Post on 24-Dec-2015
Neurobiology of Sleep-Wake StatesNeurobiology of Sleep-Wake States
Daniel J. Buysse, M.D.Daniel J. Buysse, M.D.Professor of PsychiatryProfessor of PsychiatryUniversity of Pittsburgh School of MedicineUniversity of Pittsburgh School of Medicinebuyssedj@upmc.edu
Pittsburgh Mind-Body Center Short Course on SleepPittsburgh, PADecember 8, 2006
Neurobiology of Sleep-Wake StatesNeurobiology of Sleep-Wake States
Assessment of sleep-wake statesAssessment of sleep-wake states Characteristics of wakefulness, NREM, and REM Characteristics of wakefulness, NREM, and REM
sleepsleep Physiological regulation of sleep-wake statesPhysiological regulation of sleep-wake states Neuroanatomy and neurobiologyNeuroanatomy and neurobiology Neurochemical control of sleep-wake statesNeurochemical control of sleep-wake states Integration of sleep-wake states and circadian Integration of sleep-wake states and circadian
rhythmsrhythms
Overview: Functions of sleepOverview: Functions of sleep
Ecological/ environmental advantageEcological/ environmental advantage Improves the quality of wakefulnessImproves the quality of wakefulness
– AlertnessAlertness
– MoodMood
– Cognitive (especially frontal lobe) functionsCognitive (especially frontal lobe) functions Integration of experience; learningIntegration of experience; learning Resensitization of receptors (e.g., norepinephrine, Resensitization of receptors (e.g., norepinephrine,
serotonin)serotonin) Metabolic, inflammatory effectsMetabolic, inflammatory effects LongevityLongevity
Sleepiness and sleep deprivationSleepiness and sleep deprivationBelenky, Belenky, J. Sleep ResearchJ. Sleep Research, 2003, 2003
Performance and sleep deprivationPerformance and sleep deprivationBelenky, Belenky, J. Sleep ResearchJ. Sleep Research, 2003, 2003
Sleep deprivation effects on cognitive Sleep deprivation effects on cognitive function function Drummond et al., Drummond et al., NeuroreportNeuroreport, 1999, 1999
Normal sleep – Activation of PFC, parietal, pre-motor cortex
Following sleep deprivation – Decreased activation
fMRI during serial subtraction task
Effect of sleep and sleep deprivation on Effect of sleep and sleep deprivation on motor task performance motor task performance Walker and Strickgold, Walker and Strickgold, NeuronNeuron, 2004, 2004
= pre sleep = post sleep * = significant change
n = 15 n = 15
© American Academy of Sleep Medicine
Surgery:Surgery: 20% more errors and 14% 20% more errors and 14% more time required to perform more time required to perform simulated laparoscopy post-call (two simulated laparoscopy post-call (two studies) studies) Taffinder et al, 1998; Grantcharov et al, 2001Taffinder et al, 1998; Grantcharov et al, 2001
Internal Medicine:Internal Medicine: efficiency and efficiency and accuracy of ECG interpretation accuracy of ECG interpretation impaired in sleep-deprived interns impaired in sleep-deprived interns Lingenfelser et al, 1994Lingenfelser et al, 1994
Pediatrics:Pediatrics: time required to place an time required to place an intra-arterial line increased intra-arterial line increased significantly in sleep-deprived significantly in sleep-deprived Storer et al, Storer et al, 19891989
Sleep deprivation in medical traineesSleep deprivation in medical trainees
Effects of sleep deprivation on mood in Effects of sleep deprivation on mood in medical residentsmedical residents Baldwin and Daugherty, Baldwin and Daugherty, SleepSleep, 2004, 2004
2
3
4
5
6
7
<4 4 to 5 5 to 6 6 to 7 >7
Average Hours of Sleep per Night
Res
iden
ts' R
atin
gs
Moodier & more shorttempered
Impaired my capacityto care for patients
Work hours too long
More conflict withprofessional staff
Misjudgements inpatient care
Sleep duration and body massSleep duration and body massTaheri et al., Taheri et al., PLoS MedPLoS Med, 2004, 2004
n = 1024
Bo
dy
Ma
ss I
nd
ex
Sleep duration, leptin, and ghrelin Sleep duration, leptin, and ghrelin Taheri et al., Taheri et al., PLoS MedPLoS Med, 2004, 2004
Leptin Ghrelin
Sleep restriction: Metabolic and endocrine Sleep restriction: Metabolic and endocrine effects effects Spiegel et al., Spiegel et al., J Clin End & MetabJ Clin End & Metab, 2004, 2004
n = 11
Assessment of sleep-wake statesAssessment of sleep-wake states
Self-report questionnairesSelf-report questionnaires Sleep-wake diariesSleep-wake diaries: Daily recording of sleep times and : Daily recording of sleep times and
