>> I WANTED TO WELCOME ALL OF
YOU HERE AND OPENING REMARKS
WILL BE GIVEN BY DR. WALTER
KOROSHETZ WHO IS THE DIRECTOR OF
THE NATIONAL INSTITUTES OF
NEUROLOGICAL DISORDERS AND
STROKE AND HAS BEEN A STAUNCH
SUPPORTER IN ME/CFS OVER THE
YEARS AND WITHOUT HIS HELP THIS
WOULD NOT BE POSSIBLE AT ALL.
THANK YOU, DR. KOROSHETZ FOR
COMING AND ADDRESSING US.
>> THANKS, EVERYONE WHO'S HERE AND LISTENING IN.
I'M THE DIRECTOR OF NNDS AND WE
HAVE BEEN WORKING WITH OUR OTHER
INSTITUTES PRIMARILY NIAID AND
FOR A NUMBER OF DECADES AND
TRYING TO UNDERSTAND THE BIOLOGY
AND THEN IN ME/CFS AND TRYING TO
DEVELOP TREATMENTS.
I THINK WE ALL SHARE IN THE
GENERAL FRUSTRATION AROUND THE
WORLD THAT THIS IS GOING WAY TOO
SLOW.
THERE'S TOO MUCH SUFFERING GOING
ON AND WE DON'T HAVE ANSWERS FOR
PEOPLE AND SO I'M REALLY PROUD
OF THE WORK DONE HERE BY BRIAN
WALITT AND ABBY NATH AND TRYING
TO LOOK AT PEOPLE WHO HAVE
ME/CFS USING RESOURCES HERE THAT
ARE UNIQUE AND THEY TOOK
ADVANTAGE OF THAT AND I HOPE
THAT FOLKS CAN GET A SENSE OF
WHAT THEY FOUND AND TRY TO PUT
THEM IN THE RIGHT CONTEXT.
I WOULD SAY THAT THIS ARTICLE
THAT CAME OUT SAYING THAT WE
FINALLY KNOW WHAT DRIVES CHRONIC
FATIGUE ALONG COVID IS PROBABLY
AN OVERSTATEMENT.
YOU COULD BET HEAVILY IT'S AN
OVERSTATEMENT.
I THINK THE THINGS YOU'LL BE
HEARING ABOUT TODAY AND THE
SMALL NUMBER OF PATIENTS ARE
VERY INTRIGUING.
THEY'VE BEEN CLEARLY RIGOROUSLY
STUDIED AND THE DATA IS AS
PRISTINE AS YOU CAN GET BUT
THERE'S LOTS OF QUESTION ARE
GOING IT ARISE FROM THIS AND HOW
IT ALL PANS OUT IN THE END I
THINK IS WHAT WE HOPE WILL
STIMULATE RESEARCH AROUND THE
COUNTRY AND AROUND THE WORLD TO
GET AT THE BOTTOM OF THIS
PROBLEM.
THERE IS A LOT MORE INTEREST IN
THE PROBLEM NOW AND PROBABLY A
LOT THAT COMES FROM THE FACT
THAT ME/CFS IS A MAJOR CHRONIC
ILLNESS THAT OCCURS AFTER COVID
INFECTIONS WHICH OCCURRED IN
MILLIONS IN HUNDREDS OF MILLIONS
OF PEOPLE AROUND THE WORLD.
SO THE PROBLEM HAS JUST BEEN
MAGNIFYFIDE AND UNFORTUNATELY
OUR IGNORANCE IS ALSO MAGNIFIED.
THERE WAS A NATIONAL ACADEMY A
REPORT ON ASSOCIATION OF CHRONIC
ILLNESSES.
THE HOPE IS IT WILL GAFF VANNIZE
THE SCIENTIFIC COMMUNITY
RETICENT TO STUDY ME/CFS TO MAKE
A DIFFERENCE.
ALSO, I'D SAY THAT WE'RE GOING
TO BE TALKING IN NEUROLOGICAL
TERMS A LOT OF THE TIME HERE AND
SO I THINK THAT MAY BE SOMETHING
NEW TO PEOPLE.
AND I'LL TALK ABOUT TERMINOLOGY
IN A SECOND BUT JUST TO SAY THAT
THE BIOLOGY OF FATIGUE IS POORLY
UNDERSTAND AS A GENERAL CONCEPT
AND INHERENTLY IN IMPORTANT IN
EVERYTHING WE DO IN EVERY
SECOND, EVERY MICROSECOND
THERE'S A CALCULATION GOING ON
IN OUR BRAIN ON WHAT IS THE
REWARD EFFORT MATCH AND TRYING
TO UNDERSTAND THE BIOLOGY OF
FATIGUE WHICH OCCURS CAN IN SO
MANY CONDITIONS WAS THE SUBJECT
OF A GROUP COMING FROM THE
BLUEPRINT AND PUBLISHED THIS
PAPER IN GROUP RESEARCH SOCIETY.
THERE'S CLEARLY AS I MENTIONED A
BIGGER EMPHASIS IN THE PROBLEM
GIVEN THE COVID PANDEMIC AND
ME/CFS COMING ON AS A CHRONIC
COMPLICATION OF COVID.
THERE'S WORK GOING ON TO UNRAVEL
THE TWO CONDITIONS
SIMULTANEOUSLY.
THERE MAY BE SOME DIFFERENCES
BUT WE PERSPECTIVE THERE'S WAY
MORE IN COMMON THAN DIFFERENCES.
OF NOTE THE NINDS HAS BEEN
WORKING TO DEVELOP A RESEARCH
ROAD MAP FOR ME/CFS RESEARCH
THAT WE HOPE WILL ALSO BE ABLE
TO GIVE SOME GUIDANCE TO
SCIENTISTS AROUND THE WORLD ON
WHAT THE CURRENT STATE OF
AFFAIRS ARE AND WHAT THINGS LOOK
LIKE THEY'RE WORTH MOVING INTO.
I WOULD SAY A LOT OF THE RESULTS
YOU'LL HEAR ABOUT TODAY CAME OUT
AFTER THAT SO THESE ARE GOING TO
BE WHAT YOU'LL HEAR ABOUT IS
ADDITIONAL STUFF.
I WANTED TO SAY THAT THE EFFORT
HERE AVI NATH AND BRIAN WALITT
HAVE BEEN WORK ON IS LOOKING AT
THE GENERAL PROBLEM.
YOU'LL HEAR ABOUT THE ME/CFS
STUDY AND STUDIED LONG COVID
PATIENTS WITH SIMILAR TESTING
AND TO BE ABLE TO COMPARE
RESULTS AND ALSO HAVE PROJECT
GOING ON ONE THE VETERANS
ADMINISTRATION WHERE THERE'S
SIGNIFICANT OVERLAP IN ISSUES.
THE ROAD MAP WILL BE PRESENTED
AT OUR COUNCIL DURING THE OPEN
SESSION OF OUR NINDS SESSION.
PEOPLE, PLEASE ZOOM IN FOR THAT.
THEY'RE LOOKING AT A BUNCH OF
DIFFERENT SYSTEMS AND DATA
COMING OUT OF ALL COUNTRIES,
DIFFERENT TYPES OF LABS AND
TRYING TO SYNTHESIZE BEST THEY
CAN.
BUT PUTTING IT ALL TOGETHER HAS
BEEN A PROBLEM.
HOPEFULLY THIS WILL STIMULATE
MORE WORK IN THE AREA.
THEY LOOKED AT MULTIPLE WEBINAR
TO DEVELOP THE ROAD MAP AND ALL
THESE DIFFERENT SYSTEMS AND CAME
UP WITH TARGETS TO LOOK AT AS
POTENTIAL DRIVERS.
IN TERMS OF COVID, I HAVE HERE A
SLIDE.
THIS IS THE REPORT OF THE
SYMPTOMS THAT ARE ASSOCIATED
WITH LONG COVID COMING OUT VERY
EARLY AFTER THE PANDEMIC OR
ACTUALLY DURING THE PANDEMIC.
AND YOU CAN SEE HOW IN YELLOW
WHAT THE OVERLAP IS MANY OF THE
SYSTEMS IN ME/CFS AND ACTUALLY
POST EXERTION MALAISE IS THE
SYMPTOM THAT IS THE MOST
SPECIFIC FOR LONG COVID.
THERE'S A LOT OF OVERLAP HERE.
THE RECOVER INITIATIVE WHICH IS
WELL FINANCED TO STUDY PEOPLE
WITH LONG COVID, WE'RE TRYING TO
UNDERSTAND THE PATHOBIOLOGY IN
CLINICAL TRIALS.
WE DON'T HAVE A LOT OF CLUES AS
TO WHAT'S CAUSING IT YET BUT
FOLLOWING UP ON THE PARTIAL
CLUES WE HAVE AND TRYING TO TRY
DIFFERENT SYMPTOMATIC THERAPIES
WOULD BE TRIED IN PEOPLE WITH
ME/CFS AND WORK GOING ON HERE
AND MORE IMPORTANT THAN ANYTHING
IS THERE'S THOUSANDS OF PEOPLE
WORKING ON THIS PROBLEM.
AND WHAT WE NEED TO DO IS TO
HAVE THESE FOLKS REALIZE THE
COMMONALITIES BETWEEN THESE IT
DIFFERENT CONDITIONS AS DR. NATH
AND HIS TEAM HAVE ALL ALONG.
THAT WOULD BE GREAT MOVING IN
THE FUTURE TO HAVE THIS ARMY
WORK ING ON THE PROBLEMS MOST
IMPORTANT TO PEOPLE WITH ME/CFS.
I WANT TO SPEND TIME ON HOW
NEUROLOGISTS THINK.
WE'RE ALL PECULIAR PEOPLE YOU'LL
FIND OUT MORE TODAY.
WITH TRY TO THINK HOW THE BRAIN
WORKS.
AND THERE'S A NEUROLOGY TO
EVERYTHING.
THERE'S A NEUROLOGY TO WHY THIS
GUY HERE IS MOVING HIS LEGS BACK
AND FORTH AND WHY I JUST SMILED.
IT'S EVERYTHING WE DO IS THROUGH
THESE SECTOR CIRCUITS IN THE
BRAIN AND THE CIRCUITS ARE NOT
FUNCTIONAL IN ME/CFS AND TRYING
TO FIND OUT THE PROBLEM AND THIS
IS AN AREA SO PRIMITIVE TO ANY
ORGANISM BUT SO UNDER STUDIED.
WE WHY WE EAT, DON'T EAT AND
FEEL SATIATY AND MAKING AN
EFFORT TO DO SOMETHING IS AS
PRIMITIVE AS EATING.
THERE'S CIRCUITS IN THE BRAIN
THAT ARE DEVOTED TO EVERYTHING
WE DO INCLUDING THE DECISION TO
MAKE AN EFFORT ON ANYTHING THAT
WE DO.
EVERYTHING.
NOW, THE PROBLEM IS THE WORD
EFFORT HAS CONNOTATIONS IN THE
LATE PRESS THAT DON'T APPLY TO
WHAT WE'RE DOING AS
NEUROLOGISTS.
WHAT WE'RE TRYING TO THINK ABOUT
IS HOW THE BRAIN IS MAKE THIS
DECISION, WHAT AM I GOING TO DO
ON A MICROSECOND LEVEL.
IT'S NOT LIKE I'M GOING TO TRY
TO MAKE AN EFFORT OR NOT.
THIS IS GOING ON IN YOUR BRAIN
CONSTANTLY AND YOU DON'T EVEN
KNOW WHAT'S GOING ON.
IT'S NOT IN YOUR CONSCIOUSNESS.
COULDN'T THINK EVERY MOTION YOU
DO AND DECIDE IN A DELIBERATE
WAY AM I GOING MAKE THAT MOTION.
YOU COULD MAKE 100 A DAY AND I'M
MAKE 300 IN THREE SECONDS.
SO THEN THE QUESTION IS WHAT IS
FATIGUE.
ONE THINK ABOUT DIFFERENT WAYS
AND I'M NOT AN EXPERT BUT
DR. HALLETT IS AN EXPERT AND
HE'LL TALK LATER.
THE BRAIN IS TRYING TO MAKE A
DECISION IN A SIMPLISTIC WAY IS
I'M GOING TO DO X FOR REWARD Y.
THAT'S EVERY SINGLE ACTION.
YOUR BRAIN IS MAKING THAT
COMPLICATION SO YOU HAVE TO IT
MAKE SOME ESTIMATION OF WHAT THE
WORK OR THE EFFORT IS AND THEN
YOU MAKE SOME ESTIMATION OF WHAT
THE REWARD IS AND YOUR BRAIN IS
DOING THAT ALL THE TIME.
AND THEN FATIGUE, THERE'S A REAL
PROBLEM THERE.
WE'RE NOT SURE WHAT THE PROBLEM
IS.
IT COULD BE YOU'RE
OVERESTIMATING THE EFFORT OR
COULD BE THAT YOU'RE NOT GETTING
THE REWARD SIGNAL FOR THE
EFFORT.
BUT THAT IS A COMPUTATIONAL
PROBLEM IN YOUR BRAIN.
AND PEOPLE -- IT'S IMPORTANT FOR
PEOPLE TO UNDERSTAND THIS HAS
NOTHING TO DO WITH THEY DON'T
WANT TO MAKE AN EFFORT.
IT HAS NOTHING TO DO ONE THAT.
IT'S COMPLETELY SEPARATE.
IT'S HOW YOUR BRAIN IS MAKING
THESE COMPUTATIONS.
JUST AN EXAMPLE.
IF YOU LOOK AT MUSCLE FATIGUE.
HERE'S SOMETHING SIMPLE AND
NOTHING DO WITH ANY ME/CFS IT'S
ABOUT FATIGUE.
WHEN YOU TRY TO MAKE
CONTRACTIONS AGAINST A FORCE
EVENTUALLY YOU'LL FATIGUE AND
WHAT HAPPENS IS -- WHAT YOU SEE
HERE IS THE FORCE STARTS TO DROP
OFF AFTER YOU DO IT 100 TIMES
AND THE INTERESTING THING IS YOU
WOULD SAY OKAY THE MUSCLE CAN'T
DO IT ANYMORE.
NOT TRUE.
WHEN YOU STIMULATE THE NERVE YOU
GET THE CONTRACTION TO COME
BACK.
SO THERE'S SOMETHING IN THE
CENTRAL NERVOUS SYSTEM THAT IS
TELLING THE NERVES I DON'T WANT
TO DO THIS ANYMORE.
YOU STOP FIRING.
THERE'S NOTHING WRONG WITH THE
MUSCLE -- WELL, THE MUSCLE'S
TIRED I CAN'T GET TO WHERE IT
WAS BEFORE BUT LOOK AT THE
DIFFERENCE WHEN YOU STIMULATE
DIRECTLY.
THAT IS ONE SENSE OF FATIGUE
THAT IS EVIDENCE COMING FROM A
CENTRAL CONTROLLER.
THAT'S ABOUT WHAT WE'RE TRYING
TO UNDERSTAND IN ME/CFS, WHERE'S
THE CENTRAL CONTROLLER AND
WHAT'S WRONG IN IT.
THERE'S LOTS OF THINGS TO CAUSE
YOU FATIGUE.
WE KNOW A LOT OF THE LIST OF THE
PROBLEMS AND INJECT YOU WITH
SOMETHING FOR FATIGUE BUT WHERE
IN THE BRAIN THAT'S HAPPENING IS
THE QUESTION AND WHY PEOPLE WITH
ME/CFS IS THERE THAT RESET, THAT
BALANCE BEING WHY'S IT ABNORMAL
I WANT PEOPLE TO PUT THEIR LAY
TERMINOLOGY AND THE SCIENCE WILL
GIVE THE ANSWERS.
ONCE WE UNDERSTAND WHAT'S GOING
ON IN THE BRAIN AND WHERE IT'S
OCCURRING YOU CAN MODULATE
CIRCUITS.
PEOPLE WITH SEVERE CHRONIC PAIN
STIMULATE A CERTAIN AREA, IT
GOES AWAY.
PEOPLE WITH DEPRESSION, CLOSE TO
SUICIDE, YOU TURN ON THE
STIMULATOR IT GOES AWAY.
THERE'S REAL PROMISE IN
UNDERSTANDING WHAT'S WRONG WITH
THE CIRCUITS AND WHAT YOU'LL
HEAR ABOUT TODAY FROM DR. NATH
AND THE TEAM AND HOPEFULLY THIS
MOVES US A STEP FURTHER TO
BETTER UNDERSTAND AN GET US TO
TREATMENT FOR ME/CFS.
I APPRECIATE THE TREMENDOUS
AMOUNT OF WORK THAT'S DIDN'T
DONE AND CREDIT TO AVI AN HIS
TEAM TO MAKE THIS PUBLIC AND
EXPLAIN IT IN THE BEST WAY
POSSIBLE TO THE WORLD SO THANKS
VERY MUCH.
>> THANK YOU, DR. KOROSHETZ THAT
WAS AN ELEGANT DESCRIPTION.
BETTER THAN I COULD HAVE
EXPLAINED IT MYSELF.
SO I'M JUST GOING TO GIVE A FEW
OPENING REMARKS TO PUT THIS IN
CONTEXT.
THE FIRST THING I WANT TO DO IS
TELL WHERE YOU ALL THIS RESEARCH
TAKES PLACE.
SO YOU'RE IN BILLING 10 RIGHT
NOW AND THE THREE BUILDINGS ARE
THE CLINICAL RESEARCH CENTER.
THAT'S WHERE ALL THE PATIENTS
CAME.
IT'S THE LARGEST RESEARCH
HOSPITAL IN THE WORLD BUT YET
IT'S BUILT AS A 200 BED HOSPITAL
AND ONLY 90 OCCUPIED AT THE
MOMENT.
ALL THE LARGE FOR RESEARCH AND
SMALL IN CONTEXT.
IT GIVES US THE ABILITY TO STUDY
PATIENTS IN A WAY YOU REALLY
COULDN'T OTHERWISE.
IT PROVIDES THE EASE OF BEING
ABLE TO SEE PATIENTS AND DO
RESEARCH IN THE SAME PLACE.
DON'T HAVE TO GET IN YOUR CAR TO
GO SOME PLACE.
I WANT TO THANK A LOT OF PEOPLE
WHO MADE THIS POSSIBLE.
AND FIRST OF ALL I WANTED TO
THANK THE STUDY PARTICIPANTS
BECAUSE THEY REALLY SPENT A LOT
OF TIME AND EFFORT COMING HERE
AND KNOWING THAT THERE'S NO
TANGIBLE BENEFIT TO THIS MANY AT
THE END OF THIS STUDY.
BUT YET WE PROBED THEM AND DID
ALL KINDS OF TESTS TO THEM AND
TOOK BLOOD AND SPINAL FLUID AND
IMAGING AND ALL KINDS OF THINGS
AND THEY WENT THROUGH ALL OF IT.
THEY WERE HERE FOR A WEEK AND
THEN TWO WEEKS.
SO WE'RE EXTREMELY GRATEFUL TO
THEM BECAUSE WITHOUT THEIR
VOLUNTEERING THIS WOULD NOT BE
POSSIBLE.
THE STUDY PARTICIPANTS ARE NOT
JUST PATIENTS WITH ME/CFS BUT
HEALTHY CONTROLS WHO WENT
THROUGH THE SAME PROCESS.
SO THEY'RE DEFINITELY NOT
BENEFITING IN ANY WAY BUT WERE
WILLING TO PUT THEMSELVES
THROUGH IT IN ORDER FOR US TO BE
ABLE TO FIND WAYS OF STUDYING
OTHER DISEASES.
I HAVE TO THANK THE NIH
LEADERSHIP START FROM FRANCIS
COLLINS TO DR. KOROSHETZ AND
OTHERS.
A LOT OF THE INSTITUTES REALLY
PARTICIPATED IN THIS STUDY AND
WOULD NOT BE POSSIBLE UNLESS THE
DIRECTORS OF THOSE INSTITUTES
MADE THEIR RESOURCES AVAILABLE
FOR THE STUDY ITSELF.
THE STUDY STREAM CONSISTS OF
NEARLY 75 INVESTIGATORS.
MOST OF THEM PUT ASIDE WHAT THEY
WERE DOING AND TOOK THIS ON TOP
OF WHATEVER THEY WERE DOING IN
ORDER TO CONTRIBUTE TO THE
STUDY.
ANYONE AND EVERYONE I ASKED TO
HELP THEY ACTUALLY DID.
A STUDY TEAM WAS LED BY
DR. BRIAN WALITT AND HE HAS DONE
A SUPERB JOB LEADING THIS ENTIRE
STUDY.
WITHOUT HIS HELP THIS WOULD NOT
BE POSSIBLE.
THEN WE HAD A TEAM OF
ADJUDICATORS AND THEY ADJUD
ADJUDICATED EVERY PATIENT ON THE
STUDY THAT TEAM DID A PHENOMENAL
JOB MAKING SURE WE WERE STUDYING
THE RIGHT INDIVIDUALS.
RESEARCHERS AS A MENTIONED CAME
FROM ALL THESE VARIOUS
INSTITUTES OVER HERE AND SOME OF
THEM HAVE AFFILIATIONS IN OTHER
UNIVERSITIES AND RESEARCHERS
THAT WE COLLABORATED WITH.
AND WE'RE GRATEFUL TO ALL OF
THEM.
WE HAVE TWO PANELS TODAY.
ESTEEMED PANEL OF STUDY
PARTICIPATED AND UME GRATE FOL
BOTH PANELS AND YOU'LL HEAR FROM
THEM AS WELL.
I WANT TO THANK THE ORGANIZERS
ESPECIALLY WARREN AND ALISSA AND
THE OTHERS ARE HERE AND BARBARA
AND THE AMOUNT OF WORK TO PUT
THIS EFFORT TOGETHER AND WITHOUT
THEIR HELP WOULD NOT BE POSSIBLE
AT ALL.
I WANT TO THANK FES FOR
PROVIDING COFFEE AND SNACKS FOR
THE MORNING.
THE GOAL OF THE STUDY OF TODAY'S
PRESENTATION IS TO DISCUSS THE
FINDINGS FROM THE NIH INTRAMURAL
RESEARCH O ON POST INFECTIOUS
ME/CFS.
AND WE WANT YOU TO HEAR DIRECTLY
FROM THE RESEARCHERS AND THERE'S
NO ONE WHO UNDERSTAND THE STUDY
IN ITS ENTIRETY BUT WE HAVE THE
WORLD'S EXPERTS WHO CONTRIBUTED
TIME.
I WANT YOU TO HEAR DIRECTLY FROM
THEM.
THEN WE LIKE TO DISCUSS FUTURE
DIRECTION JUST AS DR. KOROSHETZ
SAID IT'S A GOOD BEGINNING BUT
NOT THE END.
I WANT TO GIVE YOU A LITTLE HOW
I GOT INVOLVED IN THIS THING AND
I CALL IT THE IT TALE OF THREE
PANDEMICS.
MY CAREER STARTED WENL THE HIV
PANDEMIC IN THE '80s AND I
LEARNED A LOT ABOUT INFECTIONS
DUE TO THE BRAIN THROUGH DECADES
OF RESEARCH STUDYING HIV
INFECTION.
THE INTRAMURAL STUDY START AT
THE TIME I WAS INVOLVED IN THE
EBOLA PANDEMIC.
THE EARLY TELECONFERENCES I TOOK
IN LIBERIA FOR ME/CFS.
THAT'S HOW THIS ACTUALLY
STARTED.
THEN A STUDY ENDED WITH THE
COVID PANDEMIC.
SOMEWHAT ABRUPTLY BECAUSE WE
COULDN'T BRING PATIENTS IN ANY
LONGER.
THE STUDY WAS SANDWICHED BETWEEN
TWO PANDEMICS BUT WE LEARNED A
LOT FROM ALL THREE OF THEM.
AND THEY HAVE SIMILAR THINGS.
FOR EXAMPLE, IT WITH THE EBOLA
PANDEMIC WE REALIZED THERE'S A
POST-EBOLA SYNDROME THAT LOOKS
SIMILAR TO ME/CFS AND WITH THE
SARS COV2 PANDEMIC WE REALIZED
THERE'S A LONG COVID WHICH ALSO
OV
OVERLAPS WITH ME/CFS.
WHAT IS INTERESTING AS THEY'RE
ALL POST INFECTION SYNDROMES AND
OVERLAP TREMENDOUSLY WITH ONE
ANOTHER.
WHAT IS FASCINATING IS THAT WITH
THE AIDS PATIENTS THEY HAVE
PERSISTENT VIRAL RESERVOIRS.
THEY'RE PROTEINS ARE ALWAYS
BEING PRODUCED BUT NOT PRODUCE
THE CFS SYNDROME SO JUST
PERSISTENT INFECTION ALONE IS
NOT SUFFICIENT TO EXPLAIN THIS
THING.
WHAT IS INTERESTING IS THE ROUTE
OF INFECTION IS QUITE DIFFERENT.
SO IF YOU LOOK AT POST EBOLA
SYNDROME AND IT'S LARGELY A
GASTROINTESTINAL IN INFECTION
AND ME/CFS COULD BE
GASTROINTESTINAL OR OTHER AND
THESE ARE QUESTIONS UNANSWERED.
WHAT YOU'LL HEAR TODAY IS A
DESCRIPTION OF FINDINGS RELATED
TO EACH OF THESE DIFFERENT
BUCKETS WE PUT TOGETHER HERE AND
IN OUR PAPER WE PROPOSED A
HYPOTHESIS.
IT'S IMPORTANT TO SAY WE DON'T
REALLY KNOW THE PATHWAY.
IT'S A CROSS-SECTIONAL STUDY BUT
WE'VE PROPOSED A PATHWAY.
AND SO ALL THE RESEARCHERS WILL
DISCUSS VARIOUS ASPECTS OF THIS
THAT THEY ARE EXPERTS ON.
I'M NOT GOING TO GO THROUGH THIS
ENTIRETY BECAUSE I FIGURE IT
WILL BE DISCUSSED IN MORE DETAIL
LATER ON TODAY.
SO THE AGENDA FOR TODAY IS THAT
YOU'LL HEAR A DESCRIPTION OF THE
STUDY ITSELF.
WE THEN DIVIDED INTO THREE MAJOR
BUCKETS.
ONE IS ON IMMUNOLOGY AND OMICS.
THE SECOND IS ON NEUROPHYSIOLOGY
AND THE BIO ENERGETICS AND
LASTLY YOU'LL HEAR SOMETHING
ABOUT THE DATA MANAGEMENT AND
SHARING BECAUSE THAT ITSELF WAS
A HUGE MASSIVE UNDERTAKING AND
THEN WE HAVE TWO PANELS AND THEN
WE'LL WELCOME QUESTIONS AND
MULTIPLE PLACES WHERE THERE'LL
BE OPPORTUNITY FOR DISCUSSION
AND ENCOURAGE YOU TO ASK US
QUESTIONS.
SO THIS IS MY LAST SLIDE.
AND HERE I WANTED TO DIRECTLY
ADDRESS THE ME/CFS COMMUNITY.
I WANT YOU TO KNOW THAT AS
PHYSICIANS AND RESEARCHERS,
WE'RE DEEPLY COMMITTED AND HAVE
A STRONG CONVICTION TO TREATING
THIS ILLNESS AND FINDING CURES
FOR THE DISEASE.
WE'RE YOUR PARTNERS AND WE HAVE
THE SAME SHARED GOALS AND I
THINK THAT'S IMPORTANT FOR YOU
TO REAL.
AND AS SHOWN HERE IF WE WALK
TOGETHER I THINK WE CAN ACHIEVE
THE INSURMOUNTABLE.
BUT AS IN ANY PARTNERSHIP,
HEALTHY CRITICISM AND RESPECT
FOR ONE ANOTHER WILL HELP US
GROW BECAUSE WE'RE REALLY ON THE
SAME SIDE.
ALL THE SAME, WHEN YOU DOUBT OUR
INTENTIONS AND PICK APART EVERY
SINGLE WORD, YOU ALSO TEAR US A
PART.
IT CAUSES PAIN AND SUFFERING ON
BOTH SIDES AND DEMORALIZES US
AND SHATTERS OUR GOALS.
SO YOU HAVE A PHENOMENAL TEAM
WHO DEVOTED TIME AND EFFORT TO
UNDERSTAND THE FUNDAMENTAL BASIS
OF ME/CFS.
THEY'RE THE WORLD'S EXPERTS IN
THE FIELD AND TOOK ON THIS
PROJECT ON TOP OF EVERYTHING
ELSE THEY WERE DOING.
WHEN WE ASK THEM TO LEND THEIR
EXPERTISE TO THE PROJECT, EACH
ONE OF THEM SAID YES AND THEY
DELIVERED.
SO IS TOGETHER I THINK WE CAN
REALLY MAKE A HUGE DIFFERENCE IN
THIS DISEASE BUT IT'S IMPORTANT
THAT WE WORK TOGETHER AND NOT
AGAINST ONE ANOTHER.
I THINK THIS IS ALSO AN
OPPORTUNITY TO DISCUSS OUR
FINDINGS AND I URGE YOU TO NOT
MISS THE OPPORTUNITY TO THANK
THESE RESEARCHERS WHEN YOU GET A
CHANCE.
THESE RESEARCHERS ARE SHINING
THE LIGHT ON THE PATH WE NEED TO
FOLLOW AND HOLDING HANDS
TOGETHER WE'LL FIND TREATMENTS
AND CURES WE DESPERATELY NEED.
SO I'LL STOP HERE AND GOING TO
HAND IT OVER TO DR. BRIAN WALITT
WHO IS GOING TO DESCRIBE THE
CLINICAL COHORT AND THE
PROTOCOL.
DR. WALITT IS A RHEUMATOLOGIST
BY TRAINING AND HE SPECIALIZED
IN FIBFIBROMYALGIA BEFORE HE CA
TO NIH AND HE CAME AND
VOLUNTEERED TO HELP ME PUT THE
STUDY TOGETHER AND HE'S DONE AN
ABSOLUTELY PHENOMENAL JOB AND AN
ASTUTE PHYSICIAN AND VERY
CAREFUL.
HE WENT THROUGH RECORDS OF ALL
THE PATIENTS THAT CAME THROUGH
HELPED IDENTIFY THE PATIENTS,
EXAMINED THEM ON WEEKENDS AND
DAYS AND NEWTS, WHATEVER IT TOOK
TO MAKE SURE THAT EVERY ASPECT
OF THE STUDY WORKED OUT WELL.
WITHOUT HIS HELP THIS WOULD NOT
BE POSSIBLE.
DR. WALITT, I'LL LED YOU
DESCRIBE THE OVERVIEW OF THE
STUDY.
♪
OF
>> THANK YOU ALL FOR COME
THANK YOU ALL FOR COMING TODAY
AND FOR YOUR KIND WORDS AVI AND
HERE WE ARE.
SO I'M GOING TO TAKE TIME NOW TO
DESCRIBE THE COHORT OF PATIENTS
THAT WERE RECRUITED IN THE
PROTOCOL WE PUT TOGETHER TO
STUDY.
SO AS MENTIONED IT WAS ANNOUNCED
WE WERE GOING STUDY CHRONIC
FATIGUE SYNDROME AROUND 2015,
HERE WE ARE IN 2024 I'M HERE TO
PRESENT THE RESULT ARE TO YOU.
THIS IS A HAPPY MOMENT FOR ME TO
BE ABLE SO THE YOU ALL THIS WORK
WE DID.
SO, SOMEONE HAS TO EXPLAIN WHAT
MIALGIC CHRONIC FATIGUE SYNDROME
IT'S DIAGNOSIS CLINICAL.
HERE'S THE IOM, THE INSTITUTE OF
MEDICINE CRITERIA A SUBSTANTIAL
DECREASE IN FUNCTION OVER SIX
MONTHS IN TIME.
THE SYMPTOMS OF POST EXERTIONAL
MALAISE AND UNREFRESHING SLEEP
AND ORTHOSTATIC INTOLERANCE.
ON THE RIGHT IS A PICTURE A
PARTICIPANT DREW TO TRY TO
VISUALIZE THE SYMPTOMS SHE HAS.
YOU CAN SEE THE VARIOUS WAYS SHE
SUFFERS FROM HER ME/CFS.
MUSCLE ACHES, FEELINGS OF FLU,
HEADACHES, SENSITIVITY TO LIGHT,
THE SENSATION OF BRAIN FOG AND
DIFFICULTY FOCUSSING.
WHAT IT MIGHT FEEL LIKE TO HAVE
UNREFRESHING SLEEP.
SHE HAD NAUSEA AND THE IDEA OF
DIZZINESS AND THE BLACK HOLE
THAT IS THE FEELING OF
POST-EXERTIONAL MALAISE AND
THERE'LL BE MORE ON WHAT THAT IS
IN THE PRESENTATION.
WE PUT TOGETHER THE PROTOCOL.
WHEN EVERYTHING GOT STARTED WE
HAD TO GO AS FAST AS POSSIBLE
AND WERE ABLE TO WRITE A
PROTOCOL IN ABOUT A MONTH'S TIME
TO GIVE TO THE IRB.
IT WENT UNDER A FAIR BIT OF
AMENDMENT OVER TIME TO GET IT
INTO ITS FINAL FORM BUT WE MOVED
AS FAST AS POSSIBLE TO GET THIS
PROTOCOL STARTED.
THE HYPOTHESIS WAS
POST-INFECTIOUS ME/CFS WAS
TRIGGERED BY INFECTIOUS ILLNESS
THAT RESULTED IN IMMUNE MEDIATED
BRAIN DYSFUNCTION.
TO DO THIS WE WANTED TO CONDUCT
A STUDY DEEPLY PHENOTYPE
PARTICIPANT TO DEFINE ITS PATH
YO PHYSIOLOGY.
SO WHAT
PATHOPHYSIOLOGY.
WHAT IS DEEP PHENOTYPING?
I PROVIDED A REFERENCE FOR THOSE
LOOKING TO DIVE DEEPER.
THE PRECISE AND COMPREHENSIVE
ANALYSIS OF PHENOTYPIC
ABNORMALITIES WHERE THE
INDIVIDUAL COMPONENTS OF
PHENOTYPE ARE OBSERVED AND
DESCRIBED.
MEASURE EVERYTHING POSSIBLE TO
FIRST ALL THE DIFFERENT ASPECTS
OF A PERSON.
AND TO DO THIS THIS IS A LIST OF
MOST THE PHENOTYPING MEASURES WE
MADE.
SOME ARE THINGS THAT CLINICIANS
DO LIKE HISTORIES AND PHYSICAL
EXAMS.
SOME ARE MEASUREMENTS OF
PEOPLE'S BEHAVIOR, HOW THEY EAT
AND SLEEP AND MEASURES OF
PHYSIOLOGY SUCH AS THEIR SLEEP
POLY SOMNOGRAMS AND MEASURES OF
BLOOD AND CEREBRAL SPINAL FLUID
AND SO FORTH.
THIS WAYS STUDY AND MOST STUDIES
PEOPLE THINK ABOUT IS TO TEST
HYPOTHESIS.
THIS TRYING TO GENERATE A NEW
HYPOTHESIS TO GIVE US DIRECTION
TO MOVE FORWARD IN THE FUTURE.
AND FOR US OUR MISSION WAS TO
EXPLORE THE POSSIBLE
RELATIONSHIPS BETWEEN THE STUDY
MEASUREMENTS WITHOUT PRIOR
ASSUMPTIONS TO WHAT THOSE MIGHT
MEAN.
SO PARTICIPANT SELECTION WAS AN
IMPORTANT PIECE OF THE PUZZLE
FOR THE STUDY.
WE WANTED TO MAKE SURE EVERYBODY
HAD A WELL DOCUMENTED INFECTION.
THIS REQUIRED US TO LOOK THROUGH
LOTS OF MEDICAL RECORDS TO MAKE
SURE THE PATIENTS HAD NORMAL
HEALTH PRIOR TO INFECTION AND
DEMONSTRATE THESE PEOPLE WHO
WERE OSTENSIBLY HEALTHY
DEVELOPED ME/CFS FOLLOWING THE
DOCUMENTED INFECTION.
WE FELT THIS WAS IMPORTANT
BECAUSE AT THE END OF THE DAY IF
YOU LOOK AT THE CAUSE OF ME/CFS
IN THE COHORT IT'S AN INFECTION.
THESE PEOPLE ALL HAD UNINFECTION
THAT CAUSED THEIR ME/CFS.
-- HAD AN INFECTION THAT CAUSED
THEIR ME/CFS.
WE BROUGHT THEM TO CAMPUS TO DO
DETAILED SCREENING FOR MEDICAL
AND PSYCHIATRIC FACTORS.
WE DID A DETAILED IN PERSON
MEDICAL AND PSYCHIATRIC
EVALUATIONS WE'LL TALK ABOUT IN
A MINUTE AND FURTHER WE REALIZED
IN MEDICINE, NOT EVERYTHING IS
EVIDENT AT THE TIME WHEN YOU
EVALUATE SOMEBODY.
SO WE KNEW WE'D HAVE TO STAY IN
TOUCH OVER THE COURSE OF THE
STUDY TO SEE IF THINGS CHANGED,
IF THAT WOULD CHANGE HOW WE
LOOKED AT OUR PARTICIPANTS.
SO THE FOLLOW UP WAS VERY
IMPORTANT IN HELPING US
UNDERSTAND THE TRAJECTORY OF
THESE PARTICIPANTS.
LASTLY, WE DIDN'T WANT TO TAKE
IT UPON OURSELVES TO DECIDE WHAT
THE PROPER CASE IS.
WE WERE NEW IN THE FIELD AS OUR
FIRST EFFORT AS A TEAM TO STUDY
ME/CFS SO WE WORKED WITH EFFORTS
THAT WERE CLINICAL EXPERTS THAT
WERE WELL RENOWN IN THE FIELD TO
HELP REVIEW EACH OF THE CASES.
MAKE SURE THEY MEET ME/CFS
CRITERIA AND ALL THE ADJUDICA
ADJUDICATORS HAD TO AGREE THIS
WAS A GOOD CASE AND ANYONE COULD
VETO.
WE FELT OUR CAUSE SELECTION
PROCESS WAS STRONG.
THIS IS AN OVERVIEW OF THE
RECRUITMENT.
WHILE WE WERE OPEN WE HAD 484
INQUIRIES AND WOUND UP WITH THIS
AND THE SARS COV2 PANDEMIC SHUT
DOWN OPERATIONS WE WOULD HAVE
CONTINUED TO RECRUIT IF WE COULD
HAVE BUT WITH THE UNCERTAINTY OF
THE PANDEMIC AND THE CLINICAL
CENTER CLOSED TWO YEARS IT WAS
FELT WE SHOULD SHUT DOWN OUR
RECRUITMENT AND MOVE INTO OUR
ANALYSIS AS FAST AS POSSIBLE.
SO OF THE 484 PARTICIPANTS THAT
INQUIRED, 267 WERE SCREENED OUT
INITIALLY AND ON THE RIGHT SIDE
IS I PROVIDE SOME REASONS WHY
PEOPLE WERE SCREENED OUT ON THE
TELEPHONE SCREENING.
I PERSONALLY INTERVIEWED AND
REVIEWED THE RECORDS OF 217
INDIVIDUALS.
OF THOSE 146 PEOPLE WERE
SCREENED OUT AND YOU CAN SEE
SOME REASONS WHY THEY SCREENED
OUT.
AND 44 PEOPLE UNFORTUNATELY WERE
STUCK IN LIMBO THAT HAPPENED
BECAUSE OF THE PANDEMIC AND
NEVER GOT TO FINISH THE REVIEW
PROCESS.
OF THE PEOPLE THAT MADE IT
THROUGH THE SECOND SET OF
SCREENING, 25 HEALTHY VOLUNTEERS
AND 27 ME/CFS PARTICIPANTS CAME
TO CAMPUS.
AND YOU CAN SORT OF SEE HERE ON
THE RIGHT THE HEALTHY
VOLUNTEERS.
NOT EVERYBODY WHO THINK THEY'RE
HEALTHY ARE HEALTHY AND FOUR OF
THE HEALTHY VOLUNTEERS WERE
FOUND TO HAVE MEDICAL ISSUES
THAT WERE EXCLUSIONARY ON THEIR
EVALUATION AND ONE HEALTHY
VOLUNTEER WITHDREW LEAVING US
WITH 21 HEALTHY VOLUNTEERS.
IT'S WORTHY TO NOTE THE
VOLUNTEERISM OF FAMILY IS ALWAYS
SOMETHING SPECIAL AND TWO OF THE
HEALTHY VOLUNTEERS WERE FAMILY
MEMBERS OF THE PARTICIPANTS.
