1. Physiology of Sleep BLOCK 3 – 2011-12
Robert R. Terreberry, PhD
Room 142 Ph

2. EEG Scalp Electrodes Diagnosis of disease Determination of brain death
Epilepsy
Determination of brain death
Distinguish stages of sleep
Recording of electrical activity from the cerebral cortex by putting electrodes on the scalp.
The EEG is primarily caused by electrical activity of the areas of the cortex just below the scalp.
What type of activity in the cortex (action potentials or graded potentials) are largely responsible for the EEG? Hint - which area of the brain (white matter or gray matter) is closest to scalp?
Answer: Gray cortex neuronal potential just below the scalp is what EEF is measuring.
Know the weird spikes (like around F7) are seizures where you have over-firing

3. Types of EEG Waves Alpha waves Beta waves Theta waves Delta waves
Frequency 8-13 Hz, moderately low voltage (50 mV)
Beta waves
Frequency Hz, lower voltage
Theta waves
Frequency 4-7 Hz, higher voltage
Delta waves
Very low frequency (< 4 Hz),very high voltage (approx. 100 mV)
DO not memorize the values verbatim
However, you should know the trends of frequency and voltage
Highest to lowest voltage: Delta>Theta>Alpha>Beta
Highest to lowest frequency: Beta>Alpha> Theta>Delta (voltage backwards)
Terreberry’s notes:
Types of EEG Waves
Variation in the frequency and amplitude of the EEG waves can be related to changes in the level of cortical activity.
The normal EEG will display one or more of the following brain wave types
Alpha waves
Rhythmic waves with frequencies of 8-13 Hz and moderately low voltage (50 μV)
They are characteristic of patients that are awake, but resting quietly (relaxed)
Beta waves
Lower voltage and higher frequency (14-50 Hz)
During activation of the cortex in the awake patient
Observed primarily when actively concentrating (e.g., on a problem)
Theta waves
Higher voltage waves with frequencies of 4-7 Hz
Most frequently recorded in children (and primarily recorded from the parietal and temporal areas) and in adults experiencing frustration and disappointment
Also recorded in during stages 2 through 4 of slow-wave sleep and in bursts during REM sleep
Delta waves
Very slow (less than 4 Hz), high voltage waves
In normal subjects, recorded in stage 3 slow-wave sleep and especially during stage 4 slow-wave sleep
Also characteristic of coma

4. Idealized EEG Waves

5. Actual EEG Waves

6. Waveforms - Waking State
Realize that in reality, we constantly have some neurons firing, and then some off (hence the on/off pattern of the waves)
When a seizure occurs all the neurons turn on all at once (this can be just in one area of the brain if a focal seizure, or it can be the entire brain if generalized)
Alpha – person relaxed
Beta – when awake and concentrating on something (like now…maybe haha)

7. Stages of Slow-Wave Sleep
Stage 1 – Transition between asleep and awake
Stage 2 – Light sleep
Stage 3 – Deep sleep
Stage 4 – Very deep sleep
The Waking State:
Behaviorally, the waking state ranges from relaxed and inactive to very active.
The prominent EEG wave of an awake, relaxed adult (generally with eyes closed) is the alpha wave
When the eyes are opened and the person is attentive to external stimuli (or is concentrating hard with eyes closed), alpha waves are replaced by beta waves.
Stages of Sleep -
Sleep is not simply a state of decreased neural and physical activity, as once thought. Sleep consists of several distinct, complex neurophysiological stages.
The two major types of sleep are slow-wave sleep and REM (paradoxical) sleep:
1. Slow-Wave or Non-REM (NREM) Sleep
Consists of four stages of increasingly deeper sleep
Each successive stage of slow-wave sleep has an EEG pattern characterized approximately by a progressively slower frequency and higher amplitude

