GOOD AFTERNOON.
I'M DR. SHILPY DIXIT, PROGRAM
DIRECTOR AT THE NATIONAL CENTER
ON SLEEP DISORDERS RESEARCH, AND
I WANT TO THANK YOU FOR JOINING
US AT THE ANNUAL SLEEP
101 SYMPOSIUM.
THE SLEEP 101 SYMPOSIUM IS A
JOINT EFFORT OF THE AMERICAN
ACADEMY OF SLEEP MEDICINE.
THE SLEEP RESEARCH SOCIETY, AND
THE NATIONAL HEART, LUNG AND
BLOOD INSTITUTE AT THE NATIONAL
INSTITUTES OF HEALTH.
THIS SYMPOSIUM IS DEDICATED TO
HIGHLIGHTING THE LATEST ADVANCES
AND EMERGING OPPORTUNITIES IN
SLEEP AND SIR Q AND CIRCADIAN SS
WELL AS FEDERAL RESEARCH FUNDING
REPRESENTATIVES TO ENGAGE IN
CUTTING EDGE RESEARCH AND
INNOVATIVE APPLICATIONS.
TODAY, WE WILL HEAR FROM EXPERTS
ON CIRCADIAN BIOLOGY, CIRCADIAN
MEDICINE, AND CHRONOMEDICINE,
WHO WILL ADDRESS THE SIGNIFICANT
GAP WITH IT BETWEEN ADVANCING --
AND ITS CURRENT APPLICATION IN
CLINICAL SETTINGS.
ALTHOUGH RESEARCH HAS
ILLUMINATED THE CRITICAL ROLE OF
CIRCADIAN RHODE ISLAND RHYTHMSD
DISEASE, THIS KNOWLEDGE HAS YET
TO BE FULLY HARNESSED TO ENHANCE
PATIENT CARE AND PUBLIC HEALTH.
ATTENDEES WILL GAIN VALUABLE
INSIGHTS INTO HOW THESE
ADVANCEMENTS ARE RESHAPING BOTH
RESEARCH AND CLINICAL PRACTICE,
OFFERING NEW AVENUES TO IMPROVE
OUTCOMES THROUGH THE INTEGRATION
OF CIRCADIAN PRINCIPLES.
THIS WEBINAR AIMS TO BRIDGE THE
GAP BETWEEN WHAT IS KNOWN AND
WHAT CAN BE ACHIEVED BY
EXPLORING THE LATEST RESEARCH IN
IDENTIFYING NEW OPPORTUNITIES,
AND ENCOURAGES RESEARCHERS AND
CLINICIANS TO INCORPORATE
CIRCADIAN PRINCIPLES INTO THEIR
WORK TO OPTIMIZE HEALTH
OUTCOMES.
NOW BEFORE I INTRODUCE THE
SPEAKERS, I'D LIKE TO REMIND YOU
THAT YOUR AUDIO IS MUTED, AND
YOUR VIDEO IS TURNED OFF TO
MINIMIZE INTERRUPTIONS.
WE ENCOURAGE YOU TO INCLUDE ANY
QUESTIONS ON THIS TOPIC FOR ANY
OF OUR PANELISTS IN THE Q & A ON
THE ZOOM PLATFORM.
WE WILL HAVE DEVOTED Q & A
DURING THE LAST HALF-HOUR OF THE
SYMPOSIUM, AND LOOK FORWARD TO
YOUR THOUGHTFUL QUESTIONS.
NOW ALLOW ME TO INTRODUCE OUR
SPEAKERS TODAY.
DR. MATTHEW BUTLER IS AN
ASSOCIATE PROFESSOR AT THE
OREGON INSTITUTE OF OCCUPATIONAL
HEALTH SCIENCES AND THE
DEPARTMENT OF BEHAVIORAL
NEUROSCIENCE AT OREGON HEALTH
AND SCIENCE UNIVERSITY.
HIS RESEARCH EXPLORES THE ROLE
OF CIRCADIAN RHYTHMS IN HEALTH
AND DISEASE.
FOCUSING ON THE CUES THAT
SYNCHRONIZE BIOLOGICAL CLOCKS
AND THEIR RELEVANCE TO TREATMENT
STRATEGIES.
HIS WORK SPANS ANIMAL MODELS AND
COLLABORATIVE HUMAN STUDIES,
EMPHASIZING THE EFFECTS OF
ENVIRONMENTAL, NUTRITIONAL, AND
BEHAVIORAL CUES ON
CARDIOMETABOLIC HEALTH.
DR. SABRA ABBOTT IS ASSOCIATE
PROFESSOR OF NEUROLOGY AT THE
NOWRT WESNORTHWESTERN UNIVERSITG
SCHOOL OF MEDICINE, PROGRAM
DIRECTOR FOR THE SLEEP MEDICINE
FELLOWSHIP AND DIRECTOR OF THE
NORTHWESTERN CIRCADIAN MEDICINE
CLINIC.
HER RESEARCH AND CLINICAL
INTERESTS FOCUS ON THE
PATHOPHYSIOLOGY AND TREATMENT OF
CIRCADIAN RHYTHM SLEEP-WAKE
DISORDERS.
DR. NOUR MAKAREM IS AN ASSISTANT
PROFESSOR OF EPIDEMIOLOGY AT
COLUMBIA UNIVERSITY'S SCHOOL OF
PUBLIC HEALTH.
HER RESEARCH FOCUSES ON THE
CARDIOVASCULAR DISEASE
PREVENTION AND PROMOTING HEALTH
EQUITY.
PARTICULARLY THE ROLE OF SLEEP
AND CIRCADIAN HEALTH.
SHE CONDUCTS POPULATION-BASED
STUDIES AND CLINICAL TRIALS
FUNDED BY THE NIH AND THE
AMERICAN HEART ASSOCIATION AIMED
AT IMPROVING CARDIOVASCULAR
HEALTH THROUGH MULTILEVEL
INTERVENTIONS.
WE'LL KICK OFF OUR PRESENTATIONS
WITH AN OVERVIEW ON CIRCADIAN
BIOLOGY BY DR. BUTLER.
>> OKAY.
THANK YOU VERY MUCH FOR THAT
INTRODUCTION.
IT'S MY GREAT PLEASURE TO
INTRODUCE THIS SYMPOSIUM WITH A
BASIC BACKGROUND ON CIRCADIAN
CLOCKS TO HELP US BASICALLY
UNDERSTAND THE INTERACTION OF
CLOCKS WITH HEALTH AND DISEASE
AT A NUMBER OF DIFFERENT LEVELS.
I DO NOT HAVE ANY CONFLICTS OF
INTEREST TO DISCLOSE.
AND IN TERMS OF LEARNING
OBJECTIVES, THIS FIRST ONE IS
THE MOST IMPORTANT.
I WANT TO SORT OF GO OVER SOME
OF THE FUNDAMENTAL PROPERTIES OF
CLOCKS IN TERMS OF THEIR PERIOD
AND PHASE, AND I'LL HIGHLIGHT
THAT BECAUSE I THINK THAT SOME
OF THE MAJOR FUTURE
OPPORTUNITIES STILL REVOLVE
AROUND THESE AND UNDERSTANDING
HOW THESE WORK IN THE CONTEXT OF
A NETWORK OF CLOCKS THAT ARE
WORKING.
I'LL BRIEFLY TALK ABOUT THE
DIFFERENCE BETWEEN ENDOGENOUS
RHYTHMS AND THOSE THAT ARE
DRIVEN.
DESCRIBE HOW CLOCKS ARE
DISTRIBUTED THROUGHOUT THE BODY,
NOT JUST IN THE BRAIN.
I'LL TOUCH ON EATING TIME AS A
REALLY IMPORTANT MODULATOR OF
HEALTH.
AND THEN FINALLY, I JUST WANT
EVERYBODY TO HAVE AN
APPRECIATION OF THE FACT THAT
BIOLOGICAL RHYTHMS ARE REALLY
DIVERSE.
THEY ARE PHYLOGENETICALLY
DIVERSE, PHYSIOLOGICALLY DIVERSE
AND MOLECULARLY DIVERSE, LEADING
TO, I THINK, A LOT OF
COMPLICATION BUT A LOT OF
INTEREST.
SO I'LL START WITH THE
PHYLOGENY.
CLOCKS HAVE EVOLVED MULTIPLE
TIMES, STRONGLY SUGGESTING THE
CRITICAL ROLE IN FITNESS.
WHAT'S INTERESTING ABOUT IT IS
THAT DIFFERENT BRANCHES OF LIFE,
HOWEVER, HAVE EVOLVED DIFFERENT
CLOCK MECHANISMS.
THE ONE THAT WE HAVE IN OUR
BODIES IS BASED ON THE PER
OSCILLATOR, AND IT'S CONSERVED
BETWEEN INSECTS AND MAMMALS.
WHEN WE TALK ABOUT RHYTHMS, THIS
IS A NICE CARTOON TO GET US
GOING.
WE HAVE AN INDIVIDUAL WHO'S
SLEEPING, HE WAKES UP, HE GOES
TO WORK DURING THE DAY, HE GOES
TO SLEEP AT NIGHT.
AND IN THE BACKGROUND OF THIS,
THERE ARE A WHOLE SET OF
PHYSIOLOGICAL RHYTHMS THAT ARE
ONGOING.
THERE'S A RHYTHM OF GROWTH
HORMONE THAT PEAKS WHEN THE
PERSON IS ASLEEP.
TEMPERATURE IS HIGH DURING THE
DAY AND LOW DURING THE NIGHT.
PLASMA CORTISOL PEAKS DURING THE
WAKEUP TIME.
AND WHAT'S IMPORTANT TO NOTE
HERE IS THAT ALMOST ANYTHING YOU
CAN MEASURE IN THE HUMAN BODY
EXHIBITS SOME TYPE OF DAILY
RHYTHM, BUT THEY DON'T ALL HAVE
PEAKS AT THE SAME TIME.
SO WE HAVE DIFFERENT RHYTHMS
THAT HAVE DIFFERENT NAIZ PHASES,
THEIR PEAK TIME, THAT ARE
DISTRIBUTED ACROSS THE DAY.
UNFORTUNATELY, THIS LITTLE
CARTOON VERSION OF CIRCADIAN
RHYTHMS IS PROBABLY NOT VERY
WELL REPRESENTATIVE OF REALITY,
AND OUR OWN EXPERIENCE IS MUCH
MORE LIKE THIS.
SO CLOCKS ARE DISRUPTED BY A
MULTITUDE OF DIFFERENT
ENVIRONMENTAL FACTORS.
THEY CAN INCLUDE SHIFT WORK AND
JET LAG, MORE RECENTLY WE'RE
RECOGNIZING THE IMPORTANCE OF
SOCIAL JET LAG, WHICH IS THE
DIFFERENCE IN SLEEP TIME BETWEEN
WEEKENDS AND WEEKDAYS, BUT
NIGHTTIME EATING CAN DISRUPT
CLOCK, EVENINGITE WHEN EVENING E
ALL AT OUR SCREENS CAN
PATHOLOGICALLY PUSH CLOCKS ONE
WAY OR ANOTHER.
AND CLOCK DISRUPTION IN SHIFT
WORK HAVE BEEN ASSOCIATED WITH
INCREASED RISK FOR A WHOLE HOST
OF DIFFERENT CHRONIC CONDITIONS.
THAT'S NOT AN EXHAUSTIVE LIST ON
THE RIGHT, BUT OBESITY,
DIABETES, HEART DISEASE, CANCER,
INFERTILITY I INCLUDE HERE
BECAUSE I'LL BE TOUCHING ON THAT
IN A LITTLE BIT.
SO CLOCKS ARE OFTEN MEASURED BY
LOOKING AT SOMETHING THAT WE CAN
OBJECTIVELY MEASURE IN THE
LABORATORY.
IN THIS PARTICULAR CASE, THIS
DIAGRAM ON THE LEFT IS JUST
SHOWING A SCHEMATIC OF A MOUSE'S
ACTIVITY PATTERNS.
SO THE MOUSE IS INACTIVE DURING
THE DAY TIME BECAUSE IT'S
NOCTURNAL, AND THIS BLACK BAR
SHOWS THAT THE ANIMAL IS ACTIVE
DURING THE NIGHT.
AND IN A LIGHT-DARK CYCLE, THIS
ANIMAL IS STRICTLY NOCTURNAL.
IT ALWAYS BEGINS RUNNING AT THE
SAME TIME EVERY DAY, IT STOPS
RUNNING AT THE SAME TIME EVERY
DAY, AND WE CALL THIS ENTRAINED
OR SYNCHRONIZED.
TO DETERMINE WHETHER OR NOT THIS
IS ACTUALLY A TRUE RHYTHM, WE
RELEASE THE ANIMALS INTO
CONSTANT CONDITIONS.
SO IN CONSTANT DARKNESS, YOU CAN
ACTUALLY SEE THIS RHYTHM REMAINS
ROBUST.
HOWEVER, IT'S NO LONGER
SYNCHRONIZED TO THE LIGHT-DARK
CYCLE.
INSTEAD, THIS ANIMAL IS WAKING
UP AND RUNNING IN HIS WHEEL
ABOUT 30 MINUTES EARLIER EACH
DAY.
SO THIS IS A FREE-RUNNING
RHYTHM.
SO IT'S NOT SYNCHRONIZED TO
ANYTHING.
IT'S NOT EXACTLY 24 HOURS.
THEY'RE USUALLY CLOSE TO BUT NOT
EXACTLY 24.
SO THE TWO FUNDAMENTAL FEATURES
OF CLOCKS, THERE ARE A COUPLE OF
OTHERS THAT ARE IMPORTANT, BUT
FIRST IS THAT THEY ARE
AUTONOMOUS, MEANING THAT THEY
FREE-RUN IN CONSTANT CONDITIONS,
AND WE CAN MEASURE THE PERIOD OF
THAT RHYTHM.
THE NEXT IS THAT THEY ARE
ENTRAINABLE, THAT THEY
SYNCHRONIZE TO PERIODIC CUES.
IN THIS PARTICULAR CASE, THE CUE
IS A LIGHT-DARK CYCLE, AND WE
CAN DEFINE A PHASE OF THE
RHYTHM, IN THIS CASE, THE PHASE
COULD BE ACTIVITY ONSET WHEN WE
SAY THE PHASE OF ACTIVITY ONSET
IS AT THE LIGHT-DARK TRANSITION.
SO AUTONOMOUS CLOCKS THAT ARE
ENTRAINABLE, THIS IS THE KEY --
THESE ARE THE KEY FEATURES OF
ENDOGENOUS BIOLOGICAL CLOCKS
SO I'VE MENTIONED BEFORE THAT
ALMOST EVERYTHING YOU CAN
MEASURE IS INDEED RHYTHMIC, BUT
THERE ARE TONS OF RHYTHMS THAT
ARE NOT ENDOGENOUS AND THAT ARE
INSTEAD DRIVEN.
THIS IS AN EXAMPLE OF AIR
TRAFFIC, AND IT'S A LITTLE BIT
DIFFICULT TO SEE, BUT THIS
PORTION HERE THAT'S IN SHADOW IS
THE NIGHTTIME.
THIS IS THE DAY TIME OVER HERE.
IF YOU LOOK AT EUROPE, THERE'S
NOT A LOT OF YELLOW DOTS.
THESE ARE ALL THE PLANES THAT
ARE IN THE AIR.
WHEN I START THE VIDEO, YOU'RE
GOING TO SEE DAWN MOVING THIS
DIRECTION, AND YOU'LL START
SEEING A WHOLE BUNCH OF PLANES
TAKE OFF.
IN FACT, HERE YOU CAN ALREADY
SEE THIS LINE OF PLANES THAT
HAVE TAKEN OFF IN THE EVENING
THAT ARE HEADED TOWARDS EUROPE.
SO LET'S DO THIS.
I NEED TO TAKE OFF THE LASER
POINTER.
SO YOU CAN SEE AS DAWN MOVES
ACROSS, YOU CAN SEE A DRAMATIC
CHANGE IN THE NUMBER OF PLANES
THAT ARE FLYING.
NOT VERY MANY DURING THE NIGHT,
PLENTY DURING THE DAY.
BUT A PLANE CLEARLY DOES NOT
HAVE AN ENDOGENOUS CLOCK ON
BOARD.
THIS IS CLEARLY JUST A DRIVEN
RHYTHM.
THIS IS REFLECTING OUR OWN WANTS
AND NEEDS, AND SO WE WOULDN'T
CALL IT A BIOLOGICAL RHYTHM EVEN
THOUGH IT'S AN IMPORTANT RHYTHM.
IN TERMS OF ANIMALS, AND IN
TERMS OF BIOLOGICAL RHYTHMS THAT
WE CAN MEASURE IN THE
LABORATORY, WE TALK ABOUT
SOMETHING CALLED MASKING.
SO IN THAT LAST ONE, THAT WAS
SORT OF MASKING BY LIGHT ON THE
FLIGHTS OF PLANES.
WE CAN ALSO SEE THAT IN ANIMALS
AS WELL.
SO THIS IS A CRY 1 KNOCKOUT
MOUSE, SO THE DASH DASH MEANS IT
BEEN KNOCKED OUT, 1 AND 2.
SO I HAVE THE BOTTOM PANELS
COVERED UP, BUT IF YOU JUST LOOK
AT THE TOP, YOU CAN SEE THAT
THIS ANIMAL'S ACTIVITY, THESE
LITTLE BLACK HASH MARKS ARE WHEN
THE ANIMAL IS RUNNING IN THE
WHEEL, YOU CAN SEE THEY ALL LOOK
ROUGHLY SIMILAR WITH THE
ACTIVITY RESTRICTED TO THE
NIGHTTIME.
SO THEY ALL LOOK ROBUSTLY
RHYTHMIC.
IF WE LOOK AT THE WILD TYPE
MOUSE, THIS IS JUST A REGULAR
OLD MOUSE, YOU CAN SEE THAT THIS
RHYTHM REMAINS IN CONSTANT
CONDITIONS.
IT'S DRIFTING VERY SLIGHTLY TO
THE LEFT, SO THE ANIMAL IS
WAKING UP SLIGHTLY EARLIER EACH
DAY, SO THE PERIOD IS SLIGHTLY
LESS THAN 24 HOURS.
THE KNOCKOUT OF THIS CLOCK GENE,
SO IF YOU LOSE THE CRY 1 GENE,
YOU ACTUALLY HAVE A FASTER
CLOCK, MOVING MORE TO THE LEFT,
AND THE CRY 2 KNOCKOUT HAS A
SLOWER CLOCK SO IT'S MOVING MORE
TO THE RIGHT, SO THIS PERIOD IS
LONGER THAN 24 HOURS.
THIS PERIOD IS LESS THAN 24
HOURS.
BUT THEY'RE STILL RHYTHMIC IN
CONSTANT CONDITIONS.
IN CONTRAST, THE CRY 1/CRY
2 DOUBLE KNOCKOUT, SO IF YOU
REMOVE BOTH COPIES OF THIS GENE,
THE CLOCK IS COMPLETELY
ABOLISHED, THIS ANIMAL IS
COMPLETELY ARRHYTHMIC AND IT'S
GONE FROM WHAT LOOKS LIKE A NICE
RHYTHMIC BEHAVIOR IN A
LIGHT-DARK CYCLE TO ONE THAT IS
COMPLETELY ARRHYTHMIC.
SO THIS IS AN EXAMPLE OF A
MASKED RHYTHM, AND THIS IS
IMPORTANT BECAUSE THERE ARE MANY
TIMES WHERE WE'RE MEASURING
SOMETHING THAT IS PERIODIC IN
PHYSIOLOGY OR MOLECULAR
EXPRESSION, IT MAY INDEED BE
DRIVEN BY AN ENDOGENOUS CLOCK OR
IT MAY BE DRIVEN BY SOMETHING
ELSE.
IN THIS PARTICULAR CASE, THIS IS
PROBABLY DRIVEN BY THE
LIGHT-DARK CYCLE.
IT COULD BE SECONDARY TO
SOMETHING ELSE, MOTIVATION TO
RUN, MAYBE MOTIVATION TO EAT, ET
CETERA.
WE'RE NOT SURE.
THEN JUST TO FORESHADOW, ARE
THESE HEALTHY ANIMALS?
I'LL COME BACK TO THAT, AND THE
ANSWER IS PROBABLY NOT EXACTLY,
EVEN THOUGH THEY SEEM TO HAVE
INTACT CLOCKS AND SEEM TO
SYNCHRONIZE PERFECTLY.
SO WHERE DO RHYTHMS EMERGE FROM?
WE HAVE A STRUCTURE IN THE BRAIN
CALLED THE SUPRACHIASMATIC
NUCLEUS.
IT SITS RIGHT ABOVE THE CHIASM,
THIS IS A STAJ TALL SECTION
THR -- THESAGITTAL SECTION THROE
BRAIN.
THIS LITTLE AREA IS THE OPTIC
CHIAS, WHERE THE OPTIC NERVE
COMES INTO THE BRAIN AND BEFORE
THEY'VE GONE UP TO THE VISUAL
CENTERS.
RIGHT ABOVE THAT CHIASM OUTLINED
HERE IN WHITE IS A SMALL REGION
THAT IS THE SUPRACHIASMATIC
NUCLEUS AND THIS IS THE AREA
THAT HOUSES THE ENDOGENOUS
CLOCK.
