>>GOOD MORNING >>WELL, THANK YOU VERY MUCH FOR THE INVITATION TO SPEAK TODAY. I AM REALLY HAPPY TO BE HERE AT SUCH A WONDERFUL VENUE. I WILL TALK TO YOU TODAY ABOUT THE WORK WE'VE BEEN DOING FOR THE LAST 2 CAREERS, BUILDING UP TO SOMETHING I THINK WILL BE VERY EXCITING, FOR PRECISION DOSING, CUSTOM DOSING AND INVESTIGATE MECHANISM IMAGING, TRIAL DATA, SO, YOU'VE HEARD BY THIS POINT AT THE CONFERENCE ABOUT WHAT IS TDS, I DON'T HAVE TO LABOR THIS SLIDE. TDCS, SHOWS A LOT OF PROMISE, IT GENERATES 1-2-AMPS TO THE FIELD TO TISSUE, LOTS OF POTENTIAL APPLICATIONS, LOTS OF POTENTIAL PROMISE BUT I WILL ARGUE THAT THE FULL PROMISE OF THIS TECHNIQUE IS FAR FROM REALIZED AND THERE'S WORK WE CAN DO TO GET THERE SO WHAT ARE THE CHALLENGES PREVENTING US FROM REALIZING THIS PROMISE OF THIS TECHNIQUE? WELL LIKE ANY METHOD OF TREATMENT, INTERVENTION OR WHAT HAVE YOU, THERE'S VARIABILITY IN THE RESPONSE. NOW THAT IS TO BE EXPECTED. NOT ALL PHARMACEUTICALS ARE EFFECTIVE, NOT ALL BRAIN STIMULATORS ARE EFFECTIVE IN EVERY PERSON, FINE. BUT THERE ARE REASONS WHY IT'S NOT EFFECTIVE IN INDIVIDUALS AND WE NEED TO UNDERSTAND THAT BETTER. SOME OF THE KEY CHARACTERISTICS WE KNOW PLAY A ROLE IN THIS INVOLVE CURRENT DOSE. SO WE WOULD ARGUE THAT'S A KEY PLAYER. HOW MUCH CURRENT WE PUT INTO THE BRAIN AND WHERE WE PUT IT IN THE BRAIN HAS AN IMPACT ON THE EFFICACY ON THE STIMULATION OF THE TREATMENTS. YOU HEARD COMMENTS EARLIER IN THE CONFERENCE THAT ARE CHANGING THE FIELD REGARDING IN VIVO MEASURES WHICH ARE INCREDIBLY IMPORTANT TO PROGRESS AT PRESIDENT THOUGH, IT HAS BEEN FOR MRI DERIVED MODELS THAT CAN AT LEAST GIVE US A CLEAR ESTIMATE OF CURRENT AND CURRENT DELIVERY IN THE BRAIN, BUT I WOULD SAY, OUR BIGGEST CHALLENGE IN THIS FIELD THUS FAR IS THE CONTINUED RELIANCE ON A 1 DOSE FITS ALL MODEL MEANING THAT IN A PARTICULAR STUDY, PARTICIPANTS RECEIVED THE SAME DOSE ACROSS ALL PARTICIPANTS, 2 MILLI AMPS FOR A SPECIFIC LOITION, SPECIFIC AMOUNT OF TIME, ET CETERA. ET CETERA. NOW WERE WE TO TAKE YOUR FAVORITE BLOOD PRESSURE MEDICATION AND APPLY IT TO THE SAME DOSE IRRESPECTIVE OF THE SAME PERSON, YOU CAN IMAGINE HOW MUCH EFFICACY WOULD DECREASE, IF YOU DIDN'T TAKE INTO,A COUNT METABOLIC STATE, HEIGHT, WEIGHT, ET CETERA, ET CETERA. WELL IT URN ITS OUT WE CAN DO SOMETHING VERY SIMILAR TO THAT, USING IMAGING AND MODELING AND OTHER METHODS TO ATTEMPT TO CUSTOMIZE OUR DOSE, TAKE SOMETHING THAT'S DOSED OR NEAR PRECISELY DOSED AND IMAGINE THE DIFFERENCE