characteristicscharacteristics Observer ratingsObserver ratings: Unreliable: Unreliable ActigraphyActigraphy: Motion-sensitive accelerometer worn on wrist: Motion-sensitive accelerometer worn on wrist PolysomnographyPolysomnography (PSG): Modification of (PSG): Modification of
electroencephalography (EEG)electroencephalography (EEG)– EEGEEG
– Eye movementsEye movements
– Muscle toneMuscle tone
Graphic sleep diary: BaselineGraphic sleep diary: BaselineGraphic sleep diary: BaselineGraphic sleep diary: Baseline
Graphic sleep diary: Post-interventionGraphic sleep diary: Post-interventionGraphic sleep diary: Post-interventionGraphic sleep diary: Post-intervention
Actigraphy
Polysomnography:Polysomnography: Relaxed wakefulness Relaxed wakefulness (Stage w)(Stage w)
C3-REF
C4-REF
O1-REF
O2-REF
LOC-REF
ROC-REF
EMG
A
REMs
Neurobiology of Sleep-Wake StatesNeurobiology of Sleep-Wake States
Assessment of sleep-wake statesAssessment of sleep-wake states Characteristics of wakefulness, NREM, and REM Characteristics of wakefulness, NREM, and REM
sleepsleep Physiological regulation of sleep-wake statesPhysiological regulation of sleep-wake states Neuroanatomy and neurobiologyNeuroanatomy and neurobiology Neurochemical control of sleep-wake statesNeurochemical control of sleep-wake states Integration of sleep-wake states and circadian Integration of sleep-wake states and circadian
rhythms rhythms
Wakefulness, NREM, and REMWakeWake NREM NREM REMREM
ArousabilityArousability HighHigh LowestLowest LowLow
EEG amplitudeEEG amplitude Low Low HighHigh LowLow
EEG frequencyEEG frequency Fast Fast SlowSlow Mixed fastMixed fast
Muscle toneMuscle tone VariableVariable Low Low AbsentAbsent
Eye movementsEye movements Voluntary Voluntary InfrequentInfrequent RapidRapid
Heart Rate, Blood Heart Rate, Blood Pressure, Respiratory Pressure, Respiratory RateRate
VariableVariable Slow/ low, Slow/ low, regularregular
VariableVariable
O2, CO2 responseO2, CO2 response Full Full LowerLower LowestLowest
ThermoregulationThermoregulation Behavioral/ Behavioral/ PhysiologicalPhysiological
PhysiologicalPhysiological Reduced Reduced physiologicalphysiological
Mental activityMental activity FullFull None/ limitedNone/ limited Story-like Story-like dreamsdreams
PSG:PSG: Stage 1 sleepStage 1 sleep
A
B
CEMG
ROC-REF
LOC-REF
C3-REF
C4-REF
O1-REF
O2-REF
PSG:PSG: Stage 2 sleepStage 2 sleep
C3-REF
C4-REF
LOC-REF
O1-REF
02-REF
ROC-REF
EMG
S K
PSG:PSG: Stage 3 sleepStage 3 sleep
PSG:PSG: Stage 4 sleepStage 4 sleep
LOC-REF
C3-REF
C4-REF
O1-REF
O2-REF
ROC-REF
EMG
PSG:PSG: Rapid-eye-movement (REM) sleepRapid-eye-movement (REM) sleep
C3-REF
C4-REF
O1-REF
02-REF
LOC-REF
ROC-REF
EMG
Factors that affect sleepFactors that affect sleep
AgeAge– Increased wakefulness during sleep periodIncreased wakefulness during sleep period
– Decreased Stage 3/4 NREMDecreased Stage 3/4 NREM
– Earlier timingEarlier timing
– Greater daytime sleepinessGreater daytime sleepiness Sex (women have longer sleep, more Stage 3/4 Sex (women have longer sleep, more Stage 3/4
NREM)NREM) Timing: Sleep is best at night!Timing: Sleep is best at night! Illnesses, medicationsIllnesses, medications
Sleep in healthy young and older adultsSleep in healthy young and older adults
20 year old woman 71 year old woman
Sleep stages across the life spanSleep stages across the life spanOhayon et al., SLEEP 2004; 27: 1255-73Ohayon et al., SLEEP 2004; 27: 1255-73
Min
ute
s
Age (years)
Homeostatic and circadian regulation of human sleep Borbely et al., 2001
Time of Day
““Opponent Process” model of sleep Opponent Process” model of sleep regulation regulation Edgar, Edgar, J NeurosciJ Neurosci, 1993, 1993
Sleep-Wake State Switching SystemVLPO
“Sleep Switch”LHA
“Wake Stabilizer”
HomeostaticSleep Drive
CircadianTiming System
Sleep-WakeRegulatory System
Thalamus
Cognitive-Affective SystemDorsal (Cognitive)
SystemVentral (Affective)
System
Model of sleep-wake regulation relevant to Model of sleep-wake regulation relevant to insomniainsomnia
Solid arrows indicate direct anatomic or physiologic pathways. Dotted arrows indicate indirect pathways. VLPO = Ventrolateral preoptic area. LHA = Lateral hypothalamus peri-fornical area. LC = locus coeruleus. LDT = Laterodorsal pontine tegmentum. PPT = Pedunculopontine tegmentum. TMN = Tuberomamillary nucleus of the posterior hypothalamus.
