The document provides an extensive overview of normal sleep physiology, including definitions of sleep stages (NREM and REM), scoring methods, and the physiological basis of sleep. It discusses EEG patterns associated with different sleep stages, the neural mechanisms regulating sleep, the effects of sleep deprivation, and various sleep disorders characterized in the International Classification of Sleep Disorders. Additionally, it highlights the importance of sleep for cognitive function, mood, immune response, and overall health.

1. Normal Sleep Physiology
Bibhant Shah
MD Resident
Internal Medicine, NAMS

2. • Sleep  Rapidly reversible state of reduced responsiveness, motor
activity, and metabolism
• Humans – 1/3rd
of life sleeping (~8 hours/night)
• Purpose of sleep poorly understood (multiple theories):
• Restoration
• Energy conservation
• Memory consolidation

3. Polysomnography (PSG)  Primary tool for assessing sleep

4. • Sleep broadly segmented into
• Rapid Eye Movement (REM) sleep
• Non-Rapid Eye Movement (NREM) sleep
• Scoring of sleep stages by 30 second epochs based on American Academy of Sleep
Medicine (AASM) scoring rules
Sleep Staging

5. • EEG – electrodes placed on head in frontal,
central, and occipital locations
• Odd numbers – left side of head
• Even numbers – right side of head
• Requires bilateral monitoring; left and right
hemispheres may not provide identical data
• Full EEG requires placement of all 20 electrodes
• Sleep staging requires only the partial grouping
(F3 and F4, C3 and C4, O1 and O2)
• Brain waves assessed by amplitude and
frequency; different frequencies associated with
different stages of sleep

6. Brain Waves

7. Alpha waves
• Rhythmical waves
• Frequency 8 – 13 cycles / sec
• Awake individuals, in a quiet, resting state of cerebration
• Most intense in occipital region
• Voltage usually about 50 mV
• Disappears during deep sleep
• Believed to result from spontaneous feedback oscillation from thalamo-cortical
system, possibly including the reticular activating system in the brain stem as well 
causes both the periodicity of alpha waves, and synchronous activation of millions of
neurons during each wave

8. Beta waves
• When awake person’s attention directed to some specific type of
mental activity – alpha waves replaced by beta waves
• Asynchronous higher frequency, but lower voltage
• Frequencies > 14 cycles / sec (as high as 80 cycles / sec)
• Recorded mainly from parietal and frontal regions during specific
activation of these parts of the brain

9. Theta waves
• Frequencies 4 – 7 cycles / sec
• Occurs normally in parietal and temporal regions in children
• Can occur during emotional stress in some adults (disappointment
and frustration)
• Often occur in degenerative brain states

10. Delta waves
• All waves of EEG with frequencies < 3.5 cycles / sec
• Voltage 2 to 4 times greater than most other brain waves
• Occurs in very deep sleep, in infancy
• In persons with serious organic brain disease

11. Wake
• Adults – typically awake at least 2/3rd
of 24 hours
• Behavioral cues (open eyes, movement, conversation) demonstrate
alertness
• As activities wind down, people recline and close their eyes
brain waves slow to a posterior alpha rhythm (bridge between wake
and sleep)
further slowing of this rhythm  arrival of sleep

12. NREM Sleep
• Most adults enter sleep from drowsy state via NREM sleep
• Divided into 3 sub-stages:
• Stage N1
• Stage N2
• Stage N3

13. Stage N1
• Typical transition from wakefulness to sleep
• Low amplitude mixed EEG frequencies in Theta range ( 4 – 7 Hz)
• Eye movements typically slow and rolling
• Lightest stage of sleep
• Patients awakened usually do not perceive they were actually asleep
• Accounts for 5 – 10 % or less of total sleep time in young adults
• Increased N1 sleep suggests a sleep fragmenting disorder such as OSA

14. Stage N2
• Comprises largest percentage of total sleep time in a normal middle
aged adult
• Typically 45 – 55% of the night
• Characterized by
• Theta EEG frequency
• Sleep spindles and K-complexes (appears for the first time on EEG during N2)

15. • Sleep spindles
• generally short (at least 0.5 seconds)
• Frequency 11 to 16 Hz (12 – 14 Hz)
• Most prominently occur in central
(vertex) EEG leads
• K-complexes
• Well-delineated negative sharp waves immediately followed by a positive
component that stand out from background EEG
• Total duration of ≥0.5 seconds
• Maximal amplitude in frontal regions of EEG
• Benzodiazepines increase stage N2 sleep (increases spindle activity)

