Welcome to the Clinical Center Grand Rounds, a weekly series of educational lectures for physicians and health care professionals broadcast from the Clinical Center at the National Institutes of Health in Bethesda, MD. The NIH Clinical Center is the world's largest hospital totally dedicated to investigational research and leads the global effort in training today's investigators and discovering tomorrow's cures. Learn more by visiting us online at http://clinicalcenter.nih.gov TODAY IT'S MY PLEASURE TO INTRODUCE MY TWO ESTEEMED COLLEAGUES FROM THE NATIONAL INSTITUTES OF MENTAL HEALTH, AND THEY WILL BE PRESENTING RESEARCH UPDATES ON THE RESEARCH DOMAIN CRITERIA, OR R DOC, AS WE AFFECTIONATELY REFER TO IT AND ITS RELATIONSHIP TO MENTAL HEALTH DISORDERS. OUR FIRST SPEAKER IS DR. SARAH MORRIS, WHO SERVES AS AN ASSOCIATE DIRECTOR OF THE RESEARCH DOMAIN CRITERIA UNIT AT THE NATIONAL INSTITUTE OF MENTAL HEALTH. THE R DOC INITIATIVE IS AN EFFORT THAT AIMS TO TRANSFORM RESEARCH ON MENTAL ILLNESS AND TO ACCELERATE THE PACE OF RESEARCH THAT TRANSLATE BASIC SCIENCE BY UNDERSTANDING THE MULTILAYERED SYSTEMS THAT CONTRIBUTE TO MENTAL FUNCTION. SHE'S ALSO THE CHIEF OF THE SKITS /TPRECHIZOPHRENIA SPECTRUM DISORDERS PROGRAM LOCATED IN THE DIVISION OF TRANSLATIONAL RESEARCH IN OUR EXTRA MURAL PROGRAM. THAT PROGRAM SUPPORTS RESEARCH INTO THE ORIGINS, OFFSET, COURSE AND OUTCOME OF SKITS FRENEIA AND OTHER RELATED CONDITIONS, AS SKICHIZOTYPO PERSONAL DISORDERS. AFTER EARNING HER DOCTORAL DEGREE AT THE UNIVERSITY OF CALIFORNIA LOS ANGELES IN 2001, SHE CONDUCTED PSYCHOFIZPHYSIOLOGY RESEARCH AT THE BALTIMORE VETERANS AFFAIRS MEDICAL CENTER AND JOINED THE FACULTY AT THE UNIVERSITY OF MARYLAND. IN 2010, SHE CAME TO THE NATIONAL /EUINSTITUTES OF MENTAL HEALTH, WHERE SHE MANAGES A PORTFOLIO OF RESEARCH GRANTS FOCUS ON TRANSLATIONAL RESEARCH IN SKITS FRENEIA SPECTRUM DISORDERS. IN ADDITION TO HER CO-DIRECTOR CO-DIRECTORSHIP. SHE CO-LEADS THE SIGH /KOPSYCHOSIS PROGRAM AND MANAGES THE NIMH DATABASE OF COG /TPHENITIVE RE REIMMEDIAMEDIATION TRIALS IN SKITS FRENEIA. I AM GOING TO INTRODUCE YOU BOTH AND THEN -- AND OUR SECOND SPEAKER IS DR. DANIEL PINE, WHO IS THE CHIEF OF THE NATIONAL IN INSTITUTE OF MENTAL HEALTH SECTION ON DEVELOPMENTAL AND AFFECTIVE NEWUROSCIENCE. DR. PINE EARNED HIS MEDICAL DEGREE FROM THE UNIVERSITY OF CHICAGO'S SCHOOL OF MEDICINE. HE COMPLETED HIS RESIDENCY IN GENERAL PSYCHOLOGY AND CLINSHIP AT THE COLUMBIA PRESBYTERIAN MEDICAL CENTER. HE COMPLETED HIS RESEARCH FELLOW FELLOWSHIP AT THE RESEARCH TRAINING PROGRAM IN CHILD /SKAOEUBG /* PSYCHIATRY AT THE NEW YORK STATE INSTITUTION. WE ARE FORTUNATE ENOUGH TO HAVE HIM COME TO US IN 2000. HIS GROUP STUDIES THE DEGREE TO WHICH PED /KWIATRIC MOOD AND ANXIOUETY DISORDERS ARE ASSOCIATED WITH PERTURBED FUNCTION. DR. PINE, AMONG THE MANY THINGS I CAN SAY ABOUT HIM BUT I'M KEEPING IT BRIEF. SERVED AS THE CHAIR OF THE DRUG ADVISORY COMMITTEE FOR THE FDA, CHAIR OF THE DISORDERS WORK GROUP FOR THE D /S-FPSM 5 TASK FORCE AND PRESIDENT OF THE SOCIETY OF BIOLOGICAL PSYCHIATRY.% HE'S AN ELECTED MEMBER OF THE NATIONAL ACADEMY OF MEDICINE. ALSO RECEIVED THE NIMH DIRECTOR DIRECTOR'S MERIT AWARD, THE SEW SOCIETY OF BIOLOGICAL PSYCHIATRY GEORGE THOMPSON AWARD, AND IS A THOMPSON WRITERS HIGHLY CITED /ROERESEARCHER IN PSYCHOLOGY. LET'S WELCOME DR. MORRIS, OUR FIRST SPEAKER. /PHRA [APPLAUSE] >> THANK YOU VERY MUCH, AND THANK YOU FOR INCLUDING R DOC IN THE CLINICAL CENTER GRAND ROUNDS ROUNDS. SO I AM GOING TO FIRST JUST SHOW I HAVE NO DISCLOSURES. AND VERY BRIEFLY, THE RESEARCH DOMAIN CRITERIA INITIATIVE IS A WAY FOR NIMH-SUPPORTED RESEARCH ON MENTAL DISORDERS TO /SREG INVESTIGATE NEW METHODS FOR CLASSIFYING MENTAL DISORDERS. SO BY THE END OF MY PRESENTATION PRESENTATION, I HOPE THAT IT WILL BE CLEAR WHAT THE SCIENTIFIC RATIONALE FOR R DOC IS, HOW WE'VE -- WE'RE ADDRESSING CONCEPTUAL AS WELL AS PRACTICING /PHGMATIC ISSUES ASSOCIATED WIT H R DOC, AND I WILL OUTLINE SOME CURRENT AND FUTURE STEPS FOR THE R DOC INITIATIVE. SO JUST FIRST TO GIVE A LITTLE BACKGROUND ABOUT THE RATIONALE FOR R DOC AND WHY THE INSTITUTE THOUGHT IT WAS IMPORTANT. PROGRESS, TO PUT SIMPLY, PROGRESS WAS STALLING OUT OVER THE LAST FEW DECADES. WE HAD INCREASING RATES OF DISABILITY, AS SHOWN HERE, LOOKING AT THE DALIES, DISABILITY ADJUSTED LIFE YEARS NE. NEWUROPSYCHIATRIC DISORDERS ACCOUNT FOR 7.4% OF DALIES INTERNATIONALLY, RANKING ONLY SECOND AFTER CARD /KWRO /SRAFIOVASCULAR AN D CIRCUMSTANCE INTERESTTRY DISEASE AND RELATED. SO A SIGNIFICANT PUBLIC HEALTH BURDEN, BOTH IN DISABILITY AS WELL AS EARLY MORTALITY. IN FACT, ON AVERAGE, PEOPLE WITH SKITS /TPRECHIZOPHRENIA DIE 28 YEARS EARLIER THAN INDIVIDUALS IN THE GENERAL POPULATION. SO A SIGNIFICANT DISABILITY BURDEN, PREMATURE MORTALITY, IN INCREASING SUICIDE RATE, AND A STALL IN THE DEVELOPMENT OF NEW MEDICATIONS. SO NO NEW BREAKTHROUGH TREATMENTS HAVE REALLY BEEN OBSERVED OR GONE INTO CLINICS IN THE LAST SEVERAL DECADES. AND IN FACT, PHARMACEUTICAL COMPANIES WERE CLOSING DOWN THEIR PSYCHIATRIC PROGRAMS. SO RIGHT NOW THE CURRENT SYSTEMS FOR DIAGNOSING MENTAL DISORDERS, AS MANY OF YOU ARE WELL AWARE, ARE THE DIAGNOSTIC AND STATISTIC STATISTICAL MANUAL, THE DS M, THAT'S PUBLISHED BY THE AMERICAN PSYCHIATRIC ASSOCIATION. AND THE I /KR-FPCD, THAT'S PUBLISHED BY THE WORLD HEALTH ORGANIZATION. THESE PROVIDE DIAGNOSTIC CRITERIA THAT HAVE HIGH LEVELS OF RELIABILITY, SUCH AS THAT CLINICIANS AND RESEARCHERS CAN HAVE GOOD AGREEMENT FROM ONE TO THE OTHER ABOUT DIAGNOSTIC -- DIAGNOSISS. BUT THEY ARE LACKING IN VALIDITY VALIDITY, MEANING THAT THEY ARE NOT AS STRONG AS THEY COULD BE IN TERMS OF PREDICTING TREATMENT OUTCOMES, ILLNESS COURSE. AND TIME AND TIME AGAIN THE DATA ARE SHOWING US THAT NATURE DOESN'T GROUP THESE DISORDERS IN THE SAME WAY THAT WE HAVE. THE GENETIC DATA DON'T LINE UP WITH OUR CATEGORIES VERY WELL. CHANGES IN BRAIN STRUCTURE AND FUNCTION DON'T ALIGN WITH OUR CATEGORIES. AND SO WE'VE HAD DIFFICULTY IDENTIFYING BIOMARKERS FOR CURRENT DISORDERS, AS THEY ARE DEFINED CURRENTLY. WE HAVE NOT IDENTIFIED DISEASE MECHANISMS, AND WE DON'T HAVE ANY DIAGNOSTIC TESTS THAT ARE SPECIFIC FOR DISORDERS AS CURRENTLY DEFINED. SO I THINK GALOTS WILL LEAVE YOU THEIR NICE PAPER IN 2013 CAPTURED IT. GIVEN THE DIAGNOSTIC PRACTICES, WHERE THERE ARE MULTIPLE SYMPTOMS IN ORDER TO GET A DIAGNOSIS, YOU HAVE TO HAVE A CERTAIN NUMBER OF