1. Neurobiology of Sleep-Wake States Daniel J. Buysse, M.D. Professor of Psychiatry University of Pittsburgh School of Medicine buyssedj@upmc.edu Pittsburgh Mind-Body Center Short Course on Sleep Pittsburgh, PA December 8, 2006

2. Neurobiology of Sleep-Wake States  Assessment of sleep-wake states  Characteristics of wakefulness, NREM, and REM sleep  Physiological regulation of sleep-wake states  Neuroanatomy and neurobiology  Neurochemical control of sleep-wake states  Integration of sleep-wake states and circadian rhythms

3. Overview: Functions of sleep  Ecological/ environmental advantage  Improves the quality of wakefulness –Alertness –Mood –Cognitive (especially frontal lobe) functions  Integration of experience; learning  Resensitization of receptors (e.g., norepinephrine, serotonin)  Metabolic, inflammatory effects  Longevity

4. Sleepiness and sleep deprivation Belenky, J. Sleep Research, 2003

5. Performance and sleep deprivation Belenky, J. Sleep Research, 2003

6. Sleep deprivation effects on cognitive function Drummond et al., Neuroreport, 1999 Normal sleep – Activation of PFC, parietal, pre-motor cortex Following sleep deprivation – Decreased activation fMRI during serial subtraction task

7. Effect of sleep and sleep deprivation on motor task performance Walker and Strickgold, Neuron, 2004 = pre sleep = post sleep * = significant change n = 15

8. © American Academy of Sleep Medicine  Surgery: 20% more errors and 14% more time required to perform simulated laparoscopy post-call (two studies) Taffinder et al, 1998; Grantcharov et al, 2001  Internal Medicine: efficiency and accuracy of ECG interpretation impaired in sleep-deprived interns Lingenfelser et al, 1994  Pediatrics: time required to place an intra-arterial line increased significantly in sleep-deprived Storer et al, 1989 Sleep deprivation in medical trainees

9. Effects of sleep deprivation on mood in medical residents Baldwin and Daugherty, Sleep, 2004

10. Sleep duration and body mass Taheri et al., PLoS Med, 2004 n = 1024 Body Mass Index

11. Sleep duration, leptin, and ghrelin Taheri et al., PLoS Med, 2004 Leptin Ghrelin

12. Sleep restriction: Metabolic and endocrine effects Spiegel et al., J Clin End & Metab, 2004 n = 11

13. Assessment of sleep-wake states  Self-report questionnaires  Sleep-wake diaries: Daily recording of sleep times and characteristics  Observer ratings: Unreliable  Actigraphy: Motion-sensitive accelerometer worn on wrist  Polysomnography (PSG): Modification of electroencephalography (EEG) –EEG –Eye movements –Muscle tone

14. Graphic sleep diary: Baseline

15. Graphic sleep diary: Post-intervention

16. Actigraphy

17. Polysomnography: Relaxed wakefulness (Stage w) C3-REF C4-REF O1-REF O2-REF LOC-REF ROC-REF EMG A REMs

18. Neurobiology of Sleep-Wake States  Assessment of sleep-wake states  Characteristics of wakefulness, NREM, and REM sleep  Physiological regulation of sleep-wake states  Neuroanatomy and neurobiology  Neurochemical control of sleep-wake states  Integration of sleep-wake states and circadian rhythms

19. Wakefulness, NREM, and REM WakeNREMREM ArousabilityHighLowestLow EEG amplitude LowHighLow EEG frequency FastSlow Mixed fast Muscle tone VariableLowAbsent Eye movements VoluntaryInfrequentRapid Heart Rate, Blood Pressure, Respiratory Rate Variable Slow/ low, regular Variable O2, CO2 response FullLowerLowest Thermoregulation Behavioral/ Physiological Physiological Reduced physiological Mental activity Full None/ limited Story-like dreams

