Download Neurophysiology of sleep-wake states in relation to consciousness

Neurophysiology of sleep-wake states
in relation to consciousness and
information processing
ANTON M.L. COENEN
NICI, DEPARTMENT OF PSYCHOLOGY, UNIVERSITY OF NIJMEGEN,
P.O. BOX 9104, 6500 HE NIJMEGEN, THE NETHERLANDS,
TEL + 31 24 36 12545, FAX + 31 24 36 16066,
E-MAIL: Coenen@ NICI.KUN.NL
Summary
Wakefulness is accompanied by a low amplitude high frequency electroencephalogram, due to the fact that thalamocortical neurons fire in a state of tonic
depolarization. In this situation information can easily pass the low-level threshold of these neurons, leading to a high transfer ratio. The complexity of the
electroencephalogram during conscious waking is high as expressed in a high
correlation dimension. Accordingly, the level of information processing is high.
Spindles mark the transition from wakefulness to sleep. These phenomena are
related to drowsiness, associated with a reduction in consciousness. Drowsiness occurs when cells undergo moderate hyperpolarizations. Increased inhibitions result in a reduction of afferent information with a lowered transfer
ratio. Information processing subsides, which is also expressed in a diminished
correlation dimension. Consciousness is further decreased at the onset of slow
wave sleep. This sleep is characterized by a high voltage, low frequency electroencephalogram. Slow wave sleep becomes manifest when neurons undergo
a further hyperpolarization. Inhibitory activities are so strong that the transfer
ratio further drops, as well as the correlation dimension. Thus, sensory information is largely blocked and information processing is on a low level. Nevertheless, subconscious information processing and stimulus evaluation can take
place during slow wave sleep. Similar to the patterns in the electroencephalogram, the architecture of evoked potentials is dependent on the state of alertness. During waking, components in event related potentials are moderate in
amplitude, while during slow wave sleep larger waves are visible. This is caused
by more synchronized unit responses with sharper phases of excitations and
inhibitions, which results from increased hyperpolarizations. In contrast, event
related potentials belonging to rapid eye movement sleep closely resemble those
of wakefulness. This type of sleep is associated with a ‘wake-like’
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electroencephalographic pattern. Just as during wakefulness, this is the expression of a depolarization of thalamocortical neurons, The transfer ratio of
rapid eye movement sleep has not yet been determined, but seems to vary.
Evidence exists that rapid eye movement sleep, associated with dreaming, with
some kind of perception and consciousness, is involved in processing of ‘internal’ information. In line with this, rapid eye movement sleep has higher correlation dimensions than slow wave sleep. It is assumed that the ‘near-the-threshold’ depolarized state of neurons in thalamus and cerebral cortex is a necessary
condition for perceptual processes and consciousness, such as occurs during
waking and in an altered form during rapid eye movement sleep.
Waking and sleeping
A key structure in the regulation of sleeping and waking and thus of consciousness is the reticular formation, a meshwork of nuclei and tracts located in the
brainstem (e.g. Steriade and McCarley, 1990). The brainstem reticular formation roughly consists of two systems. The first is located in the rostral mesencephalic part of the brainstem and is called the midbrain reticular formation.
The second system, positioned in the caudal medullar part of the brainstem, is
known as the medullar or bulbar reticular formation. There is overwhelming
evidence for the view that the midbrain reticular formation controls the process of wakefulness and sets the general level of activation of the brain (Singer,
1977; Steriade et al, 1990). The activating influence from the mesencephalic
reticular formation on the cerebral cortex is transmitted through two ways: a
dorsal pathway to the thalamus and a ventral route to the basal forebrain
(Jones, 1990; Szymusiak, 1995). Activation of the midbrain reticular formation leads to an enhancement of the spontaneous discharges of neurons, both
in thalamus and in extended areas of the cerebral cortex (Jones, 1990; Siegel,
1990). In short, the anatomical system essential for wakefulness and vigilance
is roughly located where mesencephalon, thalamus and hypothalamus meet.
This implies that this junction and its vicinity is crucial for preparing the cerebral cortex towards a condition conducive to information processing and consciousness.