IN EFFICACY, I THINK THOSE CAN BE QUITE BIG. WE DON'T KNOW YET BUT THAT'S THE WORK WE'RE TRYING TO ACHIEVE. NOW WHAT ARE SOME OF OUR BIGGEST PROBLEMS WE KNOW? WE KNOW THAT EVERY BRAIN IS UNIQUE, IT IS A FINGERPRINT. WHILE IT IS SIMILAR, IT IS SUBTLEY DIFFERENT, WE ALSO KNOW AS WE AGE BRAIN CHANGES IN WAYS THAT VERY WELL CLASSIFIED OVER THE LAST FEW DECADES. AT THIS BOTTOM, YOU CAN SEE A FIGURE EXTRACTED FROM 1 OF OUR PAPERS IN 2019 THAT RESTATES WHAT'S BEEN SHOWN SINCE THE ADVENT OF MRI, THAT THERE ARE CHANGES IN THE WHOLE BRAIN LEVEL, IN GRAY MATTER THAT HAPPEN OVER THE LIFE SPAN BUT AT THE WHOLE BRAIN LEVEL, WHITE MATTER IS A BIT MORE STABLE, YET IF YOU MOVE TO THE TOP OF THE SCREEN, YOU SEE HERE AN EXAMPLE OF THESE 3-CENTIMETER ROIs FROM ANTERIOR VERSUS POST ERIOR REGIONS, AND IF YOU LOOK OVER TO THE LEFT, YOU SEE VERY DIFFERENT PATTERNS OF CHANGE PARTICULARLY IN THE WHITE MATTER WHICH IS IN BLUE DEPENDING ON WHERE YOU ARE IN THE BRAIN. SO THIS MEANS THERE ARE REGION SPECIFIC DEFENSES IMPACTED BY AGE. AND WE'VE DONE STUDIES AND I WILL SHOW YOU THESE IN A FEW SLIDES, THAT DEMONSTRATE THE POTENTIAL IMPACT OF ATROPHY ALONE MUCH LESS INDIVIDUAL VARIABILITY OF OTHER LEVELS RELATIVE TO DIFFERENCES IN ADIPOSE TISSUE, DIFFERENCE IN SKULL THICKNESS, ET CETERA THAT CAN IMPACT HOW MUCH CURRENT REACHES THE BRAIN AND WHERE THAT CURRENT GOES. NOW HOW DO WE DERIVE THIS INFORMATION? I TALKED ABOUT THIS A BIT. THERE ARE NEWER MOTHERS FOR IN VIVO MEASUREMENT THAT ARE VERY EXCITING BUT OUR STANDARD HAS BEEN USING THESE FINITE ELEMENT COMPUTATIONAL MODELING, IN THIS CASE, T1 WEIGHTED IMAGES AND IN THE PAST, 15 YEARS AGO, THIS WAS NOT A VERY ACCESSIBLE TECHNIQUE BUT WITH THE ADVENT OF WONDERFUL OPEN ACCESS SOFTWARE LIKE SIM NIBS OR ROAST, THIS IS A MUCH MORE ACCESSIBLE TOOL FOR BASIC MODELING APPROACHES AND WITH THIS INCREASE IN ACCESSIBILITY, WE HAVE POTENTIAL FOR DOING INDIVIDUAL MODELS IN MUCH LARGER POPULATION, MUCH MORE QUICKLY THAN IN THE PAST WHERE A SINGLE BRAIN MIGHT TAKE 6 WEEKS FROM FROM AN EXPERT SEGMENTER TO GET A SINGLE MODEL WE CAN DO THESE IN MUCH, MUCH ISSUES FASTER TIMES WITHIN THE SAME DAY THAT THE PARTICIPANT COMES INTO THE CLINIC OR THE LAB. BUT FOR US MORE IMPORTANTLY THESE TYPES OF MODELS GIVE US INSIGHT INTO DIFFERENCES BETWEEN BRAINS WHICH WE THINK AS I SAID IS VERY IMPORTANT. NOW THIS IS A MASSIVE EVERYSIMPLIFICATION OF THE PIPELINE THAT INVOLVE SAYS T1 WEIGHTED IMAGE AT A MINIMUM, VOLUME