WE CAN TAKE IT OUT AND PUT IT IN
A DISH, THANKFULLY THIS IS FROM
A MOUSE, NOT A HUMAN, AND YOU
CAN SEE ROBUST RHYTHM,
EXPRESSION OF THE PERIOD 2 GENE,
ANOTHER CORE CLOCK GENE, AND
IT'S BEEN FUSED TO LUCIFERASE,
WHICH IS SIMPLY THE ENZYME THAT
MAKES LIGHT IN A FIREFLY.
SO WE CAN WATCH THE ENDOGENOUS
RIRHYTHMICITY EACH DAY.
IT WORKS IN A DISH.
ALSO IMPORTANTLY, IF WE LESION
THE SCN, THIS ANIMAL IS A
CHIPMUNK IN THIS PARTICULAR CASE
THIS, IS DOUBLE PLOTTED SO IT'S
ON A 48-HOUR TIME SCALE, JUST
TOESE TOEASE THE VISUALIZATION.
AS SOON AS THIS SCN HAN
LESIONED, THE ANIMAL BECOMES
ARRHYTHMIC, THERE'S NEVER ANY
REKOREKOPF RREKORECOVERY OF RHY.
IN THE BACKGROUND, THERE WAS
THIS SORT OF AN ACKNOWLEDGMENT
THAT THIS WAS NOT THE ENTIRE
STORY.
AND IT EMERGED REALLY FROM
EATING BEHAVIOR, AND FOOD
ANTICIPATORY ACTIVITY.
SO FOOD ANTICIPATORY ACTIVITY IS
WHAT YOU LOVE TO SEE WHEN YOU GO
TO THE ZOO.
RIGHT BEFORE FEEDING TIME, THE
ANIMALS ARE RUNNING AROUND,
THEY'RE ANTICIPATING THAT
PERIODIC MEAL.
WE CAN STUDY THAT IN THE LAB,
AND IMPORTANTLY, IT CAN BE
STUDIED IN ANIMALS THAT ARE
ALREADY ARRHYTHMIC.
SO THIS IS AN SCN LESIONED RAT.
IF YOU LOOK AT JUST THIS TOP
PORTION, THERE'S NO CONSOLIDATED
ACTIVITY.
THIS ANIMAL IS ARRHYTHMIC.
BUT AS SOON AS FOOD IS
PRESENTED, TWO HOURS PER DAY,
AND THAT'S SHOWN HERE IN THESE
HATCHED MARK, WE SEE THIS LARGE
BOLUS OF ACTIVITY THAT PRECEDES
IT.
SO THIS IS THAT FOOD
ANTICIPATORY ACTIVITY.
WHAT'S VERY IMPRESSIVE, THOUGH,
IS THAT WHEN THE FOOD IS
PRESENTED ON A 23-HOUR SCHEDULE,
IT'S NOT THE CASE THAT THEY CAN
LEARN TO ANTICIPATE 23 HOURS.
AND WHAT HAD BEEN CONSOLIDATED
NOW BEGINS TO FREE-RUN, SO THIS
IS ACTUALLY GOING BACK TO THAT
FUNDAMENTAL PROPERTY OF CLOCKS.
THIS IS A FREE-RUNNING RHYTHM
THAT PERPETUATES EVEN THOUGH WE
HAVE THIS POTENTIAL
SYNCHRONIZING CUE THAT'S A
LITTLE BIT TOO SHORT, IT LOOKS
LIKE.
ONCE THE FOOD SCHEDULE IS
RESTORED TO 24 HOURS, THEN THE
ANIMAL IS REENTRAINED TO IT AND
RESYNCHRONIZED.
SO THIS IS SHOWING US THAT EVEN
IN THE ABSENCE OF AN SCN CLOCK
IN THE BRAIN, THERE IS THE
ABILITY FOR CLOCKS ELSEWHERE TO
SUPPORT A CIRCADIAN RHYTHM.
MOLECULARLY, THESE RHYTHMS ARE
BASED ON A NETWORK OF GENES.
THIS IS JUST THE VERY BAREST
MINIMUM.
WE HAVE TWO POSITIVE REGULATORS,
BMAL1 AND CLOCK.
THEY BIND TO E-BOXES THAT ARE IN
THE DNA AND THEY DRIVE THE
TRANSCRIPTION OF THE PER AND THE
CRY GENES, SO THIS IS THAT
CRYPTO CHROME FROM EARLIER, THIS
IS THAT PERIOD GENE FROM
EARLIER.
THEY BECOME PROTEINS, THEY
DIMERIZE AND THEY INHIBIT THEIR
OWN TRANSCRIPTION.
AND THIS LOOP TAKES ABOUT 24
HOURS.
THERE ARE A HOST OF OTHER
MOLECULAR PLAYERS THAT I DON'T
WANT TO GO INTO.
WE ARE STARTING TO LEARN A LOT
ABOUT HOW THOSE WORK
BIOCHEMICALLY, BUT WE HAVE A LOT
IN THE FUTURE TO FIGURE OUT.
SO BECAUSE THOSE CLOCK GENES ARE
OSCILLATING, WE CAN ACTUALLY
LOOK AT ALL DIFFERENT TISSUES,
AND WHEN WE DO THAT, WE ACTUALLY
FIND THAT MOST TISSUES ACTUALLY
HAVE FUNCTIONAL CLOCKS.
HERE'S EXAMPLE OF THYROID GLAND,
SKELETAL MUSCLE, ET CETERA.
IN EACH CASE, WE CAN REMOVE THIS
TISSUE, WE CAN PUT IT IN A DISH
AND WE CAN SEE MULTIPLE CYCLES
OF RHYTHMICITY AND THIS REMAINS
CLOSE TO 24 HOURS EVEN IN THE
DISH.
THIS HAS LED NOW TO A MODEL
WHERE WE HAVE AN SCN, WHICH IS
STILL A MAIN COORDINATOR OF
CLOCKS.
IT'S STILL SENSITIVE TO LIGHT.
BUT IT'S SPEAKING AND
SYNCHRONIZING POTENTIALLY
RHYTHMS OF CLOCKS IN MANY, MANY
DIFFERENT TISSUES.
IMPORTANTLY, THOUGH, NOT EVERY
CLOCK IS SENSITIVE TO THE SAME
CUES, AND EXERCISE MAY AFFECT
THINGS, FEEDING MAY AFFECT
THINGS, PATHOGENS, ET CETERA,
TEMPERATURE IS A STRONG
RESETTING CUE, AND DIFFERENT
CLOCKS MAY BE SENSITIVE TO
DIFFERENT CUES.
HERE'S A BEAUTIFUL EXAMPLE OF
THIS.
THIS HAS LED TO A LOT OF
INTEREST IN WHAT FOOD TIMING IS
DOING.
THESE WERE MICE THAT WERE SIMPLY
FED EXCLUSIVELY DURING THE
NIGHT, SO 12 HOURS OF FOOD IN
THE NIGHT OR 12 HOURS OF FOOD
DURING THE DAY.
AND THESE PICTURES ARE OF THE
BRAIN AT THE LEVEL OF SCN AND
THESE LITTLE BLACK DOTS ARE THE
EXPRESSION OF PERIOD 2, AND YOU
CAN JUST SEE THAT BETWEEN THE
TOP AND BOTTOM, THERE'S ONLY
EXPRESSION HERE TOWARDS THE END
OF THE LIGHT PHASE.
BUT IF WE LOOK AT THE SAME GENE
IN THE LIVER, NOW WE HAVE A
12-HOUR PHASE SHIFT BASED ON
THIS FEEDING.
SO THERE'S HYPER 2 EXPRESSION IN
THE NIGHT FED ANIMALS DURING THE
NIGHT AND HIGH PER 2 EXPRESSION
DURING THE DAY IN THE DAY-FED
ANIMALS.
SO THIS IS A CASE WHERE ONE
CLOCK IN THE BODY IS INSENSITIVE
TO THE FEEDING PHASE AND ONE IS
SENSITIVE TO THE FEEDING PHASE,
SO WE HAVE A MISALIGNMENT OR
UNCOUPLING OF THE CLOCKS IN THE
BODY INDUCED BY FOOD TIME.
I'LL ALSO PRESENT THIS, I DON'T
WANT TO GO INTO IT, BUT THESE
CLOCKS, THESE CORE CLOCK GENES
THAT ARE IN THE BODY IN THESE
DIFFERENT TISSUES ARE ACTUALLY
COORDINATING A VAST RHYTHMIC
TRANSCRIPTOME.
SO IF WE LOOK AT THE ENTIRE --
SORT OF THE ENTIRE TRANSCRIPTOME
AND LOOK AT ALL THE PROTEIN
CODING GENES, THE ESTIMATE IS
THAT UP TO 40% OF THOSE ARE
RHYTHMICALLY EXPRESSED IN AT
LEAST ONE TISSUE.
IF WE LOOK SPECIFICALLY AT THE
LIVER, 16% OF ALL THE PROTEIN
CODING GENES ARE RHYTHMIC.
LESS SO IN THE BRAIN, BUT I'LL
POINT OUT THE BRAIN IS ALSO
HIGHLY RETROGENIUS AND THERE
COULD BE VERY DIFFERENT PATTERNS
OF EXPRESSION, DEPENDING WHERE
YOU ARE.
THIS IS ALL WORK DONE BY THE
HOGANICH LAB.
VERY BEAUTIFUL.
SO I WANT TO PIVOT TO JUST
SHOWING A QUICK SNAPSHOT OF THE
ONGOING WORK THAT'S IN MY
LABORATORY.
WE'RE INTERESTED IN PHYSIOLOGY
AND HOW CLOCKS ARE RELATED TO
THAT, AND SPECIFICALLY HOW FOOD
TIMING AND LIGHT-DARK CYCLE
TIMING ARE BEING INTEGRATED BUT
THE ANIMAL, LEADING TO A HEALTH
OUTCOME.
WE'RE INTERESTED IN SHIFT WORK
BECAUSE IT'S BEEN ASSOCIATED
WITH A HOST OF DIFFERENT
REPRODUCTIVE HEALTH
DIFFICULTIES, REG MENSTRUAL
CYCLES, LOW BIRTH WEIGHT,
INFERTILITY, AND WE HAVE A LOT
OF PEOPLE IN THIS COUNTRY ON
NON-STANDARD WORK SHIFTS,
ESPECIALLY IN THAT AGE GROUP
THAT IS TRANSITIONING TO
PARENTHOOD, THERE'S A HIGH
PREVALENCE OF SHIFT WORK.
OVERALL, U.S. INFERTILITY IS
VERY HIGH, ESPECIALLY FOR FIRST
BIRTHS, AND THERE'S INCREASING
NEED FOR FERTILITY TREATMENTS IN
NIGHT SHIFT WORKERS, AND A
GRADUAL RECOGNITION THAT SHIFT
WORK IS A DIFFICULT CHALLENGE
FOR PEOPLE TRYING TO BECOME
PREGNANT.
ALSO IMPORTANTLY, I JUST SHOWED
YOU THE VERY STRONG EFFECTS OF
FOOD TIMING ON CLOCKS, AND SHIFT
WORK IS A VERY POTENT EFFECTOR
OF WHEN YOU EAT.
SO WE WERE INTERESTED IN TRYING
TO MODEL THIS.
IN MY LABORATORY, WE STUDY
PRIMARILY MICE, IN SORT OF THE
BASIC PORTION OF THE LAB.
AND WE'RE INTERESTED IN
INDIVIDUALS AND THEIR RESPONSE
TO FOOD TIMING, WE'RE INTERESTED
IN HOW THEY INTERACT WITH EACH
OTHER, WE'RE INTERESTED IN
PREGNANCY HEALTH, AND FINALLY
PREGNANCY SUCCESS.
SO OUR FIRST EXPERIMENT, WE
ACTUALLY JUST PAIRED ANIMALS, SO
WE'VE HAD DARK-FED MALES AND
DARK-FED FEMALES, WE PAIRED THEM
TOGETHER, AND WE SIMPLY WATCHED
THEM TO SEE WHEN THEY GAVE
BIRTH.
SO WE PAIRED THEM AT WEEK ZERO.
MICE HAVE A GESTATION TIME OF
THREE WEEKS SO YOU DON'T EXPECT
ANY LITTERS UNTIL HERE, AND LO
AND BEHOLD, AT WEEK FOUR, WE
START SEEING LITTERS BORN TO
BOTH GROUPS.
HOWEVER, THE ANIMALS THAT ARE
FED IN THEIR ACTIVE PHASE, SO
THESE ARE THE ONES FED DURING
THE DARK, BECAUSE THEY'RE
NOCTURNAL, YOU CAN SEE THAT BY
SIX WEEKS, HALF OF THEM HAVE
GIVEN BIRTH, AND BY 13 WEEKS,
ALL 100% OF THE PAIRS HAD GIVEN
BIRTH.
IN CONTRAST, THE ANIMALS THAT
WERE FED DURING THE DAY TIME OR
DURING THEIR LIGHT PHASE, THEY
ARE SLOWER TO THEIR FIRST BIRTH,
THEY DON'T HIT 50% UNTIL ABOUT Y
PLATEAU AT 75%, SO 25% OF THESE
MICE ARE SIMPLY NOT GIVING BIRTH
AT ALL.
THESE ARE OTHERWISE COMPLETELY
HEALTHY MICE.
THIS IS A VERY DRAMATIC EFFECT,
AND IN FACT, IN SUBSEQUENT
REPLICATIONS, WE KEEP SAYING THE
SAME EFFECT AND, IN FACT, IT'S
PROBABLY WORSE THAN THIS.
IT'S ACTUALLY CAUSED A LOT OF
PROBLEMS TO TRY AND GENERATE
PUPS IF YOU'RE INTERESTED IN THE
STUDY OF THE OFFSPRING.
SO TO TRY AND UNDERSTAND THE
BIOLOGICAL BASIS FOR WHY THIS
INFERTILITY MIGHT BE OCCURRING,
WE'VE GONE DOWN SEVERAL
DIFFERENT AVENUES.
I'M JUST GOING TO SHOW ONE,
WHICH IS LOOKING AT THE TIMING
OF OVULATION.
CIRCADIAN RHYTHMS AND MATING
BEHAVIOR HAVE A LONG HISTORY OF
BEING TIED TOGETHER, PARTLY
BECAUSE THE TRIGGER FOR
OVULATION IN FEMALES IS THIS
LUTEINIZING HORMONE SURGE.
IT OCCURS EVERY FOUR DAYS IN A
MOUSE ESTRUS CYCLE OR A RAT
ESTRUS CYCLE, AND IMPORTANTLY,
IT OCCURS AT THE SAME TIME OF
DAY.
IT VERY PREDICTABLE, AND OCCURS
AT THE LIGHT TO DARK TRANSITION.
AND SO WE CAN STUDY THE
LUTEINIZING HORMONE SURGE TIMING
IN OUR MICE TO TRY MCDADE A
SAND GET ASENSE OF TIMING OF OVN
MIGHT GET DISRUPTED BY THE FOOD
TIMING.
SO HERE WE HAVE A 24-HOUR CLOCK.
NOON IS AT THE TOP.
LIGHTS OFF IS AT 6:00 P.M.,
LIGHTS ON IS AT 6:00 A.M., AND
WE EXPECT ALL OF OUR LH SURGES
TO OCCUR HERE IN THIS WINDOW.
WE WERE BLEEDING EVERY TWO
HOURS, SO YOU'LL SEE PEAKS EVERY
TWO HOURS POTENTIALLY.
SO FOR OUR CONTROLS, WE HAD TWO
AT 6:00 P.M., WE HAD FOUR AT
8:00 P.M., ABOUT WHEN YOU'D
EXPECT THEM TO BE.
FOR THE ANIMALS FED IN THEIR
ACTIVE PHASE, WE FOUND ALL SIX
OF THEM AT 8:00 P.M.
THE ONES IN THE REST PHASE,
HOWEVER, WERE DISTRIBUTED AROUND
THE CLOCK.
IN A VERY UNPREDICTABLE WAY.
THEY'RE NOT HERE AS YOU WOULD
EXPECT.
THEY'RE ALSO NOT HERE, WHERE YOU
MIGHT EXPECT IF IT WAS ENTRAINED
BY THE FOOD TIMING.
INSTEAD, THE LIGHT CYCLE TIMING
AND THE FOOD CYCLE TIMING HAVE
SOMEHOW HAD SOME KIND OF
DESTRUCTIVE INTERFERENCE LEADING
TO THIS DISORGANIZED PHYSIOLOGY.
I ALSO WANT TO POINT OUT THAT
IT'S NOT JUST TIMING OF CUES, SO
REMEMBER, WE TALKED ABOUT
PERIODICITY AND WE TALKED ABOUT
SYNCHRONIZATION, AND THE PERIOD
ALSO IS VERY IMPORTANT.
SO I SAID I WAS FORESHADOWING
FOR THESE CRYPTO CHROME
KNOCKOUTS, THIS IS THIS SLIDE
HERE.
THIS WAS A VERY INTERESTING
STUDY WHERE THEY WERE JUST
LOOKING AT THE PREGNANCY RATE IN
MIDDLE AGED TO OLDER MICE.
YOU KNOW, 8 TO 12 MONTHS IS
STARTING TO BE WHERE YOU EXPECT
PREGNANCY RATES TO START TO GO
DOWN.
SO IF WE LOOK AT THE WILD TYPE
MICE, 75% OF THESE ANIMALS ARE
SUCCESSFULLY HAVING LITTERS.
IN THE CRY 1 KNOCKOUTS AND THE
CRYPTOCHROME 2 KNOCKOUTS,
REMEMBER THIS HAD THE FASTER AND
SLOWER CLOCK SPEED, YOU CAN SEE
THAT THE SUCCESSFUL PREGNANCY
RATE IS VERY LOW.
IT'S DOWN AT ABOUT 10% NOW.
SO THESE ANIMALS APPEAR TO HAVE
MAYBE ADVANCED REPRODUCTIVE
AGING.
MAYBE THEY'VE ALREADY GONE
THROUGH THEIR PRODUCTIVE PERIOD.
HOWEVER, WHAT THEY SIMPLY HOUSD
THESE WILL ANIMALS IN A
LIGHT-DARK CYCLE THAT MATCHED UP
WITH THEIR ENDOGENOUS CLOCK
SPEED.
SO THE CRY 1 KNOCKOUTS WITH THE
FASTER CLOCK, HE HOUSED THEM IN
11 AND A QUARTER HOURS OF LIGHT,
11 AND A QUARTER HOURS OF DARK.
FOR THE CRY 2 ANIMALS, IT WAS A
LONGER THAN 24-HOUR LIGHT-DARK
CYCLE, AND HE RESCUED THE
FERTILITY RATE IN THESE ANIMALS.
THIS IS THIS IDEA OF CIRCADIAN
RESONANCE, THAT THERE'S
SOMETHING IMPORTANT ABOUT THE
CIRCADIAN PERIOD OF THE CLOCK
MATCHING THE DRIVING
ENVIRONMENTAL CYCLE, LEADING TO
OPTIMAL PHYSIOLOGY AND IN THIS
PARTICULAR CASE, INCREASED
FERTILITY.
SO WHEN I THINK ABOUT THE GAPS
IN OPPORTUNITIES AS THIS FIELD
MOVES FORWARD, I REALLY THINK IT
IS STILL ABOUT THE FUNDAMENTALS
OF CLOCKS.
IT'S ABOUT PHASE, IT'S ABOUT
PERIOD, AND IT'S HOW THEY
INTERACT.
BUT INSTEAD OF SIMPLY DESCRIBING
THESE, WE NEED TO REALLY
UNDERSTAND THEIR MECHANISMS IN A
DISTRIBUTED CLOCK NETWORK.
THIS IS A NICE DIAGRAM FROM JEN
MOHAWK FROM ABOUT 10 YEARS AGO
NOW SHOWING SCN AS THIS TOP-DOWN
COORDINATOR OF CLOCKS.
WE CAN USE THE LIVER AS AN
EXAMPLE.
AND THERE ARE A LOT OF DIFFERENT
WAYS THAT TIMING INFORMATION
GETS TO THE LIVER.
GLUCOCORTICOIDS, BODY
TEMPERATURE, AUTONOMIC
INNERVATION.
FEEDING TIME IS ALSO BASICALLY
ADDING TO THIS COMPLEXITY.
THE LIGHT-DARK CYCLE IS
IMPINGING ON BOTH BEHAVIORS AS
WELL AS THE SCN DIRECTLY.
WE HAVE A STRONG INTEREST THESE
DAYS IN UNDERSTANDING MEDICATION
TIMING.
IS THAT AFFECTING THE CLOCK?
DOES ITS EFFECT DEPEND ON THE
PHASE OF THIS CLOCK?
AND DOES ITS EFFECT DEPEND ONLY
ON THE PHASE OF THIS CLOCK BUT
ALSO ON THE PHASE OF THIS CLOCK?
OR OTHER CLOCKS IN THE BODY?
SO WE CAN TALK ABOUT CIRCADIAN
MISALIGNMENT.
WHAT DOES IT MEAN WHEN CLOCKS
ARE UNCOUPLED FROM THE BODY AND
THE ENVIRONMENT?
LIKE IN SHIFT WORK?
WHAT ABOUT INTERNAL MISALIGNMENT
AMONG THE INTERNAL CLOCKS?
THIS CAN BE BOTH PHASE AND
PERIOD.
IN TERMS OF BASIC SCIENCE, I'M
VERY INTERESTED, OF COURSE, IN
SPECIES DIFFERENCES.
