NORMAL SLEEP PHYSIOLOGY

David M. Raizen, MD, PhD

Associate Professor of Neurology, Medicine, and Genetics
Division of Sleep Medicine
Perelman School of Medicine, University of Pennsylvania

Neurology Board Review

2017
 Loss of alpha waves
EYES CLOSED:

REM:
AWAKE:

N2:
N1:

N3:
Modified from Rechtschaffen & Kales, A manual…(1968)
 Features of Non-REM Sleep
• Increased parasympathetic tone
• Decreased metabolism.
• Decreased muscle tone relative to wakefulness.
• Decreased responsiveness
• Growth hormone and prolactin released during slow
wave sleep
N1

N2

N3

Modified from Rechtschaffen & Kales, eds. LA: Brain Information Service/Brain Research Institute, U.of California; 1968. A manual of
standardized terminology, techniques and scoring system of sleep stages in human subjects.
 Features of REM Sleep
TONIC PHASIC
• Desynchronized EEG • rapid eye movements
• EMG atonia • middle ear muscle
• poikilothermia activity
• penile tumescence • muscle twitches
• increased cerebral • cardiopulmonary
blood flow variability
• Pontine-Geniculo-
Occipital (PGO) waves

Modified from Rechtschaffen & Kales, eds. 1968. A manual of standardized

terminology, techniques and scoring system of sleep stages in human subjects.
 Sleep architecture in young and old adults
Stage N2REM

Slow wave sleep early in the night

Reduced slow wave sleep. Sleep

more fragmented.

Neubaur DN (1999) Sleep problems in the elderly, Am. Fam. Physician 59:2551-2558
Roffwarg, Muzio, and Dement (1966) Ontogenetic development of the human sleep-dream cycle, Science 152: 604
C. Von Economo, Sleep as a problem of localization.
J. Nervous and Mental Diseases 71, p 249 (1930)

“…the center for regulation of sleep is in the Von Economo

immediate vicinity of the other important 1876-1931
vegetative centers located in the infundibular
region…it forms with them a larger
physiological entity that is distinctly
separated from the other vegetative centers
by its localization as well as by its chemical
affinity as its affinity to the virus of
encephalitis proves, because in the acute
stage of that disease we generally do not
find other disturbances of the vegetative Horizontal hatching: Insomnia
nervous system…”
Diagonal hatching: Sleepiness
 Wake-promoting systems
Neurotransmitter nucleus Location

Norepinephrine Locus Coeruleus (LC) Pons

PedunculoPontine Tegmentum (PPT)

Acetylcholine Midbrain
Lateral Dorsal Tegmentum (LDT)

Dopamine ventral PeriAqueductal Gray (vPAG) Midbrain

Serotonin Dorsal Raphe (DR) Midbrain

posterior
Histamine TuberoMammilary Nucleus (TMN)
hypothalamus
Posterolateral
Orexin / Hypocretin Posterolateral hypothalamus
hypothalamus
Basal
Acetylcholine Basal Forebrain
Forebrain

Glutamate Parabrachial nucleus Rostral Pons

 Excitatory influences Neural mechanisms
on diencephalon: governing wakefulness
Acetylcholine

Excitatory influences
on forebrain:
•Histamine
•Serotonin
Mono
•Norepinephrine amines PB (Glu)

•Dopamine
•Orexin
•Acetylcholine
•Glutamate

Modified from Saper, Lu, and Scammel, Nature ‘05

(1) Ventrolateral How is wakefulness turned off?
preoptic nucleus
(VLPO)

GABA
Galanin

(2) Paracial zone

(PFZ)

GABA

NOTE: Also sleep-promoting

PFZ
is adenosine: Receptor
blocked by caffeine

Modified from Saper, Lu, and Scammel, Nature ‘05

How is sleep regulated?
2-Process Model

Circadian
clock

SLEEP

Prior wakefulness

Homeostatic process
 TWO PROCESS MODEL OF
SLEEP REGULATION
(Borbˇ ly)

Process C is circadian; your circadian nadir is early morning.

