J R Soc Med 2002;95:591-597
doi:10.1258/jrsm.95.12.591
© 2002 Royal Society of Medicine
What does brain damage tell us about the mechanisms of sleep?
B M Evans FRCP
Department of Clinical Neurophysiology, Mapother House, King's College
Hospital, Denmark Hill, London SE5 0RS, UK
E-mail:
bidievans{at}theorchard.swinternet.co.uk
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INTRODUCTION
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Much is now known about the factors that influence the timing
of sleep
onset, such as the circadian rhythm and the length
of time since a previous
sleep
1. There is
also information about
hormonal factors that influence sleeping and waking and
the
cerebral areas associated with
them
2. Less is known
about the
nerve fibres and cells involved in transferring the function
of the
brain and the body from a state of wakefulness to sleep
and back again at
least every twenty-four hours. This paper
outlines what is known about these
neural processes and suggests
that information about them can be derived from
the normal brain
and also the damaged brain.
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WAKEFULNESS, RAPID EYE MOVEMENT (REM) SLEEP AND NON-REM SLEEP
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Wakefulness is characterized by a state of arousal with an activated
cerebral
cortex, high cerebral blood-flow and glucose metabolism, and
fast
activity in the electroence-phalogram (EEG); autonomic
activity and muscular
tone are also high. Non-REM sleep begins
at sleep onset. The cortex is
progressively deactivated as slow
waves appear in the EEG, cerebral blood-flow
and glucose metabolism
decline and autonomic activity and muscular tone
decrease. This
process culminates in deep sleep, sometimes called stage 4 or
slow-wave
sleep from the EEG appearance. During deep sleep the heart rate
and
blood pressure are low and steady and the muscles are relaxed
but not
paralysed. Non-REM sleep comprises deep sleep and the
intermediate states
between it and wakefulness; it makes up
about 80-85% of total sleep time, and
is interrupted every 60-90
minutes by episodes of REM sleep. In these episodes
the cortex
is highly activated with fast EEG activity, enhanced cerebral
metabolism
and raised blood pressure and heart rate; the voluntary muscles
are
paralysed apart from the eye muscles, which cause the jerky
eye movements that
give this sleep its name. REM sleep makes
up 15-20% of a total night's sleep
and is associated with dreaming.
REM and non-REM sleep are controlled by
separate brainstem mechanisms.
This paper discusses only the mechanisms of
non-REM sleep, the
predominant sleep type.
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WHAT DO WE KNOW ABOUT THE MECHANISMS THAT CONTROL NON-REM SLEEP?
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In 1949 a reticular activating mechanism (RAM) was described
that switches
the brain from deep sleep to
wakefulness
3. The
RAM
arises in the brainstem reticular grey matter, a collection
of nuclei
surrounding the central canal. These nuclei receive
inputs from all the
ascending tracts of the spinal cord and
brainstem and then form relays in the
thalamus. From the thalamus
the RAM connects with the cerebral cortex by means
of a cortico-thalamic
network of nerve cells and fibres
(
Figure 1). The RAM is the
‘wake-up’
mechanism of the brain and mediates the change from
sleep to
wakefulness. It is also responsible for periods of increased
arousal
during non-REM sleep.
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Figure 1. Arousal and arousal inhibitory mechanisms of brainstem (vertical section
of monkey brain). C=cortex; CC=corpus callosum; CB=cerebellum;
MB=mid-brain; T=thalamus; RF=reticular formation. (a) Reticular
activating mechanism. Arrows show sensory input from spinal cord and mid-brain
into reticular substance of mid-brain nuclei, which then form relays in the
thalamus. Fibres of the thalamo-cortical radiation reach all areas of the
cortex. (b) Arousal inhibitory mechanism. Reticular formation input
remains the same as in (a) but the upward flow into the thalamus is
partly blocked in relation to the thalamic sleep spindles (S). The cortex
shows slow and very slow activity (SD). The slowest waves are related to the
sleep spindle
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The opposite process, from wakefulness to sleep, is not well understood. It
is often thought to be passive, related to the withdrawal of sensory input,
but recent work both in experimental electrophysiology and with positron
emission tomography indicates an active process that can be thought of as an
arousal inhibitory mechanism. First suggested in
19934, this seems to
consist mainly of an intermittent gating mechanism in the thalamus related to
the sleep spindle in the EEG. The sleep spindle, a brief burst of fast
activity, is seen in the scalp EEG in the early stages of non-REM sleep and is
present in the thalamus from the onset of drowsiness throughout the whole of
non-REM sleep. The effect of the sleep spindle on the RAM has been
demonstrated electrically by Steriade and his co-workers in naturally sleeping
cats5. They showed
that each thalamic sleep spindle was associated with an intermittent
interruption in the up-flow of brainstem activity. The spindle occurs
regularly at intervals of 3-5 s and whilst it is present in the thalamus the
brainstem activity becomes intermittent at the same frequency. The same 3-5 s
interval has been observed between the sleep spindles in
man6
(Figure 2). More recent
research from Steriade's group has shown that the slowest waves from the
cerebral cortex in deep sleep are also related to the sleep
spindle7. Thus two
factors, cortical and thalamic, combine to produce a mechanism that prevents
activation of the cortex by the RAM during slow wave sleep
(Figure 1b). Because
the thalamic gating is intermittent strong stimuli can still reach the cortex
and restore wakefulness, which explains why the cry of a baby will always wake
its mother from sleep.
