I'M JANICE LEE WELCOME TO THE "2021 INAUGURAL NIH LASKER CLINICAL RESEARCH SYMPOSIUM" THIS IS A FOUR PART SERIES. WHAT MAKES IT SPECIAL IS THE LASKER CLINICAL RESEARCH PROGRAM WAS STARTED IN 2011. IN FACT WE ARE ALSO CELEBRATING THE 10-YEAR ANNIVERSARY OF THE PROGRAM. WHAT A GREAT WAY TO HONOR WITH THIS SYMPOSIUM. ONE OF THE MISSIONS FOR INTRAMURAL IS TO PROMOTE AND HIGHLIGHT RESEARCH AND CLINICAL TRACKS AND OPPORTUNITIES RIGHT HERE AT BETHESDA. THIS SLIDE HIGHLIGHTS SEVERAL OPPORTUNITIES WITH THE TOP PURPLE HIGHLIGHTS SHOWING THE CLINICAL RESEARCH PROGRAMS AND BOTTOM BLUE SHOWING THE BASIC RESEARCH PROGRAMS. WE HAVE TRAINING OPPORTUNITIES FOR UNDER GRADUATE, THE N.I.H. SUMMER INTERNSHIP TO PROFESSIONAL SCHOOL LEVEL, MEDICAL RESEARCH SCHOLARS PROGRAM AND SEVERAL CLINICAL RESEARCH FELLOWSHIP PROGRAMS FOR THOSE WHO HAVE RECEIVED THEIR PROFESSIONAL DEGREES AND Ph.D.'S. WE HAVE STAFF CLINICIAN RESEARCH SERIES. ASSISTANT CLINICAL INVESTIGATORS. AND THE LASKER SCHOLARS WHO ARE TENURE TRACK INVESTIGATORS. THE LAST TWO CAREER OPPORTUNITIES ARE PRE-TENURE AND HAVE INDEPENDENT FUNDING WITH GOAL SEEING THESE TALENTED CLINICIAN SCIENTISTS GO ONTO INDEPENDENT TENURED POSITIONS, WHETHER HERE AT N.I.H. OR EXTRA MURAL INSTITUTION. WHILE THIS SHOWS CANDIDATES AT DIFFERENT STAGES EACH INSTITUTE WILL HAVE SIMILAR OPPORTUNITIES AND CAREER PIPELINE. TODAY WE ARE HERE TO CELEBRATE THE LASKER CLINICAL RESEARCH SCHOLARS PROGRAM. IT'S TO SUPPORT EXCEPTIONAL CLINICAL RESEARCHERS DURING THE EARLY STAGES OF THEIR CAREER TO LAUNCH THEM INTO INDEPENDENT POSITIONS. THERE ARE TWO PHASES. PHASE ONE IS HERE ON LASKER CAMPUS, INDEPENDENT TENURED TRACK INVESTIGATOR. THE SECOND IS THE LASKER SCHOLAR WHO CAN CONTINUE ON AT THE INTERMURAL RESEARCH PROGRAM OR RECEIVE THREE YEARS OF FUNDING AT AN OUTSIDE INSTITUTION. THERE ARE 34 LASKER SCHOLARS, 30 IN THE PROGRAM AND 4 WHO HAVE RECEIVED TENURE AND THEY WILL BE SHOWCASED IN THIS SERIES. OVER 50% ARE WOMEN AND 18% ARE UNDER REPRESENTED MINORITIES. THEY REPRESENT 11 INSTITUTES WHO SUPPORT THEIR RESEARCH, AS SEEN IN THIS SLIDE. THE PROGRAM WOULD NOT BE POSSIBLE WITHOUT WORK AND DEDICATION OF THE CLINICAL RESEARCH FACULTY DEVELOPMENT TEAM. PARTICULARLY CHUCK DEAROLF. IF YOU ARE INTERESTED PLEASE VISIT OUR WEBSITE FOR MORE INFORMATION. NOW I WOULD LIKE TO INVITE DR. MARILYN POWELL. SHE IS A CLINICAL DIRECTOR FOR N.M.I.H. WHO WILL INTRODUCE OUR SYMPOSIUM SPEAKER AND LASKER SCHOLAR DR. ARMIN RAZNAHAN. IT'S REALLY MY GREAT PLEASURE TO INTRODUCE ARMIN RAZNAHAN. WHO HAS AN M.D. AND Ph.D., HE IS OUR NIMH FIRST LASKER WARDEE. CHIEF OF THE SECTION ON DEVELOPMENT NEUROGENOMICKS. HE RECEIVED GRADUATE TRAINING AT KINGS COLLEGE UNIVERSITY AND HOSPITAL AND PSYCHIATRY IN LONDON IN THE U.K. AND THEN HE CAME TO THE N.I.H., N.I.M.H. AS POST DOCTORAL FELLOW WITH DR.S GEE. WORKED ON THE INTERMURAL PROGRAM. HE BECAME AN ASSISTANT CLINICAL INVESTIGATOR IN 2014 AND THEN JOINED THE N.I.H. LASKER CLINICAL RESEARCH SCHOLARS PROGRAM IN 2015 AND BECAME A TENURED SENIOR INVESTIGATOR AT THE N.M.I.H. I.R.P. IN 2020. SO DR. RAZNAHAN HAS MANY ACCOMPLISHMENTS, I WANT TO NAME A FEW. A MEMBER OF THE U.K. ROYAL COLLEGE OF PSYCHIATRISTS. U.K. ROYAL COLLEGE OF PEDIATRICS AND CHILD HEALTH AND AMERICAN COLLEGE OF NEURO PSYCHO PHARMACOLOGY. HE SERVES AS EDITOR FOR THE JOURNAL OF AMERICAN ACADEMY OF CHILD AND ADOLESCENCE PSYCHOLOGY. HE SERVES ON A.C.M.P. DIVERSITY AND INCLUSION TASK FORCE AND THE A.C.M.P. MEMBERSHIP COMMITTEE AS WELL AS ASSOCIATION FOR X AND Y CHROMOSOME VARIATION ADVISORY COMMITTEE. ORGANIZATION OF STUDY OF SEX DIFFERENCES COUNCIL AND FRENCH AUTISM AND NEURO DEVELOPMENTAL DISORDERS SCIENTIFIC ADVISORY BOARD. THE SECTION OF DEVELOPMENTAL NEUROGENETICS HAS BEEN RECOGNIZED FROM THE A.C.M.P., INCLUDING EVA KING AWARD FOR TRANSLATIONAL RESEARCH AND AMERICAN PSYCHOPATH LOGICAL ASSOCIATION FOR THE ROBIN -- AWARD. HIS RESEARCH COMBINES NEUROIMAGING GENOMIC TECHNIQUES INVOLVING LARGE DATA SETS TO BETTER UNDERSTAND THE ARCHITECTURE OF HUMAN BRAIN DEVELOPMENT IN HEALTH AND NEUROGENETIC DISORDERS. IN ORDER TO IMPROVE DISEASE PREVENTION AND DEVELOP TREATMENTS. HE HAS UTILIZED THE I.R.P. ENVIRONMENT TO GATHER DEEP PHENOTYPEIC INFORMATION TO COGNITION AND BEHAVIOR IN A TYPICALLY DEVELOPING CHILDREN. USING THESE GENETIC DISORDERS THAT ARE QUITE DIVERSE HE IS TRYING TO EMPIRICKLY DISSECT THE NEUROLOGICAL PATHWAYS THAT COULD LEAD TO SYMPTOMS. HIS EXCITING FINDINGS HAVE BEEN PUBLISHED IN NATURE COMMUNICATIONS, -- I WILL LET HIM SHARE THESE EXCITING FINDINGS TO YOU NOW. CONGRATS, ARMIN. >> MARILYN, THANK YOU FOR THAT VERY KIND INTRODUCTION. IT'S LOVELY TO BE HERE WITH YOU ALL AND GET A CHANCE TO CELEBRATE THE LASKER PROGRAM. WHICH I REALLY THOROUGHLY ENJOYED BEING PART OF. AND IT'S WONDERFUL TO BE HERE, ALBEIT VIRTUALLY AND HAVE A CHANCE TO SHARE WORK FROM MY LAB AND COLLABORATIVE PARTNERS. AS MARILYN MENTIONED MY TALKED TO WILL EXPLORE THE THEME OF "INTEGRATIVE NEUROIMAGING OF THE DEVELOPING BRAIN IN HEALTH AND DISEASE". I WILL START FROM A STARTING POINT IN MEDICINE. WE WILL GO DEEP INTO BASIC SCIENCE AND THEN BACK AGAIN. FIRST, A LITTLE BIT OF BACKGROUND ON OUR GROUP. SECTION OF INTERNATIONAL DEVELOPMENT GENOMES IS PART OF THE N.I.H. BRANCH, OUR LAB IS ON THE SCENEIC FOURTH FLOOR OF BUILDING 10 AT THE CLINICAL CENTER. WE ARE HIGHLY MULTIDISCIPLINARY GROUP SPANNING MENTAL HEALTH NURSING, PSYCHOLOGY, PSYCHIATRY, MOLECULAR BIOLOGY, NEURO SCIENCE. OUR OVERARCHING GOAL WORKING TOGETHER WITH COLLABORATORS IS SPECIFIED HERE