1. The Neurobiology of Sleep and Sleep Disorders Tamara Blutstein, Ph.D. Department of Neuroscience Tufts University School of Medicine May 1, 2013

2. What is Sleep? “a natural periodic state of rest for the mind and body, in which the eyes usually close and consciousness is completely or partially lost so that there is a decrease in bodily movement and responsiveness to external stimuli”

3. The Function of Sleep Important to overall health and well being –Severe cognitive and physical consequences of sleep deprivation –Strong rebound of sleep following sleep loss –Evolutionarily conserved There are a number of sleep disorders –Insomnia, sleep apnea, restless leg syndrome, narcolepsy Sleep disruptions are associated with a number of neurological disorders –Parkinson’s disease, Alzheimer’s disease, depression

4. Two Process Model of Sleep Balance between sleep and wake determined by 2 factors –Circadian 24hr cyclic rhythm generated by the SCN that entrains the sleep-wake cycle to the daily light-dark cycle –Homeostatic Determined by sleep need Homeostatic drive to sleep increases with time awake and peaks just before the beginning of the sleep period Lu and Zee 2010

5. Sleep Stages Wake- desynchronized EEG and high EMG activity NREM sleep- high amplitude, slow- wave EEG (delta frequency 0.5- 4Hz) and low EMG activity relative to wakefulness REM sleep- regular theta activity (4- 8Hz) on EEG, coupled with low EMG activity relative to that of NREM sleep WAKE NREM REM EEG EMG

6. Human Sleep WAKE NREM Sleep Divided into 4 stages Stage 1 2-5% of TST Transition from wake to sleep Stage 2 45-55% of TST Increased slow waves, presence of sleep spindles and K complexes Stage 3 and 4 10-20% of TST Slow-wave sleep (SWS), greatest early in sleep period REM Sleep 20-25% TST Episodes longer as sleep progresses Stiller and Postolache 2005

7. Neurobiology of Sleep: Wake-Promoting Systems Espana and Scammell 2011

8. Neurobiology of Sleep: NREM Espana and Scammell 2011

9. Regulation fo Wake and Sleep: Flip-Flop Switch Lu and Zee 2010

10. Neurobiology of Sleep: REM Espana and Scammell 2011

11. Neurotransmitters Involved in Sleep/Wake Espana and Scammell 2011

12. International Classification of Sleep Disorders Insomnias Sleep-related breathing disorders Hypersomnias of central origin Circadian rhythm sleep disorders Parasomnias Sleep-related movement disorders Isolated symptoms (apparently normal variants and unresolved issues) Other sleep disorders

13. Insomnias Most common Difficulty initiating and maintaining sleep, early morning awakening, non-restorative sleep Occurs 3-4 times per week and persisting for more than a month Sleep difficulty occurs despite adequate opportunity and circumstances for sleep and associated with daytime dysfunction

14. Primary Insomnias Adjustment insomnia Psychophysiological insomnia Paradoxical insomnia Idiopathic insomnia Inadequate sleep hygiene Behavioral insomnia of childhood

15. Secondary Insomnias Insomnia due to a drug or substance Insomnia due to a medical condition Insomnia not due to a substance or known physiological condition Physiologic Insomnia, unspecified

16. Causes of Insomnia Hyperactivity of HPA axis Imbalance of flip-flop switch regulating transition from sleep to wake

17. Treatment for Insomnias: Cognitive-Behavioral Buysse 2013

18. Treatment for Insomnias: Pharmacology Buysse 2013

19. Treatment for Insomnias: Pharmacology Buysse 2013

20. Sleep-Related Breathing Disorders Characteristic feature: disordered ventilation during sleep Primary central sleep apnea Primary sleep apnea of infancy Sleep-related hypoventilation/hypoxemic syndromes Obstructive sleep apnea

21. Obstructive Sleep Apnea CPAP Ioachimescu and Collop 2012

22. Hypersomnia of Central Origin Primary complaint is daytime sleepiness and the cause is not disturbed nocturnal sleep or misaligned circadian rhythms Daytime sleepiness: inability to stay alert and awake during the major waking episodes of the day, resulting in unintended lapses into sleep

23. Recurrent hypersomnia Idiopathic hypersomina with or without long sleep time Hypersomnia due to a medical condition Narcolepsy-cataplexy syndrome Hypersomnia of Central Origin

24. Narcolepsy-Cataplexy Syndrome Onset in adolescents and young adults Narcolepsy with cataplexy, without, and secondary narcolepsy Irresistible desire to fall asleep in inappropriate circumstances Triggered by emotional factors such as laughter, rage or anger

25. Video Narcolepsy-Cataplexy Syndrome

26. Burgess and Scammell 2012

27. Circadian Rhythm Sleep Disorders Delayed sleep phase Advanced Sleep Phase Jet lag Shift work Drake 2010

28. Circadian Rhythm Sleep Disorders Changes in the period length of the circadian clock Impaired response to light Altered function of clock genes or products Behavior therapy, Light therapy and Chronotherapy

29. Parasomnias Tinuper et al 2012

30. NREM parasomnias, impaired arousal mechanisms and the persistence of sleep drive result in a failure of the brain to fully transition into wake REM parasomnias-failure of mechanisms that induce muscle atonia Most treatments are similar to those used for insomnia Safety measures Parasomnias

31. Sleep-Related Movement Disorders Characterized by relatively simple, stereotyped movements that disturb sleep Bruxism Rhythmic movement disorder Nocturnal leg cramps Restless leg syndrome

32. Isolated Symptoms, Apparently Normal Variants and Unresolved Issues Long sleepers Short sleepers Snoring Sleep talkers Sleep related sexual disorders

33. Espana and Scammell 2011 Drug Effects on Sleep

34. Consequences of Sleep Loss Wulff et al 2010

35. Consequences of Sleep Loss Wulff et al 2010

36. Consequences of Sleep Loss Wulff et al 2010

37. Neurological Disorders and Sleep Wulff et al 2010

38. Sleep in Psychiatric Disease Wulff et al 2010

39. Sleep in Psychiatric Disease Wulff et al 2010

40. Sleep in Psychiatric Disease Wulff et al 2010

41. Sleep in Neurodegenerative Disease Wulff et al 2010

42. Therapeutic target Mechanistic overlap Identification of risk factors and vulnerability Neurological Disorders and Sleep

43. Questions? Contact info Email: Tamara.Blutstein@tufts.edu