Welcome to the Clinical Center Grand Rounds,
a weekly series of educational lectures for physicians and
health care professionals broadcast from the Clinical
Center at the National Institutes of Health in
Bethesda, MD.
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effort in training today's investigators and discovering
tomorrow's cures.
Learn more by visiting us online at http://clinicalcenter.nih.gov
TODAY, OUR SPEAKERS ARE DR. PHIL
SHAW A SENIOR INVESTIGATOR
IN AND Dr. MELISSA BROTMAN A
STADTMAN INVESTIGATOR AND CHIEF
OF THE NOTCH HE WILL.
OUR FIRST SPEAKER WILL Dr.
SHAW.
A SENIOR INVESTIGATOR IN THE
SOCIAL BEHAVIORAL RESEARCH AND
AHEAD OF THE NEURAL BEHAVIOR
CLINAL SECTION AT THE NATIONAL
HUMAN GENOME.
HE COMPLETED RESIDENCY AND
INTERNAL MEDICINE AND PSYCHIATRY
IN ENGLAND AND AS A MEMBER OF
THE RURAL COLLEGE OF
PSYCHIATRISTS AND Dr. SHAW IS
RESEARCH PROGRAM EXAMS THE INNER
PLAY OF GENOMIC AND
ENVIRONMENTAL FACTORS EFFECTED
DEVELOPMENT OF BEHAVIOR AND HIS
PROGRAM FOCUSES ON THE MOST
COMMON CHILDHOOD MENTAL ILLNESS
AND ATTENTION DEFICIT HYPER
ACTIVITIES DISORDERS AND IT HAS
07% OF THE EFFECTIVE FINE OWE
TYPE CLEANED BY GENETIC FACTORS
AND IT'S THE COR OF
UNDERSTANDING THE DISORDER AND
THERE'S RESEARCH DEFINING NOVEL
PHENOTYPES TO THE ADHD BASED AND
NEUROIMAGING, SOCIAL EX
BEHAVIORAL SCIENCES AND
IDENTIFYING THE GENOMIC FACTORS
AND TRANSLATING DISCOVERIES FOR
TOOLS AND PROGNOSIS AND NOVEL
TREATMENTS, FOLLOWING Dr.
SHAW, WE'LL HAVE Dr. MELISSA
BROTMAN, Dr. BROTMAN EARNED
HER PH.D IN CLINICAL
PSYCHOLOGIST FOR THE UNIVERSITY
OF PENNSYLVANIA AND SHE
SPECIALIZED IN COGNITIVE BEHAVE
YOUR THERAPY FOR MOOD AND
ANXIETY DISORDERS.
AFTER COMPLETING HER CLINICAL
INTERNSHIP AT THE VETERAN
AFFAIRS MARYLAND HEALTH-CARE
SYSTEM AND UNIVERSITY OF
MARYLAND BATTLE MOR, SHE PURSUED
TRAINING IN NEUROSCIENCE AND
FOCUSING ON FUNCTIONAL MAGNETIC
RESIDENTS IMAGING AND
PHENOTYPING OF IRATE ABILITY IN
YOUTH.
THE GOAL OF THERAPEUTICS UNIT
BRAIN BASED TREATMENT FOR
TREATMENT WITH SERIOUS DISORDERS
AND Dr. BROTMAN'S NEURO
TRANSLATIONAL RESEARCH
INTEGRATES BASIC AND CLINICAL
APPROACHES TO THE STUDY OF MOOD
DISORDERS IN CHILDREN AND
ADOLESCENTS AND SPECIFICALLY,
SHE USES EFFECTIVE NEUROSCIENCE
TECHNIQUES TO UNDERSTAND THE
BRAIN-BASED MECHANISMS UNDERLINE
SEVERE IRRITABILITY IN YOUTH AND
LEVERAGES THAT PAST
PHYSIOLOGICAL KNOWLEDGE TO GUIDE
THE DEVELOPMENT OF NOVEL
TARGETED INTERVENTIONS.
THE RESEARCH CONDUCTED IN HER
NNT UNIT IS PART OF NIMH'S
MISSION TO TRANSFORM THE
UNDERSTANDING AND TREATMENT OF
MENTAL ILLNESS DUE TO BASIC AND
CLINICAL RESEARCH, PAVING THE
WAY FOR PREVENTION, RECOVERY AND
CURE.
Dr. BROTMAN IS AS I FELLOW OF
THE PSYCHO PHARMACOLOGY AND PAST
CHAIR OF THE NCAP TASK FORCE AND
SHE'S RECEIVED NUMEROUS RESEARCH
AWARDS INCLUDING A SEA MORE S.
KENNY TRAINING AND PHARMACOLOGY
YOUNG INVESTIGATOR REWARD TRAVEL
AWARD AND A CAREER INSTITUTE
AWARD AND SHE'S BEEN AWARDED TWO
NIH GRANTS AND IS A CONSULT
ABILITY ON EXTRAMURAL GRANTS AND
ASSOCIATE EDITOR OF THE JOURNAL
OF THE AMERICAN ACADEMY CHILD
AND PSYCHIATRY AND ON THE BOARD
OF SEVERAL OTHER JOURNALS, NOW,
PLEASE WELCOME OUR SPEAKERS,
Dr. SHAW AND Dr. BOWMAN FOR
THEIR PRESENTATION ENTITLED "AN
ANATOMY TO APPS."
THANK YOU FOR THE KIND
INTRODUCTION AND IT'S A GREAT
PLEASURE TO BE HERE TO TALK
ABOUT THE WORK OF MY GROUP INTO
ADHD.
I HAVE NO FINANCIAL DISCLOSURES,
MY WORK IS FUNDED BY THE
INTRAMURAL PROGRAMS OF NHGRI AND
KNIFE.
AND.
I'M GOING TO TALK ABOUT TWO
YOUNG PEOPLE PARTICIPATING AT
THE CLINICAL CENTER AND LOOK AT
INSIGHTS INTO ATTENTION DEFICIT
HYPER ACTIVITY DISORDERS AND
ADHD, FROM IN VIVO AND
NEUROIMAGING AND CONSIDER SOME
RESENT POSTMORTEM BRAIN
FINDINGS.
SO I'M A PSYCHIATRIST.
EVERY FRIDAY, I'M WITH MY TEAM
IN THE CLINICAL CENTER SEEING
YOUTH AND FAMILIES EFFECTED BY
ADHD.
I WANT TO TELL YOU ABOUT A KID
CALLED PETER.
HE WAS A VERY ENGAGING AND WARM
CHILD BUT BY HIS AND HIS MOM'S
REPORT HE WAS STRUGGLING AT
SCHOOL AND HOME DUE TO HIS
ATTENTIONAL FOCUS LACK.
HE COULDN'T STAY ON A TASK FOR A
SECOND, EVEN TASKS THAT
INTERESTED HIM GREATLY.
HIS PARENTS AND TEACHERS
DESCRIBED HIM AS ALWAYS BEING
LOST IN HIS OWN THOUGHTS, AND HE
JUST NEVER SEEMED TO LISTEN.
HE WAS EXTREMELY DISORGANIZED,
KEPT LOSING ALL HIS BELONGINGS
AND WAS CONSTANTLY DISTRACTED BY
THINGS GOING ON AROUND HIM.
THESE SYMPTOMS WERE PRESENT
SINCE PRE-K AND THEY WEREN'T
TRIVIAL, THEY WERE INTERFERING
WITH HIS LEARNING AND HE
REQUIRED QUITE SUBSTANTIAL
ADDITIONAL SUPPORT AT SCHOOL.
HIS MOTHER SAID THAT KEEPING HIM
ON TASK AT HOME WAS A FULL-TIME
JOB FOR HER.
AND PETER HIMSELF WAS AWARE AND
RATHER CRITICAL OF HIS POOR
ATTENTIONAL FOCUS.
HE WAS DIAGNOSED WITH ADHD,
ATTENTION DEFICIT HYPER ACTIVITY
DISORDER AND HE HAS AN
INATTENTIVE PRESENTATION.
AND HERE IS RYAN, ANOTHER
9-YEAR-OLD CHILD TO SHARED THE
SAME CHALLENGES.
HE HAD A POOR ATTENTION FOCUS
BUT IN ADDITION RYAN CONSTANTLY
INTERRUPTED OTHERS AND DIDN'T
LET THEM FINISH THEIR SENTENCES
AND JUST COULDN'T WAIT HIS TURN
IN ACTIVITIES.
SINCE AN EARLY AGE, RYAN ALSO
HAD ALMOST DAILY EXPLOSIVE
TEMPER OUT BUSTS WHEN HE WAS
ASKED TO DO THE SLIGHTEST THING
LIKE STOP PLAYING HIS VIDEO
GAMES OR TIDING HIS ROOMS.
THIS WAS VERBAL BUT COULD BE
PHYSICAL AT TIMES.
RECENTLY, SEVERAL OUTBURSTED HAD
OCCURRED IN THE CLASSROOM
LEADING TO SEVERAL INDOOR
SUSPENSIONS.
BETWEEN THESE OUTBURSTS, HIS
PARENTS SAID RYAN WAS GROUCHY
AND ANGRY AND THEY FELT LIKE
THEY WERE WALKING ON EGGSHELLS
AROUND HIM.
HERE, RYAN'S CHALLENGES WITH HIS
SEVERE IRRITABILITY AND TEMPER
OUTBURSTS, CONTRIBUTED TO HIM
RECEIVING A DIAGNOSIS OF
DISRUPTIVE MOOD DYSREGULATION
DISORDER IN ADDITION TO HIS
ADHD.