Process S is homeostatic and builds up with wake duration.
Borbely AA & Achermann P (1999) Sleep homeostasis and models of sleep regulation, J. Biol. Rhythms 14:557-568
Ischemic strokes are most likely to occur
A.6 AM-12 noon
B.12 noon-6 pm
C.6 pm- 12 midnight
D.12 midnight to 6 AM
 What is the normal Human Period?
• Period is close to 24 hours,
with variations across
individuals and an average
slightly >24 hrs.
• Aged individuals do not
change their circadian clock
period—they only advance
the phase of the rhythm

Czeisler et al (1999) Stability, precision, and near-24-hour period of the human circadian
pacemaker, Science 284: 2177-81
Effect of aging on circadian rhythms

The tendency to go to sleep and wake earlier in older individuals is

explained by:
A. Depression
B. Shortening of circadian clock with age
C. Advancement of the phase of the circadian clock with age
D. Voluntary in attempt to catch all the early bird specials
 Components of a Circadian System

Input
(“Zeitgeber” or
Time giver*) Pacemaker
(Oscillator)

*Exercise, noise, meals, and

Output
temperature are other Zeitgebers.
Slide: Courtesy of A. Sehgal, UPenn
Circadian clock: transcription/translation loop
P P Protein CYTOPLASM
P
Degradation
CRY P

PER
NUCLEUS

Caseine kinase 1e CLK::BMAL1

per cry
period

per2
per1
per3
cryptochrome
cry cry

Per2 or caseine kinase 1 are mutated in some families with advanced

sleep phase syndrome Slide: Courtesy of A. Sehgal, UPenn
 Components of a Circadian System

Input
(“Zeitgeber” or
Time giver*) Pacemaker
(Oscillator)

*Exercise, noise, meals, and

Output
temperature are other Zeitgebers.
Slide: Courtesy of J.D. Alvarez
 Overview of neural pathways

From Reid KJ, Zee PC: Circadian rhythm disorders. Semin Neurol 2009;29:393–405.
 Retinohypothalamic Tract (RHT)

photoreceptors

Intrinsically photosensitive
retinal ganglion cells

Retinohypothalamic Tract: A small branch of the optic nerve is a

direct retinal projection to the suprachiasmatic nucleus, which
releases glutamate and Pituitary Adenylate Cyclase Activating
Polypeptide (PACAP).
Golombek DA & Rosenstein RE (2010) Physiology of circadian entrainment, Physi. Rev. 3: 1063
Light Transduction to the SCN
• A special population of
retinal ganglion cells contain
melanopsin, and respond to
light with calcium influx.
• Explains why some blind
people can still be entrained
to light.
• Melanopsin responds best to
blue light (479 nm).

Foster RG (2005) Neurobiology: bright blue times, Nature 433:741

Circadian clocks of blind patients (due to degeneration of rods/cones)

A. Are free running. i.e. cannot be entrained by light

B. Can be entrained by light.
C. Are non-existent. i.e. there is no circadian rhythm.
 Overview of neural pathways

From Reid KJ, Zee PC: Circadian rhythm disorders. Semin. Neurol. 2009, 29:393–405.
 The SCN and the Pineal Gland
• The suprachiasmatic nucleus (SCN) of the hypothalamus
is the master clock. It is located above the optic chiasm.
• The SCN regulates the pineal gland, an endocrine gland
located posterior to the thalamus.
• The pineal gland secretes melatonin during darkness.
Melatonin in humans is weakly sleep-promoting.
• Blue light suppresses melatonin production.
 Melatonin: The Hormone of Darkness

• Melatonin secretion begins 2 to 3 hours before bed.

• Melatonin feeds back to (weakly) to reset the circadian
clock through melatonin receptors in the SCN.
– Ramelteon & Tasimelteon: melatonin receptor agonists.
– Beta-blockers can suppress melatonin release
• Melatonin taken in the afternoon can phase-advance
the internal clock and can be used as a sleep aid.
 Normal sleep physiology: Summary
• During health, sleep is regulated by circadian and homeostatic processes.
• The circadian regulation of sleep is relatively well-understood both at the level
of the light input pathways and of the core cellular oscillator. Homeostatic
regulation of sleep is poorly-understood.
• Multiple wake systems are partially redundant but may each serve unique
functions. i.e. not all wake is the same. Remember: monoamines plus ACh,
Glutamate, and Orexin.
• NREM sleep control has two identified systems (VLPO and PFZ), but there are
inputs to this system (e.g. Basal forebrain)
• REM sleep is not simply a reduction in monoaminergic tone, but an active
inhibitory process in the pons. We are (mostly) paralyzed during REM sleep.
• The entire system is delicate and disturbed by medications, stressors/illness,
and age.
• Sleep is required for life and is observed in all animals yet its core function
remains a mystery.