MESSAGING, FINITE AND ESTIMATE OF CURRENT DENSITY DISTRIBUTION. THIS IS A STUDY THAT WAS LED BY A FORMER POST DOC IN MY LAB AND NOW A BRILLIANT POST DOC,OOSE A CITY FROM 587 OLDER ADULTS WITH IMAGES AND IMAGES FROM THE STUDY. THE GOAL WAS TO EVALUATE HOW AGE AND ATROPHY IMPACT CURRENT DENSITY DISTRIBUTION USING A FEW MODIFICATIONS, ANDLET MORE CLASSIC M1 SO MONTAGE IN THE LITERATURE. NOW TO THE EYE, YOU CAN SEE CHANGES AS WE MOVE THROUGH THE DECADES OF LIFE, THAT ARE EVEN OBVIOUS AT THIS POINT. BUT WHEN WE MOVE TO EVALUATE THESE AT A LARGER LEVEL, WE CAN ACTUALLY SEE THESE TRAJECTORIES OF CHANGE AND REALLY WHAT THIS FIGURE SHOWS, IS THAT AS BRAIN ATROPHY INCREASES, CURRENT DENSITY DELIVERED TO THE BRAIN DECREASES AND THE LARGE PART OF THAT IS AN INCREASED AMOUNT OF CSF WHICH DISTRIBUTES CURRENT VERY WELL ACROSS THE BRAIN BUT DISTRIBUTES IT IN A WAY TAKEN--THEY DILUTES THE OVERAWE DENSITY DELIVERED TO THE TISSUE IN ADDITION TO ITS DEPTH. SO THESE FACTORS ALONE CAN IMPACT. THERE'S ALSO SO MANY INDIVIDUAL VARIABILITY COMOPPOSITE BEHAVIORIAL PHENOTYPENTS AS I MENTIONED REGARDING ADIPOSE TISSUE, FATTY TISSUE ON THE HEAD AS WELL AS DIFFERENT TYPES OF BONE, CANC CELLUS AND NONCANCELUS, SO WE HAVE THESE DIFFERENT COMPONENTS. TURNS OUT OUT WE CAN ESTIMATE THOSE USING COMPUTATIONAL MODELS, AND IF WE CAN ESTIMATE THOSE THEN WE CAN ASK, THEY THEY PREDICT BEHAVIOR? CAN THEY PREDICT CHANGES IN THE BRAIN AND I'LL ARGUE THAT IF THEY CAN, THERE MAY BE VALUE IN PREDICTING OTHER COMPONENTS LIKE RESPONSE. SO LET'S DO A USE CASE AND IN A FORMER STUDY WE RAN AND A GRADUATE STUDENT OF MY NICONTROL NEESOME PUBLISHED IN 2019 INVOLVED A TDS STUDY LOOKING AT APPLICATIONS OF TDCS OVER F3 AND F4 AT 2 MILLI AMPS IN THE MRI ENVIRONMENT BEFORE, DURING AND--DURING ACTUAL PERFORMANCE OF A WORKING MEMORY TASK. AND WE MEASURED THIS WORKING MEMORY TASK FUNCTIONAL ACTIVATION, BEFORE, DURING AND AFTER EITHER ACTIVE STIMULATION OR SHAM STIMULATION WITH A 2 WEEK WASH OUT PERIOD. IN THIS, WHAT WE FOUND IN THAT PRIME STUDY IS AN INCREASE IN CONNECTIVITY FROM LEFT TO VLPC TO DURING STIMULATION VERSUS BEFORE OR AFTER DISP WHAT WE ASK IN THIS STUDY, AGAIN LED BY THE DOCTOR, IS WHETHER OR NOT WITH A HYPER SEGMENTED MODEL OF 10 TISSUE TYPES, THIS WAS ACTUALLY A HIGH FIDELITY MODELING APPROACH THAT IS OUTSIDE OF ROAST OR SIM NIB OR OTHER SOFTWARES USING MORE CLASSIC TECHNIQUES AND WHAT WE ATTEMPTED TO TO DO WAS TO CREATE THE BEST OVERALL MODEL POSSIBLE IN AN