CERTAIN SYMPTOMS. LOOKING JUST AT PPTSD, THEY /KPOCO COMPUTED THAT THERE ARE 636,000 WAYS TO HAVE PTSD. AND SO THE IDEA THAT YOU WOULD FIND A BIOMARKER OR A TREATMENT THAT WOULD WORK FOR THOSE PEOPLE AS /AA GROUP IS UNDERSTANDABLY -- PROGRESS HAS BEEN FRUSTRATING. TO SUM UP THIS IDEA, A QUOTE FROM RECENT PAPER SKITS /TPRECHIZOPHRENIA BECAME EFFECTIVELY THE DISEASE THAT /WWAS BORN INTO ANTI-SCOTT ANTI-PSYCHOTICS. DEPRESSION BECAME THE DISEASE THAT PONDD TO ANTIDEPRES-DEPRESSANTS AND SO ON, WHICH IS NOT A VERY SATISFYING WAY OF DEFINING DISORDERS. NOW THE FACT THAT THERE ARE BROAD CLASSES OF MEDICATIONS THAT WORK FOR THESE BROAD CLASS CLASSES OF DISORDERS SUGGESTS THAT THERE IS SOME VALIDITY TO THE CATEGORIES. HOWEVER, A LOT /OF PATIENTS MEET CRITERIA FOR MORE THAN ONE, WHEOR THEY FALL INTON BETWEEN DIAGNOSES AND THOSE TEND TO BE PEOPLE WHO GET LEFT OUT /OF RESEARCH PROJECTS, WHERE THE DIAGNOSTIC CRITERIA TEND TO BE ADHERED TO /RRE/* VERY RIDGEDLY. AND THESEMENTATION /* MEDICATION MEDICATIONS, ALTHOUGH THEY ARE LIFE-SAVING FIRE LOT /OF TEE/-OF PEOPLE, THEY DON'T WORK WELL FIRE LOT OF PATIENTS. IN FACT, ON AVERAGE PSYCHIATRIC DRUGS ARE EV /TKPHAEURBS ONLY HALF OF THE PATIENTS WHO TAKE IT BECAUSE OUR GROUPS ARE DEFINED BY HETEROGENOUS -- DEFINED AS HETEROGENOUS SYNDROMES WITH DIFFERENT MECHANISMS. AND THIS IS NOT SPECIFIC TO PSYCHIATRIC DISORDERS INTO AREAS OF MEDICINE, THERE ARE /* THEY ARE STRUGGLING WITH THIS KIND OF HETEROGENEITY AS WE PUSH TOWARD PRECISION MEDICINE. AND NIMH IS NOT THE FIRST ONES TO NOTICE THIS OR TRY TO DO SOMETHING ABOUT IT. WE ARE NOT THE FIRST ONES TO SAY IT HAS BEEN A STILL AHEEADY DRUM BEAT OF THESE KINDS /OF CONCERNS FOR DECADES. I'VE CHONE JUST /AA FEW HERE THAT I THINK ARTICULATE IT REALLY NICELY. RAISING THE CONCERN THAT SKITS FRENIA -- AND I AM TALKING ABOUT SKITS /TPRECHIZOPHRENIA BECAUSE THAT'S MY PROGRAM AREA. BUT I THINK THE SAME CAN BE SAID FOR MOST OF OUR PSYCHIATRIC DISORDERS. THAT SKITS /TPRECHIZOPHRENIA IS USUALLY STUDIED AS /AEA UNIOTY ARARY ARARY PROBLEM PROBLEM, THAT THERE IS LIKELY NO SINGLE ENTITY OF SKITS /TPRECHIZOPHRENIA. AND THEN MORE RECENTLY, JIM DEN DENOS, MORE BOLDLY SAID SKITS FRENIA DOES NOT EXIST. AND JUST TO BE CLEAR, WE'RE NOT DENYING THAT PEOPLE SUFFER FROM THE SYMPTOMS THAT ARE CAPTURED AS PART OF THE SKITS /TPRECHIZOPHRENIA DIAGNOSIS OR CERTAINLY OTHER DISORDERS AS WELL. ONLY THAT THE WAY THAT WE HAVE BEEN DEFINING AND CLASSIFYING AND DIAGNOSING DISORDERS NEEDS TO BE QUESTIONED. WE NEED TO LOOK AT OUR ASSUMPTION THAT'S WE'RE MAKING ABOUT DIAGNOSTIC GROUPS. -- ASSUMPTIONS. BUT WHY HAS IT BEEN SO HARD TO DO THAT? IF THERE IS GOOD CON/SEPSENSUS THAT THAT IS IMPORTANT? WELL, BECAUSE THESE DIAGNOSTIC CRITERIAS DRIVE THE ENTIRE RESEARCH SYSTEM. INVESTIGATORS HAVE BEEN TAUGHT AND LEARNED FROM THEIR EXPERIENCES IN REVIEW THAT IF THEY PUT IN AN /APPLICATION WITHOUT IDENTIFYING WHAT PATIENT GROUP THEY ARE GOING TO STUDY, THEY ARE UNLIKELY TO GET A COMPETITIVE SCORE AND BE FUND IF YOUED. REVIEW GROUPS LOOK FOR THOSE -- THAT INFORMATION ABOUT DIAGNOSIS DIAGNOSIS. JOURNALS ARE GROUPED, MANY OF THEM, ACCORDING TO DIAGNOSTIC CATEGORIES AND REGULATORY PROCESSES AS WELL. SO R DOC IS AN ATTEMPT, IF IT'S POSSIBLE, TO UNWRITE THE UN UNWRITTEN RULE THAT ALL HIM N GRANTS HAVE TO FOCUS ON A DS M DIAGNOSIS OR DIAGNOSES. SO MOVING ON TO TALK SPECIFICALLY WHAT IS R DOC? THE R DOC INITIATIVE IS AN NIM- NIM-EFFORT TO HELP PATIENTS WANTING TO LOOK AT /TTHAT SPECTRUM OF ILLNESS-TO-HEALTH. ARE IDENTIFIED AND CLASSIFIED FOR RESEARCH PURPOSES. SO WE ACKNOWLEDGE THAT THE DS M AND THE I /KR-FPCD ARE THE EXISTING STANDARD /SAND CONTINUE TO BE THE STANDARD FOR CLINICAL WORK, FOR INSURANCE BILLING. BUT THAT NIMH-SUPPORTED RESEARCH DOES NOT NEED TO BE CONSTRAINED BY AND ABIDE BY THOSE CATEGORIES CATEGORIES. SO INSTEAD OF GROUPING PATIENTS INTO HETEROGENOUS DIAGNOSTIC GROUPS, R DOC PROVIDES A FRAMEWORK FOR CLASSIFYING PATIENTS ON THE BASIS OF NEWURO NEUROBEHAVIORAL CONSTRUCTS, BASED ON OUR UNDERSTANDING OF BRAIN AND BEHAVIOR. SO WE KNOW MORE THAN WE EVER HAVE ABOUT BEHAVIOR NEWUROSCIENCE NEUROSCIENCE. AND THE CONCEPTUALLY -- WE WANT WANTED TO START WITH A WHITE SHEET, A CLEAN SHEET, WHAT KNOWING EVERYTHING WE KNOW ABOUT BEHAVIORAL NEWUROSCIENCE, HOW WOULD WE START TO CLASSIFY AND ORGANIZE PSYCHIATRIC DISORDERS? SO THE BUMPER STICKER VERSION. IS THAT THE NIMH IS NOT THE IN INSTITUTE OF THE D /S-FPSM. WE DIDN'T THINK IT WAS REASONABLE TO TELL THE FIELD YOU DON'T HAVE TO BE CONSTRAINED BY D /S-FPSM DIAGNOSIS WITHOUT PUTTING SOMETHING IN PLACE AS /AA FRAMEWORK. OTHERWISE IT MIGHT BE A LITTLE BIT TOO WILD WEST, ESPECIALLY FOR REVIEWERS' PURPOSES. AND SO WE DEVELOPED A FRAMEWORK CENTERED ON A SET /OF DOMAINS BASED ON WHAT WE KNOW FROM BEHAVIORAL NEWUROSCIENCE. A SET /OF UNIOTS OF ANALYSIS FOR MEASURING THESE CONSTRUCTS. SO STARTING WITH THE ACKNOWLEDGE ACKNOWLEDGEMENT THAT ALL OF THESE BRAIN SYSTEMS CHANGE AND DEVELOP OVER TIME AND ARE IM/PABPACTED BY ENVIRONMENTAL FACTORS. SO THIS IS THE -- A SKETCH OF THE R DOC MA/TREUBTRIX WITH UNIOTS OF ANALYSIS ACROSS THE TOP AND DO DOMAINS IN THE ROWS. AND IN EACH OF THE ELEMENTS, THE CELLS IN THE MA/TREUBTRIX, ARE IMPLEMENTS /* RECOMMENDATION THAT WERE IDENTIFIED IN /AA SERIES OF WORKSHOPS AS RELEVANT TO EACH CONSTRUCT. AND YOU CAN SEE THE DETAILED MA MA/TREUBTRIX WITH THOSE ELEMENT FILLED IN ON THE R DOC WEBSITE THAT I'LL SHOW AT THE END OF MY TALK. SO THESE ARE THE FIVE DOMAINS. EACH OF WHICH HAS A SUBSET OF CONSTRUCTS. THESE ARE THE CONSTRUCTS. AND I WANT TO EMPHASIZE THAT THIS IS NOT THE KIND OF THING THAT WE'VE PUT OUT THERE AND IT WILL STAY LIKE THIS STATIC UNTIL TEN OR 15 YEARS AND WE'LL REVISE IT. IT'S NOT INTENDED TO BE THAT. IT'S INTENDED TO BE DIYNAMIC AND CHANGING, AS NEW DATA AND NEW EVIDENCE COME IN TO SUPPORT CHANGES AND ADDITIONS. SO YOU WILL NOTICE THE DOMAINS AND CONSTRUCTS DON'T EXACTLY ROLL OFF /THE TONGUE. AND THAT WAS KIND OF ON PURPOSE BECAUSE WE WANTED TO GET AWAY FROM TERMINOLOGY THAT ALREADY HAS BAGGAGE AND IN ASSOCIATION WITH EXISTING DIAGNOSES. TO REALLY ENCOURAGE THE FIELD TO TAKE A STEP BACK. THERE IS NO ONE-TO-ONE CORRESPONDENCE BETWEEN ANY CONSTRUCT AND /AA DIAGNOSIS. INSTEAD, WE'RE INTERESTED IN LOOKING AT THE FULL RANGE OF THESE CONSTRUCTS, AS OBSERVED IN PATIENTS AND NON-PATIENTS. AND UNDERSTANDING HOW THESE ENFORCEMENORMATIVE PROCESSES. THESE PROCESSES