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Figure 2. Relation between sleep spindles (ss) and cyclical alternating pattern in
early sleep. The bar graph shows the intervals between the onsets of 1148
sleep spindles; pooled data from 32 individuals in stage 2-3 sleep. The
preferred interval is between 3 and 5 s. The line graph shows the interval
between the onsets of 1463 episodes of higher arousal activity in stage 1
sleep; pooled data from 52 individuals. The preferred interval is about 16 s
with subpeaks at shorter and longer intervals (the subpeaks were consistent
during collection of the data). The intervals between the subpeaks are at
about 4 s—i.e. similar to the intervals between sleep spindles
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Considerable support for the thalamic inhibitory mechanism has come from
positron emission tomography. Maquet and several other
workers8,9,10,11
have studied the differences in blood-flow in the sleeping and waking brain in
REM and non-REM sleep. These show that the blood-flows in the thalamus, basal
ganglia and upper mid brain during non-REM sleep are very low indeed,
indicating deactivation at this level. Maquet considers that his findings
provide support for those of Steriade.
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CLINICAL EVIDENCE OF INTERMITTENT CHANGES IN AROUSAL AT SLEEP
ONSET
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Regular changes are seen at sleep onset in the normal human
brain with
alterations in the level of cerebral
arousal
4,12,13,14,15,16,17,18
(
Figure 3)—a
process
often referred to as the cyclical alternating
pattern. The changes involve the
level of arousal in the EEG,
muscular tone, autonomic activity and also
cerebral
blood-flow
14 and
cerebrospinal fluid
pressure
14,19,20.
The changes are rhythmic,
with varying frequencies between about 8 and 60s.
They respond
to stimulation, so that states of low arousal can be switched
to
high by simple stimuli such as touching or calling. By contrast,
periods of
lower arousal develop spontaneously—an indication
that the motive force
is in this direction (i.e. inhibitory
rather than activatory). After
interruption by a stimulus, the
inherent rhythm
resumes
4,12.
As sleep progresses from stage
1 to stage 4 the changes become slower and
slower, and in deep
sleep no intermittent arousal activity is
seen
4,12.
No intervals
as short as the 3-5 s interval between the sleep spindles have
been
reported in any of the studies of cyclical alternating pattern;
the
shortest intervals described are in the early part of
sleep
12.
When all
the intervals between arousals in early sleep are pooled,
a preferred interval
length of 16 s is revealed (Figures
2 and
3)
but there are other faster
and slower preferred intervals that
produce the subpeaks shown on the line
graph in
Figure 2. The
intervals
between these subpeaks are about 4 s, suggesting that there
is a
link between the sleep spindle in the thalamus and the
cyclical alternating
pattern in early sleep. It is probable
that all the varying intervals between
arousals in the cyclical
alternating pattern are subharmonics of the interval
between
the sleep spindles.
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Figure 3. Polygraphic record at 1.5 cm/s showing intermittent arousal activity of
early sleep (stage 1). The upper 14 traces show the EEG with alternating
periods of faster activity (dark areas associated with higher arousal). The
intervals between the onsets of the higher arousal periods are shown by the
figures at the top. (These are the intervals used in the line graph of Figure
3.) Channel 17 is an electrocardiogram; channel 18 is respiration showing
periodic apnoea, each group of breaths associated with higher arousal. Below
is a heart rate graph showing intermittent heart rate increases with each
arousal
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FINDINGS IN THE DAMAGED BRAIN THAT RESEMBLE THE CYCLICAL ALTERNATING
PATTERN
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The first evidence of intermittent episodes of high and low
arousal came
from studies of the damaged
brain
21 and such
episodes
have since been reported in coma of many different
causes
12,13,22,23.
These
arousal changes are accompanied by simultaneous changes in the
EEG, the
autonomic
system
4,12
(Figures
4 and
5), cerebrospinal
fluid
pressure
19,20,
and somatic motor
activity
12.
Compared
with the intervals between the sleep spindles and even the arousal
alternations
of the cyclical alternating pattern the changes in activation
in
the damaged brain are very slow, lasting many seconds or
minutes, and are not
always rhythmic (
Figure 5).