8. Slow-Wave Sleep
Frequency goes down, amplitude goes up at you go into deeper sleep. Start with alpha, end with theta
Note the characteristic spindles (a) and some K complexes in stage 2 (circled in red) = bursts of activity in this stage. No one is really sure what they represent
Stage 1 Sleep
Alpha waves disappear and are replaced by low-voltage mixed frequency waves
Thoughts become dissociated, but subjects are easily aroused by low-intensity stimulation
This is a transitional stage from between drowsy (but awake) and light sleep
Thus, some experts do not even classify it as sleep at all
Stage 2 Sleep
A "light" sleep characterized by low-voltage, mixed frequency waves
Characterized by occurrence of sleep spindles and K complexes
Sleep spindles are short bursts of alpha rhythms
K complexes are single large biphasic deflections
Stage 3 Sleep
A deep sleep in which large amplitude waves (Delta waves) with a frequency generally of < 2 Hz are observed 20-50% of the time.
Stage 4 Sleep
A deep sleep in which large amplitude delta waves are observed more than 50% of the time.
During stage 1, the eyes have a slow rolling movement; in stages 2 through 4 they are relatively motionless. Other skeletal muscles are active during stages 1 through 4.

9. REM Sleep Paradoxical or REM Sleep
At each end of the slow-wave sleep cycle person goes into a short period of sleep that is the deepest, yet shows some paradoxical behavior
During this period the EEG pattern looks similar to the wide-awake pattern (beta waves) even though the person is generally dreaming during REM sleep (Fig. 5)
Additionally, it is difficult to arouse the person from REM sleep, yet the person is more likely to spontaneously awaken during REM sleep than during slow-wave sleep
REM sleep is characterized by rapid-eye movements (REM), irregular heart rate and respiration, and story-like dreaming.

10. Sleep-Wakefulness Stages
Behavior
EEG
Alert wakefulness
Awake, alert with eyes open
Beta
Relaxed wakefulness
Awake, alert with eyes closed
Mainly alpha
Relaxed drowsiness
Fatigued, tired, bored; head may droop; lapses of attention. Sleepy but not asleep
Mainly alpha, but amplitude and frequency decreased

11. Sleep-Wakefulness Stages
Behavior
EEG
Stage 1
Very light sleep, easily aroused; neck jerks
Mixed – alpha, theta, a few delta
Stage 2
Light sleep; but less readily aroused
Mixed; sleep spindles (a) and some K complexes
Stages 3 & 4
Deep sleep, difficult to arouse in 4
Theta and delta; mainly delta in 4

12. Sleep-Wakefulness Stages
Behavior
EEG
Paradoxical (REM) sleep
Deepest sleep, yet spontaneously awaken; lasts about 10 min every min. Dreaming, rapid eye movements, increased brain O2 consumption
Beta – looks like awake, alert
As the sleep cycle goes on the % of REM increases

13. New Sleep Nomenclature
Stage W = Wakefulness
Stage N1 & Stage N2 = “Light sleep”
Stage N3 = “Deep sleep”
(combines classic Stages 3 & 4)
Stage R = “Active” REM sleep
Will use slow wave 1,2,3,4 and REM on the test
Don’t worry about this other than from a clinician’s perspective

14. Sleep Architecture Sleep Architecture
Throughout sleeping a normal person cycles between slow-wave sleep and REM sleep several times during a typical 8 hr sleep period
The pattern of these cycles is referred to as "sleep architecture"
Note that sleep stages 3 and 4 are much more likely during the first few hours of sleep, and that REM sleep is more frequent late in the sleep period (morning hours)
Thus, if total sleep time is shortened, REM sleep is disproportionately reduced
Age also has an important role in determining sleep architecture
Total sleep time decrease with age
But the % of REM will stay constant regardless of how much you sleep (given that you sleep this pattern on a regular basis…ie NOT us)
Relative percentage of REM versus slow-wave sleep changes
In newborns REM sleep accounts for 50% of the total sleep time
By about age 20, REM sleep accounts for only about 20% of the total sleep time regardless of how long you sleep (if you get a regular pattern of sleep)
After age 20, total sleep time continues to decline, but the percentage of REM versus slow-wave sleep remains about 20% REM, 80% slow-wave sleep (if you get a regular pattern of sleep)
YOU CANNOT just sleep longer at another time to “make up” for lost sleep b/c your REM is so much less during initial sleep
REM is critically impt for consolidation of memories from short term  long term.