THAT HAVE E EVOLVED TO SUPPORT COMPLEX HUMAN BEHAVIOR. HOW THESE ENFORCEMENORMATIVE PROCESSES LEAD TO SYMPTOMS, PERHAPS AT THEIR EXTREMES. AND JUST AS THE BRAIN IS DEEPLY INTERACTIVE AND INTEGRATED, WE EXPECT THAT THE MOST PROMINENSING RESEARCH WILL LOOK AT INTER INTERSECTIONS BETWEEN THESE CONSTRUCTS. FOR EXAMPLE, IN GREEN, HOW DOES THE EXPERIENCE OF ACUTE THREAT DIFFERENTIALLY AFFECT ONE'S ABILITY TO CONTROL THEIR OWN CRAIG /* THINKING? OR IN RED, HOW MIGHT SUSTAINED THREAT LIKE FROM EARLY STRESS DISRUPT SOCIAL COMMUNICATION AND LEAD TO WITHDRAWAL AND POOR FUNCTIONING? EACH OF THESE CONSTRUCTS CAN BE MEASURED AT MULTIPLE UNITS OF ANALYSIS. I WANT TO HIGHLIGHT THAT ALL OF THESE UNITS OF ANALYSIS ARE ON THE SAME LEVEL. NONE IS THOUGHT TO BE MORE BASIC OR FUNDAMENTAL THAN THE OTHERS. THEY IN/TPORFORM AND CONSTRAIN EACH OTHER. IN A PROCESS OF CONVERGENT VALID VALIDATION. AND IN ESSENCE, AS A REFERRED -- THE MA/TREUBTRIX IS A SET /-OF I HOPE SO SOS TO BE TESTED -- HYPOTHESES, NOT SET IN STONE AS FACT. SO SOME GENERAL PRINCIPLES FOR R DOC RESEARCH. AGAIN TO START WITH WHAT IS KNOWN ABOUT NORMAL NEWURO NEUROBEHAVIORAL PROCESSES IN ORDER TO UNDERSTAND WHAT HAPPENS WHEN THESE THINGS GO WRONG. FOCUS ON SPECIFIC CLINICAL PROBLEMS THAT MAY SPAN DIAGNOSIS DIAGNOSES, OR IDENTIFYING SUB SUBGROUPS OF PATIENT I WANT DIAGNOSTIC CATEGORY. AND TO ASSUME DIMENSIONALITY AND NOT PRETEND THAT THERE ARE ANY BRIGHT LINES BETWEEN ILLNESS AND HEALTH. AND SELF-SUPPORTED SYMPTOMS DOES NOT NEED TO BE THE GOLD STANDARD STANDARD. IT MAY BE POSSIBLE TO DETECT ILLNESS-RELATED TRA/SKWREBJECTORIES OR CHANGES IN TRA/SKWREBJECTORIES IN OTHER MEASUREMENTS BEFORE SELF-REPORT OF SYMPTOMS IS AVAILABLE, WHICH WOULD HOPEFULLY LEAD TO EARLIER PREDICTION AND PREVENTION. SO IT MIGHT BE HELPFUL FOR THOSE OF YOU WHO INTERESTED TO SEE HOW THESE PRINCIPLES ARE PUT IN PLACE TO LOOK AT THE SUMMARIES OF GRANTS THAT HAVE BEEN FUNDED UNDER R DOC INITIATIVES AND THOSE ARE AVAILABLE AT /TTHAT WEBSITE. JUST TO GIVE YOU TWO BRIEF EXAMPLES OF R DOC PRINCIPLES AT WORK. THE BIPOLAR SKITS /TPRECHIZOPHRENIA NETWORK ON INTERMEDIATE FENE PHENOTYPES, THE B SNIP CONSORT CONSORTIUM RECRUIT AID LARGE GROUP OF INDIVIDUALS WITH SIGH S SIGH /KOCOSE /WREUS IN THREE DIFFERENT DIAGNOSTIC CLASSES. COMBINED THEM ALL TOGETHER, AND LOOKED TO SEE WHAT CLUSTERS OF PATIENTS MIGHT EMERGE USING MEASURES OF COG /TPHENITIVE CONTROL AND SENSORY MOTOR REACTIVITY. I WON'T GET INTO THE DETAILS. THE CITATION IS THERE IF YOU WANT TO LOOK UP THE PAPER. BUT IT WAS A VERY NICE EXAMPLE OF IDENTIFYING SUBGROUPS AND THEN VALID /A*ATING THEM USING GENT GENETIC MEASURES, BRAIN IMAGING AND SO ON. AND THEN JUST /AA SECOND QUICK EXAMPLE. ELISE ROBINSON HAS STUDIED INDIVIDUALS -- CHILDREN WITH AUTO/SKPWREUFPL THEIR SIBLINGS, LOOKING AT ON THIS FIGURE AT THE -- AUTISM. AND LOOKING AT /THIS FIGURE AT THE DENOVO-VARIANT BURDEN ON THE Y /AB-AXIS IN DAILY FUNCTIONING IN CHILDREN WITH AUTISM IN RED. AND IN THEIR SIBLINGS IN BLUE. AND INSTEAD OF USING KIND OF THE TRADITIONAL PATIENTS VERSUS CONTROLS APPROACH, SHE LOOKED AT THEM DIMENSIONALLY AND I THINK IT GIVES AS A MUCH MORE COMPLETE PICTURE OF THIS RELATIONSHIP BETWEEN DE/PHOEFBO VARIANT BURDENING AND FUNCTIONING. AND SHE CONCLUDES THAT CASE S S IN CONTROLS WITH EQUIVALENT QUANTITATIVE LEVELS OF IM IMPAIRMENT ARE HIGHLY SIMILAR WITH REGARD TO THEIR DENOVO- DENOVO-VARIANT BURDEN, SUGGEST SUGGESTING THAT THE CURRENT CATEGORICAL CLINICAL THRESHOLD IS LARGELY ASH /TRTRAR RIFROM BOTH A FEPHENOTYPICA AND GENETIC POINT OF VIEW. SO YOU CAN SEE PERHAPS PARALLELS WITH THINGS LIKE CHOLESTEROL LEVELS AND HYPERTENSION THAT ARE DIMENSIONAL. AND THEN THE JOB OF RESEARCHERS AND CLINICIANS IS TO FIND A MEANINGFUL CUT POINT TO IN IN/TPORINFORM DECISIONS. SO PRACTICING /PHGMATICALLY-SPEAKING, WHAT HAS R DOC MEANT FOR NIMH FUNDING FUNDING? WE HAD A SERIES OF FIVE RO1 RFAS AND FUNDED 36 GRANTS. THE FIRST /OF THOSE ARE JUST NOW BEING COMPLETED. WE HAVE AN ONGOING PROGRAM ANNOUNCEMENT TO ENCOURAGE INVESTIGATORS TO TAKE DATA THAT THEY MAY ALREADY HAVE ON HAND OR COMBINE DATA FROM OTHER RESEARCH RESEARCHERS AND DO SECOND AARY DATA ANALYSIES RELATED TO R DOC CONSTRUCTS. AND THEN WE HAVE ENCOURAGED INVESTIGATORS RIGHTS OHE- OHE-INITIATED GRANT APPLICATIONS TO ADOPT R DOC PRINCIPLES. IT IS NOT THE CASE THAT WE ONLY FUND R DOC RESEARCH, BUT WE DO ENCOURAGE IT, ALTHOUGH IT'S VERY HARD TO QUANTIFY EXACTLY HOW MANY OF THE GRANTS WE'RE FUNDING OR WHAT WE WOULD CALL R DOC BECAUSE IT IS IN ITSELF DIMENSIONAL. SO A GOOD ESTIMATE IN MY DIVISION, THE DIVISION OF TRANS TRANSLATIONAL RESEARCH, WHICH IS AMONG ALL THE DIVISIONS, MOST AFFECTED BY R DOC, IS THAT ABOUT 50% OF THE GRANTS THAT WE FUND NOW ADOPT R DOC PRINCIPLES. WE HAVE, BASED ON THIS, AS YOU CAN IMAGINE, INVESTIGATOR RESPONSE TO A CHANGE, THIS DRAMATIC IS MIXED. WE HAVE HAD A CONCERN ABOUT -- THAT R DOC POSSIBLE IN INOLOGY AND PSYCHIATRY. WE DO THINK IT'S REASONABLE TO CONSTRUCT THOSE UNIVERSE TO THOSE THAT MEET THOSE CRITERIA THERE IS A MISUNDERSTANDING THAT IT'S NOT REASONABLE TO STUDY INTER/AOBACTIONS BETWEEN CONSTRUCTS, I HOPE I HAVE MAID IT -- MADE IT CLEAR THAT THAT'S NOT THE CASE. WE HEAR THE CONCERN THAT R DOC IS REDUCTIONISTIC AND THAT POINT THAT WE'RE NOT ASSUMING THAT NEWUROBIOLOGICAL MEASURES ARE FUNDAMENTAL, MORE FUNDAMENTAL THAN BEHAVIORAL OR SELF-REPORTED EXPERIENCES. INSTEAD, THEY ARE TO CONFINE AND IN/TPORFORM EACH OTHER. AND ALTHOUGH A LOT /OF R DOC RESEARCH IS CROSS DIAGNOSTIC, IT IS NOT NECESSARILY THAT WAY. AGAIN WITH THE GOAL OF STUDYING -- OF IDENTIFYING MEANINGFUL SUB SUBGROUPS WITHIN A DISORDER. THAT WOULD ALSO BE CONSISTENT WITH R DOC. R DOC DOES NOT INCLUDE EXPERIMENTS WITH ANIMALS. THIS IS PARTIALLY TRUE. R DOC IS A FRAMEWORK FOR CLASSIFYING HUMANS WITH MENTAL DISORDERS. SO IN THAT RESPECT, IT'S NOT A FRAMEWORK FOR ANIMAL RESEARCH. HOWEVER, MANY OF THE ELEMENTS THAT ARE PART OF THE R DOC MA MA/TREUBTRIX ARE DEFINITELY INFORMED BY ANIMAL RESEARCH AND SO THERE IS AN INTER/AOBACTION THERE AND THAT THEY SHOULD IN/TPORFORM EACH OTHER. AND FINALLY, WE HEAR, WHILE R DOC ISN'T READY FOR THE SHRINK AND THAT'S TRUE ACTUALLY. THAT'S NOT A MISUNDERSTANDING. IT'S DEFINITELY NOT REALLY FOR THE SHRINK AND NO PATIENT SHOULD EXPECT TO GO AND GET AN R DOC DIAGNOSIS AT /THIS TIME. WE HOPE THAT THE R DOC INITIATE INITIATIVE WILL IN/TPORFORM DIAGNOSTIC PRACTICE IN WAYS, BIG