REALLY EXCITED TO HAVE

EVERYBODY HERE TODAY.

WE ARE GOING TO START THE VERY

BEGINNING BY GOING AROUND THE

ROOM AND INTRODUCING OURSELVES,

NAME, AFFILIATION, AND A REALLY

SHORT PHRASE ABOUT WHAT YOU DO.

SO REMINDER ABOUT THE MICS.

WE ARE ONLINE, SO THE PEOPLE

CAN'T HEAR US UNLESS WE ARE

USING OUR MIKES.

USE YOUR MIC.

BUT ONLY THREE MICS CAN BE ON AT

THE SAME TIME.

SO AFTER YOU'RE DONE TALKING,

TURN OFF YOUR MICS.

WE'LL DO INTRODUCTIONS FIRST AND

THEN AUDREY AND I HAVE A FEW

THINGS TO SAY AND THEN WE'LL GET

STARTED.

THANK YOU.

SO WE'LL GO THIS WAY.

>> I'M AUDREY THURMUX A CLINICAL

PSYCHOLOGIST AND STAFF SCIENTIST

AT THE NIMH INTRAMURAL RESEARCH

PROGRAM WHERE WE HAVE BEEN

STUDYING AUTISM AND PARTICULARLY

LOOKING IN THE YOUNG AGES AT

PRESCHOOLERS AND HAVE BEEN

WORKING A LITTLE BIT ON LOSS OF

SKILLS AS ONE OF THE THINGS THAT

WE DO.

>> I'M ELIZABETH POWELL, I'M A

DEVELOPMENTAL NEUROBIOLOGIST

MAINLY ON FOR BRAIN DEVELOPMENT

IN ANIMAL MODELS.

AND I'M AT THE UNIVERSITY OF

MARYLAND.

I'M ALSO THE CHAIR FOR SESSION

3.

>> GOOD MORNING.

I'M JEFF NEUL AT THE UNIVERSITY

OF CALIFORNIA SAN DIEGO AT THE

CHILDREN'S HOSPITAL.

I'M A CHILD NEUROLOGIST AND I

PRIMARILY WORK ON RETT SYNDROME

BOTH FROM A CLINICAL RESEARCH

AND BASIC AND TRANSLATIONAL

RESEARCH PERSPECTIVE.

I'M THE CHAIR OF SESSION 2.

>> I'M JASON WOLFF, AT THE

UNIVERSITY OF MINNESOTA WORKING

IN THE AREA OF EARLY BRAIN AND

BEHAVIORAL DEVELOPMENT IN

CHILDREN WITH AUTISM.

>> GOOD MORNING.

MY NAME IS KEERTHI KRISHNAN AND

I'M A RESEARCH INVESTIGATOR AT

COLD SPRING HARBOR LABORATORY

AND STUDY ANIMAL MODELS OF RETT

SYNDROME.

>> GOOD MORNING.

I'M ELLIOTT SHERR, A NEUROLOGIST

AT UC SAN FRANCISCO AND MY LAB

STUDIES THE NEUROGENETICS OF

DEVELOPMENTAL DISORDERS.

>> AND JASON FROM THE UNIVERSITY

OF TORONTO AND WORK IN BRAIN

IMAGING IN MICE AND HUMANS.

>> KARIN PARKER, I'M A

BEHAVIORAL NEUROSCIENTIST AT

STANFORD UNIVERSITY AND MY LAB

STUDIES BIOLOGY SOCIAL FUNCTIONS

IN PRIMATE MODELS AND PATIENTS

WITH AUTISM.

>> LISA GILATY, A PROGRAM

OFFICER AT NIM.

AND I MANAGE THE AUTISM

PORTFOLIO.

>> LAURA, A PROGRAM DIRECTOR AT

NINDS AND I MANAGE THE PORTFOLIO

OF NEURODEVELOPMENTAL DISORDERS

THAT INCLUDES AUTISM ELLIPT

ELECTUAL DISABILITIES AND

EPILEPSY.

SO RETT -- EPILEPSY, MICK DERMOT

SYNDROME, ET CETERA.

>> I'M JIM PICKLE, INTRAMURAL

PROGRAM FOR NIMH IN BETHESDA AND

RUN THE NIMH TRANSGENIC CORE

FACILITY WHERE WE MAKES

TRANSGENIC RATS AND OUR FIRST

MARMOSET.

>> I'M SUSAN DANIELS, THE

DIRECTOR OF THE OFFICE OF AUTISM

RESEARCH COORDINATION AT NIM.

AND MANAGE THE INTERAGENCIES

COORDINATING COMMITTEE.

>> I'M JILL SILVERMAN, FROM THE

UNIVERSITY OF CALIFORNIA DAVIS

AND THE MIND INSTITUTE AND I

WORK ONOON MALL MODELS.

I'M A BEHAVIORAL NEUROSCIENTIST

AND WORKING ON ANIMAL MODELS ON

AUTISM SPECTRUM DISORDER.

>> HELLO, EVERYONE, UC SAN DIEGO

AND I WORK WITH STEM CELLS

MODELS FOR NEURODEVELOPMENT OF

DISORDERS, AUTISM, RETT SYNDROME

AND THE LIKE.

>> GOOD MORNING.

I'M KASIA, CLINICAL AND

DEVELOPMENTAL PSYCHOLOGIST AT

YALE AND I STUDY AUTISM AS IT

EXPRESSES IN INFANCY AND EARLY

CHILDHOOD.

>> GOOD MORNING.

I'M ANNETTE SMITH FROM THE BURR

BECK CENTER FOR BRAIN COGNITIVE

DEVELOPMENT AT THE UNIVERSITY OF

LONDON.

I STUDY TYPICAL DEVELOPMENT AND

ALSO NEURODEVELOPMENT DISORDERS

IN INFANCY.

>> GOOD MORNING.

I'M LONNIE A DEVELOPMENTAL

PEDIATRICIAN AT THE UNIVERSITY

OF ALBERTA IN CANADA.

MY RESEARCH FOCUSES ALSO EARLY

DEVELOPMENT IN AUTISM AND

AT-RIFFING INFANTS AND WITH

JEFF, ELIZABETH AND AUDREY, I

ALSO HAVE BEEN A MEMBER OF THE

PLANNING GROUP FOR THIS WORKSHOP

AND CHAIR OF SESSION 1.

>> ANN WAGNER:  THANK YOU VERY

MUCH.

WE HAVE A COUPLE OF PEOPLE WHO

WILL COME IN A LITTLE BIT LATE.

TO LET EVERYBODY KNOW THAT

DR. CHARLES NELSON WILL BE

JOINING US VIRTUALLY INSTEAD OF

IN PERSON.

HE WASN'T ABLE TO GET HERE TODAY

BUT HE GRACIOUSLY OFFERED TO BE

ONLINE FOR US.

SO, I THINK AUDREY HAS A FEW

THINGS TO SAY.

>> AUDREY THURM:  THANK YOU FOR

INTRODUCING YOURSELF.

I THINK IT REALLY EXEMPLIFIES

HOW TRANSLATIONAL THIS MEETING

REALLY IS AND WE ARE REALLY,

REALLY EXCITED ABOUT THAT PIECE

OF IT.

AS WELL AS JUST THE FOCUS OF

THIS MEETING, WHICH IF WE WANTED

TO SUM IT UP REALLY, REALLY

BROADLY, WE WOULD SAY THE FOCUS

OF THE MEETING IS WHEN DO

SYMPTOMS OF AUTISM AND

NEURODEVELOPMENTAL DISORDERS

HAVE AN ONSET?

AND HOW IS THIS ONSET HAPPENING?

WHAT IS THE MECHANISM?

THAT IS THE REALLY, REALLY BROAD

PICTURE OF WHAT WE ARE THINKING

ABOUT HERE.

AND WE CLEARLY ARE DOING THIS IN

A TRANSLATIONAL WAY WHERE WE ARE

GOING TO TALK ABOUT WHAT WE KNOW

ABOUT THE HUMAN PHENOMENON,

ABOUT EARLY-ONSET IN TERMS OF

THE WAY SYMPTOMS PROGRESS TO

BECOME CLINICAL PHENOMENON, AND

THE PATTERNS THAT WE HAVE SEEN

IN AUTISM, IDO PATHIC AUTISM AND

WHAT WE KNOW ABOUT

NEURODEVELOPMENTAL DISORDERS

THAT PORTRAY A MODEL FOR AUTISM

AND BASED ON SPECIFIC GENETIC

ABNORMALITIES.

SO, THIS INCLUDES THE IDEA AND

THE PHENOMENON THAT LOSS OF

SKILLS OCCUR IN SOME CHILDREN

WHO GO ON TO DEVELOP AUTISM AND

THESE OTHER TYPES OF DISORDERS,

AND WE JUST WANT TO RECOGNIZE

FROM THE ONSET THAT THIS IS A

VERY, VERY DIFFICULT PHENOMENON

THAT HAPPENS IN TERMS OF

FAMILIES WITH VERY YOUNG INFANTS

WHO BEGIN TO DEVELOP SOME SKILLS

AND THEN LOSE THOSE SKILLS.

SO JUST STARTING WITH THE IDEA

THAT THIS IS SOMETHING THAT

FAMILIES GO THROUGH AND HAVE TO

NAVIGATE THEIR WAY TO EITHER GET

SCREENED AND EVENTUALLY GET

DIAGNOSED AND BE ABLE TO SORT OF

TELL THE STORY, IF NOT SHOW THE

STORY, OF THEIR CHILD HAVING

LOSS OF SKILLS.

SO GROUNDING IN FAMILIES AND

WHAT THEY ARE GOING THROUGH, I

THINK, IS FIRST AND FOREMOST BUT

THEN WHAT WE REALLY WANT TO DO

HERE TODAY IS ASK QUESTIONS AND

ASK QUESTIONS ABOUT WHAT WE DO

AND DON'T KNOW ABOUT THESE

PHENOMENON.

SO REALLY OUR FIRST QUESTION IS,

HOW ARE THESE COMMONALTIES AND

DIFFERENCES AND THESE DIFFERENT

PATTERNS OF ONSET, HOW DO

SYMPTOMS COME ONLINE?

HOW ARE THEY DIFFERENT IN THE

SYNDROMES WE KNOW ABOUT VERSUS

IDIOPATHIC AUTISM?

AND WHAT DO WE KNOW ABOUT THE

PATHOPHYSIOLOGICAL MECHANISMS OF

THESE PATTERNS OF ONSET?

AND THEN WHAT BIOLOGIC QUESTIONS

CAN WE ASK STARTING FROM THE

CLINICAL PHENOMENON?

AND WE WANT TO SPECIFICALLY THEN

ASK HOW CAN ANIMAL RESEARCH

BROADLY AND THEN USING DIFFERENT

MODELS FROM MICE, RATS,

MARMOSETS AND PRIMATES, BE ABLE

TO HELP US INFORM ABOUT THESE

MECHANISMS?

WE ALSO WANT TO GO FURTHER AND

ASK HOW CELL-BASED RESEARCH CAN

HELP US INFORM OUR UNDERSTANDING

OF THESE MECHANISMS AND THEN HOW

DO THE DIFFERENT MODELS OF

GENETIC SYNDROMES RELEVANT TO

ASD, BRING US BACK TO ASD

GENERALLY, AUTISM, IN THINKING

ABOUT HOW THESE SYMPTOMS COME

ONLINE AND THE MECHANISMS THAT

ARE UNDER THEM.

SO, THAT IS REALLY WHAT WE WANT

TO ACCOMPLISH TODAY.

NO SMALL FT. BUT WE ARE GOING TO

DO THIS BY BREAKING IT UP INTO

THREE SESSIONS, THE FIRST THAT I

WILL TURN OVER TO LONNIE RIGHT

NOW WHERE WE WILL START BY

THINKING ABOUT WHAT WE KNOW

ABOUT THE CLINICAL PHENOMENON

AND WHAT IS HAPPENING IN INFANTS

WHO DEVELOP AUTISM AND RELATED

NEURODEVELOPMENTAL DISORDERS.

SO WITH THAT, I WILL TURN IT

OVER TO LONNIE ZWAIGENBAUM AND

HE WILL BEGIN.

>> LONNIE>> ANN WAGNER:  LET ME
JUST RUN

THROUGH A COUPLE OF LOGISTICS.

JUST SO PEOPLE KNOW WHERE THEY

ARE.

SO WE ARE GOING TO TRY TO STAY

ON TIME.

SO AUDREY HAS FIVE MINUTE AND

ONE-MINUTE WARNING SIGNS FOR

PEOPLE.

AS I WE ARE BEING VIDEO CAST, AS

I SAID, WE NEED TO USE MICS AND

TURN THEM OFF WHEN WE ARE

FINISHED.

DURING BREAKS, SO THERE ARE

RESTROOMS BEHIND THE SECURITY

DESK OUTSIDE.

DURING BREAKS THERE IS A LITTLE

SNACK STORE WHERE YOU CAN BUY

SNACKS AND DRINKS.

LUNCH, I THINK MOST PEOPLE HERE

AT THE TABLE HAVE PRE-ORDERED

THEIR LUNCH.

WE'LL GET BOXED LUNCHES AND EAT

HERE.

PEOPLE NEED LUNCH AND HAVEN'T

DONE THAT, THERE IS A DELI IN

THE BUILDING NEXT DOOR WE CAN

POINT YOU TO.

AND THEN, THERE IS A SIGN UP

SHEET FOR PEOPLE WHO WANT TO

PREARRANGE FOR CABS AT THE END

OF THE MEETING.

I KNOW SOME PEOPLE HAVE TIGHT

SCHEDULES.

SO MAKE SURE YOU SIGN UP FOR A

CAB IF YOU NEED ONE AFTER.

OKAY.

NOW WE ARE READY FOR LONNIE.

THANK YOU.

>> LONNIE ZWAIGENBAUM:  THANK

YOU.

GOOD MORNING, EVERYONE.

I'LL JUST OPEN THE SESSION WITH

A FEW BRIEF COMMENTS AND THEN

I'LL JUST JOIN AN AND AUDREY

WELCOMING YOU AND LOOKING

FORWARD TO A REALLY GOOD

DISCUSSION.

SO, OUR INITIAL SESSION IS ON

NORMATIVE DEVELOPMENT AND

WORSENING DECLINING ONSET

PATTERNS IN NEURODEVELOPMENT.

AND ESSENTIALLY DEFINING WHAT IS

THE BEHAVIORAL PHENOTYPE AND

PHENOM NOLOGY WE ARE DISCUSSING

TODAY?

WE WILL HAVE THREE PRESENTATIONS

IN THIS SESSION.

THE FIRST FROM ANNETTE

KARMILOFF-SMITH WHO WILL BE

TALKING ABOUT REGRESSION IN BOTH

NEUROTYPICAL DEVELOPMENT AS WELL

AS NEURODEVELOPMENTAL DISORDERS

AND THE IMPORTANCE OF TIMING AND

CROSS-SYNDROME COMPARISONS AND

ESSENTIALLY HELPING US THINK

ABOUT HOW REGRESSION OR SKILL

LOSS CAN FALL IN THE CONTINUUM

OF TYPICAL DEVELOPMENT AND CAN

REFLECT TYPICAL DEVELOPMENTAL

PROCESSES AROUND SPECIALIZATION.

KASIA CHAWARSKA FROM YALE

UNIVERSITY, WILL ESSENTIALLY BE

TALKING ABOUT THE EARLY

DEVELOPMENTAL PHENOTYPE OF

AUTISM BOTH IN TERMS OF BEHAVIOR

AND DEVELOPMENTAL PHENOM NOLOGY

SO BEHAVIOR THAT OCCURS OVER

TIME.

AND HELPING US THINK ABOUT WHERE

SKILL LOSS FALLS ON THAT

DEVELOPMENTAL CONTINUUM AND WHAT

ONE OBSERVES EARLY IN LIFE IN

INFANT WHO DEVELOP A DIAGNOSIS

OF AUTISM.

AND THEN JASON WOLFF FROM

UNIVERSITY OF MINNESOTA WILL BE

TALKING ESSENTIALLY ABOUT THE

EARLY BRAIN PHENOTYPE OF AUTISM.

WHAT ARE WE LEARNING THROUGH

STUDYING BRAIN DEVELOPMENT

DIRECTLY USING OUR CURRENT

NEUROIMAGING AND FUNCTIONAL

TECHNIQUES IN INFANTS AT RISK OF

AUTISM.

AND HOW DOES THE EARLY BRAIN

FINDINGS MAP ON TO THE CLINICAL

AND BEHAVIORAL PHENOM NOLOGY.

I'LL JUST SORT OF POSE A COUPLE

OF GUIDING QUESTIONS TO SORT OF

HELP ORGANIZE OUR THOUGHTS AS

YOU REFLECT ON THE PRESENTATIONS

THAT YOU'RE GOING TO HEAR DURING

THE FIRST SESSION.

THE FIRST IS, WHAT NEURAL

MECHANISMS UNDERLIE SKILL LOSS

IN TYPICAL DEVELOPMENT AND IN

NEURODEVELOPMENTAL DISORDERS?

AND WHAT IS SPECIFIC AND UNIQUE

TO AUTISM VERSE WHAT IS FALLS ON

THE DEVELOPMENTAL CONTINUUM FROM

THE BROADER RANGE OF

DEVELOPMENTAL PATTERNS?

THE SECOND BROAD QUESTION IS,

WHAT DEVELOPMENTAL PROCESSES

BOTH BEHAVIORAL AND

NEUROBIOLOGICAL CHARACTERIZE

AUTISM EARLY IN LIFE AND WHERE

DOES SKILL LOSS FALL ON THAT

CONTINUUM?

SO AGAIN, WHAT IS THE EARLY

DEVELOPMENTAL PHENOTYPE OF

AUTISM BOTH IN TERMS OF

BEHAVIORAL PHENOM NOLOGY AND IN

TERMS OF BRAIN DEVELOPMENT AND

HOW DOES THAT RELATE TO TYPICAL

DEVELOPMENT AND HOW DOES THAT

RELATE TO THE MODEL SYSTEMS THAT

WE'LL BE DISCUSSING AND THINKING

ABOUT LATER TODAY?

THE THIRD QUESTION REALLY IS A

QUESTION TO HOLD ON TO FOR THE

LATER SESSIONS.

BUT CERTAINLY THOSE OF YOU WHO

ARE ARRIVING AT THIS WORKSHOP

MORE FROM A PERSPECTIVE OF MODEL

SYSTEMS AND OTHER

NEURODEVELOPMENTAL DISORDERS, I

THINK IT IS GOING TO BE GOOD TO

CONTINUE TO REFLECT ON HOW IS

AUTISM AND THESE MODEL SYSTEMS

RELATED BOTH AT A PHENOM LOGICAL

LEVELS AND NEUROBIOLOGICAL

LEVEL.

SO WITH THAT, LET ME INVITE

ANNETTE TO PRESENT HER TALK.

THANK YOU.

THANK YOU VERY MUCH FOR INVITING

ME TO THIS WORKSHOP.

WHAT I'M GOING TO DO FIRST IS TO

GIVE YOU A COUPLE OF EXAMPLES OF

NEUROTYPICAL DEVELOPMENT AND

LOOK AT HOW REGRESSION OCCURS

THERE AS WELL, A LOSS OF SKILLS

THAT OCCURS, AND TRY AND LOOK AT

THE FUNCTION THAT THIS PLAYS IN

EURO TYPICAL DEVELOPMENT.

AND THE BALANCE BETWEEN SYNAPTIC

STRENGTHENING AND PRUNING TO GET

RID OF UNUSED CONNECTIONS.

I'LL THEN GO ON TO GIVE AN

EXAMPLE FROM ANOTHER

NEURODEVELOPMENTAL DISORDER,

WILLIAM SYNDROME, WHERE I'M

ASKING THE QUESTION AS TO

WHETHER OR NOT THERE IS A LARK

OF PRUNING, LACK OF AMBULANCE

BETWEEN STRENGTHENING AND

PRUNING -- AMBULANCE -- A LACK

OF BALANCE BETWEEN STRENGTHENING

AND PRUNING I WANT TO TALK ABOUT

A LOOK AT THE THRESHOLD FOR

PRUNING IN AUTISM IS TOO HIGH

AND THEY THEREFORE GET RID OF

STRENGTHENED CONNECTIONS AND NOT

JUST THE UNUSED ONES.

AND WE ALSO LOOK AT THE SEQUENCE

OF PRUNING, SUGGESTING WE SHOULD

BE ABLE TO FIND EXAMPLES OF

MOTOR AND SENSORY REGRESSIONS

EARLY IN DEVELOPMENT AND ONLY

LATER LANGUAGE REGRESSIONS AND

EXECUTIVE FUNCTION REGRESSIONS.

THAT IS DUE THE TOO TIMETABLE OF

PRUNING THAT WE SEE ACROSS THE

BRAIN.

AND FINALLY, IF I HAVE TIME,

THESE ARE VERY SHORT TALKS.

I WANT TO LOOK AT JUST SOME VERY

EARLY DIFFERENCES BETWEEN SIBS

WHO ARE AT RISK OF DEVELOPING

AUTISM, CONTROLS AND OTHER

NEURODEVELOPMENTAL DISORDERS

WITH THE QUESTION, WHAT IS

AUTISM SPECIFIC AND WHAT IS

AUTISM OR WHAT IS GENERAL TO ANY

VULNERABLE SYSTEM THAT IS

DEVELOPING?

SO MY FIRST EXAMPLE IS A QUICK

ONE ON NEUROTYPICAL DEVELOPMENT

ON PAST TENSE AND PLEURAL

MARKING IN EARLY LANGUAGE

DEVELOPMENT.

SO TIME 1, CHILDREN ARE CORRECT.

THEY SAY THINGS LIKE, PAPA WENT,

ME CAUGHT BALL, WET FEET.

BUT I'M GOING TO ARGUE THESE ARE

RATHER ISOLATED REPRESENTATIONS

THAT THE CHILD IS LEARNING IN A

ONE-TO-ONE MAPPING.

AT TIME 2 WE SEE A BEHAVIORAL

REGRESSION.

THEY SAY THINGS LIKE PAPA GOAD,

ME CATCHED BALL, WET FOOTS.

AND HERE I WANT TO ARGUE THIS IS

NOT A REGRESSION BUT A

REPRESENTATION OF PROGRESSION

BECAUSE THEY ARE OVER

GENERALIZING SOMETHING ABOUT THE

UNDERLYING SYSTEM THAT THEY HAVE

PICKED UP ON.

AND AT TIME 3 WHEN WE HAVE THE

CORRECT BEHAVIOR AGAIN, PAPA

WENT ET CETERA, WE ACTUALLY HAVE

REPRESENTATIONS THAT ARE PART OF

A MORPHOLOGICAL SYSTEM RATHER

THAN ISOLATED REPRESENTATION SO

IN TYPICAL DEVELOPMENT, THE

FUNCTION IS CHANGING OVER TIME

SO YOU'RE ENRICHING THE

REPRESENTATIONS THAT CHILDREN

USE.

SO ONE OF THE QUESTIONS I THINK

WE NEED TO ASK OF THE AUTISM

SPECTRUM DISORDER IS, IS THE

BEHAVIOR BEFORE THE REGRESSION

THE SAME SUSTAINED BY THE SAME

UNDERLYING REPRESENTATIONS AS

THE BEHAVIOR AFTER THE

REGRESSION?

IS THE CHILD REGAINING SKILLS OR

IS THAT THE WRONG WAY TO THINK

ABOUT IT?

COULD IT BE SKILLS ARE DIFFERENT

FROM A NEUROCOGNITIVE POINT OF

VIEW EVEN THOUGH THE BEHAVIORAL

LOOKS THE SAME?

NOW A COUPLE OF EXAMPLES FROM

NEUROTYPICAL DEVELOPMENT WHERE

WE SEE A LOSS OF SKILLS.

SO, BETWEEN 3-6 MONTHS, BABIES

CAN DISCRIMINATE FACES FROM

THEIR OWN RATES AND DISCRIMINATE

FACEES FROM A RACE THEY HAVEN'T

SEEN BEFORE SO SAY THEY ARE

GROWING UP IN CAUCASIAN

ENVIRONMENT AND THEY CAN

DISCRIMINATE ASIAN ENVIRONMENTS

AND THEY ARE DISCRIMINATE FACEES

FROM OTHER SPECIES.

BY 9-10 MONTHS, THEY CAN STILL

DISCRIMINATE THEIR OWN RACE

FACES BUT THEY LOST THE ABILITY

FOR OTHER RACE AND OTHER

SPECIES.

AND THIS WE BELIEVE IS DUE TO

THE PRUNING OF THESE LESSER USED

CONNECTIONS AND THE

STRENGTHENING OF THE CONNECTIONS

FOR THEIR OWN RACE SURROUNDING

EXPERIENCE.

HOWEVER, THERE IS ONE PROVISO TO

THAT.

IF EXPERIENCES GIVEN AT 9 MONTHS

OF OTHER RACE OR OTHER SPECIES,

THEN AT 12 MONTHS, THEY SHOW THE

DISCRIMINATION AGAIN.

SO IT SUFFICES FOR A LITTLE

EXPERIENCE FOR THEM TO REGAIN

THAT POSSIBILITY AS IF THE

PRUNED CONNECTIONS ARE ACTUALLY

WAITING FOR MORE INFORMATION

THAN CAN COME UP TO BEING USED

AGAIN.

WE DON'T KNOW HOW LONG THAT

LASTS.

I DON'T THINK ANYONE HAS TESTED

THAT OVER A LONGER PERIOD.

AND ANOTHER EXAMPLE IS IN SPEECH

PROCESSING.

SO, IN THE VERY YOUNG BABIES,

THEY CAN DISCRIMINATE FROM THEIR

NATIVE TONGUE AND THEY CAN

DISCRIMINATE FROM A LANGUAGE

THEY NEVER HEARD BEFORE AND

WHICH WE FIND AS ADULTS VERY

DIFFICULT TO DISCRIMINATE, AND I

WONDER WHETHER ANYONE HAD EVER

DONE DISCRIMINATION OF OTHER

SPECIES CRIES?

I DON'T THINK THEY HAVE BUT IT

WOULD BE A POSSIBILITY THAT THEY

COULD DO THAT AS WELL.

BY 9-10 MONTHS, THE ABILITY IS

LOST FOR NON--NATIVE DUE TO THE

PRUNING EVER THINGS THEY HAVE

NOT HEARD SO LESSER STRENGTHENED

CONNECTIONS AND THE

STRENGTHENING OF THE ONES THAT

ARE DUE TO THEIR OWN MOTHER

TONGUE AND AGAIN, IF YOU GIVE

THEM SOME EXPERIENCE AT 9 MONTHS

OF A FOREIGN DISCRIMINATION,

THEN AT 12 MONTHS THEY SHOW THE

ABILITY AGAIN.

THESE STUDIES TO MY KNOWLEDGE,

HAVE ONLY BEEN DID ON SEPARATE

GROUPS OF CHILDREN.

SO, NO ONE SO FAR I THINK HAS

DONE SPEECH PROCESSING AND FACE

PROCESSING IN EXACTLY THE SAME

INFANTS.

SO WE STILL AREN'T SURE IF THIS

IS A GENERAL PHENOMENON THAT

TAKES PLACE AT THE SAME TIME OR

WHETHER THEY ARE DIFFERENT AND

MORE GERMANE-SPECIFIC

PHENOMENON.

SO, FACE AND SPEECH PROCESSING

UNDERGO WHAT WE CALIPER

SEPTEMBERUAL NARROWING IN

NEUROTYPICAL DEVELOPMENT AND

THERE IS A BALANCE BETWEEN

STRENGTHENING CONNECTIONS THAT

ARE BEING USED RELEVANT TO THE

ENVIRONMENT OF THE CHILD AND

PRUNING OF THE UNUSED ONES AND

THERE IS A PROGRESSIVE

SPECIALIZATION AND LOCALIZATION

OF NEUROFUNCTION.

AND YOU SEE THIS VERY NICELY IN

WORK DONE BY MICHELLE, MARK

JOHNSON, AND OF COURSE CHUCK WHO

IS NOT HERE TODAY.

I WOULD HAVE NODDED TO HIM,

SHOWING THAT OVER TIME, THE

PATTERN YOU SEE IN BLUE FOR THE

ADULT FACE PROCESSING AND THE

STRONG N170 THAT IS TYPICAL OF

THE STRUCTURAL ENCODING OF A

FACE, TAKES TIME FROM 6 MONTHS

TO 12 MONTHS TO GET TO THE LEVEL

OF ADULT.

AND IF YOU SEE ON THE RIGHT, THE

SKULL MAPS, YOU CAN SEE THAT

VERY EARLY IN DEVELOPMENT, THIS

BILATERAL PROCESSING IF

ANYTHING, BUT IT'S NOT

SIGNIFICANT, A SLIGHT TENDENCY

TOWARDS LEFT HEMISPHERE

PROCESSING.

BY 12 MONTHS, THIS IS CLEARLY

SHIFTED TO THE RIGHT AND IT IS

MORE LIKE THE ADULT PATTERN THAT

YOU SEE LATER.

SO AS I SAID, WITH MICROTHOMAS,

WE DEVELOPED A HYPOTHESES THAT

THERE IS DIFFERENCE BETWEEN

STRENGTHENING AND WEAKENING OF

CONNECTIONS MIGHT BE RELEVANT TO

AUTISM.

SO IN THE NORMAL -- NEUROTYPICAL

CASE, WE HAVE A NORMAL PRUNING

THRESHOLD.

THERE IS A BALANCE BETWEEN

STRENGTHENING AND PRUNING.

DIFFERENT TIMING ACROSS

DIFFERENT REGIONS.

THIS IS WORK DONE BY -- SHOWING

VERY CLEARLY THAT DIFFERENT

PARTS OF THE BRAIN ARE PRUNED AT

DIFFERENT TIMES IN DEVELOPMENT.

AND SPECIALIZATIONS IS

EXPERIENCED DEPENDENT AND

PROGRESSIVE.

I'LL TAKE ONE EXAMPLE FROM

ANOTHER NEURODEVELOPMENTAL

DISORDER, WILLIAMS SYNDROME, AND

ASK WHETHER THERE IS

UNDER-PRUNING OR A LACK OF

PRUNING AND IMBALANCE BETWEEN

THE STRENGTHENING AND WEAKENING

OF CONNECT ACTIVITY.

BUT -- CONNECTIVITY -- BUT THERE

IS A LACK OF NEUROSPECIALIZATION

DESPITE BEHAVIORAL MASTERY.

SO, DIFFERENT TEAMS THROUGHOUT

THE WORLD HAVE SHOWN THAT PEOPLE

WITH WILLIAMS SYNDROME FALL IN

THE NORMAL RANGE IF YOU STARRED

ARDIZE TASK WITH THEM.

THEY ARE VERY GOOD AT FACE

PROCESSING.

HOWEVER, IF YOU LOOK AT

INVERSION, SO WHEN FACES ARE UP

RIGHT AND YOU INVERT IT, YOU

SHOW A LACK OF MEMORY, A LACK OF

SPEED OF PROCESSING AND LACK OF

ACCURACY OF PROCESSING.

AND THIS INVERSION AFFECT THAT

YOU SEE IN NEUROTYPICAL

DEVELOPMENT DOES NOT ARISE AT

ANY POINT ACROSS THE

DEVELOPMENTAL SPECTRUM IN

WILLIAMS SYNDROME.

SO, WHAT ABOUT THE BRAIN?

WELL, A STUDENT OF MINE, SARAH,

LOOKED AT HUMAN FACE PROCESSING,

MONKEY FACE PROCESSING AND THE

PROCESSING OF CARS.

AND TO CUT A VERY LONG STORY

SHORT, REMINDING YOU THAT ALL OF

OUR SUBJECTS WERE IN THE NORMAL

RAGE ON STANDARDIZED TASK FOR

FACE PROCESSING AND WE FOUND THE

FOLLOWING.

SO IF YOU LOOK AT THE TOP YOU

CAN SEE THAT HUMAN FACE

PROCESSING AND MONKEY FACE

PROCESSING SHOW A VERY CLEAR

N170 WITH HUMAN, THE LATENCY FOR

HUMAN PROCESSING SLIGHTLY FASTER

THE CARS WERE VERY DIFFERENT IN

THE CONTROLS.

IN THE WILLIAMS CASE THEY ALL

LOOKED THE SAME.

THEY SHARE THE SAME PATTERN AS

IF THE IN PULT OF A FACE IS NO

DIFFERENT THAN OTHER INPUTS.

AND THEN IF WE LOOK AT INVERTED

AND UPRIGHT FACES IN THE BOTTOM

WE HAVE THE CONTROLS FOR UP

RIGHT FACES AND TO THE RIGHT FOR

INVERT THE.

IN THE CASE OF WILLIAMS, THERE

IS NO DIFFERENCE BETWEEN

INVERTED AND UP RIGHT FACES.

SO SUGGESTING THAT THEY PROCESS

FACES FEATUREY.

SO A DIFFERENCE IN

NEURODEVELOPMENTAL DISORDER IN

THIS BALANCE OF PRUNING AND

STRENGTHENING OF CONNECTIVITY

SHOWING A LACK OF SPECIALIZATION

IN THIS DISORDER.

SO, IN AUTISM SPECTRUM DISORDER,

WE HAVE BEEN ARGUING THAT ONE

POSSIBLE HYPOTHESES AND WE

TESTED THIS IN COMPUTATIONAL

MODEL, IS THAT IN AUTISM, THE

THRESHOLD IS VERY HIGH FOR

PRUNING.

SO THAT THEY PRUNE AWAY

CONNECTIVITY THAT IS BEING

STRENGTHENED.

NOT JUST UNUSED CONNECTIONS BUT

ALSO THE STRENGTHENED ONES.

AND REGRESSION IS SEEN IN SOME

CASES AND THIS IS WORK BY ANDREW

PICKLES WHERE SAY LANGUAGE HAS

DEVELOPED TO SOME DEGREE AND

THEN THE PRUNING OF THESE

STRENGTHENED CONNECTIONS ARE CUT

AWAY.

WHEREAS IN OTHER CASES, IF THE

LANGUAGE HASN'T DEVELOPED YET,

THEN IF YOU LIKE, THE REGRESSION

IS CAM FLANNELED BECAUSE IT

ISN'T YET IN THE OVERT BEHAVIOR

OF THE CHILD.

AND WE PUT FORWARD THE

HYPOTHESES THAT IF THIS IS

RIGHT, THEN WE SHOULD SEE

SENSORY MORTUARY AGGRESSION, SO

THINGS LIKE SAY THE PINSA GRIP

OR REACHING, SHOULD SHOW A

REGRESSION WAY BEFORE WE SEE

REGRESSION IN LANGUAGE OR IN

EXECUTIVE FUNCTION.

WHICH HAVE BEEN DOCUMENTED.

AND OUR THOUGHTS WERE THAT

PARENTS ARE MUCH LESS LIKELY TO

NOTICE THESE FINE MOTOR

DIFFERENCES THAN THEY ARE TO

NOTICE SAY LANGUAGE.

AND I THINK THERE IS SOME

INDICATION IN THE LITERATURE,

LONNIE HAS LITERATURE, SHOWING

MORTUARY AGGRESSION IN AUTISM.

SO, IN DEVELOPING THIS, WE WERE

THINKING THAT YOU DON'T

NECESSARILY NEED A SINGLE GENE

MUTATION.

THIS COULD BE A GENE OR GENE

THAT IS HAVE A RANGE OF LEVELS

OF PRUNING THRESHOLDS AND IF IT

IS TOO HIGH, THEN YOU GET THE

ASD-TYPE REGRESSION AND IF IS

TOO LOW, YOU GET ANOTHER

PHENOTYPE.

SO IT IS AN EXAGGERATION OF THE

NORMAL PROCESS.

AND THIS MEANS AS I SAID, THAT

IN AUTISM IF THE HYPOTHESES IS

RIGHT, THAT PRUNING STRENGTHENED

CONNECTIONS AND NOT JUST THE

WEAK ONES.

I THINK I SAID THIS ALREADY.

SO I WON'T SAY THAT AGAIN.

AND OF COURSE THIS IS JUST ABOUT

THE REGRESSION PHENOMENON.

THERE ARE MANY OTHER INDIVIDUAL

DIFFERENCES THAT WILL GO

TOGETHERS WITH THIS IN ORDER TO

YIELD DIFFERENT TRAJECTORIES IN

ASD.

SO, I THINK WE NEED TO CONSIDER

THIS NOTION OF A BALANCE BETWEEN

IN THE TYPICAL CASE, PRUNING AND

STRENGTHENING.

AND WONDER WHETHER WE SHOULDN'T

BE RUNNING SOME OF THESE TASKS

THAT I SHOWED YOU WHERE THERE IS

A LOSS OF SKILLS IN NORMAL

DEVELOPMENT IN FACE PROCESSING

AND SPEECH PROCESSING, IN

INFANTS AT RISK OF AUTISM

BECAUSE THEY ARE VERY STRONG

DATA AND WE COULD SEE THEM

WHETHER OR NOT THERE IS THIS

PHENOMENON HAPPENING OVER TIME

BECAUSE OURS WAS OF COURSE A

HYPOTHESES THAT WE DEVELOPED.

SO, LET ME IF I HAVE TIME

STILL -- YES?

JUST GO THROUGH SOME OF THE

DIFFERENCES THAT I PULLED OUT

EACH ONE OF THEM COULD BE A TALK

IN ITS OWN RIGHT BUT I THOUGHT I

WOULD AT LEAST MENTION THEM.

SO I WENT THROUGH A LOT OF THE

LITERATURE LOOKING AT THE

DIFFERENCES THAT PEOPLE BROUGHT

OUT FOR INFANTS AND YOUNG

TODDLERS WITH AUTISM SPECTRUM

DISORDERS, AND LOOKED TO SEE

WHETHER THEY WERE SPECIFIC TO

AUTISM OR NOT.

SO, A TYPICAL SECCADIC EYE

MOVEMENT PLANNING IS SEEN IN ANY

STUDIES IN AUTISM BUT ALSO

WILLIAMS SYNDROME.

SHORTER FIXATION DURATION TIMES

TO SOCIAL AND NONSOCIAL SCENES

IS SEEN IN DOWN'S SYNDROME AS

WELL.

WE HAVE BEEN LOOKING AT THAT

RECENTLY.

ATTENTION TO EYES DECLINES IN

AUTISM BETWEEN 2-6 MONTHS AND I

BELIEVE THIS HAS BEEN SHOWN IN

RETT SYNDROME.

I PUT A QUESTION MARK BECAUSE I

COULDN'T FIND THAT BUT I HEARD

IT IN A TALK.

DEFINITELY A TYPICAL FACE

PROCESSING, MUCH MORE FEET

RECALL, IS FOUND ACROSS THE

SPECTRUM AND IN WILLIAMS

SYNDROME.

A LACK OF TRIADIC INTERACTION SO

WORKING OUT THAT I'M FOCUSING ON

YOU AND THEN WE FOCUS TOGETHER

ON SOME EXTERNAL OBJECT WHICH IS

VERY IMPORTANT IN NAMING AND

LEARNING LANGUAGE, IS ALSO

MISSING AND ATYPICAL IN WILLIAMS

SYNDROME.

ERPs TO DYNAMIC EYE GAZE,

WHICH SEEM TO BE SPECIFIC TO

AUTISM, WE ARE NOW TESTING THIS

IN BABIES WITH WILLIAMS SYNDROME

AND DOWN'S SYNDROME TO SEE IF IT

IS SPECIFIC.

EEG FRONTAL O CYP TALL

HYPERCONNECTIVITY HAS BEEN SHOWN

IN INFANTS AT RISK AND WE HAVE

DATA FROM DOWN'S SYNDROME.

A LACK OF SPEECH PITCH RELEVANT

TO SUBSEQUENT LANGUAGE, ARE

ATYPICAL IN WILLIAMS SYNDROME

AND IN FRAGILE X SYNDROME BUT

THIS IS THE UNIQUE ONE.

AND I FOUND NO OTHER

NEURODEVELOPMENTAL DISORDER.

ENHANCED VISUAL SEARCH

ABILITIES.

YOU SEE THIS NOW HAS BEEN SHOWN

IN INFANTS AT RISK OF AUTISM AND

YOU DEFINITELY SEE IT LATER IN

THE DEVELOPMENTAL TRAJECTORY.

I HAVEN'T SEEN THAT IN ANY OTHER

SYNDROME.

I DON'T KNOW IF ANY OF THE OTHER

SPEAKERS HAVE.

AND IF YOU CAN DO THE VERY

SIMILAR EXERCISE IN TERMS OF

BRAIN.

SO, ALL THE THOUGH THERE ARE

VARYING CLEAR DESCRIPTIONS OF

HOW THE BRAIN OF PEOPLE WITH

AUTISM IS DIFFERENT FROM THAT OF

TYPICAL DEVELOPMENT, MANY OF THE

THINGS THAT ARE PULLED OUT,

DIFFERENCES IN CHORPUS CALOWS

UM, DIFFERENCES IN THE STREAM,

ARE TRUE OF MANY OTHER

DISORDERS.

IF WE MAKE CROSS-SYNDROME

COMPARISONS RATHER THAN

COMPARISONS WITH TYPICAL

DEVELOPMENT, WE ARE LIKELY TO BE

ABLE TO PULL OUT CLUSTERS OF

DIFFERENCES THAT MAYBE SPECIFIC

TO AUTISM BUT WHENEVER WE DO IT

WITH TYPICAL DEVELOPMENT,

EVERYTHING IS DIFFERENT.

SO I THINK THE CROSS SYNDROME

APPROACH COULD BE VERY RICH IN

ENLIGHTENING US ON WHAT IS

SPECIFIC TO AUTISM.

TO CONCLUDE, SO INITIALLY, IN

NEUROTYPICAL DEVELOPMENT, THERE

IS A SURPLUS OF

NEUROCOMPUTATIONAL RESOURCES.

WE KNOW THAT.

THERE WILL IS MUCH MORE GREATER

CONNECTIVITY WHEN THE CHILD IS

BORN.

AND OVER TIME, THOSE THAT ARE

BEING STRENGTHENED WILL BE

RETAINED AND THOSE THAT ARE NOT

BEING USED WILL BE PRUNED.

AND THIS PRUNING OF COURSE,

SAVES METABOLIC COSTS.

IN NEUROTYPICAL DEVELOPMENT,

SKILLS ARE NOT RE-GAINED IF WE

LOOK AT THESE EXAMPLES OF LOSS.

THEY CHANGE IN TERMS OF THEIR

UNDERLYING REPRESENTATIONS OR

THEIR FUNCTION.

AND I THINK WE NEED TO ASK THIS

QUESTION FOR REGRESSION IN

AUTISM.

IN AUTISM, AS I SAID, IT WOULD

SUFFICE TO HAVE A MUTATIONAL AND

QUITE COMMON GENE WITH A RISK

ALLELE REGULATING THE LEVEL AT

WHICH PRUNING TAKES PLACE IN

ORDER TO GET RID OF

CONNECTIVITY.

AND IN THE CASE OF AUTISM, WE

BELIEVE THAT THIS HIGH LEVEL OF

PRUNING GETS RID OF CONNECT

ACTIVITY THEY IS STRENGTHENED

RATHER THAN JUST THOSE THAT ARE

WEAK.

IF THE BEHAVIORAL DEVELOPMENT IS

SLOW, THEN REGRESSION ACTUALLY

COULD BE TAKING PLACE BUT IT'S

ACTUALLY NOT SEEN IN THE OVERT

BEHAVIOR.

IT'S CAMOUFLAGED, IN FACT.

SO THAT IS SOMETHING TO THINK

ABOUT IN TERMS OF THOSE CHILDREN

WHO SEEMINGLY DON'T SHOW

REGRESSION.

AS I POINTED OUT, THE HYPOTHESES

IS THAT WE SHOULD SEE FIRST

REGRESSION IN SENSORY MOTOR

SYSTEMS AND ONLY LATER IN

LANGUAGE AND EXECUTIVE FUNCTION.

AND I THINK THAT THE LANGUAGE

CASE IS SO NOTICEABLE BUT FOR

PARENTS, TO LOOK AT OTHER SIGNS

IN THE SENSORY MOTOR SYSTEM,

MIGHT BE A VERY IMPORTANT ONE.

CLINICIANS AS WELL.

INTERESTINGLY, IN GENERAL, IF

PRUNING IS TOO RAPID OR TOO

AGGRESSIVE, THEN YOU HAVE A LACK

OF FLEXIBLE INTERACTION WITH THE

ENVIRONMENT AND THAT COULD LEAD

TO RIGIDITY AND REPETITIVE

BEHAVIORS PERHAPS.

BUT I THINK WE NEED IN THE

FUTURE, IN ALL OUR STUDIES, TO

FOCUS MUCH MORE ON INDIVIDUAL

DIFFERENCES AND HOW DOMAINS

RELATED TO CROSS DIFFERENT

DOMAINS AND SEVERAL

CROSS-SYNDROME COMPARISONS

RATHER THAN GROUP DATA AND

COMPARING THEM JUST TO

NEUROTYPICAL CONTROLS.

AND WITH THAT, I'D LIKE TO THANK

VARIOUS PEOPLE WHOSE WORK I

MENTIONED BUT PARTICULARLY MY

COHORT, THOMAS AND THE VARIOUS

PEOPLE WHO HAVE FUNDED MY

RESEARCH.

THANK YOU.

[ APPLAUSE ]

>> ANN WAGNER:  THANK YOU THAT

WAS A REALLY GREAT TALK.

WE ARE GOING TO SAVE QUESTIONS

UNTIL THE END.

WE HAVE A HALF HOUR FOR

DISCUSSION AFTER THE SESSION.

WE WILL MOVE ON.

THE NEXT TALK IS KASIA AND

REGRESSION IN AUTISM SPECTRUM

DISORDERS.

>> KASIA CHAWARSKA:  GOOD

MORNING THIS IS A WONDERFUL

PLEASURE.

GREAT PLEASURE TO BE HERE.

THANK YOU FOR INVITING ME.

SO, I WAS ASKED TODAY TO GIVE

YOU AN OVERVIEW OF WHAT

REGRESSION IS, HOW IT EXPRESSES

ON THE PHENOTYPIC LEVEL IN

AUTISM AND GIVEN MY INTEREST IN

INFANCY, I'M GOING TO FOCUS

QUITE EXTENSIVELY ON WHAT

HAPPENS IN THE FIRST TWO OR

THREE YEARS OF LIFE.

NOW, WHEN AUTISM WAS DESCRIVED

IN 1943, HE NOTICED ALL CHILDREN

IN HIS SAMPLE EXHIBITED SYMPTOMS

AFTER BIRTH AND CONSIDERED IT TO

BE INNATE DISORDER AND THAT WAS

IT.

HOWEVER, ABOUT A DECADE LATER,

EISENBERG AND CANNER IN 1956,

PUBLISHED ANOTHER PAPER IN WHICH

THEY REVISED THE IDEA ABOUT

DEVELOPMENTAL TRAJECTORIES IN

AUTISM.

THEY FOUND A GROUP OF CHILDREN

WHO WERE ACTUALLY SEEMINGLY

DEVELOPING TYPICALLY UNTIL ABOUT

18 OR 20 MONTHS WHEN THEY LOST

LANGUAGE.

AND SO, THEY DESCRIBED THIS

PHENOTYPE OF AUTISM RELATED TO

REGRESSION AND THEY SUGGESTED

THERE ARE TWO WAYS IN WHICH

CHILDREN BECOME AUTISTIC.

ONE OF THEM WITH INNATE

DIFFICULTIES AND ANOTHER WITH

SOME LOSS OF SKILLS.

THIS WAS 60 YEARS AGO.

SO, WE ARE NOW, I'M GOING TO

GIVE YOU A VERY QUICK OVERVIEW

OF WHAT WE HAVE LEARNED IN THE

PAST 60 YEARS.

IT'S A VERY SELECTIVE
OVERVIEW.

BUT, JUST WITH THE IDEA OF

SETTING THE STAGE FOR LATER

DISCUSSION.

I THINK THE FIRST THING THAT

COMES TO MIND WHEN WE LOOK AT

THE LITERATURE ON THE REGRESSION

IS, THE VARIABILITY IN HOW THIS

CONCEPT IS OPERATIONALIZED.

I THINK WE ALL AGREE THAT

REGRESSION MEANS LOSS OF

PREVIOUSLY ACQUIRED SKILLS, BUT

IN SOME STUDIES, THE SKILLS HAVE

TO BE FUNCTIONAL FOR ONE MONTH

AND OTHERS FOR THREE MONTHS OR

SIX MONTHS.

FOR A NUMBER OF YEARS, I THINK

THERE WAS A STRONG BELIEF THAT

CHILDREN WHO ARE LOSING SKILLS

ARE ACTUALLY DEVELOPING

TYPICALLY BEFORE THIS PERIOD OF

LOSS.

HOWEVER, A VERY ELEGANT STUDY

FROM AUDREY SUGGESTS THAT

MAJORITY OF CHILDREN WHO LOSE

SKILLS EXPERIENCE SOME KIND OF

DEVELOPMENTAL CHALLENGES VERY

EARLY ON.

SO, REGRESSION ALREADY OCCURS

WITHIN A CONTEXT OF VULNERABLE

AND FRAGILE DEVELOPMENT.

TYPICALLY, THE REPORTS REGARDING

THE TIMING OF ONSET WOULD PLACE

REGRESSION SOMETIMES BETWEEN 12

AND 24 MONTHS WITH A MEDIAN

AROUND 18-20 MONTHS.

BUT WE KNOW THAT THERE ARE CASES

OF REGRESSION WHEN LOSS OF

SKILLS OCCURS IN THE FIRST YEAR

OF LIFE OR LOSS OF SKILL OCCURS

LATER IN THE SECOND AND THIRD

YEAR OF LIFE.

WHEN I THINK ABOUT REGRESSION,

WE TYPICALLY THINK ABOUT

LANGUAGE, LOSS OF LANGUAGE, AND

THIS IS THE CLASSIC AREA THAT

KANNER HIGHLIGHTED 60 YEARS AGO

AND MANY, MANY STUDIES FOCUS ON

LOSS OF FIRST WORDS, LOSS OF

PHRASE SPEECH AND DOCUMENTED

PHENOMENON IN AUTISM.

HOWEVER, THERE ARE OTHER STUDIES

WHICH ALSO SUGGEST LOSS OF

NON--VERBAL COMMUNICATIONS,

GESTURES MOST SPECIFICALLY AND

LOSS OF SOCIAL ENGAGEMENT AND

BEHAVIORS.

BEHAVIORS INVOLVING EYE CONTACT,

SOCIAL SMILING, RECIPROCAL

COMMUNICATION, ENJOYMENT IN

SOCIAL INTERACTIONS AND SO

FORTH.

IN TERMS OF PREVALENCE, WITH

SUCH A BROAD DEFINITION OR BROAD

RANGE OF DEFINITIONS OF

REGRESSION, PREVALENCE OF

REGRESSION IS QUITE BROAD.

IF WE THINK ABOUT STRICTLY ABOUT

REGRESSION WITH REGARD TO LOSS

OF LANGUAGE, THE NUMBERS ARE

ABOUT 15-20%.

HOWEVER, WHEN WE LOOK A LITTLE

BROADLY, MORE BROADLY, INTO LOSS

OF SOCIAL SKILLS, SOCIAL

BEHAVIORS, THIS NUMBER GOES UP

TO ABOUT 40-50%.

IF WE LOOK AT VERY YOUNG

CHILDREN UP AND WE STUDY THEM

PROSPECTIVELY, SIGNS OF LOSS OF

SKILLS IS ACTUALLY PRESENT IN

THE VAST MAJORITY OF THESE

CHILDREN.

AS MANY AS 80%.

NOW, THERE ARE A COUPLE OF OTHER

INTERESTING THINGSILED LIKE TO

HIGHLIGHT BEFORE I MOVE TO MORE

SPECIFIC WORK ON INFANCY.

ANOTHER THING BUT SURVEY OF THE

LITERATURE, I WAS INTERESTED IN

FINDING OUT WHAT IS THE SEX

RATIO WITH REGARD TO REGRESSION?

AND THERE IS NO STRONG DIRECT

RESEARCH ON THAT BUT MOST

STUDIES REPORT THAT THE RATIO IS

1-1 WHICH IS SOMEWHAT SURPRISING

GIVEN THE AUTISM IS FOUR TIMES

MORE LIKELY TO OCCUR IN FEMALES.

SO I'M NOT SURE WHAT THIS MEANS

AND I'M NOT SURE IF THIS IS A

REAL PHENOMENON BUT IT IS

INTERESTING OR IMPORTANT TO

FLAG.

NOW, AT A TIME WHEN WE COME UP

WITH SOME KIND OF CONSTRUCT OR

PHENOMENON THAT WE THINK IS

CLINICALLY SIGNIFICANT, WE WOULD

LIKE TO BE ABLE TO VALIDATE THIS

PHENOMENON AND SHOW IT SOMEHOW

CHANGES THE DEVELOPMENT OR HAS

SOME KIND OF IMPACT ON LONG-TERM

OUTCOME AND THERE IS A NUMBER OF

STUDIES IN THE FIELD OF

REGRESSION THAT FOCUS ON LONG

TERM OUTCOMES OF CHILDREN WHO

HAVE A HISTORY OF REGRESSION

VERSUS THOSE WHO DON'T.

AND THERE IS SOME EVIDENCE, NOT

VERY STRONG, THAT THOSE WHO HAVE

HAVE REGRESSION, MAY HAVE

SOMEWHAT LESS FAVORABLE OUTCOMES

IN TERMS OF LANGUAGE DEVELOPMENT

OVERALL COGNITION.

HOWEVER THESE RESULTS ARE NOT

TERRIBLY CONSISTENT AND WHAT

THEY SUGGEST IS IF AT ALL, IT'S

NOT A DIFFERENCE WITH REGARD TO

QUANTITY.

IT'S A SLIGHT SHIFT IN THE

DISTRIBUTION OF VALUES FOR THOSE

WHO REGRESS VERSUS THOSE WHO

DON'T.

NOW, WHAT IS ALSO IMPORTANT TO

KEEP IN MIND THAT AT THE VERY

BEGINNING, EARLY STAGES OF

RESEARCH ON REGRESSION, WE

THOUGHT REGRESSION IS ACTUALLY

YET SPECIFIC TO AUTISM.

ESPECIALLY CERTAIN TYPES OF

REGRESSION, SUCH AS LOSS OF

LANGUAGE.

IN FACT, WHEN WE LOOK AT OTHER

DEVELOPMENTAL DELAYS OR OTHER

GENETIC DISORDERS, REGRESSION IS

QUITE COMMON AND IT DOES INVOLVE

A LOSS EVER SPEECH.

OF COURSE WE HAVE NO IDEA

WHETHER THESE ARE THE SAME KINDS

OF MECHANISMS BUT AS ANNETTE

POINTED OUT, COMPARISON ACROSS

VARIOUS TYPES OF REGRESSION,

DIFFERENT SYNDROMES, CAN BE

TREMENDOUSLY INFORMATIVE WITH

REGARD TO THE UNDERLYING

MECHANISMS.

SO HOW DO WE MEASURE REGRESSION?

THIS IS SOMETHING TREMENDOUSLY

HARD TO MEASURE, RIGHT?

BECAUSE THE SYMPTOMS ONSET LET'S

SAY AT 18 MONTHS.

THE CHILD IS DIAGNOSED WHEN THEY

ARE 2 OR 3.

SOMETIME PASSES WHEN WE ASK

PARENTS, CAN YOU TELL US HOW WAS

YOUR CHILD AROUND THE TIME OF

SYMPTOMS SORT OF EMERGING?

SO THERE IS A TREMENDOUS

TIMELINE BETWEEN WHEN THE

PHENOMENON IS OCCURRING AND THE

TIME WE ARE MEASURING IT.

AND IN FACT, MOST OF THE STUDIES

WE SEE IN LITERATURE ARE BASED

ON PARENTAL RETROSPECTIVE REPORT

AND THE BEST STUDIES RELY ON THE

MOST DETAILED QUESTIONING OF THE

PARENTS BUT THERE IS A CERTAIN

LIMITATION TO THE STORY WHICH IS

REFLECTED IN INTERACTION BETWEEN

LIMITS OF PAR ENTAL RECALL AND

TIME DISTANCE BETWEEN THE ONSET

AND THE MEASUREMENT.

THE SECOND WAY OF MEASURING

REGRESSION IS TO ANALYZE HOME

VIDEOS.

SO PARENTS LOVE THEIR BABIES AND

THEY RECORD THE BABIES ON HOME

VIDEOS.

AND THEN RESEARCHERS HAVE AN

OPPORTUNITY TO LOOK FOR

BEHAVIORS THAT THEY FIND

RELEVANT.

AND THERE WAS ONE STUD WHICH

ACTUALLY DID BOTH.

THEY ASKED PARENTS, TELL US WHEN

DID YOUR CHILD START LOSING

SKILLS?

AND ALSO REVIEWED THE VIDEO

EVIDENCE.

AND THIS WAS A STUDY ON

RELATIVELY YOUNG CHILDREN AND

CAME FROM THE MIND INSTITUTE BY

SALLY.

NOW, WHAT THEY DID, THEY COUNTED

FREQUENCY OF BEHAVIORS SUCH AS

LOOKING AT PEOPLE, SMILING AT

PEOPLE, VOCALIZING PEOPLE, AND

THEY PUT IT TOGETHER AS KIND OF

AN INDEX OF SOCIAL FUNCTION,

HIGHER DISCORD, THE BETTER CHILD

DYSFUNCTIONING AND THIS IS AGE

FROM 6-24.

AND WHAT THEY FOUND IS THAT

TYPICAL BABIES FROM 6-24 THEY

GET BETTER.

THEY DO IT MORE FREQUENTLY.

THIS IS GOOD.

THIS IS WHAT WE EXPECT.

NOW SOMETIMES THE CHILDREN WITH

AUTISM, BASED ON THE

TRAJECTORIES WITH REGARDS TO

FREQUENCY OF SOCIAL BEHAVIORS

AND THEY FOUND SOMETHING VERY

INTERESTING.

THEY FOUND NO TWO GROUPS AS

DESCRIBED, BUT THREE GROUPS.

THEY WERE THE EARLY-ONSET,

CHILDREN WHO ARE MUCH VERY

DELAYED EARLY ON.

AND ANOTHER GROUP WHICH WAS KIND

OF DOING FINE AND THEN THEY

STAGNATED.

THEY ACTUALLY REACH A PLATEAU

AND STOP PROGRESSING IN TERMS OF

DEVELOPMENT SO THE DELTA BETWEEN

TYPICAL BABIES AND THIS SUBGROUP

HAS BEEN INCREASING OVER TIME.

AND THERE IS FINALLY THE GROUP

THAT WE ARE INTERESTED IN WHICH

IS THE GROUP OF REGRESSION.

SO THIS STUDY SHOWS MANY WAYS OF

GETTING TO THE COMMON DIAGNOSIS

OF AUTISM AND BY COMPARING

DIFFERENT GROUPS WITH DIFFERENT

DEVELOPMENTAL TRAJECTORIES, WE

MIGHT BE ABLE TO LEARN NOT ONLY

ABOUT REGRESSION BUT ALSO ABOUT

THE OTHER PATTERNS OF ONSET.

ALSO VERY INTERESTING OF THE

STUDY IS THAT THOSE BASICALLY NO

CONSISTENCY BETWEEN WHAT PARENTS

REPORTED AND WHAT THE

RESEARCHERS SAW.

ANOTHER WAY OF THINKING ABOUT

REGRESSION IS NOT TO THINK ABOUT

GROUPING CHILDREN OR LOOKING HOW

CHILDREN DEVELOP BUT LOOK AT

SPECIFIC SKILLS OF BEHAVIOR AND

SEE HOW THEY UNFOLD

DEVELOPMENTALLY IN YOUNG KIDS

WITH AUTISM.

AND AGAIN, SALLY CONDUCTED THE

STUDY AND CONDUCTED THE STUDY ON

A VERY PRECIOUS AND SPECIAL

SAMPLE.

THIS IS A SAMPLE OF YOUNGER

SIBLINGS OF CHILDREN WITH

AUTISM.

THESE BABIES ABOUT 20% OF THEM,

HAVE HIGH LIKELIHOOD OF

DEVELOPING AUTISM ABOUT 20-30%

OF THEM ARE LIKELY TO DEVELOP

SOMETHING WE CALL BROTHER AUTISM

PHENOTYPE FEATURES RELATED TO

THE SYNDROME BUT NOT AS

PRONOUNCED AND ABOUT 50% OF THEM

HAVE TYPICAL DEVELOPMENT.

THE DESIGN OF THE STUDY IS THAT

WE ENROLL THEM AT BIRTH AND

FOLLOW THEM UNTIL THE AGE OF 3

AND BY EXAMINING VARIOUS FACETS

OF DEVELOPMENT, WE CAN

UNDERSTAND OR LEARN WHEN IN

WHICH DOMAINS THEIR TRAJECTORIES

ARE DIVERGING FROM THOSE WITHOUT

AUTISM.

AND SHE MESHED FREQUENCY OF

BEHAVIORS INVOLVING --

MEASURED -- SOCIAL SMILING,

SOCIAL VOCALIZATIONS AND

ATTENTION TO PEOPLE IN A CONTEXT

OF INTERACTION WITH AN ADULT,

STANDARDIZED INTERACTION WITH AN

ADULT AT 6, 12, 18, 24 AND 36

MONTHS.

AND WHAT SHE FOUND WAS SOMETHING

TREMENDOUSLY EXCITING AND

INTERESTING.

DIFFERENT SKILLS FOLLOW

DIFFERENT TRAJECTORIES IN KIDS

WITH AUTISM.

SO, A COUPLE OF SKILLS INVOLVING

SOCIAL SMILING, SOCIAL

VOCALIZATION REACH A PLATEAU AND

DIVERGE SUBSTANTIALLY FROM

TYPICAL KIDS LATER ON BECAUSE

TYPICAL KIDS GET BETTER AND KIDS

WITH AUTISM DON'T.

AND THERE IS OTHER SKILLS SUCH

AS THIS.

THIS WILL IS ATTENTION TO

PEOPLE.

ATTENTION TO LOOKING AT PEOPLE.

LOOKING AT THE EXAMINER.

LOOKING AT HIS OR HER FACE.

AND THAT SKILL DECREASES OVER

TIME.

SO AN INTERESTING NEW TWIST ON

REGRESSION NOT LOOKING AT KIDS

BUT LOOKING AT BEHAVIORS.

AND I LIKE TO SHOW YOU AN

EXAMPLE OF THIS PHENOMENON AS IT

HAPPENS AS I WAS PREPARING

SLIDES FOR THIS TALK, I REMEMBER

THIS LITTLE BOY.