OF OUR 27 ME/CFS PARTICIPANT
CAME TO CAMPUS, ALL OF THEM
WOULD HAVE MET ME/CFS CRITERIA
MEASURED THAT WAY BUT TWO
WITHDREW AND FOUR WERE INCLUDE
ON OUR EVALUATION BECAUSE ONE
WAS FOUND TO HAVE A RARE CANCER,
D
DES
DESMOPLASTIC CARCINOMA AND SOME
WERE ADJUDICATED OUT ON REVIEW
BECAUSE THEY'RE CASES DIDN'T
MEET OUR HIGH THRESHOLD FOR
DEMONSTRATING INFECTIOUS
CAUSALITY LEAVING US WITH 17
CASES.
WHAT INFECTIONS DID THESE HAVE.
10 HAD UPPER RESPIRATORY TRACT
INFECTIONS, THREE WERE ACUTE
EBBSTEIN VIRAL INFECTION AND
SOME WERE RELATED TO OTHER IN
F
INFECTIONS.
WE HAVE HEALTHY VOLUNTEERS
UNBLUE AND ME/CFS IN REDDISH
SHADES.
ON AVERAGE PEOPLE WERE MATCHED
AND MID AGED IN THEIR LATE 30s,
EARLY 40s.
WE MATCHED REASONABLY WELL ON
BIRTH SEX WITH 48% OF THE
HEALTHY VOLUNTEERS BEING MEN AND
41% OF THE ME/CFS BEING MEN AND
IT SKEWED TOWARDS CAUCASIAN AND
WELL EDUCATED AND BODY MASS
INDEX WAS MATCHED AND THE ME/CFS
PARTICIPANTS WERE PRETTY
DISABLED BY THEIR SYMPTOMS.
ALL THE PARTICIPANTS MET THE
2015 CRITERIA AND 53% MET OTHER
CRITERIA CAN AND PATIENTS CAME
TO CAMPUS FOR THEIR INITIAL
EVALUATION.
THIS IS WHERE WE DID THE BULK OF
THESE PHENOTYPING MEASURES.
HERE'S A SAMPLE OF THE CALENDAR
A PARTICIPANT WOULD GET PRIOR TO
COMING TO CAMPUS.
IT WAS A VIGOROUS AFFAIR AND A
LOT OF OUR EFFORTS AS A TEAM
WERE TO HELP PEOPLE NAVIGATE ALL
THE DIFFERENT TESTS AND TIMING
AND TO ENSURE THEY HAD REST TO
RECUPERATE AND HELP CHEERLEAD
THEM THROUGH THIS GAUNTLET OF
RESEARCH WE PUT THEM THROUGH.
YOU CAN SORT OF SEE IN THE
CALENDAR WE HAD TO ENSURE FOR
OURSELVES WE HAD TO MAKE SURE
THERE WAS BREAKFAST AND LUNCH
AND TIME OUT TO REST.
WE HAD TO BUILD THAT IN THEIR
COLORS TO MAKE SURE THEY CAN
MAKE IT THROUGH THE IT RESEARCH
PROTOCOL.
OFF
AFTER THE EVALUATION WE SENT
ADJUDICATION PAMPHLETS TO OUR
PANEL AND ALL THE MEDICAL
TESTING AND HISTORY AND I WROTE
NARRATIVES ON EACH OF THE
PARTICIPANTS TO MAKE SURE I
CAPTURED THEIR STORY CORRECTLY
AND EVERY PARTICIPANT REVIEWED
THEIR STORY AND SIGNED OFF ON IT
PRIOR TO THE ADJUDICATION.
THE PANEL OF EXPERTS IN
DEPARTMENTALLY REVIEWED THESE
AND EACH MADE THEIR INDEPENDENT
DECISIONS.
IT WASN'T GROUP THINK.
IF THEY UNANIMOUSLY AGREED, A
PERSON WAS INVITED BACK OR
CONSIDERED A CASE FOR ANALYSIS
AND IF THERE WAS AN AGREEMENT WE
HAD THE PANEL MEET TO DISCUSS
THE CASE TO SEE IF WE COULD GET
TO UNANIMITY AND THANK YOU TO
THE DEBATERS.
[LISTING NAMES]
AFTER THAT THEY WERE BROUGHT
BACK FOR A SECOND VISIT TO HAVE
AN EXERCISE STRESS TEST IT
PERFORMED AND THIS IT WAS A CPAC
FOLLOWED BY 72 HOURS OF
MEASUREMENT TO UNDERSTAND THE
BIOLOGY OF POST EXERTION
MALAISE.
HERE'S SOME MEASURES WE PUT
TOGETHER AND PICTURE OF OUR
PARTICIPANTS PERFORMING THE
THIS.
AND BESIDES THE C PET THERE WERE
MEASURES OF THEIR BIO ENERGETICS
USING A METABOLIC CHAMBER AND
STOOL AND SALIVA AND THERE WAS A
LUMBAR PUNCTURE AND
NEUROCOGNITIVE TESTING AND OTHER
NEUROLOGICAL TESTS.
HERE'S AN EXAMPLE OF THEIR
SCHEDULE.
THE NICE THING IS THERE'S EIGHT
OF REST AFTER THE C PET.
IT WAS REALLY IMPORTANT TO US
WITH ALL THE PARTICIPANTS WENT
THROUGH THAT WE TRIED TO MAKE IT
POSSIBLE THAT TO GET THROUGH THE
PROCEDURING AND DO OUR MOST NOT
TO INJURY ANYBODY.
ON PHYSICAL EXAMPLE THERE WERE
FINDINGS AND TWO PATIENTS WITH
MOBILITY AND ONE PARTICIPANT HAD
A SMALL NEUROPATHY AND ONE HAD
RESIDUAL WEAKNESS FROM THEIR
HERPES ZOSTER INFECTION AND ONE
HAD WE THOUGHT HAD A DISORDER
AND CLINICALLY THERE WAS NOT A
LOT OF PATHOLOGY WE FOUND.
THERE WAS SOME MILD SLEEP APNEA
AND LIMB DISORDERS.
ANY PARTICIPANT WE FOUND TO HAVE
SLEEP APNEA WE GAVE THEM A
SIX-WEEK TRIAL OF C PAP TO SEE
IF IT MADE A DIFFERENCE AND IT
DIDN'T CHANGE ANYBODY IN A
PROFOUND WAY.
BRAIN MRI THERE WAS LESIONS IN
FIVE HEALTHY VOLUNTEERS AND THE
PARTICIPANTS.
ON THE CLINICAL LABORATORY
EVALUATION THERE WASN'T TOO MUCH
DIFFERENCE.
WE DID A BROAD PANEL OF
HEMATOLOGY AND CHEMISTRY AND
IMMUNOLOGY AND VIROLOGY AND
HEAVY METALS ANALYSIS.
ON PSYCHOLOGICAL EVALUATION THE
PARTICIPANTS WERE MORE OFTEN
DEPRESSED THAN ANXIOUS BUT NOT
SEVERELY SO.
THIS SHOWED YOU SOME OF THOSE
DIFFERENCES.
AND WHEN PEOPLE DID HAVE ISSUES
THEY WERE MILD.
AND NOT THAT DIFFERENT THE
HEALTHY VOLUNTEERS AND WE'LL
SHOW THAT YOU THAT ON THE NEXT
SLIDE.
HERE IS SYMPTOM REPORTING.
ON THE LEFT IS ALL THE DIFFERENT
MEASURES WE TOOK.
IT'S QUITE AN IMPRESSIVE LIST
BUT YOU SEE THE P VALUES FOR ALL
THESE THINGS ARE HIGHLY
SUBSTANTIAL.
IN GENERAL ON MOST SYSTEM
MEASURES PEOPLE WITH PI AND CFS
WERE TWO STANDARD DEVIATIONS
WORSE THAN WHAT WE CONSIDERED
NORMAL IN THE POPULATION.
ON THE RIGHT SIDE TO GIVE A
SENSE OF THE DIFFERENCES BETWEEN
HEALTHY VOLUNTEERS AND ME/CFS
PARTICIPANTS.
BLUE AND RED YOU CAN SEE FOR
FATI
FATIGUE THEY'RE QUITE DIFFERENT
AND FAR ENDS OF THE SPECTRUM AND
SEEMS TO BE THE MOST PROFOUND
DIFFERENCESTOWN -- DIFFERENCES
BETWEEN THE GROUPS AND THERE'S
MORE SYMPTOMS IN TERMS OF THE
PHQ15 A MEASURE OF MULTIPLE
SYMPTOMS, AGAIN YOU SEE THE
PARTICIPANTS HAD MANY MANY MORE
SYMPTOMS THAN THE HEALTHY
VOLUNTEERS.
THE MEASURE OF SUBJECTIVE
COGNITION AND AGAIN YOU CAN SEE
THERE'S A DIFFERENCE BETWEEN THE
GROUPS BUT NOT PROFOUNDLY SO.
WITH THAT I'D LIKE TO THANK ALL
THE TEAM WE CALL 3D19 THAT
DIRECTLY WORK MYTH WITH ME AND
THAT WORK WITH THE PATIENTS.
[LISTING NAMES]YTH WITH ME AND
THAT WORK WITH THE PATIENTS.
[LISTING NAMES]TH WITH ME AND
THAT WORK WITH THE PATIENTS.
[LISTING NAMES]H WITH ME AND
THAT WORK WITH THE PATIENTS.
[LISTING NAMES] WITH ME AND THT
WORK WITH THE PATIENTS.
[LISTING NAMES]WITH ME AND THAT
WORK WITH THE PATIENTS.
[LISTING NAMES]
AND THANK YOU FOR YOUR
ATTENTION.
>> NOW WE'RE GOING MOVE INTO
FIRST GROUP AND THAT IS ON THE
IMMUNOLOGY AND OMICS.
I HAVE A COUPLE INTRODUCTORY
SLIDES.
HERE WE HAVE THREE SESSIONS.
THE FIRST WILL BE ON AMINO
PHENOTYPING LED BY STEVE
DICKERSON AND YOSHIMI AND THE
GUT MICROBIOME BY JOHN AND
OMICS.
I SHOWED THE SLIDE PREVIOUSLY.
IN THIS SLIDE HERE IN THIS TALK
WE'LL BE FOCUSSING PRIMARILY ON
THESE TWO ASPECT.
ALL OF OUR PATIENTS HAD AN
INFECTION SO HOW DOES THE
INFECTION AFFECT THE IMMUNE
SYSTEM AND HOW DOES IT AFFECT
THE MICROBIOME.
AND THEN FROM THERE HOW DOES IT
REALLY AFFECT THE AFFERENT PART
OF THE NERVOUS SYSTEM WHICH IS
HOW DOES THE IMMUNE SYSTEM
AFFECT THE BRAIN AS WELL AS THE
CHANGES IN METABOLITES AND THE
MICROBIOME.
WE'RE GOING TO FOCUS ON THAT
ASPECT.
AND THIS SLIDE BRIAN JUST SHOWED
ARE THE VARIOUS TESTINGS DONE ON
THE PATIENTS AND ON THIS SECTION
OF THE TALK YOU'LL HEAR ABOUT
ALL THE OMICS DONE ON THE BLOOD
LOOKING AT THE PROTEIN, LIPIDS
AND HERE WE'VE LISTED EACH OF
THE INSTITUTES THAT CONTRIBUTED
TO IT AND THE RESEARCHERS WHO
MAKE MAJOR CONTRIBUTION TO EACH
ONE OF THEM AND SO NOW THE FIRST
PRESENTATION WILL BE MADE BY
YOSHIMI AND YOSHIMI YAKAHATA
RECEIVED HER Ph.D. IN JAPAN AND
HER POST-DOCTORAL TRAINING WAS
AT UNIVERSITY OF NEBRASKA AS
WELL AS THE VIRAL IMMUNOLOGY
SECTION AT NINDS.
SHE'S CURRENTLY A STAFF
SCIENTIST AND WORKS RESEARCH
STUDIES RELATED TO ME/CFS IMMUNE
RESPONSES.
SHE STUDIES A VARIETY OF
NEUROLOGICAL DISEASES INCLUDING
HDLD1 AND A LOT OF WORK ON
MULTIPLE SCLEROSIS AND HAS BEEN
INTERESTED IN THE IMMUNE CHANGES
AND CHRONIC VIRAL INFECTIONS AS
WELL AS INFLAMMATORY DISEASES
AND WILL TALK ABOUT THE WORK
SHE'S DONE ON ME/CFS.
>> THANK YOU FOR THE
INTRODUCTION.
I'D LIKE TO PRESENT OUR
PHENOTYPING IN ME/CFS USING FLOW
SIGHT CYTOMETRY.
IT'S A DISEASE IMPAIRING.
THE MECHANISM IS STILL NOT FULLY
UNDERSTOOD YET.
HOWEVER, IT HAS BEEN FREQUENTLY
DESCRIBED INCLUDING -- AUTO
IMMUNITY AND T CELL METABOLISM
AND SO ON.
IN ADDITION THE DISEASE ONSET OF
ME/CFS IS OFTEN REPORTED TO BE
TREAT THE BY INFECTION AND THE
LINK BETWEEN INFECTION AND
MEDIATED DISEASE IS WELL
ESTABLISHED.
IN THIS STUDY WE COLLECTED BLOOD
AND CFS IN SUBJECTS WITH ME/CFS
AND THE CONTROL TO ANALYZE THIS
IMMUNOLOGY MARKER USING MULTIPLE
FLOW CYTOMETRY AND THE MARKERS
AND FIND THE LYMPHOCYTE AND
SUBSET AND ACTIVATION AND
EXERTION.
OVER ALL THERE WAS NO
SIGNIFICANT GROUP DIFFERENCES IN
PRESENTATION OF MAJOR LEUKOCYTE
INCLUDING T CELL, CD4 AND CD 8
AND B CELL AND K CELL AND
MONOC
MONOCYTE.
ALSO THE COUNTS WERE IN THE
NORMAL RANGE.
I'D LIKE TO SHOW SOME DIFFERENCE
AND THE SUBSET B CELL AND CD 8.
SO THESE ARE ANTIBODIES THAT
PLAY AN IMPORTANT ROLE OF THE
CONTROL IN INFECTION IN THE
ME/CFS AND THE ANTIBODY
PRODUCTION HAS BEEN ASSOCIATED
WITH BOTH PROTECTIVE AND
PATHOGENIC FRACTION IN
NEUROINFLAMMATORY DISEASE AND
THIS SHOWS THE DISEASE.
IMAGINE DATA SUGGESTS THAT
MULTIPLE STEP SUCH AS SET POINT
DEFECT ON B CELL AND AFFECT OF T
CELL HELP AND ALSO THE B CELL
ACTIVATION BRINGS OUT THE T CELL
HELP MIGHT MEDIATE SEVERAL
NEUROLOGICAL DISEASE.
IN THE RESULT GROUP OF PI CFS
SHOWS A SUBSET INCLUDING
INCREASE OF B CELL AND ALSO
DECREASE OF MEMORY TYPE OF B
CELL.
IN PI-ME/CFS COMPARED TO HEALTHY
VOLUNTEER.
UNFORTUNATELY, TO THE LOW NUMBER
IN THE CFS WE WERE ABLE TO
ANALYZE THE SUBSET ONLY TWO
SUBJECT WITH ME/CFS.
IN THE PATIENT ANTIBODY
PRODUCTION WERE DETECTED OVER
THE ME/CFS.
SO NEXT WE MOVED TO THE CD 8D
CELL.
IT PLAYS A CRUCIAL ROLE AGAINST
INFECTION.
AFTER ENCOUNTERING ANTIGEN
STIMULATION, CD T CELL ACTIVATED
AND DIFFERENTIATED TO THE TARGET
CELL CYTOTOXIC FATIGUE AND
EXPOSURE OF THE ANTIGEN OR
INFECTION CD 8 T CELL WERE
EXHAUSTED AND PRESENTED
PROLIFERATION OF CYTOKINE
PRODUCTION.
THIS REGULATED THE CD 8 T CELL
WITH DAMAGE ON THE OTHER CELL IN
THE CFS.
IN CD 8D CELL INCREASED
FREQUENCY OF THE POSITIVE CD
WERE DETECTED IN THE PI ME/CFS
PATIENT.
ALSO, THE DECREASED FREQUENCY OF
CD 2 TO POSITIVE CD 8 POSITIVE
CELLS WERE DETECTED COMPARED TO
HEALTHY VOLUNTEER.
SO PD 1 AND CD 26 DESCRIBED AS
THE IMMUNOCHECK MOLECULES TO
REGULATE T CELL ACTIVATION.
PD 1 INHIBIT T CELL ACTIVATION
THROUGH THE INTERACTION WITH THE
LIGAND PD 81 AND REPORT THE T
CELL ACTIVATION THROUGH
INTERRUPTION WITH THE LIGAND CD
155.
PD 1 IS ALSO REPORTED TO
DIRECTLY INHIBIT THE
PHOSPHORYLATION OF CD 226 IN THE
DOMAIN.
IN CHRONIC VIRAL INFECTION SUCH
AS HIV IT HAS BEEN REPORTED
ANTIGEN SPECIFIC CD 8 T CELL
DECREASED CD 2 ON THE CD 8 T
CELL.
THERE IS ARE SIGNIFICANT
DIFFERENCE OF THE SUBSET OF PI
ME/CFS BY GENDER.
IN MALE PI ME/CFS SHOW INCREASED
FREQUENCY OF CXCR5 AND THE
POSITIVE CD 8 CELL ARE ON THE
HAVE TOXIC REACTION ONE THE
VIRUS AND CONTROL ANTIBODY
PRODUCTION.
IN FEMALE, PI ME/CFS SHOWED AN
INCREASE FREQUENCY OF NAIVE CD 8
T CELL.
THIS RESULT MAY SUPPORT THE
GENDER SPECIFIC ORIENTATION IN
THE CD OF THE PI ME/CFS.
SO THE CONCLUSION, TO PI ME/CFS
HAS A DISEASE SPECIFIC
IMMUNOSIGNATURE INCLUDING THE B
CELL PHENOTYPE AND THE T CELL
EXERTION AND ACTIVATION AND ALSO
THE SPECIFIC DIFFERENCE OF THE
PI ME/CFS PATIENT.
THANK YOU FOR THE ATTENTION.
>> NEXT YOU'LL HEAR FROM
DR. JOHN McKCULLOCH AND LOOKS A
PROJECTS STUDYING THE ROLE OF
MICROBIOME ON HUMAN HEALTH
PARTICULARLY CANCER AND
INTERESTED IN DISCOVERING NOVEL
APPROACHES FOR ANALYZE
MICROBIOME DATA AND OFFERED A
SOFTWARE PACKAGE ON MICROBIOME
ANALYSIS AND WILL TALK ABOUT THE
WORK HE'S DONE ON THE GUT
MICROBIOME AND ME/CFS PATIENTS.
>> GOOD MORNING.
TODAY I'LL TALK ABOUT THE
MICROBIOME ASPECT OF THE STUDY.
WHAT WE DID AND WHY WE DID IT
AND WHAT WE FOUND AND THE NEXT
STEPS WILL BE.
SO THERE'S MORE THAN MEETS THE
EYE REGARDING LIFE WHEN WE LOOK
AT A HUMAN BEING AND ALL
SURFACES OF THE BODY AND THE
GASTROINTESTINAL TRACT THERE'S A
THRIVING COMMUNITY OF ORGANISMS
THAT HAVE A MUTUALLY BENEFICIAL
RELATIONSHIP TO US, THEIR HOST.
NOW, THE STRUCTURE OF AN
INDIVIDUAL'S MICROBIOME IS NOT
STATIC THROUGHOUT LIFE.
SO AS TIME GOES ON, THIS
MICROBIOME THE COMPOSITION MAY
CHANGE AND IS HIGHLY INFLUENCED
BY A PANOPLY OF FACTORS SUCH AS
DIET, AGE, GEOGRAPHICAL LOCATION
AND WHAT FAMILY MEMBERS YOU ARE
CONTACT WITH AND PET ETCETERA.
WHAT CAN HAPPEN IS YOU CAN GET A
CONDITION CALLED DYSBIOSIS WHICH
IS OPPOSED TO UBIOSIS AND THE
COMPOSITION OF THE MICROBIOME
AND THAT HINDERS OR ABROGATES
THE MUTUALLY BENEFICIAL
RELATIONSHIP BETWEEN THE
MICROBIOME AND THE HOST.
THIS CAN OR CANNOT BE REVERSED.
GUT MICROBIOME THE FU HAVE AN
UNHEALTHY OR THIS UNSTABLE
DYSBIOTIC GUT MICROBIOME IT'S
BEEN SHOWN TO CONTRIBUTE TO THE
PATHOGENESIS OF SEVERAL
METABOLIC DISORDERS AND EVEN
MENTAL ILLNESSES.
WELL, HOW DO YOU GAUGE WHAT'S IN
THE MICROBIOME?
ONCE YOU HAVE MICROBIOME
SAMPLES, HOW DO YOU ANALYZE AND
SEE WHAT'S IN THE MICROBIOME OF
INDIVIDUALS?
SO THE FIRST STAGE IS TO ANALYZE
THE CHARACTERISTICS WITHIN EACH
SAMPLE.
SO WITHIN A SAMPLE OF THE GUT
MICROBIOME CAN BE A STOOL SAMPLE
WHICH WILL BE REFLECTIVE OF THE
COMMUNITY THAT IS CURRENTLY AT
THE TIME OF COLLECTION OF SAMPLE
AND IN THE GUT MICROBIOME OF THE
INDIVIDUAL WHO IS SUPPLYING THAT
SAMPLE.
AND TOTAL DNA IS EXTRACTED FROM
FECAL SAMPLE AND WHAT THE
COMMUNITY IS BASED ON THE
DIFFERENT KINDS OF DNA WE FIND
IN THE SAMPLE.
NOW, ONE OF THE CHALLENGES FOR
THIS ANALYSIS IS THAT THE DNA
SEQUENCE IS OBTAINED FROM THE
CURRENTLY AVAILABLE DEEP
SEQUENCES.
THEY'RE IN VERY SMALL SIZES.
SO IT'S MUCH LIKE A THE SEQUENCE
WILL GIVE YOU MILLIONS AND
MILLIONS OF READS WHICH ARE
SHORT READS AND THAT REPRESENTS
ABOUT 0.01 PERFORMANCE A VIRAL
GENOME AND THEY'RE JUMBLED UP
VOW TO UNJUMBLE IN A VALID WAY
IN ORDER TO GAUGE WHAT THE
TAXONOMIC COMMUNITY IS WITHIN
THE MICROBIOME SAMPLE.
ONE COULD MAP THE READS TO KNOWN
GENOMES BUT THE APPROACHED WE
USED WAS TO ASSEMBLE THE REGION
TO LARGER SECTIONS MUCH LIKE YOU
WILL DO ONE A JIGSAW PUZZLE AND
NOT DONE BY HAND BUT TRIED AND
TESTED SOFTWARE.
THEN YOU CLASSIFY TAXONOMICALLY
THE SECTIONS AND WHAT SAMPLE DO
THESE WHAT COMPOSE THE
MICROBIOME.
THIS WAS DONE BY US USING A
COMPREHENSIVE SOFTWARE PACK AND
WE DEVELOPED OURSELVES AND IT'S
A TRIED AND TESTED METHOD.
NOW, THE MICROBIAL SPECIES YOU
CLASSIFY AND QUANTIFY THEM AND
THEN THAT'S THE SECOND PHASE OF
THE ANALYSIS.
HAVE ALL THE INFORMATION WITHIN
EACH SAMPLE.
NOW YOU HAVE TO COMPARE BETWEEN
SAMPLES AND HOW DO YOU DO THAT?
WHAT KINDS OF THINGS ARE WE
LOOKING FOR WHEN YOU GAUGE THE
MICROBIOME.
ONE IS ALPHA DIVERSITY AND ONE
IS BETA DIVERSITY.
YOU'RE GAUGING THE DIVERSITY AND
HOW MANY THINGS YOU FIND IN EACH
SAMPLE AND WHAT IS THEIR SHARE
OF THE DISTRIBUTION.
AND UNEVEN DISTRIBUTION AND IN
THE EXAMPLE I'M GIVING HERE
IMAGINE FOUR IMAGINARY SAMPLES
AND I'M REPRESENTING DIFFERENT
MICROBIAL CELLS AND DIFFERENT
COLORS REPRESENT DIFFERENT
SPECIES.
YOU CAN SEE ALL HAVE THE SAME
NUMBER OF INDIVIDUAL CELLS BUT
THE PROPORTIONS CAN BE
DIFFERENT.
SO IN SAMPLE A YOU'VE GOT 15
SPECIES WITH UNEVEN DISTRIBUTION
AND DOMINATION OF SOME SPECIES
AT HIGH LEVELS AND FEW AT LOWER
LEVELS.
SAMPLES B AND C HAVE SIX SPECIES
BUT ONE HAS AN EVEN
DISTRIBUTION.
SO 16% OF EACH SPECIES IN SAMPLE
B WHEREAS IN SAMPLE C HAVE YOU
DOMINATION OF BASICALLY TWO
SPECIES IN THE WHOLE OF THE
SAMPLE AND SPECIES D YOU'VE GOT
10.
BUT WHEN YOU LOOK AT DIVERSITY
IF YOU'RE GOING IT GAUGE WHICH
TWO SAMPLES ARE MOST SIMILAR ONE
CAN SAY SAMPLES B AND D THOUGH
THEY HAVE DIFFERENT OVER ALL
NUMBER OF SPECIES THEY'RE
PROPORTIONATELY SIMILAR TO EACH
OTHER.
IT'S GOT THE SAME PROPORTION OF
SIMILAR SHARES OF THE SAME KIND
OF TAXA.
GIVEN ALL THE EXPLANATION LET'S
LOOK AT THE RESULT.
WHEN WE LOOK AT DIVERSITY WITHIN
THE SAMPLE AND THE FROM THE
RESULTS OBTAINED IN THE STUDY
THERE WAS A STATISTICALLY
DIFFERENCE IN THE NUMBER OF
SPECIES THE CFS SAMPLES HAVING A
NUMBER OF OBSERVED FEATURES AS
COMPARED TO THE HEALTHY
CONTROLS.
BUT WHEN WE MEASURE THE
DIVERSITY WITH THE INDEX THE
MEASURE OF THE EFFECTED NUMBER
OF PARTIES YOU'RE WEIGHTING AND
GIVING MORE VALUE TO SPECIES
WHICH REPRESENT A HIGHER
PROPORTION OF YOUR SAMPLE THEN
IS NO REAL STATISTICAL
DIFFERENCE BETWEEN THE NUMBER OF
EFFECTIVE PARTIES AND NUMBER OF
SPECIES BETWEEN THE SAMPLES FROM
HEALTHY VOLUNTEERS AND THOSE
FROM CFS.
THIS SUGGESTS THAT MOST THE
DIFFERENCE WE SEE IS IN LOW
LEVEL AND SPECIES WHICH ARE AT
LOW ROWS OF ABUNDANCE.
MOVING FROM RICHNESS TO
TAXONOMIC COMPOSITION OF SAMPLES
ONE CAN GET A VISUAL
REPRESENTATION HOW SIMILAR OR
NOT THE COMPOSITION OF TWO
SAMPLES ARE TWO EACH OTHER BY
ALGORITHMS REDUCED THE
DIMENSIONALITY SUCH AS PCLA OR
UMAC.
WE DID SEVERAL.
THE ONE I'M SHOWING IS UMAC.
YOU CAN INTERPRET THIS AS EACH
DOT IN THE PLOT AS REPRESENTING
AN INDIVIDUAL SAMPLE AND THE
FURTHER APART TWO DOTS ARE FROM
EACH OTHER THAT MEANS THEY ARE
MORE DIFFERENT IN TERMS OF THEIR
COMPOSITION.
HERE WE SEE SAMPLES IN CFS CASES
IN RED AND HEALTHY VOLUNTEERS IN
BLUE AND THE MEAN POSITION OF
ALL SAMPLES WITHIN EACH GROUP IS
THE BIG DOTS.
YOU CAN SEE AN EVIDENT
SEPARATION AND THAT'S VISUAL.
WE ALSO DID A STATISTICAL TEST
PERMUTATION MULT VAREIALITY
ANALYSIS APPLIED TO THE SAMPLE
DISTANCE MATRIX AND SHOWS THE
DIFFERENCE BETWEEN THE GROUPS
AND SAMPLES CONTAINED WITHIN
OOCH GROUP IS STATISTICALLY
SIGNIFICANT.
AS EXPECTED VARIANCE IN THE
STRUCTURE OF THE MICROBIOME
INDEPENDENT OF DISEASE STALTUS.
YOU CAN SEE SOME ME/CFS SAMPLES
DONE THERE WHICH ARE CLOSER TO
HEALTHY VOLUNTEER SAMPLES.
OVERALL THE CENTROIDS ARE
SEPARATED AND THAT DIFFERENCE IS
STATISTICALLY SIGNIFICANT.
WELL, WHEN WE LOOK AT WHAT ARE
THE MICROBIAL SPECIES EITHER
ENRICHED OR DEPLETED, THERE ARE
IN THE ORDER OF 200 DIFFERENT
SPECIES WE FOUND OVER ALL IN
SAMPLES.
IF WE LOOK AT WHICH ONES ARE
INCREASED IN HEALTHY DONORS AND
WHICH ONES ARE INCREASED IN
ME/CFS SAMPLES WE FIND THERE ARE
ABOUT 25 DIFFERENT SPECIES WHICH
ARE ENRICHED IN EITHER GROUP.
AND BY MEANING ENRICHED I MEAN
STATISTICALLY SIGNIFICANTLY
DIFFERENT AND AT LEAST A TWO
FOLD INCREASE.
TWICE AS MUCH IN TERMS OF
PROPORTION IN ONE GROUP RATHER
THAN THE OTHER.
THEY ALL HAPPEN TO BE BACTERIA.
THOUGH WE LOOKED AT VIRUSES,
FUNGI AND OTHERS AND THE 25
WHICH WERE UP OR DOWN OR HAPPEN
TO BE BACTERIA.
I'M NOT GOING TO GO THROUGH ALL
OF THEM BUT SUFFICE TO SAY
SEVERAL SPECIES ESPECIALLY THOSE
ENRICHED IN THE CFS SAMPLES WERE
ALSO FOUND TO BE ENRICHED IN
OTHER STUDIES.
THAT CONFIRMS THOUGH IT'S NOT
EXACTLY THE SAME SPECIES OVER
ALL IT CONFIRMS PREVIOUS STUDIES
THAT INCLUDE THE MICROBIOME AND
PART OF GROUPS AND THAT'S NOT
WHERE IT ENDS.
THIS IS JUST THE BEGINNING.
THERE'S MORE THAT CAN BE DONE
WITH THIS DATA.
THE GERMS PACKAGE WE USED
OUTPUTS NOT ONLY TO TAXONOMIC
DATA BUT INDEPENDENT BIOLOGICAL
FUNCTION GAUGED FROM THE
PREDICTED PROTEOME FUNCTION
INDEPENDENT OF TAX IT --
TAXONOMY AND A SECOND PAPER
FOCUSSING ON THE GUT MICROBIOME
RESULTS OF THIS COHORT.
WHICH WILL CORRELATE TO THE
MICROBIOME AND ITS FUNCTIONS TO
ALL THESE OTHER CLINICAL DATA.
ALSO, RICHARD RODRIGUEZ IS
HELPING BUILD A TRANS KINGDOM
NETWORK WITH THE INTENT OF
IDENTIFYING WHAT THE
RELATIONSHIPS ARE BETWEEN THESE
DIFFERENT CLINICAL DATA SETS AND
THE OMICS.
SO THIS MAY NOT BE A APPARENT
AND SEEING HOW DATA CONNECT TO
EACH OTHER BECAUSE YOU CAN
INFERENCE THE GUT MICROBIOME AND
FIRE THE DIETARY INTAKE AND THE
MICROBIOME WILL INFLUENCE THE
IMMUNE SYSTEM OR GUT-BRAIN AXIS
AND SO ON AND SO FORTH.
WARE TRYING TO FORMALIZE AND
FIND OUT WHAT THE DIRECTIONALITY
IS OR ABOUT WHAT THE IMPORTANCE
ASSOCIATIONS ARE.
WITH THIS I'D LIKE TO THANK
EVERYONE AT NINDS AND ESPECIALLY
AT THE GENETICS CORE FOR
SEQUENCING THE SAMPLES TO
RICHARD RODRIGUEZ AND MANY IN
THE LAB FOR HELPFUL INSIGHTS
REGARDING THE MICROBIOME OF THIS
PROJECT AND ESPECIALLY TO
DR. WALITT AND CARLOTTA AND
SCRUTINIZING THE DATA AND IT'S
BEEN A PLEASURE.
THANK YOU VERY MUCH.
>> I'LL BE TALKING ABOUT THE
VARIOUS OMIC PACKAGE WE LOOKED
AT AND THE DATA THERE.
WHAT DO I MEAN BY OMICS?
IT'S THE COLLECTIVE
CHARACTERIZATION AND
QUANTIFICATION OF POOLS OF
BIOLOGIC MOLECULES THAT FORM THE
DIYNAMICS OF AN ORGANISM OR
TRYING TO MEASURE EVERYTHING YOU
CAN.
THERE'S DIFFERENT OMICS ONE CAN
MEASURE.
THERE'S SUCH MAJOR CATEGORIES
FROM GENOMICS AND THE
METABOLOMICS AND PROTEOMICS AND
TRANSCRIPTOMICS AND IN TODAY'S
LECTURE I'LL FOCUS ON THESE
THREE WITH A DASH OF LIPID OMIC.
WHAT CAN YOU DO WITH OMICS?
THERE'S A NUMBER OF THINGS.
FIRST YOU CAN IDENTIFY MOLECULES
DIFFERENT BETWEEN GROUPS AND YOU
MEASURE THE INDIVIDUAL MOLECULES
AND COMPARE TO SEE IF THEY'RE
DIFFERENT.
YOU CAN THEN SEE HOW THE
DIFFERENCES RELATE BY PLACING
THEM INTO BIOLOGIC NETWORK AND
ANALYZING THE NETWORKS AND ARE
THE DIFFERENTLY EXPRESSED
MOLECULES RELATED.
IF THEY ARE IT SEEMS TO MAKE
THEM MORE SIGNIFICANT.
THEN THERE'S THE CONCEPT OF
CONSILIENCE DAVID GOLDSTEIN TOLD
ME ABOUT AT THE BEGINNING MUCH
THIS.
THE IDEA CAN USE MULTIPLE TYPES
OF KNOWLEDGE TO REACH NEW
CONCLUSIONS.
AND IN OUR OMICS IF WE USE AND
LOOK AT MULTIPLE OMICS
TECHNIQUES MERGE TO A SIMILAR
CONCLUSION ACROSS THE BIO
FLUIDS?
WITH THAT INFORMATION WE HOPE TO
POINT THE WAY FORWARD FOR TWO
THINGS.
ONE IS HOW CAN WE IDENTIFY NEW
BIO MARKERS TO DIFFERENTIATE
PERSONS WITH ME/CFS FROM THOSE
WHO DON'T HAVE IT AND TO HELP
IDENTIFY THERAPEUTIC TARGETS.
IN THE STUDY WE LOOKED AT
PROTEOMICS AND GOT 1300 PROTEINS
AND LIPID OMICS AND DIFFERENT
CATEGORIES AND LOOKED AT
PERIPHERAL MONONUCLEAR CELLS AND
LOOKED AT 18,000 TRANSCRIPT AND
1300 PROTEINS AND 444
METABOLITES IN THE MUSCLE
SAMPLES ABOUT 11,000 RNA
TRANSCRIPTS AND AS YOU HEARD
EARLIER FROM THE MICROBIOME
ABOUT 10,000 TAXOMICS WERE
IDENTIFIED.
WHEN HAVE YOU SO MANY SAMPLES
YOU HAVE TO CHOOSE TOOLS
EFFECTIVE AT ANALYZING THE DATA
AND THESE ARE PRINCIPLE
COMPONENT ANALYSIS AND THESE
REALLY ARE STATISTICS OF
BIOMARKER DISCOVERY.
WHAT ARE THESE TECHNIQUES LINEAR
REDUCTIONALITY TECHNIQUES USED
WHERE THE FEATURES OUT NUMBER
THE SAMPLES.
IT FITS THE DATA INTO LINES
ACROSS EACH OF THE DIFFERENT
COMPONENTS WHILE LOSING AS
LITTLE AS THE INFORMATION AS
POSSIBLE AND IT'S KNOWN AS
VARIANTS IN THE ANALYSES.
AND THEN YOU CAN USE THE
INFORMATION FOR EACH INDIVIDUAL
POINT AND SEE IF THERE'S FACTORS
THAT CAN SEPARATE ONE GROUP FROM
THE OTHER.
YOU CAN SEE A SET OF DOTS THAT
REPRESENT TWO GROUPS.
IF YOU TOOK ALL THE INFORMATION
AND PLOTTED IT TO A CERTAIN
POINT YOU WOULD END UP WITH
REDUCING A LARGE AMOUNT OF
INFORMATION TO A SINGLE POINT.
AND THEN YOU CAN SEE HOW DISTANT
OR DIFFERENT THE POINTS ARE FROM
EACH OTHER.
WHEN YOU USE A PRINCIPLE
COMPONENTS ANALYSIS OF PCA YOU
ANALYZE IT IN AN UNSUPERVISED
FASHION USING THE DATA ITSELF TO
FIND DIFFERENCES.
IN THIS CASE IMAGINE THE DATA
LOOKED LIKE ALL BLACK DOTS TO
YOU VERSUS PURPLE AND GREEN.
IF YOU LOOKED AT JUST THE
SCATTERING OF THE DOTS YOU'D
CHOOSE THE PURPLE ARROW AS THE
WAY TO DISCRIMINATE THE DATA.
HOWEVER, A PLS-DA ALLOWS US TO
CHOOSE DIRECTIONALITY AND
THERE'S PURPLE AND GREEN DATA
YOU WOULD CHOOSE A DIFFERENT
DIRECTION TO ANALYZE THE DATA.
SO PCA IS MUCH BETTER FOR
ANALYZE LINEAR RELATIONSHIPS
UNDATA WHILE PLS-DA IS SUPERIOR
FOR ANALYZING COST OF DATA AND
WE USE BOTH IN OUR ANALYSIS.
WE APPLY IT TO ME/CFS AND WE'LL
START WITH OUR PERIPHERAL BLOOD
MONONUCLEAR CELL RNA SEQUENCING.
WHEN YOU LOOK ON THE LEFT YOU
SEE DIFFERENT DOTS THAT DON'T
DISTINGUISH EACH OTHER FROM
THEMSELVES.
THE GREEN CFS AND THE RED
CONTROL DOTS SORT OF OVERLAP AND
THERE'S REALLY NO SEPARATION IN
THE GROUPS.
HOWEVER WHEN WE ANALYZE THE DATA
AND DIFFERENCE BETWEEN GROUPS WE
SEE SEPARATION ON THE RIGHT AND
THIS ANALYSIS SUGGESTS THAT
THERE'S SOMETHING THAT'S ABLE TO
BE SEPARATING IN THE DATA AND WE
NEEDED TO DIG FURTHER.
I WANT TO THANK THOSE WHO DID
MOST THIS WORK.
AS WE LOOKED AT ALL THE DATA
AGAIN THINK OF DEMOGRAPHICS, WE
SEPARATED BY BIRTH SEX AND HERE
IN PC4 YOU CAN SEE SEPARATE MALE
AND FEMALE MEN BEING GREEN AND
WOMEN BEING RED, THE GROUPS DO
SEPARATE.
SO THIS IS SUGGESTING TO US THAT
BIRTH SEX WAS HAVING AN IMPACT
ON OUR GENE EXPRESSION ANALYSIS
AND WAS CONFOUNDING OUR ANALYSIS
OF THE SAMPLES.
SO WE MIGHT DO BETTER IF WE
SEPARATED MEN FROM WOMEN AND
REANALYZE THE DATA.
THIS IS WHAT IT LOOKS LIKE WHEN
YOU DO THAT.
ON THE LEFT YOU CAN SEE THE MALE
DATA AND YOU CAN SEE THERE'S A
CLEAR SEPARATION ON THE PCA
BETWEEN THE HEALTHY VOLUNTEERS
AND PI ME/CFS MEN.
