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.