THIS LITTLE BOY IS PART OF OUR

YALE SIBLING STUDY AND WE SAW

HIM AT 3, 6 AND 9 MONTHS.

THEY STARTED SNIPPETS.

THIS IS AN EXPERIMENT IN WHICH

AN EXPERIMENTER IS TRYING TO

ENGAGE A CHILD IN A FACE-TO-FACE

INTERACTION USING A VARIETY OF

CUES AND IN THIS CASE, THE COUP

IS MOTHERING.

SO SOMEONE IS SITTING IN FRONT

OF THE CHILD, SMILES, LOOKS AT

THE BABY AND SPEAKS WITH A HIGH

REGISTER VOICE.

THIS IS RYAN AT THREE MONTHS.

SO THIS SILENT BOY AT THREE

MONTHS AND WE CANNOT HEAR.

THIS IS THE BOY AT THREE MONTHS.

--

>> THERE HE IS.

YES YOU ARE.

YES YOU ARE.

YOU ARE SUCH A SWEETIE.

>> THIS IS AT SIX MONTHS.

>> HAVE YOU BEEN WORKING HARD

HERE TODAY?

YOU HAVE BEEN WORKING SO HARD.

>> THIS IS 9 MONTHS.

>> HI, SWEETHEART.

YOU SEE THAT LITTLE THING.

THAT'S JUST FOR BABIES LIKE YOU.

HOW IS IT GOING RYAN?

SWEETHEART, GUESS WHAT?

IT'S HALLOWEEN TODAY.

>> SO YOU SAW PRETTY DRASTIC

DECREASE IN ATTENTION TO PEOPLE.

BY 12 MONTHS, WE DIAGNOSE HIM

WITH AUTISM OR HIGH LIKELIHOOD

OF AUTISM AND HE RECEIVED A VERY

INTENSIVE INTERVENTION SECOND

YEAR OF LIFE.

HE IS DOING MUCH BETTER.

HE IS DEVELOPED LANGUAGE AND NOW

ABOUT 5 OR 6 YEARS OLD AND HE

HAS AUTISM.

WE HAVE ABSOLUTELY NO IDEA

WHETHER THESE BEHAVIORS WERE

DRIVE BY A TYPICAL PROCESS OR A

TYPICAL PROCESS EARLY ON.

BUT WE CAN SEE DECLINE HAPPENING

BETWEEN 6-9 MONTHS.

IT WAS QUITE EVIDENT.

NOW IN THIS PARTICULAR CASE, WE

ARE TALKING ABOUT ATTENTION TO

PEOPLE LOOKING AT PEOPLE,

FINDING PEOPLE WITHIN THE

CONTEXT OF COMPLEX VISUAL

ENVIRONMENT.

NOW, THAT IS A VERY GLOBAL

BEHAVIOR.

THAT IS A VECTOR OF MANY

PROCESSES THAT HAS TO DEAL WITH

SELECTIVE ATTENTION, LEARNING,

MEMORY, REWARD LEARNING,

MOTIVATION AND SO FORTH.

AND A NUMBER OF GROUPS AROUND

THE COUNTRY INCLUDING OUR MY LAB

STARTED LOOKING INTO THESE

COMPONENT PROCESSES AND TRYING

TO UNDERSTAND WHAT MIGHT BE

DRIVING SOME OF THE BEHAVIOR

THAT IS I REALLY DECLINE EARLY

IN DEVELOPMENT?

AND WHAT WE FOUND IS THAT IF WE

MOVE FROM THE LEVEL OF MEASURING

THE BEHAVIOR WITHIN A SORT OF A

FACE-TO-FACE INTERACTION, WE GO

DOWN INTO MEASURING BEHAVIOR ON

A SCALE OF MILLISECONDS USING

EYE TRACKING.

WE ARE ACTUALLY BEGINNING TO SEE

DEFICITS IN SOCIAL ATTENTION,

SELECTIVE SOCIAL ATTENTION EARLY

ON.

THIS IS A STUDY FROM OUR GROUP

AT 6 MONTHS CHILDREN WHO LATER

DEVELOP AUTISM HAD TREMENDOUS

DIFFICULTY ATTENDING TO COMPLEX

SOCIAL SCENES.

THEY WERE MORE LIKELY LOOK AWAY

AT SOMETHING THAT IS VERY SIMPLE

AND NOT REALLY SOCIALLY WITH

SOCIAL CONTENT.

WHEN THEY LOOK AT THE SCENES,

THEY HAVE DIFFICULTIES

MAINTAINING ATTENTION ON SOCIAL

TARGETS SUCH AS PEOPLE AND THEIR

FACES.

AND THE GROUP ALSO SHOWED AN

INTERESTING PATTERN OF DECLINE

IN ATTENTION TO US FROM --

BETWEEN BIRTH AND THREE YEARS OF

AGE, A PATTERN THAT CAN BE

CONSTRUED AS REGRESSION.

SO, AGAIN, THIS IS A WAY OF

THINKING ABOUT REGRESSION MOVING

AWAY FROM BEHAVIOR INTO

COMPONENT PROCESS.

NOW, ANNETTE VERY STRONGLY

ARGUED THE NEED OF CROSS

SYNDROME COMPARISONS AND THERE

IS NO QUESTION THAT THIS IS

DEFINITELY A WAY TO GO.

I WOULD LIKE TO ALSO ASK --

ADVOCATE FOR LOOKING AT

DEVELOPMENTAL TRAJECTORIES, NOT

ONLY OF CHILDREN WHO DEVELOP

AUTISM BUT ALSO THOSE WHO ARE AT

RISK FOR AUTISM AND MAYBE

SHOWING A TYPICAL TRAJECTORY BUT

NEVER DEVELOP AUTISM.

AND THIS IS DATA FROM OUR LAB.

THIS IS OUR BABY SAMPLE.

AND WE HAVE ABOUT 150 BABIES,

HIGH-RISK BABY SNIPPS WHOM WE

EVALUATED WITH THE

STATE-OF-THE-ART INSTRUMENT FOR

MEASURING SYMPTOMS OF AUTISM IN

TODDLERS, AUTISMED TO LAWYER

MODULE.

WE MEASURED IT AT 12, 18 AND 24

MONTHS.

-- AUTISM AND TODDLER MODULE.

-- THEN WE GROUPED THESE

CHILDREN BASED ON THE

DEVELOPMENTAL TRAJECTORIES OF

ONSET OF AUTISM SYMPTOMS.

SO HOW DID THEY CHANGE OVER

TIME?

AND HERE WE HAVE A GROUP WHICH

IS EXPECTED, A GROUP WHICH IS

LARGELY TYPICALLY TO DEVELOP

THEIR LEVEL OF SYMPTOMSY IS

VARIATEY IS PRETTY LOW AND

CONSISTENT OVER THE FIRST SECOND

YEAR OF LIFE.

WE HAVE A GROUP THAT I'M NOT

SURE WHAT IS HAPPENING.

IS THIS ME?

SO, THIS IS A GROUP WHERE THE

SEVERITY IS INCREASING AND THE

ONLY WAY IT CAN INCREASE ON THIS

INSTRUMENT IS IF THEY ARE LOSING

SOME SKILLS.

SO THAT MEANS THEY ARE SHOWING

FEWER SOCIAL ENGAGEMENT SKILLS

IN THE CONTEXT OF VARIOUS

STRUCTURE FACE-TO-FACE

INTERACTION WITH A SKILLED

CLINICIAN.

SO, BIG INCREASE 12, 18, AND

THEN CONTINUES.

NOW LOOK AT THAT GROUP.

MOST KIDS HERE END UP HAVING

AUTISM.

NOT EVERYBODY BUT MOST.

LOOK AT THAT GROUP HERE.

THIS ALSO QUITE SIGNIFICANT

INCREASE BETWEEN 12 AND 18

MONTHS AND THEN BOOM.

SOMETHING ELSE HAPPENS.

AND THEY START REGAINING OR

DEVELOPING SKILLS IN TERMS OF

SOCIAL INTERACTION.

SO THERE IS A CRITICAL POINT OF

AROUND 18 MONTHS TRANSITION THAT

SOMETHING COMES ONLINE AND WE

ABSOLUTELY HAVE NO IDEA WHAT IT

IS.

THIS IS A STUDY THAT WE ARE

WORKING ON AND HOPEFULLY WE WILL

HAVE A BETTER SENSE WITHIN THE

NEXT MONTH OR SO.

BUT, IT HIGHLIGHTS THE NECESSITY

OF COMPARING THESE KIDS WITH

THESE KIDS IN ORDER TO HAVE

VARIETY OF CONTRASTS.

ALL RIGHT, SO THUS FAR WE TALKED

ONLY ABOUT REGRESSION IN AUTISM

IN RELATION TO BEHAVIOR.

AND THIS HASN'T BEEN TREMENDOUS

AMOUNT OF WORK DONE RELATING

REGRESSION IN AUTISM TO BIOLOGY

AND YOU GUYS MIGHT BE BETTER

SUITED TO TALK ABOUT MORE

GENETICALLY STUD NIECE MOUSE

MODELS, BUT THERE WAS ONE STUDY

THAT TRIED TO LINK REGRESSION

WITH A TYPICAL DYNAMICS OF BRAIN

GROWTH IN AUTISM.

WE KNOW THAT BABIES WHO LATER

DEVELOP AUTISM ARE BORN

TYPICALLY NORMAL CEPHALIC.

AND THEN SOMETHING HAPPENS.

AND THEIR RATE OF GROWTH

ACCELERATES IN THE FIRST YEAR OF

LIFE SO THAT TWO YEARS LATER, 3

YEARS LATER, ABOUT 15% OF THEM

END UP HAVING MACRO SELFIE.

AND HAVING AUTISM AND MACRO

SEFLY, IT'S NOT A GOOD THING

BECAUSE IT IS OFTEN ASSOCIATED

WITH POOR OUTCOME WITH REGARD TO

INTELLECTUAL FUNCTIONING.

THEY SHOWED THAT BOYS WITH

AUTISM AND REGRESSION HEAD MORE

DRAMATIC OVERGROWTH IN THE FIRST

YEAR OF LIFE AND THEN LATER,

THEY SHOW INCREASE TOTAL BRAIN

VOLUME COMPARED TO BOYS WITHOUT

MACROCEPHALY.

SO THAT IS A VERY INTERESTING,

INTRIGUING HYPOTHESES THAT THERE

MIGHT BE A LINK BETWEEN THESE

TWO PHENOMENON.

AND I'M GOING TO JUST SHOW YOU A

STUDY THAT JUST CAME OUT FROM

YALE FROM A LAB WHICH TRIED TO

GET TO THE BOTTOM OR TRIED TO

UNDERSTAND HOW BRAIN DEVELOPMENT

IN BOYS WITH MACROCEPHALY IS

DIFFERENT FROM BOYS WITHOUT

MACROCEPHALY OR FROM CONTROLS.

AND WHAT SHE DID WAS MODELED

NEUROHM DEVELOPMENT USING

IPSCs.

A SMALL SAMPLE, FIVE BOWS WITH

AUTISM AND MA MACROCEPHALY AND

THEIR FATHERS.

SHE FOUND THAT THE NEURONAL

CELLS IN BOYS WITH AUTISM WERE

DIVIDING VERY RAPIDLY.

THE CELL CYCLE WAS SICKLY

SHORTER IN THE BOYS THAN IN THE

CONTROLS THERE WAS ALSO

OVERPRODUCTION OF NEURONS

ESPECIALLY INHIBITOR NEURONS AND

PRODUCTION OF SYNAPSES AND THERE

WAS SIGNIFICANT INCREASE OF FOX

G1 EXPRESSION IN THE SAMPLE.

AGAIN, THIS IS SOMETHING THAT IS

A SIGN OF MAJOR ABNORMALITY.

I DON'T KNOW IF WE CAN EVEN

VENTURE INTO LINKING THE

HYPOTHESES THAT ANNETTE WAS

PURSUING ON MORE AGGRESSIVE

PRUNING LATER ON WITH MORE

AGGRESSIVE OVERGROWTH OF

DEVELOPMENT, NEURONAL

DEVELOPMENT, VERY, VERY EARLY

ON.

ALL RIGHT.

SO, JUST TO BRING IT ALL

TOGETHER.

HUGE BODY OF DATA.

ACCUMULATED OVER THE PAST SIX

YEARS.

REALLY SUGGESTS THAT REGRESSION

IS NOT APP EVENT.

IT DEPARTMENT HAPPEN AT A

CERTAIN POINT AND THEN BOOM,

SOMETHING CHANGES T IS A

PROCESS.

IT'S OFTEN A VERY PROACTIVE

PROCESS THAT EXTENDS OVER

MONTHS.

FOR MANY YEARS, WE HAVE BEEN IN

THE FIELD HAVE BEEN TRYING TO

FIND THE BEST WAY TO CATEGORIZE

THOSE WHO HAVE AGGRESSION AND

THOSE WHO DON'T HAVE REGRESSION.

AND IN MANY WAYS, IT HAS BEEN

LIKE DRAWING A LINE IN THE SAND.

AND IT SEEMS, BASED ON THE MORE

RECENT STUDIES, THAT WE MIGHT BE

BETTER SERVED BY CONCEPTUALIZING

REGRESSION AS A DIMENSION WITH

SOME CHILDREN HAVING NO

REGRESSION AND HAVING

IMPAIRMENTS VERY, VERY EARLY IN

LIFE AND THERE IS PROBABLY VERY

FEW OF THOSE.

CHILDREN WHO HAVE TREMENDOUS

LOSS OF SKILLS, MAYBE EVEN LATER

IN LIFE.

THERE WILL BE VERY, VERY VERY

FEW OF THOSE AND THEN THERE IS

EVERYBODY ELSE IN BETWEEN.

I THINK IT'S VERY IMPORTANT THAT

WE THINK ABOUT REVISING THE WAY

WE OPERATIONALIZE REGRESSION AND

THINK ABOUT MORE PRESIS

MEASURES, MEASURES THAT ACTUALLY

CAPTURE THE COMPONENT PROCESSES

RATHER THAN MODEL BEHAVIORS AND

OF COURSE WE HAVE TO LOOK AT THE

MULTIPLE LEVELS FROM BEHAVIOR TO

CELLS.

WHAT IS ALSO IMPORTANT BECAUSE

THIS IS A PROCESS, WE NEED TO

MEASURE THIS PHENOMENON

FREQUENTLY.

AND PROBABLY PROSPECTIVELY,

WHICH MEANS STUDYING INFANTS AT

RISK OR STUDYING INFANTS WHO

HAVE IDENTIFIED GENETIC

SYNDROMES WHICH ARE LIKELY TO BE

ASSOCIATED WITH REGRESSION.

THESE ARE HUGE SAUDIS.

EXTREMELY TIME CONSUMING STUDIES

AND RATHER EXPENSIVE.

THINKING OF CONSTRAINING THE

SEARCH FOR MECHANISMS WITH

UNDERLYING REGRESSION, WE MIGHT

WANT TO CONSIDER THE TIMING OF

LOSS OF SKILLS, SPECIFIC SKILLS,

SPECIFIC MECHANISMS THINKING

WHAT MIGHT BE DRIVING LET'S SAY

SELECTED ATTENTION TO FACES OR

SPECIALIZATION THAT WE SEE

BETWEEN 8-10 MONTHS WITH REGARD

TO FACE PROCESSING.

SEX EFFECTS MIGHT BE IMPORTANT

OR INTERESTING.

WE HAVE NO DATA ON THAT.

AND LASTLY, I THINK WHAT IS VERY

IMPORTANT IS TO KEEP IN MIND

THAT WE ARE DEALING WITH A

SYSTEM.

WE NEED TO TRY TO UNDERSTAND THE

BEHAVIORS THAT ARE REGRESSING

WITHIN A BROADER DEVELOPMENTAL

LANDSCAPE, WITHIN A CONTEXT OF

HOW THEY INTERACT WITH THOSE

WHICH STAGNATE AND THOSE WHO ARE

PRESERVED AND TRY TO UNDERSTAND

UNDERLYING NEUROBIOLOGY WITHIN

THE INTERACTIVE FRAMEWORK.

I DON'T HAVE TO SAY ANYTHING

MORE ABOUT THE CROSS SYNDROME

COMPARISON BUT ISLAND LIKE TO

THROW OUT AN IDEA THAT WE SHOULD

TRY TO UNDERSTAND ALSO

UNDERSTAND HOW KIDS DON'T GET

REGRESSION OR HOW THEY RECOVER

FROM SOMETHING THAT MIGHT LOOK

LIKE A LOSSES AND THAT THESE

WOULD BE SIBLINGS OF CHILDREN

WITH AUTISM WHO DO NOT DEVELOP

THE DISORDER BUT MAY HAVE A

ROCKY COURSE IN THE FIRST YEAR,

FIRST TWO YEARS OF LIFE.

AND I LIKE TO -- ONE MORE THING!

SO THIS IS SOMETHING -- I WOULD

LIKE TO THANK YOU FOR YOUR

ATTENTION.

SO, AUDREY ASKED ME TO MENTION

THAT I SHOWED YOU AN EXAMPLE OF

REGRESSION WHICH IS RATHER

DRAMATIC IN SOME WAYS.

BUT IT WAS NEVER AS DRAMATIC AS

YOU PROBABLY HEAR IN LITERATURE

OF THIS SORT OF TREMENDOUS

DIFFERENCE BETWEEN

PRE AND POST-REGRESSION

FUNCTIONING.

I WOULD LIKE TO SHOW YOU AN

EXAMPLE.

JUST TO SORT OF SET A STAGE OF

WHAT THAT EXTREME END OF THAT

DISTRIBUTION MAY LOOK LIKE.

AND WHEN WE THINK ABOUT THIS

EXTREME END OF THE DISTRIBUTION,

WE THINK TYPICALLY OF A CHILD

WITH A DISINTEGRATED DISORDER,

WHICH USED TO BE A SEPARATE

DISORDER AND NOW FOLDED INTO

ASD.

BUT IT IS THE DISORDER OR TYPE

OF AUTISM THAT IS REALLY DEFINED

BY A PRESENCE OF REGRESSION.

AND THAT REGRESSION HAS TO

HAPPEN LATER IN DEVELOPMENT AND

IT HAS TO BE TRULY DRAMATIC.

SO I JUST WANT LIKE TO SHOW TO

YOU WHAT IT LOOKS LIKE IN A REAL

SORT OF LIFE.

SO THIS IS A BEAUTIFUL THE BOY

WHO IS ABOUT 3 1/2 YEARS OLD AND

HE IS JUST READING A BOOK OR

LOOKING THREW THE BOOK.

>> MOMMY PICKED IT UP.

>> MOMMY DID PICK IT UP.

YES SHE DID.

>> CHILD:  WHAT IS THAT?

[ LAUGHS ]

>> DADDY:  GOOD JOB.

>> ANNETTE KARMILOFF-SMITH THIS

IS A 3 1/2-YEAR-OLD.

HE IS SHARING AND DOING FINE.

BUT A YEAR LATER, HIS LEVEL OF

ANXIETY WENT THROUGH THE ROOF

AND HE BECAME VERY AGITATED AND

OVER A PERIOD OF SEVERAL MONTHS,

HE STARTED LOSING SOME SKILLS.

IT WASN'T A DRAMATIC LOSS BUT

VERY DEBILITATING PRESENTATION

SPECIALLY WITH REGARD TO

PRESENCE OF ANXIETY.

AND THEN HE HAD ANOTHER PERIOD

OF REGRESSION AND THAT IS WHERE

YOU SEE HIM AT THE AGE OF 10.

WHERE HE IS ENTIRELY NONVERBAL

AND HAS A MAJOR COGNITIVE

INTELLECTUAL DISABILITY.

AND SYMPTOMS CONSISTENT WITH

AUTISM.

THIS LITTLE BOY HAD A MAJOR WORK

UP ON EVERY POSSIBLE END AND ALL

TESTS CAME OUT NEGATIVE.

HE NEVER DEVELOPED EPILEPSY

EITHER.

SO THIS IS SORT OF THE CASE THAT

WE SOMETIMES THINK ABOUT WHEN WE

THINK ABOUT REGRESSION IN

AUTISM.

WE NEED TO REMEMBER THAT THIS IS

EXTREMELY, EXTREMELY RARE CASE

AND IT REALLY DOESN'T EVEN FIT

WITHIN THE PARAMETERS OF HOW WE

DEFINE REGRESSION IN AUTISM.

SO, AGAIN, AT THAT, I WOULD LIKE

TO END AND THANK YOU FOR YOUR

ATTENTION.

[ APPLAUSE ]

>> ANN WAGNER:  THANK YOU.

OUR NEXT SPEAKER IS JASON WOLFF

FROM UNIVERSITY OF MINNESOTA.

>> JASON WOLFF:  THANK YOU FOR

HAVING ME.

FIRST I WANT TO ACKNOWLEDGE SOME

OF THE WONDERFUL FOLKS I WORK

WITH IN THE IBEIS NETWORK,

INFANT BRAIN IMAGING STUDY.

THESE ARE A WONDERFUL

TRANSDISCIPLINARY GROUP OF FOLKS

THAT HAVE BEEN AND ARE STILL

TRYING TO UNRALPH WHAT HAPPENS

IN TERMS OF EARLY BRAIN AND

BEHAVIORAL DEVELOPMENT IN

AUTISM.

THIS PROJECT IS LED BY JOSEPH AT

THE UNIVERSITY OF NORTH

CAROLINA.

SO, IN WAY OF ORGANIZING, I'M

GOING TO REVIEW WHAT WE HAVE

DISCOVERED IN THE FIRST COUPLE

OF YEARS IN AUTISM IN TERMS OF

BRAIN DEVELOPMENT.

IT WILL FOCUS ON THE

PRE-SYMPTOMATIC OR PRODROMAL

PERIOD OF DEVELOPMENT.

NOTICE HERE THIS KIND OF

FORWARD-SEEING QUOTE FROM LEO

CONNER FROM 1943.

HE NOTICED THAT PHYSICALLY, THE

CHILDREN -- FIRST 11 CASES HE

DESCRIBED, WERE ESSENTIALLY

NORMAL BUT FIVE HAD RELATIVELY

LARGE HEADS.

HIS SHARP EYE SEEMED TO PICK UP

THERE WAS SOME NEURAL DIFFERENCE

PERHAPS RELATED TO MACROCEPHALY

VERY EARLY ON.

THIS HAS BEEN OUR FIRST CLUE

THAT IT WAS RELATED TO

DIFFERENCES IN BRAIN

DEVELOPMENT.

OF COURSE WE GOTTEN A LOT MORE

SOPHISTICATED BUT IT IS STILL A

TRULY FASCINATING THAT FROM THE

VERY BEGINNING THE INCEPTION OF

WHAT AUTISM IS, THIS WAS

SOMETHING THAT HAS COME OUT.

SINCE THEN, WITH INCREASINGLY

SOPHISTICATED APPROACHES, WE

HAVE SEEN THAT THERE IS AN

INCREASE IN BRAIN VOL

PNEUMATISM.

STARTED USING HEAD CIRCUMFERENCE

WHICH IS AN IMPERFECT WAY OF

MEASURING THE SIZE OF THE BRAIN,

MOVED INTO THEN MRI STUDIES,

THIS IS NOT AN EXHAUSTIVE LIST

AND THERE ARE CERTAINLY STUDIES

THAT HAVE NULL FINDINGS.

BUT YOU CAN SEE HERE, THIS IS

REPLICATED MANY TIMES.

FINDING OF DIFFERENCES IN BRAIN

VOLUME.

REGIONS ARE ALL OVER THE PLACE.

AT TIMES IT'S TOTAL BRAIN

VOLUME, OTHER TIMES IT'S

TEMPORAL LOBE VOLUME.

IT'S NOT ENTIRELY CLEAR WHAT IS

HAPPENING WHEN BUT WE KNOW

SOMETHING IS LAPPING DIFFERENTLY

IN REMEMBERS IT OF HOW THE BRAIN

IS GROWING IN INDIVIDUALS WITH

AUTISM.

I WILL SAY THAT ONE PLACE THAT

WE HAVE COME THROUGH THIS

LITERATURE IS THAT THE

PHENOMENON DOES SEEM TO BE MOST

EVIDENT EARLY IN LIFE AND THAT

AS CHILDREN WITH AUTISM GROW,

THE PHENOMENON DOESN'T SEEM TO

BE AS APPARENT AND THERE IS EVEN

SOME EVIDENCE THAT BY ADULTHOOD,

PARTS OF THE BRAIN IN

INDIVIDUALS WITH AUTISM MAY

ACTUALLY BE SMALLER COMPARED TO

TYPICALLY DEVELOPING

INDIVIDUALS.

SO, ECHOING THIS POINT THESE ARE

DYNAMIC PHENOMENON AND

OVERGROWTH SEEMS TO BE FAIRLY

UNIQUE TO THAT EARLY CHILDHOOD

PERIOD.

SO ONE EXAMPLE OF WHAT WE HAVE

SEEN HERE AND THIS COMES FROM

WORK BY HEATHER LOOKING AT BRAIN

VOLUMES IN 2-4-YEAR-OLDS.

SO THESE ARE TODDLERS AND

PRESCHOOLERS WITH AUTISM.

LONGITUDINAL STUDY OF WHITE AND

GRAY MATTER VOLUME.

BOTH OF THESE ARE SIGNIFICANTLY

ELEVATED RELATIVE TO CONTROLS

OVER THIS PERIOD SO THIS IS

LOOKING AT TOTAL BRAIN FOR GRAY

AND WHITE.

THESE ARE ALSO RELATIVELY PAIR

SHRILL SUGGESTS WHATEVER

HAPPENED TO GOAT THIS POINT

HAPPENED MUCH EARLIER.

IT'S A STABLE PHENOMENON BY THE

TIME THESE CHILDREN ARE TWO

YEARS OLD.

SO THE NEXT QUESTION FOR OUR

GROUP WAS, WHAT IS HAPPENING

BEFORE THIS POINT THAT LEADS US

HERE?

AND THIS TOOK US TO AS KASIA

ALLUDED TO, BABY SIBLING STUDIES

WHERE WE ARE FOLLOWING YOUNGER

SIBLINGS OF OLDER CHILDREN WITH

AUTISM OF WHOM ABOUT 25% WILL

EVENTUALLY DEVELOP THE DISORDER.

WE RECUTE AS MAINTENANCE AS WE

CAN.

WE FOLLOW THEM FROM INFANCY UP

UNTIL ABOUT THREE YEARS OLD AND

PROSPECTIVELY LOOK AT THE

INFORMATION IN TERMS OF BRAIN

AND BEHAVIORAL DEVELOPMENT TO

TRY AND UNDERSTAND HOW THIS

PHENOMENON UNFOLDS OVER THIS

TIME.

SO, OUR FORA INTO THIS WE ARE

WORKING ON, THIS IS A

NON--PROPRIETARY, LESS BEAUTIFUL

GRAPH BUT SHOWS WHAT YOU IT IS

THAT IS HAPPENING HERE.

AROUND SIX MONTHS OF AGE, THE

CHILDREN WITH AUTISM IN THE BLUE

LINE ARE ABOUT EQUIVALENT TO

THEIR TYPICALLY DEVELOPING PEERS

AND THEIR HIGH-RISK SIBLING

PIERCE WHO DO NOT DEVELOP AUTISM

IN TERMS OF BRAIN VOLUME.

BUT BY ABOUT 12 MONTHS, THERE IS

A DIFFERENCE THAT THEN EXTENDS

OUTWARD AND YOU CAN IMAGINE FINN

WE HAD MORE DATA POINTS TO FIT A

TRUE TRAJECTORY, HOW THIS MIGHT

MAP ON TO THE PATTERN WE SEE

HERE.

IT LEADS INTO THAT.

SOMETHING IMPORTANT IS HAPPENING

BETWEEN ABOUT 6 MONTHS OF AGE

AND 12 MONTHS OF AGE.

WE ARE LOOKING HERE AT JUST

TOTAL BRAIN VOLUME BUT WE CAN

ALSO DIG INTO SOME OF THE

MECHANISMS THAT MAY BE DRIVING

THIS.

SO, IN THIS DATASET, WE

DISCOVERED THAT IT WAS SURFACE

AREA AND NOT CORTICAL THICKNESS

THAT SEEMED TO BE THE DRIVER OF

THESE DIFFERENCES.

AND REALLY HERE THERE ARE TWO

COMPONENTS THAT MAKE UP BRAIN

VOLUME I IS THE SURFACE OF THE

BRAIN AND ONE IS THE THICKNESS

OF THE GRAY OR WHITE MATTER.

AND HERE, SURFACE AREAS SEEM TO

BE WHAT MATTER MOST.

WILL THAT SAME PHENOMENON AND

POTENTIAL MECHANISM THEN EXPLAIN

WHAT IS HAPPENING HERE?

THIS IS WORK WE ARE DILIGENTLY

LOOKING INTO RIGHT NOW.

BUT OUR SUSPICION IS THAT IT IS

RELATED TO A SPECIFIC MECHANISM

AND IF THAT IS THE CASE, WE CAN

THEN AT LEAST SPECULATE WHAT IS

HAPPENING PRENATALLY THAT MAY

HAVE LED TO THIS TAKING PLACE,

FOR INSTANCE OVER ABUNDANCE OF

PROGENITOR CELLS THAT THOSE

CELLS WERE NOT SHOWING UP IN THE

LAYERS THAT WE MIGHT EXPECT IN

TYPICALLY DEVELOPING BRAIN.

A LOT OF PATHS WE GO DOWN TO

ONCE WE UNRALPH WHAT IS DRIVING

THIS DIFFERENCE.

HERE TOO IS ANOTHER PLACE WHERE

I THINK IT IS IMPORTANT TO ECHO

OUR FIRST TWO SPEAKERS IN

MENTIONING INDIVIDUAL

DIFFERENCES.

YOU CAN SEE A LOT OF RED

TRAJECTORIES IN THERE.

SOME ARE EXTREME OVERGROWTH AND

SOME SEEM TO BE RUNNING WITH

EVERYONE ELSE WHO LOOK MORE

TYPICAL.

WE, AS I THINK RESEARCHERS IN

EARLY DEVELOPMENT OF AUTISM ARE

REALLY GOOD AT ACKNOWLEDGING

THAT INDIVIDUAL DIFFERENCES

MATTER.

NOT JUST ONE AUTISM BUT WE

HAVEN'T DONE A GREAT JOB OF

EXPLAINING WHAT IS HAPPENING AND

HOW WE DISSECT THIS UMBRELLA

TERM AND PULL OUT MEANINGFUL

SUBGROUPS.

WHO IN HERE MAY SHOW REGRESSION?

HOW WILL WE MEASURE THAT

REGRESSION?

WILL THEY SHARE SOME SORT OF

NEURAL PHENOTYPE?

THESE ARE QUESTIONS THAT ARE AT

THIS POINT, UNANSWERED.

BUT WE ARE TO A PLACE I BELIEVE

WE WE COULD START GETTING THAT

INFORMATION.

SO WE'LL TALK ABOUT EARLY BRAIN

BUT HE IS A DIFFERENT ISSUE.

THIS IS ABOUT EXTRA AXIAL FLUID,

ANOTHER PLACE OUR GROUP HAS GONE

RECENTLY AND SO, EXTRA AXIAL

FLUID PRESS EVENT AROUND THE

BRAIN SOMETIMES CALLED DE9

HYDROSEP LIS, IS JUST THE --

BENIGN HYDROSELFIS.

IF IS THE FLUID OUTSIDE OF THE

BRAIN.

IT GETS WASTE OUT OF THE JANE

QUITE IMPORTANT FOR BRAIN

DEVELOPMENT.

WE KNOW FROM A NATURE PAPER THAT

CAME OUT LAST YEAR, THAT THIS

SYSTEM IS ALSO TIED IN TO THE

LYMPHATIC SYSTEM SO EVEN MORE

COMPLICATED THAN WE ONCE

BELIEVED.

THE BEHAVIOR OF THE EXTRA AXIAL

FLUID IN THE HUMAN BRAIN.

SO WE ARE LOOKING AT WHETHER OR

NOT THERE ARE DIFFERENCES HERE

IN THOSE BABIES WHO GO ON TO

DEVELOP AUTISM.

THIS WORK WAS INITIALLY STARTED

BY MARK AND DAVE AND NOW

CONTINUED BY MARK WITH THE IBIS

GROUP AND WE ARE SEEING STRIKING

RESULTS.

SO IN TERMS OF EXTRA AXIAL FLUID

IN RED, AROUND THE BRAIN, SEEMS

TO BE SIGNIFICANTLY, HIGHLY

SIGNIFICANTLY ELEVATED AT SIX

MONTHS, 12 MONTHS AND 24 MONTHS.

OF NOTE OF COURSE IS THAT IT IS

DECLINING TRAJECTORY.

WE ARE GETTING CLOSER TO THE

AMOUNT OF EXTRA AXIAL FLUID WE

SEE IN NON--AFFECTED INDIVIDUALS

AND THE HIGHEST DIFFERENCE SEEMS

TO BE VERY EARLY ON.

SO SOMETHING OF CRITICAL

IMPORTANCE IS HAPPENING AT A

EARL AS 6 MONTHS IF NOT EARLIER

IN TERMS OF EXTRA AXIAL FLUID.

AGAIN, CYTOKINES, THEIR ROLE IN

BRAIN GROWTH F THERE IS

SOMETHING DISRUPTED IN THIS

SYSTEM, ARGUABLY IT COULD AFFECT

VERY IMPORTANT PROCESSES THAT WE

EXPECT TO BE HAPPENING IN THE

BRAIN DURING THIS PHASE OF

DEVELOPMENT.

SO WE'LL NEXT MOVE INTO THINKING

A LITTLE BIT ABOUT CONNECTIVITY.

SO, HERE IS JUST A CARTOON IMAGE

OF A LARGE BUNDLE OF NERVE

FIBERS WE HAVE DEFINED IN THE

BRAINS OF OUR BABIES AND

TODDLERS USING DIFFUSION SENSOR

IMAGING.

JUST BRIEFLY WE ARE MANIPULATING

THE MOVEMENT OF WATER MOLECULES

IN THE HUMAN BRAIN AND THEN

TRYING TO DISCOVER HOW THAT

MIGHT TELL US SOMETHING ABOUT

THE UNDERLYING STRUCTURE OF

WHITE MATTER FIBER PATHWAYS SO

WE ARE LOOKING AT THE STRUCTURAL

CONNECTIONS BETWEEN BRAIN

REGIONS.

THIS IS ONE WAY TO GET AT THE

BRAIN CONNECTIVITY HYPOTHESES

THAT ARE PRETTY IMPORTANT IN

AUTISM RIGHT NOW.

AND IT IS THAT THE BRAIN SEEMS

TO BE WIRED DIFFERENTLY IN

INDIVIDUALS WITH AUTISM.

WE DON'T KNOW WHAT THAT LOOKS

LIKE EXACTLY.

IS IT UNDER WIRED?

OVERWIRED?

OR IS IT JUST A DIFFERENT TYPE

OF WIRING?

TO PUT IT IN MOST SIMPLE TERMS.

WE DON'T HAVE THE ANSWER.

BUT THE CONNECTIVITY HYPOTHESES

WILL GET US A LONG WAY TO GET US

TO UNDERSTAND WHAT IS HAPPENING.

I'M GOING DISCUSS THE STRUCTURAL

CONNECTIVITY AND I'LL MENTION WE

ARE ALSO WORKING ON FUNCTIONAL

CONNECTIVITY MEASURES IN OUR

BABIES.

THAT WORK IS LED BY JOHN PREWIT.

I WILL NOT BE SHARING THAT DATA

TODAY BUT WE ARE TRYING TO GET

THIS QUESTION FROM BOTH THE

FUNCTIONAL SIDE AND THE

STRUCTURAL SIDE.

SO OUR INITIAL QUESTION THAT WE

WENT INTO IN TERMS OF THINKING

ABOUT CONNECTIVITY IN AUTISM

WAS, WOULD WE SEE DIFFERENCES IN

THE DEVELOPMENT OF THE CIRCUITRY

IN THE BABIES WHO DEVELOPED

AUTISM, WOULD IT BEST BEFORE

THEY RECEIVED A DIAGNOSE OR

BEFORE THE DISORDER WAS FULLY

MAN NEST?

WE LOOKED AT 15 DIFFERENT WHITE

MATTER FIBER TRACTS OF THE WE

DEFINED IN A COMMON ATLAS SPACE

IN OUR STUDY SAMPLE.

HERE WE WERE LOOKING AT 64

BABIES WHO WERE AT HIGH RISK

THAT DIDN'T DEVELOP AUTISM

COMPARED TO 28 TODDLERS WHO DID

DEVELOP AUTISM.

THOSE 15 FIBER PATHWAYS YOU SEE

ARE REPRESENTED IN THAT PICTURE.

WE ARE REALLY LOOKING AT THE

WHOLE BRAIN AND NOT ISOLATING TO

ANY ONE REGION.

WE ARE INTERESTED IN HOW THE

WHOLE BRAIN MIGHT BE CONNECTED.

WHAT WE FOUND WERE SOME PRETTY

DISTINCT TRAJECTORIES.

IN WHAT INITIALLY SURPRISED US

MOST, THE KIDS IN AUTISM THERE

ARE IN RED.

IS IT THEY HAD HIGHER FRACTIONAL

AND ISOTOPES AT SIX MONTHS OF

AGE BUT SLOWER DEVELOPMENT OVER

THIS PERIOD SUCH THAT THE

CHILDREN WITHOUT AUTISM HAD

OUTPACED THEM BY THE TIME THEY

WERE 24 MONTHS.

WE DID A LOT OF WRESTLING WITH

WHAT THIS ALL MEANT.

AT THE END OF THE DAY WE DON'T

KNOW WHAT FRACTIONAL AND

ISOTOPES ARE SHOWING US IN THE

BRAIN OF A YOUNG INDIVIDUAL IN

PARTICULAR.

IN ADULT STUDIES, FRACTIONAL

ISOTOPES IS USUALLY HIGHER THE

BETTER.

IT SHOWS YOUR BRAIN IS MORE

CONNECTED BETWEEN ONE REGION AND

ANOTHER F YOU HAVE HIGHER.

IN BABIES THIS MAY NOT BE THE

CASE.

SIMPLY DUE TO SOME OF THE UNIQUE

DEVELOPMENTAL PHENOMENON TAKING

PLACE BALANCED BETWEEN ROBUST

PRUNING AND USE DEPENDENT

GROWTH.

WE DON'T KNOW WHAT THAT HIGHER

FA MEANS BUT PERHAPS INTRIGUING

CLUE THAT SOMETHING SPECIFIC IS

GOING ON DURING THAT TIME.

SO OF ALL THE 15 PATHWAYS WE

LOOKED AT, THEY ALL SORT OF

SHOWED THIS SAME GENERAL PATTERN

ABOUT 12-15 SHOWS STATISTICAL

SIGNIFICANTS.

VERY RECENTLY, ERIC'S GROUP CAME

WITHOUT A PAPER THAT FOUND IN

MOST WAYS THE EXACT SAME

PATTERN.

YOU'LL SEE THAT ON THE RIGHT

WHERE THERE IS HIGHER FA IN

THOSE BABIES WHO LATER DEVELOPED

AUTISM EARLY IN LIFE.

THE DIFFERENCE IN HIS

SCIENTISTY, IN ERIC'S STUDY IS

THAT CROSSING ELEMENT OF THE

TRAJECTORY SEEMS TO BE HAPPENING

LATER.

THIS IS PROBABLY JUST ARTIFACT

DUE TO DIFFERENCES IN SAMPLING

AND IN TIME.

BUT AGAIN, THE IMPORTANT PART

HERE IS THAT WE ARE SEEING THAT

INCREASE IN FRACTIONAL AND

ISOTROPY IN THAT FIRST YEAR OF

LIFE.

THERE ARE NOW FOUR INDEPENDENT

STUDIES THAT FOUND THAT.

AND THIS ASK A UNIQUE THING IN

AUTISM DURING THIS TIME OF LIFE.

THIS HIGHER FRACTIONAL ISOTROPY.

IF YOU LOOK AT OLDER CHILDREN

WITH AUTISM, YOU'RE GOING TO SEE

LOWER FRACTIONAL ISOTROPY.

IT'S ONLY SEEN DURING THIS MAYBE

TWO YEARS OF LIFE THAT YOU'RE

GETTING A SIGNAL THAT SUGGESTS

IT'S HIGHER.

DOES THAT MEAN THERE ARE EXCESS

EXONS THAT ARE DRIVING THE

SIGNAL AND INCREASING DA?

DOES IT MEAN THAT MILE ENATION

IS DIFFERENT?

DOES IT MEAN THE SIGNALS ARE

MESSIER AND WE DON'T KNOW.

THIS IS WHERE TRANSLATIONAL

WORK, BACKWARDS TRANSLATIONAL

WORK IS KEY.

WE CAN ONLY LEARN SO MUCH

THROUGH THE NEUROIMAGING TO

UNDERSTAND WHAT IS HAPPENING.

IT'S GOING TO TAKE WORK WITH

FOLKS THAT WORK WITH OTHER

MODELS.

SO A LITTLE BIT MORE ON

CONNECTIVITY.

FOCUSING ON THE CHORPUS CALOWS

UM.

THIS IS A MAJOR TARGET STUDIES

OF AUTISM.

IT IS THE LARGEST CONNECTION IN

THE HUMAN BRAIN AND DEVELOPS

VERY RAPIDLY EARLY IN LIFE TO

THE POINT THAT WE ARE LOSING

THOUSANDS OF EXONS IN THE

CHORPUS CALLOSUM IN JUST A

PERIOD OF AN HOUR IN A BABY'S

LIFE DURING THE FIRST MAYBE TWO

MONTHS.

BUT THAT FIRST YEAR OF LIFE, A

LOT IS HAPPENING TO CHORPUS

CALLOSUM.

IT'S SOMETHING OF A A CANARY IN

A COAL MINE IF THERE WAS

SOMETHING GO ON THAT WAS

ATYPICAL.

IT'S A SLEW OF STUDIES THAT

LOOKED AT THE CHORPUS CALLOSUM

INVOLVING OLDER CHILDREN AND

ADULTS WITH THE DISORDER.

THEY FIND ACROSS-THE-BOARD THE

CHORPUS CALLOSUM IS SMALLER IN

CHILDREN WITH AUTISM.

ADJUSTING FOR TOTAL BRAIN SIZE,

SMALLER.

THIS IS THE ONLY STUDY TO LOOK

AT LET'S SAY YOUNGER KIDS.

IN THIS STUDY THEY HAD A SAMPLE

OF 4 AND 5-YEAR-OLDS.

THAT'S AS YOUNG AS WE HAVE

GOTTEN UP TO THIS POINT.

BUT THEY ARE SEEING A SMALLER

CHORPUS CALLOSUM.

SO, WE TOOK THE SAME APPROACH

THAT OTHERS HAVE DONE AND WE ARE

LOOKING AGAIN AT BABIES FROM 6

MONTHS UP UNTIL 24 MONTHS IN

TERMS OF CHORPUS CALLOSUM.

MUCH TO OUR SURPRISE, WE FOUND

THAT THE CHORPUS CALLOSUM WAS

LARGER IN THE BABIES WHO WENT ON

TO DEVELOP AUTISM.

NOT SMALLER.

THIS OF COURSE SET OFF A LOT OF

SELF DOUBT AND WHO RAN THE TEST

WRONG OR WAS A COLUMN LABELED

INCORRECTLY?

I ASSURE YOU AFTER A MUCH

VETTING, WE ARRIVED THIS WAS

REALLY THE RESULT THAT WE HAD.

THE BABIES WITH AUTISM HAD A

SIGNIFICANTLY LARGER CHORPUS

CALLOSUM.

THESE TRAJECTORIES, THEY ARE

SORT OF CONVERGING BY THAT

24-MONTH PERIOD BUT NOT A

STATISTICAL AFFECT FOR GROUP BY

TIME HERE.

OUR HIGH POG -- HYPOTHESES IS

THERE IS A CROSSOVER WHERE THE

CHILDREN WITH AUTISM WILL START

TO THE HAVE A SMALLER CHORPUS

CALLOSUM AS THEY ARE OUT-PACED

BY THE GROUPS.

SORT OF SEE THIS PHENOMENON HERE

IF WE JUST LOOK AT A MEASURE OF

PERCENT DIFFERENCE ACROSS TIME.

SO, YOU CAN SEE HERE THAT AT SIX

MONTHS ON THE BOTTOM, THE AFFECT

IS MUCH STRONGER IN THE KIDS

WITH AUTISM VERSUS CONTROLS AND

VERSUS THOSE HIGH RISK KIDS

WITHOUT ASD.

IT STILL IS RELATIVELY STRONG AT

AGE 12 MONTHS.

BUT BY 24 MONTHS, THE AFFECT IS

SOMEWHAT WASHED OUT AND YOU'RE

EVEN STARTING TO SEE EVIDENCE IN

THE POSTERIOR REGIONS THAT IT IS

GETTING SMALLER RELATIVE TO THE

UNAFFECTED INDIVIDUALS.

SO, THIS SORT OF SUPPORTED OUR

HYPOTHESES THAT THERE WOULD BE A

CROSSING OVER.

OF COURSE THE TRULY VET THIS,

WHAT WE NEED IS DATA FROM THESE

CHILDREN WHEN THEY ARE SLIGHTLY

OLDER TO SEE WHAT EXACTLY TURNS

OUT IN THE STORY.

IT SEEMS TO BE A PHENOMENON

WHERE EARLY THE CHORPUS CALLOSUM

IS LARGER THAN THE COMPARISON

GROUPS.

BY THE TIME THESE KIDS ARE

PROBABLY PRESCHOOL OR EARLY

SCHOOL AGE, THAT HAS GONE AWAY

AND THEY ARE SHOWING A SMALLER

CHORPUS

CHORPUS CALLOSUM.

WE DON'T KNOW WHAT THAT MEANS

BECAUSE WE CAN'T AFFECTIONATELY

GET IN THERE BUT AS IMMENSED, A

LOT OF PRUNING TAKES PLACE IN

THE CHORPUS CALLOSUM.

WE ARE BORN WITH FAR MORE EXONS

IN THAT REGION THAN WE NEED.

SO THE FIRST YEAR OF LIFE IS

CHARACTERIZED BY THE REMOVAL OF

A LOT OF AXONS.

THE IT MAY BE THAT PROCESS IS

SOMEHOW DISRUPTED IN THE

CHILDREN WITH AUTISM.

AGAIN, SOMETHING WE ARE NOT

GOING TO NECESSARILY BE ABLE TO

TEASE APART USING IMAGING ALONE.

SO, KIND OF IN SUMMARY, WE CAN

THINK ABOUT A MODEL WHERE IN WE

HAVE SOME ELEMENTS THAT CONFER

RISKS FOR AUTISM RELATED TO THE

ENVIRONMENT, RELATED TO MULTIPLE

GENETIC FACTORS AND THAT THERE

IS A BACK AND FORTH BETWEEN

THOSE RISK FACTORS AND THE

CHILD'S EARLY EXPERIENCE.

THERE IS THIS EXPERIENCE

DEPENDENT NEURAL WE KNOW TAKES

PLACE OVER THESE COUPLE OF YEARS

OF LIFE.

SOMETHING HAPPENS DURING THIS

TIME THAT LEADS TO THIS THING WE

CALL AUTISM.

THESE CHILDREN AREN'T BORN WITH

BEHAVIORAL PHENOTYPE OF AUTISM.

IT COMES ABOUT OR IS NOTICEABLE

TO US USING THE TOOLS WE HAVE,

AT AGE TWO OR THREE, IN SOME

CASES EVIDENT IN 18 MONTHS.

BUT IT'S NOT EVIDENT AT AGE 12

MONTHS.

SOMETHING IS HAPPENING DURING

THE TIME THAT MAY LEAD TO THAT

AUTISM BEING MANIFEST.

THE QUESTION HERE IS, WE HAVE

THESE EVENTS SUCH AS ALTERED

STRUCTURAL CONNECTIVITY.

WE HAVE ELEVATED EXTRA AXIAL CS.

AND BRAIN OVERGROWTH ALL

APPARENT DURING THE FIRST YEAR

OF LIFE.

ARE THESE SETTING THE STAGE FOR

WHAT HAPPENS A YEAR LATER WHEN

THE CHILD FIRST SCHWARTZ SHOWING

SIGNS OF AUTISM?

FOR SOME CHILDREN, DO THESE

FACTORS SET THE STAGE FOR WHAT

WE CALL A LOSS EVER SKILLS?

IF THERE IS A CHILD WHO SEEMS TO

BE DEVELOPING TYPICALLY, IS

THERE A BUILDUP OF SOME OF THESE

NEURAL EVENTS THAT EVENTUALLY

CAUSE THE BEHAVIORAL DEVELOPMENT

TO FALTER OR POSSIBLY REGRESS?

AGAIN, AN INTERESTING BIG

QUESTION BUT AS I MENTIONED

BEFORE, WHAT WE NEED TO DO TO

GET TO THE BOTTOM OF IT IS

UNDERSTAND THE INDIVIDUAL

DIFFERENCES HERE.

THE STORY WON'T BE THE SAME FOR

EVERY CHILD WITH AUTISM.

FOR SOME CHILDREN, THERE MAY BE

THAT ALTERED STRUCTURAL

CONNECTIVITY IS LINKED TO JUST A

FLATTENING OF DEVELOPMENT.

FOR OTHER CHILDREN, IT MAY BE

THAT THEIR STRUCTURAL

CONNECTIVITY ISN'T HIT UNTIL

MUCH LATER AND THAT IS WHEN

REGRESSION TAKES PLACE.

MANY DIFFERENT PATHWAYS CAN LEAD

TO THIS SAME PHENOMENON OF

AUTISM SPECTRUM DISORDER AND OUR

CHARGE IS TO BETTER TEASE THAT

APART.

IT'S EASY TO LUMP TOGETHER WHAT

AUTISM SPECTRUM DISORDER IS.

IT'S MUCH MORE OF A CHALLENGE TO

START PICKING APART MEANINGFUL

SUBGROUPS BASED ON BIOLOGY AND

BEHAVIOR BUT I THINK THAT IS

WHERE WE NEED TO GO IN WE WANT

TO UNDERSTAND MUCH MEANING IN

AUTISM, INCLUDING DIFFERENT

PATTERNS OF ONET AND REGRESSION.

WITH THAT, THANK YOU.

[ APPLAUSE ]

>> ANN WAGNER:  THAT WAS

EXCELLENT.

LONNIE ZWAIGENBAUM WILL LEAD US

THROUGH A DISCUSSION OF THIS

SESSION.

WE ALSO HAVE A LONG DISCUSSION

PERIOD AT THE VERY END OF THE

DAY FOR PUTTING ALL THINGS

TOGETHER, BUT THIS IS A TIME FOR

YOU TO ASK QUESTIONS OR MAKE

COMMENTS RELATED TO THESE TALKS.

THANK YOU.

>> LONNIE ZWAIGENBAUM:  SO THANK

YOU TO THE THREE PRESENTERS FOR

STARTING US OFF ON AN EXCELLENT

NOTE.

I WANTED TO HIGHLIGHT A FEW OF

THE POINTS FROM THE THREE

PRESENTATIONS AND FURTHER

EMPHASIZE SOME ISSUES AROUND

PROSPECTIVE STUDIES OF INFANTS

AT RISK OF AUTISM.

AND REALLY ACKNOWLEDGE THAT WE

HAVE AN EVOLVING CONCEPTION OF

THIS EARLY AUTISM PHENOTYPE.

IF WE HAD HELD THIS MEETING 10

YEARS AGO, AS BOTH ANNETTE AND

KASIA COMMENTED, REALLY ARE

CONCEPTION OF CONCEPTION IN LIFE

WOULD COME FROM PARENTAL REPORTS

AND FROM ANALYSIS OF EARLY HOME

VIDEOS.

ALL THREE OF THE PRESENTATIONS

REALLY FOCUSED ON RELATIVELY

RECENT DATA FROM PERSPECTIVE

STUDIES OF AT-RISK INFANTS.

IT'S IMPORTANT TO ACKNOWLEDGE

AND SORT OF DISCUSS TO WHAT

EXTENT ARE INFANTS WHO DEVELOP

AUTISM WHO ARE ASCERTAINED BASED

ON A POSITIVE FAMILY HISTORY AND

A SIBLING, WHAT GROUP IS THAT

REPRESENTATIVE OF ALL CHILDREN

WITH AUTISM?

I THINK TO SOME EXTENT THE JURY

IS STILL OUT ON THAT QUESTION.

IT IS ONLY RECENTLY WE HAD

INFANT DATA FROM PERSPECTIVE

RESEARCH AND MOST OF THE DATA ON

THAT QUESTION REALLY COMES FROM

STUDIES OF FAMILIES WHERE THERE

IS ONE CHILD WITH AUTISM VERSUS

SORT OF MORE THAN ONE CHILD

WITHIN THE SIB SHIP.

FROM A CLINICAL LEVEL, IN

PREVIOUS GENETIC STUDIES, THERE

AREN'T OBVIOUS DIFFERENCES IN

TERMS OF THE OVERALL CLINICAL

PHENOTYPE, PROFILES AND SO ON.

INITIAL GENETIC STUDIES MIGHT

HAVE SUGGESTED THAT RARE

VARIANTS MAY BE MORE COMMON IN

SIMPLEX FAMILIES THAN IN

MULTIPLEX FAMILIES ALTHOUGH THEY

CAN BE INHERITED AS WELL AND

AGAIN, THERE ISN'T SORT OF A

FUNDAMENTAL DIFFERENCE IN WHAT

IS KNOWN EDIOLOGICALLY.

PERHAPS SORT OF ONE EMERGING

FINDING IS HOW ASCERTAINMENT MAY

INFLUENCE THE OVERALL BEHAVIORAL

PROFILE OF INFANTS IDENTIFIED

THROUGH PROSPECTIVE RESEARCH.

OUR GROUP, IN ADDITION TO

WORKING WITH FAMILIES WHO

HAVEOON OLDER SIBLING WITH

AUTISM, ARE ALSO INVOLVED IN A

NATIONAL LONGITUDINAL STUDY OF

CHILDREN IDENTIFIED CLINICALLY

AND DURING PRESCHOOL YEARS AND

FOLLOWED INTO MIDDLE SCHOOL.

AND ONE DIFFERENCE THAT WE ARE

FINDING IS THAT THE CHILDREN

IDENTIFIED THROUGH THESE

HIGH-RISK INFANT STUDIES ARE TO

SOME EXTENT, HAVE SOMEWHAT LESS

SEVERE SYMPTOMS AND LESS SEVERE

INTELLECTUAL AND LANGUAGE

IMPAIRMENT.

AND OUR BELIEF IS THAT IS IT A

FUNDAMENTAL BIOLOGIC DIFFERENCE

OR A LEVEL OF ASCERTAINMENT?

HISTORICALLY, CHILDREN WITH

AUTISM WHO HAVE LESS SEVERE

SYMPTOMS MAY FLY UNDER THE RADAR

AND MAY NOT BE REFERRED UNTIL

THEY ARE OLDER.

CHILDREN WITH AVERAGE

INTELLECTUAL LEVEL AND LANGUAGE

LEVEL HISTORICALLY OFTEN

IDENTIFIED DURING THE SCHOOL

YEARS RATHER THAN IN THE

PRESCHOOL YEARS.

BUT AGAIN, THIS IS PROBABLY MORE

OF A QUANTITATIVE DIFFERENCE

THAN QUALITATIVE DIFFERENCE.

AND ALTHOUGH WE RECOGNIZE THAT

THERE IS STILL MUCH TO LEARN BY

WORKING WITH INDIVIDUALS WITH

AUTISM WHO DON'T HAVE A POSITIVE

FAMILY HISTORY, THAT IS

EXEMPLIFIED FOR THE WORK IN ERIC

AND KARIN AND IN THEIR STUDY OF

INFANTS AND TODDLERS WHOASER

TAIN CLINICALLY, WE FEEL LIKE WE

ARE ON PRETTY SOLID GROUND

LEARNING ABOUT AUTISM THROUGH

THESE PROSPECTIVE STUDIES AF AT

OF RISK INFANTS.

AS KASIA OUTLINED AND ANNETTE

RAISED A REALLY IMPORTANT POINT

THAT MAY PROVIDE BILE CALL

MECHANISM, WE ARE NOW THINKING

ABOUT REGRESSION IN AUTISM

SOMEWHAT LESS CATEGORICALLY.

ALTHOUGH IT IS TRUE FOR INSTANCE

THROUGH STUDIES LIKE SALLY'S

LOOKING AT QUANTITATIVE

DIFFERENCES IN SKILL CHANGE OVER

TIME SORT OF MEASURED DIRECTLY

IN OUR -- ABLE TO IDENTIFY

CATEGORICAL SUBGROUPS BASED ON

TRAJECTORY DIFFERENCES, THERE IS

A INCREASING VOLUME OF DATA

SUGGESTING THAT ALTHOUGH THERE

ARE CHILDREN WITH AUTISM WITH

SKILL LOSS, THERE IS A MUCH

LARGER GROUP WHO HAVE ATYPICAL

DEVELOPMENTAL TRAJECTORIES WHERE

THERE ARE SPECIFIC QUANTITATIVE

ATIP CALLS IN TERMS OF COGNITIVE

AND LANGUAGE DEVELOPMENT.

SO A NUMBER OF GROUPS LOOKED AT

PERFORMANCE OF INFANTS WHO GO ON

TO DEVELOP AUTISM BY BASIC

DEVELOPMENTAL MEASURES.

SO FALLING OFF THE TRA JECT

JECTORY NOT PIERS EVEN THOUGH

THEY ARE MACKING SLOWING

PROGRESS.

WITH THE OVERPRUNING HYPOTHESES,

IF IT'S A SLOWER DEVELOPMENTAL

PROCESS, THAT MAY NOT BE

EXPRESSED IN TERMS OF FRANK

SKILL LOSS BUT RATHER ATYPICAL

DEVELOPMENT AND SORT OF SLOWING

OF ACQUISITION OF NEW SKILLS.

LIKEWISE, THE VIDEO THAT IS

KASIA SHOWED ARE QUITE

REMARKABLE.

THE INTERESTING THING IS IF ONE

EXTENDS THOSE VIDEOS SO ONE CAN

LOOK AT MULTIPLE INTERVALS OVER

TIME, IT'S APPARENT IN

PARTICULARLY THE FIRST TYPE OF

CHILD EXAMPLIFIED BY THE FIRST

INFANT, THAT THE CHANGES IN

COMMUNICATION AND SOCIAL

FUNCTION ARE ACTUALLY OCCURRING

OVER A MUCH LONGER PERIOD OF

TIME.

AND IT'S DIFFICULT SAY SORT OF

WHEN THE DISCRETE REGRESSION

OCCURRED BECAUSE ONE MAY SEE

THREE MONTH INTERVALS OVER A SO

LONGER SPAN AND THERE MAY BE

PROGRESSIVE CHANGES SORT OF

INCREMENTAL DECREASES IN SOCIAL

ENGAGEMENT AND USE OF

COMMUNICATION SKILLS.

AND AGAIN, THAT IS REALLY

HIGHLIGHTED BY THE STUDY BY

SALLY THAT KASIA REFERENCED

LOOKING AT QUANTIFICATION OF

SOCIAL BEHAVIORS LIKE DIRECTED

GAZE, DIRECTED VOCALIZATION.

EVEN IN THE CONTEXT OF A GENERAL

DEVELOPMENTAL ASSESSMENT.

IN FINDING THAT RATHER THAN SORT

OF A DISCRETE AND ACUTE DROP IN

SKILLS, IT'S REALLY SORT OF A

GRADUAL DECREASE OVER EXTENDED

PERIOD OF TIME.

AND IT'S WORTH EMPHASIZING THAT

AS ANNETTE POINTED OUT, IT

OCCURS OVER MULTIPLE DOMAINS.

AND WE ARE INCREASINGLY THINKING

OF AUTISM OF HAVING A POST-NATAL

ONSET.

SO, IN CONTRAST TO THE INITIAL

CONCEPTION BY KEN EISENBERG OF

EARLY-ONSET FROM PRESS FRIEND

BIRTH VERSUS AGGRESSIVE ONSET,

WE REVIEW THIS ON A CONTINUUM

AND IT IS INTERESTING THAT THE

PROGRESSION OF SYMPTOMS IS OFTEN

SORT OF LATER TOWARDS THE SECOND

HALF OF THE FIRST YEAR.

OTHER THING TO EMPHASIZE IS THAT

NOT ONLY ARE WE SEEING

DIFFERENCES ACROSS MULTIPLE

DEVELOPMENTAL DOMAINS BUT THERE

IS A SENSE OF A DEVELOPMENTAL

SEQUENCE.

AND AS ANNETTE AND KASIA NOTED,

IS A DIFFERENT TIMING OF

DIFFERENT SETS OF BEHAVIORAL

SYMPTOMS AND ALTHOUGH -- SO FOR

EXAMPLE, ONE DOESN'T TEND TO SEE

SORT OF ROBUST IMPAIRMENTS IN

SOCIAL COMMUNICATIVE FUNCTION

UNTIL CLOSER TO THE FIRST

BIRTHDAY EVEN THOUGH AS KASIA

WAS SAYING, THERE MAY BE MORE

SUBTLE DIFFERENCES DETECTED BY

MEASURES SUCH AS EYE TRACKING

SORT OF INDICATING DIFFERENCES

IN SORT OF SOCIAL ORIENTING AND

SOCIAL INTENTION.

SO, MORE ROBUST IMPAIRMENT SORT

OF LATER TOWARDS THE FIRST

BIRTHDAY, AND YET REPLICATED

FINDINGS LOOKING AT ATYPICAL

SENSORY REGULATION AND EVIDENCE

OF MOTOR DEPLACE MOTOR DEFICITS

ARE EARLIER IN THE FIRST YEAR --

DELAYS.

-- AND OTHER TYPES OF SYMPTOMS

SUCH AS EXECUTIVE FUNCTION THAT

MAY BE APPARENT LATER INTO THE

PRESCHOOL YEARS.

AND IT IS ALSO WORTH EMPHASIZING

THAT OUR NOTION OF THE TIMING OF

SKILL LOSS IN ATYPICAL

DEVELOPMENTAL TRAJECTORIES HAS

ALSO SHIFTED SOMEWHAT WITH THE

INCREASING FOCUS ON PROSPECTIVE

STUDIES.

AS KASIA COMMENTED, THE ORIGINAL

CHARACTER SAYS OF REGRESSION

FOCUSED ON THE SECOND YEAR OF

LIFE.

