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Nov 1 2006
PHYSIOLOGY OF HUMAN SLEEP
Steven A Shea PhD
Division of Sleep Medicine, Brigham & Women’s Hospital and
Harvard Medical School
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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
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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.
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Changes in amount and type of sleep with age
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© Emotional Rescue Ltd. , Cheltenham UK
Do we sleep to avoid sleepiness?
• Do we breathe to avoid breathlessness?
• Do we eat to avoid hunger?
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Theories Concerning Functions of Sleep
• Restorative• Growth• Immune function• Learning • Data storage (reverse learning)• Energy conservation• Protection
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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???
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From: Sleep Research Society.http://www.sleephomepages.org/sleepsyllabus/
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Stages of SleepAccording to standardized manual edited by
Rechtshaffen & Kales (1968)
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Active Wakefulness
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Transition to Stage I Sleep
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Unambiguous Stage I Sleep
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Stage II Sleep
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Stage III Sleep
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Stage IV Sleep
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REM Sleep
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Generation of Sleep Spindles by Thalamocortical Neurons
M Steriade et al
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Wake-promoting pathways
From T Scammell, C Saper et al
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Orexin/Hypocretin
From T Scammell, C Saper et al
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Non-REM sleep generation
From T Scammell, C Saper et al
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REM sleep generation
From T Scammell, C Saper et al
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Reciprocal-Interaction Model
R McCarley & A Hobson
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Figure 1 Interaction of circadian phase and sleep propensity Dijk & Czeisler, 1994
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Independent factors determined from forced desynchrony
Dijk & Czeisler, 1994
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Sleep consolidation depends on time since start of scheduled sleep
AND circadian phase
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Other Normal Sleep Phenomena
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Failure of behavioral task (SAT) at sleep onset
Carskadon and Dement, 1979
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Reduced memory consolidation during sleep
JK Wyatt et al, 1992
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Hyperpolarization of motoneurons during sleep (Chase & Morales)
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Regular breathing in NREM Irregular breathing during REM
J Krieger, 1985
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Reduction in hypercapnic ventilatory response
during sleep
Lowest responses during REM sleep
NJ Douglas et al, 1982
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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
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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.
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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)
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Obstructive Sleep Apnea: struggle to breathe vs. struggle to sleep
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Nasal Continuous Positive Airway Pressure (CPAP) therapy Obstructive Sleep Apnea
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Fragmented sleep due to
obstructive sleep apnea (left)
Rebound of REM sleep after nasal
CPAP therapy(right)
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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
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Require mechanical ventilation when asleep
Breathe relatively normally when awake
Schmid (1983) Fortschr Med 101: 217-220
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Periodic Limb Movements of Sleep
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Slow wave sleep
decreases and
awakenings increase
with age
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Neurophysiological arousal
• Internal Stimuli• Respiratory
– chemoreceptors, mechanoreceptors, respiratory drive
• Leg Movements
• ‘Spontaneous’ arousal– bladder
– sleep homeostat
– ultradian sleep cycle
– circadian cycle
• External Stimuli• Numerous
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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
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Activation of Ventrolateral Preoptic Neurons During Sleep
Sherin et. al., Science 1996;271:216-219
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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
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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)
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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)
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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)
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15 % sleep
~60 % sleep
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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
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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)
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15 % sleep
~60 % sleep
Recovery sleep (83% sleep)
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Slee
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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
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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)
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Results experiment 3
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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
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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
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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
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Perspective
• Landmark study
• Is activity in the VLPO the primary cause of sleep?– What turns the VLPO on?
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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