Dr. BROTMAN, IS GOING TO TALK
ABOUT THIS SEVERE IRRITABILITY,
SEEN IN DMDD AND I'M GOING TO
FOCUS ON PETER AND HIS SEVERE
INATTENTION.
JUST AS HE WAS ABOUT TO HAVE A
RESEARCH MRI HE ASKED WHAT MIGHT
BE GOING ON IN THE BRAIN DO YOU
THINK TO EXPLAIN THIS?
WELL THERE ARE A HOST OF BRAIN
DIFFERENCES ASSOCIATED WITH ADHD
AND HERE I'M GOING TO FOCUS ON A
THEORY OF ADHD WHICH LARGELY
DERIVED FROM NEUROIMAGING
FINDINGS AND IT'S CALLED A
DEFAULT MODE INTERFERENCE MODEL.
WHAT CAN NEUROIMAGING TELL US
ABOUT ADHD?
WELL, MRI GIVES ULSRUD A WINDOW
INTO THE DEVELOPING BRAIN AND
I'M GOING TO FOCUS ON BRAIN
FUNCTION.
PARTICULARLY THE PATTERNS OF
BRAIN ACTIVITY THAT ARE DETECTED
WHEN A SUBJECT IS AT REST IN
THIS DOING NOTHING SPECIFIC.
THIS IS THE RESTING STATE FMRI.
NOW THE MOST PROMINENT
FUNCTIONAL NETWORK TO EMERGE IN
THE BRAIN WHEN A SUBJECT IS AT
REST, INCLUDES SEVERAL DISTINCT
MID-LINE BRAIN REGIONS THAT I
SHOW HERE AND THIS IS CALLED THE
DEFAULT MODE NETWORK.
SO WHAT THE BRAIN LOOKS LIKE
DURING TASK FREE AND PROCESS
ORGANIZE WHEN THE MIND IS NOT
WANDERING.
TYPICAL KIDS, THE DEFAULT MODE
NETWORKS TENDS TO OPPOSE IS
ANTAGONISTIC OR ANTI-CORAL EIGHT
WITH THE NETWORKS THAT SUPPORT
ATTENTION AND COGNITIVE CONTROL
THAT YOU SEE HERE.
THE DEFAULT MODE NETWORK
INTERFERENCE THEORY STATES THAT
AN ADHD THERE'S A LOSS OF THIS
FINE COUNTERBALANCE BETWEEN THE
DEFAULT MODE AND THE TASK
POSITIVE NETWORKS.
AND ANALOGY IS THE ON-LINE
ACTIVITY OF THE BRAIN IS
REPEATEDLY INTERRUPTED BY THE
BRAIN GOING OFF LINE AMONGST
THOSE WITH ADHD.
NOW THERE'S GOOD DATA SHOWING
THAT SUCH INTERFERENCE IS
ASSOCIATED BEHAVIORAL WITH
ATTENTION OF LAPSES, VARIABILITY
IN RESPONSE TIME AND THE
SUBJECTIVE FEELING OF MIND
WANDERING.
IN ADDITION TO THE BRAIN'S
FUNCTIONALITY ACTIVITY, WE CAN
LOOK AT STRUCTURAL BACK BONES OF
THESE NETWORKS.
THESE BACK BONES ARE FORMED BY
WHITE MATTER TRACKS JOINED
TOGETHER DIFFERENT BRAIN
REGIONS.
WE CAN LOOK AT THE MICRO
STRUCTURE OF THESE TRACKS USING
AN MRI MODALITY CALLED IMAGING
AND SO WHEN THE EVIDENCE FOR THE
DEFAULT MODE INTERFERENCE
NETWORK?
IF YOU DO A SIMPLE TALLY OF 30
INDIVIDUAL STUDIES INTO IT, MOST
SUPPORT THE MODEL BUT SOME DON'T
AND THE SUPPORT IS AT A HIGH
LEVEL WITH MUCH LESS AGREEMENT
ON DETAILS.
TWO META ANALYSIS INTEGRATED THE
PUBLIC'S FINDINGS IN AN EFFORT
TO GET A CLEAR, MORE CONSISTENT
FINDING BUT THEY ENDED UP GIVING
DIFFERENT RESULTS, ONE BROADLY
SUPPORTED THE MODEL AND THE
OTHER DID NOT.
NOW THE INCONSISTENCY IN THE
MATTER REFLECTS DIFFERENCES IN
THIS STUDY THEY INCLUDED.
IN ADDITION, THE META ANALYSIS
RELIED ENTIRELY ON PUBLISHED
FINDINGS OF GROUP DIFFERENCES
THAT EACH INDIVIDUAL STUDY
DECLARED SIGNIFICANT AND THIS
THRESHOLD FOR SIGNIFICANCE CAN
VARY A LOT BETWEEN STUDIES.
ALSO, IT'S POSSIBLE THAT A META
ANALYSIS TO MISS A SIGNAL IF IT
FALLS JUST BELOW SIGNIFICANCE IN
SEVERAL STUDIES.
AND FINALLY I'LL NOTE, EVEN THE
LARGEST META ANALYSIS INCLUDED
AROUND 2,000 SUBJECTS WHICH IS
UNDER PAR TO DETECT SOME VERY,
VERY SMALL EFFECTS.
SO IN RESPONSE TO THESE
LIMITATIONS, MY GROUP AND SOME
OTHERS, HAVE LEVERAGED THE
INCREASING AVAILABLE OF NOT
LARGE IMAGING DATASETS SUCH AS
THE UNITED STATES STUDY OF
ADOLESCENT BRAIN DEVELOPMENT,
THE ABCD.
THESE DATA ALLOW US TO CONDUCT
IMAGING STUDIES WITH OVER 10,000
SUBJECTS AND THIS IS ABOUT TWO
ORDERS OF MAGNITUDE HIGHER THAN
THE AVERAGE INDIVIDUAL MRI
STUDY.
IN THIS WORK WE ALSO FOCUS ON
INDIVIDUAL-LEVEL RAW IMAGING
DATA.
INTEGRATING THE DATA THROUGH
META ANALYSIS.
MEGA ANALYSIS.
SO JUST TO STRESS AGAIN, THIS IS
A VERY DIFFERENT APPROACH FROM
META ANALYSIS WHICH INTEGRATE
PUBLISHED FINDINGS SUMMARIZING
GROUP DIFFERENCES AND HERE WE'RE
LOOKING AT INDIVIDUAL LEVEL RAW
DATA.
AND THIS WORK IN MY GROUP HAS
BEEN LED BY GUSTAVO, LUKE AND
MARINE AND THE FIRST FINDINGS
HAVE BEEN PUBLISHED.
SO HERE IS A OVERVIEW OF THE
PROCESS.
FIRST WE OBTAIN IMAGING DATA
FROM LARGE COHORTS AND SO FAR
WE'VE GOT DATA ON ABOUT 12,000
YOUTH.
THE UNIFORM PROCESSING PIPELINE
WE USE IS A WELL VALIDATED ONE
IMPLEMENTED ON SUPER COMMUTING
FACILITIES AT NIH.
AND ONE OF THE GREATEST
ADVANTAGES OF THIS UNIFORM
PROCESSING PIPELINE, IS QUALITY
CONTROL.
SO FOR EXAMPLE, IN OUR WORK, WE
CAN EXCLUDE THE TOP 10 OR 20% OF
SCAMS THAT SHOW EXCESSIVE MOTION
ON ANY OF THE MANY PARA AM TERES
WE CALCULATE.
AS A RESULT OF THIS, WE EXCLUDE
BETWEEN 20 TO 35% OF DATA.
GIVEN THE VERY LARGE SAMPLE
SIZE, IT IT ALSO LIES TO MATCH
ONE TO ONE ON KEY POTENTIAL COP
FINES, SUCH AS THE DEGREE OF
INSCANNER HEAD MOTION.
THE LARGE SIZE ALSO ALLOWS US TO
CONSIDER IMPORTANT FACTORS SUCH
AS THE CORRELATIONS OF
MEDICATION USE AND CO MORBID
CO-MORBIDITIES.
WE CAN ALSO CONSIDER THE ADHD AS
A DIAGNOSIS AND ADHD AS A
CONTINUOUS BEHAVIORAL TRADE.
ALL OF THESE WE'RE LOOKING FOR
ASSOCIATIONS WITH ADHD AND IN
ALL OF THEM WE CONTROL
STATISTICALLY IT WAS ACQUIRED AT
MULTIPLE DIFFERENT SITES.
SO FIRST OF ALL, LET'S CONSIDER
THE HYPOTHESIS THAT AN ADHD
THERE WILL BE CONNECTIVITY
BETWEEN THE DEFAULT AND THE TASK
POSITIVE NETWORKS.
WELL FIRST OF ALL WE DID A CASE
CONTROL CONTRAST WITH 1,300 KIDS
WITH DIAGNOSIS ABLE ADHD AND
1,300 UNEFFECTED INDIVIDUALS.
WHO WERE VERY TIGHTLY MATCHED IN
TERMS OF THEIR GENDER, AGE AND
DEGREE OF IN SCANNER MOTION.
NOW IN THE UNEFFECTED OR NEURO
TYPICAL INDIVIDUALS, WE WOULD
EXPECT THAT THE DEFAULT MODE NED
WORK WILL BE EMPTY CORRELATED OR
OPPOSED TO MOST TRAFFI TASK POSITIVE
NETWORKS.
THIS WAS IN DEED THE CASE.
