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transcript
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.