REALLY THAT THE MIDPOINT AROUND

18-20 MONTHS.

WITH THE NOTION THAT THOSE

CHILDREN WHO HAD REGRESSED WERE

RELATIVELY TYPICAL IN THE FIRST

18 MONTHS.

IN FACT, QUITE CONSISTENTLY NOW

WE ARE IDENTIFYING EARLY

FEATURES PRIOR TO THE FIRST

BIRTHDAY.

KASIA HAS REALLY CONTRIBUTED

INSTRUMENTALLY TO THIS WORK AS

WELL AS A NUMBER OF OTHER GROUPS

LOOKING AT FOR INSTANCE ATYPICAL

ALLOCATION OF ATTENTION.

AND SOCIAL ORIENTING AND

DIRECTION OF ATTENTION TO

DIFFERENT ASPECTS OF THE FACE.

WE HAVE HAD THIS NOTION OF

AUTISTIC PRO-DREAM THAT FOCUSES

ON SORT OF SUBTLE DIFFERENCES

AND SOCIAL ATTENTION SENSORY

MOTOR DIFFERENCES AND THEN

FOLLOWED BY MORE ROBUST FEATURES

LATER IN THE FIRST YEAR OF LIFE.

THAT MAY BE SOMEWHAT OF AN

ARTIFACT OF OUR CURRENT NOTION

OF AUTISM BASED ON EXPERIENCE

WITH SOMEWHAT OLDER CHILDREN.

THERE IS NO REASON TO

FUNDAMENTALLY THINK OF THESE

EARLY FEATURES AS NOT BEING AS

RELATED TO THE AUTISTIC

PHENOTYPE AS THE MORE DSM

RELATED CHARACTERISTIC FEATURES

THAT WE THINK ABOUT SORT OF IN

THE CLINIC WHEN WE SEE OLDER

CHILDREN.

THE OTHER POINT WORTH

EMPHASIZING AND REALLY SORT OF

PICKING UP ON THE POINTS MADE IN

JASON'S PRESENTATION IS THE

EARLY FEATURES OF AUTISM ARE

CONCURRENT TO EVIDENCE BY SIX

MONTHS OF AGE OF ATYPICAL BRAIN

GROWTH.

STRUCTURAL AND LIKELY FUNCTIONAL

CONNECTIVITY AS WELL AS SORT OF

BRAIN FUNCTION SO THROUGH ERP

STUDIES AND LOOKING AT

PROCESSING OF EYE GAZE,

EMOTIONAL EXPRESSION AND SO ON.

AND AGAIN, THE NOTION THAT FRANK

REGRESSION MAY EXIST ON A

CONTINUUM ATYPICAL DEVELOPMENTAL

TRAJECTORIES ANKOD AT LATEST AT

SIX MONTHS OF AGE AND PERHAPS

EVEN EARLIER SORT OF ONCE WE

DEVELOP THE KINDS OF GRANULAR

MEASURE THAT IS KASIA SUGGESTED

THAT MAY ALLOW US TO SORT OF

FURTHER UNDERSTAND SORT OF THE

ORIGINS OF THE DEVELOPMENTAL

PHENOTYPE.

SO, WITH THAT, I'D LIKE TO THANK

AGAIN THE PRESENTERS AND OPEN

THIS UP FOR DISCUSSION.

AND JUST IN TERMS OF TURNING THE

DISCUSSION OVER, I'M HAPPY TO

STAY AND DO THAT OR I CAN TURN

IT BACK TO ANN AND AUDREY.

>> GREAT IF YOU CHAIR.

BUT YOU COULD DO IT FROM YOUR

SEAT IF YOU PREFER.

>> THAT SOUNDS GREAT.

THANK YOU.

>> ANN WAGNER:  MAYBE WE'LL OPEN

IT UP TO FIRST QUESTION.

>> SO, I THINK WE'LL PROBABLY

TALK ABOUT IT MORE LATER AS WE

GO ON, BUT OBVIOUSLY ONE OF THE

THINGS THAT FOR ME, BEGS THE

QUESTION PARTICULARLY WHEN YOU

SAY ARE THERE SUBGROUPS WITHIN

THIS PROSPECTIVELY ASCERTAINED

ASD GROUPINGS, IS WHAT ARE THE

GENETICS BEHIND THEM?

IF WE KNOW THAT 20% PLUS OR

MINUS OFIEDIO PATHIC ASD WILL

HAVE SINGLE GENE HIGHLY

PENETRANT CAUSES AND THEN OTHERS

MAY NOT HAVE THOSE SINGLE GENE

CAUSES BUT MAY THROUGH

STATISTICAL ANALYSIS HAVE

SIMILAR PATHWAYS IMPLICATED, CAN

WE APPLY THOSE TOOLS TO START TO

TEASE APART THE SUBGROUPS?

AND ANY VALIDITY IN THAT

APPROACH?

>> LONNIE ZWAIGENBAUM:  IT'S A

REALLY IMPORTANT QUESTION.

THIS WORK IS JUST GETTING

STARTED IN TERMS OF AVAILABILITY

OF GENETIC DATA FROM THESE

AT-RISK COHORTS.

SO FOR EXAMPLE, A NUMBER OF

GROUPS THAT WE HAVE TALKED ABOUT

TODAY WITHIN THE BABY SIBLING

RESEARCH CONSORTIUM THAT IS

SUPPORTED BY NIH AND AUTISM

SPEAKS, OVER TIME, HAVE

COLLABORATED TO ESTABLISH A

REPOSITORY, HAVE COMPLETE

MICROARRAY DATA AS WELL AS WHOLE

GENOME SEQUENCING DATA ON EYE

PORTION OF THAT COHORT AND THAT

DATA IS BEING ANALYZED.

THE INITIAL DATA IS THAT THERE

ARE KIND OF A RELATIVELY MODEST

PORTION, 15-20%, WHO HAVE

SPECIFIC IDENTIFIED VARIANTS.

THE NUMBERS ARE RELATIVELY SMALL

AND I'M NOT SURE THAT WILL

PROVIDE THAT SORT OF BROADER

SUBGROUPING AT FIRST PASS.

WE BELIEVE PROY WILL NEED LARGER

NUMBERS.

>> ANNETTE KARMILOFF-SMITH:  CAN

I ADDING?

IT'S RELEVANT TO OUR DISCUSSION.

WE ARE LOOKING IN GREAT DETAIL

AT DOWN'S SYNDROME AT THE MOMENT

AND I'M COLLABORATING WITH

PEOPLE AT ST. THOMAS HOSPITAL

DOING FETAL IMAGING AND DOWN'S

SYNDROME AND HERE WE HAVE A

CLEAR GENETIC CAUSE.

INDIVIDUAL DIFFERENCES ARE ROUGH

EVEN IN FETAL LIFE.

SO SOME BABIES BRAINS ARE

DEVELOPING AND THEY LOOK LIKE

TYPICAL CONTROLS.

OTHERS SHOW MASSIVE DIFFERENCES

EARLY ON.

SO, WE HAVE GOT TO TAKE INTO

ACCOUNT WHATEVER CAUSES AUTISM,

THERE IS THE REST OF THE GENOME

CONTRIBUTING AND THE SAME WITH

DOWN'S SYNDROME.

>> I VERY MUCH LIKED YOUR

DISCUSSION ON THAT ABOUT

OVERPRUNING AND BUT I WAS

THINKING ALONG THE LIONS OF,

DOES THAT -- ARE YOU IMPLYING

THAT YOU REALLY THINK, AS A

HYPOTHESES, THAT IT IS OR THAT

THE MECHANISMS THAT WOULD BE

CONTRIBUTING TO PRUNING ARE

OVERACTIVE?

BECAUSE IT SEEMS THAT YOU COULD

HAVE A VERY SIMILAR THING IF YOU

JUST UNDER DEVELOPED, DIDN'T

STRENGTHEN THE CONNECTIONS

INITIALLY.

MAYBE THESE ARE TWO SUBGROUPS

EXACTLY LIKE ELLIOT WAS

IMPLYING.

THAT YOU MAY GET TO THE SAME

POINT, BUT FROM TWO DIFFERENT

REASONS.

>> ANNETTE KARMILOFF-SMITH ON

THE PLANE YESTERDAY I STARTED TO

THINK LIKE THAT AND I THOUGHT

THIS IS CONTRADICTORY BUT

ACTUALLIES WHY.

IF YOU HAVE A THRESHOLD SYSTEM,

IT IS A CONTINUUM.

SO YOU COULD GET A BIG

DIFFERENCE.

>> I'M JUST GOING TO ADD A

COMMENT TO THE OVERPRUNING THAT

I HOPE WILL COME UP LATER TODAY

AND IF IT DOESN'T, WE CAN

DISCUSS IT.

BUT, AT THE BIOLOGICAL LEVEL,

THE HYPOTHESES OF OVERPRUNING IS

SOMETHING THAT IS REALLY

APPEALED TO ME BUT ONE OF THE

THINGS THAT I WOULD LOVE THIS

FIELD TO TRY TO MOVE INTO THE

DIRECTION OF IS TO REALLY HAVE

AN EXPERIMENTAL SYSTEM WHERE WE

CAN SORT OF AT THE LEVEL OF

CAUSE AND AFFECT, BE BEYOND JUST

ASSOCIATION, AND I'M NOT SURE WE

ARE EVEN FULLY THERE WITH

ASSOCIATION.

BUT CAN WE GET TO THE PLACE

WHERE WE HAVE AN EXPERIMENTAL

MODEL WHERE WE CAN REALLY TEST

THAT HYPOTHESES ROBUSTLY?

AND I JUST PUT THIS OUT THERE AS

SOMETHING MAYBE WE CAN KEEP AN

EYE ON TODAY AND MAYBE COME BACK

TO DISCUSSING WHETHER WE ARE

THERE YET OR WHAT METHODOLOGIES

WE MIGHT NEED AT THE MICROSCOPY

LEVEL OR GENETIC MODEL LEVEL TO

GET US THERE.

>> SO THE PRUNING IS REALLY

FASCINATING IN THE FIRST YEAR OF

LIFE AND I WAS TRYING TO THINK

OF SOME POTENTIAL MECHANISM THAT

COULD BE INTRINSIC CELLULAR.

BUT WHAT ABOUT THE ROLE OF

ABNORMAL SENSORY RECEPTION IN

PROCESSING AND THE FIRST YEAR OF

LIFE?

HAVING AN AFFECT THEN ON

DEVELOPMENT AND PRUNING

MECHANISMS?

AND IF YOU THINK OF A BABY IN

THE FIRST YEAR OF LIFE, THEY ARE

PUTTING EVERYTHING IN THEIR

MOUTH.

THEY ARE EXPERIENCING.

AND WE KNOW FROM A LOT OF THE

SYNDROMIC DISORDERS, THAT THERE

IS ABNORMAL AUDITORY AND VISUAL

ERS AND SO ON AND SO FORTH.

WHAT ROLE DO YOU THINK THAT

COULD PLAY?

>> I KNOW IN THE IBEIS STUDY WE

HAVE BEEN CONSIDERING THAT.

IF WE SEE THERE IS OVER GROWTH

AND OVERCONNECTIVITY, IF WE USE

THAT TERM, THIS MAY BE THAT

THERE HAS NOT BEEN PROPER

FEEDBACK THAT LEADS TO THE

PRUNING THAT IS SUPPOSED TO TAKE

PLACE.

THAT PRUNING IS SO ROBUST AND IF

THERE IS NOT INFORMATION GETTING

INTO DRIVE THAT EXPERIENCE

DEPENDENT PROCESS, THAT MIGHT

EXPLAIN WHY THERE IS TOO MUCH OF

EVERYTHING AT LEAST IN THE

INFANT PERIOD IN THE BABIES THAT

GO ON TO DEVELOP AUTISM.

AND SO, WE ARE NOW TRYING TO DIG

INTO THAT AND SEE, CAN WE LINK

WITH THE TOOLS WE HAVE, SOME OF

THE DIFFERENCES IN BASIC SENSORY

MOTOR PROCESSING TO WHAT WE ARE

SEEING IN THE BRAIN TO TEST THAT

VERY HYPOTHESES THAT IN THE

FIRST YEAR IT'S THAT FUNDAMENTAL

DEFICIT THAT MAY SNOWBALL INTO

THE EVENTUAL AUTISM PHENOTYPE

BUT EARLY ON, IT STARTS AS

SOMETHING VERY DIFFERENT THAT

MIGHT BE ABOUT THE INFORMATION

IS NOT COMING IN PROPERLY TO

LEAD TO THE DEPENDENT

DEVELOPMENT THAT NEEDS TO

HAPPEN.

>> SO ONE THING I WANT TO ADD TO

WHAT YOU SAID, LAURA, BUT IT'S

THE INVERSE OF THIS, WHICH WE

ARE NOT TALKING ABOUT TODAY,

IS -- SO I WORKED WITH A GROUP

THAT LOOKED AT PATIENTS WITH

16P11 .2 DELETIONS AND ABOUT

25-ISH PERCENT OF THOSE KIDS GO

ON TO GET A DIAGNOSIS OF ASD.

AND THE GROUP OF PSYCHOLOGISTS

HAS BEEN FOLLOWING A LOT OF

THESE KIDS FROM EARLY ON WHEN

THE DIAGNOSIS IS MADE 6 MONTHS

OF AGE OR A YEAR OF AGE.

AND I NUMBER OF THESE KIDS --

AND I USE THIS IN QUOTES, GROW

OUT OF THE DIAGNOSIS.

SO THEY HAVE A PROVISIONAL EARLY

ASD DIAGNOSIS AND THEN THEY GROW

OUT OF IT.

ONE COULD ARGUE MAYBE IT'S A

MEASUREMENT SHALL.

YOUR ABLINGY TO ACCURATELY

MEASURE THIS PHENOTYPE AT AN

EARLY AGE OR IT MAY MEAN YOU CAN

SEE BOTH RANGES OF CHANGE OVER

TIME THAT YOU CAN -- AND THERE

MIGHT BE WAYS TO PERTURB THE

SYSTEM.

SORT OF GETTING AT WHAT YOU'RE

SAYING.

IS THERE SOMETHING ABOUT THE

FEEDBACK THAT IS POSITIVE OR

NEGATIVE?

>> AND TO FOLLOW-UP.

I MEAN, HAVE THERE BEEN ANY

STUDIES IN INFANTS WHO ARE

BIOLOGICALLY DON'T HAVE A

SYNDROME BUT ARE IN A VERY

IMPOVERISHED HIGH-STRESS

ENVIRONMENT?

AND WHETHER THAT WOULD DRIVE

SOME OF THESE CHANGES?

>> ANNETTE KARMILOFF-SMITH WE

HAVE DONE A STUDY BABIES GROWING

UP IN VERY LOW SES CONDITIONS

AND WE SEE ALREADY AT SIX MONTHS

CHANGES IN BRAIN ACTIVITY.

>> SO, I HAVE A COMMENT ABOUT

THE OVERPRUNING AND THAT MIGHT

BE SECONDARY.

SO, THERE IS TWO THINGS THAT I

THINK OF EARLIER AND THAT IS

EARLY PATTERNING AND SENSORY

EARLY CORTICAL PATTERNING.

SNOW PATTERNING IS NOT CORRECT

YOU MAY BE GOING TO MULTIPLE

TARGETS.

AND THEN FROM THE FLIP SIDE, YOU

THINK OF AXONAL GROWTH BUT THEN

WE ALSO HAVE BRANCHING.

IF YOU DON'T HAVE THE RIGHT

AMOUNT OF BARNING YOU MAY NOT

HAVE A VERY LONG CONNECTION OR

TWO OR THREE VERY SHORT OR

MULTIPLE LONG CONNECTIONS AND

SO, BOTH OF THOSE CAN LEAD TO

EXCESSIVE CONNECTIVITY EARLY ON.

NOW THE RESTING STATE,

FUNCTIONAL DATA IN HUMANS WILL

GIVE US AN IDEA OF AT LEAST

TARGET SELECTION IN THE

PATTERNING.

SO SOME OF THE ANIMAL AND HUMAN

STUDIES WE MAY BE ABLE TO SEE

THAT.

SO THOSE COULD LEAD TO AN

EXCESSIVE LARGE TARGET OR AREA

AND THEN YOU COULD HAVE ABNORMAL

PRUNING.

>> I JUST WANTED TO FOLLOW-UP ON

ERIC'S COMMENT ABOUT A SYSTEM

AND THIS IS JUST -- I'M PUTTING

THIS FORTH AS THINGS I THINK ARE

IMPORTANT TO BE THINKING ABOUT

FOR THIS OVERALL DISCUSSION,

WHICH IS EXACTLY THAT LIKE MODEL

SYSTEMS.

BUT ALSO PLACES THAT MAY BE WE

NEED NEW TECHNOLOGIES OR MAYBE

THERE ARE SOME WE JUST HAVEN'T

APPLIED, WHICH MAY HELP ADDRESS

THIS BUT IN TERMS OF ARE THERE

WAYS NON-INVASIVELY IN PEOPLE,

TO TRY TO ASSESS ISN'T GENESIS

VERSUS PRUNING?

EVEN WITH IMAGING MODALITIES OR

SOME SORT OF NEUROPHYSIOLOGICAL,

THAT WOULD HELP US SUBTYPE OR

GET AT SOME OF THESE QUESTIONS

AND BE ABLE TO BRIDGE BETWEEN

THE MODELS.

AND THE OTHER THOUGHT I HAD

LISTENING TO SOME OF THE

DISCUSSIONS REGARDING

DEVELOPMENTAL TRAJECTORIES AND

BRAIN GROWTH AND STUFF IS THAT A

LOT OF THIS IS BASED -- WE HAVE

TO -- WE ARE HAMPERED BY HAVING

TO HAVE CONVENIENCE CONTROLS.

WE HAVE OUR NONOR HIGH-RISK

GROUPS AND DEVELOP OR NOT

DEVELOP.

BUT, WHAT IS SORT OF LACKING

THEN AND MAYBE IS PART OF THE

ISSUES WHERE YOU HAVE

DISCREPANCY WHERE THERE IS TOO

MUCH CHORPUS CALLOSUM UM AND TO

LITTLE AND ALONGING AT JAY ON'S

THING WHEREAS THE GROUP

PROPERTIES THEY LOOK DIFFERENT

BUT AS INDIVIDUALS, SOME

INDIVIDUALS MAY BE DIFFERENT.

AND THAT IS HAVING THE GROWTH

WELL-DEFINED GROWTH CURVES OF

BRAIN DEVELOPMENT ACROSS PEOPLE

OF ALL OF THESE REGIONS, WHICH I

THINK IS HARD IF NOT IMPOSSIBLE

TO GET IN A NORMAL TYPICALLY

DEVELOPING PERSON.

BUT I THINK THESE ARE THE KIND

OF THINGS THAT WOULD HELP SO

THAT YOU COULD DO ONE PERSON.

AND PLOT IT.

>> IT LOOKS LIKE WE ARE RIGHT ON

TIME.

WE HAVE A BREAK SCHEDULED NOW.

ANY FINAL WORDS?

SORRY.

>> SO, MY NAME IS DWIGHT

DICKINSON, A SCHIZOPHRENIA

RESEARCHER IN THE INTRAMURAL

PROGRAM.

AND I HAVE BEEN SITTING HERE

LISTENING THIS MORNING TO THE

DISCUSSION OF REGRESSION AND THE

CONTEXT OF REALLY ONSET

DEVELOPMENTAL DISORDERS.

AND I JUST HAVE BEEN STRUCK

AGAIN AND AGAIN BY THE PARALLELS

TO ISSUES THAT WE THINK ABOUT IN

SCHIZOPHRENIA.

SO, I MEAN, THE FIRST ONE IS

JUST REGRESSION, WHICH THERE IS

AN ARGUMENT ABOUT WHETHER PEOPLE

REALLY REGRESS OR NOT.

AND IT FOLLOWS THE SAME THEMES

HERE ABOUT WHETHER IT IS A

FALLING OFF OF THE NORMAL COURSE

OF DEVELOPMENT.

BUT IT IS CLEAR IN SOME CASES

THAT PEOPLE GO FROM BEING MAYBE

THEY ARE NOT COMPLETELY NORMAL

IN TERMS OF DEVELOPMENT BUT GO

FROM PRETTY FUNCTIONAL IN HIGH

SCHOOL TO BEING JUST REMARKABLY

DISORGANIZED AND IN THERE

BEHAVIOR UNRECOGNIZABLE IN TERMS

OF WHAT THEY WERE FUNCTIONING

LIKE A FEW YEARS EARLIER.

AND IT IS ALSO TRUE THAT THERE

ARE VERY DIFFERENT PATTERNS.

WE SEE THE SAME KIND OF THEMES

IN TERMS OF THE PATTERNS WHERE

WE HAVE SOME OF THESE VERY

DRAMATIC CASES OTHER PEOPLE

WHERE IT IS MUCH MILDER

ET CETERA.

AND OF COURSE THE PRUNING

HYPOTHESES IS SOMETHING THAT

PEOPLE HAVE TALKED ABOUT FOR A

LONG TIME IN CONNECTION WITH

SCHIZOPHRENIA.

AND THEN IN REGARD TO THAT, I

WANTED TO SORT OF CALL ATTENTION

TO THE PAPER THAT WAS JUST OUT

IN THE LAST COUPLE OF WEEKS FROM

FOLKS AT THE BROAD INSTITUTE AND

AT HARVARD.

I HAD NOTHING TO DO WITH THAT

BUT IT'S BEEN A FASCINATING

THING TO LOOK AT AND IT'S REALLY

EXPLORING WHETHER THERE ARE

IMMUNE SYSTEM GENES THAT ARE IN

FACT PARTICIPATING IN THE

PRUNING PROCESS THAT MAY BE

OVERACTIVE AT CERTAIN POINTS OF

DEVELOPMENT IN REGARD TO

SCHIZOPHRENIA.

AND IN TERMS OF THE MODELS AND

THE MOUSE MODELING PEOPLE HERE

WILL KNOW A LOT MORE ABOUT THIS

THAN I DO, BUT THEY DO ACTUALLY

HAVE AN IMMUNE SYSTEM MODEL THAT

THEY USE, MOUSE MODEL, THAT HAD

TO DO WITH THE DEVELOPMENT AND

RATIONALIZATION OF THE VISUAL

SYSTEM.

AND THE PARTICIPATION OF THE

IMMUNE SYSTEM GENES AND HELPING

THAT PROCESS ALONG.

AND I'M NOT GOING TO GET THE

DETAILS RIGHT BUT INESS SENSE,

THERE IS A MOUSE MODEL.

THINK THE MODEL IS ACTUALLY

UNDERPRUNING RATHER THAN

OVERPRUNING BUT AT LEAST IT'S IN

THE SAME BALLPARK.

SO, I WANTED TO MAKE THOSE

COMMENTS.

THANK YOU.

>> ANN WAGNER:  THANK YOU FOR

THOSE COMMENTS.

WE HAD EARLIER DISCUSSIONS THAT

TOUCHED ON SOME OF THE PARALLELS

WITH SCHIZOPHRENIA SO IT IS

REALLY INTERESTING.

I THINK WE ARE REDSY FOR OUR

BREAK.

SO, WE WILL COME BACK AT 11:00.

WE ARE MOVING ON TO SESSION TWO.

WHICH IS CHAIRED BY JEFF NEUL.

FROM UNIVERSITY OF CALIFORNIA

SAN DIEGO.

AND JEFF WILL INTRODUCE US TO

THE SESSION.

>> JEFF NEUL:  GREAT.

YOU DON'T HAVE MY SLIDES.

THEY ARE LOADED.

SHOULD BE THERE.

>> ANN WAGNER:  SORRY FOR THE

DELAY.

REKNOW THE SLIDES ARE THERE.

WE JUST HAVE TO FIND THEM.

>> JEFF NEUL:  SORRY FOR THE

SLIGHT DELAY.

I'M JUST INTRODUCING THIS

SESSION AND REALLY WE ARE GOING

TO BE FOCUSING ON RETT SYNDROME.

I'M REALLY, AS THE POTENTIAL

THAT IT MAY PROVIDE SOME

INSIGHTS TO THE CONCEPT OF

REGRESSION IN AUTISM IN GENERAL.

ONE OF THE THINGS THAT

REGRESSION OF SKILLS IS REALLY

THE DEFINING FEATURE OF RETT

SYNDROME, ONE OF THE MAJOR

DEFINING FEATURES.

RETT SYNDROME PEOPLE ESSENTIALLY

HAVE NORMAL BIRTH IN EARLY

DEVELOPMENT BUT WILL START

SHOWING SOME SUBTLE OR NOT SO

SUBTLE DEVELOPMENTAL DELAYS

AFTER ABOUT SIX MONTHS OF LIFE,

POTENTIALLY EARLY BUT NOT

OBVIOUS.

AND THEN LATER THERE IS A PERIOD

OF REGRESSION FOLLOWED BY

STABILIZATION.

THAT IS AN IMPORTANT CONSENT AND

FEATURE IN RETT SYNDROME.

THE TYPICAL ONSET IS 18-LATE TOY

MONTHS OF LIFE.

-- 18-30 LIFE.

-- THERE IS SAY LOSS OF REQUIRED

HAND SKILLS.

TWO GRAPHS SHOW THE ACQUISITION

OF THIS BLUE LINE THE LATE END

OF NORMAL DEVELOPMENT AND THIS

IS A GROUP OF PEOPLE WITH RETT

SYNDROME IN THE ACQUISITION OF

THE GRAPH.

AND THEN LOSS HERE ON THE RIGHT

YOU SEE OVER TIME WITH AN

AVERAGE TIME BEING IN 18-30

MONTH WINDOW.

THE OTHER KEY REGRESSION IN RETT

SYNDROME IS THE LOSS OF SPOKEN

LANGUAGE.

SO AGAIN I SHOW THE ACQUISITION

OF SINGLE WORDS HERE IN RETT

SYNDROME AND THEN THE LOSS OF

THEM.

AGAIN IN 19-30 MONTH PERIOD.

SO, ONE THING THAT IS VERY

INTERESTING AS WE HAVE LOOKED A

LITTLE BIT CLOSER AT RETT

SYNDROME IS THAT ALTHOUGH WE

DON'T REALLY DETECT PROBLEMS

REALLY UNTIL THE REGRESSION EVEN

THOUGH WHEN WE LOOK BACK THERE

IS PROBABLY SUBTLE DEVELOPMENTAL

PROBLEMS, IF WE LOOK VERY

CLOSELY AT HEAD GROWTH, THE HEAD

GROWTH IN BLUE ON THE GRAPH

COMPARED TO TYPICALLY DEVELOPING

INDIVIDUALS IN ORANGE, IT REALLY

IS FALLING OFF THE CURVE VERY

EARLY, PROBABLY 1 1/2-TWO MONTHS

OF LIFE.

I PUT THIS UP TO HIGHLIGHT THE

BIOLOGY OF THIS IN TERMS OF THE

BRAIN FUNCTION IS PROBABLY GOING

ON MUCH, MUCH EARLIER.

SO, IN THIS SESSION WE ARE GOING

TO HAVE THREE SPEAKERS.

WE'LL START WITH HAYMOW HOW WHO

WILL BE TALKING ABOUT THE USE

ALYSSON.

UNDERSTANDING THE PATHOGENESIS

OF RETT SYNDROME.

WE WILL BE MOVING TO KEERTHI

KRISHNAN WHO IS AT COLD SPRING

HARBOR DISCUSSING SOME OF HER

WORK ON THE ROLE OF PAR VAL BU

MIN CELLS IN THE MOUSE AND THEN

FINALLY CHUCK NELSON WILL JOIN

US VIRTUALLY.

HE IS UNWELL TO TRAVEL BUT HE

GRACIOUSLY AGREED TO JOIN US

VIRTUALLY AND TALKING ABOUT

STUDYING THE VISUAL SYSTEM IN

PEOPLE WITH RETT SYNDROME.

SO, WHAT WE HAVE IS GOING FROM

THE CELL BIOLOGY TO MOUSE LEVEL

CIRCUITRY TO HUMAN RESEARCH.

AND SO, SOME OF THE THINGS WE

WILL BE MOVING ALONG SCALES AND

THERE IS A COUPLE OF QUESTIONS

I'M PUTTING UP NOW SO WE CAN

THINK ABOUT THAT I'D LIKE TO

COME BACK TO WHEN WE HAVE THE

DISCUSSION ABOUT, CAN WE

GENERALIZE IDEAS FROM ONE

DOMAIN, THE VISUAL SYSTEM IN HOW

IT DEVELOPS OR GOES WRONG, INTO

OTHER DOMAINS SUCH AS LANGUAGE

OR HAND SKILLS OR OTHER FEATURES

THAT GO WRONG IN RETT SYNDROME?

AND THEN CAN WE INTEGRATE

INFORMATION FROM THESE DIFFERENT

LEVELS OF INQUIRY FROM THE CELL

BIOLOGY THROUGH THE

NEUROCIRCUITRY TO THE HUMAN

SEARCH AND HOW CAN WE BRIDGE

BETWEEN THESE DIFFERENT LEVELS?

THAT'S AN OVERALL THEME FOR THIS

WHOLE WORKSHOP.

AND THEN REALLY FOR THIS

SPECIFICALLY, HOW CAN THESE

STUDIES HELP US UNDERSTAND

MECHANISM, POTENTIAL MECHANISM

OF REGRESSION IN AUTISM?

AND WITH THAT, WE CAN SWITCH

GEARS AND MOVE ON TO THE FIRST

SPEAKER.

>> THANK YOU FOR INVITATION.

I DECIDED TO SHARE RESEARCH WE

DO IN RETT SYNDROME GOING TO THE

VERY BASIC CELL BIOLOGY.

AND THEN I'LL NAV GET THROUGH

UNPUBLISHED DATA WHERE WE TRY TO

MIX DIFFERENT CELL TYPES TO GET

MORE INSIGHTS ABOUT THE

MECHANISM.

AND THEN I'LL FINISH WITH SOME

IDEAS ON HOW TO PERFORM

EXPERIMENTS USING THESE MODEL

SYSTEM TO ANSWER SOME OF THESE

QUESTIONS REALLY TRYING TO

ANSWER SOME PROVOCATIVE

QUESTIONS FROM JEFF WHO ASKED ME

TO DO THAT.

SO, LET'S SEE.

THIS IS THE COHORT WE HAVE.

WE HAVE WAY MORE PATIENTS NOW

BUT THESE ARE THE WELL

CHARACTERIZED CELLS WE HAVE.

AND THE MUTANTS ARE HERE.

THE SUE WE HAVE BOTH GIRLS BOYS

AND THIS IS NOT ONLY FOR TO KEEP

LIKE THE GENDER EQUITY BUT ALSO

BECAUSE IT IS A PAIN SOMETIMES

TO WORK WITH FEMALE DURING

REPROGRAMMING STUDIES.

WE HAVE THE EXON ACTIVATION AS

WELL AS ESCAPED OR RANDOM X

ACTIVATIONS.

SO THESE ARE THINGS THAT CONFUSE

WHAT YOU HAVE IN A DASH.

SO SOMETIMES WE MOVE INTO THIS

SYSTEM SO WE HAVE A VERY CLEAN

SYSTEM IN A DISH.

AND ANOTHER THING THAT WE DO

HAVE AS A SYSTEM IS ISOGENIC

CELLS WHERE WE CAN ARTIFICIALLY

CREATE MUTATIONS USING CHRIS PER

SYSTEM IN THESE CELLS -- KRIS

PER -- AND WE ALSO RESCUE ONE OF

THE MUTATIONS FROM THE PATIENT,

Q83X PATIENTS WE HAVE, AND WE

WERE ABLE TO RESCUE THAT.

SO, WE HAVE ALL OF THESE CELLS

AND ALL THE EXPERIMENTS THAT

I'LL SHOW TO YOU.

WE USE ALL THE CELLS TO DO THESE

EXPERIMENTS AND THEY VISUALLY

BEHAVE THE SAME.

SO NO MAJOR DIFFERENCES BETWEEN

MUTATIONS OR FEMALES AND MALES

OR ARTIFICIAL MUTATIONS OR

NATURAL MUTATIONS.

SO, THIS IS JUST A QUICK

PERSPECTIVE ON THE TYPE OF

CORTICAL DIFFERENTIATION PUSHING

CELLS TOWARD CORTICAL NEURONS

AND WE HAVE DIFFERENT

PRESENTATIONS OF CORTICAL

LAYNERS A DISH.

THIS IS SOME EXAMPLES OF

IMMUNOSTAININGS WE CAN PERFORM

MAKING SURE THAT THESE LAYERS

ARE REPRESENTED IN A DISH.

SOME OF THE EXPERIMENTS I WILL

SHOW YOU WAS DONE IN THE SYSTEM

WHERE THESE NEURONS ARE IN A

LESS ORGANIZED FASHION AND THEN

LATER ON I'LL SHOW YOU DATA WE

HAVE WITH MINI-BRAINS OR

ORGANOIDS WHERE THE CORTICAL

LAYERS ARE A LITTLE BIT MORE

ORGANIZED.

SO, REALLY THE FIRST THING WE

OBSERVED IN THESE RETT SYNDROME

DERIVED NEURONS WAS THE FACT OF

MORPHOLOGY.

THIS IS ONE OF THE EARLY CONT

INDICATIONS WE HAVE TO HERE.

ONE CONTROL.

WE LABELED THOSE.

WE ARE NOT PICKING A SPECIFIC

SUBTYPE OF NEURON.

THIS IS THE TYPE OF NEURONS WE

HAVE IN A DISH.

IF YOU JUST MEASURE THE DIAMETER

OF THE SOMA CELLS, YOU SEE 10%

REDUCTION COMPARED TO CONTROLS

AND YOU CAN USE S HAD.

RNAs TO SPECIFICALLY KNOCK

DOWN THE GENE AND MIMIC THE

PHENOTYPE THROUGH LOSS OF

FUNCTION.

SO ANOTHER MORPHOMATIC ASPECT WE

SAW.

THIS WAS INSPIRED FROM POST

MORTEM BRAIN TISSUES.

WE SEE ABSENCE OF PROITUTIONS IN

RETT NEURONS.

THEY DON'T HAVE AS MANY SPINES

AS WE SEE IN OUR CONTROL GROUP.

AND THE MOST DRAMATIC PHENOTYPE

OF PERHAPS THE MOST ROBUST

PHENOTYPE WE DO SEE IN A DISH IS

DECREASED NUMBER OF SYNAPSES.

AND THIS IS JUST A PANORAMIC

PERSPECTIVE OF ONE OF THE

CULTURES WE HAVE.

YOU HAVE YOUR NEURONS IN GREEN

AND ONE OF SYNAPTIC MARKERS

SNAPS IN IN RED, AND IT IS CLEAR

THAT THE RETT SYNDROME CULTURES

DON'T MAKE AS MANY SYNAPSES AS

YOU SEE IN THE CULTURE.

YOU CAN ELEVATE THE NUMBER OF

SYNAPSES EVEN TO DO THE ONSET OF

THE PHENOTYPE.

SO THIS IS GOOD NEWS.

IT SHOWS THAT THESE PHENOTYPES

CAN BE REVERTED.

SO IT'S NOT ONLY DONE BY

STAININGS.

WE CAN PATCH CLUMP.

WE HAVE A COLLABORATOR WITH

UPENN.

WE LIKE TO WORK WITH HIM BECAUSE

HE DOES EVERYTHING BLINDED.

SO JUST SHIP CULTURES TO HIM AND

HE WILL PATCH-CLAMP DO ALL THE

ANALYSIS IN A BLIND FASHION.

THIS IS ONE OF THE EXPERIMENTS

HE DID.

HE WILL PAMP CLUMP SELLS COMING

FROM THE CONTROL IN -- PATCH

CLUMP CELLS AND HE SHOWS BOTH

HAVE FUNCTIONAL ACTIVE

NEUROBVIOUS.

BUT AS HE DOES THAT, MULTIPLE

TIMES, HE NOTICED THAT THESE ARE

CLEAR DEFICIENCY IN SYNAPTIC

CURRENTS WHICH SUGGESTED LACK OF

OR DEFICIENCY IN

[ INDISCERNIBLE ]

IN THESE CULTURES WHICH IS

BASICALLY SOMETHING THAT WE SAW

WITH THE STAINS AS WELL.

SO, THE PATCH-CLAMP IS REALLY

PAINFUL TO DO.

YOU HAVE TO DO MANY NEURONS, ONE

AT A TIME.

YOU NEED LIKE SOMEONE WHO KNOWS

HOW TO DO THAT.

WE RECENTLY HAVE SHIFTED OUR

ELECTROPHYSIOLOGY ANALYSIS TO

MORE CIRCUITRY-BASED USING THESE

ARRAYS AND WE CAN DO THEM IN 2D

OR 3D BY CREATING 3D CORTICOIDS

OR BRAIN ORGINOIDS.

THERE IS A LITTLE BIT OF

ORGANIZATION AND STRUCTURAL

ORGANIZATIONS WE DON'T SEE IN A

TWO.

D. SYSTEM.

SO WE JUST PLATE THOSE ORGANOIDS

ON TOP OF THESE ELECTRODES AND

RECORD AND GENERATE ACTIVITY

MAPS THAT WE SUGGEST AND

INDICATE WHAT HAPPENED IN THESE

CULTURES.

THE BEAUTY OF THAT IS THAT YOU

CAN KEEP THE CELLS ALIVE AND

JUST RECORD OVER TIME SO YOU SEE

THAT IN THE BEGINNING, HAVE LOTS

OF RANDOM SPIKES HERE AND THERE

AS THIS CULTURE MATURED AND

PROGRESSES.

WE START TO SEE HIGHER FREQUENCY

OF SPIKES.

INTENSITY ALSO INCREASES AND

FINALLY WHAT WE HAVE IS A

SYNCHRONIZED BURST THAT APPEARS

OVER TIME.

THIS IS COMPARISON BETWEEN

CONTROLS AND RETT SYNDROME.

THIS IS OUR PLOT HERE FOUR

CHANNELS AT A TIME BUT WE HAVE

64 AND WHAT WE DO IS, WE COUNT

THE NUMBER OF BURSTS THAT ARE

SICK NIDES OVER TIME SUGGESTING

NEURONS ARE COMMUNICATED TO EACH

OTHER AND IS CLEAR IF RETT

SYNDROME WE HAD LOTS OF ACTIVITY

AS WELL, THE SYNCHRONIZATION OF

BURSTS WASN'T THERE.

YOU CAN KEEP THESE CULTURES

ALIVE UP TO 6 MONTHS, 8 MONTHS,

AND THEY WILL NEVER CATCH-UP.

WE NEVER SEE THEY ARE REACHING

CONTROL AVERAGE.

SO, ANOTHER THING WE LIKE TO DO

IS TO REALLY SPRODY INTERPLAY

BETWEEN DIFFERENT CELL TYPES AND

WE HAVE BEEN FOCUSING ON

ASTROCYTES BECAUSE IN RETT

SYNDROME THERE IS CLEAR

INDICATION THAT ASTROCYTES ARE

IMPORTANT CELL TYPES.

SO WE OPTIMIZE A PROTOCOL TO

GENERATE FROM IPS CELLS AND WE

HAVE BEEN USING THIS PROTOCOL TO

REALLY UNDERSTAND THE ROLE OF IN

SITU IN THIS TYPE OF GLIA CELLS.

ONE THING WE DID AS WE GENERATE

THESE ASTROCYTES FROM MSNC2

DEFICIENT CELLS AND CONTROL

CELLS AND DO GENE EXPRESSION AND

THIS IS JUST SOME OF THE EARLY

PRELIMINARY DATA WE HAVE FROM

THESE GLOBAL GENE EXPRESSION.

WE SEE THAT GENES THAT ARE

SUPPOSED TO BE EXPRESSED IN

ASTROCYTES, SUCH AS GFAP, AND

LITTLER, ARE HIGHLY EXPRESSED IN

RETT SYNDROME CELLS.

SO SUGGESTING THAT IN THE

ABSENCE OF ANY INSULT, THEY ARE

PRO ACTIVE ALREADY.

SO ANOTHER CLASSIVE GENES THAT

ARE VERY INTERESTING ARE

SECRETED FACTORS SUCH AS BMPs

OR DGNF.

SO THESE ARE MEDICAL COUGS THAT

HELP.

THESE ARE DOWN REGULATED IN RETT

SYNDROME ASTROCYTES.

AND ANOTHER CLASS OF GENES THAT

ARE IMPORTANT ARE FROM THE

GLUTAMATE PATHWAY AND HERE WE

SEE IT IS ALL OVER THE PLACE.

SO IT IS DIFFERENT EXPRESSION OF

DIFFERENT GENES.

AND JUST AS AN EXAMPLE OF WHAT

YOU CAN DO WITH THIS DATA IS TO

PROPOSE SOME ASSAYS FOR

INSTANCE, CAN THESE ASTROCYTES

BUFFER ACCESS OF GLUTAMATE?

SO IF YOU HAVE TOO MUCH

GLUTAMATE IN YOUR CULTURES, THIS

IS HIGHLY TOXIC FOR YOUR CELLS,

FOR YOUR NEURONS, FOR YOUR

BRAIN.

SO ASTROCYTES ARE ABLE TO KEEP

THIS HIGH LEVELS OF GLUTAMATE

UNDER CONTROL.

SO THIS IS A MONOLAYER OF

ASTROCYTES WHERE WE CHALLENGE

THEM WITH HIGH LEVELS OF

GLUTAMATE AND YOU SEE THE BLACK

BAR IS OUR CONTROL CELLS AND

THEY WERE ABLE TO BUFFER THESE

HIGH LEVELS OF GLUTAMATE AND

THEY CAN KEEP STABLE UP TO A

YEAR.

THE RETT SYNDROME ASTROCYTES

HAVE TWO DIFFERENT MUTANTS HERE.

THEY CANNOT DO THAT.

I MEAN, AS SOON AS THE CULTURE

STARTS, GLUTAMATE LEVELS JUST

START TO ACCUMULATE AND THESE

CULTURES WILL EVENTUAL

EVENTUALLY DIE.

SO, ANOTHER FUNCTIONAL ASSAY WE

CAN DO WITH GLUTAMATE IS TO

MEASURE CALCIUM WAVES AND THIS

CAN BE DONE BY CREATING THESE

LAYERS OFASTED ROW SITES AND

LOADING THEM WITH CALCIUM DYES.

YOU SEE THIS RED CIRCLE HERE?

THIS IS WHERE WE PHYSICALLY

TOUCH A SINGLE ASTROCYTE OR CAN

DON'T EVEN NEED TO TOUCH.

CAN BE LIKE A AIR PUFF.

AND YOU JUST STUDY OR VISUALIZE

HOW THE CALCIUM WAVES SPREAD

OUT.

THEY ALL BEHAVE THE SAME.

BUT LOOK WHAT HAPPENS WITH RETT

SYNDROME.

SO YOU CAN TOUCH THAT DIFFERENT

ASTROCYTES IN CULTURES.

YOU NEVER SEE THAT.

THIS IS INDEPENDENT OF CELL

DENSITY OR DIFFERENT PLATES.

YOU CAN ACTUALLY TRY TO REPEAT

THAT MANY TIMES AND THEY NEVER

CATCH-UP.

SO MAXIMUM THEY WILL DO IS

COMMUNICATE TO THE NEIGHBOR CELL

BUT YOU NEVER SEE A SPREADING OF

CALCIUM WAVES SUGGESTING THERE

IS SOMETHING WRONG BETWEEN THE

COMMUNICATION OF THESE CELLS.

SO FINALLY WE DID ONE EXPERIMENT

WAS TO PUSH THE TWO OF THEM

TOGETHER AND SEE IF WE CAN

CHANGE ANY OF THE RESULTS THAT

WE HAD BEFORE.

SO, THE IDEA WAS TO HAVE A

MONOLAYER OF ASTROCYTES AND THEN

YOU PLATE ON TOP OF THESE

CORTICAL NEURONS THAT WERE FAST

PURIFIED AND WAIT FOR TWO WEEKS

AND SEE WHAT HAPPENS.

AND I'LL SHOW YOU JUST THE DATA

THAT IS EASY TO VISUALIZE.

IF YOU HAVE RETT SYNDROME

ASTROCYTES -- CONTROL ASTROCYTES

PLATED TOGETHER WITH CONTROL

NEURONS, WHAT YOU HAVE AFTER TWO

WEEKS IS THAT THOSE NEURONS THEY

START TO SEE SOME SPINES AT A

FUNCTIONAL LEVEL THEY START TO

FIRE AND MAKE SYNAPSES.

IF YOU NOW HAVE THE SAME CONTROL

NEURONS, SAME POPULATION BUT YOU

PLATE ON TOP OF RETT SYNDROME

ASTROCYTES, YOU DON'T SEE THAT.

THEY ACTUALLY DO NOT DEVELOP.

YOU SEE THESE BIPOLAR NEURONS

VERY HARD TO FIND ONE THAT IS

ACTIVE.

THE SAME IS TRUE BETWEEN IF YOU

PLATE RETT SYNDROME ASTROCYTES

WITH RETT SYNDROME NEURONS.

HERE IS THE STRIKING DATA.

IF YOU TAKE THE RETT SYNDROME

NEURONS AND NOW YOU PLATE

TOGETHER WITH NORMAL CONTROL

ASTROCYTES, YOU BASICALLY RESCUE

EVERYTHING.

SO, IT'S AGAIN A GENETIC DEFECT.

THOSE NEURONS ARE SUPPOSED TO

BEHAVE LIKE RETT SYNDROME

NEURONS BUT IN THE PRESENCE OF

RIGHT ENVIRONMENT WITH NORMAL

ASTROCYTES, THEY BEHAVE LIKE

NORMAL NEURONS.

SO IT'S QUITE AMAZING TO SEE

THAT.

SO THIS OUR QUANTIFICATION.

WE LIKE TO DO EVERYTHING BLIND.

THIS IS POST MORTEM ANALYSIS.

SO WE SEND THE CULTURES AND YOU

CAN CLEARLY SEE THE RESCUE, THE

FIRST BAR HERE TO THE LAST BAR.

SO MANY OF THE PARAMETERS SHE

MEASURES, WE CAN RESCUE BY JUST

PLATING THE RETT NEURONS WITH

CONTROL ASTROCYTES.

SO WHAT ARE THE TOXIC FACTORS

THAT ARE COMING FROM ASTROCYTES?

THIS IS AGAIN INSIGHTS WE HAVE

SOME THE GENE EXPRESSION WHERE

WE START LOOKING AT DIFFERENT

CYTOKINES THAT ARE RELEASED BY

THESE RETT ASTROCYTES WITHOUT

ANY STIMULATION.

AND WE SEE THAT THERE IS A VERY

INTERESTING SIGNATURE OF

DIFFERENT CYTOKINES AND THIS IS

MEASURED MAKING SURE THEY ARE

BEING RELEASED IN THE CULTURE

MEDIA AND WE ARE EXPLORING THEM.

THE DIFFERENT CYTOKINES THAT

SEEMS TO BE PARTICIPATING IN

PRO-INFLAMMATORY RESPONSE.

AND JUST TO UPDATE YOU, IF YOU

TAKE SOME OF CYTOKINES WITH THE

SAME LEVELS THAT THE RETT

SYNDROME PRODUCES AND EXPOSED TO

NORMAL NEURONS, YOU MIMIC SOME

OF THE DEFECTS IN RETT NEURONS

AS WELL.

SO SUGGESTING THAT THEY ARE

CONTRIBUTING TO THE PHENOTYPES

THAT WE HAVE IN A DISH.

SO THE EXPERIMENT THAT IS THIS

WAS TOTALLY DONE BY GONG.

WE SEND THE CULTURES TO HIM AND

HE WAS INTERESTED ON THE KCC2,

WHICH IS POTASSIUM CALCIUM

TRANSPORTER TYPE OF MOLECULE.

AND THESE ACTUALLY SOMETHING

THAT HAPPENS LATE DURING

DEVELOPMENT.

YOU CAN SEE THE CONTROL, THE

GENE WILL BE ACTIVATED AFTER

THREE MONTHS OR LATER AND THIS

IS ONE OF THE IMPORTANT GENES

FOR THE GABA SWITCH BETWEEN

EXCITATIONS TO INHIBITION.

SO, HE PROPOSES THAT PERHAPS

THIS GENE IS BEING REGULATED BY

NSCP2.

AND INDEED, YOU DON'T SEE THE

EXPRESSION OF THE GENE UNLESS

YOU TREAT WITH IGF1.

SO AND IF YOU DO THAT, YOU CAN

ACTUALLY MAKE THE GABA

TRANSITION VERY EASILY.

YOU CAN DO THAT WITH IGF1 OR

GENETICALLY ENCODED WILDTYPE

NCP2 VERSIONS SO IT CAN RESCUE

THAT.

AND SO ONE OF THE IDEAS IS THAT

PERHAPS THIS IS ONE OF THE

EXPLANATIONS FOR THE REGRESSION

OF PHENOTYPE OR THE LATE ONSET

OF SYMPTOMS IN RETT SYNDROME.

IT REMAINS TO BE STUDIED.

AND HE ALSO SHOWED THIS IS A

CONSEQUENCE OF RETT.

SO IT CONTROLS THE LEVELS OF

KCC2 BY TAKING ADVANTAGE OF THE

RAT'S COMPLEX, A MOLECULAR

COMPLEX THAT HELPS TO ACTIVATE

OR SILENCE NEURONAL GENES.

SO, THIS IS THE SUMMARY OF THE

DATA I JUST SHOWED YOU.

SO MECP2 FUNCTION IS INVOLVED IN

GLUTAMATERGIC FORMATION AND CAN

CAUSE DEFECTIVE NET NEW YORK A

DISH.

RETT ASTROCYTES HAVE IMPAIRED

METABOLISM AND CAN CORRELATE BY

GENE EXPRESSION AND DISPLAY

INFLAMMATORY CYTOKINE SIGNATURE

IN RETT NEURONS REGULARS CUED BY

CULTURE WITH HEALTHY ASTROCYTES

AND THE FACT OF EXPRESSION OF

KCC2 MAY BE DUE TO MECP2

DEFICIENCIES RESULTING DELAY OF

GABA FUNCTION OF SWITCH THAT MAY

CONTRIBUTE TO THE LATE DISEASE

ONSET.

SO WHAT ARE THE IDEAS THAT WE

COULD USE TO ANSWER QUESTIONS

ABOUT REGRESSION IN A DISH?

SO, THINGS THAT WE KEEP THINKING

ALL THE TIME.

CAN WE STUDY SYNAPTIC FORMATION

OR PRUNING IN A DISH?

IS THIS POSSIBLE?

WE HAVE BEEN FOLLOWING UP THOSE

RTT CULTURES OVER TIME AND AT

LEAST FOR THE TYPE OF

EXPERIMENTS THAT WE DO, I MEAN,

IT'S REALLY HARD TO SEE ANY

EVIDENCE FOR SYNAPTIC PRUNING.

BUT MAYBE WE ARE JUST NOT

CATCHING UP WITH THE TECHNOLOGY

THAT WE HAVE.

ONE THING THAT I'M PROPOSING IS

TO TAKE ADVANTAGE OF THIS TOO,

WHICH IS PSD95-TS, TOOL

QUARTERBACKED BY ROGER CHEN, AND

YOU CAN USE DIFFERENT SYNAPTIC

GENES -- DEVELOPED BY ROGER

CHEN.

-- AND IT'S MUCH BETTER THAN A

SNAPSHOT OF ISN'TOGENESIS AT

DIFFERENT TIME POINTS BECAUSE

NOW YOU CAN FOLLOW THE

EXPRESSION OF THE GENES AND THE

LOCALIZATION OF THOSE GENES AT

THE SYNAPSES OVER TIME USING

TIME LAGS.

SO WE CAN DISTINGUISH IF THERE

IS A DEVELOPMENTAL DELAY OR IF

THE SYNAPSES ARE BEING FORMED

AND THEN DISASSOCIATED SOMEHOW.

SO WE CAN FOLLOW-UP ON THAT.

AND WE CAN MAKE THE SAME

CORRELATIONS WITH THE TYPE OF

ARRAYS WE HAVE.

WE HAVE TONSE OF DATA SUGGESTING

THAT THOSE RANDOM SPIKES APPEAR

SOMETIMES AT VERY ACTIVELY IN

THE RETT SYNDROME NEURONAL

COACHES COMPARED TO CONTROLS.

THEY JUST FAIL TO SYNCHRONIZE

BUT THE AMOUNT OF ACTIVITY IS

SOMETIMES HIGHER IN RATS

COMPARED TO CONTROLS.

SO WE DON'T KNOW EXACTLY WHY

THIS IS HAPPENING BUT IT MAY BE

THAT THERE IS AN ACCESS LEVEL OF

WEAK SYNAPSES BEING FORMED.

SO, ANOTHER THING THAT I WOULD

LIKE TO UNDERSTAND MORE IS THESE

SIGNATURE OR CONSEQUENCE OF

CYTOKINES THAT ARE BEING

EXPRESSED BY ASTROCYTES.

SO ALL OF THE ASTRO GENESIS

HAPPENS MUCH LATER IN

DEVELOPMENT.

SO IS THERE RIGHT THERE A

CONTRIBUTION EFFECT?

ONE MORE ISN'T I'LL JUST FINISH

HEREBY.

SO THE OTHER IDEA IS TO

OVEREXPRESS OR RESTORE

EXPRESSION OF KCC2 IN THE RAT

ANIMALS AND SEE IF YOU CAN REST

WITH THAT.

THAT WOULD SUGGEST THAT THESE

PROTEINS IS REALLY IMPORTANT.

AND IN THE FUTURE, THIS IS

SOMETHING THAT WE ARE THINKING

ABOUT IS HOW TO INTEGRATE

MICROBEHAVIOR IN THIS HOST

SYSTEM IN-VIVO AND IN-VITRO.

AND I'M HAPPY TO TALK MORE ABOUT

THAT.

SO I'LL FINISH HERE BY THANKING

MEMBERS OF MY LAB, MY FAMILY

ANDAGE AND THANK YOU VERY MUCH

FOR THE ATTENTION.

[ APPLAUSE ]

>> ANN WAGNER:  THANK YOU VERY

MUCH, ALYSSON.

AS BEFORE, WE'LL SAVE THE

QUESTIONS UNTIL THE END,

DISCUSSION PERIOD AT THE END OF

THE SESSION.

SO WE'LL MOVE ON TO THE NEXT

PRESENTATION BY KEERTHI

KRISHNAN.

SHAPING BRAIN CIRCUITS BY

EXPERIENCE.

>> KEERTHI KRISHNAN:  THANK YOU

TO JEFF AND THE ORGANIZERS FOR

GIVING ME AN OPPORTUNITY TO

SHARE MY RESEARCH WITH YOU

TODAY.

I WOULD BE TALKING A LITTLE BIT

ABOUT THE -- TRYING TO

UNDERSTAND PATHOGENESIS USING

MOUSE MODELS.

AS JEFF INTRODUCED NICELY, RETT

SYNDROME IS A NEURODEVELOPMENTAL

DISORDER THAT AFFECTS 1-10,000

GIRLS WORLDWIDE.

THEY GO THROUGH A NORMAL PERIOD

OF DEVELOPMENTAL 4-6 MONTHS OF

AGE WHICH THEY SHOW

DEVELOPMENTAL STAGNATION AND --

SORRY.

DEVELOPMENTAL STAGNATION AFTER

WHICH THEY GO THROUGH RAPID

REGRESSION, LOSS OF HAND SKILLS,

SOCIAL AND SPEECH ISSUES.

RETT SYNDROME IS MAINLY CAUSED

BY MUTATIONS IN A GENE CALLED

MECP2, WHICH IS THOUGHT TO BIND

DNA METHYLATED AND HYDROXY

METHYLATED DNA, AND IS THOUGHT

TO FUNCTION AS A CHROMATIN AND

TRANSCRIPTIONAL REGULATOR.

MAINLY INACTIVATED DEPENDENT

FASHION.

THE PREVAILING HYPOTHESES IS

THAT IT MAY RESULT FROM ALTERED

SYNAPTIC ACTIVITY AND MASTIFFITY

POSSIBLY THROUGH ABNORMAL

EXPERIENCE OF DEPARTMENT AND

SYNAPSES DEVELOPMENTS.

THE PATHOGENIC RECK FILMS FOR

THIS REMAINS UNCLEAR.

 MECHANISMS.

ONE OF THE MAINLY CHALLENGES

TRYING TO UNDERSTAND THE

PATHOGENESIS IS HOW DO WE GO

FROM GENES OR GENE MUTATIONS

THAT IN THAT ARE AFFECTED AND

THEN GIVE RISE TO ALTERED

CIRCUIT CONNECTIVITY AND

FUNCTION WHICH THEN GIVES RISE

TO CHARACTERISTICS, SOCIAL,

BEHAVIORAL AND COGNITIVE

DEFICITS?

THIS IS PARTICULARLY CHALLENGING

BECAUSE WE NEED TO USE AN

INTEGRATED APPROACH ACROSS

MULTIPLE LEVELS TO BE ABLE TO

UNDERSTAND THIS PROBLEM.

MAYBE AT THE MOLECULAR LEVEL

WITH IDENTIFYING TARGETS OF

MECP2 AND THE CELL CELL

COMMUNICATION LEVEL LOOKING AT

CELL AUTONOMOUS AFFECTS WE ALSO

HAVE TO TAKE INTO CONSIDERATION

THE DEVELOPMENTAL TRAJECTORY.

WE ARE LOOKING AT PRIMARY AFFECT

OF THE MUTATION THAT MIGHT GIVE

RISE TO CIRCUIT AND CONNECTIVITY

AND FUNCTION AND ALSO

COMPENSATION OR MALADAPTIVE

PLASTICITY THAT MIGHT RESULT

FROM THE CELL-CELL INTERACTIONS.

THE OTHER PROCESS WE TALKED

ABOUT THIS MORNING IS THE IDEA

OF EXPERIENCE AND PLASTICITY

WHICH IS CRUCIAL FOR LEARNING

AND BEHAVIOR IN GENERAL.

SO THE WAY WE DECIDED TO TACKLE

THIS QUESTION IS BY LOOKING AT A

SYSTEM WHERE WE KNOW SOMETHING

ABOUT THE GENES INVOLVED IN THE

MOLECULAR TARGETS INVOLVED AND

THE CIRCUIT CONNECT ACTIVITY AND

FUNCTION AND A BEHAVIORAL ASSAY

AT THE END OF IT IN WHICH CASE

THIS HAPPENS TO BE THE VISUAL

SYSTEM.

HERE IS A BRIEF INTRODUCTION TO

THE VISUAL SYSTEM HERE.

THIS IS THE SCHEMA OF THE

PRIMARY VISUAL CORTEX.

IT RECEIVES STRONG CONTRALATERAL

INPUT MARKED IN BLUE FOR THE V1

AND THERE IS A EPEES I LATERAL

PROJECTION, 1/3 IN THE PRIMARY

VISUAL CORTEX.

THIS AREA WHERE THERE IS INPUT

FROM BOTH THE CONTRALATERAL AND

EPEES I LATERAL, CELLS IN THAT

REGION RESPOND TO INPUT FROM

EITHER EYE COMING INTO THE ZONE.

GROUP ONE RESPONDS TO

INFORMATION COMING FROM FROM THE

CONTRALATERAL EYE OR RESPONDING

TO STIMULI COMING FROM FROM THE

IPSILATERAL SKY THEN CELLS IN

THE GROUP 4 AREA RESPONDING TO

COMING FROM FROM FROM BOTH ICE.

THIS CAN BE SHIFTED BY MONTH

LACKULAR DEPRAVATION, CHANGING

THE PLASTICITY IN THE SYSTEM.

SO IF YOU DO MACULAR

DEGENERATION AND THEN LOOK FOR

RESPONSE PROPERTIES OF THE GROUP

4 NEURONS, NOW THEY TEND TO

RESPOND MORE HEAVILY TO THE

NON--DEPRIVED EYE IN THIS CASE,

THE WEAKER EYE, THE LIPS LATERAL

EYE.

THIS IS OCULAR DOMINANCE

PLASTICITY.

AND IN MOUSE, THIS HAPPENS TO

HAPPEN AT A VERY SENSITIVE TIME

PERIOD IN DEVELOPMENT CALLED

CRITICAL PERIOD.

THIS IS AROUND FOUR WEEKS OF

POSTNATAL AGE IN MICE.

SO THIS CAN BE SIMILAR PROCESS

THAT YOU COULD THINK ABOUT FOR

LANGUAGE, MOTOR SKILLS OR ANY OF

THESE OTHER DEVELOPMENTAL

PROCESSES THAT WE TALKED ABOUT

THIS MORNING BUT OF COURSE IN A

DIFFERENT TIME SCALE THAN WHAT

WE SEE FOR THE VISUAL CORTEX.

SO IN ADDITION TO THIS PROCESS

THAT WE JUST TALKED ABOUT,

BINOCULAR CELLS ANOTHER

PROPERTY, ORIENTATION SELECT

ACTIVITY.

SO THEY ARE LEVELED HERE

PURPOSEEL AND YELLOW, HAVE VERY

SPECIFIC PREFERENCES WHICH

ORIENTATION A RESULT IN.

FOR EXAMPLE, THE PURPLE CELL

OVER HERE WILL RESPOND TO THE

180 DEGREE PURPLE ARROWS HERE

ORIENTATION FROM EITHER THE LEFT

EYE OR THE RIGHT EYE.

THIS IS IN ADULTHOOD AND

SOMETHING SIMILAR FOR THE YELLOW

CELL FOR A DIFFERENT ANGLE.

THIS IS REPRESENTED AS

ORIENTATION TUNING CURVES THAT

ARE PLACED RIGHT NEXT TO EACH

OTHER SHOWING THEY ARE NOT VERY

DIFFERENT IN TERMS OF THE

RESPONSE.

BUT, OUR COLLABORATORS AT

NORTHWESTERN UNIVERSITY

PUBLISHED THAT PAPER SHOWING

THIS PROCESS OF MATCHING HAPPENS

DURING THE CRITICAL PERIOD.

SO IF YOU LOOK AT THE MOUSE

BINOCULAR CELLS BEFORE THE

PRECRITICAL PERIOD, THESE CELLS

ARE ACTUALLY QUITE MISMATCHED SO

THEY RESPOND TO BOTH THE IN

FRITZ DIFFERENT ANGLES COMING

INTO THE DIFFERENT EYES.

AND SO THIS IS REPRESENTED AS

THIS MISMATCH IN HERE.