ALSO WE EXPECT THOSE WITH ADHD
TO SHOW LESS OF THIS
ANTAGONISTIC RELATIONSHIP AND
LESS OF THE ANTI-CORAL RACE.
THIS IS BROADLY COMPATIBLE WITH
THE DEFAULT MODE NETWORK
INTERFERING IN YOU LIKE, WITH
MORE TASK POSITIVE NETWORKS.
NOW THIS DIAGNOSTIC EFFECT WAS
PARTICULARLY STRONG BETWEEN THE
DEFAULT MODE AND THE ATTENTION
NETWORK SHOWN HERE.
THE RELATIONSHIP WAS REALLY
VERY, VERY SIGNIFICANT AS YOU
CAN SEE FROM THE P VALUES.
IT'S ALSO HELPFUL TO REPRESENT
CASE CONTROL DIFFERENCES AS
EFFECT SIZES AND THESE CAPTURED
THE STRENGTH OF A FINDING, NOT
JUST IT'S SIGNIFICANCE.
THE DIFFERENCE OF HOW THE
DEFAULT MODE WAS CONNECTED TO
THE ATTENTION NETWORKS, WAS
ASSOCIATED WITH AN OVER ALL
EFFECT SIZE OF ABOUT NOT .1 #,
IT IT IS SHOWN IN RED.
AND THIS IS THE MEGA ANALYTIC OR
COMBINED EFFECT SIZE THAT IS
DERIVED FROM THE INDIVIDUAL
CONTRIBUTING COHORTS IN BLACK.
IT MEANS THE DISTRIBUTION OF
THIS FUNCTIONAL CONNECTIVITY
PROPERTY AND THOSE WITH AND
WITHOUT ADHD, ARE ONLY VERY
SLIGHTLY SEPARATED BY ABOUT A
TENTH OF A STANDARD DEVIATION.
AND A SIMILAR PICTURE IN
MARRIAGE WHEN WE CONSIDERED ADHD
MUCH TRADES.
HERE MEASURED BY PARENTAL
REPORTS OF ATTENTION PROBLEMS
USING A WELL-STANDARDIZED
QUESTIONNAIRE AND DATA IN THIS
STUDY THE PAST QUALITY CONTROL
WHERE THEY LIVE ON ABOUT 10,000
YOUTH.
HERE, WE FIND THAT MORE SYMPTOMS
OF ADHD MEANT THAT THEY OFF LINE
BRAIN WAS MORE PRONE TO
INTERRUPT THE ON-LINE TASK
ORIENTED BRAIN, THERE WAS LESS
ANTI-CORRELATION.
AGAIN, THESE ARE VERY
SIGNIFICANT EFFECTS AND THEY ARE
TIED TO SMALL EFFECTS, YOU CAN
SEE THEM IN RED AND THEY HOVER
AT A VALUE OF ABOUT JUST UNDER
.1.
NOW THEY'RE VERY ROBUST FINDINGS
AND FOR EXAMPLE, THEY CAN'T BE
EXPLAINED BY THE POSSIBILITY
THAT THERE'S WITH ADHD WERE
MOVING MORE IN THIS SCANNER AND
THEY CASES IN CONTROLS WERE VERY
TIGHTLY MATCHED ON THIS
PARAMETER OF INSCANNER MOTION.
ALSO, THE FINDINGS WEREN'T DUE
TO MEDICATION EFFECTS AS THEY
HELD WHERE THEY EXCLUDE EVERYONE
WHO WAS ON ANY MEDICATIONS
INCLUDING PSYCHO STIMULANTS FOR
ADHD.
HOWEVER AGAIN I'LL * THE EFFECTS
ARE SMALL.
O WHAT OF THE BRAINS STRUCTURAL
CONNECTIONS?
REMEMBER THESE ARE THE THINGS
MADE UP BY WHITE MATTER TRACKS.
HERE THE HYPOTHESIS IS THAT ADHD
AND ITS PROBLEMS WILL BE
ASSOCIATED WITH ALTER MICRO
STRUCTURE OF THE WHITE MATTER
TRACKS THAT CONNECT THE
DIFFERENT PARTS OF THE
FUNCTIONAL NETWORKS TOGETHER.
THIS SHOWS A GLASS BRAIN AND THE
WHITE MATTER TRACKS ARE KNOWN
IT.
IN CASE CONTROL ANALYSIS, WE
FIND THAT ADHD WAS ASSOCIATED
WITH DECREASES IN A MEASURE OF
WHITE MATTER MICRO STRUCTURE
CALLED FRACTURE ANI IS SO IT TR
OPY, IT'S SHOWN HERE BY LOG P
VALUES AND DARKER COLORS
INDICATE MORE SIGNIFICANCE.
FINDINGS THAT WERE SIGNIFICANT
AFTER AN ADJUSTMENT FOR MULTIPLE
TESTING ARE SHOWN WITH THE
ASTERISKS AND THESE LIE IN THE
DEFAULT MODE AND VEN TRAL
ATTENTION NETWORKS.
THEY WERE SIMILAR FINDINGS WHEN
WE LOOKED AT ADHD TRADES
MEASURED AGAIN IN ABOUT KIDS
AGAIN THESE ARE REPORTED BY
PARENTAL QUESTIONNAIRE SO HERE
AS WE'RE FUNCTIONAL CONNECTIVITY
WE'RE SEEING THE STRUCTURAL
CONNECTIVITY CORRELATES OF ADHD
AS A DIAGNOSIS, ARE VERY SIMILAR
TO THOSE OF ADHDS TREATED AS A
CONTINUOUS BEHAVIORAL TRAIT.
HERE I UNPACK THE TWO MOST MANY
SIGNIFICANT ASSOCIATIONS BETWEEN
ATTENTION PROBLEMS AND WHITE
MATTER TRACKED MICRO STRUCTURE.
AND AS YOU CAN SEE THE P VALUES
ARE TINY AND INDICATING HIGHLY
SIGNIFICANT GROUP DIFFERENCES
BUT THE EFFECT SIZES ARE SMALL
AND NOT INDICATING THAT THE
MAGNITUDE OF THIS DIFFERENCE IS
MODEST.
HERE ARE OTHER SYMPTOM
DIMENSIONS, AS YOU CAN SEE,
SOCIAL PROBLEMS WHICH MIGHT BE
THOUGHT TO HAVE BARRING ON
AUTISTIC SPECTRUM CHALLENGES
SHOW A SIMILAR PATTERN OF
ASSOCIATION.
INTERESTINGLY, PROBLEMS WELL
MOOD OR ANXIETY WERE NOT
ASSOCIATED HERE WITH ALTERED
WHITE MATTER MICRO STRUCTURE.
HERE WE'RE FINDING THAT THE
ALTERATIONS SO SOME DEGREE OF
SPECIFICITY TO BEHAVIOR ALDO
MAIN.
SO JUST TO SUMMARIZE,
FUNCTIONSAL AND STRUCTURAL
CONNECTION ACTIVITY SHOW ROBUST
HIGHLY SIGNIFICANT ADHD
ASSOCIATED CHANGES BROADLY IN
LINE WITH THE DEFAULT MODE
INTERFERENCE MODEL.
HOWEVER, THE EFFECT SIZES ARE
SMALL, THE SUPPORT IS MODEST.
IN SHORT THIS IS A PART OF THE
STUDY AND A LARGE PART FOR A SUB
MET OF CHILDREN BUT AT MOST IT'S
ONE VERY SMALL PART OF A COMPLEX
PUZZLE.
IT'S IMPORTANT TO REALIZE THIS
ISN'T THE LAST WORD.
MIGHT LARGER ADHD DIFFERENCES BE
FIND ELSEWHERE IN THE BRAIN AND
THE ANSWER IS ALMOST YES AND
FIRST OF ALL, NEUROIMAGING IS A
RAPIDLY ADVANCING SCIENCE WHERE
ROUTINELY IMAGING AT SEVEN TESLA
COMPARED TO 1.45 TESLA IN PLACE
WHEN I JOINED NIH 20 YEARS AGO
AND THESE STRONGER FIELDS ALLOWS
TO QUANTIFY NEURO TRANSMITTERS
WITH CONSIDERABLE ACCURACY
INCLUDING GAB A AND GLUTEAMATE
WHICH I'LL TALK ABOUT LATER.
ALL THE STUDIES ARE CROSS
SECTIONAL AND TREAT ADHD AS A
UNIT ENTITY OR DIMENSION AND IT
SEEMS HIGHLY LIKELY THAT THERE
MAY BE SUBGROUPS OF CHILDREN
WITH ADHD WHO WILL SHOW MORE
PRONOUNCED NEURAL DIFFERENCES.
PERHAPS IT WILL BE CHILDREN WHO
HAVE CERTAIN GENETIC
DIFFERENCES.
CHILDREN DEFINED BY FEATURES
SUCH AS SEVERE IRRITABILITY AND
WHAT IF WE LOOK OVER TIME?
WELL IT SEEMS HIGHLY LIKELY THE
CHILD WHO HAS ADHD THAT PERSISTS
FOR 10 YEARS MAY HAVE MORE MARK
NEURAL DIFFERENCES THAN THE
YOUTH WITH ADHD AND ADMITS WITH
AGE OR FLUCTUATES WITH AGE.
MY GROUP IS PARTICULARLY EXCITED
BY THE LAST LONGITUDINAL
APPROACH AS OVER THE YEARS,
WE'VE AMASSED A CONSIDERABLE
AMOUNT OF EVIDENCE THAT
DIFFERENCES RELATED TO ADHD ARE
MUCH DIFFERENT IF IF YOU LOOK
LONGITUDINALLY RATHER THAN CROSS
SECTIONALLY AND EFFECT SIZES
MOVE FROM SMALL TOWARDS BEING
MEDIUM.