AND BROADLY WHERE OUR CLINICAL GOAL IS TO BETTER UNDERSTAND THE BIOLOGY OF NEURO DEVELOPMENTAL DISORDERS IN WAYS THAT MIGHT ULTIMATELY PREVENT DISEASE, TREATMENT AND PREVENTION. TRYING TO TACKLE THIS CLINICAL GOAL REQUIRES US TO ENGAGE IN SOME BASIC SCIENCE WORK. SO WE SORT OF ITERATE BETWEEN BASIC SCIENCE AND CLINICAL RESEARCH, I HAVE TO SHOW YOU IN THE TALKED TO. UNDERSTANDING BIOLOGY AND MENTAL NEURO DEVELOPMENTAL DISORDERS. WHAT DO I MEAN? THE CLINICAL ISSUES ARE CALLED THINGS LIKE AUTISM SPECTRUM DISORDER, A.D.H.D., SPECIFIC LEARNING DISABILITIES, TIC DISORDERS. WE HAVE NO TESTS FOR THEM AND THEY HAVE FUZZY BOUNDARIES BETWEEN EACH OTHER AND BETWEEN THEMSELVES AND NORMALITY. AFFECTING ONE IN TEN PEOPLE AND AFFECTED INDIVIDUALS OFTEN SHOW IMPAIRMENTS THROUGHOUT THEIR LIFE SPAN. THESE CONDITIONS ON SET IN EARLY CHILDHOOD ALL WITH A MALE BIAS. THEY ARE HIGHLY CO MORBID WITH EACH OTHER AND TEND TO BE CLUSTERED IN FAMILIES. ALREADY SOME HINTS WHAT I'M ABOUT TO TELL YOU THEY ARE PRESENTED AS DISTINCT CATEGORICAL CONSTRUCTS BUT CONNECTED TO EACH OTHER. HUGE AMOUNT OF RESEARCH HAS BEEN POURED IN IN SEARCH FOR BIO MARKERS, SIGNATURES THAT MIGHT AFFECT OUTCOMES IN AFFECTED INDIVIDUALS. I'M SHOWING YOU ONE READ OUT, PUBLICATIONS OVER TIME FOR EACH OF THE KEY DIAGNOSIS WITHIN THE NEURO DEVELOPMENTAL DISORDER FAMILY. UNFORTUNATELY DESPITE THESE INVESTMENTS IT'S SAFE TO SAY WE STILL LACK A SINGLE DIAGNOSTIC BIO MARKER FOR THESE CATEGORIES. WHY MIGHT THAT BE? THERE ARE MANY REASONS BUT I THINK TRACKED BACK TO THREE CHALLENGES THAT QUICKLY COMES ACROSS WHEN YOU ARE TRYING TO UNDERSTAND THE NEURO BIOLOGY OF BRAIN PHENOTYPES. THE GOOD NEWS IS TEACH OF EACH OF THESE CHALLENGES OFFERS US AN OPPORTUNITY. I WILL REVEAL THESE AS A CONTEXT FOR THE DATA I WILL PRESENT IN THE MAIN BODY OF THE TALK. CHALLENGE NUMBER ONE IS THE STAGGERING COMPLEXITY OF GENETIC RISKS FOR NEURO DEVELOPMENTAL DISORDERS. THESE CONDITIONS ARE SOME OF THE MOST HIGHLY INHERITABLE DISORDERS WE KNOW. BUT THE ARCHITECTURE OF GENETIC RISK FOR THESE CONDITIONS MAPS VERY POORLY ON THE DIAGNOSTIC CATEGORIES WE CURRENTLY USE TO CLASSIFY NEURODEVELOPMENTAL DISORDERS. I WILL SHOW YOU HERE, LET ME WALK YOU THROUGH IT. AT THE BOTTOM DIFFERENT SUBTYPE OF GENE DOSAGE DISORDERS. THIS IS A PARTICULARLY IMPORTANT CLASS OF RISK FOR NEURODEVELOPMENTAL DISORDERS. DELETIONS OR DUPLICATIONS OF CHUNKS OF THE GENOME. CHROMOSOME LIKE DOWN SYNDROME, 21 OR ABNORMAL NUMBERS OF X AND Y, CONDITIONS WE PARTICULARLY FOCUS ON OR ABNORMAL DOSAGE OF SUB CHROMOSOMAL ADDRESSES THAT HAVE THIS, 15 Q 11. LONG ARM OF CHROMOSOME 15 THAT IS ADDRESSED IN THE GENOME. AND HAVING TOO FEW OR TOO MANY COPIES OF THESE SEGMENTS, SIGNIFICANTLY INCREASES RISK FOR PSYCHIATRIC MORBIDITY. THE PROBLEM IS, THERE'S THIS REALLY GNARLY MANY TO MANY MAPPING. ANYONE OF THESE COPY VARIATIONS OR GENE DOSAGE COULD SIGNIFICANTLY INCREASE YOUR RISK FOR MULTIPLE PSYCHIATRIC OUT COMES, CALLED PLEIOTROPY. YOU CAN ARRIVE AT ANY ONE PSYCHIATRIC DIAGNOSIS, STARTING FROM SEVERAL GENETIC STARTING POINTS. GENETIC HETEROGENEITY. ESSENTIALLY WHAT THIS IS TELLING US IS THE MINUTE YOU START TO FIND A BIO MARKER FOR AUTISM, YOU ARE ALREADY LUMPING TOGETHER MANY DIFFERENT GENETIC SUBTYPES AND ALSO OVERLOOKING THE FACT THAT MANY SUBTYPES AREN'T REALLY SPECIFIC TO AUTISM AT ALL. THIS LOOKS DISHEARTENING. BUT THIS CHALLENGE IS A REAL OPPORTUNITY, IF WE FLIP OUR STRATEGY ON ITS HEAD. AND ACTUALLY TRY TO UNDERSTAND THE NEURO BIOLOGY OF THESE CONDITIONS RATHER THAN INSTEAD OF STUDYING DIAGNOSTIC GROUPS BY RECRUITING PARTICIPANTS BASED ON CARRIAGE OF HIGH GENETIC RISKS AND TAKING MULTIPLE DIFFERENT GENETIC GROUPS AND STUDYING THEM ALONGSIDE EACH OTHER. THAT'S WHAT WE TRY TO DO WITHIN THE GROUP. A CORE PLANK, THAT WOULD BE IMPOSSIBLE OUTSIDE THE INTRAMURAL PROGRAM BECAUSE OF ITS SPECIAL NEEDS, WHICH I WILL COME BACK TO IN A MOMENT. THINK OF IT AS A LARGE HADRON COLLIDER FOR THE BRAIN. SEEING HOW THEY BREAK APART IN HIGH ENERGY COLLISIONS. PARTLY ANALOGOUS WAY WE CAN THINK OF RARE GENETIC DISORDERS AS PROBES FOR MINING BRAIN ARCHITECTURE AND HEALTH AND DISEASE. CAN WE USE THE STRATEGY OF OBSERVING NATURE HITTING THE BRAIN WITH DIVERSE HIGH IMPACT GENETIC ABNORMALITIES, CAREFULLY DOCUMENT HOW THE BRAIN REACTS TO THESE DIVERSE IMPACTS AND RECONSTRUCT THAT DATA TO BETTER UNDERSTAND THE DISORDERS. I THINK A REALLY ELEGANT EXAMPLE IS THIS BEAUTIFUL STUDY FROM THE LAB OF A CLOSE FRIEND COLLABORATOR JASON LERCH. WHAT I'M SHOWING YOU JASON AND JACOB SCANNED OVER 20 DIFFERENT MOUSE MODELS FOR RISK GENES FOR AUTISM. THESE ARE THE ROWS. THEY MEASURED THE IMPACT EACH OF THESE GENETIC MODELS HAD ON THE VOLUME MANY REGIONS OF THE BRAIN. THESE ARE THE COLUMNS. SO YOU FILL OUT THIS LARGE GENOTYPE BY PHENOTYPE MATRIX. THE COLOR IS TELLING YOU HOW MORE DIRECTION AND HOW STRONGLY THE VOLUME OF EACH BRAIN REGION IS ALTERED IN EACH GENETIC MODEL. WHAT'S REALLY EXCITING IS WHEN YOU HAVE THIS MATRIX, YOU CAN CLUSTER IT. AND IN CLUSTERING IT, YOU HAVE AN EMPIRICAL DATA-DRIVEN WAY, BIOLOGICALLY INFORMED GROUPING GENES TOGETHER INTO CLUSTERS THAT SHARE SIMILAR PROFILES OF A TOMORROW CAL ALTERATION IN THE BRAIN BUT ALSO GROUPING BRAIN REGIONS IN SETS OF REGIONS THAT SHOW A SIMILAR PROFILE OF VULNERABILITY TO A RAY OF DIFFERENT GENETIC HITS, IF YOU LIKE. OUR RESEARCH PROGRAM HERE IS ESSENTIALLY TRYING TO DO THIS IN HUMANS. WE GATHER FAR, FAR DEEPER PHENOTYPIC THAN JUST THE BRAIN ANATOMY. BUT THE GENERAL ESSENCE IS CLOSELY LINKED. AND THAT'S WHAT