16. Stage N3
• ‘deep sleep’ or ‘slow wave sleep’
• Low frequency (0.5 to 2 Hz)
• High amplitude ( >75mV) Delta EEG waves
• Typically accounts for 10 – 20 % of total sleep in young to middle age adults
• Decreases with age

17. • Occurs more in the first half of the night (particularly at beginning of
night; slow wave activity during sleep represents homeostatic drive to
sleep – which is maximal after the waking period
• More difficult to arouse sleepers during stage N3 sleep compared
with N1 and N2
• Stage N3 is a typical time for NREM-parasomnias to occur

18. REM Sleep (Stage R)
• EEG
• low voltage mixed EEG pattern
• Sawtooth waves – common finding ( 2 – 6 Hz ) – sharply contoured, occur in brief
bursts
• EOG
• Rapid eye movements
• Conjugate, irregular, sharply peaked eye movements with an initial phase less than
500 milliseconds
• EMG
• Atonia – inactivity of all voluntary muscles (except extraocular muscles and
diaphragm)  result of direct inhibition of alpha motor neurons

19. Two phases of REM sleep:
• Phasic
• Bursts of rapid eye movements
• Respiratory variability
• Brief EMG activity (occasional muscle twitches)
• And/or sudden increase in sympathetic activity
• Tonic
• Exists between phasic bursts
• More limited motor activity
• Few eye movements

20. • REM sleep associated with vivid dreaming
• Accounts for less than a quarter of total sleep time ( 18 – 23 % )
• Hypothesis: REM sleep is a time of memory consolidation during which
important memories retained and less important neural connections
pruned
• Several sleep disorders related to abnormalities in REM sleep /
physiological events associated with REM sleep
• Narcolepsy
• OSA
• Pulmonary disease
• REM sleep behavior disorder

21. • REM sleep may be delayed / suppressed by
• Alcohol
• Sedative-hypnotic drugs
• Barbiturates and other antiepileptic drugs
• Beta antagonists
• MAO inhibitors
• SSRIs
• REM sleep can be increased by
• Withdrawal from alcohol
• Benzodiazepines
• TCAs

22. Arousals
• As sleep progressively deepens, specific EEG, EOG, and EMG findings will
become visible
• Arousals can occur, bringing individual from deeper to lighter sleep or to
wakefulness
• Arousal scored on EEG if there is abrupt shift of EEG frequency including
Alpha, Theta and/or frequencies > 16 Hz (but not spindles) lasting at least 3
seconds, with at least 10 seconds of stable sleep preceding the change
• Scoring arousal during REM  concurrent increase in submental EMG lasting
at least 1 second

23. Brain Circuits
• Ascending arousal system
• Clusters of nerve cells extending from upper pons to hypothalamus and basal forebrain 
activate cerebral cortex, thalamus (relays information to cortex), and other forebrain regions
• Ascending arousal neurons  monoamines (norepinephrine, dopamine, serotonin,
histamine), glutamate, acetylcholine
• Some basal forebrain neurons use GABA to disinhibit cortical inhibitory interneurons 
promoting arousal
• Additional wake promoting neurons in hypothalamus use peptide neurotransmitter orexin
(hypocretin)  reinforce activity in other arousal cell groups
Regulation of Sleep

24. • Sleep-promoting system
• Neurons in preoptic area, pons  GABA to inhibit arousal system
• Additional neurons in lateral hypothalamus containing peptide melanin-
concentrating hormone  REM sleep
• Mutual inhibition between arousal and sleep promoting systems 
neural circuit (flip-flop switch)

25. • Similar switch in brainstem for transitions from NREM to REM sleep
• GABAergic REM-Off neurons in lower midbrain  inhibit REM-On
neurons in upper pons
• REM-On group contains both GABAergic neurons which inihibit REM-
Off group (flip-flop switch)
• REM-On neurons projecting to medulla and spinal cord activate
inhibitory (GABA and glycine-containing) interneurons 
hyperpolarize motor neurons  paralysis of REM sleep

27. Homeostatic, Allostatic and Circadian Inputs
• Gradual increase in sleep drive with prolonged wakefulness, followed
by deeper slow-wave sleep and prolonged sleep episodes suggests a
homeostatic mechanism
• Prolonged wakefulness  adenosine levels rise  acts through A1, as
well as A2a receptors to directly inhibit arousal-promoting areas
• Caffeine blocks A2a receptors

28. • Allostasis – physiologic response to a challenge that cannot be
managed by homeostatic mechanisms
• Stress responses can impact need for sleep
• Sleep is also regulated by strong circadian timing signal  driven by
suprachiasmatic nuclei (SCN) of hypothalamus
• SCN sends output to key sites in hypothalamus  impose 24 hour
rhythms on a wide range of behaviors and body systems, including
sleep-wake cycle