IN THE MIDDLE IS WHAT HAPPENS
WHEN YOU DO IT WITH FEMALE DATA.
AGAIN YOU SEE THIS ENORMOUS
SEPARATION.
SOUM HOW WHEN WE REDUCE THE
NUMBER OF SAMPLES WE SEE
SEPARATION POWER OF SEX ON OUR
ANALYSIS.
AND WHAT'S LABELLED C HERE IS A
VEN DIAGRAM AND OF THE
DIFFERENTIALLY EXPRESSED GENES
IN BOTH THE GROUPS AND MEN AND
WOMEN ONLY 34 WERE THE SAME.
AND GIVES A SENSE OF HOW
DIFFERENT THE PBMCs WERE
BEHAVING BY SEX.
WHEN BIRTH SEX WERE CONSIDERED
WE WERE ABLE TO DISCRIMINATE
FROM THE HEALTHY VOLUNTEERS.
I'M SHOWING THE DATA THAT SHOWS
IT'S MOSTLY RELATED TO THE TLR9
PROTEIN-PROTEIN INTERACTOME IN
MEN AND IT'S CONSISTENT WITH THE
EXPANSION OF THE CELLS AND
DECREASED SWITCHED B CELL IN
FLOW CYTOMETRY WE PRESENTED
EARLIER AND THIS IS CONSISTENT
WITH THE OBSERVATION.
WHAT ARE WE SEEING IN THE WOMEN?
HERE WE SEE CYTOKINE CHANGES AND
PROCESSES AND B CELL BEING UP
REGULATED.
AND THIS AGAIN IS ALSO
CONSISTENT WITH EXPANSION OF
NAIVE B CELLS AND DECREASED
MEMORY B CELLS.
SO THIS SUGGESTS MORE THAN ONE
WAY TO GET TO THE IMMUNOLOGICAL
PHENOTYPE WE'RE WERE GETTING TO
EARLIER THERE MAY BE TWO IMMUNE
RESPONSES.
THAT'S AN INTERESTING PATTERN
BUT THIS IS LOOKING AT THE
PLASMA PROTEOMICS YOU SEE THE
ANALYSIS.
THIS IS THE CENTER FOR HUMAN
IMMUNOLOGY WHO DID THIS WORK AND
YOU GET A LITTLE BIT OF SPRAYING
SEPARATION BUT NOTHING REALLY
WONDERFUL.
WHEN WE SEPARATE BY MEN AND
WOMEN WOW, THAT'S A LOT OF
SEPARATION.
IT SEEMED TO BE PLAYING A ROLE
HERE.
UNFORTUNATELY YOU WOULD LOOK
CLOSELY AND SEE THE VARIANCES
THAT ARE EXPLAINED BY THE
DIFFERENCES ARE SMALL AND SO
THIS DOESN'T EXPLAIN A LOT OF
THE DIFFERENCE IN PROTEOMICS.
WHEN WE LOOK AT CEREBRAL SPINAL
FLUID AND YOU SEE THE PROFOUND
SEPARATION.
SO BIRTH SEX AGAIN HAS AN IMPACT
ON THE PROTEOMICS OF BLOOD AND
CEREBRAL SPINAL FLOOD BUT
PROTEOMICS ON AVERAGE BEHAVE
POORLY BY THE LOW VARIANCES
EXPLAINED.
HOW ABOUT IN THE MUSCLE?
HERE WE'RE LOOKING AT MUSCLE DNA
SEQUENCING.
ON THE LEFT IS ALL PARTICIPANTS
AND YOU DON'T SEE VERY MUCH
SEPARATION.
WILL THE ME SEPARATE BY BIRTH
SEX.
SEE AGAIN WONDERFUL SEPARATION
IN MEN AND WOMEN.
SO IT CAN AGAIN DISCRIMINATION
WHEN YOU CONSIDER BIRTH SEX.
THIS DATA THANK YOU TO DIAGO AND
OTHERS FOR PROVIDING THE DATA TO
US.
WHAT IS DIFFERENT IN THE MEN?
HERE YOU SEE PROCESSING AND BETA
OXIDATION NETWORK AND DOWN
REGULATION IN MITOCHONDRIAL
PROCESS.
IN THE WOMEN YOU SEE
UPREGULATION AND DOWN REGULATION
FATTY OXIDATION MITOCHONDRIAL
PROCESSING.
I'LL HAVE THAT LIPID OMICS.
AGAIN, THANK YOU FOR PROVIDING
US THE DATA AND YOU SEE THE
PATTERNS IN ALL PARTICIPANTS YOU
SEE POOR SPRAYING BUT WHEN YOU
SEPARATE BY BIRTH SEX YOU GET
NICE SEPARATION IN BOTH.
HOW ABOUT CEREBRAL SPINAL FLUID
METABOLOMIC.
YOU SEE POOR SEPARATION WITH ALL
COMERS.
BUT WHEN WE APPLY KSLDA WITH THE
DIFFERENTIAL EXPRESSION OF GENES
HERE'S THE FIRST TIME AT LOOKING
AT ALL COMERS WHERE YOU SEE
SEPARATION.
OF ALL THE BIO FLUIDS WE TESTED
ONLY THE CFS METABOLOMICS
SEPARATED BY DIAGNOSTIC GROUP.
AND IT EXPLAINS A FAIR BIT OF
THE VARIANTS THAT 35% OF THE
VARIANT.
EXACTLY WHAT IS DIFFERENT?
THERE'S GLUTAMATE, POLY AMMIN
PATHWAYS AND TCA PATHWAY
METABOLITES.
AND THESE IF YOU FOLLOW THE
LITERATURE SHE'S COME UP AGAIN
AND AGAIN
THESE COME UP AGAIN AND AGAIN
NOT ONLY IN THE CFS LITERATURE
BUT IN THE LONG COVID.
THESE DIFFERENCE ALL PARTS OF
SEVERAL PATHWAYS.
THE ARGININE PATHWAY AND THE
METABOLIC PATHWAY AND BRANCH
CHAIN AMINO ACID PATHWAYS THAT
ARE ALL FUNDAMENTAL IN CELL
REGULATION.
SO HOW ABOUT BIRTH SEX AND CFS
METABOLOMICS?
WHEN WE LOOK AT MEN AND WOMEN,
WHEN WE APPLY THE PLSDA WE
IMPROVE THE PERFORMANCE AT
SEPARATION AND IN MEN IT'S
RELATED TO TRYPTOPHAN AND
SEROTONIN SIGNALLING
DIFFERENCES.
IT MAY PROVOKE MEMORIES OF A
PAPER OF SEROTONIN REDUCTION IN
LONG COVID.
WHAT SHOULD YOU TAKE HOME FROM
THIS?
BIRTH SIX IS MECHANICALLY
RELEVANT IN ME/CFS.
DISCRIMINATIVE POWER INCREASES
DESPITE A DECREASE IN SAMPLE
SIZE.
THIS IS SEEN IN GENE EXPRESSION
AND IMMUNE CELLS AND PROTEINS
AND BLOOD AND CEREBRAL FINAL
FLUID AND IN LIPIDS IN THE BLOOD
AND MOLECULES IN THE SPINAL
FLUID.
EVERYWHERE WE LOOKED WE FOUND
THIS AND SEEMS TO BE PROFOUND
IMPORTANCE IN UNDERSTANDING THE
NATURE OF THE ME/CFS.
OF ALL THE BIO FLUIDS WE TESTED
CEREBRAL FINAL FLUID AND
METABOLOMICS WAS THE BEST AT
DISCRIMING THIS AND TO ME IT
SUGGESTS THE CENTRAL NERVOUS
SYSTEM IS THE PLACE DIVERGENT
MECHANISMS UNIFY IN THE PATHWAY
OF ME/CFS AND OF COURSE THESE
FINDINGS HAVE IMPORTANT
RAMIFICATIONS ON FUTURE
BIOMARKER DEVELOPMENT.
LIKED TO THANK EVERYBODY
INVOLVED WITH THE PROJECT.
AVI NATH AND CORY JOHNSON WITH
THE WORK AND EXTRA SHOUT OUT TO
THOSE WHOSE INSIGHT THE PERSON
WHO DISCOVERED THE BIRTH SEM
DIFFER --
SEX DIFFERENCES IN THE OMICS AND
I'D LIKE TO THANK DIAGO AND
KATHY AND ALL THE MEMBERS OF CHI
AND ALL THE HELP IN GETTING THE
ANALYSIS DONE.
THANK YOU VERY MUCH.
>> I'M GOING TO SUMMARIZE THE
KEY FEATURES FROM THE SESSION.
FIRST IS THE IMMUNOLOGY.
I THINK AS YOU HEARD, THE KEY
DEFECT IS INABILITY OF THESE
PATIENTS TO SWITCH B CELLS FROM
IGM TO IGG.
THAT IS -- THAT CAN EXPLAIN ALL
THE POOR IMMUNE RESPONSE TO
MICROBIAL ANTIGENS.
THIS IF HAVE YOU PERSISTENT OR
MICROBIAL ANTIGEN AND I PUT A
QUESTION MARK BECAUSE WE DIDN'T
REALLY DEMONSTRATE THE PRESENCE
OF IT.
IT'S A HYPOTHESIS.
ABOUT WHAT IT WILL LEAD TO THEN
IS T CELL EXHAUSTION BECAUSE THE
B CELLS AREN'T ABLE TO SWITCH
AND THE T CELLS ARE TRYING TO O
DO THEIR JOB BUT REALLY CANNOT
DO IT AND GET ACTIVATED AND THEN
GET EXHAUSTED AND THEN YOU'RE
JUST LEFT WITH THE INNATE PNEUM
SYSTEM IS A BAD WAY OF TRYING TO
GENERATE ANY MICROBE.
IT'S NON SPECIFIC ACTIVATION OF
MACROPHAGES AND MICROGLIAL CELLS
THAT CAUSE DAMAGE.
IT CAN ALL BE EXPLAINED BY ONE
ABNORMALITY.
NONETHELESS YOU CAN PROBABLY
TARGET THINGS ALONG THAT CHAIN.
WHILE THERE WAS NO SPOKING GUN,
PER SE, WE DIDN'T REALLY FIND
MUCH ALPHA DIVERSITY BUT THERE
WAS BETA DIVERSITY.
AND HE POINTED OUT MULTIPLE
DIFFERENT TYPES OF TAXONOMIC
TYPES OF BACTERIA WERE AFFECTED
AND ONE IS BUTYRATE PRODUCING
BACTERIA BEING DECREASED.
I THINK IT'S IMPORTANT BECAUSE
IN THE SPINAL FLUID OF THE
PATIENTS THEY WERE DECREASED
LEVELS OF BUTYRATE.
BUTYRATE IS NOT PRODUCED IN THE
HUMAN BODY.
THE ONLY SOURCE IS THE
MICROBIOME.
THE FACT THE LEVELS ARE
DECREASED TELLS YOU THERE'S
SOMETHING WRONG WITH THE
MICROBIOME ITSELF.
SO THEN THE OMICS STUDY I THINK
THERE'S TWO THINGS I LIKE TO
POINT OUT.
ONE IS THAT WE'RE ALL INTERESTED
IN BIOMARKERS.
AND THE BEST DIFFERENTIATING
FEATURE WE FOUND BETWEEN ME/CFS
AND THE HEALTHY VOL UNTIRES --
VOLUNTEERS WAS THE METABOLOMICS
AND THERE'S NOT A SINGLE
MOLECULE I CAN POINT TO BUT IT'S
TELLING YOU IRRESPECTIVE OF
MALE, FEMALE YOU, CAN SEPARATE
THE GROUPS WHEN YOU LOOK AT THE
METABOLOME AND SPINAL FLUID.
I THINK WE NEED TO DIG DEEPER
IN.
PROBLEMS ACCESS TO SPINAL FLUID
HAS BEEN POOR BUT IT'S CRITICAL
IF YOU WANT TO STUDY
NEUROLOGICAL DISEASE YOU HAVE TO
HAVE ACCESS TO THE SPINAL CORD.
AND WE'VE SHOWN MULTIPLE SEX
DIFFERENCES.
IF YOU'RE GOING TO DESIGN
VARIOUS KINDS OF INTERVENTIONS
TAKING INTO CONSIDERATION WHO
YOU'RE TREATING IS ABSOLUTELY
CRITICAL.
I'M GOING TO END THE SESSION
HERE AND WE'LL HAVE A FEW
MINUTES FOR DISCUSSION.
I'LL OPEN IT UP FOR DISCUSSION
HERE.
ANY QUESTIONS FROM THE AUDIENCE
WE'LL BE HAPPY TO TAKE THEM?
ANY QUESTIONS ONLINE AND YOU
CAN COME UP.
>> MY QUESTION IS A GENERAL ONE
WHERE YOU HAVE A SMALL GROUP OF
CONTROLS AND PATIENTS THE
QUESTION IS WHETHER DIFFERENCES
YOU SEE HOW THEY WOULD STACK UP
IF YOU HAD A LARGER CONTROL
GROUP.
ALL IN ALL PEOPLE IN THE WORLD
AND YOU LOOK AT THEM SO OF
COURSE THAT'S NOT POSSIBLE IN
MANY OF THESE TESTS BUT ABOUT
THE MICROBIOME WHETHER THEY
COULD LOOK AT OTHER DATA THEY
HAVE FROM FOLKS AND SEE --
>> THAT'S A GOOD QUESTION.
WE DIDN'T SHOW YOU -- THAT'S
TRUE EVEN FOR THE IMMUNOLOGY
HERE STEVE JACOBSON HAS THE
MULTIPLE SCLEROSIS AND THE OTHER
DISEASES.
WE CAN QUICKLY LOOK AT THAT AND
THEY'VE DONE SOME ANALYSIS.
WE DIDN'T REALLY PRESENT IT HERE
AND THAT'S AVAILABLE.
JOHN, DO YOU WANT TO ADDRESS IT
WITH REGARD TO THE MICROBIOME?
YOU CAN TAKE THE MICROPHONE OR
COME UP HERE SO PEOPLE ONLINE
CAN SEE YOU.
>> SO THE ISSUE WITH MICROBIOME
IS IT'S A MOVING GOALPOST
BECAUSE IT'S NOT STATIC.
TODAY I DID NOT GO TO McDONALDS
BUT MAY GO ON TUESDAY AND OTHER
FAST FOOD PLACES ARE AVAILABLE
AND THESE SMALL CHANGES, THESE
SMALL INTERVENTIONS DO CHANGE MY
MICROBIOME ALL THE TIME.
WHO HAVE I BEEN IN CONTACT WITH,
DID I TAKE ANTIBIOTICS AND THE
CHALLENGE IS IN SMALL COHORTS
THE STARTING POINT THERE'S NO
GOLD STANDARD FOR COMPARISON,
YES.
ABSOLUTELY.
RIGHT.
INDEED -- BUT ONE OF THE THINGS
THAT CAN BE DONE IS TO LOOK AT
ALL SAMPLES TOGETHER INCREASE
SAMPLE SIZE AND ALSO LOOK AT
MULTIPLE SAMPLES FROM THE SAME
PATIENT FOR A LONG TIME AND THEN
SEE BECAUSE IT'S LIKE IN A
MOVIE.
SO IF YOU LOOK AT THE ORDINATION
PLOT IT'S HOW MUCH THEY GIGGLE
IN THE CONTEXT OF OTHERS.
>> I LIKE THE CONCEPT OF GIGGLE.
>> HI, I'D LIKE TO TAKE --
>> IDENTIFY YOURSELF.
>> I'M DR. LOMEN A PATIENT WITH
ME AND HAVE DONE RESEARCH
INFORMALLY ON THIS.
THE CARDINAL SYMPTOM WAS POST
EXERTIONAL MALAISE.
HOW DO THE RESULTS YOU'VE JUST
SHOWED US FIT IN TO EXPLAINING
PEM?
THANK YOU.
>> I THINK THAT WILL BE
DISCUSSED FURTHER.
BRIAN, DO YOU WANT TO TAKE THAT
NOW OR LATER?
WHY DON'T WE TAKE PART OF IT NOW
AND DISCUSS IN MORE DETAIL
LATER.
>> AS WE TALKED ABOUT THE DESIGN
OF THE STUDY, POST EXERTIONAL
MALAISE WAS REQUIRED AS A SYSTEM
SO EVERYBODY HAD TO HAVE POST
EXERTION MALAISE.
SO IF YOU'RE LOOKING
CROSS-SECTIONALLY EVERY PERSON
HAD POST EXERTIONAL MALAISE AND
MEASURED THANE FOUR DIFFERENT
WAYS AND WE'LL TALK ABOUT SOME
OF THAT IN THE BIOENERGETICS
TALKED AND BARBARA STUSSMAN AND
OUR QUALITATIVE RESEARCHER HAD
FOCUS GROUPS AND WE HAD
DEVELOPED A PARTICULAR
INSTRUMENT FOR MEASURING
EXCHANGE IN POST EXERTIONAL
MALAISE OVER TIME.
YOU HAD TO HAVE IT TO COME AND
THE C PET WAS TO INDUCE POST
EXERTIONAL MALAISE WHILE WE
WATCHED.
THAT HASN'T BEEN FULLY STUDIED
AND OUR TEAM IS STILL WORK ON
THAT AND ONGOING DIRECTIONS BUT
WE USED THE C PET TO INDUCE POST
EXERTIONAL MALAISE IN FRONT OF
US AND MEASURE THAT PHENOMENA IN
MULTIPLE WAYS AS IT WAS
UNFOLDING.
>> THE PATHOPHYSIOLOGY.
>> THAT'S A TOUGH QUESTION
BECAUSE WE DON'T QUITE
UNDERSTAND THE PATHOPHYSIOLOGY
OF POST O EXERTIONAL MALAISE.
WE KNOW IT'S AN ENTRY CRITERIA
SO EVERYBODY HAS TO HAVE IT
WHICH MEANS ALL THESE THINGS --
WHATEVER CORRELATES WITH
POST-EXERTIONAL MALAISE AND ONE
PHYSIOLOGY IS A QUESTION WE
CAN'T ANSWER.
>> GOOD MORNING.
I'M A PHYSICIAN FROM NIAID A
RHEUMATOLOGIST THEN WORK YOU'VE
DONE IS SOMETHING TO ADMIRE AND
RECOGNIZED.
WHAT ARE THE POTENTIAL EXPANSION
OF THIS INTO PIS BECAUSE MOST
ARE ADULTS SO ANY THOUGHTS ABOUT
THAT AND FUTURE ENDEAVORS IN
THAT AREA?
>> THAT'S A POTENTIAL POPULATION
AND CONDUCTING RESEARCH ON
CHILDREN IS VERY HARD BECAUSE IF
YOU WANT TO PUT THEM IN THE
HOSPITAL FOR WEEKS AND PUTTING
SPINAL TAPS ON CHILDREN IS NOT
EASY.
YOU HAVE TO ANESTHETIZE THEM.
IT'S A MASSIVE UNDERTAKING.
WE HOPE WHAT WE LEARN CAN BE
APPLIED TO CHILDREN IN SOME
MANNER AND TEST IN A SMALLER
COHORT AND NOT HAVE TO PUT THEM
THROUGH SUCH A HUGE BATTERY OF
INVESTIGATIONS BUT THE
POPULATION NEEDS TO BE STUDIES.
>> I'M PAUL WONG AT NIH.
I WANTED TO THROW OUT A QUICK
QUESTION.
THE B CELL DIFFERENTIATION IS A
PROBLEM.
IN THE ME/CFS POPULATION ARE
THERE PROBLEMS WITH REPORTS OF
ADAPTIVE IMMUNE PROBLEMS?
>> IT DOESN'T LEAD TO IMMUNE
DEFICIENCY.
>> JOE LANSET.
I'M A PATIENT.
YOU MENTIONED BUTYRATE AS A
SIGNAL FOR MICROBIOME
DYSFUNCTION IS THAT WHAT YOU
FIND IN CFS OR A LESS INVASIVE
WAY AS A CLINICAL TEST FOR
MICROBIOME DYSFUNCTION?
>> I'M SURE YOU COULD PROBABLY
MEASURE BUTYRATE AT MANY LEVELS.
IT'S AN HBLC METHOD SHOULD BE
ABLE TO PICK IT UP AND PEOPLE
CAN DEVELOP IT IF THEY DON'T
EXIST ALREADY.
I DON'T THINK THAT'S GOING TO BE
DIAGNOSTIC OF ME/CFS.
WE WERE SURPRISED YOU CAN SHOW
DIFFERENCES.
AND MODULATE DNA EXPRESSION AND
PLAYS A ROLE AND QUITE IN
INTRIGUING BUT DON'T THINK ONE
MOLECULE ALONE WILL EXPLAIN THE
DISEASE.
[OFF-MIC]
>> THANKS.
LET ME RE -- REPEAT WHAT HE
SAID.
THE BUTYRATE ITSELF CAN AFFECT
THE GUT INTEGRITY SO THINGS CAN
MOVE FROM THE GUT INTO THE
BLOODSTREAM AND THAT COULD HAVE
A CASCADE OF EVENTS.
THE SECOND THING HE MENTIONED
WAS THE INNATE IMMUNE RESPONSES
MAY BE CRITICAL BECAUSE YOU SEE
STIMULATION OF THOSE AND THE
THIRD THING HE MENTIONED IS POST
EXERTIONAL MALAISE DOESN'T START
IMMEDIATELY BUT AFTER THE
EXERTION.
THE GAP IS INTERESTING AND SOME
THING IS HAPPENING DURING THAT
PIEFRD OF TIME IN ORDER TO LEAD
TO THAT AND THOSE ARE IMPORTANT
POINTS OF FURTHER DISCUSSION.
THANK YOU VERY MUCH.
>> WE HAN ONE QUESTION FROM OUR
VIRTUAL AUDIENCE.
WOULD DIETARY SUPPLEMENT OF
BUTYRATE POTENTIALLY HELP THESE
PATIENTS?
>> JOHN, DO YOU WANT TO TAKE
THAT ONE?
>> I DON'T KNOW BUT IT MIGHT.
THE THING IS THAT BUTYRATE
PRODUCTION WHEN YOU HAVE IT FROM
A MICROBIOME STANDPOINT IT'S
CONTINUALLY PRODUCING BUTYRATE.
IF YOU SUPPLEMENTING I DON'T
KNOW IF THAT WILL BE THE SAME.
THE ABSORPTION MAY BE IN A
DIFFERENT PLACE.
HAVE YOU GUT MICROBIOME IN
DIFFERENT SECTIONS OF YOUR
GASTROINTESTINAL TRACT AND I
DON'T KNOW IF YOU GIVE IT ORALLY
IT WILL HAVE THE SAME EFFECT.
THERE'S NOT ENOUGH BUTYRATE
CAUSING IT.
IT'S LIKE MOLES IN A SWISS
CHEESE IT'S AN ADDED AFFECT THAT
MAY CONTRIBUTE TO THE OVER ALL
APPEARANCE OF THE SYMPTOMS.
CERTAINLY IT'S WORTH LOOKING AT
BUT AGAIN WE NEED LARGER SAMPLE
SIZES.
IF BUTYRATE IS BEING PRODUCED
CONSTANTLY OR NOT SO THERE YOU
GO.
THAT'S WHAT I THINK.
>> WOULD BUTYRATE SURVIVE
DIGESTION?
>> IT SHOULD BECAUSE IT'S A
SMALL CHAIN FATTY ACID JUST FOUR
CARBONS AND A COH.
I DON'T SEE IT BEING DIGESTED BY
ANY PEPTIDE OR BY ANY ENZYME.
>> THE THING IS THAT THERE'S SO
MANY CHANGES.
I LIKE YOUR ANALOGY OF THE SWISS
CHEESE YOU PLUG ONE HOLE BUT
STILL HAVE OTHERS.
>> ALL THE HOLES HAVE TO ALIGN.
>> ALL RIGHT.
GOOD.
ANY OTHER?
IF NOT LET'S TAKE A PAUL BREAK.
WE HAVE 15 MINUTES.
>> WE'LL GET STARTED.
DR. HALLETT RECENTLY RETIRED BUT
WAS AN NIH DISTINGUISHED
INVESTIGATOR AND CHIEF OF THE
MORT CONTROL SEC AT THE
INSTITUTE OF NEUROLOGICAL
DISORDERS AND STROKES AND WAS
THE CLINICAL DIRECTOR OF THIS
INSTITUTE AND ALSO THE PAST
PRESIDENT OF THE MOVEMENT
DISORDER SOCIETY AND PAST EDITOR
AND CHIEF OF NEURO PHYSIOLOGY
AND RECEIVED MANY AWARDS FOR THE
WORK HE'S DONE AND IS THE
WORLD'S EXPERT WHEN IT COMES TO
PRINCIPLES OF MOTOR CONTROL AND
PATHOPHYSIOLOGY OF MOVEMENT
DISORDERS.
DR. HALLETT.
THANK YOU.
>> THANK YOU.
IT'S A PLEASURE TO PRESENT THE
RESU
RESULTS.
AND TO POINT OUT EVERYONE IS
CLEAR IN TERMS OF INFORMATION
ANY PARTICULAR DISEASE AND THAT
IS THE PHENOTYPE THAT WE'RE
TRYING TO UNDERSTAND HERE ONE
STARTS WITH THE ETIOLOGY AND THE
UNDERLYING CAUSES.
THOSE WHICH WE JUST HEARD ABOUT
IN THE LAST PRESENTATION SOMEHOW
LEAD TO THE PATHOPHYSIOLOGY OF
THE DISORDER WHICH WIRE GOING TO
BE TALKING ABOUT IN WHICH
DRDR
DR. KOROSHETZ WAS TALKING ABOUT
ALSO AND THE PATHOPHYSIOLOGY
LEADS TO THE PHENOTYPE WHICH
WILL BE OF THE DECREASED OR IN
THE AMOUNT OF FATIGUE.
TO GO BACK TO THIS PARTICULAR
DIAGRAM, AS YOU HEARD WE WERE
TALKING ABOUT THE FIRST TWO
COLUMNS IN THE FIRST
PRESENTATION.
NOW WE'RE GOING TO BE TALKING
ABOUT THE NEXT TWO AND A HALF TO
LEARN HOW POTENTIALLY THOSE ET
YO LOGICAL FACTORS LEAD TO THE
IDENTIFICATION OF WHERE FATIGUE
MIGHT ARISE.
THESE ARE THE SUBSET OF WHAT
WE'LL BE STRIKE NOW AND THE
OUTLINE OF WHAT YOU'LL BE
HEARING ABOUT.
REPETITIVE SUB MAXIMAL EXERCISE
IS A GOOD WAY AND TYPICAL WAY OF
ANALYZING MOTOR FATIGUE.
AND ONE CAN UNDERSTAND IT BY
LOOKING AT ELEMENTS OF WHERE THE
FATIGUE COMES FROM.
DOES IT COME FROM THE PERIPHERAL
ASPECT OF THE NEURAL MUSCULAR
SYSTEM OR THE MOTOR CORTEX OR
THE DRIVERS OF THE MOTOR CORTEX
WHERE ONE WOULD DESCRIBE IT AS
CENTRAL FATIGUE.
DR. KOROSHETZ GAVE AN
INTRODUCTION TO THAT.
YOU'LL HEAR FROM PATRICK BEDARD
WHO IS A NEUROSCIENTIST WHO HAS
BEEN WORKING SPECIFICALLY ON
THIS PROJECT FOR A NUMBER OF
YEARS NOW.
AND DR. HOROWITZ A NEUROIMAGER
WHO HAS BEEN A COLLEAGUE IN THE
MOTOR CONTROL SECTION FOR MANY
YEARS.
THE NEXT YOU'LL HEAR FROM DAVID
GOLDSTEIN HE'S A SENIOR
SCIENTIST WHO HAS BEEN AT NIH
MANY YEARS AND MADE MANY
IMPORTANT S ON THE AUTONOMIC
SURFACE SYSTEM AND HEAR MORE
FROM MARK LEVIN A CARDIOLOGIST
AND REPRESENTING NHLBI IN THE
MULTI-INSTITUTE PROJECT.
THE HEART IS A MAJOR TARGET FOR
THE AUTONOMIC NERVOUS SYSTEM AND
IMPORTANT TO UNDERSTAND.
NEUROCOGNITIVE ISSUES ARE ALSO
IMPORTANT.
JOSEPH SNOW IS A SENIOR
NEUROPSYCHOLOGIST AT NIH WITH
MANY EXPERIENCE AND HAS DONE
COMPREHENSIVE STUDIES YOU'LL
MARE ABOUT AND A POST-DOCTORAL
FELLOW WAS WORKING AT NIHM AND
NOW AT NINDS TO CONTINUE HIS
STUDIES OF EFFORT IN RELATION TO
THE WAY HE BRAIN IS ORGANIZED.
EFFORT IS ONE OF THE DRIVERS OF
THE MOTOR CORTEX, DECISION
MAKING AND REWARD VERSUS EFFORT
DR. KOROSHETZ INTRODUCED EARLIER
BUT YOU'LL BE HEARING ABOUT THAT
LATER.
SO I'M NOT GOING TO MAKE
INDIVIDUAL INTRODUCTIONS OF THE
PEOPLE.
WE ALREADY SAID A LITTLE BIT
ABOUT THEM AND GOING TO GO
THROUGH THIS AS INFORMATION ONE
TOPIC AFTER THE NEXT.
WE'LL LEAD ON NEXT TO OR FIRST
AND THIS IS PATRICK BEDARD WHO
WILL TALK ABOUT ASPECTS OF
TRANSCRANIAL MAGNETIC
STIMULATION UNDERSTANDING THE
NATURE OF FATIGUE.
>> HELLO, EVERYONE.
IN ORDER TO MAKE HOMES THE BRAIN
AND IN PARTICULAR THE MOTOR
CORTEX SEEN AS THE GREEN
STRIP -- WILL GENERATE MOTOR
COMMANDS AND ACTIVATE THE
MUSCLES AND WE'LL HAVE MOVEMENT.
IF WE REPEAT THESE HOMES WITH
ENOUGH INTENSITY IT WILL CAUSE
FATIGUE.
WE CAN ASK THE QUESTION WHETHER
FATIGUE IS REPRESENTED IN THE
BRAIN OR IN THE PERIPHERY?
IS IT CENTRAL OR PERIPHERAL?
THE GOAL IS TO EVALUATE THE
MOTOR CORTEX EXCITABILITY OR THE
AMOUNT OF AVAILABLE RESOURCES TO
MAKE MOVEMENTS.
TO DO THAT WE APPLIED THE PULSE
THE TRANS CRANIAL MAGNETIC
STIMULATION OR TMS OVER THE
PRIMARY MOTOR CORTEX TO GENERATE
MOVEMENTS AND WE GENERATE THEM
IN THE RIGHT THUMB SHOWN IN THE
PICTURE AT THE BOTTOM RIGHT.
HERE THE INTENSITY OR AMPLITUDE
IS AN INDICATION OF HOW MUCH
EXCITABILITY IS IN THE PRIMARY
MOTOR CORTEX.
WHAT WE SHOULD EXPECT TO FIND IS
WITH CENTRAL FATIGUE WE SHOULD
SEE A REDUCTION OF THE RESPONSE.
THERE'S LESS RESOURCES FOR
PRIMARY MOTOR CORTEX TO DRIVE
MOVEMENTS.
FOR PERIPHERAL FATIGUE, THE GOAL
IS TO EVALUATE THE MUSCLE
FATIGUING TEST.
A KEY FEATURE IS A SHIFT IN THE
MUSCLE ACTIVITY TOWARDS THE LOW
FREQUENCY COMPONENTS.
ONE WAY TO MEASURE THAT SWING
THE INDEX.
THIS IS THE METRIC WE WILL USE.
WE SHOULD EXPECT TO FIND WITH
PERIPHERAL FATIGUE WE SHOULD SEE
AN INCREASE IN THE MUTUAL INDEX
AND RESOURCES AVAILABLE.
TO INDUCE FATIGUE WE DESIGNED A
TASK IN WHICH PARTICIPANTS HAD
TO CONTROL THE GREEN BAR ON THE
LEFT MOVING IT UP AND DOWN BY
SQUEEZING THE DEVICE SHOWN ON
THE RIGHT.
WHAT THEY HAVE TO DO IS TO
REMAIN LEVEL WITH THE RED BAR
WHICH WAS SET AT 50% OF THE
MAXIMUM FORCE A PARTICIPANT
COULD DO ALSO KNOWN AS THE
MAXIMUM VOLUNTARY COUNTER
ACTION.
WE DID THIS TASK FOR BLOCKS OF
30 SECONDS INTERSPACED WITH
BLOCKS OF REST OF ALSO 30
SECONDS AND THEY DID THESE
BLOCKS IN MANY OF THESE BLOCKS.
THE RESULTS HAVE SHOWN THERE WAS
NO DIFFERENCE IN THE MAXIMUM
VOLUNTARY CONTRACTION BETWEEN
THE GROUPS.
HERE IN BLUE YOU SEE THE
CONTROLS AND IN RED IS THE CFS
GROUP.
BUT DURING THE TASK IT BECAME
DIFFICULT FOR THE PARTICIPANTS
OF THE ME/CFS TO MAINTAIN AND
GENERATE ENOUGH FORCE TO
MAINTAIN MATCH THE DEMANDS OF
THE TASK.
THEY CANNOT GENERATE ENOUGH
FORCE AND THE CONTROLS WE'RE
AUTOMOBILE TO STAY LEVEL WITH
THE DEMANDS OF THE TASK.
CONCERNING CENTRAL FATIGUE OR
THE MUSCLE RESPONSE TO THE TMS
STIMULATION AS EXPECTED IN THE
CONTROLS IN BLUE WE SAW A
DECREASE IN THE RESPONSE BECAUSE
THE MOTOR CORTEX BECAME LESS
EXCITABLE DUE TO FATIGUE.
IN REVERSE WE SAW AN INCREASE IN
THE RESPONSE.
INDICATING THERE WAS STILL
RESOURCES AVAILABLE TO PRODUCE
MOVEMENT.
CONCERNING PERIPHERAL FATIGUE OR
THE MUSCLE RESPONSE DURING THE
TASK WE SAW THE CONTROLS REMAIN
STABLE OR THERE WAS A SLIGHT
INCREASE BUT THERE WAS A SHARP
DECREASE FOR THE ME/CFS GROUP
INDICATING NO SHIFT TOWARDS THE
LOW FREQUENCIES AND WERE STILL
REMAINING RESOURCES IN THE
MUSCLES TO GENERATE MOVEMENT.
SO IN CONCLUSION WE STARTED THE
MOTOR NETWORK IN GENERAL
REMAINED EXCITABLE FOR THE
ME/CFS AND REMAINING RESOURCES
AND WE SAW THE SAME THING NOR
MUSCLES.
THIS SUGGESTS THERE WAS ALSO
DRIVING FORCE FROM THE MOTOR
NETWORK.
>> GOOD MORNING.
MY NAME IS SILVINA HOROVITZ AND
TALK ABOUT THE YIELD FROM FMRI.
AS DR. BEDARD TOLD US, FATIGUE
SEEMS TO BE CENTRAL.
WE DIDN'T FIND PERIPHERAL
EFFECTS.
SO WE WANT TO UNDERSTAND WHY.
FOR THIS WE WANT TO OBSERVE HOW
THE BRAIN AREAS ENGAGE OR
DISENGAGE AS THE PROCESS OF
FATIGUE IS HAPPENING.
FOR FUNCTIONAL fMRI A SCANNER
YOU CAN USE FOR OTHER RESONANCE
STUDIES AND HAS THE ABILITY TO
FOLLOW NEURAL ACTIVITY.
SO IF THE NEURONS ARE ACTIVATED
THEY'LL NEED SUPPLIES.
THE SUPPLIES WILL COME THROUGH
THE OXYGEN AND THE BLOOD WILL
BECOME THE OXYGENATOR AND
THEY'RE DIFFERENT AND THEREFORE
THE SCANNER CAN HAVE ALTERATIONS
AND THAT WILL BECOME THE SIGNAL
AS YOU CAN SEE IN THE FIGURE IN
THE FAR LEFT OF YOU.
AND THAT IS A MAP OF THE AREAS
THAT PARTICIPATED IN THE TASK.
FOR THIS WE DON'T HAVE AN
ABSOLUTE MEASURE OR THE SIGNAL
WILL TELL EXACTLY A NUMBER BUT
RATHER THE DIFFERENCE BETWEEN
TWO DIFFERENT CONDITIONS.
SO IN A BLOOD DESIGN AS SHOWN IN
THE TOP YOU HAVE REST AND TASK
OR ACTIVITY AND THAT WILL BE OUR
COMPARING AND WHAT IS IMPORTANT
TO NOTE IS THAT BECAUSE IT'S A
RELATIVE DIFFERENCE BETWEEN THE
CONDITIONS THE VALUE WE ARE
SEEING COULD BE A CHANGE IN
ACTIVATION OR CHANGE IN THE
CONDITION THAT WE CALL REST.
SO FOR OUR STUDY WE USED THE
SAME PARADIGM DESCRIBED BY
DR. BEDARD WHERE WE USE THE REST
AS RELAXING THE HAND AND THE
BLOCK TASK WAS THE FORCE USING
USED BEFORE AND ASKING THE
SUBJECTS TO MAINTAIN THAT RED
BAR THAT WILL BE AT THE 50% OF
THE MAXIMUM CONSTRUCTION THAT
THEY COULD DO.
THE TWO QUESTIONS THAT WE WANTED
TO ANSWER NOW WITHIN THE BRAIN
IS WHETHER THE DEFICITS COME
FROM THE MOTOR NETWORK OR THE
CHANGES IN FATIGUE COME
SOMEWHERE ELSEWHERE WHAT IS
HAPPENING IN THE WHOLE BRAIN
BECAUSE MOTOR CORTEX IS OUR
OBVIOUS PLACE TO LOOK FOR MOTOR
TASK BUT THE BRAIN ACTS AS A
NETWORK AND MORE INTEGRATED.
SO THE RESULTS WE HAVE ARE
SIMILAR AGAIN IN THE TASK TO
WHAT WAS FOUND IN THE EXPERIMENT
WITH TMS AND EDG.
THE NUMBER OF BLOCKS THE
CONTROLS DID IS HY THAN THE
NUMBER OF BLOCKS OF THE PATIENTS
WITH ME/CFS.
PATIENTS WERE ABLE TO PERFORM
HOWEVER, EVERYBODY DOES DID THE
TASK AND WHEN WE LOOKED AT THE
MORT TASK ACTIVATION WE CAN SEE
BOTH HAVE ACTIVITY IN THE MOTOR
CORTEX AND INDEED WITH DON'T SEE
IN THAT NETWORK A SIGNIFICANT
DIFFERENCE WHEN WE COMPARE THE
SIGNALS.
WHEN WE LOOK AT THE WHOLE BRAIN
ANALYSIS WE DO FIND DIFFERENCES.
HERE WE NEED DO THE ANALYSIS
SLIGHTLY DIFFERENT.
FOR THIS PART OF THE ANALYSIS WE
DIVIDED THE 16 BLOCKS THAT
SUBJECTS DID IN FOUR CHUNKS.
WE COMPARED HOW THE SIGNAL
EVOLVED OVER TIME AND CROSS
GROUPS.
WE FIND A DIFFERENCE IN THIS
AREA THAT IS THE TEMPORAL
PARIETAL JUNCTION AND THE
PARIETAL LOBULE AND THEY'RE
ASSOCIATED WITH MOTOR
INTEGRATION INCLUDING MOTOR
CONTROL.
WE FIND AT THE BEGINNING OF
ACTIVATION OF THE TRIAL THE
FIRST FOUR BLOCKS THERE WAS NO
GROUP DIFFERENCE IN THE WAY THAT
THESE AREAS WERE ENGAGED.
BUT AS WE PROGRESSED IN THE
BLOCKS AND CAN SEE THE
DIFFERENCE IN BEHAVIOR, WE CAN
ALSO OBSERVE IN THE BLUE LINE
THE SIGNAL INCREASED UP TO THE
POINT OF FATIGUE AND GOES DOWN.
HOWEVER, IN THE FES GROUP THE
SIGNAL CONTINUOUSLY SHOWS
DECREASE.
SO IN SUMMARY WE CAN SAY THE
MOTOR NETWORK ENGAGEMENT SHOWS
SIMILAR PATTERNS FOR BOTH
GROUPS.