MAKES IT SO HARD TO DO OUTSIDE THE INTRAMURAL PROGRAM. YOU REALLY NEED AN ENVIRONMENT THAT LET'S YOU DEEP PHENOTYPE MULTIPLE REG GROUPS OVER A PERIOD OF TIME. AS YOU CAN IMAGINE THERE ARE FEW PLACES AND INFRASTRUCTURES OTHER THAN WHAT WE ARE BLESSED WITH HERE THAT CAN SUPPORT THAT. THE SECOND MAJOR CHALLENGE IN RESEARCH IS DEVELOPMENT ITSELF. THE PROCESS OF MAKING MATURE ORGANISM FROM A SINGLE CELL INVOLVES STAGGERING COORDINATION OF ENVIRONMENTAL AND GENETIC INFLUENCES OVERTIME TO GIVE RISE TO MIND BOGGLING COMPLEXITY IN THE ADULT BRAIN. THE PROCESS OF DEVELOPMENT IS HIGHLY CONSTRAINED AND STEREOTYPED BUT THERE'S VARIATION WITHIN THESE COMPONENTS. THINK ABOUT WHETHER YOU HAVE A HAND VERSUS THE SHAPE OF YOUR FINGERS. THE DYNAMOISM, HOW DOES THIS PATIENT DIFFER FROM CONTROLS, NOW, NOW, NOW. IT'S CONSTANTLY REVISED OVER DEVELOPMENT. MORE FUNDAMENTALLY, I THINK IT'S IMPORTANT TO REFLECT ON THE FACT DEVELOPMENT IS NOT A PASSIVE CANVAS UPON WHICH DISEASE IS PAINTED. IT'S MUCH MORE LIKE A CONSTRUCTION OF CLAY WHICH BUILDS ITSELF AND MODEL BY DISEASE EFFECTS ITSELF. AND IT'S ACTUALLY THIS VERY INTERDEPENDENCY. THE FACT THEY ARE CONSTRAINED BY PROGRAMS MEANS IF WE LEARN THE LANGUAGE OF NORMAL DEVELOPMENT WE CAN IMPROVE HOW WE ASK QUESTIONS OF THE ATYPICALLY DEVELOPED BRAIN. I HOPE THAT IS DEFINED BY THIS ESCHER PAINTING HERE. THE THIRD CHALLENGE I WANT TO MENTION FOR DIVING INTO DATA IS THAT OF SCALES. OUR ORGAN OF INTEREST, THE BRAIN IS LOCKED AWAY IN A VAULT WE CAN'T EASILY ACCESS DURING LIFE. WE STOP WITH IN VIVO. THERE IS INCREDIBLY POWERFUL TECHNOLOGY SHOWING US A GREAT DEAL. BUT WE ARE CONSTRAINED TO MEASURING THE BRAIN IN MILLIMETER CUBES. THE PROBLEM IS, WE ALL KNOW THERE'S IMMENSE INFORMATION HIDDEN BELOW THAT RESOLUTION. IF WHAT I'M SHOWING YOU NOW IS WHAT IS HIDDEN INSIDE A 90 MICRON CUBE BLOCK FROM THE CORTEX OF THE MOUSE, AND IF NEUROPSYCHIATRIC DISEASES START AT THE MOLECULAR AND CELLULAR SCALE, THEN WE DESPERATELY NEED TO FIND WAYS OF SQUEEZING MORE INFORMATION OUT OF OUR IN VIVO DATA. CAN WE TRANSLATE THESE MICROSCOPIC SCALES THAT ARE SO IMPORTANT TO UNDERSTAND. THANKFULLY THERE'S A WONDERFUL OPPORTUNITY HERE. OVER THE RECENT YEARS THERE'S BEEN THIS EXPLOSION IN MICRO STRUCTURAL DATA OF THE HUMAN BRAIN THAT HAVE BEEN REGISTERED TO M.R.I. SPACE, ALLOWING YOU TO FLIP FROM MAPS OF IMAGING AND MAPS FROM THESE INCREDIBLE POST MORTEM DATABASES. I AM SHOWING YOU TWO WE USE HEAVILY IN OUR RESEARCH. THE BIG BRAIN, 3D RECONSTRUCTION OF SECTIONS OF 20, NISSL-LIKE STRAINING. PROVIDES SPATIALLY DISTINCT SAMPLES FROM THE BRAINS OF SIX ADULTS AND MEASURES OF EXPRESSION OF 20,000 GENES, THE SAME SET. SO YOU HAVE GENE EXPRESSION MAPS IN THE HUMAN BRAIN. AND WE HAVE BEEN DEVELOPING TOOLS THAT HELP US COMPARE THE SPATIAL PATTERNS WITH WHAT WE GET FROM NEURO IMAGING. I'M SHOWING YOU ONE EXAMPLE, THE SPIN TEST, DEVELOPED IN COLLABORATION WITH BLOCK AND DESCRIBED. YOU TAKE TWO BRAIN MAPS, EXPAND THEM ON A SPHERE, YOU COMPUTE THE SIMILARITY OF THE MAP ON THE TWO SPHERES AND SPIN ONE OF THE SPHERES A THOUSAND TIMES AND THAT GIVES YOU A DISTRIBUTION. SO YOU CAN MAKE PRETTY SAFE INFERENCES TWO MAPS ARE DERIVED FROM DIFFERENT WAYS OF MEASURING THE HUMAN BRAIN. SO SIMILAR TO THE WAY THAT JOHN SNOW UNDERSTOOD THE SPREAD OF CHOLERA BY OVERLAPPING MAPS OF CHOLERA DEATHS, PERHAPS WE CAN ENCODE LARGE SPATIAL THROUGH COMPARISON WITH CO-REGISTERED DATA FROM HISTOLOGY AND GENOMICS. RESEARCH PROGRAM, THE SDN TRIES TO HARNESS THESE OPPORTUNITIES TO PASS THE BIOLOGY OF RISK WITH NEUROPSYCHIATRIC DISEASE. GROUP IS DEEP PHENOTYPEIC PATIENT GROUPS WITH DIFFERENT GENETIC DISORDERS AND WE ITERATE AND BLEND WITH LARGE SCALE STUDIES OF TYPICAL BRAIN DEVELOP M. WE INTEGRATE INFORMATION IN A HADRON COLLIDER STYLE. WE INTEGRATE WITH STUDIES OF NORMATIVE DEVELOPMENT. AND THEN THE INSIGHTS THIS WORK GENERATES CAN BE DECODED BY INTEGRATING INFORMATION FROM NEURO IMAGING WITH MICRO STRUCTURAL DATA. SO THE REMAINDER OF THE TALK I WILL FLESH OUT THESE IDEAS BY COVERING THREE SETS OF STUDIES. IN THE FIRST STEP OF STUDIES YOU WILL SEE HOW OUR ATTEMPT TO PINPOINT REGIONAL PATIENTS TACKLE BASIC SCIENCE QUESTION ABOUT THE RELATIONSHIP BETWEEN BRAIN SIZE AND BRAIN SHAPE OF HUMANS. NEXT, WE WILL SEE HOW ADDRESSING THIS BASIC SCIENCE QUESTION HELPED US BETTER PINPOINT REGIONAL BRAIN CHANGES IN PATIENTS. AND FINALLY, I WILL SHOW VERY RECENT WORK WHERE WE ARE TAKING THE INFORMATION WE HAVE ABOUT REGIONAL BRAIN CHANGE IN PATIENTS AND TRYING TO UNDERSTAND WHAT MAKES ONE BRAIN REGION VULNERABLE TO A GENETIC INSULT WHILE ANOTHER BRAIN REGION IS PROTECTED. THIS INCLUDES SOME OF THE DECODING METHODS, I WAS TELLING YOU ABOUT. STARTING POINT IS LOCALIZE. LET'S DIVE IN. MY LAB FOCUSES ON SEX CHROMOSOME AS KEY MODELS OF RISK PSYCHOPATHOLOGY. SOME YOU KNOW IS X X FEMALES AND XY FOR MALES. BUT ABOUT ONE IN 400 PEOPLE ARE BORN WITH AN EXTRA X CHROMOSOME. THIS CAN COME IN MANY COMBINATIONS. THE MOST COMMON IS KLINE FELT SYNDROME, XXY RATHER THAN XY, BUT YOU COULD HAVE MALES CARRYING BOTH EXTRA X AND EXTRA Y, MALES CARRYING MULTIPLE EXTRACTS OR FEMALES CARRYING ONE OR MORE EXTRACTS. THIS ARRAY FITS NICELY WITH THIS HADRON COLLIDER STYLE APPROACH I WAS ADVOCATING FOR. WE RECRUIT PARTICIPANTS, THEY GO THROUGH THIS DEEP PHENOTYPING PROTO CAL ORE TWO DAYS WITH BIO SAMPLES IN VIVO STRUCTURAL MODELS. INVIVO IMAGING. COGNITION OF BEHAVIOR AND SURFACE PSYCHIATRIC PRESENTATIONS. AND WHAT MAKES IT PARTICULARLY AVAILABLE FOR A CHILD PSYCHIATRIST TO UNDERSTAND POTENTIALLY