FOR THOSE WATCHING ON THE VIDEO
CAST I'D LIKE TO SHARE WITH YOU
THIS VIDEOCAST IS RECORDED AND
ARCHIVED FOR FUTURE VIEWING.
YOU SEE THE SAME LINK SO WE'LL
BEGIN WITH OUR WELCOME
REMARKS -- FROM DR. LANGEVIN FOR
THE CENTER FROM COMPLEMENTARY
AND INTEGRATED HEALTH.
PREVIOUSLY SHE WAS THE DIRECTOR
OF THE CENTER FOR INTEGRATED
MEDICINE AND PROFESSOR OF
MEDICINE AT BRIGHAM WOMEN'S
HOSPITAL AND HARVARD MEDICAL
SCHOOL.
SHE HAS BEEN WELL KNOWN FOR HER
VISIONARY LEADERSHIP AND TODAY
SHE WILL SHARE WITH US HER
VISION OF HOW INTEROCEPTION
RESEARCH IS ALIGNED WITH NCCIH'S
PRIORITY.
DR. LANGEVIN PLEASE SHARE YOUR
SCREEN.
>> ALL RIGHT.
GOOD.
YOU CAN ALL SEE THIS I HOPE?
IT IS MY GREAT PLEASURE TO OPEN
THE SECOND ANNUAL NIH
INVESTIGATOR MEETING ON
INTEROCEPTION RESEARCH.
THROUGHOUT THE HISTORY OF
MEDICINE WE HAVE HAD A STRONG
TENDENCY TO THINK ABOUT THE BODY
ONE ORGAN OR SYSTEM AT A TIME.
BUT ONCE IN A WHILE WE ARE
PRESENTED WITH AN OPPORTUNITY TO
INCREASE OUR UNDERSTANDING OF
THE WHOLE.
AND THIS MEETING ON
INTEROCEPTION IS ONE OF THEM.
WHAT DO I MEAN BY THAT?
WELL, WE'LL LONG KNOWN THERE ARE
SYSTEMS IN THE BODY BY NATURE
INTEGRATIVE BE IT THE ENDOCRINE
SYSTEM FOR EXAMPLE INTERACTS
WITH ALL THE ORGANS AND THE
IMMUNE SYSTEM AND WE'RE ALSO
BEGINNING TO THINK EVEN OF THE
MICROBIOME OF BEING ANOTHER
CROSS-CUTTING SYSTEM.
AND WE HAVE KNOWN FOR OVER A
CENTURY THE AUTONOMIC SERVICE
REGULATE THE ORGANS AND SYSTEMS
AND IT WAS RECENTLY WE BEGAN TO
APPRECIATE THE LANDSCAPE OF THE
TWO-WAY CONVERSATION BETWEEN OUR
BRAIN AND OUR INTERNAL ORGANS.
AND THIS CONNECTION INVOLVES OF
COURSE THE AUTONOMIC NORM SYSTEM
AND THE INNERVATING DEEP TISSUES
WE'RE JUST BEGINNING TO
APPRECIATE.
BROADLY SPEAKING, INTEROCEPTION
REFERS TO OUR ABILITY TO SENSE
AND RESPOND TO SIGNALS GENERATED
FROM OUR INTERNAL WORLD OPPOSED
TO EXTERNAL SIGNALS SUCH AS
SOUND, FOR EXAMPLE OR FEELING ON
THE SKIN.
HOW AWARE OR HOW UNAWARE WE ARE
OF THESE SENSATIONS AND AS
CONVERSATION BETWEEN BRAIN AND
INSIDE OF OUR BODY IS A
FASCINATING TOPIC WHICH WE
LAUNCH.
THIS TOPIC GOES TREATMENT AND
PRACTICES THAT TAP INTO
MEDICATION AND YOGA AND THIS
EXCITING MEETING WILL GIVES A
CHANCE TO HEAR FROM
INVESTIGATORS EXPLORING
FUNDAMENTAL INTEROCEPTIVE
MECHANISMS THAT PROVIDE MUCH
NEEDED BASIC UNDERSTANDING OF
THE CONNECTIONS BETWEEN OUR
NERVOUS SYSTEM AND THE REST OF
THE BODY.
THESE CONCESSIONS ARE ESSENTIAL
FOR US TO ARRIVE AT AN
INFORMATION OF OUR BODY AS A
WHOLE AND HEALTH IN GENERAL.
UNLIKE DISEASE THAT MANIFESTS IN
SPECIFIC ORGANS OR SYSTEMS,
HEALTH INVOLVES THE WHOLE
PERSON.
AND SO INTEGRATIVE PROCESSES
SUCH AS INTEROCEPTION INTEGRATED
NOT JUST ACROSS ORGANS AND
SYSTEMS BUT SCALES, CELLULAR AND
MOLECULAR MECHANISMS TO WHOLE
ORGAN PHYSIOLOGY SUCH AS EATING
AND DRINKING FUNDAMENTAL TO
HEALTH.
WE'RE ALL LOOKING FORWARD
EXCITING MEETING.
WE'RE PLEASED SO MANY OF YOU
WERE ABLE TO BE HERE WITH ONE
ANOTHER IN PERSON AND I JUST
WISH I COULD BE THERE WITH YOU
AND WISH YOU ALL A GREAT
MEETING.
>> THANK YOU SO MUCH FOR THE
WONDERFULLY INSIGHTFUL COMMENTS,
DR. LANGEVIN.
WE NOW ARE GOING TO WELCOME
DR. WALLER KOROSHETZ DIRECTOR OF
THE NATIONAL INSTITUTE OF NINDS.
DLIFSHTH NATIONAL INSTITUTE OF
NEUROLOGICAL DISORDERS AND
STROKE.
DR. KOROSHETZ HAS BEEN THE NINDS
DIRECTOR SINCE 2014 AND WAS
DEPUTY DIRECTOR BETWEEN 2007 AND
2014.
PRIOR TO JOINING NINDS,
DR. KOROSHETZ WAS ALSO A
PROFESSOR OF NEUROLOGY AT
HARVARD MEDICAL SCHOOL AND
SERVED AS VICE CHAIR OF THE
NEUROLOGY SERVICE AND DIRECTOR
OF STROKE AND NEURON INTENSIVE
CARE AT MASSACHUSETTS GENERAL
HOSPITAL FOR ALMOST TWO DECADES.
DR. KOROSHETZ IS HIGHLY ADMIRED
AND LOVED LEADER WITHIN THE NIH
COMMUNITY AND HAS LED MAJOR
TRANS-NIH INITIATIVES INCLUDING
THE FAMOUS BRAIN INITIATIVE AND
THE HEAL INITIATIVE AND THE NIH
BLUEPRINT FOR NEUROSCIENCE
RESEARCH.
TODAY, HE IS REPRESENTING THE
BLUEPRINT SENIOR LEADERSHIP TO
SHARE WITH US ABOUT WHAT
BLUEPRINT IS ALL ABOUT AND HOW
IT HAS INITIATED AND SUPPORTED
THE INTERO CEPTION RESEARCH AT
THE NIH.
DR. KOROSHETZ.
>> GOOD MORNING?
HOW'S EVERYONE FEELING?
GOOD, YOUR INTEROCEPTION SYSTEM
IS WORK.
I'M HERE FOR THE BLUEPRINT.
IT'S A GROUP OF INSTITUTES AT
NIH THAT WORK TOGETHER IN
VARIOUS DOMAINS.
A LOT OF IT IS FOCUSSED ON
FUNDING TRAINING, FUNDING TOOLS.
WE WORKED ON THE MRI CONNECTOME
PROJECT AND WORKED ON WHERE BIO
TECH COMPANIES CAN COME IN AND
WORK WITH A VIRTUAL
PHARMACEUTICAL COMPANY SETUP TO
DEVELOP THERAPIES AND WE HAVE
PRETTY MUCH ALL THE NEUROSCIENCE
INSTITUTES INVOLVED IN THE
BLUEPRINT.
SOME OF THE THINGS THAT I
MENTIONED ARE THE
NEUROTHERAPEUTICS NETWORK TO GET
THERAPEUTICS OUT AND THIS
SERVICES ALL THE DIFFERENT
INSTITUTES.
IT COULD BE ON THAT MOL --
BIOLOGICS AND WE HAVE DEVICE
PROGRAMS ALSO TO MOVE THINGS TO
COMMERCIALIZATION THESE ARE
INTEGRATED WITH OTHER PROGRAMS
AT NIH PARTICULARLY FOR THIS
GROUP THE SPARK PROGRAM
DEVELOPING MAPS AND WAYS OF
MODULATING THE PERIPHERAL
NERVOUS SYSTEM FOR HEALTH.
HERE TO TALK ABOUT THE AMAZING
SCIENCE DONE IN THIS SPACE
CALLED INTEROCEPTION.
AS HELLENE MENTIONED THIS IS
UNDERSTANDING HOW OUR NERVOUS
SYSTEM WHICH INNERVATED ALMOST
ALL THE ASPECTS OF OUR BODY AND
HOW OUR BRAIN CONTROLS IT AND
HOW THE BRAIN GETS INPUTS FROM
ALL THESE DIFFERENT AREAS AND
HOW IT'S INTEGRATED INTO BRAIN
FUNCTION WHETHER IT'S AUTOMATIC
FUNCTION OR AS WE STARTED OFF
HOW WE ACTUALLY FEEL TODAY AND
WE'RE GETTING INPUTS ALL THE
TIME WE DON'T PAY ATTENTION TO.
THEY'RE PROBABLY DETERMINING A
LOT OF OUR BEHAVIORS AND SO THIS
SYSTEM AS HELENE MENTIONED THERE
IS WORK THAT SEEMS TO INCUR IN
ANIMALS IN THE '50s AND '60s AND
MAYBE WAS LEFT IN THE DUST A
LITTLE BIT.
WE'RE TRYING TO RESURRECT IT AND
LEARNING AMAZING THINGS.
SOME THINGS YOU'LL HEAR ABOUT
TODAY FROM THE INVESTIGATORS
FUNDED OUT OF THE BLUEPRINT
INTEROCEPTION PROGRAM.
THERE'S BEEN REMARKABLE
DISCOVERIES JUST MY KNOWLEDGE
THE INTERACTION BETWEEN THE
NERVOUS SYSTEM AND IMMUNE SYSTEM
AND IMMUNE SYSTEM IN THE GUT.
EVEN HOW MAYBE A MONKEY WILL
[NO AUDIO]
SOME OF THESE AREAS ARE
GROUNDBREAKING NEW PATHWAYS TO
UNDERSTAND FUNCTION.
AND NOW I THINK WE HAVE TOOLS TO
STUDY THEM SO MUCH BETTER THAN
THE PAST.
THERE'S A CHANCE FOR LOTS OF
PROGRESS.
NOT ONLY IN HOW THE BRAIN IS
RECEIVING INPUTS IN THE
ASCENDING PATHWAYS BUT ALSO HOW
IT'S CONTROLLING FUNCTION IN A
DESCENDING PATHWAYS.
IN 2020 WE HAD WORKSHOPS AND IN
2021 WE AWARDED SEVEN PROJECTS
WE'LL TALK ABOUT TODAY TOTALLING
ABOUT $18.15 MILLION OVER FIVE
YEARS AND THEY COVERED A VARIETY
OF ASSOCIATIONS BETWEEN ORGAN
TYPES SO WE HAVE PROJECTS ON
STOMACH-BRAIN INTEROCEPTION.
BRAIN AIRWAY CONTROL,
TEMPERATURE SENSE NEURONS IN THE
SYMPATHETIC ADIPOSE TISSUE.
VAGAL SENSORY NEURONS
INNERVATING THE LIVER.
NEUROCIRCUITS FOR BREATHING AND
SPINAL SENSORY GANGLIA AND GUT
SENSATION.
THOSE WERE THE MAIN TOPICS THAT
WERE FUNDED AND AS CAN IMAGINE
FROM THE TOPICS, THEY COVER A
NUMBER OF ORGAN--TYPES BUT OF
COURSE PRETTY SMALL PERCENTAGE
OF THE BODY REPRESENTED.
THERE'S A LOT OF REAL ESTATE YET
TO BE EXPLORED.
THE PATHWAYS ARE PRIMARILY VAGAL
AND SPINAL AND THE BRAIN AREAS
THAT HAVE BEEN TIED IN THE
SYSTEMS ARE SEEN ON THE RIGHT.
THE GENERAL RULE IS THAT IT THE
TIES OR INPUTS AND OUTPUTS ARE
INVOLVING THE BRAIN STEM,
HYPOTHALAMUS, SOME HIGHER AREAS
AND INSULAR CORTEX AND AMYGDALA
AND PRE FRONTAL CORTEX AND
ILLUSTRATE THE IT GENERAL ROOTS
THEY SAY WHEREBY THE
INTEROCEPTIVE SYSTEM INTERACTS
WITH THE BRAIN.
A COUPLE EXAMPLES YOU'LL
HOPEFULLY HEAR ABOUT IN MUCH
MORE DETAIL THROUGHOUT THE DAY
BUT THIS IS FROM A LAB IN MOUNT
SINAI LOOK THE GLP1 SYSTEM.
IT'S A POPULAR DRUG RIGHT NOW
FOR WEIGHT LOSS.
PROBABLY WILL BE PRETTY
REVOLUTIONARY IN REDUCING
CARDIAC AND STROKE MORBIDITY AND
HOW DOES IT ACT?
WELL, THE GROUP WAS ABLE TO
FIGURE OUT THE GLP-1 IN ITS
NATURAL STATE IS REDUCED BY
ENDOCRINE CELLS WHICH ARE FUNNY
CELLS ON THE BORDER OF NEURONS
AND WE MIGHT BE ABLE TO PROMOTE
THEM SOME DAY TO NEURONS.
AND THERE'S EVIDENCE THEY DO
MAKE SYNAPSES WITH SOME VAGAL
AFERENCE BUT IN THIS SYSTEM THEY
ARE RELEASING GLP1 TO NEURONS
AND THERE'S AN OUTPUT TO THE
STOMACH AND THE INTESTINAL TRACT
TO SLOW DOWN MOTILITY WHICH
WOULD MAKE YOU FEEL FULL AND
GOES TO THE HYPOTHALAMUS FOR
APPETITE SUPPRESSION AND WHEN
YOU KNOCK OUT THESE FUGAL FIBER
NEURONS YOU LOST THE EFFECT OF
THE GLP1.
NICE ABILITY NOW TO USE THESE
KINDS OF TOOLS TO DISSECT OUT
THE CIRCUITS BY KNOCKING OUT
DIFFERENT STEPS.
HERE'S ANOTHER ONE AND I SHOULD
SAY WENT INTO NEUROLOGY TO GET
AWAY FROM THE G.I. TRACT BUT IT
SEEMS TO BE FOLLOWING ME AND NOT
LETTING ME GET AWAY AND THIS IS
FROM THE UNIVERSITY OF MICHIGAN
LOOKING AT OSCILLATIONS IN BRAIN
FOLD ACTIVITY LINKED TO GASTRIC
SLOW WAIVES YOU CAN SEE IN THE
TOP AND WHEN YOU DO A VAGOTOMY
YOU DON'T SEE THE ACTIVITY IN
THE BRAIN.
WHY THE BRAIN NEEDS TO DO THIS
SO CLEARLY ABSOLUTE
INCONTROVERTIBLE FINDING AND
HERE'S ANOTHER ONE LOOKING AT
BREATHING CONTROL.
INCREDIBLY IMPORTANT NOW
CRITICAL NOW WITH FENTANYL
CUTTING OFF YOUR BREATHING
CIRCUITS AND THIS IS HOW HYPOXIA
AFFECTING SIGHING AS PART OF THE
CIRCUIT.
THE CAROTID BODY PICK UP THE
HYPOXIC SIGNAL AND SENDS A
SIGNAL THROUGH THE JUGULAR
GANGLION COMPLEX TO THE NUCLEUS
AND THE CIRCUIT LOCATION FOR
RESPIRATORY MOVEMENTS AND THAT
IS WHAT TRIGGERS THE SIGH.
WE'RE NOT ALL SIGHING BECAUSE
WE'RE HYPOXIC.
WE ALL SIGH BUT THERE'S PROBABLY
OTHER THINGS THAT GO INTO THIS
COMPLEX TO GET US TO SIGH AND
SOMETIMES YAWN I GUESS PROBABLY
AS WELL.
AND THIS AGAIN IS INVOLVED IN
THE BREATHING SECTOR AND THE
SERIOUS PROBLEM WHICH IS SUDDEN
DEATH AND EPILEPSY.
IT'S BEEN -- IT'S STILL DEBATED
AND HIGHLY STUDIED AS TO WHY
KIDS DIE DURING AN EPILEPTIC
SESURE.
THE QUESTION HAS ALWAYS BEEN SIT
CARDIAC OR SOMETIMES THE
CHANNELS THAT CAUSE THE SEIZURE
ALSO AFFECT THE HEART.
THERE'S A LOT OF EVIDENCE IT
INVOLVES THE RESPIRATORY TRACT
AND IN THE MICE WHICH ARE
MUTATION THAT IS SIMILAR TO WHAT
IS SEEN IN CERTAIN SIN DROYNDRO
KIDS THAT IS SIMILAR TO GERVAIS
TRIGGER RESPIRATORY ARREST.
WHAT THEY SEE IN THE MUTATED
NICE IT'S IN THE EXCITATORY
NEURONS THEY SEE SEIZURES AND
AFTER THE SEIZURE ENDS IN THE
ANNALS -- ANIMALS THAT STOP
BREATHING YOU SEE WHAT IS
ASSOCIATED WITH ABROGATION OF
BREATHING.
THEY ALL STOP BREATHING DURING
THE SEIZURE BUT IN THE ANIMALS
THAT DIE THEY NEVER REGAIN
BREATHING AND THE HEART RATE
KEEPS GOING FOR MINUTES AFTER
THIS EVENT BUT THE BREATHINGS
ARE STOPPED.
BY UNDERSTANDING SOME PATHWAYS I
THINK WE LEARN THINGS THAT ARE
INTERESTING AND LEARNING THINGS
THAT ARE ACTIONABLE AND THINGS
THAT ARE INTERESTING MAY NOT BE
ACTIONABLE TODAY BUT MAY BE
ACTIONABLE TOMORROW.
I THINK IT'S A FERTILE FIELD AND
IT'S FASCINATING TO ME AND
LOOKING FORWARD TO LEARNING FROM
THE GROUP TODAY.
SO THANKS VERY MUCH.
>> THANK YOU, DR. KOROSHETZ.
YOUR STAUNCH SUPPORT FOR THIS
TOPIC MEANS A LOT.
THIS IS HOW YOU CAN GET IN
CONTACT WITH DR. KOROSHETZ AND
HAS A TWITTER ACCOUNT ACTUALLY.
OKAY.
SO I AM NOW GOING TO CONTINUE TO
SHARE MORE HOW THIS BLUEPRINT
INITIATIVE HAS REALLY IGNITED
AND STIMULATED THE TRANS-NIH
PORTION OF THIS AND I'M A BRANCH
CHIEF WITHIN THE DIVISION OF
EXTRAMURAL RESEARCH AT NCCIH.
FIRST I WANTED TO HIGHLIGHT
THESE EFFORTS THAT YOU HEARD
ABOUT AND YOU'LL HEAR ABOUT IS
REALLY SUPPORTED AND LED BY A
LARGE TEAM OF PROGRAM AND REVIEW
OFFICERS WITHIN NIH INCLUDING
MORE THAN 25 OF US AS WELL AS AT
LEAST 15 NIH INSTITUTES AND
CENTER AND WE'RE ALL PASSIONATE
SUPPORTERS FOR YOU AND MANY WORK
TIRELESSLY BEHIND THE SCENE TO
HELP GROW THIS VERY IMPORTANT
FIELD.
MANY ARE HERE TODAY AND YOU'LL
SEE SOME OF THEM ON STAGE LATER.
SO I KNOW I'VE HEARD QUITE A BIT
ABOUT THE COMMUNITY SAYING, WHAT
A WONDERFUL PROGRAM YOU HAVE
BILLED TODAY.
I WISH I COULD TAKE CREDIT BUT I
CAN'T BECAUSE THIS IS REALLY A
PRODUCT OF MANY BRILLIANT MINDS
IN OUR PLANNING COMMITTEE.
IN PARTICULAR THE SIX NON-NIH
SCIENTISTS WHO HAVE MET WITH US
AND VOLUNTEERED TO JOIN THE
PLANNING COMMITTEE SINCE LAST
WINTER AND MET WITH US MONTHLY
TO PLAN THIS PROGRAM AND HELPED
TO SELECT THE SPEAKERS, EVALUATE
HUNDREDS OF POSTER SUBMISSIONS
AND SELECTED THE FLASH TALK
SPEAKERS AS WELL AND THIS IS
REALLY WHY WE HAVE THIS
WONDERFUL LINEUP TODAY AND IN
PARTICULAR I WANTED TO
ACKNOWLEDGE DR. AJIJOLA AND
ANDEMANN AND DR. XIN SUN FROM
UCSD AND MY COLLEAGUES FROM NIH
ON THE RIGHT SIDE OF THE SLIDE.
THIS MEETING IS ALSO NOT
POSSIBLE WITHOUT THE SUPPORT OF
THE GENEROUS FINANCIAL SUPPORT
AND LOGISTIC SUPPORT FROM THE
NIH, IN PARTICULAR THE OFFICE OF
COMMUNICATION WHO RESCUED YOU US
FROM A POTENTIAL DEBACLE ON THE
NIH CAMPUS AND PAID NOR VENUE TO
MEET TODAY TO EXPAND THIS
MEETING TO SUPPORT MORE THAN 400
PEOPLE WHO WILL BE COMING TODAY
TO JOIN THIS EVENT.
ALSO THE BLUEPRINT HAS
GENEROUSLY SUPPORT THE TRAVEL OF
YOUNG AWARDEES AND IN PARTICULAR
I WANT TO THANK THE INVITED
SPEAKERS WHO HAVE REALLY
VOLUNTEERED THEIR RESOURCE TO
COME ON THEIR OWN TO ALLOCATE
THE RESOURCE TO SUPPORT THE
YOUNG INVESTIGATORS TODAY.
I WANT TO THANK THE KEYNOTE
SPEAKERS AND THE OFFICE OF
BEHAVIOR AND SOCIAL RESEARCH OF
NIH OBSSR TO HAVE THE LIVE CAST
THROUGH THE NIH VIDEOCAST AND
THE WONDERFUL STAFF WORKING HERE
SINCE LAST NIGHT TO MAKING SURE
IT WOULD RUN SMOOTHLY.
HERE'S THE LIST OF THE TRAVEL
AWARDEES THAT SUPPORTED BY NIH
BLUEPRINT AND YOU'LL HEAR FROM
SIX OF THEM SOON AS FLASH TALK
PRESENTERS BUT I WANTED TO
HIGHLIGHT THOSE WHO DIDN'T GET
TO PRESENT A FLASH TALK BUT WILL
BE PRESENTING POSTERS AND HAVE
WONDERFUL WORK TO SHARE WITH YOU
TODAY AS WELL AND AN ENCOURAGE
YOU TO CHECK OUT THEIR POSTERS.
THE THINGS ARE MISALIGNED BUT
I'LL READ THEIR NAME.
DR. HARRAZ FROM UNIVERSITY OF
VERMONT.
DR. JACKMAN FROM COLUMBIA
UNIVERSITY AND DR. TRUONG LY
FROM USSF AND DR. SAHASRABUDHE
FROM M.I.T.
I'M SORRY IF I MISPRONOUNCED
YOUR LAST NAME.
USING THE NIH REPORTER THIS IS
OPEN RESOURCE ANYBODY CAN USE.
WE HAVE DONE SOME ANALYSIS SEE
THE IMPACT WHATEVER WE'VE DONE
ACROSS THE NIH AND INTERESTING.
2018 IS THE TIME THE NIH
BLUEPRINT WAS STARTED TO PLAN
THE WORKSHOP AND THAT PLANNING
SOMEHOW CORRELATED WITH A BIG
JUMP OF ALMOST NOTHING TO OVER
10 WITHIN THE NIH DEDICATED THE
TOPIC OF INTEROCEPTION USING THE
TERM IN THEIR APPLICATION AND
YOU CAN SEE NICE GROWTH ON THE
NUMBER OF NIH GRANTS FUNNED ON
THE TOP OF INTEROCEPTION AND
TODAY WE HAVE BETWEEN 60 AND 70
ACTIVE GRANTS IN THE FISCAL
2023.
MORE THAN A FIVEFOLD INCREASE.
THAT'S CORRELATED WITH A NICE
FUNDING, SPENDING AS WELL FROM
ALMOST NOTHING PRIOR TO 2018 AND
NOW BETWEEN $20 MILLION AND $30
MILLION ON THE TOPIC OF
INTEROCEPTION.
THIS IS PROBABLY NOT EASY TO SEE
BUT IT'S A DIAGRAM GENERATE THE
NIH REPORTER TO SHOW THE CURRENT
SNAPSHOT OF THE TYPE OF TOPICS
ASSOCIATED BUT FUNDED IN
INTEROCEPTION RESEARCH AT NIH
INCLUDING RELATED TO TALKS SUCH
AS PAIN AND EMOTIONAL REGULATION
AND IN ADDITION TO NERVOUS
SYSTEM AND INTEROCEPTION
AWARENESS AND I WANT YOU TO TAKE
THIS TOPIC AND A SNAPSHOT AND
HURE -- SURE IN A FEW YEARS WITH
YOUR EFFORTS THIS WILL TRANSFORM
IN MANY WAYS.
AND LOOKING AT HOW THE NIH
ENDEAVOR CHANGE THE SEARCH ON
THE TOPIC OF INTEROCEPTION.
RED BARS IS FUNDED BY NIH GRANTS
AND THE BLUE IS THE PUB MED
SEARCH.
THE GLOBAL RESEARCH RELATED TO
INTEROCEPTION.
YOU CAN SEE OVER THE YEARS THE
NIH FUNDED RESEARCH ON
INTEROCEPTION HAS BECOME MORE
DOMINANT CONTRIBUTOR TO THE
LITERATURE INTEROCEPTION
RESEARCH.
IT'S WONDERFUL TO SEE THAT KIND
OF CHANGE.
NOW, YOU WONDER HOW CAN I GET
FUNDING OPPORTUNITIES TO SUPPORT
MY WORK.
I LEARNED HOW TO MAKE QR CODES
SO I'LL USE THEM A LOT TODAY.
THIS QR CODE WILL LEAD YOU TO A
WEBSITE CALLED NIH GRANTS AND
FUNDING AND HAS OPPORTUNITIES
RELATED TO INTEROCEPTION
RESEARCH ACROSS THE NIH.
IN ADDITION TO NOTICE OF SPECIAL
INTEREST AND THE NATIONAL CANCER
INSTITUTE OPPORTUNITY RELATED TO
INTEROCEPTION AND LOOK AT
INTEROCEPTIVE OUTCOME MEASURES.
THE TOPIC STILL CUTTING EDGE
BECAUSE PRETTY SUBSTANTIAL
RESEARCH COMES FROM THE HIGH
RISK, HIGH REWARD PROGRAM AND
THE SECOND QR WILL TAKE YOU TO
THE WEBSITE ABOUT COMMON FUND
AND TAKE A GOOD LOOK AT IT AND
IT COVERS A WIDE RANGE OF
RESEARCH OPPORTUNITIES
SUPPORTING FROM GRADUATE
STUDENTS TO INVESTIGATORS AND
THEY ALSO HAVE A WAY CALLED
TRANSFORMATIVE RO1 TO COMPETE
ANONYMOUSLY FOR POTENTIAL BIG
FINANCIAL SUPPORT.
I WANTED TO ALSO SHARE WITH
YOU -- I WAS TRYING TO TALK
ABOUT THIS BUT MY PRESENTATION
GOT BOTCHED BECAUSE OF TECHNICAL
PROBLEMS BUT TODAY I WANTED TO
REALLY BRING TO YOUR ATTENTION
ABOUT THERE'S A STUDY SECTION
WITHIN THE NIH THAT IS DEDICATED
RESEARCH ABOUT NEUROSCIENCE OF
INTEROCEPTION AND SENSATION AND
I'M SORRY THIS ALIGNMENT HERE
WHO IS THE REVIEW OFFICER TO RUN
THE STUDY SECTION IS A NEW
MEMBER OF THE INTEROCEPTION
WORKING GROUP AND CHECK OUT HIS
QR CODE AND MAYBE SEND AN
APPLICATION TO THE STUDY SECTION
AND WANT MEDDED -- WANT NODE
THIS WANTED KNOW SHARE THIS TOOL
AND IF YOU PLUG IN YOUR ABSTRACT
OR SPECIFIC AIMS PAGE INTO THE
SYSTEM, IT WILL TELL YOU WHICH
STUDY SECTION YOU'RE APPLICATION
MAY GET ROUTED TO AND CHECK OUT
THE STUDY SECTION.
OBVIOUSLY, IF YOU HAVE A STUDY
SECTION IN MIND YOU MIGHT WANT
TO TWEAK YOUR WORDS TO TAKE YOU
TO THAT STUDY SECTION IN THE
ABSTRACT OR SPECIFIC AIMS PAGE.
LASTLY, I WANTED TO SHARE THIS
INCREDIBLE NEW COMING MEETING
SERIES AND THIS IS REALLY LEAD
BY DR. SUN AND DR. ANDERMANN AND
DR. COSTA.
THREE WORKED TIRELESSLY BEHIND
THE SCENES FROM LAST YEAR TO
APPLY AND SUCCESSIVELY GAIN THE
SUPPORT FROM KEY STONE SYMPOSIUM
WITH SUPPORT AND NOW IT WILL
OPEN UP A NEW SERIES CONFERENCE
SERIES ON INTEROCEPTION STARTING
SOME TIME IN SPRING OF 2025.
THE RUMOR I HEARD IS THE
LOCATION WILL BE AT AN EXCITING
PLACE ASSOCIATED WITH ONE OF
THOSE THREE LEADERS.
I CAN'T TELL YOU WHAT IT IS BUT
STAY TUNED AND WE'LL REACH OUT
AS THE INFORMATION BECOMES MORE
PRONOUNCED AND WILL ALLOW US TO
GET TOGETHER FOR THREE DAYS
RATHER THAN ONE DAY TO DISCUSS
THIS EXCITING AREA OF SCIENCE.
LASTLY, THANK YOU FOR YOUR
ATTENTION AND FEEL FREE TO REACH
OUT TO US BY E-MAIL.
THIS IS OUR COMMON E-MAIL BOX
THE MANY OF US HAVE ACCESS TO
AND WILL RESPOND TO AS SOON AS
WE CAN.
WE LOVE TO HEAR YOUR QUESTIONS
AND ALSO SUGGESTIONS OF HOW WE
CAN BETTER SUPPORT YOU AND WHAT
ARE YOUR BIGGEST CHALLENGE IN
YOUR RESEARCH BESIDES FUNDING,
PER SE, BUT TECHNOLOGY AND
TOPICS BECAUSE THAT WILL HELP US
TO DEVELOP PROGRAMS TO SUPPORT
YOU THE BEST AND THANK YOU VERY
MUCH AND I'LL MOVE ON TO
INTRODUCE MY WONDERFUL
COLLEAGUE, DR. DANA SCHLOESSER
AND WILL INTRODUCE AND MODERATE
THE KEY NOTE SPEECH.
>> GREAT.
I HAVE THE HONOR OF INTRODUCING
OUR KEY NOTE SPEAKER DR. KAY TYE
AND WHEN SPEAKING ABOUT NEURAL
MECHANISMS OF SOCIAL
HOMEOSTASIS.
KAY.
I WOULD LOVE FOR YOU TO COME UP
HERE AND GET STARTED.
>> GOOD MORNING.
THANK YOU SO MUCH FOR HAVING ME
HERE.
I ENJOYED THE INTRODUCT ORY
SESSION.
IT'S HUMBLING TO BE HERE IN THE
PRESENCE OF GIANTS AND AS WE
PREPPING FOR THE MEETING THEY
MENTIONED WE'D LIKE THE KEY NOTE
SPEAKER FROM OUTSIDE FIELD.
I'VE BEEN STUDYING INTEROCEPTION
FOR MY WHOLE CARREER FROM A
SLIGHTLY DIFFERENT ANGLE.
AND WE HAVE CHANGING
ENVIRONMENTAL CONDITIONS AND HOW
DO WE DECIDE WHICH POSTERS TO GO
TO, OF COURSE.
SO HOMEOSTASIS, MANY BODIES OF
BEAUTIFUL WORK INCLUDING NOBEL
PRIZE WINNING WORK INCLUDING
THERMO REGULATION HAVE BEEN
ELUCIDATED WITH HOMEOSTASIS.
EVERY HOMEOSTATIC SYSTEM HAS
DETECTERS THAT DETECT THE
TEMPERATURE OF MY BODY, FEED
THIS INPUT FORWARD TO A CONTROL
CENTER THAT COMPUTES THE
DIFFERENCE MANY OF SET POINT AND
HIGHER THAN 98.6% THAT GOES TO A
SYSTEM TO CHANGE THAT AND MOVE
ME TO THE SHADE OR BEGIN
PERSPIRING AND THIS INTERACTS
WITH THE ENVIRONMENT TO MAKE THE
CHANGE AND THESE ARE ESSENTIALLY
INTEROCEPTION SO IT'S
APREREQUISITE AND HOMEOSTASIS
HAS BEEN A HOT TOPIC AND YET
INTEROCEPTION HAS ALWAYS BEEN
NECESSARY.
WE THINK IT AS SENSING INTERNAL
STATES, HUNGER, THIRST, ORGAN
FUNCTION, IF YOU YOU HAVE TO PEE
AND ALSO FROM SHARINGTON AND
CRAIG EXPANDED THIS THIS
INCLUDES EMOTIONAL PROCESSING
AND PAIN AND WHAT IS SOCIAL
HOMEOSTASIS.
THAT REFERS TO TWO NESTED
PROJECT.
THIS IS ESSENTIALLY A PIONEER
AWARD THAT WAS AWARDED IN 2016
OR APPLIED FOR IN 2016 AND ALL
THE WORK I'LL TALK ABOUT TODAY
IS MADE POSSIBLE BY NCCIH.
AND THE DREAM IS TO PREDICT HOW
SOCIAL GROUPS OR SUPER
ORGANISMAL GROUPS CAN FUNCTION
BUT BEFORE WE CAN CREATE A
PREDICTIVE DYNAMICAL MODEL AND
CREATE A MODEL WE DON'T NEED AND
WE CAN RUN SIMULATION AND WHY IS
THAT SCIENCE FICTION?
THAT'S SCIENCE FICTION BECAUSE
WE'RE SO FAR FROM BUILDING AN
ACCURATE MODEL FOR THE
INDIVIDUAL BRAIN AND SO EVEN
THOUGH WHEN I'M REALLY
INTERESTED IN IS GROUP DYNAMICS,
IT IS REALLY IMPORTANT TO START
FROM A SOLID FOUNDATION.
THAT'S A LOT OF THE WORK I'M
GOING TO TALK ABOUT.
AND WHY DO I EVEN THINK THERE'S
SUCH A THING AS SOCIO
HOMEOSTASIS.
IT'S NOT LIKE THERMAL REGULATION
OR THIRST WHERE YOU DON'T HAVE
WATER YOU DIE.
YOU DON'T DIE IMMEDIATELY.
IT HAS HEALTH CONSEQUENCES BUT
WHY DO I EVEN THINK SOCIAL HOME
KWL
-- HOMEOSTASIS THING AND
THERE'S NEURONS IN THE DORSAL
NUCLEUS THE HOME OF SEROTONIN
NEURONS AND ABOUT 20% DOPAMINE
NEURONS IN THERE AND WE SEE S
SYNAPTIC CONNECTION AND IF WE
ACTIVATE THE NEURONS WE'LL DRIVE
EYE PRO SOCIAL BUT AVERSIVE
BEHAVIORAL STATE AND IF WE
SILENCE THE NEURONS, NOTHING
HAPPENS WHEN THE GROUP IS HOUSED
BUT IF WE PHOTO INHIBIT THE
NEURONS WE BLOCK ISOLATION
INDUCED REBOUND OF SOCIAL
INTERACTION.
INITIALLY THIS WAS CONFUSING AND
WE THINK OF WHAT MAKES US PRO
ASSOCIATION AND WHAT'S IT MEAN
TO BE HAVE A PROSOCIAL WORK
THAT'S AVERSIVE AND FROM OUR
WORK ON VALENCE YOU CAN ENGAGE
TO SEEK PLEASURE OR AVOID PAIN.
YOU CAN SEEK SOCIAL CONTACT FOR
THE SOCIAL REWARDING EXPERIENCE
OR FOR TO AVOID THE UNPLEASANT
STATE OF LONELINESS.
SO THIS IS MEAN STATE MADE US
THINK OF SOCIAL HOMEOSTASIS AS A
STATE AND WAY TO IDENTIFY.
LONELINESS WAS NOT A WORD
PREVIOUSLY USED IN NEURO SCIENCE
AND IT BREAKS DOWN FOUR
CRITERIA.
ONE, IT DRIVES A PROSOCIAL
STATE, TWO, IT'S IN AVERSIVE
UNPLEASANT STATE.
THREE, DISTINCT FROM GENERALIZED
ANXIETY AND FOUR SUBJECTIVE.
MEANING YOU CAN FEEL LONELY AT A
PARTY OR FINE ALONE IN YOUR
ROOM.
MAYBE THIS WOULD HAVE BEEN A
SHOW STOPPER.
HOW DO WE GET TO LONELINESS IN A
MOUSE.
TOUGH ONE BUT ACTUALLY EVERY
SINGLE CAGE FORM A HIERARCHY AND
THE EXPERIENCE OF EACH MOUSE
WOULD BE DIFFERENT.
IF I'M A DOMINANT MOUSE I'M
ENJOYING MY SOCIAL ENVIRONMENT
AND GETTING RESOURCES TO MATE
AND IF I'M A SUBORDINATE I'M A
VICTIM OF VIOLENCE AND
AGGRESSION AND MAYBE I FEEL
GREAT WHEN I'M ISOLATED FROM MY
AGGRESSORS AND THIS WAS THE
QUESTION.