THIS SUGGESTS IT'S NOTE CAUSE OF
THE FATIGUE AND WHEN WE LOOK AT
THE WHOLE BRAIN LABEL THE AREAS
THAT SHOW DIFFERENCES THE
TEMPORAL PARIETAL JUNCTION AND
LOBE WHERE AREAS OF HIGH ORDE
INTEGRATION AND SHOW THE
DIFFERENCE AND THIS COULD
INDICATE SOME DECREASED MOTOR
CONTROL SIGNALLING OR CHANGES IN
THE MOTOR MATCHING.
NOW DR. GOLDSTEIN.
>> I'M DAVE GOLDSTEIN.
I DIRECT THE AUTONOMIC MEDICINE
SECTION IN THE NEURAL CLINICAL
SCIENCES PROGRAM.
TODAY I'LL BE TALKING ABOUT THE
AUTONOMIC AND CAT COAL MINNER
GIC IN THE ME/CFS COMPARED TO
THIL KOL UNVEERZ.
IT'S NOT ONE THING AND IN TERMS
OF ENTERIC AND PARASYMPATHETIC
SYMPTOM AND SYMPATHETIC NERVOUS
SYSTEM.
IT WAS FOUND THERE ARE SPECIFIC
MEM CAL MESSENGERS ASSOCIATED
WITH THE DIFFERENT COMPONENTS OF
THE AUTONOMIC NERVOUS SYSTEM AND
ACETYLCHOLINE NOT ONLY THE CH
CHEMICAL MESSENGER OF THE SYSTEM
WHICH MEDIATED SWEATING.
AND THEY DEFINE THE ADRENAL
SYSTEM AS A MONOLITHIC EMERGENCY
SYSTEM TO MAINTAIN HOMEOSTASIS.
A WORD HE COINED IN EMERGENCIES.
ACTUALLY, THREES DIFFERENT
COMPONENTS AND ARE REGULATED
DIFFERENTLY AS I'LL GET INTO IN
A LITTLE BIT.
THE CHEMICAL MESSENGER OF THE
SYMPATHETIC ANNIVERSARY SYSTEM
IN CARDIOVASCULAR SECTION IS NOR
EPINEPHRINE AND EPINEPHRINE IS
THE MAIN RECENTER OF THE
NEUROENDOCRINE SYSTEM.
ONE OF THE KEY AUTONOMIC
FUNCTION TEST THAT'S DONE IS
TILT TABLE TESTING.
THIS IS BECAUSE WHEN A PERSON IS
TILTED UP THERE'S A DECREASE IN
RETURN TO THE HEART AND YOU'RE
EXAMINING THE ABILITY TO COUNTER
THAT DECREASE IN VENOUS RETURN
BY A VARIETY OF COMPENSATORY
HOMEOSTATIC PROCESSES.
THIS SHOWS THE ARRANGEMENT AT
THE TIME OF THE AUTONOMIC
FUNCTION TESTING.
IT STARTED WITH THE VALSALVIN
MANEUVER AND WON'T GO IN THE
RESULTS OF THAT AND FOCUS ON
WHAT HAPPENED DURING HEAD UP,
TILT TABLE TESTING FOR UP TO 40
MINUTES.
HERE'S SOME OF THE PHYSIOLOGICAL
DATA AS THE CONVENTION FOR OTHER
TALKS HE WILL THE VOLUNTEERS IN
BLUE AND ME/CFS GROUP IN RED.
HEART RATE INCREASED IN BOTH
GROUPS WITH INCREASE
IDENTICALLY.
FINGER SYSTOLIC BLOOD PRESSURE
WENT UP IN BOTH GROUPS.
KIND OF AN INTERESTING
PHENOMENON.
YOU WOULD THINK BLOOD PRESSURE
SHOULDN'T GO UP WITH TILTING BUT
THAT'S WHAT WAS FOUND.
STROKE VOLUME WENT DOWN IN BOTH
GROUPS.
THIS IS STROKE VOLUME ESTIMATED
BY APPLYING AN ALGORITHM CALLED
BEAT SCOPE TO THE FINGER CUFF
BLOOD PRESSURE SIGNAL.
THERE'S AN INCREASE IN STROKE
VOLUME IN THE CHRONIC FATIGUE
PATIENTS.
IN TERMS OF CATECHOLAMINES
NOREPINEPHRINE WENT UP AND
STAYED UP DURING TILTING BUT
GROUPS DID NOT DIFFER.
WHEN IT COUPLES TO EPINEPHRINE
THIS WAS AN INCREASE IN
EPINEPHRINE IN THE GROUPS TENDED
TO DIFFER.
YOU CAN SEE BASED ON THE
INDIVIDUAL RESULTS HERE THAT
SOME OF THE ME/CFS PATIENTS HAD
LARGE EPINEPHRINE RESPONSES AND
THAT EXPLAINS THE INCREASE IN
THE MEAN VALUES.
BUT THERE'S A LOT OF
VARIABILITY.
TO SUMMARIZE THE TILT FINDING
THERE WAS NO ORTHOSTATIC BY THE
FINGER CUFFING IN EITHER GROUP
AND THERE WAS NO INCREASE IN THE
FREQUENCY OF POSTURAL
TACHYCARDIA SYNDROME BY THE
HEART RATE RESPONSE TO THE
TILTING.
THE DIFFERENCE YOU SEE IS NOT
STATISTICALLY SIGNIFICANT.
THE GROUPS DID NOT DIFFER IN
SUDDEN HYPERTENSION CALLED
NEURALLY MEDIATED HYPOTENSION
AND NO DIFFERENCE IN PRE --
PRESINCOPY AND NAUSEA.
THIS IS A SCHEME THAT SHOWS THE
SOURCES OF DIFFERENT LEVELS OF
CATTICOLS IN THE SPINAL FLUID.
THIS IS INDUCED BY THIROSINE
CONVERTED TO NOREPINEPHRINE.
MAIN MEASURE OF NOREPINEPHRINE
SCORES IS DHPG.
THE MAIN NEURONAL METABOLITE OF
NOR EPINEPHRINE.
THE MAIN STORES ISN'T DOPAMINE
IT'S DOPAC ACID THE MAIN
NEURONAL METABOLITE OF DOPAMINE.
THE CATECHOLAMINE DECREASED IN
THE ME/CFS GROUP COMPARED TO
HEALTHY VOLUNTEERED AND NOTABLY,
DHGP THE METABOLITE OF
NOREPINEPHRINE WAS QUITE
DECREASED IN THE ME/CFS GROUP.
WE DID NOT FIND EVIDENCE FOR
ORTHOSTATIC HYPERTENSION IN
ME/CFS.
THERE WERE NON SIGNIFICANT
DIFFERENCES IN TACHYCARDIA
SYNDROME DEFINED ENTIRELY BY A
HEART RATE AND THERE WAS NO
DIFFERENCE BETWEEN THE GROUPS
WITH SUDDEN HYPOTENSION WAS VASO
CONSTRICTION IN THE ME/CFS GROUP
AND PLASMA NOREPINEPHRINE DURING
REST AND INCREASED NORMALLY
WHEREAS THERE WAS A SUGGESTION
THAT SOME OF THE ME/CFS GROUP
HAD LARGE RESPONSE TO TILT BUT
THE BALANCE AND THE LARGER
INCREASE IN SYMPATHETIC
AGINERGIC ACTIVITY AND THE
CATECHOL RESPONSE SUGGESTS BIO
SYNTHESIS RESULTING IN DECREASED
NOREPINEPHRINE STORES.
THANK YOU.
>> HI.
I'M MARK LEVIN A CARDIOLOGIST AT
NHLBI AS DR. HALLETT MENTIONED.
I STUDY ARRHYTHMIA AND SUDDEN
CARDIAC DEATH AND I STUDY THE
AUTONOMIC SYSTEM AND WHAT I'LL
TALK ABOUT TODAY.
THE HEART IS A PUMP COORDINATE
THE CARDIAC INDUCTION SYSTEM AND
IT'S PICTURED IN THE CARTOON.
NORMAL BEATS CONDUCTED PROPERLY
WHICH MEANS THOSE BEATS
INITIATED IN THE SINUS NODE AND
PROGRESS TO THE AV NODE
THROUGHOUT THE REST OF THE HEART
ARE CONSIDERED NORMAL BEATS.
AND THE ELECTRICAL ACTIVITY THAT
PROCEEDS THROUGH THE HEART CAN
BE GRAPHED LIKE THE PICTURE HERE
AND ONE CAN NAME COMPONENTS OR
COMPLEXES IN THAT GRAPH SO
THERE'S THE PWAVE, THERE'S THE
QRS COMPLEX AND WHEN WE TALK
ABOUT THE DISTANCE BETWEEN TWO
QRS COMPLEXES WE TALK ABOUT THE
R INTERVAL.
WHEN THOSE BEATS AREN'T NORMAL
BEATS MEANING PROPERLY CONDUCTED
THROUGH THE CONDUCTION SYSTEM WE
CAN REFER TO THEM AS AN INTERVAL
WHICH IS AN ABBREVIATION YOU'LL
SEE IN THE REST OF TALK.
IT INVOLVES COMPARING NORMAL
BEATS MATHEMATICALLY DO QUANTIFY
AUTONOMIC SYSTEM ACTIVITY.
THIS ANALYSIS ASSUMES TIME
DIFFERENCES BETWEEN DIFFERENT
NORMAL BEATS ARE ATTRIBUTABLE TO
DIFFERENCES IN AUTONOMIC NERVOUS
SYSTEM ACTIVITY AND CAN BE
FURTHER BROKEN DOWN TO
SYMPATHETIC AND PARASYMPATHETIC
ACTIVITY AND THOSE ELEMENTS CAN
BE QUANTIFIED WITH HEART RATE
VARIABILITY, PARASYMPATHETIC
MEASURES ARE PRETTY WELL AGREED
UPON AND AGREED THE SYMPATHETIC
MEASURES ARE NOT GREAT.
SOME TYPES OF MATHEMATICAL
APPROACHES YOU CAN TAKE ARE
PICTURED HERE.
THOSE INCLUDE THE TIME DOMAIN
WHICH INVOLVE STRAIGHTFORWARD
STANDARD DEVIATION OF THE
INTERVALS, FREQUENCY DOMAIN
WHICH ASSUMES THAT A WAVE FORM
CAN BE DE COMPOSED INTO
COMPOSITE SIGN WAVES AS SHOWN
HERE USING FFT TRANSFORMATION
AND COULD BE FURTHER QUANTIFIED
AND COMPARED USING SPECTRAL
POWER UP ANALYSIS AS SHOWN HERE.
FINALLY THERE'S WHAT'S CALLED
NON-LINEAR APPROACHES WHICH ARE
HIGHER ORDER MATHEMATICAL
ANALYSIS WHICH ASSUME NO
PREDICTABLE PROPORTIONAL
RELATIONSHIP AND ONE OF THOSE
TYPES OF ANALYSES ARE PICTURED
HERE WHICH INVOLVES GRAPHING THE
INTERVAL AS THE SUBSEQUENT RR
INTERVAL AND THIS INVOLVES THE
SD1 INTERVAL.
WE DID OUR ANALYSIS BASED ON
CONSENSUS GUIDELINES AND YOU CAN
SEE THE REFERENCES FOR THOSE
GUIDELINES HERE.
IN DOING THESE ANALYSIS HEART
RATE AS A SURROGATE OF
SYMPATHETIC ACTIVITY.
WHILE THERE WAS NO STATISTICALLY
SIGNIFICANT DIFFERENCE WE FOUND
A TREND TOWARDS SIGNIFICANCE IN
THAT THEIR HEART RATES IN ME/CFS
SUBJECTS LOOKED LIKE IT MIGHT BE
GREATER THAN THAT OF CONTROLS.
WITH RESPECT TO PARASYMPATHETIC
ACTIVITY WE USED SEVERAL TIME
DETAIN MARKERS AND WE FOUND
ME/CFS SUBJECTS HAD DIMINISHED
VALUES IN BOTH OF THESE
PARAMETERS.
SIMILARLY WITH RESPECT TO
FREQUENCY DOMAIN ANALYSIS WE
FOUND HIGH FREQUENCY POWER
DIMINISHED IN ME/CFS SUBJECTS
COMPARED TO CONTROLS AND FOUND
THE SAME THING IN SD 1 IN
SUBJECTS COMPARED TO CONTROLS.
WE FOUND COMPOSITE MEASURES THAT
MEASURE OVER ALL HEART RATE
VARIABILITY AND THOSE INCLUDE
SDNN INDEX AND SD 1.
WE FOUND BOTH DIMINISHED
COMPARED TO CONTROLS AS WELL.
IN CONCLUSION, HEART RATE
VARIABILITY ASSESSED FROM 24
HOURS AMBULATORY ECGs SUGGEST
THAT ME/CFS SUBJECT HAVE
DECREASED PAIR TRA --
PARASYMPATHETIC ACTIVITY AND
SD1.
THERE'S A SUGGESTION THAT
INCREASED HEART RATE IN ME/CFS
SUBJECTS COMPARED TO CONTROLS
MIGHT SUBJECT INCREASED
SYMPATHETIC ACTIVITY AND FINALLY
ME/CFS SUBJECTS HAVE DECREASED
OVER ALL HEART RATE VARIABILITY
AS COMPARED TO CONTROLS WITH
RESPECT TO SD NNI AND SD 1.
THANKS VERY MUCH.
>> HELLO, EVERYBODY.
MY NAME IS JOSEPH SNOW.
I'M AN INTRAMURAL CLINICAL
NEURAL PSYCHOLOGIST IN NIMHD.
WE PERFORM COGNITIVE TESTS
BECAUSE OF COMPLAINTS OF
COGNITIVE DIFFICULTY OR BRAIN
FOG DESCRIBED AS A CORE SYMPTOM
IN ME/CFS.
IN ADDITION COGNITIVE EXERTION
TRIGGERS POST EXERTIONAL MALAISE
AND FOUND COGNITIVE DEFICITS IN
ME/CFS.
THE GOALS WERE TO USE STANDARD
PSYCH METRIC METHODS TO EVALUATE
COGNITIVE FUNCTIONING IN ME/CFS
AND EVALUATE THEIR SUBJECTIVE
COMPLAINTS OF ME/CFS FOL
UNTEARS.
SO A VALID NEUROCOGNITIVE
EVALUATION HAS SEVERAL
REQUIREMENTS.
THERE NEEDS TO BE STANDARD
ADMINISTRATION THAT IS AN
EXAMINER MUST FOLLOW THE SAME
RULES FOR ALL RESPONDENTS.
THERE MUST BE OPTIMAL ENGAGEMENT
AND NEEDS TO BE OBJECTIVE
SCORING ALL TRAINED EVALUATORS
YIELD THE SAME RESULTS WITHIN A
MARGIN OF ERROR AND NORMATIVE
COMPARISON.
TESTEES COMPARED TO OTHERS
SIMILAR TO THEM SUCH AS IN TERMS
OF THEIR AGE AND EDUCATION.
AS PART OF OUR BATTERY WE
ADMINISTERED DIFFERENT TYPES OF
MEASURES.
SO-CALLED SUBJECTIVE MEASURES
SUCH AS ASKING TESTEES TO RATE
THEIR OWN SYMPTOMS OF
DEPRESSION, SYMPTOMS OF ANXIETY
OR THEIR COGNITIVE SYMPTOMS OR
THEIR OWN LEVEL OF TASK
ENGAGEMENT.
WE ALSO INCLUDED PERFORMANCE
VALIDITY TESTS WHICH ARE
QUANTITATIVE MEASURES TO
DETERMINE IF THERE IS AN
ACCEPTABLE LEVEL OF TASK
ENGAGEMENT AND THERE BE ASSIST
IN DETERMINING IF THE EVALUATION
ITSELF WAS VALID.
HERE ARE SOME SAMPLE
NEUROCOGNITIVE TESTS.
ON THE LEFT, WE HAVE A TASK
WHERE A LIST OF WORDS IS READ TO
THE VOLUNTEER SEVERAL TIMES AND
A NUMBER OF WORDS RECALL ON THE
TRIAL IS RECORDED AS WELL AS
FOLLOWING THE DELAY.
IN THE MIDDLE PANEL WE HAVE A
DESIGN LEARNING TASK, SEVERAL
TRIALS ARE PRESENTED AND THE
VOLUNTEER HAS TO RECALL THE
DESIGNS AFTER EACH PRESENTATION
AND FOLLOWING A DELAY.
ON THE RIGHT IS A CARD SORTING
TASK USED TO ASSESS EXECUTIVE
FUNCTIONING.
AND WE DID A WHOLE BUNCH OF
TESTS.
SOME ADDITIONAL TESTS WOULD BE
ASKING VOLUNTEERS TO GENERATE
THEIR WORDS TO CUE OR ASKING
THEM TO RAPIDLY PLACE PEGS IN
SLOTTED HOLES OR TO DO OTHER
TASK LIKE MENTAL ARITHMETIC OR A
CODING TASK.
SO THE DATA IS COLLECTED SUCH AS
A NUMBER OF ERRORS AND RAW
SCORES.
TIME TO COMPLETION AND THEN WE
ALSO COMPUTE THROUGH THE
NORMATIVE PROCESS WHERE ALL
SCORES ARE CONVERTED TO SCALE
SCORES AND T SCORES AND STANDARD
SCORES.
EACH HAS ITS OWN MEAN AND
STANDARD DEVIATION.
TO SUMMARIZE WE COLLECT SEVERAL
TYPES OF DATA CLUTH SUBJECTIVE
MEASURES, PERFORMANCE VALIDITY
AND PERFORMANCE BASED MEASURES
THE NEUROCOGNITIVE DATA PROPER.
ONE SUBJECT MEASURE IS THE MASS
CUE.
AS THEY MULTIPLE ABILITY
SELF-REPORT QUESTIONNAIRE AND ON
THIS FOR THIS QUESTIONNAIRE WE
ASKED VOLUNTEERS THE ME/CFS
PARTICIPANTS AND CONTROLS
QUESTIONS ABOUT THEIR CURRENT
LANGUAGE, ATTENTION, VERBAL
MEMORY VISUAL MEMORY AND
PERCEPTION, ETCETERA.
WE FOUND INDIVIDUALS IN THE RED
DESCRIBE MORE PROBLEMS IN EACH
OF THESE CATEGORIES THAN THE
CONTROLS.
THEN WE ALSO MEASURE DEPRESSION.
THIS WAS MENTIONED EARLIER.
WE FOUND VOLUNTEERS DESCRIBE
MORE ANXIETY THAN CONTROLS BUT
NOT VERY ELEVATED EITHER OF
THEM.
WE ALSO USED SOMETHING CALLED
VISUAL ANALOG SCALES TO HAVE OUR
PARTICIPANTS SELF-RATE THEIR
MENTAL FATIGUE AND PHYSICAL
FATIGUE AND ENGAGEMENT AND THE
TASK AND FATIGUE APPEARS TO GO
UP ACROSS TIME FOR EVERYBODY.
THE ME/CFS VOLUNTEERS HAVE MORE
SELF-REPORTED MENTAL AND
PHYSICAL FATIGUE PRIOR TO AND
DURING TESTING.
WE DO MULTIPLE MEASURES ACROSS
TIME.
BUT BOTH THE ME/CFS AND CONTROL
GROUPS ENDURE SELF-REPORTED
FATIGUE AT AN EQUAL RATE ACROSS
THE TESTING SESSION SO WE DIDN'T
SEE A DIVERGENCE OF THE TWO
LINES.
IN TERMS OF PERFORMANCE VALIDITY
TEST DESIGN TO ENSURE ADEQUATE
TASK ENGAGEMENT THERE WAS NO
DIFFERENCE BETWEEN ME/CFS AND
HEALTHY VOLUNTEERS.
SO INDIVIDUALS WITH ME/CFS DO
NOT APPEAR TO BE UNENGAGED IN
DOING WELL ON THE NEUROCOGNITIVE
TESTS.
IN TERMS OF PERFORMANCE ON
NEUROCOGNITIVE MEASURES THE LAB
MEASURES THAT HAVE BEEN WELL
VALIDATED AND USED FOR DECADES,
WE FOUND ME/CFS VOLUNTEERS
PERFORMED IN THE AVERAGE RANGE
AND THE YELLOW LINE ATTEMPTS TO
DEPICT THAT FOR EACH OF THE
CATEGORIES OF TESTS.
THE PERFORMANCE OF ME/CFS
ACCORDING TO OUR STATISTICAL
METHODS DOES NOT DIFFER FROM OUR
CONTROL VOLUNTEERS.
TO SUMMARIZE, ME/CFS VOLUNTEERS
HAVE A SATISFACTORY LEVEL OF
TASK ENGAGEMENT.
ME/CFS VOLUNTEERS DO NOT HAVE
INVALID TASK PERFORMANCE.
ME/CFS VOLUNTEERS HAVE MORE
SELF-REPORTED DEFICITS IN
ATTENTION, VERBAL MEMORY, VISUAL
SPATIAL LANGUAGE AND VISUAL
MEMORY.
ME/CFS VOLUNTEERS HAVE
SIGNIFICANTLY MORE SELF-REPORTED
DEPRESSION AND ANXIETY SYMPTOMS.
ME/CFS VOLUNTEERS HAVE MORE
SELF-REPORTED MENTAL AND
PHYSICAL FATIGUE PRIOR TO AND
DURING THE TESTING BATTERY BUT
BOTH ME/CFS AND CONTROL GROUPS
ENDURE SELF-REPORTED FATIGUE AT
AN EQUAL RATE ACROSS THE TESTING
SESSION.
FINALLY, DESPITE THOSE FINDINGS,
ME/CFS VOLUNTEERS PERFORM
NORMALLY ON STANDARDIZED
MEASURES OF COGNITION AND
PERFORMANCE COULD NOT BE
DISTINGUISHED FROM THAT OF
CONTROLS.
THANK YOU.
HELLO.
MY NAME IS NICK MADIAN AND TALK
ABOUT OUR FINDINGS TO EFFORT AND
HOW EFFORT CAN BE THOUGHT OF AS
A FEELING AND NOT JUST AN
ACTION.
WHY WE FEEL EFFORT,
EFFORT COUNTING AND PREFERENCE
AND THE EFFORT EXPENDITURE FOR
REWARDS TASK OR EFERT AND HOW
IT'S INPRESTERPRETED.
PEOPLE USE EFFORT AS AN ACTION
UNDER CONSCIOUS CONTROL.
MERRIAM WEBSTER'S CALLS IT A
CONSCIOUS EXERTION OF POWER BUT
THE COMMON DEFINITION MAY NOT BE
ENTIRELY ACCURATE.
WE NOW KNOW EFFORT CAN BE
THOUGHT OF NOT ONLY AS AN ACTION
BUT AAS A FEELING WE GET WHEN WE
TAKE ACTION.
IN THE 1900s RESEARCHERS FOUND
SOMETHING DIFFICULT AND
AGREEABLE ABOUT CERTAIN TYPES OF
WORK.
THIS FEELING IS ANYWHERE IN OUR
DAILY LIVES.
WE FEEL IT WHEN WE WALK UP A
FLIGHT OF STAIRS OR CARRY
SOMETHING HEAVY OR PICK
SOMETHING UP.
IT'S THE FEELING OF EFFORT FOR
THE SENSE OF EFFORT.
THIS FEELING IS UNPLEASANT AND
AVERSIVE.
AND IT GETS STRONGER AND MORE
UNPLEASANT THE MORE ENERGY THE
WORK REQUIRES.
WE ALSO KNOW THE EXERCISE OF
EFFORT IS NOT ENTIRELY OR EVEN
MOSTLY CONSCIOUS DESPITE WHAT
MERRIAM WEBSTER SAID WHEN IT
GETS TO BE TOO MUCH THE BRAIN
WILL BACK OFFER AND IT CAN
CHANGE BASED ON CONTEXT EVEN IF
THE EFFORT EXERTED STAYS THE
SPAM WHEN SPENDING NERG ENERGY
CAN CHANGE AND THE MORE FATIGUE
THE MORE UNPLEASANT CHANGE CAN
BE AND THE BRAIN MUST ACCOUNT
FOR ENERGY SPENT AND REWARDS TO
BE GAINED AND THE PUNISHMENTS TO
BE AVOID FOR SPENDING THAT
ENERGY.
FURTHERMORE THE, SYSTEMS MUST BE
ABLE TO COMPUTE SOME RATIO OF
COST TO BENEFITS.
THE RESULTS OF WHICH INFLUENCE
HOW THE EFFORT FEELS.
WE CAN THINK OF THIS OF BEING A
BIT LIKE THE SYSTEM ON WHICH
SIDE OF THE SCALE IS HEAVIER OR
WHETHER THE SOLUTION TO AN
EQUATION IS POSITIVE OR
NEGATIVE.
THE PROCESS BY WHICH THE BRAIN
FIGURES OUT THE COST BENEFIT
RATIO EFFORT DISCOUNTING.
THERE'S ONE MORE LAYER OF
COMPLICATION TO THE PROCESS.
THE WEIGHTS GIVEN TO THE ENERGY
COSTS OBTAINED REWARDS AND
AVOIDED PUNISHMENT SEEM TO
DIFFER ON A PERSON TO PERSON OR
BRAIN TO BRAIN BASIS.
TO THE SAME ENERGY COST AND
COULDN'T TEXT TWO BRAINS CAN
ASSIGN TWO WEIGHTS MEANING THE
FEELING OF EFFORT CAN BE
DIFFERENT FOR DIFFERENT PEOPLE.
THE SAME BRAIN MAY ASSIGN
DIFFERENT WEIGHTS AT DIFFERENT
POINTS IN TIME.
FOR EXAMPLE, WHEN ONE IS JUST
STARTING A TASK VERSUS WHEN ONE
IS FATIGUED AND THE DIFFERENCE
IN WEIGHTING MAY BE FATIGUE SELF
IT SELF AND THOUGHT TO BE IN THE
EVALUATION NETWORK.
ANOTHER REGION OF THE BRAIN IS
THE A TINY REGION IN THE BRAIN
STEM WHICH PRODUCES THE
NEUROTRANSMITTER NOREPINEPHRINE
AND CONNECTED TO SEVERAL BRAIN
REGIONS IN THE EVALUATION
NETWORK.
THE FUNCTIONING OF THESE BRAIN
REGIONS DOES NOT APPEAR TO BE
UNDER CONSCIOUS CONTROL.
THE WEIGHTS ARE WIRED
DIFFERENTLY RESULTING IN
DIFFERENT PEOPLE FEELING THE
EFFORT IN DIFFERENT WAYS.
THE INTERINDIVIDUAL VARIABILITY
THROUGH THE PROCESS IS CALLED
EFFORT PREFERENCE.
SOME AVAILABILITY IS DIFFERENT
AND HYPOTHETICAL PEOPLE A AND B
ASKED TO DO THE SAME EXERCISE,
20 PUSH-UPS FOR THE SAME REWARD,
$20.
PERSON A'S EVALUATION MAY ASSIGN
LARGE WEIGHT TO ENERGY COSTS AND
SMALL WEIGHT TO REWARD BENEFITS.
WE BELIEVE THIS PERSON WOULD
FEEL EFFORT FROM THE PUSHUPS AND
LESS LIKELY TO ACCEPT THE OFFER.
IN CONTRAST WE HAVE PERSON B
WHOSE EVALUATION NETWORK MAY
ASSIGN SMALLER WEIGHTS TO THE
COST AND LARGER WEIGHT TO
BENEFIT AND MAKE THEM MORE
WILLING TO ACCEPT THE OFFER.
THOUGH DIFFERENT BOTH ARE
EXAMPLES OF HEALTHY EVALUATION
OF NETWORK FUNCTIONING.
SOMETIMES THE NETWORK DOES NOT
FUNCTION PROPERLY.
CERTAIN NEUROLOGICAL DISEASES
CAN DISRUPT OR DAMAGE THE
EVALUATION NETWORK AFFECTING THE
EFFORT DISCOUNTING PROCESS AND
CHANGING THE WAY EFFORT IS
EXPERIENCED.
DISEASES LIKE PARKINSON'S OR
FRONTO TEMPORAL DEMENTIA AND
STROKES AND BRAIN DAMAGE FOUND
TO DAMAGE BRAIN REGIONS
AFFECTING EFFORT DISCOUNTING AND
PREFERENCE AND THE FEELING OF
EFFORT ITSELF.
WE WONDERED WHETHER SOMETHING
SIMILAR MAY HAVE HAPPENED TO
PEOPLE WITH ME/CFS.
TO TEST WHETHER THERE WERE
BEHAVIORAL SIGNS OF DISRUPTED
EFFORT DISCOUNTING IN PEOPLE
WITH ME/CFS WE HAD A TASK.
THIS IS A WELL VALIDATED TASK TO
QUANTIFY DISCOUNTING AND IT'S
BEEN USED TO STUDY EFFORT IN
SEVERAL NEUROLOGICAL DISORDERS
AND REQUIRES PARTICIPANTS TO
PERFORM TRIALS CONSISTING OF
BUTTON PRESSING SUB TASKS WITH
TWO DIFFICULTY LEVELS.
PARTICIPANTS SELECT THE
DIFFICULTY LEVELS BASED ON THE
REWARD AT STAKE WHICH VARIES
FROM TRIAL TO TRIAL.
EACH TRIAL BEGINS WITH THE 5
SECOND CHOICE PERIOD IN WHICH
PARTICIPANTS ARE PRESENTED WITH
INFORMATION WITH THE REWARD
MAGNITUDE AND THE PROBABILITY OF
RECEIVING REWARD FOR THE TRIAL.
AFTER CHOOSING THE HARD OR EASY
SUB TASK PARTICIPANTS MAKE RAPID
BUTTON TASK AND RECEIVE FEEDBACK
AND TOLD WHETHER THEY RECEIVED
REWARD BASED ON THE REWARD
PROBABILITY AND WHETHER THEY
COMPLETE THE TASK.
ALL TOGETHER IT RUNS 15 MINUTES.
THE EEFRT CAN BE INTERPRETED.
THE LEFT DEPICTS HOW TWO PEOPLE
IN THE PURPLE AND TEAL LINES
WILL RESPOND AS REWARD
INCREASES.
BOTH ASSIGN EQUAL WEIGHTS
INITIALLY AND START AT THE SAME
POINT.
THE PURPOSE WEIGHS REWARDS AND
WILL ENGAGE MORE OFTEN WHEN MORE
REWARD IS OFFERED.
THE PERSON IN TEAL DOESN'T SEE A
DIFFERENCE.
AND THE IT PERSON IN PURPLE
WEIGHS ENERGY COSTS LESS HEAVILY
THAN THE PERSON IN TEAL THUS
ENGAGE IN THE HARD TASK MORE
OFTEN AND THE LINES START AT
DIFFERENT POINTS.
BOTH PEOPLE ASSIGN EQUAL WEIGHT
INITIALLY BUT ONLY THE PERSON IN
TEAL GETS FATIGUED AND THE
PERSON IN PURPLE IS IMMUNE AND
WE FOUND FOR THE SAME LEVELS
ME/CFS ARE LESS LIKELY TO
PARTICIPATE THAN HEALTHY
CONTROLS.
SOMETHING ABOUT THE EFFORT
DISCOUNTING PROCESS IS ALTERED
IN PEOPLE WITH ME/CFS THIS IS
THE GAP AT BLEW LINE FOR THE
HEALTHY CONTROLS AND RED LINE
FOR THE PEOPLE WITH ME/CFS.
HOWEVER, WE DID NOT SEE AN
INDICATION REWARD WEIGHTING WAS
DIFFERENT BETWEEN GROUPS.
BOTH GROUPS ENGAGE AS REWARDS
WENT UP.
WE ALSO INVESTIGATED WHETHER THE
PEOPLE WITH ME/CFS PREFERS
CHANGE AND WHETHER THEY TOO
TEGED FASTER.
WE DID NOT SEE AN INDICATION OF
THIS IN OUR DATA.
THE PROBABILITY OF ENGAGING WITH
THE HARD TASK DECLINES AT
APPROXIMATELY THE SAME RATE FOR
BOTH GROUPS BUT SAW A DIFFERENCE
AT BASELINE INDICATING
DIFFERENCES IN EFFORT
DISCOUNTING.
IMPORTANTLY, WE ALSO FOUND A
STRONG POSITIVE CORRELATION
BETWEEN THE NEUROTRANSMITTER AND
THE PROPORTION OF HEART TRIALS
CHOSEN IN THE PEOPLE WITH
ME/CFS.
THIS SUGGESTS THE UNDER PINNING
INVOLVING THE SMALL PART OF THE
BRAIN FOR EFFORT DISCOUNTING IN
PEOPLE WITH ME/CFS.
NOTABLY, EFFORT HAS BEEN STUDIED
IN PARK PARKINSON'S DISEASE AND
FINDING LOOK SIMILAR.
PEOPLE WITH PARKINSON'S DISEASE
DOES NOT ENGAGE WITH THE
PHYSICAL TASK AS HEALTHY
CONTROLS.
THIS IS A TASK WHERE THE PEOPLE
WITH THE DISEASE AND HEALTHY
VOLUNTEERS COULD PERFORM EQUALLY
WELL AND THIS WAS NOT ASSOCIATED
WITH THE DISEASE.
ONCE GIVEN MEDICATIONS THAT
INCREASE THE NEUROTRANSMITTER
DOPAMINE THE PEOPLE WITH
PARKINSON'S DISEASE ENGAGED WITH
THE PHYSICAL TASK MORE READILY
FOR THE SAME CONTROLS AS THE
INCENTIVES.
INCREASING DOPAMINE CHANGE THE
EFFORT DISCOUNTING PROCESS AND
IT'S NOT A CONSCIOUS CHOICE.
TO CONCLUDE IT APPEARS PEOPLE
WITH ME/CFS EXPERIENCE SOME
ALTERATION OR DISRUPTION OF
EFFORT DISCOUNT WHICH LEADS TO
ALTERED EFFORT PREFERENCE.
THIS APPEARS TO BE RELATED TO
THE TRANSMITTER NOREPINEPHRINE
AND IT MAY BE THE CASE AND
EFFORT DISCOUNTING ARE RELATED
TO THE POST EXERTIONAL MALAISE.
FURTHER RESEARCH ON EVALUATION
NETWORK DAMAGE OR DYSFUNCTION AS
A POSSIBLE CONTRIBUTOR TO THE
SYMPTOMS IS ALSO WARRANTED.
A CLOSER INVESTIGATION
EVALUATION NETWORK FUNCTIONING
IN PEOPLE WITH ME/CFS IS ALREADY
UNDERWAY.
>> I HOPE YOU UNDERSTAND ALL THE
THINGS PRESENTED BY THE TEAM.
THEY DID A GOOD JOB IN GIVING
THANK YOU IMPORTANT DATA AND NOW
MY JOB IS TO TRY TO SYNTHESIZE
IT A LITTLE BIT BETTER PERHAPS
FOUR TO UNDERSTAND HOW WE THINK
ABOUT IT AT THE PRESENT POINT.
THERE'S FATIGUE OF CONTINUING
MUSCLE CAN CONTRACTS.
PATIENTS HAVE INDEED MUSCULAR
FATIGUE.
AND THE QUESTION IS WHERE DOES
THIS FATIGUE OF MOTOR
PERFORMANCE COME FROM?
AS WE'RE TALKING ABOUT IT FROM
THE CENTRAL OR PERIPHERAL
NERVOUS SYSTEM AND HEARD ABOUT
THE ORIGIN WANT TO HEAR ABOUT IT
IN THIS PARTICULAR STUDY.
THERE'S ATROPHY IN THE PATIENTS
THAT IS SOME BUT THE CRITICAL
FINDING IS THERE WAS NO INCREASE
IN THE SLOPE OF THE INDEX WHICH
COMES ABOUT IF THERE IS FATIGUE
IN THE MUSCLE.
LET ME DESCRIBE ENERGY
METABOLISM IN THE MUSCLE.
IN ORDER TO PRODUCE ATP WHICH IS
ENERGY, YOU NEED TO HAVE A
SUBSTRATE SUCH AS GLUCOSE AND
YOU CAN THEN METABOLIZE THAT
POTENTIALLY WITH OXYGEN.
AND YOU GREAT BY THE PROCESS OF
GLYCOLYSIS THE SUBSTRATE
UTILIZED AND IF YOU HAVE OXYGEN
LY , YOU CAN PRODUCE A LOT OF
ATP.
PEOPLE PREFER TO USE THAT
PATHWAY AS LONG AS TAY CAN.
IF YOU RUN OUT OF THE ABILITY TO
USE OXYGEN BECAUSE YOU'RE
FATIGUING THE MUSCLE, THEN
YOU'LL SWITCH TO AN ANAEROBIC
MECHANISM IN WHICH YOU PRODUCE
LACTATE.
AND LACTATE IS WHAT IS THE
DRIVER OF THE DIMITROF INDEX AND
YOU'RE NOT SWITCHING TO ANROBIC
METABOLISM AND STILL PERFORMING
AEROBICALLY AND THERE'S STILL
RESOURCES AVAILABLE TO THE
PATIENT AS FAR AS THE MUSCLE IS
CONCERN CANNED.
-- CONCERNED.
IT DOESN'T APPEAR TO BE DUE TO A
PROBLEM IN THE MUSCLE IT'S NOT
DUE TO PERIPHERAL AND THEN THE
QUESTION WAS IS IT DUE TO A
PROBLEM IN THE MOTOR CORTEX
WHICH IS THE DIRECT DRIVER FROM
THE CENTRAL NERVOUS SYSTEM TO
THE MUSCLE.
AND YOU HEARD THERE WAS NO
ABNORMALITY IN THE POTENTIALS
WHICH IS A MEASURE OF THE
DRIVING FROM THE MOTOR CORTEX TO
THE MUSCLE.
THERE WAS NO EVIDENCE THE MOTOR
CORTEX ITSELF WAS PROBLEMATIC
AND YOU SAW IN THE NEUROIMAGING
RESULTS PRESENTED THAT WHEN THE
MOTOR CORTEX IS ITSELF WERE
COMPARED THERE WAS NO DIFFERENCE
BETWEEN THE GROUPS.
SO THERE'S NO EVIDENCE THE MOTOR
CORTEX OR DIRECT DRIVERS OF
MOVEMENT ARE ABNORMAL.
NOW, THIS IS AGAIN A SIMPLE
DIAGRAM OF THE WAY THAT THE
SYSTEM IS ORGANIZE O D AND SOME
ASSOCIATED REGIONS SUCH AS THE
SUPPLEMENTARY AREA BUT THE MOTOR
CORTEX GETS DRIVEN BY VARIOUS
FACTORS THROUGH THE REST OF THE
BRAIN.
THAT'S WHY THE MOTOR CORTEX DOES
WHAT IT DOES.
IT HAS TO GET THE DRIVING
FACTORS TO ACTUALLY DECIDE TO
MAKE THESE DIFFERENT MOVEMENTS.
SO THERE APPEARS TO BE THEN A
PROBLEM WITH CENTRAL FATIGUE NOT
ARRIVING FROM THE MOTOR CORTEX
BUT ARISING FROM THE DRIVERS OF
THIS.
NOW, I THINK IN TRYING TO
UNDERSTAND THAT, THAT'S WHERE WE
COME TO A VERY INTERESTING
CORRELATION IN RELATION TO THE
DEFICIENCY OF CATECHOLAMINE AND
NOREPINEPHRINE HAS BEEN AFFECTED
AND YOU HEARD ABOUT SEROTONIN AS
BEING A POTENTIAL PROBLEM.
THERE ARE A NUMBER OF THESE
CATECHOLAMINES IN THE BRAIN.
WE SEE THIS MANIFESTATION IN
DEFICIENT OUGHT NOTTIC CONTROL
OF BLOOD PRESSURE IN THE HEART
AND IT MAY ALSO AFFECT BRAIN
METABOLISM DIRECTLY.
I THINK THESE FINDINGS IN THE
AUTONOMIC SYSTEM GIVE US A
MARKER TO AN EXTENT OF WHAT'S
GOING ON IN THE INFERENCE
SYSTEM.
WE HAVE ALL THESE
NEUROTRANSMI
NEUROTRANSMITTERS CHOLAMINER
GIC SYSTEMS AND HAVE NEUROTRANS
MITTERS EVERYWHERE AND THIS IS A
BLOWUP OF THE REGION AND YOU
HEARD ABOUT THE SOURCE IN THE
LOC
LOCUS GIVING ENERGY.
ENERGY IS ALSO NEEDED TO FUNG IN
THE BRAIN.