ATTEMPT TO PREDICT THOSE CURRENT, THOSE CHANGES IN BETA VALUES OR FUNCTIONAL CONNECTIVITY BETWEEN THESE 2 REGIONS IN THE SAMPLE AND HERE YOU CAN SEE WE WERE RABBLE TO ESTIMATE FROM THE MRIsS EXACT POSITIONING OF THE ELECTRODES, WE ACTUALLY THINK THESE SUBTLE DIFFERENCES AND ELECTRODE PLACEMENTS CAN PLAY A MAJOR ROLE IN OUR ABILITY TO ACCURATELY REDICT WHAT THE CURRENT IS DOING AND WHAT IT'S RELATED TO. AND THESE 15 PARTICIPANTS, YOU CAN SEE HERE OUR OVERALL ELECTRIC FIELD DISTRIBUTION. YOU CAN SEE TOLET EYE THE SOWBTLE DIFFERENCES BETWEEN EACH THESE INDIVIDUALS, HERE YOU GET THE CURRENT DENSITY DISTRIBUTION PATTERN AGAIN CROSS THESE 15 PARTICIPANTS EVEN TO THE EYE, YOU CAN SEE THESE ARE NOT 1 AND THE SAME. WHICH FOR A ONE-SIZE-FITS-ALL MODEL THEY NEED TO BE 1 AND THE SAME. BUT NOT SURPRISING THEY ARE IN FACT, DIFFERENT. MORE IMPORTANTLY I WILL ARGUE THESE APPROACHES CAN GIVE US INSIGHT INTEREST WHAT TACTUALLY IN THE BRAIN IS CHANGING THAT RELATES TO THE OVERALL BEHAVIORIAL OR OTHER CHANGES WE'RE MEASURING FROM TDCS, IN THIS CASE, TO BREAK DOWN THESE MEASURES VERY QUICKLY FOR THE SAKE OF TIME, WE FOUND THE CURRENT DENSITY IN THE LEFT DLPC, BUT NOT THE LEFT VLPC WERE SIGNIFICANTLY ASSOCIATED WITH THE BETA VALUE CHAIMPLES IN FUNCTIONAL CONNECTIVITY BETWEEN THESE 2 LOCATIONS MEANING THAT THE CURRENT DENSITY IN DLPFC WAS ASSOCIATED WITH CHANGE AND THIS APPEARS TO JUST BE DRIVING THE CHANGE FUNCTIONAL CONNECTIVITY OVERALL VERSUS CURRENT DENSITY IN THE VLPFC, WHICH IS EXCITING BUT MORE IMPORTANTLY FOR MY TALK, IT SHOWS THAT THESE VALUES CAN PREDICT CHANGES IN THE BRAIN AND WE'VE SHOWN SEPARATELY PREDICT CHANGES IN BEHAVIOR. SO THERE'S POTENTIAL VALUE HERE. NOW THIS IS WHERE WE INTRODUCED THE APPLICATION OF DIFFERENT AI APPROACHES. IN THIS CASE I WILL TALK ABOUT MACHINE LEARNING AND LATER I WILL TALK ABOUT SINGLE AND MULTIVARIANT GALSIAN FITTING USING OTHER APPROACHES BUT AT THE END OF THE DAY WE WENT IN A DIFFERENT DIRECTION FOR AI FOR A REASON AND WE'RE DEALING WITH A MULTIVARIANT DATA STRUCTURE THAT IS HYPER COMPLEX, YOU HAVE CURRENT DENSITY IN 3 DIMENSIONS, X, Y, Z SPECIAL WE HAVE DIRECTION AND INTENSITY OF CURRENT. THAT VECTOR INFORMATION IS COMPLEX, IT IS ALSO THROUGHOUT THE BRAIN AND WE HAVE A FOURTH DIMENSION OF INFORMATION WHICH IS TREATMENT RESPONSE. SO WHEN YOU HAVE HYPER COMPLEX DATA, STANDARD ANALYTICAL APPROACHES WORK FAIRLY POORLY. IN ADDITION, IN A CASE WHERE YOU UNDERSTAND MECHANISM FROM A DATA