They are also
often more extreme than in the normal situation and may even
be
life-threatening, especially those involving the cerebrospinal
fluid
pressure
19. The
contrast between the excessive changes
seen in the damaged brain and the
modest ones in the normal
brain suggests a process in which control mechanisms
have been
lost or damaged.
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Figure 4. Recordings from a patient aged 66 with subarachnoid haemorrhage from
anterior communicating aneurysm. Above: channels 1-3 show EEG at
1.5 cm/s. Low voltage slower activity is followed, at the time of a
spontaneous arousal, by flattening of the EEG and then by slow waves with
muscle artefact. Channel 4, respiration from a thermistor in the nose, channel
5, electrocardiogram. Note marked increase in respiratory and heart rates at
the moment of arousal and a wandering pacemaker during the period of lower
arousal. Below: graphs of respiration rate (R.R.) and heart rate
plotted at 1 s intervals. This shows that arousal events are occurring about
every 4 min. Open blocks above the respiration graph illustrate periods of
higher arousal in the EEG. Filled areas below the heart rate graph illustrate
periods when wandering pacemaker was evident. Short arrows show the section of
the cardiorespiratory graphs associated with the EEG polygraph above. X marks
a stimulus
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Figure 5. Recording from boy aged 16 with closed head injury. Above:
two pieces of polygraph, A and B. Channels 1-5 EEG; channel 6, surface
electromyogram (E.M.G.) from right leg; channel 7, electrocardiogram; channel
8, respiration from thermistor in nose. Section A is taken from a spontaneous
arousal accompanied by a decerebrate spasm and shows change in the EEG from
low voltage to higher voltage slow waves and marked increase in muscle
activity and heart and respiration rate. Section B is taken from a brief
arousal after the spasm shown in section A had subsided. EEG shows a brief
burst of slow waves with an associated muscle spasm with heart and respiratory
rate increases. Below: graph of the heart rate. Short arrows, A and
B, mark the periods of the graph related to the polygraphic traces shown
above. Open blocks illustrate occurrence of EEG change; closed blocks
illustrate muscle spasms
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EFFECTS OF BRAIN DAMAGE ON MECHANISMS OF SLEEP
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Deep non-REM sleep can be regarded as a state of physiological
reversible
unconsciousness. Many forms of brain damage result
in disturbance of
consciousness. In this paper my working hypothesis
is that coma or stupor is
the result of interference with the
non-REM sleep system by some types of
brain damage. The non-REM
sleep system can be considered at three
levels—an upper
level, consisting of the cerebral cortex and hemisphere
white
matter; a middle level, involving the thalamus and upper brainstem;
and
a lower level, comprising the lower mid-brain and pons.
Brain damage at any or
all these levels can produce coma or
in less serious cases stupor. Most
coma-producing conditions
are capable of damaging any level individually or
two or three
levels together but some conditions commonly damage one level
rather
than the others.
Level 1: the cerebral hemispheres
Level 1 damage can affect the cerebral cortex or hemisphere white
matter24 or both
together. Malfunction here can make it difficult or impossible for the RAM to
activate the cortex, even though the lower levels of the sleep mechanism in
the thalamus and brainstem remain intact. Clinically, comas of this type range
from stupor to deep unconsciousness. In milder cases some ability to sleep and
wake may be retained. There may be additional evidence of focal cortical
damage, producing localized motor or sensory changes.
Cerebral cortex
Damage to cortex is most commonly produced by metabolic imbalance, anoxia,
encephalitis or meningitis, and epilepsy (especially non-convulsive status
epilepticus).
Hemisphere white matter
Damage here is most commonly due to severe head injury. Violent shaking of
the brain within the skull tears the deep hemisphere white
matter24.
Conditions affecting both white and grey matter
Degenerative conditions such as Alzheimer's disease or
Creutzfeldt—Jakob disease are associated terminally with a stuporose or
comatose state related to widespread grey and white matter damage.
Patients with level 1 damage have continuous, severe abnormal EEG activity
consisting of high amplitude delta and subdelta with no response to
stimulation (non-convulsive status epilepticus will show continuous
spike-and-wave activity). This is indicative of widespread cortical and/or
white matter damage or malfunction. If the damage is at level 1, with partial
recovery the final result may be a state of vacant wakefulness alternating
with sleep. The undamaged thalamic sleep mechanisms allow sleeping and waking
periods to return but the cortex remains too abnormal to permit awareness.
This is one form of the persistent vegetative state.
Level 2: the thalamus and upper mid-brain
This level contains the intermittent gating mechanism of the arousal
inhibitory mechanism, related to the thalamic sleep spindle. It is damage at
this level that produces the exaggerated intermittent spontaneous changes in
arousal described above, involving autonomic, muscular, cerebrospinal fluid
pressure and EEG changes. The nature of the muscle activity depends on the
level of the injury. Damage at the thalamic/diencephalic level is associated
with semipurposeful movements, but when the upper brainstem is involved the
increase in muscle tone associated with each arousal may be decerebrate in
character, producing recurrent decerebrate
spasms13 that have
been mistaken for seizures. Intermittent arousal activity has been described
in many types of brain damage including cerebral tumours, stroke, anoxia,
encephalitis and Creutzfeldt—Jakob
disease12,13,20,22,23.