29. Circadian Rhythmicity
• Wake-sleep cycle most evident of many 24-hour rhythms in humans
• Bilateral destruction of SCN  loss of most endogenous circadian
rhythms
• Genetically determined period of the endogenous neural oscillator
(SCN) averages ~ 24.15 hours in humans  normally synchronized to
24 hours period of environmental light-dark cycle through direct input
from intrinsically photosensitive ganglion cells in retina to SCN

30. • Pineal hormone  Melatonin; secreted predominantly at night
• Reflects direct modulation of pineal activity by SCN via sympathetic
nervous system
• Melatonin secretion does not require sleep
• Melatonin secretion inhibited by ambient light  effect mediated by
neural connection from retina to pineal gland via SCN
• Sleep efficiency highest when sleep coincides with endogenous
melatonin secretion

31. • Sleep goes through multiple discrete cycles during any given night
• Occurs in fairly typical patterns of NREM and REM sleep
• Single cycle lasts approximately 90 – 120 minutes
• (first sleep cycle will typically encompass time from initial sleep onset until
patient exits from first REM period)
• 4 – 5 cycles occur during a typical 8 hour night of sleep
Sleep Architecture

32. Sleep cycles trend through a standard night in the following ways:
• First cycle of the night starts with transition from wake to stage N1 
N2  N3  REM
• As cycles continue during the night, percentage of REM sleep in each
cycle generally increase
• Percentage of stage N3 decrease over course of night, with largest
amount of N3 in the first half of the night

33. • Newborn infants sleep 16 to 18 hours / day in short blocks of time,
without a clear circadian phase
• They enter sleep through REM as opposed to NREM sleep
• At 3 months of age, they begin to develop a day / night cycle and
enter sleep through NREM sleep
• Total sleep time slowly decreases, reaching adult norms post-
adolescence

34. • Young adults – typically sleep 8 hours / night (elevated percentage of
stage N3 sleep)
• As humans transition to middle age and beyond, percentage of stage
N3 decreases and percentage of wake and N1 increase
• Percentage of REM sleep fairly stable throughout adulthood
• Often assumed to be reduced in older adults, total amount of sleep
time required by young adults and older adults does not appear to be
dramatically different

35. Physiologic effects of Sleep Stage

36. Potential functions of Sleep
• Restorative theory – body repairs and revitalizes itself during sleep state
• Growth hormone secretion peaks during sleep  contributes to muscle growth and cell
regeneration during night
• Brain metabolism during sleep clears substances such as adenosine which builds up over
course of day and likely helps induce NREM sleep
• Sleep associated with an increase in interstitial space  improved clearance of
neurotoxic waste
• Sleep plays a role in brain plasticity  promotes learning-dependent synapse formation
and maintenance

37. • Sleep insufficiency exists when sleep is insufficient to support
adequate alertness, performance, and health, either because of
reduced total sleep time (decreased quantity) or fragmentation of
sleep by brief arousals (decreased quality/depth)
• Acute sleep deprivation  no sleep or reduction in usual total sleep
time, usually lasting 1 or 2 days
• Chronic sleep insufficiency (sleep restriction)  when an individual
routinely sleeps less than amount required for optimal functioning
(volitional partial sleep loss or insufficient opportunity to sleep)
Insufficient Sleep

38. Insufficient Sleep
Syndrome
International
Classification of Sleep
Disorders (3rd
Edition):
Disorder characterized
by excessive daytime
sleepiness caused by
curtailed sleep almost
everyday for at least 3
months

39. How much Sleep do we need?

40. Effects of Acute Sleep Deprivation
• Cognitive effects
• Deficits in behavioral alertness and vigilant attention
• Mood and Judgement
• Depression / anxiety  poor mood, irritabililty, low energy, decreased libido, poor judgement, other
psychologic dysfunction
• Respiratory physiology
• Depress ventilatory responses to hypercapnia and hypoxia  hypoventilation
• Respiratory muscle endurance decreased
• End-tidal PCO2 increased
• Sleepiness and microsleeps
• Powerful drive for sleep that is not under control of the individual allowing for sleep to intrude into
wakefulness for a few seconds whenever lack of physical activity such as driving  such lapses referred as
microsleeps

41. Consequences of Chronic Sleep Insufficiency
• Accidents and workplace errors
• Decreased quality of life
• Cardiovascular morbidity
• Associated with adverse cardiovascular outcomes
• Induction and increase in proinflammatory markers (CRP) and cytokines
• Arrythmogenic effects on heart
• Immunosuppression
• Obesity and metabolism
• Short sleep duration  weight gain and increased Diabetes risk (effects on appetite and
hormones such as leptin and ghrelin)

