1. Biological Systems Influenced by Psychological Stress: Sleep Martica Hall, Ph.D. For the PMBC-II Sleep Assessment & Resources Core Pittsburgh Mind-Body Center Summer Institute Pittsburgh, PA June 5, 2008

2. Outline for today’s presentation  What is it?  How is it measured?  What affects it?  Is sleep related to psychological stress? –Classic Studies –Research Program on Heart Rate Variability During Sleep  EXTRA MATERIAL: Is sleep related to health?  Where do we go from here?

3. Overview: Description of sleep What is sleep?  behavioral state of relative quiescence  reversible changes in consciousness and physiology  seen in all mammals  essential to health and functioning What drives sleep?  prior wakefulness  circadian rhythms  Habit  Circumstance

4. 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

5. 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

6. Actigraphy Daytime activity peaks Nighttime inactivity Actigraph taken off

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

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

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

10. PSG: Stage 3 sleep

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

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

13. 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

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

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

16. Be mindful of circadian rhythms! Examples of human circadian rhythms Czeisler and Khalsa, 2000 Core body temperature Urine volume Thyroid Stimulating Hormone Growth Hormone Prolactin Parathyroid Hormone Motor activity Cortisol Time

18. Family Conflict in Childhood and Later Insomnia Gregory et al., SLEEP, 2006 N = 1037, 52% male

19. Dose-Response Relationship Between Chronicity of Family Conflict and Later Insomnia Gregory et al., SLEEP, 2006 Number of assessments at which family scores in top quartile for family conflict

20. Gene by Environment Interactions Reveal Vulnerability to Stress-Related Sleep Disturbances Brummet et al., Psychosomatic Medicine (2007) Caregivers homozygous for the s allele had greater subjective sleep Complaints compared to all other groups (p <.01)

21. Perceived Discrimination as a Mediator of the Race-Sleep Relationship Thomas et al., Health Psychology (2006) 37 African Americans (mean age 36.08 + 1.36) percent Stage 4 1.34 + 0.44 56 Caucasian Americans (mean age 35.57 + 0.96) percent Stage 4 3.89 + 0.51

22. Mid-life patients w/ insomnia and good sleeper controls, n=64) Data = self-report daily diaries collected over 3 weeks. Stressors were naturally occurring events. Prospective assessment of stress, coping, arousal and sleep Morin, Rodrigue & Ivers, Psychosomatic Medicine (2003)

23. Research Program on Heart Rate Variability During Sleep How is it evaluated? Why is it important? Is it related to stress?

26. Heart Rate VariabilityProximal Indices of Health Health Outcomes Heart Rate Variability: Why is it important?

27. Heart Rate VariabilityProximal Indices of Health Health Outcomes HRV during Sleep Heart Rate Variability & Health: It’s not just a waking phenomenon

28. Why am I interested in HRV during sleep?  Fundamental belief: Sleep is an essential restorative behavior that affects and can be affected by stress and other negative affective states. These relationships are critical to health and functioning.  Research program: Focuses on characterizing the bi-directional relationship between stress and sleep and its impact on health and functioning.  Why HRV during sleep? Evaluation of HRV during sleep provides non-invasive, continuous measure of autonomic nervous system regulation during sleep.  QEKG techniques allow us to parse signal into vagal and sympathovagal components.  These data allow us to test and refine hypotheses about the pathways linking stress, sleep and health.

29. Psychological stress and related negative affective states have been associated with prolonged physiological arousal during sleep. Might they elicit changes in heart rate variability during sleep? We evaluated this hypothesis in two studies using autoregressive spectral analysis of the EKG during NREM and REM sleep. Study 1: Acute Laboratory stress in 64 healthy undergraduates. Study 2: Stress-related coping behaviors in patients with insomnia. Whether these relationships generalize to older adults and across racial/ethnic groups is not known. Initial foray into evaluating HRV during sleep

36. SleepSCORE SWAN Sleep Study Neurobiology of InsomniaSleep in Renal Disease Treatment of Sleep Disorders in PTSD Sleep Apnea and the Metabolic Syndrome Depression in CHF PatientsSleep Deprivation and Stress Sleep and HRV in Premature InfantsBrain Metabolism during Sleep Assessment of HRV during sleep using MindWare

37. Study Sample  Participants were recruited from the Heart Strategies Concentrating on Risk Evaluation (HeartSCORE) community study of population disparities in cardiovascular risk.  HeartSCORE eligibility criteria were: age 45 – 75 years, resident of the greater Pittsburgh metropolitan area and absence of comorbid conditions expected to limit life expectancy to < 5 years.  The SleepSCORE study included a sub-sample of HeartSCORE participants, stratified by gender, race and Framingham Risk.  SleepSCORE exclusion criteria were pregnancy, current treatment of sleep apnea, regular use of sleep medications, nighttime shift work, medication for diabetes, or prior diagnosis of CVD events or interventional cardiology procedures.

