Nov 2 2005

PHYSIOLOGY OF HUMAN SLEEP

Steven A Shea PhD

Division of Sleep Medicine, Brigham & Women’s Hospital and

Harvard Medical School

Characteristics of sleep

• Sleep need builds up with prolonged time awake• Some voluntary control over when we sleep• Pre-sleep behaviors often required

– Posture

– Quiescence

– Closed eyes

• EEG changes• Reduced responses to internal and environmental changes• But, able to rapidly reverse loss of consciousness

Importance of sleepexemplified by

uni-hemispheric sleep

in swimming mammals

Nature. 2005 Oct 27;437(7063):1264-71. Clues to the functions of mammalian

sleep. Siegel JM.

© Emotional Rescue Ltd. , Cheltenham UK

Do we sleep to avoid sleepiness?

• Do we breathe to avoid breathlessness?

• Do we eat to avoid hunger?

Theories Concerning Functions of Sleep

• Restorative• Growth• Immune function• Learning • Data storage (reverse learning)• Energy conservation• Protection

Brief History of EEG and Sleep

• 1875 - Richard Cayton– Electrical rhythms in animal brains

• 1928 - Hans Berger – EEG in humans - Eyes closed vs. open

• 1937 to 1939 - Harvey, Hobart, Davis– EEG asleep vs. awake

• 1952 - Aserinsky & Kleitman– REM sleep

• 1957 - Dement and Kleitman– Sleep stages and cycles

• 1968 - Rechtschaffen & Kales– Standardization

• 21st Century - Rechtschaffen & Kales revised???

From: Sleep Research Society.http://www.sleephomepages.org/sleepsyllabus/

Sleep Architecture: NREM & REM Sleep

Pace-Schott EF, Hobson JA. Nat Rev Neurosci. 2002.

Stages of SleepAccording to standardized manual edited by

Rechtshaffen & Kales (1968)

Active Wakefulness

Transition to Stage I Sleep

Unambiguous Stage I Sleep

Stage II Sleep

Stage III Sleep

Stage IV Sleep

REM Sleep

EEG amplitude decreases with age

Slow wave sleep

decreases and

awakenings increase

with age

Changes in amount and type of sleep with age

Generation of Sleep Spindles by Thalamocortical Neurons

M Steriade et al

Wake-promoting pathways

From T Scammell, C Saper et al

Non-REM sleep generation

From T Scammell, C Saper et al

REM sleep generation

From T Scammell, C Saper et al

Reciprocal-Interaction Model

R McCarley & A Hobson

Other Normal Sleep Phenomena

Failure of behavioral task (SAT) at sleep onset

Carskadon and Dement, 1979

Reduced memory consolidation during sleep

JK Wyatt et al, 1992

Hyperpolarization of motoneurons during sleep (Chase & Morales)

Regular breathing in NREM Irregular breathing during REM

J Krieger, 1985

Reduction in hypercapnic ventilatory response

during sleep

Lowest responses during REM sleep

NJ Douglas et al, 1982

Reduction in hypoxic

ventilatory response

during sleep

Lowest responses during REM sleep

NJ Douglas et al, 1985

Tachypnea response to preoptic warming in cats exists during NREM sleep [upper]

but not during REM sleep (until arousal) [lower]

PL Parmeggiani et al, 1973

Penile tumescence increases throughout REM sleep

9 hours sleep total

Endocrine function in the presence and

absence of sleep

From: Czeisler and Khalsa. 2000. The Human Circadian Timing System and Sleep-Wake Regulation. In: Principles and Practice of Sleep Medicine 3rd Ed. Kryger, Roth, Dement, eds. Saunders, 2000.