SO TO THI END, WE HAVE 30,000 OF
MODEL DATASETS TO SEE IF THE
DIFFERENCE SYMPTOMS OF
TRAJECTORIES OF ADHD ARE TIED TO
MORE MARKED NEURAL DIFFERENCES,
PARTICULARLY IN HOW THE DEFAULT
MODE NETWORK INCOMPETENTER ACTS
WITH TASK POSITIVE NETWORK.
NOW ON TO A DIFFERENT WAY OF
LOOKING AT THE BRAIN.
I'VE BEEN TALKING A LOT ABOUT
HIGH MRI STUDIES PROVIDING A
WINDOW INTO THE BRAIN OF
CHILDREN WHO ARE GROWING UP WITH
ADHD.
HOWEVER, IMAGING HAS MANY
LIMITATIONS, FOR EXAMPLE, IT CAN
DETERMINE HOW GENES THAT MAY BE
IMPORTANT TO ADHD MIGHT DEFER IN
THEIR EXPRESSION OF THE BRAIN
AND IN THIS REGARD, POSTMORTEM
STUDIES REPEAT INVALUABLE AND
THE ABSENCE IS SUCH DATA IN ADHD
HAS BEEN A MAJOR BARRIER TOWARDS
OUR UNDERSTANDING OF MOLECULAR
MECHANISMS UNDERPINNING THE
DISORDER.
SO IN COLLABORATION WITH THE
HUMAN BRAIN COLLECTION CORE AND
IMC AND THE VALUE CORE OF NHGRI,
WE CONDUCTED THE FIRST STUDY TO
DETERMINE DIFFERENCES IN THE
EXPRESSION OF JEEP, THE
TRANSRIPTOME AND THOSE WITH AND
WITHOUT LIFETIME HISTORIES OF
ADHD.
WE FOCUSED ON TWO BRAIN REGIONS,
AND AS THESE INSTRUCTION TURES
SUPPORT COGNITIVE PROCESSES THAT
ARE OFTEN DISRUPTED IN THE
DISORDER AND WE OBTAINED TISSUE
FROM 27 DONORS WITH HISTORY OF
ADHD AND # # UNEFFECTED
COMPARISON DONORS WITH THE AGE
OF 22 AND HERE IS THE OVERVIEW
OF THE PROCESSING DETAILS AND
RNA WAS EXTRACTED AND SEQUENCES
BY OUR COLLEAGUES DATA UNDERWENT
CONTROL CONTROL AND WE HAD THE
GENE EXPRESSION RELATED TO ADHD.
WE CONSIDERED TECHNICAL FACTORS
WITH SEQUENCING BATCH AND
BIOLOGICAL FACTORS SUCH AS
POPULATION STRUCTURE AND
CLINICAL FACTORS SUCH AS
HISTORIES OF SUBSTANCE ABUSE AND
DEPRESSION.
AND SO WHAT DID WE FIND?
WELL THESE VOLCANO SHOW
DIFFERENTIAL GENE EXPRESSION
DEGREE OF DIFFERENCES ON THE X
AXIS AND SIGNIFICANCE IS ON THE
Y AXIS THE MANHATTAN PLOTS SHOW
AND THEY ARE CORRECTIONAL FOR
MULTIPLE ARE SHOWN IN RED AND
OVER ALL, THE DIFFERENTIAL
EXPRESSION AND THE CONTEXT AND
THEY WERE ALL OVER EXPRESSED IN
ADHD AND THEY'RE IN THIS CORNER
HERE.
THERE WAS ONLY ONE GENE THAT APP
TAPED DIFFERENTIAL SIGNIFICANT
EXPRESSION FOR THE QUALITY.
OF THE 14 GENES, SEVERAL HAVE
ALREADY BEEN IMPLICATED IN
PSYCHIATRIC DISORDER AND THIS
INCLUDES NOT JUST ADHD AND ALSO
ALCOHOL DEPENDABL DANCE AND A MAJOR
DEPRESSION.
THESE GENES HAVE BEEN TIED TO
NEURO PLASTIC PROCESS THAT'S
HAVE BEEN IMPLICATED IN THE
PATHOGENESIS OF ADHD.
WE ASKED IF GENES THAT WERE
DIFFERENTIALLY EXPRESSED LAY IN
ANY KEY BIOLOGICAL PATHWAYS UNS
GENE SET ENRICHMENT ANALYSIS AND
THEY DID.
THE GRAPH SHOWS THE DEGREE OF
SIGNIFICANT ENRICHMENT AND THE
TIMING POINTED TO GENES THAT ARE
INVOLVED IN NEURO TRANSMISSION,
ALL IN NEURO TRANSMITTER ARE
HIGHLIGHTED IN RED.
THESE INCLUDE TRANSIT PERCENT
TRAPS MIGHTER AND GABA THE
BRAIN'S MAJOR INHIBITORY
TRANSMITTER.
WE ASKED GENE EXPRESSION
DIFFERENCES RESEMBLE THOSE IN
PSYCHIATRIC DISORDERS AND IN
DEED THEY DID.
THIS IS SHOWN HERE.
EACH SHOWS A DIFFERENT DISORDER
AND EACH DOT REPRESENTS A
DIFFERENT STUDY.
AND YOU CAN SEE THE CORRELATIONS
WERE GENERALLY MODEST AND VARIED
BY STUDY AND OVER ALL
SIGNIFICANCE, WAS A TAPED FOR ATTAINED FOR
ADHD AND AUTISTIC SPECTRUM
DISORDERS, SCHIZOPHRENIA AND BY
OLE AR EFFECTIVE DISORDER AND SO
TO SUMMARIZE, WE FIND THAT
SIGNIFICANT DIFFERENCES IN GENE
EXPRESSION IN BRAIN REGIONS
PIVOTAL THAT ADHD AND THESE
DIFFERENTIALLY EXPRESS GENES AND
ENRICH PATHWAYS INVOLVED IN
NEURO TRANSMISSION AND JUST AS
ADHD OVERLAPS WITH MANY OTHER
PSYCHIATRIC CHALLENGES, A
CLINICAL COGNITIVE AND NEURO
LEVELS AND SO IS WE FIND
SIMILARITY IN ALTERATIONS IN
GREEN EXPRESSION ACROSS
DISORDERS.
WE'RE NOW TAKING THIS POSTMORTEM
WORK FORWARD LOOKING AT GENE
CHANGES NOT AT THE LEVEL OF
BRAIN TISSUE WE'VE DONE AND THE
LEVEL OF INDIVIDUAL NUCLEI AND
I'LL END BY ASKING HOW CAN WE
BRIDGE TOGETHER SUCH POSTMORTEM
WORK WITH IN VIVO IMAGING?
WELL TO GIVE JUST ONE EXAMPLE,
THE POSTMORTEM WORK POINTED
STRONGLY TO GENES INVOLVED IN
GABA AND GLU IT TAMATERGIC AND
WE CAN QUANTIFY BOTH GABA AND
GLUTE MATE LEVELS IN KIDS SO
WE'RE NOW ASKING IF THESE NEURO
TRANSMITTERS ARE ALTERED ACROSS
DEVELOPMENT IN CHILDREN GROWING
UP, WITH ADHD, AND A MANNER
ANALOGOUS TO THAT SCENE IN OUR
GENE EXPRESSION STUDY.
AND ON THAT NOTE I'LL JUST END,
AGAIN BY THANKING MY TEAM.
I'D LIKE TO ACKNOWLEDGE THE OPEN
DATASETDATASETS WE USED AND COLLABORATE
AND I'LL HAND OVER TO Dr.
MELISSA BROTMAN AS WE CONSIDER
THE INATTENTION TA PETER FINDS
SO CHALLENGES TO SOME OF THE
CHALLENGES THAT RYAN FACED,
THANK YOU.
THANK YOU SO MUCH FOR IN
INVITING ME TODAY.
AND THANK YOU TO Dr. SHAW FOR
SUCH A EXCITING INTRODUCTION.
HE SPOKE A LOT ABOUT TH ANATOMY OF
ADHD AND I'M GOING TO SPEAK OF
SEVERE IRRITABILITY AND MOBILE
APPLICATIONS IN APPS.
I HAVE NO CONFLICTS TO DISCLOSE,
ALL THE RESEARCH I'LL BE TALKING
ABOUT TODAY WAS FUNDED BY THE
INTRAMURAL RESEARCH PROGRAM AT
NIMH AND TWO NIH BENCH TO
BEDSIDE AWARD PROGRAMS.
SO I HAVE FOUR LEARNING
OBJECTIVES I WANT TO REVIEW
TODAY.
FIRST, WHAT I WANT TO DO, IS
REALLY DEFINE IRRITABILITY,
ADHD, AND THIS STANDARD
PSYCHOLOGICAL PROCESS OF
INHIBITORY CONTROL.
THEN WHAT I WANT TO DO IS TALK
ABOUT SOME OF THE ADVANTAGES OF
DEVELOPING MOBILE APPLICATIONS
TO PROBE THESE SPECIFIC
PSYCHOLOGICAL PROCESSES AND
THIRD I WANT TO INTRODUCE A GAME
WE DEVELOPED CALLED CALM-IT AND
THE GOAL OF THIS MOBILE APP IS
TO SPECIFICALLY MEASURE
INHIBITORY CONTROL.
FOURTH, I'M GOING TO SHARE SOME
DATA THAT DEMONSTRATES SOME
EARLY FEASIBILITY THAT IS WILL
CHILDREN ACTUALLY PLAY THE GAME?