WE FOUND IN ALL THE
MANIPULATIONS WE FOUND A STRONG
CORRELATION WITH SOCIAL RANK AND
MANIPULATING THESE IN
SUBORDINATES DOESN'T DO ANYTHING
THE ONLY TIME WE GET AN EFFECT
IS IN MORE DOMINANT ANIMALS.
WE'RE BEGINNING TO THINK OF THE
NEURONS AS CONTRIBUTING TO IT AN
ER SYSTEM -- EFFECTER SYSTEMS
AND CORRECTS THE DEFICIT AND
IMPORTANT OR THE RELEVANCE OF
THE WORK WE HAVE THE RARE
OPPORTUNITY TO REPLICATE THE
STUDY IN HUMANS.
EVEN 10 HOURS OF ISOLATION WAS
ENOUGH TO EVOKE AN AUGMENTED
SIGNAL WHEN EXPOSED TO SOCIAL
STIMULI.
SO BACK TO OUR KEY WORK HERE.
WE HAVE TO FIGURE OUT THE
CIRCUIT.
IT'S EXCITING TO HAVE IDENTIFIED
THE CELL TYPE THAT CAN BE PART
OF THE EFFECTER SYSTEM.
BECAUSE THEN WE CAN TRACE IT
UPSTREAM AND FIND THE CONTROL
SYSTEM WHICH MUST RECEIVE INPUT
THERE A VERY DISTRIBUTED
DETECTER SYSTEM.
THIS IS NOT GOING TO BE LIKE
DETECTING THINGS BUT IT'S MEMORY
SYSTEMS AND ALL THE MODALITIES
AND THE SOCIAL CONTACT IS HIGHLY
NON TRIVIAL AND I'LL COMPANY
BACK TO THIS.
ANOTHER NODE I PROPOSE WE NEED
IN THE HOMOSTATIC SYSTEM
REPRESENTS SOCIAL RANK AND THIS
NODE MUST BE ABLE TO SUPPRESS
THE EFFECTER SYSTEM OR MODULATE
THE CONTROL CENTER SET POINT.
IF I'M A SUBORDINATE MALE I WANT
TO MINGLE WITH THESAL AS IF BUT
DON'T WANT TO GET BEAT UP SO
SUPPRESS MY EFFECTER DRIVE.
ONE OF THE BIGGEST CHALLENGES
AND WE MENTIONED TECHNICAL
CHALLENGES.
ONE OF THE BIGGEST IS MEASURING
THE ENVIRONMENT.
WHAT IS THE ENVIRONMENT?
IT'S NOT JUST PUTTING OUT THE
THERMOMETER AND MEASURING THE
SOCIAL ENVIRONMENT IS
COMPLICATED SO I'LL TALK ABOUT
THE PIPELINE WE DEVELOPED TO
DEVELOP THAT.
WHAT WE KNOW SO FAR AND A
MENTION THE AND LOOK AT THE
STATE AVERSION BY DISTINCT
PROJECTIONS.
WE CAN TRACE BACKWARDS USING
TECHNOLOGY DEVELOPED AND WE CAN
LOOK AT FIND A SHORT LIST OF
CANDIDATES THAT COULD BE THIS
POTENTIAL CONTROL CENTER.
AND WORK FROM MY VERY FIRST
GRADUATE STUDENT NOW FACULTY AT
UVA AND IS HERE TODAY.
EDWARD FOUND IN HIS THESIS WORK
WITH ME IF YOU STIPULATE THE
GAGA -- GA BERRER ERGIC NEURON
GET A TYPE AND A LAB AT YALE
FUND THE LOOP IS VERY IMPORTANT
FOR AL LEARNING.
THE INTERIOR SINGULAR CORTEX
IMPORTANT FOR EXTRACTING
INFORMATION THERE AN AGENT AND
FEEDING THAT FORWARD WHERE
LEARNING CAN HAPPEN.
AND A FORMER FACULTY UNIT AT
FLORIDA FOLLOWING UP ON WORK IN
HUMANS AND RODENTS IMPLICATING
THE PFC IS IMPORTANT FOR SOCIAL
RANK AND CAN PREDICT COMPETITIVE
SUCCESS LONG BEFORE IT OCCURS.
AND BEFORE THE OVER ALL
STRUCTURE FIGURING OUT THE WHOLE
CIRCUIT, NANCY FOUND THE PFC
PROJECTION SPECIFICALLY AND NOT
THE PROJECTION TO THE PLA IS
IMPORTANT FOR DRIVING DOMINANCE
BEHAVIOR.
NOW THAT SKELETAL MAP WE CAN
THINK OF THE DYNAMICS MUCH THIS.
WE'RE STILL THINKING ABOUT THE
INDIVIDUAL RESPONSE TO SOCIAL
CONTACT HERE BUT IF YOU LOOK AT
THE LITERATURE WITH ACUTE
ISOLATION WHEN YOU REINTRODUCE
ANIMAL TO THE GROUP THERE'S A
PROSOCIAL RESPONSE BUT WITH
CHRONIC SOCIAL ISOLATION YOU GET
SOMETHING VERY DIFFERENT.
YOU GET AGGRESSIVE TERRITORIAL,
ANTITERRITORIAL AVOIDANT
BEHAVIOR.
HOW ARE WE GIVING THE SAME
MANIPULATION, SOCIAL ISOLATION
AND REINTRODUCTION IN THE SOCIAL
GROUP AND GETTING OPPOSITE
VALENCES?
THIS IS THE MODEL OF SOCIAL
HOMEOSTASIS WHEN WE FIRST PUT
THIS OUT CONCEPTUAL BASED ON
JUST IDEAS AND WEIGHT TO BE
PROVEN WRONG.
I INVITE EVERYONE TO JOIN THE
CHARGE HERE.
WE HAVE THE TERM OF QUALITY AND
QUANTITY AND AT SOME POINT IF WE
BECOME SOCIALLY ISOLATED WHAT
WE'RE DETECTING DEVIATES FROM
THE SET POINT ARE EFFECTER
SYSTEM MAY BE ACTIVATED, MAYBE
I'LL CALL AND TALK TO MY FRIEND
OR IF I'M A MOUSE I MAKE ULTRA
SONIC SOCIALIZATION AND THEN
SOCIAL HOMEOSTASIS IS MAINTAINS.
SOMETIMES YOU'RE SOCIALLY
ISOLATED AND YOU'RE MAKE ULTRA
SONIC VOCALIZATION AND CALLING
YOUR FRIENDS BUT MAYBE YOUR
ENTIRE COLONY GOT EATEN BY A
PREDATOR OR THERE'S A GLOBAL
PANDEMIC.
WHAT WE OBSERVED IS THERE SEEMS
TO BE A MERE SET FUNCTION LIKE
DROP OF CORRECTION EFFORTS MADE.
YOU CALL, YOU CALL UNTIL YOU
STOP CALLING.
YOU GO OUT AND TRY UNTIL YOU
JUST STOP GOING OUT AND DON'T
WANT TO LEAVE ANY MORE.
WE'RE SPECULATING THERE'S A SET
POINT ADAPTATION AT THIS POINT
AFTER WHICH WHEN YOU BRING YOUR
SET POINT DOWN TO YOUR NEW
NORMAL, WHEN YOU ARE
RE-INTRODUCED TO OUR SOCIAL
GROUP, YOUR PREVIOUS OPTIMUM NOW
FEELS LIKE A SURPLUS.
SO SORRY THIS ANIMATION ALSO GOT
BOTCHED BUT THE SAME Y AXIS OR
HERE IS SOMETHING WE WANT TO DIG
INTO THE QUALITY AND QUANTITY OF
SOCIAL CONTACT.
WHEN WE THINK OF SOCIAL UTILITY,
THERE'S THE QUANTITY WHICH YOU
CAN BE ISOLATED, YOU CAN BE OVER
CROWDED.
THERE'S A JUST RIGHT OPTIMUM
WHEREAS THE QUALITY IS MO
MONOTOMMICALLY MOVINGUP WARD AND
WE WANTED TO THINK ABOUT SOCIAL
ISOLATION AND ALSO SOCIAL
EXCLUSION.
SOCIAL ISOLATION INCREASES
ANXIETY AND DEPRESSION AND IN
HUMANS EVEN PERCEIVED LONELINESS
CAN INCREASE THE MORBIDITY OF
HEART DISEASE AND SIT THE
EFFECTER SYSTEM ACTIVATION AND
WE'D MAKE DIFFERENT HEALTH
RECOMMENDATIONS BASED ON THAT
KNOWLEDGE.
WE WANTED TO STUDY THIS.
APOLOGIES FOR THE TIME SCALES.
THIS IS WARPED BUT WE WANT TO
EXPLORE THE TIME COURSE OF
SOCIAL ISOLATION TO TRY TO
IDENTIFY WHICH KEY POINT IS THE
UNDER PINNINGS AND 14 DAYS IS
THE TIME POINT THAT PRODUCES
AGGRESSIVE BEHAVIOR.
WE WANTED TO EXPLORE THIS AND
ANIMALS ISOLATED FOR DIFFERENT
PERIODS.
LOTS OF GROUPS AND LOST WORK AND
THEN WE REINTRODUCED ANIMALS TO
A JUVENILE.
WHAT CHRISTOPHER LEE AND MY LAB
HAS FOUND INDEED THAT BASICALLY
WE'RE KIND OF RIGHT.
THERE DOES SEEM TO BE THIS
IMMEDIATE INCREASE IN PROSOCIAL
BEHAVIOR THAT KIND OF COMES BACK
DOWN AND AT 14 AND 28 DAYS WE'RE
BACK DOWN TO BASELINE AGAIN AND
ALSO I WANT TO POINT OUT AT
SEVEN DAYS WE'RE GETTING A LOT
OF VARIABILITY SO THAT'S
SOMETHING TO THINK ABOUT TOO HOW
DIFFERENT INDIVIDUALS WILL
RESPOND.
NOT ALL INTERACTIONS ARE THE
SAME WAY AND IT'S A CRUDE WAY TO
LOOK AT SOCIAL BEHAVIOR AND
WANTED TO GET MORE QUANTITATIVE
AND MAKE STUDYING THIS BEHAVIOR
A QUANTITATIVE AND RIGOROUS
PURSUIT.
WE BEGAN WITH POST TRACKING AND
USING A FLEXIBLE CUSTOM PIPELINE
WE CAN SELECT FOR SECOND AND
THIRD ORDER FEATURES.
HAPPY TO TAKE QUESTIONS ABOUT
THIS AT THE END, TO PUT IN AND
PERFORM DIMENSIONALITY REDUCTION
AND CLUSTERING.
WE HAVE VARYIIATIONS AND 90% OF
THE DATA I CAN'T SHOW TODAY BUT
AFTER 24 HOURS THE RECORDING IN
THE PREFRONTAL CORTEX SHOW A
LONGER TRAJECTORY.
THE IMMEDIATE EFFECTS ARE NOT
OFFENSE AND NOTHING'S JUMPING
OUT BUT THE POPULATION DYNAMICS
ARE EXPAND AT 24 HOURS EVEN
THOUGH THEY'RE REPRESENTING THE
SAME FEATURES.
BACK TO THIS QUESTION -- I WANT
TO FOCUS ON THE QUALITY.
A COUPLE YEARS IN MY PIONEER
WORK I TOUCHED BASE WITH WEN AND
SHE SAID THAT'S COOL.
SOUNDS LIKE YOU'RE MAKING
PERFECTING BUT YOU SHOULD STUDY
PAIN.
I WAS LIKE, I DON'T STUDY PAIN.
IT'S SO FAR FROM WHAT I WORK ON
BUT BEING PART OF THIS
INCREDIBLE COMMUNITY NCCIH I
THOUGHT OF MYSELF AS AN OUT OF
THE BOX RESEARCH EVER --
RESEARCHER AND THE PAIN OVERLAP
THEORY SUGGESTS AND IS BASED ON
A LOT OF THINGS BUT A LOT OF
OBSERVATIONS INCLUDING THESE
IMAGING STUDIES IN HUMANS
SHOWING SIMILAR BRAIN REGIONS
AND WHOLE FMRI WITH THE INTERIOR
INSULAR CORTEX IMPORTANT FOR
DETECTING THE INTERNAL STATE OF
ORGANS AND SELF-AWARENESS AND
EMOTIONAL AWARENESS AS CRAIG PUT
IT AND ALSO SOCIAL AND PHYSICAL
PAIN.
SO HOW DO WE GET AT THIS?
MY STUDENT DEVELOPED WHAT WE
CALL THE FOMO AND IT STANDS FOR
FEAR OF MISSING OUT AND IT COMES
FROM THIS PHENOMENON AND YOU
CHECK SOCIAL MEDIA AND WONDERING
WHAT THEY'RE DOING AND WANT TO
GET AT THIS.
WE USED A REAL TIME OBJECT
DETECTION TOOL AND YOU CAN SEE
WHAT'S HAPPENING HERE ALL FOUR
ANIMALS HAVE BEEN TRAINED THAT A
CUE PREDICTS REWARD DELIVERY AT
THIS MILK SHAKE FOUNTAIN AND ALL
LEARNED SEPARATELY ON THEIR OWN
AND THEN ONE OF THE MICE GETS
INCLUDED AND YOU CAN SEE THE
VARIATIONS OF BEHAVIOR.
SOMETIMES WHEN THE PURPLE DOT
WAS APPEARING THEY'RE EXHIBITING
FOMO AND SOMETIMES FINE.
NOT ATTENDING AND NOT GIVING
BONDY LANGUAGE THEY'RE ATTENDING
TO THE -- BODY LANGUAGE THEY'RE
ATTENDING THE SBPGS HOW
AND ALL THE FRAMES ARE SORTED BY
THE CLUSTER.
TO SHOW HOW SIMILAR AND VARIABLE
THE FRAMES ARE WITHIN THE
CLUSTER AND BETWEEN CLUSTERS.
AND NOW THE SAME VIDEO
CHRONOLOGICALLY FROM THE
BEGINNING AND EVERY FRAME HAS
BEEN ASSIGNED A FUNCTIONAL
CLUSTER ALLOWING US TO ACHIEVE A
TIME STAMP FOR EVERY SINGLE
BEHAVIOR THOUGH THERE IS A TRIAL
STRUCTURE THE BEHAVIORS ARE
CLEARLY ECOLOGICAL AND EVERY
TRIAL IS DIFFERENT FROM THE
LAST.
SO WE'VE GOT THE TASK.
NOW I'VE SHOWED THE SOCIAL
EXCLUSION AND CONTROL WHERE
THERE'S ONLY ONE MOUSE ON THE
OTHER SIDE.
THIS IS CONTROL FOR SOCIAL
EXCLUSION AND STILL ONE MOUSE
AND THE ANIMAL COULD STILL
POTENTIALLY EXPERIENCE QUOTE,
UNQUOTE, ENVY OR THE EXPERIENCE
OF WATCHING ANOTHER ANIMAL GET
THE REWARD THEY WANT THEN WE
HAVE A TONES ONLY CONTROL AND
THE MILK SHAKE IS DELIVERED AND
IT'S JUST BEING WASTED AND MAYBE
THAT'S SAD.
I'M SO SAD THE DINNER'S BEING
WASTED.
WE PUT THEM ON THE HOT PLATE AND
LOOK AT THE PHYSICAL PAIN
RESPONSES.
AND WHAT WE SEE IS ANIMAL THAT
UNDERWENT THE SOCIAL EXCLUSION
PARADIGM SHOWED A SIGNIFICANTLY
HIGHER RESPONSE TO PHYSICAL PAIN
IN TERMS OF THE LICKING OF THE
PAW RELATIVE TO ANIMALS THAT
UNDERWENT THE TONES ONLY
RESPONSE OR CONDITION.
WHAT'S GOING ON?
WHEN HAVE YOU PHYSICAL PAIN AND
SOCIAL PAIN ARE THEY SYNAPSING
ON THE SAME CELL WHICH IS A
POPULAR IDEA WHEN THE PAIN
OVERLAP THEORY.
IS THERE A CELLULAR OR SPATIAL
CONVERGENCE OR WOULD THERE BE
SIGNALS THAT HELP CREATE THIS
ADDITIVE AMPLIFICATION OF SOCIAL
PAIN PEOPLE SAY WE RECORDED IN
THE INTERIOR INSULAR COVER --
CORTEX AND THIS IS A BUSY SLIDE.
IT'S FUNCTIONALLY CLUSTER ED MAS
FOR THE FOMO STUDY AND
CO-REGISTERED THE NEURONS AND
LONG STORY SHORT IT'S KIND OF A
HOT MESS, DON'T REALLY SEE
ANYTHING AND DOESN'T SEEM LIKE
THE NAME NEURONS INVOLVED IN
SOCIAL PAIN ARE INVOLVED IN
PHYSICAL PAIN SO WE'RE GOING
MOVE ONWARDS TO THE OTHER MODEL.
AND WE WONDERED ABOUT DOPAMINE
AND OXYTOCIN AND THEN LOOKED AT
CANNABINOIDS AND WE USED THE
ENDOCANNABINOID SENSE IN THE
CORTEX AND PERFORMED THIS IN THE
SOCIAL EXCLUSION TASK.
ON TRIALS WHERE THE ANIMAL WAS A
FOMO BEHAVIOR SERVICE FINE
BEHAVIOR WE SEE INCREASED
ENDOCANNABINOID SIGNALLING
WITHIN SUBJECT COMPARISON.
SO THIS SUGGESTED PERHAPS
ENDOCANNABINOIDS ARE PRODUCING A
PROTECTIVE EFFECT FOR FOMO
DURING SOCIAL EXCLUSION.
AND FOR THE TONES ONLY MAYBE THE
OPPOSITE TREND AND WITH THE ONE
MOUSE CONTROL ALSO NO EFFECT.
THIS IS A FINDING THAT IS
SPECIFIC TO SOCIAL EXCLUSION.
THIS IS MY LAST DATA SLIDE AND
WANTED TO SEE WHAT HAPPENS WITH
ENDOCANNABINOID SIGNALLING WITH
PAINFUL STIMULUS AND THERE'S
OTHER DATA FOR THE DIFFERENT
STIMULI AND ESSENTIALLY WE'RE
SEEING THERE'S AN ELEVATED
CANNABINOID RESPONSE FOR THE
TONES ONLY SUGGESTING PERHAPS
THAT THE ENDOCANNABINOID POOL
HAS BEEN DEPLETED OR USED UP
DURING THE SOCIAL EXCLUSION OR
ONE MOUSE CONDITIONS.
DEFINITELY UNDER CONSTRUCTION.
LOTS TO DO.
THIS IS THE BEGINNING OF THE
EMBRYONIC FIELD OF HOMEOSTASIS
AND WE BARELY SCRATCHED THE
SURFACE AND IN CASE YOU'RE
WONDERING WHICH POSTERS YOU WANT
TO GO TO AND WANT TO HEAR I'LL
BE PRESENTING DURING A TALK OF
SOCIAL ISOLATION TOMORROW
AFTERNOON AND WE HAVE POSTERS
TALKING ABOUT NEUROMODULATION
AND NEW ARCHITECTURES FOR LONG
LEARNING AND LONGITUDINAL
MODULATION OF PFC NEURONS DURING
ACUTE OR SEVERE STRESS OR MILD
STRESS FROM A STUDENT FACULTY AT
UCLA AND IF YOU WANT TO HEAR
MORE ABOUT THE FOMO.
AND IF YOU'RE INTERESTED IN ANY
OF THE WORK YOU HEARD ABOUT
TODAY, I HOPE YOU'LL REACH OUT
TO ME TO JOIN OUR TEAM BUT IF
YOU YOU DON'T WANT TO MOVE OUT
TO WHERE WE ARE REACH OUT TO
FORMER TRAINEES AND WE HAVE
POSTDOCS FOR A FEW MORE MONTHS
BUT THEY'RE RECRUITING.
WITH THAT I WANT TO THANK ABOVE
EVERYTHING NCCIH FOR SUPPORTING
THIS RESEARCH PROGRAM.
EVERYONE IN MY LAB, PAST,
PRESENT AND FUTURE.
AND COLLABORATORS AND YOU FOR
YOUR ATTENTION.
THANK YOU.
>> WE'RE RUNNING SHORT ON TIME
BUT WE CAN TAKE ONE QUESTION.
>> WHEN THINKING OF THE OVERLAP
BETWEEN PHYSICAL AND SOCIAL PAIN
HAVE YOU CONSIDERED DIVIDING UP
SOMATIC VERSUS ADVERSE
COMPONENTS AND SOCIAL PAIN HAS
MORE OVERLAP WITH AFFECTIVE PAIN
OVER SOMATIC PAIN?
>> GREAT QUESTION.
WHAT I'M TAKING THAT TO MEAN ARE
WE THINKING ABOUT THE BEHAVIORAL
RESPONSES TO PAIN, LICKING THE
PAW, HOLDING THE PAW AND CRYING
RATHER THAN THEN THE DETECTION
OF THE NOCICEPTIVE STIMULUS
THRESHOLD.
WE LOOKED AT DIFFERENT MEASURES.
I WOULD SAY MOST THE MEASURES
WE'VE SEEN ARE ABOUT THE
AFFECTIVE RESPONSE.
SOMETHING THAT LOOKS LIKE IT
COULD BE AFFECTING DETECTION
THRESHOLDS AS WELL AS BUT BY AND
LARGE MOST OF OUR SIGNIFICANT
AFFECTS ARE WITH THE AFFECTIVE
COMPONENTS SO YOU'RE RIGHT.
>> TERRIFIC.
ONE MORE HAND.
TERRIFIC.
NEXT I'D LIKE TO GO AHEAD AND
INTRODUCE AND WELCOME MY
EMMELINE EDWARDS AND OLGA
TJURMINA AND THE PANELISTS AS
WELL IF YOU CAN COME UP THAT
WOULD BE TERRIFIC.
>> I'M THE DIRECTOR OF AT NCCIH
AND PLEASED TO SERVE AS
MODERATOR FOR THIS SESSION OF
YOUNG INVESTIGATORS.
AS YOU HEARD FROM DR. CHEN,
THROUGH THE EFFORT OF THE OF THE
INTEROCEPTION GROUP, WE'VE SEEN
AN AMAZE IING GROWTH IN THIS FI
SINCE 2018.
AND I THINK THIS SESSION REALLY
IS TO FOCUS ON OUR CAPACITY
BUILDING EFFORTS AND REALLY
EMPHASIZE THE WORK OF AN AMAZING
GROUP OF YOUNG INVESTIGATORS.
THIS WAS A VERY COMPETITIVE
PROCESS.
THE PLANNING COMMITTEE RECEIVED
120 ABSTRACTS AND OUT OF THOSE,
ONLY SIX WERE CHOSEN.
AND THE SELECTION CRITERIA WERE
STIFF.
THE STRENGTH OF THE HYPOTHESIS
AND FINDINGS AND USE OF NOVEL
TECHNOLOGY AND ALSO THE GROUP
DID AN AMAZING JOB IN TERMS OF
HAVING DIVERSE GROUP OF
PRESENTERS.
YOU CAN SEE THERE'S GOING TO BE
GOOD DIVERSITY IN THE ORGAN
SYSTEMS THAT WILL BE
REPRESENTED, IN THE TYPE OF
RESEARCH CLINICAL VERSUS BASIC
AND THE TOPIC THAT ARE GOING TO
BE PRESENTED.
IN ADDITION, THE GROUP ALSO PAID
ATTENTION TO DIVERSITY AND
GENDER AND ALSO IN ETHNICITY.
I THINK WE'RE PRIVILEGED TO HAVE
A GROUP OF YOUNG INVESTIGATORS
THAT HAVE A DIFFICULT TASK IN
FIVE MINUTES THEY'LL HAVE TO NOT
ONLY TELL YOU ABOUT THEMSELVES
BUT ALSO BUT EXCITING FINDING.
I'LL TURN IT OVER TO MY
COLLEAGUE DR. TJURMINA TO
INTRODUCE THE INVESTIGATORS.
>> THANK YOU.
LET ME INTRODUCE OUR SPEAKERS.
MIN
MINEL ARINNEL AND KHALIL RAMADI
ABOUT DEVICES YOU CAN EAT,
MICHAEL CARDENAS FROM THE
UNIVERSITY OF ARIZONA, MAKE AN
APPROACH-AVOIDANCE CONFLICT TASK
AND SENEGAL ALFRED MABRY FROM
CORNELL TALKING ABOUT
DIFFERENCES IN FUNCTIONAL
CONNECTIONS AND IMPAIRMENTS IN
HEART-BASED INTEROCEPTION DURING
PAR PAR KIVEN SONS DURING STRESS
AND EXERCISE AND LE ZHANG
LOOKING AT NEURO-IMMUNE
INTERACTIONS AND INTEROCEPTION
IN PRODOME JAM PARKINSON'S
DISEASE AND THEN JOSÉ HERRERO
RUBIO LOOKING AT PERSISTENT
DYSPNEA AND SOME PRESENTERS
POSTERS.
AND YOU'LL SEE THE NUMBERS AND
YOU SEE IT NOW.
YOU'RE INVITED TO ASK YOUR KE
QUESTIONS DURING THE POSTER
SESSION BECAUSE EACH PRESENTER
HAS ONLY FIVE MINUTES TO PRESENT
THEIR WORK.
NOW, PLEASE.
>> HELLO, I'M A FIFTH YEAR
STUDENT AT DUKE INVESTIGATION
AND MAPPING THE GUT BRAIN
CIRCUITRY TO ANSWER COMPLEX
BIOLOGICAL QUESTIONS.
AS SOME OF YOU ALREADY KNOW THE
GUT-BRAIN COMMUNICATION IS
ESTABLISHED BY SENSOR CELLS IN
THE GUT EPITHELIUM CELLS I'LL BE
REFERRING TO AS EECs.
THEY CAN DETECT NUTRIENTS IN THE
GUT AND CIRCULATE HORMONES AND
FORM SYNAPSES WITH VAGAL NEURONS
AND TAKES IT TO THE BRAIN TO
REGULATE FEEDING BEHAVIOR.
WHAT I'M INTERESTED IN IS
UNDERSTANDING HOW THESE SIGNALS
GO FROM EECs TO THE BRAIN AND
SPANS ACROSS THE BODY WE NEED A
MODEL ORGANISM THAT ALLOWS
ACCESS TO THE WHOLE CIRCUIT.
FOR THAT WE USED ZEBRAFISH
BECAUSE THEY'RE SMALL AND
TRANSPARENT AND MANIPULATE THE
CELLS OF THE GUT-BRAIN AXIS AND
THEY'RE A SIMPLE BUT ALSO
CONSERVED MODEL TO STUDY THIS
PHENOMENON.
TO START OFF WE FIRST WANTED TO
INVESTIGATE WHAT THEY ENCODE.
WE DEVELOPED AN ANALYSIS
PIPELINE TO EXTRACT THE
ACTIVITY.
WE CAN DETERMINE WHICH NUTRIENTS
DETERMINE THESE EECs AND WANTED
TO SEE WHETHER THEY DRIVE
REPETITIVE PANEL WAYS AND HAVE
PARTICLES WHICH UPON CONSUMPTION
DISSOLVE IF THE GUT AND EXPOSE
THE NUTRIENTS TO THE EECs.
AND WE CAN LOOK AT HOW MUCH THEY
EAT FROM THE DIFFERENT PARTICLES
AND DEVELOP A GUT MEDIATED
PREFERENCE.
WE'VE SHOWN THIS AND WHAT I'M
INTERESTED IS HOW IS THIS
ENCOENCODE
ED NERVOUS SYSTEM AND I NEEDED A
METHOD AND A DEVELOPED A METHOD
TO GUIDE A NEEDLE INTO THE GUT
OF ZEBRAFISH AND NOW THAT I'VE
DEVELOPED THIS METHODOLOGY I CAN
IMAGE VAGAL NEURONS AND I FOUND
ENCODING WHERE THE RIGHT VAGAL
GANGLION HAS MORE DELAYED AND
THE LEFT HAS MORE IMMEDIATE
RESPONSES TO THE INJECTED
STIMULUS.
I CAN EXPAND THESE PARS OUT THE
COMPONENTS TO THE INJECTED
STIMULI.
I STARTED WITH WHERE THE VAGAL
BRAIN SYNAPSES ON EXPANDING TO
OTHER BRAIN REGIONS.
LASTLY, I WANT TO PHOTO
STIMULATE THESE AND RECORD THE
NEURAL RESPONSES AND I ADAPT THE
NEEDLE TO GUIDE THE OPTIC FIBER
TO THE SIDE OF THE FISH AND
PHOTO STIMULATE THESE THROUGH
IMAGING.
AND FOR THAT WE DEVELOPED THE
EECs AND I'M WORKING ON
OPTIMIZING THESE EXPERIMENTS.
OVER ALL MY THESIS WORK AIMS TO
DEVELOP A COMPREHENSIVE
INFORMATION OF THE GUT-BRAIN
NEURAL CIRCUITRY AND WHAT THE
GUT IS COMMUNICATING TO THE
BRAIN.
WE WERE ASKED TO PRESENT
SOMETHING SPECIAL ABOUT
OURSELVES.
I'M A FIRST GEN GRAD STUDENT
BORN AND RAISED IN TURKEY AND
I'D LOVE TO GIVEBACK AND MENTOR
HIGH SCHOOL STUDENTS AND
UNDERGRAD STUDENTS.
I'D LIKE TO HIGHLIGHT WHO
AMAZING UNDER GRADS WITH ME AND
THERE'S WORK ON A PROJECT WHERE
WE INVESTIGATE THE EFFECTS OF
PSYCHEDELICS ON THE
TRANSFORMATION IN FISH.
I DON'T HAVE MUCH TIME BUT THE
MOS
POSTER MEETING IS 64 AND WILL
PRESENT TOMORROW AND MY POSTER
NUMBER FOR THAT IS 2 AND REACH
OUT BY E-MAIL OR FIND ME ON
LINKEDIN OR X.
THANK YOU.
>> THANK YOU.
KHALIL RAMADI, PLEASE.
>> GOOD MORNING, EVERYONE I'M AN
ASSISTANT PROFESSOR AT NYU AND
TODAY IN THE QUICKEST TALK ON
THIS TOPIC I'LL TALK ABOUT
INGESTIBLE MODULATION DEVICE AND
LOOKING AT STIMULATION RESEARCH
IN THE '60s AFTER PACE MAKERS
REVOLUTIONIZED CARDIOLOGY AND WE
THOUGHT WE SHOULD BE ABLE TO
MAKE THE STOMACH BEAT.
THAT LED TO WHAT WE HAVE THAT IS
CLINICALLY APPROVED GES SYSTEMS
WHICH ARE PACE MAKERS SURGICALLY
IMPLANTED WITH SUTURE TO THE
STOMACH AND HELPS PATIENTS WITH
NAUSEA, VOMITING SYMPTOMS FROM
GASTROPARESIS.
IT DOESN'T MAKE THE STOMACH BEAT
BUT THE REASON WHY IT IS FDA
APPROVED IT IS PATIENTS REPORT
BETTER OUTCOME AND WE THOUGHT
MAYBE IT'S A CENTRALLY MEDIATED
SYSTEM RESOLVED THROUGH THIS
STIMULATION.
THE HYPOTHESIS IS PERHAPS IT'S
IMPROVING NAUSEA AND VOMITING
INCREASING GHRELIN LEVELS AND TO
TEST THIS WE USED SWINE MODELS
AND WENT IN WITH ELECTRODES AND
SAMPLED BLOOD AFTER STIMULATION
UP TO 60 MINUTES AND WE SAW IF
YOU YOU LOOK AT THE CHANGE IN
GHRELIN LEVELS OVER TIME THE
CASES WHERE ANIMALS RECEIVE
ACTIVE STIMULATION SAW
SIGNIFICANT INCREASE IN GHRELIN
NOT THERE IN THE SHAM AND IF YOU
DO VAGOTOMY IT SEEMS TO BE
HORMONAL AFFECT MEDIATED SOME
NEURAL REFLEX.
THE SECOND QUESTION IS WHETHER
WE COULD ACCOMPLISH SIMILAR TYPE
OF STIMULATION THROUGH
INGESTIBLE SYSTEMS AND LED TO US
DEVELOP FLUID WE CAN CAPSULE FOR
HORMONE MODULATION AND DEVELOP A
TECHNOLOGY AND FLASH IS ROUGHLY
THE SIZE OF THE LARGEST HUMAN
CAP TOOL SIZE AND HAVE
ELECTRONICS AND PUT OUT OUT THE
SUFFER FAS AND EXISTS IN AN OPEN
SURFACE STATE AND WHEN THEY COME
INTO CONTACT STIMULATION STARTS
TO FLOW.
THERE'S A LOT OF ENGINEERING AND
ONE FEATURE WHICH WAS COUNTER
INTUITIVE AND YOU CAN SEE THE
SURFACE AND HAVE YOU GROUPS AND
WE RECOGNIZED THE PRESENCE OF
GASTRIC FLUID STIMULI CAN NO
LONGER ENTER THE TISSUES AND WE
HAVE A MEANS OF WICKING FLUID
AWAY FROM THE POINT OF CONTACT
BETWEEN THE ELECTRODE AND
TISSUE.
THIS IS A CAPSULE AND YOU CAN
SEE THE FLUID IS WICKED FROM THE
SURFACE ALLOWING FOR BETTER
CONTACT BETWEEN ELECTRODE AND
TISSUE.
IF YOU LOOKING AT THE SAME
EFFECT OF LOOKING AT GHRELIN
LEVELS OVER TIME IF YOU YOU
DELIVER ACTIVE CAPSULE OPPOSED
TO OTHERS YOU SEE ACTIVATED
GHRELIN LEVELS.
I WANT TO ACKNOWLEDGE PEOPLE IN
MY GROUP AND NYU AND FORMER
COLLABORATORS AT M.I.T. AND
FUNDING SOURCES.
I'M EXCITED ABOUT THIS INGEST
IBLE ELECTRONIC SPACE AND CAN DO
NEUROMODULATION IN A SOMEWHAT
TARGETED WAY AND WOULD LOVE
THOUGHTS AND COMMENTS AND WE'RE
RECRUITING ACROSS THE BOARD AND
MY POSTER NUMBER IS 68.
WOULD LOVE TO CHAT LATER.
THANK YOU.
>>
>> THANK YOU TO EVERYBODY
ESPECIALLY TO THE ORGANIZERS.
I'M GOING TO TELL BUT A NEW SET
OF DATA FROM OUR LAB WE'RE
EXCITE ABOUT.
WE START FROM THIS QUESTION, DO
INTEROCEPTIVE SIGNALS INFLUENCE
DECISION MAKE.
BEFORE I TELL YOU HOW WE ASK
THIS IN MONKEYS I WANT TO ASK
THE AUDIENCE TO JOIN MYSELF AND
THE REST OF TUCSON IN
UNDERSTANDING OR NOT
UNDERSTANDING BUT MAKING A
DECISION IF LIVING IN THE CITY
WITH THE BEST 23 MILES OF
MEXICAN FOOD IN THE COUNTRY IS
WORTH THE 110 DEGREE SUMMERS.
THIS SETS UP A CONFLICT AFTER
WEIGH THE COST AND BENEFITS OF
THAT OPTION.
IF WE WANT TO KNOW HOW
INTEROCEPTION INFLUENCES THESE
DECISIONS WE'RE GOING TO USE A
PERIPHERAL SPECIFIC
MANIPULATION.
WE USED A NON-SPECIFIC
ANTAGONIST THAT DOES NOT CROSS
THE BLOOD BRAIN BARRIER AND
EFFECTS OF THIS DRUG CAN BE USED
AND IT BLOCKS THE
PARASYMPATHETIC SYSTEM AND WHAT
DO WE DO WITH THE MONKEYS?
THEY'RE SEATED IN THE CHAIR WITH
A DEVICE WITH TEMPERATURE
RESTRICTED CONTROL AS WELL AS A
JUICE TUBE AND TOUCH SWITCH.
AT THE BEGINNING OF EVERY TRIAL
THE THERMO RAMPS UP TO A PRE
DETERMINED TEMPERATURE AND THE
JUICE IS DELIVERED AT A RATE OF
ONE DROP PER SECOND AND WHEN THE
MONKEY NO LONGER WANTS TO DEAL
WITH THE HEAT THEY CAN TURN OFF
THE JUICE AND HEAT.
THIS GIVES US A MEASURE OF THEIR
TOLERANCE FOR THE HEAT GIVEN THE
JUICE REWARD.
EVERY DAY WE GIVE THEM THIS FOR
25 MINUTES AND DO A ROUND OF NO
HEAT TRIALS WHERE THE HEAT
DOESN'T RAMP UP IT JUST STAYS
CONSTANT AND THEY DRINK THE USE
AND THEN AROUND THE HEAT TRIALS.
THAT CAN BE SWAPPED FROM DAY TO
DAY TO ACCOUNT FOR SATIATION AND
WHEN WE GIVE THIS IT SHIFTS BACK
INDICATING THE ANIMAL IS MORE
AVOIDANT TO THE HEAT AND IN
GENERAL LESS WILLING TO TOLERATE
IT.
WHEN LOOK AT THE NO HEAT TRIALS
THERE'S NO TIME THEY STOP THE
JUICE SAYING IT'S NOT ABOUT THE
REWARD BUT AN AVOIDANT BEHAVIOR
AND I CAN'T SHOW YOU EVERY
CONTROL BUT WE DID A LOT AND YOU
CAN COME TO THE POSTER AND WE
USE THE BETA AGONIST AND AND IT
COMES OUT SIMILAR.
AND PRIMATES SHINE ALONG THE
INTEROCEPTIVE PATHWAYS AND WE
HAVE AN AWESOME MASTER STUDENT
WHO IS APPLYING TO Ph.D. PROGRAM
SO YOU'D LIKE HER E-MAIL AN WANT
A GREAT Ph.D. STUDENT, PLEASE
LET ME KNOW.
THANK YOU.
>> THANK YOU.
WE'RE PLEASED TO HAVE SENEGAL.
>> GOOD MORNING.
I'M A THIRD-YEAR DOCTORAL
STUDENT IN THE DEPARTMENT OF
PSYCHOLOGY IN THE COLLEGE OF
HUMAN ECOLOGY AT CORNELL
INVESTIGATION.
MY ADVISERS IS ADAM ANDERSON AND
LEADERS IN THE FIELD OF EMOTION
AND NEUROCHEMISTRY.
