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

2. 25 th Birthday 9 Years of Sleep 2.5 Years of Dreaming Happy Birthday!

3. 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

4. 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

5. Definition and Qualitative Description 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 grinding, and some physical activities may also bee seen during sleep.Other behaviors: sleep walking, sleep talking, tooth grinding, and some physical activities may also bee seen during sleep.

6. Sleep is a special activity of the brain.

8. Stages of Sleep Non-rapid Eye Movement (NREM) Sleep -Stage 1 -Stage 2 -Stage 3 -Stage 4 Rapid Eye Movement (REM) Sleep -Phasic -Tonic

9. Polysomnography (PSG) Standard Physiological Variables Electroencephalogram (EEG)Electroencephalogram (EEG) Electrooculogram (EOG)Electrooculogram (EOG) Electromyogram (EMG)Electromyogram (EMG) Additional Variables Respiratory MovementsRespiratory Movements Blood Oxygen SaturationBlood Oxygen Saturation Heart RateHeart Rate Leg MovementsLeg Movements

10. Electroencephalogram(EEG)  Reflects local potentials at the level of cerebral cortex, specifically a summary of local synaptic potentials on cortical pyramidal neurons.  Type, location and mutual synchronization of these potentials is reflected in different shape, amplitude and frequency of recorded brain waves.

11. Electrode Placement A1A2 C3

12. EEG Alpha 8-13 Hz Beta > 13 Hz Theta 4-7 Hz Delta < 4 Hz FREQUENCYAMPLITUDE < 5  V 5-15  V 10-50  V > 50  V

13. Sharp wave K Complex EEG Typical EEG signs for the identification of different stages of sleep

14. 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 NREM Sleep REM Sleep

15. Electrooculogram (EOG) retina + cornea EOG is measured based on corneo-retinal potential. As eyeballs move, the electrical potential field changes with reference to electrodes.

16. Wakefulness and Transition to Non-REM Sleep

17. Non-REM Sleep: Stage 1

18. NREM Sleep: Stages 2-4 Stage 3 Stage 4 Stage 2

19. Outline of Standard Criteria for Scoring NREM sleep Stages  Stage 1 EEG: Relatively low voltage, mixed frequency; may be theta (3-7 cps) activity with greater amplitude; Vertex sharp waves; Synchronous high-voltage theta bursts in children EMG: Tonic activity, may be slight decrease from waking EOG: Slow eye movements

20.  Stage 2 EEG: 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

21.  Stage 3 EEG: ≥ 20 ≤ 50% high amplitude (> 75 V), slow frequency (≤ 2 cps); maximal in the frontal EMG: Tonic activity, low level EOG: None, picks up EEG  Stage 4 EEG: >50% high amplitude, slow frequency EMG: Tonic activity, low level EOG: None, picks up EEG

22. Orthodox of NREM Sleep DEEPER SLEEP GREATER SYNCHRONY SLEEP STAGE 1 2 3 4 AWAKE

23. Rapid Eye Movement (REM) Sleep Human Rat

24. Signs of REM Sleep EOG: Rapid eye movements (REMs)EOG: Rapid eye movements (REMs) EEG: High frequency low amplitude EEG; Sawtooth waves; theta activity; PGO/P-wavesEEG: High frequency low amplitude EEG; Sawtooth waves; theta activity; PGO/P-waves EMG: Antigravity or postural muscles are paralyzedEMG: Antigravity or postural muscles are paralyzed Muscle jerksMuscle jerks Penile/clitoral tumesencePenile/clitoral tumesence

25. Signs of REM Sleep Thermoregulation is absent (poikilothermia)Thermoregulation is absent (poikilothermia) Irregular breathing, including brief hypopneas and apneasIrregular breathing, including brief hypopneas and apneas Unstable cardiac system (variable heart rate and blood pressure). Indeed some speculate that the phasic excitation of the cardiac system during REM may trigger heart attacksUnstable cardiac system (variable heart rate and blood pressure). Indeed some speculate that the phasic excitation of the cardiac system during REM may trigger heart attacks DreamDream

26. The Progression of Sleep Stages Across a Single Night 241 2 3 4 5 6 7 Wake S1 S2 S3 S4 REM Mov. Time in Hour Sleep-Wake Stages

27. 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.

28. - 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.

29. - 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.

30. How do these wake and sleep stages play out over the night and day? Circadian Rhythm (24 hours) Sleep Homeostasis

31. Circadian Rhythm of Sleep Days 1 2 34

32. 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.

33. CIRCADIAN BODY RHYTHMS SCN

34. MELATONIN NIGHT

36. Sleep Homeostasis leepiness increases in proportion to prior awake timeSleepiness increases in proportion to prior awake time There is a “pressure” to keep awake and sleep time balancedThere is a “pressure” to keep awake and sleep time balanced There is a need for recovery sleep after sleep deprivationThere is a need for recovery sleep after sleep deprivation

37. Age-related Changes in Sleep Pattern

38. Age-related Changes in Total Amount of Daily Sleep 40 25 20 18.9 15 3.8

41. Sleep in Elderly Sleep in Elderly Earlier sleep onset Early morning awakenings Daytime sleepiness Loss of delta sleep Reduced REMs and dream recall

42. CEREBRAL CORTEX THALAMUS PONS SPINAL CORD Brain Areas ● Hypothalamus ● Hypothalamus ●Basal Forebrain ● Basal Forebrain ●Brainstem:Pons ● Brainstem:PonsNeurotransmitters ● Ach ●Glutamate ● Glutamate ● GABA ●Histamine ● Histamine ● NE ●5-HT ● 5-HT ● Peptides ●NO ● NO

43. Mechanisms of SWS Generation EEG Cortex Hpc Cerebellum Midbrain Pons Medulla Thalamus AC OX R scp Sol POA TMN

44. Brainstem Network for REM Sleep Sign Generation

45. Thank You!