Circadian Rhythms

Jess P. Shatkin, MD, MPHVice Chair for EducationNYU Child Study Center

New York University School of Medicine

VISION

SMELL, HEARING,

TOUCH

Learning ObjectivesStudents will be able to: Describe Process S and Process C Identify the site, purpose, and function

of the Circadian Rhythm Define the role of melatonin in wake

and sleep Provide a good argument for delaying

adolescent school start times Describe the major changes in sleep

phases with age

Readings Dement

Chapters 4 – 5 Moorcroft

Chapters 2 – 3

Questions How many of you feel tired right now? Are you usually tired around lunchtime

or a few hours after lunch? When are you at your most sleepy? When are you at your least sleepy? How do you expect to feel around 10

PM? How is it possible that most days you

feel sleepy in the mid-afternoon but then less sleepy in the evening, even though you haven’t slept since yesterday?

Smith, C. S., Reilly, C., & Midkiff, K. (1989)

Lark or Owl?

Factors Affecting Sleep Patterns

Behavior & circumstances Intrinsic Processes

Sleep “pressure” or debt Homeostatic (constant, stable)

Circadian timing system Variable with time of day

These factors change with age Due to biology, work/life demands,

travel, illness, etc.

Payback is a Bitch All wakefulness is sleep deprivation Every moment we are awake we incur

sleep debt (at roughly 1 hour owed back for every 2 hours awake)

Eventually, and in every case, you will sleep to repay your debt

Borbély proposed a “two process model” of sleep/wake propensity

These 2 processes act in opposition to one another to keep us awake and put us to sleep

Process S “S” stands for Sleep Pressure or

Sleep Debt Homeostatic (constant, stable) Sleep propensity increases the

longer you stay awake Sleep propensity decreases with

sleep You can think of Process S as

intensity of sleepiness or a drive to put you to sleep

Process C “C” stands for Circadian A self-sustained biological rhythm

normally synchronized to roughly 24 hours Circa means “approximately,” or “near

to” Dia means “day”

We can assess circadian rhythms by evaluating the timing of daily events

You can think of Process C as intensity of alertness or a drive to keep you awake

CIRCADIAN DRIVE FOR WAKEFULNESS

waking neurobehavioraland physiological

functions

HOMEOSTATIC DRIVE FOR SLEEP

Increased behavioral capability

Reducedbehavioral capability

Wakefulness is Regulated by Two Processes

Two Process Model of Sleep…or the Opponent Process

Model

Factors Affecting Sleep Drive

Sleep Cycles & Two Process Model

Delta power or SWS during NREM can be used to estimate Process S Delta power increases logarithmically as

waking is prolonged Core Body Temperature is often used as

a measure of Process C Sleep propensity is greatest during the

falling limb of the circadian body temp rhythm and decreases on the rising limb

Human & animal studies suggest that Process C regulates arousal and REM but that NREM is more strongly under the control of Process S

Pulling an All Nighter

Subjective Sleepiness

Ratings

Cognitive Performanc

e

Visual Reaction

Time

Core Body Temperatur

e

Neurobehavioral Functions Across

40 Hours of WakefulnessSleepiness, cognitive

errors and slowed reaction times are worse between 6 AM and 10 AM, a few hours after the circadian minimum in core body temperature and 12 hours before the end of the 40-hour vigil. Key point: Even after 40 hours without sleep, these 4 factors still respond in a circadian fashion, relatively unaffected by whether or not you sleep, but entirely driven by time of day.

Van Dongen & Dinges, 2000

Brain AutonomicHormones

Physiology and Behavior

Circadian pacemaker

~24 hour

Light Non-Photic Zeitgebers

Inputs and Outputs of the Circadian System

A biological rhythm that:

exhibits a period of ~24 hours “circa” = approximately

“dies” = day

is endogenously-generated (occurs even in the absence of changes in the environment)

“Zeitgebers” are “time-givers” and remind our bodies of what phase (awake/asleep) we should be at within a given environment.

Definition of a Circadian Rhythm

The Rhythm is the Thing

The daily rhythm (of opening the leaves during the day and closing the leaves at night) persists regardless of light. This process demonstrates an endogenous pattern. First noted by Jean-Jacques d’Ortous de Mairan in 1729.

Importance of the Circadian System

Observed in nearly all species Single cell to humans

Regulates sleep, physiology, and behavior --e.g., is responsible for an increase in

cortisol to prepare for the day; and influences behavior so that we secure a safe place during the dark, conserve energy, avoid predators, etc.

