of afreely voluntary act. Brain 106, 623–642 (1983).

17. Metzinger, T. On Being No One (MIT, Cambridge MA, 2003).18. Fosse, R., Stickgold, R. & Hobson, J. A. Brain-mind states: reciprocal variation in thoughts

and hallucinations. Psychol. Sci. 12, 30–36 (2001).19. Hobson, J. A. & Steriade, M. In Handbook of Physiology: The Nervous System Vol. 4 (eds

Mountcastle, V. and Bloom, F. E.) 701-823. (Am. Physiol. Soc., Bethesda, 1986).

Author Information Reprints and permissions information is available atnpg.nature.com/reprintsandpermissions. The author declares no competingfinancial interests. Correspondence should be addressed to J.A.H.([email protected]).



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Sleep is of the brain, by the brain and for the brain