THE BIOLOGY OF EARLY ON SET OF OF PSYCHIATRIC DISORDERS IS CARRYING OF EXTRA X CHROMOSOMES INCREASES YOUR RISK FOR PSYCHOPATHOLOGY. I'M SHOWING THIS FROM A PLOT PREPARATION BY RAU. YOU HAVE DIFFERENT DOMAINS, DIFFICULTIES WITH ANXIETY, DEPRESSION, SOCIAL FUNCTIONING, ATTENTION WITH AGGRESSION. ON THE Y AXIS THE MAGNITUDE OF IMPAIRMENT. THE POPULATION AVERAGE IS 50. THESE LINES SHOW THE SCORES ON THESE DOMAINS YOU SEE ACROSS FOUR DIFFERENT SEX CHROMOSOME GROUPS. YOU CAN SEE ALL OF THESE FOUR GROUPS SHOW ELEVATED SCORES. BUT INTERESTINGLY, THEY SHARE THESE PARTICULAR PEAKS HERE. SEX CHROMOSOME INDUCES A BROAD INCREASE IN RISK FOR PSYCHOPATHOLOGY BUT IT SEEMS TO PARTICULARLY HIT AT LANGUAGE, WE KNOW FROM OTHER STUDIES, SOCIAL FUNCTIONING, I'M SHOWING HERE. AND ATTENTIONAL FUNCTIONING. THE QUESTION THAT BEGINS THE JOURNEY ON THE TALK WE HAD. IF CHANGING NUMBERS OF X AND Y DOSAGE HAS THIS PATTERNED EFFECT ON DIFFERENT DOMAINS OF COGNITION AND BEHAVIOR, IS THAT ACCOMPANIED BY SEX CHROMOSOME, HAVING A PATENTED EFFECT ON REGIONS OF THE BRAIN. WE DID THAT IN THIS COHORT SHOWN HERE IN THE TABLE. WHICH REPRESENTS AN INDIVIDUAL WITH MULTIPLE DIFFERENT SEX CHROMOSOME DOSAGES AND ON ALL INDIVIDUALS WE HAD T-1 WEIGHTED STRUCTURAL MRI SCANS SHOWN ON THE RIGHT. WE WANTED TO USE THESE SCANS TO PINPOINT BRAIN REGIONS AFFECTED BY ADDITIONAL X AND Y CHROMOSOMES. WE IMMEDIATELY HIT A PROBLEM. IT IMPACTS THE SIZE OF THE OVERALL BRAIN. AS YOU GO UP IN X CHROMOSOME DOSAGE TYPICALLY YOU GET STEP Y PRODUCTION IN TOTAL BRAIN VOLUME. YOU HAVE DIFFERENT SEX CHROMOSOME GROUPS. ON THE Y AXIS, HE CAN SEE SIGNIFICANT VARIATION ACROSS THE GROUPS. THIS IS A REAL PROBLEM BECAUSE THE WHOLE BRAIN ON AVERAGE IS SMALLER, FOR EXAMPLE, IN XXY SYNDROME, RATHER THAN XY MALES. WHICH MEANS FOR EVERY REGION YOU MEASURE YOU TEND TO SEE REDUCTION IN ANATOMY WHICH MAKES IT HARD TO PINPOINT THIS PROPORTION OF CHANGES. ESSENTIALLY THE PROBLEM WE HAD, WE WANTED TO RESOLVE HOTSPOTS OF ANATOMICAL CHANGE BUT WE HAVE TO DEAL WITH THE FACT THE WHOLE BRAIN IS ALTERED IN ITS SIZE. IN OUR FIELD, ADDITIONAL WAY OF DEALING, CONTROLLING IS CALLED PROPORTIONALISATION, I'M SHOWING THAT IN THIS CARTOON. IMAGINE THE BRAIN IS THE SIZE OF THE BIG BOX. INTERESTED IN COMPARING IS THIS SMALL RED BOX. THIS IS THE CONFIGURATION OF XY MALES AND THIS IS CONFIGURATION IN XXY MALES. TOTAL BRAIN SIZE DIFFERS SUBSTANTIALLY. THE WAY IT WORKS YOU DIVIDE THE SIZE OF THE SMALL RED BOX WITH THE SIZE OF THE BIG BOX TO CONTROL FOR THE VARIATION OF THE SIZE OF THE TOTAL BRAIN. WHEN YOU DO THAT, YOU CONCLUDE THAT XXY SYNDROME IS ASSOCIATED WITH AN EXPANSION OF THE SIZE OF THE RED REGION. BUT THERE'S A PROBLEM HERE. THE PROPORTIONALISATION METHOD HAS A KEY ASSUMPTION. IT ASSUMES IF YOU TAKE A TYPICALLY DEVELOPING INDIVIDUAL, AND YOU LOOK AT A SMALLER BRAIN EXAMPLE OF THAT INDIVIDUAL, THE BRAIN PROPORTIONS WILL STAY THE SAME. IT ASSUMES THE ANATOMICAL CONFIGURATION OF THE HUMAN BRAIN IS INVARIANT AS A FUNCTION OF VARIATION IN BRAIN SIZE. AND TYPICALLY DEVELOPING INDIVIDUALS THERE'S A TWO FOLD VARIATION IN TOTAL BRAIN VOLUME. SO WE WANTED TO ASK WHETHER THIS ASSUMPTION WAS SAFE. WE DIDN'T WANT TO USE PROPORTIONISATION IF WE WEREN'T SAFE ASSUMING THE HUMAN BRAIN KEEPS STABLE REGARDLESS OF BRAIN SIZE VARIATION. THE QUESTION IS WHAT IS OUR BRAIN PROPORTION CONSTANT AGAINST DIFFERENT BRAIN SIZES. EVIDENCE FROM COMPARATIVE WORK ACROSS DIFFERENT ANIMALS ANSWERS THAT WITH A RESOUNDING NO. WHAT I'M SHOWING ON THE LEFT IS A PLOT THAT ARRANGES MAMMALS ON THE X AXIS AS A FUNCTION OF INCREASING BRAIN SIZE. ON THE Y AXIS IT SHOWS PROPORTION OF THEIR BRAIN THAT IS MADE UP BY DIFFERENT COMPONENTS, SUB COMPONENTS. YOU COULD SEE CLEARLY AS BRAIN SIZE INCREASES THERE'S A SYSTEMATIC EXPANSION OF NEOCORTEX. IN EVOLUTION AGAINST DIFFERENT ANIMALS IT'S HIGHLY VARIABLE AS A FUNCTION OF BRAIN SIZE. THIS LOVELY PAPER SHOWS THAT ALSO HOLDS WHEN YOU JUST LOOK WITHIN THE PRIMATE FAMILY. THERE ARE TWO OF THE MAIN ROUTES TO GROWING HAVING A BIGGER BRAIN AS A PRIMATE IS EVOLVING ONE. ADULT MACAQUE AND ADULT HUMAN. AND GROWING ONE IN DEVELOPMENT, ADULT HUMAN VERSUS INFANT HUMAN. WHAT HILL DID, THEY DID FUNCTION OF SPECIES CORTICAL SIZE AND DEVELOPMENTAL DIFFERENCES IN CORTICAL SIZE. IN BOTH CONTRASTS THERE WAS A DRAMATIC REORGANIZATION OF SHAPE AS A FUNCTION OF BRAIN SIZE. AS BRAIN SIZE INCREASED YOU GOT THIS DISPROPORTIONATE EXPANSION OF THESE RED REGIONS, BUT RELATIVE CONTRACTION IN THE SIZE OF THESE BLUE REGIONS, WHICH TYPICALLY RESIDE WITHIN VISUAL AND SENSORIMOTOR PARTS OF THE BRAIN. THIS SHIFTS AS A FUNCTION OF EVOLUTIONARY AND DEVELOPMENTAL CHANGES IN BRAIN SIZE. WHAT ABOUT THE QUESTION WE HAD TO ANSWER? FOR OUR CLINICAL RESEARCH. WHAT ABOUT STANDING NATURALLY OCCURRING INTERINDIVIDUAL VARIATION, DOES THAT CHANGE BRAIN PROPORTIONS. THERE WASN'T AS ANSWER AT THE TIME. WE WORKED WITH A LARGE GROUP OF COLLABORATORS TO TACKLE THIS. WONDERFUL STUDY LED BY TWO WONDERFUL N.I.H. PARTNERSHIP STUDENTS, KIRK REARDON AND JAKOW SEIDLITZ. WE WANTED TO MAKE SURE THAT WE DID THIS THOROUGHLY AS WE COULD. WE LOOKED AT THREE INDEPENDENT BRAIN IMAGING DATA SETS. THE PHILADELPHIA NEURO DEVELOPMENT ALICO HORST, 1,300 3T STRUCTURAL SCANS OF THE BRAIN. N.I.H., 1,500 SCANS OF THE DEVELOPING HUMAN BRAIN AND HUMAN CONNECTOME PROJECT. WE PROCESSED ALL THESE SCANS THROUGH TWO DIFFERENT PIPELINES. WE WANTED TO MAKE SURE THERE WASN'T ANY PIPELINE INFLUENCE IN OUR FINDINGS. FREE SURFER AND CIVET. BOTH PLATFORMS FOR ANY SCAN YOU