OR SMALL. IT'S AN EM/PPIRICAL QUESTION. CLINIC. SOME OF THE MORE SUBSTANTIVE CHALLENGES THAT WE'VE HAD FIRST RELATE TO GREEN SIZE. WHAT'S THE RIGHT GRANULEITY FOR SUCCESSFUL TREATMENT? FOR EXAMPLE, THE TRANSDIAGNOSTIC CONCEPT OF AN HA DONIA VERSUS MORE NEWUROSCIENCE DERIVED CONSTRUCTS OF EFFORT VALUATION, AWARD /* REWARD PREDICTION. WE'VE LEARNED TOWARD HAVING THE NEWUROSCIENCE DRUG CONCEPTS IN THE RDOX MA/TREUBTRIX BUT IT MAY BE THE BROADER CLINICAL CONCEPTS ARE MORE USEFUL FOR THESE PURPOSES AND AGAIN THAT IS AN EM EM/PEPIRICAL QUESTION. WE JUST NEED TO STUDY IT IN THAT DIMENSIONAL WAY. WE GO BACK /SAND FORTH ON WHETHER IT'S MORE IMPORTANT TO FOCUS ON SYMPTOMS VERSUS FUNCTIONING. THE RELATIONSHIP BETWEEN SYMPTOMS AND DAILY FUNCTIONING IS COMPLICATED. THERE ARE SOME PATIENTS WHO HAVE VERY SEVERE SYMPTOS AND YET SEEM TO MANAGE OKAY IN THEIR DAY DAY-TO-DAY LIVES AND VICE VERSA. SO THAT IS A QUESTION FOR ONGOING DISCUSSION. I REFERRED ALREADY TO THE QUESTION OF HOW /TO DETERMINE CUT POINTS FOR CONTINUOUS FEN /OPHENOMENON BECAUSE A LOT /OF TREATMENT DECISIONS ARE BINARY DECISIONS, NOT DIMENSIONAL. AND THEN FINALLY, A METHOD LODGE LODGEICAL CHALLENGE TO THE FIELD OF HOW BEST TO INTEGRATE ACROSS MEASURES. AS FAR AS POTENTIAL CONSEQUENCES OF THE R DOC INITIATIVE AND WHAT WE HOPE TO SEE IN THE FUTURE. WE ANTICIPATE THAT THERE WILL BE MODIFICATIONS TO EXISTING DIAGNOSTIC SYSTEMS TO INCREASE THEIR VALIDITY. OPTIMALLY IN THE FUTURE DIAGNOSES SHOULD BE MORE CLOSELY LINKED TO MECHANISM AND MORE IN IN/TPORPFORMATIVE FOR TREATMENT DECISIONS. BUT WE'RE OPEN TO THE IDEA THAT THESE CHANGES MAY BE SMALL OR THEY MAY BE BIG AND I THINK GREG MILLER SAID IT NICELY. R DOC ATTEMPTS TO FREE RESEARCH ON PSYCHOPATHOLOGY FROM THE CON CONSTRAIGHTENS OF D /S-FPSM, BUT IF THAT ACCRUING LITERATURE LEADS US BACK TO D /S-FPSM CONCEPTS AND CRITERIA, THEN WE WOULD EMBRACE THOSE. BUT IT'S AN EM/PEPIRICAL QUESTION AND WE WON'T KNOW UNTIL WE SUPPORT THAT RESEARCH. AS FAR AS CLINICAL /TRAOEUTRIALS, AS I SAID IN THE BEGINNING, THIS IS CLOSELY RELATED TO PERSONALIZED MEDICINE AND RELATEDLY TO THE EXPERIMENTAL THERAPEUTICS A APPROACH. WE ENCOURAGED CLINICAL /TRAOEUTRIALS TONE ROLE PATIENTS BASED ON IM IMPAIRMENT IN /AA SPECIFIC SPECMECH MECHANISM RATHER THAN A BROAD DIAGNOSTIC CATEGORY. TO MEASURE TARGET ENGAGEMENT AND TO VALID /A*ATE THOSE TARGET BY LOOKING AT THEIR RELATIONSHIP WITH CLINICAL OUTCOMES. AND WE'RE ENCOURAGED TO SEE THAT THE FDA AND THE EUROPEAN EQUIVALENT GAVE APPROVAL FOR COGNITION AS AN /KAEUINDICATION IN DEPRESSION AS WELL AS IN SKITS /TPRECHIZOPHRENIA. SO INDICATING THAT THAT IS A LEGITIMATE TARGET FOR DRUG DEVELOPMENT, EVEN THOUGH IT ISN'T IN /SAND OF ITSELF A DIAGNOSTIC CLASS. NIMH HAS PUBLISHED A SERIES OF R RFAS TO SUPPORT CLINICAL TRIALS AND SO THIS IS JUST THE LANGUAGE FROM THAT RFA THAT I THINK REFLECTS HOW IDEAS ABOUT R DOC AND DIMENSIONAL APPROACHES TO PSYCHOPATHOLOGY ARE GETTING INTO CLINICAL /TRAOEUTRIALS. NOVEL TREATMENT TARGETS AND HOW THEY RELATE TO FUNCTIONAL DO DOMAINS OR SYMPTOMS, AS OPPOSED TO BROAD DIAGNOSTIC CATEGORIES. SO FINALLY I JUST WANT /TO WRAP UP WITH THE IDEA, I THINK IT'S VERY NICE IN 1843 JON STEWART MILLER ANTICIPATED R DOC KINDLY AND SAID THAT THE TENDENCY HAS ALWAYS BEEN STRONG TO BELIEVE THAT WHAT RECEIVED A NAME MUST BE AN ENTITY OR BEING AND IF NO REAL ENTITY ANSWERED TO /TTHAT NAME, WE DIDN'T SUPPOSE IT DIDN'T EXIST BUT IMAGINED IT WAS OB/STRAOUS AND MYSTERIOUS. SO R DOC ENCOURAGES RESEARCHERS TO EXAMINE THEIR ASSUMPTIONS ABOUT THE THINGS TO WHICH WE HAVE GIVEN NAMES. AND ASK HOW WE MIGHT DO A BETTER JOB OF IDENTIFYING ENTITIES THAT ARE MORE REAL AND LESS OB OB/STRAOUS AND MYSTERIOUS. I WANT TO ACKNOWLEDGE THE CURRENT AND PAST MEMBERS OF THE R DOC WORK GROUP AND THE UNIT. WE HAVE REPRESENTATION FROM ALL OF THE NIMH DIVISIONS, INCLUDING THE IRP. AND FINALLY THERE IS -- A WEBSITE AND OUR TWITTER HANDLE IF ANYBODY WANTS TO FOLLOW US. AND I HAVE A FEW MINUTES FOR QUESTIONS. >> BIPOLAR DISORDER? >> SO THE QUESTION WAS HAS R DOC DONE RESEARCH ON BIPOLAR DISORDER? SO FIRST, I ENCOURAGE TO YOU TAKE A LOOK AT THE LIST OF FUND FUNDED GRANTS. AND YOU CAN SEE EXACTLY WHAT -- SO ON R DOC PROJECT WOULDN'T BE FOCUSED ON EXPLAINING BIPOLAR DISORDER OR UNDERSTANDING BI BIPOLAR DISORDER AS /AA CLASS. BUT THERE HAVE BEEN -- BIPOLAR DISORDER MIGHT BE A DIAGNOSTIC CLASS THAT WOULD BE USEFUL FOR IDENTIFYING PEOPLE WITH CERTAIN ASPECTS OF PSYCHOPATHOLOGY THAT WOULD BE USEFUL IN /AA STUDY OF A MORE SPECIFIC ASPECT OF PSYCHOPA PSYCHOPATHOLOGY. SO TON GET TOO FAR IN THE WEEDS BUT IT WOULD MAKE SENSE SOMETIMES, DEPENDING ON ONE'S HYPOTHESES, TO /RRECRUIT PATIENT WITH BIPOLAR DISORDER OR SKITS FRENIA IN ORDER TO GET THE PSYCHOPATHOLOGY THAT IS NEEDED TO TEST /THE HYPOTHESIES PROPOSED, IF THAT MAKES SENSE. >> YEAH. >> YEAH. ANY OTHER QUICK QUESTIONS? >> ALL RIGHT. SO THIS IS GOING TO NATURALLY FOLLOW FROM WHAT SARAH JUST DID. AND I AM GOING TO TRY TO TAKE OFF FROM KIND OF THE BROAD PERCESPECTIVE THAT SHE WAS JUST TALKING ABOUT AND GIVE ONE CONCRETE EXAMPLE RELATED TO ANXIOETY. AND AGAIN, HOW THAT WILL HAPPEN ABO WILL BECOME CLEAR IN A MINUTE. I AM GOING TO TRY TO END WITH TEN MINUTES, BUT DEFINITELY AT LEAST FIVE FOR PLENTY /OF QUESTIONS. PROBABLY THE MOST RELEVANT THING TO SAY HERE IS THAT I AM GOING TO BE TALKING ABOUT TREATMENT, NOVEL TREATMENT. NONE OF IT REALLY SHOULD BE A APPLIED OR USED CLINICALLY YET. IT'S TOO EARLY, THOUGH. IT IS INTERESTING AND EXCITING. AND THERE IS REALLY THREE MAIN THINGS THAT I AM GOING TO WANT TO DO. PROBABLY THE BIGGEST ONE AND THIS RELATES TO SOME OF THE LAST THINGS THAT SARAH WAS TALKING ABOUT IS TO EMPHASIZE THE COMPLEMENT AR /KWREITY TWIN A CLIN CLINICIAN OR CLINICAL-BASED LIKE D /S-FPSM AND SOMETHING LIKE R DOC THAT'S REALLY BASED ON THE BRAIN. THIS ISN'T AN EITHER/OR KIND OF DOMING I THINK THAT'S ONE OF THE MAJOR MISCONCEPTIONS. THE TWO HAVE TO WORK TOGETHER. HIGH-IT'S DIFFICULT TO DESCRIBE HOW THEY WORK TOGETHER WITHOUT SOMETHING CONCRETE. I AM SO GOING TO REALLY DO THAT BY TALKING ABOUT ANXIOETY AND YOU WILL SEE THESE TWO POINTS HOPE HOPEFULLY WILL BE VERY OBVIOUS. AND SO I'LL MAKE A FEW GENERAL COMMENTS REALLY HE CECHOING THE THINGS THAT SARAH JUST TALKED ABOUT AND THEN TALK ABOUT ONE ASPECT OF ATTENTION AND ONE ASPECT OF AN R DOC CONCEPT. ALL RIGHT. SO AGAIN THESE ARE THREE MAIN POINTS THAT SARAH ALREADY