MY WORK EXAMINES THE HEART-BRAIN
AXIS IN PARKINSON'S DISEASE AND
THIS IS MY TEAM.
THAT'S US ATTENDING MOVING DAY
IN RODCHESTER SUPPORTING
FAMILIES WITH PARKINSON'S DAY.
IT'S ONLY WORKING WITH TEAMS
WHERE WE'VE BEEN ABLE TO LOOK AT
WHERE THE DISEASE FIRST STARTS
AND THE AUTONOMIC SYSTEM CHANGES
AND THE HISTORY OF HEART ATTACK,
AND HISTORY OF SMOKING REDUCES
THE DIAGNOSIS.
THERE'S JUST THE BEGINNING OF
UNDERSTANDING WHAT'S HAPPENING
IN THIS CONDITION.
HERE'S AN EXAMPLE OF BEING
EMBEDDED IN THESE COMMUNITIES
SUPPORTS QUESTIONS AND WE'VE
BEEN WORKING TO UNDERSTAND HOW
THIS INTERESTING CARDIO
PULMONARY WORKOUT REDUCES MOTOR
GAIT SYSTEMS AND HE SAID WHEN
THEY COME OFF THE MACHINE IT'S
LIKE THEY DON'T FEEL ANYTHING
AND WE ASKED HOW STRONGLY CAN
THEY FEEL THEIR HEART RATE
DURING THREE EXERCISE TRAINING
SESSIONS.
EACH 45 SECONDS EACH AND FOUND
THE TRAINING SESSIONS LED TO A
20 BEATS PER MINUTE HEART RATE
INCREASE.
FIRST, THE HOST LIKELY RESPONSE
ACROSS THE BASELINE THE REACT 1
AND REACT 3 AND RECOVERY PERIOD
WERE NOT AT ALL.
NOT AT ALL BEING ABLE TO FEEL
THEIR HEARTBEAT.
I'M PLAYING MY SLIDES QUICKLY
FOR YOU RIGHT NOW OF THEIR
ACTUAL RESPONSES PLOTTED AGAINST
HEART RATE AND FOR THE MOST PART
THERE'S NOT A STRONG POSITIVE
RELATIONSHIP BETWEEN HEART RATE
AND RESPONSE.
WE'RE SEEING A STRONG NEGATIVE
RELATIONSHIP FOR ONE OF OUR
PARTICIPANTS WHERE INCREASE IN
HEART RATE IS MOVING THEM TO
REPORT NOT AT ALL FOR THEIR
HEART RATE RESPONSE AND LOOKING
AT EACH INDIVIDUAL PARTICIPANT
WE'RE SEEING ONLY TWO IS THERE
DIFFERENCES BETWEEN THE MEDIANS
OF RESPONSES ON THIS QUESTION OF
HOW STRONGLY CAN THEY FEEL THEIR
HEART RATE.
NEXT WE ALSO WANTED TO COLLECT
SOME DATA ON STRESS.
NOT JUST EXERCISE BUT TAKING
THEM IN THE CORNELL MAGNETIC
IMAGING FACILITY AND RECORDING
THEIR RESPONSES WHERE THEY'RE
PAYING ATTENTION TO THE SCREEN
AS A BASELINE LOOKING AT A
RESTING STATE AND FIXATION AND
THEN TELLING THEM YOU HAVE TWO
MINUTES TO PREPARE A SPEECH
ABOUT WHY YOU'RE A GOOD FRIEND
AN TELLING THEM THE COIN FLIP IS
THE DECIDING TO NOT MAKE THE
SPEECH AND THAT'S OUR BASELINE
AND STRESS AND RECOVERY AND WITH
STRESS WE'RE SEEING 20 MINUTES A
MINUTE HEART RATE INCREASE AND
SEEING AN INDICATION THERE'S
MORE PHYSIOLOGIC CONSEQUENCES OF
STRESS IN PARKINSON'S AND WE
HAVE THEM -- THEY'RE RESPONSES
ARE ROUGHLY THE SAME ON STRESS
MAYBE PEOPLE WITH PARKINSON'S
RECOVER LATE SLOWER BUT OUR
INTEROCEPTION QUESTION HOW
STRONGLY THEY CAN FEEL THEIR
HEARTBEAT THEY SAY NOT AT ALL SO
WE'RE STILL SEEING THEM STRUGGLE
TO TAP INTO THEIR INTEROCEPTIVE
ABILITY.
I MENTIONED THIS IS HAPPENING
WITH A RESTING STATE FUNCTIONAL
MRI SCAN AND IT'S STRONG
CONNECTIVITY WITH ITSELF AND
LOOKING SIMILAR ACROSS THE
PARKINSON'S AND HEALTHY CONTROL
AND IN STRESS WE'RE SEEING
INCREASES IN FUNCTIONAL
CONNECTIVITY FOR OUR HEALTHY
PARTICIPANT IT'S POSITIVE
INCREASES PARTICULARLY IN THE
CEREBELLUM AND FOR FOLKS WITH
PARKINSON'S NEGATIVE IN THE
CEREBELLUM A CRITICAL REGION FOR
CARDIAC REPRESENTATION AND PLAYS
A ROLE IN THE AUTONOMIC NERVOUS
SYSTEM AND PARKINSON'S SYMPTOMS.
WE'LL CONTINUE TO LOOK AT THE
INTER
INTERIOR INSULA CEREBELLUM AND
THANK YOU TO MY CORNELL TEAM AND
THE MARINE BIOLOGICAL SPINES
PROGRAM AND UNIVERSITY OF
WISCONSIN AND FIND ME AT THE
SOCIETY FOR NEUROSCIENCE POSTER
HALL.
THANK YOU VERY MUCH.
>> THANK YOU.
DR. ZHANG, PLEASE.
>> THANK YOU FOR THE
OPPORTUNITY.
I'M AN ASSISTANT PROFESSOR OF
NEUROLOGY AND NEUROSCIENCE AT
YALE UNIVERSITY FOR THREE YEARS
AND UNDERSTANDING PARKINSON'S
DISEASE WITH INTERACTIONS AND
BRAIN COMMUNICATION.
PARKINSON'S DISEASE IS THE
SECOND MOST COMMON NEURO
DEGENERATIVE DISEASE.
THE PATIENT HAS SYMPTOMS
INCLUDING G.I. SYMPTOMS.
THE PATHOLOGY LOOKING AT
INITIATION IN THE GUT AND THE
VAGAL NERVE TO THE BRAIN.
OUR T CELLS HAVE BEEN IDENTIFIED
IN THE PARKINSON'S PATIENT
SUGGESTING IN ADDITION TO THE
ACCESS MEDIATED BY THE NERVES.
IMMUNE CELLS BRING CONNECTION TO
PARKINSON'S DISEASE.
OUR CENTRAL HYPOTHESIS AT THE
SUBSET OF PATIENTS, PARKINSON'S
INCLUDING NUCLEI IN THE GUT AND
IT'S A DISEASE IN THE BRAIN.
OUR STUDIES FOCUSSING ON HUMAN
RESEARCH WE RELY ON HUMAN
CONTROLS FROM EARLY PARKINSON'S
DISEASE WHO HAVE REM SLEEP
BEHAVIOR AND ACT OUT THEIR DREAM
DURING SLEEP.
FROM THE SAME PATIENT DONORS
BLOOD AND GUT BIOPSY WE ISOLATED
THE CELLS ACROSS ORGANS AND
PERFORMED SINGLE CELL RNA
SEQUENCING AND T CELL SEQUENCING
CAN SERVE AS A POSSIBLE CURE FOR
THE T CELL ACROSS ORGANS.
CSF IS A WINDOW TO SEE WHAT'S
HAPPENING IN THE BRAIN AND.
AND THIS IS THE INTEGRATION OF
THE T CELLS FROM ORGANS
INCLUDING THE CSF TO THE
COLLECTION OF T CELLS AND THE
COLON.
THE T CELLS FROM THE ORGANS HAVE
A UNIQUE SIGNATURE FOR IMPULSE
ENRICHED IN THE CSF AND THE
CHEMICAL RECEPTOR AND IT IS
PLAYING AN ESSENTIAL ROLE IN T
CELL TRAFFICKING AND FUNCTION BY
YIELDING T CELL SEQUENCING WHERE
WE'RE ABLE TO IDENTIFY THE
SHARED CLONAL TYPE IN THE GUT
AND ALSO ABLE TO TRACK IT IN THE
BLOOD AND MORE IMPORTANTLY IN
THE CNS.
AND LOOKING AT THE PATIENT WE
IDENTIFIED THE IT PULSES WHICH
MEANS THERE'S MORE CELLS IN THE
CNS COMPARED TO CONTROL AND THE
INFLAMMATION INCLUDES MACRO
PHAGE.
IT'S HIGHLY ENRICHED IN RBD AND
BD PATIENT WITH THE SIGNATURE
AND SIMILARLY THE BRAIN
MACROPHAGE.
OUR FUTURE DIRECTION IS TO BUILD
TOOLS TO UNDERSTAND HOW THE
BRAIN ACCESS CAN CONTRIBUTE OR
LEAD TO THE INFLAMMATION IN
PARKINSON'S DISEASE.
WITH THAT I WOULD LIKE TO THANK
MY FUNDING AGENCY IN FUNDING MY
WORK IN THE CENTRAL NERVOUS
SYSTEM WITH GRANTS FROM NIH AND
THE PARKINSON'S DISEASE
FUNDATION FOR FUNDING OUR
RESEARCH AND THANK MY LAB
MEMBERS FOR THEIR GREAT EFFORT
AND FOR LEADING OUR TEAM.
AS A Ph.D. SCIENTIST OUR HUMAN
RESEARCH IS BASED ON THE CLOSE
COLLABORATION WITH OUR TEAM.
THANK YOU.
>> THANK YOU.
>> GOOD MORNING I'M JOSÉ HERRERO
AT THE FEINSTEIN INSTITUTE OF
MEDICAL RESEARCH ON PERSISTENT
DYSPNEA INSIGHTS FROM THE
INVASIONIVE HUMAN RECORD OF
RESPIRATORY RELATED BRAIN
OSCILLATIONS DURING RESPIRATORY
CHALLENGE AND THIS IS IT WHEN
YOU FEEL SHORTNESS OF BREATH
WHEN YOU GO TO THE GYM AND AN
ARTICLE IN THE NEW YORK TIMES
THERE WAS A TOMORROW OF SLEEP
APNEA WHICH AFFECTS TO MOST
PEOPLE LOOKS AT THE MONITORS FOR
LONG PERIODS OF TIME.
THIS BREATH CAUSES SUSPENSION
PERIODS THAT CAN BEING LONG AND
FREQUENT AND THE PERSON IS NOT
AWARE OF THEM.
IT HAPPENS MORE OFTEN IF YOU
HAVE A SEDENTARY LIFE.
TO SPECULATE THE MECHANISMS THAT
UNDER LIE UNAWARE BREATHE HOLD
PERIODS WOULD BE FROM DIFFERENT
AREAS IN THE BRAIN SENDING
SIGNALS TO TO THE BRAIN
RESPIRATORY CENTERS SUPPRESSING
RESPIRATORY SYSTEMS AND REPRESS
MUSCLES AND RESULT IN BREATH
HOLD PERIODS.
THE THIRD CLAIM THIS IS
SUSTAINED FOR LONG PERIOD OF
TIME CAN RESULT IN MORE
PATHOLOGICAL BREATHING
ABNORMALITIES INCLUDING DYSPNEA.
WHILE THIS NEEDS TO MORE
RESEARCH NEEDING TO BE DONE AND
WE HAVE AN INCREASING INCIDENCE
OF THOSE BEING DIAGNOSED WITH
THIS SINCE COVID AND THOSE WHO
WEAR FACE MASKS FOR A LONG
PERIOD AND OPIOID USERS AND THE
OTHER AND THE LUNGS ARE NORMAL
OR RELATIVELY NORMAL AND THE
SIGNALS TO THE BRAIN ARE NORMAL
HOWEVER, THERE IS AN ABNORMAL
SENSATION OF THE PROCESSING AND
SUPPRESSES THIS IN THE BRAIN
STEM AND WE PUBLISHED A PAPER
AND CHALLENGED THE TRADITIONAL
VIEW THAT BRAIN STEM CONTROLS
ALL ASPECTS RESPIRATION AND WE
FOUND THERE WERE NEURONAL
EXCITABILITY WITH THE BREATHING
CYCLE.
THIS HELPED REFURISH -- THIS WAS
LOOKING AT RESPIRATORY DISORDERS
AND HOW THESE GO TO PEOPLE WITH
BREATHING PROBLEMS SUCH AS
DYSPNEA.
THE PRIMARY TREATMENT AND IF
THAT DOESN'T WORK WHERE HE
PRESCRIBE OPIOIDS WITH DIFFERENT
SIDE S AND THEY TARGET THE BRAIN
RATHER THAN LUNGS SO WHY NOT
UNDERSTAND WHAT THE BRAIN IS
DOING AND COME UP WITH
ALTERNATIVE TO OPIOIDS.
WE WERE AT THE WARSAW MEETING IN
2019 WITH A CLEAR MESSAGE.
WE NEED BETTER TOOLS TO EVALUATE
THE INTEROCEPTION.
TOGETHER WITH MY TEAM WE
COLLABORATED AND THIS WAS DONE
TO DEVELOP A BETTER MODEL OF
DYSPNEA AND MAP THE DISEASE AND
WE USE THE DETECTION TASK AND
HAVE A BALLOON INFLATED AND WE
RECORD AND THERE'S AN EXAMPLE
TRIAL WHERE YOU YOU CAN SEE THE
MOUTH INCREASING AFTER
VENTILATION AND INCREASING
FURTHER WHEN THERE'S AN
OCCLUSION PERIOD.
THIS WAS RECORDED WITH THE MOTO
CORTEX AND THE PRELIMINARY
RESULTS WE FOUND THIS
SUPPRESSION IN OSCILLATIONS
WITHIN THE OCCLUSION TIME FOR CO
SECONDS AND ENHANCE GAMMA
OSCILLATIONS AND WAS NOT THE
FIRST TIME REPORTED THE
INHALATIONS HAS BEEN RECORDED
ALSO FOR FINGER MOVEMENT.
WE'RE LOOKING AT OTHER BRAIN
AREAS AND MAPPING AND LOOKING AT
THE COMPONENTS OF DYSPNEA.
AND WE ARE ASKED TO SAY
SOMETHING SPERM ABOUT THIS AND
IN MY FREE TIME I'M A DEEP SEA
DIVER AND LOVE TO HOLD MY BREATH
UNDER WATER AND CATCH FISH.
>> THANK YOU.
>> HOW TO OUR WONDERFUL
SPEAKERS.
THIS SESSION IS ADJOURNED.
WE'LL HAVE 15 MINUTES BREAK AND
POSTER SET UP IN THE CABINET
ROOM.
PLEASE COME BACK AT 10:50 FOR
THENEXT SESSION.
ALL RIGHT.
I'D LIKE TO WELCOME EVERYONE TO
SESSION 2, TECHNOLOGY AND
TRANSLATION , REVERSE
TRANSLATION AND INFECTION
RESEARCH AND I'M TODD HOROWITZ
AND WE HAVE AN EXCELLENT LINEUP
FOR YOU TODAY AND I'M GOING TURN
THE PODIUM TO OLGA TO INTRODUCE
OUR LINEUP OF DISTINGUISHED
SPEAKERS.
>> THANK YOU.
IT'S A TINY STAGE SO I HOPE NO
ONE FALLS.
IT'S A PLEASURE TO BE HERE AND
WONDERFUL TO SEE EVERYONE IN THE
ROOM.
IT'S TERRIFIC.
ANY JOB IS TO INTRODUCING THIS
SPEAKER LIST THIS MORNING OUR
FIRST TALK WILL BE FROM KARL
DEISSEROTH FROM STANFORD
UNIVERSITY AND THEN SAHIB KHALSA
LOOKING AT THE PER TUSHING THE
RHYTHMS WITHIN CARDIORESPIRATORY
AND GASTROINTESTINAL INSIGHT AND
THEN TODD COLEMAN ADVANCING THE
METHODS OF TECHNOLOGIES TO
MONITOR MODULATE COUPLINGS
BETWEEN THE HUMAN BRAIN STOMACH
AND THEN DANA SMALL AND FINAL IS
BY SARAH GARFINKEL FROM
UNIVERSITY OF COLLEGE LONDON
TALKING ABOUT CARDIAC
INTEROCEPTIVE TRAINING ENHANCES
INSULA CONNECTIVITY AND REDUCES
ANXIETY.
>> THANK YOU FOR THE INVITATION
AND INTRODUCTION AND ORGANIZING
THE GREAT MEETING.
I'VE ENJOYED IT SO FAR.
I WANT TO SHARE THIS HAS BEEN A
REAL INTERESTING JOURNEY TO GET
TO THIS POINT.
I FIRST BECAME INTERESTED IN
INTEROCEPTION AS A PSYCHIATRY
RESIDENT WHEN WE WERE TAUGHT IF
SOMEONE COMES TO YOU WITH A
PANIC DISORDER YOU HAVE TO THINK
ABOUT THEIR HEART AND THERE'S A
SIGNIFICANT FRACTION OF PEOPLE
WHO WILL HAVE A PRIMARY DISORDER
OF ARRHYTHMIAS AND THAT ALWAYS
INTRIGUES ME.
HOW COULD A CARDIAC PROBLEM LEAD
TO A PSYCHIATRIC DISORDER.
THE INTEROCEPTION OF OUR WORK
ALLOWED US TO MAKE HEADWAY ON
THE QUESTION.
THE PROTEINS WERE NOT WHAT YOU
MIGHT LIKE AND I WANTED TO SHARE
ON THE GENES BECAUSE IT WAS
CRITICAL TO MAKE THE HEADWAY AND
IT'S A BIG FAMILY.
THE GREEN BLOB IS THE PUMPS
PROTONS DISCOVERED IN 1970.
FAST FORWARD A LITTLE BIT AND WE
DISCOVERED CHANNEL RHODOPSIN.
AND A FEW YEARS AFTER THAT FROM
THIS LITTLE ORGANISM WHERE HE
FOUND OUT WHAT TURNED TO BE A
LARGER FAMILY AND THIS ALLOWED
US TO MAKE THE HEADWAY WE WERE
HOPING TO MAKE ON THIS QUESTION
OF INTERACTION BETWEEN CARDIAC
AND PSYCHIATRIC STATES.
WHAT MADE CHRMINE IN RESPONSE TO
SHORTER POWER DENSITIES THAN THE
OTHER AND LOOK AT HOLEGRAPHIC
METHODS IN 2020 RICHIE CHAN
STARTED HIS LAB AT UCSF.
HE FOUND THIS WAS SO SENSITIVE
YOU COULD ACTIVATE DEEP BRAIN
NEURONS WITH HIGH TEMPORAL
RESOLUTION WITH COMPLETELY
NONINVASIVE LIGHT DELIVERY AND
SKULL FIBER.
WE FOLLOWED THAT UP WITH WORK
ABOUT A YEAR AGO FROM THE LAB
SHOWING YOU COULD CONTINUE THIS
THREAD AND KEEP YOUR LIGHT
SOURCE OUTSIDE THE BODY, THE
SKULL EVEN AND CAN DO
OPTOTAGGING AND DRIVING A CELL
AND JUST REPORTING WITH AN
ELECTRODE AND TURNED OUT TO BE
USEFUL RELYING ON A POTENT SET
OF PROPERTIES CHRMINE HAD.
AND WHAT WE DESCRIBED WITH
RICHIE AND A NEUROSURGERY
RESIDENT AND A GRADUATE STUDENT
AT THE LAB AT THE TIME ALLOWED
US TO ADDRESS THIS INTERESTING
AND THORNY QUESTION THAT OTHERS
HAD THOUGHT ABOUT AND
ARTICULATED FOR A LONG TIME
WHICH GETS TO THE NATURE OF THE
EMOTION.
HE WAS ABLE TO ARTICULATE AN
INTERESTING IDEA WHICH THE
PEOPLE IN THE ROOM ARE FAMILIAR
WITH WHICH IS IF YOU REMOVE THE
BODILY SENSATIONS, WOULD YOU
REALLY STILL HAVE AN EMOTION
LEFT AT ALL.
HE WAS OF THE OPINION YOU
WOULDN'T.
THIS WAS HARD TO TEST PRECISELY
BECAUSE IT WAS HARD TO CAUSE THE
BODILY FUNCTIONS IN A CLEAN WAY
AND YOU CAN HAVE SOMETHING BUT
IT COULD AFFECT THE NEURONS AND
ENDOTHELIUM AND OTHER PROFESSORS
AND ELECTRODES DRIVE NEURONS AND
THE CARDIO MYOCYTES AND THEY
FIGURED OUT HOW TO ADMINISTER
CHRMINE THROUGH A PROMOTER TO
GET EXPRESSION THROUGH THE
VENTRICULAR WALL, THE MOUSE
HEART.
BECAUSE OF THE SENSITIVITY WE
CAN DRIVE THE HEART RATE AT
LEVELS THAT WE WANTED.
WE COULD USE A PSYCH THAT WILL
DIDN'T CAUSE HEATING BUT COULD
TAKE THEM FROM THE BASAL HEART
RATE UP TO 800 OR 900 BEATS PER
MINUTE RELIABLY.
THE FIRST THING WE ASKED WAS DID
THE MOUSE CARE THIS WAS
HAPPENING.
AND WE TEST THE REAL TIME PLACE
REFERENCE TEST AND MOVE FREELY
FROM CHAMBER TO CHAMBER AND ONLY
RECEIVES STIMULATION IN ONE
CHAMBER.
THERE WAS NO PREFERENCE AND
THERE WAS AN EFFECT.
THE NORMAL PREFERENCE FOR THE
CLOSED ARMS WAS PHASED WITH THE
CHRMINE BASED APPROACH.
AND SIMILARLY IN A TASK WHERE
THERE'S A VERY SMALL RISK OF
GETTING A SHOCK IF A THIRSTY
MOUSE DRINKS WATER IT DOESN'T
ATTEMPT THE SPEED BUT THE HEART
WAS BEING PACED IT DID AFFECT
THE LATENCY WITH WHICH THE MAN
WOULD GO OR THE RISK.
SO APPREHENSION IN THE RISK OF
IMMEDIATE THREAT AND WE WERE
CURIOUS HOW THIS WOULD BE
MANIFESTED IN THE BRAIN.
I'LL HIGHLIGHT INTERESTING
FINDING.
WE LOOKED THE BRAIN USING
GENE-BASED SCREEN AND MANY
REGIONS WERE NOT AFFECTED AND
VISUALLY AUDITORY AND PREFRONTAL
DIFFERENCES SEEING AN INSULA
PROMINENCE CHANGES IN RESPONSE
TO CARDIAC PACING.
WE WANTED TO SEE WHICH CHANGES
MATTERED AND WE SAW THEY WERE
ACTIVATED DIDN'T KNOW THEY WERE
CAUSALLY RELATIVE TO A STATE
CHANGE.
AND WE WANTED TO DO LOSS OF
FUNCTION IN THOSE BRAIN REGIONS
AND SEE WHICH WAS IMPORTANT.
WE WERE ABLE TO MAKE CONDUCTED
OPTIONS AND A CHLORIDE RHODOPSIN
WAS THE ONE WE WENT FOR TO USE
AND WE HAD A TUBE PACING THE
HEART WITH CHRMINE AND
INHIBITING DIFFERENT BRAIN
REGIONS WITH THIS RHODOPSIN AND
JUST TO SAY THAT'S THE ESSENCE
OF THE EXPERIMENT AND TESTED
INHIBITI IING PREFRONTAL OR INSR
CORTEX AND DID NOT SEE THAT
EFFECT WITH THE MEDIAL
PREFRONTAL CORTEX.
NOT TO SAY PREFRONTAL CORTEX
ISN'T INVOLVED BUT ON THE TIME
SCALE WE DIDN'T SEE AN EFFECT
WHEREAS WE DID SEE IT WITH
INSULA.
THAT WAS INTERESTING.
WE CAN POINT TO THE INSULA
MEDIATING ASPECT OF THE
REPRESENTATIVES.
AND WE HAVE TO WONDER -- AND I
THINK THE PREFRONTAL CORTEX WAS
INTERESTING AND YOU SAY MAYBE WE
COULDN'T CONTROL ENOUGH OF
PREFRONTAL CORTEX ENOUGH WITH
POTENCY.
AND I WANTED TO SHARE OUR NEW
TOOLS THAT MAY HELP ADDRESS
QUESTIONS LIKE THIS ININCRECREA
VIRG VIGOR AND POTENCY.
MAYBE SOMETHING WAS MISSING.
MAYBE THE PREFRONTAL CORTEX
ISN'T INVOLVED OR IS AND WE'RE
MISSING IT.
COULD IT BE WE DON'T HAVE ENOUGH
SPATIAL EXTENT OR NOT OPERATING
ON LONG ENOUGH TIME SCALES FOR
THIS TO BE RELEVANT?
NOW, WE'VE BEEN WORKING ON
CHANNELRHODOPSIN PROPERTY TO
MAKE SURE WE CAN ACCESS THE
REGIMES OF BEHAVIORAL
INTERVENTION.
WE'VE BEEN MAKING
CHANNELRHODOPSIN'S INHIBITORY
AND OPERATE ON LONG TIME SCALES.
A COUPLE MUTATIONS THE C128 AND
D156 RESIDUES AROUND THE RING
SHOWN IN ORANGE WE SHOWED WE CAN
CREATE RHODOPSIN'S WITH LONG
PHOTO CURRENTS AFTER A LONG
PULSE OF LIFE AND CAN HAVE
EFFECTS OF 10 MINUTES OR MORE
AND THOSE ARE ILLUSTRATED HERE.
THIS IS AN INHIBITORY VERSION
MADE OF CHANNELRHODOPSIN AND
FLASH IT WITH ANOTHER LIGHT.
WE DID THIS WITH THE CANONICAL
CHANNELRHODOPSIN BUT THE CHRMINE
FAMILY WITH HIGHLIGHT
SENSITIVITY PROPERTIES AND WITH
CHANNEL RHODOPSIN AND WE ALWAYS
WANTED TO CREATE AN INHIBITORY
VERSION OF CHRMINE AND WE WERE
NEVER ABLE TO DO IT.
WE KNEW THE MODIFICATIONS TO
CHANGE THE CHANNELRHODOPSIN AND
THIS IS A TOOL WHERE WE USED THE
HIGH RESOLUTION STRUCTURE OF
CHRMINE TO CREATE RS CHRMINE.
TO THE WERE ABLE TO SLIGHTLY
SHIFT IT TO THE RED BUT ON THE
LEFT YOU CAN SEE THE PROMINENT
REDUCTION OF THE BLUE WHICH IS
USEFUL FOR INTEGRATING IT
TOGETHER IN THE BLUE LIGHT
ACTIVATED READOUTS LIKE CALCIUM
INDICATORS.
WE HAD A GOOD STRUCTURE AND WERE
GOOD AT ENGINEERING CHRMINE BUT
WEREN'T ABLE TO MAKE AN
INHIBITORY CHRMINE BUT MADE A
LONG ACTING.
AND WHAT TURNED OUT TO BE USEFUL
WERE OTHER MEMBERS OF THE PINK
FAMILY ON THE LEFT.
I MENTIONED CHRMINE LED US TO
UNDERSTAND THIS BRANCH OF THE
CHRMINE TREE AND IT'S ALSO
SELECTIVE.
CANONICAL CHANNEL REDUCTIONS
WITH MAGNESIUM AND PROTONS AND
IT'S INTERESTING AND WE'RE
WORKING ON FIGURING THIS OUT AND
A GROUP FOUND OUT LATER THERE'S
ANOTHER BRANCH OF THIS FAMILY
THE POTASSIUM CHANNEL REDUCTING
CHANNELS AND INTERESTING SUB
BRANCH OF THE FAMILY.
THEY WEREN'T PERFECT.
THE MINUS 65 IS IN THE RIGHT
DIRECTION.
WE DESCRIBED THE STRUCTURE OF
THE POTASSIUM CHANNELRHODOPSIN
STRUCTURE TO MODIFY THEM AND THE
STRUCTURE CRITICAL GETTING US TO
THE POINT TO MAKE THE
MODIFICATIONS WE WANTED AND FOR
THE SAKE OF TIME I WON'T GO INTO
ALL THE DETAILS BUT TO SAY KCRs
LIKE CHRMINE ARE TRIMERS AND OUR
EFFORTS WE FOUND FOUND A
POTASSIUM FILTERING STRUCTURE
DIFFERENT FROM THE TETROMERIC
FEATURE SOME ARE LAID OUT.
THERE'S NO FOURFOLD SYMMETRY BUT
THE MUTANT IMPROVES IT AND GETS
IT DOWN TO MINUS 500 WHICH IS
QUITE A DIFFERENCE AND WE WERE
ABLE TO MAKE LONG ACTING
VERSIONS OF THIS.
THERE'S A SIMILAR PLOT
UNPUBLISHED BUT YOU CAN SEE THE
K1CTs AND POTASSIUM RHODOPSINS
AND HAVE A HUGE PHOTO CURRENT
AND SEE THE ONE, TWO AND THREE
NANO AMPS AND THE LONG ACTING
ASPECT IN TERMS OF SECONDS HERE.
THAT'S WHAT WE WANTED.
LOOKING FORWARD WE'RE MAKING
MOUSE LINES AND MADE CHRMINE
COMBINANT DEPENDENT MOUSE LINES
AND MAKING CALCIUM MOUSE LINES
AND ACTIVATED INHIBITORS AND
HAPPY TO SHARE THOSE AS SOON AS
THEY'RE READY.
I'LL WRAP UP THERE.
I THINK SOME OF THESE TOOLS
MAYBE USEFUL FOR A BROAD
DIVERSITY OF PROJECTS IN THIS
ROOM.
WE THINK ABOUT BRAIN-BODY
INTERACTION AND THINK LARGE
REGIONS AND SENSITIVITY AND LONG
ACTING EFFECTS MAY BE USEFUL.
I WANT TO HIGHLIGHT OUR AMAZING
COLLEAGUES AND EVERYBODY ELSE
ALONG THE WAY.
THANKS FOR YOUR TIME.
>> THANK YOU FOR THAT TERRIFIC
TALK.
MAIN WE CAN TAKE ONE QUESTION.
ARE THERE ANY BURNING QUESTIONS?
DO YOU MIND SPEAKING TO THE
MICROPHONE, PLEASE.
>> THANK YOU.
I'M A FELLOW AT CHILDREN'S
HOSPITAL AND LOOKING AT
NATURALLY OCCURRING RHODOPSINS
THEY'RE TRANS MEMBRANE PROTEINS
AND I WANTED TO KNOW WHAT IS
YOUR PERSPECTIVE ON NATURALLY
OCCURRING RHODOPSIN AND HOW THEY
GO THROUGH CHANNELS.
>> HERE I WOULD DRAW THE
DISTINCTION BETWEEN THE DIRECT
ION CHANNEL RESPONSIVE ONES AND
THE ONES THAT SIGNAL THE
CASCADES.
THE INTERESTING ASPECT ABOUT THE
WEDNESDAY YOU MENTIONED ARE
TYPICALLY THE TYPE 2 RHODOPSINS
CAN BE VERY SENSITIVE BECAUSE
THEY COUPLE TO THE CASCADES.
THERE'S AMPLIFICATION AND THAT'S
ANOTHER WAY TO GO IF YOU'RE
INTERESTED IN HIGH POTENCY
RELATIVE TO PHOTONS.
DOWN SIDE IS YOU LOSE TEMPORAL
RESOLUTION AND YOU DEPEND ON
NATIVE COMPONENTS OF THE
PATHWAY AND YOU CAN GET SIGN
FLIPS THAT COULD HAPPEN.
SO DEFINITELY WORTH EXPLORING.
A LOT OF THINGS WE CARE ABOUT IT
TEMPORAL PRECISION AND KNOWING
WHETHER YOU'RE GETTING
EXCITATION AND LOOK AT THE
RHODOPSIN'S NATURALLY OCCURRING
AND COMPLEMENTARY TOOLS AND SAME
EXPRESSION SYSTEMS COULD BE USED
FOR THE RHODOPSIN'S AS WELL.
THANK YOU AS MUCH.
>> I'M VERY PLEASED SO SPEAK
ABOUT CARDIORESPIRATORY AND
GASTROINTESTINAL INSIGHTS IN
PSYCHIATRIC DISORDERS AND I'D
LIKE TO THANK OUR TRAINEES FOR
THEIR DEDICATION TO OUR WORK AND
COLLABORATIONS AND INSTITUTION.
I WANT TO IT START WITH AN
UPDATED VIEW OF INTEROCEPTION
PUBLICATIONS.
YOU HAVE YOU NOBEL LAUREATES AND
AT THE END IN PART FOR DISCOVERY
OF THE RECEPTOR BUT THAT'S NOT
WHERE IT ENDS.
THE START OF INTEREST WAS
IGNITED IN THE EARLY PART OF THE
CENTURY BY BUD CRAIG WHO DIED IN
AT 71 AND WOULD LIKE TO TAKE A
MOMENT TO ACKNOWLEDGE HIS
CONTRIBUTIONS TO THE FIELD OF
NEUROSCIENCE.
AS A CLINICIAN I'D ALSO LIKE TO
REFLECT ON THIS QUOTE FROM A
UROLOGIST WHO REVIEWED A BOOK ON
INTEROCEPTION THOUGH WE'VE BEEN
AWARE THERE'S BEEN FEW METHODS
OF UNDERSTANDING THE UNDERLYING
PRINCIPLES IN HUMANS UNTIL THE
ADVENT OF FUNCTIONAL IMAGING.
WHILE I'D AGREE WITH HER
FUNCTIONAL NEUROIMAGING
FACILITATED MECHANISTIC
ASSESSMENTS IN CERTAIN PATIENTS
THERE'S LACK OF TOOLS FOR
PROBING HUMAN INTEROCEPTION.
THAT'S STARTING TO CHANGE.
AND MY TAKE HOME MESSAGE IS
PERIPHERAL ORGAN SIGNALS IS AN
OPTIMAL WAY TO UNDERSTAND HOW IT
CAUSES SYMPTOM PERCEPTION TO YOU
ARE IN A DISORDER-RELEVANT
FASHION.
OUR INTERNAL ORGANS ARE NOT
MERELY PHYSIOLOGIC WORKHORSES
AND THEY COME INTO SHARP FOCUS
WEN THE PHYSIOLOGY IS DISRUPTED
OR THREATS ARE PERCEIVED.
CAN SEE EXAMPLES HERE.
USING MECHANISMS THE BRAIN THEN
BUILDS PRECISE MODELS OF THE
BODY IN THE EXTERNAL WORLDS AND
ALLOW INDIVIDUAL TO TAKE
PREVENTIVE ACTIONS TO FOCUS ON
PREVENTING AVERSIVE ONES AND I
THINK ANIMALS DO IT TOO AND CAN
MODEL SIMILAR PROCESSES.
I'VE WORKED TO MEASURE
INTEROCEPTIVE PROCESSES IN
SYSTEMS AND LOOKING AT HUMANS
WITH UNDERLYING PSYCHIATRIC
DISORDERS AND LOOKED AT
SIGNALLING AND WHILE THERE'S
BEEN FOCUS ON THE AFFECT OF
CORTISOL SIGNALLING ON THE BRAIN
LESS WORK HAS BEEN FOCUSSED ON
EXAMINING THE PROCESS OF
GABAERGIC SIGNALS AND LOOKING AT
DRUGS SIMILAR TO ADRENALINE
WE'VE MADE PROGRESS.
IT GIVES US A NICE MODEL FOR
MANIPULATING THE PERIPHERAL
CIRCUITS.
WE'VE ESTABLISHED THE
REPEATABILITY ON INCREASING
CARDIAC ACTIVITY.
AND USING A CONTINUOUS RATING
DIAL WE CAN SEE A REAL-TIME
INDICATOR OF RESPIRATORY
SENSATION.
YOU MAY THINK THIS AS A PANIC
PATIENT COMING IN TO YOUR E.R.
COMPLAINING OF A DYSPNEA AND
SOME ELICIT STRONG SENSATIONS
AND OTHERS ELICIT LOWER BUT
DETECTABLE RESPONSES AND WE'LL
COME BACK TO THAT IN A BIT.
OVER ALL WE'RE ABLE TO DETERMINE
THE INTEROCEPTIVE AWARENESS AND
WE CAN RELIABLY INCREASE SIGNALS
WITH DISCREET LOCALIZATION TO
AREAS WHERE THE HEART STRIKES
AGAINST THE ANTERIOR WALL AS --
ASSIYSTOLE AND WE HAVE AN
INDICATOR OF THE
CARDIORESPIRATORY SENSATIONS AND
THE OTHER STUDY STAFF ON THE
OTHER SIDE.
AND THE DISORDER REVEALED THE
RESPONSE TO THIS AND THIS WAS
MOST APPARENT IN 0.5 MICRO S NOT
THE 2 MICROGRAM DOSE AND
REPORTED REPORTING AT THE SAME
SENSATION.
ON THE BOTTOM IS THE HEART RATE
RESPONSE AND THE DIFFERENCE
BETWEEN THE TWO GROUPS AND THE
DIAL RATING AND THE INTENSITY
DIFFERENCES IN THE ONGOING
MOMENT TO MOMENT PERCEPTION.
THOUGH WE NOTED DOSE-DEPENDENT
DIFFERENCES IN THE INSULAR THERE
WAS A HYPOACTIVATION OF THE
CORTEX ASSOCIATED WITH CARDIAC
SENSATION AND ONLY OCCURRED AT
THE 0.5 MICROGRAM DOSE.
THIS SUGGESTS IT MAY REFLECT A
FAILURE TO CONSTRAIN LOW TO
MODERATE LEVELS OF THE
ASYMPATHETIC AROUSAL.
THIS FINDINGS COULD HAVE
POTENTIALLY THERAPEUTIC
IMPLICATIONS AND MORE NEEDS TO
BE STUDIED.
THIS IS COMPATIBLE WITH THE
MOUSE OPTOGENETIC STUDY BY CARL
IN THE INTEROCEPTIVE PROCESSING.
I WAS BLOWN AWAY WHEN I READ THE
STUDY AND IT'S A FANTASTIC
DEMONSTRATION OF ANIMAL AND
HUMAN FINDINGS AND THIS RAISES
SEVERAL NEW QUESTIONS.