PROVIDING NOVEL INSIGHTS INTO THE OVERALL REASONS THAT THESE TREATMENT RESPONSES ARE THERE. AND SO WE CHOSE TO GO IN THIS DIRECTION EXPW TO DO THIS, WE TOOK AS PROOF OF PRINCIPLE DATA FROM ANOTHER 1 OF OUR RECENT TRIALS, WELL, RECENT AT THE TIME, 2019, AGAIN, THIS WAS A 28 PERSON COGNITIVE TRAINING TRIAL IN OLDER ADULTS WHERE THIS PILOT TRIAL LOOKED AT COGNITIVE TRAINING PAIRED WITH TDCS, OR SHAM FOR A 10 DAY PERIOD. WE MEASURED PREAND POST CHANGES IN WORKING MEMORY AND FUNCTIONAL ACTIVITY AND A VARIETY OF OTHER MEASURES. IN THIS CASE, WE SAW NICE CHANGE IN WORKING MEMORY PERFORMANCE ON A 2 BACK TARGET ACCURACY FOR 1 OF OUR OUTCOME TASKS AND FOR THIS WE THEN SEGMENTED EACH BRAIN INDIVIDUALLY ACROSS EACH SESSION AND PERFORMED THESE SAME BASIC ANALYTICS TO DERIVE THESE FINITE MODELS ACROSS ALL PARTICIPANTS THAT RECEIVE STIMULATION AND THEN APPLYING MACHINE LEARNING APPROACHES, SO IN THIS CASE, SUPPORT MACHINE VECTOR APPROACHES, WE TEND TO ASK THE QUESTION OF WHICH PATTERNS OF CURRENT DENSITY ACROSS THE PARTICIPANTS RECEIVING ACTIVE STIMULATION WERE MOST STRONGLY ASSOCIATED WITH TREATMENT RESPONSE SO CHANGE IN WORKING MEMORY PERFORMANCE AND SO WITH THIS, THESE AMALSIS PRODUCED A MODEL THAT OVERALL IN THE SMALL SAMPLE AND WE WERE USING 10 K FOLD ACROSS VALIDATION BECAUSE OF THE SMALL SAMPLE SIZE AND 86% RACKERACY AND AUC OF 80% BUT THAT'S NOT PERFECT BUT IN A SMALL SAMPLE SIZE THAT SHOWS PROMISE. WE NEED LARGER DATA TO REALLY DRIVE THROUGH, BUT IMPORTANTLY, THERE'S INFORMATION, IN ADDITION TO THE FACT THAT WE CAN REDICT FROM A T1 WEIGHTED IMAGE WHO RESPONDED TO TREATMENT VERSUS NOT, WE CAN ALSO GAIN INSIGHT INTO THESE REGIONS THAT WERE IDENTIFIED AS BEING THE BEST PREDICTORS OF TREATMENT RESPONSE VERSUS TREATMENT NONRESPONSE AND GAIN INSIGHT INTO WHAT'S HAPPENING OR WHAT'S BEING DELIVERED TO THOSE PARTICULAR REAMINGIONS. AND WHAT WE FIND WHEN WE INVESTIGATE THIS, IS THAT BY AND LARGE WHEN YOU LOOK AT THE RESPONDER PROFILE VERSUS NONRESPONDER PROFILE, THOSE ARE THE RESPONDERS IN THESE REGIONS THAT BEST PREDICTED TREATMENT RESPONSE, WE'RE SEEING MORE CURRENT WITHIN THESE REGIONS, THAN THE NONRESPONDERS. NOW THIS IS FROM A PAPER LED BY 1 OF MY GRADUATE STUDENTS IN A COLLABORATION ACROSS A LAB AND BY O MEDICAL ENGINEERING LED BY [INDISCERNIBLE] AND BY ME AND DR. [INDISCERNIBLE]. THIS ACTUALLY GAVE US SOME REALLY NICE INSIGHT INTO THESE CHARACTERISTICS, GREAT, WONDERFUL, MORE CURRENT IN THESE REGIONS IS BETTER. YEAH, PROTEIN