Synchronizes organ systems at an optimal phase relationship

Entrains the organism to the environmental light/dark cycle

Clock Dependent Alerting Opposing homeostatic sleep pressure is the

alerting effect of the biological clock (expressed as circadian rhythm)

The alerting mechanism (Process C) is not constant, in contrast to sleep homeostasis (Process S)

CDA is active in the daytime and inactive at night, with lowered activity in the early afternoon

CDA is much stronger during the evening than the morning (due to the accumulating effects of sleep debt) And once we’ve slept through the night, our sleep

debt is low, so we don’t need our CDA to be as strong

And weaker CDA in the morning allows us to sleep in

Where is the Clock?• Suprachiasmatic nucleus

(SCN)• Located at the optic

chiasm, where the optic nerves cross, within the hypothalamus

• Keeps the body on a roughly 24-hour clock but not perfectly and so still requires environmental cues (zeitgebers) to calibrate daily

Influences on timing of the circadian pacemaker

PhoticNon-Photic Zeitgebers

e.g. exercise, meals

SCN

The period of the circadian pacemaker is not exactly 24 hours; organisms rely on external time

cues to align their circadian system with the environment (entrainment).

Zeitgebers: Time Givers

Increased firing rate during biological day compared to biological night

Circadian Time (hours)

Mul

tiuni

t Act

ivity

[Hz]

Biological Day Biological Night

Neuronal Firing Rate of SCN has Circadian Rhythm

Modified from Meijer et al., Brain Res, 1997

Dale Edgar’s Monkeys

Edgar et al, 1993

The Genetic Feedback Loop

Clock genes are found in many organisms, from bacteria to fruit flies to mammals

The genes are regulated in a cyclical manner in the SCN and peripheral tissue

These genes allow us to entrain to a roughly 24 hour circadian periodicity even in the absence of zeitgebers

CLOCK/BMAL1 genes activate the circadian rhythm by causing PER/CRY genes to produce PER/CRY proteins

PER/CRY proteins slow the circadian rhythm of CLOCK/BMAL1 by a feedback inhibition loop

Nucleus Cytoplasm

E-BoxPer 1

BMAL CLOCK

PERsP

P

CKIe

degradation

Per 2

Per 3Cry 1

Cry 2

CRYs

Genetic Components of Mammalian System

Night

Outputs of the Circadian Timing System

Hastings, British Med J, 1998

Heart (blood circulation)Brown adipose tissue (temperature

regulation)Kidney (electrolyte balance)Liver (glucose metabolism)Pancreas (glucose stability) Adrenal cortex (corticosteroid release)White adipose tissue (leptin release, energy

storage)

SCN Projects to Peripheral Tissues via ANS

Delayed Sleep Phase Syndrome(DSPS)

Normal

Non-24-h Sleep-Wake Syndrome (“Free-running”)

Advanced Sleep Phase Syndrome (ASPS)

Sleep Pattern in Circadian Rhythm Sleep Disorders

Modified from Ebisawa, J Pharmacol Sci, 2007

The Clock is Everywhere

This molecular clock program exists in every cell in the body, where it presumably acts to influence release of hormones, neural activity, etc.

Popliteal light study suggests you can even reset your circadian rhythm by flashing light directly onto skin and avoiding the eyes Light pulse before lowest CBT delayed

rhythm Light pulse after lowest CBT advanced

rhythm Campbell & Murphy, 1998

So Where is Process S? We know the site of Process C Where does sleep drive come from?

Adjusting the Clock Jet lag Shift work Exercise Chronotherapy Melatonin

Melatonin A naturally occurring hormone found

in animals, plants and microbes Synthesized from tryptophan Secreted into the blood by the pineal

gland Also found in high concentrations in bone

marrow, lymphocytes, and epithelial cells (not regulated by the photoperiod in these cells)

Secreted in darkness Inhibits secretion of luteinizing

hormone (LH) and follicle-stimulating hormone (FSH) from anterior pituitary gland

Pineal Gland

Chemical Production of Melatonin

Melatonin (2) Causes drowsiness and lowers core

body temperature Production by the pineal gland is

inhibited by light to the retina and permitted by darkness Blue light (460-480 nm) suppresses

melatonin Wearing glasses that block blue light in the

hours before bedtime may prevent melatonin loss (and help to adjust to an earlier bedtime, e.g., advance the clock)

Also has a role as an antioxidant, interacts with immune system

Melatonin with Age Production of melatonin decreases with

age Adult melatonin production begins

around 6-8 PM and peaks until 4 AM, stopping production around 5 AM

Adolescent melatonin production begins around 11 PM and peaks until 7 AM, stopping around 8 AM Explains the adolescent delayed sleep phase,

relative to adults So waking an adolescent at 7 AM is like

waking an adult at 4 AM Carrell et al, 2011

Melatonin is high during the night and low during the day when under constant dim light conditions.