AND THEY ALSO HAVE SHOWN THAT IF

YOU VISUALLY DEPRIVE DURING

CRITICAL PERIOD, OR AFFECT

GENETICALLY, DIFFERENT THINGS

ABOUT GAB INHIBITION, FOR

EXAMPLE, THEN YOU ALSO STILL GET

A MISMATCH IN THIS ORIENTATION

TUNING PROPERTIES CALLED

BINOCULAR MATCHING.

SO, THE PROCESS THAT I JUST

TALKED TO YOU ABOUT EARLIER

ABOUT DEPRIVATION, THINK ABOUT

IT MORE OR LESS AS AN INJURY

MODEL WHERE YOU'RE AFFECTING

INPUT COMING FROM ONE EYE AND

THEN SEEING WHAT IS HAPPENING TO

THE BRAIN IN TERMS OF

PLASTICITY.

BUT IN TERMS OF THIS, THERE IS

NO MANIPULATIONS BEING

HAPPENING, IT'S JUST A QUESTION

OF DOING DIFFERENT KINDS OF

ORIENTATION TUNING AND SEEING

WHAT THE CELLS ARE RESPONDING

TO.

SO THE IDEA FROM THIS WORK IS

THAT THE CRITICAL PERIOD

ACTUALLY ALLOWS FOR VISUAL

EXPERIENCE TO DRIVE THE MATCHING

OF YENITATION TUNING.

THIS IS THE NORMAL PHYSIOLOGICAL

FUNCTION OF HAVING A CRITICAL

PERIOD IN GENERAL IN THESE MICE.

AND THIS IS VERY IMPORTANT

BECAUSE THIS IS SOMETHING THAT

IS IMPORTANT FOR DEPTH

PERCEPTION AND ALSO FOR TRYING

TO COMBINE INFORMATION

ESSENTIALLY FROM THE TWO EYES

WHERE WE ARE SEEING ONE FULL

IMAGE IN FRONT OF US.

THESE COULD BE THE PROCESS THAT

MIGHT BE IMPORTANT FOR THIS

PROCESS.

SO, I MENTIONED TO YOU ABOUT THE

ONSET AND THE PEAK OF THE

POLITICAL PERIOD IN THE MOUSE.

WORK HAS SHOWN THAT THIS

CRITICAL PERIOD CAN BE CHANGED A

LITTLE BIT.

BY ENHANCING GABA FUNCTION WITH

BDNF OVEREXPRESSION OR TREATING

MICE WITH BENZODIAZENINE WHERE

YOU SHIFT THE CRITICAL PERIOD

EARLIER OR DELAY THE CRITICAL

PERIOD BY REDUCING GABA FUNCTION

BY DARK REARING OR GENETIC

MANIPULATIONS FOR AN ENZYME THAT

MAKE GABA.

MULTIPLE DIFFERENT CELL TYPES

ARE PRESENT AND THEY ARE THOUGHT

TO BE BORN FOR THIS PROCESS BUT

A KEY ONE HAPPENS TO BE THIS ONE

HERE CALLED --

[ INDISCERNIBLE ]

A FAST-SPIKING INTRANEURON AND

FORMS SYNAPSES ON THE PARAMEATAL

NEURONS AND AFFECTS THE OUTPUT.

FURTHERMORE, THE INTERESTINGLY,

THE MATURATION OF THE CRITICAL

PERIOD COINCIDES WITH THE

MATURATION OF THE NETWORK

BETWEEN THE NEURONS AS WELL AND

THIS IS ALSO VERY MUCH DEPENDENT

ON GAD 67 EXPRESSION THIS IS THE

GREAT LIMITING KEY ENZYME THAT

PROMOTES GABA INHIBITION.

SO THAT SAUL MAINLY FOR THE

ONSET OF CRITICAL PERIOD.

THERE IS ANOTHER MARKER.

THESE ARE EXTRACELLULAR MATRIX

PROTEINS THAT INHIBIT EXON

GROWTH AND STRUCTURAL PLASTICITY

AND THEY ARE MAINLY FOUND ON IN

THE VISUAL CORTEX.

AND THEY SIGNAL CLOSURE OF

CRITICAL PERIOD.

IN 2002, YOU COULD REMOVE

PERINATAL BY AN ENZYME THAT EATS

UP EXTRACELLULAR MATRIX AND

REACTIVATE VISUAL CORTEX

PLASTICITY IN THE ADULT ANIMALS

LATER ON.

SUGGESTING THAT THERE MAY BE

MECHANISMS IN PLACE TO TRY TO

CLOSE CRITICAL PERIOD AND REOPEN

IF NECESSARY.

THAT MAKES A LOT OF SENSE FOR US

ADULTS IN A WAY BECAUSE WE ALSO

STILL LEARN WHILE WE ARE GROWING

UP AND IN ADULTHOOD, IT'S NOT

SOMETHING THAT IS ESSENTIALLY

CLOSED OFF EARLIER IN TIME.

SO, THE IDEA THAT THERE MIGHT BE

STRUCTURAL PROTEINS THAT ARE

INVOLVED IN OPENING UP AND

CLOSING AND LETTING OR LEARNING

ALLOW THE PROCESS OF LEARNING TO

CONTINUE, IS SOMETHING THAT

SEEMS TO BE INHERIT IN THE

BRAIN.

SO, I HAVE GIVEN YOU A BRIEF

OVERVIEW OF THE VISUAL SYSTEM

AND THE DIFFERENT PROCESSES AND

THE TIME POINTS THAT WE COULD

LOOK AT AND SOME OF THE SPECIFIC

THINGS WE COULD LOOK AT IN TERMS

OF MARKERS FOR THE GABAERGIC

CIRCUITS, IN TERMS OF GAD 67

EXPRESSION OR PD EXPRESSION, AT

LEAST IMMUNOSTAINING OF MARKERS

AND THE IDEA OF THE CRITICAL

PERIOD OR THE TIMING OF THE

CRITICAL PERIOD REGULATED BY THE

PD POSITIVE NEURONS AND THE

ULTIMATE FUNCTION IS THE

DEVELOPMENT OF THE VISUAL

FUNCTION IN THIS CASE, THE

BIMACULAR MATCHING PROCESS

ITSELF.

HOW DOES THAT LOOK?

WE USE THE GERMLINE DELETION

FROM ADRIENNE BIRD'S LAB FOR OUR

ASSAYS AS ALYSSON JUST

MENTIONED.

AND TOWARDS THE END OF IT, I'LL

SHOW YOU DATA FROM THE FEMALE

SIDE.

FOR NOW IT'S ALL ON THE MALE

SIDE.

SO THESE ARE BRAIN SECTIONS

LOOKING AT IN WILDTYPE AND MECP2

NULL ANIMALS OF P15 BEFORE

PREKIT CALL PERIOD AND AFTER

EYE-OPENING.

AND -- PRECRITICAL -- THIS IS

LAYER 5 RIGHT HERE, HIPPOCAMPUS

IS DOWN HERE.

FOR IMMUNOSTAINING FOR GAD 67,

WHICH IS A MARKER THAT I JUST

MENTIONED THE GREAT LIMITING

ENZYME FOR GABA SYNTHESIS IN

GREEN AND PB LABELED IN RED.

THE ARROWHEADS ARE POINTING

TOWARDS CELLS THAT HAVE HIGH

LEVEL EXPRESSION OF BOTH GAD 67

AND PD IN THE MECP2 NULL

ANIMALS.

MORE NUMBER OF CELLS ARE

EXPRESSING THIS AND THAT IS

QUANTIFIED IN THIS AREA.

WE HAVE DONE A LOT OF ASSAYS TO

SHOW IT IS NOT AN INCREASE IN

CELL NUMBER OF GAD 67 OR PD BUT

IT HAPPENS TO JUST BE THE

EXPRESSION LEVEL CHANGES THAT

ARE HAPPENING IN THE ANIMALS.

AND THIS IS NOT JUST HAPPENING

AT THE SOMA.

WE ALSO SEE IT IN THE SYNAPTIC

PROCESSES.

THESE ARE HERE LOOKING AT

SYNAPSES THAT ARE BEING FORMED

ON THE PARAMEATAL CELLS.

AND THE QUANTIFICATION HERE IS

LOOKING AT THE INTENSITY OF THE

EXPRESSION AND THE PERCENTAGE

THAT ARE OVEREXPRESSING THIS

HIGH INTENSE CELLS AND WE ARE

SEEING THAT GAD 67 IS AGAIN

OVEREXPRESSED IN THE MECP2 NULL

ANIMALS.

A LOT OF OTHER MARKERS AND THE

CONCLUSION FROM ALL OF THIS IS

THAT THERE IS A RECOURSE

INCREASE IN THE KEY COMPONENTS

OF GABA TRANSMISSION.

WE ALSO HAVE DONE SLICES ASSAYS

TO SHOW SOMETHING ABOUT THE

INTRANSIVE PROPERTIES AND THE

SYNAPTIC DYNAMICS OF THIS

REGULATION AND I'M THEME TALK

ABOUT IT MORE DURING THE

DISCUSSION.

NOW WE WANT TO SEE IF THERE IS A

CLOSURE ALSO AFFECTED.

THIS IS A MARKER FOR

PERINATAL -- STAINS BY

EXTRACELLULAR MATRIX PROTEIN.

AND WHAT WE SEE IN WILDTYPE OF

P15 ESSENTIALLY LOOKS LIKE

BACKGROUND STAINING.

YOU DON'T REALLY SEE MUCH OF A

FEENEYO TYPE OF THIS STAGE BUT

WHEN WE LOOK AT FULL IMAGES OF

THIS, THESE STRUCTURES ARE

CALLED IMMATURE CLOUDS

ESSENTIALLY THE EXTRACELLULAR

MATRIX AND WHEN WE LOOK AT MORE

OF THEM IN THESE STRUCTURES OVER

HERE IN THE LAYER 5 AREA, WE

BEGIN TO SEE THE NET LIGHT

STRUCTURES.

AND IN MECP2 NULL ANIMALS WE SEE

OVEREXPRESSION OF PERINEURONAL

LENSES IN THESE ANIMALS AND

THESE ARE THE SAME STRUCTURES

YOU SEE OVER HERE.

AND THIS IS QUANTIFIED OVER HERE

WHERE WE SEE THAT EVEN AT P15

AND ALSO P30 AND OTHER TIME

POINTS, THERE IS CONSIDERABLE

INCREASE IN EXPRESSION OF MATURE

CELLS.

THIS IS IMAGE SHOWING

COLOCALIZATION OF THE PV LABELED

IN RED.

SO, WHAT WE SEE IS THAT THERE IS

A RECOURSE MATURE FORMATION IN

THE NULL ANIMALS AT EARLY STAGE.

SO BOTH DATA SHOWED US THAT

MAYBE THE TIMING OF THE CRITICAL

PERIOD MIGHT BE AFFECTED IN

THESE NULL ANIMALS SO WE

COLLABORATED WITH OTHERS AT

NORTHWESTERN UNIVERSITY TO LOOK

AT THE OCULAR DOMINANCE

PLASTICITY I INTRODUCED EARLY

AND USING IMAGING, WHICH ARE

STANDARD ASSAYS USED FOR

MEASURING, WE LOOKED AT

DIFFERENT TIME POINTS.

IN THE WILDTYPE ANIMALS, NORMAL

CRITICAL PERIOD WOULD BE AROUND

P26-P31 TIME POINT.

AND WHAT WE SEE IS THAT IN THE

WILDTYPE ANIMALS, WE SEE THIS

OCULAR DOMINANCE SHIFT AS WE

EXPECTED FROM PREVIOUS STUDIES.

WHILE IN THE NULL ANIMALS WE SEE

NO PLASTICITY AT THIS TIME

POINT.

BUT OUR IMMUNEY STAINING DATA

SUGGESTS THIS WOULD BE RECOURSE

IN THE MOUSE SO RELOOKED AT THE

EARLIER TIME POINTS DURING THE

PRECRITICAL PERIOD AND THEN

RECORDING AT THE NORMAL TIME

PERIOD RIGHT BEFORE THE TIME

PERIOD IN THE PREKIT CALL TIME.

AND WHAT WE SEE IN THE WILDTYPE

ANIMALS AGAIN THERE IS NO

PLASTICITY OF THE TIME POINT AS

IS EXPECTED BUT IN THE MEC

APPROXIMATE.

2 NULL ANIMALS WE SEE A SHIFT IN

THE OCULAR DOMINANCE PLASTICITY

SUGGESTING A CORRELATION BETWEEN

WHAT WE SAW WITH THE MOLECULAR

MARKERS WITH THE TIMING OF

CRITICAL PERIOD BEING CHANGED

AND THE PHYSIOLOGY DATA SHOWING

THE PLASTICITY IS AFFECTED.

SO NOW WHAT ABOUT BIMACULAR

MATCHING?

FROM OUR COLLABORATORS WORK

SUGGESTED THAT THERE NEEDS TO BE

A PROPER CRITICAL PERIOD FOR

THIS PROCESS TO OCCUR NORMALLY

AND SO, IN THE NULL ANIMALS,

THERE IS A CRITICAL PERIOD IT'S

JUST HAPPENING EARLIER.

SO THESE ARE POLAR PLOTS SHOW

THIS.

SO WHEN THERE ARE ORIENTATION

TUNING BARS THAT ARE BEING

PLACED IN FRONT OF THE EYE OF

THE ANIMAL WHILE RECORDING IS

BEING DONE, WHAT WE SEE IS THAT

THIS IS AN EXAMPLE SELLOFF A

WILDTYPE EITHER FOR THE

CONTRALATERAL OR IPSILATERAL.

THEY RESPOND SIMILAR TOW TO THIS

PARTICULAR ORIENTATION.

SO THE BAR IS MOVING IN THIS

DIRECTION.

BUT IF WE DO THIS IN THE MECP2

NULL ANIMAL, THIS CELL IS

RESPONDING TO DIFFERENT

ORIENTATION COMING FROM THE 90

DEGREE ANGLE FOR ONE EYE AND

THEN A DIFFERENT ANGLE FOR

ANOTHER EYE.

THIS IS JUST AN EXAMPLE BUT WE

SEE THIS VERY SIMILARLY IN

MULTIPLE DIFFERENT ANGELS AND

CELL TYPES SUGGESTING THAT IT IS

NOT ENOUGH TO JUST HAVE A

CRITICAL PERIOD.

IT HAS TO BE AT THE RIGHT TIME

POINT FOR THE CIRCUIT TO WORK.

SO IN COG COLLUSION, WE SEE

NA -- CONCLUSION -- IT REGULATES

THE TIMING OF CRITICAL PERIOD

PLASTICITY AND IT IS HAPPENING

THROUGH THE POSITIVE

INTRANEURONS IN THE VISUAL

CORTEX.

WE SEE INCREASE IN THE

COMPONENTS OF THEM AND SEE THERE

IS A RECOURSE ONSET AND

TERMINATION IN THE CRITICAL

PERIOD AND WHAT WE SEE AS A

CONSEQUENCE OF ALL OF THIS IS

THAT THERE IS AN ABARENT VISUAL

FUNCTION MEASURED BY THIS

MATCHING PROCESS WE TALKED

ABOUT.

I DON'T VIDEO TIME TO SHOW DATA.

QUI CAN RESCUE AFFECTS BY

REDUCING GAD 67 LEVELS IN THESE

ANIMALS PREVIOUSLY OVEREXPRESSED

IN THESE ANIMALS.

WE ARE ABLE TO RESCUE SOME

ASPECTS BY CHANGING GABA

INHIBITION.

SO, THIS IS MAINLY SHOWING

TOWARDS THE MODEL WHERE WE ARE

ABLE TO SHOW DEVELOPING VISUAL

CORTEX AS A CONTEXT IDENTIFYING

A PARTICULAR CELL TYPE FOR

PARAALBUMIN CELL TYPE AS A KEY

NODE IN THIS PATHWAY.

THE IDEA IS THAT IT IS THE

TIMING OF PLASTICITY THAT SEEMS

TO BE AFFECTED IN THESE ANIMALS.

WE ARE USING A COMPLETELY

DIFFERENT MODEL TO STUDY THIS

AND THE ADULT AUDITORY CORTEX

USING THE FEMALE MICE, AND WE

ARE USING A BEHAVIORAL PARADIGM

FOR THIS.

AND THE IDEA FROM ALL OF THIS IS

THAT IT'S THE SAME NETWORK THAT

SEEMS TO BE AFFECTED IN TERMS OF

PARAVAL BU MIN AND THE TIMING OF

PLASTICITY.

I'M HAPPY TO TALK TO PEOPLE MORE

ABOUT THIS.

THIS IS AN OVERVIEW OF THE

VIDEO.

THIS IS BEHAVIORAL WORK WHERE WE

STATER THE PUPS IN DIFFERENT

CORNERS OF THE CAGE AND THIS IS

THE MOTHER WHO IS PERFORMING THE

BEHAVIOR.

THIS IS DONE IN THE DARK.

THEY USE AUDITORY CUES WHEN THE

PUPS VOCALIZE ULTRASONICALLY.

SO THE MOTHER GOES, FIND THEM,

BRINGS THEM BACK TO THE NEST.

THIS IS LIVE VIDEO.

SO THERE IS NO SPED UP OR

ANYTHING LIKE THAT.

AND YOU CAN SEE HOW CLEARLY SHE

GOES TO THE PUPS, GRABS THEM AND

BRING THEM BACK.

WHEN WE DO THE SAME ASSAY WITH

THE HETEROZYGOUS FEMALES, WHICH

WE'LL SHOW UP IN THE NEXT VIDEO,

THEY DON'T PERFORM VERY WELL IN

THIS BEHAVIOR AT ALL.

SO THIS IS THE HETEROZYGOUS

FEMALE AND AGAIN IT'S DONE IN

THE DARK.

AND SHE SEEMS -- THIS PARTICULAR

FEMALE SEEMS TO BE ABLE TO

IDENTIFY THE PUPS BUT SHE

DOESN'T KNOW TO BRING THEM BACK

INTO THE NEST.

AND WE HAVE CHARACTERIZED THIS

BEHAVIOR QUITE WELL AND WE SEE

AGAIN IT'S THE SAME PATHWAY, THE

PAIR VAL BU MIN PATHWAY THAT

SEEMS TO BE AFFECTED IN THE

HETEROZYGOUS FEMALES IN ADULTS.

THIS GIVES US AN IDEA IT COULD

BE THE LEARNING PROCESS BY

ITSELF THAT MIGHT BE INHIBITED

IN THESE ANIMALS.

THIS GOES ON FOR THE NEXT SIX

MINUTES SO I WON'T GO INTO THAT.

SO THE SPECULATION FROM ALL OF

THIS IS THAT IN THE FIRST PART

OF THE TALK, I WAS SHOWING YOU

ABOUT STEREO TYPIC VISION, BEING

ABLE TO LOOK AT ONE IMAGE IN

FRONT OF US AND HAVE DEPTH

PERCEPTION WHERE YOU HAVE TO

INTEGRATE INFORMATION COMING IN

FROM TWO EYES.

THAT IS AFFECTED IN THE MECP2

NULL ANIMALS.

PERHAPS THE SECOND ASPECT WHERE

WE TALK ABOUT MULTISENSORY

INTEGRATION, THE MOTHER HAS TO

LISTEN TO THE PUP CALLS,

IDENTIFY THEM, BRING THEM BACK

TO THE NEST.

A LOT OF INTEGRATION NEEDS TO

HAPPEN THROUGHOUT THAT PROCESS.

THAT SEEMS TO BE AFFECTED IN THE

FEMALES.

AND SO WE LIKE TO SPECULATE THAT

THIS IS SOMETHING THAT IS

HAPPENING IN BOTH THE MOTOR

SENSORY FEEDBACK AND ALSO SOCIAL

AND EMOTIONAL INTERACTIONS AS

WELL LIKE SYNTHESIS WE TALKED

ABOUT EARLIER IN THE FIRST PAM

SESSION.

SO, WE THINK THAT THE MECP2 IS

REGULATING TIMING OF THIS

PLASTICITY.

EXPERIENCE DIFFERENT PLASTICITY

AND OTHER BRAIN SYSTEMS AS WELL

AND ESSENTIAL FOR ALL OF THESE

BECAUSE THEY ARE QUITE WIDELY

EXPRESSED INTO VERY IMPORTANT

ROLLS IN THIS PROCESS.

THE OTHER INTERESTING ASPECT

TESTIFY IS FIR FOR A LONG TIME

PEOPLE TALKED ABOUT SOCIAL

PHENOTYPES AS ONE OF THE MAIN

KEY THINGS FOR AUTISM SPECTRUM

AND TODAY WE ARE TALKING A LOT

MORE ABOUT HOW SENSORY

PROCESSING IS ALSO AFFECTED IN

BOTH RETT SYNDROME AND AUTISM

SPECTRUM PATIENTS SUGGESTING WE

ARE LOOKING AT SOMETHING THAT

MAY BE A PRIMARY AFFECT THAT IS

HAPPENING WHICH MIGHT THEN LEAD

AND GIVE RISE TO THE SOCIAL

CONTEXT OF THE SOCIAL ISSUES WE

ARE TALKING ABOUT IN RETT

SYNDROME AND AS WELL AS AUTISM

SPECTRUM DISORDER PATIENTS.

WITH THAT, I WOULD LIKE TO THANK

MY MENTOR AT COLD SPRING HARSHER

AND ALL THOSE WE ARE

COLLABORATING WITH ON THIS WORK.

AND MY OTHER COLLABORATORS AND

FUNDING.

THANK YOU.

[ APPLAUSE ]

>> ANN WAGNER:  THANK YOU.

I BELIEVE WE HAVE DR. CHARLES

NELSON ON THE LINE.

SO WE'LL GET HIS SLIDES UP.

CHUCK, ARE YOU THERE?

>> CHARLES NELSON:  I'M HERE.

>> ANN WAGNER:  SORRY YOU'RE NOT

FEELING WELL.

>> CHARLES NELSON:  GIVE ME A

SHOUT WHEN YOU WANT TO START.

SO SORRY EVERYONE, I CAN'T BE

THERE AND AS YOU WILL HEAR IN A

MOMENT, I AM STARTING TO SOUND

MORE AND MORE LIKE AN NPR

ANNOUNCER.

SO GO TO THE NEXT SLIDE AFTER

THE TITLE SLIDE.

I'M GOING TO TALK ABOUT RETT

SYNDROME AND BEFORE I DIVE INTO

THE DATA, I WANT TO TELL YOU A

LITTLE BIT ABOUT WHAT RETT

SYNDROME IS ALTHOUGH I THINK

MANY OF YOU ARE FAMILIAR WITH

THIS.

IT'S AN X LINKED SPONTANEOUS

MUTATION OF THE MEWP2 GENE.

LESS THAN 1% OF CASES TEND TO BE

INHERITED AND PRIMARILY AFFECTS

FEMALES AND PREVALENCE IS

1-10,000 AND TYPICALLY

CLASSIFIED BY REGRESSION THAT

CURSE THROUGH THE TODDLER

PERIOD, LOSS OF HAND USE, LOSS

OF ACQUIRED SPEECH AND GAIT

ABNORMALITIES AND STEREOTYPES.

THERE ARE THREE AIMS TO THE WORK

THAT WE HAVE BEEN DOING IN MY

LAB AND THE FIRST IS TO

ESSENTIALLY QUANTITATIVELY

EVALUATE CORTICAL FUNCTION IN

GIRLS WITH RETT USING EEG, AND

EVENT RELATED POTENTIALS AND THE

VISUAL POTENTIALS.

TODAY I'M GOING TO FEC US ON THE

VISUAL POTENTIAL.

THE NEXT AIM IS TO MONITOR AND

MEASURE NEUROLOGICAL SIGNS OF

RESPONSE TO PHARMACOLOGICAL

TREATMENT.

SO WITH WALTER KAUFFMAN, WE HAVE

BEEN ENGAGED IN A CLINICAL TRIAL

OF IGF1 FOR THE LAST FEW YEARS

NOW AND USING A WHOLE BATTERY OF

MEASURES AND WITH THE VEP BEING

ONE OF THEM.

THIS WORK IS BEING DONE IN

PARALLEL WITH MOUSE WORK BEING

DONE BY MAKAYLA.

I HAVE NO DATA TO REPORT ON THE

CLINICAL TRIAL ALTHOUGH WE ARE

VERY CLOSE TO STARTING TO LOOK

AT THE PRELIMINARY DATA.

AND THE THIRD AIM IS TO DEVELOP

A COGNITIVE ASSESSMENT THAT

CIRCUMVENTS THE CONFOUNDS OF

IMPAIRMENT IN MOTOR FUNCTION AND

EXPRESSIVE LANGUAGE WHEN

ASSESSING DOMAINS OF RECEPTIVE

LANGUAGE AND VISUAL RECEPTION.

SO, THESE GOALS ARE

EXTRAORDINARILY DIFFICULT TO

EVALUATE USING STANDARDIZED

INSTRUMENTS LIKE THE MULLIN AND

WHAT WE HAVE BEEN DOING IS

ADAPTING THE MULL IN IN TWO

WAYS, TO MAKE ADAPTATION TO MAKE

IT EASIER TO GET A RESPONSE FROM

THE GIRLS BUT THE ONE I'LL TALK

ABOUT TODAY IS AN ADAPTATION

USING EYE TRACKING AND THAT IS

RESTRICTED TO THE RECEPTIVE

LANGUAGE AND VISUAL RECEPTION

SKILLS.

AND I'LL TURP MY ATTENTION TO

THAT LATER.

SO NEXT SLIDE.

IN TERMS OF CORTICAL FUNCTION,

THE GOAL HERE IS TO EVALUATE

CORTICAL FUNCTION USING VEP.

AND THEN THE SECOND PART OF MY

TALK WILL BE THE DEPONENT WHICH

WE CAN LOOK AT COGNITIVE

FUNCTION USING EYE TRACKING

VERSION OF THE MULLINS SCALE OF

EARLY LEARNING.

SO NEXT SLIDE.

THIS IS TITLED VEP AS A

TRANSLATIONAL BIOMARKER IN RETT.

SO, WHOEVER IS ADVANCING JUST GO

ALONG WITH ME AS YOU GO.

RATHER THAN ME KEEP SAYING

ADVANCE.

SO, THE VEP REFLECTS SUMMATION

OF A CORTICAL RESPONSE TO A

VISUAL STIMULUS.

IT'S A ROBUST SIGNAL WITH

QUANTIFIABLE COMPONENTS.

MATURES WITHIN THE FIRST YEAR OF

LIFE.

THIS IS IMPORTANT BECAUSE THIS

MEANS THAT WE HAVE A REALLY VERY

GOOD ASSAY THAT CAN BE USED

DEVELOPMENTAL THAT AFTER ABOUT A

YEAR OR SO BECAUSE IT DOESN'T

CHANGE WITH AGE ANYMORE, ANY

DIFFERENCES WE SEE SHOULD BE DUE

TO UNDERLYING CONDITION OR

SEVERITY OR TREATMENT, EFFICACY

AND THINGS LIKE THAT.

IT'S A PASSIVE TASK NOT

DEPENDENT ON ATTENTION.

NON-INVASIVE, QUICK, COST

EFFECTIVE.

THE QUESTION FOR US IS, CAN WE

USE THE KNOWLEDGE GAINED IN

MOUSE MODELS OF RETT TO BETTER

UNDERSTAND THE CELLULAR AND

CIRCUIT IMPAIRMENTS IN RETT

PATIENTS AND INFORMED

TREATMENTS?

SO NEXT SLIDE.

SO, THE DATA I'LL REPORT TODAY

INCLUDE 34 GIRLS WITH RETT AND

20 GIRLS WHO ARE TYPICALLY

DEVELOPING.

YOU CAN SEE THEIR CHRONOLOGICAL

AGE IS ROUGHLIY THE SAME.

THE AGE RANGE IS ALSO ROUGHLY

THE SAME.

NEXT SLIDE.

SO, YOU CAN SEE HERE A CHECKER

BOARD PATTERN THAT IS SPACIAL

FREQUENCY.

AND WHAT WE DO IS PRESENT THESE

CHECKER BOARDS CONTINGENT ON EYE

POSITION.

SO EVERYTHING IS DONE -- OUR EEG

SYSTEM IS INTEGRATED WITH EYE

TRACKER AND ONLY PRESENT STIMULI

WHEN WE KNOW THE CHILD IS

LOOKING AT THE SCREEN WHERE THE

STIMULI IS MOVED AND PRESENTED.

RECORDING USING HIGH DENSITY

NETTLEFUL 128 ELECTRODES AND

THEN THE BOTTOM HALF OF THE

SLIDE YOU CAN SEE THE ARRAY OF

SENSORS.

THE ONE IN YELLOW AT THE BACK IS

WHERE WE WILL FOCUS OUR

ATTENTION WHICH IS SITTING OVER

THE VISUAL CORTEX AND THEN THE

RIGHT IS SORT OF THE

PROTOTYPICAL VEP.

AND A FEW SLIDES I'LL DECOMPOSE

THIS INTO DIFFERENT ASPECTS OF

THIS RESPONSE.

SO THE NEXT SLIDE WHERE IT SAYS

VEP IS ABNORMAL.

SHEAR WHAT I WANT TO YOU DO.

LEFT ARE TYPICALLY DEVELOPING

GIRLS.

[ COUGH ]

EXCUSE ME.

AND ON THE RIGHT ARE THE GIRLS

WITH RETT.

THE -- EACH LINE REPRESENTS A

SINGLE CHILD.

THE DARKER LINE THAT YOU CAN SEE

ON THE LEFT AND ON THE RIGHT,

THE DARKER RED OR DARKER BLACK,

REPRESENTS THE GRAND AVERAGE.

THAT'S, THIS IS THE AVERAGE OF

AVERAGES.

SO THOSE SOLID LINES REPRESENT

THE AVERAGE OF THE INDIVIDUAL

CHILDREN.

THE FIRST THING TO NOTE IN BOTH

GROUPS YOU SEE LET GENERATEY AND

VARIABILITY IN THE RESPONSE BUT

NOTICE IN THE CONTROLS THAT THE

VAST MAJORITY OF KIDS SHOW THIS

COMPONENT THAT SHOWS UP AT THE

P1 COMPONENT.

IT IS ABOUT 100 MILLISECONDS.

YOU'LL NOTICE ON THE RIGHT IT'S

MORE VARIABLE AND SMALLER.

THIS IS SHOWN A LOT MORE CLEARLY

HERE.

THIS IS THE GROUP DIFFERENCES

SLIDE.

WHAT YOU SEE HERE IS THE GRAND

AVERAGE OF THE 20 CONTROLS AND

THE 34 GIRLS WITH RETT.

VEP AND CONTROLS YOU'LL SEE M1

COMPONENT THAT CURSE BETWEEN

50-75 MILLISECONDS, THAT IS

NEGATIVE COMPONENT FOLLOWED BY

P1 AND THEN FOLLOWED BY THIS N2.

THESE ARE ALL LABELED IN THIS

SLIDE.

YOU'LL NOTICE THAT THE GIRLS

WITH RETT SHOW A VERY ATYPICAL

RESPONSE.

NOW IF YOU MOVE TO THE RIGHT TO

THE HISTOGRAMS, YOU'LL SEE

DRAMATIC REDUCTION IN THE

AMPLITUDE OF THE P1 IN THE RETT

GIRLS COMPARED TO THE CONTROLS

AND A PROLONGATION OF THE N2

LATENCE IN THE GIRLS WITH RETT

COMPARED TO THE CONTROLS.

NEXT SLIDE.

SO HAVING ESTABLISHED AT THE

GROUP LEVEL WE SEE DIFFERENCES,

WE WANTED TO START THE DATA

BASED ON A COUPLE OF DIMENSIONS.

AND I'LL START WITH REGRESSION.

SO WE LOOKED AT THE GIRLS WITH

RETT TO SEE WHETHER THERE WAS A

DIFFERENCE IN THOSE GIRLS THAT

WERE IN THE MIDST OF ACTIVE

REGRESSION VERSUS

POST-REGRESSION.

SO ANY SKILL LOSS WITHIN 12

MONTHS PRIOR TO THE VEP TESTING.

SO BOTTOM LASTFUL SLIDE WHAT YOU

CAN SEE HERE, IS AGAIN THE BLACK

IS REPRESENTING THE TYPICALLY

DEVELOPING GIRLS AND YOU CAN

STEVE THAT ON THE LEFT AND ON

THE HISTOGRAM ON THE RIGHT.

AND WHAT YOU SEE IS THE

PROGRESSIVE DECLINE IN AMPLITUDE

BASED ON WHETHER THE CHILD IS IN

THE MIST OF ACTIVE REGRESSION OR

IN THE POST REGRESSIVE STAGE SO

THAT THE AMPLITUDE IS SMALLEST

IN THE GIRLS WHO ARE POST

REGRESSION AND THEN A LITTLE BIT

BIGGER IN THE GIRLS IN THE MIST

OF ACTIVE REGRESSION.

THEN ON FAR RIGHT, N2 TIME

DOESN'T DISTINGUISH REGRESSION

VERSUS POST REGRESSION.

SO, AGAIN, AS I SHOWED IN THE

PREVIOUS SLIDE, THE N2 TIME IS

PROLONGED IN THE GIRLS WITH RETT

BUT IT'S NO DIFFERENT IN ACTIVE

VERSUS POST REGRESSION.

ONLY THE P1 DISTINGUISHES THE

REGRESSION STAGE.

NEXT SLIDE, PLEASE.

SO NOW THIS SLIDE IS THE VEP

SENSITIVE TO CLINICAL SEVERITY.

ON THE LEFT ARE THE VARIOUS

DIMENSIONS INTO WHICH WE COMPUTE

A CLINICAL SEVERITY SCORE DONE

BY WALTER'S GROUP.

AND ON THE RIGHT, IF YOU CAN PUT

ALL OF THESE UP NOW, YOU CAN SEE

THAT FOR THE P1, THE CHILDREN IN

THE MIST WHO HAVE OR WHO ARE

SCORED LOWER IN CLINICAL

SEVERITY, HAVE A HIGHER P1

AMPLITUDE THAN THE GIRLS IN THE

HIGH SEVERITY GROUP.

SO THE P1 AMPLITUDE IS INDEX OF

CLINICAL SEVERITY DURING

POST-REGRESSION STAGE BUT NO

DIFFERENCES IN N2 TIME.

SO, FIRST WE DISTINGUISHED THOSE

IN ACTIVE VERSUS POST REGRESSION

AGE AND NOW WE ARE SHOWING THAT

IN THE GIRLS WHO WERE POST

REGRESSION THOSE IN HIGH

CLINICAL SEVERITY HAVE A SMALLER

P1 AMPLITUDE THAN THOSE IN LOW

CLINICAL SEVERITY.

THE NEXT ATTEMPT TO LOOK TO SORT

THE DATA IN THE NEXT SLIDE IS,

WE SORT BY MUTATION TYPE.

NEW YOU'LL NOTICE THAT SAMPLE

SIZES ARE VERY SMALL HERE.

TOP LEFT IS MILD.

GENES ARE GOING TO THE MILD

MUTATION VERSUS SEVERE MUTATION

AND WE BALANCE OUT IN TERMS OF

OVERALL SAMPLE SIZE BUT THERE IS

N1 OR N3 IN EACH GROUPS.

IF YOU GO TO THE BOTTOM, YOU SEE

FOR THE P1 NOW, THERE IS NO

DIFFERENCE IN THE P1 FOR THE

MILD VERSUS SEVERE MUTATION

TYPE.

AGAIN BOTH ARE SMALLER OF COURSE

IN THE CONTROLS.

BUT NOW N2 LACANCY DIFFERS SO

THE GIRLS WITH THE MORE SEVERE

MUTATION HAVE THE LONGEST N2

LATENCY.

IN FACT, THE N2 LATENCE WITH THE

GIRLS WITH MILD ISN'T DIFFERENT

FROM CONTROLS WHERE P1 IS

DIFFERENT.

SO THE NEXT THING WE TURN OUR

ATTENTION TO -- I APOLOGIZE FOR

COUGHING.

IS THE EXTENT TO COME WHICH WE

CAN USE DEP TO MEASURE SPACIAL

RESOLUTION OR VISUAL ACUITY.

IF YOU PUT UP THE WHOLE SLIDE,

ON THE LOWER LEFT YOU'LL SEE

BLACK AND WHITE CHECKS OF LOW

SPACIAL FREQUENCY WITH THE CHECK

PATTERN IS KIND OF COURSE AND ON

THE RIGHT YOU'LL SEE HIGHER

SPACIAL FREQUENCY AND ON THE TOP

LEFT YOU'LL SEE GENERALLY THE

FUNCTION THAT WE OBSERVED AT THE

AMPLITUDE OF THE P1 DECLINES AS

A FUNCTION OF SPACIAL FREQUENCY.

SO THE HIGHER SPACIAL FREQUENCY,

THE SMALLER THE P1.

AND IT BASICALLY IS ARGUING THE

SLIDES START TO BECOME A GRAY

FIELD, AND YOU NO LONGER SEE IT,

THEN THE P1 DISAPPEARS.

SO GO TO THE NEXT SLIDE.

WE TESTED ACUTEY IN THE RETT

PATIENTS USING DE.

AND LOWER CONTRAST STIMULI TO

AVOID EYESTRAIN.

AND IF YOU AT ADVANCE SLIDES.

I CAN'T SEE WHAT IS GOING ON.

WE HAVE ON THE BEGINNING IS A

CHECK PATTERN THAT IS BASICALLY

3X4.

THOSE WHO WEAR GLASSES AND ARE

SITTING EVEN CLOSE TO THE SCREEN

AS YOU GO ALONG, YOU'LL NOTICE

THAT YOU TAKE YOUR GLASSES OFF,

IT GETS HARDER AND HARD TORE SEE

THIS CHECK PATTERN.

SO IF YOU PUT UP ALL THE SLIDES,

YOU NOTICE AS YOU GO FROM LEFT

TO RIGHT, IT'S HARDER AND HARDER

TO RESOLVE THIS.

IF YOU HAVE 2020 VISION YOU CAN

PROBABLY MOVE OVER CLOSER TO THE

RIGHT SIDE BUT IF YOUR VISION IS

20100 OR 20200, YOU MAY ONLY GET

THROUGH THE TOP ROW AND THEN GO

THROUGH ALL THE NEXT SERIES OF

SLIDES AND YOU CAN SEE THE

PROGRESSION.

FOR SOME OF YOU THE SCREEN IS A

GRAY FIELD.

WHAT CAN YOU SEE HERE IS MOVING

FROM THE TOP LEFT TO THE TOP

RIGHT THE DEP FOR THE TWO GROUPS

OF GIRLS CONTROLS AND THOSE

GIRLS WITH RETT.

DIFFERENT SPACIAL FREQUENCIES

WHAT CAN YOU SEE IS THAT WHEN

IT'S.3 CYCLES OF DEGREE, IT IS

VIRTUALLY IDENTICAL.

YOU'LL NOTICE THE MINUTE YOU

MOVE TO .7 THE GIRLS WITH RETT

PLUMMET AND YOU CAN SEE THAT IN

THE GRAPH IN THE LOWER PART OF

THE SCREEN WHEREAS THE GIRLS

WITH THE CONTROL GIRLS TYPICALLY

DEVELOPING GIRLS SHOW A BIG P1

UP UNTIL PAST 1 1/2 OR SO

SECONDS PER DEGREE AND IT'S

STILL PRESENT AT 2 .7 CYCLES.

THE GIRLS WITH RETT FOLLOW-UP

DRAMATICALLY BEFORE ONE CYCLE

PER DEGREE.

SO THIS IS A WAY TO LOOK AT

VISUAL ACUITY IN THE GIRLS.

SO, THE LAB FOUND THAT THE

KNOCK-OUT MICE PROVES VEP ACUITY

AND INSPIRED US TO LOOK TAT IN

THE GIRLS AND WE IDENTIFIED

QUANTIFIABLE ALTERATIONS IN THE

WAVE FORMS AND THESE ALTERATIONS

WERE DIFFERENTIALLY IN PACTED BY

DISEASE STAGE AND MUTATION TYPE

INDICATING THE VEP CAN BE USED

AS A BIOMARKER AND WE IDENTIFIED

THE FUNCTIONAL IMPACT ON SPACIAL

RESOLUTION IN THESE GIRLS THAT

LOOKS A LOT LIKE THE MICE AND IN

OUR PAPER WE PUBLISHED RECENTLY,

THE MOUSE DATA LOOKED SIMILAR TO

THE HUMAN DATA SO IN SUMMARY:  

[ READING ]

...

AND AGAIN, BECAUSE IT MATURES SO

EARLY IN LIFE IT CAN BE USED IN

CLINICAL TRIALS AND EXTEND OVER

A LONG PERIOD OF TIME.

NOW GO TO GAPS OF KNOWLEDGE AND

RETT SYNDROME.

I'M GOING TO TURN MY ATTENTION

TO COGNITIVE FUNCTION GENERALLY.

AND THE CONTEXT WAS THAT WE FELT

WE WERE NOT GETTING AN ACCURATE

READING ON THE GIRL'S COGNITIVE

FUNCTION BECAUSE OF THEIR LACK

OF SPEECH AND LANGUAGE, THEIR

LACK OF COORDINATED HAND

MOVEMENTS.

IT WAS VERY HARD TO ADMINISTER A

STANDARDIZED TEST.

SO WE STARTED TO MODIFY AND

ADAPT THE MULLINS SCALES FIRST

BEHAVIORALLY WHERE WE TOOK SOME

SHORTCUTS IN HOW WE ADMINISTERED

IT BUT WHAT I WANT TO FOCUS ON

IS HOW WE ADAPTED TO ASPECTS OF

IT FOR EYE TRACKING.

GOING TO PART II COGNITIVE

FUNCTIONING.

AND THIS BASICALLY SAYS WHAT I

JUST SAID.

SO THE GOAL TO ASSESS COGNITIVE

SKILLS MINIMIZING COM POINTS

FROM FINE SHORT EXPRESSIVE

LANGUAGE DEFICITS.

AND SO, I'M GOING REPORT 36

GIRLS AVERAGE AGE.

SO IF YOU GO TO MULLEN SCALE OF

EARLY MORNING.

FOR THOSE NOT FAMILIAR WITH THE

DIMENSIONS THERE ARE 5 DOMAINS

OF SCALES

[ READING ]

SOME KNOW THAT EYE TRACKERS ARE

HELPING GIRLS MUNICIPAL KATE

WITH THEM.

SO WE TOOK ADVANTAGE OF THAT WE

TRANSLATED VISUAL RECEPTION AND

ASPECTS OF THE RECEPTIVE

LANGUAGE ON POWERPOINTS.

I'M GOING TO REPORT EYE TRACKING

DATA ON GIRLS.

THE NEXT IMAGE SHOULD BE A

MOVIE.

NOTICE THE GIRL LOOKS LIKE HER

ATTENTION IS WANDERINGERING AND
HARD

TO FIGURE OUT WHAT IS BEING

ASKED IN THIS PARTICULAR ASPECT

OF THE TASK.

SHE IS BEING ASKED WHICH

MATCHES.

AND IF YOU BASED IT ON -- SHE IS

SUPPOSED TO BE REACHING FOR

THIS.

AND BASED ON HER REACHING OF

COURSE, THIS IS VERY AMBIGUOUS,

IT'S HARD TO KNOW.

AND SO, LET'S THREAT RUN A

LITTLE BIT MORE.

SO NOW THE SCREEN IS BACK.

HERE IS A CLEAR EXAMPLE FROM THE

SAME MATCHING TASK.

SO, NOW WE ADAPTED IT.

A LITTLE BIT.

AND SHE HAS TO MATCH OR

BASICALLY POINT TO THE KEY,

WHICH IS MATCHING WHAT THE STAFF

PERSON IS HOLDING.

NOW SHE'S LOOKING AT IT AND NOW

WE'LL MOVE TO THE EYE TRACKER.

SO WHAT YOU'RE GOING TO SEE NOW

IS HER GAZE PATTERNS WHERE SHE

HAS TO MATCH AND NOW THERE IS A

SAMPLE.

NOTICE WHAT SEE DOES.

SO WITH HER GAZE, NOW SHE --

IT'S VERY CLEAR SHE IS MATCHING

THE FAMILIAR STIMULUS WITH THE

SAMPLE ON THE TOP.

WHEREAS IT WAS MUCH MORE

AMBIGUOUS WHEN BASED ON HAND

MOVEMENTS.

SO GO TO THE NEXT SLIDE.

SO, IF YOU PUT THE WHOLE SLIDE

UP, IT SAYS ADAPTIVE VERSUS HIGH

TRACKING.

IF YOU LOOK ON THE LEFT, WHERE

IT SAYS MATCHING OBJECTS, YOU'LL

SEE THE TIME IT TAKES TO

ADMINISTER THIS PARTICULAR ITEM

IS MUCH LESS IN THE EYE TRACKING

VERSION AND ON THE RIGHT, WE ARE

SHOWING THE SCORES FOR THIS ITEM

ARE IDENTICAL IN THE EYE

TRACKING VERSUS ADAPTED VERSION.

THERE ARE ALL KINDS OF

COMPLEXITIES IN VALIDATING THIS

MEASURE.

THIS IS STILL VERY EARLY DAYS

FOR US BUT I THINK IT IS

ENCOURAGING THAT WE CAN USE EYE

POSITIONING AND EYE GAZE AS A

SUBSTITUTE FOR HAND MOVEMENTS IN

ORAL AND LANGUAGE TO LOOK AT

THIS THIS WILL IMPACT PARENTS

HOW THEY CAN COMMUNE WAIT WITH

THEIR CHILD AND THE EYE GAZE

REPRESENTS IMPORTANT AVENUE FOR

COGNITIVE ASSESSMENT IN RETT AND

OTHER DISORDERS WITH FINE MOTOR

LANGUAGE LIMITATIONS.

THE LAST SLIDE IS THE DVEP

REFLECT COGNITIVE FUNCTION?

WE ARE LOOKING AT REGRESSION

PLOTTING VEP AMPLITUDE AGAINST

VISUAL RECEPTION.

AND YOU CAN SEE THAT A STRONG

POSITIVE CORRELATION.

THAT AS THE GIRLS WITH THE

HARMEST P1 AMPLITUDE ARE THE

GIRLS WITH THE BEST SCORES IN

THE VISUAL RECEPTION.

AND TO SUM UP:

[ READING ]

A COUPLE OF THINGS WE FROM IN

OUR FUTURE IS TO COMPLETE THE

EYE TRACKING VERSION FEDERAL

RECEPTIVE LANGUAGE.

TO CONTINUE TO FURTHER ADAPT

ITEMS FOR THE RETT, TO

INCORPORATE THE DE.

AND EYE TRACKING INTO OUR

CLINICAL TRIAL WORK AND THEN TO

FURTHER GROUND THE VEP WORK INTO

ANIMAL MODELS WHICH IS VERY

IMPORTANT.

SO ON THAT NOTE I'LL END AND I

CAN'T HEAR ANYTHING BUT IF YOU

HAVE ANY QUESTIONS, PLEASE FEEL

FREE TO ASK.

THANK YOU.

>> ANN WAGNER:  YOU'RE HEARING

CLAPPING.

A LOT OF CLAPPING, CHUCK.

THANK YOU VERY MUCH.

AND THANK YOU FOR JOINING US

VIRTUALLY.

I THINK IT WAS REALLY GREAT TO

GET THIS CLINICAL PRESENTATION

IN WITH THE OTHERS.

SO --

>> CHUCK WE HAVE A LITTLE

DISCUSSANT THE CHAIR WILL

PRESENT SOMETHING.

ARE YOU GOING TO BE ABLE TO HANG

AROUND?

>> YES.

>> CAN WE'LL ASK QUESTIONS NOW.

>> WE WILL HAVE ELLIOT CHAIR.

HE WILL GIVE A VERY BRIEF

PRESENTATION BUT HE IS GOING TO

LEAD OR MAKE COMMENTS FOR TO GET

THE DISCUSSION GOING.

>> ELLIOTT SHERR:  THANK YOU TO

THE ORGANIZERS FOR INCLUDING

THIS IN THE SESSION.

SO JUST WANT TO SAY I THINK THE

WORK THAT HAS BEEN GOING ON WITH

MEC P2 AND RETT SYNDROME IS

REALLY EXCELLENT.

ONE THING TO POINT OUT, WHICH IS

BOTH THE CLINICAL RICHNESS OF

MEC P2 AND ALSO POTENTIALLY ITS

COMPLEXITY, IS THE FACT THAT IT

IS A CHROMATIN REMODELING GENE

AND SO, MANY DOZENS OR HUNDREDS

OR MAYBE EVEN THOUSANDS OF GENES

ARE DIFFERENTIALLY REGULATED BY

MEC P2'S ABSENCE OR DYSFUNCTION.

AND SO THAT MAKES IT BOTH

INTERESTING BUT CHALLENGING TO

THINK OF APPROACHING FROM A

MECHANISTIC POINT OF VIEW.

AND SO WHAT I WANT TO DO IS JUST

SHOW AN EXAMPLE WHERE IT IS A

SINGLE GENE THAT MAY BE ALSO HAS

TROPEIC AFFECTS BUT MAY ALSO

SERVE AS A WAY TO GENERALLY

THINK ABOUT PROGRESSION.

SO, THIS IS A PATIENT THAT I

TOOK CARE OF MANY YEARS AGO LONG

BEFORE WHOLE EXOME SEQUENCING

WAS AVAILABLE.

AND HE HAD A LOT OF DIFFERENT

DIAGNOSIS THEY WON'T GO INTO BUT

THE IMPORTANT POINTS HERE IS

THAT EARLY ON, HE HAD EVIDENCE

OF DEVELOPMENTAL DELAY.

SO AT 16 MONTHS, HE HAD A

BAILIES THAT HE WAS AT

APPROXIMATELY AN EIGHT MONTH

DEVELOPMENTAL LEVEL.

BUT BY 3 1/2 YEARS WAS WALKING

AND HAD 2-3 WORD SENTENCES.

SO, IN THAT INTERVAL FROM 16

MONTHS TO 3 1/2 YEARS, HE MADE

DEVELOPMENTAL PROGRESS ALTHOUGH

HE WAS ALWAYS BEHIND HIS

TYPICALLY DEVELOPING PEERS.

BUT THEN, AT ABOUT 4 YEARS OF

AGE, HE STOPPED WALKING,

COMPLETELY, AND ALL SPEECH

SEIZED.

SO QUITE ABRUPTLY.

AN MRI AT THAT TIME SHOWED

WORSENING CEREBRAL AND CEREBELLA

ATROPHY.

SUGGESTING HE HAD BOTH CLINICAL

SIGNS OF CLEAR REGRESSION AND

ALSO SOMETHING GOING ON WITH

BRAIN FUNCTION THAT WAS LEADING

TO ATROPHY.

AND AGAIN, THE OTHER THING TO

POINT OUT THAT WE HAVE BEEN

TALKING ABOUT, MEC P2 IS ALSO

ASSOCIATED WITH WHAT WE REFER TO

AS ACQUIRED MY CROW SELFIE.

SO FREQUENTLY BABIES WITH MEC P2

ARE BORN WITH NORMAL HEAD

SURCOMPANY FRANCES IN THIS CASE,

THERE IS MICROSELFY AND NORMAL

HEAD SIZE.

AND THEN I TOLD YOU WHAT THE

PUNCH LINE WAS AT THE BEGINNING.

THAT ALL OF THESE INDIVIDUALS

HAVE MUTATIONS IN THE GENE.

RIGHT HERE IS ANOTHER PATIENT

WHO ALSO HAS A MUTATION.

SO ONE OF THE THINGS THAT IS

INTERESTING ABOUT THIS IS THAT

IT'S THE SAME MUTATION BUT THE

KEY PIECE IS THAT THOSE

MUTATIONS ARE BOTH DENOVO.

SO, THEY ARE OCCURRING

APPROXIMATELY -- IF YOU LOOKED

AT ANY ONE AND WILL LOOKED AT

THEIR MOM AND DAD, ON AVERAGE,

ALL OF US WOULD HAVE

APPROXIMATELY ONE NUCLEOTIDE

THAT IS DENOVO SWITCHED FROM OUR

PARENTS PER GENERATION IN THE

EXOME.

THANK YOUFULLY FOR MOST OF US,

THAT MUTATION IS NOT PROFOUNDLY

DELETERIOUS.

BUT FOR SOME IT CLEARLY IS.

AND THERE ARE CLEARLY ARE

HOTSPOTS.

SO THIS CONCEPT OF HAVING

REPETITIVE MUTATIONS IS

SOMETHING WE ARE SEEING A LOT OF

WHEN LOOKING AT EXOME SEQUENCING

FOR DEVELOPMENTAL DISORDERS.

SO NOT ONLY DO THESE FOLKS HAVE

A RECURRENT MUTATION, YOU CAN

SEE ALSO HERE THAT THIS ARGININE

216 IS IT ALSO SENSITIVE AS YOU

HAVE ANOTHER ONE INSTEAD OF

CYSTEIN YOU HAVE A HITTA DEAN

MUTATION.

SO THE LOW SIDE COULD BE QUITE

SENSITIVE.

ALL INDIVIDUALS HAD SIGNIFICANT

GLOBAL DEVELOPMENTAL DELAY.

ONE PATIENT DIED FROM PNEUMONIA

AND ALL OF THEM HAD EVENTUAL

ACTUAL REGRESSION AS WE SHOWED

DOWN HERE AND MANY OF THEM HAD

OTHER FEATURES INCLUDING

SEIZURES.

AND AS I SUGGESTED ON OUR

PATIENT, THERE WAS ACTUAL

EVIDENCE OF VOLUME LOSS.

AND SO, THIS IS PATIENT NUMBER 1

AT NINE MONTHS AND IF YOU LOOK

HERE, THIS IS -- THESE ARE MID

LINE IMAGES.

THIS IS THE CEREBELLUM AND

ALREADY I CAN TELL YOU THAT TO

MY EYES AND TO PEOPLE WHO LOOK

AT THIS ALL THE TIME, THAT'S A

LITTLE BIT SMALL.

BUT YOU CAN SEE QUITE CLEARLY BY

APPROXIMATELY A YEAR AND A HALF,

THAT THERE IS MUCH MORE

SIGNIFICANT LOSS OF THE

CEREBELLUM VERMIS.

AND IF YOU LOOK AGAIN ON A

PATIENT NUMBER 2, AGAIN AT 10

MONTHS, YOU CAN SEE A RELATIVELY

NORMAL CEREBELLUM VERMIS, BY

ALMOST TWO YEARS, FURTHER

REGRESSION AND THEN BY 5, THE

CEREBELLUM VERMISIS COMPLETELY

ALMOST -- AND THEN DOWN HERE

THAT SAME INDIVIDUAL YOU CAN SEE

HERE LOOKING AT THE

CEREBELLUM -- SORRY, AT THE

CEREBRUM, THAT THE LATERAL VENT

CALLS ARE PROBABLY A LITTLE BIT

ENLARGED FOR THAT PATIENT BUT

THEN IF YOU LOOK OVER TIME THERE

IS INCREASED SIZE OF THE LATERAL

VENT CALLS.

AND THIS IS A SCHEMATIC OF THE

CUFF 1A.

AND IT IS ONE OF THE MOTORS ON

MICROTUBIALS SO INVOLVED

PARTICULARLY KIF1A IS INVOLVED

IN TRANSLOCATING SYNAPTIC

VESICLES AND OTHER STRUCTURES

FROM THE CELL BODY ALL THE WAY

DOWN THE EXON.

SO, IN THE MOST EXTREME CASES,

WHERE YOU HAVE A MOTOR NEURON

THAT IS HAVING CELL BODY IN THE

SPINAL CORD AND THEN THE ONE

THAT MOVES YOUR BIG TOW FOR

EXAMPLE, THEN THAT IS A MOTOR

NEURON THAT IS MANY FEET LONG.

SO A SINGLE EXON HAS TO

TRANSLOCATE VESICLES THAT

DISTANCE AND YOU CAN SEE WHY

SOMEBODY MIGHT HAVE PHYSICAL

DEFICITS ALONG WITH COGNITIVE

DEFICITS WHEN THAT IS

DYSFUNCTIONAL.

BUT THESE MUTATIONS, THERE WAS A

PRIOR DISORDER, AUTOSOMAL

RECESSIVE DISORDER ASSOCIATED

WITH SPASTIC PARALYSIS AND

PERIPHERAL NEUROPATHY AND THOSE

INDIVIDUALS ARE IN BLUE.

BUT THE ONES IN BLACK ARE

INTELLECTUAL DISABILITY.

AND SO YOU CAN SEE THESE CHANGES

HERE, ALANIN TO VEILINE AND THEN

SOME OF THESE OTHERS AS WELL AND

SO THE QUESTION IS, CAN YOU

DISTINGUISH BETWEEN THEM?

SO, ONE WAY TO DISTINGUISH

BETWEEN THEM IS TO

COMPUTATIONALLY PREDICT WHERE

THE MUTATIONS OCCUR.

AND THIS IS A 3D STRUCTURE OF

THE KINASE IN MOTOR DOMAIN.

AND AND YOU CAN SEE RIGHT HERE,

THIS IS WHERE THE ATP BINDING

POCKET IS AND THIS CHEMICAL

STRUCTURE HERE IS THE ACTUAL ATP

THAT IS BINDING.

AND THEN, HERE IS THE THREE

A1999 THAT -- THE 3 A1999, THE

CURRENT MUTATION.

AND WE GENERATED AN ASSAY THAT

LOOKS AT THESE MUTATIONS BY

MAKING MUTATIONS IN THE KINASE

IN PROTEIN.

AND AND HERE IS A POLYMORPHISM

SO SOMETHING JUST IN THE GENERAL

POPULATION AND YOU CAN SEE THAT

IS ALSO MOVING.

BUT INTERESTINGLY RECESSIVE

MUTATION ALSO DOESN'T SEEM TO

IMPAIR MICROTUBIAL MOTILITY.

NOW, IF YOU LOOK HERE, I HAVE

SELECTED THREE DIFFERENT DE NOVO

DOMINANT MUTATIONS OR WHAT WE

THINK ARE DOMINANT MUTATIONS,

AND THIS IS THE 3 A19 TO METHIGH

19 POSITION 99.

AND THERE IS ALMOST NO MOVEMENT

AT ALL.

SO THERE IS ESSENTIALLY NO

MOVEMENT OF THE MICROTUBULES AND

I'LL SKIP THAT.

AND THESE ARE THE INDIVIDUALS

WHO DID THAT WORK.

AND QUICKLY, IN SUMMARY, THIS IS

ANOTHER EXAMPLE OF A TRUE

REGRESSIVE DISORDER WHERE IN

THIS CASE, WE CAN ACTUALLY

PREDICT THE REGRESSION BASED ON

THE SITE OF THE MUTATION AND

IMPACT ON PROTEIN FUNCTION.

>> I THINK I'D LIKE TO GO BACK

TO MY GENERAL QUESTIONS I POSED

AT THE BEGINNING, WHICH ARE

NUMBER 1, WHAT ARE WAYS -- WHAT

CAN WE LEARN POTENTIALLY LEARN

FROM RETT SYNDROME THAT MIGHT

GIVE US SOME INSIGHT INTO

REGRESSION IN GENERAL?

IN AUTISM?

TWO, HOW CAN WE INTEGRATE

BETWEEN THESE DIFFERENT LEVELS

OF UNDERSTANDING?

THESE DIFFERENT SCALES BETWEEN A

CELLULAR CIRCUIT LEVEL AND THE

HUMAN?

AND SELLE AND AGAIN THIS IS

PROBABLY A BIGGER THING WE WILL

DISCUSS.

WE TALKED ABOUT IT AMONG THE

PLANNING OF CONCEPTS OF BRIDGING

FUNCTIONS OR THINGS THAT WOULD

HELP US MOVE FROM THE DIFFERENT

LEVELS OF SCALE.

SO THAT IS WHAT I'M PUTTING

FORTH AGAIN AS THINGS I'D LIKE

TO HEAR PEOPLE'S THOUGHTS AND

THEN AGAIN, THE OTHER WAS, IF WE

HAVE IDEAS FROM SOME OF THE WORK

THAT WAS PRESENTED, IN TERMS OF

THINGS WE DIDN'T REALLY KNOW,

VISUAL ACUITY OR VISUAL PROBLEMS

IN RETT SYNDROME WE DIDN'T HAVE

AN IDEA ABOUT THAT UNTIL THE

WORK THAT CHUCK PRESENTED.

AND THEN IDEAS OF IF WE SAY

THERE IS A PAR VAL BU MIN

ABNORMALITY FROM THE MOUSE WORK,

HOW CAN WE GENERALIZE THAT INTO

OTHER SYSTEM?

I'D LIKE TO HEAR OTHER IDEAS.

>> SO THE PERINEURAL NETS ARE

ACTUALLY COMPOSED OF BOTH

NEURONAL AND ASTROCYTIC

COMPONENTS.

HAVE YOU LOOKED AT EITHER IN THE

MINIBRAINS WHAT THE ASTROCYTES

ARE LOOKING LIKE IN THERE, OR IN

THE INTACT BRAINS WHAT IS OR WHO

IS MAKING OR CONTRIBUTING TO

THAT?

>> KEERTHI KRISHNAN YES, THAT'S

A GREAT QUESTION.

THEY ARE COMPOSED OF 40 OR SO

PROTEINS BEING SECRETED BY

MULTIPLE CELL TYPES AND THEN

FORM THESE STRUCTURES.

I HAVEN'T LOOKED AT THESE

PERSONALLY BUT GAIL LOOKED TAT A

LOT AND SHOWN THAT

SO IN THE INTACT BRAIN I WOULD

SAY THERE SEEMS TO BE A SORT OF

BALANCE ISSUE THAT'S GOING ON.

>> THANK YOU FOR THOSE REALLY

FASCINATING TALKS.

ALL OF THEM.

AND I THINK IT'S REALLY

INTERESTING TO CONSIDER ALL OF

THIS STUFF GLOBALLY AND

ESPECIALLY TALKING ABOUT THE

CRITICAL PERIODS AND HOW THAT

MIGHT RELATE TO REGRESSION AND

WHAT IS GOING ON THERE.

AND THERE ARE SO MANY THINGS

HAPPENING THAT ARE COMPLICATED.

WHAT ALYSSON WAS SAYING ABOUT

DECREASING KCC2, YOU WERE SAYING

INCREASE IN GABAERGIC ACTIVITY,

WHICH THOSE TWO THINGS ARE

NOT -- YOU DON'T USUALLY THINK

OF THEM AS GOING ON TOGETHER.

AND THAT MAY ALSO BE

SOMETHING -- BUT MAY HAVE TO DO

WITH THE TIMING.

IT MAY -- THAT MAY BE REALLY

IMPORTANT COMPONENT HERE.

