1

Sleep and Wakefulness 2011

Dante G. Simbulan, Jr. PhD Dept of Physiology, with Grp 14a. 14b. 15a. 15b
-----------------------------------------------------------------------------------------------------------
I. THE RETICULAR FORMATION & THE RETICULAR ACTIVATING SYSTEM; WAKEFULNESS
(Another name for the reticular activating system is: Ascending Arousal System.)

Definition of Reticular Activating

System (RAS): a complex polysy-
naptic pathway in the brainstem reticular
formation comprising the
non-specific ascending pathways.
(It receives inputs from the somatosen-
sory, auditory, visual and olfactory
systems, as well as descending inputs from the
cortex), and projects diffusely to the whole neocortex.

1. Part of RAS bypasses the thalamus, to

project diffusely to the cortex.
2. Another part ends in the intralaminar and
related thalamic nuclei, and from there
projects diffusely to the whole
cortex.
3. The activity of the Recticular Activating System (Ganong) [ also known in other literature as the
Ascending Arousal system (Kandel) , or Ascending Reticular Activating System (ARAS, Guyton)
keeps us awake !
It produces the CONSCIOUS, ALERT STATE that makes perception possible.
4. Other systems make us drowsy and sleep (see below for mechanisms of sleep).

II. THE THALAMUS & THE CEREBRAL CORTEX (Read section in Chapter 11, Ganong); more on
this during Lecture on Hemispheric Specialization).
Thalamic Nuclei: What are Thalamo-cortical oscillations ? (Ganong, 21 st edition, p. 200;
tonic and phasic burst-like activity of thalamo-cortical neurons).
Cortical Organization

III. EVOKED CORTICAL POTENTIALS

What is the Primary Evoked Potential ?
What is the Diffuse Secondary Response
A. Primary Evoked Response - from any
of the primary sensory areas depending on
specific pathway activated; specific ascending
pathway to thalamic relay nuclei  specific
cortical receiving area (specific area of parietal
or occipital cortex). (See A)

B. Diffuse Secondary Response – from

most of cortical Surface; activation of non-
specific Ascending pathway; nonspecific
ascending pathway (enters brainstem
reticular formation)  enters intralaminar Recorded response evoked in the contralateral
thalamic n. and diffusely projects to  sensory cortex by stimulation. In addition B
Whole of neocortex. See B.) can be recorded in most parts of cortex. (Explain
why.)

which
IV. THE is surface-negative)
ELECTROENCEPHALOGRAM; SLEEP WAVES DURING STAGES OF SLEEP

Characteristics of Sleep
1. a recumbent posture•
2. a raised threshold to sensory stimulation•
3. alow level of motor output
4. a unique behavior – dreaming
 2
ADULT: Remember “BAT-D-B”, (from Beta waves of wakefulness  Alpha ,  Theta,  Delta
waves Then Beta waves in REM)
ALERT WAKEFULNESS (see also “desynchronizing mechanisms below, section VI.B.)
New: What are gamma oscillations ? Beta Waves (14- 30 Hz) During
(Beta Rhythm ) Alert Wakefulness : lower amplittude,
frontal region and over other regions during
intense mental activity: (ALERTING A
RELAXED SUBJECT results in so-called
“”desynchronization” of the EEG, with
reduction in ALPHA activity and an increase
RELAXED WAKEFULNESS, Drowsy , with eyes closed in BETA.)
(Alpha Rhythm appears)
ALPHA WAVES (8 – 13 Hz) During
RELAXED WAKEFULNESS – 8-13 Hz
(typical of relaxed wakefulness; parietal
and occipital sites)

NREM Sleep, stage 1, 2 THETA waves ( 4-7 Hz)( NREM Stages

( Theta ryhtyms appear; While not shown here, K complexes 1, 2) (according to Schmidt/ Kandel)
and Sleep spindles also appear in stage 2 together with theta
waves– see real recording below for K complexes and sleep
spindles) DELTA waves - 0.5 – 4 Hz
(dominant during late slow-wave
sleep, NREM stages 3, 4)

BETA waves again: Waves similar to

wakefulness (Beta waves, low-
NREM Sleep, NREM STAGE 3, and STAGE 4 amplitude, fast waves) again appear
(Delta rhythms) appear and become dominant  ALSO during REM sleep.
CALLED SLOW WAVE SLEEP
What is an alpha block ?
Desynchronization or
(Hz) synchronization of sleep waves ?
Ganong (21st edition) states that dominant
waves in REM sleep are like those in stage
REM SLEEP (also known as Paradoxical Sleep) 1; however, major sleep researchers state
(low amplitude, fast waves similar to Beta waves of wakefulness)that they are like the Betardwaves if
wakefulness. Ganong (23 edition) makes
correction, adding REM sleep waves
resemble that seen in awake, aroused state
(B-waves) and in stage 1 sleep (p. 234, 23rd
edition).
 3