Pla

sma

mel

aton

in (p

mol

/L)

Hours relative to start of habitual waketime

Example of an Endogenous Circadian Rhythm

Modified from Zeitzer et al., J Clin Endocrinol Metab, 2000

Light During Night Suppresses Melatonin

Redrawn from Czeisler et al., N Engl J Med, 1995

Pla

sma

mel

aton

in (p

mol

/L) 300

200

100

0

Time of Day (hr)12

Exposure tobright light

18 24 6 12 18 24 6 12

Sighted individuals are normally entrained to the light/dark cycle (with a period of 24 hr)

24.0 hr

Normally entrained

Circles indicate dim light melatonin onset

Circadian Entrainment in Sighted Humans

Modified from Sack et al., N Engl J Med, 2000

Day

s of

Sam

plin

g

Time of Day (hrs)

Circadian Entrainment in Blind Humans

Redrawn from Sack et al., N Engl J Med, 2000

Subject

Blind subjects without circadian photo-reception

are often not entrained to the light-dark cycle

Shapes indicate dim light melatonin onset

Melatonin can be administered to entrain blind subjects who are not normally

entrained to the light-dark cycle

Melatonin trialPlacebo trial

Entrainment by Melatonin in the Blind

Modified from Sack et al., N Engl J Med, 2000

What have you done, Thomas Edison?!

A Marker for the End of Adolescence?

Roenneberg et al., Curr Biol, 2004

We’re not the only ones…

Monday Night Football 25-year retrospective study of NFL

(MNF) of West Coast (WC) vs. East Coast (EC) teams

MNF begins at 9 PM ECT (6 PM WCT) WC teams closer to peak athletic

performance EC teams closer to nadir of performance

WC teams won 63.5% (EC 36.5%), p<0.01 WC teams win by 14.7 points/game (ave) EC teams win by 9 points/game (ave)

WC teams performed significantly better than predicted by Las Vegas point spread (;<0.01)

Smith et al, 1997

• WC teams won 63.5% of MNF games

• EC teams won 36.5% of MNF games

• WC teams won 59.3% of home games and 71% of MNF home games

• EC teams won 56.5% of home games but only 43.8% of MNF home games

• When EC teams play a team other than a WC team on MNF, their winning percentage increases by 23.7% to 67.5%

• Likewise, when WC teams play a team other than an EC team on MNF, their winning percentage decreases by 12.9% to 58.1%

Sports, Sleep, & Circadian Rhythms

The Circadian Advantage The same effect has been observed

in figure skating, rowing, golfing, baseball, swimming and diving

Runners, weightlifters, and swimmers are more likely to break world records when competing during the second burst of Process C

Randall, 2012

Implications for You? When should you take classes? When should you study? When should you take an exam? When should you have important

conversations, give important talks, perform for others, etc?

When should you do your laundry?

Jet Lag

Core Body Temperature There is a small window related to the

endogenous body temperature rhythm (as it approaches its daily minimum) during which time we may fall asleep and maintain sleep throughout the night

Misaligning CBT minimum with the light/dark cycle is a major target for jet lag desynchrony

Vosko et al, 2012

CBT and Melatonin Melatonin is thought to adjust the CBT set-

point, thus allowing more blood flow to distal areas of the body and cooling of the core We “chill out” when our core cools Chilling out is relaxing and sleep promoting The words we use to describe relaxation clearly

recognize this fact: “chill out,” “cool down,” “cool your jets,” etc. (as do those to describe someone who is upset: “hot head,” “hot under the collar,” “steamed,” etc.)

Thermosensitive neurons in the distal body then send temperature info back to the preoptic anterior hypothalamus, which contains sleep active neurons that send inhibitory projections to arousal-promoting circuits in the brain (Vosko et al, 2012)

Effects of Jet Lag Generally transient and include:

Difficulty sleeping Excessive daytime sleepiness General malaise Impaired performance Gastrointestinal upset

Usually influenced by direction of travel: Slower adaptation when traveling east Increases with the number of time zones

crossed

Eastward Travel The sleep cycle is shifted ahead (e.g., it’s

earlier where you arrive) or advanced Usually people sleep well the first night in

the new locale (especially if they stay awake the day of arrival and sleep at the new locale’s usual bedtime) Probably due to Process S and a large sleep

debt that accumulates, despite a misaligned Process C

Marked increase in Stage 2 sleep on first night in new time zone; compensatory increase in REM several nights later