FOR EXAMPLE, WHY DOES SILENCING
THE INSULA MITIGATE BEHAVIORS IN
MICE AND MAY THINK ABOUT THE
DIFFERENCES BETWEEN ANIMALS AND
HUMANS IN TERMS OF COGNITION AND
COGNITIVE RESTRUCTURING WORK IN
COGNITIVE BEHAVIORAL THERAPY.
FINALLY, HOW ARE OTHER NEURAL
INDICATORS OF CARDIAC
INTEROCEPTION WITH GENERALIZED
ANXIETY DISORDER.
I'D LIKE TO POINT YOU TO THE
POSTER OF A POSTDOC IN THE LAB
POSTER NUMBER 3 AND HAS A POSTER
TOMORROW.
AND STIMULATION CAUSED
CONNECTIVITY REDUCTIONS BETWEEN
CENTRAL AUTONOMIC BRAIN MOTORS
AND OTHER REGIONS.
THESE FUNCTIONAL CONNECTIVITY
CHANGES SUGGEST STATE-DEPENDENT
SIGNALLING BETWEEN CENTRAL
AUTONOMIC AND SENSORIMOTOR ARE
LINKED TO EXCITATION AND
VISCERAL REGULATION IN THE END.
I'D LIKE TO SWITCH FROM SO THESE
ANIMAL AND HUMAN STUDIES RAISE
AN IMPORTANT QUESTION REGARDING
INTEROCEPTION AND CORTICAL
FUNCTION.
IS THE INSULAR CORTEX TRULY THE
INTERFA FAFACE FOR THE BOTTOM-U
PROCESSES.
AND IT'S IMPORTANT TO NOTE
THERE'S NO ANATOMICAL HYPOTHESES
REGARDING THE POSTERIOR INSULA
AND REGARDING FUTURE ORIENTED
BODILY STATES AND THE MID
INSULAR CORTEX IN PROCESSING.
SO WE'VE BEEN INVESTIGATING IN
THE LAB WHERE IN THE BRAIN IE
INSULA THESE ACROSS FOR
PSYCHIATRIC DISORDERS.
TO LEARN MORE CHECK OUT THE FSM
POSTER BY A GRADUATE STUDENT IN
THE LAB.
I'D LIKE TO SWITCH TO A NEW
METHOD FOR PERTURBING GUT-BRAIN
COMMUNICATION DEVELOPED.
INVOLVING A MINIMALLY INVASIVE
DEVICE TO EVOKE MECHANO
SENSATION.
THIS IS A SUMMARY OF THE METHODS
FROM THE PAPER.
A CAPSULE YOU ACTIVATE IN A
BASE, YOU SWALLOW IT.
SHORTLY AFTER IT STARTS
VIBRATING ACCORDING TO A
PRE-DETERMINED METHOD.
WE ASK PARTICIPANTS TO INDICATE
WHETHER THEY FEEL A SENSATION IN
THE ABDOMEN THEY ASCRIBE TO THAT
STIMULATION.
WE ELICIT ABOVE THRESHOLD
CHANGES IN PERCEPTION TO DRIVE
THE PERCEPTUAL ACCURACY AND
BECAUSE IT'S A CAPSULE AND MOVE
IN THE GUT WE LOOKED TO IF WE
COULD TRACK THIS AND WE DIDN'T
SEE STRONG EVIDENCE OF CHANGES
IN ELECTROMYOGASTRIC SIGNALLING
AND WE'LL HEAR MORE FROM TODD.
AND ALSO WE SIDEFIDE THE MIDLINE
POSTERIOR SIGNAL NOT IN THE
REGION WE WORLD HAVE EXPECTED
BUT FOR A VARIETY OF REASONS
MAKES SENSE AND THESE ERP SIGNAL
CHANGES CORRELATED WITH
PERCEPTUAL ACCURACY.
THE VIBRATING CAPSULE RAISES
MANY UNANSWERED QUESTIONS.
WHAT ARE THE INTEROCEPTERS IN
THE INDUCED MECHANICAL FORCES
AND WHETHER IT PLAYS A ROLE AS
SUSPECTED FROM THIS GROUP AND
OTHER RELATES TO WHAT ARE THE
PERIPHERAL PATHWAYS PROVIDING
THE SENSORIES TO THE BRAIN AND
THERE'S EVIDENCE OF CELLULAR
PROCESSES AND MECHANICAL STRETCH
IN THE NTS.
ADDITIONALLY, THE POSTERIOR MID
LINE RAISES THE POSSIBILITY OF
THE DEEP MID LINE STRUCTURE SUCH
AS THE PRECUNIUS AND HAS
SENSATIONS OF SEPARATION FROM
THE BODY OR EVEN A SENSATION OF
FLOATING.
AND SIGNALS CAN INCREASE THE
SENSATION OF FLOATING AND
AWARENESS OF OTHER SENSATIONS IN
A THERAPEUTICALLY RELEVANT
MANNER.
I HAVE ONE SLIDE.
AND WE USE A NON-PHARMACOLOGIC
TOOL REDUCED ENVIRONMENTAL
STIMULATION THERAPY AND WHEN WE
ADD VISUAL, AUDITORY, SOMATO
SENSITIVE AND MOVEMENT RELATED
WE DO THIS BY HAVING PEOPLE LAY
IN A HIGHLY ENGINEERED
ENVIRONMENT A SHALLOW POOL OF
WATER WITH DENSE EPSON SALT
SOLUTION AND FLOAT EFFORTLY AND
ELICIT CARDIORESPIRATORY
SENSATIONS BUT IN A POSITIVELY
VALENCED MANNER VERSUS THE
NEGATIVE VALENCED MANNER.
OUR STUDIES HAVE SHOWN FLOATING
INDUCES A SHORT TERM EFFECT
LASTING UP TWO DAYS IN ANXIOUS
INDIVIDUALS AND SUSTAINED BODY
IMPROVE
IMPROVEMENTS.
WE ARE BEGINNING TO USE THIS IN
FLOAT-ASSISTED PSYCHO THERAPY
AND JUST YESTERDAY SHE GOT HER
NOTICE OF AWARD FOR HER K23
CAREER DEVELOPMENT AWARD FROM
NIMH SO CONGRATULATIONS.
IN SUMMARY, HUMAN STUDIES USING
INTEROCEPTIVE PERTURB BASE ARE
ENRICHING OUR GRASP OF THE
NEURAL CIRCUITS OF INTEROCEPTION
AND APPROACHES IN THE FUTURE.
THANK YOU.
>> THANK YOU FOR THE EXCELLENT
TALK.
>> GREAT TALK.
YOU LOOK AT ANY OTHER SYMPTOMS
OTHER THAN THE CARDIAC
SENSATIONS THAT COME WITH A
PANIC ATTACK.
>> WE HAVE A 2016 PAPER WHERE WE
USE THIS PARADIGM TO ELICIT IN
THE LAB PANIC ATTACKS USING THE
RESEARCH TO FIND CRITERIA.
CAN ELICIT PANIC ANXIETY IF YOU
ELICIT WITH A .4 MICROGRAM DOSE
AND CAN SEE DIZZINESS AND OTHER
COGNITIVE SYSTEMS.
THERE'S A FIGURE THAT WILL
DEMONSTRATE THE PANIC-RELATED
WITH SOMATIC SYMPTOMS IN THERE.
THAT PAPER WAS TRD INTERESTING
TO SHOW PATIENTS WITH AMYGDALA
LESIONS CAN REPORT FEELING
ANXIETY AND FEAR AND ONE PATIENT
EXPERIENCED A PANIC.
>> I'M RELATIVELY NEW TO THE
FIELD.
I THOUGHT I'D FIRST TELL YOU THE
STORY HOW I GOT HERE AND MY
ORIGINAL BACKGROUND IS IN
EELECTRICAL ENGINEERING AND I
DID A POSTDOCTORAL STUDY WITH
EMERY BROWN AND I BEGAN TO WORK
AT THE INTERSECTION OF
NEUROSCIENCE AND ANALYTICS AND
HAVE DONE SOME TECHNOLOGY
DEVELOPMENT AND THINGS WE'VE
DONE IS PARTNERING TO BUILD THIN
FLEXIBLE SENSORS IN THE SKIN AND
APPLY THEM MANY PLACES INCLUDING
ON THE FOREHEAD TO EXTRACT
THINGS LIKE EEG AND DEVELOP
AUTOMATED METHODS AND APPLIED
PROBABILITY.
WHAT LED ME DOUBLE THE PATH OF
INTEROCEPTION.
THIS IS ME AND MY DAD AT A
FAMILY REUNION AND I LOST HIM TO
PAN
PANCREATIC CANCER IN 2011 AND HE
LOST HIS FATHER TO GASTROCANCER
AND I THOUGHT THERE'S CANCER IN
THE FAMILY AND I THOUGHT WHAT
THE EKG HAS DONE FOR THE HEART
AND WHAT THE EEG HAS DONE FOR
THE BRAIN CAN WE PLACE
ELECTRODES ON THE ABDOMEN AND
EXTRACT INFORMATION FROM THE GUT
AND WHAT UNDER LIES THIS
APPROACH IS TO TAKE INTO ACCOUNT
THE STOMACH HAS CLEARLY HAS
MUSCLE CELLS TO PINCH AND
THERE'S ELECTRICAL PACEMAKER
CELLS AND THEY ALWAYS ARE
GENERATING OSCILLATION EVEN WHEN
THERE'S NO FOOD AND THE
MAGNITUDE OF OSCILLATION
INCREASES THROUGH INPUTS AND YOU
SEE MUSCLE TONE CHANGES.
AND WHAT'S INTERESTING IS THIS
IS ORGANIZED AN ELECTRICAL WAVE
MOVING FOOD DOWN THE TRACT.
WE TOOK ADVANTAGE OF THE
INFORMATION TO EXTRACT NOT JUST
BASIC FREQUENCY INFORMATION DONE
SINCE THE 1980s BUT TO EXTRACT
THE PATTERNING OF WHAT'S
OCCURRING.
WE HAVE HAD A SEQUENCE OF PAPERS
AND MONITORING THIS IN PATIENTS
WITH THINGS LIKE GASTROPARESIS
TALKED ABOUT PREVIOUSLY.
WE DEVELOPED FLEXIBLE
TECHNOLOGIES, ETCETERA TO DO
THAT.
ONE THING WE FOUND IN 2019 WAS
THE SPATIAL PATTERNS WHICH YOU
MAY THINK SHOULD GO FROM THE
ESOPHAGUS TO THE SMALL
INTESTINES DOESN'T ALWAYS OCCUR.
SOMETIMES THEY OPERATE IN
ABERRANT FASHIONS AND WITH THESE
WE CAN PICK UP THE INFORMATION
AS YOU CAN SEE IN THE ANIMATION
RIGHT HERE.
WITH THE SPATIAL INFORMATION AND
DOING APPROPRIATE SIGNAL
PROCESSING WE CAN ASSOCIATE THAT
WITH TO THE SYMPTOM SCORES USED
IN GASTROENTEROLOGY AND HOW BAD
IS YOUR BLOATING AND THIS AND
THAT.
THE EXTENT TO WHICH THIS SLOW
WAVE WAS NOT PROPAGATE FROM THE
ESOPHAGUS TO THE SMALL
INTESTINES AND THE WAY IT WAS
ABNORMAL CORRELATED WITH THESE
SYSTEMS AND GET AGGREGATE WILL
TO A ZERO AND PERCENTAGE OF SLOW
WAVES ABNORMAL.
WE FOUND A CORRELATION HERE.
THIS CORRELATES WITH THE SYSTEMS
AND IF WE DON'T EQUATE WITH HOW
SOMETHING FEELS HOW USEFUL ARE
THEY AND THE CONNECTION TO
INTEROCEPTION BECOMES
INTERESTING BECAUSE THE NINDS
PROGRAM OFFICER SPOKE ABOUT WORK
FROM THE UNIVERSITY OF MICHIGAN
WHERE THEY DID SOMETHING WHERE
THEY SEVERED THE VAGUS.
THANE PAPER AND THIS GOES BACK
TO HYPOTHESIS THE SLOW WAVE
OCCURRING IS PRIMARILY AN
AFFERENT TYPE OF SIGNAL.
TAKING THAT INTO CONSIDERATION
IS DUE TO AFFERENT SIGNALLING
AND THERE'S A SIMPLE DIAGRAM
WHEN YOU CONSUME A MEAL THERE'S
A VAGAL-VAGAL REFLEX THAT OCCURS
AND THE SENSATION LEADS TO
AFFERENT STIMULATION AND BRAIN
AREAS AND THE CORTEX HAS A
PRIMARY SENSORY COMPONENT OF THE
INSULA AND IT GETS INFORMATION
AND SENDS IT BACK DOWN STREAM
AND GO FROM THE BRAIN STEM BANG
TO THE STOMACH.
ONE OF THE THINGS WE GOT
INTERESTED IN IS IN SOME
PATIENTS SOME SYMPTOM SEVERITY
EXCEEDED WHAT WAS PREDICTED FROM
THE GASTRIC SLOW WAVES AND
THAT'S NOT SURPRISING IF YOU
HANG AROUND GASTROENTEROLOGISTS
LONG ENOUGH AND IF YOU LOOK AT
PATIENTS WITH GASTROPARESIS OR
DISPEPSIA AND THERE'S INTEREST
IN IDENTIFYING THE TYPES IS THIS
DUE TO X OR Y.
AND MY COLLEAGUE HAD DONE
INTERVENTIONS AND THESE
INTERVENTIONS DID NOT TARGET THE
SLOW WAVE.
THINGS LIKE GIVING SOMEONE BOTOX
ON THE BOTTOM OF THE STOMACH
WHICH CAN HELP WITH THE OPENING
AND CLOSING TO THE SMALL
INTESTINES OR PROVIDE
PROKINETIC.
AND THE SYSTEMS UPON TREATMENT
DIDN'T TARGET THE SLOW WAVE AND
GOT TO THE REGRESSION LINE.
ALL THE PATIENTS WHO WERE ON THE
REGRESSION LINE THEIR SYSTEMS
WERE UNCHANGED.
THIS IS FURTHER CONFIRMATION
WHAT THIS REGRESSION LINE
ASSOCIATED PREDICTED FROM THE
SLOW WAVE IS TELLING US ABOUT
THE SEVERITY OF SYSTEMS
ASSOCIATED WITH THE SLOW WAVE
AND CAN SEE IF THE SYMPTOM
SEVERITY EXCEEDS THAT SUGGESTS
OTHER ALTERNATIVES CAN BE
USEFUL.
THIS WAS IMPORTANT IN TAKING A
LOOK AT THE SLOW WAVE
INFORMATION AND ASSOCIATION WITH
INTEROCEPTION.
AND ONE THING WE ALSO WANTED TO
DO WAS GO BEYOND YOU WAITING SIX
MONTHS TO SEE THE G.I.
SPECIALIST.
WHEN THEY ASK THE QUESTIONNAIRE
IT'S OVER THE LAST SIX MONTHS OR
YEAR WHAT OCCURRED AND GET
MEASURED ONCE.
THIS ASSOCIATION IS NOT EXACTLY
CORRECT TEMPORALLY.
WHAT IF WE CAN PROVIDE AN
AMBULATORY DEVICE AND TRACK YOUR
SYMPTOMS AND WE DEVELOPED A
TECHNIQUE AND ONE THING WE CAN
DO IS YOU CONSUME A MEAL AS YOU
SEE IN THE PLOT AND WE CAN SEE
THE AMPLITUDE OF THE
OSCILLATIONS WHEN THE STOMACH
RESPONSES AND FEW DESCENDED TO
THE STOMACH AND GIVES RISE TO
THE OSCILLATION AS MANIFESTED IN
THE SPECTRAL POWER INCREASING
BECAUSE OF OUR ARRAY IT CAN
TRACK TEMPORAL THE SPATIAL
PATTERNS THAT OCCUR AND WHAT ARE
THE SYMPTOMS THAT OCCUR AND WHEN
DO WE SEE ABNORMALITIES.
WHEN WE THINK WITH THE
CONNECTION WITH THE BRAIN STEM
IT'S MEDIATED BY THE VAGUS NERVE
AND NOT OPERATING CORRECTLY.
I TALKED TO SOME CARDIOLOGY
BUDDIES AND ASKED ARE THERE
INTERESTING WAYS WE CAN THINK OF
TRACKING THE HEART FOR THE
SYSTEM AND THEY SAID BE CAREFUL
BECAUSE THE HEART IS RESPONDING
TO COMMANDS FROM THE BODY ALL
THE TIME BUT WHEN YOU'RE ASLEEP
IT'S INTERESTING BECAUSE THERE'S
NOT MANY DEMAND AND THE
PARASYMPATHETIC NERVOUS SYSTEM
IS MORE ACTIVE WHEN YOU SLEEP
AND CAN GET THE HEART BEATS AND
DEVELOP LOOKING AT THE HEART
RATE AND CONTRIBUTION FROM
SYMPATHETIC AND PARASYMPATHETIC
NERVOUS SYSTEM AND WHEN THE
PATIENT WENT TO SLEEP THIS
THERE'S MORE PARASYMPATHETIC
INTERVENTION WHEN YOU SLEEP.
THE BOTTOM PLOT IS WITH SOMEONE
WITH APARESIS.
THERE'S NO CHANGE IN THE RATIO
IN SLEEP VERSUS WAKE SUGGESTING
THE PARASYMPATHETIC IS MORE
ACTIVE DURING SLEEP.
MOREOVER THE RATIO IS NOT AS
LARGE.
IT'S MUCH ATTENUATED ACROSS THE
BOARD.
AND THE PATIENT WITH DIABETIC
GASTROPARESIS.
WE TAKE THE INFORMATION ABOUT
THE MEAL RESPONSE I ALLUDED TO
AND LOOKING AT THE INTENSITY AS
WELL AS THE REGULATION AND HOW
MUCH DID IT CHANGE BEFORE AND
AFTER CONSUMPTION OF A MEAL AND
LOOKING AT THE SAME INFORMATION
WITH THE HEART ASSOCIATED WITH
THE PARASYMPATHETIC NERVOUS
SYSTEM AND WE SAW SEPARATION
AGAIN GROUPS AND COULD BUILD
CLASSIFIERS THAT COULD SEPARATE
HEALTHY FROM CONTROLS AND
DIABETIC GASTROPARESIS VERSUS
NON WITH HIGH ACCURACY.
I GOT INTERESTED IN WE MOVED TO
PROBING OF INTEROCEPTION WAS A
BIT INDIRECT AND WERE NOT
AMERICA INFORMATION FROM THE
BRAIN SIMULTANEOUSLY.
ONE THING I GOT INTERESTED IN
DOING WAS EXPLORING IN HUMANS
CAN WE DO THIS AND WE GOT LUCKY
BECAUSE AS A RESEARCHER AND I'VE
BEEN SINGING HER PRAISES SINCE
THE 2017 PAPER AND PUBLISHED A
PAPER DOING MEG FOR THE BRAIN
AND THE ELECTROGASTROGRAM AND
SAW AT REST TWO THINGS COUPLED
AND PHASED AMPLITUDE COUPLING
AND SLOWS THE AMPLITUDE OF THE
MEGs.
THE BAD NEWS IS A LOT OF US KNOW
YOU CAN'T DO MEG EVERYWHERE.
THESE ARE THE STATES WHERE
THERE'S A CLINICALLY AVAILABLE
MEG LOCATION AND IN MANY STATES
THERE'S ZERO WE DON'T HAVE ONE
AT STANFORD.
THERE'S ONE AT UC SAN DIEGO AND
UCSF AND NOT ONE HERE AND WE
MEASURED ELECTROMAGNETIC
ACTIVITY AND CAN WE DO ANALOGOUS
STUDIES.
WE DID SIMULTANEOUSLY STUDIES
TRYING TO MIRROR WHAT SHE DID IN
HER 2017 PAPER REPLACING THE MEG
WITH ENG AND WERE ABLE TO LOOK
AT THE COUPLING AND WE EXPLORED
NOT DURING THE RESTING STATE BUT
ENGAGING IN COGNITIVE TASKS AND
THERE'S GREATER COUPLING IN THE
RESTING STATE TO WORKING MEMORY
AND MIGHT RELATE TO WHAT WAS
TALKED ABOUT WHEN WHERE YOU PUT
SOMEONE IN THE TANKS WHERE
THERE'S NO INPUT AND THIS COULD
MAGNIFY THE STRENGTH OF THE
INTEROCEPTION AND IT WAS
MODULATED BY SATIATION AND THE
LEFT FRONTAL REGION AND WE TRIED
TO MIRROR THIS MOTION OF THE
GASTRIC NETWORK FOUND WITH THE
MEG WORK AND DOING THAT IN AN
ANALOGOUS EEG ELECTRODES AND THE
STRENGTHS OF THE COUPLING
CORRELATED WITH THE WORKING
MEMORY TASK.
THIS IS OUR ATTEMPT TO MIRROR
WHAT'S BEEN DONE BUT IN A MORE
SCALABLE FASHION LIKE WITH EEG
INSTEAD.
IF THESE TWO ORGANS ARE
ELECTRICALLY CONNECTED COULD WE
TREAT THE BRAIN BY STIMULATING
THE OTHER ORGAN CONNECTED NAMELY
THE STOMACH.
WE PARTNERED WITH CARDIOLOGY
FOLKS AT UCLA AND TRIED TO
EXPLORE IF WE CAN CHANGE
PARAMETERS AND IT'S WIRELESS AND
SO THERE'S A THIN USING
INDUCTIVE COUPLING AND CAN PLACE
IT IN A LARGE VEIN AND COUPLE IT
AND WE TOOK THIS APPROACH AND IN
A PIG MODEL WE IMPLANTED THE
PACING DEVICE AND ALSO PLACED
ELECTRODES ON THE SIDE OF THE
STOMACH WHERE THE SLOW WAVE WAS
CREATE AND MEASURE THE SPATIAL
PATTERNS OF THE SLOW WAVE AND
PLACE ELECTRODES ON THE
ABDOMINAL SURFACE AND WHEN WE
TURN THE PACING DEVICE ON WE CAN
EN TRAIN THE SLOW WAVE WELL AND
HAVE THE GROUND TRUTH BECAUSE WE
HAVE THE ELECTRODE ON THE
STOMACH AND WE SHOW UP TO AN
ORIENTATION CHANGE.
WE BASICALLY GET CONSISTENT
INFORMATION ABOUT THE SLOW WAVE
DIRECTION FROM THE ELECTRODES ON
THE AND ABDOMEN AND DEVELOP
CONTROLS.
CAN WE TAKE AN AB NORMAL SLOW
WAVE GIVING RISE TO THE SYSTEMS
AND MAKE CONSISTENT WAVE FROM
THE ESOPHAGUS TO THE STOMACH?
THINKING IN SHORT WHAT UNDER
LIES HOW WE THINK ABOUT OUR
RESEARCH RATHER THAN PLAYING IN
RED OCEAN AREA WHERE THERE'S
EXISTING CUT-THROAT AREAS LOOK
AT BLUE OCEAN AREAS AND HAVE
PLACE FOR GROWTH AND WITH THAT I
YIELD MY TALK.
>> ANY QUESTIONS?
THANK YOU.
>> THANK YOU FOR THE EXCITING
TALK.
THE 24-HOWEVER MONITORING WAS
PARTICULARLY EXCITING AND
WONDERING WHETHER YOU ANALYZED
YOUR DATA OR TOOK DATA ABOUT
WHAT THE PATIENTS WERE EATING
AND WHAT THE NUTRITIONAL CONCEPT
WAS AND WHETHER IT SHOWED
ANYTHING IN TERMS OF AFFECTING
ANY CHANGE IN --
>> I WANT TO START BY THINKING
THE ORGANIZERS TODD AND
>> WE HAVE A PATHWAY DISCOVERED
IN 2018 DISCOVERED BY A GROUP
AND THEY'RE COLLEAGUES AND IT'S
A PATHWAY THAT CONNECTS THE
NUTRIENT SENSING AND UPPER
INTESTINE WITH DOPAMINE CIRCUITS
IN THE BRAIN.
AND THEY HAD PROJECTIONS THROUGH
THE VAGUS SERVE TO THE MID BRAIN
DORSAL STRIATUM AND INSPECT THE
CELLS THAT RECEIVE THE
INFORMATION FROM THE UPPER
INTESTINE WITH CHANNELRHODOPSIN
AND ALLOWS THE ANIMALS TO NOSE
POKE TO RECEIVE STIMULATION THAT
BASICALLY SIMULATES THIS SIGNAL
FROM THE UPPER INTESTINE.
YOU CAN SEE THE ANIMALS LEARN
OVER DAYS TO SELF-STIMULATE
INCLUDING IN TER EXTINCTION AND
WHEN THEY LOOKED AT DOPAMINE
EFFLUX IN THE DORSAL STRIATUM
YOU CAN SEE IN THE BLUE CIRCLES
THIS IS A RISE IN EXTRA CELLULAR
DOPAMINE WHEN THEY WERE
SIMULATING THOSE CELLS IN THE
NOTICE RECEIVE FROM THE UPPER
INTESTINE AND IN GREEN AN
ADJACENT GROUP OF CELLS AND THIS
IS GUT INDUCED AWARD.
UNDER PHYSIOLOGICAL CONDITIONS
THE PATHWAY IS NOT SENSITIVE TO
THERE'S ER -- TO LASERS BUT
LIPIDS.
THIS SHOWS MICRODIALYSIS.
AND WHAT WAS INTERESTING FOR ME
IS THEY SAW THIS IN ANIMALS FED
A LOW FAST DIET AND DIET ALONE
LENDS TO THIS PATHWAY AND HERE'S
WHAT HAPPENS WHEN YOU INFUSED
ANIMALS IN HIGH FAT DIET FOR 16
WEEKS AND DID NOT GAIN ANY WAY.
IT WAS ACCOMPANIED BY BEHAVIORAL
CHANGE ON THE Y AXIS THE ANIMALS
ARE LOOKING TO RECEIVE INFUSION
OF A LOW FAT EMULSION AND IN THE
DARK GREEN CIRCLES THOSE ARE THE
ANIMALS IN THE LOW FAT DIET AND
INDIFFERENT TO THE LOW FAT
NUTRIENT IN THE GUT.
REMARKABLY WHAT THEY ARE ALSO
SHOWED IS IF YOU CAN INFUSE OEA
INTO THE RATS THAT HAVE UNDER
GONE THE HIGH FAT DIET AND
REVERSE THE EFFECTS.
HERE YOU SEE AGAIN EXTRA
CELLULAR DOPAMINE AND OEA
INFUSION AND FOLLOWING
INTERLIPID THE TOP LINE IS THE
OVA AND.
AND YOU SEE THEM LICKING THE
EMULSION AND THEY INCREASE THEIR
RESPONDING FOR LOW FAT SO THE
ACUTE OEA ADMINISTRATION IS
CHANGING DOPAMINE AND CHANGING
PERCEPTION.
I THOUGHT SUPER COOL.
WE'VE BEEN DOING STUDIES IN
HUMANS TO SEE IF THIS TRANSLATES
AND THE FIRST STUDY IS A
COLLABORATION WITH A GROUP AT
THE INSTITUTE FOR METABOLISM
RESEARCH.
THEY HAD DEVELOPED THIS TEMPORAL
CLUSTERING TECHNIQUE USING PET
DATA AND LOOKING AT NOT WHERE IN
THE BRAIN YOU WERE SEEING
CHANGES BUT WHEN.
AND WE USED THIS TECHNIQUE IN A
GROUP OF INDIVIDUALS IN THE PET
SCANNER BEING SCANNED OVER 60
MINUTES.
THE RADIO LIGAND IS INJECTED AT
ZERO MINUTES AND PEOPLE ARE ALL
HUNGRY AND FROM THE 20 TO 30
MINUTES WE START INFUSING THEM
IN PREDICTED MILK SHAKE TO GET
THE SIGNAL AND YOU CAN SEE IN
FACT THERE ARE TWO SEPARATE TIME
POINTS OF CHANGES IN BINDING
POTENTIAL.
ONE CORRESPONDING TO WHEN THE
HUMAN IS CONSUMING THE MILK
SHAKE TO THE ORAL AND WITH TO
THE SAME GROUP IS MARK ON THE
RIGHT AND HIS POSTDOC AND MY
POSTDOC AT THE TIME AND THIS IS
ANOTHER STUDY AND WE RECRUITED
50 PEOPLE HEALTHY WEIGHT AND
CAME IN FOR A PRE TEST AND WE
DID STUDIES AND PREFERENCE TESTS
AND THE NEUROIMAGING STUDIES WAS
LOOKING AT BRAIN RESPONSE TO
CUES PREDICTING A MILK SHAKE AND
RESPONSE AND DID A TASK THAT HAS
NOTHING TO DO WITH FEEDING AND A
PROBABILISTIC LEARNING TASK
WHERE PEOPLE HAVE TO LEARN TO
ASSOCIATE TONES WITH THE SIGHT
OF A FACE OR PLACE AND THIS IS
USED TO MODEL THE FUNDAMENTAL
PREDICTION AND THE OTHER GROUP
HAD HIGH PROTEIN LOW FAT SUGAR
AND WE TOOK A SAMPLE AND WEIGHED
THEM AND AT POST TEST WE REPEAT
THE STUDIES.
AND FIRST OF ALL WHAT YOU CAN
SEE HERE IS THERE WAS NO CHANGE
IN ADIPOSITY OR MED METABOLIC
MATTERS AND NOTHING IS
SIGNIFICANT ACROSS THE TIMES.
IN THE ANIMAL STUDIES THERE'S NO
CHANGE IN ADIPOSITY.
WE WANTED THIS TO BE A DIETARY
MANIPULATION.
THOUGH THERE WAS NO CHANGE IN
ADIPOSITY OR METABOLISM YOU CAN
SEE THE HIGH FAT-HIGH SUGAR
GROUP IN BLUE COMPARED TO THE
LOW-FAT, LOW SUGAR GROUP AFTER
THE MANIPULATION REPORTED LIKE
IT LOW-FAT PUDDINGS LESS THAN
THE BEGINNING AND WANTING THEM
LESS.
THAT'S SIMILAR TO WHAT THEY WERE
OBSERVING IN MICE WHERE THE
ANIMALS WERE INDIFFERENT TO THE
GASTRIC INFUSION OF THE LOW-FAT
EMULSION AND YOU AND IN THE GRAY
BARS THERE'S NOT.
THE PEOPLE WHO HAVE THIS SMALL
MANIPULATION THEIR BRAIN
RESPONSE TO FOOD CUES VISUAL AND
THE TASTE OF THE MILK SHAKE IS
ENHANCED.
IN THE MID BRAIN AND PREFRONTAL
CORTEX AND RESPONSE WHEN THEY
RECEIVE THE HILL -- MILK SHAKE
AND YOU'RE HEARING A TONE AND
INDICATING IF YOU THINK YOU'LL
SEE A FACE OR PLACE AND WE USED
THIS MODELLING TO EXTRACT THE
PREDICTION ERROR CODE AND LOOK
AT THE SENSITIVITY OF TRACKING
BEFORE AND AFTER THE DIET.
AND INDIVIDUAL TRACKING AND
LEARNING SIGNAL WHICH IS
DOPAMINE DEPENDENT IS ENHANCED
AND THERE'S ENHANCED TRACKING OF
PREDICTION OF THIS LEARNING
SIGNAL.
NOTHING WHATSOEVER TO DO WITH
FEEDING SUGGESTING THIS
MANIPULATION CHANGES AT A
GENERAL LEVEL DOPAMINE
SIGNALLING IN HUMANS.
AND WHETHER OR NOT OF COURSE
THIS IS RELATED TO BLUNTING OF
THE TONIC SIGNAL RELATED TO
POSTSIGNAL IS SOMETHING WE'RE
LOOKING AT NOW WITH PET AND MRI
AND THE LAST THING I WANT TO
SHOW YOU IS THE OBA.
THIS IS A LARGE CLINICAL TRIAL
WE'RE IN THE MIDDLE OF AN
NIH-FUNDED STUDY LOOKING AT OEA
VERSE YOU PLACEBO WITH
INDIVIDUALS OVERWEIGHT OR OBESE
AND TRYING TO SEE IF IT CAN
REVERSE THE CONDITION IN MICE
AND I CAN SHOW YOU DATA WE USED
AS PILOT DATA TO GET THE
FUNDING.
WHAT YOU SEE HERE IS A GRAPH OF
WEIGHT LOSS IN FOUR GROUPS OF
INDIVIDUALS AND FOCUS ON THE
ORANGE AND RED LINES BECAUSE
THESE PEOPLE WERE SUPPLEMENTING
WITH THE PRECURSOR WITH OEA AND
OVER 36 WEEKS.
BOTH GROUPS THE RED AND ORANGE
ARE RECEIVING THE PHOSPHOLINE
AND THERE WAS BEHAVIORAL WEIGHT
LOSS INTERVENTION HERE.
WHAT YOU YOU CAN CLEARLY SEE IS
THE INDIVIDUALS IN THE RED LINE
THOSE ARE THE PEOPLE WOULD AT
THE BEGINNING WHEN THEY ENROLLED
IN THE STUDY FOOD DIARIES
INDICATED THEY WERE FREQUENT
HIGH FAT FOOD CONSUMERS AND IN
ORANGE PEOPLE WERE NOT EATING A
LOT OF SATURATED FAT AND THE OEA
IS DIFFERENTLY EFFECTIVE SO IF
YOU HAVE A HIGH-FAT DIET AND
BLUNTING THAT CAN HELP WITH
WEIGHT LOSS OUTCOME AND HAVE
DONE A SMALL STUDY WITH ALCOHOL
USE DISORDER LOOKING AT DOPAMINE
DEPENDENT BEHAVIORS AND THIS
FALSE ALARM RATE WENT DOWN IN
INDIVIDUALS SUPPLEMENTING
RELATED TO MAXIMUM DRINKS PER
DAY.
THIS IS POTENTIALLY AN
INTERESTING GUT-BRAIN TARGET FOR
WEIGHT LOSS BUT ALSO POTENTIALLY
FOR OTHER CONDITIONS IN WHICH
THERE'S ADAPTATIONS IN THE
DOPAMINE SYSTEM AND TO THANK MY
COLLABORATORS AND THE INSTITUTE
AND THE NIH FOR FUNDING AND IT
YOU FOR YOUR ATTENTION.
>> NO QUESTIONS?
AND DR. GARFINKEL.
>> SUCH A PLEASURE TO BE HERE
AND HEAR SO MANY AMAZING TALKS.
TODAY I'M GOING TO TALK TO YOU
ABOUT A CLINICAL TRIAL WE
DEVISED TO ENHANCE INDIVIDUAL'S
ON THE AUTISM SPECTRUM
CONDITIONS ON NEURODEVELOPMENT
CONDITIONS DISPLAYING AND
DIFFICULTIES IN EMOTION
RECOGNITION AND ANXIETY HIGH UP
AUTISM SPECTRUM DISORDER 23-60%
AND THE SENSORY LOOKING AT THE
SENSITIVITY TO LIGHT, SOUNDS AND
ALSO EMERGING EVIDENCE
INTEROCEPTION MAYBE ALTERED.
INDIVIDUALS AUTISTIC WILL HAVE A
LOT OF SOMATIC COMPLAINTS
SUGGESTING THE HYPERSENSITIVITY
TO INTEROCEPTIVE KEYS AND
FEATURES OF AUTISM ARE ACTUALLY
CONSISTENT WITH REDUCED
SENSITIVITY SUCH AS THE REDUCED
CAPACITY TO UNDERSTAND EMOTIONS,
DIFFERENCES IN HUNGER AND
SOCIETY AND SHARED DECISION
MAKING WHICH CAN BE GUIDED BY
INTEROCEPTIVE KEYS AND KIDS
DON'T ALL KNOW WHEN THEY NEED TO
GO TO THE BATH ROOM ROOM AN
INTEROCEPTIVE SENSE AND WE'VE
LOOKED AT SUBJECTIVE AND
BEHAVIORAL MEASURES OF
INTEROCEPTION.
IF YOU ASK SOMEONE HOW OR HOW
AWARE YOU ARE TO INTEROCEPTION
THE DOESN'T ALIGN AND SOMETHING
THAT FASCINATES ME IS PEOPLE
DON'T HAVE INSIGHTS INTO HOW
ACCURATE THEY ARE.
SO AUTISTIC INDIVIDUALS WILL SAY
THEY'RE VERY AWARE OF
INTEROCEPTIVE SENSATIONS BUT IF
YOU MEASURE THE ACCURACY IN THE
LAB THEY MAY HAVE LOW AC RAS
YO -- ACCURACY AND SEE IT'S
CORAL ED -- CORRELATED TO LOWER
SENSITIVE AND WE DEVISED
TRAINING IN 160 INDIVIDUALS AND
TAUGHT THEM TO BE MORE ACCURATE
AT DETECT BEING CARDIAC
SENSATIONS.
IN THE SUBSET OF INDIVIDUALS WE
SCANNED THEIR BRAINS BEFORE AND
AFTER TO LOOK AT THE CHANGES IN
BRAIN CONNECTIVITY AND LOOKED AT
CHANGES IN ANXIETY.
WE COMPARED THESE INDIVIDUALS TO
AN ACTIVE CONTROL GROUP OF
AUTISTIC INDIVIDUALS.
NOW THEY'LL OFTEN SAY THEY FELT
ANXIOUS NOT KNOWING WHAT EMOTION
THE OTHER PERSON'S FEELING.
THIS ACTIVE CONTROL WE TAUGHT
THEM WILL RECOGNITION WHEN IT'S
SAID IN A SAD OR ANGRY WAY AND
HELPED THEM UNDERSTAND THE
SPEECH EN OTHER AS A TRAINING TO
REDUCE ANXIETY.
AND FOR OUR INTEROCEPTIVE
TRAINING WE GOT INDIVIDUAL TO DO
EXERCISE AS A MEANS TO MAKE THE
CONTACT SIGNAL MORE OBVIOUS.
THEN WE GAVE THEM HAS TO TASKS
WELL USED IN THE LITERATURE.
ONE IS THE DETECTION TASK WHERE
INDIVIDUALS SILENTLY COUNT HOW
MANY HEART BAEM
HEARTBEATS THEY FEEL AND HOW
ACCURATE THEY WERE TO JUDGE THE
SYNCHRONICITY.