V. FURTHER DESCRIPITON OF SLEEP PHASES; DISTRIBUTION OF SLEEP STAGES

A. During the night (early adulthood)

The NREM and REM Phases alternate throughout sleep 4- 6 times, at intervals of 90 minutes.
1) NREM period – A young adult enters NREM sleep, passes through stages 1 and 2, and
spends 70-100 minutes in stages 3 and 4.
2) REM period follows – The time period of REM ranges from 2 – 10 minutes, shorter at first,
but becomes longer in the latter part of the sleep cycle. (There are about 4-6 REM periods per
night).

B. From Infants to Adults

AS A CHILD DEVELOPS, SLEEP

GRADUALLY BECOMES RESTRICTED
TO THE NIGHT.

I. Polyphasic (multiphase) sleep following

birth changes first to biphasic (two-phase)
sleep among preschool children and later to
monophasic (single-phase) sleep. Among
the elderly, periods of sleep during the day
become more frequent again. (See figure )

1) Note that REM sleep occupies

80 % of total sleep per night
in premature infants(no figure),
and 50 % in a full-term newborn
infant Thereafter the proportion
of REM sleep falls rapidly and
plateaus at about 20 – 25 % .

2) Children have more total

sleep time (see figure ) and
stage 4 sleep than
adults (see Figure in Ganong).
 4

C. Description of the Two Phases of Sleep (NREM and REM sleep)

C.1 What is Polysomnography ? Polysomnography is measuring the Sleep state using

the:
(a) EEG (electro-encephalography) for cortical activity, The record is the encephalogram.
(b) EOG (electro-oculography)for eye movements, The record is the electro-oculogram.
(c ) and EMG (electro-myography) for muscle tone. The record is the electromyogram. See
below for samples of polysomnography.

C.2 Characteristics of NREM SLEEP (slow-wave sleep) (see additional figures

on sleep effects on autonomic functions)
1. EEG records show a progressive slowing of brain waves, arising from a well-
described sequence of thalamocortical events.
2. People have little or no recall of conscious experience in deep NREM sleep.
3. Heart rate, blood pressure, respiration rate diminishes in NREM sleep.
4. Neuroendocrine activity increases (growth hormone and sexual maturation
hormones from the pituitary is maximal during sleep), with over 95 % of daily
output during NREM sleep.
5. People aroused from NREM sleep are confused, have difficulty reporting
conscious experience or recalling dreams in detail; return to sleep rapidly
6. After about 4 stages of the NREM sleep phase, REM sleep phase follows.

C.3 Characteristics of REM sleep (see additional figures below on sleep effects on
autonomic functions)
1.. characterized by fast, low voltage activity in EEG records .
2. muscle atonia with intermittent muscle twitches (EMG)
3. rapid eye movements (as seen in EOG)
4. postural shifts precede and follow REM sleep.
 5
5. penile erection or clitoral engorgement occur during REM sleep
6. HEART RATE – increases during phasic REM
7. Subjects aroused from REM sleep, give detailed reports of dreams characterized by
vivid hallucinations, bizarre thinking, and intense emotion – dreaming is the
behavior associated with activation of brain during REM sleep.

C.4 Effects of Sleep on Respiratory Muscles

1.) Wakefulness exerts a tonic

stimulating effect on motoneurones
2. ) This stimulating effect is withdrawn
in non-REM sleep (via disfacilitation),
so the primary effect of non-REM sleep
is to decrease activation of motoneurones
and muscles.
3.) Motoneuron activity is
generally decreased in REM sleep.
This takes place through processes
of inhibition and further dis-facilitation.
4.) Similar processes may occur at
respiratory motoneurones that
drive respiratory muscles.

VI. PHYSIOLOGICAL BASIS OF THE EEG, CONSCIOUSNESS, & SLEEP

A. Source of the EEG:
 6

The surface EEG reflects the activity of cortical neurons close to the EEG electrode.