Brainstem-HypothalamicArousal System
LC, Raphe, LDT/PPT, TMN
Brainstem and hypothalamic arousal Brainstem and hypothalamic arousal systems systems Saper, Saper, NatureNature, 2005; 1257-63, 2005; 1257-63
Effect of VLPO on arousal systems Effect of VLPO on arousal systems Saper, Saper, NatureNature, 2005; 1257-63, 2005; 1257-63
The “flip-flop” sleep switchThe “flip-flop” sleep switchSaper, Saper, Nature Nature 2005; 437:1257-632005; 437:1257-63
Extracellular adenosine in basal forebrain
3
Prolonged waking
1 2 3 4 5 6 1 2 3
250
200
150
100
50
0
Ade
nosi
ne (%
of h
our 2
)
Hours
Recovery
Adenosine and sleep-wake regulationAdenosine and sleep-wake regulationPorkka-Heiskanen, Porkka-Heiskanen, ScienceScience, 1997, 1997
REM sleep systemsREM sleep systems
“REM-On”Laterodorsal and pedunculopontine tegmentum (Ach)
“REM-Off”Locus coeruleus (NE)and raphe nuclei (5-HT)
Reciprocal interaction model of NREM-REM sleep Pace-Schott and Hobson, 2002
Sleep stages and physiological activitySleep stages and physiological activity Saper, Saper, TINSTINS, 2001, 2001
WakeWake NREMNREM REMREM
EEGEEG Fast, low Fast, low voltagevoltage
Slow, high Slow, high voltagevoltage
Fast, low Fast, low voltagevoltage
Eye movementEye movement Vision-relatedVision-related Slow, irregularSlow, irregular RapidRapid
Muscle toneMuscle tone ++++ ++ 00
LDT/PPTLDT/PPT ++ 00 ++++
LC/DR/TMNLC/DR/TMN ++++ ++ 00
VLPO VLPO (Cluster)(Cluster) 00 ++++ +?+?
VLPO VLPO (Extended)(Extended) 00 +?+? ++++
HypocretinHypocretin ++++ 0?0? 0?0?
The “flip-flop” sleep-wake switchThe “flip-flop” sleep-wake switchSaper, Saper, TINSTINS, 2001, 2001
Neurochemical control of sleep-wake statesNeurochemical control of sleep-wake states
NeurotransmitterNeurotransmitter LocationLocation ActionAction
AcetylcholineAcetylcholine LDT, PPT (pons)LDT, PPT (pons) REM, wakeREM, wake
HistamineHistamine TMN (posterior TMN (posterior hypothalamus)hypothalamus)
WakeWake
GABA, galaninGABA, galanin VLPOVLPO NREM sleepNREM sleep
SerotoninSerotonin Raphe nucleiRaphe nuclei Wake, NREMWake, NREM
NorepinephrineNorepinephrine Locus coeruleusLocus coeruleus WakeWake
HypocretinHypocretin Later hypothalLater hypothal WakeWake
Neurochemical control of sleep-wake statesNeurochemical control of sleep-wake states
DopamineDopamine AdenosineAdenosine Nitrous oxideNitrous oxide Cytokines (IL-1, IL-6, TNF-Cytokines (IL-1, IL-6, TNF-αα)) ProstaglandinsProstaglandins Hormones: melatonin, growth hormone, VIP NPYHormones: melatonin, growth hormone, VIP NPY Delta sleep-inducing peptideDelta sleep-inducing peptide
Neurobiology of Sleep-Wake StatesNeurobiology of Sleep-Wake States
Assessment of sleep-wake statesAssessment of sleep-wake states Characteristics of wakefulness, NREM, and REM Characteristics of wakefulness, NREM, and REM
sleepsleep Physiological regulation of sleep-wake statesPhysiological regulation of sleep-wake states Neuroanatomy and neurobiologyNeuroanatomy and neurobiology Neurochemical control of sleep-wake statesNeurochemical control of sleep-wake states Integration of sleep-wake states and circadian Integration of sleep-wake states and circadian
rhythms rhythms
Integration of circadian rhythms and sleep-wake states Pace-Schott and Hobson, 2002