15. Physiological Changes During Sleep
Skeletal muscle
Activity declines during slow-wave sleep; tonic inhibition during REM sleep, except for eye and respiratory muscles
Cardiovascular and Respiratory
Activity declines during slow-wave sleep; wild oscillations during REM sleep (sometimes life-threatening)
Terreberry specifically said “I think these two things are important to remember”…know this slide well.
1. Skeletal Muscle
Skeletal muscle activity declines during slow-wave sleep. During most of REM sleep, there is a general tonic inhibition of skeletal muscle activity, which is nearly complete except for some notable exceptions.
One exception, noted earlier, is the eye muscles; during REM sleep, rapid bursts of eye movements occur. The motor neurons to the primary muscles of respiration (esp. diaphragm) also normally escape the generalized inhibition.
Additionally, periodically occurring twitches and muscular tremors of the face and limbs frequently occur during REM sleep. Thus, during REM, periodic bursts of excitatory activity break through the generalized tonic inhibition.
2. Cardiovascular and Respiratory Systems
During slow-wave sleep there are relatively steady decreases in blood pressure, heart rate, and respiratory rate.
Metabolism needs are lower so respiratory needs are lower
In contrast, REM sleep is associated with general increases and large oscillations in blood pressure, heart rate and respiratory rate. Very high phasic blood pressures experienced during REM sleep have been associated with strokes and heart attacks.
For 70 years it has been known that fatal heart attacks are most common from 5-6 a.m., when most people are in longer cycles of REM sleep.
People stroke out
Other information in Terreberrys notes (he didn’t discuss these):
Endocrine
During slow-wave sleep, there are pulsatile releases of growth hormone and the gonadotropic hormones from the anterior pituitary
In children, growth hormone is secreted exclusively during sleep. Growth hormone secretion in children generally peaks during early portion of the sleep period, during non-REM stages 3 and 4. However, during puberty and adolescence, patterns of secretion change. Though the major peak generally still occurs during sleep, several other peaks occur throughout the day.
Prolactin secretion occurs almost entirely during sleep, with secretion being maximal in the early morning hours
Cortisol secretion reaches its minimum early in the sleep period and peaks at the end of the sleep period
Thyroid-Stimulating Hormone (TSH) secretion peaks prior to the onset of sleep and then declines during sleep
Luteinizing Hormone (LH) drives male testosterone production. LH increases during sleep are responsible for male puberty. In adult males LH secretion is less related to sleep.
Follicle Stimulating Hormone (FSH) follows a similar pattern as LH. During female puberty LH and FSH peak during sleep
  4. Other
Body temperature exhibits a highly stable circadian (approx. 24 hr) rhythm. As the night progresses, the core body temperature falls, reaching its minimum during slow-wave sleep in the early morning hours. During REM sleep, however, body temperature increases slightly.
Changes in renal function also occur during sleep, characterized by a decrease in urine volume and increased osmolality

16. Functions of Sleep Slow Wave REM Sleep Rest and Restoration?
Physical changes necessary for learning and memory
Mental health
Functions of Sleep
Why do we need sleep? It really isn't clear.
Traditional view that sleep is necessary to "rest" the brain and/or body, is not the total answer
Slow-wave sleep may largely serve as a time of the body's rest and metabolic restoration.
But even during slow-wave sleep, some functions are enhanced.
REM sleep is thought to be needed for the physical changes necessary for long-term memory and learning.
REM sleep may be needed to sort through short-term memory stores, deleting unnecessary data and the chemical and structural changes necessary for transferring important information into long-term memory
Babies sleep more perhaps because they need time to develop new connections, etc.
REM sleep may also allow for the expression, through dreams, of "subconscious" anxieties and concerns
People who don't get enough REM sleep have hallucinations, often disturbing in nature.
You cannot “store up” and “make up” for lost sleep and regain that time of lost REM