39. Participant Characteristics PercentMean (s.d.) PercentMean (s.d.) Males54% African American42% BMI29.6 (4.9) Income (below $40,000)46% Education (no college degree)50% Smoke (current) 7% Perceived Stress (PSS)4.1 (2.6) Symptoms of Depression (CES-D) 7.5 (7.6) Symptoms of Anxiety (STAI)6.3 (5.4) Hostility (CM-Ho)1.5 (1.4)

40. Sleep Characteristics Mean (s.d.) Mean (s.d.) Sleep Quality (PSQI) 6.3 (3.1) Time Spent Asleep (mins.)361.0 (66.9) Sleep Efficiency (percent) 77.0 (11.1) NREM Stage 1 (percent) 9.2 (5.9) NREM Stage 2 (percent) 61.4 (9.2) NREM Stage 3+4 (percent) 6.5 (7.3) REM Sleep (percent) 22.8 (6.0) AHI 4.6 (17.5)

42. NREM differs from Wakefulness & REM HF PowerLF:HF

48. Brachial artery diameter is a significant correlate of LF:HF HRV during NREM sleep r = 0.25, p <.01

49. Brachial artery diameter is a significant correlate of LF:HF HRV throughout NREM sleep BAD > 3.7 BAD < 3.7

53. HEALTH SLEEP SLEEP Sleep Restriction/Deprivation Sleep Duration Sleep Continuity Sleep Architecture Sleep/Wake Rhythms Sleep Disorders Extra Material Mind-Body Sleep Research: Bridging the Gap Between Behavioral Medicine and Sleep Medicine

54. Sleep Restriction: Sleepiness & Performance (n= 16, sleep restriction to 33% below habitual sleep duration) Dinges et al., SLEEP. 20:267-77 (1997).

55. 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

56. Sleep Restriction & Glucose Metabolism Glucose Effectiveness 30 – 40% decrease Sympathovagal Balance (trend) increase Spiegel et al., Lancet, 354:1435-9 (1999). Ghrelin : Leptin 70% increase Carbohydrate Craving 30% Increase Spiegel et al., Ann Intern. Med, 141:846-50 (2004). GLUCOSE(mg/dL)LEPTIN(ng/ml)

57. Sleep Duration and Mortality -- one example: Kripke et al., 2003, Arch Gen Psychiatry, 59:131-136. Sleep Duration and Cardiovascular Disease (CVD) Ayas et al., Arch Intern Med, 163:205-209, 2003. Heslop et al., Sleep Medicine, 3:305-314, 2002. Qureshi et al., Neurology, 48:904-11, 1997. 9 9 RRRRRRRR Total CHD1.391.181.10--1.38 Nonfatal MI1.521.321.23--1.35 Fatal CHD1.120.910.83--1.45 Sleep Duration and Health

58. 3.02.752.52.252.01.751.51.251.00.750.5 < 6 6 7 8 >8 Mortality Hazards Ratio Mortality Hazards Ratio Sleep Duration, Compared to Reference of 7 Hours Crude Adjusted 1 Adjusted 2 Markers of Inflammation Attenuate the Relationship Between Short Sleep and Mortality: The Health ABC Study of Older Adults Hall, Newman et al. (under review)

59. Sleep Continuity: Survival as a Function of PSG-Assessed Sleep Latency Dew et al., Psychosomatic Medicine (2003) Latency, < 30 min. Latency, > 30 min. 0 100 200 300 400 500 600 700 800 900 1000 Weeks 1.0 0.8 0.6 0.4 0.2 0.0 Cumulative Survival Log rank test = 9.63 p =.002

60. Sleep Duration & the Metabolic Syndrome Hall et al., SLEEP (2008) Aim To evaluate the relationship between reported habitual sleep duration and the metabolic syndrome in a community sample of healthy men and women. Hypothesis Short sleep duration is associated with an increased risk of having the metabolic syndrome after adjusting for age, sex, race, and symptoms of depression. Study: Adult & Human Behavior Project (AHAB; HL-04962) Exclusions: clinical history of atherosclerotic disease; cancer diagnosis or treatment w/in the past year; chronic liver or kidney disease; use of insulin, weight loss or psychotropic medications.