INPUT GIVE YOU A MEASURE OF THE TOTAL X SURFACE AREA OF THE CORTICAL SHEET OF THAT SCAN. AS WELL AS SURFACE AREA OF TENS OF THOUSANDS OF POINTS PEPPERED ON THE SHEET. WE WERE READY TO TEST OUR HYPOTHESIS. WE COULD USE THESE DATA TO ASK, TO QUANTIFY HOW VARIATION IN SURFACE AREA AT EACH OF THE TENS OF THOUSANDS OF POINTS ON THE CORTICAL SHEET WAS RELATED TO VARIATION IN THE TOTAL SIZE OF CORTICAL SHEET. THIS IS TYPICALLY DONE WITH A LOG LOG FRAMEWORK. IN THE LOG THE COEFFICIENT YOU GET IS SCALING COEFFICIENT. THE COEFFICIENT OF ONE MEANS FOR A GIVEN VERTEX, IF YOU DOUBLE THE SIZE OF THE TOTAL CORTICAL SHEET THE AREA OF THAT VERTEX DOUBLES. BUT YOU COULD ALSO HAVE A SITUATION WHERE A VERTEX HAS A SCALING COEFFICIENT OF LESS THAN ONE WHICH WE CODE IN BLUE, NEGATIVE SCALING. THAT MEANS THE SIZE OF THAT VERTEX, THAT PART OF THE BRAIN BECOMES PROPORTIONALLY SMALLER AS BRAIN SIZE GOES UP. CONVERSELY, YOU COULD HAVE AN INSTANCE WHERE THE COEFFICIENT IS GREATER THAN ONE. THE SIZE OF THAT REGION BECOMES DISPROPORTIONATELY LARGE. JUST TO ORIENT, RED IS POSITIVE, BLUE ENCODES NEGATIVE SCALING, REGIONS TENDING TO BECOME RELATIVELY CONTRACTED AS BRAIN SIZE GOES UP AND LINEAR SCALING IS WHITE. IN AS THE NULL HYPOTHESIS. IF THE HUMAN BRAIN KEEPS ITS SHAPE CONSTANT, ACROSS DIFFERENCE IN BRAIN SIZE, THEN THE MAP THAT WE WOULD SEE WOULD BE ENTIRELY WHITE. THAT'S DEFINITELY NOT WHAT WE SAW. I'M SHOWING YOU THE MAP HERE. I PROJECTED THE SCALING COEFFICIENT ON THE CORTICAL SHEET AND SHOWING YOU A SPINNING BRAIN. THERE'S THIS BILATERALLY PATTERN THE REGIONS IN THE FRONTAL, PARIETAL BACK DISPROPORTIONATELY EXPANDED. WHEREAS THESE BLUE REGIONS, MOTOR VISUAL AND VENTRAL PARTS OF THE BRAIN TEND TO BECOME RELATIVELY SMALLER IN LARGER BRAIN INDIVIDUALS. THIS MAP WAS HIGHLY REPRODUCIBLE ACROSS ALL THE DATA SETS WE STUDIED. WHAT DID THE MAP MEAN? WHAT ASPECTS OF CORTICAL ORGANIZATION DIFFERENTIATE THESE BLUE AND RED REGIONS? WE USE THIS SPIN TEST I MENTIONED FOR COMPARING MAPS TO COMPARE THE SCALING MAP WITH SEVERAL OTHER CORE ASPECTS OF CORTICAL ORGANIZATION. FIRST PERHAPS MOST IMPORTANTLY, WE FOUND THE CORTICAL SCALING WITHIN HUMANS RECAPITULATES THE SPATIAL PATTERN OF CORTICAL SCALING SEEN IN THE TWO OENK AXIS OF PRIMATE BRAIN SIZE, EVOLUTIONARY DEVELOPMENT. THIS IS QUITE PROFOUND. THERE ARE THREE DOMINANT AXIS, YOU CAN EVOLVE A BIGGER ONE, GROW A BIGGER ONE IN DEVELOPMENT OR AN INDIVIDUAL IN YOUR SPECIES WHO HAPPENS TO HAVE A BIGGER BRAIN. IT TURNS OUT ALL THREE OF THESE FORMS OF BRAIN SIZE VARIATION ASSOCIATED WITH A VERY SIMILAR REMODELING OF THE CORTICAL SHEET, WHERE LARGER BRAIN INDIVIDUALS HAVE EXPANSION OF THESE POSITIVE SCALING REGIONS ALONGSIDE RELATIVE CONTRACTION OF THESE BLUE REGIONS. SECOND, WE FOUND THE RED CORTICAL REGIONS THAT BECOME DISPROPORTIONATELY LARGE TEND TO SIT WITHIN A PARTICULAR NETWORK WITHIN THE BRAIN. A PARTICULAR FUNCTIONAL CONNECTIVITY CALLED THE DEFAULT MODE NETWORK. THAT'S STRIKING BECAUSE WE KNOW THE DEFAULT MODE NETWORK IS CAPTURES THE MOST ABSTRACTED LEVEL OF INFORMATION WITHIN THE HUMAN BRAIN AND SITS A TOP A HIERARCHY OF CONNECTIVITY NETWORKS IN THE BRAIN, THOUGHT TO BE PARTICULARLY IMPORTANT INTEGRATING INFORMATION AMONGST OTHER BRAIN SYSTEMS. THIRD, THIS THEME OF INTEGRATION AND CONNECTIVITY WAS REINFORCED WHEN WE LOOKED AT COMPARED THIS MAP TO MAPS OF CORTICAL CYTOARCHITECTURE. THE RED REGIONS, POSITIVE SCALING REGIONS ALL TENDED TO LIE WITHIN THIS GREEN SET OF AREAS WHICH WERE, DESCRIBED AS -- 3 CORTEX. EXPANDED SUPER GRANULAR LAYERS IMPORTANT FOR LARGE RANG CORTICAL CONNECTIVITY. THE RED POSITIVE SCALING AREAS ALSO VERY GREEDY FOR OXYGENATED BLOOD AT EGG REST. WE COMPARED TO GENE EXPRESSION. WE FOUND THESE RED POSITIVE SCALING REGIONS SHOW PARTICULARLY HIGH EXPRESSION OF GENES THAT RESIDE WITHIN THE MITOCHONDRIA. WE HAD TO ADDRESS THIS BASIC QUESTION ABOUT BRAIN SCALING IN HEALTH. WE FOUND THE PROPORTIONS OF THE HUMAN BRAIN ARE REORGANIZED QUITE DRAMATICALLY, AS YOU INCREASE BRAIN SIZE. THERE'S THIS RED REGION, THESE RED SET OF ASSOCIATED CORTEXES EXPENSIVE IMPORTANT POOR LONG RANGE CONNECTIVE IN THE CORTEX AND INTEGRATING INFORMATION ACROSS OTHER BRAIN SYSTEMS. THIS BASIC SCIENCE INSIGHT, IT'S BEEN VALUABLE FOR US. WE HAVE BEEN ENERGIZED BY WHAT'S HAPPENED WHEN WE HAVE TAKEN THIS BASIC SCIENCE INSIGHT AND CYCLED IT BACK IN OUR CLINICAL WORK. THERE ARE AT LEAST A COUPLE WAYS IT IMPACTS CLINICAL WORK. IT PROVIDES NEW THEORETICAL CONTEX. THEY CONVERGE ON STRUCTURAL AND FUNCTIONAL CHANGES WITHIN THE DEFAULT MODE NETWORK WITHIN THIS RED POSITIVE SCALING SYSTEM. IT SEEMS TO BE THIS SYSTEM THAT IS DISPROPORTIONATELY EXPANDED IN HUMANS. MAY ALSO BE A SEAT OF SOME OF OUR VULNERABILITY TO PSYCHIATRIC DISORDERS. BUT IT ALSO, THIS BASIC SCIENCE INSIGHT ALSO HELPED US BACK WHERE OUR JOURNEY BEGAN. WE NOW HAD A PROPER FRAMEWORK FOR CONTROLLING BRAIN SIZE VARIATION AND PINPOINTING WHICH REGIONS OF THE HUMAN BRAIN ARE PARTICULARLY SENSITIVE TO ABNORMAL CARRIAGE OF X AND Y CHROMOSOMES. THAT'S THE SECOND SET OF DATA I WANT TO BRIEFLY ADDRESS. HOW THESE IMPROVED MODELS OF BRAIN SCALING IN HEALTH HELP BRAIN ALTERATION IN PATIENTS. THE SERIES OF STUDIES WAS LED BY AN AMAZING SET OF TALENTED POST BACCALAUREATES WE WERE LUCKY ENOUGH TO HAVE IN THE LAB. THEY HAD ALL LED STUDIES THAT FIRST DEFINE SCALING IN HEALTH AND USE THOSE NORMS TO PINPOINT, BETTER PINPOINT BRAIN CHANGES IN PATIENTS IN ANEUPLOIDY. WE OBSERVE ANEUPLOIDY HAS PROFOUND EFFECT ON ATTENTION, SOCIAL FUNCTION AND LANGUAGE. ARE