Sleep is controlled by the medullar or bulbar reticular formation. In this area a
population of neurons is maximally active when slow wave sleep occurs (Siegel,
1990). It is thought that this part influences GABA-containing neurons in the
dorsolateral pontine tegmentum lying there intermingled with excitatory cholinergic neurons. These GABA-ergic cells could dampen the activity of adjacent
projection neurons, such as the cholinergic ones, or directly influence distant
structures, such as thalamus or cerebral cortex (Jones, 1990). Thalamic inhibitory interneurones located in the thalamic reticular nucleus as well as the
short-axoned interneurons located in the thalamic relay nuclei itself, also play
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part in the decrease of activation of thalamocortical neurons (Steriade and
McCarley, 1990). Parts of the hypothalamic region such as the preoptic area
and even adjacent basal forebrain areas are further involved in the regulation
of slow wave sleep (Szymusiak, 1995). Thus, slow wave sleep generation involves interaction among several brainstem, diencephalic and forebrain cell
groups (Siegel, 1990).
Neuronal activities and the electroencephalogram
A relationship exists between the patterns in the electroencephalogram (EEG)
and the level of vigilance and consciousness. Active wakefulness is accompanied by low amplitude high frequency (beta) waves in the EEG, whereas the
EEG of slow wave sleep is composed of high voltage, low frequency (delta)
waves. During waking, thalamocortical cells are in a state of tonic depolarization with relatively stable membrane potentials of around -60 mV. Neurons fire
in the ‘tonic’ or ‘relay’ mode, implying a sustained and high spontaneous activity (Glenn and Steriade, 1982; Steriade and McCarley, 1990). This variable
discharge pattern with a low synchronization between cells is the reason why
EEG electrodes, which summate the electrical activity of numerous cells, record
small but irregular waves with a high frequency of fluctuations. The tonic mode
of firing is the substrate of beta waves (Figure 1).
Figure 1:
At the left side the EEG of alert wakefulness is shown in the upper trace
and the EEG of deep slow wave sleep in the lower trace. At the right side
the spontaneous activity of a corticothalamic neuron in the same states is
shown. Note the ‘tonic’ firing mode of wakefulness in the upper trace and
the ‘burst’ firing mode of slow wave sleep in the lower trace. Bursts have
the same frequency as the mean frequency of the large delta waves in the
EEG. [The right panel is taken from Glenn and Steriade, 1982].
The occurrence of spindles, often a sign for drowsiness or light sleep, marks
the transition from alert wakefulness, with its low voltage high frequency waves,
to slow wave sleep, with its large amplitude low frequency (delta) waves. Spindles become manifest when thalamocortical relay cells undergo a moderate
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hyperpolarization with membrane potentials lower than -60 mV (Steriade, 199l).
This firing mode can be called the ‘oscillatory’ mode. The high voltage, irregular and low frequency waves of slow wave sleep, become manifest when neurons undergo a further hyperpolarization to about -70 till -90 mV. Delta waves
have a large amplitude, which implies that extended populations of neurons
fire rather synchronously in bursts, interspersed with prolonged
hyperpolarizations (Figure 1). Inhibitory interneurones play a role in the lowering of the membrane potential of relay cells; they are also responsible for the
strong synchronization of these cells by tying them together by powerful inhibitory activities. In contrast to spindles, delta waves are not rhythmical but
highly irregular. This mode of activation results in pause-burst discharges of
many cells and is called the ‘burst’ mode (Steriade, 1991; Steriade et al, 1993).
‘Rapid eye movement’ (REM) sleep is controlled by the pontine reticular formation. This is a third system in the brainstem roughly located between the
mesencephalic and medullar reticular formation (Jouvet, 1967; Hobson and
Steriade, 1986). Characteristic for REM sleep are the ‘ponto-geniculo-occipital’
(PGO) waves originating in this part of the pons. These waves propagate rostrally
and project through the lateral geniculate nucleus and other thalamic relay
nuclei to the cerebral cortex (Siegel, 1990). PGO waves are the pacemakers for
the activation of thalamus and extended cortical areas. As during waking, neurons become tonically depolarized and start to fire in the tonic mode (Glenn
and Steriade, 1982). Although the high spontaneous activity characteristic of
REM sleep is not limited to the sensory areas of the cortex but also include the
motor areas, the activity of the latter parts is not expressed at a bodily level. A
deep hyperpolarization of neurons in the peripheral motor system is the underlying mechanism for muscular relaxation (Chase and Morales, 1989). This
mechanism prevents gross overt movements during REM sleep and with exception of the tiny muscles of eyes and extremities, all muscles are relaxed.