ARE THESE MECHANISMS CO CONSERVD
ACROSS ALL SPECIES, ACROSS ALL
BODY SIZES OF SPECIES, BUT ALSO
ACROSS TISSUES, IF WE SEE THAT
CLOCKS ARE IN EACH TISSUE AND WE
KNOW THE TRANSCRIPTOMES THAT
THEY ARE COORDINATING ARE
DIFFERENT, WHAT DOES THAT MEAN
FOR HOW THE CIRCADIAN MOLECULAR
NETWORK IS AFFECTING THE
FUNCTION OF DIFFERENT CELLS IN
DIFFERENT TISSUES?
I THINK THESE ARE ALL REALLY
TIMELY AND IMPORTANT QUESTIONS
TO ANSWER AS WE MOVE FORWARD.
AND FINALLY, ONE OF THE
FUNDAMENTAL DIFFICULTIES IS,
OFTEN, HOW DO YOU MEASURE TIME?
DO WE RELY ON CLOCK GENES, DO WE
RELY ON THE CLOCK GENE
DOWNSTREAM EFFECTORS, AND HOW DO
WE MEASURE THEM?
HOW DO WE MEASURE THEM IN HUMANS
WHERE WE CAN'T DO INVASIVE
TESTING, WHAT KINDS OF POTENTIAL
BIOMARKERS ARE THERE THAT ARE
OUT THERE THAT CAN HELP US MOVE
FORWARD TO UNDERSTANDING THESE
INTERACTIONS.
WITH THAT, I'D JUST LIKE TO SAY
THANK YOU TO THE PEOPLE IN MY
LAB THAT HAVE CONTRIBUTED TO
THIS.
ALSO TO THE FACULTY MEMBERS WHO
HAVE BEEN IMPORTANT MENTORS FOR
ME AS I MOVE THROUGH AS A JUNIOR
FACULTY MEMBER.
MY COLLABORATORS ELSEWHERE,
FUNDING FROM NIH, THE AMERICAN
SLEEP MEDICINE FOUNDATION, AND
THE STATE OF OREGON.
AND I'LL JUST LEAVE YOU WITH
THIS, THAT WHEN WE THINK ABOUT
THE THREE PILLARS OF HEALTH, OF
DIET, SLEEP AND EXERCISE, WE
REALLY UNDERSTAND THAT THE
TIMING OF ALL OF THESE MATTERS.
IT'S NOT JUST WHAT YOU EAT, IT'S
WHEN YOU EAT.
IT'S NOT JUST HOW MUCH YOU
SLEEP, IT'S WHEN YOU SLEEP.
SAME FOR EXERCISE.
AND SO MOVING FORWARD, I THINK
WE HAVE A GREAT OPPORTUNITY TO
UNDERSTAND HOW THE CIRCADIAN
CLOCK IS INTERACTING WITH THE
ENVIRONMENT IN COORDINATING AND
ORGANIZING THESE.
THANK YOU VERY MUCH.
>> THANK YOU SO MUCH,
DR. BUTLER.
NEXT UP, DR. SABRA ABBOTT WILL
GIVE US A PRESENTATION ON
CIRCADIAN MEDICINE.
>> ALL RIGHT.
SO THANK YOU SO MUCH TO THE
ORGANIZERS FOR INVITING ME TO
SPEAK IN THIS SYMPOSIUM.
AND I HAVE TO SAY, I'M
ABSOLUTELY THRILLED TO SEE HOW
MANY PEOPLE ARE INTERESTED IN
THIS TOPIC.
AND I THREW THIS SLIDE IN AT THE
VERY -- RIGHT BEFORE WE STARTED
TODAY BECAUSE I THINK IT
HIGHLIGHTS JUST HOW FAR WE'VE
COME AS A FIELD.
WHEN I WAS GETTING STARTED IN
THIS FIELD, THIS IS A PIECE OF
MAIL THAT I GOT.
IT WAS A TRANSCRIPTION FROM A
MEDICAL RECORDS DEPARTMENT AND
WE WERE TELLING THEM THE ADDRESS
WAS THE CIRCADIAN RHYTHM SLEEP
LAB AND YOU CAN SEE THEY DID
THEIR BEST TO TRY TO FIGURE OUT
WHAT ON EARTH THESE WORDS WERE
THAT I WAS EVEN SAYING AND THEY
CAME UP WITH SIRCAD.
IAN RIBBON SO
I THINK WE'RE LUCKY WE'VE COME
TO THE POINT WHERE MOST PEOPLE
REALIZE CIRCADIAN RHYTHMS EXIST
AND WE'RE MOVING IT INTO THE
FIELD OF MEDICINE.
I DON'T HAVE ANY RELEVANT
CONFLICTS OF INTEREST.
TO GO THROUGH OUR LEARNING
OBJECTIVES, I'M GOING TO TAKE
THIS SESSION INTO THE DIRECTION
OF THE CLINIC AND TALK ABOUT
SOME OF THE WORK THAT I DO WITH
PATIENTS WITH PRIMARY CIRCADIAN
RHYTHM DISORDERS.
SO WE'RE GOING TO TALK ABOUT
SPECIFICALLY TWO OF THE
DISORDERS I SEE MOST OFTEN,
DELAYED SLEEP-WAKE PHASE
DISORDER AND NON-24-HOUR
SLEEP-WAKE RHYTHM DISORDER.
WE'RE GOING TO TALK ABOUT HOW
THESE DISORDERS HAVE UNIQUE
CAUSES, EVEN WITHIN A SINGLE
DISORDER, AND WE NEED TO START
THINKING ABOUT INDIVIDUALIZED
TREATMENT STRATEGIES FOR THESE
PATIENTS.
AND THEN LASTLY, I'M GOING TO
GET ON MY OWN LITTLE PERSONAL
SOAP BOX AND TALK A LITTLE BIT
ABOUT THE ROLE FOR ACTIDRAPHY
AND MELATONIN TESTING IN THE
DIAGNOSIS OF CIRCADIAN RHYTHM
SLEEP-WAKE DISORDERS.
SO JUST TO KIND OF SET THE STAGE
HERE, HOW DID I EVEN GET INTO
THIS SPACE?
I ACTUALLY GOT MY START IN THIS
FIELD TWEFN YEARS AGO NOW
WORKING AS A GRAD STUDENT AND
SPENDING A LOT OF TIME SITTING
IN A DARK BASEMENT HANGING OUT
WITH THESE GUYS, SO THIS IS A
C57 BLACK 6 MOUSE AND SPENDING A
LOT OF TIME WATCHING THEM RUN ON
RUNNING WHEELS.
SO YOU'LL NOW BE FAMILIAR WITH
WHAT THIS MOUSE RUNNING WHEEL
DATA LOOKS LIKE AFTER THE LAST
PRESENTATION, BUT JUST GIVING
YOU A SENSE OF WHAT THEY LOOK
LIKE WHEN THEY'RE ENTRAINED AND
WHEN THEY'RE IN FREE-RUNNING
CONDITIONS.
AND AS I WAS WRAPPING UP MY
GRADUATE SCHOOL TRAINING,
THERE'S ALWAYS THE QUESTION OF
WHAT DO YOU WANT TO DO FROM A
MEDICAL PERSPECTIVE.
AND MY SORT OF PIE IN THE SKY
DREAM AT THAT POINT WAS TO
REALLY FIGURE OUT A WAY TO TAKE
THIS PHENOMENAL BASIC CIRCADIAN
SCIENCE THAT EXISTED AT THE TIME
AND FIGURE OUT WAYS THAT WE CAN
ACTUALLY APPLY THAT WITHIN THE
CLINICAL SPACE, SO I COMPLETED A
NEUROLOGY RESIDENCY, SLEEP
MEDICINE FELLOWSHIP AND ENDED UP
AT NORTHWESTERN WHERE THEY WERE
JUST IN THE PROCESS OF STARTING
A CIRCADIAN MEDICINE CLINIC.
SO THIS WAS ACTUALLY -- I'M
GOING TO WALK YOU THROUGH SOME
OF THE LESSONS AND QUESTIONS
THAT I LEARNED FROM WORKING WITH
SOME OF THESE PATIENTS.
AND IT WAS PROBABLY ON MY FIRST
MONTH AS A BRAND NEW ATTENDING,
THIS PATIENT WALKED THROUGH MY
DOOR AND WE ENDED UP GETTING
ACTIGRAPHY ON HIM AND JUST TO
ORIENT YOU, EACH OF THESE LINES
REPRESENTS 24 HOURS, AND YOU CAN
SEE THAT THIS PARTICULAR
PATIENT, EVERY SINGLE DAY, HE
WAKES UP A LITTLE BIT LATER AND
A LITTLE BIT LATER AND A LITTLE
BIT LATER.
SO AS SOMEBODY WHO KIND OF CUT
THEIR TEETH LOOKING AT
FREE-RUNNING MICE, I FELT RIGHT
AT HOME WITH THIS PATIENT
BECAUSE IT FELT LIKE I WAS BACK
IN THAT CIRCADIAN LAB AGAIN.
BUT THE ADDED BENEFIT WAS THAT
NOW UNLIKE THE MICE, THESE
PATIENTS CAN TALK TO ME.
THEY CAN TELL ME ABOUT THEIR
EXPERIENCE, THEY CAN TELL ME
WHAT IT FEELS LIKE WHEN THEY GET
PUSHED INTO THESE RHYTHMS, WHEN
I GIVE THEM INTERVENTIONS, HOW
DO THEY RESPOND, DO THEY FEEL
LIKE THEY ACTUALLY ARE ADJUSTING
AND ADAPTING AND DID THEY FEEL
GOOD OR DID THEY FEEL LIKE
THEY'RE ONLY GETTING THERE
THROUGH SHEER WILLPOWER FORCING
THEMSELVES TO BE ON THIS
SCHEDULE BUT WE'RE NOT ACTUALLY
REALLY ACHIEVING THEIR GOALS.
SO I FEEL LIKE I HAVE -- IT'S AN
IMMENSE HONOR TO BE ABLE TO TALK
TO THESE PATIENTS AND WORK WITH
THEM AND LEARN FROM THEM SO
WE'RE GOING TALK THROUGH SOME OF
THE QUESTIONS MY PATIENTS HAVE
CHALLENGED ME WITH AND HOW THESE
HAVE SORT OF TURNED INTO
RESEARCH QUESTIONS.
SO THIS PARTICULAR PATIENT HAD
SOMETHING CALLED NON-24-HOUR
SLEEP-WAKE RHYTHM DISORDER.
AS YOU CAN IMAGINE, HE HAS A
CONSOLIDATED TIME OF REST AND
TIME OF ACTIVITY THAT SHIFTS
EVERY SINGLE DAY.
SO SOMETIMES HE'S ASLEEP AT
NIGHT, SOMETIMES DURING THE DAY.
SOMETIMES THESE PATIENTS HAVE A
CLEAR SENSE OF WHAT'S GOING ON,
SOMETIMES THEY JUST COME IN WITH
THIS DISORGANIZED HISTORY THAT
THEY CAN'T REALLY TELL YOU WHEN
THEY PREFER TO SLEEP.
THEY KNOW THAT SOMETIMES THEY
CAN'T SLEEP, SOMETIMES THEY
CAN'T WAKE UP WHEN THEY WANT TO
AND THEN SOMETIMES THINGS ARE
OKAY.
I'VE INCLUDED HERE, THESE ARE
THE INTERNATIONAL CLASSIFICATION
OF SLEEP DISORDERS CRITERIA,
THAT THESE SHOULD BE PRESENT FOR
THREE MONTHS, AND THEN I WANT TO
HIGHLIGHT THAT REALLY TO
RECOGNIZE THIS, YOU DO WANT TO
GET SLEEP LOGS AND PREFERABLY
ACTIGRAPHY MONITORING TO REALLY
DEMONSTRATE WHAT'S GOING ON.
AND THEN OBVIOUSLY IT'S NOT
BETTER EXPLAINED BY ANOTHER
SLEEP DISORDERS.
WHAT'S REALLY INTERESTING ABOUT
THAT PATIENT I STARTED WITH, WE
OFTEN THINK OF NON-24 HOUR
SLEEP-WAKE DISORDER AS BEING A
DISORDER OF PEOPLE WHO ARE
BLIND.
WE KNOW WE RESPOND TO
ENVIRONMENTAL LIGHT, AND SO IF
YOU DO HAVE RETINAL PATHOLOGY SO
YOU DON'T GET THAT LIGHT INPUT,
IT'S UNDERSTANDABLE THAT YOU MAY
FOLLOW YOUR ENDOGENOUS RHYTHM,
YOUR ENDOGENOUS PERIOD, BUT
THERE'S ACTUALLY A WHOLE
COLLECTION OF PATIENTS INCLUDING
THIS ONE THAT THEY HAVE NORMAL
IMAGE-FORMING VISION, SO THEY BY
ALL OF OUR DESCRIPTORS CAN SEE,
BUT THEY STILL EXHIBIT THESE
CIRCADIAN BEHAVIORS AS THOUGH
THEY'RE NOT RESPONDING TO LIGHT.
THE OTHER THING THAT'S VERY
INTERESTING ABOUT THESE
PATIENTS, THESE ARE JUST SOME
EXAMPLES OF VARIOUS ACTIGRAPHY
FROM DIFFERENT PATIENTS HERE,
YOU CAN SEE THAT MANY OF THEM,
INSTEAD OF FOLLOWING THIS
PREDICTIVE EVERY SINGLE DAY IS A
LITTLE BIT LATER COMPARED TO THE
DAY BEFORE, THEY WILL GO THROUGH
THESE TIME PERIODS OF WHAT HE
WITH CALL RELATIVE ENTRAINMENT,
SO THEY MAY END UP BEING DELAYED
FOR A WHILE, THINGS JUST GET SO
BAD, THEY BECOME NON-24, THEN
THEY'RE DELAYED FOR A WHILE.
SO THERE'S OFTEN AN OVERLAP
BETWEEN PATIENTS WITH DELAYED
SLEEP WAKE-PHASE DISORDER AND
SIGHTED NON-24.
SO WHAT IS DELAYED SLEEK
WAKE-PHASE DISORDER?
IN THIS CASE THESE ARE PEOPLE
WHO HAVE A REGULAR PATTERN OF
FALLING ASLEEP AND WAKING UP
THAT IS MUCH LATER THAN
CONVENTIONAL TIMES, AND IT'S
ALSO MUCH LATER THAN THEY WOULD
DESIRE TO BE, SO THEY WANT TO GO
TO BED EARLIER AND WAKE UP
EARLIER OR THEY NEED TO BECAUSE
OF WORK REQUIREMENTS, AND THEY
JUST ARE UNABLE TO.
THE OTHER DIAGNOSTIC CRITERIA
ARE THE SAME AS FOR NON-24.
AND I THINK ONE OF THE FIRST
QUESTIONS THAT'S SPARKED BY
THIS, HAVING TALKED TO MANY OF
THESE PATIENTS AND REALLY
GETTING A SENSE THAT THIS IS A
FRUSTRATING PHENOMENON WHERE
THEY ARE TRYING, THEY'RE GETTING
INTO BED, THEY'RE FOLLOWING ALL
OF THE RIGHT SLEEP HYGIENE
RECOMMENDATIONS, THEY'RE SETTING
MILLIONS OF ALARMS AND THEY
CANNOT FALL ASLEEP AND WAKE UP
WHEN SOCIETY WANT THEM TO.
AND SO IT REALLY SUGGESTS
THERE'S SOME SORT OF STRONG
UNDERLYING BIOLOGICAL FACTOR
THAT'S DRIVING THIS, SO WHAT ARE
SOME OF THE POTENTIAL CAUSES FOR
THAT?
SO OVER HERE ON THE LEFT, I JUST
HAVE A CARTOON ILLUSTRATING SORT
OF THE BASICS OF HOW IT IS THAT
MOST OF US ARE ASLEEP AT NIGHT
AND AWAKE DURING THE DAY TIME.
SO MOST OF US HAVE AN ENDOGENOUS
PERIOD A LITTLE BIT LONGER THAN
24 HOURS, SO IF I PUT YOU IN A
CAVE EVERY SINGLE DAY, YOU WOULD
GET A LITTLE BIT LATER AND A
LITTLE BIT LATER, BUT IT'S THAT
DAILY EXPOSURE TO LIGHT DURING
THE DAY THAT PROVIDES A PHASE
ADVANCING SIGNAL THAT SHIFT YOU
EARLIER, AND SO THE ULTIMATE
EFFECT IS THAT YOU END UP BEING
ALIGNED SO YOU FALL ASLEEP WHEN
IT'S DARK AND AWAKE WHEN IT'S
LIGHT.
ONE POTENTIAL WAY YOU CAN
DEVELOP THIS IS BECAUSE MAYBE
THESE ARE PEOPLE WHO TEND TO BE
STAYING UP LATER, THEY'RE
GETTING LATER LIGHT EXPOSURE AT
NIGHT SO MAYBE THEY'RE GETTING
TOO MUCH LIGHT AT NIGHT THAT'S
GIVING THEM A GREATER PUSH IN
THEIR OWN DIRECTION AND MAYBE
THEY'RE NOT GETTING ENOUGH LIGHT
IN THE MORNING, THE NEXT DAY, SO
THEY'RE NOT GETTING ENOUGH OF
THAT SIGNAL TO PUSH THEM
EARLIER, SO THEN THAT BALANCE IS
THAT THEIR SLEEP-WAKE WINDOW IS
SKEWED A LITTLE BIT IN THE LATER
DIRECTION.
SO WE HAVE A LITTLE BIT OF DATA
LOOKING INTO THAT.
THIS IS TAKING TWO GROUPS OF
INDIVIDUALS EITHER CONTROLLED
WHO FOLLOW A CONVENTIONAL
SLEEP-WAKE TIME VERSUS A GROUP
OF PEOPLE WHO ARE DELAYED BUT
ABLE TO FOLLOW THEIR HABITUAL
SLEEP-WAKE KEL.
WHAT YOU CAN SEE IS IF YOU LOOK
AT THEIR DAILY LIGHT EXPOSURE
PATTERNS AND MAP THOSE BASED ON
CLOCK TIME, YOU CAN SEE THAT THE
INDIVIDUALS WHO ARE DELAYED TEND
TO GET MUCH MORE LIGHT BETWEEN
THE HOURS OF 10:00 P.M. AND 4:0S
TEND TO GET MUCH MORE LIGHT THAN
THE DELAYED INDIVIDUALS BETWEEN
ABOUT 6:00 A.M. AND NOON.
BUT WHAT WE KNOW ABOUT CIRCADIAN
RESETTING IS THAT IT'S NOT BASED
ON EXTERNAL CLOCK TIME, IT'S
ACTUALLY BASED ON YOUR INTERNAL
CIRCADIAN TIME.
AND SO IF WE LOOK AT THE PROFILE
OF MEL TOE MELATONIN PRODUCTIOF
THE MARKERS WE HAVE OF CIRCADIAN
PHASE AND THEN LOOK AT THAT
LIGHT EXPOSURE RELATIVE TO THAT,
IT TURNS OUT THAT THIS WINDOW
OUT HERE, WHERE WE WOULD EXPECT
THAT TOO MUCH LIGHT MIGHT PUSH
THEM TOO LATE IN THE WRONG
DIRECTION, THEY AREN'T ACTUALLY
GETTING THAT MUCH MORE LIGHT
WITHIN THAT WINDOW BASED ON
THEIR BIOLOGICAL TIME.
THERE'S JUST A LITTLE BIT OF A
DIFFERENCE SORT OF OUT HERE,
SORT OF LATE IN THE
MORNING/EARLY AFTERNOON, WHERE
THEY MAY BE GETTING JUST A
LITTLE BIT LESS OF THAT MORNING
ADVANCING LIGHT LIGHT SIGNAL.
SO THIS MAY NOT BE THE PRIMARY
EXPLANATION.
SO THEN THE OTHER POSSIBILITY IS
PERHAPS THESE INDIVIDUALS HAVE A
PHYSIOLOGIC DIFFERENCE IN TERMS
OF HOW SENSITIVE THEY ARE TO
LIGHT.
SO MAYBE THEY'RE GETTING THE
SAME AMOUNT OF LIGHT AT NIGHT,
BUT IT HAS A STRONGER EFFECT, SO
IT PUSHES THEM LATER.
OR THEY'RE GETTING THE SAME
AMOUNT OF LIGHT IN THE MORNING
BUT THEY'RE NOT AT RESPONSIVE TO
IT, THEIR EYES JUST DON'T
PERCEIVE IT IN THE SAME WAY, SO
THEY DON'T RESPOND TO IT.
AND SOME OF THE HINTS FOR THIS
ACTUALLY COME FROM THE PATIENTS,
AND SO ESPECIALLY IN THESE
PATIENTS WITH EXTREME DELAYED
SLEEP-WAKE PHASE DISORDER OR
SIGHTED NON-24, I OFTEN GET THIS
RESPONSE OF I HATE LIGHT AND IT
DOESN'T WORK.