MADE. AGAIN, THE MAIN THING THAT I AM GOING TO TRY TO TALK ABOUT IS COMPLEMENT AR /KWREITY. HOW DO WE USE CLINICAL-BASED AND A NEWUROSCIENCE-BASED CLASSIFICATION TOGETHER? AND I TEND TO THINK ABOUT IT IN THIS FIGURE RIGHT HERE. AND THIS REALLY, REALLY I WILL ILLUSTRATES THE CLINICAL END OF THINGS. SO THE THING THAT I AM GOING TO BE TALKING ABOUT. I AM GOING TO BE TALKING ABOUT DIFFERENT ASPECTS OF INDIVIDUVIGILANCE ATTENDING TO SOMETHING THAT'S FRIGHTENING. AND AVOIDING IT, NOT PAYING ATTENTION TO IT WITH. NOW CLINICALLY, WE TEND TO USE A BUNCH OF DIFFERENT WORDS FOR TALKING ABOUT THESE KINDS /OF BEHAVIORS. AS YOU WILL SEE IN A MINUTE, I AM GOING TO THINK ABOUT WHAT WE KNOW ABOUT THESE BEHAVIORS FROM NEWUROSCIENCE X I AM GOING TO COME BACK CLINICALLY, AND I AM GOING TO SEPARATE THESE BEHAVIORS INTO SOMETHING THAT'S A CALL AN ACTION AND SOMETHING THAT I CALL A REACTION OUT /OF NEWUROSCIENCE. AND AGAIN, THAT WILL BE CLEAR HOW I DO THAT IN /AA SECOND. BUT THE IMPORTANT THING TO SAY IS /TKPWAOERG GET TO /TTHAT POINT BY REALLY STARTING FROM NEWURO NEUROCIRCUMSTANLATORY AND STARTING FROM ONE VERY PARTICULAR BEHAVIOR, WE'RE GOING TO START THINKING ABOUT HOW THAT BEHAVIOR BEHAVIOR'S RELEVANT CLINICALLY AND WHAT THAT'S GOING TO DO BY LOOKING AT /THIS RELATIONSHIP BETWEEN ATTENTION AND THE R DOC CONCEPT OF ACUTE THREAT. IT'S GOING TO CHANGE THE WAY WE THINK ABOUT BEHAVIORS IN THE CLINIC AND ULTIMATELY CHANGE THE WHICH WE THINK ABOUT TREATING THEM. AND SO REALLY AGAIN FOR THIS TALK, IT'S THINKING ABOUT THESE BEHAVIORS THAT ARE KIND OF HALF WAY BETWEEN NEWUROSCIENCE AND HALF WWAY BETWEEN CLINICALLY THAT IS REALLY HOW R DOC GETS COMBINED WITH A CLINICAL-BASED NO, SIROLOGY IN /THIS PARTICULAR EXAMPLE. THE OTHER THING TO SAY ABOUT THIS IS THAT SARAH WENT OVER /THE IDEA OF /AA CONSTRUCT. SO WE DO THINK ABOUT THE ITEMS IN R DOC AS CONSTRUCTS IN THE CLASSIC SENSE, AS LATENT VARIABLES THAT WE TRY TO UNDERSTAND BY USING MULTIPLE DIFFERENT INDICATORS OF EACH OF THESE LATENT VARIABLES. SO I AM GOING TO IN A MINUTE START TALKING ABOUT THIS TASK RIGHT HERE, AND WE'RE GOING TO COLLECT DATA ON BEHAVIOR AND TALK TO YOU ABOUT THAT, THAT MIGHT BE AN INDICATOR HERE OF THE BEHAVIOR IN THE LABORATORY. BUT WE WANT TO DO THE SAME THING WITH BRAIN FUNCTION. WE'RE JUST GETTING STARTED TO DO THIS. AND THIS IS THE KIND OF THING THAT WE'RE ALREADY DOING A LOT CLINICALLY. AND WE'RE GOING TO TALK ABOUT ANXIOETY BECAUSE THERE IS A STRONG CROSS SPECIES CONSERVATION IN ANXIOETY, AND WE'RE GOING TO THINK ABOUT A LITTLE BIT HOW R DOC RELATE TO THESE THREE SETS OF QUESTIONS, BUT THE MAIN ONE THAT WE'RE GOING TO BE TALKING ABOUT IS IM IMPROVING -- AND WE'RE GOING TO DO IT BY TALKING ABOUT ONE VERY SPECIFIC BEHAVIOR. THAT'S WHERE THINGS ARE GOING TO START. AND THIS SHOWS YOU THE BEHAVIOR RIGHT HERE. SO THIS IS AN EXAMPLE OF ACUTE THREAT. IT'S AN /EUINSTANCE WHERE THIS GUY GUY'S WALKING THROUGH THE WOODS, AND THERE IS A DANGEROUS STIM STIMULUS THAT IS PRESENTED RIGHT IN FRONT OF HIM. ALL RIGHT? AND THAT CORRESPONDS TO THE IDEA OF THE ACUTE THREAT CONSTRUCT IN R DOC. AND KEY THING THAT WE'RE GOING TO BE LOOKING AT HERE IS /THE BEHAVIOR THAT IS EVOKED BY THIS INSTANCE RIGHT HERE. AND THIS IS A FAIRLY COMPLEX BEHAVIOR, BUT ONE OF THE THINGS THAT WE LEARNED FROM THE NE NEUROSCIENCE IS THAT WE CAN PARSE THIS BEHAVIOR INTO TWO SETS OF COMPONENTS. AND THIS IS REALLY BASED ON WORK THAT JOE LED U STARTED DOING IN LARGELY RODENTS AND HE REALLY EMPHASIZED THAT THERE IS KIND OF THIS FAST COMPONENT AND WE'RE GOING TO CALL THAT A REACTION, ALL RIGHT? THEN THIS SLOWER COMPONENT THAT WE'RE GOING TO CALL AN ACTION. ALL RIGHT? THESE TURN OUT TO BE QUITE IMPORTANT CLINICALLY. OUT IN WAY WE ASSESS THESE IN THE LABORATORIES WE HAVE A BUNCH OF TASKS. THE MAIN TASK WE USE IS SOMETHING CALLED THE DAT PROBE TASK. BASICALLY SUBJECT GATES WARNING CUE AND THEY HAVE TO MAKE SOME BEHAVIOR, SOME NEUTRAL BEHAVIOR AND YOU CAN THINK ABOUT THIS AS WALKING THROUGH THE WOODS. IT'S A NEUTRAL TASK. AND THEN YOU CAN THINK ABOUT THIS EVENT AS SOMETHING LIKE THE SNAKE A APPEARING. NOW THERE IS A LOT MORE TO SAY ABOUT THIS AND I AM NOT GOING TO SAY A LOT ABOUT IT EXCEPT TO SAY THAT IT'S HIGHLY COMPLICATED. IT'S A HIGHLY COMPLICATED BEHAVIOR. AND WHILE THIS TASK RIGHT HERE IS KIND OF /AA GOOD STARTING POINT POINT, IN MY GROUP AND IN GROUPS THAT I WORK WITH, PARTICULARLY LED BY BAR HAIM, WE'RE TRYING TO DO BETTER AND I'LL TALK ABOUT A COUPLE /OF SUCH TASKS NIM. -- IN A MINUTE. SO WE GET AN INDEX OF HOW DISRUPTING THIS THREAT IS ON THIS NEUTRAL TASK THAT WE CALL ATTENTION BIAS. AND THAT'S EVOKE INCREDIBLY RAPIDLY. AND YOU CAN SEE IT /HAOHERE I WILL ILLUSTRATED IN /THIS FIGURE RIGHT HERE /TO A GROUP OF ANXIOUS AND NON-ANXIOUS INDIVIDUALS. AND SO THAT SHOWS YOU THAT THERE IS A GREATER EFFECT OF THESE THREATS ON ATTENTION, ON THIS BEHAVIOR. THE OTHER IMPORTANT THING TO SAY ABOUT THIS IS -- AND THIS RELATE TO HOW R DOC CAN BE USEFUL -- HA IT HELTELLS US SOMETHING ABOUT WHAT HAPPENS TO CHILDREN WITH THIS KIND OF REACTION OVER TIME. WHEN WE FOLLOW THEM OVER TIME, EITHER WHEN THEY'RE INFANTS OR WHEN THEY'RE SLIGHTLY OLDER, THESE ARED TODDLERS, AND WE MEASURE THIS BEHAVIOR AND FOLLOW THEM OVER TIME. KIDS WHO TEND TO HAVE THIS REACTION WHERE THEY ATTEND TOWARDS THREAT BEHAVIORALLY, IT PREDICTS A BAD OUTCOME IN THEIR ANXIOETY. NOW, THIS IS QUITE DIFFERENT FROM WHAT WE SEE IN ANXIOETY THAT FOLLOWS FROM AN ACUTE STRESSOR, AS IN PTSD. HERE WE SEE A REACTION WHERE KIDS MONITOR THREAT, PREDICT A BAD OUTCOME. WE SEE SOMETHING VERY, VERY DIFFERENT IN PTSD, AND THAT HAS DIFFERENT IMPLICATIONS IN TERMS OF THE TREATMENT. SO WE'RE GOING TO COME BACK TO THIS WHEN WE START TALKING ABOUT TREATMENT. ALL RIGHT, WE JUST TALKED ABOUT THIS BEHAVIOR. AND I SAID THAT THIS BEHAVIOR BEHAVIOR -- THESE BEHAVIORS ARE REACTIONS. THEY'RE THEY'RE NOT ACTIONS. THE REASON QUESTIWE KNOW THAT IS BECAUSE OF THE NEWUROSCIENCE. SO THE PAPER THAT I MENTIONED SHOWS YOU THE PAPER. IT WAS PUBLISHED LAST MONTH, AND THIS IS WITH JOE LED U AND IT MAKES THE POINT THAT WE'RE USED TO THINKING ABOUT FEAR THIS WAY. AND KIND OF THE PRER DOC /KWHRAEUPBL IS WE KIND OF THINK OF TASS THIS MON /OLITHIC CONSTRUCT THAT GOES FROM A THREAT TO A SENSORY SYSTEM. THIS MON /OLITHIC FORM OF FEAR, AND /AA WHOLE BUNCH OF BEHAVIORS THAT ALL KIND OF GO TOGETHER. WELL, WE LEARNED, BY EXTENDING AND I'LL SHOW YOU A