Abnormal sleep physiology: detected with Polysomnography

• Sleep / arousal patterns (EEG, EOG, EMG)

• Breathing Efforts (Thorax / Abdomen)

• Airflow (thermistors, nasal pressure, snoring)

• Arterial Oxygen Saturation

• Position

• ECG

• Leg movements (anterior tibialis EMGs)

Obstructive Sleep Apnea: struggle to breathe vs. struggle to sleep

Nasal Continuous Positive Airway Pressure (CPAP) therapy Obstructive Sleep Apnea

Fragmented sleep due to

obstructive sleep apnea (left)

Rebound of REM sleep after nasal

CPAP therapy(right)

Congenital Central Hypoventilation Syndrome (CCHS)

• ~200 living children worldwide

• Diagnosed in the absense of primary – neuromuscular disease– cardio-pulmonary disease– identifiable brainstem lesion

• Ability to voluntarily hyperventilate• Seriously hypoventilate during NREM sleep• Relatively normal breathing during REM sleep

Require mechanical ventilation when asleep

Breathe relatively normally when awake

Schmid (1983) Fortschr Med 101: 217-220

Periodic Limb Movements of Sleep

Neurophysiological arousal

• Internal Stimuli• Respiratory

– chemoreceptors, mechanoreceptors, respiratory drive

• Leg Movements

• ‘Spontaneous’ arousal– bladder

– sleep homeostat

– ultradian sleep cycle

– circadian cycle

• External Stimuli• Numerous

Arousals disturb sleep but some frequency of arousals is natural

• ASDA criteria (“Preliminary report” 1992)

• What frequency is normal?– Frequency of EEG arousal from nocturnal sleep in

normal subjects. Mathur R and Douglas NJ. Sleep. 1995: 18: 330-333.

• N = 55 controls, single night sleep study

• Awakenings (R+K) = 4/hr

• Mean arousal frequency (ADSA 3 sec criteria) = 21/hr

• Arousal frequency increased with age

• Arousal frequency unaltered by exclusion of snorers

Activation of Ventrolateral Preoptic Neurons During Sleep

Sherin et. al., Science 1996;271:216-219

Background

• 1930: Baron Constantin von Economo:

– encephalitis lethargica - injury to posterior hypothalamus

– severe insomnia - injury to anterior hypothalamus

• 1930 onwards: ablation and electrical stimulation studies in animals verify

– posterior hypothalamus may promote wakefulness

– anterior hypothalamus may promote sleep

Preliminary Observations

Brain activity (#Fos immumoreactive cells) decreases globally when rats killed during light cycle (i.e. asleep) except in:

Supra-chiasmatic nucleus (circadian)

Intergeniculate leaflet (circadian)

VLPO (? sleep or circadian)

(and other regions active in both states)

Hypotheses

1. Activity in the pre-optic area of the hypothalamus increases with sleep

2. VLPO is under sleep rather than circadian control

3. VLPO projects to the TMN (arousal center)

Sleep influences (experiment 1)

7 71913 1

N = 8 N = 7 N = 5(16% sleep)(68 % Sleep

except 2 rats)

•Examined sleep history (% time) in the hour before euthanasia.•Stained for FOS protein

•FOS protein (appears 1-2 h after activation, dissipates within ~ 4 h)

15 % sleep

~60 % sleep

Expt. 1 Conclusion & Limitations

• VLPO activity increases with sleep (hypothesis 1)

• Could not separate different sleep states (i.e. REM and NREM)

• A large amount of scatter? Limitation of FOS protein staining

• Recent sleep may be at the start or the end of the hour before sampling

Circadian influences (expt. 2)

7 719

7 71913 1

9 to 12 h sleep deprivation

12 to 15 h sleep deprivation

Sleep/circadian influences (expt. 1)

15 % sleep

~60 % sleep

Recovery sleep (83% sleep)

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• VLPO is sleep not circadian active (hypothesis 2)

• Not enough circadian phases examined

• REM vs. NREM?

• What ‘switches on’ the VLPO?