THIS IS A REALLY IMPORTANT TASK
BECAUSE THE FREQUENCY OF THE
TONES ARE THE SAME IRRESPECTIVE
WHETHER THEY'RE IN SYNC OR OUT
OF SYNC AND NOTHING THAT ALLOWS
THEM DO THIS NO HIGHER ORDER
HEART RATE AND SO IT'S VERY
DIFFICULT.
THEY HAD HEIGHTENED
INTEROCEPTIVE FEEDBACK AND WE
GAVE THEM EXETERO CEPTIVE
FEEDBACK.
AND THIS TRAINING WHILE THE
HEART RATE COMES BACK TO REST.
IDEA THEY SHOULD BE ABLE TO TEST
THIS FOLLOWING TRAINING WE
REPEATED THIS INTEROCEPTIVE
TRAINING SIX TIMES WITH
30-MINUTE SESSIONS.
IN TERMS OF INTEROCEPTIVE
ACCURACY, ADIE IS STANDS FOR
ALIGNING INTERVENTIONS OF
INTEROCEPTIVE EXPERIENCE AND OUR
MEASURE ON THE Y AXIS IS FOR THE
IN SYNC-OUT OF SYNC TEST AND
IT'S A STRINGENT MEASURE AND
WERE ABLE TO ENHANCE
INTEROCEPTIVE ACCURACY IN OUR
TRAINING GROUP.
AND THE ONE-YEAR DATA ALSO
MAINTAINED AND HAD A
PREREGISTERED THRESHOLD WE
CALLED RECOVERY IN THE SENSE WE
QUANTIFIED A CLINICALLY
MEANINGFUL DRUG AND MADE THE
BELOW THRESHOLD.
ACCORDING TO THIS PRE REGISTERED
CRITERION A THIRD OF OUR
TRAINING GROUP MET THIS
CRITERION AND HALF OF OUR
CONTROL INDIVIDUALS.
WHAT THIS SUGGESTS TO ME IS
WHILE YOU DO SEE MODEST DROPS OF
ANXIETY WHICH IS SIGNIFICANT AT
THE GROUP LEVEL ACTUALLY THERE'S
PROBABLY A THIRD OF INDIVIDUALS
THAT THIS REALLY HELPS.
AND THIS REMINDS ME OF OVER
ANALYSES SUCH AS DEPRESSION AND
INFLAMMATION AND MAYBE THERE'S A
THIRD OF INDIVIDUALS WHERE THE
INTEROCEPTIVE PROCESSES IN
ANXIETY MAY BE WAY TO HELP THEM
WHEN WE DIRECTLY TARGET THEM.
IN TERMS OF THE PRE-POST
NEUROIMAGING STANDING WE SAW
CHANGES IN FUNCTIONAL CONNECTIST
-- CONNECTIVITY THINKING OF THE
EARLIER DATA AND THIS INCREASE
IN RIGHT INSULAR FUNCTIONAL
CONNECTIVITY CHANGES CORRELATED
WITH INCREASED INTEROCEPTIVE
ACCURACY AND SAW LEFT INSULA
FUNCTIONALITY AT IN THE REGION
AND INVOLVED WITH HELPING WITH
AUTONOMIC CONTROL AND AROUSAL.
MAYBE THIS IS SOMETHING ABOUT
CREATING COHERENCE IN OUGHT --
AUTONOMIC AROUSALS AND I THOUGHT
SOME PEOPLE WHO UNDERWENT THE
STUDY WERE INFORMATIVE.
ONE INDIVIDUAL REPORTED A
REDUCTION IN SENSORY OVERLOAD
SPECIFICALLY THEY SAID AS THE
INNER CHANNEL GETS CLEARER THE
OUTER CHANNEL GETS MORE QUIET
AND AGAIN THIS MADE ME THINK OF
WHEN YOU CREATE SENSORY THAT
EXTERNAL SENSES YOU GET STRONGER
INTERNAL SENSES AND IF YOU CAN
MAKE THIS INTEROCEPTIVE CHANNEL
STRONGER THEN POTENTIALLY HAVE
YOU THE POSSIBILITY OF SAMPLING
EXETER JOE SO SECEPTIVE SENSORY
REQUIRE MORE HYPOTHESIS TESTING
IN THE FUTURE AND ANOTHER
INDIVIDUAL SAID WHEN I NOTICE
THE IMPACTS OF ANXIETY IN MY
BODY I'M MORE AWARE AND ABLE TO
ASSURE MYSELF IT'S JUST A
PHYSICAL REACTION AND THEY ALSO
SAID BETTER ABLE AT TAKING DEEP
BREATHS AND TRYING TO SLOW MY
HEART RATE DOWN INSTEAD OF
LETTING IT SPIRAL.
I THINK IT SPEAKS TO THE
INTEROCEPTIVE ACCURACY GIVES A
POTENTIAL FOR CONTROL AT AN
EARLIER POINT.
AUTISTIC INDIVIDUALS WILL SAY
THEY SUDDENLY WERE OVERWHELMED
IN A PANIC ATTACK AND IF YOU CAN
HELP PEOPLE FEEL WHEN THEIR
HEART RATE STARTING TO
ACCELERATE IT GIVES AN EARLIER
TIME POINT REGULATE THE CELLS
AND SOMEONE SAID I BELIEVE IT
INCREASED MY AWARENESS OF HUNGER
AND AS A RESULT I REMEMBER TO GO
TO TO EAT, DRINK AND GO TO THE
TOILET AND IT SUGGESTS JUST
TARGETING ONE INTEROCEPTION
DIMENSION MAY INFLUENCE OTHER
AXES AND IT REQUIRES SYSTEMATIC
INVESTIGATION IN THE FUTURE.
TO COMPLETE, INTEROCEPTIVE
TRAINING CAN REDUCE ANXIETY IN
AUTISTIC ADULTS AND EXTENDED
THIS TO A NON-AUTISTIC
POPULATION AND COULD HELP
NON-AUTISTIC INDIVIDUALS MANAGE
ANXIETY AND HELP INDIVIDUALS.
AND WE SHOWED ENHANCED INTERO
CHANGES INVOLVED IN
INTEROCEPTION AND MADE EMOTION
REGULATION.
THANK YOU SO MUCH TO HUGO
CRITCHLEY AND IT WAS SO MUCH
WORK AND WE DID IT TOGETHER AND
THANK YOU FOR THE TEAMS AND
FUNDING AGENCIES AND THANK YOU
FOR LISTENING.
>> THANK YOU.
THAT WAS TERRIFIC.
THERE'S A QUESTION MAYBE BEFORE
THE QUESTION I THINK WHAT WE'LL
DO IS TAKE THE QUESTION AND OPEN
IT UP TO QUESTIONS FOR THE REST
OF THE SPEAKERS.
I KNOW WE'RE GETTING CLOSE TO
LUNCH AND WE DON'T WANT TO STAND
TOO MUCH IN BETWEEN YOU AND
LUNCH AND MAYBE GO 10 MINUTES
INTO THE BREAK AND THEN WRAP UP.
>> GREAT WORK, CONGRATULATIONS.
>> GEORGE WASHINGTON UNIVERSITY.
MY FIRST QUESTION WAS THE
APPLICABILITY OUTSIDE OF
AUTISTIC INDIVIDUALS WHICH IS
EXCITING AND MY SECOND QUESTION
IS WHETHER OR NOT YOU CAN HELP
WITH ANXIETY.
>> WE FOCUSSED ON BRAIN METRICS
TO LOOK AT CHANGE BUT WE HAVE
CARDIAC DATA SUCH AS HEART RATE
AND HEART RATE VARIABILITY WE'VE
NOT LOOKED AT SYSTEMATICALLY
YET.
I CAN'T SPEAK TO THAT.
WE'RE ABOUT TO DO MORE TRAINING
GOT A TRAINING AND LOOKING AT
GASTRIC, RESPIRATORY AND CARDIAC
AND DOING MORE DETAILED
CHARACTERIZATIONS AND HOPE TO
LOOK AT PERIPHERAL MEASURES IN
GREATER DETAIL.
I HOPE THAT'S SOMETHING TO SPEAK
TO IN MORE DETAIL IN THE FUTURE.
>> THERE'S MICROPHONES ON THE
SIDE OF THE ROOM.
>> GREAT SET OF TALKS.
I'M AN ASSOCIATE PROFESSOR AT
THE UNIVERSITY OF BALTIMORE.
DR. GARFINKEL YOU SAID ANXIETY
WAS MISMATCHED BETWEEN SOMEONE'S
PERCEIVED ACCURACY AND ACTUAL
ACCURACY.
CAN YOU TALK ABOUT DID YOU LOOK
AT THAT AS AN OUTCOME AS A
RESULT OF YOUR TRAINING AND
WHETHER DID THE ACCURACY AND
MISMATCH BETWEEN ACTUAL AND
PERCEIVED ACCURACY CONTRIBUTE TO
INDEPENDENT AND CAN YOU COMMENT.
>> IT'S AN INTERESTING QUESTION.
IF I HAD MORE TIME I WOULD HAVE
PUT IN WHAT IS MY FAVORITE SLIDE
WHICH IS SHOWING THIS AWARENESS
MEASURE WE ASKED HOW AWARE ARE
YOU OF THE SENSATION AND THAT'S
WHAT WE USE AS OUR SUBJECTIVE
MEASURE FOR THE MISMATCH.
PEOPLE WHO BECOME MORE ACCURATE
SUBSEQUENTLY REPORT BEING LESS
AWARE WHICH FIND ENDLESS I
FASCINATING.
YOU CAN ACCOUNT FOR IT IN A
PREDICTED POSING WAY BUT IF
PEOPLE ARE MONITORING A LOT AND
HAVE STRONG BELIEFS WITH THE
BODY OR THEY HAVE PRODUCED
PRECISION THEN MAYBE THEY NEED
TO USE POTENTIAL RESOURCES
BECAUSE THEY HAVE TO USE
PRECISION.
IF YOU CAN INCREASE THE
PRECISION THEN THEY'RE ABLE TO
PAY ATTENTION TO THAT WHEN IT'S
MEANINGFULLY CHANGED.
IT TAKES UP LESS MONITORING AND
RESOURCES.
WE DO FIND THIS BEAUTIFUL
OPPOSITE DIRECTION SO IT'S
LOVELY EFFECTIVE ACCURACY
INCREASE AND MONITORING
DECREASES AND TO THE GAP ALSO
DOES REDUCE.
>> WAYNE STATE UNIVERSITY IN
DETROIT.
DRAET PRESENTATIONS FROM ALL --
GREAT PRESENTATIONS FROM ALL OF
YOU BUT A QUESTION FROM STANFORD
BEING A CLINICIAN, THESE
FINDINGS EXPLAIN WHY DRUGS THAT
ACROSS THE BLOOD-BRAIN BARRIER
ARE BETA BLOCKERS LIKE ATENOLOL
THAT DON'T CROSS THE BLOOD BRAIN
BARRIERS AND SHOULD WE TREAT
WITH THOSE THAT REDUCE HEART
RATE FOR ANXIETY?
>> THANK YOU.
AND WHATEVER SERVICE THEY'RE ON,
ICU, NEUROLOGY SERVICE AND
PATIENTS WHO ARE ANXIOUS I WOULD
AGREE REDUCING HEART RATE SHOULD
BE CONSIDERED POSSIBLY AS AN
INTERVENTION IN ITS OWN RIGHT TO
ADDRESS ANXIETY.
THAT'S SOMETHING PEOPLE SHOULD
CONSIDER.
THERE'S BEEN DRUGS FOR TREATMENT
BUT WILL LOWER THE HEART RATE
AND IMPROVE MORBIDITY BUT MAKE
PATIENTS FEEL BETTER IN QUALITY
MEASURE.
>> THANK YOU FOR THAT QUESTION.
QUE WE DO THINGS THAT WE THINK
WILL HELP PEOPLE BEFORE AND
AFTER THE STUDY'S COMPLETED AND
WORTH TRYING.
>> THERE'S A DIFFERENCE BETWEEN
ACUTE AND CHRONIC ANXIETY AND
THERE'S CONDITIONS WHERE PEOPLE
HAVE LONG-TERM ANXIETY AND
TACHYCARDIA IS NOT MUCH OF A
CONCERN BUT BRADYCARDIA AND
BENZODIAZEPINES DON'T WORK FOR
THEM EITHER.
WHEN YOU THINK OF ACUTE ANXIETY
MAYBE THERE'S MORE OF A ROLE
THERE.
>> I'M A GASTROENTEROLOGIST AT
UNIVERSITY OF GEORGIA.
THE VIBRATING CAPSULE IS FDA
APPROVED FOR CONSTIPATION.
WHEN YOU DEVELOP POTENTIALS FOR
THE STOMACH WERE THEY THE SAME
AS IN THE COLON OR DID YOU CHECK
THAT?
>> IT'S NOT FDA APPROVED.
IT'S JUST ALLOWED FOR MARKETING
AND NON-SIGNIFICANT RISK DEVICE.
WE'RE ABLE TO USE IT UNDER THAT
AUSPICE.
WE DID START WITH A PLAN TO TO
LOOK AT VIBRATIONS IN THE
STOMACH AND OTHER SEQUENCE IN
THE COLON.
WHEN WE STARTED THINKING ABOUT
THE PHYSIOLOGY AT PLAY AND HOW
EVEN WITHIN A 30-MINUTE TIME
SPAN THE CAPSULE COULD MOVE OUT
OF THE STOMACH WAITING FOR THIS
CAPSULE TO GET IN THE COLON
AFTER EIGHT HOURS AND WE HAVEN'T
STARTED WITH OTHER SEGMENTS OF
THE G.I. TRACT BUT WE'RE AT THE
BEGINNING STAGES.
>> IT IS NOW FDA APPROVED FOR
CONSTIPATION.
>> OKAY.
>> I HAVE A QUESTION FOR CARL.
WHEN YOU DO THE PACING THE HEART
I WONDER IF YOU SEE A CHANGE IN
FREQUENCY.
THE HEART PACING SO BASICALLY MY
QUESTION IS DO YOU THINK THE
BRAIN IS SENSE THE CHANGE OF THE
HEART RATE OR IS IT POSSIBLE
IT'S SENSING THE CHANGE OF SOME
OF THE HEART FUNCTIONS?
>> WHAT OUR INTERVENTION DOES IS
DIRECTLY CAUSES VENTRICULAR
CONTRACTION AND IN THAT SETTING
WE CAN NO LONGER SEE THE WAVES
THAT WOULD TYPICALLY APPEAR.
IS THERE A CONSEQUENCE OF THAT
OR INFORMATION THAT IS SOMEHOW
TRANSMITTED SENT BACK TO THE
BRAIN?
I CAN'T RULE THAT OUT.
THE VENTRICULAR CONTRACTION CAN
MANIFEST THROUGH BLOOD PRESSURE
CHANGES AND POSSIBLE MECHANISMS
BY WHICH THE EFFECT COULD BE
MANIFESTED.
A LOT OF THIS IS ON THE POSTER
AND HEALING BE FOLLOWING UP A
LOT OF THESE MECHANISTIC
QUESTIONS.
I WILL SAY THE BLOOD PRESSURE I
TEND TO THINK IS NOT A MECHANISM
BY WHICH THE EFFECT IS
TRANSMITTED BACK TO THE BRAIN.
THAT'S WHERE A NUMBER OF REASONS
INCLUDING DATA WE PRESENTED IN
THE PAPER AND OTHER PHARMACOLOGY
AND THE DIRECTION BLOOD
PRESSURE'S GOING IN.
THE PRECISE MECHANISMS LOTS OF
INTERESTING QUESTIONS WE'RE
WORKING ON AND WE'LL BE
FOLLOWING UP ON.
>> AND ONE MORE OVER HERE.
>> I'M A POSTDOC AT VANDERBILT.
I HAVE ANOTHER QUESTION FOR
DR. GARFINKEL.
I'M CURIOUS FROM A PRECISION
MEDICINE STANDPOINT IF THERE'S
ANY PARTICIPANT FEATURES YOU
THINK ARE PREDICTING AND THE
ONE-THIRD OF RESPONDERS.
>> AND WE'RE DOING COMPUTATIONAL
MODELS TO TRY AND BUILD UP
BETTER UNDERSTANDING OF WHAT
COULD BE MOST PROTECTIVE.
I DON'T WANT TO SPEAK TOO MUCH
TO THOSE FINDINGS BUT THERE
SEEMS TO BE THEY HAVE THIS.
LOWER PRECISION MEASURE THAT
SEEMS TO POINT TO SOMETHING
ABOUT THE PERIPHERY BUT WE'RE
LOOKING FURTHER INTO IT.
I'M SORRY I CAN'T ANSWER THAT
YET AND HOPE TO HAVE BETTER
ANSWERS SOON BECAUSE I AGREE
FROM A PRECISION MEDICINE
PERSPECTIVE THAT'S WHAT WE NEED
TO UNDERSTAND.
>> I'LL ASK DR. COLEMAN A
QUESTION.
I'M A CLINICAL CARDIOLOGIST.
A SUBSET OF PATIENTS I SEE HAVE
THE SAME FUNCTIONAL
GASTROINTESTINAL COMPLAINTS
DISCUSSED THEY OFTEN GET
REFERRED TO CARDIOLOGIST AND THE
HEART RATES DON'T BEHAVE AS THEY
SHOULD.
PARTIALLY SOMETIMES DURING
ORTHOSTATIC CHANGES.
WE SEE WHAT'S LABELLED AS A
DYSAUTONOMIA AND WHERE YOU WERE
ABLE TO CAPTURE THE HEART RATE
DID YOU SEE ANYTHING BEYOND
HEART RATE VARIABILITY WHETHER
THERE'S DIFFERENCES IN THE
HEART-RATE RELATED METRICS AND
THE VISION WITH THE
GASTROINTESTINAL PARTS.
>> FIRST I WANT TO RESPOND TO
THE GENTLEMAN FROM WAYNE STREET,
GO BLUE.
BUT WE DID NOT TARGET THAT
DIRECTLY BUT THE ONE THING THIS
IS AN AMBULATORY REPORTING WHERE
PEOPLE WERE GOING AROUND AND NOT
A CONTROLLED SETTING AND WE'D
HAVE TO -- WE HAVE AN METER ON
AND YOU CAN SEE WHEN YOU WENT
FROM LAYING DOWN, STANDING UP,
ETCETERA WE HAVE THE DATA BUT
DIDN'T DIRECTLY TARGET THAT SO I
APPRECIATE THAT SUGGESTION.
>> ALL RIGHT.
JUST BEFORE WE WRAP UP, I WANT
TO REMIND EVERYBODY WE NOW HAVE
A TWO-HOUR BREAK.
WE'RE RUNNING SLIGHTLY LATE BUT
WE STILL WANT TO COME BACK AT
12:30.
AND THE POSTER SESSION WILL BE
RUNNING CONCURRENTLY -- 2:30,
SORRY.
A H, THE POSTERS WITH ODD
NUMBERS FROM 1:25 AND BEFORE YOU
YOU DISAPPEAR LET'S HAVE A BIG
ROUND OF APPLAUSE FOR ALL OF OUR
SPEAKERS. SEE YOU IN LESS THAN TWO HOURS.
HELLO.
IT IS MY PRIVILEGE TO WELCOME
YOU TO OUR AFTERNOON SESSION ON
BRAIN-MULTIORGAN SYSTEM
CONNECTIONS.
MY NAME IS JULIA BERZHANSKAYA.
I AM A PROGRAM OFFICER AT THE
OFFICE OF INNOVATION, NATIONAL
HEART, LUNG AND BLOOD INSTITUTE,
AND IN THIS POSITION, I'M
RESPONSIBLE FOR INITIATIVES
RELATED TO PRODUCT DEVELOPMENT.
I WOULD LIKE TO INTRODUCE MY
CO-MODERATOR, DR. ENTER
ANDERMANN, A -- DR. ANDERMANN,
AT HARVARD MEDICAL SCHOOL.
>> HI, EVERYBODY, WE'VE GOT A
GREAT AFTERNOON LINEUP.
I HOPE YOU CAN STICK THROUGH IT
FOR THE WHOLE TIME.
WE'LL START WITH A TALK FROM
ARDEM PATAPOUTIAN FROM SCRIPPS
RESEARCH ON THE ROLE RF PIEZ02
IN ENTEROSEPTION, THEN WE'LL --
ENTER ON ACCEPTING -- ON
INTEROCEPTION THEN WE'LL HERE
FROM JULIA PILITSIS, THEN WE'LL
HEAR FROM JOHN OSBORN, AND THEN
HEAR FROM RUI CHANG ABOUT THE
CODING LOGIC OF ENTEROSEPTION IN
THE VAGUS NERVE, THEN HEAR FROM
RICHARD LANG WHO WILL TALK ABOUT
EXTRAOCULAR LIGHT SENSING WI
ATHE OPSIN GPCR'S R HOPEFULLY
TIME AFTER FOR ONE QUESTION AND
REMEMBER YOUR QUESTIONS BECAUSE
WE'LL HAVE A Q & A AT THE END.
WE'LL START BY ASKING ARDEM TO
PRESENT.
>> HI, EVERYBODY.
WILL FIRST, I SHOULD START BY
SAYING THAT I DID NOT APPRECIATE
ARE KAY TYE TALKING ABOUT THE
FORMAL ASSAY BECAUSE I FELT LIKE
I WAS THAT MOUSE ON THE PLEX
PLEXIGLASS SIDE WATCHING YOU
GUYS CONSUME SCIENTIFIC
MILKSHAKE.
I'M HAPPY TO BE VIRTUAL WITH YOU
TODAY TO TALK ABOUT WORK WITH
ION CHANNEL PIEZ02 AND ENTER OH
SPTION.
14 YEARS AGO BY LAB IDENTIFIED
THE CHANNELS CALLS PIEZ02 AND PI
EZO1, THIS IS THE STRUCTURE OF
THE TRIEMER, EACH PROTOMER HAS
38 TRANSMEMBRANE, MORE
TRANSMEMBRANE DOMAINS THAN ANY
OTHER PROTEIN IN THE GENOME, ON
TOP OF IT, THEY COME TOGETHER AS
A TRIMER FORMING THIS ALMOST
MILLION DALTON MASSIVE MEMBRANE
PROTEIN ION CHANNEL AT THE
PLASMA MEMBRANE AND THIS IS WORK
BY ASDO -- S AOTOME AND OTHERS.
FLATTENING AND ALLOWING CATIONS
INTO THE CELL INITIATING AN
ACTION POTENTIAL FOR EXAMPLE IN
SENSORY NEURONS.
SO OVER THE YEARS, WE'VE DONE A
VARIETY OF THESE MOUSE GENETICS
TO FIND WHAT THE ROLES OF THESE
ION CHANNELS ARE R PIEZ02 IS
STROJLY EXPRESSED IN THESE THAT
HELP US SENSE SENSATION, AND IN
THIS ASSAY YOU CAN SEE, FOR
EXAMPLE, IN A CERTAIN PIEZ02
KNOCK-OUT THEY HAVE SEVERE
UNCOORDINATION, A SIGN OF LACK
OF APPROXIMATE PROPRIOCEPTION
AND BELOW YOU CAN SEE WE THINK
THIS IS DIRECT THE CR MECHANO
TRANSDUCTION, BECAUSE IF YOU GET
RIZ OF PIEZ02 THE STRETCH
ACTIVATED NEURONAL ACTIVITY AT
THE TERMINI ARE COMPLETELY WIPED
OUT, ALMOST COMPLETELY WIPED OUT
IN SEVEN OUT OF EIGHT TRIES THAT
OUR COLLABORATOR TRIED.
ONE OF THE INCREDIBLE RESULTS
ACTUALLY CAME NOT FROM OUR LAB
BUT ALEX SCHLOESSER'S LAB THERE
AT THE NIH AND THEY ACTUALLY
IDENTIFIED INDIVIDUALS WHO ARE
LOSS OF FUNCTION OF PIEZ02 IN
HUMANS, THIS IS COMPLETE NULL
MUTATIONS AND THEY RECAPITULATED
MANY OF THE SOMATOSENSORY TYPES
WE OBSERVED IN THE MICE,
INCLUDING LACK OF TYPE AND
PROPRIOCEPTION AND THIS VIDEO
WILL SHOW THIS INDIVIDUAL WHO IS
A PIEZ02 NULL, SHE'S HARNESSED
FOR HER OWN PROTECTION,
BLINDFOLD AND HAD SIMPLY ASKED
TO WALK IN A STRAIGHT LINE, AND
SOMETHING THAT MOST OF US WILL
HAVE A VERY EASY TIME, AS YOU
CAN SEE, SHE STRUGGLES WITH
THIS, AGAIN, THIS LACK OF
COORDINATION IS A SIGN FOR LACK
OF PROPRIOCEPTION.
SO I'LL JUST SUMMARIZE ABOUT
OVER TEN YEARS OF WORK IN THIS
SLIDE.
THIS AND MANY OTHER STUDIES TOLD
US THAT POSE 2 MAINLY -- THAT
PIEZ02 IS MAINLY RESPONSIBLE FOR
SENSE OF TOUCH, PROPRIOCEPTION,
ALSO CLINICALLY IMPORTANT
TACTILE ALLODYN I A WHEN TOUCH
BECOMES PAINFUL, AS WELL AS
MECHANICAL ITCH, BY PIES RPIEZO1
AND ARE SCRATCHY SWEATER OR BUGS
FEELING LIKE CRAWLING ON YOUR
SKIN.
WE GOT ENTERED IN WITH THIS IDEA
THERE'S LOTS OF WORK ALREADY
DONE THAT NODOSE GANGLION
INNERVATES MANY OF THE INTERNAL
ORG ORGANS, BUT NOT ONLY WERE
SENSORS NOT KNOWN, IN MANY OF
THESE CASES, WHAT IS THE ROLE OF
MECHANO TRANSDUCTION IN SENSING
THESE INTERNAL ORGANS WAS
UNKNOWN, SO A VARIETY OF
COLLABORATIONS WITH ADAM
SCHLOESSER'S LAB, WE HAVE SHOWN
FOR EXAMPLE THAT BOTH IN MICE
AND HUMANS ARE PIEZ02 IS
REQUIRED FOR LONG STRETCH,
REFLEX AND ACTUALLY IN
INDIVIDUALS WITHOUT PIEZ02 HAVE
MASSIVE RESPIRATION PROBLEMS
RIGHT AFTER BIRTH AND ARE
HOSPITALIZED FOR THIS, THERE ARE
MANY WAYS TO SENSE AND CONTROL
BLOOD PRESSURE, THE NEURONAL
SENSORY MECHANISM TO THE VAGUS
IS CALLED BEARER RECEPTION AND
WE'VE SHOWN THAT BOTH PIEZO1 AND
2 IN THIS CASE ARE REQUIRED FOR
THE SENSE OF BETTER RECEPTION.
MARSHALL WAS AN ALUMENT NUS P
FROM THE LAB -- ALUM NUPS FROM
THE LAB EXRRKS RUNS LAB AT
BAYLOR ARE COLLEGE OF MEDICINE,
ALSO IN THE AUDIENCE TODAY,
SHOWS BLADDER STRETCH, THIS
SENSE THAT TELLS YOU WHEN YOU
NEED TO GO TO THE RESTROOM BOTH
IN MICE AND IN HUMANS ONCE AGAIN
DEPENDS ON PIEZ02, THESE
INDIVIDUALS WITHOUT PIEZ02 THEY
LEARN AS THEY GROW UP THAT
THEY'RE NOT GETTING THIS
SENSATION, SO THEY GO TO THE
RESTROOM TO A SCHOOL TWO TO
THREE TIMES A DAY TO AVOID
ACCIDENTS.
IN ADDITION, WE JUST RECENTLY
PUBLISHED THERE IN THE LAB THAT
AGAIN BOTH IN MOUSE AND HEUMANN
GULT MOTILITY IS REGULATED VIA
POSE PIEZ02.
SO ALL OF THIS IS GREAT, BUT
WHAT I WANT TO TALK ABOUT NOW
AND WHAT THE LAB IS REALLY
FOCUSING IS I CALL PHASE 26
STUDYING PIEZO'S IN
INTEROCEPTION, THAT IS
EVERYTHING I DESCRIBED TO YOU
BEFORE WAS KIND OF KNOWN THAT
HAPPENS.
WHAT I MEAN BY THAT IS WE KNEW
THAT YOUR BLADDER STRETCHES
EXPUF GET A SENSATION FROM --
AND YOU GET A SENSATION FROM IT,
SAME WITH LUNG AND
PROPRIOCEPTION AND PAIN.
BUT WE ALSO KNOW THAT THE INT
ERS RG HE ONS ALSO INNERVATE
PANCREAS, ADIPOSE, KIDNEY, I CAN
LIST TEN MORE AND THE ROLE OF
THE SENSORY NEURONS AS WELL AS
MECHANOSENSATION IS REALLY NOT
WELL UNDERSTOOD.
AND YU WANG A GRADUATE STUDENT
IN THE LAB SHOWED WITH LI YE
ALSO AT SCRIPPS WANTED TO TACKLE
THIS PROBLEM, FOCUSED ON ADIPOSE
TISSUE.
THE TEXTBOOK VERSION OF HOW
ADIPOSE TISSUE COMMUNICATES WITH
THE BRAIN IS THAT THEY IS HE
SECRETE HORMONES, LEPTIN AND
THESE HORMONES GO TO THE BRAIN
AND ASSESS YOUR WHOLE M
METABOLIC CONDITION AND THROUGH
THE MOTOR SYMPATHETIC NERVOUS
SYSTEM REGULATES ADIPOGENESIS,
THERMOGENESIS, ET CETERA.
HOWEVER, THERE WERE ANECDOTAL
INFORMATION THAT THE SENSORY
NEURONS ALSO INNERVATING THE FAT
PAD AND YI WANTED TO FIND OUT
WHAT DO THESE NEURONS DO.
SHE FIRST LOOKED AND SHOWED THAT
THERE IS ROBUST DRG INNERVATION
OF FAT THAT I'M SHOWING YOU, BUT
TO LOOK AT THE FUNCTION, SHE
FOCUSED ON THIS INGUINAL WHITE
ADIPOSE TISSUE THAT ALSO HAS
ESPECIALLY WHEN INDUCED BY
STRESSES SUCH AS COLD HAS BROWN
ADIPOSE TISSUE, THERMOGENIC
PROPERTIES AS WELL, AND SHE HAD
TO DO LOTS OF NEW TECHNOLOGY
DEVELOPMENT TO BE ABLE TO DO
THESE STUDIES, INCLUDING
EVOLVING NEW AAV VIRUSES THAT
SHE COULD DELIVER, IT CREATE THE
ADIPOSE TISSUE FOR EXAMPLE.
SHE MENTIONED DUAL SYSTEM, CRE
COMES IN FROM AEV BEING INJECTED
INTO THE FAT PAD.
IN MICE INFECTED WITH AEV
PREINDEPENDENT IF TOXIN
EXPRESSING SO THIS IN THIS CASE
ONLY DRG NEURONS THAT INNERVATE
THIS FATALITY PAD WOULD BE
ABLATED.
SYMPATHETIC NERVOUS SYSTEM WOULD
BE NORMAL AND DRG INNERVATING
OTHER TISSUES WOULD BE NORMAL.
WHEN SHE DID THIS, REMARKABLY
SHE SAW A VERY STRONG PHENOTYPE,
AS YOU CAN SEE HERE, THERE'S
MASSIVE EN RIDGEMENT RF ADIPOSE
SITES AS WELL AS UPREGULATION,
RNA SEC FROM FAT PADS FROM
ABLATED VERSUS CONTROL ANIMALS,
RNA SEQ SUGGEST THAT HAD
UPREGULATION IN MANY OF THE
TYPES OF GENES THAT WE KNOW
WOULD BE ALSO UPREGULATED IF YOU
ACTIVATE THE SYMPATHETIC NERVOUS
SYSTEM.
SO THE CONCLUSION HERE IS THAT
IT SEEMS LIKE ABLATING THE DRG
NEURONS IS EQUIVALENT OF
ACTIVATION OF THE SYMPATHETIC,
SO IT'S ALMOST A NEGATIVE
FEEDBACK LOOP, LIKE MANY OTHER
SENSORY SYSTEMS, INCLUDING THE
BEARER RECEPTOR SYSTEM OF THE
BUT THE QUESTION WAS, WHAT ARE
THE SENSORY NEURONS ACTUALLY
SENSING IN THE FAT PAD?
INITIALLY WE THOUGHT IT MIGHT BE
MANY THINGS, BUT PROBABLY NOT
MECHANOSENSATION.
SO THE REST OF THE WORK IS
UNPUBLISHED WORK FROM YI'S
THESIS.
SO FIRST SHE WANTED TO SEE IF
PIEZ02 FIBERS -- PIES POSITIVE
FIBERS WERE EXPRESSED IN FAT
PAD.
SHE SHE TAKES AN AAV THAT'S
FLOXED, SO CRE-DEPENDENT
FLUORESCENT MARKER EXPRESSING
AND DOES THIS IN A PIEZ02 CRE
MICE SO WHEN SHE INJECTS DRG SHE
CAN WATCH THE NEURONS EXPRESSING
PIEZ02 ALL THE WAY INTO THE FAD
PAT SO THIS IS A CLEARED AND
LIGHT SHEET MIE CROSS MICROSCOPY
IMAGE OF WHAT WE LOOK AT AND
THERE'S MASSIVE INNERVATION OF
PIEZ02 POSITIVE NEURONS.
SO IF YOU LOOK CLOSELY AT THIS
YOU CAN SEE THAT SOME OF THESE
NEURONS ARE WRAPPED AROUND BLOOD
VESSELS WITHIN THE FAT, SOME
COME VERY CLOSE TO THE ACTUALLY
ADIPOSE SITES, SO IN CLOSE
PROXIMITY TO THEM.
I'M SHOWING YOU, BUT SHE ALSO
DID RETROGRADE TRACING SHOWING
THAT HALF OF FAT-INNERVATING
NEURONS EXPRESS PIEZ02.
AGAIN, THIS IS REMARKABLE
BECAUSE THIS IS ALMOST THE SAME
NUMBER WE GET IF WE LOOK AT SKIN
CELLS.
SKIN TISSUE WHICH HAS BEEN
STUDIED FOR DECADES HAS THE SAME
AMOUNT OF PIEZ02 INNERVATING
NEURONS AND YET NOTHING IS KNOWN
ABOUT THESE NEURONS INNERVATING
THE FAT PAD.
IF YOU LOOK AT THE FUNCTION OF
THESE NEURONS, NOW, INSTEAD OF
ABLATING NEURONS, WE'RE SIMPLY
DELETING PIEZ02 FROM DRGS
INNERVATING FAT PAD AND IN THIS
CASE YOU DID INTERNAL CONTROL.
SO ONE SIDE, SHE'S INJECTING CRE
IN THE FAT PAD OF ONE SIDE AND
CONTROL IN THE OTHER, IN PIEZ02
LOSS OF FUNCTION ANIMAL, SO ONLY
THE DRG NEURONS EXPRESSING
PIEZ02 WILL DELETE THE ONES THAT
ARE INNERVATING THE FAT PAD
ITSELF.
WHEN SHE TAKES THE FAT PADS
AFTERWARDS AND DOES RNA SEQ,
REMARKABLY SHE SEES ALL THE
GENES THAT WERE UPREGULATED FOR
ABLATION OF DRG'S INNERVATING
THE FAT PAD ARE AGAIN COMING UP.
THIS IS QUITE STRIKELY.
IF I SHOW YOU THIS PLOT WHERE
WE'RE COMPARING THE GENES
UPREGULATED IN DRG ABLATION ON
THE X AXIS COMPARED TO LOSS OF
FUNCTION OF PIEZ02 ONLY, YOU CAN
SEE THERE'S A VERY NICE POSITIVE
CORRELATION.
SO IT SEEMS LIKE NOTHING BUT
PIEZ02 CAN RECAPITULATE THE PR
PHENOTYPE OF COMPLEES DRG THERE
REGULATION.
CR DOES THIS IN THE PRESENCE OF
HIGH FAT DIET AND COME BACK TO
THIS.
WHEN YOU GET A SURPRISING RUMENT
LIKE THIS, WHICH IS PIEZ02
SENSING SOMETHING MECHANICAL IN
FAT PAD IT'S VERY NICE TO GET
GENETIC EVIDENCE FROM ANOTHER
TYPE OF STUDY AND GENETICISTS
LOVE TO LOOK AT BOTH GAIN OF
FUNCTION AND LOSS OF FUNCTION
AND SINCE WE HAVE CONFIRMED GAIN
OF FUNCTION MICE WITH PIEZ02
SAID WHAT HAPPENS IF WE DID THE
SAME EXPERIMENT WITH THESE GAIN
OF FUNCTION ANIMALS.
SAME TYPE OF ERNS SPEMPLET, CRE
ON ONE SIDE, CONTROL ON THE
OTHER, BY GAIN OF FUNCTION I
MEAN THIS IS A GENE STILL
MECHANICALLY ACTIVATED BUT MORE
SLOWLY INACTIVATING SO YOU GET A
CERTAIN AMOUNT OF STIMULUS.
DID THIS IN RNA SEQ ON FAT PAD
SHE DIDN'T SEE ANYTHING.
BUT YU ALWAYS HAS A BACKUP AND
HAD ALSO DONE THESE EXPERIMENTS
IN THE PRESENCE OF HIGH FAT
DIET, AND HIGH FAT DIET WE
THOUGHT WAS IMPORTANT BECAUSE
THERE'S MORE MECHANICAL
STIMULATION IN THIS CONDITION.
SO THE FA PADS GET BIGGER,
STIFFER DURING HIGH FAT DIET, AS
LONG AS CELLS EXPAND, THERE'S
MORE CELLS AND THERE'S VASO
VASODILATION THAT'S A RELEVANT
STIMULUS.
WHEN SHE DID THIS AND COMPARED
THE TWO SIDES OF THE FAT PADS,
NOW SHE SAW THAT MANY OF THE
GENES THAT WERE BEING
UPREGULATED IN THE KNOCK-OUT OR
ABLATION NOW ARE DOWN REGULATED
IN THE CRE POSITIVE SIDE.