AND WE TRY EVERYTHING WE CAN
WITH MAKING SURE THAT IT'S BEING
GIVEN AT THE RIGHT TIME, AND IT
JUST DOESN'T HAVE THE EFFECT
THAT WE WOULD EXPECT, AND THEY
OFTEN TEND TO FIND IT MUCH MORE
IRRITATING AND, IN FACT, ONE OF
THE WAYS I'VE STARTED TO TEASE
SOME OF THESE PATIENTS APART IS
ACTUALLY ASKING THEM, IF YOU
COULD CHANGE THE LIGHT INTENSITY
IN THIS ROOM, IF YOU COULD MAKE
IT BRIGHTER OR YOU COULD MAKE IT
DIMMER, WHAT WOULD B YOU PREFER?
THERE'S A NUMBER OF PATIENTS
THAT WOULD PREFER TO BE IN THAT
DIMMER ENVIRONMENT, SO ALL OF
THIS SUGGESTS MAYBE THERE IS
SOMETHING DIFFERENT ABOUT HOW
THESE INDIVIDUALS ARE PERCEIVING
LIGHT PHYSIOLOGICALLY.
SO WE'VE ALREADY TALKED A LITTLE
BIT ABOUT THE SUPRACHIASMATIC
NUCLEUS, THE PRIMARY PACEMAKER
WITHIN THE BRAIN, AND THE WAY
THAT WE GET LIGHT TO THE SCN, IF
WE LOOK OVER HERE ON THE LEFT,
THIS IS AN ENLARGED
CROSS-SECTION OF THE RETINA, OF
YOUR EYE.
WE HAVE OUR TRADITIONAL ROD AND
CONE PHOTO RECEPTORS HERE.
BUT THEN THE CIRCADIAN LIGHT
SIGNAL IS ACTUALLY TRANSMITTED
THROUGH THESE INKRIN SICKLY
FOCUSED RETINAL GANGLION CELLS.
THEY SEND PR PROJECTIONS TO THES
CN BUT PREVIOUSLY FOR US THEY
ALSO SEND PROJECTIONS TO YOUR
BRAINSTEM, WHERE THEY SIN APPS
WITH THE PRETACTILE NUCLEUS AND
THAT GOES BACK TO YOUR PUPIL.
SO WE CAN ACTUALLY USE MEASURES
OF HOW YOUR PUPIL RESPONDS TO
LIGHT AS A SURROGATE MARKER FOR
HOW WELL THESE CELLS ARE
WORKING.
AND SO WE UNDERTOOK A PROJECT
ACTUALLY LOOKING AT LIGHT
SENSITIVITY IN THESE PATIENTS,
AND SO WE TOOK THREE GROUPS,
EITHER CONTROLS, WHO SORT OF
FOLLOWED CONVENTIONAL SLEEP-WAKE
TIMING, INDIVIDUALS WHO HAD
DELAYED SLEEP-WAKE PHASE
DISORDER BUT HAD NEVER GOTTEN TO
THE POINT WHERE THEY ACTUALLY
WENT AROUND THE CLOCK AND GOT
LATER AND LATER EACH DAY.
THEN A THIRD GROUP OF
INDIVIDUALS WHO SORT OF TOWED
THAT LINE BETWEEN BEING DELAYED
ADD NON-24 ALL WITHIN THAT
SIGHTED NON-24 CATEGORY.
AND ESSENTIALLY WHAT WE FOUND IN
THIS CASE, A LARGER PIPR MEANS
THOSE CELLS ARE WORKING BETTER.
SMALLER PIPR MEANS THEY'RE NOT
WORKING AS WELL, SO THE NON-24
PATIENTS HAVE A SIGNIFICANT
DECREASE IN THE FUNCTION OF
THESE CELLS AND A SIGNIFICANTLY
SMALLER PIPR.
FURTHERMORE, IF YOU LOOK AT THEM
WHEN ALL OF THESE PATIENTS ARE
IN A STATE OF RELATIVE
ENTRAINMENT AND YOU LOOK AT THE
MIDPOINT OF THEIR SLEEP, SO WHEN
THEY GET TO SLEEP ON THEIR
PREFERRED SCHEDULE, HOW LATE IS
THAT TIME, AND THE LATER YOUR
BODY WANTS TO SLEEP, THE SMALLER
THAT PIPR IS, SUGGESTING, GOING
BACK TO OUR CARTOON HERE, THAT
WE FOUND A POPULATION OF
INDIVIDUALS WHO MAY HAVE A
DECREASE IN LIGHT SENSITIVITY
EVEN THOUGH THEY HAVE NORMAL
IMAGE-FORMING VISION.
NOW WHAT'S REALLY INTERESTING
ABOUT THIS IS THAT AT THE SAME
TIME THAT WE WERE DOING THIS
WORK, AND I FORGOT TO HIGHLIGHT
HERE, A SHOUT OUT TO THE
AMERICAN SLEEP FOUNDATION, BUT
AS WE WERE DOING THIS WORK, AT
THE SAME TIME THERE WAS A GROUP
IN AUSTRALIA ASKING SOME OF THE
SAME QUESTIONS SO THEY ACTUALLY
FOUND A POPULATION OF
INDIVIDUALS WITH DELAYED
SLEEP-WAKE PHASE DISORDER BUT IN
THEIR CASE, THEY ACTUALLY FOUND
THEY HAD GREATER LIGHT
SENSITIVITY, AND SO THEY SHOWED
GREATER PHASE SHIFTS TO EVENING
LIGHT, AND GREATER MELATONIN
SUPPRESSION.
SO IT LOOKS LIKE SOME PEOPLE
WITH DSPD CAN FALL ON ONE END OF
THE SPECTRUM WHERE THEY HAVE
INCREASED LIGHT SENSITIVITY AND
OTHERS CAN FALL ON THE OTHER END
OF THE SPECTRUM WHERE THEY HAVE
DECREASED LIGHT SENSITIVITY.
NOW, WHAT I LOVE ABOUT THIS
PROJECT IS, IT ACTUALLY HAS LED
TO A COLLABORATION BETWEEN OUR
GROUP AND THE AUSTRALIAN GROUP,
AND TRYING TO FIGURE OUT WHY OR
HOW THESE DIFFERENT PHENOTYPES
EXIST AND WHAT WE CAN DO FOR
THEM.
SO THIS IS A MODEL THAT ANDREW
PHILLIPS PUT TOGETHER TRYING TO
EXPLAIN THIS, BECAUSE ONE OF THE
MOST INTERESTING THINGS BETWEEN
OUR TWO POPULATIONS WAS THAT OUR
LOW LIGHT SENSITIVITY
INDIVIDUALS TENDED TO HAVE MUCH
LATER HABITUAL SLEEP TIMES THAN
THEIR HIGHLIGHT SENSITIVITY
INDIVIDUALS.
SO WHAT HE'S PUT TOGETHER HERE,
JUST TO WALK YOU THROUGH THIS,
IS A GRAPH LOOKING AT HOW
SENSITIVE YOU ARE TO LIGHT, SO
HIGHER AND LOWER, AND THEN WHAT
YOUR INTRINSIC CIRCADIAN PERIOD
IS.
SO MOST OF US ARE RELATIVELY
CLOSE TO 24 HOURS HERE, BUT SOME
INDIVIDUALS WITH THE CIRCADIAN
DISORDERS TEND TO HAVE LONGER
PERIODS.
SO IF YOU'RE OUT HERE WHERE
YOU'VE GOT A RELATIVELY NORMAL
PERIOD AND IT DOESN'T REALLY
SEEM TO MATTER WHAT YOUR LIGHT
SENSITIVITY IS, BUT AS YOU GET
TO A POINT WHERE YOUR PERIOD IS
LONGER, IF YOU HAVE EITHER HIGH
OR LOW LIGHT SENSITIVITY, YOU
COULD HAVE DEVELOPED A SLEEP
WAKE PHASE -- YOU COULD EVEN
HAVE NORMAL LIGHT SENSITIVITY
AND STILL DEVELOP DSPD, AND THEN
IF YOU'RE UNFORTUNATE ENOUGH TO
HAVE BOTH A LONG PERIOD AND LOW
LIGHT SENSITIVITY THEN YOU MAY
FALL INTO THE NON-24 CATEGORY.
STHIS IDEA THAT WE HAVE DIFFERET
PATHWAYS TO DSPD AND DIFFERENT
PHENOTYPES IS NOT NEW.
SO THIS IS A PAPER THAT WAS
PUBLISHED IN 2017 THAT WAS
TRYING TO RECRUIT PATIENTS WITH
DSPD.
AND BASED ON CLINICAL INTERVIEW,
THEY ALL MET THE CRITERIA THAT I
OUTLINED FROM THE ICSD AND THEY
ALL MET THE CRITERIA FOR DSPD.
THEY THEN TOOK A MEASURE OF
MELATONIN, WHICH IS ONE OF THE
MARKERS THAT CAN HELP INDICATE
CIRCADIAN TIMING, AND THEY FOUND
THAT ABOUT 60% OF THEM HAD A
DOWN LOW OCCURRING BEFORE
BEDTIME WHEREAS ABOUT 40% DO
NOT.
WE CAN GO THROUGH SORT OF AN
EXAMPLE HERE.
IF WE HAVE OUR CONTROL KIND OF
OUR CONVENTIONAL SLEEP-WAKE
TIMING HERE, UNDER NORMAL
CONDITIONS, YOUR MELATONIN ONSET
SHOULD BE ABOUT TWO HOURS BEFORE
YOUR H HABITUAL BEDTIME, SO
SOMEBODY WHO'S SLEEPING FROM
10:00 P.M. TO 6:00 A.M., WE
WOULD EXPECT THEIR DLMO TO OCCUR
ABOUT HERE.
WE HAVE TWO DIFFERENT PEOPLE
HERE WITH DSPD, BOTH ARE FALLING
ASLEEP AT 2 AND WAKING UP AT 10
BUT YOU CAN IMAGINE BOTH OF THEM
MAY WANT TO GO TO BED AT 10 AND
WAKE UP AT SIX.
THE QUOTE-UNQUOTE CIRCADIAN
DSWPD INDIVIDUAL, THEIR DLMO IS
OCCURRING PAST THEIR -- THIS
OTHER GROUP IS REALLY
INTERESTING, SO THE
NON-CIRCADIAN DSPD, THEIR DLMO
IS OCCURRING AT THE SAME TIME AS
SOMEBODY WHO CAN FALL ASLEEP AT
10:00 BUT THEY'RE NOT ABLE TO
FALL ASLEEP UNTIL 2:00 A.M.
NOW WHAT'S REALLY INTERESTING
ABOUT THIS POPULATION IS THAT
THEY'RE PRESUMABLY ABLE TO DO
THIS NIGHT AFTER NIGHT, AND SO
THERE SEEMS TO BE A DESYNCHRONY
OR A MISMATCH BETWEEN THAT MEL
TOE NEN SAIR CADEIAN MARKER AND
THAT MARKER OF SLEEP THAT
PERSISTS.
SO THIS INDIVIDUAL, I DON'T
THINK IS THE SAME AS THIS
INDIVIDUAL, BUT I'M NOT SURE
THAT THEY DON'T HAVE A CIRCADIAN
PROBLEM.
I THINK IT MAY JUST BE A
DIFFERENT CIRCADIAN PROBLEM THAN
OUR MIDDLE INDIVIDUAL.
BECAUSE OF THAT, WE SUGGESTED
MORE NEUTRAL TERMINOLOGY UNTIL
WE BETTER FIGURE OUT THE
PATHOLOGY, SO PACEICALLY JUST
TAKING THAT CIRCADIAN GROUP AND
CALLING THEM DSPD TYPE 1 AND
TYPE 2 UNTIL WE CAN BETTER
UNDERSTAND WHY THESE TWO
PHENOTYPES EXIST.
AND WHY IS THAT IMPORTANT?
AND FOR THAT, I WANT TO CIRCLE
BACK TO SOME OF THE QUESTIONS
THAT MY PATIENTS HAVE POSE THE.
WHAT I HAVE HERE IS THE 2007
PRACTICE PARAMETERS FOR CLINICAL
EVALUATION AND TREAT M OF
CIRCADIAN RHYTHM SLEEP
DISORDERS.
THAT PATIENT I SHOWED YOU AT THE
BEGINNING ON HIS VERY FIRST
APPOINTMENT, HE WALKED IN WITH
THIS PAPER IN HAND, AND HE SAID,
THESE WERE PUBLISHED IN 2007.
AT THAT TIME, THE ONLY
RECOMMENDATIONS WERE TO USE
LIGHT AND MELATONIN.
IT'S NOW 2013.
WHAT ELSE IS AVAILABLE?
AND THAT REALLY STRUCK ME AT THE
TIME, ESPECIALLY WHEN OUR 2015
GUIDELINES CAME OUT AND WE
ACTUALLY ENDED UP WITH EVEN LESS
TO OFFER HIM AT THAT POINT.
SO IF YOU LOOK AT THE 2015
TREATMENT GUIDELINES, THE
QUESTION IS WHAT HAPPENED TO
LIGHT AT THAT POINT?
AND IT'S NOT THAT LIGHT WAS
DEMONSTRATED TO BE HARMFUL AT
ALL IN THIS POPULATION.
IT'S JUST THERE WAS INSUFFICIENT
EVIDENCE TO SUPPORT EFFICACY OF
LIGHT THERAPY USING THEIR OUT
COME MEASURES, SO THEY WEREN'T
ABLE TO MAKE A RECOMMENDATION.
I THINK PART OF THAT, AND THIS
IS ME THEORIZING, COMES FROM THE
FACT THAT THEY HAVE THIS SORT OF
MUDDY POPULATION WHERE WE'RE PUT
AGO CLINICAL PHENOTYPE TOGETHER
WHEN THEY MAY HAVE DIFFERENT
UNDERLYING PATHOPHYSIOLOGY.
JUST TO ILLUSTRATE THAT, ONE OF
THE PAPERS THAT WAS CITED TO SEE
IF WE COULD RECOMMEND LIGHT IS
THIS ONE HERE, THESE -- A BRIGHT
WHITE LIGHT MASK OR PLACEBO,
THEY GIVE THEM LIGHT FOR FOUR
HOURS ON AWAKENING, AND THEY
FOUND THAT OVERALL, THE RESULTS
WERE NOT SIGNIFICANT, BUT IF
THEY DID A SUBGROUP ANALYSIS
LOOKING AT THOSE INDIVIDUALS WHO
HAD LATER MELATONIN ACROPHASES,
THEY ACTUALLY DID RESPOND
COMPARED TO THE REST OF THE
GROUP.
AND SO YOU CAN THEORIZE THAT
MAYBE THEY HAD THEM -- THOSE WHO
HAD A LATER AND MORE CONCORDANT
DLMO WERE THE ONES WHO ACTUALLY
RESPONDED TO LIGHT AND IT MAYING
THAT THIS POPULATION DOESN'T
RESPOND AS WELL TO LIGHT AND WE
NEED TO START BETTER PHENOTYPING
TO FIND BETTER TREATMENTS.
SO THIS IS KIND OF LAYING OUT
WHAT THAT MIGHT LOOK LIKE.
IF YOU HAVE SOMEBODY WHO IS DS
PD-1 WITH HIGH IS THE LIGHT
SENSITIVITY, AVOID EVENING
LIGHT, SEEK MORNING LIGHT.
IF YOU HAVE DS PD-1 WITH LOW
LIGHT SENSITIVITY, YOU CAN
OPTIMIZE NON-PHOTI, ZEITGEBERS,
ANYTHING LIGHT-BASED THAT HELPS
YOUR BODY KNOW WHAT TIME IT IS,
AND PHARMACOLOGICALLY WE'RE
LOOKING AT ARE THERE -- CAN WE
RESCUE THE CIRCADIAN LIGHT
RESPONSE.
IS THIS SOMEBODY THAT MAY HAVE
THE CIRCADIAN STATE, BUT THEY --
THAT HELPS THEM TO FALL ASLEEP
THEN, AND ARE THERE -- CAN WE
PULL FROM THINGS WE DO IN
INSOMNIA AND ELSEWHERE TO TRY TO
HELP THIS PARTICULAR POPULATION
AN WHY IS IT THAT THEY HAVE THAT
INTERNAL DESYNCHRONY.
SO WE WERE ASKED TO KIND OF
HIGHLIGHT GAPS IN AND AREAS OF
REAR SEARCH.
WE DO NEED TO TAKE INTO ACCOUNT
THESE DIFFERENT -- I THINK IT
WILL HELP US COME UP WITH
BETTER, MORE TARGETED
TREATMENTS.
ALSO, AS WE'RE TALKING ABOUT
TREATMENTS, AGAIN GOING BACK TO
THAT PATIENT AFTER I STARTED
SEEING HIM, THIS STUDY WAS
RELEASED LOOKING AT TASIMELTEON
FOR NON-24 HOUR SLEEP-WAKE
DISORDER.
IN THIS PARTICULAR TRIAL, THEY
DID FIND THAT ABOUT 20% OF THE
PATIENTS WHO ARE ENROLLED DID
ENTRAIN WITHIN ONE MONTH
COMPARED TO ABOUT 3% IN THE
PLACEBO GROUP.
AND I PUT HERE THE ACTUAL
VERBIAGE FROM THE FDA ABOUT THE
APPROVAL OF THIS MEDICATION FOR
USE IN NON-24.
YOU CAN SEE INDICATIONS AND
USAGE, BUT AS A CLINICIAN, IT
HAS BEEN PARTICULARLY CHALLENGES
BECAUSE IF THE INSURANCE
COMPANIES IF BACK TO THE PRIMARY
DATA, THEY SAY THIS MEDICATION
WAS ONLY STUDIED IN BLIND
INDIVIDUALSMENT AND SO THEY
OFTEN DENY IT FOR MY CITED
PATIENTS EVEN THOUGH THE FDA
SPECIFICATIONS DON'T SPECIFY.
SO MY AREA OF RESEARCH NEED,
NUMBER TWO, IS TO MAKE SURE
YOU'RE CONSIDERING THE FACT THAT
BOTH SIGHTED AND BLIND
INDIVIDUALS MAY HAVE NON-24,
THEY MAY -- RIGHT NOW WE HAVE
ALMOST NOTHING TO RECOMMEND FOR
THEM.
IT'S ALL SORT OF EXPERIMENTAL.
AND THEN LASTLY, JUST TO BRIEFLY
GET ON MY CLINICIAN SOAP BOX, I
HIGHLIGHTED THE ICSD DIAGNOSTIC
CRITERIA FOR DSPD, AND JUST TO
POINT OUT HERE, ONE OF THE TOOLS
WE USE TO DIAGNOSE IS A
RECOMMENDATION FOR ACTIGRAPHY
MONITORING.
NOW, AS A FIELD, I THINK ANYBODY
WHO PRACTICES SLEEP OR SAADE
MEDICIRCADIANRESEARCH, THIS STUS
PUBLISHED SEVERAL YEARS AGO
SHOWING ALL THE SPACES
ACTIGRAPHY CAN BE HELPFUL FOR
OUR PATIENTS.
ANY TIME YOU ACTUALLY TRY TO USE
ACTIGRAPHY IN THIS CASE AND TRY
TO GET IT -- AGAIN, WE'RE BACK
TO BEING DENIED BY -- TRYING TO
FIGURE OUT WHAT IS THE RATIONALE
WHEN AS A FIELD, WE'RE SAYING WE
NEED THIS AND THE INSURANCE
COMPANIES ARE PUSHING BACK AND
SAYING NO, AND SO GOING INTO THE
COVERAGE GUIDELINES AND ACTUALLY
READING AND TRYING TO GET A
PERSPECTIVE OF WHERE THEY'RE
COMING FROM, THIS IS WHERE THAT
DENIAL IS COMING FROM, WHICH IS
BASICALLY THAT ACTIGRAPHY IS
CONSIDERED EXPERIMENTAL,
INVESTIGATIONAL AND/OR UNPROVEN,
AND IT'S REALLY THAT THEY'VE SET
THE BAR FOR WHETHER OR NOT
ACTIGRAPHY IS BENEFICIAL RIGHT
HERE.
WHICH SAYS, DOES THE USE OF ACT
GA FEE IN THE USE OF SLEEP
DISORDERS IMPROVE THE NET HEALTH
OUTCOME?
WHICH IS KIND OF A HARD BAR TO
HIT.
COMPARING ACTIGRAPHY TO THINGS
LIKE GSP AND SLEEP DIARIES AND
ESSENTIALLY WHAT THEY CAME DOWN
TO BOTH FOR ADULTS AND FOR
CHILDREN WAS THAT THE EVIDENCE
IS INSUFFICIENT TO DETERMINE
THAT THE TECHNOLOGY RESULTS IN
AN IMPROVEMENT IN THE NET HEALTH
OUTCOMES.
OUTCOME.
MY FINAL CHARGE IS FOR YOU TO
MAKE USE OF THESE CON DER FULL
TOOLS WE HAVE IN THE CLINIC.
ONE OF THE BIGGEST BARRIERS WE
HAVE RIGHT NOW IS MAKING SURE
THAT OUR PATIENTS ARE ABLE TO
GET THESE DIAGNOSTIC TOOLS PAID
FOR.
SO IF WE'RE GOING TO PLAY THE
INSURANCE GAME, WE NEED MORE
TRIALS TO DEMONSTRATE THE
BENEFIT OF INCLUDING ACTIGRAPHY
AND ALSO MELATONIN TESTING, FOR
THE CLINICAL OUTCOMES OF THESE
POPULATIONS.
