Circadian Rhythm Disturbances: What Happens When Your Biological Clock Is In The Wrong Time Zone

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1 Circadian Rhythm Disturbances: What Happens When Your Biological Clock Is In The Wrong Time Zone Steven A. Thau MD Chief, Pulmonary, Sleep Department. Phelps Hospital, Northwell Health

2 Internal Clock Examples of Normal/Natural Biological Rhythms Suprachiasmatic Nucleus Clock Proteins Altering our Rhythm Treatment of Sleep Disorders

4 The first demonstration of a circadian rhythm by Jean Jacques d Ortous de Mairan in 1729 Princ & Prac Sleep Med 2011

5 Phylliis Zee Sleep Academic Award

6 Princ & Prac Sleep Med 2011

7 36 hr wake Princ & Prac Sleep Med 2011 Biological Clock

8 Biological Clock Many living organisms have Biological Clocks Evidence for this can be seen in physical activity, hormone levels and cognitive function Individual cells and Non CNS tissue have biological clocks

9 Clock in the Brain Overwhelming evidence indicates that the suprachiasmatic nucleus (SCN), a paired structure located in the anterior hypothalamus 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.

10 SCN

11 SCN SCN Wikipedia

12 SCN lesion disrupts circadian activity in the Squirrel Monkey Albers et al., 1982, Neuroscience Letters Phylliis Zee Sleep Academic Award

13 Clock in All Cells Pituitary and Lung Tissue in Vitro, Princ & Prac Sleep Med 2011

14 Suprachiasmatic Nucleus SCN is the master controller of the biological clock It is located near the optic chiasm

15 The Cellular Clock Circadian rhythms exist in single cells. Protein synthesis is necessary. Specific genes code for circadian rhythms.

16 Circadian Clock Genes Highly conserved between Drosophila and mammals Utilize an autoregulatory feedback loop with translocation of the protein products to the nucleus Rates of transcription and / or degradation are affected by light

17 Clock Genes Nature Reviews Genetics

18 Control network in mammalian

19 The Circadian Timing System Light Limbic System Other Eye SCN Immediate Early Genes Clock Genes Pineal Output Rhythms Phylliis Zee Sleep Academic Award Physiological Behavioral Melatonin Sleep / wake

20 Clock Genes In many cells there are genes that function in a circadian manner. The activation and deactivation of these proteins is partly controlled by phosphorylation. The SCN can modify the rhythm of these proteins in many different cells and organ systems

21 Modulating the Clock Zeitgeber (from German for "time giver," or "synchronizer") is any exogenous (external) cue that synchronizes an organism's endogenous (internal) timekeeping system (clock).

22 Zeitgeber The strongest zeitgeber, for both plants and animals, is light. Non-photic zeitgebers include temperature, social interactions, pharmacological manipulation, exercise, and eating/drinking patterns.

23 Phylliis Zee Sleep Academic Award

24 Activity Zeitgeber Hamsters forced to exercise in restricted periods, Princ & Prac Sleep Med 2011

25 Eating Zeitgeber Hamsters with ad lib eating A vs restricted eating times D Rats with restricted eating B +/- light vs restricted eating constant light C Princ & Prac Sleep Med 2011

26 Modulating the Biological Clock Light is by far the most effective Melatonin may help Eating, physical activity and social cues may also have an impact Before we can modulate the biologic clock we have to know what time zone we are in so we don t accidently make the problem worse.

27 Modulating the Biological Clock Sleep logs- cheap, easy but yes are very effort dependent. It doesn t work if the patient is filling it out in the waiting room! Actigraphy- More scientific more expensive, not well or not at all reimbursed. Looking for periods of little or no movement compared with activity but very helpful for pts who can t dp a sleep log such as pts w/ neurodegenerative disease. iphone/apps/ wearables may not be the same. Core body temp- Used to be the most common method usually with a probe (rectal, skin, catheter etc).