IT'S NOT ONLY IN THE MUSCLE AND
ENERGY METABOLISM IS A LITTLE
BIT DIFFERENT IN THE BRAIN AS IT
IS IN THE MUSCLE GENERALLY WE
HAVE OXYGEN MOST OF THE TIME BUT
STILL IT'S IMPORTANT TO HAVE A
SUBSTRATE SUCH AS GLUCOSE AND
YOU HAVE TO PRODUCE PIRUVATE.
IT TURNS OUT NEURONS LIKE TO
HAVE LACTATE WHEN THEY HAVE TO
FIRE QUICKLY.
IT'S AN IMPORTANT SUBSTRATE IN
THE BRAIN COMING FROM GLUCOSE IN
THE LONG RUN BUT THE SHORT RUN
YOU CAN JUST HAVE LACTATE
ITSELF.
NOW LACTATE IN THE BRAIN IS
SUPPORTED BY THE GLIAL CELLS.
THE ASTROCYTES IN THE BRAIN
SUPPLY NEURONS WITH A LOT OF THE
LACTATE THAT THEY USE WHEN THEY
NEED IT.
NOW, ONE OF THE OTHER
INTERESTING FEATURES IT TURNS
OUT IS THAT NOREPINEPHRINE IS AN
IMPORTANT NEUROTRANSMITTER THAT
HELPS THE ASTROCYTE TRANSMIT
LACTATE TO THE NEURON.
WE SEE THE ABNORMALITY OF
NOREPINEPHRINE THAT IS PRESENT
THERE.
NOREPINEPHRINE IS HELPING THE
ASTROCYTE SUPPLY NOREPINEPHRINE
TO THE NEURONS AND THEREFORE
THERE COULD WELL BE AN ENERGY
PROBLEM WITH THIS FUNCTION
WITHIN THE BRAIN.
WE HAVE ALL THESE DRIVERS AND WE
SEE A SPECIFIC DRIVER THAT IS
DIMINISHED WHEN WE LOOK AT THE
WHOLE BRAIN IMAGINING AND IT'S A
DECLINE IN THE ACTIVITY OF THE
RIGHT TEMPORAL PARIETAL JUNCTION
AND NEARBY PARIETAL LOBE.
THESE REGIONS AS SHE NOTED ARE
IMPORTANT FOR SENSORY MOTOR
INTEGRATION.
BOTH THE SENSE OF FEELING ABOUT
MOVEMENT AND THE INTERPRETATION
OF MOVEMENT AND ALSO DRIVING OF
MOVEMENT.
THAT'S PART OF THEIR ROLE AND
THEY CAN ALSO PLAY A ROLE
PRESUMABLY IN COGNITION AND
OTHER ASPECTS AS WELL.
SO THERE APPEARS TO BE A DECLINE
OF ENERGY FOR THAT EFFORT I
POINT THE OUT.
THIS PRESUMABLY IS EXPERIENCED
AS CENTRAL FATIGUE.
SO WHAT WE UNDERSTAND THEN IS WE
HEARD ABOUT THE ETTIO --
ETIOLOGICAL SYSTEMS WHICH WILL
THEN POTENTIALLY INFLUENCE THE
HYPOTHALAMUS AND BRAIN STEM TO
REDUCE THE NEUROTRANSMITTERS.
THEY THEN INFLUENCE OTHER PARTS
OF THE BRAIN THAT WILL GIVE RISE
TO THE DIFFERENT SYMPTOMS WE'VE
BEEN TALKING ABOUT AND
EMPHASIZED HERE PARTICULARLY
DECREASED MOTOR CONTROL.
AND THESE SYSTEMS WILL DRIVE THE
CARDIO RESPIRATORY SYSTEM AND
YOU'LL HEAR MORE ABOUT THAT IN
THE NEXT SERIES BUT FOR THE
MOMENT WE'LL STOP HERE WITH THIS
PARTICULAR PART OF THE
PATHOPHYSIOLOGY THAT'S THEN OF
OUR PRESENTATION AND WE'LL BE
HAPPY TO DEAL WITH QUESTIONS AND
PERHAPS THE PANELISTS WHO MADE
PRESENTATIONS CAN COME DOWN SO
WE CAN ANSWER THE QUESTIONS
ANYONE MIGHT HAVE FOR US SO
THANK YOU.
>> MY NAME IS DR. LOMEN.
I'M A PATIENT.
ALSO HAVE DONE IN FORMAL
RESEARCH.
I WOULD LIKE TO DIRECT THIS
QUESTION TO DR. SNOW AND MADIAN.
WHEN YOU STUDY THE SUBJECTS, FOR
INSTANCE, WHEN YOU WERE DOING
THE NEUROCOGNITIVE STUDIES DID
YOU ALSO CORRELATE THAT TO
WHETHER THE PATIENTS WERE
SYMPTOMATIC WITH THEIR BRAIN FOG
AND IT COMES AND GOES.
SAME WITH MUSCLES.
DID YOU LOOK AT THE FINDINGS OF
THE MUSCLES WHEN THE PATIENTS
WERE EXPERIENCING THEIR PEM.
THANK YOU.
>> GOOD QUESTION.
PERHAPS THE QUESTION SHOULD BE
IN THE MICROPHONE.
DR. SNOW.
>> CORRELATION AS A STATISTICAL
TE
TERM, NO.
BUT I PRESENTED THE VISUAL
ANALOG SCALES AND PEOPLE DOES
ENDURE DURING OUR SESSION THEY
WERE FATIGUED AND WERE HAVING
PROBLEMS PHYSICAL AND MENTAL
FATIGUE AT THE TIME.
THAT WOULD INDICATE THAT THERE
WAS SOME AND IT WENT UP AS THE
SESSION PROGRESSED.
I WON'T SAY THAT WE WERE ABLE TO
NECESSARY CAPTURE THEM WHILE
THEY WERE HAVING BRAIN FOG LIKE
WE DIDN'T -- I'M NOT SURE AND
BRIAN, DID YOU WANT TO SAY
SOMETHING?
>> THERE MAY BE ANOTHER WAY TO
ANSWER THE QUESTION AND IN THE
POPULATION YOU SAW HOW MANY HAD
COMPLAINTS OF NEUROCOGNITIVE
DYSFUNCTION?
>> ALL THEM.
>> 100% HAD BRAIN FOG THAI WERE
COMPLAINING ABOUT.
>> SIMILAR QUESTION OF THE
MUSCLE.
AT THAT STAGE OF BEING TESTED,
WERE THEY AT THE BASELINE OR DID
YOU FEEL THEY WERE ALREADY
COMPLAINING OF MUSCLE FATIGUE.
THAT WAS A SYMPTOM THEY HAD
ORDINARILY.
>> AT THE BEGINNING OF THE
MEASUREMENT BOTH GROUPS WERE THE
SAME LEVEL BUT BUT IN TIME THE
RESPONSES CHANGED.
>> WE TALKING OVER A DAY?
WE DIDN'T DO THAT MEASUREMENT.
>> GREAT.
>> HI THERE AGAIN.
SO OVER THE COURSE OF ALL OF
THESE TASKS, WE WERE PERFORMING
VISUAL ANALOG SCALE SO
FUNCTIONAL MRI AND TMS BEGINNING
IN THE MIDDLE AND END WE WERE
WATCHING THE PROGRESSION OF
THEIR SYSTEMS SEEING IF THEY
WERE CHANGING WITH THE TASK AND
IN GENERAL A HIGH FATIGUE OR
SYMPTOMOLOGY AND WHEN HAVE YOU
PARTICIPANTS TELL YOU ABOUT
THEIR EXPERIENCES, MANY SAID
THEY WERE PEM MOST OF THE
EVALUATION WHEN YOU ASKED THEM
DIRECTLY.
WE ALSO MEASURED QUESTIONS
THROUGHOUT THE WEEK AND THEY
ALWAYS HAD HIGH LEVELS OF BOTH
PHYSICAL AND COGNITIVE.
>> THERE'S A QUESTION FOR
PATRICK AND MAYBE OTHERS AS WELL
BUT SO THIS MOTOR CORTEX M1 I
DON'T KNOW MUCH ABOUT THIS TMS
STIMULATION BUT IS THERE A
POSSIBILITY THEY COULD FATIGUE
OF THE BRAIN SAY SECONDARY TO
MITOCHONDRIAL DISORDER?
MY INTEREST IS IN MITOCHONDRIA
AND WONDERING IF IN PRIMARY
MITOCHONDRIAL DISEASES WHERE
THERE'S SIMILAR FINDINGS
OBSERVED IN THIS TESTING, TMS
MOSTLY.
>> RIGHT.
MOTOR CORTEX METABOLISM WAS
NORMAL AT BASELINE.
THERE WASN'T ANY CHANGE IN THE
WAY THAT MOTOR CORTEX WAS
FUNCTIONING AND AS YOU SAW WITH
THE IMAGING, IT FUNCTIONED
NORMALLY IN TERMS OF GOING UP
WITH THE EXERCISE.
THE MOTOR CORTEX METABOLISM WAS
NORMAL AND CHANGED NORMALLY WITH
EXERCISE.
THERE WAS NO EVIDENCE OF
ABNORMALITY OF THE MOTOR CORTEX.
THE ABNORMALITY WAS IN A
DIFFERENT PART OF THE BRAIN.
AND THAT AS I WAS POINTING OUT
COULD BE DUE TO A METABOLIC
ABNORMALITY.
>> I GUESS I'M TRYING TO PUT IT
ALL TOGETHER LIKE WITH DAVID'S
FINDING WITH THE METABOLISM ALL
REQUIRE THE MITOCHONDRIA AND SO
IF THERE'S DYSFUNCTION YOU COULD
KIND OF PUT ALL THIS TOGETHER IN
THE BRAIN.
>> QUESTION, THAT IS SORT OF THE
WAY WE WERE DOING IT.
>> TWO QUESTIONS.
ONE IS WAS THERE A CORRELATION
BETWEEN ANXIETY AND LEVELS OF
CATECHOLAMINE AND THERE WAS ANY
REFERENCE TO NUCLEUS CIRCUMBENS
AND WONDER IF THERE'S SOMETHING
YOU COULDN'T SEE OR THERE WAS NO
ABNORMALITIES.
THANK YOU.
>> THAT DID NOT SHOW DIFFERENCE
BETWEEN GROUPS AND THE OVER
QUESTION ABOUT CORRELATION
BETWEEN ANXIETY, THESE ARE WE
DID MANY CORRELATIONS ACROSS
DIFFERENT THINGS.
I DON'T RECALL WHETHER WE DID
THAT PARTICULAR CORRELATION OR
NOT.
BRIAN, DO YOU RECALL WHETHER
THAT WAS DONE?
>> NOREPINEPHRINE IS WORTH
LOOKING AT.
IF WE DID IT WE DON'T RECALL WE
DID IT.
THAT IS EASY ENOUGH TO CHECK.
>> WE HAVE QUESTIONS FROM THE
VIRTUAL AUDIENCE.
CREATORS OF THE EEFRT STATE THE
DATA IS NOT VALID IF
PARTICIPANTS ARE NOT ABLE TO
CONSISTENTLY COMPLETE THE TASK.
WHY DID YOU PROCEED WITH THE
DATA AS EVIDENCE OF IMPAIRED
PREFERENCE WHEN THE DATA APPEARS
TO BE INVALID ACCORDING TO THE
GUIDELINES SET BY THE TEST
VALIDATERS.
>> FIRST I WANT TO EXPRESS MY
THANKS FOR THE QUESTION AND I
WAS INFORMED THE QUESTION HAD
BEEN RAISED AND WANTED TO FIELD
IT BECAUSE I HAD DONE WORK WITH
THIS TASK AND SIMILAR TASKS.
I'M FAMILIAR WITH THE ORIGINAL
PUBLICATION THE QUESTION
MENTIONED AND NEVERTHELESS I
STILL REALLY WANTED TO MAKE SURE
I DID MY DUE DILIGENCE SO SPENT
A SIGNIFICANT OF TIME BEFORE THE
MEETING REVIEWING THE
PUBLICATION IN QUESTION CLOSELY
TO MAKE SURE I'M REPRESENTING IT
ACCURATELY.
WA THE PAPER DESCRIBES IS THAT
EEFRT WAS DESCRIBED TO THE
SAMPLE OF PATIENTS USED IN THE
ORIGINAL STUDY COULD
CONSISTENTLY COMPLETE THE TASK.
THIS DOES NOT MEAN THAT EVERYONE
WHO TAKES THE TASK MUST BE ABLE
TO COMPLETE WITHOUT ISSUE FOR
THE ADMINISTRATION OR DATA TO BE
VALID OR INTERPRETABLE.
IT SEEMS THAT THE CREATORS
WANTED TO ENSURE THAT IN GENERAL
AS MANY PEOPLE AS POSSIBLE WOULD
BE ABLE TO COMPLETE THE TASK BUT
WITHOUT COMPRISING THE TASK
ABILITY TO CHALLENGE.
FURTHERMORE, I THINK IT BEARS
MENTIONING THOUGH ME/CFS
PARTICIPANTS DOES NOT COMPLETE
IT AT THE SAME RATE IN THE
ORIGINAL STUDY, OR AT THE SAME
RATE AS OUR HEALTHY CONTROLS
THEY STILL COMPLETE THE TASK THE
LARGE MARJORITY OF THE TIME AND
TO CONSISTENTLY COMPLETE THE
TASK IS NOT NECESSARY FOR THE
VALID AND BELIEVE THE TEST IS
VALID AND INTERPRETABLE AS A
MEASURE OF EFFORT DISCOUNTING.
>> THANKS.
>> WE HAD ANOTHER QUESTION.
WHAT IS YOUR RATIONALE FOR
REFRAMING THE EEFRT AS A MEASURE
OF EFFORT PREFERENCE RATHER THAN
USING AN ESTABLISHED
INTERPRETATION?
>> WE HAD HEARD ABOUT THIS
BEFORE SO BRIAN WILL ANSWER THIS
QUESTION.
>> THE ANSWER IS PRETTY SIMPLE.
I THINK NICK DID A WONDERFUL JOB
TALKING ABOUT WHAT EEFRT FOR US
AND THE UNCONSCIOUS TASK.
IT'S TYPICALLY FRAMED AS REWARD
MOTIVATION AND EFFORT ALLOCATION
OR EFFORT-BASED DECISION MAKING.
THESE TERMS EFFORT ALLOCATION
AND EFFORT-BASED DECISION MAKING
FRAME TASK PERFORMANCE AS A
VOLITION ACTION AND MEASURE THE
CONSCIOUS AND UNCONSCIOUS
ASPECTS AND THE MOMENT TO MOMENT
CHOICES DURING THE EFFORT TEST.
>> I THINK WE'RE RUNNING A
LITTLE BIT BEHIND SO WE HAVE ONE
MORE QUESTION.
IT SEEMS NOTABLE YOUR STUDY
FOUND NO EVIDENCE FOR POTS IN
THE SAMPLE AS IT APPEARS TO BE
PREVALENT CLINICALLY.
CAN YOU SAY MORE ABOUT THE
SEEMING DICHOTOMY?
>> I DIDN'T UNDERSTAND THE
QUESTION.
>> THE QUESTION, IT SEEMS
NOTABLE YOUR STUDY FOUND NO
EVIDENCE FOR POTS IN THE SAMPLE
AS IT APPEARS TO BE PREVALENT
CAN YOU SAY MORE ABOUT THE
DICHOTOMY.
>> OTHER GROUPS POTS IS VERY --
THE FACTS ARE THE FACTS.
IT'S A SMALL STUDY BUT MAINLY A
MATTER OF REFERRAL BIAS.
THERE'S INTO REFERRAL BIAS BUT
WITH OTHER GROUPS WHEN THEY'RE
ASKED HOW FREQUENT IS POTS IN
CHRONIC FATIGUE SYNDROME IT'S
VERY COMMON.
I THINK TO AN IMPORTANT EXTENT
THE REFERRAL BIAS CAN RESULT IN
OVER ESTIMATION OF THE FREQUENCY
OF POTS IN THE ME/CFS
POPULATION.
>> LET ME ADD ONE MORE THING TO
IT THAT IS IN THE NEXT SESSION I
THINK YOU'LL HEAR LATE ABOUT
AUTONOMIC DYSFUNCTION AND I
THINK THERE IS ENOUGH AUTONOMIC
DYSFUNCTION SUGGESTING DYSAUTO
NOMIA AND A LARGE COHORT HAD
POTS.
WHAT MAKES IT DIFFERENCE IS NOT
THE PARTICIPANTS DIDN'T HAVE
POTS BUT THE HEALTHY VOLUNTEERS
DID ALSO.
THEY HAD CRITERIA AND WE HAD
HEALTHY VOLUNTEERS AND MAYBE
POTS IN CHRONICALLY ASYMPTOMATIC
PEOPLE IS MORE THAN PEOPLE REELS
AND NOT THE PATIENTS DIDN'T HAVE
POTS, BUT THE HEALTHY VOLUNTEERS
DID.
THANK YOU.
>> MAYBE WE CAN NOW END THE
SESSION AND THEN COME BACK AFTER
LUNCH AND SO IT'S 12:17, AND
LET'S GIVE YOU A ROUND OF
APPLAUSE.
LUNCH IS SCHEDULED TO 12:45 AND
MAYBE WE CAN COME BACK AT 1:00.
LET'S COME BACK AT 1:00.
>> THE NEXT IS ON BIOENERGIES
LED BY THE CO-DIRECTOR OF THE
METABOLIC CLINICAL RESEARCH UNIT
ALSO CHIEF OF THE ENERGY
METABOLISM SECTION AND DIRECTOR
OF THE HEALTH ENERGY AND BODY
WEIGHT REACTION CORE.
HIS GROUP DEVELOPED TECHNIQUES
USED TO MEASURE THE RATE OF
EXPENDITURE ON MINUTE BY MINUTE
LEVEL FOR HOURS OR DAYS.
AND MEASURE ENERGY, METABOLISM
AND RESPONSES AND LED THE
STUDIES ON ME/CFS AND WE LOOK
FORWARD TO HEARING FROM HIM AND
HIS GROUP.
THANK YOU.
I HAVE THE PLEASURE AND HORN TO
INTRODUCE SOME SPEAKERS FIRST
THE CONCEPT OF BIO ENERGETICS.
YOU MAY HAVE HEARD SOME TERMS
AND PARTICULARLY ENERGY SO IN
OUR VIEW, ENERGY IS THIS IS AN
INTERESTING SYSTEM.
NEVERTHELESS, YOU'LL SEE THIS
PERSON ON THE RIGHT AND WE TALK
ABOUT ENERGY AND THE CALORIES IN
OR OUT AND IT COULD BE DIRECTLY
MEASURED BY HEAT OR IN OUR CASE
INDIRECTLY THAT WOULD MEASURE
THE CARBON DIOXIDE PRODUCTION
AND CONSUMPTION AND HEAR FROM
THE WHOLE ROOM SETTING AS WELL
AS EXERCISE SETTING WHERE YOU
WEAR A MASK.
THIS ENERGY ESPECIALLY IN THE
DIET ON THESE CHEMICAL ENERGY,
CARBOHYDRATE, FATS AND OTHERS IS
CONVERTED TO ATP.
WE CAN MEASURE THAT AND WE'LL
INTRODUCE TO YOU MEASURES OF
INTAKE AND THE CAR MACRO ENERGY
AND HOW WE COLLECT THE
EXPENDITURE AND REPRESENTED
METABOLISM AND MEASURE THE BODY
COMPOSITION THE FAT STORAGE.
ANYWHERE IN THE SYSTEM IF THEY
PROBLEMS WE MAY SEE THE
SIGNATURES.
WE'VE EXPERIENCED WITH PATIENTS
WITH CHRONIC DISEASES SUCH AS
KIDNEY AND CARDIOVASCULAR
DISEASE AND THYROID, DIABETES,
NEUROMUSCULAR DISEASE SHOWING
VARIOUS BIO ENERGETIC
SIGNATURES.
BY IDENTIFYING THEM WE CAN
REVIEW THE MECHANISM OF
PATHOPHYSIOLOGY AND THAT'S OUR
RATIONALE OF STUDYING THIS
GROUP.
AS SHOWN IT'S STEP WISE PROCESS
IN DEEP PHENOTYPING AND EXERCISE
STRESS TEST.
LIKE OTHER WE'LL TAKE DIFFERENT
PIECES AND YOU'LL FIRST HEAR
FROM BARBARA STUSSMAN ON THE
POST EXERTION MALAISE.
THIS IS THE LAST SESSION YOU'LL
HEAR THE BEST PART.
BARBARA WILL PRESENT THAT AND
SHANNA WITH HER COLLABORATION
WITH SARA TURNER THE DIETARY
EVALUATIONS AND MY LAB WILL
PRESENT THE BODY COMPOSITION
DATA BODY FAT AND LEAN MASS
DISTRIBUTION AND WEARABLE
EXCELOMETER DATA AND --
ACCELOMETER DATA AND HEAR ABOUT
THE EXERCISE TEST ITSELF.
THIS IS THE TESTS AND LISA WILL
BE DOING THE TALKING AND PRESENT
THE WHOLE BODY EXPENDITURE DATA.
LAST BUT NOT LEAST WE'LL HEAR
FROM PAUL WONG TAKING THE MUSCLE
SAMPLES AND LOOKING AT THE MACRO
LEFT AND STRESS AND
MITOCHONDRIAL FUNCTION AND
PIECES IN THE MEASUREMENT.
ARE THERE PHENOTYPIC SIGNATURES
AND BALANCE MEASURES AND WITH
THE EXERCISE CHALLENGE ARE THIS
UNIQUE CHANGES.
WITH THAT SAID, BARBARA.
>> THANK YOU, DR. CHEN.
I'LL GIVE AN OVERVIEW OF OUR
RESEARCH IN TWO PAPERS.
THE FIRST CONDUCTED TO LEARN
MORE ABOUT PEM AND INFORM THE
STUDY PROCEDURES IN THE MAIN
STUDY.
THE SECOND PAPER DESCRIBES OUR
MIX METHODS SYSTEM TO ASSESS PEM
AT A SINGULAR TIME POINT.
WHAT IS POST EXERTIONAL MALAISE?
ACCORDING TO THE INSTITUTE OF
MEDICINE REPORT ON ME/CFS THEY
DESCRIBED IT AS A WORSENING OF
SYSTEMS AFTER PHYSICAL, MENTAL
OR EMOTIONAL EXERTION THAT WOULD
NOT HAVE CAUSED A PROBLEM BEFORE
THE ILLNESS AND PUT THE PATIENT
IN RELAPSE THAT LAST LONGER THE
SYMPTOMS GET WORSE AFTER THE
EXPOSURE AND CAN LAST FOR DAYS
OR WEEKS.
WE DISCUSSED HOW TO BEST USE
QUALITATIVE METHODS TO STUDY
PEM.
AT THAT TIME IT WAS NOT WELL
STUDIED AND THERE WERE NO
VALIDATED MEASURES.
THAT'S HOW TO HE FOCUS GROUP
STUDY WAS INITIATED.
I WANT TO ACKNOWLEDGE MY
CO-AUTHORS HERE.
THE OBJECTIVES WERE TO INFORM
THE STUDY DESIGN OF THE MAIN
STUDY.
SPECIFICALLY WE WANTED TO
DETERMINE INDIVIDUAL PEM
SYMPTOMS TO QUANTIFY AND THE
SPECIFIC TIME POINTS FOR
ASSESSING PEM BEFORE AND AFTER
THE C PET.
WE CHOSE FOCUS GROUPS AS WAS
POST EXERCISAL MALAISE AND TOPIC
AREAS.
WE HAD 43 FROM NOVEMBER 2016 TO
AUGUST 2019 RANGING FROM AN HOUR
40 MINUTES TO TWO HOURS.
THEY WERE CONDUCTED OVER THE
PHONE TO ALLOW PARTICIPATION
FROM PEOPLE WHO COULD NOT
OTHERWISE TRAVEL EASILY.
PEM IS TRIGGERED BY COGNITIVE
EFFORT, PHYSICAL ACTIVITY AND
EMOTIONAL TRIGGERS.
SEE EXAMPLES ON THE SLIDE.
THE WORD CLOUD SHOWS PEM
SYMPTOMS AFTER C PET REPORTED BY
THE PARTICIPANTS THE SIZE OF THE
WORDS ARE PROPORTIONAL TO THE
FREQUENCY OF THE SYMPTOM
REPORTED.
YOU CAN SEE THERE WERE A WIDE
RANGE OF SYMPTOMS.
THERE WERE THREE CORE SYMPTOMS
MENTIONED BY VIRTUALLY EVERY ,
EXHAUSTION, DIFFICULTY THINKING
AND MUSCULAR COMPLAINTS.
WE CHARTED THE ONSET PEAK AND
RECOVERY AFTER C PET.
PARTICIPANTS SAID THAT OCCURRED
FROM IMMEDIATELY TO 48 HOURS
FOLLOWING THE C PET.
THE PEAK RANGE FROM IMMEDIATELY
TO A WEEK FOLLOWING.
PARTICIPANTS SAID THEY RETURN
ARE ED FROM THEIR PRELEVEL TO
SOME REPORTING THEY NEVER FULLY
RECOVERED.
SOME PARTICIPANTS REPORTED A
LONGER RECOVERY AFTER THE TWO
DAY VERSUS ONE-DAY C PET.
THERE WERE SEVERAL IMPLICATIONS.
WE DEVELOPED OUR OWN SYSTEM FOR
ASSESSING PEM THAT WE USED IN
THE MAIN STUDY QUALITATIVE
INTERVIEWS BEFORE AND AFTER C
PET ALONG WITH THE VISUAL ANALOG
SCALES MENTIONED THIS MORNING.
DURING THE INTERVIEWS WE ASKED
EVERY PATIENT HOW THEY WERE
FEELING FIGURATIVELY,
COGNITIVELY AND EMOTIONALLY AND
MOST BOTHERSOME SYMPTOMS AND
SOME HAD A MORE DIFFICULT
RECOVERY AFTER THE TWO DAY THAN
ONE DAY C PET AND THEY DESCRIBED
THE SEVERITY OF THE SYMPTOMS
FOLLOWING THE C PET AND THE
DIFFICULTY OF THE TRAVEL
REQUIRED WE ALLOWED ALL PATIENT
TO REST TWO DAYS AT THE CLINICAL
CENTER TO REDUCE POTENTIAL HARM.
NOW I'LL TALK ABOUT OUR SECOND
PAPER WHICH WAS PUBLISHED IN
FEBRUARY THIS YEAR DETAILING AND
VALIDATING OUR SYSTEM FOR
ASSESSING PEM AFTER C PET.
I'D LIKE TO ACKNOWLEDGE MY
CO-AUTHORS HERE.
WE ANALYZED TRANSCRIPTS FROM
INTERVIEWS AND CONDUCTED THE
INTERVIEWS AT SIX TIME POINTS
BEFORE AND AFTER C PET WHICH
GENERATED HUNDREDS OF PAGES OF
TRANSCRIPTS PER EACH
PARTICIPANT.
FOUR RESEARCHERS READ THEM AND
PLOT THE TRAJECTORY OF PEM AND
PEAK AND MOST BOTHERSOME
SYSTEMS.
WE ACHIEVED 100% CON CENSUS AND
HAVING IN DEPTH DISCUSSION TO
ADJUDICATE DISAGREEMENTS.
IF HE PATIENT STARTED WORSE
BEFORE THE BASELINE AND PEAKED
AT 24 HOURS AND STARTED TO GET
BETTER.
THE RED DOTTED LINE SERVED AS A
BENCHMARK REPRESENTING A SEVERE
EPISODE OF PEM THE PATIENT
PREVIOUSLY EXPERIENCED IN THEIR
DAILY LIFE.
TO MEET THE THRESHOLD THE
PREVALUE AND PEAK RATING OF AT
LEAST 3 WAS REQUIRED.
3 WAS CHOSEN BECAUSE IT WAS
CLINICALLY NONE EXPERIENCED PEM
AND ALL THE ME/CFS S EXPERIENCED
PEM.
NEXT WE OVERLAID THE PEM DATA
WITH THE VISUAL SCALES AND THEY
PROVIDE A CONTINUUM FROM NOT AT
ALL TO MOST EXTREME.
PATIENTS MARK THE SYMPTOMS ON
THE CONTINUUM.
VISUAL ANALOG SCALES WERE DONE
AT THE INTERVIEWS AND CREATED A
COMPOSITE VAS THAT COMBINE 12 OF
THE INDIVIDUAL SYMPTOMS.
THIS SHOWS ONE PATIENT AS AN
EXAMPLE.
THE FATIGUE VAS IN BLACK AND
COMPOSITE VAS IN PURPLE REMAIN
FLAT AND THE PEM RATING IN BLUE
SHOWS MORE GRANULARITY.
THIS TABLE SHOWS CORRELATIONS
BETWEEN PEM INTERVIEW RATING AND
VAS SCALES.
IN THE INTEREST OF TIME I WON'T
GO THROUGH THE WHOLE TABLE BUT
THE MAIN POINT IS WHEN WE
SINGLED OUT THE ME/CFS PATIENTS
MOST BOTHERSOME SYSTEMS THE
MEASURES WERE STRONGER AT ALL
THREE DATA POINTS.
PRE-C PET AND CHANGE FROM PRE-C
PET TO CHANGE AND THIS IS THE
MOST BOTHERSOME SYSTEM OF
ME/CFS.
IMPLICATIONS FROM OUR MIXED
METHODS STUDY THAT USING OUR
NOVEL ASSESSMENT TOOL ALL
PATIENTS WERE DETERMINED TO HAVE
PEM FOLLOWING THE C PET.
DUE TO THE WIDE BREADTH OF
SYSTEM THE ABILITY TO SYNTHESIZE
MULTIPLE SYSTEMS INTO A SIMPLE
HOLISTIC EXPERIENCE WORKS BETTER
THAN LOOKING AT SINGULAR
INDIVIDUAL SYMPTOMS.
ISOLATING THE MOST BOTHER SYSTEM
SYMPTOMS SEEMED TO IMPROVE THE
PERFORMS OF THE VAS SCALES.
THE MIXED METHOD APPROACH HAS
PROMISE FOR RESEARCHERS TO USE
AND CURRENTLY OF USING THE
SYSTEM IN OUR COVID PATIENTS.
THANK YOU.
>> GOOD AFTERNOON, EVERYONE.
I'LL BE TALKING US THROUGH THE
CHALLENGE DONE AS PART OF THE
STUDY.
YOU MAY HAVE HEARD IT REFERRED
TO AS STRESS TEST OR CARDIO
PULMONARY TEST OR C PET FOR
SHORT.
SUBJECTS ARE REQUESTED TO CYCLE
AT A REQUESTED CADENCE AND
DURING THIS TIME INTENSITY IS
INCREASED OVER TIME.
THE EXERCISE TASK IS STOPPED
WHEN PARTICIPANTS ARE NO LONGER
ABLE TO MAINTAIN A SET CADENCE.
AS SEEN IN THE IMAGE, THERE IS
SEVERAL NON-BASIC PHYSIOLOGICAL
MEASURES TAKEN DURING THIS TASK.
FOR INSTANCE, YOU HAVE GAS
EXCHANGE THAT IS MEASURED
MEASURING OXYGEN AND CO2 AND
OXYGEN SATURATION.
ALL OF THIS IS CAPTURED THROUGH
THE CPET ASSESSMENT AND STIM --
STIMULIZING MEASUREMENTS AND
THESE WERE BASED OFF PREDICTED
FITNESS.
SO BECAUSE WE KNOW THAT PIMES
PARTICIPANT HAVE A LOWER
CAPACITY THEY WERE GIVEN A 15
WATT PER MINUTE INCREMENT.
FOR HEALTHY THEY COULD HAVE A 15
OR 20 WATT INCREMENT INSTEAD.
TO HIGHLIGHT THAT AGAIN THE
LEVEL OR INCREASE IN THE WORK
RATE WAS RELATED TO TRYING TO
OPTIMIZE 8 TO 12 DURATION FOR
NEARLY EVERYONE.
THAT'S REPORTED AS PEAK VO2 AND
HAVE DISASSOCIATED WORK RATE
SHOWN AS PEAK.
AND WE HAVE CO2 AND DETERMINE
THE AT FOR SHORT.
SO THE A.T. IS A POINT SHOWN
HERE IN THIS FIGURE WHERE
FATIGUE IS IMMINENT.
ACTIVITIES BELOW THIS A.T. LEVEL
ARE THEORETICALLY ACTIVITIES YOU
CAN SUSTAIN WITHOUT IN OCCURRING
FATIGUE AND IF YOU CAN DO THEM
ABOVE A.T. THAT'S WHEN FATIGUE
WOULD DEVELOP.
OTHER MEASURES TAKING DURING THE
CPET TEST LOOK AT HEART RATE AND
THERE'S A STEADY INCREASE
TOWARDS PEAK AS EXERCISE
INCREASES OR WORK RATE
INCREASES.
WE TOOK MEASURES AT THE LOCAL
MUSCLE LEVEL.
HERE WE'RE LOOKING AT MUSCLE
OXYGEN SATURATION.
YOU SEE A SLIGHT DECLINE OR
DECLINE THAT'S HAPPENING BECAUSE
OF THE MUSCLE IS EXTRACTING
OXYGEN FROM THE MICROVASCULATURE
AS EXERCISE PROGRESSES.
TURNING OUR ATTENTION TO THE
RESULTS.
WE'RE LOOKING AT RESPIRATORY
EXCHANGE RATIO OR RER FOR SHORT.
THAT'S THE RATIO OF CO2, 2OT.
YOU CAN SOMETIMES USE THE RER TO
REFLECT WHETHER GAVE IT A GOOD
ATTEMPT ON THE EXERCISE TASK.
ALMOST EVERYONE HAD A GREATER
SCORE THAN 1.1 AND PEAK
PERFORMANCE WAS ACHIEVED IN BOTH
GROUPS.
THOSE WHO TRENDED TOWARDS A
LOWER PEAK POWER IN THE
PARTICIPANTS LOWER PEAK VO 2
VERSUS HEALTHY VOLUNTEERS AND
WHEN YOU LOOK AT PEAK VO2 AS A
PERCENTAGE OFF SEX, AGE AND
WEIGHT THE MAJORITY AT THESE
ALMOST ALL BUT ONE PARTICIPANTS
WAS LESS THAN 84% OF PREDICTED
VO2 CONVERSELY IN THE HEALTHY
VOLUNTEERS THE MAJORITY OF
PARTICIPANTS WERE OVER 84% OF
PREDICTED PEAK VO2.
IT'S A LOWER CAPACITY OBSERVED
AT PEAK AND THE ANAEROBIC
THRESHOLD IN TERMS OF HEALTHY
VOLUNTEERS.
LET'S LOOK AT PRACTICAL TERMS.
THIS IS SHOWING THE METABOLIC
EQUIVALENT OF TASK WHERE ONE IS
ENERGY REQUIREMENT JUST TO SIT
QUIETLY HERE.
ALONG THE RIGHT YOU'LL SEE
DIFFERENT COMMON ACTIVITIES AND
THE ASSOCIATED VALUES.
CARING A 15 POUND LOAD IS 5
MEANING FIVE TIMES THE ENERGY
REQUIREMENT THAN AT REST.
ALSO, DOWN HERE IT'S WHERE YOUR
DAILY ACTIVITIES OF DAILY LIVING
WOULD RESIDE.
THESE ARE TALKING ABOUT BASIC
SELF-CARE OF FEEDING, GROOMING,
DRESSING.
THIS IS CLEANING, COOKING AND
DAILY ACTIVITY.
HAVE YOU HERE ON THE RIGHT THE
PEAK EXERCISE BUT WHAT WE'RE
SEEING AS A GROUP IS HAVE YOU
ME/CFS PARTICIPANTS HAVING LOWER
AT A.T. AND PEAK EXERCISE.
FOR SHE'S INDIVIDUALS SHOWN
BELOW THE LEVEL FOR A.T.
PERFORMING INSTRUMENTAL
ACTIVITIES OF DAILY LIVING WILL
BE DIFFICULT.
COMPOUND THAT IF THEY WERE ALSO
HAVING A MET LEVEL OF LESS THAN
5 AT PEAK EXERCISE.
KNOWING IT'S UP TO SIX FOR
MODERATE ACTIVITIES SEE AROUND
WHAT IS STILL TERM THERE'S A
FAIR AMOUNT OF PARTICIPANTS THAT
WOULD BE AT THEIR PEAK LIMITS.
THERE WAS A HEART RATE RESPONSE
IN THE ME/CFS PARTICIPANTS BUT
NOT AMONG THE HEALTHY
VOLUNTEERS.
TO WRAP UP IN TERMS OF
AMBULATORY EFFICIENCY HOW WELL
THE LUNGS FUNCTIONED TO EXPEL
CO2 THERE WAS NO REAL DIFFERENCE
BETWEEN THE GROUPS AND
MECHANICAL EFFICIENCY AND
SIMILAR BETWEEN THE GROUPS AND
THE MICROVASCULATURE LOOKING AT
THE MUSCLE OXYGEN SATURATION AND
THERE WAS NO REAL DIFFERENCE
BETWEEN THE GROUPS AND THERE WAS
A LOT OF VARIABILITY.
SIMILAR EFFICIENCY AS WELL AS
MUSCLE TISSUE OXYGEN WERE FOUND
BETWEEN THE GROUPS.
THANK YOU.
>> I'M SHANNA YANG AM AND WE
LOOKED AT THE LITERATURE AND NOT
SUPER SURPRISINGLY THERE WASN'T
A WHOLE LOT OUT THERE DESCRIBING
DIET IN THE POPULATION BUT MIXED
REPORTS IN WHAT WAS OUT THERE.
SOME MENTIONED FREQUENT
AVOIDANCE OF DIETARY ITEMS OR
FOOD GROUPS INCLUDING DAIRY,
GLUTEN, SUGAR WHICH WE HEARD
ANECDOTALLY AND OTHER STUDIES
FOUND NUTRIENT INTAKE WAS NOT
DIFFERENT BETWEEN HEALTHY V
VOLUNTEERS AND THE REGULAR
POPULATION.
THE MIXED RESULTS LED US TO
THINK TO LOOK FURTHER IN THIS.
THE OTHER REASON IS THERE'S
INTERESTING INTERVENTION AND IN
2017 A REVIEW ARTICLE MENTIONED
DIFFERENT INTERVENTION TRIALS
LOOKING AT DIET MOSTLY FOCUSSED
ON SUPPLEMENTS AND DIETS LIKE
LOW SUGAR AND LOW YEAST DIET.
BECAUSE OF THIS ANOTHER REASON
WE THOUGHT I WAS IMPORTANT TO
QUANTIFY DIET.
WE USED TWO DIFFERENT TOOLS.
THE FIRST IS THE DIET HISTORY
QUESTIONNAIRE DHQ2.
A COMPREHENSIVE FOOD FREQUENCY
QUESTIONNAIRE THAT COVERS
DIETARY HABITS OVER A LONG TERM
PERIOD IN THIS CASE IN THE PAST
YEAR AND 134 FOOD ITEMS.
IT'S USED TO ASSESS TYPICAL
NUTRIENT INTAKE OVER THE PAST
YEAR AND DOES QUANTIFY PORTION
SIZE AS WELL AND WEB BASED AND
SELF-ADMINISTERED AND COMPLETED
FROM ALL PARTICIPANTS AT THEIR
FIRST VISIT.
THIS PROVIDED A GENERAL
ASSESSMENT OF DIETARY PATTERNS
OVER A LONG-TERM PERIOD OF TIME.
THESE ARE SCREEN SHOTS OF THE
QUESTIONNAIRE.
IT ASKS ABOUT ALL THESE FOODS
AND IT GOES ON TO ASK IN FURTHER
DETAIL AND WHAT'S YOUR PORTION
SIDE ETCETERA.
IT'S VERY COMPREHENSIVE.
THE SECOND TOOL WERE FOOD
RECORDS AND ASKED EACH
PARTICIPANT TO KEEP A SEVEN DAY
FOOD RECORD FOR THE WEEK PRIOR
TO THEIR VISIT AT THE CENTER
THIS COVERED THE SAME PERIOD.
WE REVIEWED THIS FOOD REPORT FOR
ACCURACY AND COMPLETENESS AND
VERIFIED BRAND NAMES, COOKING,
METHODS, AMOUNTS, ETCETERA AND
PROBED FOR MISSING OR FORGOTTEN
ITEMS AND CODED THE INFORMATION
INTO A SOFTWARE CALLED NUTRITION
SYSTEM DATA FOR RESEARCH TO
QUANTIFY INTAKE DOWN TO THE
NUTRIENT LEVEL.