By the second night, however, Process S is less influential because much of the excess sleep debt has been repaid

Westward Travel Changes in sleep quality after a phase

delaying westward flight lasts fewer days for most people

Westward travelers show an increase in slow wave activity on the first night in the new time zone (showing an increase in sleep pressure, like eastward travellers) This makes sense because most westward

travellers stay awake during the flight and then stay awake until the usual new destination bedtime, so they’ve accumulated more sleep pressure

Over the next few days, people often fall asleep easily but have late insomnia (early awakening) due to the alerting effects of Process C

East vs. West In general, following phase changing

travel, there is little trouble falling asleep the first night upon arrival because of an increase in sleep pressure (process S)

East Usually people have more difficulty

initiating sleep following eastward travel (a few days to a week) because they’ve been advanced

West More difficulty maintaining sleep later

into the night because they’ve been delayed (but restored within a few days)

Eastward Phase Advance

--melatonin at night--sunglasses at

night--bright light in AM

Westward Phase Delay

--bright light at night

--melatonin in AM--sunglasses in AM

Advance and Delay

Light Exposure & Jet LagLight exposure during the

traveler’s biological night (as would happen upon arrival in the

new time zone) would cause a westward phase delay (opposite to

what is needed for eastward travel). So, the eastward traveler should avoid bright light and/or wear sunglasses until after the

habitual time of awakening in the home time zone; then the traveler

should exposure him/herself to bright light. Each day the time of

exposure to bright light can be advanced by 1-2 hours.

When traveling west, the traveler should remain awake during the

trip (using caffeine and naps strategically). Exposure to bright

light should occur during the entire trip and until just before bedtime in the new time zone.

REM Changes with Jet Lag REM increases the night following a phase

advance (e.g., 8-hour change from Los Angeles to London), resulting in a decreased REM latency This is likely due to REM rebound (due to a loss

of REM during the schedule shift or a shift of REM timing in relation to the new sleep time)

Melatonin taken in the early evening advances the clock (as does early morning light exposure)

Whereas traveling east results in a decrease in REM latency (earlier & more REM), traveling west results in an increased REM latency (later & less REM) Jet lag is associated with an increase in sleep

paralysis, brought on by an increase in REM density

The Sleep Cycle in Jet Lag

Jet lag induces an initial increase in NREM, due to Process S, independent of Process C

The increase in NREM suppresses REM initially but eventually triggers a compensatory REM rebound; during rebound REM increases and so does sleep paralysis

Of note, seizures (more prevalent during NREM) also increase following transmeridian travel

Fixing Jet Lag 1. Short trips

One possibility is to keep to your usual schedule, in your home time zone

Or you can take sleeping pills for a few nights to put you on the new schedule

And/or you can use wake promoting agents, like modafinil and stimulants, to promote awakening in the new environment

Fixing Jet Lag (2) 2. Long Trips

Begin a few days prior to travel by timing bright light exposure progressively later in the day (for a westbound trip to delay cycle) or earlier in the morning (for an eastbound trip to advance cycle)

Light boxes can be used (containing light with wavelengths in the blue range)

Give melatonin in the early evening to phase advance the clock or in the morning to delay the clock

Doses of melatonin should be “circadian,” not pharmacologic (e.g., 100 mcg every hour for 3-4 hours, not 3-10 mg in a bolus dose as for insomnia)

Light & Melatonin AM

Light advances the clock Melatonin delays the clock

PM Light delays the clock Melatonin advances the clock

Travel Advice When going east, use low dose melatonin

in the early evening and avoid light at night to make yourself sleepy (starting night #2); expose yourself to sunlight or bright light in the morning (after habitual wake time in prior zone) 100 – 300 mcg every hour from 8 PM – 12 AM Bolus dose of melatonin if needed at bedtime

When going west, use low dose melatonin in the morning (if needed) and avoid light in the early morning to keep yourself asleep; expose yourself to light at night to keep yourself awake (if necessary)

More Advice Your clock can adjust naturally about

an hour a day – but you can push it by an extra hour to adjust about 2 hours per day

Simply change the time you exposure yourself to light and darkness by 2 hours each day, from the time zone you’ve been in to the time zone you’re now at

Examples…

Exercise Exercise may also contribute to

recovery from jet lag The timing is key and probably

approximates what we do with melatonin

Generally, it’s thought that exercise in the morning leads to phase delay and exercise in the evening phase advances

However, one study has shown the opposite, which is also my personal experience (van Reeth et al, 1994)

Jess Lag Statistically, I’m atypical, but here’s what

works for me:1. Going east, take a night flight and sleep as

much as possible (take a sleeping pill if I can)1. Arrive in the morning and stay awake all day

the following day; use sleep pressure (Process S) to your advantage, and sleep up to 12 hours that night

2. Day 2 is a bit more difficult, but if I stay on the new country’s schedule, I’m usually fine by day 3. No more than one alcoholic drink before bed until adjusted.