>> SO YES, THAT IS ONE OF THE

KEY THINGS I DOESN'T HAVE A

CHANCE TO GO INTO IT BUT OUR

WORK WAS PUBLISHED AND IT'S

SOMETHING WE SEE.

THE CONNECTIVITY BETWEEN THE PBP

B-CELLS VERSUS PB PARAMEATAL

CELLS.

SO WE LOOK AT EARLIER ON, WE

DON'T SEE A DIFFERENCE IN THE

PARAMEATAL NEURONS BUT WE DO

LATER ON.

SO, IN OUR CASE WITH THE NULL

ANIMALS, WE ARE SEEING THE

PHENOTYPE EMERGE EARL EARL IN

THE MEC P2 CELLS AND THEN THAT

AFFECTS THE PARAMEATAL CELLS AND

WE ARE SEEING THE PHENOTYPE IN

THEM.

>> AND MAYBE AT THAT POINT, THE

KCC2 IS NOT CHANGED YET?

WHY YOU LOOKED AT DIFFERENT

TIMES WITH THE KCC2?

>> NO.

BUT WE DO THINK ABOUT THOSE

ISSUES AND ONE THING THAT WE

WANT TO KNOW IS, PROVIDE THE

HUMAN NEURONS WITH ENVIRONMENT

WHERE WE CAN KEEP THAT FOR

LONGER PERIOD OF TIME AND

PERHAPS USE SOME KIND OF

EXPERIENCE DEPENDENT ASSAYS TO

PROBE HOW THESE HUMAN NEURONS

BEHAVE AND OUR WAY OF DOING THAT

ASS FOR NOW IS TO GENERATE CAME

ERIC BRAINS IN THE MOUSE BRAIN

AND WE HAVE -- CHIMERIC -- AND

WE HAVE A NORMAL ANIMAL.

THE POSTDOC ISET GOING GOOD AT

PLACING NEURONS IN THE RIGHT

PLACE.

ONE OF THE PLACES WE WANTS TO

PUT IS IN THE INDIVIDUAL CORTEX.

WE HAVE BEEN OR SHOW SUCCESS ON

THE WHISKERS VERSION AS WELL SO

WE CAN MANIPULATE WISSERS AND

SEE HOW THEY DO ON THE HUMAN

NEAR ON RESPONDED SO BE ABLE TO

TRANSPLANT CONTROLS AND RAT

SYNDROMES IN THE SAME BRAIN, WE

MAY BE ABLE TO ANSWER THOSE

QUESTIONS AND WE CAN KEEP UP TO

THE LIFE OF THE ANIMAL.

>> I THINK YOUR POINT REGARDING

THE DIFFERENCE BETWEEN MAYBE A

ACCELERATED DEVELOPMENT OF PV

NEURON AND WHICH WOULD SUGGEST

OVERACTIVE GABAERGIC AND MAYBE

THIS BEING UNDERACTIVE, IS VERY

IMPORTANT AND I THINK THAT SOME

OF THE WORK -- COMES BACK TO THE

QUESTION I WAS THINKING ABOUT

WHEN ALYSSON WAS PRESENTING.

IT THOS DO WITH AUTONOMOUS

VERSUS NONAUTONOMOUS AFFECT AND

ESPECIALLY IN A BRAIN IN THE

DISEASE STATE WHERE THEY ARE

MOSAIC.

IT'S A SINGLE LOSS OF COPY

FUNCTION AND BECAUSE OF X

CHROMOSOME ACTIVATION IN THE

BRAIN, IT'S A MIXTURE OF GOOD

CELLS AND BAD CELLS.

SO SOMETHING THAT DISTRIBUTED

ASPECT OF THE ABNORMALITY.

SECOND OF ALL, USING THE MOUSE

MODELS TO DO GENETICS AND

CONDITIONAL KNOCKOUTS AND

REMOVING IT FROM ALL GABAERGIC

NEURONS, IT REPRODUCED MANY OF

THE PHENOTYPES.

THEY DIDN'T DO THESE SPECIFIC

ASSAYS BUT OF COURSE THE

GABAERGIC NEURONS ARE

MULTI-FORM.

OF COURSE YOU KNOW THIS FROM

JOSH JUAN'S LAB.

BUT I MEAN, PARAVAL BU MIN ARE

THE ONES THAT ARE SNAPSING ON TO

THE SOMA PERISYSTEMATIC VERSUS

THE STAT IN ONES IN THE

PERIPHERY.

SO THERE MAY BE DIFFERENT ROLES

AND DIFFERENT MATURATIONS.

WE MAY HAVE THE PARVALBUMIN

RETURNING TOO SOON AND OVER

ACTIVE BUT THE METASNATINS

UNDERACTIVE FOR VARIOUS REASONS

N YOUR CULTURE SYSTEM YOU'RE NOT

DIFFERENTIATING THAT WELL OF THE

DIFFERENT CELL TYPES.

I THOUGHT OF ONE THING TOO

DURING ALYSSON'S TALK REGARDING

NOT REALLY SEEING PRUNING IN THE

DISH.

AND IS THAT POTENTIALLY A

FUNCTION OF NOT MAYBE HAVING A

TRUE TRIARCHS PARDON TIGHT OR

TETRAPAR TIED IN THE MIKE

REGLEIA THAT YOU WON'T SEE IN A

DISH REALLY EFFECTIVE PRUNING

BECAUSE YOU DON'T HAVE MAY BE

THE WHOLE MACHINERY INVOLVED

IN -- MAYBE A MATURATION ISSUE

TOO.

THIS IS JUST MAYBE A QUESTION.

>> YOU'RE RIGHT.

AND WE ARE MAKING EFFORTS ON

GENERATING CELLS TO MAKE THIS IN

A DISH.

AND THERE ARE ASSAY THAT IS WE

CAN DO WITH OR INDUCING CULTURE

AND SEE WHAT WE HAVE NOW.

IT'S MACROPHAGES BUT LET'S

SUPPOSE ONE DAY WE GET MICROGLIA

AND WE CAN ASSAY.

I DO THINK IT IS POSSIBLE.

YES.

I THINK WE CAN DO IT.

>> SO I DON'T KNOW WHETHER YOU

GUYS ARE SPECIFICALLY WORKING ON

IT.

BUT SINCE THERE IS ALSO THE MEC

P2 DUPLICATION BEING A

SIGNIFICANT MODEL DURING

DEVELOPMENTAL DISORDERS, WHETHER

YOU SEE SIMILAR CHANGES WHETHER

YOU SEE A RECIPROCAL CHANGE IF

THAT IS MEASURABLE.

AND HOW YOU THINK THAT FITS IN

WITH THE SORT OF CIRCUIT PLANS?

>> EVERYTHING THAT I SHOW YOU

FOR THE KNOCKOUTY WITH SEE

OPPOSITE IN THE DUPLICATION

SYNDROME.

SO THIS IS A GREAT MODEL AND IT

SHOWS LIKE HOW IMPORTANT THOSE

ARE IN NEURONS.

>> AND SIMILARLY, ELLIOT,

BESIDES THE SYNAPTIC WHERE YOU

HAVE LOW SYNAPSES AND RETT MEC

P.2 NULLS AND MANY, YOU SEE A MY

TONIC RELATIONSHIP WITH mTOR

WHERE YOU HAVE LESS MEC P2 AND

TOO MUCH MEC P2 AND TOO MUCH

MTOR.

SO IT MAY BE THIS GOES BACK TO

WHAT WE WERE DISCUSSING

PREVIOUSLY IN REMEMBERS IT OF

SUBGROUPING MOLECULAR

SUBGROUPING OF AUTISM OF SOME

ALONG -- THAT'S A VERY SIMPLE

PLISTIC THING ON THE mTOR BUT

AN IDEA ARE THEIR VEP CLINICAL

ANALYSIS IN THE DUPLICATION?

>> IN THE DUPLICATION YOU SAID?

I MISSED THAT LAST PART.

VEP ANALYSIS IN WHAT?

>> WE WERE TALKING ABOUT WHAT

WAS MENTIONED WAS THAT AT LEAST

AT THE CELLULAR LEVEL THERE ARE

OPPOSITE PHENOTYPES IN THE RETT

GIRLS AND THE DUPLICATION BOYS.

SO CLINICALLY, WHEN YOU LOOK --

HAVE YOU LOOKED AT VEP IN MEC P2

DUPLICATION PATIENTS?

>> NO.

WE HAVEN'T.

>> BUT PETERS AT VANDERBILT HAS

LOOKED AT AEPs, AUDITORY

POTENTIALS IN BOTH.

THEY ARE BOTH DISRUPTED AND I

THINK IT IS DIFFICULT SOMETIMES

TO DO SHE SPENT MORE TIME

LOOKING AT THE DUPLICATION BOYS

ACTUALLY.

>> CHARLES NELSON IT'S OFF THE

ASSEMBLE OF RETT BUT WE HAVE

DONE THAT IN 16P BUT WE LOOKED

AT THE DUPES VERSUS DELETIONS

AND THEY ARE QUITE DIFFERENT AS

YOU EXPECTS.

THE DUPES ARE MUCH MORE SIMILAR

TO TYPICALLY DEVELOPING GIRLS OR

CHILDREN OTHER THAN THE

DELETIONS ARE.

>> BUT CHUCK, THAT MIGHT BE JUST

BECAUSE THE DUPES ARE MILDER.

>> CHARLES NELSON:  EXACTLY.

THAT'S WHAT MAKES IT SO HARD TO

INTERPRET.

>> SO ALONG THOSE LINES, JEFF,

DO THE DUPES NOT RESPOND ON IGF1

IN THE CELL MODELS?

>> ALYSSON?

>> I HAVEN'T TRIED.

>> SO I'D LIKE TO ASK A

QUESTION, UNFORTUNATELY I THINK

KARIN JUST WEPT OUT OF THE ROOM.

ONE OF THE THINGS IS REALLY SO

IMPRESSIVE, I THINK ABOUT RETT

MODEL IS THE DIFFERENT

EXPERIMENTAL MODELS AS YOU GO

FROM HUMAN TO MOUSE TO PATIENT

POPULATION AND THE ABILITY TO

TRANSITION FROM GENES TO

CELLULAR MECHANISMS, CELLULAR

MECHANISMS TO CIRCUITS.

AND CIRCUITS TO INTERACTION WITH

BEHAVIORAL FUNCTION.

HOWEVER WILL WE BE ABLE TO GO --

HOW FAR WILL WE BE ABLE TO GO TO

CIRCUIT-BASED BEHAVIORS AND THEN

SECONDLY, WHAT WILL THE ROLE

ABOUT FOR THE NONHUMAN PRIMATE

MODELS THAT ARE EMERGING IN THE

MEC P2 TO BRIDGE BETWEEN

IN-VIVO, RODENT TOWARDS THE

PRIMATE?

>> I THINK WE SHOULD WAIT FOR

KARIN'S TALK AND DEAL WITH THAT

THE DISCUSSION PART IN SESSION

3.

DOES THAT SEEM FINE?

>> CHARLES NELSON:  SHE SENT ME

AN E-MAIL 20 MINUTES AGO SAYING

SHE WANTS TO TALK TO ME ABOUT

DOING VEP IN THE MONKEY.

WE TALKED ABOUT THIS FOR TWO

YEARS AND HASN'T BEEN DONE YET.

>> MAYBE COMMENT ON THE IPS CELL

BECAUSE THERE ARE A LOT OF -- ON

GENERATING ORGANOIDS TO ASK

SIMILAR QUESTIONS.

IT'S VERY RUDIMENTARY NOW BUT

AND IMH IS LOOKING ALSO MAKING

MEC P MORE PRODUCIBLE AND STUFF

LIKE THAT.

SO I DO SEE THAT IN THE FUTURE

WE WILL HAVE BETTER WAYS OF

DOING THAT, PERHAPS INTEGRATED

CPTs.

>> IF I COULD MENTION JUST FOR A

SECOND WITH WHAT JEFF WAS ASKING

EARLIER ABOUT CELL AUTONOMOUS

AND NON-CELL AUTONOMOUS AFFECTS.

THIS IS THE PART I DIDN'T GET A

CHANCE TO TALK ABOUT THE.

IN THE HETEROZYGOUS FEMALES WE

DON'T SEE CHANGES IN THE

PERINATAL NETS UNTIL WE DO THE

BEHAVIORAL ASSAY ON THEM.

SO, IN THE NULL ANIMALS, IT

COMES ON WITH VISION BECAUSE THE

EYE OPENS AND THAT'S THE

ACTIVITY ABOUT YOU IN THE

HETEROZYGOUS FEMALES IT'S THE

BEHAVIORAL ASSAY THAT

TRIGGSTHERS CHANGE IN

PHYSIOLOGICAL MEASURES AS WELL.

THE IDEA IS I'M SURE THERE ARE

CELL AUTONOMOUS AND NON-CELL

AUTONOMOUS MECHANISMS AND OTHER

PEOPLE HAVE WORKED ON THIS.

THEY ARE DEFINITELY A

INTERACTION BETWEEN THE CELLS

THAT ARE POSITIVE AND NEGATIVE

AND THAT HAS AFFECT ON IT.

BUT WE ARE SAYING RIGHT NOW THE

IDEA IS THAT IS IT GOING TOWARDS

HOW THE EXPERIENCE AFFECTS THAT

CHANGE PROCESS ITSELF.

>> AN ASIDE, LAURA, I MISSPOKE T

WASN'T AUDITORY VOKE POTENTIALS.

IT WAS IN THE CUE INDICATION.

IT WAS GAMMA OSCILLATIONS IN

RESPONSE TO MATERNAL VOICE.

AND IT WAS AN OPPOSITE DIRECTION

BETWEEN THE RETT AND THE MEC P2

DUPLICATION.

>> THE ONLY QUESTION WAS WHETHER

THEY CONTROLLED FOR SEX YET.

>> NO.

THEY DID, ALL THE RETT KIDS WERE

GIRLS AND ALL THE MEC P2

DUPLICATIONS WERE BOYS.

>> I KNOW.

SO I HAD A QUESTION FOR CHUCK

BEFORE HE LEAVES US.

SO FOR THE VISUAL EVOKE

POTENTIAL, WHAT IS THE YOUNGEST

AGE YOU HAVE IN RETT SYNDROME

GIRLS YOU HAVE LOOKED AT?

DO YOU SEE IF YOU HAVE GONE TO

REALLY YOUNG GIRLS, DO YOU SEE A

DEVELOPMENTAL PROGRESSION IN THE

EVOKE POTENTIAL?

>> CHARLES NELSON:  GOOD

QUESTION.

SO THE YOUNGEST GIRLS WE HAVE

SEEN HAVE BEEN PROBABLY CLOSE TO

18-24 MONTHS.

I HAVE TO LOOK UP THE EXACT AGE.

I'M SORRY.

BUT, TO ANSWER THE SECOND

QUESTION, WE DON'T SEE.

AND THAT WAS THE NATURE OF MY

COMMENT ABOUT THIS MATURING IN

ABOUT A YEAR.

WE ARE NOT SEEING ANY AGE

AFFECT.

AND I THINK WE HAVE AN ANALYSIS

IN THE AN ULS OF NEUROLOGY PAPER

TO REPORT THAT.

SO IF YOU LOOK AT AGE, THERE IS

REALLY NO DIFFERENCE IN AGE.

WHICH IS KIND OF INTERESTING

BECAUSE THERE IS A REPORT AND

MIGHT BE TIM ROBERTS THAT THAT

IS NOT TRUE FOR THE AUDITORY

EVOKE POTENTIAL WHICH I FIND

VERY SURPRISING BECAUSE THE

AUDITORY SYSTEM DEVELOPS EARLIER

THAN THE VISUAL SYSTEM IN SOME

RESPECTS.

BUT DEP SEEMS TO TOP OUT GIVE OR

TAKE A YEAR OR SO OF AGE.

THAT DOESN'T MEAN THAT YOU MIGHT

NOT SEE MORE SUBTLE CHANGES WITH

HIGHER SPACIAL FREQUENCIES OR

DIFFERENT CONTRASTS LATER ON,

BUT FOR THE CONTRAST IN SPACIAL

FREQUENCIES YOU'RE USING WE

DON'T SEE A CHANGE IN AGE.

WAS EMBEDDED PART OF YOUR

QUESTION THOUGH, HOW YOUNG CAN

WE TEST THE CHILD?

OR JUST THE ISSUE OF DOES IT

CHANGE WITH AGE?

>> I DIDN'T ASK THAT BUT THAT'S

A GREAT QUESTION.

HOW LONG CAN YOU TEST THE CHILD?

>> CHARLES NELSON:  I SPENT MOST

OF MY CURRENT STUDIES DOING

BABIES.

I HAVE DONE AT BIRTH BUT

GENERALLY WE CAN DO IT STARTING

AT 2-3 MONTHS.

WITH RETT THE GIRLS AREN'T

IDENTIFIED THAT YOUNG.

BUT WITH OUR OTHER PATIENT

POPULATIONS, TS AS AN EXAMPLE,

WE ROUTINELY SEE THE KIDS BY 6

MONTHS.

THAT'S HAY DIAGNOSE DONE

PRENATALLY.

SO NO ISSUES OF THEM BEING

UNABLE TO TOLERATE THE

PROCEDURE.

AND I SHOULD HAVE SAID THE

COMMENT ABOUT GAMMA OSCILLATIONS

MADE ME THINK THIS.

WE ALWAYS BEGIN WITH WHAT WE

CALL A BASELINE EEG.

AND THOSE ARE THE DATA WE ARE

NOW WORKING ON FOR RETT.

SO WE HAVE A BASELINE EEG WHERE

WE CAN DO TRADITIONAL FFTs AND

THE LIKE AND MUCH MORE COMPLEX

COMPUTATIONAL APPROACHES AND

THEN THE VEP AND THEN WE CAN DO

DEPENDING ON WHAT POPULATION,

MORE SOPHISTICATED COGNITIVE

TESTING LIKE MEM ROW OR SOCIAL

PERCEPTION AND THINGS LIKE THAT.

AND FROM START TO FINISH, THE

WHOLE THING USUALLY IS AFTER THE

KIDS NETTED, MAYBE 25 MINUTES.

>> THANKS.

I THINK WE ARE PROBABLY ABOUT IT

UNLESS PEOPLE HAVE OTHER --

>> CAN I JUST HAVE ONE COMMENT?

I AM CURES JUST TO BRING

ELLIOT'S PRESENTATION INTO THE

DISCUSSION.

IN MORE GENERALLY INTO THE

DISCUSSION OF REGRESSION.

TO THE EXTENT THAT WE ARE

TALKING ABOUT MECHANISMS IN

REGRESSION AND WE DISCUSSED

PRUNING AND OTHER MECHANISMS,

I'M WONDERING WHETHER YOU THINK

THE KIFF1A EXAMPLE IS MORE OF AN

EXAMPLE OF FRANK

NEURODEGENERATION AND TO WHAT

EXTENT WE THINK BROADLY THAT

SOME ASPECT OF REGRESSION ACROSS

ALL OF AUTISM WILL REFLECT SOME

ELEMENT OF YOUR

NEURODEGENERATION?

>> SO, I MEAN I THINK THAT IT'S

NOT AS PROFOUND AN EXAMPLE AS

SAY, A LYSOSOMAL STORAGE

DISEASE.

BUT I DO THINK THAT WHEN WE

THINK ABOUT THEIDEIO PATHIC

AUTISM REGRESSION, WE SHOULD BE

THINKING REALLY BROADLY ABOUT

LOTS OF DIFFERENT CELLULAR

MECHANISMS AND THE FACT THAT YOU

KNOW, WE TALKED ABOUT THE

EXUBERANT OVERGROWTH OF BRAIN

DEVELOPMENT EARLY ON BUT THAT

THE INVERSE IS ALSO TRUE WHERE

YOU ACTUALLY SEE A DECELLERATION

OF BRAIN GROWTH OR AT LEAST HEAD

GROWTH IN A LOT OF AUTISTIC KIDS

AND IS THAT FROM OVEREXUBERANCE

OF PRUNING OR OTHER DEGENERATIVE

MECHANISMS AT PLAY?

I THINK WE SHOULD ENTERTAIN ALL

THE POSSIBILITIES AND DEFINITELY

SOMETHING LIKE KIFF1A WOULD FIT

PARTICULARLY FOR KIDS THAT HAVE

MOTOR DEFICITS THAT GO ALONG

WITH THEIR COGNITIVE DEFICITS.

>> AND IN RETT SYNDROME, WE HAVE

NO EVIDENCE FROM PATH OR OTHER

THINGS THAT THERE IS ANY

DEGENERATION IN THE BATH.

THE PROGRESSION WHERE YOU HAVE A

REGRESSION BUT A STABILIZATION

IS JAI ALAI DIFFERENT THAN

SOMETHING LIKE BALT EN'S DISEASE

OR SOMETHING WHERE YOU YOU HAVE

A RELENTLESS DOWNWARD COURSE.

>> LONNIE?

>> I THOUGHT IT WAS A BEAUTIFUL

EXAMPLE OF DROPPING THE

MECHANISM UNDERLYING PHENOTYPIC

PROGRESSION.

IT'S A WORTHWHILE ISSUE TO

RETURN TO THIS AFTERNOON THAT

ACROSS THE CONTINUUM OF

DEVELOPMENTAL PATTERNS INCLUDING

AUTISM, IS THERE SOME BOUNDARY

WE CAN ESTABLISH AT WHICH POINT

OTHER PATTERNS OF REGRESSION ARE

MAY NOT BE SUFFICIENTLY SIMILAR

TO WHAT WE SEE IN AUTISM.

SO I THINK I DON'T WANT TO -- I

THINK PREMATURE TO CLOSE

DISCUSSION ON ANY POINT BUT IT

IS A POINT WORTH RETURNING TO IN

TERMS OF SORT OF HOW ONE WOULD

FOCUS ONE'S EFFORTS IN MODELING

AUTISM.

>> THANK YOU CHUCK FOR BEING

ABLE TO JOIN US.

>> CHARLES NELSON:  MY PLEASURE.

SORRY I COULDN'T BE THERE.

I'M GOING TO SIGN OFF.

>> ANN WAGNER BYE, CHUCK.

THANK YOU.

SO WE ARE READY FOR LUNCH.

SO WE SHOULD HAVE LUNCHES

AVAILABLE HERE.

YES, IN THE BACK.

SO PEOPLE CAN GET YOUR LUNCH.

EAT HERE OR IN A CHAIR OR

WHATEVER YOU LIKE TO DO.

THANK YOU.

 WE ARE RESTARTING

THE WORKSHOP ON LOSS

OF SKILLS AND ONSET PATTERNS AND

NEURODEVELOPMENTAL DISORDERS.

AND WE ARE UP TO SESSION 3.

ELIZABETH POWELL IS THE CHAIR

WITH OPENING REMARKS TO MAKE.

>> ELIZABETH POWELL:  GOOD

AFTERNOON.

FIRST I'D LIKE TO THANK AUDREY

AND ANN AND LONNIE AND JEFF FOR

ALL OF OUR CONVERSATIONS AND

ORGANIZING THIS MEETING.

AND FOR THE SESSIONS 1 AND 2

THAT I LEARNED SO MUCH SO FAR.

THE SESSION 3 AND THEN FINALLY

THE REALLY WORKSHOP PART OF

SESSION 4 ARE BRANCHING OUT INTO

OTHER IDEAS OF HOW TO MOVE

FORWARD WITH SCIENCE.

AND IDEALLY START THINKING OR

ENTERTAINING IDEAS FOR TREATMENT

OR OTHER WAYS OF HELPING OUT THE

PATIENTS.

AND SO, TODAY'S SESSION 3 WE ARE

GOING TO TALK ABOUT OTHER TOOLS

THAT WE HAVE AND OTHER WAYS OF

LOOKING AT THE SCIENTIFIC DATA.

AND THEN WE'LL MOVE INTO THE

WORKSHOP.

SO, I'M GOING START INITIALLY

WHERE SESSION 3 AND I WANT TO --

I HAVE MADE A VERY BRIEF

SCHEMATIC LOOKING AT DEVELOPMENT

BECAUSE I'M A DEVELOPMENTAL

BIOLOGIST AND THESE COLOR BARS

SHOW THE OVERLAP BETWEEN

PROLIFERATION AND MIGRATION,

MATURATION AND THEN FINALLY

RESTING STATE IN A CENTRAL

NERVOUS SYSTEM.

AND IT GOES FROM PRENATAL TIME

TO BIRTH THROUGH THE ADULT.

AND SO I HAVE DRAWN A GENERAL

TRAJECTORY HERE FOR TYPICALLY

DEVELOPING.

AND WE COULD BE -- THIS COULD BE

THE ONSET OF SKILL, A NUMBER OF

SYNAPSES, IT COULD BE THE

BUILDUP OF A NUMBER OF CELLS OR

ANOTHER BIOMARKER.

AND I HAVE DRAWN OTHER

TRAJECTORIES.

AND WHEN I START THINKING ABOUT

THIS, YOU CAN THINK OF

REGRESSION AS MAYBE STARTING OFF

AT A LOWER LEVEL LIKE WE SEEN IN

SOME TRAJECTORIES TODAY AND MUCH

LOWER MARKER THAN TYPICALLY

DEVELOPING.

WE COULD ALSO HAVE IT MATURE

EARLIER AND WE SAW A LITTLE

ABOUT THAT WITH THE PARRAL BU

MIN CELLS IN THE VISUAL CORTEX

AND THEN YOU HAVE A DROP THAT

CAN GO BACK DOWN TO REGRESSION
AND WE

KNOW THE NUMBER OF CELLS AFTER

PURITY -- PUBERTY, YOU HAVE A

SLIGHT DECREASE.

THAT IT IS NORMAL.

I'D LIKE TO THINK ABOUT WHAT

HAPPENS IF YOU DON'T HAVE A

DECREASE.

AND IF THAT GIVES YOU?

SORT OF PATHOLOGY.

MOO I LAB, AND I WANT TO BRING A

LITTLE VIGNETTE IN HERE BECAUSE

THIS PUZZLED US FOR A LONG TIME.

MY LAB WORKS ON A SET OF

MOLECULES REALLY DON'T MATTER

BUT I'LL GIVE THEM TO YOU

BECAUSE PEOPLE ARE CURES.

IT'S UPAR, A RECEPTOR THAT IS

NOW ASSOCIATED WITH LANDAU

CLEFNER AND ACTIVATES HEPATOCYTE

GROWTH FACTOR ASSOCIATED WITH

HUMAN SCHIZOPHRENIA AND A SLIGHT

ASSOCIATION WITH AUTISM AND HGF

IS THE LIGAND FOR THE MET

RECEPTOR, ONE OF THE

SUSCEPTIBILITY ALLELES FOR BOTH

AUTISM AND SCHIZOPHRENIA.

WE LEARNED EARLY ON, WHEN I

STARTED, THAT LOSS OF UPAR IN

EARLY DEVELOPMENT REDUCED THE

NUMBER OF INTERNEURONS AND THEN

WE WENT AND THAT WAS AT BIRTH IN

THE EMBRYONIC PERIOD.

AND THEN WE LOOKED AT THE ADULT

AND HAD A HUGE LOSS OF THE

PARALBUMIN CELLS AND IT WAS

SPECIFIC AND CURES BECAUSE IT

WAS IN THE FRONTAL CORTICAL

AREAS AND THE PARIETALS.

AND SO, ONE OF OUR FIRST EASY

WAYS WAS, CAN WE FIX THIS?

WE KNEW THESE ANIMALS HAD SOME

DEFICITS.

THEY HAD SEIZURES.

THEY HAD DEFICITS AND ANXIETY

AND LEARNING MEMORY DEFICITS AND

THE VERY SIMPLISTIC WAY WAS TO

PUT HGF BACK AND SEE IF WE COULD

FIX IT.

NOW WE THOUGHT WE HAD FEWER

INTERNEURONS AT BIRTH AND FEWER

INTERNEURONS IN THE ADULT SO WE

WENT AND LOOKED AT THE

INTERNEURONS POSTNATALLY.

AND MUCH TO OUR SURPRISE WHEN WE

LOOKED AT THE TRAJECTORY.

THE OTHER CELLS ARE ALWAYS

NORMAL.

THE OTHER SUBGROUPS.

AND THIS IS PUBLISHED.

AND WE SEE THAT PV, WHICH IS

DRIVEN BY ACTIVITY, SO THE

NUMBER OF CELLS IN THE MET

SENSORY CORTEX INCREASES A HUGE

JUMP BETWEEN P30 AND P21 AND P30

IN THE MOUSE AND FURTHER

INCREASE AND THEN A SLIGHTLY

LEVELING OFF IN THE ADULT IN THE

WILDTYPE.

IN THE UPAR ANIMAL WHAT WE SAW

WAS A RECOURSE EARLY INCREASE IN

PARALBUMIN ACTIVITY.

EARLY ON, P30 WHICH IS THE END

OF JUVENILE PERIOD.

LOOKS IDENTICAL.

AND THEN A HUGE DROP.

SO, THAT CHANGED OUR WAYS OF

THINKING BECAUSE WE ALWAYS

THOUGHT THERE WAS A DEFICIT BUT

ACTUALLY THERE IS AN EARLY

ACTIVATION OF THESE CELLS.

AND THEN WHEN WE LOOKED AT THE

WAY TO FIX IT EITHER ADDING HGF

ALONE OR HGF TOGETHER WITH THE

UPAR, WHICH WAS THE RESCUE

ANIMAL, WE STILL SEE THIS

RECOURSE INCREASE IN PARALBUMIN

CELLS AND CORTEX AND SEEN IT IN

FRONTAL CORTEX.

THESE TWO RESCUE ANIMALS END UP

WITH NORMAL LEVELS IN THE ADULT.

SO WHAT I WILL TELL YOU IS THAT

WHEN WE LOOKED AT THE PHENOTYPES

OF THE ANIMALS, WHEN WE DID THIS

EARLY UPAR INCREASE IN DELAY OR

INCREASE IN LOSS, THESE CELLS OR

THESE MICE IN SOME BEHAVIORS,

SUCH AS THE SEIZURES IN SOME

COGNITION SUCH AS REVERSAL

LEARNING, WERE ACTUALLY

IMPROVED.

IN OTHER THINGS SUCH AS

DECISION-MAKING, AND SOCIAL

BEHAVIOR, THEY WERE NOT

IMPROVED.

SO IN THIS CASE, TRYING TO PUT

SOMETHING BACK THAT WAS MISSING

HAD IMMEDIATE AFFECT.

THIS INCREASE HAD MORE CELLS ALL

THE WAY THROUGH THE ADULT AND

THIS ANIMAL I WOULD ARGUE HAS

MORE DEFICITS WITH MORE

INTERNEAR ONS THAN SOME OF THE

UPAR ANIMALS ITSELF.

AND SO THE MORAL OF THIS STORY

IS THAT THERE IS REALLY AN

OPTIMUM NUMBER IN TOTAL NUMBER

OF CELLS IN INTERNEURONS AND THE

TIMING CHAT THEY ARE TURNED ON

AND INTEGRATED INTO THAT

CIRCUITRY AND WHEN WE HAVE TOO

FEW, WE HAVE PROBLEMS SUCH AS

SEIZURES AND COGNITIVE DISORDERS

AND IF WE HAVE TOO MANY, WE CAN

HAVE OTHER ISSUES.

SO STARTING WITH, THAT WE WILL

TALK THE REST OF THE SESSION AND

TRY TO FIND THE BASIC TOOLS FOR

BASIC SCIENCE.

THIS IS IN A NUTSHELL, HUMAN

BRAIN DEVELOPMENT.

THE EMBRYONIC TO 36 WEEKS.

THE POSTNATAL ALL THE WAY

THROUGH 24 YEARS.

ALTHOUGH I THINK NIH SAYS AN

ADULT IS UNTIL 35.

AND SO, WE ARE TRYING TO LOOK IN

THIS SESSION IN THIS WORKSHOP

BETWEEN THE 18-36.

AND HERE IS SAGE TALL SECTIONS

OF MOUSE DEVELOPMENT, ALTHOUGH

RAT BRAIN LOOKS SIMILAR AND WE

ARE TRYING PROBABLY IN THE

RODENT SOMEWHERE BETWEEN P4 AND

P28 WOULD BE SIMILAR TO THAT

PERIOD WE HAVE BEEN TALKING

ABOUT.

AND WE ARE GOING TO SEE IF WE

CAN ALIGN WITH RODENT AND WITH

HUMAN.

AND FIRST, WE ARE GOING TO START

WITH JILL SILVERMAN WHO WILL

TALK ABOUT SOME RODENT BEHAVIOR

ASSAYS.

AND IN SOME OF THE BEHAVIORAL

DOMAINS THAT WE SEE IN THE

REGRESSION.

AND THEN JASON IS GOING TO DO

SOME ANATOMY OF RODENT AND HUMAN

AND MR I AND IMAGING.

AND THEN WE ARE GOING TO HAVE A

LITTLE BREAK FROM THE PREVIOUS

SESSION AND ERIC WILL TALK ABOUT

GENETICS BEFORE WE OPEN IT UP.

SHARON WILL TALK ABOUT

DEVELOPMENT AS A POSSIBLE ANIMAL

MODEL SOMEWHERE BETWEEN MY MIND

BETWEEN RODENT AND PRIMATE AND

THEN KARIN PARKLER TALK ABOUT

HER WORK IN PRIMATE SOCIAL

BEHAVIOR WHICH SHE CAN ALSO

RELATE TO HUMAN SOCIAL BEHAVIOR.

SO, WITHOUT ANY OTHER DELAY,

PLEASE, JILL.

>> JILL SILVERMAN:  THANK YOU

VERY MUCH ELIZABETH AND AUDREY

FOR INVITING ME AND FOR ALL THE

ORGANIZERS.

I'M REALLY EXCITED TO TALK TO

YOU ABOUT SOME OF THE THINGS WE

HAVE BEEN WORKING ON.

MY TALK IS GOING TO BE A LITTLE

BIT DIFFERENT THAN THE TALKS WE

SAW THIS MORNING.

WE WANTED TO FOCUS ON TOOLS AND

ASSAY DEVELOPMENT AND JUST BASIC

IDEAS OF HOW WE WOULD LOOK AT

THIS CONCEPT OF REGRESSION AS

OPPOSED TO ME GIVING A VERY

DETAILED DATA TALK.

I ALSO WANT TO INTRODUCE MYSELF

BY SAYING THAT I HAVE ABOUT 17

YEARS OF ANIMAL MODELING

EXPERIENCE.

I HAVE DONE NOTHING BUT WORK

WITH RODENT MODELS MY WHOLE

ENTIRE CAREER AND SPENT A LOT OF

TIME THINKING ABOUT THESE

BEHAVIORAL ASSAYS SO IF THERE IS

ANYTHING THAT -- THERE WILL BE A

LOT I MISS IN THIS SPORT TALK

BUT PLEASE FEEL FREE TO TALK TO

ME ABOUT IT AFTERWARDS.

SO, WHEN WE STARTED THINKING

ABOUT AUTISM AND I THINK THAT

AUTISM DOESN'T NEED TO BE

INTRODUCED TO THIS AUDIENCE BUT

I WANTED TO GO OVER JUST LIKE

THE WHOLE COMPLEX SYMPTOM DOMAIN

OF IT BEING THAT WE HAVE THIS

TRIAD OF CORE SYMPTOMS THAT IS

OVERLYING WITH A LOT OF

INTELLECTUAL DISABILITY AND THEN

WE HAVE SO MANY EXTRA

NEUROLOGICAL ASSOCIATED

SYMPTOMS.

SLEEP DISORDERS, HYPERACTIVITY,

JUST TO NAME A FEW AND THEN A

LOT OF CO-MORBID MEDICAL

CONDITIONS, SEIZURES, GI ISSUES

AND IMMUNE DYSFUNCTION THESE ARE

PROBABLY HAPPENING IN 30% OF

PATIENTS WITH ASD.

THIS IS A REALLY COMPLEX

HETEROGENOUS CONDITION AND HOW

COULD WE THINK ABOUT MODELING

SOMETHING SO COMPLEX?

THERE IS PRECLINICAL AS AS

AVAILABLE IN ALMOST EVERY SINGLE

ONE OF THESE DOMAINS IN WHICH WE

CAN MEASURE.

SIGN LANGUAGE A LITTLE BIT

TRICKIER BUT WE ARE GOING TO

MAKE SOME STRIDES THERE SOON.

AND SO, THEN HAVING SAID THAT,

WITH AUTISM BEING UNIQUELY

HUMAN, HOW CAN ANIMAL MODELS

PROVIDE INSIGHT INTO BIOLOGY?

WE ARE USING THESE MODELS AS

MODELS.

THEY ARE MODEL ORGANISMS SO WE

CAN INVESTIGATE DIFFERENT TYPES

OF GENETICS ENVIRONMENT CAUSES

AND THOSE TWO CAUSES AND HOW

THEY INTERACT WITH EACH OTHER TO

LOOK AT CAUSE AND POTENTIALLY WE

COULD USE THESE MODELS TO

DEVELOP THERAPEUTICS.

BUT, ANIMALS ARE NEVER GOING TO

HAVE AUTISM.

THE PRIMATES, RODENTS, MICE, ARE

NOT GOING TO HAVE AUTISM AND

CELLS DON'T HAVE AUTISM AND I

THINK THAT'S A IMPORTANT POINT

TO TALK ABOUT.

NOT REALLY  IN THIS GROUP BUT I

THINK THAT WE ALWAYS NEED TO

THINK ABOUT THAT.

IN MODELING ANY DISORDER.

SO, I HAD MADE THIS TIMELINE A

WHILE BACK ABOUT -- BECAUSE I

GET ASKED THIS QUESTION A

MILLION TIMES ABOUT -- AND I'M

SURE EVERYONE GETS ASKED, WHY

DID I NEVER HEAR OF AUTISM FOR A

LONG TIME AND WHY IS IT EVERY

NOW AND HOW COME WE HAVEN'T MADE

SUCH GREATER GAINS IN WHAT WE

BEEN AUTISM GIVEN THAT IT WAS

DESCRIBED IN 1943?

BUT IF YOU THINK ABOUT BASIC

RESEARCH IN AUTISM OR ANIMAL

MODELS, I WOULD ARGUE THAT THAT

PROBABLY DIDN'T ACTUALLY START

OCCURRING UNTIL LATER IN THE TWO

THOUSANDS AS THE DISORDER

BECOMES MORE PREVALENT AND WE

HAVE A DIAGNOSTIC THAT IS

ACTUALLY SAYS OKAY, AUTISM, THIS

IS ONE SPECIFIC DISORDER.

AND SO, OUR EFFORTS IN BASIC

RESEARCH BEGIN BASICALLY IN A

BLOCK BOX.

WE HAVE NO IDEA WHAT CAUSES OR

TREATS IT.

HOW DO WE MAKE ANIMAL MOD ELSE?

WHAT I CALL THE FIRST GENERATION

ANIMAL MODELS ARE BASICALLY WE

LOOK AT WHAT MAKES YOU SOCIAL,

RIGHT?

SO PEOPLE STARTED TO LOOK AT

OXYTOCIN GENETICALLY MODIFIED

ANIMALS, ANIMALS THAT HAD

INHERENT HIGH-SOCIAL BEHAVIOR OR

LOW-SOCIAL BEHAVIOR.

WE ALSO FACED ALL THE MODELS AND

LOOKED AT LESIONS WHICH HAVE

ALTHOUGH MAY NOT HAVE CONSTRUCT

VALIDITY, IF WE LESION A CERTAIN

AREA INVOLVED IN A CERTAIN

BEHAVIOR, THEY MAY END UP A LOT

OF VALIDITY.

THAT'S WHERE WE WERE WITH FIRST

GENERATION AND THEN RECENTLY,

LIKE THINK ABOUT THE FACT THAT

THAT'S 2007 AND WILL SO IT IS

NOT EVEN 10 YEARS THEN WE HAVE

THIS SECOND GENERATION OF HUGE

CONSTRUCT VALID MODELS AND

IDENTIFIED ALL OF THESE SEPARATE

SYNDROMES, FRAGILE X, RETT,

McDERMOTT DUPLICATION -- AND

WE HAVE LOTS OF MODELS NOW FOR

ALL OF THESE SYNDROMES WHERE WE

KNOW THAT THEY END UP CAUSING

AUTISM AND OVERLYING I

INTELLECTUAL DISABILITIES AND

SYMPTOMS.

IT'S AN EXCITING TIME TO BE IN

THIS FIELD.

AND NOW TODAY WHAT I THINK WE

CAN TALK ABOUT -- SO I WANTED TO

SAY THAT IN PRIOR TO THAT, LIKE

FOR ANIMAL BEHAVIOR FOR RODENT

BEHAVIOR, AUDREY HAD FIRST ASKED

ME THIS CONCEPT OF, THERE IS A

TEXTBOOK ON NORMATIVE

DEVELOPMENT ON THE HUMAN.

WHERE IS THAT IN THE MOUSE?

AND I WAS SAYING, THERE IS A

TEXTBOOK OF NORMAL BRAIN

DEVELOPMENT.

I DON'T YEN THERE IS NOT A

TEXTBOOK FOR NORMAL SOCIAL

DEVELOPMENT IN THE MOUSE.

AND THEN I WENT THROUGH A LOT OF

THE LITERATURE THROUGH 50 YEARS

OF LITERATURE TO REALIZE THAT

PEOPLE REALLY IN ANIMAL MODELS

WERE STUDYING ON KNOWLEDGE TONY

OF SOCIAL DEVELOPMENT FROM A

VERY DIFFERENT PERSPECTIVE.

THEY WEREN'T INTERESTED INTO HOW

SOMETHING REGRESSES.

THEY ARE INTERESTED IN HOW IT

ONETS AND HOW SEX BEHAVIOR

ONSETS AND AGGRESSIVE BEHAVIOR

ONSETS; WHICH WE CAN NOW USE TO

OUR ADVANTAGE.

SO I THINK THIS POINT PUTS US

NOW AT A UNIQUE TIME WHERE WE

ARE ABLE TO LOOK AT MANY OF

THESE MODELS AND SYNDROMES AND

LOOK AT LOSS OF DEFICITS IN

ANIMAL MODELS.

WE CALL IT THE RELAUNCH

GENERATION.

SO, HERE IS THE QUESTIONS THAT I

HAVE BEEN FOCUSED ON AND THESE

ARE SORT OF DISCUSSION POINTS

THAT I WAS HOPING WE COULD GET

UP TODAY AND THESE ARE THE TWO

THAT I HAD BEEN FOCUSED ON WHEN

I WAS A POSTDOC, SO HOW WOULD --

WHICH HUMAN SYMPTOMS ARE MOST

ESSENTIAL TO ANIMAL MODEL?

DURING MY POSTDOC YEARS WE

FOCUSED ON THE CORE SYMPTOM

DOMAINS OF ASD.

THIS IS SOCIAL BEHAVIOR,

REPETITIVE AND RESTRICTIVE

BEHAVIOR, BEHAVIORAL AND

NECKSABILITY AND TRYING TO START

TO DEVELOP WHAT WE COULD

CONSIDER OR MAYBE MAKE A

MILDINAL ANALOGY TO

COMMUNICATION.

WHICH OF THOSE PHENOTYPES HAVE

AN EN DOE PHENOTYPE IN THE

MOUSE?

NOT ALL OF THEM BUT MOST OF THEM

DO.

AND SO THAT'S WHAT I'LL SHOW YOU

A LITTLE BIT OF.

BUT THEN I WANTED TO EXPAND

SPECIFICALLY FOR THE FOCUS OF

THIS WORKSHOP WHICH IS, WHICH OF

THESE PHENOTYPES UP HERE

RELEVANT TO OUR DISORDER OF

AUTISM SPECTRUM DISORDERS CAN BE

QUANTIFIED OVER DEVELOPMENTAL

TIME COURSE?

SO I THINK THAT THERE IS A LOT

OF ARTICLES OUT THERE THAT WOULD

ARGUE THAT THEIR BEHAVIORAL DATA

HAS BEEN CHARACTERIZED OVER

DEVELOPMENTAL LIFESPAN BECAUSE

THEY LOOK AT PUPS AND THEN LOOK

AT JUVENILES AND SHOW SOMETHING

IN ADULT BUT I WOULD ARGUE THAT

THAT IS NOT TRULY A

DEVELOPMENTAL LIFESPAN.

A TRUE REPRESENTATION OF

DEVELOPMENTAL BEHAVIOR

CONSIDERING THAT AS ELIZABETH

SHOWED YOU ON THE SLIDE IN THE

INTRODUCTION, THAT THERE IS A

CRUCIAL AMOUNT OF DEVELOPMENT

HAPPENING FOLLOWING PUPS BEFORE

JUVENILE WEANING.

AND THEN ALSO WE NEED TO NOT

ONLY THINK ABOUT HUMAN BEHAVIORS

WE WANT TO MODEL BUT WE HAVE TO

UNDERSTAND THAT MICE AREN'T

HUMANS AND THAT THEY HAVE

BEHAVIORS THAT ARE DIFFERENT SO

THEY HAVE TO BE RELEVANT BUT

THEY ARE LAB ANIMALS.

SO EIGHT LOGICAL RELEVANCE IN

WILD MICE BUT LAB MICE ARE NOT

NECESSARILY WILD MICE.

-- EIGHT LOGICAL.

AND SO THIS IS WHAT I MENTIONED

BEFORE.

SO, HERE IS WHERE WE ARE TO

DATE.

ONE OF THE TWO MOST COMMON

ASSAYS THAT YOU SEE IN THE

LITERATURE, ONE FOR -- I PICKED

OUT ONE FOR ADULT SOCIAL

BEHAVIOR AND ONE FOR PUP SOCIAL

BEHAVIOR.

SO PUPS SEPARATED ULTRASONIC

VOCALIZATIONS ARE INHERENT.

THEY HAPPEN IN THE PUPS.

WE DO THESE ASSAYS CALLED

DEVELOPMENTAL MILESTONES

BASICALLY LIKE THE WELCHECK

VISITS YOU TAKE YOUR BABY TO.

WE GATHER THEIR WEIGHT ACROSS A

DEVELOPMENTAL TIME COURSE AND

THEN WE ISOLATE THE PUPS AND

WHEN THEY ARE ISOLATED FROM THE

MOTHER THEY EMIT THIS ULTRASONIC

CALL THAT WE CAN'T HEAR BUT

MICROPHONES CAN PICK UP AND OUR

SOFTWARE CAN PICK UP AND COUNT

THE CALLS.

AND SO WHAT WE SEE TO

CHARACTERIZE QUOTE/UNQUOTE

NORMAL DEVELOPMENT IS OVER THE

POSTNATAL DAY PERIOD, SO WHEN

THEY ARE VERY SMALL POSTNATALS

TWO, 3, 4, THEY HAVE ALMOST NO

CALLS AT ALL BECAUSE THEY ARE

SMALL AND THERE IS NOT A LOT OF

STRENGTH TO THEIR VOCAL CHORDS

AND EVERYTHING.

AND THEN AS THEY GET A LITTLE

BIT OLDER, SOMEWHERE BETWEEN DAY

7 AND 8, THE CALLS PIQUE AND

THEY GET LOUD AND THERE IS A LOT

OF THEM AND THEY'LL PIQUE HERE.

AND THEN AS THE TIME GOES ON AS

A DEVELOPMENTAL TIME COURSE GOES

ON, THE ANIMALS START TO CALL

LESS AND LESS AND THEN ONCE

THEIR EYES OPEN, CALLS STOP.

SO WE DON'T SEE CALLS AFTER

EYE-OPENING AT ALL.

SO THAT LEAVES A GAP FROM WHEN

WE CAN LOOK AT ANYTHING THERE.

SO I WANTED TO PLACE SOME

EXAMPLES FOR YOU BECAUSE A LOT

OF PEOPLE IN THE MOUSE MODELING

FIELD FOCUSED ON THE DIFFERENT

CATEGORIES AND THE DIFFERENT

CALL TYPES AND WE HAVE BEEN

INTERESTED IN THIS IDEA OF IF

THESE SUBTYPES OF ULTRASONIC

VOCALIZATIONS COULD HAVE

MEANING.

AND SO -- I'LL JUST PLAY SOME

SAMPLES.

THAT'S AN UPWARD CALL WHICH

SOUNDS UPWARD IN FREQUENCY.

AND THEN THERE IS A DOWNWARD

CALL AND THEN THIS IS OUR TWO

SYLLABLE CALL.

AND THERE IS DEBATE.

WE HAVE 10 OR 8-10 DIFFERENT

SUBTYPES OF CALL CATEGORIES.

SO, WITH AUTO - AS WE GET BETTER

AND BETTER AT OUR GENETIC

TECHNOLOGY AND WE ARE INTERESTED

IN TRYING TO DO CROSS SPECIES,

WITH THE RATS BECAUSE THE RATS

OBVIOUSLY ARE BIGGER AND HAVE

LARGER BRAINS AND ARE ABLE TO DO

MORE WITH THEM AND THEY ARE 23

MILLION YEARS MORE OF EVOLVED

THAN THE MICE.

I WANTED TO SHOW PICTURES OR

VIDEOS BECAUSE I THINK THAT THE

VIDEOS SPEAK LOUDER THAN WORDS

HERE.

SO, THIS IS OPTIMAL AMOUNT OF

MOUSE PLAY HERE.

THIS IS BASICALLY A

COREYOGRAPHED MOVIE OF MOUSE

PLAY.

THIS IS A FEMALE MOUSE WITH A

MALE MOUSE AND THEY HAVE SOME

SENSE ON THEM.

SO WE MADE THIS VIDEO TO SHOW

THE HIGHEST LEVEL OF MOUSE PLAY

YOU COULD EVER SEE.

YOU'LL SEE ONE ANIMAL FALSE AND

THEY CHASE EACH OTHER A LITTLE

BIT.

BUT IT'S NOT SO MUCH THAT LIKE

YOU COULDN'T SIT THERE AND

QUANTIFY IT REALTIME ONE PERSON

TRAINED OBSERVER.

THIS IS NOT STAGED, NOT

CHOREOGRAPHED OR OPTIMIZED AT

ALL.

JUST A RANDOM SESSION OF RAT

PLAY.

SO, THESE BEHAVIORS ARE NOT ONLY

MORE COMPLEX AND SOPHISTICATED

BUT THIS IT TRUE PLAY.

THESE ANIMALS PLAY LIKE DOGS,

THEY ROUGH AND TUMBLE, PIN EACH

OTHER, CHASE EACH OTHER, THEY DO

POSTURES CHASING.

THE NUMBER OF AMOUNTS OF PLAY

BELTS WE HAVE IN THE RAT IS JUST

OVERWHELMING TO ME.

IT'S 3 TIMES LARGER THAN WE SEE

IN THE MOUSE AND IT MAKES ME

REALLY EXCITED.

I CAN'T EVEN IMAGINE HOW KARIN

WOULD FEEL LOOKING AT MY

PLEASELY RAT VIDEOS BECAUSE THE

NONHUMAN PRIMATES ARE MUCH

BETTER AS WELL.

SO, JUST TO TALK ABOUT THIS

POINT A LITTLE BIT.

I DO THINK THAT USING RATS CAN

GET AT THE IDEA OF REGRESSION IN

A BETTER WAY THAN THE MOUSE CAN

JUST BECAUSE SIMPLY, WE HAVE A

BIGGER SIGNAL.

AND BECAUSE WE HAVE A BIGGER

SIGNAL, WE ARE GOING TO BE ABLE

TO DETECT DIFFERENCES THAT WE

HAVE NOT BEEN ABLE TO DETECT SO

FAR.

DETECTING A DIFFERENCE IN THAT

MOUSE SOCIAL INTERACTION IS VERY

HARD BECAUSE THE SIGNAL IS VERY

LOW.

THE OTHER THING IS TO HIT ON

THIS COMMUNICATION POINT SO I

WAS TELLING YOU ABOUT THE MOUSE

CALLS BEING IN DIFFERENT

CATEGORIES AND US NOT REALLY

KNOWING WHAT THEY MEAN.

THAT THEY JUST EMIT THESE

DIFFERENT CALL CATEGORIES, THE

RAT PEOPLE HAVE BEEN ON THIS FOR

A REALLY LONG TIME, MUCH LONGER

THAN ASD MODELING PEOPLE HAVE.

AND SO THE RAT CALLS DO HAVE

DIFFERENT MEANINGS.

SO HERE IS A DIFFERENCE

FREQUENCY.

SO THE FREQUENCY HERE IS BETWEEN

50-75.

THIS IS WHAT WE CALL A 50K HERTZ

PRO SOCIAL FILLATIVE CALL AND IT

WILL SOUND LIKE THIS.

THESE ARE GOING TO BE THE PUP

CALLS THEY GET WHEN THEY ARE

ISOLATED AND DISTRESSED BECAUSE

THEY ARE GOING TO GET THE CALLS

THAT WE GET IF WE SHOW THEM A

CAT OR PREDATOR ODOR.

THESE ARE DISTRESS CALLS.

THEY ARE LOW IN FREQUENCY AND

LOW AND FLAT SHAPED.

THE SHAPES DON'T LOOK THE SAME.

THE SOUNDS DON'T SOUND THE SAME.

THE REACTION TO THE OTHER RATS

IS NOT THE SAME.

SO WE TOOK A MODIFIED RADIAL ARM

MAZE AND HAS ALL SORTS OF

SPEAKERS AROUND IT AND ON THIS

SIDE HERE WE ARE PLAYING BACK

50K HERTZ USBs.

THE ONES WHISTLING AND PRO

AFFILLATIVE AND HE LOOKED AT

DIFFERENT SORTS OF ISOLATION

CONDITIONS BEFORE AND DURING AND

YOU DON'T HAVE TO WORRY ABOUT

ALL THE DATA OR ANYTHING.

I'M JUST GOING TO TELL YOU THE

SUMMARY TESTIFY HERE.

WE HAD ALL OF THE CONTROLS

PLAYING BACK NOISE, PLAYING BACK

LOW FREQUENCY STRESS

VOCALIZATIONS ON THIS SLIDE.

THE ANIMALS DEFINITELY GO TO THE

PRO AFFILIATIVE 50K HERTZ CALLS

AFTER VERY SHORT ISOLATION AND

DON'T AND -- AND THEY AVOID AND

DON'T EVER GO TO THE SIDE WITH

THE NEGATIVE CALLS.

SO INITIALLY WHAT I WAS TALKING

ABOUT WAS IN MY POSTDOC, WE HAD

BEEN USING THE CHAMBER SOCIAL

APPROACH TASK AND THIS TASK IS

AMAZING.

IT HAS SO MANY POSITIVE AWESOME,

QUICK -- IT'S QUICK AND YES OR

NO, IT'S CLEAR.

ARE THE ANIMALS SOCIAL?

SPENDING MORE TIME WITH THE

NOVEL MOUSE?

OR ARE THEY SPENDING MORE TIME

WITH THE NOVEL OBJECT?

OR DO THEY NOT CARE?

BASICALLY JUST SPENDING MORE

TIME EQUALLY ON EITHER SIDE.

THIS IS AUTOMATED AND WHEN I

STARTED IT WAS ONE AT A TIME AND

THEN WE HAD 10 AT A TIME AND NOW

WE HAVE LIKE TWO ROOMS AND THEY

GO ON AND ON AND THEY ARE

AUTOMATED AND BEAUTIFUL.

THIS IS KIND OF AN EXAMPLE OF

WHAT THAT LOOKS LIKE.

WE DON'T HAVE TO AREY ABOUT IT.

SO, I THINK MOST PEOPLE IN THIS

ROOM PROBABLY SEEN THIS TASK AT

ONE POINT OR THE OTHER.

THE ANIMAL ALWAYS SPENDS TIME --

NORMAL MICE, 99% OF THE TIME

WILL SPEND MORE TIME IN THE

CHAMBER WITH A NOVEL MOUSE OVER

THE NOVEL OBJECT.

YOU ABOUT, EVEN THOUGH THIS TASK

IS A QUICK YES OR NO AND IT

GIVES US THIS ANSWER, ARE THEY

SOCIAL OR NOT?

THERE ARE IS A THE OF THINGS WE

ARE MISSING HERE.

SO FOR EXAMPLE IF THE ANIMAL

CAN'T WALK VERY WELL OR HAS ANY

SORT OF MINIMAL MOTOR

IMPAIRMENT, IT'S NOT MAKING IT

BACK AND FORTH AROUND THESE TWO

BOXES VERY WELL.

OR BACK INSIDE THESE CHAMBERS

VERY WELL.

SO IF THERE IS IMPAIRMENTS IN

MOTOR ACTIVITY, WHICH THERE IS

IN NEARLY ALL OF THESE DISORDERS

THAT WE WERE TALKING ABOUT

EARLIER, YOUR SOCIAL APPROACH

DATA IS CONFOUNDED.

IF ANIMAL IS HYPERACTIVE OR

GIVEN PSYCHOSTIMULANTS, BECAUSE

THEY ARE SO ACTIVE AND RACING

BACK AND FORTH BETWEEN THE

CHAMBER, YOU'LL ALSO SEE NO

SOCIOABILITY.

IF YOU HAVE LOW -- AND HOW MANY

OF THESE HAVE CO-MORBID

HYPERACTIVITIY?

A LOT.

SO I THINK WE SHOULD START TO

INTERPRET SOMETHING AS SIMPLE AS

SOCIAL APPROACH WITH A LITTLE

BIT OF CAUTION BECAUSE OF THE

FACT THAT IT'S SO EASILY

CONFOUNDED BY MOTOR.

SO THEN, TO REALLY GET ON THE

FOCUS OF THIS WORKSHOP IS TO TRY

TO LOOK AT SOCIAL EARLIER.

AND TO GET ON MY POINT ABOUT

MOTOR, I HAVE A REALLY PERFECT

EXAMPLE TO SHOW YOU.

SO THIS IS A 10 MOUSE PUB EYES

CLOSED AND JUST WANTED TO SEE

FOR THE PURPOSES OF THE

WORKSHOP, COULD THE ANIMAL

SOCIAL APPROACH?

OBVIOUSLY MODIFIED THE SIZE I

WAS ASKING IT TO MOVE AROUND.

AND SO THIS MOUSE IS AN AWESOME

EXAMPLE OF WHAT A PND10 PUP

LOOKS LIKE.

IT'S NOT FOR LACK OF TRYING.

IT JUST CAN'T, RIGHT?

SO, WE WANTED TO LOOK AT TO SEE

IF HE COULD -- IF SHE INTERESTED

OR HE OR SHE, IS INTERESTED AND

COULD GO AND APPROACH AS WE

MEASURE IT AND WE COULDN'T.

SO, BUT, IF GIVEN THE MOM, SAME

PUP, HE CAN TOTALLY DO IT.

SO THEN I WAS WONDERING FOR THIS

AUDIENCE, CLINICAL PEOPLE, DOES

THE SALIENCE OF THE STIMULUS

MATTER?

IT DEFINITELY MATTERS FOR THE

ANIMALS DOES IT MATTER FOR THE

TRANSLATIONAL VALUE?

I DON'T KNOW.

I WOULD ASK PEOPLE IN THE

AUDIENCE TO GIVE ME THEIR

OPINION ON THAT.

REPETITIVE BEHAVIORS I REALLY

THINK WE HAVE GOTTEN A GOOD

HANDLE ON IN THE ANIMAL MODELS.

WE CAN SEE ALL OF THESE

BEHAVIORS HERE THAT I'LL SHOW

REALLY QUICK VIDEOS ON

THROUGHOUT THE LIFESPAN.

SO WE SEE THESE ON PRETTY EARLY

OVERLATE.

SO THAT IS WHAT WE HAVE.

GROOMING BEHAVIOR IN NA MODEL.

10E THERE IS JUMPING BEHAVIOR IN

THIS MOUSE.

THESE ARE C58 MICE AND WE HAD A

FEW GENETIC LINES THAT DO THIS

SAME SIMILAR JUMPING BEHAVIOR.

HERE IS A GOOD EXAMPLE.

THESE ARE 16P11 .2 MICE THAT DO

THIS REPETITIVE SIMPLING

BEHAVIOR.

IT'S EASY  IN THISIS CA.

YOU SEE WHICH ONE IS THE MUTANT.

PRETTY OBVIOUS THAT GUY IS THE

GENETIC MUTANT.

SO, THIS I THINK FOR

REPETITIVE -- WE HAVE A LOT OF

GOOD ASSAYS THAT COULD BE USED

AT EARLIER TIME POINTS.

AND THEN MY LAST IDEA IS THAT I

HAVE BEEN USING THESE TOUCH

SCREEN ASSAYS TO MEASURE

COGNITION.

I'M GOING SHOW YOU A VIDEO.

NOT TO OVER DO IT ON THE CUTE

MOUSE VIDEOS BUT IT JUST PROVES

THE POINT REALLY WELL.

THIS IS AN 8-WEEK OLD MOUSE SO,

WE ARE THINKING, 56 DAYS BUT IT

TOOK HIM 15 DAYS TO GET TRAINED

AND THEY ARE FOOD RESTRICTED.

BUT AFTER 15 DAYS OF TRAINING,

RIGHT HERE IS A REWARD WELL

WHERE HE IS GETTING STRAWBERRY

MILK SHAKE AND THEN ON THE OTHER

SIDE WE ARE GOING TO ASK HIM A

QUESTION, WHICH IS CORRECT, THE

SPIDER OR PLANE?

WHICH IMAGE, ONCE I POKE IT WITH

MY NOSE OR TOUCH IT LIKE YOU

TOUCH YOUR iPAD, WHICH GETS ME

THE REWARD?

AND SO, HE STARTS THE TRIAL.

SPIED SER CORRECT.

HE GETS THE REWARD.

SO THEN THIS LOOPS AGAIN IN SLOW

MOW, ACTUALLY.

SO HE TOUCHING THE SPIREDDER AND

GETS REWARD.

SO WE SLOWED IT DOWN BECAUSE IT

HAPPENS REALLY FAST.

AND WE HAVE BEEN DOING THESE

TASKS IN MICE FOR A REALLY LONG

TIME.

AND THEY ARE REALLY INFORMATIVE

AND CAN GET REALLY HARD AND WE

CAN MAKE THEM SOPHISTICATED AND

COMPLEX AND DO REVERBALS BUT IT

TAKES A REALLY LONG TIME.

LIKE IT TAKES US 15 DAYS TO GET

HIM FOOD RESTRICTED AND

PRE-TRAINED BEFORE WE START

ASKING HIM THE QUESTION WHICH IS

CORRECT, SPIDER OR PLANE?

AND SO, THAT'S ALSO WHERE I

THOUGHT THE RATS WOULD GIVE US A

BIGGER SIGNAL SO WE STARTED

USING RATS NOW IN THE TOUCH

SCREEN AND WE CAN GET THE RATS

TO AT LEAST TOUCH THE SCREEN AND

START TO DO THE TASK IN AS YOUNG

AS PND21, WHICH IS RIGHT AT

NEONATE.