THIS PROVIDES GRANULAR DATA RICH
IN DETAIL AND PRECISION BUT ONLY
COVERS A SHORT TERM PERIOD AND
DOESN'T LOOK AS MUCH AS THE
PATTERNS AS MUCH AS THE PRECISE
DETAIL.
FROM BOTH SCHOOLS WE DIDN'T SEE
MUCH DIFFERENCE BETWEEN HEALTHY
VOLUNTEERS AND ME/CFS
PARTICIPANTS.
THERE WAS NO DIFFERENCE IN
ENERGY ACROSS THE BOARD.
THE ONLY MACRO NUTRIENTS LOOKING
AT CARBOHYDRATE, FAT, PROTEIN,
ALCOHOL WE DID FIND A DIFFERENCE
IN WAS SATURATED FAT WHERE WE
SAW THE PERCENT OF CALORIES WAS
HIGHER IN PI ME/CFS AND FIBER
WAS SLIGHTLY HIGHER IN OUR
HEALTHY VOLUNTEERS.
MOVING TO THE MICRONUTRIENTS
LOOKING AT ONLY DIETARY INTAKE
AND DOES NOT INCLUDE
SUPPLEMENTATION.
WE DIDN'T SEE MUCH DIFFERENCE IN
TERMS OF INTAKE.
THE ONLY DIFFERENT WAS IN TERMS
OF FOLATE WITH HEALTHY
VOLUNTEERS TAKING MORE.
DURING THE SECOND VISIT WE
CONTROLLED DIET FOR PART OF THE
STUDY.
THEY WERE NO LONGER EATING THEIR
TYPICAL DIET BUT WHAT WAS
PROVIDED TO THEM AND TWO REASONS
WE DID THIS.
THE FIRST WAS AS YOU ALREADY
HEARD WHOLE BODY ENERGY
METABOLISM ANALYZED IN
RESPIRATORY CHAMBERS.
WHEN WE LOOK AT ENERGY OUT WE
FEED TO BE ABLE TO QUANTIFY
ENERGY IN PRECISELY.
WE NEED TO KNOW PRECISELY WHAT
PREME EATING.
WE CONTROLLED THEIR DIET DURING
THE PERIOD OF TIME WHILE THEY
WERE IN THE RESPIRATORY
CHAMBERS.
AND IT'S IMPORTANT TO CONTROL
DIET TO ISOLATE INDIVIDUAL
FACTORS AND KNOW IT'S SOMETHING
RELATED TO THE INDIVIDUAL
METABOLISM VERSUS SOMEONE EATING
HIGH CARB OR FAT OR A DIFFERENCE
LIKE THAT.
THAT'S ONE OF OUR COOKS
PREPARING A METABOLIC DIET HOW
WE CONTROLLED WHILE METABOLISM
WAS BEING ASSESSED.
WE PROVIDED A DIET CONTROLLED IN
DIFFERENT NUTRIENTS.
EVERY FOOD AND BEVERAGE WAS
WEIGHED OUT TO THE EXACT GRAM.
AS PLANNED THE DIETS WERE
CONTROLLED FOR ENERGY.
THE ENERGY WAS CALCULATED TO
MEET INDIVIDUALIZED ENERGY NEEDS
USING STANDARD ACTIVITY FACTOR
AND MACRO NUTRIENTS WERE
STANDARDIZED ACROSS ALL
PARTICIPANTS WITH 30% OF ENERGY
FROM FAT AND 15% FROM PROTEIN
AND 55% FROM CARBOHYDRATE.
PARTICIPANTS WERE ASKED TO
CONSUME THE DIET IN ENTIRETY AND
ANY REFUSED ITEMS OR UNABLE TO
FINISH WERE WEIGHED BACK TO
CALCULATE THE CONSUMED DIET DATA
TO TAKE INTO ACCOUNT AND YOU'LL
HEAR MORE WHEN YOU HEAR ABOUT
THE RESULTS OF THAT RESPIRATORY
CHAMBER.
THANKS.
>> GOOD AFTERNOON.
MY NAME IS SAM LOVE
SAM LAMUNION AND WE LOOK AT
BONE, LEAN AND FAT MASSES.
AND YOU MIGHT WONDER HOW DOES IT
RELATE AND FAT FREE PASS
ACCOUNTS FOR 70% AND 80% OF
RESTING ENERGY EXPENDITURE AND
YOU CAN SEE ON THE FIGURE ON THE
RIGHT RESTING EXPENDITURE IS 60%
TO 70% BUT IT VARIES BY
INDIVIDUAL.
HOW DO WE MEASURE THIS?
YOU'LL SEE THE SCANNER WHICH WE
USED IN THE METABOLIC SUITE AND
DUEL ENERGY OR DEXA FOR SHORT
AND PATIENTS COMPLETED A WHOLE
BODY DEXA SCAN AT THE DEEP
PHENOTYPING VISIT.
AND WE'RE ABLE TO GET OUTPUT ON
WHOLE BODY AND REGIONAL
COMPOSITION OF FAT MASS, LEAN
MASS AND ESTIMATED VISCERAL FAT
AROUND THE VITAL ORGANS.
OUR QUESTION WAS WHAT DOES BODY
COMPOSITION LOOK LIKE IN PI
ME/CFS COMPARED TO HEALTHY
VOLUNTEERS.
YOU SEE THE IMAGE NOT FROM
ANYONE IN THE STUDY BUT TO GIVE
AN IDEA OF WHAT THE IMAGE OUTPUT
LOOKS LUKE.
WHAT WE FOUND WAS BODY
COMPOSITION WAS NORMAL OR AT
LEAST NOT DIFFERENT FROM THE
THEY WILL HI VOLUNTEERS THAT
PARTICIPATED IN THE STUDY.
YOU'LL SEE IN ALL THE PANELS
LEAN BODY MASS WAS NOT
DIFFERENT.
THERE WERE NO STATISTICAL
DIFFERENCES FOR ALL THE MEASURES
FOR LEAN BODY MASS AND FAT MASS
AND BODY FAT PERCENTAGE AND
VISCERAL FAT MASS ESTIMATE AND
DOMINANT ARM LEAN MASS AND LEGS
LEAN MASS.
WITHIN BOTH GROUPS THE HEALTHY
VOLUNTEERS AND PI ME/CFS YOU SEE
INDIVIDUAL DIFFERENCES.
WE SEE THIS IN THE POPULATION WE
SEE LOTS OF PATIENTS WITH
DIFFERENT CHRONIC DISEASES AND
IT'S EQUIVALENT TO VARIABILITY
ACROSS INDIVIDUALS.
THE NEXT PART WHAT IS THE
RELATIONSHIP BETWEEN ENERGY AND
ENERGY EXPENDITURE AND THE TOP
PART OF THE FIGURE IS PHYSICAL
ACTIVITY AND ENERGY EXPENDITURE
AND HOW DOES THAT RELATE TO
TOTAL ENERGY EXPENDITURE.
WITH DEFECTIVE FEEDING YOU'LL
HEAR ABOUT MOMENTARILY THE LAST
PART FOR ENERGY EXPENDITURE
MAKES UP 15% TO 20% OF TOTAL
DAILY EXPENDITURE.
THERE'S HIGH INDIVIDUAL
VARIATION DAY TO DAY AND ACROSS
INDIVIDUALS.
THIS COULD BE ESTIMATE FROM
VARIABLE DEVICE DATA.
AND YOU SEE THE FIGURE SPLIT IN
TWO CATEGORIES, ENERGIZE
EXPENDITURE GOING WALK OR RUN OR
SOME ACTIVITY OR NON-EXERCISE
AND THERMO GENESIS OR INCIDENTAL
ACTIVITIES OF DAILY ACTIVITY.
THINGS YOU DO TRANSPORTATION AND
THAT SORT OF THING.
THAT CAN BE MEASURED WITH
ACCELER OM TRY.
WE DID SAYS FREE LIVING OR
HABITUAL BEHAVIOR BETWEEN VISITS
ALIGNED WITH THE OUT PATIENT
DIET FOOD RECORDS AND WAS IT
DIFFERENT FROM HEALTHY
VOLUNTEERS?
WE USED A SMALL PORTABLE DEVICE
RECORDED LOCALLY ON THE DEVICE
AND THIS IS AMERICA MOVEMENT IN
THREE PLANES AND NO OTHER
PHYSIOLOGICAL OUTCOMES, JUST
MOVEMENT.
WE COLLECTED RAW AT 80 HERTZ AND
LATER COLLAPSED TO ONE MINUTE IN
ACTIVITY COUNTS.
AND THIS WAS STANDARDIZED SO
PEOPLE WHO DIDN'T WEAR IT AS
MUCH AS GOT NOT INCLUDED IN THE
ANALYSES.
WE USED THE VALIDATED CUT POINT
FOR ESTIMATING MODERATE TO
VOIG VIGOROUS ACTIVITY.
WE'LL LOOK AT MEAN TOTAL STEPS
PER DAY AND THE PI ME/CFS TOOK
SIGNIFICANTLY FEWER STEPS
COMPARED TO HEALTHY VOLUNTEERS.
IN THE MIDDLE IS THE MAGNITUDE,
TOTAL ACTIVITY COUNTS AND THE
SQUARE ROOT OF THE SUM OF THE
SQUARES.
DON'T WORRY ABOUT THE MATH.
IT'S SUMMARY MEASURE OF THE
NUMBER OF COUNTS PER DAY SO THIS
IS AN INTEGRATED SUMMARIZED
METRICS.
MORE COUNTS TRANSLATES TO MORE
MOVEMENT.
ANOTHER VOLUME MEASURE AND SAW
THE PI ME/CFS GROUP HAD LESS
TOTAL MOVEMENT PER DAY FOR THIS
MEASURE AND LASTLY FOR INTENSITY
MEASURE DR. CHEN HIGHLIGHTED,
MODERATE INTENSITY ACTIVITY IS
ASSESSED AND STARTING AT 3
MOBILE EQUIVALENTS OF TASKS AND
A CUT POINT FOR EVERYBODY OR
ADULTS AND WE SAW THE PI ME/CFS
GROUP DID ACCUMULATE OR ENGAGE
IN SIGNIFICANTLY LESS MODERATE
INTENSITY PHYSICAL ACTIVITY ON A
DAILY BASIS AND AS HIGHLIGHTED
WITHIN EACH GROUP WE SAW
VARIABILITY AND THIS DOES AGAIN
VARIES WITH INDIVIDUAL DAY TO
DAY AND WITHIN INDIVIDUALS
WITHIN THE GROUP.
WITH THAT I'LL TURN IT OVER TO
DR. BRYCHTA.
>> I'M A STAFF SCIENTIST AT
NIDDK AND I'LL TALK ABOUT OUR
MEASUREMENTS OF WHOLE BODY
ENERGY EXPENDITURE.
A LITTLE DIAGRAM WHAT WE USED TO
USE TO MEASURE THIS RESPIRATORY
CHAMBER OR METABOLIC CHAMBER.
WE SEE IN THE WHITE IS THE ROOM
AND YELLOW IS AIR BUFFER AROUND
THE ROOM A CORRIDOR AROUND THE
ROOM.
AND FRESH AIR CAN GO IN THE ROOM
THROUGH A SMALL PORTAL.
AND THE REST OF ROOM IS SEALED.
PEOPLE STAY IN THE ROOM AND
CHANGE THE COMPOSITION OF THE
AIR BY CONSUMING OXYGEN AND
PRODUCING CARBON DIOXIDE.
WE PULL AIR OUT OF THE ROOM SO
THERE'S A ONE-WAY FLOW OF AIR
AND MEASURE THE FLOW OF AIR OUT
OF THE ROOM AND SAMPLE THE
COMPOSITION OF THE AIR USING AN
OXYGEN AND CO2 ANALYZER TO
MEASURE THE CONCENTRATION OVER
TIME AND COMPARE WHAT'S GOING ON
INSIDE OF THE ROOM GETTING
CHANGED BY THE SUBJECT TO WHAT'S
GOING IN TO THE ROOM IN THE
FRESH AIR, THE COMPOSITION OF
THE OXYGEN AND CO2 WHICH IN THE
FRESH AIR IS PRETTY STABLE.
NOW, HERE IS AN EXAMPLE OF OUR
METABOLIC CHAMBER AT NIDDK
BETHESDA.
PEOPLE SPENT FROM 4:00 P.M. TO
8:00 A.M. IN THIS STUDY AND MOST
SPENT FOUR TO FIVE NIGHTS IN THE
METABOLIC CHAMBER.
IT LOOKS LIKE A WALK-IN FREEZER
IF YOU'LL NOTICE.
ON THE TOP THERE'S THE SAMPLING
PORTS WHICH ARE METAL AND
THERE'S MOTION SENSORS TO TELL
IF PEOPLE ARE MOVING OR NOT
MOVING AND ASLEEP.
AS DR. LAMUNION POINTED OUT WE
CAN MEASURE THE DAILY EXPEND
YOU'RE USING THE DEVICE BUT THE
TIME CONSTRAINTS AND PEOPLE'S
SCHEDULE DOING THIS INTENSIVE
STUDY WE MEASURED THEM.
THESE PARTICULAR SUBJECTS FROM
4:00 P.M. TO 8:00 a.m.
WE'RE BASICALLY CONCENTRATING ON
MEASUREMENTS OF THEIR RESTING
AND SLEEPING ENERGY EXPENDITURE.
AND PARTICULARLY THE RESPONSE TO
THE CPET.
TO DO THAT ACROSS THE PEOPLE
HEALTHY VOLUNTEERS AND PATIENTS,
WE MINIMIZED THE VARIABILITY OF
THEIR ACTIVITY ENERGY
EXPENDITURE.
THEY REMAIN SEDENTARY OR ASLEEP
DURING THE STUDY.
THEY BASICALLY WHEN THEY WEREN'T
ASLEEP THEY WERE WATCHING TV AND
RELAXING AND MINIMIZED THE
VARIABILITY IN THERMO EFFECTIVE
FOOD OR ENERGY RESPONSE TO
BREAKING DOWN THE FOOD OF THEIR
DIET.
EACH PERSON GOT ONE MEAL IN THE
CHAMBER AND THE MEALS ARE
STANDARDIZED AND THE DIET IS
WEIGHT MAINTENANCE DIET FOR EACH
PERSON'S NEED.
THIS IS A 24-HOUR TRACING WHAT
WE SEE IN THE CHAMBER AND THIS
IS A PERSON FROM A DIFFERENT
STUDY.
YOU SEE THE SLEEPING ENERGY
EXPENDITURE HIGHLIGHTED IN RED
AND THIS IS THE MOST STEADY AND
MINUTE TO MINUTE VARIABILITY AND
MOST REPRODUCIBLE FROM NIGHT TO
NIGHT AND CORRELATED TO YOUR FAT
FREE MASS AND RESTING ENERGY
EXPENDITURE AND SLEEPING ENERGY
EXPENDITURE EXPLAINED BY 70% TO
80% OF THE VARIATION AND THAT'S
EXPLAINED BY YOUR FAT FREE MASS.
THIS IS DIFFICULT TO MEASURE YOU
CAN IMAGINE IF YOU'RE MEASURING
OXYGEN AND CO2 VIEWED TO WEAR A
MASK AND THAT'S DIFFICULT TO
SLEEP IN.
HERE'S WHAT WE FOUND WITH OUR
SLEEPING ENERGY EXPENDITURE AND
THIS IS AT BASELINE THE NIGHT
BEFORE THE CPET.
HERE AGAIN THE PI ME/CFS
PATIEPATIENT
S ARE IN RED AND HEALTHY
VOLUNTEERS IN BLUE AND MEN WILL
SQUARES AND WOMEN ARE CIRCLES.
IN GENERAL WOMEN HAVE A LOWER
FAT FREE MASS THAN MEN AND ON
THE LEFT CORNER OF THE GRAPH
BECAUSE WOMEN ARE GENERALLY
SHORTER THAN MEN SO THEY'RE
GOING TO HAVE LESS FAT FREE MASS
BUT YOU CAN SEE ACROSS THE WHOLE
GROUP THE FAT FREE MASS AND
EXPENDITURE IS HIGHLY CORRELATED
AND THERE'S NOT REALLY MUCH OF A
TREND BETWEEN THAT
DIFFERENTIATES THE HEALTHY
VOLUNTEERS AND ME/CFS
PARTICIPANTS AND THE R SQUARED
IS .78.
IT'S ABOUT 78% OF THE VARIATION
IS EXPLAINED BY THEIR FAT FREE
MASS.
WHEN YOU LOOK AT TOTAL ENERGY
EXPENDITURE IT'S ONLY FROM 4:00
P.M. TO 8:00 A.M. MOSTLY RESTING
AND MOST TIME IS SLEEPING BUT
AGAIN IT'S EXPLAINED BY ABOUT
75% OF THE VARIATION IS
EXPLAINED BY THEIR FAT FREE
MASS.
SO WHEN WE LOOK AT SHE SLEEPING
ENERGY EXPENDITURE FROM BEFORE
THE CPET TO AFTER THE NIGHT
AFTER THE CPET, AND THAT -- IS
IN THE OPEN CIRCLES AND SQUARES
AND A LINE CONNECTING EACH
PARTICIPANT TO THEIR BASELINE
MEASUREMENT BEFORE THE CPET TO
AFTER MEASUREMENT ANN CAN SEE
THE RED DOTTED LINE WHICH THE
REGRESSION OF FAT FREE FALLS ON
TO THE CPET.
THERE WASN'T MUCH OF AN EFFECT.
WE SEE WHERE THE REGRESSION
LINES OF TOTAL ENERGY
EXPENDITURE FALL ON ONE OF ONE
NORTH AND COMPARING THEMSELVES
WE DON'T SEE DIFFERENCE NIGHT
BEFORE TO AFTER THE CPET.
NOW THE OTHER THING WE CAN LOOK
AT WITH THE METABOLIC CHAMBER IS
CALLED THE RESPIRATORY QUOTIENT
OR LEE -- LISA REFERRED TO IT
AS THE MEASURE OF CARBON DIOXIDE
EXPIRED TO OXYGEN CONSUMED.
WHEN YOU'RE EXERCISING THIS IS A
MEASURE OF YOUR EFFORT OR HOW
MUCH YOU'RE EXPENDING AND WHEN
YOU'RE AT REST THIS REFLECTS
WHAT FUEL YOU'RE USING WHERE THE
MAJORITY OF YOUR ENERGY IS
COMING FROM.
A RATIO OF .7 WOULD BE PURELY
FAT IN THE DIET AND 1.0 WOULD BE
PURELY CARBOHYDRATE AND THE
STANDARD MIXED MEAL IS SOME
PLACE IN BETWEEN.
WE CAN SEE AT REST OR AT SLEEP
THERE WAS NO DIFFERENCE BETWEEN
THE PEOPLE COMPARED TO
THEMSELVES IN THEIR SLEEPING
RESPIRATORY QUOTIENT WHICH IS A
LITTLE BIT LOWER THAN THEIR
RESPIRATORY QUOTIENT WHILE THEY
WERE HAVING A MEAL.
THERE'S REALLY -- THERE WAS NO
DETECTED DIFFERENCE BETWEEN THE
NIGHT BEFORE AND THE NIGHT AFTER
THE CPET THANE MEASURE.
-- IN THAT MEASURE.
WITH THAT I'LL GIVE IT TO
DR. HWANG.
ALL RIGHT.
I'M PAUL HWANG AN INVESTIGATOR
IN NATIONAL HEART, LUNG AND
BLOOD INSTITUTE AND START BY
THANKING THE ORGANIZERS FOR
GIVING ME THE OPPORTUNITY TO
PRESENT OUR WORK.
WHAT I'D LIKE TO DO IS SHARE A
PROJECT OVER THE PAST SEVERAL
YEARS TRYING TO DETERMINE THE
MOLECULAR MECHANISM OF THE
MUSCLE OF PATIENTS WITH ME/CFS.
WE HAD REPORTED EARLY IN OUR
STUDIES INDIVIDUALS WITH THE
SYNDROME A CANCER DISORDER
CAUSED BY GERM LINE MUTATIONS OF
P53, SORRY.
THAT IS THE EARLY ONSET CANCER
DISORDER HAVE DECREASED
MITOCHONDRIAL DYSFUNCTION AND
INCREASED ENDURANCE.
A PATIENT HAD READ OUR WORK ON
THE WEB E-MAILED ME SAYING SHE
WAS THE EXACT OPPOSITE AND WAS
ALWAYS FATIGUED AND HAD TERRIBLE
EXERCISE ENDURANCE.
THIS IS THE CASE OF A
38-YEAR-OLD WOMAN WITH
LI-FRAUMENNI SYNDROME AND
STARTED IN HER TEEN AGE YEARS
AFTER SHE CONTRACTED
MONONUCLEOSIS AND THE FATIGUE
SYMPTOMS NEVER WENT AWAY AND HAD
EXTENSIVE CLINICAL WORKUP AND
MITOCHONDRIAL DISEASE EVALUATION
AND GENOME SEQUENCING WHICH WERE
ALL UNREMARKABLE AND HAD TYPICAL
SYMPTOMS ASSOCIATED WITH ME/CFS.
THERE'S BEEN MANY MECHANISMS
PROPOSED BUT SOME HAVE INCLUDED
DYSFUNCTION OF THE MITOCHONDRIA
BUT NO SPECIFIC MEDIATOR HAS
BEEN IDENTIFIED.
WE STUDIED PATIENTS AND NONE HAD
REPORTED FATIGUE SYMPTOMS AND
WERE INTRIGUED BY THE REPORT AND
DECIDED TO STUDY THE PATIENT.
WE INVITED HER AND SHE'S
INDICATED HERE AS SIBLING S1.
WE DID A PHOSPHORUS NONINVASIVE
TEST OF THE EXERCISE MUSCLE AND
SHOWN BY OTHER INVESTIGATORS AS
A MARKER OF MITOCHONDRIAL
DYSFUNCTION.
WHEN WE PERFORMED THIS TEST ON
THE PATIENT WE WERE AMAZED HOW
SLOW HER RECOVERY TIME WAS AT 80
SECONDS OVER TWO DIFFERENT TIME
PERIODS IN A SIX MONTH TIME
PERIOD.
AND WE WERE UNFORTUNATE TO
INVITE THE BROTHER ALSO HAD THE
SYNDROME BUT DIDN'T HAVE THE
FATIGUE SYMPTOMS.
HIS RECOVERY TIME WAS 30 SECONDS
AND THAT'S IN THE REALM OF WHAT
WE HAD PREVIOUSLY OBSERVED IN
OTHER SYMPTOMS.
IT'S FASTER THAN NON-CARRIERS IN
THE REALM OF 36 SECONDS.
WE OBTAINED BIOPSIES AND MADE
FIBROBLASTS AND DID A SIMPLE
EXPERIMENT LOOKING AT OXYGEN
FUNCTION AND THE PATIENT S1
OXYGEN CONSUMPTION IN THE BASAL
AND MAXIMAL STATE WAS
SIGNIFICANTLY LOWER THAN THE
BROTHER'S CONSUMPTION.
THIS WAS AN INTERESTING FINDING
AND WE PURSUED THIS FURTHER AND
BASICALLY SUMMARIZED A LARGE
BODY OF WORK AND WERE ABLE TO
IDENTIFY OF THE POTENTIAL
MEDIATOR OF THE MITOCHONDRIAL
DYSFUNCTION.
FINDING THIS INVOLVED TRACING
THIS SIGNALLING THAT WE OBSERVED
INVOLVING P53 PHOSPHORYLATION
AND P38 KINASE ACTIVATION.
IN RETROSPECT THE SIGNALLING
ABNORMALITIES WERE SECONDARY TO
PRIMARY DEFECT IN MITOCHONDRIAL
FUNG IN THE KRILZ.
-- CELLS.
WE IDENTIFIED FOR THE PROTEIN
FOUND AND THE GENE THAT'S
MUTATED IN THIS IMMUNODEFICIENCY
AND FAMILY GENE IN THE SYNDROME.
AND INTERESTINGLY WE REPORTED A
NUMBER OF YEARS AGO IT WAS A TOP
CANDIDATE GENE ASSOCIATED WITH
ME/CFS IN A LARGE BIO
INFORMATICS META-ANALYSIS BUT
NOT MUCH MORE HAD BEEN DONE
SUBSEQUENT TO THE REPORT.
IT WAS KNOWN TO INTERACT WITH
ACTIN POLYMERIZATION FOR THE
CYTOSKELETON OF THE CELL AND A
SCAFFOLDING PROTEIN FOR
COMPLEXES.
IT'S ALSO KNOWN TO INFORM CELL
MIGRATION AND HAS BEEN STUDIED
IN THE CANCER FIELD.
ONE EARLY EXPERIMENT WE DID WAS
TO DOWN REGULATE THE PROTEIN
LEVELS IN THE PATIENT CELLS THE
S 1 PATIENT CELLS USING THE RNA
AND FOUND SIGNIFICANT
IMPROVEMENT IN OXYGEN
CONSUMPTION WHEN WE DECREASED
THE LEVELS AND ASSOCIATED WAS A
NICE INCREASE IN THE
MITOCHONDRIAL COMPLEX 4 PROTEINS
YOU CAN SEE HERE.
WE ALSO DID OPPOSITE EXPERIMENT
OF OVEREXPRESSING THIS IN
MYOBLASTS AND WHEN WE
OVEREXPRESSED THE PROTEIN OXYGEN
CONSUMPTION IS DECREASED AND YOU
CAN SEE WHEN WE LOOK AT THE
DIFFERENT COMPLEXES, COMPLEX 4
SUB UNIT PROTEIN COX 1 SUB UNIT
IS DECREASED WHILE THE OTHER
COMPLEX 5, 3 AND 1 PROTEINS ARE
NOT CHANGED.
THE REASON FOR THIS BECOMES
CLEARER BASED ON FURTHER
MECHANISTIC STUDIES AND AGAIN TO
SUMMARIZE OUR WORK WE SHOWED
THAT THE WAS 3 PROTEIN ENRICHED
THE MITOCHONDRIA AND USING
PROXIMITY LIGATION ASSAYS
LOOKING AT THE INTERACTION
BETWEEN WAS 3 AND SOME
MITOCHONDRIAL RESPIRATORY
PROTEINS WE WERE ABLE TO SHOW
WAS CAN INTERACT WITH THE
RESPIRATORY COMPLEX 3 SUB UNIT
PROTEINS AND THAT WAS 3 IS OVER
EXPRESSED IT DISRUPTS THE
ASSEMBLY OF THE PROTEINS AND
WELL KNOWN IN THE LITERATURE
WHEN YOU DESTABILIZE COMPLEX 4
PROTEINS THEY GET DEGRADED.
THAT EXPLAINS WHAT WE OBSERVED
WITH THE PROTEIN LEVEL WHEN IT
EXPRESSED THE PROTEINS WITHOUT.
BESIDES MAKING A MOUSE MODEL
EVERY EXPRESSED WAS 3 AND
SHOWING A DECREASE IN EXERCISE
CAPACITY OF NICE ON TREADMILL WE
OBTAINED SAMPLES FROM THE STUDY
AND LOOKED AT WHAT WAS STORED IN
PATIENTS COMPARED TO HEALTHY
VOLUNTEERS AND OBSERVED
SIGNIFICANT INCREASE IN THE
PROTEIN LEVELS IN THE MUSCLE
SAMPLES OF THE PATIENTS AND THEN
YOU CAN SEE HERE THE INVERSE
RELATIONSHIP BETWEEN THE
EXPRESSION AND COMPLEX IN THE
PROTEINS FROM THE MUSCLE SUB
UNITS.
IN TERMS OF WHAT MIGHT BE
INCREASING THE WAS 3 PROTEIN
LEVELS THERE WAS EVIDENCE IN THE
LITERATURE E.R. STRESS IS
INVOLVED IN INCREASING THE
PROTEIN LEVELS.
WE LOOKED AT ONE OF THE MARKERS
OF THE PROTEIN MARKER COMPARED
TO HEALTHY VOLUNTEERS.
WE WERE ABLE TO TAKE THE PATIENT
CELL WITH CHRONIC FATIGUE AND
CELLS IN CULTURE AND ADD A
SPECIFIC STRESS INHIBITOR.
IT WORKS SPECIFICALLY BY
INHIBITING KINASE THAT IS
INVOLVED IN REGULATING E.R.
STRESS AND ABLE TO SHOW IN A
DRUG-DOSE DEPENDENT MANNER WE
ARE ABLE TO RECOVER THE
MITOCHONDRIAL FUNCTION OF THE
PATIENT'S CELLS YOU CAN SEE
HERE.
IN PARALLEL WE WERE ABLE TO SHOW
RECOVERY OF THE SUPER COMPLEX 3
DIMER AND COMPLEX 4 PROTEINS
WERE INCREASED AGAIN IN THE
PATIENT S1 CELLS BY THE ADDITION
OF THE DRUG THE CHEMICAL WHILE
THE PROTEIN LEVELS OF COMPLEX 4
WAS UNCHANGED.
AGAIN THAT SPEAKS TO WHAT I
SHOWED YOU EARLIER WITH THE
SPECIFICITY OF THE INTERACTION
THAT SEEMS TO BE LOCALIZED
COMPLEX 3 PROTEIN.
SO BASICALLY JUST TO SUMMARIZE I
HOPE I'VE SHOWED YOU PATIENT ONE
ME/CFS HAVE INCREASED EXPRESSION
OF WAS 3 IN THE SUBSET OF THE
PATIENT AND WAS 3 MOLECULARLY
DISRUPTS BY PREVENTING COMPLEX
FORM AND DISABLIZING COMPLEX 4
AND INDUCED STRESS AND
MITOCHONDRIAL DYSFUNCTION
SUGGESTING A TREATMENT STRATEGY
WE CAN PURSUE IN THE FUTURE.
>> WE TALK ABOUT BIO ENERGETICS
AND HEARD FROM THE DIFFERENT
ASPECTS BOTH IN THE SCOPE OF THE
WHOLE BODY AS WELL AS THE LAST
CASE IN THE MUSCLE CELLS.
YOU CAN SEE HOW WE TRY TO FIT
THAT IN THE LAST PART OF THE
FIGURE.
THE PERIPHERAL.
IT'S EVERYTHING WE STUDY IS
BELOW THE NECK EXCEPT YOU
BARBARA, YOU STUDY THE BRAIN
LEVEL.
AND IT'S REFLECTED IN THE PEM.
KEY QUESTION ONE IS THERE
PHENOTYPIC SIGNATURES IN THE
WHOLE BODY ENERGY BALANCE
MEASURES COMPARED TO THE HEALTHY
NORMAL CONTROLS.
THERE WERE NO DIFFERENCE THESE
AND A COUPLE OTHERS BUT SLIGHT
TRENDS IN LESS FIBER AND FOLATE
AND MORE SATURATED FAT INTAKES.
THERE WERE NO DETECTABLE
DIFFERENCES IN THE OUTPUT IN
TOTAL ENERGY EXPENDITURE IN
SLEEPING AS WELL AS THE 4:00
P.M. TO 8:00 A.M. AND OXIDATION
THERE'S COMPARABLE FATIGUE
GROUPS AT BASELINE AND AS WELL
AS AFTER ONE NIGHT AFTER THE
CPET.
THEY WENT INTO DETECTABLE
DIFFERENCE IN BODY COMPOSITION
AND BONE MASSES.
THE PATIENTS HAD FREE LIVING
PHYSICAL ACTIVITY.
IT CONFIRMS THE SELF-REPORTS AND
LITERATURE.
ONE THING THAT STRUCK US MOST
THERE'S INDIVIDUAL DIFFERENCES.
PARTICULARLY IN THE CPET TEST
YOU'VE SEEN IT'S A WIDE VARIETY
AND THERE ARE SOME COUPLE
PATIENTS THAT HAD ONE OF THE
HIGHER OXYGEN CAPACITIES.
WHEN IT COMES TO QUESTION 2, ARE
THERE UNIQUE CHANGES AFTER THE
CPET COMPARED TO THEMSELVES AS
WELL AS PATIENTS VERSUS CONTROL
AND NO DETECTABLE DIFFERENCES IN
THE MECHANICAL DEFICIENCY AND
MEASURED IN THE CPET PROCESS
WHETHER THERE'S LOWER PEAK VO2
ANROBIC THRESHOLD AND HEART RATE
RESPONSE DURING THE CPET AND NO
DE TECTABLE DIFFERENCES IN
SLEEPINESS EXPENDITURE OR
OXIDATION RATE AFTER THE CPET.
AGAIN, THERE WAS CONSIDERABLE
BETWEEN INDIVIDUAL DIFFERENCES
IN THE CPET AND PM PATTERNS.
SO OUR INTERPRETATION IS THE
PATIENTS WITH PI ME/CFS HAVE A
WIDE RANGE OF BIOENERGETIC
CAPACITIES WE CAN'T ASSESS THEM
BEFORE THE DISEASE AND CAN'T
TEASE OUT THE CAUSE AND WHILE
THE ENERGY BALANCE IS PRESERVED
AT TESTING IT REDUCED PEAK
CAPACITY SKELETAL MITOCHONDRIAL
DYSFUNCTION ARE EVIDENT AT LEAST
IN SOME PATIENTS.
LET ME ASK THE PANEL BACK DOWN.
IF YOU HAVE QUESTIONS
SPECIFICALLY TO THESE AREAS
WE'LL BE HAPPY IT ANSWER THEM.
>> JOE LANCET I'LL A PATIENT.
WHAT WOULD A VALIDATED MEASURE
FOR POST EXERCISAL MALAISE LOOK
LIKE AND WHY DOES THE CPET FOT
QUALIFY AS A MEASURE AS IT'S
CURRENTLY BEING USED FOR
DISABILITY EVALUATIONS.
THANK YOU.
>> THERE WERE NO VALIDATED
MEASURES AND NOW THERE'S
QUESTIONNAIRES TO ASSESS PEM BUT
TO MY KNOWLEDGE NO VALIDATED
MEASURES TO ASSESS AT POINT IN
TIME BEFORE AND AFTER CPET.
THERE'S THE VAS SCALES USED
TRADITIONALLY BUT HAVE NOT BEEN
VALIDATED FOR THAT PURPOSE BUT
I'LL LET DR. WALITT HAND THAT
WILL.
>> THE QUESTIONNAIRE WAS VOL
DATED AS AN INSTRUMENT TO
MEASURE THE POLL QUESTIONNAIRE
WAS VALIDATED EDD AS AN INSTRU
TO MEASURE IN A PERSON AFTER
STARTED.
THERE WASN'T ANY INSTRUMENTS
WHILE THEY WERE STARTING.
THAT WOULD BE THE GO TO AND USED
IN LONG COVID RESEARCH AS A
MEASURE OF PEM.
IN TERM OF THE TWO-DAY CPET IT'S
MEASURING FURTHER DELAYED
RESPONSE TO EXERCISE SOMEBODY
FEELS.
WHAT MIGHT BE PHYSIOLOGICAL
MEASUREMENTS ISN'T CAPTURING
WHAT THE EXPERIENCE OF POST
EXERTIONAL MALAISE IS AND IT'S
NOT A MEASURE OF PEM BUT CARD
YEAR OVER YEAR --
CARDIORESPIRATORY PERFORMANCE.
>> ISN'T IT TRUE AFTER THE FIRST
CPET THESE PATIENTS ARE PRETTY
EXHAUSTED.
A SECOND DAY WOULD HAVE BEEN --
>> WITH BARBARA'S INSTRUMENT
EVERYBODY HAD PEM AFTER ONE DAY
AND TWO OF DAY CPET WASN'T
NECESSARY TO PUT THEM --
>> WOULD END UP HURTING THEM.
>> WE COULD HAVE.
>> HAVE THE FINDINGS OF WAS 3
AND MITOCHONDRIAL DYSFUNCTION
BEEN SEEN IN FIBROMYALGIA
PATIENT.
>> GREAT QUESTION.
FIBROMYALGIA WOULD BE GREAT TO
LOOK AT IN THE RUMATO LOGIC
DISCOVEREDS AND THEY'RE GREAT
THINGS TO DO AND HOPE OTHERS
THAT WILL HAVE READ OUR PAPER
THAT WILL ALSO DO THESE STUDIES.
>> WHAT DO THEY TELL US ABOUT
THE LOWERING OF ANAEROBIC
MEASURES IN THE SECOND DAY OF
THE TEST.
>> REPEAT THE QUESTION.
ON THE SECOND DAY OF CPET?
>> YEAH, WHAT DO THE
BIOENERGETIC STUDIES ABOUT THE
LOWERING OF THE ANAEROBIC
STUDIES OF THE SECOND DAY.
>> WE DIDN'T DO A SECOND DAY
CPET.
IT WOULD BE HARD TO SPECULATE
WHAT IS RELATED.
>> THANK YOU.
>> I WONDER IF YOU CAN COMMENT
ON CHRONOTROPIC INCONTINENCE.
THERE'S ONE OTHER ELEMENT I
WONDER IF WE HAVE EXPLANATION
FOR.
>> LISA.
>> FROM THE MEASUREMENTS FROM
THE HEART RATE AND WE WERE
LOOKING BASED ON THE AGE
PREDICTED HEART RATE PRESERVE
AND FIVE OF THE EIGHT SHOWED
THEY HAD MET THE CRITERIA AND
WHEN WE LOOKED ACROSS THE
EXERCISE DURATION OR DURING
EXERCISE TESTS WE COULD SEE
THOSE SLOPES WERE LOWERED.
THERE'S A LOWER HEART LATE
RESPONSE ACROSS THE DIFFERENT
WORK RATES IN ME/CFS VERSUS THE
HEALTHY VOLUNTEERS.
SO WHETHER THIS IS RELATED BACK
TO SOME OF THE AUTONOMIC
DYSFUNCTION COULD BE RELATED BUT
THAT'S WHAT WE'RE FINDING.
>> THE FINDING IS CLEAR.
I WONDER WHAT THE EXPLANATION
IS.
>> WHERE DOES IT COME FROM?
>> IT'S THOUGHT TO BE A DISA
DISAUT
DISAUTONOMIA ISN'T KICKING IN.
[OFF-MIC]
>> DO YOU WANT TO COME TO THE
MICROPHONE?
THIS IS WHY WE HAVE A WHOLE TEAM
OF PEOPLE HERE.
>> THERE IS A SYSTEMATIC
APPROACH TO CHRONOTROPIC
INCONTINENCE AND BOILS DOWN TO
DOSE RESPONSE WITH ISOPREL AND
THERE'S A CATECHOLAMINE AND YOU
CAN MEASURE THE INCREASE IN
HEART RATE FOR A GIVEN LEVEL AND
MORE IMPORTANTLY, THERE'S A
RELEASE OF NOREPINEPHRINE BY
STIMULATING VEGA2 RECEPTORS.
BY MEASURING THE RESPONSE TO
ISOPREL YOU CAN PINPOINT THE
BASIS FOR CHRONOTROPIC
INCONTINENCE FROM THE BASAL
RECEPTOR MEDIATED PROCESSES.
>> WHEN YOU SAY THE FINDINGS
DECREASE NOR EPINEPHRINE COULD
BE RELATED TO WHY WE'RE SEEING
CHRONOTROPIC INCOMPETENCE IN THE
INDIVIDUALS?
>> IT'S A MISSTATEMENT.
WHAT WE FOUND WAS THE SPINAL
FLUID, QUITE INDEPENDENT OF THE
NOREPINEPHRINE IN THE PLASMA AS
A MEASURE OF SYMPATHETIC
OUTFLOW.
IT'S A POWERFUL BLOOD BRAIN
BARRIER FOR CATECHOLAMINE.
YOU SEE VERY INDIRECTLY RELATED
OR NOT RELATED AT ALL TO WHAT
YOU SEE IN THE PERIPHERY.
WHAT WE FOUND IN THE PERIPHERY
WAS NOREPINEPHRINE WAS NORMAL.
IT'S SUPPOSED TO INCREASE WHEN
TILTED AND DID INCREASE AND
INCREASED NORMALLY IN THE ME/CFS
GROUP.
THERE'S THE DATA ABOUT S
SYMPATHETIC RESPONSES IN THE
STUDY ARE SAY INCONSISTENT AND
DIDN'T SEE A PROBLEM IN THE
STUDY.
>> HOW ABOUT THE INCREASED
EPINEPHRINE LEVELS IN SOME
PARTICIPANTS?
>> AS I SHOWED IN MY SLIDE AND
YOU GET THE CATECHOLAMINES
PUMPING IT'S NOT ALL TRUE.