Transfer of information
All information is encoded in electric impulses by the sensory organs. The
transfer of this information over the sensory pathways to the thalamus and
further to cortical areas is dependent of the state of vigilance. The concept of
the ‘transfer ratio’ was introduced by Coenen and Vendrik in 1972. They performed research on the flow of transmission from the peripheral visual organs
to the visual cortical areas during sleeping and waking. Using intracellular recordings of cells in the lateral geniculate body of the cat, Coenen and Vendrik
(1972) showed that during wakefulness the ratio between the output and the
input of a thalamocortical relay neuron varies between 0.7 and 1.0. The latter
value is reached under circumstances of alert wakefulness and implies that all
action potentials of retinal ganglion cells produce excitatory postsynaptic
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potentials (EPSPs), which easily pass the low-level threshold of geniculate neurons firing in the tonic or relay mode. Obviously, this can be regarded as the
underlying process of the high transfer ratio. All EPSPs generate outgoing action potentials and the transmission occurs in a way of ‘one input to one output
action potential’ (Coenen, 1995, 1998, Steriade et al, 1993). This means that
the complete message as coded by the peripheral receptors, reaches the sensory parts of the cortex in its entirety. A massive thalamocortical and corticothalamic traffic is the result (Steriade et al, 1993).
The transfer ratio goes down till about 0.7 when the animal becomes drowsy.
Then the output decreases while the input remains identical. Nevertheless, the
peripheral sense organs transform sensory stimuli in series of impulses just as
during waking and independently from the state of vigilance of the organism.
The information reaching the cortical level strongly decreases during slow wave
sleep. This process is called ‘thalamic’ or ‘sensory gating’ (McCormick and Bal,
1994). Thus, a decline of the processing of information becomes manifest when
the states of drowsiness and light slow wave sleep appear. A further increase of
the hyperpolarization of thalamocortical neurons is associated with slow wave
sleep. This results in a further inability of the EPSPs, produced by the incoming action potentials, to reach the increased threshold. The burst mode in which
the system fires, continuously blocks a major part of the afferent information
at the thalamic level. The blocking of the incoming series of spikes becomes so
strong that the transfer ratio drops further to about 0.3 or 0.4. Thus, the transfer ratio or sensory gating strongly depends of the level of vigilance (Figure 2).
Livingstone and Hubel (1981) extended and extrapolated these findings to the
primary visual cortex.
When the animal is awakened by an external arousing stimulus, the transfer
ratio immediately returns shortly back to about one (Figure 2) (Coenen and
Vendrik, 1972). This was confirmed by electrical stimulation of the mesencephalic reticular system of a cat, which also causes an arousal response (Singer,
1977). Singer could also demonstrate that electrical stimulation of the rostral
part of the brainstem was associated with a reduction of intrathalamic inhibition and with an induction of a depolarized state in cells of the lateral geniculate body, initiating a high and sustained spontaneous activation and an opening of the sensory channels. Thus, facilitation of the transfer of impulses through
the thalamic relay nuclei is controlled by the activating reticular system of the
brainstem.
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Figure 2:
Responsiveness of a neuron in the lateral geniculate body of a cat to visual
stimuli. A flash of light is given every second and the vertical lines represent the spike response of the cell (output). The upper, horizontal interrupted line indicates the input to the cell. Following an arousal stimulus
to the cat (arrow), the sleep EEG desynchronizes into a wake EEG, which
is accompanied by an increase of the spike response to the flash. At that
point the transfer ratio increases from about 0.5 to about 1, shortly later
followed by a small decline to 0.7 or 0.8. [Adapted from Coenen and
Vendrik, 1972].
During slow wave sleep there is no conscious perception which, however, does
not imply that cognitive activities must completely be excluded. The transfer
ratio is low but does not come beyond 0.3 till 0.4, which indicates that some
information still reaches the cortical levels. The analysis of this information
remains intact to a certain degree during slow wave sleep. Stimulus evaluation,
for example, is an automatic process that can take place under lower levels of
consciousness. Thoroughly investigated is stimulus evaluation which takes place
during sleep. It is well known, for example, that the threshold for awakening is
lower for a relevant stimulus than for a physically identical stimulus which has
no relevance for the individual (Langford et al, 1974). This shows that during
the state of slow wave sleep only a shade of the original information reaches
cortical levels. It might be possible that the amount of information passing
through the thalamus during sleep is just enough for a shallow, subconscious
evaluation.