B. Neural Mechanisms Producing EEG Arousal (related: see also beta waves above);
“Desynchronizing” mechanisms (mechanisms which produce the low-amplitude, fast ,
irregular Beta- waves of wakefulness)

: Effects of E.S.: High-frequency stimulation of the brainstem reticular formation (midbrain

tegmentum, and of the nonspecific projection nuclei of thalamus, which forms the Reticular
Activating System, RAS, mentioned in Section I ) “desynchronizes” the EEG (i.e.,produces Beta
waves). The activity of the RAS is the neural basis of EEG arousal (desynchronization).
Effects of Lesion: Lesions in midbrain tegmentum (which disrupts the reticular activating
system, RAS) result in COMA for long periods. (replaced with characteristic slow-waves =
“synchronized” pattern, see Figure B below ).
Large lesions of lower brain stem isolating the brain from incoming sensory signals through
the spinal cord in a preparation called: ENCEPHALE ISOLE’ does not result in coma. Animals
with this lesions are awake, respond to trigeminal sensory (CN V) as well as visual and
auditory cues, and move their faces and eyes in a a normal fashion. The EEG of such animals is
typically low voltage and fast, a desynchronized pattern typical of waking. (See Figure A
below). In addition, lesions of the lateral and superior portions of the midbrain that interrupt he
medial lemnisci and other ascending specific sensory systems (leaving behind the reticular core
intact) fail to prevent the EEG arousal to sensory stimulation.

In Figure A (above) , RAS still intact, thus EEG arousal intact. In Figure B (above) , RAS
damaged, therefore EEG arousal does not take place, and comatose situation develops,
characterized by slow-waves.

C. Effect of RAS Stimulation on Cortical Neurons: RAS activation inhibits burst activity
of thalamo-cortical neurons (which occurs during slow-wave sleep). Detailed discussion
omitted here. These results in the low-voltage, irregular fast waves of wakefulness.

D. Arousal Following Cortical Stimulation: Thoughts, and emotions (intra-cortical

signals) also increase activity of RAS, and EEG arousal, through corticofugal fibers
descending to the brainstem reticular formation. This
corticofugal pathway to
The brainstem reticular formation
can keep us awake.
 7

E. Neural Substrates and the Genesis of Slow-wave-Sleep (NREM Sleep);

“Synchronizing” mechanisms (e.g. which produce slow-waves)

E.1. Slow wave sleep (including “synchronized waves” of NREM 3,4) can be produced
experimentally by stimulation of at least 3 subcortical “synchronizing” regions below (see
figure below):
1. Diencephalic sleep zone (posterior/ lateral hypothalamus and intralaminar thalamic
and anterior thalamic nuclei. With low frequency stimulation at 8 Hz  slow wave
sleep; faster stimulation produces arousal). Involves pathways ascending to the
thalamus.
2. Medullary synchronizing zone (in the Medullary Reticular Formation, at low Hz
stimulation produces slow-wave sleep, while faster stimulation produces arousal .)
Involves pathways ascending to the thalamus.
3. Basal forebrain sleep zone (preoptic area and the diagonal band of Broca; high or
low frequency stimulation produces slow wave sleep. This may involve descending
pathways which inhibit neurons in the Reticular Activating System of the brainstem.)

E.2 The natural development of slow-wave sleep in a human subject or experimental

mammall can arise from:
1. In part, absence of desynchronized activity transmitted via the ascending reticular
system. meaning , absence of arousing sensory inputs from the environment, or from
the cortex (lack of worrying or exciting thoughts/ memories) which descend to excite
the brainstem ascending reticular system in the reticular formation.
2. Actively produced by the three “synchronizing regions” mentioned above, and shown
in figure below (see F.1).
 8

F. Neural substrates and Genesis of REM Sleep

Nuclei in Pontine Reticular Formation – triggers REM sleep mechanism. (PGO spikes,
ponto-geniculo-occipital spikes, characteristic of REM sleep, originate in the lateral pontine
tegmentum). Below is a neuronal mechanism of REM sleep originating from the pontine reticular
formation.

LEGEND: AHC, anterior horn; CT, cortical; FT, reticular tegmental nuclei; LC, locus ceruleus; P,
peribrachial region; PT cells, pyramidal cells; RN, raphe nucleus; TC, thalamocortical; III,
oculomotor nucleus; IV, trochlear nucleus; VI, trigeminal motor nucleus.