ESPECIALLY IN FAINTING REACTION
AND IT INVOKED HYPOTENSION
THERE'S A DISASSOCIATION BETWEEN
WHAT HAPPENS TO NOREPINEPHRINE.
IF YOU REMEMBER THE INDIVIDUAL
SPAGHETTI PLOTS.
NOT OVER ALL IN THE GROUP.
YOU HAVE TO KEEP IN MIND THE
SYSTEM NOT ONE THING.
>> NOT SURE THAT ANSWERED YOUR
QUESTION.
MARK'S ASKING A CRITICAL
QUESTION AND LET ME ASK BY
BRIAN'S EARLIER REMARKS THIS IS
A HYPOTHESIS GENERATING STUDY
AND GET TO MECHANISM OF SKELETAL
MUSCLES.
WE'RE JUST GETTING STARTED.
WITH SAW EARLIER THE OMICS
ANALYSIS AND CLEAR
DIFFERENTIATION BETWEEN GENDERS
DID YOU SEE THAT WITH YOUR
RESULTS?
>> WE HAD A MIX OF SAMPLES.
WE DIDN'T REALLY SEE A GOOD
CORRELATION.
WE LOOKED AT 14 INDIVIDUAL
SAMPLES.
PROBABLY MORE WOMEN SAMPLES THAN
MEN.
WE DIDN'T SEE A CLEAR
CORRELATION AND SPECTRUM OF
LEVELS.
CAN'T COMMENT ON THAT.
>> I BELIEVE WE'RE RUNNING OUT
OF TIME.
THERE'S ANY OTHER QUESTIONS
WE'LL BE ABLE TO ADDRESS THEM
OVER E-MAILS.
>> I'M A PATIENT.
ANY GUESSES, DR. H WANG ON
WHAT'S CAUSING THE ENDO
RETICULUM STRESS IN THE
MITOCHONDRIAL DYSFUNCTION?
>> GREAT QUESTION.
THE FIBROBLAST HAS NOTHING TO
BIG DO WITH MUSCLE COMPARED TO
THE BROADER SIBLING.
IF I WAS TO SPECULATE THE STRESS
IS A RESPONSE OF NORMAL PROTEIN
HOMEOSTASIS AND YOU SEE WITH
INFECTIONS AND VIRAL INFECTIONS
THE VERY WELL TRIES TO SHE SUT
DOWN PRODUCTION OF VIRAL
PROTEINS AND ME/CFS IS
ASSOCIATED WITH A
POST-INFECTIOUS STATE AND IF I
CAN SPECULATE ABNORMAL
ACTIVATION AND IT WOULD BE GREAT
TO HAVE EXPERTS IN THE FIELD.
GOOD QUESTION.
>> I'LL TALK ABOUT DATA SHARING
AND ONGOING WORK TO COME.
ONE OF THE MOST IMPORTANT THINGS
WE CAN DO IS FOLLOW THE TENETS
OF OPEN SCIENCE AT THE
RECOMMENDATIONS OF OPEN SCIENCE
ARE HERE FOR YOU.
TRYING TO MAKE IT OPEN AND
INCLUSIVE TO PEOPLE WITHOUT SIDE
OF TRADITIONAL SCIENCE.
IT'S TO MAKE IT.
LY AVAILABLE AND USABLE TO
INCREASE SCIENTIFIC
COLLABORATIONS AND SHARING OF
INFORMATION FOR THE BENEFIT OF
ALL AND OPEN THE PROFESSOR OF
SCIENTIFIC KNOWLEDGE CREATION TO
EVERYBODY THAT'S INTERESTED IN
BEING INVOLVED.
THERE ARE FIVE TENETS OF OPEN
SCIENTIFIC KNOWLEDGE AND I'LL
TALK ABOUT THE ONES APPLIED TO
US.
THE FIRST BEING MAKE SCIENTIFIC
PUBLICATIONS AVAILABLE TO ALL.
MANY DON'T REALIZE THAT IT COSTS
A LOT OF MONEY TO MAKE A
SCIENTIFIC PUBLICATION WIDELY
AVAILABLE.
YOU HAVE TO BE PART OF A
UNIVERSITY OR HAVE A FRIEND TO
GET YOU A COPY OR PDF THERE
ANOTHER FRIEND.
THIS GETS IN THE WAY OF SHARING
OF INFORMATION.
WE UNDERSTOOD THAT AND MADE SURE
OUR PUBLICATION IS PUBLICALLY
AVAILABLE AND CAN GOOGLE NATURE
AND WALITT AND GET THE WHOLE
ARTICLE THAT EASILY.
SECOND IS TO OPEN DATA TO
EVERYBODY.
WE BENT OVER BACKWARDS TO MAKE
SURE OUR DATA IS AVAILABLE AND
THIS IS THE STATEMENT IN THE
PAPER ITSELF WHICH IS MULTIPLE
PARAGRAPHS I'LL MAKE EASIER BY
TALKING ABOUT THE CONTENTS ARE
AND WHERE TO FIND OUR DATA.
ALL OUR DATA IS CCBY4.0 THROUGH
CREATIVE COMMONS.
IT SAYS WHEN YOU SHARE DATA HOW
ARE OTHER PEOPLE ALLOWED TO USE
IT AND WHAT YOU NEED TO DO.
WITH OUR DATA EVERYONE IS FREE
IT SHARE IT, COPY IT,
REDISTRIBUTE THE MATERIAL ANYWAY
YOU WANT.
IF YOU CAN FIND COMMERCIAL
VALUE, HAVE FUN.
YOU CAN ADAPT THE DATA AND BUILD
ON IT EVEN IF YOU'RE LOOKING TO
MAKE COMMERCIAL SUCCESS THROUGH
THAT.
WE WON'T REVOKE THOSE FREEDOMS.
ONLY THING WE SKIN RETURN IS YOU
ATTRIBUTE US AS THE SOURCE OF
DATA.
IF YOU'RE GOING TO USE OUR DATA
JUST GIVE APPROPRIATE DATA WHERE
THE DATA CAME FROM.
OUR DATA IS MAINLY PLACED IN A
NEW DATABASE DEVELOPED BY NINDS
FOR ME/CFS RESEARCH.
THOUGHTS OF DIFFERENT GROUPS ARE
STARTING TO USE THE SECURE DATA
PLATFORM AND THERE'S TOOLS
EMBEDDED IN THE PLATFORM AND OUR
DATA SETS CAN BE FOUND HERE.
WHAT WE DID IS RECODED OUR CODED
DATA TO USE THE DATA IDENTITIES.
ALL THE DATA IDENTITIES AND THE
DATA SETS ARE THE SAME.
IF ONE WANTED TO LOOK AT THE
CORRELATION BETWEEN ANXIETY AND
NOREPINEPHRINE YOU CAN TAKE BOTH
DATA SETS AND DO IT ON YOUR OWN.
YOU DON'T NEED TO WORK THROUGH
US TO DO THAT.
WE'LL TRY TO USE THE I.D.s
ACROSS OUR DATA SETS EVEN ON
OTHER PLATFORMS.
IF YOU'RE INTERESTED IN LEARNING
MORE HERE'S THE E-MAIL AND
WEBSITE FOUR.
-- FOR YOU.
OUR RAW DATA IS STORED IN
CLASSIC RAW DATA ARCHIVES AND
SEQUENCE READS ARE IN SEQUENCE
READ ARCHIVE AND METABOLOMICS
DATA IS AT THE METABOLOMICS WORK
BENCH AND HERE'S THE INFORMATION
IF SOMEONE WANTS TO SEE THEM.
fMRI AND OTHER DATA CAN BE FOUND
IN THE NEWER ARCHIVE FUNDED BY
NINDS.
IT'S DEVELOPED TO HOST THIS
COMPLICATED TYPES OF DATA SETS.
IF YOU WANT TO LOOK AT OUR MRI
DATA THIS IS WHERE YOU WOULD GO.
COMING SOON WE'LL HAVE OUR EEG
DATA AND ACTIGRAPHY DATA IN THE
RESOURCE PICTURED HERE.
THE NSRR HOSTS A LOT OF
DIFFERENT POLYSOME --
POLYSOMNOGRAM DATA AND I'D LIKE
TO TAKE A MOMENT TO THANK SAM
BECAUSE HE REALLY PUT EFFORT
REQUIRED TO GET OUR CODE
TOGETHER AND TO REANALYZE OUR
DATA TO MAKE SURE EVERYTHING WAS
VALID.
THE DATA USED IN OUR PAPER, EACH
OF THE FIGURES HAS ITS OWN DATA
FILE TO BE KERRIED.
-- QUERIED.
EACH TABLE HAS ITS OWN DATA FILE
TO BE QUERY.
YOU CAN TWO BACK AND SEE IF YOU
CAN PRODUCE ALL THE DATA AND THE
DATA FILES ARE LINKED TO THE
PAPER ITSELF.
THE GITHUB REPOSITORY YOU'LL
FIND THE DIFFERENT CODES IN THE
PAPER.
AND YOU CAN SEE THE CODE WITHIN
OUR REPOSITORY IN AN EFFORT TO
TRY TO MAKE IT TOTALLY
UNDERSTANDABLE HOW WE CAME TO
THESE CONCLUSIONS.
I'LL TAKE A MOMENT TO TALK ABOUT
VALUE ADDED.
YOU SEE THE FIRST BROAD PATHS OF
ALL THE DATA.
THE BIG FIRST PAPER BUT IT
DOESN'T MEAN THERE CAN'T BE MORE
EFFORTS OF THINGS HAPPENING.
THERE WERE PAPER CAME ABOUT AS
WE WERE TRYING TO GET THE PAPER
OUT THE DOOR.
THE PAPER ON POST-EXERTION
MALAISE AND WAS3 AND THERE'S
BEEN OTHER PAPERS WITH OUR DATA
AS WELL.
THESE THREE PAPERS AND IT'S
INTERESTING TO ME AS A
RHEUMATOLOGIST AND THERE'S EXTRA
DATA AND THEY CAN SERVE AS A
WELL CHARACTERIZED COHORT FOR
COMPAR
COMPARISON.
WE HAVE A CHARACTERIZATION OF
THE GUT MICROBIOME AND STUDY
POST EXERTION MALAISE MORE
DEEPLY AND SAMPLES COLLECTED AT
MULTIPLE TIME POINTS RUNNING
THEM THROUGH MULTIPLEX ANALYSIS.
THERE'S WIDE POTENTIAL FOR
STUDYING SLEEP DEEPLY.
WE ONLY TALK IN BROAD STROKES
ABOUT CLINICAL SLEEP DISORDERS
BUT WE DIDN'T DO MUCH WITH
LOOKING AT SLEEP
MICROARCHITECTURE OR CIRCADIAN
RHYTHM ANALYSIS.
SAME WITH OUR ACTIGRAPHY DATA.
THERE'S POTENTIAL TO STUDY THAT
FURTHER.
THE DATA ONCE AVAILABLE
PUBLICALLY FOR THOSE INTERESTED
AND WANT TO WORK WITH US WE'RE
HAPPY TO AND THERE'S WORK BEING
DEVELOPED TO LOOK AT THE
MULTI-MODAL NEUROIMAGING OF
PHYSICAL FATIGUE AND SHOWS THE
fMRI DATA AND BECAUSE THERE'S
WISE COMBINE THEM INTO UNIQUE
INFORMATIONS.
ALSO I KNOW OUR COLLEAGUES I
PRESENTED TODAY ARE WORKING ON
CONNECTIVITY ANALYSES TO
UNDERSTAND HOW THE
NEUROEPINEPHRINE RICH BRAIN
AREAS MAY BE PLAYING A ROLE ON
THE INITIAL S.
WE PLAN ON ADDITIONAL MODELLING.
WE HAVE ARE WORKING WITH THE
V.A.
WE HAVE THE FIRST V.A.
INTRAMURAL NIH COLLABORATION TO
STUDY THE DISEASE AT NIH.
PROJECT IN DEPTH IS THE EFFORT.
I'M WORKING WITH THE
COMPUTATIONAL BIOLOGY TEAM TO
USE THEIR MODELLING WORK ON OUR
DATA TO LOOK AT IMMUNE
SIGNALLING NETWORKS AND TO USE
THEIR DRUG TARGETS SELECTION
PROCESS BY CROSS REFERENCING OUR
NETWORK ANALYSIS WITH DATABASES.
LASTLY, WE HAVE METHODOLOGIES.
ONE OF THE BIG QUESTION PEOPLE
HAVE IS LONG COVID AND ME/CFS
THE SAME THING ARE THEY
DIFFERENT?
WHEN WE COLLECT ENOUGH SAMPLES
WE CAN COMPARE THE DATA ONE WILL
THE NEW DATA WE'RE GENERATING.
I WANT TO THANK EVERYBODY SOME
PEOPLE WHO CONTRIBUTED LARGE AND
SMALL OVER THE EIGHT YEAR WE DID
THIS WORK.
I WANT TO THANK ALL THE PEOPLE
TONE RIGHT AND THEIR
CONTRIBUTIONS FROM FRANCIS
COLLINS TO INITIATING THE
PROJECT AND WALTER KOROSHETZ FOR
SUPPORTING US AND THOSE LISTED
HERE AND THE PEOPLE PART OF THE
PROJECT THAT CAME AND GO AND
SORT OF WHO HAVE PASSED OVER
THIS TIME.
OUR ETERNAL GRATITUDE TO THE
PARTICIPANTS TOE TO TRUST US AND
HEALTHY VOLUNTEERS WHO DID THE
SAME.
WITH THAT, THANK YOU.
WE'LL MOVE ON TO OUR PANELS.
>> NOW WE HAVE TWO PANELS.
THE FIRST IS THE STUDY
PARTICIPANTS PANEL CHAIRED BY
VICKY WHITTEMORE.
SHE'S A NEUROSCIENTIST IN THE
PROGRAM AT NINDS.
SHE'S A PROGRAM DIRECTOR AND
OVERSEES THE ME/CFS PROGRAM AND
HAS A BROAD UNDERSTANDING OF THE
DISEASE AND IS GOING TO CHAIR
THE PATIENT PANEL.
THANK YOU.
>> IT'S MY PLEASURE TO INTRODUCE
THIS PANEL AND THANK ALL THE
INDIVIDUALS WHO VOLUNTEERED AS
PARTICIPANTS AND THANK THE
SCIENTISTS PART OF THE STUDY.
IT'S BEEN AMAZING TO HEAR YOUR
RESULTS PRESENTED HERE TODAY.
THANK YOU VERY MUCH.
TODAY YOU'LL HEAR FROM DAVID
RHYMER AND HIS SISTER SUE AND
SELLA AND SOME RECORD MESSAGES
AROUND WE'LL LISTEN TO THEM NOW.
I'M NOT SURE HOW WE GET THEM
PLAYING.
>> I HOPE TO BE ABLE TO PROVIDE
MORE CONTEXT I BECAME SICK
QUICKLY IN THE DAY AFTER
THANKSGIVING 2014 I CAME DOWN
WITH WHAT WAS DIAGNOSED AS
BACTERIAL BRONCHITIS.
THE MEDICATIONS GIVEN DID THEIR
JOB AND FELT BETTER IN TERMS OF
THE BRONCHITIS BUT I KEPT
GETTING WEAKER AND WEAKER AND MY
BODY FELL LIKE LED AND A MONTH
LATER I WAS IN ABLE TO GET TO
THE DINING ROOM TABLE AND
FORWARDING TO 2017, 2018 I WAS
STUCK IN BED AND FRUSTRATED AN
ANGRY AND I CHANNELLED THAT
ENERGY INTO FIVE CLAIM TRIALS
THE NIH THE MOST TAXING AND MOST
EFFECTIVE ONE.
I WAS THRILLED WHEN I WAS
INVITED TO PARTICIPATE AND THE
ENTIRE PROCESS SHOWED THEY WERE
THOROUGH AND CARING.
I WAS THERE TWO WEEKS THE FIRST
TIME IN 2018 AND TWO WEEKS IN
2019.
I USED MY WHEEL CARE AND
ASSISTANCE FROM MY HUSBAND AND
FRIEND HOWEVER, I WAS SO CRASHED
AFTER THE TEST THEY WAS ONLY
ABLE TO GET TO ANY KIND OF
TESTING ON A STRETCHER.
I WAS A BED PAN AND UNABLE TO DO
ANYTHING AND NOT EVEN ABLE TO
SIGN THE CONSENT FORM.
I THINK IT WAS BEFORE THE LONG
HAUL WHERE THEY NOTICED I COULD
NOT LIFT MY HAND AND RIGHT MY
OWN NAME AT THAT POINT VERY
WELL.
IT WAS VERY TOUGH.
IT WAS WORTH THE EFFORTS
ABSOLUTELY.
SO I ALSO REALIZED THAT THE WAY
I CRASH EVEN IF I WAS ABLE TO
SIT ON THE EXERCISE BIKE FOR THE
CPET FOR SOME TIME IT I WOULD
ABSOLUTELY BE UNABLE TO BE IN A
METABOLIC CHAMBER 24 HOURS
WITHOUT ASSISTANCE.
I THEREFORE WAS NOT ABLE TO
PARTICIPATE IN THE CPET PART BUT
THEY INVITED KNOW DO A MODIFIED
PROTOCOL SO I WAS ABLE TO GO FOR
A SECOND VISIT.
I ALWAYS FELT THE TEAM LISTENED,
CARED FOR ME AND WANTED TO MAKE
PROGRESS FOR ALL OF US.
ONE EXAMPLE WOULD BE WHEN I
ARRIVED IN THE SECOND VISIT
THERE WAS A NEW RULE THAT WAS
SUPPOSED TO BE IMPLEMENTED
THROUGHOUT THE ENTIRE CLINICAL
CENTER WE HAD TO MARCH UP PLACE
STANDING SHOWING OUR STABILITY
AND THOSE THINGS TWICE A DAY.
FOR ME THAT WOULD HAVE BEEN A
HUGE EFFORT JUST TO DEMONSTRATE
I WAS FAILING A LOT OF THESE
FUNCTIONAL TESTS.
I EXPRESSED MY CONCERNS TO
DR. WALITT AND HE IMMEDIATELY
WENT TO THE HIGHEST LEVEL OF THE
NIH TO REQUEST AN EXEMPTION SO I
WOULDN'T HAVE TO SPEND MY ENERGY
ON SHOWING I CAN'T SIT UP, STAND
UP, WHAFRT WAS.
-- WHATEVER IT WAS.
I FELT TAKEN SERIOUSLY AND CARED
FOR AND WE ALL LEARN HOW TO PACE
AND MAKE OUR OWN CHOICE O AND
WHAT TO PEND EFFORT AND ENERGY
ON AND I WAS DETERMINED TO PUT
EVERYTHING IN TEST RESULTS AND
NOTHING ELSE.
USUALLY BY THEN OF MY VISIT I
WAS COMPLETELY CRASHED.
I WOULD SAY MOST THE RESULTS
THEY GATHERED 279 RESULTS IN MY
CHART.
MOST PDM OR CRASH RESULTS
BECAUSE I WAS NOT IN GOOD SHAPE.
GETTING HOME WAS DIFFICULT SO MY
HUSBAND HAD TO DRIVE FROM
CHICAGO TO BETHESDA WITH
MATTRESS IN THE BACK OF THE VAN
AND I WAS WEARING A DIAPER AND
IT WAS PRETTY UNPLEASANT.
THE APPLICATION PROCESS AND
AFTER THE CARE TEAM SURPASSED MY
EXPECTATIONS AND CHECK ON HOW I
WAS DOING AND SHOWED THE UTMOST
CARE AND THOUGHTFULNESS.
I'M VERY GRATEFUL FOR THEIR WORK
AND IT WAS DIFFICULT TO PROCESS
THE CRITICISM I SAW AFTER THE
PUBLICATION OF THE RESULTS.
IT WAS IN SUCH CONTRAST TO MY
PERSONAL EXPERIENCES.
I HOPE THIS WAS HELPFUL TO SEE
HEAR FROM A PARTICIPANT WHAT
CONDITION THEY WERE IN AND
ALWAYS FELT EVERYONE IN THE TEAM
AND BRIAN WALITT THERE DOING A
LOT OF THE TESTS HIMSELF ALWAYS
FELT ACCESSIBLE AND WANTING TO
TAKE CARE OF HIS PARTICIPANTS AS
BEST HE POSSIBLY COULD.
I HOPE THIS LEADS MORE AND A
THANK YOU FOR LISTENING.
>> I'M PLEASED FOR HERE IN THE
NIH STUDY TO SOLVE ME/CFS.
ONE OF THE MOST DIFFICULT
DECISIONS WAS DETERMINING TO
LIVE A CONTRIBUTING LIFE DESPITE
HAVING ME/CFS.
PRIOR I A BUSY PERSON.
IT WAS NOT UNUSUAL FOR KNOW GO
TO WORK 60 TO 80 HOURS AND THE
REMAINING HOURS DOING HOUSEWORK,
VARIOUS ACTIVITIES AND HELPING
OTHERS.
MY MORNINGS WOULD START EARLY
AND GET MY HUSBAND TO WORK.
I LOVED MY LIFE.
IT WAS FULFILLING.
MARCH 6, 2014 MY LIFE SHIFTED I
COULD NOT WALK WITHOUT
ASSISTANCE OR CALL MY HUSBAND
AND COULD NOT SPEAK ABOVE A
SLIGHT WHISPER AND NEEDED HELP
TO SHOWER, BRUSH MY TEETH.
I SAW MYSELF STOPPED.
I WAS AWAKE AND TAKE A CALL IT
LASTED LESS THAN A MINUTE.
MY SWEET HUSBAND AND FAMILY
BECAME MY ADVOCATES.
MY HUSBAND, CHILDREN AND
DAUGHTERS AND SON IN-LAWS AND
EXTENDED FAMILY RALLIED AROUND.
I REQUIRED THAT MANY PEOPLE TO
HELP.
I FELT I HIT A WALL THAT WAS
INSURMOUNTABLE.
I HAD DAILY TASKS AND A DAUG
DAUGHTER-IN-LAW TO BUY ME
GADGETS FOR DEVICES TO KEEP IN
TOUCH.
AND VARIOUS TREATMENTS WERE
TRIED AND NOT PAID FOR BY
EXPERIENCE AND EXPENSIVE.
SIGNS OF CRASHES WERE OBSERVED
AND SHARED SO EVERYONE CAN HELP
ME LEARN TO MANAGE EXERTION.
I COULD NOT ACTIVITY PARTICIPATE
IN LIFE TWO YEARS.
MY PRACTICER HELPED ME AND IT
WAS ARDUOUS TO FILL OUT THE
PAPER AND VERIFY WHETHER I HAD
ME/CFS WAS A BLESSING TO BE
ACCEPTED AND GIVE ME A NEW SENSE
OF USEFULNESS.
UPON LEARNING I WAS ACCEPTED WE
BEGAN A SERIES OF PREPARATORY
TEST TO SEE IF I CAN WITHSTAND
THE TRAVEL AND MY HUSBAND BOUGHT
A VAN TO TOTE ME AROUND AND ONE
TOOK ONE TRIP 1200 MILES AND
FOUND SITTING AT A 30 DEGREE
ANGLE AND UP RIGHT I COULD
TRAVEL AN HOUR AND A HALF AND I
HAD TO FIGURE OUT HOW TO BET
ACROSS THE COUNTRY WITHOUT
CAUSING ME HARM.
THE NIH PROVIDED A SCHEDULE IT..
AT THE TIME THE SLEEP PATTERNS
WERE 18 TO 22 HOURS OF SLEEP A
DAY.
THE LONGEST I STAYED WEAK WAS
ONE HOUR.
THE SCHEDULE WAS GOING REQUIRE
MORE.
I COULD STAY AWAKE AND UNRIGHT
FOR 15 TO 22 MINUTES AT 25
MINUTES I'D START TO SHAKE, FALL
FORWARD AND FEELING OF SHOOTING
PAIN A REFER TO AS ELECTRICALS
AND LIGHT AND SOUND WOULD BE
UNBEARABLE AND I'D HAVE TO LIE
DOWN.
I THOUGHT IF I CAN PARTICIPATE
IN THE DATA WOULD HAVE A NEW
DEPOSIT.
IT'S DIFFICULT TO DESCRIBE MY
EXPERIENCE WITH NIH.
MUCH TIME WAS SPEND TRYING TO
STAY AWAKE.
AS THE SURVEYS WERE IT MAY HAVE
BEEN MORE OR LESS BUT FELT
INTERNAL.
I NEVER EXPERIENCED SUCH DEVOTED
CARE AS I DID WITH THE STAFF AT
NIH.
STARTING WITH THE FIRST CONTACT
FROM DR. NATH AND BEING CHECKED
ON A FEW MONTHS AGO, MY TRUST IN
THE TEAM OF STRANGERS WAS
VALIDATED AN OWED THEM MY
DETERMINATION TO CONTINUE TO
LIVE WITH MY BEST EFFORT.
MY SWEET HUSBAND AND ONE OF MY
NIECES, TWO DAUGHTERS AND
SON-IN-LAW ALL MAKE SURE I HAVE
SUPPORT.
THEY'VE COME FROM AS FAR AS
UTAH, NEW YORK AND WASHINGTON,
D.C. TO MAKE SURE I FILL STEEL
CONNECTED AND MY WORK WAS VALUE.
THERE WAS AN OCCUPATIONAL HEALTH
PERSON WHO HELP ME GET BENEFITS
TO THE MAXIMUM AND THEN TALKED
ABOUT MY SORROWS AND MY LOSS OF
OCCUPATION AND TAKING CARE OF MY
FAMILY.
SHE KNEW WHAT QUESTIONS TO ASK
AND HELPED ME COME UP WITH A
SOLUTION AND FACE THOSE AND WHEN
I SAY I COOK OCCASIONALLY I MEAN
THREE TIMES IN ONE YEAR.
BUT IT HELPED AND I'M GRATEFUL I
WAS ABLE TO DO THOSE THREE
TIMES.
THERE WAS ANOTHER TEST THAT WAS
PARTICULARLY AN ELECTROMAGNETIC
TESTING AND SCIENTISTS CONCERNED
ABOUT MY COMFORT AND MY TEAM
SENT JOY TO BE THERE FOR THE
ENTIRE TIME AND ENSURE THEY DID
NOT CAUSE ANY HARM.
EVERYONE WAS SO VERY CAREFUL TO
LISTEN.
ANOTHER TIME THINGS WERE
PROTECTIVE WAS WHEN I WAS HAVING
MY SPINAL TAP.
THE SECOND ONE AND THEY ARE VERY
UNCOMFORTABLE AND HE SAID FIT
BECOMES TOO MUCH SAY STOP AND
WE'LL STOP.
SO I WEEKLY SAID STOP AT THE
POINT WHERE THEY NEEDED TWO CCs
MORE.
AND THE SCIENTISTS DID NOT HEAR
AND DR. WALITT WAS THERE AND
SAID, SHE SAID STOP.
AND THE WHOLE ROOM STOPPED.
THAT LEVEL OF PROTECTION IS
INVALUABLE.
SINCE READING THE SYNOPSIS OF
THE RESULTS AND ATTEMPTING TO
READ THE FULL STUDY I FEEL
RELIEF.
I'M GRATEFUL TO KNOW MY BODY HAS
ADD A SYSTEM DISRUPTION.
I KNOW SCIENTISTS CAN MOVE
FORWARD WITH ADDITIONAL
INFORMATION TO HELP STUDIES.
I ACCEPTED THE IMPACT ON MY
ABILITY TO FUNCTION.
IT TOOK NEARLY EIGHT MONTHS TO
RETURN TO MY LEVEL OF
FUNCTIONALITY PRIOR TO
PARTICIPATING IN THE STUDY.
IT'S DIFFICULT TO HAVE AN
ILLNESS.
DEVELOPING A DATA BANK IS
CRITICAL.
THE ME/CFS PATIENTS NEED ANSWER.
I'M GRATEFUL TO HAVE
PARTICIPATED.
I, A PATIENT WITH ME/CFS HOPE MY
CHILDREN'S GENERATION WILL SEE
BENEFIT AND BY THE CDC THE
MEDICAL COMMUNITY AND THE REST
OF THE SCIENTIFIC BODIES WORKING
ON THIS.
I HOPE MY GRANDCHILDREN'S
GENERATION INTERVENTIONS TO
MANAGE THIS DEBILITATING
ILLNESS.
AGAIN I WOULD LIKE TO THANK YOU
FOR THE OPPORTUNITY TO GIVE YOU
THE SCIENTISTS WE DEPEND ON A
SENSE OF MY GRATITUDE FOR YOUR
WILLINGNESS TO RESEARCH AND FIND
INFORMING TO SEEK OUT THE CAUSES
AND SOLUTIONS FOR ME/CFS.
IT IS A VERY COMPLEX AND
MISUNDERSTOOD AND UNDER FUNDED
DISEASE AND I APPRECIATE YOUR
SACRIFICE.
THANK YOU.
>> HELLO.
MY NAME IS DAVID REMER.
RETIRE TO ME/CFS WAYS FAMILY
PHYSICIAN WITH TRAINING IN
TROPICAL MEDICINE.
I WORKED IN INNER CITY TORONTO
AND THEN IN THE HIMALAYAN
COUNTRY FOR FIVE YEARS BEFORE
SETTLING INTO A SMALL TOWN
GENERAL PRACTICE IN CANADA AS
WELL AS MEDICINE I WITH YOU
INVOLVE IN NURSING HOME AND
TEACHING COMMUNITY GROUPS AND
SET ASIDE TIME FOR WIFE AND
THREE CHILDREN.
I'VE ENJOYED CHALLENGING MYSELF
WITH ACTIVITIES, WILDERNESS CA
CANOEING AND RUNNING.
ON A FAMILY TRIP I PICKED UP THE
VIRUS THAT RESULTED IN MY AND
STEP BY STEP I LOST THE ABILITY
TO DO ALL OF THESE THINGS.
WHEN IT WAS CLEAR I HAD THIS
POORLY UNDERSTAND CONDITION I
LOOKED FOR RESEARCH STUDIES
INVESTIGATING ME/CFS THAT WOULD
CONTRIBUTE TO BETTER INFORMATION
OF IT AND MAYBE EVEN OF HELP
PERSONALLY.
SO IT WAS VERY ENCOURAGING TO
FIND THE STUDY IN PROGRESS WITH
EXTENSIVE RESOURCES TRYING TO
FIGURE OUT WHAT WAS GOING ON.
I WAS IMPRESSED WITH HOW
THOROUGH THE INTAKE PROCESS WAS
AT RULING OUT OTHER POSSIBLE
CAUSES FOR MY SYSTEMS.
AND IT WAS FASCINATING BEING AT
THE NIH A PART OF HIGH TECH
TESTING SUCH AS THE METABOLIC
CHAMBER.
GENETIC SEQUENCING AND TABLE
TESTING AND THE MAGNETIC
STIMULATION.
POSITIONING THEIR MAGIC WAND
OVER THE PRECISE PLACE IN MY
HEAD TO STIMULATE A SINGLE
MUSCLE IN MY RIGHT FOREARM.
THROUGHOUT THE STUDY THE TEAM
WAS ACCOMMODATING OF MY NEED FOR
QUIETNESS AND REST BREAKS AND
OTHER ASSISTANCE.
OVER ALL, PARTICIPANTS WAS
AFFIRMING AND INTERESTING.
THANK YOU TO THE RESEARCH TEAM.
GRATEFUL TO HAVE BEEN ABLE TO
PARTICIPATE.
AT MY LOWEST IN THE YEAR
FOLLOWING THE STUDY, I WAS
APPROXIMATELY 15 OF 100 ON THE
DISABILITY RATING SCALE.
I'VE IMPROVED SIGNIFICANTLY
SINCE THEN BUT BY THIS TIME IN
THE AFTERNOON I'LL BE SLEEPING
AND NOT ABLE TO TAKE PART IN THE
DISCUSSION.
I HAVE A SUPPORTIVE FAMILY.
SO MUCH SO MY SISTER TOOK PART
AS A HEALTHY CONTROL AND HAS HER
OWN STORY.
>> I'M DAVE'S SISTER SUSAN.
I PARTICIPATED AS A HEALTHY
VOLUNTEER AND SAW MY BROTHER
SUFFERING FROM THIS STRANGE
ILLNESS.
I SIGNED UP IN HOPES OF LEARNING
ABOUT THE CONDITION AN HELP FIND
A CURE FOR MY BROTHER.
PARTICIPATING IN THE STUDY WAS A
FASCINATING EXPERIENCE AND HAD
ME BUSINESS AGREE DAWN TO DUSK
FOR A WEEK.
IT WAS INTIMIDATING TO BE
MONITORED BY SUCH BRILLIANT
MINDS DOING MATH EQUATIONS IN
THE fMRI MACHINE.
DURING THE MUSCLE BIOPSY I SENT
THIS PHOTO TO MY BROTHER WITH
THE CAPTION TEAM DAVE.
DR. WALITT WAS MONITORING FOR
REST RESULTS BETWEEN MY BROTHER
AND A.
PARTICIPATING WAS TRANSFORMATIVE
AND INSPIRED ME TO TAKE MY
HEALTH MORE SERIOUSLY.
I TOOK UP RUNNING AND TRAINED
FOR A HALF MARATHON AND WENT
BACKPACKING.
AFTER THE LOCKDOWN I CONTRACTED
A SERIOUS CASE OF COVID DESPITE
BEING FULLY VACCINATED.
I NEVER THOUGHT IT WAS HAPPEN
FROM ME AND I ALWAYS RECOVERED
BUT I BECAME PROGRESSIVELY WORSE
AND MY BODY WAS DYSREGULATE AND
SOON AFTER I WAS DIAGNOSED WITH
LONG COVID.
EIGHT THIS POINT I REACHED OUT
TO DR. WALITT.
GIVEN HOW THOROUGHLY I WAS
TESTED I FELT IF THEY TESTED ME
AGAIN IT WOULD RESULT IN
VALUABLE DATA.
I CAME BACK TO NIH AND
PARTICIPATED AN POST-CORONAVIRUS
STUDY WHICH CAN BE SEEN AS A
SEQUEL TO THE ME/CFS STUDY.
PARTICIPATING IN THE MORE RECENT
LONG COVID STUDY HAS BEEN SUCH A
BLESSING BREAKING DOWN THE
LONELINESS AND GAVE ME AN
OPPORTUNITY TO BRING GOOD FROM
MY OWN STORY.
THANK YOU FROM THE BOTTOM OF MY
HEART TO DOCTORS, WALITT, NATH
AND THE NIH STAFF FOR YOUR
WISDOM, COMPASSION AND SOUND
GUIDANCE.
I'M VERY AWARE MY STORE
SCOMBREERT OF-- MY STORY IS A PT
OF THE BIGGER STORY AND GLAD I
COULD PLAY A PART.
THANK YOU.
>> THANK YOU.
ARE THE INDIVIDUALS ON ZOOM?
ANY COMMENTS?
>> I WOULD START BY THANKING
EACH ONE.
NOT ONLY FOR PARTICIPATING BUT
SHARING THEIR STORIES AND JUST
MAKING THE VIDEOS IS NOT EASY
WHEN YOU SUFFER FROM THIS
DISEASE.
SHARING YOUR OWN ILLNESS
REQUIRES COVERAGE.
THESE PATIENTS ARE THE MOVERS
AND SHAKERS AND MAKE THINGS
HAPPEN THAT WOULDN'T HAPPEN
OTHERWISE FOR THAT WE'RE
EXTREMELY GRATE.
.
-- GRATEFUL.
WE HAVE OTHER PATIENTS HERE IN
THE AUDIENCE.
THAT HAVE IDENTIFIED THEMSELVES
PREVIOUSLY.
I WELCOME THEM TO COME OVER AND
MAYBE COMMENT IF YOU WANT.
TALK ABOUT YOUR EXPERIENCE AND
WE LEARN FROM YOU SO HERE'S A
GREAT OPPORTUNITY FOR YOU TO DO
THAT.
>> JOE HANSON AGAIN, PATIENT.
EVERYONE WORKED HARD IN THIS
STUDY.
BUT HAVING EXPERIENCED
POSTEXERTIONAL MALAISE OFF AND
ON FOR 19 1/2 YEARS, I HONESTLY
DO NOT CONSIDER IT TO BE A
SUBJECTIVE EXPERIENCE.
THAT WOULD BE THE LAST WAY I
WOULD DESCRIBE IT.
THANK YOU.
>> I'LL JUST SAY THERE'S SIMILAR
EXPERIENCES.
THANK YOU.
>> DO YOU HAVE ANYTHING I'D LIKE
TO COMMENT ON BEFORE WE WRAP UP
THE PANEL?
>> I'D LIKE TO THANK EVERYONE
AGAIN.
IT'S BEEN A TRANSFORMATIVE
EXPERIENCE AND GRATEFUL TO THE
TEAM.
THANK YOU.
>> ALSO, ABSOLUTELY GRATITUDE IS
MOST PREVALENT FEELING AND HOPE
AND EXCITEMENT IT'S JUST THE
BEGINNING AND WILL LEAD TO MORE
TO COME.
THANK YOU, EVERYONE.
>> THANK YOU EVERYONE.
>> NOW WE HAVE AN ESTEEMED PANEL
OF EXPERTS AND WELCOME THEM UP
FRONT AND TWO ONLINE.
A HYBRID PANEL.
WE'LL SEE HOW WE CAN MAKE THAT
WORK.
WE HAVE EXPERTS FROM A WIDE
VARIETY OF EXPERIENCES WITH
RESEARCH WITH ME/CFS AND I WANT
TO INTRODUCE THEM TO YOU.
VICKY WHITTEMORE IS THE PROGRAM
DIRECTOR AT NINDS.
SHE OVERSEES THE ME/CFS RESEARCH
PROGRAM AND WAS INSTRUMENTAL IN
PUTTING TOGETHER THE ROAD MAP
FOR ME/CFS.
THAT ENSURES THE RESEARCH WILL
CONTINUE AS LONG AS ANNIVERSARY
TO CURE THE DISEASE.
JOE BREEN HAS BEEN A STRONG
SUPPORTER OF ME/CFS RESEARCH.
TOGETHER THEY OVERSEE THE ENTIRE
PORTFOLIO ACROSS THE COUNTRY
FUNDED THROUGH NIH.
THEY HAVE A GREAT DEPTH AND
BREADTH OF KNOWLEDGE WITH THE
DISEASE.
NEXT I WANTED TO EINTRODUCE
DR. KOMAROFF AND SENIOR
PHYSICIAN AT THE BRIGHAM AND
MANY LEADERSHIP POSITIONS AND
WAS A PIONEER IN GETTING CLOSER
TO ME/CFS RESEARCH AND HAS BEEN
A STRONG ADVOCATE OF THIS
RESEARCH AND DISEASE AND
PATIENTS THEMSELVES AND WE'VE
LEARNED A TREMENDOUS AMOUNT FROM
THEM.
HE WAS ON OUR ADJUDICATION PANEL
AND WHEN WE FIRST STARTED THE
STUDY HE GAVE US EXCELLENT
ADVICE ON HOW TO SHAPE IT AND
WHAT TO DO AND THROUGHOUT THIS
PROCESS HE'S CONTINUED TO BE A
CHAMPION FOR US.
WE THANK HIM FOR THAT AND THANK
HIM FOR TAKING THE TIME TO SERVE
ON THIS PANEL.
I KNOW HE WOULD HAVE LIKED TO BE
HERE IN PERSON BUT HAD A LONG
TR
TRIP.
NEXT IS NANCY KLIMAS ON ZOOM AND
HAS OVER 40 YEARS ON ME/CFS AND
TAKE CARING OF THESE PATIENTS.
WE HAVE LEARNED A TREMENDOUS
AMOUNT FROM HER AS WELL.
SHE'S INSTRUMENTAL IN REFERRING
PATIENTS TO US AND DIRECTOR OF
THE INSTITUTE OF NEUROIMMUNE AT
NOVA SOUTHWESTERN COMMUNITY AND
DRUSHLTH DIRECTOR
CHAIR OF THE DEPARTMENT OF
CLINICAL IMMUNOLOGY.
THANK YOU FOR SERVING ON THE
PANEL.
I'D LIKE TO INTRODUCE A CLOSE
COLLABORATOR FRIEND AND EXPERT,
DR. LIPKIN.
THE THE JOHN SNOW PROFESSOR OF
EPIDEMIOLOGY AT COLUMBIA
UNIVERSITY AND DIRECTOR FOR THE
CENTER OF INFECTION AND IMMUNITY
AND MOST KNOW HIM AS THE VIRUS
HUNTER.