AND SO WITH THAT, I WOULD JUST
LIKE TO WRAP UP BY ACKNOWLEDGING
BOTH PHYLLIS AND KATHY, WHO
REALLY HELPED ME WITH GETTING
THE CIRCADIAN CLINIC GOING, AS
WELL AS TRANSITIONING FROM
ANIMAL TO HUMAN RESEARCH, OUR
COLLABORATORS IN YOU -- AS WELLS
OUR STAFF WHO COLLECTED MUCH OF
THE DATA I SHOWED AS WELL AS THE
FUNDING AND LAST BUT CERTAINLY
NOT LEAST, ALL OF THE PATIENTS
WHO ALCOHOL E CHALLENGED ME ANDE
ABOUT THIS DISEASE.
THE PHRASE THAT IS CONSTANTLY IN
THE BACK OF MY MIND, WHICH IS,
IT'S 2024, WHAT ELSE DO WE HAVE
NOW?
I HAVE TO SAY, MY PATIENT IS
VERY KIND.
HE DOES NOT COME TO EVERY SINGLE
APPOINTMENT AND SAY THAT OVER
AND OVER, BUT IN THE BACK OF MY
HEAD, EVERY TIME I TURN THE
CALENDAR, THAT'S THE PHRASE
THAT'S OUT THERE AND I THINK
REMEMBERING THAT WE HAVE
PATIENTS SITTING IN CLINIC RIGHT
NOW LOOKING FOR THESE ANSWERS
FOR US.
SO WITH THAT, I WOULD BE HAPPY
TO WRAP UP.
>> THANK YOU SO MUCH.
AND DEFINITELY SOMETHING TO
REMEMBER.
WE HAVE SOME EXCELLENT QUESTIONS
IN THE CHAT.
I JUST WANTED A QUICK REMINDER,
KEEP PUTTING YOUR -- OR IN THE Q
& A BOX.
KEEP PUTTING YOUR QUESTIONS IN
THE Q & A BOX FOR THE DESIGNATED
Q & A SESSION FOLLOWING THE NEXT
TALK.
AND NOW I'D LIKE TO INTRODUCE
DR. NOUR MAKAREM FOR A
PRESENTATION ON CHRONOMEDICINE.
>> GOOD AFTERNOON, EVERYONE.
AND THANK YOU SO MUCH TO THE
ORGANIZERS FOR INVITING ME TO
PRESENT.
MY PRESENTATION WILL ADDRESS
ADVANCES AND OPPORTUNITIES IN
CHRONOMEDICINE FOR HEALTH
PRESERVATION AND CHRONIC DISEASE
PREVENTION.
I HAVE NO CONFLICTS OF INTEREST
TO DISCLOSE.
IN TERMS OF THE LEARNING
OBJECTIVES FOR MY TALK, BY THE
END OF THIS PRESENTATION,
ATTENDEES SHOULD BE ABLE TO
DEFINE CHRONOMEDICINE AND
UNDERSTAND ITS POTENTIAL ROLE IN
HEALTH PRESERVATION AND CHRONIC
DISEASE AND TREATMENT, TO
DESCRIBE -- FOCUSING ON
CARDIOMETABOLIC OUTCOMES AND
CARDIOVASCULAR DISEASE, AND ALSO
TO DESCRIBE HOW OPTIMIZING IF --
COULD ENHANCE PREVENTION AND
TREATMENT APPROACHES.
I'LL END BY OUTLOONING
CHALLENGES TO ADVANCING
CHRONOMEDICINE RESEARCH AND ALSO
HIGHLIGHTING KEY RESEARCH
PRIORITIES TO ADVANCE THIS FIELD
AND LEVERAGE CHRONOMEDICINE
APPROACHES FOR EXTENDING
HEALTHSPAN AND PREVENTING
CHRONIC DISEASE.
SO I'LL START WITH BASICS WITH
THE DEFINITION OF CHRONOMEDICINE
WHICH ESSENTIALLY TELLS US THAT
TIMING MATTERS.
CHRONOMEDICINE IS AN INNOVATIVE
SUBDISCIPLINE OF MEDICINE THAT
IS FOCUSED ON THE ROLE OF TIME
IN PHYSIOLOGY, ENDOCRINOLOGY,
METABOLISM AND BEHAVIOR AT
MULTIPLE ORGANIZATIONAL LEVELS
TO PRESERVE HEALTH AND TO
PREVENT, DIAGNOSE AND TREAT
DISEASE.
NOW CHRONOMEDICINE HAS MANY
APPLICATIONS AT THE INDIVIDUAL
AND THE POPULATION LEVEL THAT
ARE PHARMACOLOGIC OR
NON-PHARMACOLOGIC.
FORM ENCLOSE JIK APPLICATIONSPHE
TOXICITY AND SIDE EFFECTS.
SO REALLY GOOD EXAMPLES OF THIS
WOULD INCLUDE PAYING ATTENTION
TO THE TIMING OF CHEMOTHERAPY
AMONG CANCER PATIENTS, OR
BEDTIME DOSING MEDICATION TO
IMPROVE THE BLOOD PRESSURE
PATTERN DURING SLEEP AND
ATTENUATE THE MORNING SURGE.
BUT IN MY TALK TODAY, I'M GOING
TO FOCUS MORE ON THE
NON-PHARMACOLOGIC APPLICATIONS,
SPECIFICALLY ADDRESSING THE
TIMING OF ENVIRONMENTAL CUES AND
BEHAVIORAL FACTORS TO OPTIMIZE
CIRCADIAN RHYTHMS AND TO PROMOTE
HEALTH, MAXIMIZE DISEASE
PREVENTION AND DIESEL B DECELERE
BIOLOGICAL AGING.
SO AS THE PRIOR SPEAKERS HAVE
ALREADY INDICATED, OUR CIRCADIAN
RHYTHMS ARE CLOALED BY A MASTER
CLOCK THAT IS ENTRAINED BY
LIGHT.
BUT OUR OUR BEGANS, INVOLVED IN
METABOLIC PROCESSES, ALSO HAVE
THEIR OWN CLOCKS THAT REGULATE
THEIR FUNCTION AND THESE CLOCKS
ARE ALSO ENTRAINED BY OUR
EATING, SLEEP AND ACTIVITY
PATTERNS.
SO WHEN EATING, SLEEP AND
ACTIVITY PATTERNS OCCUR AT
UNCONVENTIONAL CIRCADIAN TIMES
OR ARE IRREGULAR, THESE PRIF RAM
CLOCKS BECOME MISS ALIGNED WITH
THE MASTER CLOCK IN THE BRAIT
CREATING A CASE OF CIRCADIAN
MISALIGNMENT WHICH LEADS TO
OBESITY, TYPE 2 DIABETES,
HYPERTENSION, HEART DISEASE, AS
WELL AS OTHER THINGS LIKE CANCER
AND OTHER PSYCHIATRIC DISORDERS.
IN MY NEXT SET OF SLIGHTS, I'M
GOING TO PROVIDE A HIGH LEVEL
SUM REAL OF WHAT IF WE KNOW
ABOUT THIS.
AND I'LL START WITH
CHRONONUTRITION WHICH REALLY
FOCUSES ON THE TIMING AND
REGULARITY OF EATING PATTERNS IN
THE 24-HOUR DAY AND ACROSS DAYS,
WHICH MAY BE AN IMPORTANT TARGET
FOR PROMOTING OUR CIRCADIAN
HEALTH.
SO ASPECT OF CHRONONUTRITION,
LIKELY CONTRIBUTES SUBSTANTIALLY
TO THE CHRONIC DISEASE BURDEN
THAT WE OBSERVE AT THE
POPULATION LEVEL, PARTICULARLY
THAT AMERICANS HAVE A TENDENCY
FOR LATER EATING TIMING,
SIGNIFICANT NIGHTTIME EATING AND
ERRATIC -- SHOWS THAT U.S.
ADULTS ESSENTIALLY EAT AROUND
THE CLOCK AND THERE'S A
FIVE-HOUR WINDOW BETWEEN 1 AND
6A.M. DURING WHICH -- MOST OF
THE CLORK INTAKE TENDS TO OCCUR
LATER IN THE DAY, AND THERE
SEEMS TO BE SUBSTANTIAL DAY TO
DAY VARIABILITY IN EATING TIMING
PATTERNS, WHICH BECOMES MOST
PRONOUNCED WHEN WE COMPARE
WEEKDAYS TO WEEKENDS.
NOW THESE METRICS HAVE BEEN MOST
EXTENSIVELY STUDIED IN RELATION
TO OBESITY RISK.
HERE ON MY SLIDE, I A COUPLE OF
LANDMARK FIGURES.
THESE ARE FINDINGS FROM A LARGE
PROSPECTIVE OBSERVATIONAL STUDY
OF U.S. AND CANADIAN ADULTS
RECRUITED FROM SEVENTH DAY
CHURCHES AND THEY EVALUATED THE
TIMING OF THE LARGEST MEAL IN
RELATION TO BMI AND THEY FOUND
THAT RELATIVE TO THOSE -- HAD A
SIGNIFICANT DECREASE I DURING TE
SEVEN-YEAR FOLLOW-UP PERIOD.
THE FIGURE ON THE RIGHT SIDE OF
MY SLIDE ARE FINDINGS FROM A
MEMETA-ANALYSIS OF RCTs AND THE
RESULTS CLEARLY SHOW EARLIER
EATING IMPROVES WEIGHT LOSS BY
23% WHICH IS A REALLY CLINICALLY
MEANINGFUL RESULT.
NOW ALTHOUGH EATING TIMING HAS
BEEN MOSTLY STUDIED TO OBESITY
RISK, IT'S ALSO BEEN RELATED TO
A -- THE FINDINGS GENERALLY TEND
TO SHOW THAT EARLIER EATING
TIMING IS RELATING TO LOWER
LEVELS OF LDL CHOLESTEROL,
BETTER FLY SEE MIBG REGULATION
-- BETTER GLYCEMIC -- NOWANOTHF
CARDIOMETABOLIC OUTCOMES IS THE
VARIABILITY IN EATING TIMING
PATTERNS.
AND HERE I'M PRESENTING FINDINGS
FROM A COUPLE OF PAPERS THAT WE
PUBLISHED IN MY RESEARCH GROUP
WHICH EVALUATED DAY TO DAY
VARIABILITY IN EATING TIMING AS
WELL AS EATING JET LAG IN
RELATION TO CARDIOMETABOLIC
OUTCOMES, SO WHAT WE DID IN THIS
STUDY IS THAT WE USED THE MIH'S
SAS24 TO OBTAIN ELECTRONIC FOOD
RECORDS, AND THESE DATA WERE
USED TO EX-PRAK THE TIMING OF
THE FIRST AND THE LAST EATING --
AND WE USED THE STANDARD
DEVIATION OF THESE VARIABLES AS
A MEASURE OF DAY TO DAY
VARIABILITY IN EATING TIMING
PATTERNS AND WEEKDAY/WEEKEND
DIFFERENCES AS A MEASURE OF WHAT
WE CALLED EATING JET LAG.
WHAT WE FOUND IS GREATER DAY TO
DAY VARIABILITY IN EATING TIMING
WAS ASSOCIATED WITH
SIGNIFICANTLY HIGHER BMI, HIGHER
WASTE CIRCUMFERENCE, HIGHER
BLOOD PRESSURE, AND HIGHER
LEVELS OF CRP AS A MARKER OF
SYSTEMIC INFLAMMATION.
NOW TIGHTLY INTERTWINED WITH THE
TIMING AND REGULARITY OF OUR
EATING PATTERNS IS, OF COURSE,
THE TIMING AND REGULARITY OF OUR
SLEEP-WAKE PATTERNS, WHICH IS
ALSO AN IMPORTANT TARGET FOR
PROMOTING CIRCADIAN HEALTH.
IT IS WELL ESTABLISHED THAT
LATER SLEEP TIMING, WHICH WE
TYPICALLY OBSERVE IN EVENING
OROTATING SHIFT WORK AND IN --
AS WELL AS SLEEP DURATION AND
SLEEP TIMING ARE BOTH RINKED --
METABOLIC SYNDROME, DIABETES,
HYPERTENSION, AND ALSO TO HIGHER
ODDS OF HAVING POOR
CARDIOVASCULAR HEALTH AS DEFINED
BY THE AMERICAN HEART
ASSOCIATION FRAME WORKS.
BUT BEYOND JUST LOOKING AT SLEEP
TIMING AND REGULARITY, WE CAN
INTEGRATE INFORMATION ON SLEEP
AND ACTIVITY FROM MULTIPLE DAYS
TO -- THESE REPRESENTING SENT
THE MAGNITUDE TIMING -- IN THE
24-HOUR DAY AND ACROSS DAYS AND
CAN SERVE AS A MEASURE OF
CIRCADIAN RHYTHMICITY IN A
FREE-WORLD SETTING.
NOW BEFORE I JUMP INTO SOME
FINDINGS ABOUT REST ACTIVITY
RHYTHMS IN RELATION TO CHRONIC
DISEASE, I JUST WANTED TO
MENTION THAT WE CAN USE
PARAMETRIC AND NON-PARAMETRIC
APPROACHES TO MEASURE REST
ACTIVITY RHYTHMS.
IN MY SLIDES I'M GOING TO FOCUS
MORE ON THE NON-PARAMETRIC REST
ACTIVITY RHYTHM VARIABLES
BECAUSE THEY ARE -- I FEEL THAT
THEY ARE EASIER TO INTERPRET AND
MORE EASILY TRANSLATED INTO
PUBLIC HEALTH GUIDELINES.
SO THE FIRST METRIC IS ENTER
DAILY STABILITY, WHICH IS A
MEASURE OF INVARIABILITY BETWEEN
DAYS AND SYNCHRONIZATION TO
LIGHT AND DARK CYCLES WHEREBY
HIGHER VALUES INDICATE GREATER
STABILITY.
THE SECOND METRIC IS INTERDAILY
VARIABILITY, WHEREBY HIGHER
VALUES INDICATE A MORE
FRAGMENTED RHYTHM AND
INEFFICIENT SLEEP.
WE ALSO EXTRACT THE COUNTS AND
THE MIDPOINT OF THE MOST ACTIVE
10-HOUR PERIOD AND THE LEAST
ACTIVE FIVE-HOUR PERIOD.
FOR THE MOST -- AND A HIGHER
MIDPOINT WOULD REPRESENT BEING
ACTIVE LATER ON IN THE DAY.
FOR THE LEAST ACTIVE FIVE HAD
BEEN HOUR PERIOD, HIGHER COUNTS
WOULD INDICATELESS RESTFUL SLEEP
AND A LIGHTER -- AND FINALLY WE
USE THESE MEASURES TO COMPUTE
RELATIVE AMPLITUDE WHICH WE CAN
THINK OF AS A SUMMARY RE SURE OF
THE ROBUSTNESS OF THE OVERALL
ACTIVITY RHYTHM WHERE HIGHER
VALUES REPRESENT A GREATER
OVERALL CIRCADIAN RHYTHMICITY.
SO JUST TO SHOW YOU WHAT THIS
TYPICALLY LOOKS LIKE, THE
ACTIGRAPHY DATA LOOKS LIKE WHAT
YOU SEE HERE IN THE TOP FIGURE
ON MY SLIDE.
YOU SEE A VERY CLEAR REST
ACTIVITY PATTERN WITH HIGH
LEVELS OF ACTIVITY DURING WAKE
TIME, AND CONSOLIDATED SLEEP
PERIODS AT NIGHT.
WHEREAS SOMEONE -- HERE CAN YOU
SEE FROM THEIR ACTIGRAPHY, THAT
THEIR RHYTHM IS REALLY SPORADIC
AND THERE IS NO CLEERM PATTERN.
SO THESE ARE GENERALLY OBSERVED
IN A NUMBER OF NEURODEGENERATIVE
DISEASES AND PRE-CLINICAL
ALZHEIMER'S DISEASE AND CANCER
PATIENTS AND PSYCHIATRIC
DISORDERS, PARTICULARLY AMONG
INDIVIDUALS WITH DEPRESSION,
AND -- HIGHER RISK FOR POOR COG
NICKS, ACCELERATE BID BIOLOGICAL
AGING AND ALSO TO ANNUM BER OF
CARDIOMETABOLIC DISEASES AS I
WILL SHOW IN THE NEXT COUPLE OF
SLIDES.
SO HERE I'LL GIVE AN EXAMPLE
FROM A STUDY THAT WE PUBLISHED
ON REST-ACTIVITY RHYTHMS IN
RELATION TO CARDIOVASCULAR
DISEASE, HYPERTENSION, OBESITY
AND CENTRAL ADIPOSITY IN A
NATIONALLY REPRESENTATIVE SAMPLE
OF U.S. ADULTS.
AND IN THAT STUDY, WE SHOW THAT
GREATER DAY TO DAY STABILITY IN
SLEEP WAKE AND REST ACTIVITY
PATTERNS, A MORE ACTIVE WAKE
PERIOD AND MORE ROBUST OVERALL
RHYTHM ARE ASSOCIATED WITH UP TO
72% LOWER ODDS OF PREVALENT
CARDIOVASCULAR DISEASE, WHEREAS
HAVING A MORE FRAGMENTED RHYTHM
AND LESS RESTFUL SLEEP WERE
ASSOCIATED WITH UP TO THREE
HOLDS -- NOW WHEN WE EVALUATED
THE ASSOCIATIONS OF THESE REST
ACTIVITY WITHIN VARIABLES WITH
OTHER CARDIOMETABOLIC OUTCOMES,
SPECIFICALLY HYPERTENSION,
OBESITY AND CENTRAL ADIPOSITY,
AGAIN WE OBSERVED SIMILAR
ASSOCIATIONS, PARTICULARLY FOR
OBESITY, THE ASSOCIATIONS
EXACTLY MIRRORED WHAT WE
OBSERVED FOR CARDIOVASCULAR
DISEASE, WITH YOU ONE THING ON
REST ACTIVITY RHYTHMS IN
RELATION TO DPSH EMERGES AS A
VERY STRONG PREDICTOR.
SO THIS REALLY UNDERSCORES THE
IMPORTANCE OF CIRCADIAN
RHYTHMICITY FOR PREVENTING
DISEASE AT THE CHRONIC
POPULATION LEVEL.
NOW IN THE PREVIOUS STUDY THAT I
SHOWED YOU, WE DID NOT LOOK AT
TYPE 2 DIABETES AS AN OUTCOME,
BUT I DID WANT TO SHARE THESE
FINDINGS FROM ANOTHER ANALYSIS
IN A DIFFERENT COHORT,
SPECIFICALLY THE -- JUST TO SHOW
THAT THE ASSOCIATIONS
ESSENTIALLY MIRRORED WHAT WE SAW
FOR KRARD YOE VASCULAR DISEASE,
AND THIS IS VERY NICELY
ILLUSTRATED IN THIS FIGURE HERE,
WHERE WE PREIVET THE PREVALENCE
OF -- AND YOU CAN SEE VERY
CLEARLY THAT THOSE WHO ARE IN
THE HIGHEST QUINTILE OF RELATIVE
AM BLI TEUD, HAD THE LOWEST
PREVALENCE OF TYPE 2 DIABETES AT
13% COMPARED TO THOSE IN THE
LOWEST QUINTILE OR THOSE WHO
HAVE THE LOWEST RHYTHMICITY THE
PREVALENCE WAS MUCH HIGHER AT
32%.
OH ?T PREVIN THE PREVIOUS SLIDEI
PROVIDED A SUMMARY OF THE
ASSOCIATION BETWEEN BEHAVIORAL
RHYTHMS AND A NUMBER OF
TRADITIONAL CARDIOMETABOLIC
OUTCOMES THAT ARE TYPICALLY
CAPTURED IN A CLINICAL SETTING
OR A PUBLIC HEALTH SETTING.
BUT ONE IMPORTANT THING TO
REMEMBER IS THAT THESE CLINICAL
INDICATORS OR THESE
CARDIOMETABOLIC RISK FACTORS
THEMSELVES HAVE RHYTHMS THAT MAY
BE INFLUENCED BY BEHAVIORAL
RHYTHMS AND THAT MAY OFFER
PROGNOSTIC SIGNIFICANCE BEYOND
WHAT IS TYPICALLY CAPTURED IN A
CLINICAL AND PUBLIC HEALTH
SETTING.
AND A REALLY GOOD EXAMPLE OF
THIS IS BLOOD PRESSURE.
SO OUR BLOOD PRESSURE FOLLOWS A
DIURNAL PATTERN THAT COULD BE
MEASURED BY AMBULATORY BLOOD
PRESSURE MONITORING, SO AN
INDIVIDUAL WEARS TH THE MONITORR
A 24 HOUR PERIOD AND GOES ABOUT
THEIR DAILY ACTIVITIES, AND IT'S
MONITORED TO MONITOR SAY EVERY
30 MINUTES.
THIS ALLOWS US TO EXTRACT
MEASURES LIKE MEAN 24-HOUR BLOOD
PRESSURE, NOW IN HEALTHY
INDIVIDUALS, THE BLOOD PRESSURE
VARIATION PATTERN OVER 24 HOURS
TYPICALLY IS SUCH THAT BLOOD
PRESSURE IS HIGHER DURING
WAKEFULNESS AND LOWER DURING
SLEEP.
AND IN FACT THE IN A HEALTHY
INDIVIDUAL SHOULD DIP10 TO 20%
DURING THE SLEEP PERIOD.
THIS IS NOT NECESSARILY THE
PHENOTYPE, THERE ARE MANY OTHER
PHENOTYPES.