61. Reported Habitual Sleep Duration (hrs/night) 600500400300200100 0 8 to 9 8 to 9 number

62. Metabolic Syndrome and its NCEP-Defined Components 8 8 n = 187 n = 402 n = 525 n = 100 Metabolic Syndrome 1.59 1.34 ref 1.69 (1.1 – 2.4) (.99 – 1.9) (1.00 – 2.9) (1.1 – 2.4) (.99 – 1.9) (1.00 – 2.9) Abdominal Obesity 1.55 1.48 ref 1.51 (1.1 – 2.2) (1.1 – 2.0) (.96 – 2.4) (1.1 – 2.2) (1.1 – 2.0) (.96 – 2.4) Glucose 1.62 1.13 ref 1.68 (1.1 – 2.4) (.83 – 1.5) (1.04 – 2.7) (1.1 – 2.4) (.83 – 1.5) (1.04 – 2.7) Blood Pressure 1.07.94 ref.98 (.73 – 1.6) (.70 – 1.3) (.6 – 1.6) (.73 – 1.6) (.70 – 1.3) (.6 – 1.6) Triglycerides 1.21 1.42 ref.92 (.80 – 1.8) (1.03 – 2.0) (.51 – 1.7) (.80 – 1.8) (1.03 – 2.0) (.51 – 1.7) High Density 1.24 1.15 ref 1.52 Lipoproteins (.86 – 1.8) (.85 – 1.5) (.98 – 2.4)

63. DAY 1 DAY 4 DAY 1 DAY 4 DAILY: Fill out Sleep Diary and Wear Wrist Actigraph (LENGTH OF STUDY: 1 menstrual cycle or 35 days) DAY 14 FINAL STUDY DAY PSG Sleep Study (3 nights) SWAN Sleep Study: Protocol Hall et al. (under preparation) SWAN Sleep Study: Protocol Hall et al. (under preparation) Core SWAN Visit w/in 6 months pre- or post-sleep study: Metabolic Syndrome determination by clinic blood pressure; blood draw; waist measurement; height & weight.

67. Shiftwork and Ulcers Drake et al., SLEEP (2004) 2036 174 360 N = 2,570 18 – 65 52% Male

68. Insomnia Epidemiology Ohayon, Sleep Med Rev, 2002 Insomnia symptoms + daytime consequences 9-15% Insomnia symptoms -Overall prevalence 30-48% -Often or always: 16-21% -Moderate to extreme: 10-28% Insomnia diagnosis 6% Direct economic costs of insomnia in the US are estimated ~ $14 billion

69. Insomnia Is a Risk Factor for Psychiatric Disorders 0 2 4 6 8 10 12 14 16 18 Depression*Anxiety*AlcoholDrug* Incidence (%) More Than 3.5 Years Insomnia (n = 240) No Insomnia (n = 739) *95% CI for odds ratio excludes 1.0. Breslau N et al. Biol Psychiatry. 1996;39:411-418.

70. Association of insomnia and CHD events Schwartz, J Psychosom Res, 1999; 47:313-33 Combined estimate Individual studies Meta-analysis of seven cohort and longitudinal studies

75. Sleep disorders are under-diagnosed  As many as 95% of people with a sleep problem remain unidentified and undiagnosed  Few health care providers question patients about sleep  Little content in medical schools  Essentially everything learned about sleep is in post-graduate courses (a booming academic business)

76. Sleep Disorders are Costly  Possibly 100,000 motor vehicle accidents annually are sleep-related.  The annual direct cost estimate of sleep-related problems is $16 billion, with an additional $50- $100 billion in indirect costs: –Accidents –Litigation –Property destruction –Hospitalization –Death

78. Sleep disorders medicine and mind-body interactions  Sleep medicine is in its adolescence as a field  Understanding mind-body interactions with respect to sleep is in its infancy  Fundamental processes relating sleep as a mediator of M-B processes is very much needed