COMPLEX NOT MORE SURPRISING BUT WE ALSO ARGUE THAT MORE CURRENT IS NOT NECESSARILY ALWAYS BETTER, IT'S JUST DIFFERENT AND WE NEED TO HAPPENED WHAT THE CURRENT IS DOING. NOW WHAT'S REALLY IMPORTANT IS WE KNOW WHERE IT WAS SUPPOSEDLY IMPORTANT AND WE KNOW HOW MUCH CURRENT IS SUPPOSEDLY IMPORTANT FOR TREATMENT RESPONSE IN THIS PARADIGM AND IF WE KNOW THOSE THINGS, WE'RE 1 STEP OFF FROM BEING ABLE TO DIVE INTO THESE DAT AND ARGUE THAT THERE ARE SPECIFIC REGIONS THAT WE SHOULD FOCUS ON STIMULATING AT A SPECIFIC LEVEL OF CURRENT, FOR A SPECIFIC DIRECTION OF FLOW OF CURRENT THROUGH THOSE BRAIN REGIONS. AND IN FACT, THAT'S THE PREMISE BEHIND THE OVERALL APPROACH. WE STARTED TO FOR YEARS AGO, OF TAKING TDCS, TRAINING DATA BUT THIS CAN BE ANY PARADIGM WE'RE LOOKING AT BEHAVIOR CHANGE OR TREATMENT RESPONSE WITH TDCS, ACQUIRING T1 WEIGHTED MRIs, FINDING ELEMENT MODELING, TRAINING A CLASSIFIER, TAKING THAT RESPONDER CLASSIFIER SOLUTION AND THEN ULTIMATELY FITTING IT INTO A NEW BRAIN, TO THEN DETERMINE A PRECISION DOSE OF SPECIFIC ELECTRODE LOCATIONS AND SPECIFIC ELECTRODE INTENSITY TO DELIVER TO TRY TO DELIVER THE TREATMENT RESPONDER PROFILE OF CURRENT INTO THIS NEW BRAIN WE HAVEN'T SEEN BEFORE. SO THIS OVERALL APPROACH LOOKS SOMETHING LIKE THIS. WE HAVE THESE MRIs FROM THESE DATA SETS, WE FIT THE BRAIN WITH AN FEM AND THEN IDENTIFY FROM OUR PRIOR TRAINING DATA THESE REGIONS OF SPECIFIC INTEREST WHERE WE NEED TO DELIVER A SPECIFIC AMOUNT OF CURRENT AND THEN WE PERFORM A SINGLE GALSIAN FITTING ACROSS THE BRAIN USING EVERY POSSIBLE COMP BINNATION OF CURRENT LOCATIONS AND INTENSITY DELIVERED TO IDENTIFY THE SPECIFIC MONTAGE AND INTENSITY SO DOSE THAT BEST MATCHES THE TREATMENT RESPONDER PROFILE. ON THE RIGHT YOU CAN SEE A GROUP LEVEL TREATMENT RESPONDER PROFILE THAT WE THEN ATTEMPT TO FIT INTO A NEW BRAIN. WE ARE USING THE SINGLE GALSIAN AND OTHER WORK IS USING MULTIGALSIAN APPROACHES FOR FITTING AND WE SPEEDING PROCESSING TIME FELT. IN THE EARLY DAYS IT WOULD TAKE SICK WEEKS TO FIT A BRAIN, NOW IT'S DOWN TO 6 MINUTES SO WE'VE HAD IMPROVEMENT ON THAT FRONT BECAUSE 6 WEEKS IS WAY TOO LONG TO WAIT. AT THE END OF THE DAY, THIS IS CASE DAILY BASIS THEA WHERE WE TOOK THE NONRESPONDERS FROM IT AND ATTEMPTED TO REFIT THE DATA TOI DENTIFY WHAT THE APPROPRIATE DOSE FOR RESPONDER CHARACTERISTICS AND THEN HERE YOU CAN SEE THE 95% CONFIDENCE LIMITS OF THE TREATMENT RESPONSE PROFILE, THESE ARE THE PRETREATMENT NONRESPONTDER, OR