AGAIN I'M SHOANG THE CORRELATIOE
LAKES OF THE GAIN OF FUNCTION
VERSUS LOSS OF FUNCTION IN HIGH
FAT DIET, NOW YOU SEE VERY
STRIKING NEGATIVE CORRELATIONS.
SO IN SUMMARY, FAT HAS FEELINGS
TOO.
INNERVATION OF THE FAT PAD SEEMS
TO HAVE AN INHIBITORY BREAK ON
THE SYMPATHETIC SYSTEM.
SURPRISINGLY, WE FIND THAT
MECHANOSENSATION IS VERY
CRITICAL FOR THIS PROCESS.
WE'RE VERY INTERESTED IN WHAT
MECHANICAL FORCES ARE AT PLAY IN
FAT.
THIS IS VERY DIFFICULT TO
ANSWER.
IT'S GOING ON REQUIRE NOVEL
TECHNOLOGY DEVELOPMENT FOR US TO
KNOW WHAT'S HAPPENING IN VIVO IN
FAT PADS IN RESPONSE TO VARIOUS
CONDITIONS BUT AS I MENTIONED IT
COULD BE THE STIFFNESS OF THE
FAT PAD, COULD BE THE ACTUAL
CELLS ENLARGING AND PUTTING
PRESSURE ON THE NERVE ENDINGS,
IT COULD BE VASODILATION.
BUT FINALLY I THINK THIS IS
MAINLY A PROOF OF CONCEPT OF THE
MANY DIFFERENT ROLES IN THE NEXT
DECADE WE'RE GOING TO FIND OF
THE SENSORY NERVOUS SYSTEM
PLAYING IMPORTANT ROLE OF
REGULATING AND SENSING VARIOUS
INTERNAL ORGANS.
SO I WOULD JUST LIKE TO THANK
FOR MORE OF THE INTRODUCTION
PART, MANY OF THE -- THEY
STARTED MANY OF THESE KNOCK-OUT
STUDIES, I MENTIONED KARA
MARSHALL WHO IS THERE DID THE
BLADDER WORK, ROSE HILL DID THE
ITCH WORK AND ON THE PRACTICES
WHERE THESE PEOPLE ARE RIGHT NOW
AND ROSE IS ON THE JOB MARKET
AND SHE'S FANTASTIC, YOU SHOULD
LOOK INTO HER, TALK TO HER.
WE'VE COLLABORATORS THAT I
MENTIONED AND SOME OF THIS WORK
AT LEAST WAS FUNDED BY AN
NINDS NIH R35 MECHANISM WHICH
I'M VERY GRATEFUL FOR.
THE WORK ON THE FAT INNERVATION
IS LED BY YU WANG AS I MENTIONED
IN A COLLABORATIVE EFFORT WITH Y
RERKS LAB MY NEIGHBOR AND IN
THIS WE HAVE A WONDERFUL RO1
FROM NIH WHICH AGAIN I'M VERY
GRATEFUL FOR.
THANKS AGAIN FOR YOUR ATTENTION.
>> THANK YOU VERY MUCH, ARDEM.
TIME FOR ONE QUESTION.
PLEASE IF YOU HAVE A QUESTION,
STEP UP TO THE MIC.
>> HI.
I'M CURIOUS TO KNOW IF YOU THINK
THAT OTHER CELL TYPES RESIDENT
IN THE FAT TISSUE LIKE MICROGLIA
MIGHT BE TUG OG THIS PIEZO
FIBERS?
>> ABSOLUTELY.
I DIDN'T MENTION IT BUT WE ARE
CONSIDERABLE POTENTIAL IMMUNE
AND RELATED CELLS BEING POSSIBLY
THE SOURCE OF THE MECHANICAL
STIMULATION.
AS I SAID, I THINK WE WOULD LOVE
TO HAVE SOME KIND OF SENSOR THAT
WOULD TELL US IN VIVO DURING
EITHER NORMAL PHYSIOLOGY OR
PATHOPHYSIOLOGY WHAT FORCES ARE
AT PLAY, AND IT'S VERY, VERY
EXCITING I THINK DIRECTION THAT
OVER THE NEXT FEW YEARS
HOPEFULLY WE CAN COLLABORATE AND
COME UP WITH SOMETHING.
>> GREAT.
>> ONE MORE QUICK QUESTION.
>> ANY IDEA WHAT YOU THINK THE
NERVE FIBERS AROUND THE BLOOD
VESSELS ARE DOING?
THAT'S WHERE THE SIM PA THET IKS
WOULD BE AS WELL.
-- SYMPATHETICS WOULD BE AS
WELL.
>> YES, SO JUST REMEMBER THAT
ALL OF YU'S ASSAYS ARE FROM
DIRECTLY INJECTING THE DRG'S SO
WE KNOW THESE ARE SOMATOSENSORY
NEURONS INNERVATING THE BLOOD
VESSELS, BUT OF COURSE THERE ARE
SIM PA THETD I CAN AS WELL.
-- SYMPATHETIC AS WELL.
IN MANY OF THESE SITUATIONS, FOR
EXAMPLE, IF YOUR FAT PAD IS
GOING TO GROARKS YOU'LL NEED
MORE BLOOD CIRCULATION, AND
THERE'S GOING TO BE VASODILATION
AND THIS COULD VERY WELL BE A
SOURCE OF THE MECHANICAL FORCE
ACTING IN THE FAT PAD ON THESE
NERVE ENDINGS.
WE SEE THIS ACTUALLY IN MANY
DIFFERENT INTERNAL ORGANS THAT
WE'RE LOOKING AT.
THERE'S USUALLY SOME, SOME OF
THESE SENSORY NERVES ARE ALWAYS
ASSOCIATED WITH BLOOD VESSELS.
>> GREAT.
OKAY.
SO WE'LL MOVE ON NOW.
THE NEXT SPEAKER IS JULIA
PILITSIS.
-- IS JULIE PILITSIS.
>> I THINK IT'S STILL SHARING.
OH, I GOT THE THUMBS UP.
>> THANK YOU ALL FOR ATTENDING
THIS AND THANK YOU TO THE
PLANNING COMMITTEE FOR THE
OPPORTUNITY TO BE HERE TODAY.
I'M EXCITED TO TALK TO YOU
SPECIFICALLY ABOUT CHRONIC PAIN
AND MY MODEL SYSTEM, WHICH IS
HUMANS.
IN TERMS OF MY DISCLOSURES, YOU
KNOW, SOME OF THESE ARE RELEVANT
TO THE TRAINING AND EDUCATION IN
THIS TRAINING, AS WELL AS MY
FUNDING.
SO WHEN WE THINK ABOUT CHRONIC
PAIN, I CAN'T THINK OF -- YOU
KNOW, I STARTED OUT AS I WAS
PRACTICING FOR THIS TALK TODAY
SAYING I CAN'T THINK OF ANY
DISEASE WHERE INTEROCEPTION IS
MORE RELEVANT BUT AS I'VE HEARD
MY COL LEAK SPEAK, THERE ARE SO
MANY PLACES THIS -- COLLEAGUES
SPEAK, THERE ARE SO MANY PLACES
THIS TOUCHES.
REALLY WHAT I'M HOPING TODAY IS
TO TALK A COUPLE OF YOU IN THE
AUDIENCE INTO THINKING ABOUT
CHRONIC PAIN BECAUSE THIS IS
REALLY SOMETHING THAT AFFECTS SO
MANY PEOPLE, UPWARDS OF
50 MILLION PEOPLE.
YOU KNOW, WE HAVE IMAGING AND
FUNCTIONAL IMAGING TO STUDY
THIS, BUT WE NEED BETTER TOOLS
AND WE NEED BETTER TECHNIQUES,
ESPECIALLY AS WE EXPAND OUR
MODEL SYSTEMS.
SO I'VE HAD A VARIETY OF --
[PAUSE] THESE AND I'LL TALK A
LITTLE BIT.
ONE OF THE THING I DO AS A
NEUROSURGEON IS I IMPLANT SPINAL
CORD DEVICES IN THE EPIDURAL
SPACE THAT ALLOW FOR STIMULATING
SPINAL AND SOMATIC PATHWAYS, AND
AS MUCH AS SOME OF YOU HAVE
HEARD ABOUT DEEP BRAIN
STIMULATION AND HOW WE CAN DO
MANY STUDIES INTRAOPERATIVELY,
SIMILAR TO --
ARE PLEXON IN RATS, DURING
SURGERY, WE CAN BETTER
UNDERSTAND ELECTROPHYSIOLOGY AND
REALLY HOW SPINAL AND SOMATIC
PATHWAYS CAN BE INVOLVED IN
INTEROCEPTION.
I KNOW MANY OF YOU HAVE SEEN
THIS CARTOON, YOU KNOW, QUICK
GOOGLE SEARCH, THIS IS WHAT POPS
UP.
I THINK IT'S REALLY INFORMATIVE
AS A CARTOON.
SO JUST THINKING ABOUT PAIN,
YOU'RE GOING TO TOUCH THE FLOWER
OR TOUCH THE THORN AND YOU SAY
OUCH.
AND WHERE IS THAT SIGNAL GOING?
SO IT STARTS ALTHOUGH YOUR
FINGER -- STARTS AT YOUR
FINGERTIPS AND TALKS ABOUT THE
PAIN RECEPTORS THAT WE HAVE ALL
THE WAY UP THE ARM TO THE
BRACHIAL PLEXUS, TO SPINAL CORD,
BRAINSTEM, RELAY STATIONS, BACK
DOWN THE DESCENDING PATHWAYS IN
ORDER TO HAVE THAT REACTION.
THAT'S WHAT HAPPENS IN YOU OR I
AND PEOPLE DHEENT SUFFER FROM
CHRONIC PAIN.
BUT ONE OF THE INTERESTING
THINGS ABOUT PAIN IS WHEN YOU
HAVE PAIN FROM MORE THAN -- PAIN
FOR MORE THAN THREE MONTHS, THE
WHOLE PATHWAY SHIFTS AND THIS
MECHANISM OF INTEROCEPTION
SWITCHES.
SO WE MAY NOT KNOW ENOUGH ABOUT
IT IN A NORMAL STATE, THEN WHEN
WE TAKE THE DISEASE STATE OF
CHRONIC PAIN, IT GETS EVEN MORE
COMPLEX.
SO ON THE LEFT ILLUSTRATES WHAT
I WAS SAYING IS HOW THIS CAN
AFFECT SO MANY PARTS AS YOU GO
OUT, BUT THEN -- AS YOU GO ON.
BUT THEN LET'S THINK ABOUT WHAT
HAPPENS DURING CENTRAL
SENSITIZATION AND MAKES US MORE
COMPLICATED.
EVERYBODY HAS DONE SOMETHING
WHERE THEY TWIST THEIR INC. HE
WILL OR HURT THEIR KNEE -- TWIST
THEIR ANKLE OR HURT THEIR KNEE.
WHAT HAPPENS?
YOU START LIMPING, FAVOR THE
OTHER SIDE, OTHER SIDE HURTS,
BACK IS OUT OF WHACK AND CAN'T
SLEEP AND YOU'RE MISERABLE AND
ALL THESE THINGS HAPPEN THAT
INVOLVE ACUTE PAIN AND HOW WE
FEEL IN THE INTEROCEPTION.
SO THIS CAN BE COMPENSATORY
OVERUSE, THIS CAN BE MUSCLE
SPASM.
THE MUSCLES CAN GET SO TIGHT, IN
FACT, THEY CAN COMPRESS THE
NERVES AND ALTER OUR RECEPTORS
AND INFLAMMATION AND WHOLE
SYSTEMIC PROCESSES CAN HAPPEN.
THIS IS NORMAL PAIN.
WHEN YOU GO INTO THE CHRONIC
PAIN CYCLE, ALL THOSE RESPONSES,
AGAIN, AND ALL THOSE WAYS WHERE
PAIN CAN OCCUR ARE ALTERED, AND
AGAIN, ADDING TO, YOU KNOW, JUST
THIS MULTI-LAYER COMPLEXITY WHEN
YOU LOOK AT THIS DISEASE.
I TOO LIKED DR. TYE'S FOMO
14R50EUD AND ONE OF THE
THINGS -- SLIDE AND ONE OF THE
THINGS I WAS THINKING ABOUT WHEN
SHE WAS TALKING ABOUT THIS IS
CHRONIC SPAIN A RESPONSE THAT IN
THAT CASE THE ANIMAL MIGHT HAVE
TO THE SITUATION OR THE HUMAN
HAS TO THEIR SITUATION, TWHING
YOU'LL ALSO NOTICE AND I DON'T
KNOW HOW YOU MIMIC THIS IN AN
ANIMAL MODEL, BUT I'M SURE
SHE'LL FIND OUT, IS WHEN YOU SEE
PATIENTS WITH CHRONIC PAIN, IT'S
ALMOST THEY'RE SO DIFFERENT, BUT
SOME OF THE BEHAVIORS YOU SEE IN
THE CLINIC ARE THE SAME.
IT GETS EXHAUSTING NOT ONLY FOR
THE PATIENT BUT FOR THE FAMILY
MEMBER, THE FAMILY MEMBERS
INEVITABLY IN THE BACK PLAYING
ON THEIR PHONE AND HOW DO YOU
ADDRESS THAT?
AND HOW CAN YOU MIMIC WHAT
THEY'RE FEELING IN THEIR WHOLE
ECOSYSTEM AS THEY RESPOND TO
THINGS?
WE DON'T HAVE GOOD TOOLS.
RIGHT NOW, YOU KNOW, WHEN WE
THINK ABOUT PAIN, WE'RE STILL ON
THE NUMERIC RATING SCALE SCORE,
OH, WHAT'S YOUR PAIN?
ONE THROUGH TEN.
THERE'S MULTIPLE REASONS WHY
THIS IS INEFFECTIVE.
THIS HAS BEEN SHOWN TO IRCHTD
DIFFERENT MEN AND WOMEN, IT
DEPENDS ON WHO ASKS THE
QUESTION.
OLDER PEOPLE ARE RELUCTANT TO
GIVE HIGHER PAIN SCALES BECAUSE
THEY THINK, YOU KNOW, THEIR
MORBIDITY AND MORTALITY IS
ASSOCIATED WITH IT.
SO THEN WE HAVE A WHOLE BATTERY
OF SUBJECTIVE TESTS THAT WE USE,
AND THIS GIVES US AN IDEA, AND
WE'VE BEEN ABLE TO DO SOME FUN
THINGS WITH PREDICTING OUTCOMES
WITH MACHINE LEARNING, BUT IT'S
STILL ASKING THE PATIENTS
SUBJECTIVELY HOW THEY'RE
FEELING.
WHEN DR. GARFUNKLE SPOKE EARLIER
TOO, YOU KNOW, WHEN SHE TALKED
ABOUT HOW PRECISION GOES UP AND
THEN AWARENESS GOES DOWN, WE'VE
PLAYED AROUND WITH SOME OF THE
INTEROCEPTION SCALES TOO IN OUR
PATIENTS, AND IT IS INTERESTING
BECAUSE ASPECTS OF INTEROCEPTION
CAN BE VERY HELPFUL.
BUT THEN IF YOU GET
HYPER-FOCUSED ON THINGS, IT CAN
REALLY BE TO YOUR DETRIMENT AS
WELL.
SO, YOU KNOW, THESE ARE THINGS
THAT WE ALL HAVE TO CONSIDER
WHEN WE'RE LOOKING AT THIS.
SO IN TERMS OF OBJECTIVE
MARKERS, STILL SO LIMITED,
FUNCTIONAL IMAGING, WE'VE
STARTED IN SPINAL CORD
STIMULATION TO AT LEAST BE ABLE
TO KNOW THAT WHAT WE'RE
DELIVERING TO RELIEVE PAIN IS
HITTING THE TARGET.
JUST SIMPLE PHYSIOLOGY, WE'RE
DELIVERING A STIMULUS AND WE
HAVE THIS CHANGE IN ACTION
POTENTIAL THAT YOU SEE ON THE
RIGHT SIDE.
THAT TELLS ME THAT I'M GETTING
THE STIMULUS THERE, DOESN'T SAY
A THING ABOUT PAIN RELIEF, BUT
AT LEAST I KNOW THAT I'M
DELIVERING SOMETHING.
SO HOW CAN WE KNOW HOW THIS CAN
AFFECT PAIN RELIEF?
SO I HAVE, WE'RE FORTUNATE
ENOUGH THAT WHEN I STARTED
PRACTICE, I MADE A GOOD DECISION
AND STARTED A DATABASE OF ALL
THE PATIENTS I HAD I AM
IMPLANTED WITH THESE DEVICES AND
DID MULTIARE -- MULTIPLE
BATTERIES, BEFORE SURGERY, THREE
MONTHS, SIX MONTHS, NINE MONTHS,
TWELVE MONTHS, SO ON.
WE HAVE SUBJECTIVE DATA AND
STARTED LOOKING AT OBJECTIVE
DATA.
HIGH RESOLUTION G, WE WERE ALSO
FORTUNATE TO WORK WITH A HIGH
RESOLUTION SPINAL CORD
STIMULATION PANEL AND THEN WE
TRACK OUTCOMES USING THOSE
PROSPECTIVELY AND LONGITUDINALLY
TO SEE IF WE COULD MAKE ANY
PREDICTIONS ABOUT WHAT PEOPLE
ARE FEELING.
SO ROUTINELY WHEN I ROUTINE
THESE SURGERIES I USE
INTRAOPERATIVE MONITORING AND
WHAT WE DO IS ONE THIS CAN BE
USED FOR SAFETY BUT TWO THIS CAN
ALSO BE USED TO DELIVER SIGNAL
TO THE EPIDURAL SPACE, HERE IS
OUR HIGH RESOLUTION PANEL EIGHT
COLUMNS, MEDIAL LATERALLY,
GENERALLY WE PUT THESE IN THE
THORACIC LEVEL, AND WE CAN SAY,
OKAY, WE'RE GOING TO STIMULATE
THROUGH THAT.
DO WE GET A RESPONSE THAT
CORRESPONDS WITH THE DERMATOME
WHERE THE PATIENT HAS PAIN?
WE ALSO PUT A SWIM CAP ON THAT'S
HIGH RESOLUTION EEG AND THE IDEA
HERE IS WE'RE TIME STAMPING THAT
RESPONSE IN THE SPINAL CORD TO
WHAT'S GOING ON IN THE BRAIN.
THERE'S A TON OF DATA THAT WE
GET.
DR. COLEMAN PRESENTED EARLIER,
AND HE KIND OF BREEZED THROUGH
ALL THE STUFF THAT HE WAS DOING,
AND I WAS JUST GOING, OH, MY
GOSH, THAT'S SO MUCH DATA AND
THAT'S SO MUCH WORK JUST IT EVEN
GET THE DATA POINTS BECAUSE
EVERY TIME YOU STIMULATE WITH AN
ELECTRIC ELECTRICAL DEVICE, YOU
KNOW WHAT HAPPENS, A TON OF
ARTIFACT COMES OUT AND ONE OF
THE HARDEST PARTS IN THIS FIELD
IS KNOWING HOW TO FILTER THIS
AND HOW TO PROCESS THIS, AND YOU
WANT TO GET RID OF THE ARTIFACT
BUT YOU DON'T WANT TO LOSE THE
IMPORTANT PARTS OF THE SIGNAL.
YOU WANT TO BE ABLE TO VISUALIZE
THIS SO YOU CAN SEE HOW MUCH
DATA YOU'RE DEALING WITH.
SO WHAT WE'VE DONE IS CREATED
GRAPHICAL USER INTERFACES, GONE
THROUGH AND LOOKED AT A VARIETY
OF DIFFERENT PROCESSING
TECHNIQUES TO GET WHERE WE
NEEDED TO GO.
SO THIS IS AN EXAMPLE OF US
LOOKING AT A MAXIMUM ROOT MEAN
SQUARE.
WE HAD THE ROUTINE DEVICES THAT
WE IMPLANT FOR SPINAL CORD
STIMULATION AND THIS HIGH
RESOLUTION PADDLE.
WHY I WANT TO SHOW YOU THIS, IF
WE LOOK AT T6 AND LOOK AT THE
HIGH RESOLUTION PADDLE, IT HAD
EIGHT CONTACTS, COMMERCIAL
PADDLE ONLY HAS ABOUT FOUR
CONTACTS OR FOUR CLUSMS THAT
WE'RE LOOKING -- COLUMN THAT
WE'RE LOOKING AT, WE ARE ABLE ON
THE Y AXIS TO SEE ALL THOSE
INDIVIDUAL MUSCLE GROUPS THAT
WE'RE STIMULATING WITH THIS
DEVICE.
NOW, WHY IS THIS IMPORTANT?
JUST AS THE BRAIN HAS A
MEMUNCULUS WHEN YOU THINK ABOUT
THE CORTEX, I WOULD ARGUE THAT
THE SPINAL CORD DOES TOO, EXCEPT
THERE ARE SO MANY LEVELS OF IT,
IT VARIES FROM PLACE TO PLACE.
AND UNLESS WE START LOOKING AND
DEVELOPING TOOLS IN ORDER TO DO
THIS, IT WILL BE REALLY HARD TO
UNDERSTAND THE SOMATIC PATHWAYS
AND THE ROLE IN INTEROCEPTION AS
WELL AS OTHER THINGS, YOU KNOW,
SPINAL CORD STIMULATION IS ALSO
USED FOR SPINAL CORD INJURY.
HOWEVER, THAT HAS A DRAMATIC EE
IF HE CAN ON THE AUTONOMIC
SYSTEM, HOW ARE WE GOING TO KNOW
WHAT TO DO THERE?
SO THIS IS REALLY IMPORTANT.
SIMULTANEOUSLY, WE LOOKED AT
THIS HIGH RESOLUTION EEG.
SO THE DATA ON THE RIGHT IS
ACTUALLY FROM PATIENTS WHERE WE
DID THIS PREOP -- AND THEN AT
THREE MONTHS POSTOP S IN THE
BRAIN, DIFFERENT REGIONS, WE
CAN'T WITH EEG LOOK AT THE
INSULA OR THALAMUS BUT WE CAN
LOOK AT MULTIPLE CORTICAL
REGIONS, THIS IS LOOKING AT THE
SOMATOSENSORY CORTEX.
AT THE BOTTOM OF THE RIGHT-HAND
SIDE OF THE SLIDE WE SEE
NONRESPONDERS THOSE AT THREE
MONTHS THAT DON'T HAVE RELIEF OF
THEIR PAIN HAVE SIMILAR SENSORY
DISTRIBUTION FROM PRE AND POSTOP
IN SOMATOSENSORY CORTEX, YOU SEE
THE DIFFERENCES BETWEEN THE
PURPLE AND GREEN LINE ON THE TOP
FOR THE RESPONDERS.
SO THIS IS EXCITING BECAUSE THIS
IS ACTUALLY CORRELATING WITH A
RESPONSE, AS OPPOSED TO SOME OF
THE THINGS THAT ARE DONE WITH
ECAP THAT ARE JUST TELLING YOU
THAT THE SIGNAL IS GETTING HERE.
NOW WE'RE STARLGT TO HAVE
ELECTROPHYSIOLOGICAL RESPONSES
THAT CORRELATE WITH PAIN RELIEF
AND HOW ALL THE PATHWAYS WORK
TOGETHER.
SO I JUST WANTED TO TOUCH UPON,
YOU KNOW, I TALKED ABOUT SPIEBL
CORD STIMULATION -- SPINAL CORD
STIMULATION.
I LIKE ARDEM AND EXTREMELY
EXCITED ABOUT THE DORSAL ROOT
GANGLIA AS WELL.
WE HAVE DEVICES AVAILABLE IN THE
CLINIC FDA APPROVED WHERE WE
IMPLANT PATIENTS WITH
STIMULATORS ON THE DORSAL ROOT
GANGLION, THESE ARE THE LEADS
THAT GO OUT ON THE X-RAY THROUGH
THE FORAMEN.
THESE ARE A LITTLE BIT OF
CHALLENGE FOR SURGEONS TO PUT IN
JUST BECAUSE SOMETIMES WE CAN'T
VISUALIZE THE ANATOMY.
BUT WHY DID I KEEP DOING THIS?
THE PATIENTS WERE DOING
REMARKABLY WELL.
SO THIS WAS GREAT FOR
DERMATOMES, RIGHT?
SO YOU'RE ONLY GOING TO BE ABLE
TO TARGET CERTAIN DERMATOMES
WITH THIS THERAPY.
BUT WE HAVE THIS BARRIER TO USE
BECAUSE IT'S REALLY HARD TO DO.
SO ELECTRICAL STIMULATION IS NOT
THE ONLY WAY TO MODULATE THIS.
WHAT WE STARTED WORKING ON AS
PART OF THE BLUEPRINT PROJECT
WAS FOCUSED ULTRASOUND DEVICE
TARGETING THE DORSAL ROOT
GANGLION IN ORDER TO MIMIC WHAT
WE WERE SEEING IN DERMATOMAL
PAIN.
SO WHAT WE DID WAS IN SWINE, WE
TOOK A MODEL WHERE, YOU KNOW,
THE WE DID BEHAVIORAL TESTING,
CREATED A LESION TYING OFF THE
COMMON PERONEAL NERVE, DID SOME
MORE BEHAVIORAL TESTING AND THEN
CAN A THREE-MINUTE TREATMENT
WITH THIS FOCUSED URLT SOUND
DEVICE TO -- ULTRASOUND DEVICE
TO NEURO MODULATE THE TISSUE.
WE WERE ABLE TO SEE A VARIETY OF
THINGS D A VARIETY OF RAT WORK
BEFORE WE GOT HERE WITH CAUDAL
AND DISTAL CHANGES IN PATHWAYS,
BUT, YOU KNOW, SOMETIMES A
PICTURE IS WORTH 1,000 WORDS.
SO I JUST WANTED TO TALK A
LITTLE BIT ABOUT THE VALUE OF
LARGE ANIMAL MODEL INSIDE THIS
SPACE.
I THINK IT CAN BE REALLY
IMPORTANT.
THIS IS OUR PIG WHEN WE WERE
JUST GETTING USED TO DOING THE
LIGATION MODEL. SO WE PULLED A
LITTLE TOO TIGHT AND GAVE HIM A
LITTLE BIT OF A FOOT DROP THERE,
BUT AGAIN, ONE THREE-MINUTE
DPREEMENT WE CHANGED A LOT OF
THINGS.
ONE THING THAT'S NEAT ABOUT PIGS
IS THEY MIMIC SOME HUMAN
BEHAVIOR.
SO THEY GUARD.
LIKE WHEN YOU HAVE, YOU HURT
YOUR ARM AND YOU DON'T WANT
SOMEBODY TO BUMP INTO T YOU GO
LIKE THIS.
PIGS WILL DO THE SAME THING.
THIS TREATMENT STOPPED THEM FROM
GUARDING.
SO HERE IS HIM AFTER.
AND WE LOOK FORWARD IN THIS
STAGE OF BLUEPRINT TO GETTING
THIS TO HUSM STUDIES.
-- TO HUMAN STUDIES.
SO AGAIN, I KNOW I'M TOTALLY
BIASED, BUT INTEROCEPTION AND
CHRONIC PAIN, YOU KNOW, ARE SO
RELATED, AND WE NEED TO ANSWER A
LOT OF THE QUESTIONS IN ORDER TO
SUCCESSFULLY TREAT THESE
PATIENTS.
WE NEED TO DEVELOP BETTER TOOLS
TO DO THIS.
LARGE ANIMAL MODELS AS WELL AS
HUMANS ARE IMPORTANT.
AND IF YOU NEED TO CHANGE
ANYTHING ABOUT YOUR OWN
INTEROCEPTION, YOU KNOW, NOW AND
ACUTELY, SOME OF THOSE BREATHING
EXERCISES OR MINDFULNESS-BASED
THERAPIES ARE THE WAY TO DO THAT
NOW.
I HAVE A LARGE TEAM, A BIG
THANKS TO DR. QUINTERO WHO IS IN
THE AUDIENCE AND HAD A POSTER
TOAD AS WELL AS A NUMBER OF MY
TEAM MEMBERS.
IF YOU WANT TO LEARN MORE ABOUT
HOW PAIN AND THE HUMAN SYSTEM
INTERACT BETWEEN DID I NITIONS,
SCIENTISTS AND ENGINEERS --
BETWEEN CLINICIANS, SCIENTISTS
AND ENGINEERS.
THANK YOU VERY MUCH.
>> WE HAVE TIME FOR ONE
QUESTION.
ALL RIGHT.
THANK YOU VERY MUCH AGAIN,
JULIE.
>> THANK YOU.
>> HEY, EVERYBODY, THANKS.
IT'S A GREAT PLEASURE TO BE HERE
AND HONOR TO BE PART OF THIS
MEETING.
THIS TALK IS GOING TO BE A DATA
LIGHT TALK EXPIT COMING TO
TRACTION.
SO I'LL TELL YOU WHAT THAT MEANS
IT A SECOND.
SO I'M UP HERE REPRESENTING A
TEAM OF PEOPLE.
ON THIS SLIDE ARE SHOWN PI'S OF
THE GRANT AND THE STUDY I'LL
TALK B RESEARCH EVALUATING VAGAL
EXCITATION AND ANATOMICAL LINKS
IN HUMANS, REVEAL STUDY.
MYSELF, Z I AD NAHAS OVER HERE
FROM THE DCHT PSYCHIATRY
BEHAVIORAL SCIENCES, HUBERT LIM,
SAYEED IKRAMUDDIN, LYNN EBERLY,
VAUGHAN MACEFIELD.
THIS STUDY FUNDED BY NIH, VAGAL
RESEARCH AND GET TO
INTEROCEPTION IN A SECOND.
THIS IS WHERE IT STARTED
DECEMBER 2021.
THERE WAS A FUNDING OPPORTUNITY
ANNOUNCEMENT, CALLED VESPA, VNS
ENDPOINTS FROM STANDARDIZED
PROGRAM TERDZ, WHICH IS
OBVIOUSLY VESPA RED ON THE LEFT
AND ITALIAN FOR WATCH ON THE
RIGHT.
HERE IS WHAT PUT OUT A STUDY TO
DO.
THE PURPOSE OF THE FOA IS TO
SOLICIT APPLICATIONS FOR A U54
RESEARCH CENTER, TO CONDUCT A
LARGE MULTISITE CLINICAL STUDY
OF THE MULTIORGAN EFFECT OF
VAGUS NERVE STIMULATION, AS MANY
ORGAN SYSTEMS AS YOU CAN ENGAGE
WITH VAGAL STIMULATION IN
RESPONSE TO STANDARDIZED RANGE
OF PARAMETERS.
DATA WILL BE SHARED PUBLICLY FOR
EVERYONE TO GET WHEN WE'RE DONE
AND TO INFORM HOW TO OPTIMIZE
VAGAL NERVE STIMULATION FOR THE
TREATMENT OF A VARIETY OF
THINGS, RIGHT?
AND THEN LOOK AT HOW IT AFFECTS
SYSTEMS PHYSIOLOGY AND THE
FUNCTIONAL CONNECTIVITY OF THE
VAGUS NERVE.
I'M UP HERE BECAUSE THANK GOD WE
WERE AWARDED THIS GRANT TO MOVE
AHEAD, AND I'M GOING TO GIVE YOU
AN OVERVIEW WHAT THE STUDY IS
ABOUT AND THEN MOVE INTO WHAT
THE INTEROCEPTION ASPECT IS IN A
SECOND.
SO BASICALLY, RIGHT NOW THESE
RIM PLANTED FOR
TREATMENT-RESISTANT DEPRESSION
AND DRUG-RESISTANT EPILEPSY IN
PATIENTS, AND THE IDEA IS WE'LL
HAVE 144 PARTICIPANTS WITH LEFT
VAGUS NERVE IMPLANTEDDED, WHICH
IS WHERE IT'S IMPLANTED FOR
DEPRESSION AND EPILEPSY, 96 OF
THOSE NEWLY IMPLANTED AND
REMAINDER WOULD BE PREVIOUSLY
IMPLANTED.
THE IDEA IS TO MEASURE
PHYSIOLOGIC RESPONSES TO VAGAL
STIMULATION.
THIS IS THE THING, NOBODY HAS
MEASURED IN HUMANS WHAT IT'S
DOING TO THE BODY'S SYSTEMS EVEN
THOUGH WE ARE DOING THINGS ON
THE BRAIN, NOT TO THE BODY.
SO IN THIS CONSTITUTED CAN I
WE'LL -- IN THIS STUDY WE'LL
MEASURE WILL MRS. RESPONSES TO
HUMANS H HAD VAGAL NERVE
STIMULATION WILL CHANGE
AUTONOMIC NERVOUS SYSTEM ON THE
TOP, IMPACTS OTHER SYSTEMS,
IMMUNE, CARDIOVASCULAR,
METABOLIC, WE'LL LOOK AT
SHORT-TERM RESPONSES AND
LONG-TERM RESPONSES.
THERE'S SOME ANCILLARY PROJECTS
WHICH I WON'T HAVE TIME TO GET
INTO.
SO UNIVERSITY OF MINNESOTA IS
THE BASE FOR THSM THE CLINICAL
CO-DIRECTORS, Z I AD I ALREADY
MENTIONED AND HUBERT LIM AND TOM
HENRY WHO IS AN EPILEPTOLOGIST
RUN THE CLINICAL CORE, ALSO SIX
PARTNER SITES TO DO THIS STUDY
SHOWN HERE.
MEDICAL UNIVERSITY OF SOUTH
CAROLINA WITH MARK GEORGE, HIM
AND ZI AD DID VIRS I AM
PLABILITY FOR DEPRESSION, NOLAN
WILLIAMS, CHUCK CONWAY, TERRY
O'BRIEN AND VAUGHAN, MAYO CLINIC
90 MILES DOWN THE ROAD FROM US
WITH GLEG AND SARA AND
SHEPPARD PRATT IN BALTIMORE FOR
TREATING DEPRESSION.
SEVEN SITES.
I'LL SUMMARIZE BRIEFLY WHAT
WE'RE GOING TO DO IN THESE
SUBJECTS, IF YOU LOOK AT THE
TOP, COMMON STUDY PROTOCOLS,
CSP, THESE WOULD BE SUBJECTS
THAT ARE ALREADY IMPLANTED FOR
JUST SIMPLICITY, OKAY?
ONCE THEY'RE CONSENTED, THE
DEVICE, SO THE DEVICE HAS BEEN
ON, IT'S TURNED OFF FOR TWO TO
THREE WEEKS, WHICH IS SAFE
BECAUSE IT TAKES A LONG TIME TO
BE EFFECTIVE, IT TAKES A LONG
TIME TO WEAR OFF.
SO WE'LL GET A BASELINE AND THEN
THEY HAVE 24-HOUR AMBULATORY
BLOOD PRESSURE AND ECG, THEN
THEY COME TO ONE OF THREE SITES
THAT I'LL TALK ABOUT FOR STUDY
VISIT ONE.
THIS IS THE DAY WHERE THEY COME
IN TO MEASURE ACUTE RESPONSES TO
VAGAL NERVE STIMULATION IN THE
CLINIC.
THEN THEY WILL HAVE THE DEVICE
SET AT A RANDOMIZED SETTING G
AWAY FOR THREE MONTHS, COME BACK
AND DO IT AGAIN, AND THAT'S
STUDY VISIT TWO.
OKAY?
SO ACUTE AND CHRONIC RESPONSES.
THE BOTTOM ARE NEWLY IMPLANTED
BUT IT'S BASIC THE SAME STUDY
DESIGN.
SO WHAT DO THESE STUDY VISIT
LOOK LIKE?
THESE ARE, WE HAVE THREE SITES
THAT ARE DOING THESE ACUTE
STUDIES IN THE LABORATORY.
UNIVERSITY OF MINNESOTA, MONASH
AND MAYO CLINIC.
ONE DAY, VAUGHAN CAME IN, WORKED
OUT THE PROTOCOL WITH SARA --
AND THEY'RE SHOWN MEASURING THE
SUBJECT, MEASURING VARIABLES
DURING VAGAL STIMULATION.
WE'RE MEASURING ONE OF THE KEY
VARIABLES IS MUSCLE SYMPATHETIC
NERVE ACTIVITY.
IF I DW BACK, YOU SEE AN
ELECTROPLACED IN THE PERONEAL
NERVE, BASE OF THE KNEE THERE,
ON THE TOP YOU SEE ECG, BLOOD
PRESSURE, RESPIRATION AND THAT
BLUE IS MUSCLE SYMPATHETIC NERVE
ACTIVITY DIRECT MEASUREMENT IN
HUMAN.
THE REASON THIS IS IMPORTANT IS
IF THAT RESPONDS IN ANY WAY TO
VAGAL STIMULATION, THAT MEANS
YOU STIMULATED THE AFER TOANS
THE BRAIN WHICH REFLEX ALLY
AFFECTS, THAT'S SYMPATHETIC
NERVE.
DIRECT MEASUREMENT.
WE KNOW IF IT RESPONDS, WE HAD
TO GO UP THROUGH THE REFLEX
PATHWAYS IN THE BRAIN TO GET A
RESPONSE.
SO THE PATIENT IS -- THE
PARTICIPANT IS INSTRUMENTED FOR
IS THAT, THIS IS THE MORNING OF
THE STUDY.
BASICALLY THEY'RE LAYING ON THE
TABLE, YOU MEASURE THE RESPONSE
OF BASAL BLOOD PRESSURE, HEART
RATE, ECG, SYMPATHETIC ACTIVITY
TO DIFFERENT STIMULUS
PARAMETERS.
THREE SETTINGS, IN BETWEEN THOSE
YOU GET A BLOOD SAMPLE, AND THEN
THE LAST PART SAYS CHRONIC
SETTING ANS REFLEX TESTING, WE
DO SOME REFLEXES TO ENGAGE THE
AUTONOMIC NERVE SYSTEM AND SEE
WHAT VAGAL NERVE STIM
STIMULATION DOES TO THAT AND
THERE'S AN ECHOCARDIOGRAPHY DONE
IN THE AFTERNOON.
REFLEX TESTING, TILT TABLE TEST,
COMMON AM DONE WHEN YOU GO
FROM -- COMMONLY DONE WHEN YOU
GO FROM SUPINE TO UPRATE,
ACTIVATE THE VAGAL NERVOUS
SYSTEM.
COUPLE OTHERS AS WELL.