LITTLE DATA ON THIS, EXTENDING JOE'S IDEAS THROUGH IMAGING IS ONE /WAEWAY WE CAN PARSE THESE DIFFERENT BEHAVIORS IS WE CAN SEPARATE THEM INTO ACTIONS. AND THESE ARE SLOWLY DEPLOYED RESPONSES. AND AGAIN I AM GOING TO GIVE YOU AN EXAMPLE WHEN WE START TALKING ABOUT HITTING A BASEBALL. THAT'S A GOOD CLINICAL EXAMPLE. THESE ARE SLOWLY DEPLOYED THINGS THAT WE CAN DESCRIBE VERSUS REACTIONS, WHICH ARE THESE VERY RAPID PERTURBATION S S IN ATTENTION ATTENTION. THESE HAVE DIFFERENT /KEURBGTS /* CIRCUITS AND WE CAN START THINKING ABOUT THEM FROM THIS PERCESPECTIVE. THE KEY THING TO KNOW ABOUT THIS IS THAT WHEN WE STUDY THE UNDER UNDERLYING BRAIN CIRCUMSTANLATORY, WE CAN TEASE APART THESE DIFFERENCE DIFFERENCES. AND WE FIND THAT THE DIFFERENCES IN TERMS OF HOW THEY RELATE TO ANXIOUS BEHAVIOR OUT IN THE WORLD RELATE TO THE WAY IN WHICH A CIRCUIT THAT CONNECTS THE A A/PHEUG /TKEMYGDALA AND THE VENN TRILATERA L PART OF THE PREPHENOMENAL CORTEX AND WE THINK THAT THAT IS PART OF THIS FEAR REACTION THAT GOES WRONG. IN PEOPLE WHO ARE ANXIOUS. WE'VE BEEN STUDYING THIS FOR ABOUT, OH, A GOOD TEN YEARS /TIN MY GROUP AND WE'VE COME UP WITH BETTER AND BETTER IDEAS ABOUT HOW /TO STUDY THIS. IN THE INTEREST OF TIME I AM NOT GOING TO GO OVER /THE DETAILS OF THIS, EXCEPT TO SAY THAT THROUGH THE NEWUROSCIENCE WE LEARNED THAT THE UNDERLYING NEWUROCIRCUMSTANCLATORY OF THESE RAPID REACTIONS ARE UNIQUE AND DISTINCT RELATIVE TO OTHER KINDS OF ACTIONS THAT WE THINK ABOUT THAT ARE DEPLOYED MORE SLOWLY. SO HOW DO WE USE THIS TO DESIGN AN INTERVENTION SO, THE MAIN THING TO KNOW HERE IS THAT THESE REACTIONS THAT WE'RE TALKING ABOUT HAPPEN SO RAPIDLY THAT PEOPLE ARE NOT AWARE OF THEIR TENDENCY TO HAVE THESE REACTIONS REACTIONS. SO IF WE WANT TO START BY JUST TALKING TO PEOPLE ABOUT CHANGING THEIR BEHAVIOR, THAT'S NOT A GREAT WAY TO START. WE NEED TO START THINKING ABOUT DOING OTHER THINGS. AND IN PARTICULAR, WE NEED TO USE WHAT WE KNOW ABOUT HOW WE CHANGE OTHER RAPIDLY DEPLOYED BEHAVIORS. AND AGAIN, I'LL TALK ABOUT SOME EXAMPLES IN A MINUTE. BUT WE KNOW THAT PRACTICING A VERY SPECIFIC RAPIDLY DEPLOYED BEHAVIOR OVER AND OVER AND OVER AGAIN, THAT'S HOW WE CHANGE THOSE KINDS /OF BEHAVIORS. SO, ABOUT TEN YEARS AGO, THIS NOVEL TREATMENT WAS DEVELOPED THAT TRIED TO DO EXACTLY WHAT I AM TALKING ABOUT. AND WHAT IT DOES. IT USES THE EXACT SAME TASKS THAT WE'VE BEEN STUDYING IN MY GROUP FOR 20 YEARS NOW, AND WHAT IT DOES IS IT ALWAYS PUTS THE TARGET THAT THE INDIVIDUAL HAS TO FIND, FUR TRYING TO SHAPE ATTENTION AWAY FROM A THREAT. IT ALWAYS PUTS THE TARGET BEHIND THE NEUTRAL, RATHER THAN THE THREATENING FACE AND WHAT HAPPENS. IF YOU SUPPOSE /* /SPOEXPOSE CHILDREN OR ADULTS TO THIS TRAINING REGIMEN OVER AND OVER AGAIN, PEOPLE DEVELOP A DIFFERENT REFLEX THAT, WHENEVER THEY SEE THIS ANGRY FACE, THEY SHIFT THEIR ATTENTION OVER HERE, AND THEY LEARN TO AVOID, TO HAVE AN AVOIDING REACTION. AND THIS IS VERY DIFFERENT FROM AVOIDING ACTION. THEY'RE NOT PLANNING TO DO THIS. IT'S LIKE A REFLEX. AND YOU KNOW, I AM GOING TO TRY TO THREAD A NEEDLE HERE /TO SAY THAT THE RAND /O*OMIZED CONTROLLED TRIALS OF THIS THERAPY ARE PROMISING. THEY'RE NOT GREAT, AND WE HAVE A LOT MORE WORK TO DO AND THERE ARE PROBLEMS WITH THIS TASK. BUT THIS IDEA OF SEPARATING REACTIONS AND ACTIONS IS A VERY FRUITFUL WAY TO GO. THAT AGAIN COMES OUT OF THE NEWUROSCIENCE. AND ONE OF THE REASONS I HEZ HESITATE A LITTLE BIT WHEN I TALK ABOUT THIS IS THE MORE RESEARCH THAT WE'RE DOING, THE EFFECT VISE GETTING MOTHERLY AND SMALLER. AND THERE IS A LOT MORE TO SAY ABOUT THAT, BUT PART OF THE PROBLEM IS THAT THE METHODS THAT WE HAVE FOR CHANGE IN REACTIONS ARE NOT VERY GOOD, THERE ARE A COUPLE /OF THINGS THAT WE'RE TRYING TO DO /TO IM/PROFPROVE THEM. AND AGAIN, BAR HAIM IS REALLY ONE OF THE LEADER AT /THIS. SO ONE THING THAT WE'RE DOING IS WE'RE TRYING TO PAY ATTENTION TO THE KIND OF ABNORMAL REACTION PEOPLE HAVE AND TAILORED A TRAINING TOWARDS THAT. SO I MENTIONED THAT FINDINGS IN PTSD ARE DIFFERENT. PEOPLE WITH PTSD TEND TO HAVE THE OPPOSITE PROBLEM WITH THEIR REACTION THAN PEOPLE WITH OTHER KINDS /OF ANXIOUETY DISORDERS. PEOPLE WITH ANXIOETY DISORDERS TEND TO HAVE A BIAS TOWARDS THREAT. PEOPLE WITH PTSD TEND TO HAVE A BIAS AWAY. SO HE DEVELOPED THE IDEA THAT IN PTSD, PARTICULARLY WHEN INDIVIDUALS ARE ACUTELY EXPOSED, WE SHOULD DO THE OPPOSITE THING. WE SHOULD TRAIN PEOPLE TO MONITOR THREATS SO THE THING THAT WE WOULD THINK WOULD HARM AN INDIVIDUAL WITH AN ANXIOETY DISORDER, WOULD ACTUALLY HELP SOMEBODY WITH PTSD. AND THIS TURNS OUT TO MAYBE BE TRUE. THIS IS VERY, VERY DIFFERENT FROM THINGS LIKE COG /TPHENITIVE BEHAVIORAL THERAPY OR S /S-FPSRIS, WHERE WE REALLY DON'T THINK THEY ACT FUNDAMENTALLY DIFFERENTLY IN TRAUMA-RELATED AND NON-TRAUMA NON-TRAUMA-RELATED KINDS /OF ANXIOETY. AND HE WENT SO /TPFAR TO CONVINCE THE ISRAELI DEFENSE FORCE TO DO A PRESTIVE TRIAL OF THIS TREATMENT BEFORE THE WAR TWO YEARS AGO. PREVENTIVE. AND HE AND I WOULD DISAGREE ON HOW STRONG THE EVIDENCE WAS, BUT THERE WAS SOME EVIDENCE THAT THIS ACTUALLY REDUCED THE RISK OF PTSD TO THE POINT WHERE -- AND AGAIN I DON'T DISAGREE WITH THIS, BUT IT IS OPEN FOR DEBATE -- WHERE NOW IN THE ISRAELI ARMY ARMY, ALL SOLDIERS BEFORE THEY GO INTO COMBAT, GET THIS SAME TRAINING. THE TRAINING THAT WE THINK WOULD MAKE ANXIOETY PATIENTS WORSE, THAT IT PROTECTS AGAINST PTSD. SO THAT'S ONE THING THAT WE CAN DO DIFFERENTLY. THE OTHER THING IS WE CAN COME UP WITH BETTER MEASURES AND BETTER TRAINING. AND AGAIN, THIS IS HIS WORK. JUST CAME OUT FRIDAY. AND AS /I MENTIONED, THERE ARE ALL KIND OF PROBLEMS WITH THE PROBE TASK THAT I AM NOT GOING TO DWELL ON. BUT THIS MEASURE SOLVES MANY OF THOSE PROBLEMS. AND SO THE WAY THE MEASURE WORKS IS THAT INDIVIDUALS ARE ASKED TO JUST LOOK AT /THIS ARRAY OF FACES AND WHAT WE FIND IS AS YOU WOULD THINK, ANXIOUS PATIENTS, MUCH LIKE THEIR ATTENTION IS CAPTURED BY THREAT, ANXIOUS PATIENTS ATTEND /* TEND TO LOOK AT THESE ANGRY FACES MORE AND LONGER THAN NON-ANXIOUS PATIENTS. THEY TEND NOT TO LOOK AT THE ANGRY FACES AS MUCH. SO WHAT HE DID WAS HE HAD PATIENTS COME IN TO /THE LAB AND HE HAD THEM BRING IN MUSIC OR SELECT MUSIC THEY LIKED BE AND THEN WHAT HE DID IS HE HAD SUBJECTS, WHILE THEY WERE LOOKING AT THESE ARRAYS OF FACES FACES, THEY WERE PLAYING THE SUBJECT'S FAVORITE SONG IN THE BACKGROUND. AND WHAT HAPPENED IN THE ACTIVE GROUP IS THAT WHENEVER INDIVIDUALS WOULD