THERE PARTICULAR BRAIN SYSTEMS THAT SEEM TO BE HIT HARD BY ANEUPLOIDY. AJAY, KIRK AND ANASTASIA FOUND, I'M SHOWING A SPINNING MAP OF THE CORTEX AT THE TOP AND SPINNING MAP OF THE THALAMUS. THAT BRAIN REGION IS DISPROPORTIONATELY -- WHERE YOU SEE WHITE, THESE BRAIN REGIONS AREN'T IMPACTED AT ALL IN THEIR RELATIVE SURFACE AREA BY SEX CHROMOSOME ANEUPLOIDY. RED REGIONS CHANGE THEIR SIZE WHEN YOU ADD EITHER AN X OR Y CHROMOSOME. GREEN REGIONS ONLY CHANGE THEIR SIZE WHEN YOU ADD AN X. AND BLUE REGIONS ONLY CHANGE THEIR SIZE WHEN YOU ADD A Y. SO THIS IS REALLY VIKING FOR US. -- STRIKING FOR US. ONE IT TOLD US NOT ALL ARE EQUAL IN VULNERABILITY TO SEX CHROMOSOME ANEUPLOIDY. SOME REGIONS COULDN'T CARELESS ANATOMICALLY HOW MANY SEX CHROMOSOMES YOU CARRY. WHICH IS KIND OF A STRANGE THING TO OBSERVE. THIRDLY, IT RAISED THE QUESTION WHAT DO THESE REGIONS DO, ARE THEY PARTICULARLY SENSITIVE TO SEX CHROMOSOME ANEUPLOIDY AND IMPORTANT FOR DOMAINS OF FUNCTION. TO ANSWER THE QUESTION, WE SUBMITTED THE MAP OF ANATOMICAL CHANGE TO AN ONLINE PLATFORM CALLED NEURO -- IT CROSS-REFERENCES YOUR MAP WITH OVER 10,000 FUNCTIONAL IMAGING STUDIES IN ITS DATABASE. AND GIVES BACK TO YOU A LIST OF COGNITIVE FUNCTIONS THAT ARE PARTICULARLY ASSOCIATED WITH THE BRAIN REGIONS HIGHLIGHTED IN YOUR MAP. SO WHAT THIS MATRIX SHOWS IS THE ROWS OUR BRAIN REGIONS WE INPUT. THESE ARE THE AREAS SENSITIVE TO SEX CHROMOSOME ANEUPLOIDY AND COLUMNS ARE THE COGNITIVE TERMS ASSOCIATED WITH THESE BRAIN REGIONS. THE MORE GREEN THE COLOR, THE STRONGER THE ASSOCIATION BETWEEN THAT COGNITIVE TERM AND THAT BRAIN REGION. WHEN YOU CLUSTER THIS MATRIX IT TELLS YOU THE BRAIN REGIONS THAT SEEM TO BE IMPACTED MOST BY SEX CHROMOSOME ANEUPLOIDY ARE PARTICULARLY IMPORTANT FOR PROCESSING BIOLOGICAL MOTION, LANGUAGE, AUTOBIOGRAPHICAL MEMORY, REWARD AFFECT AND INTERROCEPTION. THESE DOMAINS ARE AT LEAST AT FACE VALUE HIGHLY RELEVANT FOR THE CLINICAL IMPAIRMENTS WE SEE IN PATIENTS WHO WALK THROUGH THE DOOR OF OUR CLINICAL CERTAINTY IN OUR PROTOCOL. JUST TO SUMMARIZE BEFORE WE DIVE INTO THE FINAL PART OF THE TALK. OUR STARTING POINT WAS TRYING TO RESOLVE GENETIC EFFECTS ON BRAIN ANATOMY IN HUMANS. THAT FORCED US TO TACKLE THE BASIC SCIENCE QUESTION, THE RELATIONSHIP BETWEEN BRAIN SIZE AND BRAIN SHAPE IN HUMANS. ADDRESSING THAT QUESTION, WE IMPROVED OUR TOOLS FOR CONTROLLING BRAIN SIZE VARIATION. AND THEN WE USED THOSE TOOLS TO MORE ACCURATELY PINPOINT WHICH REGIONS OF THE HUMAN BRAIN ARE VULNERABLE, MOST VULNERABLE TO SEX CHROMOSOME ANEUPLOIDY. BUT THIS PROCESS LEFT US WITH AN EVEN DEEPER QUESTION. WHAT DETERMINES THIS MAP ON THE RIGHT? WHY IS IT THAT SOME BRAIN REGIONS REALLY CARE HOW MANY SEX CHROMOSOMES YOU HAVE. AND AS I SAID, SOME BRAIN REGIONS COULDN'T CARE LESS, APPARENTLY. IF WE CAN UNDERSTAND THE BIOLOGICAL FACTORS THAT MIGHT MAKE ONE BRAIN REGION REALLY SENSITIVE TO SEX CHROMOSOME ANEUPLOIDY AND ONE BRAIN REGION RELATIVELY PROTECTED THAT COULD BE A REALLY USEFUL MECHANISTIC INSIGHT. THAT'S WHAT WE HAVE BEEN TRYING TO TACKLE IN RECENT ONGOING STUDIES I'M GOING TO SHARE WITH YOU NEXT. WE HAVE BEEN USING SPATIAL ANALYSES TO TAKE THIS MAP WE HAVE OF REGIONAL BRAIN CHANGE ANEUPLOIDY AND TRY TO DECODE AND UNDERSTAND ARE THERE MOLECULAR PATHWAY OR CELLS THAT SEEM TO PREDICT VULNERABILITY TO ANEUPLOIDY WHEN HIGHLY REPRESENTED IN ONE REGION. AS WE WERE PINPOINTING THESE BRAIN CHANGES, MAKING THAT SORT OF SPINNING COLORED MAP I SHOWED YOU, THERE WAS SOME EMERGING EVIDENCE AT THE SAME TIME THAT REGIONAL BRAIN VULNERABILITY TO NEUROPSYCHIATRIC DISORDERS MIGHT ACTUALLY BE PARTLY ORGANIZED BY INTRINSIC EXPRESSION OF DISEASE RELEVANT GENES APPARENT IN THE HEALTHY HUMAN BRAIN. WE CALL THIS THE TRANSCRIPTIONAL VULNERABILITY MODEL. FIRST GENERATED A MAP OF ANATOMICAL CHANGE IN PATIENTS WITH SCHIZOPHRENIA, COMPARED TO CONTROLS. THEY THEN TOOK THAT MAP AND THEY COMPARED THAT MAP TO THE MAPS OF GENE EXPRESSION FOR EACH OF 15,000 GENES AT ALLEN INSTITUTE DATABASE. THEY FOUND THEY RANKED THE GENES BY HOW CLOSELY THEIR EXPRESSION MAP CORRELATED WITH THIS ANATOMICAL CHANGE MAP. AND THEY FOUND WHICH GENES HAVE EXPRESSION PATTERNS IN THE BRAIN IN HEALTH THAT LOOK MOST LIKE THIS MAP. AND AT THE TOP OF THEIR LIST, WHEN THEY LOOKED AT WHICH GENES SAT THERE, THEY FOUND GENES THAT HAD ALREADY BEEN REPORTED TO BE IMPORTANT RISK FACTORS FOR SCHIZOPHRENIA. SO WHAT THAT'S TELLING YOU IS, IT MAY BE THAT THE INTRINSIC GRADIENTS PARTLY PREDICT WHICH BRAIN REGIONS ARE VULNERABLE WHEN YOU MESS WITH WHICH GENES. SO THE GENETIC DEFINE NEURO DEVELOPMENTAL WE STUDY PROVIDE A UNIQUE OPPORTUNITY TO TEST THIS TRANSCRIPTIONAL VULNERABILITY. THE PATIENT GROUPS AREN'T DEFINED BEHAVIORALLY, AS IN THE CASE WITH SCHIZOPHRENIA, BUT DEFINED BY THE FACT THEY HAVE ABNORMAL DOSAGE OF A KNOWN GENE SET. IT PROVIDES REALLY POWERFUL QUASI EXPERIMENTAL OPPORTUNITY TO MAP BRAIN CHANGE IN THOSE PATIENTS WHO HAVE A PARTICULAR GENETIC DISORDER. FIND WHICH GENES HAVE EXPRESSION MAPS IN THE BRAIN THAT CORRELATE MOST WITH THAT ANATOMICAL CHANGE MAP AND SEE IF THOSE GENES ARE THE ONES THAT YOU KNOW DEFINE THE DISORDER IN THE FIRST PLACE. AND THIS IS WHAT WE SET OUT TO DO. THIS IS WORK LED BY JAKOB SEIDLITZ. CONTROL REPRESENTED 600. HAD AN EXTRA X, EXTRA Y, OR EXTRA 21 OR THEY LACKED AN X, OR THEY LACKED A SUB REGION OF CHROMOSOME 22 ASSOCIATED WITH VENA -- MANY INVOLVE COLLABORATIONS WITH OTHER INVESTIGATORS HERE. JOAN HAHN. WHAT JAKOB WAS ABLE TO DO IS TAKE THESE SIX DIFFERENT GENE DOSAGE DISORDER AND MAYBE A