I'LL GET TO INTEROCEPTION PRETTY
QUICK HERE.
JUST TO MENTION THE DATA
ANALYSIS THAT'S SHOWN HERE, WE
HAVE FOUR SYSTEMS WE'RE
STUDYING, AUTONOMIC NICK ON THE
LEFT, CARDIOVASCULAR, IMMUNE AND
METABOLIC.
FIRST LAYER IS THE
STRAIGHTFORWARD THINGS YOU WOULD
MEASURE IN A SUBJECT.
BLOOVMENT MUSCLE SAME PATHETIC
NERVE ACTIVITY.
HEART RATE.
IMMUNE SYSTEM STANDARD CYTOKINE
PANEL FOR EXAMPLE.
METABOLIC, HEE GLOW BIN A1C.
THEN WE GO DOWN TO DIFFERENT
LAYERS WHICH ARE MUCH MORE
COMPLICATED ANALYSIS.
FOR EXAMPLE, WITH METABOLIC WE
GET INTO METABOLOMICS, WE GET
INTO ALL THE OMICS.
FOR IMMUNE SYSTEM AND METABOLIC
SYSTEM SO WE CAN LOOK AT HOW
THESE VARIABLES RESPOND.
AND THEN JUST TO MAKE THAT
POINT, THOSE ARE DONE THROUGH
THE BLOOD SAMPLING WE GET AND
THESE ARE THE INVESTIGATORS AT
MINNESOTA THAT RUN THE IMMUNE
SYSTEM AS ASSAYS AND THEN --
ASSAYS AND THEN PETER CRAWFORD
DOING THE METABOLIC SYSTEM.
THAT'S THE STUDY, WE'RE ABOUT TO
ENROLL THE FIRST PARTICIPANT.
WE'RE INTO YEAR ONE, WE'RE ABOUT
READY TO GET STARTED.
SO THAT'S WHY I SAID THIS IS
LIKE COMING TO TRACTION.
NOW WHAT ABOUT INTEROCEPTION?
SO ZI AD WHO IS HERE AND I'M UP
HERE SPEAKING FOR HIM, AS A
SUPPLEMENT FOR THIS STUDY, TO
LOOK AT THE EFFECTS OF VNS ON
CENTRAL AUTONOMIC NETWORK AND
INTEROCEPTION, HOW GREAT WOULD
IT BE IN THE SAME SUBJECT TO
MEASURE WHAT'S HAPPENING IN THE
BODY AND WHAT'S HAPPENING IN THE
BRAIN, PUT IT ALL TOGETHER AS WE
TALKED ABOUT THIS MORNING THAT
WOULD BE IDEALLY WHAT WOULD
HAPPEN.
THIS NICE DIAGRAM HERE OF THE
ENTEROSEPTION NETWORK FROM
REVIEW BY LANG I PUTTER UP HERE
TO MAKE NOINLT.
AS YOU ALL KNOW, THE VAGUS NERVE
IS 80% AFFERENT FIBERS TO THE
BRAIN 20RBGS% OUT TO THE BODY.
-- 20% OUT TO THE BODY. SO IF
YOU HAVE AN ELECTRODE ON YOUR
VAGUS NERVE YOU'RE OBVIOUSLY
ACTIVATING A LOT OF AFFERENT
ACTIVITY TO THE BRAIN, USED FOR
ADDICTION SHES EPILEPSY, OTHER
THINGS, ALSO GOING OUT TO THE
ORGANS.
PART OF THE STHING TO DO BOTH.
THE IDEA SO DO BRAIN IMAGING AND
LOOK WHAT'S HAPPENING, I'LL GO
INTO THAT FOR A LITTLE BIT.
SO THIS IS A PAPER OF ZI -- THIS
IS A PAPER OF ZIAD FROM 2007,
FMRI IN PARTICIPANTS DURING
VAGAL NERVE STIMULATION.
ON THE RIGHT YOU SEE SHOWING
RESPONSES IN THE INSULA, AND
THAT IS THE CORRELATION AND I'LL
SHOW THAT IN A MINUTE, THE
ACTIVATION OF THAT AREA
CORRESPONDS TO THE RATING FOR
DEPRESSION FOR THAT PARTICULAR
PARTICIPANT.
BOTTOM RIGHT IS SOMATOSENSORY
CORTEX SHOWING IT CREASES HE
WITH INTENSITY, WHICH SHOWS YOU
IT'S AN INTERNAL CONTROL.
INCREASES.
ON THE LEFT IS THAT THESE
RESPONSES DECREASE OVER TIME.
SO THAT WAS 2007.
AND THIS IS DATA FROM THAT PAPER
AGAIN.
SO WHAT I WANT YOU TO SEE ON THE
RIGHT-HAND SIDE FOR THE RIGHT
INSULA BEGINNING AT WEEK ZERO
AFTER IMPLANTATION THE INITIAL
RESPONSE IS ACTIVATION OF THE
RIGHT INSULA.
YOU GO OUT TO 120 WEEKS.
WHEN YOU GET OUT TO ABOUT 32,
33, ABOUT EIGHT MONTHS, YOU GO
FROM ACTIVATE THAT GO TO
DEACTIVATING IT, SO OVER TIME
YOU SEE GOING FROM ACTIVATION
GOING TO DEACTIVATION.
SAME THING IN THE RIGHT MIDDLE
FRONTAL CORTEX.
SHOWS CORRELATION BETWEEN
HAMILTON DEPRESSION RATING SCORE
AND THAT ACTIVATION AND THE
SPOINT YOU SEE THAT GOING TO THE
LEFT WOULD BE LESS DEPRESSION
CORRELATED TO THAT LESS
ACTIVATION.
SO IN OTHER WORDS, THOSE PRAP ON
THE BOTTOM INDICATE OVER TIME
YOU'RE TREEG THE DEPRESSION BY
SEEING THESE TIME-DEPENDENT
CHANGES IN THIS REGION.
SO THAT WAS 2007.
SO NOW WHAT THE GOAL IS WITH THE
SUPPLEMENT THAT ZI AD IS GOING
TO RUN IN SOME OF THESE
PARTICIPANTS OF OUR STUDY IS TO
FIRST LOOK AT THE EFFECTS OF VNS
ON THE INTEROCEPTION NETWORK
USING RELATED VNS MRI SO BEING
ABLE TO LOOK AT WHAT'S HAPPENING
IN THE BRAIN WHILE THE DEVICE IS
ON, THAT'S NUMBER ONE.
THE SECOND TO LOOK HOW CHRONIC
VNS CHANGES THE DYNAMIC CHANGES
IN A LARGE-SCALE IN THE
FUNCTIONAL NETWORK AND HOW
THAT'S CORRELATED TO THESE
CHANGES IN AUTO NICK AND
CARDIOVASCULAR -- AUTONOMIC AND
CARDIOVASCULAR ACTIVITY WE
TALKED ABOUT. SO BASIC IS
PROACH IS -- BASIC APPROACH IS
SHOWN HERE, PROTOCOL I 140ED
EARLY EARLIER BUT ON THE LEFT IN
THE RED WE'LL GET A RESTING
STATE FMRI BEFORE THE DEVICE
GOES IN, THEY GO THROUGH THE
PROTOCOL WE'RE RUNNING AND YOU
GET TO THAT STUDY VISIT ONE
WE'LL DO BRAIN IMAGING IN THEM
AND THEN LOOK AT THE FMRI AS
WELL TO LOOK AT WHAT'S HAPPENING
IN VNS IN THE MOMENT.
THEY COME BACK AFTER A FEW WEEKS
AND WE DO THAT AGAIN AND GET
ANOTHER RESTING STATE FMRI.
SO IN 25 PARTICIPANTS OUT OF
THIS 144, THE GOAL IS TO DO
SIMULTANEOUS BRAIN IMAGING AND
MEASURING THESE OTHER RESPONSES
SO WE CAN LOOK AT NOT ONLY
AUTONOMIC, WHICH IS OBVIOUSLY
GOING TO CHANGE, BUT THE
ENTEROACCEPTTIVE NETWORK AS
WELL.
SO THAT'S THE OVERALL GOAL.
SO I THINK THE IDEA OF THE
PRESENTATION HERE IS TO LET THE
COMMUNITY KNOW THAT WE'RE ABOUT
TO EMBARK ON THIS STUDY, WHICH
IS VERY EXCITING SO STAY TUNED
FOR RESULTS FROM THAT.
THIS IS A LARGE, GLOBAL STUDY.
WE'RE ABOUT TO START.
WE HAVE TWO YEARS TO DO THIS.
SO STAY TUNED AND WE'LL COME
BACK HOPEFULLY WITH THE RESULTS
TO COME.
THANK YOU.
>> THANK YOU, JOHN.
QUESTION?
>> GREAT TALK.
I'M FROM THE UNIVERSITY OF SOUTH
FLORIDA.
SO WHAT I WANTED TO ASK IS, YOU
KNOW, FOR SOME OF US WHO HAVE
STUDIED VAGAL NEUROPHYSIOLOGY
FOR SOME TIME, WE'RE ASTONISHED
BY VAGAL NERVE STIMULATION
DOESN'T DO THE THINGS WE THINK
IT SHOULD DO.
SO IN TERMS OF, ARE YOU GOING TO
ASK THE PARTICIPATE WHANTS THEY
FEEL -- PARTICIPANTS WHAT THEY
FEEL AS WELL?
LIKE DO THEY FEEL SCRATCHY,
COUGHY, FULL?
YOU KNOW, ORGAN SENSATION?
ARE YOU GOING TO DO THAT?
>> DURING THE ACUTE
MEASUREMENTS?
>> THE THE THREE MONTHS,
OBVIOUSLY.
>> SURE.
YES, WE ARE.
YEAH, I FORGOT TO MENTION AS
WELL, AND I APPRECIATE, ONE OF
THE ANCILLARY STUDIES VAUGHN
MACEFIELD IS GOING TO MEASURE
DIRECTLY FROM THE VAGUS NERVE
DURING THE VAGAL NERVE
STIMULATION TO CHARACTERIZE
DIFFERENT FIBER TYPES, THOSE
KINDS OF THINGS.
BUT TO WHAT YOU'RE SAYING, THAT
WILL OBVIOUSLY COME UP, RIGHT,
DURING THE ACUTE.
BUT KEEP IN MIND THAT THE COMMON
STUDY PROTOCOL ARE THE CLINICAL
PARAMETERS THAT ARE TYPICALLY
USED, RIGHT?
SO I MEAN, THAT'S OUT THERE
ALREADY, I'M SURE.
BUT WE CAN LOOK INTO THAT
DETAIL.
>> THANKS.
>> YEAH.
>> THANKS VERY MUCH, JOHN.
NEXT UP IS RUI CHANG.
>> FIRST I WANT TO THANK THE
WHOLE COMMITTEE FOR THIS
FANTASTIC MEETING, IT'S AMAZING,
AND ALSO FOR GIVING ME THIS
WONDERFUL OPPORTUNITY TO PRESENT
OUR RESEARCH AMONG SO MANY
GIANTS IN THE FIELD.
I REALLY FEEL LIKE VERY EXCITED.
SO MY LAB IS INTERESTED IN THE
INTERACTIONS BETWEEN THE
VISCERAL ORGANS AND HOW THIS
INTERACTION REGULATES OUR
PHYSIOLOGY AND BEHAVIORS.
TODAY I'LL SHARE WITH YOU SOME
OF OUR RESULTS ABOUT THE CODING
LOWJ I CAN OF INTEROCEPTION
AND -- LODGE I GO.
USING MOUSE AS MODEL AND
HOPEFULLY OUR WORK IN THE BASIC
SCIENCE CAN BE TRANSLATED TO
HUMAN SOMEDAY NOT FAR RNTLE.
NOT FAR.
SO INTEROCEPTION IS CRITICAL FOR
OUR SURVIVAL AND WE ARE ACTUALLY
VERY GOOD AT THIS.
FOR EXAMPLE, WE CAN DETECT --
EVERY SINGLY HEARTBEAT AND
PROVIDE -- FOR COLLEAGUES, WE
KNOW MEEZ YAITD BY THE CHANNELS.
WE CAN CONSTANTLY SENSE THESE
CONTENTS, OR INGESTED MATERIALS
LIKE NUTRIENTS AND TOXINS, AS
WELL AS RELEASE CHEMICALS LIKE
HORMONES AND SIGNALS, AND
SENSING THESE SIGNALS WILL HELP
US MAINTAIN PHYSIOLOGICAL
HOMOEOSTASIS, PROVIDE
MOTIVATIONAL -- AND EVEN SHAPE
OUR THOUGHTS AND EMOTIONS.
SO MANY OF THESE INTERNAL
VISCERAL ORGAN SIGNALS ARE
COMMUNICATED TO THE BRAIN VIA
THE VAGUS NERVE, WHICH IS A
MAJOR IN TERMS OF THE SYSTEM AND
CRITICAL BODY TO BRING ACCESS.
SO IN ADDITION TO IT'S VERY WELL
CHARACTERIZED AND KNOWN ROLE IN
THE PARASYMPATHETIC CONTROL OF
THE ORGANS, THE VAGUS NERVE ALSO
CONTAINS MANY SENSORY NEURONS
THAT PROVIDE EXTENSIVE
INNERVATION, THE MAJORITY OF THE
VISCERAL ORGANS INCLUDING THE
LUNG, HEART, STOMACH, INTESTINE,
LIVER, KIDNEY AND PANCREAS AND
MANY ORGANS EVEN NOT LISTED
HERE.
THESE SENSORY NEURONS CAN DETECT
NUMEROUS CHANGES WITHIN THE
VISCERAL ORGANS, AND THEY WILL
PRESENT THIS INFORMATION OUT TO
THE BRAIN.
SO NOW YOU CAN IMAGINE THAT
THESE NEURONS MUST BE VERY
COMPLEX AND HETEROGENEOUS, AND
INDEED, OVER THE PAST DECADE
ALSO, THERE ARE MANY, MANY
STUDIES FOCUSING ON THIS VERY
CRITICAL BODY-BRAIN AXIS AND HOW
THESE NEURONS CONTROL FUNCTIONS
IN THE RESPIRATORY,
CARDIOVASCULAR, DIGESTIVE,
METABOLIC, IMMUNE AND EVEN THE
COGNITIVE SYSTEMS.
AND RECENTLY, THIS NERVE IS ALSO
VERY HOT TOPIC FOR VERY MANY
NEUROLOGICAL DISORDERS INCLUDING
PEAS AS WE HEARD EARLIER THIS
DHAISH INCLUDING PARKINSON'S
DISEASE AS WE HEARD EARLIER THIS
MORNING.
RS STILL VERY LITTLE IS KNOWN
ABOUT HOW THIS NEW OWN AL
CAPACITY AND DIVERSITY ACTUALLY
FACILITATES INTEROCEPTION CODING
AT A SYSTEMS LEVEL.
SO WE KNOW THAT THESE NUMEROUS
BODY SIGNALS CAN BE VERY PRE
SIETIONLY DISTINGUISHED --
PRECISELY DISTINGUISHED IN THE
BRAIN, BUT HOW IS THIS ACHIEVED?
SO HERE WE ARE ASKING THIS
QUESTION, YOU KNOW, HOW IS THE
VAGAL INTEROCEPTION SYSTEM
ORGANIZED TO PRESENT NUMEROUS
BODY SIGNALS TO THE BRAIN IN A
VERY PRECISE AND EFFICIENT WAY?
AND TO ADDRESS THAT QUESTION, WE
FIRST NEED TO THINK ABOUT WHAT
IS IMPORTANT FOR INTEROCEPTION
SNAM?
WHAT FEATURES DOES THE BRAIN
NEED TO KNOW TO RECOGNIZE WHAT
SIGNAL IT IS?
WE THINK THERE ARE AT LEAST
THREE INDEPENDENT KEY FEATURES
THE BRAIN NEEDS TO KNOW ABOUT
THE INTEROCEPTION SIGNAL.
THE FIRST ONE IS VISCERAL ORGAN
AND WE HAVE MANY VISCERAL
RESIDUAL ORGANS AND SIGNALS FROM
DIFFERENT ORGANS CLEARLY TELLING
THE BRAIN DIFFERENT THINGS GOING
ON IN THE BODY.
SECOND SOMEONE THE TISSUE LAYER.
EVEN WITHIN THE SAME VISCERAL
ORGAN THERE ARE MANY DIFFERENT
FISH EWE COMPOSITION AND IS
DIFFERENT LAYERS OF TISSUES AND
FROM THE SAME ORGAN, THE SIGNAL
FROM THE SAME ORGAN BUT
DIFFERENT TISSUE LAYERS IS ALSO
COMIENTING DIFFERENT
PHYSIOLOGICAL CHANGES TO THE
BRAIN.
THE THIRD ONE IS STIMULUS
MODALITY WHAT, THE SIGNAL IS,
WHETHER IT'S MECHANICAL CHANGES
OR THIS IS SOME CHEMICAL SIGNAL,
FOR EXAMPLE H THE ONES SIGNALS
RELEASED DURING FOOD INTAKE.
A FAITHFUL CODING OF ALL THESE
FEATURES IN THE VAGUE AT NEURONS
IS NECESSARY FOR ACCURATE SIGNAL
DISCRIMINATION IN THE BRAIN.
TO BETTER UNDERSTAND HOW ORGANS
ARE CODED WITHIN THESE SENSORY
NEURONS WE DEVELOPED A TOOL
CALLED PROJECTION SEQ BASED ON
SINGLE CELL RNA SEQUENCING SO
THE CONCEPT IS WE ARE
INTRODUCING MULTIPLEX BARCODES
INTO THESE VIRAL TRACERS SO WE
CAN LABEL THE NEURONS THAT
PROJECT TO DIFFERENT ORGANS
SIMULTANEOUSLY IN THE SAME
ANIMAL AND WE CAN STUDY THEIR
GENETIC SIGNATURES.
SO HERE IN DESCRIBING ONE
EXPERIMENT THAT WE INJECTED
SEVEN VISCERAL MAJOR ORGANS IN
THE ANIMAL SIMULTANEOUSLY EACH
ORGAN GETS A UNIQUE BARCODE AND
THEN WE CAN TAKE OUT THESE VAGAL
SENSORY NEURONS, WE DO SINGLE
CELL RNA SEQ AND KNOW WHAT GENE
IS EXPRESSED AND BASE #-D ON THE
BARCODES THEY EXPRESS WE KNOW
WHICH ORGANS THEY PROJECT TO.
ROOTITE I'M SHOWING YOU THIS MAP
OF THE VAGAL SENSORY NEURONS AND
EACH DOT REPRESENTS A NEURON AND
COLOR CODES FOLLOW THE ORGANS
THEY INNERVATE.
EVEN FROM THIS MAP YOU CAN
CLEARLY SEE THAT THE NEURONS
ENTER VAITING DIFFERENT NEURONS
ARE LARGELY GENETICALLY
DISAGGREGATED DISH SEGREGATE.
VISCERAL ORGAN TRAJECTORY SEEMS
TO CODE THE ORGANS ALONG THE
BODY REQUEST CAUSAL AXIS.
SO ONE SIDE IS EXPLUNGZ
ESOPHAGUS -- EXPLUNGZ ESOPHAGUS,
UPPER, AND ON THE OTHER SIDE,
LIKE INTESTINAL ORG EXPANS
COLON.
9 LOCATION OF THE ORGANS IS LONG
THE BODY STRUCTURE CAUDAL AXIS
MATCHES VERY WELL WITH THE
LOCATION OF THESE NEURONS ALONG
THIS ORGAN TRAJECTORY.
SO THIS SUGGESTS THAT
DIFFERENTIAL GENE MODULES IN THE
VAGUE VAGUS NERVE ARE ACTUALLY
CODING THE LOCATION OF THE
VISCERAL ORGANS ALONG THE BODY'S
RAUSTRAL-CAUDAL AXIS AND ALSO
FOLLOWING GRADIENTS TO THEIR
TARGET ORGANS.
INTERESTINGLY IN ADDITION TO
THIS VISCERAL ORGAN TRAJECTORY,
WE FURTHER IDENTIFIED A SECOND
TRAJECTORY HERE AND ALSO WONDER
IF THE SECOND TRAJECTORY MAY
ALSO CAUSE ESSENTIAL
INFORMATION.
FOR THAT PURPOSE WE FURTHER
ANALYZED THE GENES THAT
DIFFERENTIALLY EXPRESS IN THIS
SECOND TRAJECTORY AND USE TOOLS,
MORE SPECIFICALLY CORRESPONDING
CRE MOUSE MICE TO GAIN GENETIC
TARGETS OF THESE CELLS.
USING CRE MOUSE LINES WE
INJECTED VIRUS INTO TO LABEL
CELLS NOT ONLY THEIR CELL BODIES
BUT THEIR ENTIRE PROJECTIONS
WITHIN THE BODY.
THEN FOO THESE ANIMALS WE CAN
TAKE OUT THE PARTICULAR VISCERAL
ORGANS, FOR EXAMPLE HERE I'M
SHOWING YOU THIS IS A MOUSE
HEART AND WE CAN DO TISSUE
CLEARING AND SO THAT WE CAN
IMAGE THE ENTIRE FLUORESCE ENLT
LABEL NERVE FIBERS WITHIN THE
ENTIRE ORGAN.
ON THE RIGHT I'M SHOWING YOU
THIS IS A MOUSE SENSORY
INNERVATION OF THE ENTIRE HEART,
OF THE ENTIRE MOUSE HEART AND WE
CAN FURTHER ZOOM IN TO LOOK AT
MANY DIFFERENT DETAILS SUCH AS
THEIR TERMINAL STRUCTURES.
THOUGH STRIKINGLY, WHAT WE
IDENTIFIED IS THIS SECOND
TRAJECTORY ACTUALLY CODE THE
TISSUE LAYERS.
SO NEURONS ON ONE SIDE OF THIS
TRAJECTORY WILL INNERVATE THE
SURFACE OF THE ORGAN IN MANY
DIFFERENT ORGANS, AND THE
NEURONS ON THE OTHER SIDE OF
THIS TRAJECTORY WILL INNERVATE
THE INNERMOST OF THE ORGAN CLOSE
TO THE LUMEN.
SO THIS DATA AGAIN SUGGESTS THAT
THERE'S A DIFFERENT SET OF GENE
MODULES THAT CODE THE TISSUE
WITHIN THE VAGUS NERVE.
BECAUSE THIS VISCERAL ORGAN
TRAJECTORY AND TISSUE LAYER ARE
ORTHOAGO NO, SUGGESTING TWO
DIFFERENT FEATURES ARE CODING
TWO INDEPENDENT CODING
DIMENSIONS IN THE VAGUS NERVE,
SO TOGETHER, THEY CONSTITUTE A
TWO-DIMENSIONAL GENETIC
REPRESENTATION OF THE BODY'S
INTERNAL FACE, WHICH PRECISE AM
TELL THE NEURON WHERE THE
SIGNALS COMING FROM.
NEXT WE ASK, YOU KNOW, HOW IS
THE STIMULUS CODED WITHIN THESE
NEURONS?
HOW DOES THE NEURON KNOW WHICH
STIMULUS IS DETECTING?
TO PRECISELY DETERMINE THE JECTD
IDENTITIES OF THE NEURONS
RESPOND TO GO A PARTICULAR ORGAN
CHANGE, WE DEVELOPED ANOTHER
TOOL WE CALL V CATFISH, CUPLIED
IN VIVO CALCIUM IMAGING.
IDENTIFYING NEURONS THAT RESPOND
SPECIFICALLY TO DIFFERENT ORGAN
CHALLENGES, DIFFERENT CHANGES.
THEN YOU TAKE THE GANGLION AND
THEN CUT THEM INTO SECTIONS AND
DO SPATIAL TRANSCRIPTOMICS AND
USE MATHEMATICAL APPROACH TO
REGISTER TWO DIFFERENT DATASETS
SO WE CAN PRECISELY DETERMINE
THE GENETIC SIGNATURE OF THOSE
NEURONS THAT RESPOND TO
DIFFERENT ORGAN CHALLENGES.
FOR THE SAKE OF TIME, I WON'T BE
ABLE TO RUN INTO THE TECHNICAL
DETAILS HERE, SO WHAT WE
DISCOVER IS, SO FIRST THE SINGLE
CELL DEFINE VAGAL SENSORY NEURON
POPULATIONS HAVE VERY SIMILAR
RESPONSE PATTERNS ACROSS
DIFFERENT ORGANS, SUGGESTING
THAT THEIR RESPONSE PATTERNS
STIMULUS MODALITIES AND VISCERAL
ORGANS ARE INDEPENDENTLY CODED.
FOR EXAMPLE, ON THE LEFT I'M
SHOWING YOU THIS IS ONE NEURON
TYPE THAT RESPOND TO SNRECH A
VERY SUSTAINED KINETICS IN MANY
DIFFERENT ORGANS AND THERE ARE
ALSO GENETICALLY DEFINED NEURON
TYPES THAT WILL HAVE THIS
TRANSIENT RESPONSE TO STRETCH IN
DIFFERENT ORGANS.
ON THE OTHER HAND, WE ARE ALSO
VERY SURPRISED TO SEE THAT THE
NEURON RESPONSE PATTERNS ARE
LARGELY UNCOUPLED FROM THEIR
SENSORY ENDINGS, WHICH
REPRESENTS THEIR TISSUE LAYERING
INFORMATION, SUGGESTING THAT
RESPONSE PATTERNS OR THE
STIMULUS MODALITIES ALSO CODED
INDEPENDENTLY OF THE TISSUE
LAYERS.
FOR EXAMPLE, WE HAVE NOTICED
MANY CASES THAT THE NEURONS WITH
DIFFERENT GENETIC SIGNATURES
WILL INNERVATE THE SAME ORGAN,
FORM THE SAME TYPE OF TERMINAL
STRUCTURES BUT THEY DETECT VERY
DIFFERENT SIGNALS FROM THOSE
LOCATIONS.
ON THE OTHER HAND, THE NEURONS
WITH THE SAME GENETIC
SIGNATURES, THEY SHARE THE SAME
BASICALLY VERY SIMILAR RESPONSE
PATTERNS, FOR EXAMPLE, FOR ALL
THE DETECTING STRETCH, IN
DIFFERENT -- FROM DIFFERENT
ORGANS BUT THEY FORM VERY
DIFFERENT TERMINAL STRUCTURES
WITHIN DIFFERENT ORGANS.
SO PUTTING EVERYTHING TOGETHER,
OUR STUDY SHOW THAT THREE
INDEPENDENT FEATURES TOURS OF
INTEROCEPTION SIGNAL ARE CODED
IN THREE INDEPENDENT CODING
DIMENSIONS IN THE VAGUS NERVE
AND THIS MULTIDIMENSIONAL CODING
ARCHITECTURE ACTUALLY ENABLES
THE VAGUS NERVE TO GENERATE THIS
TO EXPAND VERY EFFECTIVELY FOR
ITS DIVERSITY AND GENERATES
NUMEROUS PARALLEL STREAMS TO
PRESENT THE SIGNALS FROM THE
PERIPHERAL ORG TOONS THE BRAIN.
AND THEY BELIEVE THIS IS A
PERFECT EXAMPLE OR DEMONSTRATION
OF THE EFFICIENT SENSORY CODING
THEORY IN THE INTEROCEPTION
SYSTEM, THE SENSORY NEURONS USE
THE MINIMUM RESOURCES TO CODE
THE MAXIMUM INFORMATION H HAD.
SO IN SUMMARY, TODAY I'M SHOWING
YOU OUR STUDY REVEALED A
MULTIDIMENSIONAL CODING
ARCHITECTURE OF THE VAGAL
INTEROCEPTION SYSTEM USING THIS
CODING STRATEGY THE VAGUS NERVE
IS ABLE TO GENERATE A LARGE
NUMBER OF PARALLEL STRINGS TO
PRESENT THE SIGNALS FROM THE
PERIPHERAL ORG TOONS THE TBLAIN
A VERY EFFICIENT -- TO THE BRAIN
IN A VERY EFFICIENT AND
EFFECTIVE MANNER.
I WANT TO THANK EVERYONE
INVOLVED IN THIS PROJECT, MOST
OF THE WORK WAS DONE ABOUT VERY
TALENTED POST-DOC CURRENTLY ON
THE JOG MARKET, QIANCHENG ZHAO,
AN AMAZING GRADUATE STUDENT WHO
PERFORMED ALL THE EXPERIMENTS
AND OUR LONG-TERM COLLABORATOR
LE ZHANG, DEVELOPED THIS SEQ
APPROACH AND DATA ANALYSIS AND
WE ALSO THANK ALL THE FUNDING
AGENCIES INCLUDING NCCIH FOR
FUNDING REALLY IMPORTANT FUNDING
FOR OUR WORK AS WELL AS NIR
DIRECTORS AND MANY OTHER
FOUNDATIONS AND THANK YOU FOR
YOUR ATTENTION.
>> OKAY.
WE HAVE TIME FOR A QUESTION.
>> SAME CONCEPT.
>> THIS WAS A GREAT TALK.
MY QUESTION WAS, DO YOU HAVE ANY
ONGOING EXPERIMENT LOOKING AFT A
CODING ARCHITECTURE ABOVE THE
NODUS GANGLION INTO A CORTICAL
OR BRAINSTEM OR OTHER CORTICAL
STRUCTURES?
GROO THAT IS A GREAT QUESTION.
CURRENTLY WE DON'T HAVE ANY
LOOKING AT ABOVE THAT, BUT MY
POST-DOC MENTOR STEVE -- LAB IS
LOOKING AT NTS CODING LOOKING AT
IMAGE SO THERE'S SOME REALLY
INTERESTING WORK THERE.
AND THE CODING SEEMS TO BE
SLIGHTLY DIFFERENT FROM THE
CODING LOGIC WITHIN THE -- BUT I
BELIEVE THERE'S A REASON FOR IT
BECAUSE WE DO HAVE A LARGE
NUMBER OF NEURONS THAT CAN SPEND
A LOT OF COMPUTATIONAL EFFORT
ONTO CODING THE INFORMATION
EXPINT GRATING THE INFORMATION.
WE ONLY HAVE VERY, VERY FEW
NUMBER OF SENSORY NEURONS IN
VAGUS NERVE.
SO FOR EXAMPLE, IN MOUSE WE ARE
TALKING ABOUT 5,000 NEURONS IN
TOTAL FROM BOTH THE NERVE, SO
THEY MUST USE VERY DIFFERENT
STRATEGIES -- VERY DIFFERENT
CODING STRATEGIES FOR
TRANSMITTING.
>> THANK YOU.
>> THANK YOU VERY MUCH, RUI.
SO OUR LAST SPEAKER BEFORE THE
GENERAL DISCUSSION IS RICHARD
LANG.
>> THANK YOU VERY MUCH TO THE
ORGANIZERS FOR INCORPORATING ME
INTO THIS MEETING.
I'M DELIGHTED TO BE HERE.
I THINK YOU MIGHT FIND THIS ONE
IS A LITTLE BIT DIFFERENT.
I WOULD LIKE TO START WITH THIS.
THIS IS JUST A LITTLE REMINDER
ABOUT WHERE WE LIVE.
THIS IS OBVIOUSLY THE BALL OF
ROCK SUSPENDED IN SPACE.
THIS BALL OF ROCK ROTATES, AND
BECAUSE WE HAVE A STAR CLOSE BY,
IT MEANS WE ARE WASHED WITH THIS
RHYTHMIC PATTERN OF EM RADIATION
EVERY DAY.
AND THAT'S BEEN A REALLY
INTERESTING OPPORTUNITY FOR
EVOLUTIONARY PROCESSES.
SO WE HAVE EVOLVED A WHOLE
SERIES OF PHOTON DETECTION
MECHANISMS THAT ARE ADAPTIVE.
AND YOU'RE USING ONE OF THEM
NOW, THE VISUAL SYSTEM, AND IT'S
THIS REMARKABLE SYSTEM THAT CAN
DECODE OBJECTS BASED ON PHOTONS
THAT BOUNCE OFF THOSE OBJECTS,
YOU CAN DETERMINE TEXTURE AND
SHAPE AND ALL OF THESE
PROPERTIES OF THAT LOGIC --
PROPERTIES OF THAT OBJECT, BUT
THERE ARE ALSO OTHER LICE SEEN
PATHWAYS YOU'RE FAMILIAR --
LEISOSENE PATHWAYS YOU'RE
FAMILIAR W THERE'S THE CIRCADIAN
CLOCK SYSTEM, RESPONSIBLE FOR AT
LEAST A LOT OF OUR RHYTHMIC
PHYSIOLOGY, ALL OF OUR
PHYSIOLOGY IS RHYTHMIC, THE
CIRCADIAN CLOCK DOES SOME OF
THAT.
THERE ARE OTHER MECHANISMS FOR
GENERATING RHYTHMICITY AND THIS
CLOCK CAN BE PHOTON ENTRAINED
THROUGH LIGHT DETECTION IN THE
EYES.
BUT MY LAB HAS BEEN PARTICULARLY
INTERESTED IN THIS QUESTION, AND
THAT IS WHETHER THERE ARE OTHER
LIGHT DECODING PATHWAYS THAT
MATTER FOR OUR PHYSIOLOGY, AND
IT TURNS OUT THAT THERE ARE.
SO FOR THOSE OF YOU WHO ARE
UNFAMILIAR WITH THE OPSINS, THE
STRUCTURE YOU SEE ROTATING THERE
IS PALCZEWSKI'S CRYSTAL
STRUCTURE OF IT RHODOPSIN, FIRST
STRUCTURE THAT WAS SOLVED AND
THIS IS THE STRUCTURAL MOTIF FOR
ALL THE OPSINS.
THE CHART ON THE RIGHT IS
SHOWING YOU THE PHOTON
SENSITIVITY OF ALL THE HUMAN
OPSINS AND WHAT'S CLEAR FROM
STUDIES FROM MANY DIFFERENT
GROUPS OVER MANY YEARS IS THAT
THEY HAVE THESE DID I STINGT
RANGES OF PHOTONS THEY ARE
SENSITIVE TO, THAT PROBABLY
MATTERS FOR SOME OF THE
PHYSIOLOGY BECAUSE FOR EXAMPLE
COLOR VISION, YOU ARE COMPARING
THE ACTIVATION OF YOUR THREE
CONE OPS TO PERCEIVE A
PARTICULAR COLOR.
AND TODAY I'LL BE PRIMARILY
FOCUSING ON THE THREE CIRCLED
NONVISUAL OPSIN THAT IS ON OPN3,
OPN4 AND OPN5, THESE ARE ALL
STIMULATED PRIMARILY BY SHORT
WAVELENGTH PHOTONS.
SO THESE HAVE BEEN AROUND FOR
ABOUT 600 MILLION YEARS, BUT OF
COURSE EXCEPT FOR ABOUT THE LAST
200 YEARS WHEN WE INVENTED
ARTIFICIAL LIGHT, THE PRIMARY
SOURCE OF PHOTON LIE GANS FOR
THOSE OPSINS WAS THE SUN.
IT TURNS OUT IT PROBABLY
MATTERS.
SO WE GOT STARTED IN
INVESTIGATING THESE PATHWAYS
WITH WORK WE DID ON THE VISUAL
SYSTEM, AND THEM IMAGINE JUST
SHOWS YOU IN GREEN ANTIBODY
LABELING OF MELANO OPSIN IN
GANGLIA CELLS AND IN RED FOR O5
GANGLION CELLS, WE INVET GATED
WHAT THESE LIGHT SENSING CELLS
DID DEVELOPMENTALLY AND THIS IS
THE SCHEMATIC THAT DESCRIBES THE
MECHANISM AND BASICALLY WE
SHOWED THAT BOTH OF THOSE
LIGHT-SENSING PATHWAYS WERE
INVOLVED IN REGULATING VASCULAR
DEVELOPMENT IN THE EYE BUT ALSO
OTHER DEVELOPMENTAL EVENTS, AND
THE MECHANISM THAT'S SHOWN HERE
IS NOT SO IMPORTANT FOR TODAY'S
DISCUSSION, BUT SOME OF THE
CONCLUSIONS ARE.
SO ONE CONCLUSION WAS THAT LIGHT
COULD BE A DEVELOPMENTAL TIMING
CUE.
THAT WAS A LITTLE BIT UNUSUAL.
THE SECOND CONCLUSION WAS THAT
MAMMALIAN DEEP TISSUE LIGHT
SENSING WAS POSSIBLE, AND THE
REASON WE LEARNED THAT FROM
THESE STUDIES WAS THAT THE FIRST
PHASE OF BLUE LIGHT STIMULATION
MELAN OPSIN ACTUALLY OCCURRED IN
THE FETAL MOUSE EYE PRIOR TO
BIRTH SO IT WAS AN INDICATION
THAT PHOTONS COULD PENETRATE
SUFFICIENTLY TO STIMULATE THAT
OPSIN IN THE FETAL MOUSE EYE.
THIS REINFORCES THE IDEA THAT
OPSINS OFTEN WORK IN COMBINATION
IN PAIRS AND TRIPLETS TO GIVE
YOU INFORMATION DECODING.
NOW, WHEN WE WERE ASSESSING THE
EXPRESSION DOMAINS OF THESE
THREE OPSINS WE CAME ACROSS SOME
FAIRLY PROVOCATIVE LOCATIONS.
WHAT YOU'RE SEEING THERE IN THAT
IMAGE IS THE LINEAGE MARK FOR
OPSIN 5 IN THE PREOP PARTICULAR
AREA OF THE HYPOTHALAMUS,
RAISING THE POSSIBILITY THAT
MAMMALS HAD A DEEP BRAIN
PHOTORECEPTOR.
WE KNOW THAT THE BRAIN IS
IMPORTANT NUCLEUS FOR CONTROL OF
ENERGY METABOLISM, CLEARLY SOME
OF THE BIOLOGY WE'LL BE LOOKING
AT AND IN PARTICULAR IT CAN
REGULATE THERMOGENESIS AS WELL
AS OTHER ASPECTS OF ENERGY
HOMOEOSTASIS.
THE OTHER FAIRLY PROVOCATIVE
LOCATION FOR OPSIN EXPRESSION
WAS OPSIN 3 IN THE DIPLOSIGHTS
-- DIPLOSITES,
ENERGY STORAGE CELL, WHITE
ADIPOSE TISSUE HAS ENDOCRINE
FUNCTION AND WE OF COURSE FACE
THIS QUESTION ARE THOSE
EXTRAOCULAR TISSUES
LIGHT-SENSING?