42. International Classification of Sleep Disorders (ICSD) 3rd
Edition
categories:
• Insomnia
• Sleep-related breathing disorders
• Central disorders of hypersomnolence
• Circadian rhythm sleep-wake disorders
• Parasomnias
• Sleep-related movement disorders
• Other sleep disorders
Classification of Sleep Disorders

43. Insomnia
• Chronic insomnia disorder
• report of a sleep initiation or sleep maintenance problem, an adequate
opportunity and circumstances to sleep, and daytime consequences as the result
of the insomnia symptoms  symptoms at least three times per week over a
duration of three or more months
• Short-term insomnia disorder
• must meet the same criteria as chronic insomnia except that the symptoms have
been present for less than three months
• Other insomnia disorder
• when the patient has insomnia symptoms but does not meet criteria for the other
two types of insomnia

44. Sleep-related Breathing disorders
• Central sleep apnea syndromes
• Obstructive Sleep Apnea (OSA) disorders
• Sleep-related hypoventilation disorders
• Sleep-related hypoxemia disorder

45. Central disorders of Hypersomnolence
• Primary complaint  daytime sleepiness not due to another sleep disorder, including
disturbed sleep or misaligned circadian rhythms
Disorders include:
• Narcolepsy type 1
• Narcolepsy type 2
• Idiopathic hypersomnia
• Kleine-Levin syndrome
• Hypersomnia due to a medical disorder
• Hypersomnia due to a medication or substance
• Hypersomnia associated with a psychiatric disorder
• Insufficient sleep syndrome

46. Narcolepsy
• Narcolepsy type 1
• patients with excessive sleepiness plus cataplexy and/or hypocretin-1
deficiency
• diagnosed by either CSF hypocretin-1 deficiency (<110 pg/mL or a mean sleep
latency of ≤8 minutes and two sleep onset rapid eye movement periods
(SOREMPs; within 15 minutes of sleep onset) on an overnight
polysomnogram), along with a history of clear cataplexy episodes
• Narcolepsy type 2
• diagnosed same criteria as type 1; however, cataplexy and/or CSF hypocretin-
1 deficiency (if measured) are not present

47. Circadian rhythm sleep-wake disorders
• chronic or recurrent sleep disturbance due to alteration of the
circadian system or misalignment between the environment and an
individual's sleep-wake cycle – duration at least 3 months
• Shift work disorder and jet lag disorder – most common

48. Parasomnias
• undesirable physical events (complex movements, behaviors) or
experiences (emotions, perceptions, dreams) that occur during entry
into sleep, within sleep, or during arousals from sleep

49. NREM-related parasomnias
• Disorders of arousal (confusional arousals, sleepwalking, sleep terrors,
and sleep-related eating disorder)
• General criteria include:
• Recurrent episodes of incomplete awakening associated with abnormal
behaviors and/or experiences
• Absent or inappropriate responsiveness
• Limited or no cognition or dream report, and
• Partial or complete amnesia for the event

52. REM-related parasomnias
• intrusion of the features of REM sleep into wakefulness (eg, sleep paralysis)
• exaggeration of the features of REM sleep (eg, nightmare disorder)
• or aberrations of REM sleep physiology (eg, lack of atonia as observed in
REM sleep behavior disorder)
• Diagnosis  repeated episodes of behavior or vocalization during REM
sleep with evidence of REM sleep without atonia during polysomnography
• Nightmare disorder  recurrent, highly dysphoric or anxiety-laden dreams
that are clearly recalled upon awakening; result in significant distress or
impairment

53. Other parasomnias
• Other parasomnias bear no specific relationship to sleep stage
• These include:
• exploding head syndrome
• sleep-related hallucinations
• sleep enuresis
• parasomnia associated with medical disorders
• parasomnia due to a medication or substance
• unspecified parasomnia

54. Sleep-related movement disorders
• simple, stereotypic movements that disturb sleep
• patients may or may not be aware of these movements
Disorders include:
• Restless legs syndrome
• Periodic limb movement disorder
• Sleep-related cramps
• Sleep-related bruxism (teeth grinding)
• Sleep-related rhythmic movement disorder
• Benign sleep myoclonus of infancy
• Propriospinal myoclonus at sleep onset
• Sleep-related movement disorder due to a medical disorder
• Sleep-related movement disorder due to a medication or substance
• Sleep-related movement disorder, unspecified

57. References
• Guyton and Hall Textbook of Medical Physiology – 13th
Ed.
• Harrison’s Principles of Internal Medicine – 20th
Ed.
• UpToDate 2019
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