SOME EARLY VALIDITY, THAT IS IS
DOES THE GAME ACTUALLY MEASURE
THE CONSTRUCT OF INHIBITORY
CONTROL, RELIABILITY THAT IS
PERFORMANCE, IS IT STABLE OVER
TIME AND SOME EARLY CLINICAL
ASSOCIATIONS THAT IS PERFORMANCE
ON THIS MOBILE APP ASSOCIATED
WITH SPECIFIC SYMPTOMS OF
PSYCHOPATHOLOGY AND I'LL END BY
TALKING ABOUT SOME FUTURE
DIRECTIONS OF OUR WORK.
SO, AS Dr. SHAW TALKED ABOUT,
IRRITABILITY AND ADHD ARE AMONG
THE MOST COMMON REASONS YOUTH
ARE BROUGHT IN TO BE PSYCHIATRIC
EVALUATION AND CARE.
WHAT DO WE MEAN BY IRRITABILITY?
AN IRRITABILITY, IT'S DEFINED
ESSENTIALLY AS AN INCREASE ON
PRONENESS TO ANGER, THESE
CHILDREN HAVE A PRO TENSE TEE
TOWARDS AN ANGRY, GRUMPY, CRANKY
MOOD AND A LOW THRESHOLD FOR
TEMPER OUTBURSTS.
AND AS Dr. SHAW MENTIONED,
THERE'S A RELATIVELY NEW
DIAGNOSIS IN DSM5 CALLED
DISRUPTED MOOD DYSREGULATION
DISORDER WHERE YOUTH ARE
SPECIFICALLY CHARACTERIZED BY
CHRONIC IRRITABILITY AND TEMPER
OUTBURSTS.
NOW, FOLKS TEND TO BE SOME WHAT
MORE FAMILIAR WITH THE DIAGNOSIS
OF ATTENTION DEFICIT HYPER
ACTIVITY DISORDER.
OR ADHD.
WHICH AS WE KNOW IS ASSOCIATED
WITH GENERAL INATTENTION, TRACT
ABILITY AND HYPER ACTIVITY.
NOW INTERESTINGLY, BOTH YOUTH
WITH IRRITABILITY AND CHILDREN
DIAGNOSED WITH ADHD, HAVE
DIFFICULTY INHIBITING RESPONSES.
AND IN CLINICALLY, IF WE THINK
ABOUT THIS, THIS MAKES SENSE.
WHEN AN IRRITABLE CHILD GETS
REAL HE'S ANGRY, THEY OFTEN
YELL, SCREAM, MAY THROW
SOMETHING, SLAM A DOOR, AND KIDS
WITH ADHD HAVE PROBLEMS
INHIBITING THEIR RESPONSES.
THEY OFTEN CALL OUT ANSWERS,
SPEAK OUT OF TURN, ACT BEFORE
THEY THINK.
SO WHAT IS INHIBITORY CONTROL?
INHIBITORY CONTROL IS A VERY
SPECIFIC COGNITIVE PROCESS THAT
PSYCHOLOGISTS MEASURE AND IT'S
SPECIFICALLY DEFINED AS ONES'
ABILITY TO MODIFY A PRE POTENT
OR DOMINANT RESPONSE.
THAT IS, IT'S DEFINED AS ONES'
ABILITY TO SUPPRESS GOAL
IRRELEVANCE STIMULI IN ORDER TO
EXECUTE A SPECIFIC BEHAVIOR.
AND THIS BEHAVIORAL PROCESS HAS
BEEN EXTENSIVE LEASE STUDIED AND
MAPPED ON TO SPECIFIC
NEUROCIRCUIT TREE AND INCLUDING
AREAS OF THE PREFRONTAL CORTEX,
INTERIOR SINGULAR CORTEX AND
AREAS IN THE DEFAULT MODE
NETWORK AS Dr. SHAW DISCUSSED.
NOW, NOT SURPRISINGLY, THESE ARE
AREAS WE OFTEN SEE DYSFUNCTION
IN YOUTH STRUGGLING WITH
IRRITABILITY AND ADHD.
AND OVER THE PAST SEVERAL
DECADES, PSYCHOLOGISTS HAVE
DEVELOPED A LARGE SUITE OF
BEHAVIORAL TASK THAT ASSESSED
ONES' ABILITY TO WITH HOLD OR
CHANGE A PRE POTENT RESPONSE
INCLUDING THE STOP LAY TASK THAT
THE AXCPX AND THE FLANKER.
NOW THESE TASKS ARE EXTREMELY
ROBUST AND THEIR ABILITY TO
ASSESS PER DEFICITS IN
INHIBITORY CONTROL, HOWEVER,
THESE TASKS TEND TO BE QUITE NOT
TIME INTENSIVE THAT THEY'RE VERY
BORING.
IF YOU ASK CHILDREN, THEY REPORT
THIS.
ALSO, THEY'RE NOT GENERALLY
ACCESSIBLE TO THE COMMUNITY AT
LARGE.
SO IN THE PAST SEVERAL YEARS,
TECHNOLOGICAL ADVANCES HAVE
PROVIDED CLINICIAN AND
RESEARCHERS WITH MORE ACCESSIBLE
PLATFORMS INCLUDING MOBILE
APPLICATIONS AND MOBILE AND
WEARABLE DEVICES.
SO, SOME OF THE ADVANTAGES OF
THESE MOBILE APPS, OF COURSE,
THEY'RE MUCH MORE ACCESSIBLE TO
THE COMMUNITY AND WE SAW THIS TO
BE ESPECIALLY TRUE DURING THE
PANDEMIC WHEN WE WEREN'T ABLE TO
SEE CHILDREN AND FAMILIES IN THE
CLINIC, WE COULD DEVELOP AND
PUSH THESE MOBILE APPS TO
CHILDREN TO COMPLETE AT HOME OR
OUTSIDE THE CLINIC.
WE ALSO LEARNED THE IMPORTANCE
OF GATHERING THESE DATA I AM IN VIVO,
WHERE THESE INTENSE EMOTIONS AND
DYSFUNCTIONAL BEHAVIORS ARE MOST
LIKELY TO OCCUR.
WE ALSO HAD THE ABILITY TO HAVE
THESE CHILDREN PLAY THESE GAMES
MULTIPLE TIMES OVER THE DAVE AND
MULTIPLE TIMES OVER THE DAY
WITHIN A WEEK.
AND BY HAVING CHILDREN PLAY
THESE GAMES, MANY TIMES, WE CAN
CAPTURE VARIABILITY IN
PERFORMANCE OVER TIME.
AND WE CAN ALSO CAPTURE CHANGES
IN EMOTION.
AND THESE MULTIPLE REPLICATES
CAN START TO GIVE US A WINDOW
INTO CAUSALITY AND THAT IS, IT
GIVES US THE OPPORTUNITY TO
START TO ASK QUESTIONS LIKE, DO
SPECIFIC BEHAVIORS LIKE IMPAIRED
INHIBITORY CONTROL, TEND TO BE
WORSE BEFORE SAY A TEMPER
OUTBURST IN A CHILD WITH SEVERE
AND IMPAIRING IRRITABILITY.
AND IF WE CAN ACTUALLY PREDICT
TEMPER OUTBURSTS BEFORE THEY
OCCUR, ULTIMATELY WE MAY BE ABLE
TO INTERVENE BEFORE THAT
DYSFUNCTIONAL EMOTIONAL EVENT
PRESENTS ITSELF.
SO AS A RECAP, INHAD HIB TORI
CONTROL IS A ESTABLISHED
PSYCHOLOGICAL PROCESS DEFINED AS
ONES' ABILITY TO WITH HOLD OR
MODIFY A PRE POTENT RESPONSE.
INHIBITORY CONTROL IS ASSOCIATED
WITH IRRITABILITY AND ADHD.
AND WE HAVE THESE VERY ROBUST
STANDARDIZED TASK BUT THEY'RE
NOT PARTICULARLY ACCESSIBLE TO
THE COMMUNITY.
MUCH SOP OUR GOAL AND THIS IS
PARTICULARLY TRUE DURING THE
ACUTE STAY AT HOME ORDERS DURING
COVID-19 WAS TO DEVELOP AND TEST
AN ENGAGING MOBILE APP THAT
COULD RELIABLY PROBE INHIBITORY
CONTROL IN VIVO AND THAT IS
NATURALISTIC LEASE, WELL KIDS TO
PLAY THE GAMES AT HOME.
WE CREATED THIS GAME THAT COULD
BE DOWNLOADED ON AN iPHONE AND
THAT TAKES PLACES IN SPACE.
EACH GALAXY REPRESENTS A
DISTINCT LEVEL OR BLOCK OF
TRIALS AND WHILE EXPLORING THE
GALAXY, PARTICIPANTS ARE
INSTRUCTED TO DESTROY OR NOT
SWIPE THEIR FINGER ACROSS THIS
SCREEN, CERTAINLY TARGETS AND
NOT SWIPE OR INHIBIT THEIR MOTOR
RESPONSE TO OTHER TARGETS.
SO, WHAT I'M GOING TO SHOW YOU
HERE, IS A CHILD'S PLAYING A
GAME AND I'M GOING TO WALK YOU
THROUGH WHAT THEY'RE DOING.
THE CHILDREN ARE BEING INSTRUCT
TODAY WIPE THE RED, PURPLE AND
YELLOW CIRCLES BUT NOT THE
YELLOW SUN.