LOOK AT THESE ANGRY FACES, THE MUSIC WOULD STOP. NOW THERE WAS A CONTROLLED GROUP WHAT WOULD HAPPEN INTHE CONTROLLED GROUP IS WE WOULD USE TIMING FROM SOME OF THE OTHER SUBJECTS SO THAT THEY GOT THE EXACT SAME EXPOSURES IN TERMS OF DURATION. BUT IT WAS TOTALLY UNLINKED TO WHERE SUBJECTS WERE LOOKING. AND THERE ARE A COUPLE THINGS TO SAY ABOUT THIS. ONE IS THAT THERE WAS A MUCH BIGGER EFFECT IN TERMS OF THE CHANGE IN THE ATTENTION MEASURE JUST SEE THIS HERE. YOU CAN DRIVE A TRUCK THROUGH IT HOW BIG IT WAS. AND THERE WAS ALSO A STRONGER CLINICAL EFFECT. THE? SO AGAIN, I THINK IT'S A GOOD PLACE TO START, AND THERE YOU GO SEE THE CLINICAL EFFECT THAT EN ENDURED OVER SIX MONTHS. THE CLINICAL EFFECT THAT YOU CAN SEE THERE IN REALLY ALL THE MEASURES. ALL RIGHT, SO THIS IS THE WAY I THINK ABOUT IT AS /I MENTIONEDED. THE WHOLE LONG STORY THAT I TELL ABOUT THIS. FOR TIME I AM NOT GOING TO TELL IT, EXCEPT TO SAY THAT REALLY HITTING A BASEBALL AND TED WILLIAMS MADE THE POINT IT'S LIKE DRIVING A CAR. IT HAS TWO COMPONENTS AND HE WOULD TEACH ALL OF HIS COMPARES /* PLAYERS DERB DIDN'T VALCALL THEM ACTIONS BUT HE /SAESAID BEFORE YOU WENT TO BAT, YOU NEED TO STUDY YOUR HITTING TENDENCIES JUST NEEDED TO ARRANGE ALL THE PITCHES THAT YOU WOULD SEE AND YOU NEED TO FIGURE OUT WHAT ARE YOUR BEST PITCHES. SO TED WILLIAMS FIGURED OUT THAT THAT WAS HIS BEST PITCH. SO HE SPENT A LOT /OF TIME SLOWLY LEARNING THAT. SO WHEN HE WOULD THINK ABOUT HIS NEXT AT-BAT HE WOULD SAY PARTICULARLY IF I DON'T HAVE ANY STRIKES, I ONLY WANT /TO SWING AT A PITCH RIGHT THERE. SO WE CAN THINK OF THAT, IF YOU ARE DRIVING CAR, IT'S LIKE LEARNING THE RULES OF THE ROAD. OR IF YOU'RE SOMEBODY WHO IS ANXIOUS, LIKE ME, WHAT WE TELL OUR PATIENTS IS IF YOU'RE STARTING TO FEEL YOURSELF GET ANXIOUS, HAVE A SAFE PERSON. SO MELISSA IS MY SAFE PERSON. I'LL LOOK AT MELISSA. THESE ARE ALL SLOW, DELIBERATIVE THINGS THAT WE DEPLOY AND THINK ABOUT VERY SLOWLY. THE THING TO HAT TED WILLIAMS SAID ABOUT HITTING THE BASEBALL IS THAT ONLY PART OF THE STORY. WE ALSO HAVE TO PRACTICE SWING SWINGING THE BAT OVER AND OVER AND OVER AGAIN. BECAUSE ONCE A PITCHER GOES INTO HIS WIND-UP, ALL THE THOUGHT ABOUT THIS GOES OUT THE DOOR, ALL RIGHT? IT'S ONLY THE PERSON WHO HAS SWUNG THE BAT A THOUSAND TIMES WHO REALLY IS A GOOD SHIRT AND THAT'S WHY WE DON'T LET KIDS JUST GO OUT AND START DRIVING A CAR THE FIRST TIME WHEN THEY LEARN THE RULES OF THE ROAD. THEY HAVE TO PRACTICE THIS ANOAF AND OVER AGAIN. WE THINK IT'S THE SAME WAY WITH THIS ATTENTION REACTION. WE THINK IT ACTS ON A DIFFERENT PART OF THE BRAIN THAN CD T DOES DOES. AND WE THINK, BY COMBINING THE TWO, WE THINK WE'RE GOING TO GET BETTER TREATMENT. HITTER. ALL RIGHT, LAST THING IN 3 MINUTES. MAKE A COUPLE POINTS. SO THIS IS REALLY THE PIECE OF RESISTANCE WHERE WE PUT IT ALL TOGETHER AND START DIRECTLY MEASURING THE BRAIN TO TEST OU SOME OF THE THESE IDEAS. AND SO REALLY AGAIN COMING BACK TO THIS TED WILLIAMS IDEA THAT CAN WE LOOK AT A TREATMENT WHERE WE BOTH TEACH KIDS THE STRIKE ZONE AND HAVE THEM SWING THE BAT OVER AND OVER AGAIN AND DOES THAT ACTUALLY WORK BETTER THAN YOU KNOW, NOT DOING THAT? SO THE CIRCUIT THAT WE'RE LOOKING AT IS /THE ONE THAT CONNECTS THE A/PHEUG /TKEMYGDALA TO THE IN IN/SSULA AND THIS IS OUR MOST CONSISTENT FINDING. AND YOU CAN SEE IT RIGHT HERE THAT PATIENTS HAVE A STRONG DIFFERENCE FROM HEALTHY SUBJECTS IN THE FUNCTIONING OF THIS CIRCUIT AND WE THINK AGAIN THIS IS A REFLECTION OF THIS DEFENSIVE REACTION, ALL RIGHT? AND SO WE'RE GOING TO TAKE THESE PATIENTS -- THIS IS HALF PATIENTS, HALF HEALTHY SUBJECTS. BUT WE'RE GOING TO TAKE THE /SKPAEURBGTS GIVE THEM ALL CB T. SO EVERYBODY'S GOING TO LEARN THE RULES OF THE ROAD AND THE STRIKE ZONE. HALF OF THEM ARE GOING TO GET THE ACTIVE BATTING PRACTICE, THE ACTIVE SWINGING THE BAT, THE ACTIVE AB AND T AND HALF THEM ARE GOING TO GET A PLACEBO AB AND T. SO WE'RE GOING TO PLAY THE SAME GAME BUT WE'RE NOT GOING TO CHANGE THE LOCATION OF THE THREATS. ALL RIGHT, THE LOT/PWOPLBOTTOM LINE AND THIS IS IN 85 SUBJECTS -- THERE IS A SIGNIFICANTLY BETTER RESPONSE TO THE INDIVIDUALS WHO GOT C /PW-FPB T WITH THE ACTIVE ABT VERSUS THE PLACEBO. IT'S NOT A HUGE RESPONSE. IT IS STATISTICALLY SIGNIFICANT. AND IF YOU COMPARED THE MAG MAGNITUDE OF THE EFFECT, IT IS COMPARABLE TO THE EFFECT OF ADDING AN S /S-FPSRI TO C /PW-FPLB T. THAT'S HOW I WOULD THINK ABOUT IT. IT'S NOT A GREAT ATTENTION TRAINING, BUT AGAIN AGAIN I THINK IT'S REALLY PROMISING. MORE IMPORTANTLY, WE SEE THAT IN THIS SAME REGIONWE SEE THIS INDIVIDUAL DIFFERENCE, WE SEE THATOVER ALL-THERE IS THIS ASSOCIATION BETWEEN THE WORSE THEIR ABNORMALITY AT BASE LINE, THE WORST THEIR TREATMENT RESPONSE, BUT THE MOST EXCITING THING ABOUT IT IS IT'S SELECTIVE IN ONE OF THE ABMT GROUPS. SO THIS INCLUDES ALL 50OD INDIVIDUALS, HALF OF WHOM GOT ACTIVE. HALF OF WHOM GOT PLACEBO. THIS IS ENTIRELY DRIVEN BY THE RESPONSE IN ONE GROUP. ALL RIGHT? SO THE IDEA IS -- AND AGAIN, I WOULDN'T USE THESE MEASURES BECAUSE I THINK THEY'RE NOT GOOD ENOUGH YET. BUT EVENTUALLY WE ARE GOING TO HAVE A MEASURE THAT WE ARE GOING TO BE ABLE TO USE PRIOR TO TREATMENT TO STEER INDIVIDUALS INTO COMBINATIONS OF THESE KIND OF TREATMENT. ALL RIGHT. THE /HRALAST THING TO SAY IS -- ANOTHER THING THAT OTHER COLLABORATORS ARE STARTING TO DO DO. WE NOW ALSO KNOW HOW /TO DIRECTLY STIMULATE THE CIRCUIT, THE BRAIN CIRCUIT. AND AGAIN NOT IN MY GROUP, BUT COLLABORATORS ARE ACTIVELY DOING THE EXACT SAME ABMT THAT I DESCRIBED HERE. AND USING BRAIN STIMULATION TECHNIQUES AND SHOWING THAT YOU CAN IM/PROPROVE THE ROBUSTNESS OF THE TRAINING BY DOING THAT KIND OF MANIPULATION. SO AGAIN I THINK THE THING -- MAIN THING TO PULL BACK /SAND MAYBE TURN ON THE LIGHTS AND ASK SARAH TO COME UP -- THE MAIN THING IS TO GIVE YOU A CONCRETE I WILL /STHRAOEUFGS WE REALLY NEED TO WORK TOGETHER WITH BOTH ANXIOETY CLINICAL CONSTRUCTS, AS WELL AS NEWUROSCIENCE-BASED CONSTRUCTS. THAT'S REALLY THE WAY THAT WE GO FORWARD. AND HOPEFULLY THERE WILL BE QUESTIONS, BOTH FOR ME AND SARAH ABOUT THAT. AND I AM JUST GOING TO CALL ATTENTION TO DISH CONSTANTLY HAVE TO UPDATE THIS SLIDE. BUT IN PARTICULAR, ALL OF OUR WORK ON ATTENTION REALLY INVOLVESIA HEIR AND ELLEN, WHO DOES -- THERE IS A LOT /OF BAD I DO THAT DOESN'T INVOLVE ELLEN BUT THERE IS NOTHING GOOD THAT I DO THAT DOESN'T INVOLVE ELLEN. SO I THANK FOR EVERYBODY THEIR ATTENTION. I THINK WE