SHE'S DISCOVERED MORE VIRUSES
THAN ANYBODY ON THE PLANET FROM
WEST NILE TO SARS AND HAS BEEN
INVOLVED IN THE SARS COV2
PANDEMIC AS WELL AND HAS BEEN
STRONGLY COMMITTED TO STUDYING
ME/CFS AND DEVOTING THE REST OF
HIS ACADEMIC CAREER TO THIS
DISEASE AND HAS BEEN A STRONG
FOR TREATMENT TRIALS ON THE
DISEASE.
WE LEARNED TREMENDOUSLY FROM HIM
AND WAS TELLING ME HOW TO DO
ANALYSIS AND WHO TO TALK TO FOR
WHICH I GREATLY PATIENT.
THANK YOU FOR SERVING ON THE
PANEL.
I'LL TURN IT OVER TO YOU NOW TO
DISCUSS FINDINGS AND WHERE TO
GO.
>> THANK YOU FOR ALLOWING KNOW
PARTICIPATE.
A COMMITMENT ON THE WEST COAST
MADE IT IMPOSSIBLE TO BE THERE
TODAY.
I WANT TO START WITH SHORT
COMMENTS FOR CONTEXT.
40 YEARS AGO WITH INTEREST IN
ME/CFS RESURFACED WE DIDN'T
IDENTIFIED UNDERLYING
ABNORMALITIES THAT COULD EXPLAIN
THE SYMPTOMS AND THAT LED SOME
PEOPLE TO SAY THERE'S NOTHING
REALLY WRONG WITH PEOPLE WITH
THIS ILLNESS.
OVER 40 YEARS THERE'S NOW ABOUT
10,000 PER REVIEWED PUBLICATIONS
THAT INVOLVE THOUSAND OF
PATIENTS WITH THIS ILLNESS THAT
ARE REVEALED REPLICATED
UNDERLYING BIOLOGICAL
ABNORMALITIES OF THE BRAIN,
IMMUNE SYSTEM AND ENERGY
METABOLISM AND GUT MICROBIOME
AND CARDIO VASCULAR SYSTEM AND
THE STUDY PRESENTED TODAY IS THE
MOST INTENSIVE STUDY OF PEOPLE
WITH ME/CFS THAT HAS EVER BEEN
DONE AND MORE MEASUREMENTS OF
BODY SYSTEMS THAN HAS BEEN DONE
BEFORE.
IT CONFIRMED MANY PAST STUDIES
AND IN OF NEW ABNORMALITIES NOT
PREVIOUSLY RECORDED.
IF YOU WANTED TO BOIL DOWN WHAT
THE COMPLICATED STUDY WITH
MASSIVE AMOUNTS OF DATA HAS
SAID, IT SAYS ME/CFS IS A BRAIN
DISEASE LIKELY INDUCED BY
EXHAUSTION.
ONE NOVEL FINDING IS THIS
INVOLUNTARY UNDERLYING
ABNORMALITY IN ONE PART OF THE
BRAIN THAT INVOLVES DEFICIENCY
OF THE BRAIN CHEMICAL
NOREPINEPHRINE.
THAT ABNORMALITY IN THE IMMUNE
EXHAUSTION FOUND BY THE STUDY
HAVE BEEN IDENTIFIED BY THE
STUDY AT TARGETS FOR POTENTIAL
TREATMENTS AND WILL OPEN THE
DOOR TO STUDYING THE UNDERLYING
BIOLOGY OF THE ILLNESS.
I THINK THIS IS ALL REALLY GOOD
NEWS THAT ADDS TO THE GROWING
RECOGNITION THAT ME/CFS AND LONG
COVID-19 AND OTHER POST ACUTE
SYNDROMES IS A MEASURE OF THE
RECOGNITION AND PARADOXICALLY
TIME MAGAZINE ANNOUNCED THE MOST
INFLUENTIAL PEOPLE IN GLOBAL
HEALTH INCLUDING ALL DISEASES
AND ALL PEOPLE OVER THE WORLD AN
OF THOSE ONE IS A PATIENT WITH
ME/CFS.
A PATIENT ACTIVIST AND SIGNSS -
SCIENTISTS INCLUDING DR. NATH.
I THINK CONGRATULATIONS TO THEM
GOOD NEWS IT'S RECOGNIZED MORE
AND MORE.
LET ME THROW IT TO THE PANEL FOR
S ON TODAY.
-- OBSERVATIONS ON TODAY.
>> I'VE THAT'D PLEASURE OF WORK
WITH TONY FOUR YEARS.
HE'S GOOD AT SUMMING UP THE
STATE OF KNOWLEDGE.
I WANT TO ECHO HIS COMMENTS WITH
THE STUDY.
THAT NOWHERE BUT THE NIH WHERE
THIS COULD HAVE BEEN DONE AND
THE LEADERSHIP IS EXTRAORDINARY.
IS THIS THE LAST WORD ON ME/CFS?
OBVIOUSLY NOT.
I WANTED TO TRY TO SUMMARIZE
WHAT A TOOK FROM TODAY'S
CONVERSATION AND DISCUSS THE
IMPLICATIONS OF SOME FINDINGS.
THE IMMUNOLOGY OF ME/CFS GOES
BACK A LONG TIME.
WE FOUND EVIDENCE OF
ABNORMALITIES OF B CELLS IN THE
'90s AND CHANGE IN CELL COUNTS.
TODAY WE HEARD ABOUT THIS
MOLECULE CALLED PD1 ASSOCIATED
WITH IMMUNE EXHAUSTION.
THIS IS TARGETED IN PEOPLE WITH
CERTAIN TYPES OF CANCERS LIKE
MELANOMA WITH ANTIBODIES.
YOU CAN SUPPRESS ITS ACTIVITY.
THE IMPORTANCE OF THIS COVERS
SEVERAL AREAS.
ONE IS IF THERE'S A PERSISTENT
INFECTION AND NOT SAYING THERE
IS BUT IF THERE WERE, INCREASED
LEVELS OF PD1 OR ANY OF THE
ASSOCIATED MOLECULES WOULD
RESULT IN DIFFICULTIES IN
CLEARING INFECTIONS.
THAT BRINGS US AND THIS
PARTICULAR STUDY WAS FOCUSSED ON
PATIENTS WHO HAD INFECTION BUT I
THINK REPRESENTS THE MAJORITY O
OF PEOPLE WITH ME/CFS.
WHAT DO WE KNOW ABOUT INFECTIONS
WITH ME/CFS?
WE'VE BEEN TALKING ABOUT THAT
FOR A LONG TIME.
OUR CENTER HAS BEEN TRYING TO
FIND BACTERIA, VIRUSES, FUNGI
LINKING THEM TO ME/CFS FOR MANY
YEARS.
WE HAVE NOT FOUND SUCH EVIDENCE
EXCEPT FOR THE MICROBIOME WORK
I'LL TALK ABOUT IN THE NEXT
SECTION.
EITHER WE'RE NOT LOOKING IN THE
RIGHT PLACE OR AT THE RIGHT TIME
OR RIGHT SAMPLE OR THERE MAY
HAVE BEEN HIT-AND-RUN MECHANISM
I FAVOR SO YOU'RE NOT GOING TO
FIND IT USING DIRECT METHODS.
YOU HAVE TO LOOK FOR FOOT PRINTS
OF EXPOSURE AND THIS BRINGS US
TO ANTIBODIES.
THE CHALLENGE WITH ANTIBODIES IS
THERE IS NO HUGE TEST THAT
ALLOWS TO YOU SIMULTANEOUSLY
TEST IN A RIGOROUS WAY FOR
EXPOSURE.
THERE ARE METHODS COMING TO DO
THIS TO SOME EXTENT.
I THINK IT WILL BE IMPORTANT.
THE OTHER ISSUE GETS BACK TO
TIMING.
IF DO I CROSS-SECTIONAL FALSE
AND LOOK AT ONE POINT --
ANALYSIS AND LOOK AT ONE POINT
IN TIME AND A YEAR LATER I MAY
HAVE MISSED A DISEASE THAT
TRIGGERED AND THAT'S IMPORTANT.
THE TWO APPROACHES REFERRING TO
WORK WE'RE DOING TOGETHER WE
LOOK AT INDIVIDUALS WITH AN
EXACERBATION IN THE SYMPTOMS AND
SPECIFICALLY LOOK TO SEE IF WE
CAN FIND EVIDENCE OF INFECTION
AT THAT POINT POINT AND LOOK FOR
EVIDENCE IN ANTIBODY PROFILES
THAT HAVE CHANGED.
THE OTHER APPROACH IS TO USE A
REPOSITORY AT THE DEPARTMENT OF
DEFENSE USED TO LOOK AT TRIGGERS
FOR MULTIPLE SCLEROSIS AND YOU
CAN LOOK FOR PEOPLE WHO
SUBSEQUENTLY DEVELOPED ME/CFS OR
RELATED SYNDROME AND ASK WHETHER
OR NOT THE YEAR PRIOR BECAUSE
THE SAMPLES WERE COLLECTED
ANNUALLY WHETHER THERE'S AN
EXPOSURE THAT MIGHT BE LINKED.
AND WHAT SOME PEOPLE ALLUDED TO
IS THE INNATE IMMUNE SYSTEM.
IT'S PRIMITIVE.
YOU CAN FIND IT IN FRUIT FLIES
AND WORMS AND ELIMINATING
VIRUSES AND BACTERIA FUNGI AND
IF NOT CONTROLLED YOU CAN FIND
OF THE EXPRESSION OF VARIOUS
MOLECULES THAT GIVE RISE TO
SICKNESS BEHAVIORS, FOR EXAMPLE.
THEY CAN HAVE INDIRECT AND
DIRECT EFFECTS ON MITOCHONDRIA
AND IMPACT THE FUNCTION.
BUTYRATE MODULATES IMMUNE
RESPONSES AND MAINTAINS THE
INTEGRITY OF THE CLONIC
EPITHELIUM AND KEEPS WHAT'S
SUPPOSED TO BE OUTSIDE OF THE
BODY AND PREVENTS IT FROM GOING
INSIDE.
THE IMPLICATIONS ARE IF WE CAN
FIND WAYS TO DAMPEN THE IMMUNE
RESPONSES PARTICULARLY INNATE
IMMUNE RESPONSES IT HAS TO BE
DOWN SAFELY AND RIGOROUSLY BUT
WHERE THE TIME HAS COME.
SIMILARLY WITH BUTYRATE AND THE
THERE ARE WAYS BY USING
PREBIOTICS SPECIFIC FOODS THAT
ENCOURAGE THE GROWTH OF SPECIFIC
BACTERIA AND PROBIOTICS THAT
CHANGE THE COMPOSITION OF THE
GUT.
THESE ARE THINGS WE CAN BE
PURSUING AND I THINK AGAIN THE
TIME HAS COME TO START THINK
ABOUT HOW TO DO THIS.
AS I THINK ABOUT THE DISEASE TO
THE METABOLIC FACTORS.
THERE'S A VARIETY OF SMALL
MOLECULES RELEASED TO MEASURE
PROFILE.
THE IF YEAR INTERESTED IN
SOMETHING HAPPENING IN SIDE OF
THE CELL THAT FACTOR MAY BE
DILUTED BY THE TIME IT GETS OUT
INTO A FLUID LIKE PLASMA TO
MEASURE.
NONETHELESS, DESPITE THE LACK OF
SENSITIVITY, WE AND OTHERS ARE
FINDING SIGNALS THAT WILL BE
VERY IMPORTANT.
NOW, WHAT WE DIDN'T TALK A LOT
ABOUT TODAY WERE SEX SPECIFIC
DIFFERENCES AND I THINK THIS IS
AN OVERSIGHT.
PROBABLY BECAUSE THERE WEREN'T
ENOUGH SUBJECTS.
IN OUR EXPERIENCE MORE WOMEN ARE
AFFECTED THAN MEN AND WOMEN HAVE
DIFFERENT METABOLIC
ABNORMALITIES AND WE FOUND
RESULTS IN THE ELABORATION OF
THE ENERGY MOLECULES AND ATP YOU
HEARD ABOUT THERE'S THERE'S ALSO
LIPID PROBLEMS ASSOCIATED WITH
INFLAMMATION.
SOME MAY REMEMBER THE MOVIE
CALLED SUPER SIZE ME?
DOES ANYBODY REMEMBER THAT?
HE GOES ON THIS DIET TO
McDONALDS AND EVERY TIME THEY
SAY SUPER SIZE ME AND EATS IT
AND GETS THE IT INFLAMMATORY
DISEASE ASSOCIATED.
I'M TRYING TO SAY LIPIDS AREN'T
NECESSARY GOOD FOR YOU.
>> THEY'VE FOUND ABNORMALITIES
AND THE FINDINGS ON
CATECHOLAMINE WERE INTERESTING.
I'M WONDERING WHETHER EVERYTHING
WAS WITH DECREASE IN SYNTHESIS
AND WHETHER THERE'S PROBLEMS IN
REUP TAKE AND I DON'T FLOW IF
GOLDSTEIN IS STILL HERE.
AND THERE'S THINGS LIKE REUP
TAKE INHIBITERS.
WE DON'T HAVE ENOUGH RESOURCES
WHAT WE NEED TO DO AND IF I
LEARNED ANYTHING AT 40 YEARS OF
DOING THIS WORK WE NEED BETTER
ADVOCATES.
THE SQUEAKY WHEEL GETS TE
GREASE.
OVER.
>> CAN I ASK VICKY WHITMORE TO
COMMENT ON TODAY'S PRESENTATION.
SURE, THANK YOU TONY AND IAN.
NICE SUMMARY.
I ASKED ABOUT AUTONOMIC DISEASE
AND I LEARNED A LOT AND THE
WINDOW IN THE RESEARCH HAS AND
WHEN DR. KOROSHETZ AGREED TO
TAKE OVER COORDINATING THE TRANS
NIH ME/CFS WORKING GROUP AND
MOVED THAT TO NINDS AND JOE AND
I HAVE BEEN WORKING CLOSELY WITH
DR. KOROSHETZ SINCE THEN.
LOOKING AT THE DATA AND RESEARCH
BEING DONE THERE WAS AND WHERE
WE ARE TODAY, WE'RE CONSIDERING
THE LENGTH OF ILLNESS THE ITSELF
OF THE INDIVIDUAL AND CONSIDER
ABOUT WHAT IS POTENTIALLY THE
TRIGGER OF THE DISEASE AND
FACTORS IF YOU LOOK AT THE OLDER
LITERATURE EVERYONE WAS PUT INTO
ONE BUCKET WHETHER YOU'D BEEN
ILL FOR THREE YEARS OR 30 YEARS.
WE'RE FINDING FROM THE RESULTS
OF THE COLLABORATIVE CENTERS
THERE'S A SIGNIFICANT DIFFERENCE
BETWEEN THE INDIVIDUALS WHO HAVE
BEEN ILL FOR A FEW YEARS VERSUS
ILL FOR 10 MORE YEARS.
THOSE WILL ARE CRITICALLY
IMPORTANT AS WE THINK ABOUT THE
DISEASE AND THINK ABOUT
PERFORMING RIGOROUS RESEARCH ON
THE DISEASE.
YOU HEARD THE RESEARCH ROAD MAP
WE'VE WORKED ON FOR A YEAR AND A
HALF.
TUNE IN ON THE AFTERNOON OF MAY
15 WHEN THE REPORT WILL BE
PRESENTED TO THE NINDS ADVISORY
COUNCIL AND IT'S JUST THE
BEGINNING OF CONTINUING TO MOVE
FORWARD AND STIMULATE RESEARCH.
I'M NOT GOING STEAL THE THUNDER
OF THE PRESENTATION BUT WE WENT
INTO DEVELOPING THE REPORT WITH
THE PREMISE ASKING ALL THE
SPEAKERS WHO PARTICIPATED IN THE
WEBINARS WHAT DO WE KNOW AND
DON'T WE KNOW AND NEED TO KNOW
TO NOVE CLINICAL TRIALS.
PUT THE FOCUS ON THE SCIENTIFIC
EVIDENCE TO AS RAPIDLY AS
POSSIBLE GET CLINICAL TRIALS
GOING FOR INDIVIDUALS WITH
ME/CFS WHO HAVE BEEN WAITING FOR
SO LONG.
CLEARLY THEY NEED TO BE SAFELY,
RIGOROUSLY AND THOUGHTFULLY.
THAT'S THE FUTURE DIRECTION OF
WHERE THE RESEARCH ROAD MAP WILL
HELPFULLY TAKE US TO ACCELERATE
THE RESEARCH INTO NEW TREATMENTS
FOR INDIVIDUALS WITH ME/CFS.
SO I THINK ALL THE DATA
REPLICATES SOME DATA AND I THINK
OPENS AVENUES FOR EXTENSIVE
RESEARCH.
WHEN YOU SEE THE RESEARCH REPORT
YOU'LL SEE WE HAD SIGNIFICANT
DIFFICULTY NARROWING DOWN THE
RESEARCH PRIORITIES.
THERE ARE PROBABLY MORE THAN 100
RESEARCH PRIORITIES IN THE
RESEARCH ROAD MAP BECAUSE THAT
JUST INDICATES HOW MUCH IS YET
TO BE KNOWN AND HOW MUCH IS YET
TO BE DONE TO MOVE TOWARDS
TREATMENTS BUT THE RESEARCH DONE
AT NIH HAS BEEN SIGNIFICANT AND
HELPED IN WAYS THAT COULDN'T
HAVE BEEN DONE ANYWHERE OTHER
THAN HERE AT THE CLUB CLINICAL
CENTER.
THANK YOU.
>> JOE BREEN, ANY THOUGHTS?
>> A FEW THOUGHTS.
NIAID HAS HAD A LONG STANDING IN
ME/CFS BECAUSE OF THIS
CONNECTION WITH POSTINFECTION
AND THE CONNECTION IS THERE THE
EPIDEMIOLOGIC DATA IS CLEAR TA
LOOKS LIKE A VIRUS BUT HAVEN'T
BEEN ABLE TO ISOLATE WHATEVER IT
IS.
I HAVE A FEW THOUGHTS FROM
TODAY.
I GUESS WE JUST HEARD FROM SOME
PATIEN
PATIENTS AND I WAS STRUCK BY
THEIR CONTRIBUTIONS TO THE STUDY
BUT THE IDEA THE HOPE THAT
GRANDKIDS WOULD BENEFIT STRUCK
ME.
I HOPE WE DON'T HAVE TO WAIT
THAT LONG.
THAT HIT ME HARD AND WANTED TO
NOTE THAT.
THAT SHOWED A LOT OF GRACE FRANK
FLIP -- FRANKLY.
WE STARTED THIS EFFORT 10, 15
YEARS AGO WHEN WE
REOESHREOESHRGANIZED
THE DISEASE AND I WAS IN
POST-LYME DISEASE AND I'M STRUCK
BY OTHER O SIMILARITIES AND
POSTINFECTIOUS SEQUELAE AND LONG
COVID NOW I EXPECT SOME OF THE
BENEFITS WILL TRANSLATE AND THE
STRUCTURE IN HOW TO STUDY IT
WITH OUTCOMES THAT ARE PATIENT
DERIVED AND STANDARDIZED ACROSS
DIFFERENT MECHANISMS AND
INTERVENT
INTERVENTIONS I DON'T KNOW
ME/CFS IDENTIFIED BEFORE COVID
IS SAME AS LONG COVID.
PERHAPS WHEN WE HAVE THE RESULTS
OF THE MORE IN DEPTH PHENOTYPING
WE'LL HAVE THAT BUT WE DON'T
HAVE THAT YET.
I'M HOPEFUL BECAUSE I SAW NEW
AVENUES OF RESEARCH AND
UNDERSTANDING THAT SHOULD
HOPEFULLY LEAD TO DIFFERENT
INTERVENTIONS I WOULD HAVE
GUESSED FROM AN EXHAUSTED T CELL
PHENOTYPE FOR EXAMPLE OR PD1
PATHWAY UTILIZING SOME
NEUROLOGY.
WE SAW INCLUDE FROM THE DECEMBER
ABOUT BRAIN IMAGING AND fMRI IN
THE NATURE PAPER.
THOSE ARE ALL AREAS THAT CAN BE
THOUGHT ABOUT BY A NUMBER OF
GROUPS AND EXPLORED.
I'M ENTHUSIASTIC BUT TEMPERED
FROM THE TALK OF THE PATIENT
THAT TODAY THEY FEEL TERRIBLE
AND THESE THINGS THEY TAKE TIME
TO DEVELOP.
I LOOK FORWARD TO THE CHALLENGE
BUT HEALTHY RESPECT OF THE
SUFFERING OCCURRING AT THE SAME
TIME.
>> THANK YOU, JOE.
FINALLY PROFESSOR KLIMAS.
TELL US YOUR THOUGHTS
>> WE FIRST TALKED ABOUT THIS IN
THE EARLY '90s.
>> I THINK LATE '80s.
>> I REMEMBER THAT.
SOME THINGS DISCOVERED IN THE
EFFORT WERE IN THE EARLY PAPERS.
THE CHRONIC IMMUNE ACTIVATION
AND THE INFLAMMATORY MARKERS AND
SO ON.
THE STUDY SHOWED IMMUNE
EXHAUSTION AND WAYS OF MEASURING
THAT.
THERE'S AN IMPORTANT CLINICAL
OBSERVATION WE ACT ON IN OUR
CARE AND OTHERS HAVE REMARKED.
IT'S IMPORTANT TO KNOW NOT JUST
IF THE CELLS ARE BROKEN
ENERGETICALLY SPEAKING BUT WHEN
DID THEY GET THAT WAY?
THESE ARE IMPORTANT AND CUTTING
EDGE QUESTIONS.
WHAT'S SPECIAL ABOUT THE STUDY
AND THE ELEPHANT AND BLINDFOLDED
WISE PEOPLE SAYING IT'S A
BIOLOGIC DISEASE, NO IT'S
MICROBIOME AND OTHERS AND HAVE
YOU THE WHOLE ELEPHANT IN THE
STUDY.
THE DEPTH OF THE WORK DONE IN
EVERY ASPECT EVERY WAY YOU CAN
PIER -- PEER THROUGH THE ONE --
WINDOW AND LOOKED AT THE ILLNESS
AND DEMONSTRATED WHAT THE VIEW
WAS.
THE REAL STRENGTH THAT WILL COME
FROM THIS IS TAKING THE DATA AND
MODELLING IT TO MECHANISMS OF
ILLNESS AND TARGETS FOR
THERAPEUTIC INTERVENTION.
WHAT BRIAN TALKED ABOUT DATA
SHARING AND OPEN ACCESS TO DATA
HOW AMAZING WE CAN DO IT IN A
WAY THAT CAN POTENTIALLY TEACH
US NEW THINGS.
OUR GROUP HAS BEEN DOING DYNAMIC
MODELLING AND COMING UP WITH
MODELS AND INTERVENTIONS A
NUMBER OF YEARS NOW AND LOOKED
AT IT THROUGH THE IMMUNE WINDOW
AND THROUGH NEUROPEPTIDES AND
CELLULAR FUNCTION.
NOT WHAT'S THE BRAIN DOING?
YET IT'S THE MOST IMPORTANT.
HOW COOL WE'LL BE ABLE TO TAKE
THE NEUROPHYSIOL DATA AND DROP
IT IN THE MODELLING SYSTEMS AND
THE MOST GRANULAR DATA SET AND
MOST DATA TO PULL IN THE MODEL.
ONE THING THAT'S EXCITING IS
THEY'RE NEVER COWED BY TOO MUCH
DATA.
MORE IS BETTER.
I LOVE THAT.
I THINK THAT'S EXCITING.
AND COMPARING ANY ME/CFS TO
OTHER ILLNESSES WITH ACUTE BRAIN
TRIGGERS LIKE LONG COVID OR IN
THE CASE OF THE STUDY THE V.A.
IS IS PROCEEDINGS TO DO IN
PARTNERSHIP WITH DR. NATH IN
GULF WAR ILLNESS A NEUROTOXIC
INJURY IN 1991 WITH 1 IN 3
VETERANS DEPLOYED STILL
SUFFERING FROM NEUROTOXIN AND IT
PRESENTS IDENTICALLY TO ME/CFS
AND I ASKED HOW THINGS GOT
STARTED AND BIO LOGICALLY THERE
ARE DIFFERENCES AND
SIMILARITIES.
THE DIFFERENCES MATTER.
THAT MIGHT INFLUENCE TREATMENT.
WHAT'S THE COMMONALITY BETWEEN
THE ILLNESSES THAT HAS A
CLINICIAN LIKE ME SCRATCHING MY
HEAD AND I DIDN'T KNOW THE
HISTORY AND COULDN'T TELL LONG
COVID FROM ME/CFS OR ANOTHER
MOLD EXPOSURE INJURY OR TOXIC
INJURIES.
THEY PRESENT IN SIMILAR WAYS.
WHAT WE LEARNED CALLING A.I. AND
COMPUTATION MODELLING FOR A LONG
TIME WILL GIVE INSIGHTS THAT ARE
TRANSLATABLE TO INTERVENTION.
WE KHAVE BEEN TAKING CARE OF
THESE PATIENTS A LONG TIME AND
WANTING TO MOVE THE NEEDLE AND
GET FOCUSSED THERAPIES WITH
SYMPTOM MANAGEMENT AND YOU NEED
THIS KIND OF SCIENCE TO PUSH
THAT THROUGH.
IF I WOULD UNDER SCORE WHAT
HAPPENS NEXT?
LET'S GET CLINICAL TRIALS.
LET'S TAKE THIS TYPE OF DATA AND
DO THE NEXT LEVEL OF STUDIES AND
TAKE THE THINGS VALIDATED BY THE
STUDY AND ACT ON THAT
INFORMATION.
WE WOULDN'T HAVE REASONABLE
HYPOTHESES THAT INVOLVE A
CLINICAL TRIAL TO TEST TO GET
PEOPLE BACK TOWARDS HEALTH.
GREAT STUDY.
AND YOU CAN DO END OF ONE
MODELLING AND THAT.
YOU CAN GET TO A SINGLE
INDIVIDUAL AND MODEL THE DISEASE
THANE ONE PERSON.
THAT'S VERY COOL.
IF YOU CAN DO THE MODELLING WITH
THE GROUP ANALYSIS AND BREAK THE
MEN AND WOMEN A PART AND TAKE
ONE AT A TIME AND MODEL EACH
PERSON'S UNDER PINNINGS OF
ILLNESS AND FIND WHERE THEY
OVERLAP.
THAT'S ANOTHER SCIENTIFIC
APPROACH OUR GROUP IS ENGAGING
IN AND THIS HIGHLY GRANULAR DATA
SET WILL ALLOW THAT.
>> THANK YOU.
SPEAKING OF NEXT STEPS, THAT'S
THE NEXT PANEL IN THIS MEETING.
>> TONY, WE'VE TALKED ABOUT
EARLY VERSUS LATE DISEASE.
THIS IS IMPORTANT.
WHEN YOU LOOK AT CYTOKINES THEY
TEND TO BE UP AND PEOPLE BURN
OUT AND THE LEVELS DROP AS
YOU'RE ASSESSING DIFFERENT
POPULATIONS.
YOU HAVE TO MAKE SURE WHAT
YOU'RE COMPARING PEOPLE RECENT
ONSET VERSUS 10 YEARS LATER.
IF YOU MIX THOSE TWO POPULATIONS
YOU MAY MISS SIGNAL.
THE OTHER THING ABOUT THE
THERAPEUTIC RESPONSE THE TIME
COURSE IS NOT GOING TO BE SHORT.
AS WE DEVELOP CLINICAL TRIALS
IT'S IMPORTANT TO MAKE SURE
WHATEVER THE INTERVENTION IS
CONTINUES FOR MONTHS BECAUSE IT
TOOK MONTHS TO GENERATE THE
PROBLEM AND WON'T BE SIMPLE
THINGS.
EVEN THOSE CLINICAL TRIALS WE
THINK IT'S UNLIKELY IT'S GOING
PAN OUT AND RESULT IN
IDENTIFICATION OF PANNEE SEE YA
AND -- PANACEA AND IT'S
IMPORTANT TO TEST THE THINGS
EVEN THEY YIELD SOME NEGATIVE
RESULT WILL RESULT DOWN STREAM
IN PEOPLE SHIFT FROM THINGS
INAPPROPRIATE AND ALLOW TO US
FOCUS ON THINGS THAT MIGHT BE
CONSTRUCTIVE.
THANKS.
>> THANKS TO ALL THE PANELISTS
AND TURN IT BACK TO DR. NATH FOR
SUMMARY AND FUTURE DIRECTION.
>> THANK YOU VERY MUCH.
THANKS FOR YOUR SUPPORT OF OUR
STUDIES AND ADVICE NOW AND
THROUGHOUT THE STUDY.
A COUPLE SLIDES HERE.
IN SUMMARY ME/CFS MAY HAVE
UNDERLYING TREATABLE DISEASES
AND SOME PATIENTS THEN WERE
STUDIED AND FOUND THERE WERE
OTHER DISEASES UNDERLYING AND
WERE MISSED.
I THINK IT'S IMPORTANT AS A
PHYSICIAN WHEN YOU SEE THEM THEY
BE CLOSELY FOLLOWED.
IT'S IMPOSSIBLE TO DO A MILLION
DOLLAR WORKUP BUT IF YOU FOLLOW
ALONG YOU'LL DISCOVER AN
UNDERLYING DISEASE.
WE LEARNED SOME RECOVER.
THAT IS FASCINATING TO IDENTIFY
WHAT THAT HAPPENS CAN TEACH US
ABOUT THE DISEASE AND HOW TO
DESIGN TRIALS.
THE THIRD IS MULTIPLE BIOLOGICAL
SYSTEMS ARE INVOLVED.
WE'RE FOCUSSED ON THE BRAIN AND
WHAT YOU'RE SEEING THROUGH THE
WORK DONE THE ANNIVERSARY SYSTEM
PLAYS AN IMPORTANT CRITICAL ROLE
AND WE NEED TO PAY MORE
ATTENTION TO OTHER SYSTEMS AND
STUDY THEM EXTENSIVELY.
THEN THERE ARE MULTIPLE TARGETS
FOR INTERVENTION.
THAT'S AN IMPORTANT OUTCOME OF
THE STUDY AND THERE ARE KEY SEX
DIFFERENCES IN THE PATH YO
PHYSIOLOGY AND NEED TO PAY
ATTENTION TO WHO WE'RE TREATING
AND SELECT THE RIGHT POPULATION.
ONE SIZE MAY NOT FIT ALL.
WHAT ABOUT THERAPEUTICS?
GOING BACK TO THAT FIGURE IN
MANY WAYS I WANT TO NOW SHOW YOU
WHEN YOU THINK ABOUT
THERAPEUTICS YOU CAN DIVIDE THEM
INTO TWO PARTS.
THE FIRST IS IS IT POSSIBLE YOU
ATTACK THE EARLY STAGES THE
IMMUNE SYSTEM ITSELF COULD YOU
REVERSE THE DISEASE OR HALT IT?
MAYBE YOU CAN INTERVENE AND
CAUSE SYSTEMATIC TREATMENT AND
INTERVENE AND HELP THE PATIENT
IN MANY WAYS.
THE QUESTION IS IF YOU WERE TO
BE ABLE TO ACT HERE CAN YOU
PREVENT EVERYTHING DOWN STREAM?
I DON'T KNOW THAT IS POSSIBLE OR
NOT.
IF IT'S REACTIONRY IT MAY BE
POSSIBLE TO CATCH IT EARLY ON
ABLE TO MAKE AN INTERVENTION
PREVENT THIS DOWN STREAM AND
THIS COULD BE SELF-PERPETUATING.
THAT HAPPENS WITH PAIN SYNDROME.
YOU COULD TREAT THE UNDERLYING
CAUSE OF THE PAIN RESEARCH.
IF THAT'S THE CASE YOU NEED
BOTH.
AT THE SAME TIME YOU ARE GOING
TO NEED THIS.
YOU'LL NEED COMBINATION
THERAPIES.
I'LL TALK ABOUT THE EARLY PART.
IF THERE'S AN IMMUNE PHENOMENON
WHAT CHOICES DO WE HAVE?
WE SHOULD STUDY ME/CFS BUT CAN
ALSO STUDY LONG COVID PATIENTS.
THE PROBLEM THEY HAVE VACCINES
AND COVID.
IT BECOMES DIFFICULT TO SORT OUT
WHAT IS DOING WHAT.
THERE'S AN OPPORTUNITY TO DO
CLINICAL TRIAL CAN HELP IN
STUD
STUDIES.
WHAT WE NEED TO DO IS LOOK AND
SEE WHAT CATEGORY THE PATIENTS
FALL INTO.
ONE THING I'M KEEN TO STUDY IS
THE POPULATION WITH IMMUNE
EXHAUSTION AND CHECK INHIBITORS
TO MAKE A DIFFERENCE IN THE
DISEASE?
SOME HAVE D CELL ACTIVATION AND
AUTO ANTIBODIES.
WE EXCLUDED THOSE BUT AS THE AN
OPPORTUNITY THERE TO BE ABLE TO
INTERVENE INDIVIDUALS WITH B
CELL ACTIVATION AND THERAPEUTIC
AGENTS AVAILABLE AND SAME WITH T
CELL ACTIVATION AND THE INNATE
IMMUNE ACTIVATION AND NON
SPECIFIC IMMUNE MODULA MODULATOE
PATIENTS HAVE PROFOUND SIDE
EFFECT PROFILES.
I URGE WE DO THEM IN THE CONTEXT
OF CLINICAL TRIALS.
THERE'S NALL TREXON AND ABILIFY
AND VARIOUS SUPPLEMENTS.
WE NEED TO LOOK AT THESE AND TRY
TO SEE WHAT MAKES THE BEST SENSE
WHATTED TO TRY.
-- WHAT TO TRY.
IF YOU WERE TO STUDY ONE
COMPOUND AFTER ANOTHER IT WOULD
TAKE A CENTURY TO GO THROUGH THE
LAST AND LIFE SPANS ARE SHORT
AND MINE IS SHORTER THAN MOST
YOU.
WE NEED OTHER INNOVATIVE WAYS OF
DOING TRIALS.
ONE IS DOING PLATFORM STUDY.
YOU CAN STUDY MULTIPLE DRUGS
COMPARED TO A SINGLE PLACEBO ARM
AND COMPARE AND CONTRAST.
THAT'S IMPOSSIBLE AT A SINGLE
SITE AND THAT'S ONE WAY TO GET
TO HELP OUR ANSWER.
ANOTHER WAY IS CROSSOVER
STUDIES.
PATIENTS ARE PUT ON A SINGLE
DRUG.
MULTIPLE DRUGS ARMS.
THEY HAVE AN OPPORTUNITY AFTER
THEY FINISH ONE ARM TO MOVE ON
TO THE NEXT.
EVERY PERSON WHO WAS IN PLACEBO
HAS CROSSOVER DESIGNS.
OTHER FUTURE DIRECTIONS WE NEED
TO PURSUE AND THAT IS CONTINUE
THE ANALYSIS AND PUBLICATION OF
DATA AND SAMPLES COLLECTED AND
DATA TO OUTLINE THE FUTURE
DIRECTIONS AND RE-ANALYSIS OF
DATA BY OTHER RESEARCHERS AND
VALIDATION OF FINDINGS AND OTHER
COHORTS.
AND DISCUSS PLANS FOR CLINICAL
TRIALS AND CONTINUE TO STUDY THE
CONTEXT OF CLINICAL TRIALS.
THAT'S IMPORTANT.
YOU CAN NEVER DO ENOUGH
PATHOPHYSIOLOGY AND THERE'S
ALWAYS ANOTHER QUESTION.
IF YOU KEEP WAITING YOU'LL NEVER
GET TO THE CONTEXT OF CLINICAL
TRIALS.
YOU CAN CONTINUE TO STUDY
PATHOPHYSIOLOGY.
WHAT I WOULD ADVOCATE WITH WE
HOLD HANDS TOGETHER AND MOVE
FORWARD WITH THE PATIENT
COMMUNITY AND RESEARCHERS AND
THERE'S LIGHT AT THE END OF THE
TUNNEL AND I'M HOPEFUL WE'LL
FIND CURES FOR THIS DISEASE.
I'LL END HERE AND IF DR. SCHOR
IS THERE ONLINE I'LL ASK OR THE
GIVE CLOSING REMARKS.
SHE'S THE DEPUTY DIRECTOR OF THE
INTRAMURAL PROGRAM AT THE
NATIONAL INSTITUTES OF HEALTH
AND USED TO BE THE CHAIR IN
PITTSBURGH AND THEN DIRECTOR OF
PEDIATRICS AT UNIVERSITY OF
RODCHESTER AND CAME TO NIH AS TE
DEPUTY DIRECTOR OF NINDS.
THIS STUDY STARTED AND HAS BEEN
STRONGLY SUPPORTIVE OF OUR
EFFORTS.
SHE WAS NOT ONLY THE DEPUTY
DIRECTOR BUT ACTING SCIENTIFIC
DIRECTOR.
SHE PLAYED A CRITICAL ROLE IN
THE INTRAMURAL PROGRAM AT EVERY
LEVEL AND I'LL GIVE THE PODIUM
TO HER FOR CLOSING REMARKS.
SHE'S CURRENTLY IN RODCHESTER
AND HAS A BUSY SCHEDULE BUT MADE
SURE SHE'D BE AVAILABLE FOR
THIS.
>> THANK YOU FOR THOSE WHO MADE
IT POSSIBLE FOR KNOW PARTICIPATE
VIRTUALLY AND WATCH THE
CONFERENCE ON VIDEOCAST.
PRIVILEGE TO BE WITH YOU IN
WHATEVER FASHION.
I WANT TO UNDER SCORE THE
COMPLEXITIES YOU HEARD WITH
REGARD TO THIS DISORDER,
DISEASE, SYNDROME ALL THESE
COMPLEXITIES ARE WHAT MAKE IT SO
THAT THIS IS A TEAM APPROACH
KIND OF DISORDER.
THIS NOT A DISEASE WE'LL SOLVE
OR CURE OR PREVENT WITH ISOLATED
SCIENTIST IN A LABORATORY OR
CLINIC.
YOU HEARD THIS DISORDER INVOLVES
THE IMMUNE SYSTEM AND
INFLAMMATION AT EVERY LEVEL THAT
CAN INVOLVE THE MICROBIOME AND
CHANGES THAT OCCUR THERE.
IT CAN INVOLVE THE AUTONOMIC
NERVOUS SYSTEM AND INJURY TO
THAT SYSTEM.
BECAUSE OF THAT IT TAKES MANY
PEOPLE APPROACHING IT FROM MANY
ADVANTAGE POINTS.
IT'S ALSO NOT A DISEASE THAT'S
GOING TO BE INVOLVED BY
SCIENTISTS AND PHYSICIANS ALONE.
THE PARTNERSHIP WITH COLLEAGUES
WHO ARE PATIENTS AND ADVOCATES
IN THIS COMMUNITY UNIVERSITY AND
GOVERNMENT AND ARE IMPORTANT.
I'M GRATEFUL TO ALL WHO HAVE
COME TOGETHER TODAY IN THE
CONTEXT AND PARTICIPATED IN
THESE STUDIES YOU HEARD ABOUT
TODAY AND WHAT WE DO IN THE
FUTURE.
WITHOUT ALL OF YOU, WITHOUT THE
TEAM AND WITHOUT PARTNERSHIP
THERE IS NO WAY WE WILL SOLVE
THE KINDS OF DISORDERS THAT ARE
LEFT FOR US TO SOLVE.
AND SO IT IS IN THIS SPIRIT OF
GRATITUDE AND SPIRIT OF HOPE AND
PARTNERSHIP AND COLLEAGUESHIP I
THANK YOU FOR BEING A PART OF
THIS IMPORTANT CONFERENCE TODAY
FOR AND PARTNERING WITH EACH
OTHER, FOR EDUCATING ME AND FOR
ALLOWING SCIENTISTS LIKE BRIAN
AND CLINICIANS TOE TO COME
TOGETHER AND REALLY BRING MANY
PERSPECTIVES TOGETHER IN THE
PURSUIT OF TREATMENT, CURE AND
PREVENTION FOR ME/CFS.
THANKS TO ALL OF YOU FOR MAKE
THIS HAPPEN TODAY.
>> THANK YOU.
THE MEETING IS ADJOURNED.