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At this time the transfer ratio of REM sleep has not been determined. Nevertheless, anecdotal data can be gathered, suggesting that this ratio varies with the
fluctuating threshold of awakening during REM sleep. Presumably, the ratio is
quite high when the awakening threshold is low at the end of a REM sleep
period. Evidence for this view is the presence of a depolarized state of the
neurons analogous to waking (Steriade and McCarley, 1990) and further the
identical shape of visual evoked potentials made during REM sleep and waking
(van Hulzen and Coenen, 1984). Obviously, a depolarized state of thalamocortical cells is a necessary condition for perceptual processes such as occur during waking and dreaming, the latter being associated with REM sleep. The easy
integration of external events in an on-going dream also points to a high transfer ratio during REM sleep.
Correlation dimension and evoked potentials
A reasonable supposition suggests that the small amplitude high frequency ‘wake’
EEG, generated by a large number of relatively non-synchronized independently firing cells, is more complex than the large amplitude low frequency ‘sleep’
EEG. As mentioned above, the latter EEG pattern is the result of the synchronized pause-burst firing mode of neurons, which are coupled by inhibitory
interneurons. The complexity of the EEG can be expressed by correlation dimension, a quantitative estimation of the degrees of freedom contributing to
the generation of the signal under study. The number of factors contributing to
the composition of the EEG varies with the states of sleeping and waking
(Babloyantz et al, 1985). In general, it appeares that the beta EEG of wakefulness needs more than ten degrees of freedom for its description. This number
decreases during the relaxed state accompanied by alpha activity in the EEG
to around six or eight, and further decreases during slow wave sleep (Lopes da
Silva, 1991). By applying this nonlinear analysis, it soon became clear that the
dimension of REM sleep was significantly higher than that of slow wave sleep,
implying that during REM sleep more modes are activated in the brain.
Achermann et al (1994) also showed that correlation dimensions were rather
high during REM sleep. Values of 9 were no exceptions. In short, the values of
correlation dimension closely follow the level of vigilance.
Van Hulzen and Coenen (70) registered the visual evoked potential (VEP) in
the cortical EEG of the rat during the main states of alertness (Figure 3). It is
remarkable that the VEP produced during REM sleep is almost similar to that
obtained during wakefulness, which again underlines the consonant characters of these brain states. In contrast, the VEP derived during slow wave sleep
reveals the differential nature of this state. The most striking distinction is the
shape and amplitude of the N1-P2-N3 complex. This complex is substantially
larger in amplitude during slow wave sleep, while the small N2-P3 complex on
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Figure 3:
The influence of wakefulness (W), slow wave sleep (SWS) and REM sleep
(PS) on the shape of the averaged visual evoked potential (VEP) of a rat
(left). To the right the cortical EEGs associated with the states of alertness
are presented, together with the individual evoked potentials. Flashes are
indicated by points. Note in the VEP the large N1-P2-N3 complex of slow
wave sleep and the similarity between the VEP of wakefulness and that of
REM sleep. Note also the various background EEGs with the prominent
theta-rhythm in the lowest trace, indicating REM sleep. Negativity is upwards directed. [Adapted from Van Hulzen and Coenen, 1984].
the slope of the large P2-N3 wave, is no longer observable. The increased synchronization of thalamocortical unit discharges during slow wave sleep is expressed in an enlargement of evoked potential components. The stimulus acts
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as a trigger pulse producing a resonance in the synchronized neural assembly.
For the reason that cells are already firing in a bursting mode during slow wave
sleep, this resonance is more prominent as that produced by the same triggering of the neural net, when neurons fire in the asynchronous, tonic mode during wakefulness and REM sleep. In the latter situations, the waves of the N1-P2N3 complex are smaller and less sharp, whereas the tiny N2-P3 complex is
manifest. The response on a flash of a neuron expressed in a poststimulus time
histogram (PSTH) shows that the discharge frequency is lower during slow
wave sleep. But what is still more relevant for the building of evoked potentials
is that the slow wave sleep PSTH is composed of sharper peaks. Both the primary and the secondary excitations are smaller and more time-locked, giving
rise to larger amplitude but narrower components in the evoked potential. A
comparison between flash responses of both kinds of neurons in the visual part
of the thalamus with a cortical VEP, reveals a striking temporal correspondence. This comparison strongly suggests that N1, the first wave of the VEP, is
comprised of the primary discharges of the ON-cells. On the other hand, P2 is
produced by the joint and simultaneously inhibitory actions of both ON- and
OFF-cells, whereas N3 is the result of the secondary firing of the ON-neurons
facilitated by the primary bursts of the OFF-cells (Figure 4) (Coenen, 1995).