MAP. HE USED THAT USING MORPH -- I WON'T GO INTO THAT BECAUSE OF TIME. IT DOESN'T JUST LOOK AT ONE MEASURE OF THE CORTEX SURFACE AREA OR THICKNESS OR HOW CURVED THE CORTEX IS BUT LOOKS AT ALL OF THEM AT THE SAME TIME AND GIVES A SUMMARY MEASURE OF HOW ANATOMICALLY DISRUPTED EACH BRAIN REGION IS. JAKOB APPLIED THIS TECHNIQUE HE PREVIOUSLY DEVELOPED HIMSELF, TO MAKE MAPS OF BRAIN CHANGE IN EACH OF THESE SIX CONDITIONS. I'M SHOWING YOU THOSE MAPS HERE. THESE ARE MAPS OF ALTERED MORPH METRIC SIMILARITY, WHEN YOU ADD AN X, Y, 21, TAKE AWAY AN X IN WAGOSYNDROME. THEN WE WERE READY TO TEST THIS HYPOTHESIS. I WILL WORK THROUGH THE FLOW USING THE PLUS X BRAIN CHANGE MAP AS AN EXAMPLE. SO WE TOOK, JAKOB TOOK HIS MAP OF ALTERED REGIONAL CORTICAL ANATOMY IN PATIENTS WHO CARRIED AN EXTRA X. HE COMPARED IT WITH THE ATLAS FOR GENE EXPRESSION. HE IDENTIFIED THAT HAVE EXPRESSION MAPS THAT LOOK MOST LIKE THIS ANATOMICAL CHANGE MAP AND THEN HE ASKED DO THOSE GENES TEND TO BE ON THE X CHROMOSOME. THAT WOULD BE THE PREDICTION FROM THE TRANSDESCRIPTION VULERABILITY MODEL. WHAT WAS EXCITING WE DIDN'T JUST HAVE TO RELY ON THE X CHROMOSOME. WE COULD DO IT FOR EACH OF THE OTHER GENE DOSAGE DISORDERS, WHICH EACH PREDICTED A DIFFERENT GENE SET SHOULD LOOK LIKE THE ANATOMICAL CHANGE MAP. HERE WE SAID ARE WE FINDING X GENES. HERE ARE WE FINDING THE Y GENES LOOK MOST LIKE THIS. FOR DOWN SYNDROME, ARE WE FINDING THE CHROMOSOME 21 GENES HAVE EXPRESSION PATTERNS THAT LOOK MOST LIKE THIS, ETC. AND FOR US, THIS RESULT WAS KIND OF FALL OFF YOUR CHAIR MOMENT. I'M SHOWING THE RESULTS FOR THE PLUS X MAP HERE. WHAT WE FOUND IS THAT THOSE BRAIN EXPRESSED GENES THAT HAVE EXPRESSION PATTERNS THAT LOOK MOST LIKE THIS MAP TEND TO RESIDE ON THE X CHROMOSOME. THAT IS THE X CHROMOSOME HIGHLIGHTED HERE. THIS PLOT IS SHOWING CHROMOSOMES ON THE Y AXIS AND HOW ENRICHED THE CHROMOSOME IS FOR GENES THAT HAVE EXPRESSION PATTERNS THAT LOOK LIKE THIS MAP. BUT THIS WASN'T JUST THE CASE FOR THE X CHROMOSOME. WHEN WE REPEATED THIS FOR ADDITION OF Y, ADDITION OF 21, WE FOUND THE SAME CORRESPONDING GENE SET ENRICHED. FOR EXAMPLE, THE MAP MORPHO METRIC FOR DOWN SYNDROME TENDS TO BE ASSOCIATED WITH 2 1 GENES IN THE HUMAN BRAIN. THE MODEL I'M PROPOSING AND SEEM TO BE EMERGING FOR US LOOKS A LITTLE BIT LIKE THIS. IN A NORMAL INDIVIDUAL WHO HAS TWO COPIES OF EACH GENE AND EACH GENE HAS A CERTAIN EXPRESSION WITHIN THE BRAIN. YOU CAN IMAGINE AN INDIVIDUAL WHO CARRIES A GENE DOSAGE DISORDER, COPY NUMBER VARIATION, WHERE THEY HAVE EXCESS COPIES OF THESE GENES, FOR SOME OF THOSE GENES, THE SPATIAL PATTERN OF THEIR EXPRESSION DICTATES OR PARTLY DETERMINES WHICH BRAIN REGIONS ARE THEN ALTERED IN ANATOMICAL CONFIGURATION BY THE ADDITION OF THE EXTRA SET OF GENES. BUT THAT THEN JUST PUSHED OUR QUESTION BACK ONE STEP FURTHER. IF THESE INTRINSIC MAPS OF GENE EXPRESSION ARE IMPORTANT FOR DEFINING REGIONAL VULNERABILITY OF THE BRAIN TO GENETIC INSULTS, WHAT DETERMINES THESE GENES? WHAT ACCOUNTS FOR THE REGIONAL DIFFERENCES IN GENE EXPRESSION IN THE HUMAN CORTEX? AS WE WERE THINKING THIS THROUGH THE FIELD OF SINGLE CELL TRANSCRIPTOMICS WAS EXPLODING. IT'S THE CELLULAR COMPOSITION OF THE CORTEX. DIFFERENT CELLS HAVE DIFFERENT EXPRESSION SIGNATURES. AND DIFFERENT CORTICAL REGIONS ARE COMPOSED OF DIFFERENT COMPILATIONS OF CELLS. AND THAT ACCOUNTS FOR THE DIFFERENCES IN EXPRESSION. SO WE ASKED OURSELVES, WELL MAYBE, THE CELLULAR PATTERNING OF THE CORTICAL SHEET IS ACTUALLY THE KEY LOGIC THAT DETERMINES REGIONAL VULNERABILITY. SO WE COMPILED GENE MARKER LISTS FROM ALL LARGE SCALE SINGLE CELL STUDIES OF THE CORTEX AT THE TIME. AND WE CLUSTERED THESE DATA AND WHAT WE GOT BACK ARE INSILICO MAPS. BY PROCESSING IN THIS MANNER WE GENERATED A MAP OF ASTROCYTE, ENDOTHELIAL, MICROGLIA CELL. WE ARE IN A POSITION TO COMPARE WITH THE BRAIN CHANGE MAPS WE ARE SEEING IN OUR PATIENTS. SO WE INTERSECTED THE MAPS OF DIFFERENT CELL TYPES. WHICH I'M SHOWING HERE IN THE COLUMNS, WITH THE MAPS OF BRAIN CHANGE IN DIFFERENT PATIENT GROUPS, SORRY, THE MAPS OF CELL TYPES, I'M SHOWING THE ROWS WITH THE MAPS OF BRAIN CHANGE IN OUR DIFFERENT PATIENT GROUPS WHICH I'M SHOWING IN THE COLUMNS. AND WHAT THIS ENABLED US TO DO IS TO DETECT INSTANCES WHERE A GIVEN GENETIC DISORDER HAS A MAP OF BRAIN CHANGE THAT LOOKS VERY MUCH LIKE A PARTICULAR CELL TYPE. AND WHEN THAT CELL TYPE IS THE MARKER LIST OF THAT CELL TYPE INCLUDES GENES THAT DEFINE THE DISORDER. SO JUST TO WALK YOU THROUGH THAT A LITTLE BIT, THIS IS THE MAP OF ANATOMICAL CHANGE IN DOWN SYNDROME. AND WE FOUND THE SPATIAL PATTERN OF THIS MAP WAS SIGNIFICANTLY ALIGNED TO THE SPATIAL PATTERN OF OLIGODENDRIC SITE GENE EXPRESSION. ONE IS ON CHROMOSOME 21 IS PCP 4. THE IDEA IS TO DEVELOP A BIO FORMATIC PIPELINE, PUBLICLY AVAILABLE TRANSCRIPTOMIC DATA, HOW DIFFERENT GENETIC DISORDERS TARGET DIFFERENT BRAIN SYSTEMS. SO WHAT'S HELPFUL FOR US, WE THINK, IN THIS SORT OF WORK, IS WE NOW HAVE A BETTER SENSE OF IF YOU WANT TO UNDERSTAND REGIONAL BRAIN VULNERABILITY IN DOWN SYNDROME THIS HELPS US PRIORITIZE CELL TYPES AND PARTICULAR GENES WITHIN THEM WE GO AFTER. THAT'S SOMETHING WE ARE DOING NOW, TRYING TO VALIDATE THIS, USING POST MORTEM SINGLE CELL -- SO JUST TO WRAP UP. I WANT TO ZOOM BACK OUT AND REASSEMBLE WHAT I HAVE JUST SHOWN YOU WITHIN THIS OVERALL RESEARCH STRATEGY I MENTIONED EARLIER. I SHOWED YOU HOW WE STUDIED THE BRAIN ORGANIZATION IN HEALTH TO DEVELOP THIS TECHNIQUE, MORPHOSIMILARITY. WE DECODED THOSE PATIENT MAPS AGAINST PUBLICLY AVAILABLE MEASURES