Neurobiology of Sleep Subimal Datta Sleep Research Laboratory Department of Psychiatry Boston University School of Medicine, Boston, MA.

Neurobiology of Sleep

Subimal DattaSleep Research LaboratoryDepartment of Psychiatry

Boston University School of Medicine, Boston, MA

25th Birthday

9 Years of Sleep

2.5 Years of

Dreaming

Happy Birthday!

Sleep Medicine• Sleep ranks among the 3 most important

considerations in maintaining good health

– Accompanied by good nutrition and stress management

• 62% of US population experiences sleep problems

• 80% of US adults have NEVER discussed sleep problems with their physician

• Societal bias equates sleepiness with laziness

Objectives of this Lecture

To describe methods for the objective identification of different stages of sleep

To describe the patterns of sleep, and factors influencing those patterns

To describe circadian and homeostatic aspects of sleep

To describe neuronal substrates of sleep

Definition and QualitativeDescription of Sleep

• Sleep is a reversible behavioral state of perceptual disengagement from, and unresponsiveness to, the environment.

• Species-specific postural recumbenceSpecies-specific postural recumbence• Behavioral quiescenceBehavioral quiescence• Elevated arousal thresholdElevated arousal threshold• Rapid arousal after moderate stimulationRapid arousal after moderate stimulation• Perceptual disengagement from environmentPerceptual disengagement from environment• DreamsDreams

• Other behaviors: sleep walking, sleep talking, tooth Other behaviors: sleep walking, sleep talking, tooth grinding, and some physical activities may also bee seen grinding, and some physical activities may also bee seen during sleep.during sleep.

Sleep is a special activity of the brain.

Stages of Sleep

• Non-rapid Eye Movement (NREM) Sleep

-Stage 1

-Stage 2

-Stage 3

-Stage 4

• Rapid Eye Movement (REM) Sleep

-Phasic

-Tonic

Polysomnography (PSG)

Standard Physiological VariablesStandard Physiological Variables• Electroencephalogram (EEG)Electroencephalogram (EEG)• Electrooculogram (EOG) Electrooculogram (EOG) • Electromyogram (EMG)Electromyogram (EMG)

Additional VariablesAdditional Variables

• Respiratory MovementsRespiratory Movements• Blood Oxygen SaturationBlood Oxygen Saturation• Heart Rate Heart Rate • Leg MovementsLeg Movements

Electroencephalogram(EEG)Electroencephalogram(EEG)

Reflects local potentials at the level of Reflects local potentials at the level of cerebral cortex, specifically a summary of cerebral cortex, specifically a summary of local synaptic potentials on cortical local synaptic potentials on cortical pyramidal neurons.pyramidal neurons.

Type, location and mutual synchronization Type, location and mutual synchronization of these potentials is reflected in different of these potentials is reflected in different shape, amplitude and frequency of shape, amplitude and frequency of recorded brain waves.recorded brain waves.

Electrode Placement

A1 A2

C3

EEGEEG

Alpha 8-13 Hz

Beta > 13 Hz

Theta 4-7 Hz

DeltaDelta < 4 Hz < 4 Hz

FREQUENCY AMPLITUDEAMPLITUDE

< 5 < 5 VV

5-15 5-15 VV

10-50 10-50 VV

> 50 > 50 VV

Sharp wave

K Complex

EEG

EEG

EEG

EEG

EEG

EEG

TypicalEEG signs for the identification of different stages of sleep

Electromyogram (EMG)

• Three electrodes are placed beneath the chin, overlying Mentalis/submentalis muscles.

• Sometime, the Anterior tibialis EMG is important to evaluate patients with PLM disorder.

Awake

NREMSleep

REMSleep

Electrooculogram (EOG)Electrooculogram (EOG)

retinaretina++ corneacornea

EOG is measured based on corneo-retinal EOG is measured based on corneo-retinal potential. As eyeballs move, the electrical potential potential. As eyeballs move, the electrical potential field changes with reference to electrodes.field changes with reference to electrodes.

Wakefulness and Transition toNon-REM Sleep

Non-REM Sleep: Stage 1

NREM Sleep: Stages 2-4

Stage 3

Stage 4

Stage 2

Outline of Standard Criteria for Scoring NREM sleep Stages

Stage 1EEG: Relatively low voltage, mixed frequency; may be theta (3-7 cps) activity with greater amplitude; Vertex sharp waves; Synchronous high-voltage theta bursts in childrenEMG: Tonic activity, may be slight decrease from wakingEOG: Slow eye movements

Stage 2EEG: Sleep spindles (waxing and waning at 12-14 cps, ≥ 0.5 sec); K complex (negative sharp wave followed immediately by slower positive components; maximal in vertex; spontaneous or in response to sound)

EMG: Tonic activity, low level

EOG: Occasionally slow eye movements near sleep onset

Stage 3EEG: ≥ 20 ≤ 50% high amplitude (> 75 V), slow frequency (≤ 2 cps); maximal in the frontalEMG: Tonic activity, low levelEOG: None, picks up EEG