Figure 4:
Responses of two
visual thalamic neurons of a cat to light
flashes, expressed in
poststimulus time
histograms (PSTHs).
In the upper traces
the PSTH-response of
both a lateral geniculate ON- and OFFneuron are shown. In
the bottom trace a
visual evoked potential (VEP) of a rat is
presented. The temporal correspondence is
discussed in the text.
[Adapted
from
Coenen, 1995].
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Neuronal phenomena associated with consciousness: an integration
A survey of the main characteristics of the neuronal activity of the brain in
relation to the states of vigilance and consciousness is presented in Table I
(Coenen, 1998).
Table 1:
Neuronal characteristics and states of vigilance. [Adapted from Coenen,
1998].
Membrane
potential
Firing
mode
< - 60 mV
‘tonic’ or ‘relay’
0.7 - 1.0
‘oscillatory’
> -70 mV
< - 60 mV
- 60 - -70 mV
Transfer Correlation
ratio
dimension
EEG
pattern
State of
Vigilance
8 - 10
beta
wakefulness
0.5 - 0.7
6-8
alpha or spindles
drowsiness
‘burst’
0.3 - 0.5
4-6
delta
slow wave sleep
‘tonic’
?
6 - 10
beta-like
REM sleep
In this table several neuronal characteristics, such as the membrane voltages
of the neurons and associated firing modes, the transfer ratio’s and the correlation dimensions of the different EEG patterns of the main sleep-wake states
(wakefulness, drowsiness, slow wave sleep and REM sleep) are shown. It should
be stressed that data are gathered from both human and animal research and
are rather simplified. Nevertheless, the consistent correlations of parameters
characteristic for the several states of vigilance are remarkable. When the activity of the mesencephalic reticular formation drops under a critical level, the
inhibitory interneurons start to inhibit the thalamocortical neurons. These begin
to oscillate and when inhibition is still further carried upwards, resulting in low
membrane voltages, neurons start to discharge irregularly in a corresponding
burst-pause firing mode. Sensory information is largely blocked and information processing is at a low level. The burst firing mode of large groups of highly
synchronized neurons results in the typical high amplitude low frequency EEG,
associated with slow wave sleep. The number of factors involved in generating
the EEG is accordingly low. Perceptive processes do not occur and the level of
vigilance and consciousness is low. This does, however, not exclude that stimu-
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lus evaluation is still possible to a certain degree during this brain state. On the
other end of the sleep-wake continuum there is wakefulness, with its characteristic low amplitude high frequency beta-pattern in the EEG, composed of a
relatively spontaneous activity of nerve cells with membrane voltages near the
threshold, firing in the tonic mode. This results in an easy passing of sensory
information through the thalamic relay nuclei to the sensory cortex, leading to
a high transfer ratio. The level of information processing is high and many
processes, such as perception, evaluation and recognition take place. In all,
this implies that a great number of factors play a role in the composition of the
EEG. The correlation dimension estimates the degrees of freedom to be about
ten.
A mysterious state of existence is REM sleep, not fitting into the normal continuum from deep slow wave sleep to alert wakefulness. Neuronal characteristics
show that there is a high spontaneous neuronal activity comparable to that of
wakefulness. Muscle paralysis prevents that the high brain activity is overtly
expressed. During dreaming mentation, which is associated with REM sleep, there
are perceptual phenomena mostly of an internal origin. In all, REM sleep is associated with some kind of perception and consciousness. It has to be regarded as
a third state of existence, next to wakefulness and slow wave sleep. Contrary to
these states, REM sleep is not a uniform state. Awakening thresholds and presumably transfer ratio’s heavily fluctuate, dependent on time of the night and the
stage in a particular REM phase. This might also true for correlation dimensions.
Sometimes, REM sleep is more ‘sleep-like’ and sometimes more ‘wake-like’. This
curious state is accompanied by a state of consciousness which can currently
best be regarded as a physiological form of altered consciousness.
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Pathophysiology of narcolepsy
M. BILLIARD
GUI DE CHAULIAC HOSPITAL, MONTPELLIER, FRANCE
The pathophysiology of narcolepsy is still far from being totally understood.
However significant progress has been made within the last feefteen years.
In this presentation we will first focus on the dysregulation of the states of sleep
and wakefulness in narcolepsy and on the monoamine - cholinergic imbalance
at the origin of excessive daytime sleepiness and cataplexy. Then, in a second
part, we will consider the pathogeny of the condition including genetic and
environmental factors.
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