28 Modulating the Biological Clock Melatonin- The hormone of darkness The circadian rhythm signals the pineal gland to produce melatonin about min before typical bed time as long as it is dark. (Bright light suppresses melatonin production) DLMO- Dim Light Melatonin Onset- The most objective way to determine the circadian rhythm BUT very labor intensive and useful for research and not clinically available. Involves sampling of saliva usually (can be blood) ever min 6 hours before until 1 hour after sleep. The time melatonin rises to >threshold is a reliable indicator of circadian phase position. May be useful in in very difficult cases or if trying to shift phase with bright light or melatonin.

29 2008 by The Physiological Society Burgess H J et al. J Physiol 2008;586:

30 Melatonin profiles for the three treatment groups: placebo (n = 15), 0.5 mg (n = 16), and 3.0 mg (n = 13). Revell V L et al. JCEM 2006;91: by Endocrine Society

31 Wikipedia Phase Response Curves

32 Clinical Application Modulating the Biological Clock Can help treat: Jet Lag Phase Delay / Insomnia Shift work! Some Dementia Symptoms Non-24

33 Circadian Rhythm Disturbances Extrinsic Jet Lag Shift work Advanced Sleep Phase Delayed Sleep phase Intrinsic Non-24 Irregular Sleep- Wake rhythm. Advanced Sleep Phase Delayed Sleep phase

34 Overall activity rhythm : Morning or evening bright light increases strength of rhythm Days 6-10 vs. baseline: Before Light During Light Nursing Home Residents Ancoli-Israel, 2002;2003

35 Effect of light plus melatonin on daytime activity Dementia Patients, Dowling GA, JAGS 56(2)239-46, 2008

36 Jet Lag Temporary desynchronization between internal circadian rhythms and external time cues Symptoms Malaise Insomnia / hypersomnia Fatigue Poor performance

37 Sleep Academic Award 37

38 Traveling East Start 3 5 days before you leave Take Melatonin 0.5 mg approximately 3 5 hours before your bedtime Get up one hour earlier each day Get bright light exposure as soon as you get up On the first day you will get an hour less sleep On the second day begin going to bed a hour earlier Avoid bright light in the evening If necessary can use low dose Provigil mg on arrival Less effective sleeping pills, zaleplon or zolpidem

39 Traveling West Start 3 5 days before you leave Exposure to bright light in the evening Go to bed an hour later each day If possible sleep an hour later each day If needed can use Provigil mg If needed use short acting medication Zaleplon or Zolpidem

40 Insomnia 38 y/o woman with no significant PMH presents with difficulty falling asleep. She typically goes to bed at 10:30 PM. No significant bad habits. She reports it takes her about 2 hours to fall asleep. One to 2 days a week she will wake up in the middle of the night and then take ½ hour to fall back to sleep. She wakes to start her day at 6:00 AM to get her kids ready for school.

41 Insomnia On Friday and Saturday she will go to bed at 12 12:30 AM. She sleeps through the night. Her husband will let her sleep and she gets up at 9 AM. Thoughts?

42 Treatment Delayed her bedtime to 12 MN for one week Wake up time 6 AM during the week and 6:30 AM on the weekends. Avoid bright light during the evening. Melatonin 1 mg before dinner Second week exposure to bright light for 15 min as soon as she woke up Go to bed 30 min earlier the 2 nd and 3 rd week In three weeks follow-up. BT 11PM WT 6AM

43 Conclusion There is a biological clock in almost all animals and in many individual cells In mammals, the biological clock control center is the SCN Proteins are produced and broken down in an elaborate feedback system to produce this rhythmic pattern The biological clock can be moved

44 Conclusion Light exposure is best zeitgeber Melatonin, exercise and social cues can also modulate the clock Modulating the biological clock can help some symptoms of dementia, Jet lag, shift work and insomnia Understanding the biological clock may help treatment of diseases such as stroke, asthma, heart disease

45 Thank You

Index. sleep.theclinics.com. Note: Page numbers of article titles are in boldface type.

Index. sleep.theclinics.com. Note: Page numbers of article titles are in boldface type. Note: Page numbers of article titles are in boldface type. A Accidents, at work, effect of shift work disorder on, 263 264 Acetylcholine, in circadian rhythms, 100 105 Acrophase, definition of, 301 Actigraphy,