THEY ARE NOT FOOD RESTRICTED AND

ON THE FIRST DAY THEY ARE

ALREADY TOUCHING THE SCREEN.

BUT I DON'T ACTUALLY HAVE DATA

TO SHOW OW THIS YET BECAUSE WE

JUST STARTED.

AND SO, I WOULD SAY THAT THIS

TASK IS REALLY, HAS A LOT OF

POTENTIAL BECAUSE ALL THE MODELS

TO DATE SHOULD HAVE COGNITIVE

IMPAIRMENTS ALONG WITH THEIR

MOTOR DYSFUNCTION AND THIS TASK

YOU SAW THE WAY THE MOUSE WAS

MOVING BACK AND FORTH.

IT HAS VERY LOW LOAD.

LIKE YOU DON'T NEED A LOT OF

MOTOR ABILITY TO DO THESE TASKS.

THEY WERE DESIGNED TO LOOK AT

DISEASES OF NEURODEGENERATION

WHERE THE MODELS WERE LOSING

MOTOR FUNCTION BEFORE COGNITIVE

FUNCTION.

SO NOW I THINK WE CAN LEVERAGE

THAT FACT TO SOME OF OUR

NEURODEVELOPMENTAL DISORDERS AND

LOOK AT THIS IN A

NEURODEVELOPMENTAL WAY.

AND THIS JUST GOES ON TO THE

FACT THAT THOSE TOUCH SCREENS

CAN GET EVEN THOUGH THEY ARE

PRETTY SIMPLE TO LEARN THE

DIFFERENCE BETWEEN SPIDER AND

PLANE, WE CAN DO COMPLEX TASKS.

THIS IS AN EXAMPLE OF A

INFERENCE TASK THAT WOULD BE

GIVEN IN HUMANS.

IT'S LOGIC PROBLEM THAT YOU ALL

KNOW LIKE JANE IS TALLER THAN

JACK AND JACK IS TALLER THAN SUE

AND SUE IS TALLER THAN FRANK AND

YOU KNOW THAT THEY WERE IN IN
THE

MIDDLE JUST BAUDS WE HAVE ALL

DONE THOSE LOGIC PROBLEMS IN OUR

LIFE.

SO WE GIVE THE MICE THIS TASK

AND I NEVER THOUGHT THIS WOULD

WORK, WHERE WE TOLD THE MICE

THAT THE SPIDER WHEN PAIRED WITH

THE PLANE BUT INCORRECT IF IT'S

PAIRED WITH THE SPIDER BUT

CORRECT IF IT'S PAIRED WITH THE

PIN WHEEL AND SO FORTH PIN WHEEL

IS CORRECT OVER MARBLE ARRAY.

AND THEN THIS IS ACUTE PHOTO OF

HOW THE STUDY WAS DONE YEARS AGO

DEALING WITH ODORS SO THE POINT

OF THIS STUDY WAS TO SEE IF THEY

COULD DO IT WITH VISUAL STIMULI

WHICH ARE NOT AS SALIENT AS

ODORS FOR RODENTS AND THEY

COULD.

WHEN WE TESTED THEM ON THE

ANCHOR PAIRS THIS IS AE AND THIS

IS BD AND OBVIOUSLY AE IS VERY

EASY BECAUSE THE SPIDER IS

ALWAYS ALWAYS RIGHT.

IT'S NEVER BEEN WRONG.

AND PLANE, THE B HAS SOMETIMES

BEEN RIGHT AND SOMETIMES WRONG

AND SO, THEY GET IT EVEN THOUGH

IT'S MORE DIFFICULT FOR THEM.

SO I THINK IT HAS A LOT OF

POTENTIAL FOR THERE.

AND THIS IS JUST WHAT I'M GOING

TO CONCLUDE ON OUT OF NOWHERE.

AND IT DOESN'T REALLY RELATE TO

MY TALK SO FAR BUT I'M REALLY

CONCERNED ABOUT THE INBRED

GENETICS WE ARE ALWAYS FOCUSED

ON.

AND I THINK THIS SHOULD BE A

DISCUSSION POINT FOR THE GROUP

AS WELL IN MODELING.

BECAUSE WHILE INBRED MICE ARE

EXCELLENT CONTROLS FOR US AND

THAT IS WHAT WE WANT.

WE DON'T WANT MIXED BACKGROUNDS

BECAUSE WE DON'T KNOW WHAT

AFFECTS EACH BACKGROUND STRAIN

IS HAVING, IS A PURE CONGENIT

B6, THE EQUIVALENT OR ACCURATE

OF THE GENETIC DIVERSITY WE ARE

GOING TO SEE IN PATIENT

POPULATIONS?

THE ANSWER TO THAT QUESTION HAS

GOT TO BE NO.

SO, THAT'S JUST SOMETHING ELSE

TO CONSIDER.

AND THEN I'D LIKE TO THANK

EVERYBODY THAT SUPPORTS ME AND

ALL MY FUNDING SOURCES AND THE

NEME MY LAB.

THANK YOU.

[ APPLAUSE ]

>> ANN WAGNER THANK YOU, JILL.

THAT WAS GREAT.

SO WE ARE MOVING ON TO A TALK BY

JASON LERCH ON MOUSE ARRAY

IMAGING.

>> JASON LERCH:  THANK YOU FOR

THE INVITATION.

IT'S BEEN FASCINATING WORKSHOP.

I'LL TALK ABOUT MOUSE BRAIN MRI

AND ALSO JUST LIKE JILL, I DON'T

HAVE ANY DATA AT ALL ON

REGRESSION OR IMAGING REGRESSION

SO THESE ARE SOME EXISTING DATA

WE HAVE THAT MIGHT HINT AT WHAT

THESE TECHNIQUES CAN DO.

SOME OLDER EXPERIMENTS TO THROW

OUT AS A POTENTIAL THOUGHT

PROVOKING, CAN THIS BE USED FOR

ANSWERING THESE KINDS OF

QUESTIONS?

SO THE GOAL FOR ME IS REALLY DO

WE HAVE A TECHNIQUE OF MEASURING

DIVERGENCE IN TIME?

SO WHETHER IT IS REGRESSION OR

EARLY-ONSET, ET CETERA.

IN AN IN-VIVO WAY IN ANIMALS.

AND I WOULD STRESS MRI CAN DO

THIS OR COULD BE MRI OF ANY

ANIMALS BUT I'LL FOCUS ON MICE

IN THIS CASE AND GIVE TWO

EXAMPLES ON THE EMERGENCE OF SEX

DIFFERENCES IN THE BRAIN IN

EARLY POSTNATAL DEVELOPMENT AND

RATHER THAN THE REGRESSION PART,

MORE OF RESCUE PART IN TERMS OF

TREATMENT AND NOW FINISH WITH A

QUICK ASIDE ON THE HETEROGENEITY

IN AUTISM, WHAT SOME OF THE

GENETIC ORIGINS MIGHT BE AND YOU

CAN HELP WITH THAT.

AND THE TECHNIQUES WE TALKED

ABOUT WAS MRANISM RODENTS.

JUST ABOUT IDENTICAL WHETHER WE

DO IN HUMANS.

SON SEPTEMBERUALY WHAT YOU'RE

MEASURING IS THE SAME.

SO WHAT WE DO WITH MIR IN THE

MOUSE, WE HAVE TO ANESTHETIZE

THE ANIMAL.

SO IN THIS CASE, EACH ANIMAL IS

PUT ON TO THIS SLAT YOU SEE HERE

WHICH HAS RESPIRATION AND TEMP

SENSORS AND MOST PEOPLE RELY ON

HEART RATE AND BREATHING TO MAKE

SURE THE ANIMAL IS DOING FINE.

THEN PUT INSIDE THESE TUBES AND

THEN PUT INTO THIS ARRAY.

ONE OF THE THINGS WE DO

DIFFERENTLY FROM GROUPS

ELSEWHERE IS RATHER THAN IMAGING

ONE MOUSE AT A TIME, WE DO

MULTIPLE MICE AT THE SAME TIME

IN THE SAME SCANNER WITH

SEPARATE COILS FOR EACH ANIMAL

TO GIVE US THROUGHPUT WE NEED.

ONE OF THE THINGS YOU WILL FIND

IN MR IS THE SMALLER THE OBJECT

YOU'RE TRYING TO IMAGE, THE

HARDER TIME HAVE YOU WITH IT.

SO YOU CAN MAKE UP WITH THAT

WITH SOME HIGHER MAGNETIC

FIELDS, WITH SPECIALIZED

HARDWARE COILS BUT ONLY UP TO A

POINT.

SO THE EQUIVALENT OF WHAT WOULD

TAKE FOR A HUMAN IN MR SYMPT

ABOUT 5 MINUTES OR SO TO DO IN

THE CLINIC.

FOR US IT'S ANY HALF HOUR TO

HOUR-AND-A-HALF DEPENDING ON HOW

MUCH RESOLUTION YOU WANT WANT.

SO EVERYTHING TAKES LONGER AND

IS HARDER TO DO.

IN OUR CASE, WE ANESTHETIZE THE

MICE WITH ISOFLOR EN.

IN SOME CASES IF YOU NEED, YOU

CAN DO INJECTABLES BUT THEY ARE

HARD TORE KEEP CONSISTENT ACROSS

MICE.

SO THIS IS AN EXAMPLE OF WHAT IT

LOOKS LIKE IN-VIVO.

IN-VIVO WE IMAGE EITHER 100 OR

90 MICRON ISOTROPIC RESOLUTION

WHICH MEANS 90 BY 90 BY 90.

IN HUMANS THE EQUIVALENT OF WHAT

PEOPLE COMMONLY DO A MILLIMETER.

SOME YOU CAN GET TOWN TO 400 --

NOT MANY STUDIES IN KIDS THAT DO

THAT YET.

THE OTHER THING WE DO TO GET

BETTER CONTRAST, WE INJECT THE

MICE WITH MANGANESE CHLORIDE

WHICH HAS WONDERFUL MR

PROPERTIES AND A LITTLE BIT

TOXIC.

AND ALSO A CALCIUM ANALOGUE SO

YOU GET A BEAUTIFUL HIGHLY

INTENSE SIGNAL WHERE THERE IS

LOTS OF CALCIUM UPTAKE.

SO FOR EXAMPLE, THIS IS AN AXIAL

SLICE.

IF YOU LOOK AT THE DENTE

GYREEROUS, HIPPOCAMPUS, HIGHLY

ENHANCED SAME WITH OLFACTORY AND

THE THALAMUS AND CEREBELLUM

CORTEX.

SO YOU GET VERY DETAILED HIGH

RESOLUTION IMAGES THAT GIVE YOU

GOOD CONTRAST WITH WHAT THE

SHAPE OF THE BRAIN IS LIKE.

ALL THE EXAMPLES I'M GIVING YOU

IS DONE AT 7 TESLA AND IN

ADDITION TO DOING IN-VIVO SCANS

WE DO QUITE A BIT OF WORK

EX-VIVO.

TWO REASONS BUT IT DOESN'T GIVE

YOU TIME COURSES.

SO NOT THAT PARTICULARLY

RELEVANT.

BUT GIVES YOU HIGHER RESOLUTION.

SO YOU'RE ALMOST AT A

MICROSCOPIC RESOLUTION.

YOU CAN'T SEE INDIVIDUAL CELLS

YET BUT CAN DEFINITELY SEE SOME

LAYERS IN THE BRAIN QUITE

CLEARLY.

AND THIS TO GET THE THROUGH PUT

WE NEED RATHER THAN DOING ONE AT

A TIME, WE DO 16 SAY TIME SO YOU

HAVE SEPARATE COILS AND EACH ONE

OF OF THEM WILL GET A MOUSE

BRAIN.

AND THEN AGAIN, ONE OF THE BIG

REASONS FOR DOING EX-VIVO IS IT

MAKES COLLABORATIONS SO MUCH

EASIER.

GET PEOPLE TO SEND US BRAINS

RATHER THAN HAVING TO IMPORT

MICE FOR EXPERIMENTS TO THE

FACILITY.

SO ONCE WE HAVE ALL OF THE SCANS

FROM A PARTICULAR STUDY, WE USE

A SERIES OF AUTOMATED IMAGING

PROCESSING PIPELINES TO GET

INFORMATION.

I'M FOCUSING HERE.

ONE IS WE CAN TAKE A

PRE-EXISTING ATLAS, EVERY COLOR

YOU SEE OVER HERE CORRESPONDS TO

A DIFFERENT BRAIN AREA.

THAT WAS SIGNIFICANT TURED BY

INPUT ONCE AND THEN WE TAKE

THOSE IMAGES AND MAPS AND MAP

THEM BACK TO EACH INDIVIDUAL

SCAN WHICH GIVES US VOLUME OF

THE HIPPOCAMPUS AND OTHERS

ET CETERA.

SO IF YOU IMAGINE THIS IN A

CARTOON SETTING, YOU HAVE A

MOUSE WITH A LARGER BRAIN AND

ONE WITH A SMALLER, WE TWIST AND

MESH THE IMAGES ABOUT UNTIL

THERE IS AN IDENTICAL POINT, THE

AVERAGE OF ALL THE SCANS IN THE

PARTICULAR STUDY AND TAKE THE

TRANSFORM, SO WHAT DOES THIS

LOOK LIKE IN BETWEEN?

SO INVERT AND TAKE THE

DETERMINANT OF THE DEFAMATION

FIELD TOL ASK IF THIS POINT IS

ANY BIGGER OR SMALLER COMPARED

TO ALL THE OTHER MICE IN THIS

STUDY THEN WE CAN SAY IT IS

DIFFERENT BIDE AGE, GENOTYPE OR

WHATEVER ELSE.

ON TO DEVELOPMENT.

WE CAN DO THESE SCANS FROM DAY

ONE ONWARDS.

THE BREAKTHROUGH IN THIS CASE

WAS LIKE HUMAN IN CONTRAST GENE

QUITE A BIT IN EARLY LIFE.

AND I'M SURE JASON CAN TELL YOU

ALL ABOUT THE JOYS OF TRYING TO

IMAGE YOUNG KIDS AND TRYING TO

ALIGN DIFFERENT SCANS FROM EACH

OTHER.

SO THE MANGANESE CONTRAST GIVES

US THIS EQUAL CONTRAST ACROSS

THE DIFFERENT AGES.

AND TO GET MANGANESE INTO THE

BRAINS OF THE PUPS WE INJECT THE

DAM AND THEN IT GOES TO THE PUPS

FOR THE MILK.

AND SO THIS IS ONE MOUSE HERE,

SCANNED AT P1, P3, P5 -- AND YOU

CAN SEE THE BRAIN GROWING.

THIS IS A P3 PUP IN THIS CASE.

UNDER ANESTHESIA.

THEY DO PRETTY WELL.

IT TAKES A LOT OF EXPERIMENTING

AND PRACTICE TO GET USED TO IT

TO MAKE SURE THE DAM AS DON'T

CANNIBALIZE THE PUPS AFTER YOU

TAKE THEM AWAY BUT IF YOU RUB

YOUR HANDS IN ENOUGH POO IT

TENDS TO WORK.

WE CAN MAP FROM TIME POINT TO

TIME POINT SO SEE THE EVOLVING

CEREBELLUM FOILATING OVER THE

FIRST 10 DAYS OF LIFE.

HERE YOU CAN MAP THE GROWTH OVER

10% SHOWN IN COLOR AS YOU GO

FROM DAY ONE TO DAY 11 OVER

TIME.

SO THIS IS JUST NORMAL

DEVELOPMENTAL TIME WARP.

IN THIS CASE AN FEB MOUSE LINE

BUT IT GIVES US TECHNOLOGY TOW

MAP TIME COURSES FAIRLY DENSELY

EARLY POSTNATALLY ACROSS THE

CRIMINAL CALL PERIODS WE ARE

LOOKING FOR AND THEN START

ASKING QUESTIONS ABOUT IT.

SO WE HAVE BEGUN TO EXPLORE THAT

IN THE CONTEXT OF LOOKING AT SEX

DIFFERENCES IN THE BRAIN.

SO THIS IS JUST TWO CAMP PLOTS

HERE.

THIS IS THE OVERALL BRAIN VOLUME

AND IN THIS CASE WE OTHER STAKED

IMAGING AT DAY 3.

THE BRAIN IS 100 MILLIMETERS

CUBED AND THEN GROWS TO ABOUT

250 OR SO AT DAY 60 IN THIS

CASE, SORRY, IT'S 450

HEMISPHERES INTO ACCOUNT.

AND YOU CAN SEE THE MALE AND

FEMALE BRAINS ARE FAIRLY SIMILAR

IN SIZE.

ABOUT A 3-4% DIFFERENCE BY

ADULTHOOD BUT THE CONFERENCE

INTERVALS TEND TO OVERLAP.

SO FOR EXAMPLE THE NUCLEUS, ONE

OF THE MOST SEXUALLY MORPHIC

STRUCTURES IN THE BRAIN, IT'S

HARD TO SEE BECAUSE THEY ARE SO

MUCH SMALLER HERE THAN AS YOU GO

UP IN TIME.

BUT YOU CAN SEE IT SEEMS TO BE

THERE FROM THE BEGINNING AND

STUDY ROBUSTLY PRESENT IN THE

BRAIN AS TIME GOES ON.

WE CAN MAP THIS EMERGENCE AT

EVERY POINT IN THE BRAIN ACROSS

TIME.

SO IN THIS CASE, I'M DISPLAYING

IMAGES ON THE BACKGROUND OF AN

ADULT MOUSE BRAIN TO KEEP IT

CONSISTENT.

ANYTHING YOU SEE IN BLUE IN THIS

DARKER COLOR HERE IS LARGER IN

MALES AND ANYTHING YOU SEE IN

RED IS LARGER IN FEMALES.

SO AT DAY 3, THE MOUSE BRAIN IS

MOST PLEA BIGGER IN MALES AND IF

YOU CONTROL FOR BRAIN VOLUME,

YOU SEE THE NICHOLAS HERE AND

SOME OF THE BRAIN CORTEX BIGGER

IN MALES AND AS YOU GO ON IN

TIME, YOU STILL SEE NUCLEUS

BIGGER IN MALES, STAYS BIGGER IN

MALES AND LOOKS SIMILAR BY THE

TIME YOU GET TO P10.

AS YOU GET TOWARDS WINING AND

PUBERTY, THE AMOUNT OF INCREASES

IN MALES BECOME FEWER ACROSS THE

BRAIN.

NUCLEUS REMAINS.

AND THEN BY THE POINT YOU GO

THROUGH PUBERTY AND PAST

PUBERTY, YOU HAVE THE ENLARGED

CORTEX WHICH YOU SEE IN ADULTS

COMING ON PAST PUBERTY AS WELL.

SO BY P65, YOU HAVE LARGER

SENSORY CORTEX IN FEMALES AND

JUST NUCLEUS REMAINS LARGER IN

MALES IN THIS PARTICULAR CASE.

SO AGAIN, THE EXAMPLE OF HOW TO

BEGIN TO CATCH DIVERGENCE OF

TIME AND SEE WHERE THEY COME

ABOUT IN TERMS OF BRAIN SIZE.

AND LOOKING AT TREATMENT EFFECTS

IN THE MEC P2 MOUSE.

THE SAME MODEL DESCRIBED EARLIER

BUT WE USED THIS MODEL

CONDITIONAL.

SO WHAT THEY DID IS TOOK A STOP

CASSETTE ON THE -- WHICH RESULTS

IN A NULL GENE.

BUT THE STOP CASSETTE IS

SURROUNDED BY TWO LOXP SITES AND

IF YOU TAKE THE MOUSE AND GREET

IT WITH A EXPRESSION CONTROL,

YOU CAN INDUCE THAT STOP

CASSETTE BEING CUT OUT AT A TIME

POINT OF YOUR CHOOSING.

SO WONDERFUL EXPERIMENTS IN 2007

BY JACKIE GUY AND THEY FOUND

THAT EVEN IF YOU RESCUE THE MEC

P2 MOUSE IN ADULTHOOD AFTER THE

ONSET OF SYMPTOMS, YOU GET A

SIGNIFICANT RECOVERY OF THOSE

SYMPTOMS IN THIS ANIMAL.

SO IN SOME WAYS A MODEL OF WHAT

A PERFECT RESCUE WOULD BE LIKE.

BECAUSE YOU'RE TURNING THE GENE

BACK ON AND THIS WAS THE WORK

OF --

[ INDISCERNIBLE ]

SO THE WAY WE SET IT UP IS

SYMPTOMS BEGIN TO EMERGE IN DAY

20 OR 25.

WE HAVEN'T REALLY LOOKED THAT

MUCH EARLIER BUT THE CORE MOTOR

SYMPTOMS RELEASE AROUND THEN.

WE RE-ACTIVATED DAY 50 AND

BECAUSE OF THE MOUSE, YOU CAN

GIVE THE TAMOXIFEN REACTIVATION

ALL AT ONCE.

IT WOULD KILL THE ANIMAL.

DO IT OVER A PERIOD OF 4 WEEKS

EAR SO AND WE ADD IMAGING TIME

POINT BEFORE AND AFTER.

AND JUST TO CONVINCE YOU, THIS

IS WHAT A EXPERIMENT SHOULD LOOK

LIKE BEHAVIORALLY.

SO THIS IS A 7-DAY OLD MEC P2

MOUSE, HAVE HAVE ALL THE TREMORS

AND THEN YOU SEE NEXT ONE OF THE

TWO MICE IS THE SAME MOUSE YOU

SAW JUST NOW BUT AFTER

REACTIVATION.

THIS ONE UP HERE.

AND YOU SEE HIM MOVING AROUND.

THERE IS SOME SLIGHT WIDENING OF

STANCE, NOT PERFECT RECOVERY BUT

BASICALLY BECOME MOBILE AGAIN.

BEHAVING MOSTLY NORMALLY

COMPARED TO THE SEVERE STATE IT

WAS IN BEFORE.

SO IF YOU LOOK AT BODY WEIGHT AT

DAY 50 AND I HAVE EVERYTHING IN

THREE COLORS.

RED IS THE CONTROLS.

SO MEC P2 IS FUNCTIONAL.

IN GREEN YOU HAVE THE

RE-ACTIVATED SO WHEN WE STARTED

TO TURN THE GENE BACK ON.

AND IN BLUE YOU HAVE THE SILENT.

SO BODY WEIGHT, INCREASES A BIT

IN THE SILENT MICE AT DAY 80.

NO NOTICE AT DAY 50.

PHENOTYPE SCORE AN EXTRA POINT

FOR EVERYTHING THAT GOES WRONG

SO FOR THE BREATHING PROBLEMS

AND TREMORS AND MOTOR

IMPAIRMENTS, YOU HAVE SOME

ALREADY PRESENT AT DAY 50 WHEN

WE START THE TREATMENT AND THEN

IF YOU GO ON TO DAY 80, THE MICE

RE-ACTIVATED SHOW NO CHANGE IN

TIME OR SIGNIFICANT WORSENING OF

SYMPTOMS IF YOU GIVE THEM OIL

RAN TAMOXIFEN.

WE WERE STARTING TO GET INTO

BRAIN IMAGING DATA OR EVEN AT

DAY 50, THE MEC P2 HAVE SMALLER

BRAIN VOLUME AND AS TIME GOES

ON, IF YOU RESCUE THE MICE, THE

BRAIN VOLUME DOESN'T INCREASE

BUT IT STAYS CONSTANT.

MICE GIVE OIL INSTEAD SHOW

CONTINUING DETERIORATION IN

TERMS OF TOTAL BRAIN VOLUME.

SO YOU ARRESTED VOLUME AND

DECREASES AND NOT CAUSING ANY

FURTHER INCREASES.

IF YOU LOOK LOCALLY, BEGIN TO

MAP WHERE THESE AFFECTS ARE

OCCURRING.

SO THIS IS THE DIFFERENCE IN

TIME BETWEEN DAY 50 AND 80 IN

MEC P2 SILENT WHERE BLUE IS

DECREASES AND SMALL RES AREAS

ARE INCREASES.

SO THE MEC P2 MICE CONTINUE TO

LOSE A LOT OF CORTICAL VOLUME,

LOOSE CEREBELLUM VOLUME AS WELL.

HIPPOCAMPAL VALIUM AS YOU SEE

HERE.

THE RESCUED MICE STILL LOSE SOME

CORTICAL VOLUME, SPELL FRONTAL

CORTEX AND CINGULATE.

BUT SIGNIFICANT GAINS IN VOLUME

IN STRAIGHT AND CEREBELLUM AND A

FEW CORTICAL AREAS AS WELL.

AND IF YOU TAKE THE DIFFERENCE

AND PLOT IT OUT, IF YOU LOOK

OVER HERE IN THE SINGULAR

CORTEX, IT STARTS LARGER IN THE

MICE THAT HAVE FUNCTIONAL MEC

P2, STAYS ABOUT THE SAME SIZE

50-80 AND NO AFFECT OF RESCUE IN

THIS PARTICULAR PART OF THE

BRAIN SINGULAR CORTEX.

SO TWO LINES ARE THE SAME.

IF YOU LOOK AT THE NUCLEAR SER

CUMBENCE, IT CONTINUES TO GROW

IN THE WILD TIKES AND SHRINK IN

THE SILENT APPLIES AND FULL

FUNCTIONAL RECOVERY IN THE

RESCUED MICE.

IT'S A FAIRLY STRONG MOTOR

NETWORK WHERE THE STRONGEST

AFFECTS WE SEE IN THEERN

CUMBENCE AND NUCLEUS AND

CEREBELLUM AND NUCLEI AND

BRAINSTEM AND MUGGED LA AND VTA

RECOVERY AS WELL.

IF YOU GET A STRONG MOTOR

NETWORK OF RECOVERY.

IN SOME PARTS OF THE RAIN, DONE

SEEM TO RECOVER AFTER TREATMENT.

THEN A QUICK ASIDE.

WE HAD A FEW MICE WHERE WE

RESCUED THE ONES SILENT AND

STARTED TO RESCUE THEM AT DAY 80

ONWARDS.

SO IF YOU LOOK OVER HERE, AT DAY

50, THE THREE RESCUE GROUPS,

SMALLER BRAIN VOLUMENTS.

ARREST THE BRAIN VOLUME AT DAY

80.

AND THEN THE PURPLE ARREST THEM

FURTHER DETERIORATION OF BRAIN

VOLUME IF YOU START REACTIVATE

AT DATE 80.

SO YOU CAN STOP THE PROGRESSION

WHEN YOU START TREATING IN THIS

CASE AND LOCALLY YOU CAN RESCUE

EVEN MORE.

SO I'LL FINISH WITH A QUICK

ASIDE TO BRING THIS MORE BACK TO

AUTISM.

WE HAVEN'T DONE TIME COURSES.

WE ARE TRYING TO GET AS MANY

MOUSE MODELS AS WE CAN.

SO IN THIS CASE HERE IN THE Y

AXIS, YOU HAVE THE AFFECT SIZE

MEASURES IN STARRED DEVIATION SO

EACH MOUSE LINE WAS COMPARED TO

OWN CONTROL FROM THE SITE WE

WERE GETTING IT FROM.

AND THEN EAR HERE HIPPOCAMPUS

AND TOTAL BRAIN VOLUME.

26 DIFFERENT LINES ARE OV HERE

AND THEY RANGE FROM SIGNIFICANT

DECREASING IN BRAIN VOLUMES AND

EVERYTHING IN BETWEEN.

SO WE KNOW THE HETEROGENEITY WE

ARE SEEING SEEMS TO GO ALL THE

WAY FROM THE GENETICS TO THE

FINAL OUTCOME WE SEE AND ISN'T

JUST ON VARIABILITY WE SEE IN

HUMANS AS WELL.

SO HERE ARE POSSIBLE NEXT SNIPPS

TERMS OF LONGITUDINAL DATA.

I THINK THIS LONGITUDINAL

IMAGING HAS A LOT OF PROMISE IN

BEING ABLE TO CATCH REGRESSION

AND DIVERGENCE IN TIME BECAUSE

IT IS IN-VIVO.

WE CAN DO IT IN FAIRLY DENSE

TIME COURSES, VERY EARLY.

THERE ARE REALLY A LOT OF OR TWO

MAIN CAVEATS I WANT TO POINT

OUT.

ONE IS THAT EVEN THOUGH IT CAN

BE DONE IN-VIVO, IT IS STILL

SOMEWHAT INVASIVE.

IN OUR CASE WE ARE GIVING THE

MICE MANGANESE BUT MORE

IMPORTANTLY WE ARE ANESTHETIZING

THEM.

WE KNOW THERE IS AN AFFECT IN

ANESTHESIA IN ANIMALS AND HAVING

TO TAKE THEM AWAY FROM THEIR

MOMS AND NO WAY AROUND THOSE

PARTICULAR CONFOUNDS AND THEY

MIGHT INTERACT WITH WHATEVER

GENETIC MOUSE MODEL YOU'RE

LOOKING AT AND THEN THE USUAL

PROBLEM WE FIND VERY SENSITIVE

TO SUBTLE CHANGES IN THE BRAIN

BUT NONSPECIFIC TO WHAT THE

UNDERLYING CELLULAR AND

MECHANICAL CHANGES MIGHT BE.

SO I'LL FINISH WITH THAT AND

TURN OVER TO NEXT SPEAKER IN THE

DISCUSSION.

[ APPLAUSE ]

>> ANN WAGNER:  THANK YOU VERY

MUCH, JASON.

SO, NOW AS ELIZABETH SAID, WE

ARE DOING THREE SHORT

PRESENTATIONS BY SOME FOLKS

TALKING ABOUT SOME DIFFERENT

MODELS.

SO ERIC MORROW IS GOING FIRST.

>> ERIC MORROW:  SO I SUPPOSE

NOW WE'LL HAVE SHORT TALKS AND

THEN HAVE THE PANEL LEAD THE

DISCUSSION:  SO AS A DISCUSSANT,

I DON'T HAVE A SLIDE BUT I'LL

TELL YOU A LITTLE BIT ABOUT ME

AND HOW I HAVE COME TO THIS

CONFERENCE AND THEN I'LL DO MY

BEST TO PULL TOGETHER A COUPLE

OF THE THOUGHTS FOR THE PURPOSES

OF DISCUSSION.

I THINK I WAS ASKED JUST TO TAKE

3-5 MINUTES.

SO, I'M A BROWN UNIVERSITY,

NEURODEVELOPMENTAL BIOLOGIST AND

A GENETICIST.

I WORK IN PATIENTED WHO HAVE

RARE GENETIC SYNDROMES THAT ARE

RELATED TO AUTISM AND THEN MOUSE

AND STEM CELL MODELS AND IN

PARTICULAR, I WORK IN A SYNDROME

CALLED, CHRISTENSEN SYNDROME, AN

AUTISM-RELATED DISORDER THAT

INVOLVES REGRESSION AND I GAVE A

TALK ABOUT CHRISTIANSEN SYNDROME

AND I THINK IT RESONATED WITH

AUDREY WHERE WE TALKED ABOUT

WHERE I PRESENTED -- I THINK

WHAT I WOULD LIKE TO SEE FOR

THIS FIELD OF REGRESSION AND I

CAN'T PRESENT OUR RESULTS

BECAUSE IT'S STILL ONGOING.

WE DON'T HAVE THIS MODEL

EXPERIMENTAL MODEL SYSTEM IN MY

LAB.

BUT THIS IS WHAT WE ARE TRYING

TO STRIVE FOR AND I THINK IT

WOULD BE VALUABLE IN THE FIELD.

WHICH IS WE HAD SOME SORT OF

EXPERIMENTAL SYSTEM WHICH I

THINK WOULD INVOLVE AN

EXPERIMENTAL ANIMAL.

IN OUR CASE WE ARE USING MOUSE,

WHERE WE HAVE AN ANTI-SEED ENT

OF SOME KIND SO PERHAPS INSULT.

FOR SOME ANTECEDENT IT FLOODS

BEHAVIOR THAT MODEL REGRESSION.

AND THEN LOOK AT THE MOLECULAR

AND PERHAPS NEUROPHYSIOLOGICAL

LEVEL AND SEE A CHANGE THERE IN

A CIRCUIT IS STRONGLY CORRELATED

WITH THE CHANGE IN BEHAVIOR IN A

CAUSED AND AFFECT SORT OF WAY.

SO THAT IF YOU DON'T HAVE THE

ANT SEED ENTER, THE DON'T HAVE

THE CHANGE.

YOU DON'T HAVE THE CHANGE IN

BEHAVIOR, IF YOU CAN RESCUE THE

MORPHOLOGICAL OR MOLECULAR

CHANGE REGARDLESS OF THE

ANTECEDENT, YOU RESCUED THE

BEHAVIORAL LOSS.

AND THAT IS SOMETHING THAT I

THINK WOULD BE VERY IMPORTANT

FOR THE FIELD.

IN A WAY, I FEEL LIKE WE CAN

DISCUSS THIS AT THE DISCUSSION

PERIOD.

WE ARE NOT QUITE THERE, ALTHOUGH

THIS HAS BEEN A REALLY EXCITING

CONFERENCE TO SEE THAT THERE ARE

MANY, MANY PIECES I THINK IN

HAND AND WE COULD OR SHOULD BE

THERE, IF NOT NOW, SOON.

AND THAT'S OPEN FOR DISCUSSION.

SO I'LL INTRODUCE A COUPLE OF

THINGS FROM THE POINT OF VIEW

FROM GENETICS.

BECAUSE I THINK I WAS SUPPOSED

TO TALK A LITTLE BIT ABOUT

GENETICS.

SO THERE ARE GOOD NEWS FROM THE

GENETICS IN AUTISM, THERE ARE

NOW MANY, MANY DIFFERENT GENETIC

LOCI THAT HAVE BEEN IMPLICATED.

I'M GOING TO ARGUE AND THIS IS

OPEN FOR DISCUSSION, THAT I

THINK A LOT OF THE RECENT

FINDINGS IN GENETIC HAVE FOCUSED

A LOT ON GENE CORRELATION FROM

NETWORKS FROM THE ALLEN BRAIN

ATLAS FROM THE POINT OF VIEW

FROM REGRESSION OF FOCUS NESTS

MY VIEW, IN THE WRONG

DEVELOPMENTAL EPIC TO LOOK AT

REGRESSION.

SO I THINK SOME OF THE MOST

IMPORTANT PAPERS RECENTLY MATT'S

GROUP AND DAN'S GROUP, WHERE

THEY CORRELATED THE DE NOVO GENE

NITS AUTISM WITH GENE

CORRELATION NETWORKS THAT HAVE

FOCUSED DOWN ON THE BIOLOGY OF

INTRAUTERINE EVENTS, IN

PARTICULAR DEEP LAYER CORTICAL

PROGRAM TAR NEURONS DURING THE

SECOND TRIMESTER.

WE CAN DISCUSS THIS BUT I THINK

THAT WHILE THAT BIOLOGY IS

PROBABLY RELEVANT, I THINK THAT

IS SORT OF A LAMP POST AFFECT.

AND THAT BIOLOGY MAY NOT BE AS

RELEVANT TO WHAT WE'RE TALKING

ABOUT TODAY.

I THINK THAT IPSCs IS ANOTHER

REALLY IMPORTANT AREA.

I THINK ALYSSON'S WORK PRESENTS

THAT AS DOES OTHER WORK.

BUT THE QUESTION THERE TOO IS,

ARE THE IPSCs REALLY GOING TO

GET US TO SOME OF THE LATER

CIRCUIT EVENTS, CIRCUIT-BASED

EVENTS POSTNATAL BRAIN

DEVELOPMENT THAT HAVE BEEN THE

FOCUS OF THE DISCUSSION TODAY?

AND WE CAN TALK ABOUT THAT.

THERE ARE WAYS TO PUSH THOSE

MODELS, FOR EXAMPLE CAME ERIC

MODELS BY PUTTING THEM INTO

ANIMAL MODELS AND LOOKING AT

CIRCUIT-BASED EVENTS THERE.

BUT SO I PUT THIS UP FOR

DISCUSSION ON WHETHER THE

IPSCs WILL GET US THERE.

WE REALLY NEED ANIMAL MODELS AND

WHETHER THEY ARE THE MOUSE OR

WHETHER WE WANT TO LOOK FORWARD

TO PEOPLE EMPLOYING NONHUMAN

PRIMATE TO GET US TOWARDS ANIMAL

MODEL THAT IS CLOSER TO HUMAN.

SO ONE OF THE LAST THOUGHTS I'LL

END ON AND I THINK IT FOLLOWS

NICELY FROM JASON'S TALK IS, DO

WE REALLY HAVE -- AND THE

EARLIER TALK WITH JILL.

DO WE HAVE THE BEHAVIORAL AS

WELL AS THE NEUROIMAGING METHODS

TO REALLY SEE WHAT WE WANT TO

SEE?

SO THE MRI IMAGING IS POWERFUL

AND I WAS VERY IMPRESSED TO SEE

DATA OF THE MRI AND THE RETT

MOUSE.

BUT IS THAT GOING TO REALLY GET

US DOWN TO THE CIRCUIT-BASED

CHANGE THAT IS WE REALLY WANT TO

SEE?

OR ARE WE GOING TO REALLY LOOK

FORWARD TO NEW IMAGING

METHODOLOGIES LIKE LIGHT SHEET

MICROSCOPY, TISSUE -- BRAIN

TISSUE CLEARING AND LIGHT SHEET

MICROSCOPY?

TO REALLY UNDERSTAND HOW THE

CIRCUIT-BASE CHANGES MIGHT BE

CORRELATED WITH REGRESSIVE

BEHAVIOR.

I WAS ENCOURAGED, I GUESS OUR

SCHIZOPHRENIA COLLEAGUES HAVE

LEFT BUT ONE OF THE VERY

INTERESTING QUESTIONS IN

POST-NATAL BRAIN DEVELOPMENT AS

IT RELATES TO NEUROPSYCHIATRIC

DISORDERS IS THE QUESTION OF

SCHIZOPHRENIA AND WHY DOES

SCHIZOPHRENIA PRESENT WHEN IT

PRESENTS?

I'LL JUST OPEN THAT UP AS A

QUESTION AS IT HAS BEEN EARLIER.

IS THE POSTNATAL BRANCH CHANGES

WE ARE THINKING ABOUT IN

REGRESSION MAY BE SIMILAR AT A

CELL BIOLOGICAL LEVEL AT LEAST

TO SCHIZOPHRENIA AT AT LEAST A

SUBSET OF REGRESSION IN AUTISM?

AND AT THE END, I THINK I'LL

JUST LAY THIS OUT AS A POINT FOR

DISCUSSION.

I THINK ONE OF THE THINGS THAT

WERE VERY INTERESTED IN

REGRESSION FOR IS NOT JUST THAT

IT'S AN IMPORTANT AND

INTERESTING BIOLOGICAL

PHENOMENON BUT IS IT POTENTIALLY

A TREATMENT TARGET FROM THE

POINT OF VIEW THAT IF WE WERE

ABLE TO PREVENT REGRESSIONS

COULD WE HELP OUR PATIENTS

ATTAIN A BETTER OUTCOME?

AND EVEN MORE SO IF WE

UNDERSTOOD WHAT THE ANTECEDENTS

WERE FOR REGRESSION, COULD WE

POTENTIALLY PREVENT THOSE

ANTECEDENTS AND PREVENT

REGRESSION AND IN THIS WAY, IS

IT A NEW TREATMENT TARGET FOR

WHICH IT IS IMPORTANT TO

UNDERSTAND THE BIOLOGY OF IT AND

THE ANTECEDENT?

SO THAT'S JUST MY INTRODUCTORY

COMMENTS.

I DON'T KNOW IF IT WAS 3-5

MINUTES JUST FOR THE DISCUSSION

PERIOD.

>> ANN WAGNER:  THANK YOU THAT

WAS PERFECT.

[ APPLAUSE ]

SO WE WILL HEAR FROM SHARON

JULIANO.

>> SHARON JULIANO:  THANK YOU

VERY MUCH FOR ASKING ME TO DO

THIS.

IT'S REALLY GIVEN ME AN

OPPORTUNITY TO SEE SOME VERY

EXCITING AND INTERESTING DATA

AND INFORMATION AND SO, I WAS

INVITED HERE TO PRESENT SOME

INFORMATION ABOUT THE FERRET AS

AN INTERESTING MODEL TO USE FOR

DEVELOPMENTAL DISORDERS AND

ESPECIALLY FOR LOOKING AT SOME

PROBLEMS ASSOCIATED WITH

REGRESSION.

WHAT I'M GOING TO DO IS NOT

REALLY SHOW YOU ANY OF OUR DITA

OR ANYTHING LIKE THAT, BUT I'VE

JUST PICKED OUT A FEW FEATURES

THAT I KNOW ABOUT HAVING WORKED

WITH THE FERRET FOR ALMOST A

MILLION YEARS, AND HOPE THEY ARE

INTERESTING TO YOU.

SO, THIS IS -- IT WASN'T SO LONG

AGO WHEN I FIRST STARTED WORKING

WITH THE FERRET, THAT PEOPLE DID

NOT KNOW WHAT A FERRET LOOKED

LIKE.

SO, I OFTENTIMES USE THIS

PICTURE WHICH IS PAINTED BY

LEONARDO DIVINCI IN THE 14

HUNDREDS.

I FORGET THE EXACT TITLE NOW.

IT'S SOMETHING LIKE WOMAN

HOLDING A FERRET.

AND IF ANY OF YOU SAW MONUMENT

MEN, THIS WAS ONE OF THE IMAGES

THAT SHOWED UP AT THE END THERE

THAT WAS BEING RETURNED FROM

BEING STOLEN BY THE NAZIS.

SO THESE ARE FERRETS.

SO THIS IS A PICTURE ON THE TOP

THERE, THIS IS -- ON THE TOP IS

SHOWING THIS IS AN ADULT FERRET.

AND ON THE BOTTOM IS PART OF A

MOUSE BRAIN, AN ADULT MOUSE

BRAIN, AND SOME OF THE FEATURES

I WANTED TO POINT OUT THAT ARE

VERY DIFFERENT BETWEEN THE MOUSE

AND THE FERRET IS THAT THE

FERRET IS A GIANT -- ANIMAL.

SO HAS SOLSA AND GIRYE SIMILAR

TO THE HUMAN (?) AND ALSO HAS

LOTS OF WHITE MATTER AND THE

RATIO OF THE WHITE TO GRAY

ESTIMATOR VERY SIMILAR TO WHAT

WE SEE IN HUMAN WHICH IS VERY

DIFFERENT FROM WHAT WE SEE IN

THE MOUSE.

PRACTICALLY JUST THE CHORPUS

CALLOSUM AND THAT'S T OVERALL

MORPHOLOGY OF THE BRAIN AND WHAT

IT LOOKS LIKE IS MUCH MORE

SIMILAR TO A HUMAN THAN IT IS TO

RODENTS OR MANY OTHER SMALLER

ANIMALS.

ONE OF THE THINGS IS THE

HIPPOCAMPUS.

THE HIPPOCAMPUS IN THE MOUSE HAS

NEVER MIGRATED LIKE WE HAVE IN

THE HUMANS, AND THIS IS

ACTUALLY -- THE HIPPOCAMPUS IS

JUST BEGINNING HERE.

JUST A LITTLE ANTERIOR TO THE

HIPPOCAMPUS.

THIS IS WHERE IT IS IN THE HUMAN

AND THIS IS WHERE IT IS IN THE

FERRET AS WELL.

SO THIS IS JUST SOME OF THE

MORPHOLOGY THAT MAKES A FERRET

AN INTERESTING ANIMAL TO LOOK

AT.

NOW, THERE ARE ALSO SOME OTHER

PROCESSES THAT GO ON

DEVELOPMENTALLY, WHICH ALSO MAKE

THE FERRET A VERY INTERESTING

ANIMAL TO STUDY.

SO, SOME OF THE THINGS, THERE IS

MANY OF THEM BUT I JUST POINT

OUT A COUPLE OF THEM HERE.

SO, I'M SURE MOST OF YOU KNOW

THAT WHEN THE CEREBRAL CORTEX

DEVELOPS, THIS IS IN A MOUSE,

THERE IS A ZONE THAT LINES THE

VENTRICLE CALLED THE VENTRICULAR

ZONE, CELLS ARE GENERATED HERE

AND THEY MIGRATE INTO THE CORTEX

AND THIS IS GOING THIS WAY HERE

IN THE MOUSE AND YOU CAN SEE

THESE CELLS ARE GENERATED AND

THE CORTEX GETS BIGGER AND

BIGGER BUT OF COURSE WE MAY IT

IS IN THE MOUSE.

NOW THE OTHER THING THAT IS

INTERESTING ABOUT THIS

DEVELOPMENT IS THAT OVER THE

PAST FAIRLY RECENT, THE PAST

SEVERAL YEARS, WE HAVE REALIZED

THAT THERE ARE A COUPLE

PROLIFERATIVE ZONES OF SO IT'S

NOT JUST A VENTRICULAR ZONE

SHOWN VERY BIG HERE BUT AS THE

ANIMAL DEVELOPS, THERE ARE OTHER

VENTRICULAR ZONES OUTSIDE OF

HERE CALLED THE INNER AND OUTER

SUB VENTRICULAR ZONE.

SO THESE REGIONS ARE DIVIDED UP

AND THESE REGIONS ALSO ARE

PLACES OF CELL PROLIFERATION.

SO THERE IS CELL PROLIFERATION

GOING ON IN THOSE ZONES AS WELL

BUT IN THE MOUSE, WHAT YOU FIND

IS THAT THESE ZONES ARE NOT VERY

WELL DIFFERENTIATED BETWEEN THE

INNER AND OUTER SUBVENTRICULAR

ZONE.

AND IN THE FERRET, LIKE WE SEE

IN THE HUMAN, YOU HAVE THE SAME

KIND OF GENERAL ORGANIZATION.

YOU HAVE THE VENTRICULAR ZONE,

CELLS ARE MIGRATED IN AND AS THE

ANIMAL DEVELOPS, YOU HAVE A VERY

CLEAR DIFFERENTIATION BETWEEN

THE INNER AND OUTER

SUBVENTRICULAR ZONES AS WE DO IN

THE HUMAN THAT ARE ALSO VERY

DISTINCT SOURCES OF CELLS THAT

ARE MIGRATING INTO THE CORTEX.

WE STILL DON'T KNOW EXACTLY WHAT

CELLS ARE BEING GENERATED IN THE

ZONES.

THEY MAY BE GLIAL SELLS,

ASTROCYTES, WHICH WOULD BE VERY

INTERESTING.

BUT THEY ARE VERY IMPORTANT TO

OVERALL DEVELOPMENT OF THE

CEREBRAL CORTEX AND THEY ARE

VERY DIFFERENT IN THE MOUSE AND

THE FERRET.

NOW, I SHOULD SAY I THINK I

JUST -UE CAN ALSO SEE THE KIND

OF DEVELOPMENTAL PATTERN OF

SOLSIGH IN THE FERRET HERE AND

THIS IS P7 AND -- SO THE FERRET

STARTS OUT AS BEING

[ INDISCERNIBLE ]

BUT THIS GOES TO P7 BUT BY P14,

THE SULSIGH AND GIRYE ARE PRETTY

MATURE.

SUBSTANTIAL DEVELOPMENT OCCURS

POSTNATALLY IN THE FERRET.

SO THIS IS AN EXAMPLE FROM ONE

OF OUR STUDIES WHERE WE HAVE

MADE A SLICE OF POSTNATAL FERRET

BRAIN AND STUDYING NEURONS AS

THEY MIGRATE INTO THE CEREBRAL

CORTEX.

SO POSTNATALLY, DEPENDING ON THE

PERIOD OF CORTEX OR THE PART OF

THE CORTEX YOU'RE LOOKING AT,

DEVELOPMENT CAN OCCUR OVER

SEVERAL WEEK PERIOD.

THIS IS AFTER BIRTH BUT

MAINSAILS ARE MIGRATING INTO THE

BRAIN.

SO WHAT THAT MEANS -- MANY

CELLS -- SO THAT MEANS THERE ARE

A NUMBER OF MANIPULATIONS THAT

YOU CAN DO SO WHEN YOU WORK WITH

THE POSTNATAL FERRET, IT'S LIKE

WORKING WITH AN EMBRYONIC MOUSE

WHICH IS NOT THE SAME AS HUMAN

BUT IT IS AN INTERESTING FEATURE

THAT COULD BE USED

EXPERIMENTALLY TO GREAT

ADVANTAGE.

AND THEN, THE LAST SLIDE I HAVE

IS JUST FROM A VERY OLD PAPER OF

OURS WHERE WE WERE LOOKING AT

CORTICAL GENESIS IN THE FERRET

AND AGAIN, I JUST WANT TO POINT

OUT THAT IN THE FERRET, THE

PERIOD OF CORTICOGENESIS IS

PROTRACTED.

AS IT IS IN A HUMAN.

SO IT TAKES A LONG TIME FOR A

NEURON TO BE GENERATED AND

MIGRATE INTO THE CEREBRAL

CORTEX, WHICH IS ALSO AN

IMPORTANT FEATURE.

AND THEN HERE IS A PICTURE OF

THE POSTNATAL, THIS IS NOT TO

SCALE BY THE WAY.

OF THE POSTNATAL FERRET JUST

SHOWING THE LAYERS HAVE NOT

FORMED YET AND THERE IS STILL

MIGRATING INTO THE CEREBRAL

CORTEX.

SO I END ON THIS SLIDE.

I WANTED TO HOPE MAYBE DISCUSS

THIS A LITTLE BIT FURTHER AS TO

SOME OF THE OTHER REASONS WHY

THIS MIGHT BE A GREAT MODEL TO

STUDY DEVELOPMENTAL DISORDERS.

JUST MENTION THAT WE DO STUDY

DEVELOPMENTAL DISORDERS IN OUR

LAB SO WE'RE NOT EXACTLY AUTISM,

BUT SIMILAR.

SO WE HAVE A LOT OF INFORMATION

ABOUT HOW USEFUL THIS MODEL

MIGHT BE.

THANK YOU.

[ APPLAUSE ]

>> ANN WAGNER:  THANK YOU,

SHARON.

WE HAVE KARIN PARKER WHO WILL

TALK ABOUT PRIMATE MODELS.

>> KARIN PARKER:  I WANT TO

THANK THE ORGANIZERS.

I THINK I WAS BROUGHT IN TO BE

THE PRIMATE DISRUPTER.

SO I'M GOING TO GIVE YOU A BRIEF

OVERVIEW OF THE WORK MY LAB

DOES, TALK A BIT ABOUT WHAT I

THINK WE NEED TO BEEN

CONCEPTUALLY IN REMEMBERS IT OF

BUILDING GOOD, VALID ANIMAL

MODELS THAT HAVE TRANSLATIONAL

UTILITY AND THEN TALK A LITTLE

BIT ABOUT THE PRIMATE WORK WE

ARE DOING IN WAY TO LEVERAGE THE

MODELS WE HAVE BUILT TO THINK

ABOUT ADDRESSING REGRESSION.

SO, I RUN THE SOCIAL

NEUROSCIENCES RESEARCH PROGRAM

AT STANFORD AND WE STUDY COMPLEX

SOCIAL FUNCTIONING BOTH ATYPICAL

AND TYPICAL IN HUMAN AND

NONHUMAN PRIMATES.

AND SO, THE CLINICAL PIECE OF

OUR WORK HAS INVOLVED BIOMARKER

DISCOVERY.

NEUROPEP TIES AND OXYTOW SIN --

WE HAVE DONE WORK AT LOOKING AT

SOCIAL FUNGING IN KIDS WITHIEDIO

PATHIC AUTISM AND WILL TWO

ONGOING TREATMENT TRIALS, ONE

ADMINISTERING OXYTOCIN WHICH

SHOULD BE CLOSING SOON, AND THEN

THE FIRST IN THE WORLD STUDY OF

INTRANASY -- FUNDED BY NIMH AND

WE SHOULD HAVE DATA ON THAT

PRETTY SOON AS WELL.

WE HAVE ALSO HAD BECAUSE I

HAD -- MY CORE BACKGROUND HAS

BEEN IN DEVELOPING NOVEL MONKEY

MODELS OF NEUROPSYCHIATRIC AND

NEURODEVELOPMENTAL DISORDERS, WE

HAVE STARTED BUILDING FUNDING

WITH THE NICHD, A MONKEY MODEL

THAT CAPITALIZES ON NATURALLY

OCCURRING INDIVIDUAL DIFFERENCES

IN SOCIAL FUNCTIONING AND I'LL

RETURN TO THAT AT THE END OF THE

TALK.

AND IN THAT, WHAT WE ARE TRYING

TO DO IS PARALLEL LINES OF WORK

WHERE WE DO BIOMARKER DISCOVERY

AND THEN HOPEFULLY BIOMARKER

INFORMED THERAPEUTICS IN THESE

MONKEY MODELS.

I APOLOGIZE.

I HAVE A LITTLE BIT OF A LIKE

CHUCK, I THINK I HAVE A LITTLE

BIT OF LARYNGITIS.

SO THESE ARE REALLY CRITICAL

QUESTIONS THAT I THINK SPAN ALL

MODELS, JILL AND I HAD A GREAT

CHAT EARLIER TODAY ABOUT REALLY

THINKING DEEPLY ABOUT THESE

ISSUE.

SO ONE, WE NEED TO THINK ABOUT

ONSET.

LOTS OF TIME WE ARE STUDYING

ADULT ANIMALS BUT NOT MUCH

EMPHASIS ON THINKING ABOUT AS

JILL SAID IN HER TALK, THINKING

ABOUT WHAT IS THE REAL

NEURODEVELOPMENT OF NEUROTYPICAL

RODENTS OR NEUROTYPICAL MONKEYS?

THERE IS PEASES OF THIS BUT

THERE HASN'T BEEN A CONCERTED

EFFORT TO THINK ABOUT THAT AND

IF WE ARE GOING TO BE THINKING

ABOUT REGRESSION, WE NEED TO

HAVE A REALLY CLEAR

UNDERSTANDING OF WHAT

NEUROTYPICAL DEVELOPMENT LOOKS

LIKE TO BE ABLE TO GET A

FOOTHOLD INTO THINKING ABOUT

REGRESSION.

WE ALSO, JILL AND I PROBABLY

SHOULD HAVE DONE THIS TALK IN

TANDEM BECAUSE THE OTHER DIRTY

SECRET IS THAT A LOT OF THIS

STUFF UNTIL VERY RECENTLY HAS

ALWAYS BEEN DONE IN MALES WHICH

IN THIS DISEASE, MAY NOT BE A

BAD THING.

BUT I THINK THE FLIP SIDE OF

THAT IS FEMALES CAN BE PROTECTED

AND WE CAN LEARN A LOT FROM

FEMALES AND WE NEED TO BE

THINKING ABOUT THE SYSTEMS AND

MODELS WE STUDY AND THINK ABOUT

WHETHER IS THERE A GENDER BIAS

PREVALENCE IN THE EXPRESSION OF

THESE BEHAVIORAL AND BIOMARKER

OR CIRCUITS WE ARE INTERESTED

IN.

THERE IS ALSO THE ISSUE OF

HOMOLOGUES VERSUS ENDOPHENOTYPIC

ANIMAL MODELS.

SO DOING WITH SOMETHING LIKE

DIABETES, YOU CAN HAVE A

HOMOLOGOUS ANIMAL MODEL.

YOU CAN HAVE DIABETES IN A

ANIMAL.

THIS SUGGESTER KEY KEY POINT.

I THINK IT'S VERY DIFFICULT TO

SAY EVEN WITH A MONKEY WE HAVE

AN AUTISTIC MONKEY.

I HAVE NEVER NEVER WRITTEN A

GRANT APPLICATION THAT SAYS I

HAVE AN AUTISTIC MONKEY.

WHAT IS CRITICAL IS TO THINK

ABOUT WHAT YOU'RE MOST

INTERESTED IN OR WHERE YOU HAVE

THE STRONGEST PLAY.

FOR US, WE HAVE BEEN FOCUSED ON

CORE SOCIAL DEFICITS SO WE HAVE

A PHENOTYPIC PIECE OF THIS

AUTISTIC MODEL AND ALSO FACE

VALIDITY.

SO WE WANT TO MAKE SURE THAT WE

WORRY MEASURING IN ANIMALS IS

FACE VALID WITH WHAT WE SEE IN

TERMS OF SYMPTOMS WE SEE IN

PATIENTS.

AND SOY THING CAN BE TRICKIER

ACROSS DIFFERENT LEVELS OF

ANALYSIS BUT IN TERMS OF

MONKEYS, WE CAN LOOK AT THINGS

LIKE DEFICITS IN EYE GAZE, JOINT

ATTENTION, RECOGNIZING AND

RESPONDING TO EMOTIONS AND

OTHERS, UNDERSTANDING OTHERS'S

EMOTIONAL INTENT SO THERE IS

SOME CONTROVERSIAL THEORY OF

MIND.

I THINK THERE HAS BEEN OKAY

EVIDENCE THAT THE RHESUS MONKEY

CAN COMPLETE SOME OF THESE TASKS

AND THEN LOOK AT COMPLICATED

SOCIAL RECIPROCAL INTERACTIONS

AND THE DEVELOPMENT OF PEER

RELATIONSHIPS.

LOVELY WORK HAS BEEN DONE AT THE

CALIFORNIA RESEARCH CENTER WHERE

I WORK ON RHESUS MONKEY

FRIENDSHIPS.

ONE THING I'M INTERESTED IN

ASKING IS SOCIALLY IMPAIRED

MONKEYS, DO THEY HAVE FRIENDS?

THAT'S SOME PLACE I'D LIKE TO

HEAD.

AND THEN ESTABLISH KNOW

CONSTRUCT VALIDITY IS DIFFICULT.

AND SO SOMETIMES WHEN YOU'RE

THINKING ABOUT, I WANT TO

DEVELOP A THERAPEUTIC, THE

DISEASE BIOLOGY IS WELL

ARTICULATED IN IN HUMANS BUT

DIFFICULT TO BUILD ANIMAL MODELS

WHEN WE ARE TRYING TO STUMBLE

AROUND IN THE DARK IN TERMS OF

PATHO PHYSIOLOGIY AND IDIOPATHIC

AUTISM.

AND THEN WE NEED TO BE MIND OF

OF PREDICTIVE VALIDITY.

WHAT IS THE MODELS ABILITY TO

IDENTIFY AND TEST DRUGS WITH

THERAPEUTIC VALUE FOR PATIENTS

IN ONE THING THAT IS CRITICAL TO

CONSIDER IS THERE IS A LOST

TESTING PARTICULARLY IN THE

NEUROPEPTIDE FEELS WHERE

OXYTOCIN HAVE BEEN GIVEN DURING

EARLY DEVELOPMENT AND

NEUROTYPICAL ANIMALS AND THEN

THERE IS VAST GENERALIZATIONS

ABOUT WHAT THIS MEANS FOR

NEURODEVELOPMENTAL DISORDERS.

AND MY FEELING TENDS TO BE THAT

YOU NEED TO DO THIS IN ANIMAL

THAT IS SYMPTOMATIC, THAT HAS

SOCIAL DEFICITS AND THEM ASK DO

THESE DRUGS CHANGE THESE

BEHAVIORS.

BUT THIS ISN'T A PRACTICE THAT

HAS BEEN FULLY APPRECIATED BY

OUR FIELD AND I THINK IT IS

IMPORTANT THAT THIS CAN'T BE

OVERSTATED.

SO, I LOVE THIS GRAPH.

ONE OF JEREMY'S REVIEW ARTICLES.

SORT OF GIVES YOU THE SENSE WHEN

YOU'RE TALKING TO A NON--AUTISM

AUDIENCE ABOUT THE LET GENERATEY

AND COMPLEXITY OF AUTISM IN

THESE RELATED SYNDROMIC

DISORDERS.

AND SO WHEN WE STARTED DOING

WORK IN THE FIELD, THERE SEEMED

TO BE TWO POINTS OF ENTRY IN

THINKING ABOUT ANIMAL MODELS AND

THIS IS THE ONE OUR GROUP

ATTACKED FIRST WHICH IS A

BEHAVIOR FIRST APPROACH.

SO THINKING ABOUT FACE VALIDITY,

WE WERE HOPING TO MOVE INTO THE

SECOND LINE OF WORK WHICH HAS

BEEN UNDERTAKEN IN MANY RODENT

MODELS, GENETICS-FIRST APPROACH

WHICH ALLOWS YOU TO THINK ABOUT

CONSTRUCT SO THE

PATHOPHYSIOLOGICAL MECHANISMS

SHARED BETWEEN THE ANIMALS AND

THE PEOPLE.

SO I'M JUST GOING TO GIVE YOU A

QUICK OVERVIEW OF THE WORK WE

HAVE BEEN DOING AND THEN THINK

ABOUT HOW THAT MIGHT BE RELEVANT

TO STUDY REGRESSION.

SO, OUR FIRST POINT OF ENTRY WAS

THINKING ABOUT WHERE IS THE VAST

MAERT.

>>> Y OF GENETIC BURDEN?

AND THE VAST MOTOR JORITIY OF

GENETIC BURDEN IS POLYGENIC.

WHAT WE WANTED TO DO WITH JOHN

CONSTANTINEO AND OTHERS SHOWING

THESE NATURALLY OCCURRING

INDIVIDUAL DIFFERENCES IN SOCIAL

FUNCTIONING, WHAT WE WANTED TO

DO IS ASK, IN THIS VERY LARGE

POPULATION OF RHESUS MONKEYS AT

THE CALIFORNIA NATIONAL RESEARCH

INSTITUTE, IF WE COULD CREATE A

STATISTICAL CLASSIFICATION

ALGORITHM THAT ALLOWED US TO

RAPIDLY IDENTIFY MONKEYS AT THE

SOCIAL EXTREMES.

COULD WE START TO PERFORM

BIOMARKER DISCOVERIES, SOME

GENETICS WORK AND SOME SOCIAL

TESTING?

AND THAT IS WHAT WE HAVE BEEN

DOING.

SO, WHAT WE HAVE -- AND THIS IS

WORK IN COLLABORATION WITH JOHN

CAPTAINY AND ELLIOTT SHERR IN

THE AUDIENCE HERE.

AND SO QUESTIONS WE WANT TO ASK

IS, ARE SIGNALING PATHWAYS THAT

ARE ALTERED IN AUTISM ALSO

ALTERED IN THESE MONKEYS?

ARE THERE THESE PATHOGENIC

VARIANTS ASSOCIATED WITH ASD,

CAN WE ESTABLISH CONSTRUCT BY

VALIDITY BY ASKING IF THERE IS

AN ACCESS BURDEN OF THESE IN

THOSE LOW SOCIAL MONKEYS?