3. Caffeine upon awakening.

Jess Lag (2)

1. Going west, I have much more trouble if it’s more than 3 time zones due to early morning awakening

1. Wear sunglasses once it gets dark in the time zone from which you’ve just arrived (delayed by two hours each day)

2. Take melatonin with middle of night awakening3. Avoid early morning sunlight4. Caffeine upon awakening

Damn Those Kentucky Drivers

Nearly 10,000 students in one Kentucky County, grades 6 – 12, provided self-report on sleep habits (bed and awake times), naps, daytime functioning, and difficulty staying awake in 1998 & 1999.

During Year I, schools started at the usual time (7:30 AM for high school & 8 AM for middle school)

During Year II, schools started one hour later (8:30 AM for high school & 9 AM for middle school)

Auto accidents dropped by 16.5% in Year II Teen auto accidents increased by 8% in Year II

throughout the rest of the state Danner & Phillips, 2008

Later Start Times = More Sleep

More Sleep = Fewer Crashes

County vs. State

Land of 10,000 Lakes Edina and Minneapolis changed their school

start times from: 7:15 AM to 8:40 AM (Minneapolis) 7:25 AM to 8:30 AM (Edina)

Students tend to keep the same bedtime when start time is delayed, so kids do, in fact, get more sleep (by 1 hour in this study) when school start time is delayed

Findings included: Less EDS, less sleepy during homework, less tardiness, & better attendance

Top 10% of students increased SAT scores from 1288/1600 to 1500/1600

Wahlstrom, 2002

From Zs to As Most studies are correlational Compared to summer months (when adolescents

presumably obtain their optimal amount of sleep), students lose as much as 120 minutes of sleep per school night (Hansen et al, 2005)

IQ test scores are lower during early morning hours (Goldstein et al, 2007)

US Air Force Academy study examined 6165 college freshmen from 2004 – 2008 They found that when a student was randomly assigned

to a 7 AM or 7:30 AM starting course time (versus 8 AM) that they did worse not only in the first period course but in all courses throughout the day

Carrell et al, 2011

Grade Distribution by Start Time

The circadian clock naturally advances with age Older adults may get sleepy earlier in the

evening and awaken earlier in the morning than younger adults.

Disturbed sleep in the older adult may be associated with Decreased quality of life Poor mood Decreased alertness Difficulty with concentration Attention and memory Reduced vigilance

The Aging Clock

Ancoli-Israel and Cooke, J Am Geriatr Soc, 2005

It is unclear if the need to sleep decreases with age

However, the ability to sleep does decrease with age Changes in the rhythm and consolidation

of sleep Influence of medical and psychiatric

illness Influence of medications on sleep Presence of specific sleep disorders.

Need to Sleep vs. Ability to Sleep

Ancoli-Israel and Cooke, J Am Geriatr Soc, 2005

Recording Time (%)

0

5

10

15

20

25

16-25 26-35 36-50 51-60 61-70 71-83Age

Slow Wave Sleep

Modified from Van Cauter et al., JAMA, 2000

Age Group (years)

Perc

ent

Large-scale community survey of non-institutionalized American adults, aged 18 to 79 years

Insomnia Increases with Age

Modified from Mellinger, et al., 1985;Foley, et al., 1995

(n=9282)

Perc

ent

Complaints of Insomnia Increase with Age

Modified from Foley et al., Sleep, 1995

(n=9282; mean age 74 years)

trouble falling asleep

General Sleep Complaints Increase

Modified from Foley et al., Sleep, 1995

Sleepy Go to

bed

Wake up

Wake up

Sleepy–Go to bed

18.00

21.00

24.00

3.00 6.00 9.00 12.00

Advanced phase

Standard phase

Time of Day

Advanced Sleep Phase

Modified from Ancoli-Israel,All I Want is a Good Night’s Sleep, 1996

Difficulty sustaining attention Slowed response time Difficulty with memory Decreased performance May all be misinterpreted as

dementia

Consequences of Disturbed Sleep among Elderly

Ancoli-Israel and Roth, Sleep, 1999Ancoli-Israel, Sleep, 2000