17. Sleep Areas of the Brain
The sleep-wake cycle and passage through the various stages of sleep are controlled by the cyclical action of different systems of the hypothalamus and brain stem.
The circadian rhythm of approximately 8 hr sleep and 16 hr awake is due to the cyclical nature of the interaction of these systems
Sleep Areas in the Brain - Sleep is actively induced and modulated by a number of centers within the brain
Suprachiasmatic nucleus of the hypothalamus
The basic circadian rhythm is controlled by the biological clock located in the suprachiasmatic nucleus of the hypothalamus
Receives input from retinal and other inputs which modulate circadian rhythm
Thus, the body "clock" is affected by environmental cues (particularly light/dark cycles through hormone melatonin). Jetlag and working alternating shifts confuses these cues
A major determinant of sleep-wake rhythms are the interactive systems, largely in the brainstem, one an arousal system and the other an inhibitory sleep-promoting system. Thus, neurons in some brainstem regions are most active during waking and are inhibited during sleep, while neurons in other regions show the opposite activity pattern.
Arousal systems in the brain
Cholinergic neurons in the upper pons activate thalamic nuclei and adrenergic neurons in the upper brainstem stimulate the cerebral cortex
Peptidergic neurons in the hypothalamus, containing orexins (hypocretins) and melanin concentrating hormone also activate thalamic nuclei, and stimulate the cerebral cortex and brainstem arousal areas
The arousal system of the brainstem (largely the Raphe Nuclei) is part of the Reticular Activating System (which sets the general level of arousal/alertness)
This is area in which amphetamines act to promote arousal and decrease sleep
Excitatory neurons (which release norepinephrine or serotonin) in the Reticular Activating System, which are active during the waking state, lead to arousal and enhanced attention to the outside world
The excitatory neurons also inhibit cholinergic brainstem neurons
During waking, the excitatory neurons dominate, whereas during REM sleep the cholinergic neurons are dominant

18. Sleep Areas - Hypothalamus
Suprachiasmatic Nucleus
Sets basic circadian rhythm
Visual inputs important
Preoptic Area of Hypothalamus
GABA promotes slow-wave sleep
Inhibits excitatory pathways
Posterior Hypothalamus
Histamine promotes wakefulness
Probable site of antihistamine action
Sleep systems in the hypothalamus
Inhibitory neurons in the preoptic nucleus of the hypothalamus inhibit arousal areas of the brainstem
Orexin-containing neurons in the lateral hypothalamus activate arousal areas
Histamine-containing neurons in the posterior hypothalamus project to the Reticular Activating System and promote wakefulness
The drowsiness associated with anti-histamines is thought to be due to inhibition of these neurons

19. Sleep Areas - Brainstem
The Arousal System
Raphe nucleus of Reticular Activating System (sets overall arousal/alertness)
Slow-Wave Promoting System
Nucleus Tractus Solitarius
REM Promoting System
Pontine tegmentum; superimposes REM on slow-wave sleep
REM-promoting areas
Areas in the brainstem (pontine tegmentum and ventrolateral periaqueductal gray) are largely responsible for the cyclical imposition of REM sleep upon slow-wave sleep
If you LESION the PONS you could never go into REM  death eventually

20. Sleep-Promoting Factors
Prostaglandins
Peptides
VIP, hypocretins, DSIP
CCK
Sleepiness after large meal??
Melatonin
Secreted by pineal gland. Acts on suprachiasmatic nucleus. Treats insomnia in elderly, jet lag.
In addition to the classical neurotransmitters (ACh, serotonin, NE, etc.), several (>30) other sleep-promoting and sleep-inhibiting factors have been suggested to contribute to the sleep-wake cycle, among them
Prostaglandins (PGD2 - sleep, PGE2 - wakefulness)
Peptides
Especially VIP, hypocretins and Delta Sleep-Inducing Peptide (DSIP). The latter induces delta waves. DSIP does not initiate sleep, but keeps sleep/wake cycle in proper order
Hypocretins (orexins)
Peptides discovered in 1998 that are released from neurons whose cell bodies are largely located in the lateral hypothalamus, but whose axons project throughout the brain
They are very similar in structure to the GI hormone secretin and they stimulate appetite
Recently shown to activate thalamic nuclei, and stimulate the cerebral cortex and brainstem arousal areas
Lipopolysaccharide
Interleukin-1
Interferon-alpha-2
Tumor necrosis factor
Serotonin
Cholecystokinin (CCK)
Probably contributes to drowsiness associated with a large meal
ADH – may promote REM sleep
Melatonin
Hormone secreted by the pineal gland
Acts on the suprachiasmatic nucleus via specific receptors that lead to gene transcription of proteins involved in circadian rhythms
Melatonin has been shown to be useful in treatment of jet lag and insomnia in the elderly (probably because melatonin production decreases with age), but not as a general “sleeping pill”