AND CAN WE CREATE?

-- WE HAVE NEW MONEY FROM NI

WHY.

HD TO START CREATING THE FIRST

PRIMATE SOCIAL BEHAVIOR TEST

BATTERY WITH FACE VALIDITY TO

CORE AUTISM SYMPTOMS.

SO, BUT THIS IS ALL DONE IN

ADULT ANIMALS AND SO WE HAVE

SOME REALLY PROMISING

PRELIMINARY DATA.

WHERE I THINK WE COULD POTENTIAL

GE IN THINKING ABOUT REGRESSION,

WOULD BE POTENTIALLY SELECTIVELY

BREEDING.

SO THIS LOW SOCIAL FUNCTIONING

IS HERITABLE AND SO COULD WE

SELECTIVELY ADDRESS OR BEAD

THESE ANIMALS WHO HAVE SOCIAL

IMPAVEMENTS?

CAN WE IDENTIFY BIOMARKERS?

WE HAVE A OR HAVE BEEN ABLE TO

THROW ALL OUR BIOMARKERS IN INTO

A HOPPER AND CLASSIFICATION

ANALYSIS WHICH AT 93% PREDICTS

MONKEYS WHICH SOCIAL IMPAIRMENTS

VERSUS THOSE THAT DON'T.

CAN WE USE THIS BIOMARKER

ALGORITHM TO ASK, DO THESE

BIOMARKERS PREDICT IF YOU WILL

GROW UP AND HAVE SOCIAL

IMPAIRMENTS?

AND THEN THE TEST BATTERY CAN BE

MODIFIED FOR YOU THINK YOER

ANIMALS AND WE CAN START PUSHING

THIS DOWN IF WE HAD AN EARLY

VENING PROGRAM WE COULD

IMPLEMENTCOLOGYNY-WIDE.

THE NEXT IDEA THAT WE STARTED

WORKING WITH, SO THIS IS WORK

THAT PROBABLY FAMILIAR WITH

STEVE ASSUMEY'S WORK AND PIERRE

FERRARI'S WORK ON SOCIAL

MIMICKRY EARLY IN LIFE.

THEY HAVE BEEN DOING THIS WORK

IN NURSERY ANIMALS, MATERNALLY

DEPRIVED AND SO, THAT CONSTRUCT

VALIDITY FOR NEURODEVELOPMENTAL

DISORDERS ISN'T AS MAYBE

PROVOCATIVE AS THE FACABILITY

WOULD BE.

WHAT WE HAVE BEEN DOING IS

STARTING STUDIES AND THERE IS

PRELIMINARY EVIDENCE SUGGESTING

THAT THESE MONKEYS HAVE VERY

PROFOUND INDIVIDUAL DIFFERENCES

IN THEIR ABILITY TO SOCIALLY

INTERACT WITH THEIR MOMS.

SO, WE ARE HOPING TO DO IS START

ESTABLISHING WHETHER MONKEY --

BABY MONKEYS THAT HAVE POOR

SOCIAL AND EMOTIONAL

RECIPROCITY, IF THEY GO ON TO

HAVE IMPAIRED SOCIAL

DEVELOPMENTAL OUTCOME AND SO

WHAT YOU CAN IMAGINE IS THAT WE

MIGHT ESPECIALLY WITH A

COLONY-WIDE ASSESSMENT, START

BEING ABLE TO ASK QUESTIONS

ABOUT REGRESSION ABOUT THESE

DEVELOPMENTAL PATHWAYS IN THIS

GROUP OF MONKEYS.

AND SO AGAIN, THERE IS 5500

ANIMALS AND SO WE CAN SCREEN

SOMETHING LIKE 900 A YEAR.

SO YOU CAN IMAGINE RUNNING

FAIRLY LARGE-SCALE STUDIES WHERE

WE CAN ALSO HAVE DATABASES THAT

PEOPLE CAN MINE AND THEN

FINALLY, WE -- I THINK WE RAISED

THE IDEA OF KRIS PER IN MONKEYS

SO WE HAVE STARTING TO SET UP AN

INITIATIVE TO SORT OF START

DIPPING OUR FOOT INTO THE

GENETICS FIRST APPROACH IN

MARMOSETS.

SO I'M GOING TO STOP HERE.

I THINK WE HAVE PROBABLY VERY

ELEMENTED DISCUSSION TIME AT

THIS POINT.

SO I'M GOING TO END.

IF YOU HAVE QUESTIONS FOR ME, OR

WE CAN JUST TURN IT BACK TO THE

PANEL, PROBABLY.

[ APPLAUSE ]

>> ANN WAGNER:  THANK YOU, P.M.

KARIN.

SO I THINK WE'LL TRY TO DISCUSS

WHAT THE SPEAKERS HAVE SAID AND

ANYTHING THAT HAS TO DO WITH

TREATMENT WE WILL LEAVE FOR

SESSION 4.

DOES THAT SOUND REASONABLE?

SO LET'S KEEP THE DISCUSSION

BEFORE THE BREAK TO THE ACTUAL

SPEAKERS AND TOOLS AND SOME OF

THE CONSTRUCTS.

WHO WANTS TO GO FIRST?

>> I GUESS I'LL JUST ASK, DO WE

HAVE WHAT I PROPOSE THAT -- I

SORT OF FEEL LIKE WE WANT IN

TERMS OF AN EXPERIMENTAL MODEL

WHERE WE HAVE ANIMAL THAT HAS A

BEHAVIORAL LOSS THAT YOU CAN MAP

ON TO A CERTAIN MORPHOLOGICAL

IDEALLY CIRCUIT-BASED

MORPHOLOGICAL CHANGE AT THE

CELLULAR AND MOLECULAR LEVEL.

DO WE HAVE THAT?

OR DO PEOPLE EVEN AGREE THAT IS

A IMPORTANT CONSTRUCT TO ASPIRE

TO?

MY OWN FEELING I'M NOT AWARE WE

HAVE THAT YET BUT I DO THINK

THAT THAT IS A VERY IMPORTANT

THING TO DEVELOP.

SORT OF FEEL LIKE WE OUGHT TO BE

CLOSE IN SOME OF THE MODEL

SYSTEMS LIKE RETT OR OTHERS.

>> I GUESS MY BIAS IS THAT MOST

OF THE BEHAVIORAL PROFILING THAT

WE HAVE DONE, WHETHER IN ANIMAL

OR HUMAN, IS DESIGNED TO LOOK AT

AN ACQUIRED TRAIT OR SKILL AND

WHAT YOU ARE REALLY LOOKING AT

IS THE POPULATION THAT IS IN A

DEFICIT.

AND WE HAVE VERY LITTLE DATA OUT

THERE FOR ACQUISITION OF SKILLS.

RIGHT?

AM I WRONG?

WE DON'T REALLY -- WE CAN'T

EASILY MAP OUT FOR SIMPLE SKILL,

HOW IT IS DONE.

NOW I KNOW THE EDUCATION PEOPLE

CAN TALK ABOUT HOW YOU LEARN

READING.

BUT I THINK FROM THE

NEUROSCIENCES POINT OF VIEW, WE

DON'T FULLY UNDERSTAND ALL THE

CIRCUITRY AND HOW THE CIRCUITS

INTERACT WITH EACH OTHER.

WE CAN TELL YOU THAT IF WE

LESION PART A OF THE BRAIN THAT

THIS RESPONSE WON'T HAPPEN.

BUT I THINK WE DON'T DO IT THE

FORWARD-THINKING WAY IN KNOWING

THAT HOW ARE THESE AREAS

REMODELED?

WHEN I THINK OF THE RODENT

SENSORY PROCESSING, WE KNOW

SOMETHING ABOUT HOW THE FIELD IS

REMODELED AND WE KNOW WHAT

HURDLES AND STEPS NEED TO BE

DONE TO MAKE IT FUNCTION

PROPERLY.

WE DON'T HAVE THAT FOR MOST OF

THE HIGH-ORDER SILLS.

KEY HAVE A SYSTEM BUT HAVE TO

TURN OURSELVES UP SIDE DOYNE TO

APPROACH THE ISSUE OF HOW IT IS.

>> AND I THINK YOU BROUGHT UP

THE BARREL CORTEX.

I THINK THAT VISUAL CORTEX,

THOSE ARE SYSTEMS THAT WE HAVE A

GOOD IDEA ABOUT I THINK THERE IS

A LOT TO BE SAID ABOUT DOING --

IF THERE ARE GENETIC MODELS THAT

YOU CAN SHOW THERE IS

ABNORMALITY IN THE DEVELOPMENTAL

THERE JECTORY AND ESPECIALLY NOT

AN AB NORMALITY IN THE

MAINTENANCE BEING AT THAT STATE

AND HAS REGRESSION, THAT THERE

IS UTILITY IN EXPLORING THE

CELLULAR AND CIRCUIT LEVEL

ABNORMALITIES THAT OCCUR WITHIN

THOSE CIRCUITS.

EVEN IF WE SAY THE WISKER SYSTEM

IS VERY, VERY DIFFERENT IN

RODENTS AND MICE THAN IT IS IN

ME.

BUT I THINK THAT THERE IS A

BASIC -- THOSE ARE GOOD SYSTEM

TO UNDERSTAND NEUROBIOLOGY AND I

THINK YOU SHOULDN'T OVERSTATE

THE IMPORTANCE.

JILL MENTIONED THIS ABOUT, THEY

ARE NOT AUTISTIC MICE.

MODELS USEFUL TO OR MOUSE MODEL

IS USEFUL TO EXPLORE

NEUROBIOLOGY CIRCUITS BUT NOT

NECESSARILY BECAUSE THAT YOU

WANT THE RIGHT PHASE CIRCUIT TO

EXPLORE.

AND THEN GOES BACK TO HOW YOU

WANTED TO TRY TO FIGURE OUT WAYS

TO SEE IF THAT CIRCUIT LEVEL

DYSFUNCTION IS THE SAME IN

THINGS THAT ARE MORE -- WHICH

PROBABLY ARE ULTIMATELY PEOPLE.

RIGHT?

>> PART OF IT IS WITH AUTISM, WE

FOCUS ON THESE VERY COMPLICATED

THINGS LIKE LANGUAGE AND SOCIAL

INTERACTION.

JILL BROUGHT UP PLAY BEHAVIOR

AND SHARON KNOWS THAT FERRETS

ARE GREAT ANIMALS FOR PLAY.

SO MAYBE WE HAVE TO COME

SOMEWHERE IN THE MIDDLE LIKE

RATS PLAY, MICE DON'T PLAY.

PUPPIES PLAY VERY WELL.

SO MAYBE WE NEED TO GO SOMEWHERE

BETWEEN A VERY COMPLICATED

BEHAVIORS AND A SIMPLE SENSORY

AND APPROACH FROM MULTIPLE

SIDES.

>> I GUESS I WOULD AGREE.

I'D BE HAPPY WITH AN

INTERMEDIATE MODEL SYSTEM THAT

LOOKS AT A BEHAVIOR THAT DOES

NOT HAVE TO BE ANYWHERE AS

COMPLEX AS SOCIAL COMMUNICATION

BUT LOOKS AT A BEHAVIOR.

AND I THINK JEFF, YOU SAID

SOMETHING IN MY MIND THAT IS

KEY, WHICH IS THAT WE STARTED

WITH A SESSION THAT TALKED ABOUT

OVERPRUNING AND HOW THAT

HYPOTHESES OF OVER PRUNING IS SO

APPEALING BUT YET DO WE HAVE --

THE WORD YOU SAID WAS

MAINTAINED.

DO WE HAVE A MODEL WHERE WE HAVE

A BEHAVIOR AND EVEN IF IT IS

VISUAL BEHAVIOR OR SOME

BEHAVIOR, SOME QUANTITATIVE

ASSAYABLE BEHAVIOR.

DOESN'T HAVE TO BE SOCIAL

COMMUNICATION.

WHERE WE COULD OBSERVE THE LOSS

OF BEHAVIOR AND FAILURE TO

MAINTAIN A CIRCUIT CONSISTENT

WITH THIS OVER PRUNING

HYPOTHESES.

DO WE HAVE SUCH AN EXPERIMENTAL

SYSTEM?

>> I'M JUST GOING TO MENTION

SOMETHING ABOUT THE RETT BECAUSE

I THINK THIS IS IMPORTANT AND A

MISSING PIECE.

A LOT OF OUR THINGS ARE LOOKING

AT ADULTS AND SEEING DEFICITS

AND WE SAY THERE IS ABNORMAL

MOVEMENT BUT WE HAVEN'T DONE A

LOT TO SAY THEY WERE, HAD A

NORMAL BEHAVIOR AT SOME POINT

AND THEN GOT LOST.

I EMPHASIZE THAT REGRESSION

DEFINES RETT BUT WE HAVEN'T

SPENT A LOT OF TIME

CHARACTERIZING THAT IN MICE.

I DO KNOW THAT IN THE MOUSE

MODELS OF RETT, BOTH MALE AND

FEMALE ANIMALS, THEY ARE

BREATHING IS NORMAL EARLY ON.

AND THEN IT BECOMES ABNORMAL.

NOW, AND BREATHING IS ABNORMAL

IN GIRLS WITH RETT SYNDROME AND

IT WAS NORMAL AT ONE POINT.

SO THAT IS A REGRESSION AND WE

COULD STUDY THAT CIRCUIT AND I

THINK WE WILL TO LOOK AT THAT

CHANGE.

AND MAYBE THAT IS BROADLY

GENERALIZABLE BUT IT MIGHT BE

MORE INTERESTING TO DEAL WITH

THESE CORTICAL CIRCUITS.

AND I WOULD SAY IN RETT

SYNDROME, WE HAVE BEEN LOOKING A

LITTLE BIT AT THIS IN TERMS OF

LIKE REACHING TASKS.

THAT ARE THEY NORMAL AT ONE

POINT AND THEN DECLINE?

AND THAT IS WHAT IT LOOKS LIKE.

NOW WE HAVE TO -- THE VISUAL

SYSTEM IS VERY APPEALING BECAUSE

THE CIRCUIT STRUCTURE IS VERY

WELL-KNOWN.

THAT IS -- AND THE CRITICAL

WINDOWS ARE VERY WELL-KNOWN.

BUT IT MIGHT BE NICE TO THEN TRY

TO MOVE TO OTHER BEHAVIORAL

PHENOTYPES.

>> JUST TO CLARIFY ON THE POINT

WITH THE VISUAL SYSTEM SO THAT

IS SOMETHING CHEN PUBLISHED WORK

ON IN NULL ANIMALS IN THIS.

THE VISUAL PATHWAY GOES FROM THE

LGN AND THALAMUS TO THE CORTEX

AND BACK DOWN AGAIN.

SO OUR DITA IS SHOWING THE

CORTEX IS RECOURSE IN THE NULL

ANIMALS BUT IN THE LGN, THERE IS

DATA SHOWING THAT THE PATHWAY IS

FINE AT THE TIME POINTS WE ARE

LOOKING AT.

BUT LATER ON, PEOPLE 30 AND P45

IN THESE ANIMALS THEY LOUIS

SYNAPSES THAT THEY ORIGINALLY

HAD.

SO THERE IS THIS IDEA THAT THE

INPUT PATHWAY INTO THE CORTEX IS

NORMAL BUT THE OUTPUT IS NOT.

AND THAT MIGHT BE AFFECTING HOW

THE THALAMUS IS, WHOING.

AGAIN GOING BACK TO THIS, THIS

IS SOMETHING AS A CIRCUIT WE

KNOW WELL THE VISUAL CORTEX SO

WE CAN LOOK AT THIS IN MORE

DETAIL AND ESPECIALLY THIS IDEA

OF SNAPSES AND PRUNING AND

THINGS LIKE THAT.

THERE DOESN'T SEEM TO BE A

NORMAL AMOUNT FROM THE BEGINNING

AND THEN THERE ARE REMOVED WHERE

THEY SHOULD BE.

>> SO, IF IF I COULD JUMP IN

ABOUT THE FERRET.

I THINK THAT SO WE ARE WORKING

ON A MODEL OF DISRUPTED CORTICAL

DEVELOPMENT.

AND UNFORTUNATELY, MOST OF WHAT

WE ARE LOOKING AT HAS BEEN

CELLULAR AND FUNCTIONAL MEANING

ELECTROPHYSIOLOGY.

BUT WE DO HAVE SOME CASUAL

OBSERVATIONAL BEHAVIOR OF OUR

FERRETS BECAUSE WE HAVE THEM AS

BABIES AND THEN THEY GROW UP AND

WE WATCH THEM AND THEY DO LIKE

TO PLAY.

SO, WE LET THEM PLAY FREQUENTLY,

LET THEM ALL OUGHT AND THEY CAN

KIND OF PLAY TOGETHER.

AND WE HAVE OBSERVED THAT IN

SOME OF OUR FERRETS, TREATED

FERRETS WHO HAVE THIS DISRUPTED

DEVELOPMENT, THEY START OUT

PLAYING WITH THE GROUP.

YOU CAN'T -- IF YOU LOOK AT

THEM, THEY DON'T LOOK ANY

DIFFERENT.

THEY LOOK THE SAME AS ANY OTHER

FERRET BUT THEY DO START OUT

PLAYING AND THEN AS THEY MATURE,

THEY ARE MORE STANDOFFISH.

THEY STAY AWAY.

THEY DON'T GET INVOLVED IN THE

GROUP.

WE DEFINITELY VE DISRUPTED

CIRCUITS.

PROBLEMS WITH GABAERGIC CELLS,

IMPAIRED MIGRATION ONE OF THE

THINGS WE WERE LOOKING AT IN THE

ONE OF THE SLIDES I SHOWED YOU,

THE CELLS DON'T MIGRATE PROBABLY

AND END UP IN THE WRONG

LAYERSMENT SO, IT'S A MODEL THAT

WE ARE USING THAT DOES SHARE

SOME SIMILARITIES WITH AUTISM

BUT IT'S NOT AUTISM.

SO, I THINK THERE MIGHT BE WAYS

TO USE ANIMAL SUCH AS FERRET TO

GET AT MORE SPECIFICS.

>> I DON'T KNOW WHETHER YOU

HAVE, ALYSSON, A HYPOTHESES

ABOUT THE MOLECULAR MECHANISM BY

WHICH THERE IS AN

UNDERPRODUCTION OF SYNAPSES.

AND SO, WHEN I THINK ABOUT IT, I

MEAN, I THINK CIRCUIT ANALYSIS

IS REALLY EXCITING AND

INTERESTING WHEN WE ARE TRYING

TO UNDERSTAND THE BEHAVIOR.

BUT, IF IT IS PROTEIN LIKE

EXPRESSED IN PROBABLY EVERY

NEURON IN THE BRAIN AND

POTENTIALLY ALL THE GLIAL CELLS

AS WELL.

IT MIGHT NOT BE -- IF THE GOAL

IS -- IF THE POINT IS, AS ERIC

SAID, THAT REGRESSION SUGGESTS

THERE IS A WEDGE FOR

INTERVENTION, IF WE WAIT UNTIL

WE FIGURE OUT ALL THE CIRCUITS,

MAYBE MISSING AN OPPORTUNITY

WHEREAS HAVING AN ORGANOID MODEL

OR IPS CELL MODEL WHERE YOU

COULD DO HIGH-THROUGHPUT

SCREENING TO LOOK AT THINGS THAT

ADDRESS THE CELL AUTONOMOUS

PHENOTYPES AS A WAY TO MOVE THE

QUESTION FORWARD.

WE INVESTIGATED AND WE GOT HITS

LIKE EVERYBODY ELSE AND mTOR

PATHWAYS AFFECTED AND THIS SEEMS

LIKE TO MATCH WITH EVERYBODY

ELSE HAS.

WHAT WE ARE DOING NOW IS DOING

THE SAME KIND OF GENE EXPRESSION

BUT NOW IN THIS SYSTEM.

AND SEE IF THAT WILL CHANGE BUT

ONLY LOOKING AT THE RESPONSE

FROM THE NEURONS.

AND SEE WHAT ELSE CAN CHANGE BUT

THE IDEA TO USE THE SYSTEM AS A

DRUG SCREENING PLATFORM, THAT'S

WHAT ATTRACTEDIS TO THE FIELD

AND WE ARE DOING THAT.

SO WE DEFINITELY HAVE A COUPLE

OF DRUGS THAT CAN EITHER

INCREASE OR DECREASE ISN'T

GENESIS.

WE ARE INVESTIGATING.

SOME OF THEM ALTER GLUTAMATE

LEVELS.

OTHERS ARE GENETIC DRUGS.

>> I'LL KEEP THIS BRIEF BECAUSE

I THINK IT SORT OF I THINK WE

ARE MAYBE A GOOD SEGUE IN TERMS

OF THE SESSION AFTER THE BREAK

WE'LL TRY TO PULL TOGETHER THE

THREE SESSIONS.

I WANTED TO COME BACK BRIEFLY

TOW YOUR COMMENTS ERIKA ABOUT

THE IDEAL SITUATION OF HAVING

REAL TESTABLE HYPOTHESES THAT

INVOLVES ANTI-SEED THAT HE WENT

LEADS TO MORPHOLOGICAL AND

BEHAVIORAL CHANGE IN A WAY OF

RESIDENTS CUEING IT.

ON ONE OBSERVATION IS WE ARE

JUST STARTING TO LEARN ABOUT

THESE RELATIONSHIPS IN AUTISM

THAT WHEN WE TALK ABOUT

PROSPECTIVE DATA, THE

PROSPECTIVE BEHAVIORAL DATA IS

ONLY BE10 YEARS OLD AND THE

BRAIN-BASED DATA, IN A WAY IT'S

ONLY LIKE IN THE PAST COUPLE OF

YEARS WE REALLY HAD SORT OF

ASSESSMENT THAT PROCEEDS

DIAGNOSIS, CLEARLY THE TODDLER

AND PRESCHOOL DATA THAT HAVE

BEEN AROUND FOR LONGER HAS BEEN

HIGHLY INFORMATIVE BUT IN TERMS

OF UNDERSTANDING EARLY

RELATIONSHIPS, JUST STASHING TO

HAVE THE OPPORTUNITY TOY MAP

PHENOTYPES.

AND THEN THE NOTION OF SORT OF

FINDING THAT RIGHT MIDDLE GROUND

IN TERMS OF THE COMPLEXITY OF

THE PHENOTYPE.

I THINK A RELATED ISSUE IN

MAPPING IT BACK TO THE HUMAN

EXPERIENCE IS THAT WITH

INCREASED COMPLEXITY, THERE ARE

ACTUALLY SORT OF OTHER

NON-AUTISM SPECIFIC FACTORS THAT

SORT OF INFLUENCE THOSE

PHENOTYPES.

IN AUTISM THERE MAY BE

ABNORMALITIES IN QUALITY AS WELL

AS QUANTITY CAPTURED IN THE

ANIMAL MODELS.

BUT IN KIDS WITH AUTISM AND

THINKING BACK TO LEARN THE

ORIGINAL CLASSIFICATION, KIDS

ARE GENERALLY QUITE GREG AIRUOUS

CHARACTERIZED.

ACTIVE BUT ODD.

KIDS HIGHLY SOCIALLY MOAT VADED,

THE QUANTITY OF THE BEHAVIOR MAY

BE THERE BUT SOMETHING MIGHT BE

DIFFERENT QUALITATIVELY.

AND THEN KIDS MAY BE ALOOF WHO

HAVE VERY LITTLE SOCIAL BEHAVIOR

AND SORT OF PARSING THIS OUT IS

CHALLENGING IN A HUMAN LEVEL AND

I CAN IMAGINE IN ANIMAL LEVEL

ALTHOUGH THERE ARE MEASURES

QUALITY THAT IT IS SOMETHING

THAT WILL HAVE TO BE TAKEN INTO

ACCOUNT.

SO JUST TO ACKNOWLEDGE ON THE

CLINICAL SIDE, WE STILL HAVE A

LOT OF WORK TO DO IN TERMS OF

REALLY CHARACTERIZING THE

PHENOTYPE TO INFORM THE SYSTEM

AND AT THE SAME TIME RECOGNIZING

TRADE OFFICE IN TERMS OF THE

SIMPLICITY VERSUS COMPLEXITY OF

THE PHENOTYPES.

>> CAN I FOLLOW-UP WITH A

QUESTION AND ADDRESS -- THIS

QUESTION COULD ADDRESS SEVERAL

PEOPLE IN THE GROUP.

THE MODEL A PROPOSED HAD THE

EXPERIMENTAL MODEL I PROPOSED

HAD INVOLVED AN ANTECEDENT AND

I'M NOT SURE HOW MUCH WE

DISCUSSED THAT HERE TODAY.

SO I GUESS THERE ARE A FEW

QUESTIONS HERE AND IN YOUR

CLINICAL PERSPECTIVE EXPERIENCE,

ARE THERE ANTECEDENT TO

REGRESSION?

IN THE MOUSE MODEL OF RETT WHERE

THEY HAVE NORMAL RESPIRATORY

BEHAVIOR AND THEN HAVE ABNORMAL

RESPIRATORY BEHAVIOR?

ARE THERE ANTECEDENTS YOU SEE?

BY WHICH I THINK I MEAN I SHOULD

BE MORE SPECIFIC.

ENVIRONMENTAL ANTECEDENTS.

ALYSSON'S DATA IL6 IMPLIES THERE

MIGHT BE NEUROINFLAMMATORY.

SO I GUESS I'M OPENING UP THIS

QUESTION TO THE FLOOR IN THE

BIOLOGY OF REGRESSION.

WHAT WILL WE EXPECT WITH REGARD

TO SOMETHING THAT MAY INDUCE THE

REGRESSION OR IS IT JUST

SPONTANEOUS OR BOTH?

>> JASON?

DID YOU HAVE A QUESTION?

>> SO THAT IS A VERY GOOD

QUESTION.

SO I WONDER IF WE NEED EVEN MORE

WORK AND HUMANS BEFORE WE KNOW

HOW TO ADAPT OR PICK ANIMAL

MODEL TO -- FOR REGRESSION.

AND I WONDER LONNIE, IF YOU

THINK LIKE WE ALWAYS WORK WITH

HIGH-RISK POPULATION FOR AUTISM.

DO YOU THINK WE HAVE ENOUGH

INFORMATION TO IDENTIFY THOSE

WHO ARE AT HIGH RISK FOR

REGRESSION?

>> SO THESE ARE REALLY IMPORTANT

FUNDAMENTAL QUESTIONS.

THERE IS RELATIVELY LITTLE

INFORMATION TO PROVIDE

DEFINITIVE ANSWER.

I MEAN THERE IS TWO POINTS TO

PICK UP ON AND THEN ONE IS THAT

UNTIL RECENTLY, MOST OF WHAT

WE -- OUR UNDERSTANDING OF

REGRESSION WAS BASED ON

RETROSPECTIVE DATA AND I THINK

THE ABILITY TO SORT OF

ARTICULATE HYPOTHESES ARE

PROBABLY INFLUENCED BY THE LENSE

OF TRYING TO COME UP WITH AN

ASSOCIATION LOOKING IN

RETROSPECT.

I ALSO THINK THAT THIS IS NOT AN

AREA THAT IN ANY RESPECTS FULLY

EXPLORED.

SO THINKING ABOUT WHAT ARE

PLAUSIBLE HYPOTHESES SORT OF

IDENTIFYING SORT OF SPECIFIC

CAUSES AND TESTING THEM IN

ANIMAL SYSTEM AS WELL AS

EPIDEMIOLOGICALLY.

ALICE, YOUR QUESTION ABOUT IS

THE HIGH RISK DESIGN SUFFICIENT?

I MEAN, I THINK PROBABLY THE

SHORT ANSWER IS, NO.

BECAUSE GIVEN THAT BY

DEFINITION, THAT GROUP OF

FAMILIES ARE -- HAVE SORT OF

MULTIPLE INCIDENTS CASES, I

THINK THERE MAY BE PHENOTYPIC

SIMILARITIES AND THERE IS EVEN

SORT OF LIKELY VERY HIGH

IDEOLOGICAL OVERLAP AND I DON'T

THINK IT EXCLUDES THE

POSSIBILITY THERE ARE SPECIFIC

RISK FACTORS THAT MIGHT BE MORE

PARTICULAR TO SPORADIC CASES OR

FAMILIES WHERE THERE IS ONE

CHILD RATHER THAN RECURRENT

CASES OF AUTISM.

>> I DON'T MEAN THE HIGH RISK

WITHIN THE HIGH RISK FOR AUTISM

POPULATION BUT DO WE EVEN HAVE

THE KNOWLEDGE BASE FOR HIGH RISK

REGRESSION IN GENERAL?

>> IN TERMS OF -- I THINK YOU'RE

RIGHT.

SO IN A WAY IT REARTICULATE'S

ERIC'S QUESTION AND I'M NOT SURE

THAT WE HAVE GOT -- I DON'T KNOW

WE HAVE A LOT OF INFORMATION

ABOUT WHAT CONSTITUTES A CHILD

WHO IS AT RISK OF AUTISTIC

REGRESSION.

I CERTAINLY WELCOME MY

COLLEAGUES TO WEIGH IN ON THIS

AND AGAIN THIS MAY BE SOMETHING

WE PICK UP AFTER THE BREAK.

>> ONE OF THE THINGS THAT MIGHT

HELP THAT IS TO GET THE

INFORMATION FROM THE BABY SIBS.

>> OF COURSE WE MOVED TO THIS

NOTION THAT ENVIRONMENTAL RISK

AND GENETIC AT RISK ARE NOT

MUTUALLY EXCLUSIVE.

>> MAYBE A QUICK COMMENT.

I'M NOT SURE IF WE REALLY NEED

THE BEHAVIOR THE WAY YOU WERE

PHRASING THE IDEAL MODEL FOR A

MODEL SYSTEM TO BE USEFUL.

I CAN IMAGINE FINN WE IDENTIFY A

GENE THAT IS VERY CLEARLY

IMPLICATED IN THE HUMAN

POPULATION, AND WE SEE A MOUSE

OR RAT OR MONKEY MODEL OF IT,

WHICH CLEARLY HAS CIRCUIT

DEFICIT EVEN THOUGH WE CAN'T

FIND THE BEHAVIORAL EQUIVALENT

IN THAT ANIMAL AND WE CAN FIND

WAYS TO RESCUE THAT CIRCUIT

DEFICIT, I THINK WE WILL BE ALL

VERY EXCITED ABOUT IT.

SO, A LOT OF THE BEHAVIOR IN

HUMANS IS GOING TO BE HARD TO

MODEL IN A MOUSE.

EVEN IF A RAT.

MAYBE EVEN A MONKEY.

SO I THINK IT IS REALLY NICE TO

HAVE.

I DON'T THINK IT IS ESSENTIAL.

IT SHOULDN'T BE A SHOW-STOPPER

WE NEED TO HAVE THAT BEHAVIOR OR

TO GET AN INTERESTING BASIC

SCIENCE MODEL THAT FINDS

REGRESSION AND FINDS DEFICITS

THAT CAN BE PHARMACOLOGICALLY OR

RESCUED IN OTHER WAYS.

TO BE AN INTERESTING MODEL FOR

HUMAN DISORDERS.

>> I WANT TO COMMENT.

I DO WORRY A BIT ABOUT SOMING

THAT IS A CIRCUIT LEVEL

ABNORMALITY THAT PRODUCES

NOTHING AND THEN I WOULD SAY,

YOU'RE FIXING NOTHING.

SO IT'S NOT THAT I DON'T THINK

IT IS RIGHT, I'M JUST SAYING

UNLESS YOU MAKE THE CORRELATION

THAT THE CIRCUIT LEVEL

DYSFUNCTION DOES CORRELATE WITH

SOMETHING, NOT MAYBE IN THAT

ANIMAL BUT MAYBE AGAIN THIS GOES

BACK TO MY BRIDGING AND CIRCUIT

BRIDGE TO THAT IF THAT IS THE

SAME CIRCUIT LEVEL ABNORMALITY

YOU SEE IN THE PEOPLE THAT HAVE

THAT PROBLEM, THAT'S FINE.

YOU CORRECT THE ANIMAL AND BRING

IT.

IF YOU ARE JUST CORRECTING AN

EPIPHENOMENON THAT DOESN'T

ACTUALLY HAVE OVERALL THINGS, AS

A CLINICIAN, I WOULD NEVER BING

THAT TO THE CLINIC.

>> A GREAT EXAMPLE IS LOOKING AT

THE FOX B2 MOUSE LINES.

SO VERY CLEARLY A LANGUAGE GENE.

YES SOME INDICATIONS THE CALLS

IN THE MOUSE ARE A BIT DIFFERENT

BUT I'M NOT CONVINCED THEY ARE A

GOOD BEHAVIORAL MODEL.

BUT IF YOU UNDERSTAND WHAT THE

CIRCUITS ARE, THAT IS EXCITING

FOR LANGUAGE IMPAIRMENTS.

FOR ALL WE ARE TRYING, NATURE

ANIMALS ARE HARD TO GET AND THE

WAY WE ARE TESTING THIS IS

ALMOST ALWAYS NOT PERFECTLY

VALID.

YOU TAKE A MOUSE DURING SLEEPING

CYCLE AND THEN PUT IT INTO AN

ANXIETY INDUCING ENVIRONMENT FOR

A FEW MINUTES.

WE ARE GETTING BETTER BUT WE ARE

STILL NOT VERY GOOD.

SO MIGHT BE BECAUSE WE ARE NOT

SUBTLE ENOUGH YET TO CATCH

ANYTHING.

>> LONNIE GETS THE LAST POINT.

>> I KNOW WE NEED TO MOVE TO THE

BREAK.

I WANT TOO OBSERVE THAT

COMPLEXITY MAY NOT BE JUST AN

ISSUE OF THE EXPRESSION OF

ANIMAL LEVEL BUT EVEN THE

LIMITED DATA WE HAVE SUGGESTS

THERE ISN'T THE ONE-TO-ONE

RELATIONSHIP BETWEEN GENETICS,

BEHAVIOR AND THE NEUROANATOMY.

THAT YOU MAY VERY WELL HAVE

CIRCUIT ABNORMALITIES AND YET

FOR WHATEVER REASON, THEY ARE

NOT CLINICALLY EXPRESSED IN THE

HUMAN AND THAT COMPLEXITY IS

REALLY INTERESTING TO EXPLORE

AND WHERE WE ALL NEED TO WORK

TOGETHER ON THIS.

>> ANN WAGNER:  A GREAT COMMENT

FOR THE END OF THE SESSION.

SO, WE WILL TAKE A 10 MINUTE

BREAK.

340 WE WILL COME BACK AND THEN

OPEN UP AND HAVE A BROADER

DISCUSSION.

I'M GOING TO TURN THIS

SESSION TO AUDREY TO FACILITATE.

THANK YOU.

>> AUDREY THURM:  WE DECIDED WE

ARE GOING TO HAVE THE SESSION

CHAIRS SORT OF CHAIR MANY

SESSIONS OF THIS LAST

DISCUSSION.

YES, WE DID.

BUT ELIZABETH AGREED TO BE THE

FIRST AND LONNIE UNFORTUNATELY

HAS TO LEAVE AT 4:30.

AT 4:15 WE ARE GOING TO TURN IT

TO HIM NO MATTER WHERE WE ARE,

OKAY?

DO YOUMENT TO PUT UP

YOUR -- - DO YOU WANT TO PUT UP

YOUR THINGS?

SO LIES BETH HAS MADE A SCHEMA

THAT WE DON'T WANT TO CONSTRAIN

US BUT WE WANT TO HAVE SOME

ORGANIZATION.

SO, LOOK AT IT BUT DON'T FEEL

BOUND TO IT.

CAN IT GET BIGGER?

>> I DON'T THINK IT CAN GET

BIGGER.

BUT IF WE WANT, WE CAN ALWAYS

PROVIDE IT TO PEOPLE.

SO WE WERE TRYING TO COME UP

WITH IDEAS OR WAYS OF TRYING TO

TAKE THIS ISSUE OF SCALE FROM

GENES ALL THE WAY TO CLINICAL

PREEN PRESENTATION AND HOW THEY

INTERACT AND THEN I THINK OF

MORE OF TREATMENT AND WHAT

TREATMENTS ARE GOOD AND WHAT ARE

THE SIDE EFFECTS AND HOW DO WE

GET TO SOME SORT OF TREATMENT OR

SOME SORT OF RESOLUTION?

SO WHAT WE HAVE UP TOP ARE WHAT

I THINK OF AS THE MAIN

CATEGORIES AND THE INDIVIDUAL

UNIT AND IT STARTS WITH GENES.

ENVIRONMENTAL BIOMARKERS AND

SKILLED ASSESSMENTS.

AS I PULL IT OFF THE TABLE, WE

HAVE A LIST OF THINGS UNDER

ENVIRONMENTAL AND WE PURPOSELY

DID NOT DISCUSS THAT DURING THIS

MEETING BECAUSE WE, AS A

COMMITTEE, STRUGGLED SO MUCH

WITH JUST DEFINING THE

REGRESSION IN WHAT WAS GOING ON.

SO, I'LL MAKE A COMMENT WE ARE

FULLY AWARE THERE COULD BE MANY

OTHER OUTSIDE INFLUENCES THAT

COMPLIMENT GENETIC INFLUENCES

BUT WE DON'T THINK WE ARE AT THE

MATURITY LEVEL TO EVEN CONSIDER

THAT.

THAT'S WHY THAT'S IN GRAY.

WITH GENE, SOME OF THE THINGS

THAT WE DIDN'T THINK OF AND

DIDN'T HAVE A CHANCE TO ADDRESS

ARE PENETRANTS AND AUDREY WAS

TALKING ABOUT WITH RETT, WE

DON'T -- IF I'M CORRECT IN MY

HEARING, WE DON'T REALLY

UNDERSTAND WHAT ARE THE

MUTATIONS IN ALL OF THE CHILDREN

WITH REGRESSION THAT ARE RETT,

STRA TRUE?

WE DON'T KNOW THAT IF YOU

HAVE.

>> [ OFF MIC ]

>> SO WE NEED TO GET AT WHAT ARE

THE PENETRANTS OR SUSCEPTIBILITY

WITH DIFFERENT GENE ALLELES AND

THEN WITH -- I KNOW THAT MANY

PEOPLE TALKED ABOUT MOSAIC

SIMPLE.

SO WITH AN EXCELLENT GENE THE

CELLS IF YOU'RE A GIRL, HAVE YOU

TWO X LINKS, X GENES AND MANY

GENES ACTUALLY ONE OF THOSE GETS

TURNED OFF IN THE CELL.

EVEN IF YOU HAVE A MUTATED GENE

IN A TISSUE, YOU MAY NOT HAVE

HALF OF THAT GENE DOSAGE IN ALL

CELLS.

SO HAVE YOU CLUSTERS AND THAT

MAKES IT VERY, VERY TRICKY IN

ANIMAL MODELS BECAUSE WE HAVE NO

WAY OF PREDICTING WHAT THE

MOSAICS WILL BE IN ANY ANIMAL

UNTIL POSSIBLY LATER THERE ARE

SOME TECHNIQUES THAT ARE HIGHLY

INTENSIVE THAT YOU COULD

POSSIBLY QUANTIFY IT POST-MOTOR

EM.

SO, THAT MAKES WITH AN X LINKED

DISEASE LIKE RETT, THAT MAKES IT

INCREDIBLY CHALLENGING.

JUST ADDS ANOTHER LAYER OF

COMPLEXITY.

SO, AND THEN ONE OF THE ISSUES

THAT I THINK IS BROUGHT UP WHEN

WE TALK ABOUT GENES IS THAT

GENES ARE EXPRESSED IN DEFINED

AREAS AND DEFINED TIMES.

AND IN DEFINED LEVELS.

AND SO SOME GENES LIKE ACTIN, IN

EVERY CELL, IS ON ALL THE TIME.

BUT SOME OF THESE OTHER

GENESSURE ON FOR A SHORT TIME

PERIOD OR OUT IN THE ADULT AND

WE THINK WE HAVE TO KEEP THAT IN

MIND THAT IT MAY BE TEMPORALLY

SPECIFIC AND WE ARE LOOKING AT

TREATMENTS.

WE MAY HAVE TO DECIDE IF THAT

GENE IS ON TOO LONG OR TOO SHORT

AND WHAT IS THE WINDOW?

AND THEN BACK TO TISSUE

SPECIFICITY.

ISSUES OF EPIGENETIC

HETEROGENEITY.

SO, THERE IS GENES TURNED ON AND

OFF.

THE EPIGENETICS USED TO BE ON OR

OFF WITHIN THE SAME TISSUE.

OUR CURRENT UNDERSTANDING OF

BIOLOGY IS THAT IS VERY RANDOM

WITHIN THE SAME TISSUE.

SOME GENES CAN BE TURNED ON AT

HIGH LEVEL AND OTHERS NOT.

SO THAT IS ANOTHER LAYER OF

COMPLEXITY.

AND THERE CAN BE MULTIPLE

ENVIRONMENTAL FACTORS BOTH FROM

CHEMICAL FACTORS, STRESS

FACTORS, THAT CAN CHANGE YOUR

EPIGENETIC READ OUT.

SO THAT IS A REASON WHY

ENVIRONMENTAL BECOMES VERY

DIFFICULT BECAUSE WE DON'T KNOW

WHAT ALL THE TARGETS ARE.

AND THEN FINALLY THINGS LIKE

WHAT OTHER GENES ARE AFFECTED?

ALMOST ALL THE ANIMAL MODELS WE

LOOK AT AND MOST OF OUR HUMAN

STUDIES ARE LOOKING AT ONE GENE

AT A TIME.

ALTHOUGH, OFTEN IF ONE GENE IS

AFFECTED, A WHOLE CLUSTER LIKE

THE DUPLICATION YOU HAVE A

CLUSTER, BUT IF YOU'RE HAVING A

TRANSCRIPTION FACTOR, YOU COULD

HAVE 1000 TARGETS SINCE YOU'RE

ACTUALLY GOING DOWNSTREAM TO

MULTIPLE GENES BEING AFFECTED.

SO THE PROBLEM BECOMES

EXPONENTIAL PRETTY QUICKLY.

SO MAGICALLY ONCE YOU GET THAT

FIGURED OUT, THAT ROLES INTO THE

MOLECULAR PATH BASE IF WE COULD

START LOOKING AT TARGETS, THE

SAME QUESTIONS APPLY.

ARE THEY BRAIN SPECIFIC FOR

PATHWAYS.

WE TALKED ABOUT ALMOST

EXCLUSIVELY IN THIS MEETING

ABOUT BEHAVIOR IN CNS BUT WE

KNOW THAT SOME OF THESE GENES

ARE IN OTHER ORGAN SYSTEMS

CLINICALLY WE KNOW THAT OTHER

ORGANS CAN BE AFFECTED AND THAT

IS SOMETHING WE ALSO HAVE TO

CONSIDER IN OUR ANIMAL MODELS IN

THE PHYSIOLOGY IN BACK INTO THE

BEHAVIOR AND THEN FURTHER DOWN

THE LINE IN THE TREATMENT IF YOU

START AFFECTING EVEN LIKE WE

THINK WITH PAIN, YOU SEE THE NEW

ADS FOR OPIATE-INDUCED

CONSTIPATION?

IF YOU'RE GIVING A DRUG TO FIX

PART OF REGRESSION, WHAT ELSE

ARE YOU AFFECTING DOWN THE LINE?

AND SOMETHING WE JUST HAVE TO

KEEP IN MIND.

AND THEN, GOING TO THE

BIOMARKERS, JASON TALKED A

LITTLE BIT ABOUT MRI.

WE DIDN'T TALK ABOUT PET BUT WE

COULD CONSIDER PET TO LOOK AT

ACTIVATION OR GENE EXPRESSION OF

DIFFERENT TRANSMITTERS.

WE ARE STILL WORKING ISSUES OF

BLOOD TESTS AND THEN I PUT

CO-MORBIDITIES BECAUSE OFTEN A

LOT OF THESE CLINICAL

PRESENTATIONS DO HAVE A

HIGH-TIGHTLY LINKED OTHER

ISSUES.

AND THEN THE SKILLS ASSESSMENT

AND THIS IS WHERE I THINK WE

HAVE HIGHLIGHTED THE FAB THAT WE

STILL DON'T KNOW ALL OF THE

STEPS GO INTO ACQUISITION OF A

TYPICALLY DEVELOPING INDIVIDUAL

SKILLS.

AND I THINK THAT IS ONE OF THE

THINGS THAT COME OUT OF TODAY.

THAT THERE IS STILL A LOT OF BIG

QUESTIONS INTO SKILL

ACQUISITION.

AND THEN, SO WE LOOK AT THESE

FEEDING INTO MOLECULAR PATHWAYS

AND FEED INTO THE

NEUROSUBSTRATES WHICH IS MY

VERSION OF SAYING CIRCUITRY.

WHAT ARE THE PARTS OF THE BRAIN

THAT ARE ACTUALLY AFFECTING

WHERE THESE GENES AND MOLECULES

ARE EXPRESSED AND HOW DO THEY

CONTROL DIFFERENT BEHAVIORS?

WE HAVE CIRCUITS THAT INTERTWINE

WITH EACH OTHER THAT CAN GIVE

DIFFERENT OUTPUTS AND SOME

ASSOCIATE WITH OTHERS AND THEN

FINALLY IT LEADS TO AN ACTION

AND THESE ARE JUST MORE

TREATMENT QUESTIONS OF TIMING OF

TREATMENT.

DO WE DO SINGLE TREATMENTS?

MULTIPLE TREATMENTS?

THE SEX AFFECT IT?

WHAT IS OUR OUTCOME AND THEN

ISSUES OF RISKS OFF TARGETS AND

THEN BACK TO THE WHOLE IDEA OF

PRECLINICAL VALIDITY.

CAN WE HAVE PRECLINICAL MODELS

THAT CAN HELP US ASPECTS ALONG

THE WAY?

SO THIS WAS MY IDEA OF TRYING TO

PULL IT ALL TOGETHER.

IT'S OPEN FOR ANYONE ELSE TO

DISCUSS.

PULL THINGS OFF, ADD TO.

JILL?

>> JILL:  I WOULD LIKE TO ADD

ONE THING.

WE KNOW THAT THE ANIMAL MODELS

ARE GOING TO BE CRITICAL WHETHER

THEY BE GENETIC ANIMAL MODELS,

RAT ANIMAL MODELS, PRIMATE

ANIMAL MODELS.

AND SO, AS WE ALL BROUGHT UP,

OTHER THAN WE DON'T KNOW WHAT

TYPICAL DEVELOPMENT LOOKS LIKE

IN THE ANIMAL MODELS EITHER, SO,

WITHOUT THE WAY THE PAST HAS

BEEN, PEOPLE WERE LOOKING AT A

SPECIFIC DRUG TREATMENT, A

SPECIFIC GENE, A SPECIFIC

LESION.

NO ONE ACTUALLY GONE AND

QUANTIFIED TYPICAL DEVELOPMENT

IN A MODEL SYSTEM.

AND SO, WE ARE LACKING THAT AS

WELL.

>> SINCE IT WAS DRONE OUT, A

SMALL COMMENT ABOUT PET.

AT LEAST IN CANADA, IT IS ALMOST

IMPOSSIBLE TO BE ALLOWED TO GIVE

RADIOACTIVE TRACERS TO KIDS.

SO I DON'T KNOW IF IT'S

DIFFERENT.

>> SAME HERE.

>> UNLESS YOU'RE IN DETROIT AND

YOUR NAME IS THING

[ INDISCERNIBLE ]

>> UNLESS IT'S CLINICALLY

INDICATED I THINK IS WHAT --

[ LAUGHS ]

>> SO, THEN WE HAVE AN

ALTERNATIVE TO DEAL WITH

ACTIVATION FROM A RELATIVELY

NON-INVASIVE WAY.

>> THAT KIND OF GOES BACK TO

WHAT I HAVE BEEN ASKING THE

WHOLE TIME, WHICH IS, AND I WAS

JUST JOTTING SOME THINGS DOWN

WHILE YOU WERE TALKING ABOUT IT.

IS WHAT I WAS REFERRING TO THE

BRIDGING THING AND BRINGING IT

TO PEOPLE AND TRYING TO EXPLORE

A PARTICULAR HYPOTHESES AND I'LL

USE THE PRUNING OR THE GABA AS

TWO HYPOTHESES THAT WE WERE

DISCUSSING REGARDING CHANGES IN

CIRCUIT STRUCTURE THAT MIGHT

UNDERLIE REGRESSION.

AND I WAS THINKING IN ONE OF THE

MAJOR CHALLENGES IS, IDENTIFYING

AND THEN UTILIZING OR INVENTING

NEW TECHNOLOGY THAT WILL ALLOW

NON-INVASIVE ANALYSIS HOPEFULLY

NON-SEDATING IN PEOPLE THAT WE

CAN ESPECIALLY THAT WE CAN

FOLLOW THE TYPICAL DEVELOPMENT

PATHWAYS OVER TIME.

THAT'S WHY NONRADIOACTIVE,

NON-SEDATING THAT WE COULD THEN

ASK THOSE QUESTIONS.

>> I THINK A MORE COMPLETE OR

BETTER ROLE FOR PET FOR THE

ACTIVATION WITH PET GIVES YOU IS

THE MOLECULAR SENSITIVITIES.

YOU DON'T HAVE THEM ANY OTHER

WAY.

FOR THAT ACTIVATION, THE BIG

ISSUE IS ALWAYS MOTION IS WHERE

VERY BAD DEALING WITH MOTION.

WE ARE GETTING BETTER AT IT FOR

ANATOMICAL SCANS BUT FOR

ANYTHING ELSE, IF THE KID MOVES,

YOU'RE IN TROUBLE AND THE LOWER

FUNCTIONING THE KID IS, THE

HARDER IT IS TO GET THEM TO STAY

STILL.

WE CAN DO SLEEP SCANS BUT IT ALL

WILL BE A BIG CHALLENGE TO MAKE

THAT LARGELY APPLICABLE TO

EVERYONE.

>> THERE IS NEUROPHYSIOLOGY

OPTION FOR ACTIVATION.

>> THAT IS REALLY WHAT I WAS

IMPLYING BY MY THINKING BUT I

WAS HOPING THAT SOMEONE WOULD

COME UP WITH SOME MAGIC.

>> I DON'T HAVE MAGIC BUT I WILL

COMMENT THAT AT LEAST WHEN THE

CHILDREN ARE SLEEPING, WE ARE

CONTROLLING FOR ANY DIFFERENCES

RELATED TO DISORDER THAT THEY

MIGHT HAVE AND IF WE ARE LOOKING

EARLY ENOUGH IN LIFE, ZERO-3, WE

CAN RELIABLY GET THOSE KIDS TO

SLEEP IN THE SCANNER ACROSS

GROUPS WITHOUT HAVING ANYTHING

EVASIVE TAKE PLACE THAT ALLOWS

US TO DO THE FUNCTIONAL IMAGING

AND STRUCTURAL IMAGING.

>> SO, I'M WONDERING WHAT KIND

OF ROLE MARKER TASKS CAN PLAY IN

STUDYING INFANTS AND PRIMATES

WHERE THERE IS CERTAIN MARKER

TASKS OR ASSAYS WHICH TAP INTO

CERTAIN CIRCUITS AND WE CAN

DEVELOP SIMILAR TASKS FOR

INFANTS AND TEST THEM WITHOUT

INVASIVE NEUROPHYSIOLOGY OR

IMAGING.

THERE IS WONDERFUL EXAMPLE IN

HISTORY OF DEVELOPMENTAL SCIENCE

OF WORK OF PATRICIA GOLDMAN AND

ADELE DIAMOND WHO WORKED OUT

CIRCUITRY OF THE PREFRONTAL

CORTEX AND PARIETAL CORTEX WITH

REGARD TO WORKING MEMORY, THE

FAMOUS TASK.

THERE ARE MANY OTHER TASKS THAT

WE CAN ADAPT AND WE HAVE BEEN

ADAPTING IN OUR LABORATORIES.

PERHAPS YOU NEED A LITTLE BIT

MORE CROSS TALK.

YESTERDAY AT DINNER WE TALKED

ABOUT SET SHIFTING AND WE WERE

LEARNING AND WE CAN DO THAT IN

BABIES WITH NO PROBLEM AT ALL.

SO AT LEAST FROM OUR LEADER,

THERE IS THE POSSIBILITY AND

CHUCK NELSON TALKED ABOUT THIS

WITH VISUAL ACUITY AND IF YOU

LOOK AT DEPUTY PERCEPTION IN

KIDS, THEN THERE IS SOME

HANDBOOK THAT SOME KIDS HAVE

PROBLEMS WALKING DOWN STAIRS

BECAUSE THEY ARE NOT ABLE TO --

THE ONES THAT MOVE MAY HAVE

PROBLEMS WITH THAT AREA BECAUSE

THEY DEPTH PERCEPTION ISSUES.

IF THAT IS SOMETHING IN MOBILE

KIDS WE ARE TALKING ABOUT 12

MONTHS AND UPWARDS, IF THEY ARE

ABLE TO LOOK AT THAT IN MORE

DETAIL THEN FROM THE MOUSE MODEL

ONWARDS, WE CAN START LOOK AT

THAT MORE AS WELL.

IT'S NOT A COMPLEX BEHAVIORAL

ASSAY BUT IT'S A SENSORY THING

AND WILL GIVE US SOME IDEA IF WE

ARE ON THE RIGHT TRACK.

>> AND IT SEEMS WE HAVE FAR MORE

SENSORY DEFICITS THAN I THOUGHT

GOING INTO THIS, CONSIDERING THE

REGRESSION IS USUALLY DEFINED BY

LOSS OF THESE MORE COMPLEX

SKILLS.

THERE WAS A SENSE OF MODALITY

THAT WAS NOT MENTIONED?

>> JUST ONSET OF SENSORY

HYPERSENSITIVITY WHICH VERY MUCH

GOES ALONG THE SAME TIMELINE AS

THE LOSS OF SOCIAL SKILLS AND

LANGUAGE.

AND WE HAVE A LITTLE BIT OF DATA

THAT SHOWS THAT THAT SOME OF

THOSE THINGS ACTUALLY PRECEDE IT

WHEN YOU DO RETROSPECTIVE PARENT

REPORT SOME OF THE REPETITIVE

BEHAVIOR STARTS EARLIER AS WELL

AS THINGS LIKE SENSITIVITY TO

SOUND PROBABLY IS EITHER

CONTEMPORANEOUS OR POSSIBLY EVEN

BEFORE ONSET OF LOSS.

>> JUST TO ADD TO THAT,

INTERESTING FLIP SIDE IS

ANNETTE'S COMMENT ABOUT ONE OF

THE TRULY UNIQUE SENSORY

FEATURES OF AUTISM IS ACTUALLY

THE ENHANCED VISUAL SEARCH AND

DETAIL ORIENTED PROCESSING AND

IF ONE COULD MAP -- SO IT'S

UNIQUE STRENGTH BUT IF ONE COULD

MAP THE CIRCUITRY AND KNOWING

THAT IT SEEMS TO BE A FEATURE

THAT ONSETS FAIRLY EARLY, THAT

WOULD PROVIDE ANOTHER WAY OF

LOOKING WITHIN ANIMAL SYSTEM AT

A FEATURE OF AUTISM THAT ISN'T

ACTUALLY ABOUT SKILLED LOSS BUT

ENHANCED SKILL.

>> SO MAYBE ADAPTING ONE OF

OUR --

>> ONE CAUTION TO THAT IS MICE

ARE REALLY NOT VISUAL.

I MEAN, THEY ARE VERY OLFACTORY

THE WAY THEY NAVIGATE T MIGHT BE

THAT THE EQUIVALENT IN THE MOUSE

MIGHT BE OLFACTORY AS OPPOSED TO

ANYTHING VISUAL.

>> I THINK QUITE OFTEN WE

CONTINUED TO EQUATE TOO MUCH AND

THAT WE SHOULD LOOK IN THE

SPECIES-SPECIFIC BEHAVIORS FOR

THINGS THAT ARE LIKELY TO BE THE

ONE THAT MIGHT SHOW ENHANCEMENT.

>> IF I MAY ANSWER THAT COMMENT

A LITTLE BIT.

IT MAY BE TRUE THAT THE MOUSE IS

NOT VISUAL IN THE SENSES BUT AS

WE SAW FROM THE BEHAVIOR ASSAYS,

THERE ARE PLENTY OF PEOPLE DOING

THIS WITH TOUCH SCREENS NOW,

THEY DO USE VISION AND THINGS

LIKE MATCHING WHERE YOU'RE

RECORDING FROM SINGLE CELLS,

THEY ARE DOING THE SAME THINGS

THAT HUMANS DO.

SO THEY MAY NOT BE USING IT IN

THE SAME WAY BUT THEY ARE CAPE

ABLE OF DOING THESE KIND OF

ASSAYS SO AT A DO USE THEIR

VISION FOR SOME THINGS.

>> SO I THINK TO ADD ON TO THAT,

A COMMON MISCONCEPTION IS THAT

MICE ARE CERTAIN STRAINS OF MICE

ARE BLIND OR HAVE RETINAL

DEGENERATION GENES BUT THIS

DOESN'T ONSET UNTIL 5 OR 6

MONTHS OF AGE.

SO SINCE WE ARE TALKING ABOUT

DEVELOPMENT AND EARLY, THE

VISION IS NO PROBLEM AT ALL.

>> KARIN WHAT ABOUT LUKING AT

PRIMATE SENSORY IN ADDITION OR

AS INTERFACES WITH THE SOCIAL?

>> I THINK THAT IS REALLY

IMPORTANT.

SO ALYSSON I WAS IN CONVERSATION

ABOUT USING EYE TRACKING AND HOW

IT CAN BE HAVING SOMETHING FROM

MONKEYS TO PEOPLE.

AND I THINK A LOT OF THE VISUAL

TASKS YOU MENTIONED, WE COULD

EASILY DO IN PRIMATES.

I THINK THE CHALLENGE WITH

PRIMATES IS IT IS PAY TO PLAY

AND SO, IF ANYONE EVER LOOKED AT

A PRIMATE BUDGET, YOU SNEEZE AND

IT'S AN R21 AND IT REALLY IS

EXTREMELY EXPENSIVE TO DO THE

WORK.

AND SO IT'S VERY CHALLENGING.

SO, BE THINKING ABOUT TASKS

THERE IS ALWAYS A BALANCE

BETWEEN TRAINING OR SOMETIMES

TRAINING THE ANIMALS CAN TAKE A

LOT OF TIME BUT TO THE PER DIEM

COST OF 25 DOLLARS A DAY, THAT

COULD BE REALLY EXPENSE ITCH.

SO, I THINK THE ISSUE IS REALLY

THINKING ABOUT AND ALSO GETTING

MONEY TO DO JUST BEHAVIOR AS WE

ALL KNOW CAN ALSO BE TRICKY.

SO IT HAS TO BE IN THE CONTEXT

OF SOMETHING ELSE.

SO I THINK IT'S DOABLE.

IF THERE IS A COMMITMENT TO

DEVELOP THE THANKS, THEY CAN BE

DONE.

-- TASKS.

WE HAVE BEEN DEVELOPING A SOCIAL

BEHAVIOR TEST BATTERY TO LOOK AT

THESE CORE SYMPTOMS AND THINKING

ABOUT INTENTION, IT WAS

SOMEBODY'S SLIDE ABOUT HOW KIDS

WITH 2016 PAPER ABOUT EYE GAZE

SO THAT KIDS WITH AUTISM FOLLOW

BODY MOVEMENT BUT THE EYE GAZE

IS WHAT IS IMPAIRED.

AND I ALREADY JUST LIKE MADE

NOTES FROM MY POSTDOC.

WE NEED TO MODIFY OUR TEST TO

MAKE SURE WE HAVE BOTH OF THESE

COMPONENTS BECAUSE I LEARNED

THIS TODAY ABOUT THINKING ABOUT

THIS WITH PATIENTS.

SO I THINK THAT HAVING THE

DIALOGUE IS REALLY IMPORTANT AND

HAVING -- WHEN YOU'RE A BASIC

SCIENTIST IN THE CLINICAL

DEPARTMENT, IT'S EASIER BECAUSE

YOU GO KNOCK ON THE PSYCHIATRIC

OR NEUROLOGIST DOOR AND YOU CAN

TALK TO THEM ABOUT THEIR

PATIENTS.

AND I THINK MORE OF THAT NEEDS

TO HAPPEN.

>> I THINK THAT EMPHASIZES THAT

THE SHIFT TO PERSPECTIVE STUDIES

EARLY DEPARTMENT OF AUTISM, I

THINK ON ONE HAND REALLY SORT OF

REINFORCE WHAT PARENTS TALKED

ABOUT FOR MANY YEARS IN

RETROSPECT IN TERMS OF GIVING US

THE RIT CRITICAL PICTURE OF THAT

PATTERN OF DEVELOPMENT.

BUT BY WORKING PROSPECTIVELY,

ONE CAN QUANTIFY USING SPECIFIC

EXPERIMENTAL TASKS THAT MAY BE

MORE READILY TRANSLATED TO OTHER

SYSTEMS.

SO IT'S POSSIBLE TO SORT OF WORK

IN CLOSER COLLABORATION BECAUSE

WE HAVE MORE CONTROL OVER THE

WAY WE ARE COLLECTING DATA.

>> AND JUST TO ADD, AND ADDRESS

YOUR CONCERN THAT WHAT WE LEARN

FROM BABIES, SIBS, WE NAY NOT

GENERALIZE TO BROADER POPULATION

OF CHILDREN WITH AUTISM.

THE PREVALENCE OF REGRESSION IN

MULTIMR.ICS AND SIMPLEX CASES IS

IDENTICAL.

AND ALSO THE CONCORDANCE RATES

AMONG SIBLINGS WITH AUTISM ARE

CLOSE RELATIVES IS ALSO NOT

INCREASED BEYOND WHAT WE WOULD

EXPECT BASED ON CHANCE.

SO MAYBE WE DON'T HAVE TO

NECESSARILY WORRY TREMENDOUSLY

THAT WHAT WE ARE LEARNING FROM

BABIES MAY NOT GENERALIZE TO

REGRESSION AND MAYBE VERY 71

MULTIPLEX CASES.

>> NOW WE ARE GOING TO SWITCH

OVER AND GIVE LONNIE A FEW

MINUTES TO GIVE HIS NOTES ABOUT

THINGS TO WRAP UP WITH.

BUT AS WE DO THAT, I KNOW

EVERYBODY HAS HAD GREAT IDEAS

THAT THEY HAVE BEEN JOTTING DOWN

BUT WE ALSO WANT TO ENCOURAGE

PEOPLE TO THINK ABOUT BROADER

BIGGER IDEAS BEFORE NEXT STEPS.