However, it is most commonly seen in subarachnoid haemorrhage and head
injury.
Subarachnoid haemorrhage
This condition often causes spasm of the arteries of the circle of Willis,
with consequent ischaemia at the thalamic/ diencephalic level. In addition,
deeply seated hemisphere clots are common in relation to a bleeding aneurysm.
Intermittent arousals occur with changes in the EEG—usually bursts of
higher voltage slow
waves12,13
accompanied by periods of rapid respiration and heart rate. These changes may
be hard to identify clinically, as the patient remains comatose throughout;
often the only sign is a slight movement with rapid breathing.
Figure 4 shows recordings from
a patient with subarachnoid haemorrhage. Rhythmic arousals are seen at about 4
min intervals. Each arousal is associated with pronounced changes in heart
rate and respiration rate. The electrocardiogram shows a wandering pacemaker
during the low-arousal periods.
Head injury
Here the brain is damaged at a slightly lower level than in subarachnoid
haemorrhage. Closed head injuries can result in a ‘knock-out
effect’ when the hemispheres move in relation to the brainstem at the
upper mid-brain level. This impacts on the arousal mechanisms in the upper
mid-brain, causing instant unconsciousness. If the dysfunction is longlasting
the patient often develops spontaneous changes in the level of arousal, with
associated respiratory, heart rate and muscular changes. The motor changes may
take the form of decerebrate spasms or uncoordinated movements, often violent.
The changes are usually very irregular with long periods of high or low
arousal lasting many minutes at a time. There are also brief arousal
‘spikes’, usually preceding or following a long high-arousal
episode. Figure 5 shows
recordings from a deeply unconscious 16-year-old boy with a closed head
injury: frequent prolonged episodes of high arousal were associated with
decerebrate movements, mainly involving the left arm. These episodes sometimes
lasted up to 10 min and, when the arousal subsided, there were frequent brief
decerebrate motor spasms followed by a long period of continuous low arousal.
Each upward arousal change was associated with slow activity in the EEG, a
precipitate increase in heart and respiration rate and decerebrate muscle
activity. In head injury the EEG arousal activity is prognostically useful.
The presence of any sort of EEG change to arousal, either spontaneous or in
response to stimulation, predicts a favourable
outcome25. The
young man in Figure 5 did make
a good recovery. In modern practice it is usual to sedate patients with severe
head injury and ventilate them artificially, so that the clinical features
described here may not be immediately apparent. Recognition of the underlying
situation may make it easier to interpret sudden swings in blood pressure,
cerebrospinal fluid pressure or cerebral blood-flow that can occur even in the
sedated state, especially if the patient is stimulated.
Level 3: the lower mid-brain and upper pons
Damage at this level involves the lowest part of the RAM where most of the
sensory input is received. This prevents even strong arousal stimuli from
reaching the higher cerebral levels. There is always evidence of other
brainstem malfunction in the pupils, eye movements and motor and reflex
responses. Most fatal comas finish in this
state24. The final
result is brainstem death, with failure of spontaneous respiration, absent
responses to stimulation and an isoelectric EEG. In this state there is no
sleeping or
waking24.
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CONCLUSION
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Comatose states are universally assessed by the Glasgow coma
scale
26—simple
clinical
tests that yield the most useful description of coma and the
most
accurate prognosis of its outcome at present available.
The tests deal with
many of the phenomena described in this
paper and will continue to offer a
practical clinical measurement
of comatose states. Nevertheless, the scale is
empirical, rather
than based on understanding of the underlying neural
mechanisms.
This paper presents evidence from many sources to suggest that a dedicated
neural mechanism, the non-REM sleep system, underlies the changes between
sleep and wakefulness. The system consists of two opposing
subsystems—the reticular activating mechanism, which wakes the brain up,
and the arousal inhibitory mechanism, which sends it to sleep. When the
non-REM system is damaged, coma or stupor results. An analogy can be drawn
with the pyramidal system in voluntary movement, or the visual system in
sight. The clinical phenomena accompanying any particular coma are related to
the site and nature of the damage and provide information that helps in
understanding the way the system works. Sleep, as a study, should not be
confined to the disciplines of psychiatry, respiratory medicine and psychology
but should enter the mainstream of neurological thinking as an important
function whose action is still poorly understood.
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Acknowledgments
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I thank Professor A Nicholson for his help and advice.
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INTRODUCTION
WAKEFULNESS, RAPID EYE MOVEMENT...