HAVE A GOOD FIVE MINUTES. /PHRA [APPLAUSE] JUDI? >> HI. THANK YOU BOTH FOR THE TALK. IT'S ALWAYS I /HRAOULUM NATING. WHAT'S INTERESTING TO ME IS THAT THE HELPFUL INITIAL DESCRIPTION OF R DOCS LEFT OUT WHAT AN EARLIER PRESENTATION HAS INCLUDEED AND NEED TO HAVE A BIO BIOMARKER AS PART OF THE DEFINITION. AND I WASN'T SURE IF THAT WAS JUST YOUR -- I HAVE FOUR THINGS TO SAY. SO I HOPE YOU CAN REMEMBER. BUT CERTAINLY SEEMED REASONABLE. AS SOMEONE WHO HAS BEEN IN THE FIELD MORE YEARS THAN I WILL PUBLICLY ADMIT, REALLY MY OVEROF OVEROFALL REACTION IS WHAT'S THE PART THAT'S NEW? SINCE THE EARLY 50'S, EXTRAMURAL NIMH HAS OFTEN BEEN DOMINATED BY PSYCHOLOGISTS, THERE BEING MORE OF THEM, ALWAYS MUCH BETTER TRAINED IN METHODOLOGY. AND FROM THE VERY BEGINNING, I STARTED MY EXTRAMURAL GRANTS BEFORE I END UP MORE HAPPILY HERE WITH GETTING A LOT /OF GOOD ADVICE FROM PROGRAM MANAGERS. AND VERY FIRST THING THEY SAID WAS "SCREEN ALL YOUR CASE POPULATIONS OF CHILDREN." BROADLY. AND THEY HAD CHECKLISTS, USUALLY 90 TO 100 OF CHECKLISTS. THEY ARE DOWN TO MORE POPULAR. AND THEY HAVE CLUSTERS OF SYMPTOMS IN EACH OF THE CATEGORIES THAT YOU SO WELL SHOWED. AND BY SYMPTOM COUNTS YOU COULD SHOW THAT CO-MORBIDITY WAS HUGE NO MATTER WHO YOU WERE STUDYING. WHAT WE DIDN'T HAVE WAS GREAT COMPUTER ACCESS BUT IT WAS CLEAR THAT ANYONE IN YOUR CLINIC WAS AT LEAST SUBCLINICAL IN OTHER WAYS IN /AA MORE /STPEUFSOPHISTICATED WAY WAY, THE OTHER SCIENTIFIC FIELD, OTHER THAN PSYCHOFARPHARMACOLOGY THAT'S DRIVEN PSYCHIATRY SO WELL WELL, HAS BEEN EPIDEMIOLOGY. AND THERE WE HAVE HUNDREDS, IF NOT THOUSAND /S OF PAPERS WITH DIMENSIONAL MEASURES ON MEASURES AND CONTINUOUS, AS WELL AS DICHOTOMOUS APPROACHES. SO I SUPPOSE WHAT'S UNFAIR TO BOTH OF YOU IS NEITHER OF YOU STARTED /EPBGT /PREPBGTD R DOCS TO THE WORLD. BUT I WOULD SAY THAT PERHAPS THE BIGGEST CRITICISM THAT I WOULD HAVE HAD MORE TO DO WITH THE PRESENTATION. BECAUSE YOU WOULD HAVE MANY LIFETIMES OF DATA SITTING THERE FROM EVERY GRANT /THAEFR GOT FUNDED. EVEN IN THE GOOD DAYS YOU WOULDN'T DO A GRANT WITHOUT ALL OF THESE ITEMS I RECOMMENDED. SO THERE IS ALMOST NO SUCCESSFUL GRANT THAT GOT FUNDED THAT SOME SOMEWHERE PROBABLY DUNT HAVE ALL OF THIS. I ENJOYED BOTH PRESENTATIONS, AND THANK YOU VERY MUCH. THIS IS NOT MEANT TO BE /AA CRITICISM OF EITHER PRESENTATION PRESENTATION. >> I'M HAPPY TO -- >> GO AHEAD. >> YOU FOE, I WOULD SAY A COUPLE THINGS. FIRST OF ALL /SKWR-RB, I WOULD -- THE FIRST THING I WOULD SAY IS I THINK EVERYBODY DOES AGREE THAT THE FIELD IS KIND OF STOCK, AND SARAH TALKED ABOUT THAT. AND I DO THINK THE BIG QUESTION IS EMPHASIS. AND I THINK WHAT HAPPENED WITH R DOC -- AND WE CAN DEBATE THE PARTICULARS ABOUT EXACTLY HOW IT WAS ROLLED OUT -- BUT I THINK A LOT /OF PEOPLE FELT THAT NIMH, AS A FUNDING AGENCY, WAS NOT PUTTING ENOUGH EMPHASIS ON CHANGING WHAT WE WERE DOING. NOW, YOU KNOW, YOU CAN ARGUE ABOUT HOW THAT WAS HANDLED, BUT I THINK THE GOAL WAS TO EMPHASIZE NEWUROSCIENCE MORE. I THINK -- IS THAT FAIR? >> HMM-HMM. >> SO WHAT'S THAT THE -- THAT'S WHAT THE BIG DEAL WAS. AND PLENTY ENOUGH? THE LEADERSHIP DIDN'T THINK SO. >> AND THE NEW TREATMENTS THAT CAME OUT. THEY ARE LIMITED. THE DEEP BRAIN STIMULATION, WHICH HAS BEEN THE NEW THING GENERATED BY NEWUROSCIENCE CAME FROM CIRCUITRY. THAT WAS CONTINUOUS AND MEASURED MEASURED. AND I THINK THEY CERTAINLY DID THAT. I ALSO THINK THAT IN SOME WAYS TOM'S FAMOUS SLIDE WHERE HE SHOWS HOW MANY DRUGS USED TO BE AND THERE ARE ALMOST NONE. IF SHE HE HAD PICKED THE TOP MEDICAL FIELDS, THEY DON'T LOOK SO DIFFERENT AND THERE IS HOURS OF DISCUSSIONS ABOUT WHY THAT IS IS. >> I DON'T WANT /TO -- HE WAITED TO PATIENTLY. I'M SORRY, JUDY. I DO WANT /TO HEAR YOUR QUESTION. >> JUST /AA BRIEF BRENT /* COMMENT. YOU TALKED ABOUT IN TERMS OF YOUR NEW CLASSIFICATIONS IN TERMS OF ENVIRONMENTAL. AND I THINK ONE THING YOU MISSED ON WAS THE ZIKA CRISIS BROUGHT TO THE ATTENTION THE MATERNAL AFFECTION OF CELLS THAT CAN ACROSS /* CROSS THE PLACENTA AND AFFECT THE SPECTRUM KNOWN AS AUTISM DISORDERS AT /TTHIS POINT IN TIME. IF YOU MEASURED THE CIYTOKINES AND KNEW EXACTLY WHAT CORRELATED A LOT /OF THIS INFORMATION WITH THE MATERNAL IMMUNOLODGGICAL PROFILE, YOU WOULD COULD PROBABLY RE REDUCE THE HETEROGENEITY OF THE AUTISM CASE THAT'S THAT YOU ARE TREATING AND SAY OH, MY GOSH. THIS MOTHER HAD THIS AND THIS AUTISM IS THIS. NOW THIS DRUG IS GOING TO BE SPECIFICALLY FOR THIS, WHICH GOES INTO THE GENOMIC MEDICINE. ONE OTHER COMMENT, WHEN YOU ARE TALKING ABOUT BIOMARKERS, YOU DIDN'T SPECIFICALLY SAY. YOU TALKED ABOUT /SWAOEUTD ONE POINT, AND /AI ASSUME THAT'S GOING TO GO INTO YOUR CLASSIFICATION IN TERMS OF WHAT PATIENTS HAVE A RISK OF SUICIDE. IT'S IMPORTANT TO KNOWS THAT THOSE OF US WHO PRACTICE FORENSICS ARE TRYING TO FIGURE OUT IF SOMETHING IS SUICIDE OR NOT, THERE'S A CKAPPA, WHICH IS A STATISTIC MEANING THERE IS AN INTEROBSERVER VARIABILITY THAT ISN'T ALWAYS GOING TO BE THERE. MOST PEOPLE CONSIDER DEPTH THE BEST MARKER. BUT A SUICIDE IS DECLARED BY A MEDICAL EXAMINER, WHO IS 50 /STAESTEPS AWAY FROM THE PSYCHIATRIST IS NOT GOING TO BE YOUR GOLD STANDARD, I DON'T THINK. THANK YOU. >> TWO THINGS ABOUT THAT. ACTUALLY THREE. THE NUMBERS I SHOWED ABOUT THE DISABILITY LIFE YEARS ACTUALLY PROBABLY UNDERESTIMATE THE /PRE PREMATURE MORTALITY BECAUSE OFTEN SUICIDE IS CLASSIFIED AS AN ACCIDENTAL OR SELF-INFLICTED INJURY THAT DOESN'T COUNT IN THOSE DATA AS /AEA MENTAL DISORDER. AND THEN YOUR POINT -- I CAN SAY A WORD ABOUT BIOMARKERS. IT'S KIND OF /AA TROUBLING TERM. IT'S A WORD WE'VE THROWN AROUND A LOT IN THE LAST TEN, 20 YEARS. BIOMARKERS FOR WHAT? SO BIOMARKER OF TREATMENT RESPONSE? BIOMARKER OF DISEASE? SO I THINK R DOC WOULD ASK US TO QUESTION HOW WE'RE USING THAT TERMINOLOGY OF BIOMARKER. AND THEN ONE LAST THING ABOUT THE -- YOUR FIRST POINT. THAT'S FULLY CONSISTENT WITH DECADES OF RESEARCH ON -- FROM EPIDEMIOLOGY AND VIRAL LOAD AS IT RELATES TO SIGH /KOPSYCHOSIS RISK, FOR EXAMPLE. BUT I THINK WE WOULD MOVE THAT RESEARCH ALONG IF WE THOUGHT DIFFERENTLY ABOUT WHAT WE WERE TRYING TO EXPLAIN USING THOSE KINDS OF APPROACHES. AND WE'RE CERTAINLY SEEING A LOT OF INTEREST IN THOSE KIND OF MEASURES COMING INTO THE EXTRA MURAL PROGRAM. >> THANK YOU. >> SURE THING. I HAVE SEEN A BIG HOOK COMING OUT. SO THANK EVERYBODY FOR THEIR ATTENTION. AND WE'LL BE DOWN HERE FOR /AA FEW MINUTES, IF PEOPLE HAVE OTHER QUESTIONS. /PHRA [APPLAUSE]