THESE ARE THE NONRESPONDERS BEFORE MODIFICATION TO THEIR DOSE AND THIS IS MOW MODIFIED DOSE. NOW THIS IS STILL THEORETICAL, WE HAVEN'T BROUGHT THESE BACK AND STIMULATED THEM TO TRY TO CHANGE THEIR BEHAVIOR, WE HAVE A COUPLE OF PILOT TRIALS GETTING OFF THE GROUND SO WE DEMONSTRATE THIS DIRECTLY IN TERMS OF POTENTIAL SUPERIOR EFFECTS FROM PRECISION DOSING. AT THIS POINT IT'S BEEN PRIMARILY COMPUTATIONAL IN NATURE, AND NOW WE'RE ATTEMPTING TO DETERMINE WHETHER THIS IS SPECIFICALLY GOING TO BE EFFECTIVE. IN ADDITION, THIS TECHNIQUE IS DRIVEN BY THE NEEDS FOR LARGE AMOUNTS OF DATA. THE MORE DATA WE CAN HAVE ON TREATMENT RESPONSE AND T1 WEIGHTED IMAGES TO TRAIN THESE CLASSIFIERS, THE BETTER WE CAN BE AT IDENTIFYING DOSE TO ACCURATELY LEAD TO BETTER PERFORMANCE AND WE RECENTLY COMPLETED THE AUGMENTIVE COGNITIVE TRAINING IN ADULTS, 3 IS A 379 PERSON TRIAL, IT SHOULD BE RF1, THIS IS THE RO-1 THAT FOUNDED THIS TRIAL AND WE ALSO HAVE AN RF1 TO DO SECONDARY DATA ANALYSIS AND CREATING COMPUTATIONAL ANALYSIS ON 11 DIFFERENT INDIVIDUALS AND 11 DIFFERENT TYPES OF HIGH DEFINITION MODELS AND THIS RF1 IS GEARED TOWARD DIVING AND RUNNING AND ALL THESE METHODS TO DERIVE DOSING BASED ON CHAISKTISTICS OF RESPONSE AND TREATMENTS IN THIS LARGE TRIAL WHICH WAS RECENTLY COMPLETED. IF THERE'S ANY OTHER TRIALS OF THIS TYPE WHETHER IT'S DEPRESSION, ANXIETY OR WHAT HAVE YOU, AS LONG AS THERE ARE TREATMENT AND OUTCOME DATA WE CAN WORK CAN WITH IT, TO DERIVE DOSING TO PUT BACK INTO THE COMMUNITY TO TRIEF THIS FIELD AWAY FROM ONE-SIZE-FITS-ALL TO BRAIN SPECIFIC, PERSON SPECIFIC MODELS. SO I WILL END THERE AND I WILL NOTE WE HAVE STWO NIH FUNDED POST DOC POSITIONS IN THE LAB AT PRESENT AND A RESEARCH SCIENTIST POSITION, THE RESEARCH SCIENTIST POSITION WILL BE RESPONSIBLE FOR MANAGEMENT OF TRIALS IN THE LAB. WE HAVE 4 NIH TRIALS, INDIVIDUALS WILL WORK WITH ME AND DR. [INDISCERNIBLE] ON A NUMBER OF INTERESTING THINGS. IF YOU KNOW PEOPLE INTERESTED SEND AN E-MAIL AND THANK YOU FOR YOUR TIME AND THE VERY MANY PEOPLE THAT MADE THESE STUDIES POSSIBLE AND ESPECIALLY OUR FUNDING AGENCY, THE NATIONAL INSTITUTE ON AGING. [ APPLAUSE ] >>THANK YOU VERY MUCH. WE HAVE TIME FOR PROBABLY 2-3 QUESTIONS. >> THANK YOU FOR A GREAT TALK AND GREAT WAY TO START THE DAY. WITH REGARD TO MACHINE LEARNING PORTION, I WAS CURIOUS WHAT YOUR NOTION OR MAYBE YOU HAVE DATA ON ITS EFFICACY WITH REGARD TO MORE VARIABLE BRAINS AND I HAVE IN MIND STROKE BRAIN, I CAN SEE