SOME HAVE -- OTHERS ARE EXTREME
DIPPERS MEANING IT DIPS TOO MUCH
AND OTHERS HAVE A RISER PATTERN
WHICH MEANS PRESSURE GOES UP
DURING THEIR SLEEP.
OF COURSE THE EXTENT OF THE
MORNING SURGE CAN ALSO VARY.
FROM PERSON TO PERSON.
AND THESE DIFFERENT PHENOTYPES
HAVE DIFFERENTIAL ASSOCIATIONS
WITH CHRONIC DISEASE RISK.
INDEED STUDIES ARE INCREASINGLY
SHOWING THAT LOSS OR DISRUPTION
OF THE CIRCADIAN RHYTHM --
SORRY, LOSS OR DISRUPTION OF
BLOOD PRESSURE CIRCADIAN RHYTHM
IS LINKED TO A NUMBER OF ADVERSE
OUTCOMES INCLUDING DEMENTIA,
CHRONIC KID KNEES DEED.
YOU CAN CLEARLY SEE THAT
INDIVIDUALS WHO HAD HIGHER
NIGHTTIME BLOOD PRESSURE AND A
HIGHER NIGHT TO DAY RATIO AND
NON-DIPPING PATTERN IN ADDITION
TO A HIGHER DAY TIME BLOOD
PRESSURE HAVE SIGNIFICANTLY
HIGHER RISK OF CARDIOVASCULAR
DISEASE AND A SIGNIFICANTLY
HIGHER RISK OF MORTALITY AND
THESE ASSOCIATIONS ARE NOT JUST
OBSERVED IN INDIVIDUALS WITH
HYPERTENSION, THEY'RE ALSO
OBSERVED IN THE GENERAL
POPULATION.
IN ADDITION THERE IS EMERGING
EVIDENCE THAT NIGHTTIME BLOOD
PRESSURE MAY BE A STRONGER
PREDICTOR OF DISEASE RISK THAN
DAY TIME BLOOD PRESSURE, AND
THAT HAVING A HIGH NIGHTTIME
BLOOD PRESSURE IN ADDITION TO A
RISER OR A NON-DIPPER PATTERN
CAN BE ASSOCIATED WITH HIGHER
RISK OF OVERALL CARDIOVASCULAR
DISEASE, ATHEROSCLEROSIS AND
HEART FAILURE.
NOW DESPITE THIS EMERGING
LITERATURE, WE ACTUALLY KNOW
VERY LITTLE ABOUT HOW BEHAVIORAL
RHYTHMS INFLUENCE DIURNAL
PATTERN OF BLOOD PRESSURE IN
REALTIME AND CURRENT DIAGNOSTIC
AND THERAPEUTIC APPROACHES LACK
SUFFICIENT ATTENTION TO BLOOD
PRESSURE CIRCADIAN RHYTHMICITY.
ANOTHER REALLY GOOD EXAMPLE IS
BLOOD GLUCOSE WHICH ALSO FOLLOWS
A DIURNAL PATTERN THAT IS
DISTINCT IN INDIVIDUALS WHO ARE
HEALTHY COMPARED TO INDIVIDUALS
WHO HAVE TYPE 2 DIABETES.
IN HEALTHY INDIVIDUALS, GLUCOSE
TOLERANCE AND INSULIN
SENSITIVITY ARE LOWER IN THE
EVENING COMPARED TO THE MORNING.
AND NOW WL TH WITH THE INTRODUCN
OF CONTINUOUS GLUCOSE MONITORING
WE'RE ABLE TO USE IT NOT JUST
AMONG TYPE 2 DIABETES PATIENTS
BUT ALSO IN RESEARCH SETTING
AMONG HEALTHY INDIVIDUALS AND
INDIVIDUALS WITH PREDIABETES TO
EXTRACT ADDITIONAL MARKERS OF
DIURNAL GLUCOSE VARIATION.
SPECIFICALLY RELATED TO INTERAND
INTRADAILY GLYCEMIC VARIABILITY.
HERE I JUST WANTED TO GIVE AN
EXAMPLE OF THIS STUDY WHICH I
THINK ILLUSTRATES THIS REALLY
NICELY.
THIS WAS A STUDY IN PARTICIPANTS
WHO DON'T HAVE TYPE 2 DIABETES.
AND DATA FROM CONTINUOUS GLUCOSE
MONITORING WAS USED TO EXTRACT
THE MEAN AMPLITUDE OF GLYCEMIC
EXCURSION OR MAGE, WHICH ALSO
SERVES AS AN INDEX OF GLYCEMIC
VARIABILITY.
YOU CAN SEE VERY CLEARLY THE
CARDIOVASCULAR DISEASE EVENT
RATE WAS SUBSTANTIALLY HIGHER IN
THOSE WITH HIGH MAGE COMPARED TO
LOW, AND INDIVIDUALS WITH HIGHER
MAGE OR GLYCEMIC VARIABILITY HAD
A 5.6 FOLD INCREASE IN
CARDIOVASCULAR DISEASE RISK,
WHICH IS A REALLY PROFOUND
ASSOCIATION.
BUT JUST LIKE BLOOD PRESSURE,
AGAIN, WE DON'T HAVE VERY MUCH
STUDIES ON HOW BEHAVIORAL
RHYTHMS INFLUENCE THIS DIURNAL
PATTERN IN REALTIME, AND THE
DIURNAL PATTERN OF GLUCOSE IS
NOT NECESSARILY INCORPORATED
INTO CURRENT PREVENTION AND
THERAPEUTIC APPROACHES.
SO THIS BRINGS ME TO THE LAST
PORTION OF MY TALK, WHICH IS ON
CHALLENGES AND OPPORTUNITIES.
AND AGAIN FOCUSING ON CHALLENGES
AND OPPORTUNITIES FOR
POPULATION-BASED AND COMMUNITY
ENGAGED RESEARCH.
SO THE FIRST CHALLENGE IS THAT
MOST POPULATION AND
COMMUNITY-BASED COHORT STUDIES
LACK TIME STAMPED DATA ON
LIFESTYLE BEHAVIORS.
THIS IS PARTICULARLY PRONOUNCED
FOR DIET.
MOST COHORT STUDIES USE FOOD
FREQUENCY QUESTIONNAIRES TO
MEASURE DIET WHICH HAVE NO
INFORMATION ON CHRONONUTRITION
METRICS.
ANOTHER CHALLENGE IS THAT IN
MOST COHORT STUDIES WE DON'T
ROUTINELY COLLECT INFORMATION ON
THE DIURNAL PATTERN OF A NUMBER
OF BIOMARKERS AND
CARDIOMETABOLIC RISK FACTORS.
I KNOW THERE ARE NOW SOME
ANCILLARY STUDIES IN SOME
COHORTS THAT INCLUDE ABPM AND
CGM BUT UNFORTUNATELY THIS TENDS
TO BE A CROSS-SECTIONAL
ASSESSMENT AND THAT IS NOT
CONCURRENT WITH THE ASSESSMENT
OF LIFESTYLE.
SO THE OPPORTUNITY HERE IS THAT
WE NEED TO COLLECT MORE
TIME-STAMPED LIFESTYLE DATA THAT
IS CONCURRENT WITH CLINICAL
INDICATOR DATA TO UNDERSTAND
BETTER HOW THE TIMING OF
LIFESTYLE BEHAVIORS INFLUENCES
MULTIPLE CHRONIC DISEASE
OUTCOMES IN EEK LOGIC SETTINGS
AT THE POPULATION LEVEL USING A
LIFECOURSE APPROACH.
NOW A SECOND CHALLENGE OR
RESEARCH GAP IS THAT MUCH OF THE
EXISTING LITERATURE FOCUSES ON
THE TIMING OF LIFESTYLE
BEHAVIORS RELATIVE TO CLOCK TIME
AND NOT NECESSARILY RELATIVE TO
BIOLOGICAL TIME.
NOW DIM LIGHT MELATONIN ONSET OF
COURSE IS CURRENTLY THE GOLD
STANDARD APPROACH FOR
DETERMINING BIOLOGICAL TIME AND
IT REALLY IMPORTANT TO LOOK AT
BECAUSE A GOOD EXAMPLE OF THIS
FROM THE FIELD OF
CHRONONUTRITION IS WHAT IS
CONSIDERED LATE NIGHT EATING FOR
SOMEONE WHO HAS DIM LIGHT
MELATONIN ONSET AT 7:00 OR
8:00 P.M. IS DIFFERENT FROM
SOMEONE WHOSE DIM LIGHT
MELATONIN ONSET OCCURS LATER,
BUT WE HAVEN'T REALLY
DISENTANGLED THESE ASSOCIATIONS
YET.
MAINLY BECAUSE IT'S REALLY
COSTLY AND TEDIOUS TO DO DIM
LIGHT MELATONIN ONSET MEASURES
IN PUBLIC HEALTH SETTINGS AND IN
POPULATION STUDIES.
SO THE OPPORTUNITY HERE IS THAT
WE NEED TO DEVELOP MORE
INNOVATIVE RELIABLE APPROACHES
TO ASSESS BIOLOGICAL TIMING AND
WE NEED TO DEVELOP MARKERS OF
CIRCADIAN BIOLOGY THAT CAN BE
MORE EASILY INTEGRATED INTO
CLINICAL AND EPIDEMIOLOGIC
RESEARCH.
BUT IN THE MEANTIME, WE DO NEED
TO CONDUCT MORE STUDIES THAT
EVALUATE THE TIMING OF BEHAVIORS
IN RELATION TO BIOLOGICAL TIME
BY USING SOME SUITABLE PROXIES
FOR BIOLOGICAL TIME LIKE SLEEP
TIMING.
A THIRD GAP THAT I WANTED TO
HIGHLIGHT IS THAT WE KNOW VERY
LITTLE ABOUT THE MECHANISMS
UNDERLYING CIRCADIAN
RHYTHM-MEDIATED CLINICAL RISK
FACTOR REGULATION OR THE DIURNAL
PATTERNS OF SOME OF THESE
CARDIOMETABOLIC RISK FACTORS
THAT I MENTIONED.
FOR EXAMPLE, WE KNOW DIE URGE
GLUCOSE AND BLOOD PRESSURE
RHYTHMICITY PARAMETERS ARE
DRIVEN IN PART BY ENDOGENOUS
RHYTHMS AND DRIVEN IN PART BY
ENVIRONMENTAL AND BEHAVIORAL
RHYTHMS BUT THESE ASSOCIATIONS
ARE UNDERSTUDIED.
IT'S ALSO UNCLEAR WHAT THE
BENEFITS OF THERAPIES AND
PREVENTION APPROACHES THAT
CONSIDER THESE DIURNAL PATTERNS
OF BLOOD PRESSURE GLUCOSE AND
OTHER INDICATORS, IF THEY'RE
ACTUALLY BENEFICIAL.
THE BENEFIT ARE UNKNOWN.
SO THE OPPORTUNITY HERE IS THAT
WE NEED MORE STUDIES TO
UNDERSTAND HOW EPIGENETIC,
ENVIRONMENTAL, PSYCHOSOCIAL AND
BEHAVIORAL FACTORS INFLUENCE THE
DIURNAL PATTERNS OF THESE
CARDIOMETABOLIC RISK FACTORS,
AND TO DETERMINE WHETHER HIGH
RISK PHENOTYPES CAN BE REVERSED
OR MODIFIED TO DEVELOP MORE
INNOVATIVE INTERVENTIONS.
SO A REALLY GOOD EXAMPLE OF THIS
IS, FOR EXAMPLE, WE'RE NOW
SEEING THAT GLYCEMIC VARIABILITY
MAY BE A RISK FACTOR, BUT WE
DON'T KNOW IF THIS COULD BE --
IF THIS CAN BE AND TO WHAT
EXTENT IT CAN BE IMPROVED OR
REVERSED BY MODIFYING BEHAVIORAL
RISK FACTORS, FOR EXAMPLE.
AND LAST BUT CERTAINLY NOT
LEAST, I THINK THE ROLE OF
CHRONOMEDICINE IN ADDRESSING
HEALTH INEQUITIES IS VERY
UNDERSTUDIED.
THERE IS A DERTH OF EVIDENCE
FROM RACIALLY AND ETHNICALLY
DIVERSE COHORTS, AND MINORITIZED
POPULATIONS BROADLY SPEAKING.
SO THE OPPORTUNITY HERE IS THAT
WE NEED MORE SUFFICIENTLY
POWERED POPULATION STUDIES TO
UNDERSTAND DIFFERENCES BY SEX,
RACE, ETHNICITY, AND TO QUANTIFY
THE CONTRIBUTION OF CIRCADIAN
HEALTH INEQUITIES TO THE BROADER
HEALTH INEQUITIES THAT WE
OBSERVE AT THE POPULATION LEVEL.
I TH -- IN REAL WORLD SETTINGS.
SO I THINK UPON ADDRESSING THESE
RESEARCH GAPS, WE CAN TRULY
UNLOCK THE POTENTIAL OF
CHRONOMEDICINE TO PRESERVE AND
RESTORE CIRCADIAN HEALTH.
SOME REALLY IMPORTANT FUTURE
APPLICATIONS COULD BE ENHANCING
DISEASE RISK PREDICTION
ALGORITHMS, FINALLY
INCORPORATING THE CONCEPT OF
TIME INTO GUIDELINES,
SPECIFICALLY LIFESTYLE
GUIDELINES, AND DEVELOPING
CONTEXTUAL BEHAVIORAL
INTERVENTIONS THAT WORK NOT JUST
IN A LAB BUT ALSO IN A REAL
WORLD SETTING TO ADDRESS HEALTH
INEQUITIES, EXTEND HEALTHSPAN
AND LIFESPAN, AND OPTIMIZE
CHRONIC DISEASE PREVENTION AND
MANAGEMENT.
SO THE TAKE-HOME MESSAGE FROM MY
PRESENTATION TODAY, I HOPE, IS
THAT ENHANCE BEING THE
RHYTHMICITY OF HEALTH BEHAVIORS
AND OPTIMIZING DIE URGE PATTERNS
OF PHYSIOLOGICAL RISK FACTORS
MAY REPRESENT AN IMPORTANT
APPROACH TO EXTENDED HEALTHSPAN
AND LIFESPAN BUT THERE'S A LOT
MORE RESEARCH GAPS THAT NEED TO
BE ADDRESSED.
IT HAS NOT BEEN FULLY HARNESSED
FOR IMPROVING HUMAN HEALTH.
THANK YOU ALL FOR YOUR ATTENTION
THIS AFTERNOON.
AND I JUST WANT TO ACKNOWLEDGE
THE NIH, THE AHA FOR FUNDING MY
WORK, AND ALL THE RESEARCH
PARTICIPANTS, RESEARCH STAFF AND
COLLABORATORS THAT CONTRIBUTED
GREATLY TO A LOT OF THE WORK
THAT I SHOWED YOU TODAY.
THANK YOU.
>> THANK YOU ALL SO MUCH!
WE HAD THREE VERY AMAZING
PRESENTATIONS.
AND WE HAVE SOME EXCELLENT
QUESTIONS IN THE CHAT.
SO AGAIN, IF YOU HAVE QUESTIONS,
PLEASE PUT THEM IN THE Q & A.
THE Q & A BOX IS LOCATED ON THE
MENU BAR LOCATED AT THE BOTTOM
OF YOUR SCREEN.
PLEASE PUT YOUR QUESTIONS IN THE
CHAT.
WE WILL NOT BE BRINGING
PARTICIPANTS OFF MUTE.
THANK YOU.
SO ONE QUESTION THAT I DID WANT
TO HIGHLIGHT FROM THE Q & A BOX
WAS BROUGHT UP BY A PARTICIPANT,
AN ATTENDANT, BARBARA PERI.
CAN YOU PLEASE ADDRESS -- THIS
IS TO EVERYBODY.
SO IF WE CAN SPOTLIGHT EVERYBODY
ON THE PANEL TODAY.
CAN YOU PLEASE ADDRESS SEX AND
AGE EFFECTS?
SO THIS IS DEFINITELY A RESEARCH
PRIORITY ACROSS NIH AND FOR
THOSE OF YOU WHO MAY OR MAY NOT
KNOW, THE NATIONAL CENTER ON
SLEEP DISORDERS RESEARCH, WHILE
HOUSED AT THE NATIONAL HEART,
LUNG AND BLOOD INSTITUTE,
ACTUALLY DOES COORDINATE SLEEP
AND CIRCADIAN RESEARCH ACROSS
THE NIH.
AND SO WHEN WE CONSIDER THESE
BIG QUESTIONS ABOUT SLEEP AND
CIRCADIAN RESEARCH, WE LOOK AT
PRIORITIES ACROSS THE NIH AS
WELL.
AND SO THIS QUESTION ABOUT SLEEP
AND CIRCADIAN CLINICAL RELEVANCE
ACROSS THE LIFESPAN, AND OF
COURSE WITH -- THROUGH THE LENS
OF SEX AND GENDER DO COME UP IN
OUR RESEARCH PRIORITIES, AND OUR
RESEARCH QUESTIONS.
SO TO THE PANELISTS, WHAT SORT
OF CRITICAL QUESTIONS ARE
CONSIDERED WITH CIRCADIAN
BIOLOGY, WITH CIRCADIAN
MEDICINE, WITH CHRONOMEDICINE
WITH REGARD TO SEX AND ACROSS
THE LIFESPAN?
I KNOW THAT'S A VERY BROAD
QUESTION.
TELL US ALL THE THINGS ABOUT
ACROSS THE LIFESPAN.
HOW DOES CIRCADIAN BIOLOGY
CHANGE AS WE AGE?
>> I'LL JUST START AND JUMP IN
BY SAYING THAT WITHIN THE ANIMAL
LITERATURE, IT VERY WELL
ESTABLISHED THAT AS YOU -- AS
THE ANIMALS GET OLDER, THEIR
CIRCADIAN RHYTHMS DO START TO
FRAGMENT.
YOU SEE SOMETHING LIKE WHAT NOUR
WAS SHOWING IN TERMS OF THIS
AMPLITUDE OF -- THE AMPLITUDE OF
THE RHYTHMICITY IS DREE
CREASING.
AN --DECREASING.
IN TERMS OF HOW THAT'S
ASSOCIATED WITH THE ANIMAL'S
HEALTH, I DON'T KNOW.
THERE'S ALSO, OF COURSE, STRONG
DIFFERENCES BETWEEN THE SEXES.
SO FEMALES HAVE A VERY
INTERESTING PATTERN, IT'S
SOMETIMES CALLED SCALLOPING,
WHERE THERE'S A CHANGE IN THEIR
RHYTHM PHASE EVERY FOUR DAYS IN
CONCERT WITH THEIR ESTRADIOL
LEVELS AND THEIR ESTRUS CYCLE.
AND THAT WAS USED, OF COURSE,
FOR DECADES TO SAY THAT LET'S
NOT STUDY THEM BECAUSE IT'S TOO
COMPLICATED.
IT TURNS OUT, THOUGH, THAT
EXCEPT FOR THAT SCALLOPING, THE
ACTUAL CIRCADIAN PATTERN OF
RUNNING WHEEL ACTIVITY IN
FEMALES IS MUCH MORE STABLE
ACTUALLY THAN IN MALES.
SO THERE'S A HORMONAL EFFECT ON
THE RHYTHMS ITSELF, BUT CLEARLY
A SEX DIFFERENCE AS WELL IN HOW
THOSE RHYTHMS ARE ORGANIZED.
>> HOW DOES THAT TRANSLATE TO
HUMAN STUDIES AND CLINICAL
IMPLEMENTATION, CLINICAL
QUESTIONS?
>> I CAN TAKE THE NEXT STAGE UP
MAYBE, AND I THINK FROM A
CLINICAL STANDPOINT, THERE ARE A
COUPLE OF THINGS TO KEEP IN
MIND.
FROM AN AGING PERSPECTIVE IN A
HUMAN POPULATION, IT'S BEEN WELL
DESCRIBED THAT WE KNOW THAT
EVERYBODY, NO MATTER WHAT YOUR
UNDERLYING CHRONOTYPE IS, TENDS
TO GET LATER WHEN THEY GO
THROUGH ADOLESCENCE, AND THEN AS
THEY GET OLDER, THEY TEND TO GET
EARLIER.
SO JUST FROM A RECOGNITION
STANDPOINT, I THINK IT'S REALLY
IMPORTANT TO REALIZE THAT OUR
PATIENTS WITH THESE CIRCADIAN
DISORDERS ARE GOING TO START
PRESENTING IN THAT ADOLESCENT
AGE.
THAT'S WHEN THEY'RE REALLY GOING
TO START STRUGGLING, AND I THINK
KEEPING IN MIND THAT IT ISN'T
NECESSARILY JUST THAT THEY'RE AN
ADOLESCENT WHO DOESN'T WANT TO
PUT DOWN THEIR DEVICE AND GO TO
BED AND DOESN'T WANT TO GET UP
FOR SCHOOL.
THERE MAY BE AN UNDERLYING
DISORDER, SO KEEPING THAT LEVEL
OF AWING IN MI -- OF AGING IN MK
IS REALLY IMPORTANT.
THE QUESTION OF SEX AND GENDER
IS A REALLY INTERESTING ONE
BECAUSE IF YOU LOOK AT
ALL-COMERS FOR MOST OF THE
DELAYED SLEEP-WAKE PHASE
DISORDER STUDIES, IF YOU JUST
SORT OF PUT A GENERAL POLL OUT
THERE AND SAY WE'RE LOOKING FOR
PEOPLE WITH DSPD, ALMOST ALWAYS
UNLIKE MOST OTHER RESEARCH
STUDY, YOU TEND TO GET MORE MEN
ENROLLING THAN YOU DO WOMEN.