21. Sleep Pathologies DIMS DOES Dysomnias Parasomnias
Disorders initiating and maintaining sleep
DOES
Disorders of excessive somnolence
Most common: narcolepsy
Dysomnias
Circadian rhythm disturbances
Parasomnias
Nightmares, night terrors, sleep walking, sleep apnea
Sleep disorders fall into four major categories
DIMS
"Disorders Initiating and Maintaining Sleep"
Often a problem of children; associated with sleep onset associations (wrong pillow, absent teddy bear, etc.)
DOES
"Disorders Of Excessive Somnolence"
The most common is narcolepsy, which affects about 1 in 2000 people
Narcoleptics are chronically sleepy, and have an abnormal tendency to progress suddenly from being awake to REM sleep, often in response to a strong emotional stimulus
This abnormal REM sleep is accompanied by a sudden loss of muscle tone
Recently, it has been shown that most instances of narcolepsy are associated with a loss of hypocretin-producing cells in the hypothalamus
Similarly, in experimental animals, genetically-induced hypocretin deficencies produce narcolepsy
Dysomnias
Disturbances of the normal circadian rhythmicity of sleep (e.g., “jet lag”)
Parasomnias
A broad set of normally undesirable behaviors that either occur exclusively during sleep or are exaggerated by sleep.
Nightmares, night terrors, sleepwalking, etc.
Nightmares are story-like bad dreams that most often occur during REM sleep
In contrast, night terrors are certain types of dreams occurring during slow-wave sleep characterized by "feelings" as opposed to specific images
During night terrors a person wakens abruptly, often screams and runs about disoriented and unable to speak coherently
The episode lasts 3-4 minutes, then the person goes back to sleep
Sleepwalking can involve fairly complex motor behaviors while the person is in slow-wave sleep
Sleep apnea
Sleep is characterized by frequent periodic breathing pauses
Central vs. obstructive sleep apnea
Obstructive sleep apnea is caused by a physical blockage of the airway, usually due to collapse of soft tissue in the rear of the throat. It is often associated with obesity
Central sleep apnea is caused by REM skeletal muscle inhibition extending to respiratory muscles too

22. Pharmacology of Sleep – Sleep Promoting
Alcohol
Hypnotics – prescription sleeping pills
Anti-histamines – OTC sleeping pills
DSIP – maintains normal sleep architecture
Sleep Promoting
Alcohol
Can cause insomnia; although more frequently induces sleep due to relaxation
Hypnotics
Primarily sleep-inducing (prescription "sleeping pills")
Anti-histamines
Most over the counter sleeping pills.
DSIP (Delta Sleep-Inducing Peptide)
Given to insomniacs, maintains proper sleep architecture.

23. Pharmacology of Sleep – Sleep Inhibiting
Caffeine
Common cause of insomnia
Amphetamines & cocaine
Stimulants that suppress REM sleep
Classic treatment for narcolepsy
Newer non-amphetamine drugs with fewer side-effects now available for narcolepsy
Caffeine
A common cause of insomnia
Can cause decreased sleep for 8-14 hr
Amphetamines/Cocaine
Suppress REM sleep
Narcoleptics traditionally were most often treated with stimulants such as amphetamines, or with antidepressants
In the past few years, newer non-amphetamine stimulants with fewer side effects, have begun to be used for the treatment of narcolepsy

24. Questions??