neurobiology of sleep-wake states daniel j. buysse, m.d. professor of psychiatry university of...

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