OF GENE EXPRESSION IN THE HUMAN BRAIN, TO PREDICT, OR NOMINATE PARTICULAR MOLECULAR AND CELLULAR COMPONENTS OF THE BRAIN THAT MIGHT BE RESPONSIBLE FOR MAKING ONE BRAIN REGION VULNERABLE TO A GIVEN GENETIC DISORDER WHERE ANOTHER BRAIN REGION IS NOT. SO WE HOPE USING THESE STUDY DESIGNS AND INTEGRATING INFORMATION FROM TYPICAL BRAIN DEVELOPMENT AND STUDIES IN RARE PATIENT GROUPS, HELPS IN A SORT OF SYNEGETIC, BOOT STRAPPING. WHILE SIMULTANEOUSLY PROVIDING BASIC SCIENCE INSIGHTS. IN THE FINAL THREE SLIDES I WANT IT HIGHLIGHT WHERE WE ARE GOING NEXT. TYPICAL BRAIN DEVELOPMENT WE ARE LOOKING AWAY FROM JUST LOOKING AT ANATOMY AND SIMULTANEOUSLY INCORPORATING BRAIN STRUCTURE AND MICRO STRUCTURE. WE AREN'T LOOKING AT ONE ANATOMICAL MEASURE BUT USING MULTIVARIANT MODELS THAT COMBINE FROM MULTIPLE SIMULTANEOUSLY. AND WE ARE TRYING TO FIND IMAGING SIGNATURES THAT MAXIMIZE OUR ABILITY TO PREDICT VARIATION AND BEHAVIOR. OR TO MAKE BRAIN MAPS THAT ALIGN WITH MICRO STRUCTURAL DATA. BECAUSE WE THINK IF WE CAN FIND THESE MAPS THAT ARE PREDICTIVE OF BEHAVIOR AND SIMILAR TO IN PATTERN TO MICRO STRUCTURE, THESE ARE IMPORTANT TO PORT OVER INTO OUR PATIENT WORK. IN OUR PATIENT WORK WE HAVE BEEN FOCUSING ON ANEUPLOIDIES BUT WE WANT TO LOOK AT MULTIPLE OTHER GENETIC DISORDER GROUPS AT THE SAME TIME. AND CROSS LEVELS OF EXPLANATION IN EACH GROUP. TRY TO UNDERSTAND DOES INTERINDIVIDUAL GENE EXPRESSION RELATE TO INDIVIDUAL VARIATION IN BRAIN CHANGE OR BEHAVIORAL CHANGE. WE ALSO WANT TO SAY, ASK OURSELVES IF THE PATTERNS WE ARE SEEING IN THE RARE GENETIC DISORDERS CAN HELP TO UNDERSTAND WHAT'S GOING ON IN THE MAJORITY OF PATIENTS WITH A NEURO DEVELOPMENTAL DISORDER WHO DON'T HAVE AN IDENTIFIABLE SINGLE GENETIC CAUSE. AND THEN FINALLY, AS WE ARE DOING THIS ITERATIVE WORK BETWEEN TYPICAL DEVELOPING GROUPS AND PATIENTS WITH RARE GENETIC DISORDERS WE ARE TRYING TO IMPROVE THE TOOLS WE USE TO DECODE IMAGING MAPS INTO CELLULAR MOLECULAR INFORMATION. AS I MENTIONED WE ARE TRYING TO VALIDATE OUR WORK IN PATIENTS AGAINST POST MORTEM TISSUE DIRECTLY. AND JUST THE MOST IMPORTANT SLIDE OF ALL IS THE BEST TO END ON. THAT IS THE ONE THAT ACKNOWLEDGES THE INCREDIBLE STUDENTS COLLABORATORS FRIENDS AND COLLEAGUES THAT I HAVE BEEN LUCKY ENOUGH TO BE ON THIS JOURNEY WITH. TO LET YOU ALL KNOW THERE ARE Ph.D. AND POSTDOC OPENINGS IN THE GROUPS, SO PLEASE GET IN TOUCH IF YOU ARE INTERESTED. I WANT TO THANK THE FAMILIES IN THE STUDY AND MY OWN FAMILY WHO HAVE BEEN A CRITICAL PART OF THIS JOURNEY WITH ME AND NONE OF WHAT I'VE SHOWN YOU WOULD HAVE BEEN POSSIBLE WITHOUT THEM. THANK YOU ALL FOR YOUR ATTENTION AND I'M HAPPY TO TAKE QUESTIONS IN THE REMAINING TIME. THANK YOU. >> THANK YOU SO MUCH, ARMIN FOR YOUR TIME, LASKER, FROM SOUP TO NUTS. IT'S GREAT TO SEE THE ORIGINAL APPLICATION. WHAT'S IMPORTANT THIS CAME FROM PATIENT WORK AND PATIENT OBSERVATION BUT I APPRECIATE YOU USING THE BOTTOM-UP APPROACH AND TRYING TO GET TO IDENTIFY FROM THE MORAS FROM CHILD PSYCHOLOGY. ARE THERE DIFFERENCES WHEN COMPARING MEN AND WOMEN. >> THAT'S A GREAT QUESTION AND OFTEN COMES UP. AS FAR AS WE CAN TELL THERE ARE NOT. THERE SIGNIFICANT AND REPRODUCIBLE DIFFERENT IN TOTAL BRAIN VOLUME BETWEEN MALE AND FEMALE. BUT THE VARYING BRAIN SIZE AND SHAPE SEEMS TO BE HIGHLY REPRODUCIBLE BETWEEN THE TWO SEXES. >> I WAS WONDERING IF YOU COULD EXPAND A LITTLE BIT MORE ON THE OPPORTUNITIES THAT WERE AFFORDED YOU THROUGH THE LASKER AND SORT OF YOUR JOURNEY ONCE YOU ACCOMPLISHED THE I.R.P. PORTION OF IT? >> ABSOLUTELY. IT'S HARD, I WAS SHOCKED BY JUST HOW DIFFICULT THIS WORK IS. GATHERING DEEP PHENOTYPIC DATA ON RARE GROUPS. JUST TO GATHER THE DATA SET I DESCRIBED BETWEEN COGNITION BEHAVIOR, IMAGING AND TISSUE SAMPLES ON 65 INDIVIDUALS CARRYING AN EXTRA Y TOOK TWO AND A HALF THOUSAND PERSON HOURS. AND MULTIPLE I.C.'S WITHIN THE CLINICAL CENTER. YOU REALLY CAN'T DO THIS WORK UNLESS YOU HAVE AN ENVIRONMENT THAT HAS MULTIPLE SPECIALTIES ALL IN THE SAME PLACE. THAT COULD BE MOBILIZED ALL TOGETHER WITHIN A TWO-DAY VISIT. YOU NEED THE STABILITY OF FUNDING AND THE LEVEL OF FUNDING THAT LET'S YOU ACTUALLY ASSEMBLE RELATIVELY LARGE NUMBERS OF RARE GROUPS. AND YOU NEED THAT FUNDING IT BE IN PLACE FOR A LONG TIME. BECAUSE LOOKING AT ANY ONE OF THESE GROUPS IS A SIGNIFICANT EFFORT THAT COULD SPAN A NUMBER OF YEARS. BUT THE REAL POWER OF THIS APPROACH ONLY EMERGES WHEN YOU HAVE ASSEMBLED DATA FROM MULTIPLE RARE COHORTS AMONG EACH OTHER. THAT'S WHY WE FEEL REALLY LUCKY TO BE IN THIS ENVIRONMENT. >> GREAT. AND THE LAST QUESTION, I WILL SAY, HAVE YOU TRIED APPLYING ANY OF THESE TECHNIQUES TO DEMENTIAS. THAT'S NOT REALLY OUR PARTICULAR FOCUS BUT -- >> IT'S A GREAT QUESTION. >> ARE YOU AWARE OF ANYBODY DOING THAT? >> YES, YES. WE KIND OF HAVE SCIENTIFIC CRUSHERS AND FAN DOME ON THE NEURO GENETICS COMMUNITY DOING THIS IN THE CONTEXT OF NEURO GENETIC DISORDERS. THE PROBLEMS WITH TACKLING ARE SIMILAR. IT'S INTERESTING THAT QUESTION CAME UP BECAUSE INCREASINGLY WE ARE TALKING WITH COLLEAGUES WITHIN THE INTERMURAL COMMUNITY WHO STUDY, BUT ALSO OUR COLLABORATIVE NETWORK AND TRYING TO TAKE SOME OF THESE TECHNIQUES WE ARE USING AND BEGIN TO ASK WHETHER THEY CAN INFORM DEGENERATIVE PROCESSES AND LEARN FROM OUR COLLEAGUES STUDYING DEGENERATIVE PROCESSES AND SEE IF WE CAN BORROW SOME OF THOSE AND BRING THEM BACK IN DEVELOPMENT. BOTH ENDS OF THE LIFE SPAN SEEM TO HAVE A LOT TO TELL AND TEACH EACH OTHER. >> GREAT. WE WANT TO THANK YOU FOR AN EXCELLENT PRESENTATION. AND THANK YOU ALL FOR JOINING US.