NOW, DO WE KNOW THAT THE
PREVALENCE OF DSPD IS HIGHER IN
MEN?
I'M NOT SURE, AND WE'RE
CONDUCTING A STUDY RIGHT NOW
TRYING TO BETTER PHENOTYPE THESE
INDIVIDUALS BUT I THINK IT WILL
BE VERY INTERESTING TO LOOK INTO
WHAT THOSE DIFFERENCES ARE AND
WHY IS IT WE'RE TENDING TO SEE
THAT MORE OFTEN THAN IF WE'RE
JUST PUTTING GENERAL CALLS OUT
THERE FOR PEOPLE WITH DSPD.
>> I'LL JUST JUMP IN AND I GUESS
TALK ABOUT THE POPULATION
RESEARCH.
IN TERMS OF THE RESEARCH ON REST
ACTIVITY RHYTHMS, THESE
DEFINITELY TEND TO CHANGE WITH
AGE.
A LOT OF THE RESEARCH ON REST
ACTIVITY RHYTHMS IN RELATION TO
HEALTH OUTCOMES IN POPULATION
STUDIES IS CROSS-SECTIONAL, BUT
IN GENERAL, WE'RE MORE LIKELY TO
SEE DISRUPTED REST ACTIVITY
RHYTHMS IN OLDER INDIVIDUALS.
WE KNOW THAT CIRCADIAN RHYTHMS
CAN ALSO DAMPEN WITH AGING AND
THIS IS REFLECTED ALSO WITH REST
ACTIVITY RHYTHMS, AND THIS IS
WHY WE SEE ALL THESE STRONG
ASSOCIATIONS WITH AGE-RELATED
DISEASE AND AGING-RELATED
OUTCOMES.
IN FACT, I THINK THERE'S
PROBABLY MORE WORK ON REST
ACTIVITY RHYTHMS IN AGING THAN
THERE IS ON SOME OF THE
CARDIOMETABOLIC OUTCOMES THAT I
WORK ON AND PRESENTED ON TODAY.
IN TERMS OF SEX DIFFERENCES,
THOUGH, I WILL SAY THAT WHEN WE
STRATIFY BY SEX IN THIS WORK,
FROM AT LEAST IN THE WORK THAT I
DO ON REST ACTIVITY RHYTHMS AND
CARDIOMETABOLIC OUTCOMES, THE
ASSOCIATIONS TEND TO BE THE SAME
INTENTINAND TEND TO PERSIST IN H
SEXES.
SIMILARLY WITH THE WORK ON
CHRONONUTRITION, ONE THING THAT
I WILL HIGHLIGHT AS I WAS
PREPPING FOR THIS PRESENTATION
IS THAT WHEN WE THINK ABOUT THE
DIURNAL MARKERS OF
CARDIOMETABOLIC RISK FACTORS,
THERE'S DEFINITELY MUCH LESS
WORK IN FEMALE POPULATIONS AND I
BELIEVE THIS WAS SOMETHING THAT
WAS HIGHLIGHTED IN THE NHLBI
WORKSHOP ON CHRONOTHERAPY AND
BLOOD PRESSURE.
I THINK THERE IS MUCH LESS
EVIDENCE IN FEMALES COMPARED TO
MALES.
>> THANK YOU FOR HIGHLIGHTING
THAT.
ACTUALLY THERE WAS ANOTHER
QUESTION, AND I DID WANT TO
JUST -- IT SORT OF PIGGY BACKS
OFF OF THIS, BUT IT IS VERY
SPECIFIC TO YOUR TALK,
DR. MAKAREM.
CAN YOU SPEAK TO THE
RELATIONSHIP BETWEEN BEHAVIORAL
AND CIRCADIAN RHYTHMS?
THIS IS COMING FROM STEVEN
CARLSON, WHO'S IN ATTENDANCE
TODAY.
HE SAYS, I COULD IMAGINE IF
THESE ARE BIDIRECTIONAL, BUT IS
THERE ANY EVIDENCE THAT THERE IS
A STRONGER RELATIONSHIP IN ANY
PARTICULAR DIRECTION?
AND I'M SURE ALL OF YOU CAN
SPEAK TO THIS RELATIONSHIP
BETWEEN VIECIALT TALL OR
BEHAVIORAL CUES AS WELL AS
CIRCADIAN CUES.
DO YOU THINK -- IN YOUR
OPINIONS, I GUESS, IS CIRCADIAN
STRONGER THAN EXTERNAL CUES, OR
IS THERE CONTEXT OR NUANCE TO BE
CONSIDERED IN THESE CASES?
>> I KNOW THIS QUESTION WAS
DIRECTED TO ME, BUT I FEEL LIKE
MY COLLEAGUES MIGHT ANSWER THIS
BETTER BECAUSE IN POPULATION
RESEARCH, LIKE I MENTIONED,
BECAUSE A LOT OF THIS,
ESPECIALLY THESE ACTGRAPHYSTUDIO
BE CROSS-SECTIONAL.
BUT OF COURSE THERE IS A
BIDIRECTIONAL RELATIONSHIP, I
WOULD IMAGINE, BETWEEN I MAIJ
CIRCADIAN RHYTHMS AND BEHAVIORAL
RHYTHMS.
IN TERMS OF DIE URGE PATTERNS OF
BIOMARKERS, THAT WAS ONE OF THE
AREAS I HIGHLIGHTED AS A GAP
BECAUSE LIKE I SAID, OFTENTIMES
THE EVALUATION OF THE BEHAVIORAL
RHYTHMS IS NOT CONCURRENT WITH
THE EVALUATION OF THE DIURNAL
PATTERNS OF THE BEHAVIORAL RISK
FACTOR, SO IT'S BEEN REALLY HARD
TO TEASE OUT WHAT THOSE
ASSOCIATIONS LOOK LIKE IN
REALTIME.
I DON'T KNOW IF THE OTHER
PRESENTERS HAVE MORE INSIGHT
FROM CLINICAL WORK AND BASIC
SCIENCE.
>> I HAVE LOTS OF THOUGHTS ON
THIS.
SO I THINK WHAT IT BOILS DOWN TO
IS WHETHER OR NOT THERE'S SOME
OPTIMAL TIME OF THE CIRCADIAN
CYCLE IN WHICH THESE BEHAVIORS
NEED TO OCCUR, OR WHETHER YOU
CAN SOLVE EVERYTHING BY SIMPLY
HAVING ALL THE BEHAVIORS AT THE
SAME TIME, AND SORT OF IGNORE
THE CIRCADIAN CLOCK.
AND I THINK THERE'S EVIDENCE FOR
BOTH OF THOSE.
SO WHETHER THERE WAS A NICE STM
THE ESCOBAR LABORATORY ABOUT 10
OR 15 YEARS AGO, AND I THINK
THEY HAD RATS EATING A HIGH FAT
DIET DURING THE DAY TIME, SO IN
THEIR INACTIVE PHASE AND THOSE
ANIMALS GOT FAT, AS YOU MIGHT
EXPECT.
AND THEN THEY SIMPLY ALLOWED
THOSE ANIMALS TO -- THEY PUT
THEM IN A WHEEL THAT WAS MOVING
TO KEEP THEM AWAKE AND MOVING
DURING THAT DAY TIME WHEN THEY
HAD THE FOOD.
SO NOW THEY'RE PAIRING HIGHER
ACTIVITY WITH THE TIME OF
EATING, AND IT COMPLETELY SOLVED
EVERYTHING.
EVEN THOUGH THEIR CIRCADIAN
CLOCK IN THEIR BRAIN, IN THEIR
SCN WOULD STILL BE ENTRAINED TO
THE LIGHT-DARK CYCLE NORMALLY.
SO THAT WOULD ARGUE FOR THE FACT
THAT AS LONG AS YOU HAVE ALL
THESE BEHAVIORS PAIRED TOGETHER
AT THE SAME TIME, THAT WOULD BE
IMPORTANT.
IF WE THINK ABOUT THAT FOR
HUMANS, THEN YOU COULD SAY OKAY,
MAYBE IT DOESN'T MATTER IF
THEY'RE SHIFT WORKERS, AS LONG
AS THEY'RE EXERCISING AND EATING
AND DOING ALL THOSE THINGS AT
THE SAME TIME OF DAY, AND TRYING
TO KEEP THEM STABLE.
WE ALL KNOW ONE OF THE BIG
CHALLENGES FOR SHIFT WORKERS IS
THAT THEY HAVE ONE PARTICULAR
WORK SCHEDULE BUT THEN THEY HAVE
FAMILY DEMANDS, THEY HAVE KIDS
SOCCER GAMES TO GO TO ON THE
WEEKENDS, ET CETERA.
HOWEVER, I'LL ALSO SAY THAT
THERE'S BEEN A LOT OF INTEREST
IN TIME RESTRICTED EATING, AND
HOW THAT COULD BE A
CHRONONUTRITION,
CHRONOTHERAPEUTIC FOR CHRONIC
CONDITIONS, AND THE EVIDENCE
REALLY SUGGESTS THAT EARLY TIME
RESTRICTED EATING MAY BE BETTER
THAN LATER TIME RESTRICTED
EATING.
SO THAT THERE IS SOME BENEFIT
ACTUALLY TO HAVING THE CALORIES
MATCHED UP TO THE CIRCADIAN
CYCLE.
I THINK THAT THIS IS AN AREA
THAT IS REALLY RIPE FOR FURTHER
RESEARCH, BECAUSE THE KINDS OF
FOOD THAT PEOPLE MIGHT BE
SELECTING IF THEY'RE EARLY
EATERS VERSUS LATE EATERS MIGHT
BE DIFFERENT.
I WOULD BE SHOCKED IF THE
CIRCADIAN SYSTEM IS NOT
IMPORTANT IN THIS, HOW FAR
ITS TENDRILS EXTEND INTO THE
PHYSIOLOGY.
BUT I'LL LEAVE ITBU AT THAT.
>> AND I'LL JUST CHIME IN FROM
MY STANDPOINT.
I THINK THIS KIND OF GETS AT THE
HEART OF WHAT I THINK
MYCO-SPEAKERS ALSO TOU TOUCHED ,
WHICH IS THAT ONE OF THE
CHALLENGES WE HAVE WITH
CIRCADIAN TIMING OVERALL IN THE
CONTEXT OF PATIENTS WITH
CIRCADIAN DISORDERS IS, WHAT
IS OUR ULTIMATE GOAL IF WE'RE
TRYING TO OPTIMIZE THEIR HEALTH?
IS IT THAT WE ADJUST THEIR
ENVIRONMENT SO THAT THEY'RE ABLE
TO FOLLOW THERREL BIOLOGICALLY
PREFERRED SCHEDULE?
IT JUST DOESN'T MATCH UP WITH
EVERYBODY ELSE?
AND IT'S MISALIGNED WITH THE
ENVIRONMENTAL LIGHT-DARK BUT
THEY'RE AT LEAST NOT GETTING
SLEEP RESTRICTED, THEY GO TO BED
AT THE SAME TIME,AM WE'VE GIVEN
THEM THAT REGULARITY BY
ADJUSTING THEIR SCHOOL START
TIMES, WORK SCHEDULES AND THOSE
TYPES OF THINGS, OR IS IT MORE
IMPORTANTLY THAT WE SHIFT THEIR
RHYTHM AND PUSH THEM SO THAT
THEY'RE SLEEPING AT NIGHT LIKE
EVERYBODY ELSE IS, AND WHAT IS
THE WORST DRIEMP THERE?
IS IT THE APPROPRI THE INAPPROPT
EXPOSURE D AS WE TRY TO FIGURE
OUT HOW DO WE OPTIMIZE THE
HEALTH BECAUSE WE HAVE
POPULATION-BASED DATA SHOWING
THAT THEY DO HAVE WORSE HEALTH
OUTCOMES BUT WHAT COMPONENT OF
THAT IS IT THAT'S CONTRIBUTING
TO THAT IN THAT POPULATION.
AND THAT TIES TOGETHER BOTH
THEIR BEHAVIORS OF WHEN THEY'RE
DOING THINGS AND THOSE THAT ARE
MISALIGNED WITH THE EXTERNAL
ENVIRONMENT.
>> SO THERE IS SOME
POPULATION-BASED EVIDENCE AND
THERE IS SOME CLINICAL-BASED
EVIDENCE TO SUGGEST THAT
SHIFTING THE TIMING OF, SAY,
REST ACTIVITY, CALORIC INTAKE,
THINGS LIKE THAT, CAN MODIFY
HEALTH BUT WE HAVE THIS OTHER
VARIABLE OF BEHAVIOR THAT ALSO
NEEDS TO BE CONSIDERED AND
REALLY THE HUMAN CONDITION.
OKAY.
EXCELLENT.
I WOULD LIKE TO JUMP OFF OF
DR. ABBOTT, YOUR -- THERE WERE
SEVERAL QUESTIONS WITH REGARD TO
THE DESIGN OF YOUR EXPERIMENTS
IN SOME OF THESE -- I WAS REALLY
LOOKING FOR A WAY TO BRIDGE INTO
LIKE THE NITTY GRITTY OF SOME OF
THESE QUESTIONS, BUT YOU CREATED
THE BRIDGE FOR US.
SO REGARDING THE DIFFERENT
FINDINGS, THIS IS FROM REBECCA
COX, WHO'S AN ATTENDANT,
REGARDING THE DIFFERENT FINDINGS
OBSERVED FROM PIPR IN DELAYED
SLEEP-WAKE, IS IT POSSIBLE THAT
THESE DIFFERENCES COULD BE DUE
IN PART TO WHEN PIPR WAS
ASSESSED RELATIVE TO CIRCADIAN
TIMING?
>> HI, REBECCA.
THAT IS A GREAT QUESTION, AND I
DIDN'T GET INTO ALL OF THE
DETAILS OF IT BUT YOU'RE
ABSOLUTELY RIGHT.
SO THE PIPR DOES CHANGE WITH
TIME OF DAY BUT IT TENDS TO BE
MOST SENSITIVE TO THOSE CHANGES
RIGHT AROUND THE TIME OF DLMO,
SO SHORTLY BEFORE SLEEP ONSET.
IN OUR INITIAL PILOT STUDY, WE
WEREN'T ABLE TO PRECISELY
CONTROL FOR TIME SINCE WAKE FOR
EVERY SINGLE PIPR ASSESSMENT
BECAUSE SOMETIMES WE WERE JUST
PULLING THEM FROM CLINIC AND
BRINGING THEM OVER, BUT THAT
BEING SAID, THE FINAL WAS ABOUT
ONE TO SIX HOURS, I THINK, SO
THEY ALL STAYED OUTSIDE OF THAT
KNOWN WINDOW, THE PIPR DOES
CHANGE.
WE DID AN ANALYSIS WHERE WE
ADJUSTED FOR TIME SINCE WEIGHT
IN THE WHOLE ANALYSIS AS WELL
AND IT DIDN'T SEEM TO PLAY A
ROLE IN IT.
SO DEFINITELY A GREAT QUESTION,
SOMETHING WE THOUGHT ABOUT, AND
AS WE'RE DOING A MORE DETAILED
DIVE INTO THIS POPULATION, WE'RE
GOING TO MORE STRICTLY CONTROL
WHEN EXACTLY THAT PIPR
ASSESSMENT IS DONE.
>> DOES MELATONIN OFFSET HAVE
ANY ROLE IN PREDICTINGRE OUTCOMS
OF CIRCADIAN DISORDERS?
THIS IS FOR ANYBODY.
EVERYBODY IS GIVING ME THE NO
FACE.
>> I THINK THAT THE ANSWER TO
THAT WOULD BE YES.
I WOULD DEFER TO MY COLLEAGUE
HERE, ANDREW MACHILL WHO'S
STUDIED THIS IN THE INTENSIVE
PHYSIOLOGY IN LAB EXPERIMENTS,
BECAUSE WHEN WE LOOK AT THE
PEOPLE THAT HAVE LATER DLMOs,
OFTEN A LOT OF THEM DO TEND TO
HAVE A LATER OFFSET, AND IT
MEANS PEOPLE ARE AWAKENING,
THEY'RE HAVING THEIR FIRST MEAL
POTENTIALLY AT A TIME WHERE
MELATONIN IS EITHER STILL HIGH
OR BECAUSE OF BRIGHT LIGHT, IT'S
BEEN CURTAILED ARTIFICIALLY, SO
THEY'VE HAD KIND OF A REDUCED
TOTAL MELATONIN DURATION.
BUT UNFORTUNATELY APOLOGIES TO
ANDREW, I DON'T REMEMBER THE
EXACT RESULTS OFF THE TOP OF MY
HEAD.
>> WITH REGARD TO LIGHT, AND
LIGHT BEING ONE OF THE STRONGEST
CUES, IS THERE A SIGNIFICANT
DIFFERENCE BETWEEN EXPERIMENTAL
LIGHT, LET'S SAY, FOR EXAMPLE,
THE INDOOR LIGHT INTENSITY THAT
WE USE FOR EXPERIMENTS LIKE,
LET'S SAY, 3,000, RIGHT, THAT
WAS NOTED IN DR. ABBOTT'S
SLIDES, VERSUS OUTDOOR, AS FAR
AS IT BEING A RELEVANT CUE, AND
DOES LIGHT SENSITIVITY CHANGE
ACROSS THE DAY TYPICALLY, AND
HOW DOES THAT NEED TO BE
CONSIDERED IN A CLINICAL
ENVIRONMENT OR CLINICAL TESTING?
>> I'LL START WITH THAT ONE IF
ANYONE ELSE WANTS TO CHIME IN AS
WELL.
IT'S A GREAT QUESTION AND I
THINK IT GETS AT ONE OF MY
PERSONAL PET PEEVES WHEN IT
COMES TO LIGHT STUDY, WHICH IS
THAT I THINK WE'VE REACHED A
POINT WHERE AS GENERAL
POPULATION, WE HAVE STARTED TO
VIEW LIGHT AT NIGHT AS BAD.
AND THERE'S ALL OF THIS WORK TO
SORT OF AVOID LIGHT AND BLUE
LIGHT BLOCKING GLASSES AND
EVERYTHING ELSE, BUT IT TURNS
OUT THAT REALLY, IT'S YOUR SUM
LIGHT EXPOSURE THAT MAKES A
DIFFERENCE.
AND SO IT'S NOT SO MUCH, FOR
EXAMPLE, THAT THE MOST IMPORTANT
THING YOU NEED TO DO IS AVOID
LIGHT BEFORE BEDTIME.
BUT IT'S ACTUALLY THE MORE LIGHT
YOU GET DURING THE DAY, THE MORE
PROTECTIVE IT IS AT NIGHTTIME.
SO IF YOU'RE IN A STRONG
AMPLITUDE HIGHLY LIT ENVIRONMENT
ALL DAY LONG, YOU'RE ACTUALLY
GOING TO BE LESS SENSITIVE IN
MOST CASES TO THAT EVENING LIGHT
EXPOSURE.
SO I THINK IT'S REALLY IMPORTANT
TO THINK ABOUT LIGHT IN SORT OF
YOUR OVERALL CUMULATIVE EXPOSURE
AND NOT JUST SINGLE INTENSITY
HERE OR THERE.
ALSO I THINK THE OTHER THING
THAT WE'RE REALLY MOVING AWAY
FROM IS IT'S NOT JUST THE
INTENSITY IN TERMS OF LUX BUT
IT'S REALLY THE SPECTRUM OF
LIGHT.
SO THE MELANOPIC EXPOSURE YOU'RE
GETTING AS OPPOSED TO HOW
INTENSE IT IS, SO ARE YOU
ACTUALLY ACTIVATING THOSE
IPRGCs VERSUS GETTING OTHER
LIGHT EXPOSURE.
SO ALL OF THESE THINGS PLAY INTO
IT SO LIGHT CONTINUES TO BE MORE
AND MORE COMPLEX TO ACTUALLY
STUDY BECAUSE YOU HAVE TO TAKE
INTO ACCOUNT THE WAVELENGTH, THE
FREQUENCY, THE TIME AND YOUR
LIGHT HISTORY WHEN YOU'RE
ANALYZING IT.
>> ALL RIGHT.
VERY COOL.
WE HAVE A QUESTION FROM THE
CHAT -- OR FROM THE Q & A BOX
FROM AN ATTENDANT, OLIVIA WALSH.
WHAT ARE YOUR THOUGHTS ON SUR ON
CIRCADIAN AMPLITUDE?
WHAT DOES IT MEAN TO YOU AND
WHAT DO YOU THINK OF IT AS A
TARGET FOR INTERVENTION?
>> I'M HAPPY TO START WITH THIS
ONE.
I DON'T WANT TO HOG THE
CONVERSATION, BUT I AM A BIG FAN
OF AMPLITUDE.
AND I WILL ACTUALLY SAY THAT
THIS IS ONE OF THE AREAS I HAD
MENTIONED PARTICULARLY THAT
NON-24 PATIENTS, IT'S VERY, VERY
HARD TO FIND APPROPRIATE
TREATMENTS FOR THEM.
AND RATHER THAN A LOT OF WHAT WE
DO A VERY SPECIFIC CIRCADIAN
TIME INTERVENTIONS WE'VE BEEN
FOCUSING ON AMPLITUDES -- HAVING
A HIGH EXPOSURE DURING THE DAY,
AND SET LIGHT WINDOWS OF TIME
FOR THEM -- SO THEY GET THE
AMPLITUDE.