20. PSG: Stage 1 sleep A B C EMG ROC-REF LOC-REF C3-REF C4-REF O1-REF O2-REF

21. PSG: Stage 2 sleep C3-REF C4-REF LOC-REF O1-REF 02-REF ROC-REF EMG SK

22. PSG: Stage 3 sleep

23. PSG: Stage 4 sleep LOC-REF C3-REF C4-REF O1-REF O2-REF ROC-REF EMG

24. PSG: Rapid-eye-movement (REM) sleep C3-REF C4-REF O1-REF 02-REF LOC-REF ROC-REF EMG

25. Factors that affect sleep  Age –Increased wakefulness during sleep period –Decreased Stage 3/4 NREM –Earlier timing –Greater daytime sleepiness  Sex (women have longer sleep, more Stage 3/4 NREM)  Timing: Sleep is best at night!  Illnesses, medications

26. Sleep in healthy young and older adults 20 year old woman 71 year old woman

27. Sleep stages across the life span Ohayon et al., SLEEP 2004; 27: 1255-73 Minutes Age (years)

28. Homeostatic and circadian regulation of human sleep Borbely et al., 2001 Time of Day

29. “Opponent Process” model of sleep regulation Edgar, J Neurosci, 1993

30. Sleep-Wake State Switching System VLPO “Sleep Switch” LHA “Wake Stabilizer” Homeostatic Sleep Drive Circadian Timing System Sleep-Wake Regulatory System Thalamus Cognitive-Affective System Dorsal (Cognitive) System Ventral (Affective) System Model of sleep-wake regulation relevant to insomnia 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-Hypothalamic Arousal System LC, Raphe, LDT/PPT, TMN

31. Brainstem and hypothalamic arousal systems Saper, Nature, 2005; 1257-63

32. Effect of VLPO on arousal systems Saper, Nature, 2005; 1257-63

33. The “flip-flop” sleep switch Saper, Nature 2005; 437:1257-63

34. Extracellular adenosine in basal forebrain 3 Prolonged waking 1 2 3 4 5 6 1 2 3 250 200 150 100 50 0 Adenosine (% of hour 2) Hours Recovery Adenosine and sleep-wake regulation Porkka-Heiskanen, Science, 1997

35. REM sleep systems “REM-On” Laterodorsal and pedunculopontine tegmentum (Ach) “REM-Off” Locus coeruleus (NE) and raphe nuclei (5-HT)

36. Reciprocal interaction model of NREM-REM sleep Pace-Schott and Hobson, 2002

37. Sleep stages and physiological activity Saper, TINS, 2001 WakeNREMREM EEG Fast, low voltage Slow, high voltage Fast, low voltage Eye movement Vision-related Slow, irregular Rapid Muscle tone +++0 LDT/PPT+0++ LC/DR/TMN+++0 VLPO (Cluster) 0+++? VLPO (Extended) 0+?++ Hypocretin++0?0?

38. The “flip-flop” sleep-wake switch Saper, TINS, 2001

39. Neurochemical control of sleep-wake states NeurotransmitterLocationAction Acetylcholine LDT, PPT (pons) REM, wake Histamine TMN (posterior hypothalamus) Wake GABA, galanin VLPO NREM sleep Serotonin Raphe nuclei Wake, NREM Norepinephrine Locus coeruleus Wake Hypocretin Later hypothal Wake

40. Neurochemical control of sleep-wake states  Dopamine  Adenosine  Nitrous oxide  Cytokines (IL-1, IL-6, TNF-α)  Prostaglandins  Hormones: melatonin, growth hormone, VIP NPY  Delta sleep-inducing peptide

41. Neurobiology of Sleep-Wake States  Assessment of sleep-wake states  Characteristics of wakefulness, NREM, and REM sleep  Physiological regulation of sleep-wake states  Neuroanatomy and neurobiology  Neurochemical control of sleep-wake states  Integration of sleep-wake states and circadian rhythms

42. Integration of circadian rhythms and sleep-wake states Pace-Schott and Hobson, 2002