THE CHILD IS SWIPING THE
TARGETS, AVOID THAT YELLOW SUN.
SWIPING THE TARGETS.
THEY SWIPED THE SUN.
SWEEPING THE TARGETS.
AND THEN SWEEPING THE YELLOW SUN
AND TO POINT OUT, WHEN THE
CHILD'S SWIPES THE TARGET, THEY
GAIN POINTS -- WE COULD SEE IF THE
CHILD SWIPED THE PURPLE, BLUE OR
RED CIRCLE OR NOT.
AND USING THESE INDIVIDUAL
RESPONSES, WE CAN THEN CALCULATE
EACH CHILD INHIBITORY CONTROL
PERFORMANCE BY USING A METRIC
CALLED DEPRIME.
DEPRIME IS A MEASURE OF
SENSITIVITY WHEREBY WE SUBTRACT
THE STANDARDIZED RATE OF THOSE
YELLOW HIT SUNS THAT IS IS THE
NUMBER OF TIMES THAT THEY SWIPED
NOT WHEN THEY WEREN'T SUPPOSED
TOP OR THE NUMBER OF MISTAKES
FROM THE STANDARDIZED RATE OF
HIT CIRCLES THAT IS GOOD
PERFORMANCE AND A HIGHER DEEP
CRIME INCOMPETENT GATES BETTER
PERFORMANCE OR INHIBITORY
CONTROL.
WE ADMINISTERED THIS TASK TO 148
YOUTH AND CHILDREN BETWEEN THE
AVERAGE OF EIGHT AND 18 WITH A
LITTLE OVER A LITTLE OVER HALF
BEING NOW.
WHEN CHILDREN PLAYED THE GAME WE
ACTUALLY ALSO ASKED CHILDREN AND
PARENTS TO COMPLETE SYMPTOM
MEASURES ASSESSING LEVELS OF
IRRITABILITY AND ADHD, AND
ANXIETY, AND DEPRESSION.
AND NOTABLY WE RECRUITED
CHILDREN FROM OUR ON GOING
CLINICAL CHARACTERIZATION
STUDIES WHERE EACH CHILD HAD A
PRIMARY DYING KNOW IS OF EITHER
DISRUPTIVE MOOD DYSREGULATION
DISORDER, DMDD AND THESE ARE
CHILDREN WHO ARE ENRICHED OF
HIGH LEVELS OF IRRITABILITY AND
TEMPER OFFERS AND A DIAGNOSIS OF
HYPER ACTIVITY DISORDERS AND
CHILDREN WITH THE PRIMARY
DIAGNOSIS OF ANXIETY DISORDERS
AND SEPARATION ANXIETY AND
SOCIAL PHOBIA AND KIDS WITH
OPPOSITION DEFINED DISORDER ALSO
ENRICHED FOR IRRITABILITY AND
TYPICALLY DEVELOPING HEALTHY
CONTROL YOUTH WITH NO CLINICAL
DIAGNOSIS.
WE PRE REGISTERED THIS REPORT
OUTLINING THE MAIN HYPOTHESIS
AND QUESTIONS, THE FIRST AUTHOR
IS Dr. ALYSE CARDINALLY WHO A
TENURE TRACK PROFESSOR AT
CATHOLIC UNIVERSITY.
AND WE HAVE FOUR PRIMARY
QUESTIONS.
FIRST, FEASIBILITY.
IS IT FEASIBLE TO DEVELOP AN
INHIBITORY CONTROL MOBILE APP
AND THAT IS, WILL THE DATA BE
USEABLE AND AND THEY ARE ENGAGE
AND PLAY THE GAME PROPERLY
SECOND, IS THE TASK VALID, THAT
IS DOES THE APP IN FACT MEASURE
THIS CON INFRASTRUCTUR CONSTRUCT OF CONTRO L.
SPECIFICALLY IS PERFORMANCE ON
THIS MOBILE APP RELATED TO THESE
STANDARDIZED ESTABLISHED
MEASURES OF INHIBITORY CONTROL
TASKS.
IS THE TASK RELIABLE, IF
CHILDREN PLAY THE GAME MULTIPLE
TIMES HOW STABLE IS THEIR
PERFORMANCE OVER TIME.
AND IS THE TASK CLINICALLY
RELEVANT THAT IS IS IS
PERFORMANCE ON THE TASK
ASSOCIATED WITH SPECIFIC
SYMPTOMS OF IRRITABILITY AND
ADHD?
SO QUESTION ONE, ALMOST CHILDREN
PLAY THE GAME WELL IN BRIEF, WE
FOUND IN 148 YOUTH, WE FOUND
THAT 99 THE DATA WERE USEABLE.
WERE THEY ENGAGED IN TRYING TO
SWIPE THE RED, BLUE AND PURPLE
COLORED CIRCLES AND ALSO YES AND
WE FOUND THAT 91% OF THE TRIALS
THAT THE CHILDREN APPEARED TO BE
ENGAGED, AND TRYING TO SWIPE
THOSE TARGETS.
SO THE BOTTOM LINE HERE IS IS
THIS SHOWS PRELIMINARY
FEASIBILITY OF THIS TASK AND
QUESTION TOO AND WAS PERFORMANCE
ON THE TASK RELATE TODAY'S THIS
STANDARDIZED TASK PERFORMANCE.
SO AS YOU RECALL WE HAVE THESE
ESTABLISHED TASK THAT'S WE KNOW
MEASURE INHIBITORY CONTROL AND
IN A SUBSET OF 91 YOUTH OF THE
148 WHO COMPLETED THE APP, WE
HAD THEIR PERFORMANCE ON SOME OF
THESE STANDARDIZED TASKS AND I'M
NOT REQUESTINNOT GOING TO GET INTO ALL THE
DETAILS BUT THE BOTTOM LINE IS
WE CAN EXTRACT A LATE ANT
VARIABLE BUT EACH CHILD'S
PERFORMANCE ON THE STANDARDIZED
TASKS AND THIS BLATANT VARIABLE
REPRESENTS THAT THE SHARED
VARIANCE ASSOCIATED WITH THE
UNDERSTAND LYING CONSTRUCT AND
INHIBITORY CONTROL ACROSS THESE
STANDARDIZED TASKS.
AND THEN WHAT WE DID IS WE
LOOKED AT THE RELATIONSHIP
BETWEEN THE PERFORMANCE ON THIS
APP AND THE PERFORMANCE ON THIS
INHIBITORY CONTROL LATE ANT
FACTOR.
WHAT WILL WE SEE IS A
SIGNIFICANT POSITIVE
ASSOCIATION.
THAT IS YOUTH DEPRIME
PERFORMANCE ON THE APP WAS
POSITIVELY CORRELATED WITHEL
OVER ALL INHIBITORY CONTROL LATE
ANT FACTOR AND THIS DEMONSTRATES
PRELIMINARY VALIDITY OF COMET CALM-IT
PERFORMANCE.
NEXT, WE WANTED TO KNOW IF
CHILDREN PLAYED THE GAME
MULTIPLE TIMES, WAS THEIR
PERFORMANCE STABLE OVER TIME?
WHAT WE DID HERE, WAS WE
ADMINISTERED THE TASK TO A
SUBSET OF YOUTH NINE DAYS APART.
WE CALCULATED RELIABILITY, TWO
WAYS.
AND IN DEED, WHAT WE SEE HERE IS
THAT YOUTH'S CALM-IT IT
PERFORMANCE WAS RELIABLE OVER
TIME.
FINALLY AND WHAT IS MOST
INTERESTING TO ME IS WE WANTED
TO SEE IF THIS TASK PERFORMANCE
WAS CLINICALLY RELEVANT.
THAT IS IS THE COMET DEEP PRIME
ASSOCIATED WITH SIM?
AS YOU RECALL, WE EXPECT THE
PERFORMANCE TO BE SPECIFICALLY
ASSOCIATED WITH SYMPTOMS OF
IRRITABILITY AND ADHD.
SO WHAT WE SEE HERE ON THESE TWO
GRAPHS, THESE ARE RATINGS ARE
IRRITABILITY AND ON THE X AXIS,
WE HAVE THAT CALM-IT IT DEPRIME
PERFORMANCE IN THE Y AXIS WE SEE
PAIR RATED IRRITABILITY ON THE
BOTTOM WE SEE CHILD RATED
IRRITABILITY AND WHAT WE SEE
HERE IS THAT HIGHER DEPRIME
PERFORMANCE, OR BETTER
PERFORMANCE ON INHIBITORY
CONTROL, WAS ASSOCIATED WITH
LOWER LEVELS OF PARENT AND CHILD
REPORTED IRRITABILITY.
HIGHER LEVELS OF IRRITABILITY AS
RATED BY THE PARENT AND THE
CHILD, WERE RELATED TO FOUR
INHIBITORY CONTROL PERFORMANCE
ON THIS MOBILE APP.
WE FOUND THIS SIMILAR PATTERN AS
WE LOOKED AT THE ASSOCIATION
BETWEEN COMET DEPRIME
PERFORMANCE AND SYMPTOMS OF
ADHD.
AGAIN, LOWER PERFORMANCE ON THE
INHIBITORY CONTROL METRICS WAS
ASSOCIATED WITH HIGHER SYMPTOMS
OF ADHD.
SO WHAT WE'RE SEEING HERE IS
SOME SPECIFIC ASSOCIATION ON THE
DEEP PRIME INHIBITORY CONTROL
PERFORMANCE ON THE MOBILE APP
INEL YOUTH WITH IRRITABILITY AND
ADHD.