Stage 4EEG: >50% high amplitude, slow frequencyEMG: Tonic activity, low levelEOG: None, picks up EEG

Orthodox of NREM SleepDEEPER SLEEPDEEPER SLEEP

GREATER SYNCHRONYGREATER SYNCHRONY

SLEEP STAGESLEEP STAGE

11

22

33

44

AWAKEAWAKE

Rapid Eye Movement (REM) SleepHuman

Rat

Signs of REM Sleep

• EOG: Rapid eye movements (REMs)EOG: Rapid eye movements (REMs)

• EEG: High frequency low amplitude EEG; EEG: High frequency low amplitude EEG; Sawtooth waves; theta activity; PGO/P-wavesSawtooth waves; theta activity; PGO/P-waves

• EMG: Antigravity or postural muscles are EMG: Antigravity or postural muscles are paralyzedparalyzed

• Muscle jerksMuscle jerks

• Penile/clitoral tumesencePenile/clitoral tumesence

Signs of REM Sleep• Thermoregulation is absent (poikilothermia)Thermoregulation is absent (poikilothermia)

• Irregular breathing, including brief Irregular breathing, including brief hypopneas and apneashypopneas and apneas

• Unstable cardiac system (variable heart rate Unstable cardiac system (variable heart rate and blood pressure). Indeed some speculate and blood pressure). Indeed some speculate that the phasic excitation of the cardiac that the phasic excitation of the cardiac system during REM may trigger heart system during REM may trigger heart attacksattacks

• DreamDream

The Progression of Sleep Stages Across a Single Night

24 1 2 3 4 5 6 7

Wake

S1

S2

S3

S4

REMMov.

Time in Hour

Sle

ep-W

ake

Sta

ges

Generalizations About Sleep in the Normal Young Adult Human

• Sleep is entered through NREM.

• NREM sleep and REM sleep alternate with a period near 90 min.

• Slow wave sleep predominates in the first third of the night and is linked to the initiation of sleep.

• REM sleep predominates in the last third of the night and is linked to the circadian rhythm of body temperature.

- Continuation• Wakefulness within sleep usually accounts

for less than 5 percent of the night.

• Stage 1 sleep generally comprises about 2 to 5 percent of sleep.

• Stage 2 sleep generally comprises about 45 to 55 percent of sleep.

• Stage 3 sleep generally comprises about 3 to 8 percent of sleep.

- Continuation

• Stage 4 sleep generally comprises about 10 to 15 percent of sleep.

• NREM sleep, is therefore, is usually 75 to 80 percent of total sleep.

• REM sleep is usually 20 to 25 percent of total sleep, occurring in four to six discrete episodes.

How do these wake and sleep stages play out over the night and day?

• Circadian Rhythm (24 hours)

• Sleep Homeostasis

Circadian Rhythm of Sleep

Days1 2 3 4

Clock in the Brain• Overwhelming evidence indicates that the

suprachiasmatic nucleus (SCN), a paired structure located in the anterior hypo-thalamus contains a circadian pacemaker.

• Circadian rhythms are abolished with complete lesions of the SCN.

• SCN transplants into the third ventricle and hypothalamus restores rhythmicity in previously arrhythmic animals.

CIRCADIAN BODY RHYTHMSCIRCADIAN BODY RHYTHMS

SCN

MELATONINMELATONIN NIGHT

Sleep HomeostasisSleep Homeostasis

• Sleepiness increases in proportion to leepiness increases in proportion to prior awake timeprior awake time

• There is a “pressure” to keep awake There is a “pressure” to keep awake and sleep time balancedand sleep time balanced

• There is a need for recovery sleep There is a need for recovery sleep after sleep deprivationafter sleep deprivation

Age-related Changes in Sleep PatternAge-related Changes in Sleep Pattern

Age-related Changes in Total Amount of Daily Sleep

4025

20

18.915 3.8

Sleep in ElderlySleep in Elderly

Earlier sleep onsetEarlier sleep onset

Early morning awakeningsEarly morning awakenings

Daytime sleepinessDaytime sleepiness

Loss of delta sleepLoss of delta sleep

Reduced REMs and dream recallReduced REMs and dream recall

CEREBRAL CORTEXCEREBRAL CORTEX

THALAMUSTHALAMUS

PONSPONS

SPINAL CORDSPINAL CORD

Brain AreasBrain Areas ● ● Hypothalamus Hypothalamus ● ● Basal Forebrain Basal Forebrain ● ● Brainstem:PonsBrainstem:Pons

NeurotransmittersNeurotransmitters● ● AchAch●● GlutamateGlutamate● ● GABAGABA●● HistamineHistamine● ● NENE●● 5-HT5-HT● ● PeptidesPeptides●● NONO

Mechanisms of SWS Generation

EEG

Cortex

Hpc

Cerebellum

Midbrain

Pons

Medulla

Thalamus

AC

OX

R scp

SolPOA TMN

Brainstem Network for REM Sleep Sign Generation

Thank You!