WE CERTAINLY HAVE BEEN TALKING

ABOUT IT ALL, BUT JUST NOW IS

THE TIME TO START ARTICULATING

THEM AND THINGS THAT WE LIKE AS

NEXT STEPS IN GENERAL FROM THIS

WORKSHOP.

>> I YOU KNOW, I FEEL LIKE I

HAVE LEARNED A TREMENDOUS AMOUNT

SORT OF FROM THE WORKSHOP TODAY

AND I THINK BRINGINGS ALL

TOGETHER AND TO GIVE OUT THESE

DIFFERENT PER SUSPECT AND I WAS

PARADIGMS IS REALLY HELPFUL IN

THINKING ABOUT THE VALUE OF A

MORE SORT OF COLLABORATIVE AND

INTEGRATED APPROACH.

I'M THINKING ABOUT KARIN AND

JILL'S PRESENTATIONS AND REALLY

SORT OF FOR SOMEONE WITH MORE OF

A CLINICAL BACKGROUND, HELPING

ME THINK ABOUT THE NOTION THAT

IT'S NOT ABOUT NECESSARILY

MODELING THE SYNDROME, PER SE

BUT MODELING PARTICULAR

COMPONENTS AND ERIC SAYING

COMING UP WITH STRATEGIES OF

TESTING SPECIFIC HYPOTHESES

AROUND BEHAVIOR AND POTENTIALLY

ANTECEDENT RELATIONSHIPS.

AND AS I COMMENTED BEFORE, I

FEEL LIKE AMONG THE FIRST

SESSION DISCIPLINES REPRESENTED

AND I INVITE THE OTHER PEOPLE IN

THAT SESSION TO WEIGH IN.

THERE IS A LOT OF WORK TO DO

AROUND DEFINING THE PHENOTYPE

AND IN IN PARTICULAR, DEFINING

THE BRAIN BEHAVIOR RELATIONSHIPS

AND AGAIN TO EMPHASIZE THAT EVEN

THOUGH AUTISM HAS BEEN

CHARACTERIZED FOR 60 YEARS HAS

PROBABLY BEEN -- AUTISM IS

PRESENT IN HISTORY FOR MUCH

LONGER BEFORE, AND SOME OF THE

BASIC OBSERVATIONS LIKE AROUND

SORT OF HAD OVER GROWTH WERE

PRESENT FROM THE VERY START, IN

TERMS OF MAPPING EARLY BRAIN

DEVELOPMENT IN AUTISM, IT'S

REALLY NOT IMPOSSIBLE BEFORE

PERSPECTIVE STUTTIES.

IF KIDS WEREN'T -- STUDIES - IF

KIDS WEREN'T DIAGNOSED IN

3-PHEIFFER YEARS OLD, THERE IS

NO DIRECT DATA ON BRAIN

DEVELOPMENT OTHER THAN HEAD

CIRCUMFERENCE PRIOR TO THESE NEW

STUDIES.

WE ARE COMMENTING BEFORE THE

BREAK.

WE ACCEPT THAT THERE IS CLINICAL

DIVERSITY IN AUTISM.

WE RECOGNIZE THAT THERE IS

EDIOLOGGIC DIVERSITY AS WELL.

I THINK WE ARE STILL TRYING TO

GET A HANDLE ON THE MECHANISMIC

DIVERSITY AND TO WHAT EXTENT THE

DIFFERENT CAUSES MOUNT TO MUCH

SMALLER PATHWAYS VERSUS THERE

ARE GENUINELY DIFFERENT

MECHANISMS OF AUTISM AND WILL IT

COMES BACK TO ALYSSON'S QUESTION

ABOUT THE POTENTIAL OF

ENVIRONMENTAL TRIGGERS FOR

REGRESSION AND THE NOTION THAT

THIS IS OR IT COULD BE RELATED

TO A PARTICULAR INSULT VERSUS

MORE DEVELOPMENTAL.

I THINK WE ARE STILL LEARNING

ABOUT THAT.

AND WE NEED TO PARSE OUT THIS

HETEROGENEITY AND UNDERSTAND

THESE RELATIONSHIPS AND FOR NOW,

I THINK CONTINUE TO HAVE AN OPEN

MIND ABOUT WHAT THESE

RELATIONSHIPS MIGHT BE AND TAKE

THE OPPORTUNITY TO NOT ONLY

GENERATE HYPOTHESES BUT TEST

THEM WITHIN MODEL SYSTEMS.

SO, IT'S A WORK IN PROGRESS BUT

I THINK THERE IS A LOT THAT WE

CAN DO TOGETHER.

LET ME INVITE ANNETTE, AND KASIA

AND IF YOU HAVE ANY FURTHER

THOUGHTS ON HOW YOUR WORK REALLY

COULD INFORM FURTHER HYPOTHESES

TESTING AND DISCOVERY AROUND

MECHANISMS OF REGRESSION.

>> EVERY LAYER WE PULL BACK WE

KEEP THINKING WE WILL GET TO THE

LAYER THAT WILL HELP EXPLAIN

EVERYTHING BUT IN FACT IT ADDS

LAYERS OF THE PUZZLE THAT WE

HAVE TO NOW TRY TO FIGURE OUT

AND PUT BACK TOGETHER.

AND SO, WHEN WE LOOK INTO THE

IMAGING AND BEHAVIOR AND THESE

VERY YOUNG KIDS, WHAT WE FIND IS

THERE ARE SO MANY POTENTIAL

AUTISMS THAT WE HAVE NOT COME TO

UNDERSTAND THAT I REALLY THINK

WE NEED TO THINK MORE ABOUT THIS

DEEP PHENOTYPING THAT INVOLVES

LOTS OF DIFFERENT KINDS OF

MEASURED BEHAVIORS OVER TIME AND

BRAIN DEVELOPMENT OVER TIME TO

UNDERSTAND THE DYNAMICS AND THE

DIFFERENCES THAT LEAD TO AUTISM.

SOMEWHERE IN ALL THOSE PATHWAYS,

THERE ARE ONES WE MIGHT CALORIE

AGGRESSION, BUT EVEN THOSE,

THERE WILL BE MORE THAN ONE

EXTHEY WILL LOOK DIFFERENT.

AND WE ARE NOT THERE YET.

SO I THINK THERE IS A LOT OF

WORK FOR FOLKS LIKE US TO DO TO

GET SOMETHING MORE SOLID IN

FRONT OF BENCH SCIENTIST TO GIVE

THEM LEADS TO RUN WITH.

>> WHEN I THINK ABOUT TYPICAL

DEVELOPMENT, WHEN YOU SEE LOSS

OF SKILLS, THEY ACTUALLY COME

OUT OF A COMPETITION IN THE

SYSTEM FOR SOMETHING ELSE GOING

ON.

AND I THINK WE TEND TO FOCUS TOO

NARROWLY AND SHOULD BE LOOKING

AT WHAT ELSE IS GOING ON IN THE

SYSTEM THAT MAKES YOU REGRESS

AND IT COULD BE OUTSIDE THE

PHENOTYPE OF CHILDREN.

>> JUST TO ADD TO THAT, I THINK

I HAVE BEEN DOING THIS OVER 10

YEARS AND I THINK WHEN WE ALL

WENT INTO THE FIELD, WE SORT OF

WERE ASSUMING THAT WE ARE GOING

TO SEE IN BABIES, FIRST YEAR OF

LIFE, SAME SYMPTOMS WE SEE IN

SLIGHTLY OLDER CHILDREN SO WE

WERE NOT REALLY THINKING A LOT

LIKE DEVELOPALLISTS.

PROBABLY DEINFOING THE AREA OF

INTEREST A LITTLE TOO NARROWLY

AND I THINK WHAT WE LEARNED OVER

THE PAST 10 YEARS IS THAT FIRST

OF ALL WE NEED TO EXTEND OUR

AREA OF RESEARCH TO GO TO

SENSORY BEHAVIORS AND MODEL

BEHAVIORS.

SO SIGNS OF REGRESSION OR AUTISM

MIGHT BE DIFFERENT THAN WHAT WE

SEE OR THINK ARE THE CORE

SYMPTOMS IN EARLY DEVELOPMENT.

AND THAT SORT OF FREES US MORE

TO COME UP WITH BETTER THEORIES

OR HYPOTHESES IN TERMS OF WHICH

SYSTEMS ARE LIKELY TO BE THE

MOST GAITING SYSTEM THAT MAY

STAND BETWEEN THE EARLY

PATHOGENIC FACTORS AND THEN

DEVELOPMENTAL OUTCOMES WE SEE AT

18 MONTHS.

>> JUST DIGGING INTO THE INFANCY

PHASE OF JUST SORT OF PLATEAUING

VERSUS THE SCAFFOLDING THAT

NEEDS TO OCCUR.

ONE SHIFT THAT WE DON'T SEE IN

THE INFANT MOVING INTO TODDLER

HOOD IS DEVELOPMENT OF

INITIATION OF JOINT ATTENTION WE

TALKED ABOUT THE INTENTIONALITY

IN GENERAL IN COMMUNICATING SO I

JUST WANTED TO MAKE SURE THAT

THAT SORT OF GETS ACROSS IN

TERMS OF THE OTHER MODELING.

THAT'S WHERE YOU EITHER SEE THE

STAGNATION OR THE LOSS OF THAT.

EARLY SIGNS THAT THERE MAY BE

INTENTIONALITY BUT THEY ARE

ACTUALLY NOT VERY EXPLICIT.

BABBLING, IS THAT REALLY

DIRECTED SOME SORT OF GESTURES

THAT AREN'T REALLY PURPOSEFUL?

THEM NOT MOVING INTO WHAT YOU

SEE BY 9 MONTHS OF REALLY CLEAR

INTENTIONALITY AND

COMMUNICATION.

SO WHETHER THAT LOOKED LIKE IT

WAS THERE OR WAS THERE OR NEVER

DEVELOPED, IT IS THAT PIECE THAT

TO ME IS SORT OF THE PIVOTAL

PHASE IN TERMS OF WHERE IT LOOKS

LIKE IT IS REGRESSION AT THAT

POINTED IN THAT 9 MONTH

DEVELOPMENTAL PHASE.

SO JUST THINKING ABOUT THAT IN

THE MODELING.

THE MOST CONSISTENTLY

AFFECTED -- ISN'T ON THE

CONSISTENT BECAUSE THERE IS

QUITE A BIT OF VARIABILITY, THE

DEEP CEREBELLUM NUCLEAR AND

OUTPUTS MAYBE AS LINK BETWEEN

THE WHOLE INHIBITION AND

EXCITATION AND LATE MATURATION

OF THE CEREBELLUM AND THE FACT

THAT IT LINKS THE MOTOR

BEHAVIORS TO SOME OF THE MORE

HIGHER COGNITIVE BEHAVIORS.

AGAIN, NOT SURE WHERE TO TAKE

THAT BUT THROW IT OUT THERE THAT

THE SYSTEMS WE THINK ARE

IMPLICATED MIGHT NOT BE THE

SYSTEM SYSTEM ARE THE PRIMARY

CAUSE.

>> IF I COULD JUST THROW IN ONE

THING THAT IS RELATED BUT

ESPECIALLY TO WHAT LONNIE SAID

EARLIER WAS THAT THIS IS AUTISM

SPECTRUM DISORDERS AND I THINK

THAT POINT IS SO IMPORTANT THAT

WE ALTHOUGH I DON'T EXACTLY

STUDY AUTISM, ARE MAYBE STUDYING

MORE THAN ONE DISORDER.

AND MAYBE MORE THAN ONE SET OF

MARKERS OR MORE THAN ONE DISEASE

THAT'S ACTUALLY HAPPENING.

AND I THINK THAT SOMETHING WE

REALLY NEED TO KEEP IN OUR MINDS

AS A STRONG POSSIBILITY.

I JUST WANT -- YOU SAID IT BUT I

WANTED TO EMPHASIZE HOW

IMPORTANT I THINK THAT IS.

>> I JUST WANT TO ADD ONE THING

TO THAT.

SO IN THE ANIMAL MODELS WE ARE

ACTUALLY NOT -- STUDYING THE

GENETIC DISORDERS FOR THE MOST

PART SO THEY ARE ACTUALLY NOT

IDIOPATHIC AUTISM.

SO, I LOT OF THE FINDINGS ARE

DRIVEN BY MORE COGNITIVE MOTOR

IMPAIRED DISORDERS THAT ARE

ASSOCIATED WITH AUTISM AND SO,

WE HAVE THAT PROBLEM AS WELL.

>> JUST TO ADD TO YOUR COMMENT

ABOUT THE HETEROGENEITY AND

POSSIBILITY WE ARE DEALING WITH

REALLY VERY DIFFERENT PHENOTYPES

MAYBE DRIVEN BY DIFFERENT

BIOLOGICAL SUBSTRATES.

EVEN IF WE LOOK AT BOYS AND

GIRLS, WE SEE TREMENDOUS

VARIABILITY IN REMEMBERS IT OF

PHENOTYPE.

AND -- IN TERMS OF PHENOTYPE.

IN THE FIRST YEAR OF LIFE, WE

FOUND THAT GIRLS WHO ARE AT RISK

OF AUTISM HAVE VERY DIFFERENT

BEHAVIORS IN ENVIRONMENTS

COMPARED TO BOYS.

THEY APPEAR TO BE MORE VIGILANT

AND INTERESTED WHICH IS LIKELY

TO PRODUCE DIFFERENT PHENOTYPE

LATER ON.

SO, THAT'S WHY I WAS MENTIONING

SEX DIFFERENCES HERE BECAUSE

THAT IS LIKELY TO ALSO IMPACT

WHAT WE ARE GOING -- NOT ONLY

BECAUSE OF HORMONAL INFLUENCES

OR JET NIC BUT ALSO OTHER

INFLUENCES GIRLS BRING INTO PLAY

IN A VERY DIFFERENT WAY THAN

BOYS.

>> STARTING TO LOOK AT THAT MORE

IN ANIMAL MODELS?

[ OFF MIC ]

THERE IS LITERATURE, OLD

LITERATURE, THAT SHOWS THAT RAT

MALES PLAY MORE IN A ROUGH AND

TUMBLE WAY THAN FEMALE RATS BUT

WE HAVEN'T STARTED OR REALLY

LOOKED THAT THE AT ALL.

BUT WOULD BE COOL.

BUT WE -- CAN I JUST -- WE

ALWAYS LOOK AT BOTH SEXES

BECAUSE THAT'S THE ADVANTAGE OF

HAVING THE MOUSE AND THE RODENT.

WE BREED THEM AND THEY GIVE

BIRTH TO 16 PUPS AND WE HAVE

BOTH SEX THERES AND WHY ARE WE

NOT GOING TO USE THEM WHEN THEY

ARE THERE.

KARIN AND THE NONHUMAN PRIMATES

STUDYING CHILDREN, YOU DON'T

HAVE THAT ADVANTAGE BECAUSE

YOU'RE BRINGING IN YOUR

POPULATION AND SHE GETS ONE

MODEL PER BIRTH.

SO THIS IS REALLY WHERE WE

SHOULD FIGURE OUT THE SEX

DIFFERENCES USING THE MORE

PRIMITIVE ANIMAL MODELS.

>> WE USE BOTH SEXES IN FERRETS

BECAUSE THEY ARE PRETTY

EXPENSIVE TOO.

>> JUST TO ADD TO THAT.

SO, EVEN THOUGH RATS SYNDROME IS

SOMETHING THAT YOU SEE MOSTLY IN

FEMALES, THAT'S AGAIN MOST OF

THE LITERATURE IS NOW MALES AS

WE SAW TODAY.

BUT SO THAT'S SOMETHING THAT I'M

PLANNING ON WORKING ON.

I GAVE YOU A SNIPPET OF IT BUT

IT'S SOMETHING WE ARE LOOKING AT

IN MORE DETAIL FOR THIS REASON

THAT IT IS MOSAIC AND VARIABLE

AND IT IS IN FEMALES BUT WE HAVE

TO TACKLE IT BECAUSE THAT'S THE

PLACE WHERE THE DISORDER IS IN

HUMAN POPULATIONS.

SO IF WE ARE GOING TO FIND

ANYTHING ABOUT THE CIRCUITRY OR

ANYTHING ABOUT THE MOLECULAR

MECHANISMS, IT HAS TO BE IN THE

FEMALE REGARDLESS OF HOW

DIFFICULT PEOPLE THINK IT IS.

>> SO, I THINK SOME OF THE

THINGS I HEARD, AND I HEARD IT

REPEATEDLY AND I THINK IT GOES

BACK TO THINGS LIKE THE BABY

SIB, BUT THE NEED FOR MORE

PROSPECTIVE LONGITUDINAL

PRE-SYMPTOMATIC THINGS FOLLOWING

IT.

I DO THINK, ALTHOUGH YOU MADE A

GOOD ARGUMENT ABOUT HOW MAYBE

THE BABY SIB IS A GOOD

REPRESENTATION, I THINK BACK TO

THIS NOTION OF IT BEING A

SPECTRUM DISORDER.

I THINK WE ARE ALL AWARE OF

THAT.

AND I THINK THAT THE PEOPLE WHO

HAVE AUTISM, WHO ARE SEEN IN

NEUROLOGY CLINICS, ARE HIGHLY

DIFFERENT THAN THE PEOPLE WHO

HAVE AUTISM WHO ARE SEEN IN

DEVELOPMENTAL PEDIATRICS CLINICS

AND THE ONES DIFFERENT SEEN BY

PSYCHOLOGIST IN THE YALE STUDY

CENTER.

ALL THESE THINGS ARE VERY

DIFFERENT AND THEY PROBABLY --

THERE IS PROBABLY IDEOLOGICAL

SIMILARITIES BUT THERE MAY BE

HIGHLY DISCORDANT SOURCES IN

THESE THINGS.

I THINK THE PEOPLE WHO ARE IN

NEUROLOGY CLINICS ARE MUCH MORE

SYNDROMIC.

THEY HAVE MANY MORE OTHER

CO-MORBIDITIES AND ET CETERA.

AND, JUST I THINK THAT YOU MAY

BE -- THERE MAY BE A

REPRESENTATION FOR A BABY SIB

WHEN YOU ALREADY HAVE AFFECTED

INDIVIDUALS TO A CERTAIN TYPE.

SO THE QUESTION, AND I THINK

THIS IS WHERE I GO TO A

CHALLENGE AGAIN IS HAVE YOU EVEN

REMOTELY DESIGNED A STUDY

PROSPECTIVELY STUDYING PEOPLE

WHO ARE UNAFFECTED FROM LIKE

BIRTH AND THEN TRACK THEM?

BECAUSE THAT'S WHAT YOU LIKE.

IF YOU WERE GOING TO -- IF YOU

DID A EXPERIMENT AND YOU SAID,

WE WOULD LIKE TO JUST LIKE TO

TRACK 1000 PEOPLE, 10,000

PEOPLE, LONGITUDINALLY AND HAVE

THE THINGS I WAS ASKING FOR AS

SOME SORT OF NON-INVASIVE,

NON-SEDATING, NONRADIOACTIVE

METHODS TO PROBE, I LIKE THE

PSYCHOLOGICAL METHODS YOU WERE

MENTIONING AND BRIDGING WITH

SOME SORT OF THINGS OF NEWO

BIOLOGY AT THE SAME TIME AND

THEN WE -- NEUROBIOLOGY.

AT 3 YEARS OLD WE SAY OKAY THIS

IS AUTISM OR NOT.

AND THAT WOULD BE THE PERFECT

THING BUT IS THIS A WAY TO THINK

OF SOMETHING THAT WOULD FIT INTO

THE REALITY OF TIME AND MONEY?

SO THAT IS JUST MY FIRST

COMMENT.

BECAUSE I THINK IT IS IMPORTANT.

I THINK WE NEED -- THAT WOULD

GIVE US A WHOLE LOT OF

LONGITUDINAL DATA, TYPICAL

DEVELOPMENT AS WELL.

WHICH I THINK IS VERY IMPORTANT

ESPECIALLY IF YOU'RE DOING

DEEPER PHENOTYPING WE ARE

DESCRIBING THE WAY WE PROBABLY

NEED.

THE OTHER ASPECTS I WAS THINKING

ABOUT WAS -- AND ALONG WITH

THAT, I WOULD ARGUE VERY

STRONGLY THAT PROSPECTIVE

STUDIES LIKE THE BABY SIBS AND

STUFF, SHOULD REALLY INCORPORATE

GENETICS FROM THE BEGINNING.

I MEAN, BECAUSE I THINK THAT IS

IN REMEMBERS OF EAT IDEOLOGICAL

STRATIFICATIONS, THAT IS WHAT WE

HAVE.

YES, WE ALL BELIEVE THAT THERE

ARE PROBABLY OTHER FACTORS,

ENVIRONMENTAL FACTORS, THAT ARE

EITHER CAUSING OR ENHANCING THIS

WHOLE RELATIONSHIP BUT I THINK

WE HAVE TO CHIP AWAY AT THE

THINGS WE CAN DESCRIBE BEFORE WE

CAN GET TO THE NEXT LEVEL OF

THINGS.

THAT'S EVEN HARD TORE SORT OF

REALLY DIG INTO.

I THINK THAT THE IDEA OF

ANOTHER -- TALKING ABOUT

ENVIRONMENTAL.

JUST IN TERMS OF A WINDOW.

AND WHAT ERIC WAS MENTIONING,

ANTECEDENT OR SOMETHING LIKE

THAT.

GOING BACK TO WHEN ANNETTE WAS

MENTIONING ABOUT PRUNING AND WE

MIGHT EXPECT DIFFERENT TIMING OF

REGRESSION WITH DIFFERENT THINGS

BASED ON WHAT WE KNOW FROM HUMAN

PRUNING DATA.

BUT I MENTIONED THAT LIKE WITH

RETT, I GIVE YOU THE EXAMPLE

IT'S THE FINE SHORT LANGUAGE

BOTH BEING LOST ABOUT THE SAME

TIME AND IT'S THAT 18-30 MONTH

WINDOW AND THAT'S WHAT I'M

HEARING FOR ANY SENSE OF

REGRESSION.

NOW PEOPLE KNOW ABOUT THIS.

MAYBE OTHER ONES ARE EARLIER IN

AUTISM BUT THAT IS A WINDOW THAT

A LOT OF TIMES -- SO, THE

QUESTION IS, IS THERE SOMETHING

FUNDAMENTAL ABOUT BRAIN

DEVELOPMENT AT THAT TIME THAT

MAKES IT PRONE TO, IF YOU ARE AT

RISK TO HAVE THIS, THAT THAT IS

THE WINDOW YOU'RE GOING TO SEE

IT?

OR IS IT THAT IS JUST THE WINDOW

AND PEOPLE NOTICE IT?

I MEAN, BIOLOGICAL REASON

AURASSER ATTAINMENT REASON?

IT'S REALLY THE QUESTION --

ASCERTAINMENT.

I THINK IN RETT THERE IS

BIOLOGICAL REASON.

I'M JUST PUTTING THAT OUT THERE.

SOMETHING ABOUT THAT WINDOW OF

TIME THAT MIGHT PREDISPOSE TO

IT.

AND THEN, THE OTHER THING --

JUST A COMMENT REGARDING THE

SENSORY SYSTEM AND THE ATTENTION

TO DETAIL.

AND I HAVE BEEN WONDERING ABOUT

THIS IN TERMS OF - EYE KNOW

OTHER PEOPLE HAVE TOO.

IT'S NOT SOME UNIQUE THOUGHT FOR

ME.

IN TERMS OF AUTISM AND SENSORY

SYSTEM, IS THE ATTENTION TO

DETAIL A LACK OF REFINEMENT TO

DEVELOP THE SURROUND FIELD

ASPECT LIKE WITH GAITING?

IS THIS A PROBLEM OF GAITING

THAT YOU'RE NOT FILTERING?

THERE IS NOT A GOOD FACILITY

TORE DEVELOP A SENSE OF SALIENCY

OF A PARTICULAR THING.

INSTEAD IT'S LIKE FOCUSING ON

EVERYTHING ALL AT ONCE AND IT'S

CREATING AN OVERWHELMING PROBLEM

AND IS THAT A COMMONALTY IN

AUTISM?

IS THAT MAYBE A UNIVERSAL THING?

OR IS THERE A SUBSET OF PEOPLE

WHO HAVE IT?

IS IT A DISTINGUISHING FEATURE?

AND THEN FINALLY, THIS REFLECTS

PART OF MY BIAS BUT I THINK IN

MODELING, I THINK THAT FOCUSING

ON THINGS THAT HAVE HIGH

CONSTRUCT VALIDITY IS MORE

IMPORTANT THAN FOCUSING ON HIGH

FACE VALIDITY MAINLY BECAUSE IF

WE ARE TALKING ABOUT THINGS LIKE

RODENTS AND THIS GOES BACK TO

POTENTIALLY WHAT JASON WAS

MENTIONINGIGES IF YOU HAVE A

JANINE THAT YOU KNOW IS HIGHLY

LINKED TO AUTISM IN PEOPLE AND

REMOVE IT IN ANIMALS, IF THEY

HAVE VARIOUS DEFICITS THAT

CAUSE -- YOU BUT THEY DON'T HAVE

SOCIAL INTERACTION

ABNORMALITIES, I DON'T THINK

THAT IS IMPORTANT.

I THINK WHAT IS IMPORTANT IS

THEN YOU USE THAT AS THE CIRCUIT

YOU'RE STUDYING TO UNDERSTAND

THE BIOLOGY.

AND THAT IS MORE IMPORTANT THAN

SAYING, THIS IS EXACTLY HAS A

PERFECT FACE VALIDITY.

IT HAS A STRONG CONSTRUCT AND

YOU CAN UNDERSTAND THE BIOLOGY.

>> I THINK ONE CRITICAL ASPECT

WOULD BE IF IT INVOLVES

PREFRONTAL CORTICAL CIRCUITRY, A

RODENT HAS A VERY MODEST

PREFRONTAL CORTEX, IF YOU WILL,

AND A PRIMATE HAS NONHUMAN

PRIMATES PARTICULARLY OLD-WORLD

MONKEYS ARE ARE FAR BETTER

ENDOWED IN TERMS OF PREFRONTAL

CORTEX.

IF YOU'RE MISSING A KEY PIECE OF

A CIRCUIT THAT WE KNOW IN HUMANS

IS INVOLVED IN COMPLEX SOCIAL

COGNITION, YOU MAY BE PICKING

THE WRONG ANIMAL MODEL.

SO, EVEN IF HAVE YOU CONSTRUCT

ABILITY THAT ISN'T THE RIGHT

ANIMAL MODEL.

SO I THINK IF -- I DON'T THINK

IT IS EITHER-OR.

BE AMBITIOUS, PICK BOTH.

SO I THINK IT JUST DEPENDS.

>> I HAVE TO BELIEVE YOU GET

BOTH IN ONE.

WE WOULD HAVE GREAT CONSTRUCT IN

PRIMATES.

THEY ARE EASY TO BREED A LOT OF

THEM BUT I THINK THAT IS LIKE MY

PERSPECTIVE FOLLOWING STUDY.

IT'S LIKE THE PERFECT THAT IS

NEVER GOING TO BE THERE SO -- I

THINK YOU'RE RIGHT.

IF YOU WANT TO UNDERSTAND

PRECORTICAL OR PREFRONTAL

FUNCTION, YOU HAVE TO USE

PRIMATES.

YOU HAVE TO EXPLORE THAT FOR

SURE.

IF YOU WANT TO DIG INTO JUST

SPECIFIC BIOLOGICAL CIRCUITRY OF

HOW -- OF A GENE YOU KNOW IS

INVOLVED THEN YOU CAN DO IT

WITHOUT WORRYING ABOUT THE

COMPLEX SOCIAL INTERACTION

ABNORMALITIES.

HOPEFULLY THEN THE PRIMATES CAN

CREATE GOOD CONSTRUCT VALIDITY

VALID MODELS THAT CAN HAVE GREAT

FACE VALIDITY AT THE SAME TIME

WITH COMPLICATED SOCIAL

BEHAVIORS.

>> I ARGUE THE ANIMAL MODELS

YOU'RE PICKING FOR CONSTRUCT

VALIDITY, WANT TO LOOK AT

REPETITION AND SENSORY

ABNORMALITIES AND SOCIAL

FUNCTIONING THAT DON'T INVOLVE

PFC AS MUCH AND THEN YOU COULD

ALSO DO THAT.

BUT I REALLY THINK THAT

LEVERAGING MODELS IN WAYS THAT

ARE MOST APPROPRIATE IS THE ONLY

WAY FOR US TO MOVE FORWARD AS A

FIELD.

WE KNOW THE FIELD IS LITTERED

WITH VERY BAD CHOICES OF ANIMAL

MODELS.

AND THERE IS A REASON WHY 93% OF

BRAIN DRUGS THAT ARE EFFICACIOUS

IN RODENTS FAIL IN HUMAN

CLINICAL TRIALS.

AND SO, I THINK THAT THAT IS

SOMETHING WE NEED TO BE VERY

MINDFUL OF AS WE MOVE FORWARD IN

SELECTING MODELS AND I THINK

RODENT MODELS ARE GREAT FOR SOME

THINGS AND PRIMATE MODELS ARE

GREAT FOR SOME THINGS.

I THINK WE JUST HAVE TO BE

REALLY CAREFUL AS WE GO FORWARD.

>> IF I COULD AD A COMMENT TO

THAT.

I UNDERSTAND THE IMPORTANCE OF

THE PREFRONTAL CORTEX AND HOW

IMPORTANT IT IS FOR HUMAN

DEVELOPMENT.

I'M PROBABLY FOR PRIVATE DEVELOP

AS WELL.

I WANT TO POINT OUT THAT EVEN IN

A SENSORY SYSTEM, EVEN THE

VISUAL CORTEX OR THE AUDITORY

CORTEX, THERE ARE STUDIES THAT

SHOW IF YOU REMOVE PIECES OF

THAT AREA, THE ANIMAL CAN STILL

FUNCTION FINE WITH THOSE

PARTICULAR THINGS.

SO, I WOULD ARGUE THAT WE

ACTUALLY DON'T REALLY HAVE VERY

GOOD IDEAS OF WHAT A CORTEX IN

GENERAL IS DOING LET ALONE

SPECIFIC REGIONS OF THE CORTEX

ARE DOING.

SO, IF WE ARE LOOKING AT

BEHAVIORS IN THIS MODEL AND IF

WE -- I'LL GIVE MY EXAMPLE, FOR

THIS AWE TORY CORTEX BEHAVIOR,

WE KNOW THAT IF WE DO LESIONS OF

THE AUDITORY CORTEXES, THE

ANIMAL DOESN'T DO THIS BEHAVIOR

BUT WE ALSO KNOW THAT IT

REQUIRES OLE' FASHION TO DO THIS

AND IT IS DOING IT IN THE

AUDITORY CORTEX.

SO THERE ARE STUDIES SHOWING

THAT THE CIRCUIT IS REDUNDANT IN

A LOT OF DIFFERENT WAYS AND IT

IS USING MULTIPLE NOSED TO DO

IT.

SO, I UNDERSTAND THE RODENT

PREFRONTAL CORTEX IS PRACTICALLY

NIL BUT MAYBE THE OTHER REGIONS

IF YOU'RE DOING NEUROLOGICAL

BEHAVIORS IN THESE ANIMAL

MODELS, THEN THOSE ARE THE

REGIONS WE SHOULD BE LOOKING AT

RATHER THAN THE OTHER WAY

AROUND.

>> I THINK IT REALLY MATTERS

WHAT YOU'RE STUDYING.

YOU CAN'T MODEL A THEORY OF MIND

DEFICIT IN ANIMAL THAT NEVER

EVOLVED ONE.

TO GO DOWN THAT PATH IS FOOL

HEARTY AND A WASTE OF MONEY.

I THINK YOU JUST FIGURE OUT WHAT

THE MODEL IS GOOD FOR AND YOU

LEVERAGE IT FOR ITS STRENGTHS.

AND YOU MITIGATE AGAINST THE

WEAKNESSES AND THAT IS TRUE FOR

ANY ANIMAL MODEL.

PRIMATES SUCK IN A LOT OF WAYS.

I'M NOT GOING TO BE LIKE THE ONE

SAYING WE SHOULD ONLY DO MONKEY

WORK.

A LOT OF REASONS WHY MONKEYS ARE

EXPENSE EYE -- ALL KINDS OF

REASONS.

I'M VERY AWARE THERE IS COST AND

BOASTS ANY MODEL BUT I WILL

STICK BY THE FACT THAT YOU NEED

TO SEE THE BEHAVIOR IN A

NEUROTYPICAL ANIMAL AND BE

MINDFUL OF THAT.

I THINK WE HAVE DONE A VERY POOR

JOBBA AS A FIELD AND BEEN VERY

SLOPPY.

>> THAT'S WHAT I WANT TO CLARIFY

JUST TO --

[ MULTIPLE SPEAKERS ]

>> JUST TO SHIFT GEARS BUT I

WANTED TO MAKE ONE LAST POINT

BEFORE STEPPING OUT AND OF

COURSE THANK YOU EVERYONE.

SO THE ISSUE AROUND TIMING.

SO I THINK TOO MAJOR CAVEATS.

CLEARLY THERE IS CONSIDERABLE

INDIVIDUAL VARIABILITY AND WE

ARE STILL KIND OF DEVELOPING A

GRASP OF THIS AND CLEARLY THE

PERSPECTIVE STUDIES MAY NOT BE

FULLY REPRESENTATIVE BUT ALL OF

THAT SAID, IT DOES SEEM SORT OF

BASED ON WHAT WE ARE SEEING

BEHAVIORALLY AND IN TERMS OF THE

NEUROIMAGING FINDINGS, IT IS

SHIFTING OUR FOCUS SOMEWHAT

EARLIER STAGE AND THAT HAS BEEN

A VERY INTERESTING PROCESS AND

ONE CAN SPECULATE ABOUT THAT IF

FOR SOME CASES AT LEAST IT'S

LESS DISCRETE AND MORE SORT OF

EVOLVING OVER TIME, IT MAY VERY

WELL BE THAT FOR SOME FAMILIES

THERE IS SORT OF A THRESHOLD AT

WHICH THE CHANGE IS DETECTED

WHICH PLACES IT THAT SORT OF THE

RECOLLECTION AND A BIT OF A

LATER DATE.

BUT THERE IS SOME CONVERGENCE IN

TERMS OF THE SORT OF DERAILING

DEVELOPMENTAL TRAJECTORIES AS

WELL AS THE DATA BOTH VOLUMETRIC

AND CONNECTIVITY WHICH JASON

SPOKE ABOUT.

SORT OF SHIFTING IT TO EVEN

PERHAPS BEFORE THE FIRST

BIRTHDAY WHICH DOES HAVE

IMPLICATIONS FOR HOW WE MODEL

IT.

>> THANK YOU.

>> EVEN THOUGH WE MIGHT NOT BE

ABLE TO MEASURE IT TOO WELL.

>> I HAVE A QUICK COMMENT ABOUT

TIMING.

SO, WE KNOW IN MOST OF THIS IS

FROM RODENT AND SOME VALIDATED

IN HUMANS, IS THAT THERE ARE A

SERIES OF NEUROTRANSMITTERS AND

RECEPTORS THAT ACTUALLY CHANGE

FROM AN INFANTILE FORM INTO A

MATURE FORM IN THAT 18 OR IN

THAT SAME TIME PERIOD.

AND I THINK WE IGNORED IT AND IT

CHANGES NEUROAND WANTS CONNECT

ACTIVITY AND THAT'S AN AREA THAT

HAS BEEN UNDER DEVELOPED IN THE

RODENT FIELD AND I THINK HAS

BEEN LARGELY NEGLECTED IN ANY

SORT OF PRIMATE FIELD AND THAT

MAY BE WHEN YOU'RE CHANGING

PROPERTIES, IF IT'S ALL -- IF

THAT TIMING IS GONE, OR THE

PERCENTAGE OF TURNOVER COULD BE

ONE OF THE KEY THINGS FOR

CERTAIN HUMANS POST MORTEM

TISSUE, RIGHT?

OR YOU COULD BE ABLE IN PRIMATE,

YOU MAY BE ABLE TO DO LIKE DRUG

AFFECTS BECAUSE RECEPTOR YOU

COULD LOOK OR DO PET.

SO YOU COULD LOOK AT THAT BUT

YOU WOULD NEED TO KNOW, NEED TO

GO BAB TO THE CELLULAR LEVEL AND

LOOK AT THE DYNAMICS AND LOOK AT

THE ACTIVATION BUT THAT IS GOING

CELL ALL THE WAY UP.

SO HOW DO YOU STUDY REGRESSION

PROSPECTIVELY?

IT'S A BIG THING?

SO I'M A COMPULSIVE

PROBLEM-SOLVER.

WE AFFECTIONATELY IN OUR CLINIC,

I ALSO IN ADDITION TO RUNNING A

LAB, SOCIAL COGNITION LAB, I

ALSO RUN A CLINIC FOR CHILDREN

WITH AUTISM AND WE TYPICALLY GET

REFERRALS OF CHILDREN WHO ARE

ABOUT 16-18 TO 20 MONTHS OLD.

SO THEY ARE PRESENTING FIRST

DIAGNOSE OF AUTISM AND THESE ARE

CHILDREN BOTH MULTIPLEX AND

SIMPLEX AND AT PRESENT AT THE

TIME WHEN REGRESSION OCCURRED OR

IS ABOUT TO OCCUR AND THIS IS A

MARVELOUS POPULATION FOR US TO

STUDY AND IF WE I HAVE A STRONG

SET OF HYPOTHESES, WE CAN

ACTUALLY EVALUATE WHETHER AT

THIS SPECIFIC VERY IMPORTANT

DEVELOPMENTAL JUNCTION WE DO SEE

DIFFERENCES IN SENSORY

PROCESSING AND FUNCTION AND

LEARNING AND SO FORTH.

WHY KNOW SOMETHING WILL WORK.

WE WANT TO SEE HOW THEY GOT

THERE.

AND THESE STUDIES ARE NOT

ENTIRELY INSANE IF WE FOCUS ON

THE DISTRIBUTION OF THE TRAIT OF

AUTISM WITHIN THIS POPULATION

BECAUSE OF THE 100 BABIES WE

WILL HAVE 50 WITH SOME KIND OF

TRACES OF AUTISM.

AND THAT COULD BE FRUITFUL WAY

OF EXAMINING REGRESSION OR OTHER

TRAJECTORIES WITHIN THIS

POPULATION.

IT'S NOT THAT HARD TO GET 200

BABIES IN 5 YEARS IT'S NOT

CHEAP.

>> I THINK I FULLY APPRECIATE

VERY WELL IT'S DIFFICULT TO

STUDY REGRESSION BEFORE IT

HAPPENS.

I'M IMPRESSED AT LEAST WITH

PERIREGRESSION.

HE DIDN'T GET ANYBODY WHO IS

PREREGRESSION.

HE GOT PEOPLE WITHIN A YEAR OF

REGRESSION AND THAT SYNDROME

NATURAL HISTORY STATE WE HAVE AS

1200 PEOPLE WE ENROLLED AND

FOLLOWED LONGITUDINALLY.

I CAN PROBABLY COUNT ON ONE

MAYBE TWO HANDS THE PEOPLE WHO

HAVE BEEN IDENTIFIED

PREREGRESSION WITH MUTATIONS AND

THEN ABLE TO FOLLOW-UP.

IT'S SO SMALL AND WE REALLY

DON'T SEE THEM BEFORE TWO YEARS

OLD.

EVERY NOW AND THEN SOMEBODY HAS

A TESTING BECAUSE THEY ARE

DELAID.

STILL SYMPTOMATIC BUT DELAYED.

SO I THINK THAT IS -- BUT THAT'S

THE CHALLENGE.

HOW DO YOU GET PEOPLE EARLY.

IT'S VERY HARD.

A COMMENT ABOUT THE VALIDITY

ISSUE.

I THINK WHERE I WAS GETTING THE

PRIMATE MODELS AND FOCUSING ON

TOO MUCH OF THE FACE VALIDITY

AND RODENT MODELS.

I WORRY PEOPLE SPEND A LOT OF

TIME OBSESSING ABOUT THAT AND I

THINK IT IS MORE IMPORTANT TO

JUST HAVE PHENOTYPES.

BUT I DO THINK IT GOES BACK TO

IMPORTANT THING AND I THINK YOU

REALLY HIGHLIGHTED THIS THAT NEW

MODELS ARE USEFUL WHEN THEY DO

SOMETHING DIFFERENT.

I THINK THE -- JILL'S

PRESENTATION ABOUT THE RAT MODEL

AND PLAY BEHAVIOR SHOWS A NEW

THING F A RAT MODEL OF SOMETHING

FRAGILE X JUST SHOWED THE SAME

PPI DEFICITS, IT WOULDN'T BE

REALLY HELPFUL BUT IF IT HAS A

NEW ASPECT AND IT IS HELPFUL AND

I THINK PRIMATE MODEL IF IT WILL

SHOW PREFRONTAL CORTEX, THAT

WILL BE HELPFUL.

NOT IF IT HAS A MOTOR DEFICIT.

THAT'S NOT REALLY -- WE ALREADY

KNEW THAT FROM OTHER THINGS.

WHERE IT MAKES MORE SENSE.

SO THAT IS THE EMPHASIS I WANTED

TO MAKE ON THAT.

>> CAN I ADD A POINT ON THAT?

SO, A LOT OF THE REASON ON THE

HIGH RATE OF CLINICAL TRIAL

FAILING FROM RODENT MODELS WE

HAVEN'T THOUGHT ABOUT IS THAT IN

THAT TRANSITION WE WENT FROM RAT

TO MICE BECAUSE THE GENETICS

DECIDED TO SEQUENCE THE MOUSE

GENOME FIRST AND SO, ALTHOUGH

ALL PHARMACOLOGY AND TOXICOLOGY

AND METABOLISM AND APPROXIMATE.

K STUDIES AND BINDING STUDIES

AND EVERYTHING THAT DRUG

COMPANIES DO TO DEVELOP DRUGS,

IS BASED ON THE RAT AND THEN WE

STUDY MICE WHO HAVE A MUCH

DIFFERENT METABOLISM AND

DIFFERENT TOXICOLOGICAL PROFILES

AND MISSING A TON OF IMMUNE

GENES THAT ARE IN THE RAT THAT

ARE MISSING THEM THROUGH

EVOLUTION.

SO, THE RAT MAY BE A GOOD

SOLUTION.

>> I WANTED TO ADDS A COMMENT.

I DON'T HAVE ALL THE ANSWERS BUT

CERTAINLY THE SPECIFIC GENETIC

DISORDERS ARE MODEL WHERE NOT

EVERYBODY DEVELOPS AUTISM

OBVIOUSLY.

PEOPLE WHO DON'T DEVELOP AUTISM

ALSO HAVE ABNORMALITIES.

BUT WE WERE GOING TO FOCUS A

LITTLE BIT MORE ON TSC AT THIS

MEETING BUT WE DIDN'T.

THERE IS A STUDY GOING ON

LOOKING AT TSC BECAUSE IT'S

BEING DIAGNOSIS VERY, VERY EARLY

NOW.

THAT'S A WAY OF BEING ABLE TO

LOOK AT THE TRAJECTORY OF AUTISM

ON SCHNET THAT POPULATION AND

THE IDEA THAT EPILEPSY PLAYS A

ROLE IN THAT DISORDER AND A LOT

OF OTHER DISORDERS RELATING TO

AGGRESSION.

ON THE RECORD, EVEN THOUGH WE

DIDN'T DECIDE TO TALK ABOUT THAT

TODAY.

>> SO, I THINK WHAT WE ARE GOING

TO DO IS TRANSITION A LITTLE BIT

TO NEXT STEPS AND SO, THISES HAS

BEEN A GREAT DAY AND LOTS AND

LOTS OF REALLY GREAT IDEAS AND

EVERYBODY CAN GO HOME AND THINK

ABOUT THINGS THEY WANT TO DO

INDIVIDUALLY BUT WE COULD ALSO

THINK ABOUT THINGS WE MIGHT WANT

TO DO COLLECTIVELY OR WHAT WE

THINK WILL BE HELPFUL

COLLECTIVELY TO DO NEXT.

ONE IDEA THAT HAS COME UP ON

SOME SCHEDULES WITH SESSION

SHARES A WHITE PAPER.

THERE MAY BE OTHER THINGS.

SOMETIMES THERE IS VALUE IN

GETTING TOGETHER AGAIN TO

CONTINUE DISCUSSIONS.

I'M TOTALLY OPEN TO THOUGHTS AND

IDEAS.

BUT I SORT OF WOULD THINK IT IS

NICE IF IT DOESN'T JUST STOP

HERE AND EVERYBODY GOES HOME AND

MULC IT OVER ON THEIR OWN BUT

THAT WE SORT OF THINK ABOUT

SOMETHING.

SO IF YOU HAVE BEEN SITTING

AROUND THINKING ABOUT IT, IT

WOULD BE GREAT TO DO SOMETHING,

NOW IS THE TIME TO EXPRESS IT.

SO I'D LIKE TO HEAR YOUR IDEAS.

>> I LEARNED A LOT AT THIS

MEETING AND I THINK ONE OF THE

INTERESTING THINGS SOMEBODY FROM

COLD SPRING HARBOR, NO CLINICAL

EXPERIENCE, NOWHERE NEAR IT, IS

HOW DIFFERENT THE PHENOTYPES ARE

AND WHAT IS IT WE ARE LOOKING

FOR IN THE MOUSE MODELS?

GIVEN ALL THE SPECIES

DIFFERENCES AND ALL THESE THINGS

WHAT IS IT WE ARE LOOKING FOR

FROM THE PATIENT SAMPLES ON INTO

THE MODELS THAT WE ARE LOOKING

AT?

SO I WOULD SUGGEST MAYBE IF IT'S

POSSIBLE TO MAYBE DO SOME SORT

OF A FELLOWSHIP OR SOME SORT OF

SABBATICAL OR A THREE-MONTH KIND

OF THING WHERE WE COULD HAVE

INTERACTION BETWEEN A CLINICAL

AND A BASIC RESEARCHER SO WE

COULD GO AND SEE WHAT IT'S LIKE

TO AND MAYBE LOOK AT PATIENTS

AND HOW THEY ARE ACTUALLY BEING

DIAGNOSED AND WHAT ARE THE

FEENEY TYPES YOU'RE LOOKING AT

SO MAYBE WE CAN TAKE THAT BACK

AND TRY TO MODEL THEM IN ANIMALS

BETTER FROM THAT.

IT'S NEVER GOING TO BE EXACTLY

THE SAME AS WE DISCUSSED BUT

MAYBE WE WILL BE ABLE TO HIT AT

SOME SPECIFIC CIRCUITS OR THINGS

THAT WE CAN DO BETTER IN MOUSE

MODELS.

SO THAT WOULD BE --

>> SO WAYS FOR MORE BASIC PEOPLE

TO GET MORE EXPOSURE TO THE

CLINICAL SIDE?

>> YES.

>> WE HAVE A CONSORT GLUM LONDON

AND I SPENT A LOT OF TIME IN A

MOUSE LAB AND LEARNED A MASSIVE

AMOUNT ABOUT WHAT MICE CAN DO.

I THINK IT GOES BOTH WAYS.

THAT KIND OF COLLABORATION IS

REALLY -- SO WE ARE LIKE WE HAVE

PEOPLE FROM IPS, MOUSE MODELS,

PSYCHIATRISTS, PSYCHOLOGISTS,

GENETICISTS WORKING TOGETHER

ANDOOSE BEEN INCREDIBLY

ENRICHING.

>> ONE OF THE THINGS I WAS

THINKING IS ASKING VALUE TO

GETTING PEOPLE WHO ARE DOING

WORK IN EARLY DEVELOPMENT ACROSS

SPECIES TO SIT AND TALK ABOUT

COMMON CONSTRUCTS AND MEASURES.

THAT MIGHT BE EMBEDDED IN ALL

THE STUDIES AND I KNOW I WAS

THINKING THERE ARE A LOT OF

PEOPLE WHO ARE DOING A

PROSPECTIVE STUDY OF INFANTS

EITHER AT RISK FOR AUTISM BY

VIRTUE OF FAMILY OR COMMUNITY

SAMPLES AND MAYBE EVEN GETTING

THOSE PEOPLE EMBEDDING SOME OF

THE SAME MEASURES ACROSS

STUDIES.

BUT IT COULD ALSO BE A LITTLE

BIT BROADER AND THINK ABOUT WHAT

THINGS COULD BE MEASURED IN BOTH

HUMANS AND ANIMAL MODELS AND

WHAT WOULD BE THE MEASURES.

SO, THAT WOULDN'T BE THE SAME

THING AS EMBEDDING SOMEBODY IN A

CLINIC BUT IT COULD BE SOMETHING

THAT COULD BE DONE VIRTUALLY IN

A MEETING OR IN A SYMPOSIUM

THING IN A LARGER NATIONAL

MEETING OR SOMETHING LIKE THAT.

>> SO I ONCE HAD THE WONDERFUL

PLEASURE OF PARTICIPATING IN A

NETWORK THAT WAS BEING RAN IN A

PREVIOUS LIFE I DID A LOT OF

WORK ON RESILIENCE AND STRESS

VULNERABILITIY AND I'M NOT SURE

WHAT THE FUNDING MECHANISM IS

BUT WHAT WAS REALLY SPECTACULAR

IS THAT IT WAS A GROUP OF

SCIENTISTS THEY HAY GROUP OF

RODENT RESEARCHERS AA GROUP OF

MONKEY PEOPLE AND THEN A COUPLE

OF DIFFERENT HUMAN LINES OF WORK

AND THEY WERE MODELING THE

INFLUENCES OF SEVERE EARLY

DEPRIVATION SO I THINK THEY WERE

STUDYING ROMANIAN ORPHANS AND

THEN A GROUP DOING DOING

AMYGDALA CONNECT ACTIVITY AND A

MONKEY MODEL OF MATERNAL ABUSE

AND THEN LONG SEPARATIONS IN

RAT.

AND THEY USED MANY OF THE SAME

MEASURES ACROSS THEIR STUDIES

AND I THINK THEY ALL BENEFITED

UNBELIEVABLY FROM THE

INTERACTIONS THAT THEY HAD IN

TERMS OF EVEN JUST GETTING

FEEDBACK AS THEY WERE DESIGNING

STUDIES OF WHAT TO PUT INTO IT.

AND OFTEN WHEN YOU HAVE A GRANT

GO THROUGH A STUDY SECTION, AS A

REVIEWURE YOU'RE NOT ALLOWED TO

SAY THESE ARE THE THINGS YOU

SHOULD HAVE DONE.

SO HAVING SOME SORT OF FORMAL

WAY AS YOU'RE DEVELOPING

WHATEVER IT IS TO HAVE CROSS

SPECIES INPUT, I THINK WOULD BE

SUPER VALUABLE.

I DON'T KNOW THE FORM IT TAKES

OR WHAT THE BUDGET LOOKS LIKE

BUT I THINK SOMETHING LIKE THAT

WOULD BE GREAT FOR THIS SORT OF

APPROACH.

>> SO, JUST TO KIND OF EXTEND

THAT A LITTLE FURTHER.

SORT OF ANSWER JEFF'S QUESTION

HOW DO WE GET 100,000 AT RISK

KIDS TO PARTICIPATE IN A STUDY?

[ OFF MIC ]

>> SO BUT IF WE COULD TARGET OR

USE THE RESOURCES THAT WE HAVE,

MEANING ACCESS TO ALL THE

FAMILIES THAT HAVE A CHILD WITH

ASD, AND WE CREATED A SOCIAL

MEDIA SORT OF VENUE FOR THEM TO

COLLECT INFORMATION, AND IF WE

INSTRUCTED THEM HOW TO COLLECT

INFORMATION, VIDEOTAPING THEIR

KIDS DEVELOPMENTAL MILESTONES,

YOU MIGHT BE ABLE TO GET

PRELIMINARY DATA THO KNOW HOW TO

THINK ABOUT THIS.

AND THEN YOU WOULD BE ABLE TO GO

BACK AND RECRUIT THOSE

INDIVIDUALS FOR WHOM THERE WAS

CLEAR REGRESSION.

SO, I DON'T KNOW.

JUST A THOUGHT.

I TOTALLY AGREE WITH YOU.

WE REALLY NEED -- A LOT OF THIS

IS HAND WAVING AND WITHOUT A

REAL DENOMINATOR AND REAL DATA,

WE ARE KIND OF STUCK WITH

IMPARTIAL -- I MEAN, IMPERFECT

SYSTEM.

AND THIS WILL HAVE LITTLE OWN

FLAWS BUT MIGHT GIVE US A

DENOMINATOR TO THINK ABOUT WHAT

IS HAPPENING.

>> I THINK THAT DEFINITELY --

I'M SURE THAT THE STUFF YOU'RE

MENTIONING MAYBE IT COULD BE

TASKS THAT COULD BE DONE EASILY

EVEN IN A PARENT COULD DO A TASK

WITH A CHILD AND VIDEOTAPE IT

AND STUFF.

I MEAN, I GUESS I WOULD LOVE TO

AGAIN IN MY FANTASY WORLD, THAT

WE WOULD HAVE ALSO SOME SORT OF

NICE NEUROBIOLOGICAL CORRELATE

OF SOME MEASURE THAT WE WOULD

ALSO BE DOING AND WE WOULD BE

ASSESSING TYPICALLY 98IVE ONCE

THAT ARE ABNORMAL TO BASICALLY

BE IDENTIFYING EARLY NEURO--

EARLY BIOMARKERS.

>> SO, A NUMBER OF COMPUTERS I'M

POINTING TO THE CAMERA ON MY

LAPTOP.

>> [ OFF MIC ]

>> BUT I HAVE A PATENT THAT.

SO, IF THEY HAVE OBVIOUSLY TWO

CAMERAS AND A NUMBER OF THEM ARE

STARTING TO, THEN YOU CAN DO EYE

TRACKING.

AND YOU CAN EMBED THAT WITH

THINGS THAT THE KIDS COULD BE

WATCHING ON THE SCREEN.

SO THERE ARE WAYS TO SORT OF

ACQUIRE ENDOPHENOTYPIC DATA.

>> SO THERE ARE A GROWING NUMBER

OF EYE TRACKING AND TECHNOLOGY

EXPERTS THAT ARE INVOLVED IN

AUTISM SO I WOULD WANT TO HAVE

THEM AS THIS MEASURES.

>> I'M THINKING THAT THERE COULD

BE LOTS OF DIFFERENT POPULATIONS

THAT ARE LOOKING AT THIS AGE

RANGE.

EVEN THOUGH THEY ARE VERY

DIFFERENT, DIFFERENT GENETIC

DISORDERS OR WHATEVER, AND THAT

COULD ACTUALLY BE USEFUL IF THEY

ARE USING THE SAME MEASURES

ACROSS ALL OF THOSE.

AND IT WOULDN'T BE A DEFINITIVE

ANSWER PROBABLY BUT IT COULD BE

SOME CLUES ABOUT WHERE TO LOOK.

>> TAPPING INTO WHAT WAS

DISCUSSED EARLIER, ERIC

MENTIONED AND PREVIOUS ONE

INTRAMURAL PEOPLE WHO WAS HERE,

A CONNECTION WITH SCHIZOPHRENIA.

WE DO KNOW SOME OF THESE GENETIC

RISK FACTORS ARE OVERLAPPING.

NOW YOU HAVE MAYBE IDENTIFIED

FAMILIES AND THIS CHANGE IS

OCCURRING MUCH LATER IN LIFE.

SO YOU PROBABLY COULD BE

FOLLOWING THINGS A LITTLE MORE

PROSPECTIVELY.

>> JITS 49IA FIELD DID A SIMILAR

THING.

I DON'T THINK THEY WERE

INCLUDING ANIMALS BUT GOT

RESEARCHERS TOGETHER WHO WERE

LOOKING AT THE PRODROMAL PHASE

AND DECIDED ON MEASURES ACROSS

DIFFERENT STUDIES TO INCLUDE SO

IT WOULD BE A LARGER NUMBER.

SO SOMETHING THAT HAS BEEN DONE.

>> AND I WAS THINK TO CONNECT

THEM WITH THE PEOPLE IN AUTISM

TO TRY TO SEE HOW THEY WOULD

CROSS-FERTILIZE.

>> SO THERE SEEMED TO BE

INTEREST IN THE WHITE PAPER WITH

THE CHAIRS.

IS THERE ANY IN THAT?

DO PEOPLE HAVE THE IDEA OF ABOUT

THE SCOPE OF WHAT THAT WOULD BE

AND WHAT THEY THINK WOULD BE

USEFUL IN TERMS OF DISSEMINATING

IDEAS FROM THIS WORKSHOP?

>> I THINK WE'D IDENTIFY THE

QUESTION AND THEN OUTLINE

CURRENT KNOWLEDGE AND THEN

CLEARLY IDENTIFY GAPS AND MAKE

RECOMMENDATIONS ON FUTURE STEPS

WHICH WE HAVE BEEN DISCUSSING

RIGHT NOW AND I WOULD THINK THAT

THE KIND OF THINGS I WROTE DOWN

ARE BETTER UNDERSTANDING

LONGITUDINAL STUDIES POTENTIALLY

USING WHAT ELLIOT WAS MENTIONING

IN TERMS OF CROWD SOURCING AND

THE IDEAS MORE NON-INVASIVE

IDEAS CONNECTIONS BETWEEN THE

DIFFERENT CELLULAR CIRCUIT HUMAN

LEVEL UNDERSTANDING OF THE

PROBLEM.

WHAT ELSE?

>> ALSO THINK OF COMMON

ENDOPHENOTYPES WITHIN THE ANIMAL

MODELS.

EITHER -- AND WE MAY BE ABLE TO

GO ACROSS SPECIES OR CERTAIN

AREAS WHERE WE DON'T HAVE IT, IF

WE DON'T HAVE A DIFFERENT

SPECIES FOR THIS PHENOTYPE, IT'S

A CHALLENGE.

CAN WE MAKE IT?

AND DOES THE CIRCUITRY SIMILAR

OR DIFFERENT?

BECAUSE IT COULD BE THE

CIRCUITRY IS BECOMING MORE

COMPLEX AS YOU'RE GROWING CLOSER

TO HUMAN AND YOU NEED TO ADD THE

COMPONENTS IN.

>> AND WE COULD ALSO ADD REVIEW

OF THE SYSTEMS THAT WE SUSPECT

ARE EFFECTIVE EARLY IN

DEVELOPMENT AND LAY THE

FOUNDATION IN TERMS PHENOTYPES

WE SEE EMERGENT IN PHENOTYPES WE

SEE IN TODDLERS WITH AUTISM AND

WILL I REFER TO CLINICS.

>> I GUESS I THINK IT IS VERY

IMPORTANT THAT AS ANNETTE

POINTED OUT THERE IS A NORMAL

REGRESSION PHASE IN SEVERAL OF

THESE PROCESSES AND IT'S NOT ALL

NEGATIVE THAT THAT REAGGRESSION

A NORMAL PART OF DEVELOPMENT.

-- REGRESSION --

>> SO I HAVE BEEN INVOLVED IN

SEVERAL WORKSHOPS LIKE THIS THAT

ENDED WITH UP WITH A WHITE PAPER

AND IT'S BEEN REALLY A GOOD

EXPERIENCE TO DO.

BUT I HAVE FOUND THAT IT IS

USUALLY HELPFUL TO HAVE A SMALL

GROUP START WITH FIGURING OUT

THE OUTLINE AND THEN BRINGING IN

A LARGER GROUP AND MAYBE HAVING

DIFFERENT PEOPLE WORK ON

DIFFERENT PARTS.

SO, ARE THERE ANY VOLUNTEERS TO

BE PART OF THAT SMALL GROUP?

THAT'S A GREAT IDEA.

SO TO TAKE THE LEAD?

THE TWO OF YOU?

OKAY.

>> [ OFF MIC ]

>> SO ONCE IT IS FLUSHED OUT, WE

CAN GET BACK TO THE WHOLE GROUP

AND PEOPLE CAN OPT IN OR OUT AT

THAT POINT.

SO SOMETIMES NOT EVERYBODY

PARTICIPATES BUT EVERYBODY IS

ACKNOWLEDGED AS PARTICIPATING IN

THE WORKSHOP THAT GENERATED IT.

BUT IT'S UP TO PEOPLE'S INTEREST

AND TIME, REALLY.

WE CAN DO THAT.

WE ARE GETTING CLOSE TO THE END.

ANY OTHER CONCRETE STEPS OR

THINGS THAT WE SHOULD BE DOING?

IF NOT, WE'LL TAKE ALL OF THIS

INTO CONSIDERATION AND CIRCLE

BACK TO EVERYBODY HERE.

SO, I JUST -- WE ARE AT THE WRAP

UP PHASE SO I JUST WANTED TO

THANK EVERYBODY A LOT FOR ALL OF

YOUR INPUT AND YOUR ENTHUSIASM

FOR PARTICIPATING, WHICH WAS

VERY NICE AND REWARDING.

AND SESSION CHAIRS, IN

PARTICULAR, PUTTING IN A LOT OF

TIME BUT I KNOW ALL OF YOU DID

AND YOU'RE ALL VERY, VERY BUSY

PEOPLE AND SO I REALLY

APPRECIATE THE EFFORT TO PUT

TOGETHER THE TALKS AND BE ON

PHONE CALLS AND ALL OF THAT.

I ALSO WANT TO THANK AUDREY MY

CO-CHAIR WHO DID AN ENORMOUS

AMOUNT OF WORK AND PLANNING

COMMITTEE PEOPLE.

I WANTED TO ESPECIALLY THANK

SUSAN DANIELS AND HER OFFICE,

OFFICE OF AUTISM RESEARCH

COORDINATION BECAUSE THEY

PROVIDED THE FUNDING FOR THIS

AND THEY REALLY --

[ APPLAUSE ]

THEY ARE REALLY GREAT LOGISTICAL

SUPPORT.

SOLENA PEREZ, ABI SMITH AND

CHIPPER AND JENNIFER ADONNA WHO

WERE HERE.

SOME OF THEM ARE STILL HERE.

JUST WERE AMAZINGLY GOOD AT

MAKING THIS GOOD SMOOTHLY.

SO THANK YOU TO ALL OF YOU

FOLKS.

ANYTHING ELSE?

>> LAST THING.

I WOULD LIKE TO GIVE A HUGE

ROUND OF APPLAUSE TO ANN BECAUSE

SHE DID SO MUCH WORK FOR THIS.

[ APPLAUSE ]

>> THANK YOU.

IT WAS REALLY A GREAT DAY.

SO THANKS.

VERY MUCH.