AND THE ANSWER TO THAT QUESTION
IS A FIRM -- IS AFFIRMATIVE.
IN THE NEXT FEW SLIDES I'LL
SUMMARIZE FOR YOU WHAT WE FOUND.
SO IN THIS PAPER, WE SHOWED THAT
MAMMALS HAVE A DEEP BRAIN PHOTO
SENSOR, OPN5 IS SENSITIVE TO
VIOLET LIGHT.
WE REALIZED THAT SOME OF OUR
COLLEAGUES MIGHT BE FAIRLY
SKEPTICAL ABOUT THAT PROPOSAL,
SO WE BORROWED SOME MEASUREMENT
METHODS FROM THE PHYSICS WORLD
TO ACTUALLY SHOW THAT THE PHOTON
FLUX AT THAT LOCATION IN THE
PREOP PARTICULAR AREA WAS
SUFFICIENT TO ELICIT OPSIN
RESPONSES.
WE COULD ALSO SHOW, FOR EXAMPLE,
THAT IF YOU TOOK SLICE CULTURES
FROM THE PREOP PARTICULAR AREA
YOU COULD GOT A VERY NICE LIE
LET LIGHT-DEPENDENT RESPONSE --
VERY NICE LIGHT-DEPENDENT,
VIOLET LIGHT-DEPENDENT RESPONSE,
THE GREEN LINE ON THE CHART.
BLUE LINE IS -- ANIMALS YOU
DON'T SEE A RESPONSE, AND THEN
POSITIVE CONTROL.
THAT WAS A PRETTY GOOD
INDICATION THAT THESE NEURONS
WERE DIRECTLY LIGHT-SENSING.
I ALREADY MENTIONED THAT PROCEED
OPTIC AREA NEURONS REGULATE
THERMOGENESIS SO IT WASN'T A BIG
SURPRISE WHEN WE LEARNED WITH
TEMPERATURE TELEMETRY SEN TORS
THAT THE -- SENSORS THAT THE O5
HAVE -- OPN5 HAVE HIGH
TEMPERATURE, BLUE LIGHT, YOU CAN
SEE IT GOES THROUGH THE
CIRCADIAN PATTERN, IT'S JUST
MUCH HIGHER THAN IT SHOULD BE
EXT DELTA BETWEEN THE CONTROL
THE GRAY TRACE AND OPN5 IS MUCH
LARGER DURING THE DAY, DO YOU
RECOLLECT THE LIGHT PHASE.
SO WE WERE ABLE TO SHOW USING
WHOLE ANIMALS THAT VIOLET LIGHT
STIMULATION COULD ELICIT ACUTE
CHANGES IN BODY TEMPERATURE AND
SO OF COURSE WE'RE THINKING
ABOUT THE PONLT THAT THIS
LIGHT-SENSING PATHWAY IS
PROVIDING TIME OF DAY
INFORMATION FOR MODULATING THE
NORMAL BODY TEMPERATURE CYCLE
YOU FIND IN A MAMMAL.
SO AS YOU WILL ALREADY HAVE
GUESSED, THE WAY THIS WORKS IS
THAT THIS OPN5 PREOP PARTICULAR
AREA HAS A SIM -- PRE-OPTIC AREB
ACTIVATION BY VIOLET NEURONS IS
TO SUPPRESS BROWN ADIPOSE TISSUE
MAKING SENSE BECAUSE NOCTURNAL
ANIMAL LIKE A MOUSE HAS LOW BODY
TEMPERATURE DURING LIGHT PHASE,
ITS INACTIVE STAGE.
BLUE LIGHT STIMULATION, WHITE
ADIPOSE POSE TISSUE, THE BLUE
LIGHT STIMULATION ENHANCES IN
LIE POLLICIS -- LYPOLISIS
RESPONSE, FATTY ACIDS, OUR
ENERGY THROUGHOUT THE BODY, BUT
IN PARTICULAR FOR BROWN ADIPOSE
CYTES, ANOTHER CIRCUMSTANCE
WHERE YOU HAVE TWO OPN5 AND OPN3
REGULATING BODY TEMPERATURE
HOMOEOSTASIS.
GIVEN THESE FINDINGS WE THINK
THESE PATHWAYS ARE FUNDAMENTALLY
ABOUT GIVING YOU ENERGY
HOMOEOSTASIS AND PROVIDING TIME
OF DAY INFORMATION TO CREATE THE
RIGHT ENERGY STATE FOR A GIVEN
PART OF THE DAY.
AND WE ARE VERY CURIOUS ABOUT
THE POSSIBILITY OF SENSORY
FEEDBACK, OF COURSE, THERE WILL
BE SOME BEAUTIFUL WORK ON THAT
RECENT -- THERE'S BEEN SOME
BEAUTIFUL WORK ON THAT RECENTLY.
WHAT WE'RE SUGGESTING HERE IS
THAT WE HAVE IDENTIFIED A NEW
MECHANISM FOR THE MECHANISM OF
ENERGY METABOLISM IN WHICH THERE
IS INTIMATE CUP THROING THE
SUNLIGHT CYCLE -- COUPLING TO
THE SUNLIGHT CYCLE.
WE'RE PARTICULARLY INTERESTED IN
SENSORY FEEDBACK PARTLY BECAUSE
OF THESE DATA.
SO WHAT YOU'RE SEEING IN THE
ROTATING IMAGE ON THE LEFT IS A
DORSAL ROOT GANGLION IN WHICH
WE'VE IMAGED REPORTERS FOR OPN3
EGF AND LYNN LINEAGE MARK
FOR OPN5, AI14 THIS.
A FEATURE OF ALL LEVELS OF DRG,
WORK DONE BY JONATHAN RAIS THE
GENTLEMAN IN THE HAT, AND YOU'RE
ALSO SEE ON THE RIGHT-HAND SIDE
HERE THE TRIGEMINAL GANGLION
SIMILARLY EXPRESSES BOTH,
RAISING THE POSSIBILITY THAT
THESE NURS ONS ARE -- NEURONS
ARE LIGHT SENSING.
THERE'S EVIDENCE OUT THERE TO
SUGGEST THAT THE TRIGEMINAL
GANGLION IS LIGHT SENSING
EX-VIVO AND WE'VE ALSO GENERATED
QUITE A BIT OF DATA LATELY TO
SUGGEST THIS IS THE CASE.
SO THAT GIVES US ANOTHER WHOLE
LEVEL OF POSSIBILITY WHEN WE
THINK ABOUT OUR GRAND SCHEME FOR
HOW LIGHT-SENSING PATHWAYS MIGHT
REGULATE ENERGY HOMOEOSTASIS.
SO OBVIOUSLY WHAT WE'RE SUING --
SO OBVIOUSLY WHAT WE'RE
SUGGESTING HERE IS THAT THE ROOT
GANGLIA MIGHT PROVIDE FEEDBACK
TIME OF DAY INFORMATION THAT
REGULATES INPUT CENTRALLY AND
WE'LL PROBABLY BE TALKING ABOUT
LIGHT-DEPENDENT MODULATION OF
EXISTING INPUT.
THE DRG'S THAT EXPRESS OPN5 AND
OPN3 FALL INTO MECHANOSENSES,
SOME OF THE RESPONSES WE'LL BE
LOOKING AT.
I WOULD ADD WE'RE ESPECIALLY
INTERESTED IN HOW THE LUNG MIGHT
BE INVOLVED IN THIS PATHWAY
BECAUSE IN THIS CIRCUIT, BECAUSE
OBVIOUSLY IT'S THE ORGAN THAT
TAKES UP THE OXYGEN THAT IS A
CRUCIAL COMPONENT OF ENERGY
HOMOEOSTASIS.
WE'RE CURRENTLY WORKING WITH --
ON PROSECUTING SOME OF THIS
ANALYSIS AND WE ACTUALLY FOUND
THAT OPN3 IS EXPRESSED IN SOME
OF THE NEURONS OF THE VAGAL
GANGLIA.
THAT IS THE GRAND SCHEME WITH
LOTS OF QUESTIONS REMAINING, BUT
I THOUGHT I WOULD FINISH BY JUST
SHOWING YOU THIS.
THIS IS A SCHEMATIC THAT SHOWS
YOU ALL THE MOUSE BODY PARTS
THAT WE NOW KNOW ARE LIGHT
SENSING, AND OF COURSE OBVIOUSLY
WE HAVE RETINA AND CORNEA, I
COULD ALSO TELL YOU THAT THE
OCULAR LENS, THAT STRANGE
TRANSPARENT OBJECT THAT YOU HAVE
IN THE MIDDLE OF YOUR EYE IS
ALSO INDEPENDENTLY LIGHT SENSING
I TOLD YOU ABOUT PRE-OPTIC
NEURONS DIRECTLY LIGHT SENSING.
I HAVEN'T MENTIONED MELANOCYTE
PRECURSORS, SO WORK FROM MY
COLLABORATORS HAVE SHOWN
MELANOCYTE PRECURSORS IN THE
SKIN ASSOCIATED WITH HAIR
FOLLICLES THAT EXPRESS OPN5 AND
ARE LIGHT SENSE AND GO THEY
ACTUALLY FUNCTION AS A PACEMAKER
CELL FOR CIRCADIAN CLOCK IN THE
SKIN THAT FUNCTIONS QUITE
INDEPENDENTLY OF THE OTHER
CIRCADIAN RHYTHMS.
SO THEN WHITED ADIPOCYTES AND
TRIGEMINAL GANGLION, DORSAL ROOT
GANGLIA, OTHER EXAMPLES OF LIGHT
SENSING TISSUES COMING, THE
IMPRESSION YOU GET IS THAT THE
MAMMALIAN SYSTEM IS ENTIRELY SET
UP TO DECODE LIGHT INFORMATION
ON REGULATE OUR PHYSIOLOGY AND
SINCE WE CHOOSE TO LIVE THE WAY
WE DO, INSIDE, NOT IN SUNSHINE,
WE HAVE A FEW LITTLE PROBLEMS
AND WE CAN TALK ABOUT WHAT THE
DISEASE IMPLICATIONS MIGHT BE.
BUT HERE IS THE GRAND
CONCLUSION, A REMINDER THAT
THERE IS INTIMATE LINKAGE
BETWEEN MAMMALIAN PHYSIOLOGY AND
THE PHOTON LIGANDS FOR THE OPSIN
PROTON RECEPTORS PRODUCED BY THE
SUN.
LASTLY TO ACKNOWLEDGE ALL THE
PEOPLE THAT DO THE WORK, THIS IS
MY CURRENT LAB CREW IN THE
PICTURE, FORMER AND PRESENT LAB
MEMBERS, ALL OF WHOM MADE A
WONDERFUL CONTRIBUTION TO THIS
WORK.
I'VE HAD SOME EXCEPTIONAL
COLLABORATORS AND I PARTICULARLY
WANT TO IDENTIFY RAN DID I
SEALEY TUCKER, AND -- VENTURING
INTO THE WORLD OF METABOLISM.
WITH THAT, THANK YOU VERY MUCH
FOR YOUR ATTENTION.
>> THANK YOU VERY MUCH.
WE HAVE TIME FOR A QUESTION.
>> I'M FROM THE UNIVERSITY OF
ARIZONA.
THIS IS ABSOLUTELY FASCINATING.
FANTASTIC WORK.
I WOULD LIKE TO KNOW WHETHER YOU
HAVE ANYTHING ON THE GREEN LIGHT
BECAUSE -- FROM THE UNIVERSITY
OF ARIZONA SHOWED GREEN LIGHT IS
ANTI-ENERGETIC, ESPECIALLY WITH
BRAIN DISORDERS THAT INVOLVE
INTEROCEPTION.
>> FASCINATING STUDY THAT IS.
ONE OF THE SORT OF DIFFICULTIES
IN WORKING WITH OPSIN SS IF YOU
PROVIDE ENOUGH LIGHT, ENOUGH
PHOTONS OF ANY WAVELENGTH YOU
CAN STIMULATE ANY OPSIN.
SO WHEN I HEAR ABOUT STUDIES
LIKE THAT, I WONDER WHETHER YOU
MIGHT BE STIMULATING SOME OF
THESE OPSINS BECAUSE GREEN LIGHT
IS CLOSE ENOUGH TO SOME OF THESE
THAT YOU COULD.
HAD AND, YOU KNOW, TO BE HONEST,
I'M NOT ENTIRELY FAMILIAR WITH
THE DETAILS OF THAT STUDY.
I HAVE TO LOOK AT IT AGAIN.
BUT YEAH, IT'S A REALLY
INTERESTING PROPOSAL.
I MEAN, OF COURSE, WE THINK THAT
YOU MAY BE ABLE TO MODULATE PAIN
RESPONSES SIMPLY BY USING THE
PHOTON AS A DRUG.
>> THANK YOU.
>> SO WE HAVE TIME FOR ONE MORE
QUESTION.
>> DANA SMALL, MIGUEL
UNIVERSITY.
THANK YOU.
REALLY THOUGHT PROVOKING.
I'M WONDERING IF THE OPSIN
ADIPOSE SENSING MECHANISM MIGHT
BE RELATED TO THE NUTRIENT
PARTITIONING CIRCADIAN RHYTHMS.
>> ALMOST CERTAINLY THIS WHOLE
SYSTEM IS INTEGRATED WITH THE
CIRCADIAN CYCLE IN SOME WAY WE
DON'T CURRENTLY UNDERSTAND.
YOU KNOW, ONE OF THE FEATURES OF
NULL CELLS IS THAT THEY HAVE A
DIMINISHED AMPLITUDE CIRCADIAN
RHYTHM.
SO, YOU KNOW, MONITORING
INDIVIDUAL CELLS THAT EXPRESS
OPN3 YOU CAN SEE REDUCED
AMPLITUDE OSCILLATIONS SO THAT'S
ACTUALLY PRETTY LIKELY FOR THAT
PARTICULAR OPSIN.
>> THANK YOU.
>> I'M GOING ON TAKE A
PREROGATIVE ASK A QUESTION ON
BEHALF OF ALL THE GENETICISTS IN
THE AUDIENCE SNRIEF AN ANSWER
FOR YOU.
>> IN PARTICULAR, SHOULD WE GO
BACK TO HAMMERING ALL OF THESE
TWARGTS TEN MILLIGRAMS LIGHT TO
GET DEPOLARIZATION BLOCK?
>> YOU JUST NEED TO DO THE
WILD-TYPE CONTROL.
SO I THINK THESE ARE SLOW ACTING
OPSINS.
SO I MEAN, THE SORT OF TIME
SCALE OVER WHICH WE SEE
RESPONSES IS SORT OF FIVE, TEN,
TWENTY MINUTES.
SO WHEN YOU USE SOME OF THESE
REALLY FAST-ACTING OPTOGENETIC
TOOLS, I DON'T THINK ITS AN
ISSUE.
BUT YOU STILL NEED TO DO THE
WILD-TYPE CONTROL.
>> UNDERSTOOD.
SO BEHALF OF EVERYONE.
SO WE HAVE FIVE MINUTES LEFT.
I FIRST WANT TO MAKE SURE THAT
EVERYBODY WHO PRESENTED GETS A
CHANCE TO ANSWER ANY BURNING
QUESTIONS THAT YOU MIGHT HAVE.
IF YOU DO HAVE ANY, PLEASE STEP
UP.
OKAY.
WE HAVE ONE.
QUESTION.
>> QUICK QUESTION.
THE VISCERAL ORGANS, DO WE KNOW
IF THEY'RE INNERVATED BILY (?)
FIBERS -- IF THEY'RE INNERVATED
BY (?) FIBERS?
IN THE VISCERAL ORGANS.
>> DID YOU HEAR THE QUESTION?
YOU CAN REPEAT IT.
>> SO MY QUESTION WAS ABOUT THE
INNERVATION OF THE PIEZ02 IN THE
VISCERAL ORGANS, ARE THEY
INNERVATED BY (?) FINE RS OR --
>> YOU HAVE ACTUALLY DONE SOME
SINGLE CELL RNA SEQ FROM FAT
INNERVATING NEURONS AND
REMARKABLY THEY HAVE EVERY
SUBCATEGORY MOLECULARLY DEFINED
AS SKIN INNERVATING NEURONS, SO
WE FIND THE MYELINATED P
UNMYELINATED, MULTIPLE TYPES OF
CGRP, EVERYTHING YOU HAVE IN THE
SKIN, EXCEPT FOR ONES THAT WERE
KNOWN TO BE VERY SPECIFIC ONES.
SO VAST MAJORITY OF THE DRG
SUBTYPES ALSO SEEM TO INNERVATE
THE FAT.
>> THANK YOU.
>> THANK YOU FOR A GREAT SESSION
TO ALL SPEAKERS.
SO MY QUESTION IS FOR RUI.
I'M -- DEVELOPMENTAL BIOLOGIST
AND YOUR FINDING THAT THE
TERMINAL SHAPE OR TERMINAL
MORPHOLOGY IS TO THE SPECIFIC TO
THE LAYERS BUT NOT TO THE
SENSORY SIGNAL TYPE.
CORRECTED?
>> YES.
>> SO MY QUESTION
DEVELOPMENTALLY IS, ARE YOU
PREDICTING THAT A SIMILAR TYPE
OF SIGNAL IS DICTATING THE
SHAPE, WHETHER THAT SIGNAL IS
FROM A CARDIAC MUSCLE VERSUS A
SMOOTH MUSCLE VERSUS A SKELETAL
MUSCLE VERSUS OTHER TISSUE?
>> THAT WOULD BE THE PREDICTION,
ALTHOUGH WE HAVE NO DATD ON IT
YET, BUT THAT'S SOMETHING WE ARE
THINKING OF, THAT THE TERMINAL
STRUCTURE, AT LEAST THE
CROSS-TERMINAL STRUCTURES ARE
FORMED BECAUSE OF THEIR
INTERACTIONS WITH THE LOCAL
ENVIRONMENT.
SO THAT'S HELPING THEM TO ADAPT
TO THE LOCAL ENVIRONMENT.
AND SO WHAT TYPE OF STIMULUS
THEY'RE ACTUALLY SENSING THAT,
DEPENDS ON THE RECEPTORS
EXPRESSED, AND MAYBE THE OTHER
STRUCTURES THAT THE RECEPTORS
WILL FORM.
>> GREAT.
THANK YOU.
>> THANK YOU VERY MUCH TO ALL
THE SPEAKERS.
RICHARD, THIS QUESTION IS FOR
YOU.
WITH REGARDS TO SINCE YOU
BROUGHT UP THE WORLD VIEW
PICTURE, I'M CURIOUS, SOMETHING
THAT YOU MAY OR MAY NOT HAVE
BEEN THINKING ABOUT OR I'M
GUESSING YOU HAVE OR SOMEONE HAS
ASKED THIS QUESTION BEFORE, IN
THE CONTEXT OF ARTIFICIAL BLUE
LIGHT AND ALL THAT WE'RE EXPOSED
TO AND HOW MUCH TIME WE SPEND
BEING EXPOSED TO ARTIFICIAL BLUE
LIGHT, DO YOU HAVE ANY THOUGHTS
WITH REGARDS TO HOW THIS IS
CHANGING THE REGULATION OF
OPSINS WITHIN THE BRAIN AND HOW
THAT COULD IMPACT IN A SORT OF
GENETIC, HE JCT WAY -- HE VECT
WAY -- EPIJ GE -- EPIGENETIC
BETWEEN HUMANS?
>>S INTERESTING FOR HAD ARE
DEFICIENT IN HUMANS, THE LEAD
DEFICIENT DISEASE IS ACTUALLY
MYOPIA, SO I WOULD GUESS 30% OF
THE AUDIENCE PROBABLY HAS
MYOPIA, PROBABLY ABOUT RIGHT,
AND WE THINK WE KNOW WHY THAT IS
NOW, BASICALLY BECAUSE WE LIVE
IN A LIGHTING ENVIRONMENT WHERE
WE'RE NOT STIMULATING OPN5 IN
THE RETINA AND TURNS OUT THAT
OPN5 IS REALLY IMPORTANT FOR
SUPPRESSING ABNORMAL ELONGATION
OF THE EYE AND, YOU KNOW, THAT'S
MYOPIA.
WHEN THE EYE ELONGATES
ABNORMALLY, YOU'RE NEARSIGHTED.
SO THAT'S -- THE EVIDENCE OF
THAT NOW IS REALLY, REALLY
STRONG.
SO OBVIOUSLY WHAT WE'RE DOING
THERE IS GETTING SERIOUS ABOUT
CREATING LIGHTING SYSTEMS THAT
DO PRODUCE THE VIOLET PHOTONS TO
STIMULATE OPN5.
YOU CAN SOLVE THIS PROBLEM BY
GOING OUTSIDE FOR A COUPLE OF
HOURS EVERY DAY, SO YOU DON'T
NEED ONE OF THESE LIGHTING
SYSTEM, BUT THAT'S THE SORT OF
CAUSATION ARGUMENT THAT'S
EMERGING.
BUT THERE ARE VERY SIMILAR
CAUSATION ARGUMENT FOR METABOLIC
DISEASE, OBVIOUSLY I'VE SHOWN
YOU WHAT OPN5 CAN DO IN ENERGY
HOMOEOSTASIS, THAT'S VERY LIKELY
TO BE CONSERVED IN HUMANS, SO WE
ARE THINKING THAT, YOU KNOW,
THERE'S THIS ACCELERATING
PREVALENCE OF METABOLIC SYNDROME
AND DIABETES, MUCH LIKE THERE'S
AN ACCELERATING PREVALENCE OF
MYOPIA, SO THERE'S THIS REALLY
INTERESTING QUESTION ABOUT THOSE
DISEASES THAT ARE ALSO A RESULT
OF DEFICIENT LIGHTING SYSTEMS.
SO YEAH.
>> THANK YOU.
>> GREAT TALKS.
ASSOCIATE PROCEED SES SORE FROM
THE UNIVERSITY OF MARYLAND
MARYLAND BALTIMORE.
INTERESTING TALK.
I HAVE A CLARIFICATION QUESTION.
I WAS USED TO THINKING ABOUT
KIND OF THE MAPPING OF BODY TO,
YOU KNOW, ASCENDING NERVES AS
LIKE A SOMATOPIC MAP BUT YOU'RE
ALSO SHOWING THERE'S EN CODING
OF THE SPACE -- ENCODING OF THE
SPACE, WHICH ORGAN IS INNERVATED
AND WHAT PART OF THE ORGAN BY
THESE GENETIC EXPRESSION
DIFFERENCES, THAT SEEMS LIKE
KIND OF REDUNDANT, LIKE COULDN'T
THE NERVES JUST HAVE A SOMATOPIC
MAP THAT GOES FROM ONE PLACE IN
THE PERIPHERY TO ONE PLACE IN
THE SPINAL CORD OR IN THE
BRAINSTEM AND YOU WOULDN'T NEED
THESE DIFFERENCES?
SO THAT'S JUST A CLARIFICATION.
IS THIS A SENSE OF LIKE A
REDUNDANCY THAT WE'RE SEEING?
>> THAT IS A GREAT QUESTION, AND
SO WE KNOW THAT THERE IS A MAP
IN NTS.
THE QUESTION IS WHETHER THERE IS
A MAP IN THE VAGUE VAGUS NERVE
AND SO FAR PREVIOUS STUDIES
INCLUDING SOME OF OURS SHOW THAT
THERE'S NOT A VISCERAL MAP IN
THE -- SO ONE OF THE
POSSIBILITIES, COULD BE LIKE
YOU'RE RATE, THE VALG -- YOU'RE
RIGHT, THE VAGUS NERVE SERVES
APPEARS THE CONNECT TORDZ, BASIC
YOU CAN SEE THEM APPEARS THE
WIRES, THEY JUST CONNECT A TO B
AND ONCE IT'S CONNECTED, YOU'RE
DONE, RIGHT?
YOU DON'T NEED TO KNOW WHICH ONE
IS CONNECT TO DO WHICH BECAUSE
IT'S ALREADY THE CONNECTION IS
ALREADY SET UP.
BUT THAT'S NOT WHAT WE OBSERVED.
ACTUALLY, WE ARE ALSO VERY
SURPRISED TO SEE THIS.
AND THE MORE WE THINK ABOUT IT,
THE MORE WE FEEL LIKE THERE
MIGHT BE A BIOLOGICAL REASON FOR
T OF COURSE, WE DON'T HAVE ANY
EXPERIMENT DATA TO BACK UP.
ONE POSSIBILITY IS BECAUSE THESE
NEURONS DON'T REGENERATE AND YOU
DO HAVE DAMAGE OF THE PERIPHERY
NERVES, VERY COMMONLY, AND THEY
WILL DO REGENERATION TO A
CERTAIN DEGREE.
ONE POSSIBILITY IS LIKE THESE
NEURONS THAT ARE AT THIS STAGE
STILL KEEP THAT SPATIAL
INFORMATION LIKE AND WILL
POTENTIALLY BECAUSE THEY DO NEED
TO RECOGNIZE THE SAME SPOT
AGAIN.
SO THERE'S ONE EXPERIMENT WE DO
TALK ABOUT, WE HAVEN'T STARTED
TO DO IT YET, IS TO DAMAGE THOSE
NEURONS WITH A GENETIC LABEL
POPULATIONS AND REALLY SEE IF
THOSE NEURONS WILL GO BACK TO
THE SAME LOCATION OR DO THEY
STILL KNOW WHERE THEY SHOULD GO.
SO I THINK THAT IS A POSSIBILITY
THAT MAKES WHY THESE STIMULUS
STILL NEED TO KEEP THOSE
INFORMATION.
>> MAY I ASK A FOLLOW-UP?
>> PLEASE.
>> OKAY, THANK YOU.
SO THEN THAT IS A GREAT ANSWER,
THANK YOU.
THEN THE FOLLOW-UP IS, IS IT
THAT ALL OF THESE GENETIC
EXPRESSION DIFFERENCES THAT YOU
OBSERVE THAT KIND OF REPLACE THE
SOMATOTOPIC MAP THAT IS THERE IN
OTHER PART OF THE NERVOUS SYSTEM
IS ONLY THERE TO MODULATE THE
FIRING OF THOSE NERVES?
THROUGH ION CHANNELS OR THE WAY
THAT THE NEURONS RESPOND?
IS THAT BASICALLY INSTEAD OF THE
SOMATOTOPIC MAP KNOWING THAT ONE
NERVE GOES FROM PLACE A TO PLACE
B EACH TIME, IT'S THAT THE
FIRING PATTERN OR SOMETHING IS
ENCODING THE SOMATOTOPIC MAP?
>> THAT IS AN INTERESTING
QUESTION.
WE HAVEN'T STARTED TO LOOK AT
THAT BECAUSE OF THE TOOLS WE ARE
USING IS BASICALLY IMAGING THAT
DOES GIVE SOME SPIKING
INFORMATION FREQUENCY BUT NOT
EXACTLY RECAPITULATING THE
ELECTRICAL SIGNALS.
ON THE OTHER HAND, MOST OF THE
GENES WE ACTUALLY SEE FROM THOSE
GENE MODULES FOLLOW ORGAN CELL,
TISSUE LAYERS R THE GENES
INVOLVED IN AXON GUIDANCE AND
NEURON ATTRACTIVE CUES, SO I
DON'T THINK THAT THAT KIND OF
SUPPORTS THE IDEA THAT IT'S USED
TO MAINTAIN THIS INTERACTION
WITH LOCAL TISSUES, IF THAT
ANSWERS YOUR QUESTION.
>> YEAH.
THANK YOU VERY MUCH.
REALLY FASCINATING.
>> NOW WE'LL OPEN UP THE FLOOR
TO ALL THE STUDENTS WHO HAVE
BURNING QUESTIONS.
OKAY.
AND IF THAT'S NOT HAPPENING,
THEN I'LL JUST ASK ONE LAST ONE.
IS THERE ONE?
OH, FANTASTIC.
MUCH BETTER.
>> THIS IS A QUESTION FOR THE
WHOLE PANEL.
I JUST WANT TO KNOW IF THE LINK
BETWEEN THE SOMATOSENSORY
PATHWAY AND THE SYMPATHETIC,
PARASYMPATHETIC, IT'S WHAT'S
UNDERLYING INTEROCEPTION AS IN
WE HAVE INTEGRATING SYSTEMS IN
THE BRAINSTEM THAT HAVE THE
MEANS OF RECEIVING THE SIGNAL
AND THEN RESPONDING TO THAT
SIGNAL.
SO NOW THAT WE HAVE HUMAN
INTERVENTIONS THAT ARE SEEKING
TO DO THAT, I WONDER IF IT'S
WORTH DELVING INTO THE
INTERACTION BETWEEN THESE TWO
SYSTEMS AND IF THAT WOULD INFORM
A LITTLE BIT ABOUT WHAT THE
PREVIOUS QUESTION WAS ABOUT HOW
WE GENERATE THIS VERY SPECIFIC
RESPONSES TO THIS WIDELY VARIANT
STIMULI.
>> WERE YOU TALKING ABOUT
TEMPERATURE?
IS THAT WHAT YOU STARTED OFF
SAYING?
>> I AMINE ALONG WITH
TEMPERATURE BURKT THE MECHANICAL
RESPONSES THAT ARDEM WAS TALKING
ABOUT, THE CHEMICAL RESPONSE
THAT IS HAPPEN IN THE STOMACH
AND IN THE MUSCLES, YEAH, THIS
IS WIDE.
>> SO ARE YOU ASKING FOR US TO
EXPLAIN HOW THAT ALL GETS
INTEGRATED?
>> YES, AND --
>> I'M WITH YOU.
RIGHT?
>> RIGHT.
>> THAT'S WHY WE'RE ALL HERE.
RIGHT.
>> I CAN JUST SIMPLY SAY FOR OUR
SYSTEM, YU HAS FOUND THAT I TOLD
YOU THAT THE SENSORY SEEMS TO BE
ACTING AS A BLOCK OF FEEDBACK TO
THE SYMPATHETIC, WE KNOW THE
SYMPATHETIC SIGNAL IS REQUIRED
FOR THE EFFECT OF THE DRG
ABLATION FOR EXAMPLE, BUT WE
HAVE NO IDEA WHERE IN THE
CIRCUITRY THE COMMUNICATION IS
HAPPENING.
SO I THINK FOR THAT, I THINK
THIS IS A GREAT SYSTEM TO START
LOOKING AT AS PEOPLE LIKE RUI
AND OTHERS ARE LOOKING AT
SENDING PATHWAYS AND HOW THIS
AND WHAT LEVELS IS THERE
COMMUNICATION WITH THE AUTONOMIC
NERVOUS SYSTEM IS AN INTERESTING
QUESTION INDEED.
>> CAN I FOLLOW UP ON THAT AS
WELL?
SO MY OTHER HALF OF MY LIFE IS
STUDYING THE SENSORY NERVES FROM
THE KIDNEY TO THE BRAIN AND WHAT
THEY DO.
THEY DO MODULATE, SYMPATHETIC
ACTIVITY, BUT FOLKS IN THE LAB
THAT ARE HERE ARE FINDING THAT
SIGNALS THAT REGULATE THIRST,
SALT APPETITE, HORMONE RELEASE,
EVERY ORGAN IS TALKING TO THE
BRAIN ALL THE TIME.
RIGHT?
TO MODULATE, NOT JUST AUTONOMIC
BUT ALL THESE BEHAVIORAL
RESPONSES WHICH I THINK IS
PRETTY FASCINATING BUT TAKE A
WHILE TO FIGURE OUT.
>> ALL RIGHT.
I'M GOING TO END UP WITH ONE
LAST QUESTION FOR THE WHOLE
PANEL HERE.
I THINK WHAT WE'VE HEARD THIS
AFTERNOON IS PRETTY AMAZING
DIVERSITY OF INPUTS THAT OFTEN
HAVE SPECIFICATION AT THE LEVEL
OF TOPOGRAPHY AND LAYER WITHIN
AN ORGAN MAPPING ONTO DISTINCT
MOLECULAR SIGNATURES, SO I GUESS
MY QUESTION FOR ALL OF YOU IS,
YOU KNOW, IS THE VAGUS NERVE
STIMULATION OF THE FUTURE GOING
TO BE TARGETABLE TO SPECIFIC
CELL TYPES INNERVATING SPECIFIC
ORGANS AND WHAT ARE THE
PROSPECTS FOR THAT?
I CAN START WITH -- I'LL MAKE IT
MORE SPECIFIC.
I'LL START WITH RUI.
WHEN YOU LOOK AT YOUR SCWERNSING
DATA, ARE WE HAVING TO TARGET --
SEQUENCING DATA, ARE WE HAVING
TO TARGET FIVE DIFFERENT
PROMOTERS IN ORDER TO GAIN THAT
SPECIFICITY THAT YOU SEE IN YOUR
UMAP PLOT OR IS THERE A SIMPLER
TARGETING OF JUST A FEW UNIQUE
GENES?
>> WELL, FROM THE MOUSE POINT OF
VIEW -- AND FROM A SINGLE CELL
POINT OF VIEW, YOU JUST NEED ONE
PROMOTER TO TARGET AND THERE ARE
SOME NEURON POPULATIONS THAT YOU
DO NEED MULTIPLE GENES TO
TARGET.
BUT HOW DOES THIS TRANSLATE TO
HUMAN APPLICATIONS IS STILL A
QUESTION.
I MEAN, I DO BELIEVE THAT THERE
ARE THE NEURONS FROM DIFFERENT
SUBTYPES DO HAVE DIFFERENT
THRESHOLD FOR ELECTRICAL
STIMULATIONS, BUT ON THE OTHER
HAND, WHETHER THAT THRESHOLD
DIFFERENCE IS BIG ENOUGH THAT WE
CAN SOMEHOW TARGET IT IN HUMAN
IS A QUESTION.
ANOTHER THING I'M ACTUALLY
THINKING ABOUT IS IF IT'S
FEASIBLE TO COMBINE THE
ELECTRICAL PARAMETERS WITH
BRANCH SPECIFIC STIMULATION.
I THINK THAT MAY GIVE A BETTER
EFFICACY OF THE VAGUS NERVE
STIMULATION IN THE FUTURE.
>> IN TERMS OF THE HUMAN WORK,
THE IDEA WITH THAT STUDY THAT
WE'RE DOING IS TO GENERATE A
HUGE DATASET AND THEN DO
ADVANCED MODELING TO LOOK AT
STIMULUS PARAMETERS SO WE CAN
SAY, OKAY, LET'S JUST GET THE
ANTI-INFLAMMATORY EFFECT WITH
THESE PARAMETERS AND LET'S JUST
GET THIS EFFECT ON DIABETES OR,
YOU KNOW, THAT'S THE GOAL,
RIGHT?
THAT'S A LONG WAY AWAY.
BUT THAT'S THE IDEA THROUGH THAT
APPROACH.
YEAH.
>> ALL RIGHT.
I COULD LISTEN TO THIS FOR HOURS
AND ASK QUESTIONS, BUT IT'S TIME
TO CLOSE.
SO I WANTED TO GIVE THANKS TO
OUR DISTINGUISHED PANEL.
AND I ALSO WANTED TO INVITE
DR. WEN CHEN TO CLOSE.
>> WELL, I NORMALLY DON'T DO THE
CLOSING REMARK, I ASK FOR IC
DIRECTOR TO DO IT, BUT THEY
DECLINED.
SO THEY ASKED I DO THIS PUMPING
UP.
I ASKED, WOULD YOU LIKE TO DO
IT, WALTER?
SO I DON'T KNOW WHY, THEY SAID
YOU NEED TO GIVE AN ENTHUSIASTIC
CLOSING.
SO I DON'T KNOW, I WAS TRYING TO
GET TO A LITTLE BIT MORE
INTEROCEPTION JUST NOW BECAUSE I
GOT OVERLOADED BY THE
EXTRASENSORY INPUT TODAY.
AND THEN I INSTANTLY FELT MY
RACING HEARTBEAT, SO I WAS LIKE,
OKAY, THAT'S NOT GOOD.
BUT ANYWAY, I JUST WANT TO THANK
ALL OF YOU FOR COMING TODAY AND
FOR THE ONLINE VIEWERS.
I KNOW THERE ARE HUNDREDS OF YOU
THERE, AND YOU CAN WATCH THIS
VIDEO LATER ON IF YOU MISSED
SOME EARLIER OF THE DAY.
AND I ALSO WANT TO THANK ARDEM
PATAPOUTIAN WHO HAS BEEN GETTING
UP AT 6:00 OR MAYBE EVEN
EARLIER, TO STAY WITH US THE
WHOLE DAY, HE TOLD ME HE WAS
THERE FROM THE VERY BEGINNING
AND I KNOW THAT'S A VERY EARLY
TIME.
AND ALSO, I WANTED TO SORT OF
SHARE, I KNOW I HURRIED
MANUFACTURE YOU OUT OF YOUR
POSTER BEFORE THE SESSION, I
PROMISED, YOU CAN GET BACK AT
FOUR, I KNOW WE'RE A LITTLE BIT
LATE, BUT THIS IS NETWORKING
TIME, WE RESERVED THIS TIME FOR
YOU TO CONTINUE YOUR WONDERFUL
DISCUSSIONS, YOU CAN GO BACK TO
THE POSTER SESSION, YOU CAN STAY
THERE UNTIL 5:30.
YOU DO HAVE TO TAKE THEM ALL
DOWN BY 5:30.
AND ALSO, TO CONTINUE.
SO THAT'S WHERE IT IS.
AND ALSO, I WANTED TO MAYBE
LET'S SEE IF THIS IS THE -- I
WANTED TO REMIND YOU ALL, IF YOU
LIKE THE EXCITEMENT TODAY, I
PROMISE IT WILL BE CONTINUED FOR
THREE DAYS IN A ROW IN 2025, I
GUESS, THE SEASON.
OH, YEAH, THAT SLIDE WAS NOT
UPDATED.
BUT IT'S IN THE SPRING OF 2025.
AND PLEASE LOOK OUT FOR IT, AND
WE HAVE A WONDERFUL DPAISH IS WE
HAVE WONDERFUL ORGANIZERS LISTED
HERE.
AND THANK YOU ALL FOR BEING WITH
US TODAY.
AND PLEASE STAY IN TOUCH WITH
US.
WE WANT TO BE HERE AND HELP AND
SUPPORT ALL OF YOU.
THANK YOU.