(Explanation of Figure)
The network of neurons responsible for generating REM sleep is distributed over many levels of the
brain. The network is shown as three systems of neurons that mediate the electrographic
phenomena of REM sleep (see Figure above).
1.In many places (the thalamus and cortex), the architecture of the systems is known to be far more
complex than indicated here. An increase in the firing of reticular, thalamocorticular, and cortical
neurons DESYNCHRONIZED the EEG (fast, irregular waves of REM sleep similar to
wakefulness)..
2.Tonic disinhibition and phasic excitation of burst cells results in pontine-geniculate-occipital (PGO)
waves.
3.Phasic firing by reticular and vestibular cells causes RAPID EYE movements; vestibular
(vestibular nuclei) cells directly excite oculomotor neurons.
4.Tonic postsynaptic inhibition of spinal anterior horn cells by the pontomedullary reticular formation
causes MUSCLE ATONIA.
5.Muscle twitches occur when excitation by reticular and “pyramidal tract” motor neurons
(corticospinal) occasionally overcomes the inhibition of the anterior horn cells.
 9

VII. NEUROCHEMISTRY OF SLEEP AND WAKEFULNESS; Neurotransmitters and Sleep Factors

A. CHANGES IN THE ACTIVITY PROFILES OF NORADRENERGIC,

SEROTONINERGIC, AND CHOLINERGIC NEURONS DURING WAKEFULNESS
AND SLEEP.

Legend and Explanations: LC – Locus ceruleus (noradrenergic neurons); DRN – Dorsal Raphe
nuclei (serotoninergic neurons). LC and DRN neurons are in the brainstem reticular formation). Ch
1- 4 – cholinergic neurons in the forebrain; CH 5 – cholinergic neurons in the midbrain tegmentum.

Explanation of figure above:

State-dependent changes in aminergic and cholinergic neuronal function. Schematic
representation of progressive decrease of aminergic neurotransmitter release in cerebral
cortex as an animal passes from wakefulness through NREM to REM sleep.
Cortical concentrations of norepinephrine and serotonin are highest in waking, lowest in
REM sleep, and intermediate in NREM sleep. Top panel illustrates sagittal sections of the
brain with aminergic neurons of nucleus locus coeruleus (noradrenergic) and dorsal raphe
nucleus (serotonergic).
Bottom panel illustrates cholinergic neurons of Ch 1-4 (in basal forebrain) and of Ch 5 of
peribrachial pontine tegmentum. Cholinergic neurons release levels of acetylcholine as high
in REM sleep as they are in waking; release in NREM sleep is lower.

The graph below summarizes the

changes in levels of activity of
serotoninergic, noradrenergic and
cholinergic neurotransmitter systems
(This figure below is similar to the
figure above).
Pontine
tegmentum
1.Decreasing noradrenergic, cholinergic Locus Dorsal Raphe m
pontine
and serotoninergic activity Ceruleus Nuclei
tegmentum
characterizes drowiness and
NREM (slow-wave) sleep.

2. There is almost
silent activity of these serotoninergic
and noradrenergic systems
in REM sleep, while the cholinergic
system increases its activity again (cholinergic neurons in the pontine reticular formation).

3. Wakefulness is characterized by
high levels of noradrenergic,
serotoninergic and cholinergic
activity, (Note similarity of increased
cholinergic activity in REM with that
of wakefulness.)
 10
[Note that in current sleep literature, serotonin’s role is disputed, as there was this old serotonin
hypothesis about sleep. . However, sleep researchers have confirmed the discussion above with
evidence for serotonin’s role (an increase in concentration) in wakefulness, and not sleep, thus
debunking the old serotonin hypothesis.]

B. Other Sleep-inducing factors:

(1)Muramyl peptides (related to the bacterial cell walls)
(2) Interleukin – 1 ( a cytokine that may mediate effects of muramyl peptides, and immune
responses)
(3) Adenosine
(4) delta-sleep inducing peptide (a substance isolated from blood of sleeping rabbits)
(5) Prostaglanding D2 –
(6) cis-9,10-octadecenoamide
(7) MELATONIN – mixed results
(8) Other sleep peptides – the search continues

VIII. SOME SLEEP DISORDERS (Be sure to define the following terms. see Ganong.)
Insomnia

Problems associated with NREM (slow-wave) sleep:

Sleepwalking (somnambulism)
Bed-wetting (nocturnal enuresis)
Night terrors

Problem associated with REM (paradoxical ) sleep:

Narcolepsy
Sleep apnea
REM behavior disorder

VIII. What are other Clinical Uses of the EEG ?

Read on Epilepsy and Seizures

IX. What are the passive and active theories of sleep ? Functions of sleep and dreaming
X. ANNEX: More on Neural Mechanisms of sleep
There is yet no complete agreement by different sleep physiologists and research
laboratories on how the various brainstem, hypothalamic, and thalamic mechanisms mentioned
above are integrated to produce sleep and wakefulness. Updates on progress in this field are of
great interest, and should be followed by students through extra readings through the years.
When time permits, such updates will also be occasionally presented during lecture sessions.