I'VE HAD SOME, IF THEY VIN
CREASED ACTIVITY AMPLITUDE OVER
THE DAY, SO THEIR OVERALL
ACTIVITY IMPROVES, WE ALSO SEE
IMPROVEMENTS THERE, SO ANS
LUTELY I THINK AMPLITUDE IS THE
FUTURE IN TERMS OF REALLY
PROVIDING THOSE CONTRASTS AS
OPPOSED TO THINKING OF CIRCADIAN
RHYTHMS AS KIND OF A SINGLE
TIMED INTERVENTION.
>> I HAVE NOTHING TO ADD.
BUT I AGREE WITH DR. ABBOTT
ABOUT ESSENTIALLY ADDRESSING
BEHAVIORS AND CUES ACROSS THE
24-HOUR CYCLE.
AS OPPOSED TO A SPECIFIC TIME OF
DAY.
>> OKAY.
SO BASICALLY ALL IN FAVOR.
>> YEAH.
THE ONLY THING I WOULD ADD TO
THAT IS THAT IN SOME OF THE
ASSOCIATION STUDIES, LOW
AMPLITUDE RHYTHMS IN, SAY,
ACTIGRAPHY, IT'S HARD TO
DIFFERENTIATE A CIRCADIAN
COMPONENT TO THAT VERSUS, SAY,
LIKE THE SICK COMPONENT OR
PEOPLE ARE STRESSED, ANXIOUS OR
DEPRESSED.
THERE ARE A LOT OF DIFFERENT
BEHAVIORAL REASONS FOR WHY THOSE
AMPLITUDES CHANGE, SO
UNDERSTANDING THE MECHANISMS
BEHIND THE AMPLITUDE DIFFERENCES
IS REALLY A CRITICAL FEATURE.
>> ALL RIGHT, GOOD TO KNOW.
GOOD POINT.
ALL RIGHT.
SO PIVOTING TO PATIENT CARE AND
CLINICAL SETTINGS.
HOW WELL ARE PHENOTYPES FOR
HUMAN SIR CADE CIRCADIAN RHYTHMS
CHARACTERIZED, AND WILL THIS BE
PART OF -- WILL THIS BE PART OF
OUR WORKUP AT PHYSICAL AND --
LIKE WILL THIS BECOME PART OF
OUR PHYSICAL, LIKE PART OF OUR
CLINICAL WORK WORKUP AND OUR GUE
ON MAINTAINING GOOD HEALTH?
AND DO YOU THINK IT SHOULD BE?
>> ABSOLUTELY --
>> DOES THIS BECOME A VITAL SIGN
IS BASICALLY THE QUESTION.
>> ABSOLUTELY.
I DON'T THINK I HAVE ANY
DISAGREEMENT FROM MY FELLOW
PANELISTS WITH THAT.
AND I THINK THERE ARE KIND OF
TWO COMPONENTS TO THAT.
SO I THINK THERE'S THE IDEA OF
ACROSS ANY GENERAL PCP
POPULATION AS THEY'RE SEEING
PATIENTS, I THINK THEY SHOULD BE
ASSESSING SOME OF THESE THINGS.
IT'S CHALLENGING BECAUSE THEY'VE
GOT A VERY SHORT, LIMITED TIME
VISIT, SO I THINK IT'S SORT OF
THE BURDEN IS ON US TO COME UP
WITH EASY, QUICK ASSESSMENTS
THAT THEY CAN BUILD INTO THEIR
CLINIC THAT CAN HELP WITH
GETTING SOME OF THAT INFORMATION
SO THAT WE CAN PROVIDE THAT
DATA.
IN TERMS OF WHAT ASSESSMENTS WE
SHOULD BE DOING IN THE CIRCADIAN
CLINIC, CAN I GO I CAN GO INTOE
OF THAT IF WE NEED TO BUT I WANT
OTHER PANELISTS TO WEIGH ON WHAT
WE SHOULD BE DOING TO ASSESS
THIS IN THE GENERAL POPULATION.
>> I AGREE, OF COURSE, WITH WHAT
DR. ABBOTT SAID.
I THINK I REALLY AGREE WITH THE
POINT YOU MADE ABOUT THAT
UNFORTUNATELY, THESE THINGS
WOULD BE VERY TEDIOUS TO ASSESS
IN A CLINICAL SETTING, WHICH IS
WHY THEY'RE NOT FEES FEASIBLE A
POPULATION OR HEALTH SETTING.
I THINK P T
ASSESSING -- I'M TALKING IN A
PUBLIC HEALTH SETTING, PROXIES
FOR ASSESSING THOSE THINGS COULD
BE EVALUATING PEOPLE'S
CHRONOTYPE OR, AGAIN, LOOKING AT
SLEEP TIMING, SO USING SOME
PROXIES OF BIOLOGICAL TIMING AND
SEEING INTERVENTIONS -- CONSIDER
THOSE THINGS WOULD WORK AND
WOULD OPTIMIZE CURRENT
BEHAVIORAL APPROACHES.
I THINK WE ALREADY HAVE IN
CERTAIN WAYS EVIDENCE THAT
PAYING ATTENTION TO TIMING AND
REGULARITY DOES OPTIMIZE
BEHAVIORAL INTERVENTIONS.
WE KNOW THIS FROM SOME OF THE
TRIALS ON SLEEP, WHICH HAVING
REGULAR SLEEP SCHEDULES CAN
REALLY IMPROVE CARDIOMETABOLIC
RISK FACTORS AND TRIALS, WE KNOW
FOR SOME OF THE CHRONONUTRITION
STUDIES ALSO THAT EATING TIMING
MATTERS, AND THERE'S SOME
CONFLICTING EVIDENCE ON THIS,
BUT OFTEN THAT EVEN WITH
TIME-RESTRICTED FEEDING, THAT
EARLIER TIME-RESTRICTED FEEDING
IS WHAT IS MOST HELPFUL TO
IMPROVE CARDIOMETABOLIC HEALTH.
BUT THAT WAS, I THINK, FROM A
POPULATION STANDPOINT WHY IN THE
OPPORTUNITIES SECTION OF MY
TALK, I MENTIONED THAT WE NEED
MORE METHODOLOGICAL ADVANCEMENT
FOR FINDING MARKERS THAT CAN BE
MORE INTEGRATED INTO DEEM
LOGIC RESRS AND INTO COMMIT CAL
SETTING, WE CAN'T REALLY MAKE
ANY PRESCRIPTIONS, I THINK.
IN A PUBLIC HEALTH SETTING OR A
CLINICAL SETTING.
SO YES, IT'S IMPORTANT, BUT MORE
RESEARCH IS NEEDED BEFORE IT
ACTUALLY HAPPENS, I THINK IS
THE -- IS THE SHORT SUMMARY.
>> FOR THE PANEL -- DR. BUTLER,
DO YOU HAVE ANYTHING TO ADHERE?
GO AHEAD.
>> I DON'T HAVE ANYTHING
SIGNIFICANT TO ADD TO THAT, NO.
THAT WAS PER FORECAST.
>> WEPERFECT.>> THEN I WOULD LIW
UP WITH, DO YOU THINK THERE WILL
EVER BE A SIMPLE TEST OF
BIOMARKERS, SOMETHING FOR
DIAGNOSING OR IDENTIFYING
CIRCADIAN PHENOTYPES THAT COULD
BE DEPLOYABLE AT THE CLINIC
LEVEL OR AT THE POPULATIONUL
LEVEL, AND WHAT IS THE BARRIER,
WHAT IS STANDING IN THE WAY, I
MEAN, YOU CURRENTLY TOUCHED ON
IT, DR. MAKAREM, SO I DON'T WANT
YOU TO GO OVER IT AGAIN, BULL
WHAT IS THE BIGGEST THING THAT
IS STANDING STANDING IN THE WAYF
VALIDATED BIOMARKERS FOR
CIRCADIAN BIOLOGY, OR FOR SLEEP
RESEARCH AS WELL?
>> I THINK FOR VALIDATED
MARKERS, I THINK MAYBE THAT'S
MORE A QUESTION FOR THE OTHER
PRESENTERS, BUT IN TERMS OF SOME
OF THE THINGS I TALKED ABOUT, IF
WE TAKE BLOOD PRESSURE AS AN
EXAMPLE, AMBULATORY BLOOD
PRESSURE MONITORING, EVEN THOUGH
IT IS A GOLD STANDARD APPROACH
TO EVALUATE BLOOD PRESSURE, IT'S
NOT NECESSARILY ALL AWLS
REIMBURSABLREIMBURSABLE AND SOME
IT AS HIGHLY BURDENSOME AND
DON'T WANT TO DO IT.
PARTICULARLY WHEN WE'RE DOING A
STUDY ON SLEEP AND IF THEY'RE
SAYING IT'S DISRUPTING MY SLEEP,
THIS DOESN'T MAKE ANY SENSE.
AND SIMILARLY FOR CGM, I THINK
THE USE SO FAR HAS BEEN IN TYPE
2 DIABETES PATIENTS FOR
MONITORING GLYCEMIC CONTROL.
WEAR USING A LITTLE MORE IN
RESEARCH SETTINGS NOW BUT IT'S
NOT SOMETHING WE ROUTINELY USE
TO ASSESS SOMEONE'S USE.
FROM A BARRIER POPULATION
STANDPOINT, WE NEED MORE
EVIDENCE REALLY ON HOW MUCH
THOSE INDICATORS THAT WE EXTRACT
FROM CG M&A BPM PREDICT FUTURE
DISEASE RISK AND HOW AND IF THEY
COULD BE MODIFIED BY BEHAVIORAL
RHYTHMS.
SO THAT'S FROM THE RESEARCH
POPULATION STANDPOINT.
BUT I DON'T KNOW IF MY
COLLEAGUES HAVE ANYTHING TO ADD
ABOUT BIOLOGY INDICATOR OR
BIOMARKER.
>> I'LL JUST SAID, I THINK
PROBABLY THE CIRCADIAN MEDICINE
TO ANY OTHER FIELD OF MEDICINE,
IS WHAT IS THE MARKER YOU'RE
ACTUALLY INTERESTED IN?
ARE YOU INTERESTED IN PHASE, ARE
YOU INTERESTED IN AMPLITUDE, ARE
YOU INTERESTED NR INTERNAL
MISALIGNMENT AND EACH OF THOSE
HAS A DIFFERENT MARKER.
I'M NOT GOING TO SAY THAT
DIABETES IS EASY, BUT THEY HAVE
AN A1C THAT TELLS THEM HOW HIGH
THEIR GLUCOSE LEVELS ARE AND
THAT CAN KIND OF TELL THEM
GENERALLY WHAT THE
PATHOPHYSIOLOGY IS.
BUT I THINK IT'S THE CHALLENGES,
WHAT ARE YOU -- SO I THINK WE'VE
GOT SOME PRETTY GOOD TARGETS OUT
THERE RIGHT NOW IN TERMS OF
BLOOD TESTING THAT MAY TELL YOU
WHAT YOUR CIRCADIAN PHASE IS,
BUT TAKING THAT INTO THE
POPULATION, IS THAT THE MARKER
WE CARE ABOUT, OR IS IT THAT WE
WANT TO FIGURE OUT SOMEBODY THAT
FIGURE SOMETHING THAT'SA GOOD I,
THAT'S WHERE IT BECOMES MUCH
MORE CHALLENGING ON A POPULATION
LEVEL, AND THEN TAKING IT INTO
KIND OF THE MORE ESOTERIC
CIRCADIAN CLINIC LEVEL, I OFTEN
DO GET THIS QUESTION OF CAN'T
YOU JUST COME UP WITH A SIMPLE
BIOMARKER, CAN'T YOU JUST MAKE
IT MUCH EASIER TO DIAGNOSE THESE
PATIENTS?
THE PROBLEM IS IT'S NOT JUST A
MATTER OF SAYING YOUR MELATONIN
ONSET - -- WHEN IS YOUR PREFERRD
CIRCADIAN TIME, WHEN ARE YOU
ACTUALLY FALLING ASLEEP, DOES
THAT OR DOES THAT NOT INTERFERE
WITH WHAT YOU'RE DOING?
BECAUSE YOU MAY BE A SECOND OR
THIRD SHIFT WORKER AND IT
ACTUALLY WORKS JUST FINE FOR YOU
TO HAVE A DELAYED CIRCADIAN
PHASE, OR MAYBE YOU ARE VERY
ADVANCED AND YOU HAVE TO BE AT
WORK AT 6:00 A.M. SO IT'S HARD
TO SIMPLIFY IT DOWN TO A SINGLE
VALUE THAT TELLS US IS THERE A
PROBLEM OR IS THERE NOT A
PROBLEM.
GLI WANT TO ADD TWO THINGS.
I THINK ONE OF THE CHALLENGES
THAT WE CERTAINLY SEE IS THE
FACT THAT WE DON'T KNOW WHAT THE
CIRCADIAN PHASE IS OF INDIVIDUAL
ORGANS THAT MAY BE OF INTEREST.
AND SO TRYING TO UNDERSTAND HOW
TO NOT JUST FIND BIOMARKERS OF
PHASE, BECAUSE THERE HAVE BEEN
SOME VERY NICE STUDIES TA TAKINA
LOOK AT THIS NUMBER OF PROTEINS,
THIS NUMBER OF GENES AND YOU CAN
GET PHASE, PHASE AS DEFINED BY
SLMO ESSENTIALLY, THEY'RE TRYING
TO SAY WHEN SLMO WOULD BE OR
WHEN CORE BODY TEMPERATURE WOULD
BE MINIMUM.
BUT TRYING TO -- BLOOD, OF
COURSE, IS SORT OF A HOMOGENIZED
OUTPUT OF A WHOLE LOT OF
DIFFERENT THINGS, SO TRYING TO
FIGURE OUT WHAT KIND OF ORGAN
SPECIFIC BIOMARKERS MIGHT BE
AVAILABLE IN BLOOD, URINE,
SALIVA, I THINK THAT'S A BIG
CHALLENGE.
THE OTHER THING I WOULD SAY,
THOUGH, IS MAYBE WE DON'T NEED
TO ACTUALLY FIND A BIOMARKER FOR
ALL THOSE PHASES.
ONE OF THE THINGS THAT HAS COME
UP IS THIS IDEA OF REGULARITY
OF CHANGES IN ACTIVITY PATTERNS.
SABRA SHOWED THAT KIND OF
RELATIVE COORDINATION OR
ENTRAINMENT WHERE PEOPLE ARE
GOING THROUGH PERIODS WHERE
THEY'RE SHIFTING AND
NON-SHIFTING OR JUST DAY TO DAY
OR WEEKEND TO WEEKDAY.
IT MIGHT BE THAT WITH WEARABLES
AND WITH HAVING A LONGER
LONGITUDAL TIME SPAN OF DATA, WE
MIGHT ACTUALLY END UP BEING ABLE
TO INFER CLOCK FUNCTION FROM
THINGS THAT ARE HAPPENING IN
THEIR DAY TO DAY.
SO IF WE -- IF THEY HAVE SORT OF
DEFINED WORK SCHEDULES AND WE
CAN SEE HOW THEIR ACTIVITY IS
SHIFTING RELATIVE TO THOSE, WE
MIGHT ACTUALLY BE ABLE TO DANCE
AROUND THE IDEA OF EXTRACTING
PHASE SPECIFICALLY AND DEFINE IT
BASED ON CHANGES THAT ARE
OCCURRING IN OTHER PARAMETERS.
>> VERY INTERESTING.
SO IT IS DIFFICULT BECAUSE
CONTEXT MATTERS AND IT IS VERY
PERSONAL, IT IS VERY
INDIVIDUALIZED.
ONE QUESTION FROM THE CHAT BUT
ALSO SOMETHING THAT I'M CURIOUS
ABOUT, IS THERE ANY RECORDED
EPIGENETIC MODIFICATION TO
CIRCADIAN RHYTHMS OR LIKE TO THE
CORE CLOCK GENES THAT ARE
INFLUENCED BY ENVIRONMENTAL
CUES, BEHAVIORAL CUES?
>> SO IN TERMS OF E EPIGENETIC
MODIFICATIONS ON THE CORE CLOCK
GENES, I DON'T -- I CAN'T
REMEMBER OFF THE TOP OF MY HEAD.
BUT IT'S CERTAINLY THE CASE THAT
IF YOU LOOK AT, FOR EXAMPLE,
HISTONE MARKERS THAT ARE
INSTRUMENTAL IN CONTROLLING
TRANSCRIPTION OF DIFFERENT
GENES, THERE IS A VERY DEFINED
TIME COURSE OF HISTONE MARKERS
THAT ARE SORT OF GETTING PUT IN
AND OUT OF THE HISTONES THAT
SEEMS TO PLAY A ROLE IN
ORGANIZING THE TEMPORAL
STRUCTURE OF THE TRANSCRIPTOME.
THAT WAS WORK THAT CAME OUT OF
JOE TACK TAKAHASHI'S LAB ABOUT0
YEARS AGO.
THEY SHOWED ALSO THAT PAPER
THAT THIS CORE CLOCK GENE IN
ADDITION TO SIMPLY INTERACTING
WITH EACH OTHER, THEY ARE ALSO
BINDING TO THOUSANDS OF
LOCATIONS IN THE GENOME, SO THAT
THEIR EFFECTS COULD BE VERY
WIDESPREAD, AND PART OF THAT
COULD BE PURELY CLOCK AND --
PLEIOTROPIC EFFECTS WITH MANY OF
THESE GENES THAT COULD BE
MODIFIED THROUGH EPIGENETIC
MECHANISMS AS WELL.
>> AND WHAT SORT OF CLINICAL
IMPLICATIONS WOULD THOSE HAVE
OVER TIME?
FOR OUR OTHER PANELISTS IF YOU
WANTED TO SPECULATE?
>> WELL, I PUT IN THAT THERE'S
THIS VERY INTERESTING IDEA OF
REPETITIVE INSULTS IN THE
ENVIRONMENT THAT YOU CAN KIND OF
ALMOST GET A CRYSTALLIZATION OF
EP GENETIC CONTROL LI LIKE YOU N
GET A WHOLE BUNCH OF
METHYLATIONS ON THE GENOME, AND
WE'RE VERY INTERESTED TO
UNDERSTAND WHETHER OR NOT SHIFT
WORK COULD, OVER MANY YEARS,
EVENTUALLY HAVE A RESIDUAL
EFFECT IN TERMS OF THE GENOMIC
CONTROL.
WE'D DONE A STUDY A NUMBER OF
YEARS AGO JUST LOOKING AT
TRANSIENT PHASE SHIFTING IN
MICE, AND FOUND THAT THE -- JUST
THE CIRCADIAN PATTERN OF A
SINGLE HISTONE METHYLATION
MARKER WAS REALLY DYSREGULATED
AFTER THOSE EIGHT WEEKS.
WE HAD THE EIGHT WEEKS, LET THEM
REENTRAIN, AND YET THINGS WERE
STILL KIND OF ALL OVER THE PLACE
IN TERMS OF THE TIMING OF THOSE
METHYLATION MARKS ACROSS GENES.
>> WOW, THAT'S ACTUALLY KIND OF
WHAT I WAS GETTING AT, IS THAT
LONG TERM, HOW WOULD THIS
IMPACT, HEALTH OUTCOMES, PER
POPULATION.
WITH THAT, I THINK WE'RE OUT OF
TIME.
THAT VERY INTERESTING NOTE.
SO I WOULD LIKE TO THANK YOU,
DR. BUTLER, DR. ABBOTT, DR. MA
DR. MAKAREM.
THANK YOU FOR JOINING US FOR THE
ANNUAL SLEEP 101 SYMPOSIUM.
YOUR ENGAGEMENT IS VITAL TO
ADVANCING THE CONVERSATION
AROUND CIRCADIAN SCIENCE AND ITS
APPLICATION TO RESEARCH,
CLINICAL PRACTICE AND POPULATION
HEALTH.
AS WE MOVE FORWARD, WE ENCOURAGE
YOU TO CONTINUE TO EXPLORE THE
INNOVATIVE APPROACHES WE
DISCUSSED TODAY, AND TO CONSIDER
HOW TO -- HOW CAN YOU INFORM
YOUR WORK AND IMPROVE PATIENT
OUTCOMES AND PUBLIC HEALTH.
SO WE HOPE THIS SYMPOSIUM HAS
SPARKED NEW IDEAS, AND
COLLABORATIONS, AND THAT YOU
WILL TAKE THESE CONVERSATIONS
FURTHER IN YOUR RESEARCH AND IN
YOUR PRACTICE.
SO ON BEHALF OFF THE AMERICAN
ACADEMY OF SLEEP MEDICINE, THE
SLEEP RESEARCH SOCIETY AND THE
NATIONAL CENTER ON SLEEP
DISORDERS RESEARCH AT THE
NATIONAL HEART, LUNG AND BLOOD
INSTITUTE, WE LOOK FORWARD TO
SEEING YOU IN THE FUTURE.
A RECORDING OF THIS PRESENTATION
WILL BE AVAILABLE AT
VIDEOCAST.NIH.GOV IN THE COMING
DAYS.
THANK YOU AGAIN FOR YOUR
PARTICIPATION.
GOODBYE, EVERYBODY.
>> THANK YOU.
BYE.