WE'RE SEEING NO ASSOCIATIONS OF
DEEP PRIME INHIBITORY CONTROL
PERFORMANCE WITH ANXIETY AND
DEPRESSION.
WE FOUND FEE ABILITY IN YOUTH
ENGAGE AND COMPLETED THE TASK
AND WE FOUND SOME EARLY
INDICATIONS OF VALIDITY AND THAT
THIS ACT PERFORMANCE WAS RELATED
TO A LATE APARTMENT FACTOR OF
INHIBITORY CONTROL AND WE FOUND
SOME SUPPORT OF RELIABILITY IN
THAT THE APP PERFORMANCE WAS
STABLE OVER TIME.
AND WE FOUND SOME SUPPORT FOR
CLINICAL RELEVANCE, AND THAT THE
INHIBITORY CONTROL PERFORMANCE
AS MEASURED BY THE MOBILE APP
WAS ASSOCIATED WITH SPECIFIC
CLINICAL PHENOTYPES OF
IRRITABILITY AND ADHD.
SO, WHAT ARE OUR NEXT STEPS?
WELL, WE'RE STARTING TO REPEAT
THESE CALM-IT IT GAMES MULTIPLE
TIMES OVER THE DAY AND PAIR IT
IT WITH IN VIVO CLINICAL
PHENOTYPING, AGAIN, MULTIPLE
TIMES OVER THE DAY.
OVER SEVERAL DAYS.
THE VIDEO ON THE LEFT IS RATE-IT
WHICH IS ANOTHER APP WE
DEVELOPED WHICH IS AN ECOLOGICAL
MOMENTARY ASSESSMENT APP WHICH
ESSENTIALLY ASKS QUESTIONS AS TO
HOW WORRIED THE CHILD IS FEELING
IN THE MOMENT.
WHAT LEVELS OF ANGER,
FRUSTRATION, AND IRRITABILITY
ARE THEY EXPERIENCING?
AND WE'RE HAVING CHILD
PORNOGRAPHY AND THEIR PARENTS
RATE THE SYSTEMS MANY TIMES OVER
THE COURSE OF COGNITIVE
BEHAVIORAL THERAPY TO GET A
DEVELOPS GRANULAR ASSESSMENT OF
THE TEMPORAL DYNAMICS OF THESE
SYSTEMS OVER THE COURSE OF
TREATMENT.
WE CAN THEN SEE IF THESE
INHIBITORY CONTROLS DEFICITS
INCREASE SAY PRIOR TO A TEMPER
OUTBURST OR IF THERE'S CERTAIN
PATTERNS OVER THE COURSE OF DIE DAY OR
THE COURSE OF WEEK AND SEE IF
TEMPER OUTBURST, SAY PROCEED
POOR INHIBITORY CONTROL AND WE
CAN ALSO SEE HOW THE SYMPTOMS
AND CALM-IT IT DEPRIME
PERFORMANCE CHANGE OVER THE
COURSE OF PSYCHOTHERAPY.
SO OUR LONG-TERM GOAL IS TO
BUILD A MOBILE PLATFORM TO
REALLY DEVELOP THERAPEUTICS,
THAT IS, WE WANT TO INTEGRATE
DIGITAL CLINICAL PHENOTYPING
WITH TREATMENT.
SO, WHAT WE WANT TO DO HERE IS
REAL IS REALLY GATHER THESE
GRANULAR, CLINICAL SYMPTOMS,
NATURALISTICALLY IN VIVO AND
ALONG WITH THIS DEEP BEHAVIORAL
PHENOTYPING, SUCH AS IDENTIFYING
DEFICITS AND INHIBITORY CONTROL
AND THE CLIP CAL AND BEHAVIORAL
DEFICITS TO TARGET THESE
POTENTIAL DEFICITS TOGETHER AND
ULTIMATELY WITH THE GOAL OF
INTERVENING AND PREDICTING
BEFORE AN OUTBURST MAY OCCUR.
HOWEVER, I WANT TO KNOWS THAT
WE'RE IN THE VERY EARLY DAYS OF
THIS WORK AND THE SPECIFIC
CONCRETE CLINICAL BENEFITS ARE
LIKELY MANY YEARS AWAY.
SO, IN SUMMARY, I DEFINED
IRRITABILITY, WE TALKED ABOUT
ADHD AND INHIBITORY CONTROL.
WE TALKED ABOUT SOME OF THE
ADVANTAGES OF DEVELOPING MOBILE
APPS.
AND I INTRODUCED CALM-IT IT AND
DEMONSTRATED EARLY FEASIBILITY,
VALIDITY, RELIABILITY AND
CLINICAL ASSOCIATIONS WITH
IRRITABILITY AND ADHD.
AND I TALKED ABOUT SOME FUTURE
DIRECTIONS OF OUR WORK.
AND WITH THAT, I WANT TO THANK
THE AUDIENCE FOR THEIR TIME AND
ATTENTION.
I SPECIFICALLY WANT TO THANK THE
PATIENCE AND THEIR FAMILIES FOR
THEIR DEDICATION TO RESEARCH.
THE NIMH-IRP, DR. SEUSS ANNA
MORE A AND -- COLLABORATORS, AND
POSTDOCS IN THE LAB.
AND FOR THAT, I WANT TO END BY
SEEING IF WE HAVE TIME FOR
QUESTIONS TO OPEN UP TO THE
GROUP.
>> Tom Burklow: THANK YOU AND WE
HAVE A LOT OF INTERESTING
QUESTIONS AND WE HAVE SOME TIME
TO ANSWER THAT.
SO, FIRST I WANT TO THANK YOU
FOR SHARING YOUR REALLY
IMPORTANT AND WORK WHICH IS
OFFERING SOME REALLY UNIQUE AND
CRITICAL INSIGHTS INTO COMMON
DISEASE IN CHILDHOOD, WHICH HAS
OBVIOUSLY A VERY SIGNIFICANT
PSYCHOSOCIAL AND EDUCATIONAL
MORBIDITY.
SO, LET ME JUST SEE WHAT WE
HAVE.
SO, THE FIRST QUESTION IS FOR
Dr. BROTMAN.
WAS THE CALM-IT IT APP MODELED
AFTER THE FRUIT AND NINJA GAME?
DID THEY PLAY THE GAME BEFORE?
THEORETICALLY THE CHILDREN MIGHT
BE BETTER AT THE GAME IF THEY
PRACTICED THE GAME BEFORE.
>> Melissa Brotman: YES, IT
ACTUALLY WAS, IT'S SIMILAR TO
THE FRUIT NINJA GAME AND WE
INTEGRATED ASPECTS OF THE FRUIT
AND NINJA GAME ALONG WITH THE
STANDARDIZED INHIBITORY CONTROL
TASKS OF THE STOP SIGNAL.
WE DID ASK INDIVIDUALS HOW MUCH
THEY HAD PLAYED AND IT DOES NOT
SEEM TO BE RELATED.
HOWEVER IT WAS A BASELINE AND
APARTMENT TO BUILD FROM.
>> GREAT, THANK YOU.
AND BEING THE EMPTY NESTER, I
DON'T KNOW WHAT THE FRUIT NINJA
GAME IS.
IT WAS NEW TO ME.
SECOND QUESTION, WAS IT CALM-IT
IT ADMINISTERED IN A LAB OR HOME
SETTING.
IF THE HOME, WAS THE SETTING WAS
THE APP RECORDED, FOR EXAMPLE,
TIME OF DAY AND DURING OR AFTER
SCHOOL, WAS THEIR MOOD EFFECTING
THEIR PERFORMANCE AND YOU
TOUCHED ON IT A LITTLE BIT BUT
CAN YOU ELABORATE?
>> YES, THAT'S AN EXCELLENT
QUESTION.
SO, YES, IN DEED, WE DID GET
VERY SPECIFIC DATA AS TO WHEN
THE CHILD WAS PLAYING THE GAME
AND WHAT TIME OF DAY AND WE DID
GET THOSE PARENT EX CHIL AND METRICS OF
IRRITABILITY AND ADHD AND SANITY
AND WHAT OUR NEXT STEP IS TO DO
IS TO REALLY PAIR IT WITH THAT
RATE-IT MAP WHERE WE GET A
SPECIFIC ASSESSMENT OF CLINICAL
SYMPTOMS AT THE TIME OF THE GAME
PERFORMANCE.
SO WE CAN SEE REALLY
SPECIFICALLY IF IRRITABILITY SAY
WITHIN THE PAST HOUR PRIOR TO
THE GAME PERFORMANCE INFLUENCED
IT AND THE METRICS WE GOT NOW
THAT WERE THE PARENT AND CHILD
REPORT, WERE OVER THE COURSE OF
THE WEEK SO IT IT WAS LESS TIED
TO THE SPECIFIC TIME IN WHICH
THE CHILD PLAYED THE GAME.
BUT IN OUR NEXT ROUND OF
RESEARCH, THAT'S ACTUALLY
SPECIFICALLY WHAT WE DO WANT TO
DO.
>> Tom Burklow: THANK YOU, VERY
MUCH.
THIS QUESTION IS FOR Dr. SHAW.
IT WAS MENTIONED IN THE
INTRODUCTION THAT THE GENETIC
FACTORS ACCOUNT FOR A LARGE
PREPORTION OF THE PHENOTYPE IN
CHILDHOOD CASES OF ADHD.
QUESTION IS, ARE SIMILAR
PATTERNS OF DIFFERENCES IN
FINANCINGAL AND STRUCTURAL
CONNECTIVITY BETWEEN PARENT AND
CHILD?
>> Melissa Brotman: THAT'S A
GREAT POINT.
