Circadian Rhythms

Jess P. Shatkin, MD, MPH

Vice Chair for Education
NYU Child Study Center
New York University School of Medicine

VISION

SMELL,
HEARING,
TOUCH

Learning Objectives
Students 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
havent slept since yesterday?

Lark or Owl?

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

Factors Affecting Sleep Patterns

Behavior & circumstances

Intrinsic Processes

Sleep pressure or debt

Circadian timing system

Homeostatic (constant, stable)

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
Borbly 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

Wakefulness is Regulated by Two Processes

HOMEOSTATIC DRIVE FOR SLEEP
Increased behavioral
capability

Reduced
behavioral capability

waking
neurobehavioral
and physiological
functions

CIRCADIAN DRIVE FOR WAKEFULNESS

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

Core Body Temperature is often used as a

measure of Process C

Delta power increases logarithmically as waking is

prolonged

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

Neurobehavioral
Functions Across 40
Hours of Wakefulness
Sleepiness, 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

Subjective
Sleepiness
Ratings

Cognitive
Performance

Visual
Reaction Time

Core Body
Temperature

Inputs and Outputs of the Circadian System

Non-Photic Zeitgebers

Light
Circadian
pacemaker

Brain

Hormones

~24 hour

Physiology and Behavior

Autonomic

Definition of a Circadian Rhythm

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.

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
dOrtous de Mairan in 1729.

Importance of the Circadian System

Observed in nearly all species

Regulates sleep, physiology, and behavior

Single cell to humans

--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 weve slept through the night, our sleep debt is
low, so we dont 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

Zeitgebers: Time Givers

Influences on timing of the circadian
pacemaker
Non-Photic Zeitgebers
e.g. exercise, meals

Photic

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).

Neuronal Firing Rate of SCN has Circadian Rhythm

Multiunit Activity [Hz]

Increased firing rate during biological

day compared to biological night

Biological Day

Biological Night

Circadian Time (hours)

Modified from Meijer et al., Brain Res, 1997

Dale Edgars 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

Genetic Components of Mammalian System

Nucleus

Cytoplasm

degradation

BMAL CLOCK
Per 1
E-Box

PERs

Per 2
Per 3

CKI
Cry 1
Cry 2

CRYs

Outputs of the Circadian Timing System

Night
Hastings, British Med J, 1998

SCN Projects to Peripheral Tissues via ANS

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)

Sleep Pattern in Circadian Rhythm Sleep Disorders

Normal
Delayed Sleep Phase Syndrome
(DSPS)
Advanced Sleep Phase Syndrome
(ASPS)
Non-24-h Sleep-Wake Syndrome
(Free-running)

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

Plasma melatonin (pmol/L)

Example of an Endogenous Circadian Rhythm

Hours relative to start of habitual waketime

Melatonin is high during the night and low during the day
when under constant dim light conditions.
Modified from Zeitzer et al., J Clin Endocrinol Metab, 2000

Light During Night Suppresses Melatonin

Plasma melatonin (pmol/L)

Exposure to
bright light
300

200

100

0
12

18

24

12

18

24

12

Time of Day (hr)

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

Circadian Entrainment in Sighted Humans

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

Days of Sampling

Normally entrained
Circles indicate dim
light melatonin onset

24.0 hr

Time of Day (hrs)

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

Circadian Entrainment in Blind Humans

Blind subjects without circadian photo-reception
are often not entrained to the light-dark cycle
0

Shapes indicate dim light

melatonin onset

Subject
1
2
3
4
5
6
7

10

20

Day of Sampling

30

40
0

10

20

30

40

Hour

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

Entrainment by Melatonin in the Blind

Melatonin can be administered to entrain blind

subjects who are not normally entrained to the lightdark cycle
Placebo trial

Melatonin trial

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

Were 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

Sports, Sleep, & Circadian Rhythms

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%

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., its 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 locales 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 theyve
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 theyve been advanced

West

More difficulty maintaining sleep later into the

night because theyve been delayed (but restored
within a few days)

Advance and Delay

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

Light Exposure & Jet Lag

Light exposure during the travelers
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 youve been
in to the time zone youre 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, its 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, Im atypical, but heres 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.

2.

3.

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
Day 2 is a bit more difficult, but if I stay on the new
countrys schedule, Im usually fine by day 3. No more
than one alcoholic drink before bed until adjusted.
Caffeine upon awakening.

Jess Lag (2)

1.

Going west, I have much more trouble if its more

than 3 time zones due to early morning awakening
1.

2.
3.
4.

Wear sunglasses once it gets dark in the time zone from

which youve just arrived (delayed by two hours each
day)
Take melatonin with middle of night awakening
Avoid early morning sunlight
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 Aging Clock

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

Need to Sleep vs. Ability to Sleep

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.

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

Slow Wave Sleep

25
20

15

Recording
Time (%)

10
5

0
16-25

26-35

36-50

51-60

61-70

71-83

Age
Modified from Van Cauter et al., JAMA, 2000

Insomnia Increases with Age

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

30

Percent

25

25

20

20

15
10

14

15

18-34

35-49

5
0
50-64

65-79

Age Group (years)

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

Complaints of Insomnia Increase with Age

60

Percent

50

(n=9282)

57

40
30
20
10

12

0
Chronic Insomnia

NoSleepComplaints

Modified from Foley et al., Sleep, 1995

General Sleep Complaints Increase

(n=9282; mean age 74 years)
13

waking not rested

waking too early

19

trouble falling asleep

19
25

daytime napping

29

insomnia

30

nocturnal waking

43

Initiating/maintaining

10

20

30

40

50

Percent
Modified from Foley et al., Sleep, 1995

Advanced Sleep Phase

Standard phase

Sleepy

18.00

21.00

Sleepy
Go to bed

Go to
bed

24.00

Wake
up

Wake
Advanced phase
up

3.00

6.00

9.00

12.00

Time of Day

Modified from Ancoli-Israel,

All I Want is a Good Nights Sleep, 1996

Consequences of Disturbed Sleep among Elderly

Difficulty sustaining attention

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

Ancoli-Israel and Roth, Sleep, 1999

Ancoli-Israel, Sleep, 2000