Expt. 2 Conclusion & Limitations

VLPO mechanisms for sleep (Expt. 3)

• Hypothesis that VLPO projects to the TMN (arousal center)– Injected cholera toxin-B into the TMN + control sites – ~ 1 week rats sacrificed during the light cycle (N = 15)– stain for CTB and Fos protein– check injection sites (histamine + CTB)

Results experiment 3

VLPO sleep generating mechanisms Discussion

• Hypothesis that VLPO innervates the TMN is supported

• N = 3 / 15, rats were injected in the TMN (small numbers)

• Hypothesize VLPO inhibits TMN via GABA

• Subsequently proven

Critique: Good

Scientific verification of clinical data

Plausible hypotheses

Sufficient data to answer H1

Compelling data with sleep deprivation (virtually superimposable results)

Good control for stress of sleep deprivation

Critique: Bad

Insufficient data to distinguish

NREM vs REM (sub-hypothesis 1)

All circadian phases (sub-hypothesis 2)

Anatomical links do not prove physiological significance (esp. H2 and H3)

Control data (SCN and IGL) not shown

Perspective

• Landmark study

• Is activity in the VLPO the primary cause of sleep?– What turns the VLPO on?

Interaction of circadian and homeostatic drives

2-process modelBorbely (1982) Hum Neurobiol 1:195-204

2-process threshold modelDaan (1984) Am J Physiol 246:R161:R178

Notes

Histaminergic neurons active awake, less active in NREM, silent in REM

Background

• 1930: Baron Constantin von Economo:

– encephalitis lethargica - injury to posterior hypothalamus

– severe insomnia - injury to anterior hypothalamus

• 1930 onwards: ablation and electrical stimulation studies in animals verify

– posterior hypothalamus may promote wakefulness

– anterior hypothalamus may promote sleep

Awake

Asleep

Amines (locus coeruleus, dorsal raphe,tuberomammillary nucleus)

Acetylcholine (LDT/PPT, basal forebrain)

Orexin

GABA (ventrolateral preoptic nucleus)

Wake Non-REM REM

O

O

O

O

O

Activity of state-regulatory nuclei

Orexin/Hypocretin

From T Scammell, C Saper et al

• Normal sleep physiology– Behavior– Respiratory– Cardiovascular– Motor control– Temperature

• Normal sleep patterns– Effect of aging on sleep

• EEG changes with sleep• Abnormal sleep physiology

– Obstructive sleep apnea– Periodic Limb Movements of Sleep

Plan

Claude Bernard Walter Cannon (1813-1878) (1871-1945)

EEG waves differ across behavioral states

Alpha (8-13 Hz)

Theta (4-7 Hz) Delta (< 4 Hz)

Cortical activity in NREM sleep

NREM Sleep(4 stages)

• Light sleep Stage 1

• Approximately 2-5% of total sleep time• Low voltage, mixed frequency EEG

Stage 2• Approximately 45-55% of total sleep time• Marked by K complexes and sleep spindles on EEG

• Slow wave sleep (SWS) Stage 3

• Marked by 20-50% high voltage (delta) waves on EEG Stage 4

• Marked by >50% high voltage (delta) waves on EEG

Comella CL, et al. Textbook of Clinical Neurology. 1999.

REM Sleep

• ~ 20-25% of total sleep duration

• ~ 90 min. ‘ultradian’ cycles

• Low voltage, mixed frequency EEG

• ‘Phasic’ events including rapid eye movements

• ‘Tonic’ periods without rapid eye movements

• Numerous other physiological changes – temperature, breathing, heart rate, organ blood flow

REM sleep

• Cortical activation

• Dreams are vivid, emotional, and bizarre

• Paralysis

• Rapid eye movements

• Autonomic fluctuations

• Arrhythmias and sudden death

Non-REM sleep

• Cortical synchrony

• Difficult to wake out of deep NREM sleep

• Dreams brief and less vivid

• Increased parasympathetic activity

Generation of Delta Waves by Thalamocortical Neurons

From RW McCarley; based on work of DA McCormick &HC Pape, and M. Steriade

Corticothalamic networks underlying EEG changes

M. Steriade et al (1994)

REM neurons

Obstructive Sleep Apnea

Wake System

GABAGAL

HIST

5-HT NE

ACh

WAKESLEEP

Saper CB, et al. Trends Neurosci. 2001.

Sleep System

GABAVLPO

HIST

5-HT NE

ACh

ThalamusThalamus

WAKESLEEP

Saper CB, et al. Trends Neurosci. 2001.