AS YOU MENTIONED, ADHD IS ONE OF
THE MOST INHERITABLE OF ALL THE
NEURO DEVELOPMENT CHALLENGES AND
IT'S UP THERE WITH AUTISTIC
SPECTRUM DISORDER AND
SCHIZOPHRENIA AND BY POLAR AND
80% OF THE PHENOTYPES ARE
ATTRIBUTABLE TO INHERITABLE
FACTORS.
SO THAT'S MUCH HIGHER THAN MOOD
AND ANXIETY WHICH IS 20% OR 30P.
IT'S VERY, VERY HERITABLE AND
IT'S A BEHAVIOR ABLE TRAIT WITH
ADHD AT THE EXTREME END.
YOU ARE ASKING ABOUT THE
HERITABILITY OF STRUCTURAL AND
FUNCTIONAL CONNECTIONS BUT IN
THE BRAIN.
WE STUDIED THAT.
WE BROUGHT IN A STUDIES A WHILE
BACK, ONE OF THE NICE THINGS
ABOUT BEING HERE IS YOU CAN DO
STUDIES LIKE THIS.
WE GOT AN EX TENDED
MULTI-GENERATIONAL FAMILIES AND
WHICH MANY, MANY INDIVIDUALS
WERE AFFECTED BY ADHD AND ON
AVERAGE THERE WAS AT LEAST A
THIRD OF THE INDIVIDUALS ACROSS
GENERATIONS, HAD A DIAGNOSIS OF
ADHD.
IN ADULTS IT WAS ABOUT A 10%
INCREASE AND THE POPULATIONEL
PREVALENCE SO IT'S A VERY, VERY
ENRICHED ADHD FAMILY.
SO WE BROUGHT THE FAMILIES IN
AND ALL OF THE FAMILIES, ALL THE
DIFFERENT GENERATIONS HAD
NEUROIMAGING, MAPPING THE
STRUCTURAL AND FUNCTIONAL
CONNECTIVITY AND WE DID EX LEASE
MANY, WHAT YOU SUGGESTED, WE
LOOKED AT THE INHER ABILITY OF
THE STRUCTURAL AND FUNCTIONAL
CONNECTIONS ACROSS THE BRAIN AND
WE FOUND THAT SOME OF THEM ARE
EXTREMELY HERITABLE AND VERY
STRONGLY TIED TO ADHD.
FOR EXAMPLE, PARTS OF THE CORPIS
COLOSAL IS VERY HERITABILITY AND
ASSOCIATED WITH SYSTEMS OF ADHD.
THE NEAT THING ABOUT THIS SORT
OF WORK, IS YOU CAN IMAGINE
THERE'S STACKS OF POTENTIAL
THINGS WE CAN LOOK AT IN THE
BRAIN AND AMONG STRUCTURAL AND
FUNCTIONAL CONNECTIONS WHEN WE
GO GENE HUNTING.
WE CAN NARROW THAT SPACE DOWN BY
PRIORITIZING THE PROPERTIES IN
THE BRAIN THAT ARE BOTH
CHARITABLE, HIGHLY HERITABLE AND
STRONGLY ASSOCIATED WITH ADHD.
THAT NARROWS THE TARGETS DOWN
FOR GENETICS.
SO YES, THAT'S SOME WORK WE'VE
DONE.
>> Tom Burklow: THANK YOU.
QUESTION FOR Dr. BROTMAN, ARE
YOU LOOKING FOR ANY CLINICAL,
COMMUNITY SITES TO TEST A
CALM-APP?
>> Melissa Brotman: SO, THERE'S
ACTUALLY BEEN QUITE A LOT OF
INTEREST.
FIRST AMONG RESEARCHERS,
EXTRAMURAL RESEARCHERS WHO ARE
INTERESTED IN USING THIS ALONG
WITH SOME OF THEIR CURRENT
STUDIES WHEREBY THEY'RE
ASSESSING INHIBITORY CONTROL IN
THEIR PATIENT POPULATIONS.
AND SO THAT IS THE FIRST STEP IN
SEEING THAT OTHER EXTRAMURAL
RESEARCHERS WANT TO SEE IF THEIR
ASSOCIATIONS WITH OTHER CLINICAL
PHENOMENONS, WE ALSO HAVE BEEN
ASKED BY GENERAL INDIVIDUALS AND
CHILD PORNOGRAPHY WHO HAVE
PLAYED THE GAME AND ENROLLED IN
OUR STUDY WHO THEN WANT TO HAVE
THEIR FRIENDS PLAY.
AT THIS POINT IN TIME IT'S
ACTUALLY NOT ON THE APP STORE
AND WE'RE HOLDING BACK ON THAT
FOR NOW FOR IRB AND OTHER
REASONS.
BUT THAT IS KIND OF THE NEXT
GENERATION OF WHAT WE WANTED DO
WHEN WE HONE THE SPECIFIC TASK
MORE SPECIFICALLY AND REALLY
DRILL DOWN ON ITS VALIDITY OF
RELIABILITY AND WHAT WE'RE DOING
ALSO NOW IS SEEING IF THERE ARE
ALSO ASSOCIATIONS WITH ACTUAL
NEURO CORRELATES WHEN WE BRING
KIDS INTO THE CLINIC TO PLAY
RELATED I AM HI INHIBITORY CONTROL TASKS
IN FMRI.
>> Tom Burklow: THANK YOU.
ANOTHER QUESTION TO BE Dr.
SHAW.
WHETHER OR NOT THESE CHANGES
THAT ARE BEING NOTED EVOLVE WITH
AGE AND TREATMENT AND ARE THERE
MARKERS OR CHANGES THAT ARE
SPECIFICALLY ASSOCIATED WITH
RESPONSE AND MEDICATIONS?
>>
>> Philip Shaw: ABSOLUTELY.
THE INTERACTION, THE WAY THE
DIFFERENT NETWORKS OF THE BRAIN
TALK TO EACH O. DEFINITELY
EVOLVES WITH AGE AND GENERAL
NETWORKS GET MORE SEGREGATE AND
CLEVER AND THEY CROSS TALK
BETWEEN NETWORKS WITH AIMING
BECOMES MORE REFINED.
THERE'S AN ARGUMENT THAT KIDS
WITH ADHD WHAT IS HAPPENING IS
THEY'RE GOING TO GET THERE BUT
IT MIGHT TAKE A LITTLE BIT
LONGER DEVELOPMENTALLY FOR THEM
TO END UP AT THE SAME POINT.
AND THE OTHER EXCELLENT QUESTION
IS WHAT'S THE EFFECT OF
MEDICATIONS?
VERY INTERESTINGLY THE MOST
COMMON MEDICATION AND WIDELY
USED MEDICATIONS FOR ADHD ARE
PSYCHO STIMULANTS SUCH AS ADD
ORAL AND RIDDERRAL AND HIGHLY
EFFECTIVE TREATMENTS.
WHEN YOU LOOK AT THE SCANNER,
WHEN THE MEDICATIONS IS AT ITS
PEAK, THIS ACTUALLY CROSS TALK
BETWEEN THE NETWORKS IS SHIFTED
IN ADHD TOWARDS MORE TYPICAL
PATTERNS ACUTELY X WHE.
WHEN THE MEDICATION WASHES OUT
IT GOES BACK TO HOW IT WAS
BEFORE SO IT'S A VERY
FASCINATING FINDING THAT SICKO
SIM YOU PLANT MEDICATION ONLY
AND REAL OWE ONLY AT ITS PEAK IT
IT WASHES OUT QUICKLY ACTUALLY
AND IT WILL SHIFT THE WAY THAT
NETWORKS TALK TOO ONE ANOTHER IN
MORE TYPICAL PATTERN WHICH OF
COURSE MAKES PERFECT SENSE
BECAUSE YOU WATCH A CHILD WHO IS
ON A STIMULANT AN THEIR INTENTIONAL
INCREASE WHEN THEY TAKE THE
MEDICATIONS.
>> Tom Burklow: THANK YOU, Dr.
SHAW.
WE HAVE TIME FOR ONE MORE
QUESTION.
THIS IS ACTUALLY FOR Dr.
BROTMAN AND THAT IS, DO CLASSIC
MEDICATIONS FOR ADHD SUCH AS
STIMULANTS IMPROVE THE
INHIBITORY CONTROL?
>> Melissa Brotman: IT'S
ACTUALLY A REALLY INTERESTING
QUESTION.
IN DEED, YES, WHEN INDIVIDUALS
ARE PRESCRIBED STIMULANTS,
PARTICULARLY THOSE WITH ADHD AR
THOSE STRUGGLING WITH
IRRITABILITY, WE DO SEE
IMPROVEMENTS IN INHIBITORY
CONTROL ON THOSE STANDARDIZED
TASKS.
IT IT MAKES US GET TO
UNDERSTANDING SOME OF THE
MECHANISMS WHEREBY SOME OF THESE
TREATMENTS MAY ACTUALLY BE
WORKING.
SO IN DEED, WE DO SEE
IMPROVEMENT THIS IS INHIBITORY
CONTROL AS A FUNCTION OF
STIMULANT RESPONSE.
>> Tom Burklow: GOOD.
WELL, I THINK WITH THAT THAT
BRINGS US UP TO THE HOUR.
I WANT TO THANK BOTH OF YOU FOR
YOUR BRILLIANT AND INFORMATIVE
PRESENTATIONS TODAY.
AND SO THE NIH COMMUNITY, THANK
YOU FOR JOINING US AND HAVE A
WONDERFUL AFTERNOON.
THANK YOU.
>> THANK YOU.