WHERE THIS WOULD BE BETTER OR WORSE, SO I WOULD LIKE TO HEAR WHAT YOU THINK ABOUT THAT? >>GREAT QUESTION. WE'RE--THE REALITY IS THE MODELING APPROACH IS ONLY AS GOOD AS THE DATA WE PUT IN. STROKE HAS BEEN 1 OF THE MOST COMPLEX APPROACHES FOR US AND MOST DIFFICULT TO MODEL. THERE'S GREAT PEOPLE OUT THERE DOING WORK WHERE THEY'RE SHOWING REALLY NICE, VERY ACCURATE MODELS WITH STROKE. IN THIS CASE, IF WE CAN DERIVE THE ELEMENT MODEL THAT'S RELATIVELY ACCURATE TO GEF US, YOU KNOW PERSON BY PERSON DATA WE CAN APPLY THESE SAME TECHNIQUES BUT AS YOU'RE SUGGESTING, THE MORE NOISE YOU'RE CREATE IN THE SYSTEM, THE LESS EFFICACIOUS IT VERY LIKELY WILL BE, HOWEVER WE'VE BEEN WORKING SEPARATELY BOTH WITH VIDEO AND TEAMS WITH A DIFFERENT DIFFERENT LABS AT UF TO IMPROVE AND CREATE SOME VERY AUTOMATED APPROACHES FOR SEGMENTATION ACROSS HIGHLY VARIABLE BRAINS. NONAPOPTOTIC YOU WE'RE STARTING WITH THE SIMPLE 1S LIKE, YOU KNOW ACROSS THE LIFE SPAN OR WITH ALZHEIMER'S DISEASE WHERE YOU HAVE HYPER ATROPHY OR HIPPOCAMPUS SCLEROSIS, IN VARIOUS OTHER CHANGES AND REGIONS AND TRYING TO CREATE AN APPROACH THAT WILL ALLOW US TO OWG MENTORSHIP SKILL AND MODEL THAT DATA WITH VERY LITTLE INN PUT BUT ALSO DIRECTLY GENERATE FROM THE RAW DATA THESE JMAPS OR ELECTRIC FIELD MAPS BUT GET THAT IN SOMETHING COMPLEX AS STROKE WILL TAKE QUITE A BIT OF WORK. SO, YEAH, GREAT QUESTION. >>THANKS VERY INTERESTING TALK. I AM WONDERING, SO THERE'S A BIG DISCUSSION IN MACHINE LEARNING AND IF YOU GO APPROXIMATE THERE FROM HIGH DIMENSIONAL DATA YOU PREDICT A SINGLE OUTPUT. LOOKING AT THESE PARAMETER MAPS OR FEATURE MAPS IS NOT SIMPLE. THERE MIGHT BE CORRELATION TO INPUT DATA AND CERTAIN AREAS LIGHT UP JUST BECAUSE OF THOSE CORRELATIONS. SO I'M WONDERING, YOU DIDN'T SHOW THE DATA WHEN YOU BRING THE PEOPLE BACK IN WITH THE MONTAGES BUT IF YOU LOOK AT THOSE FEATURE MAPS YOU DO YOU SEE AREAS THAT LIGHT UP THAT MAKE SENSE YORE, YOU KNOW THEY REQUIRE SORT OF PATCHY THESE [INDISCERNIBLE] YOU'RE SHOWING? >>YEAH, WE SAW THAT MAP, I WAS LIKE OH GREAT, THIS LOOKS LIKE NOISE AND SO THEN WE LOOKED INSIDE OF THAT AND I THINK PART OF THE PROBLEM WE HAVE IS IT WAS A SMALL DATA SET OF THE ALSO WE'RE TRYING TO MOVE COGNITION IN THESE DATA SETS WHICH IS HYPER DISTRIBUTED AND PROBABLY THE HARDEST TEST CASE WE COULD POSSIBLY HAVE PICKED. IN CONTRAST, WE'VE BEEN WORKING WITH ANDRE OUT OF SAO P A OLO, AND WORKING WITH HIS UNIVERSITY AND DATA WITH DEPRESSION SO CLINICALLY DEPRESSED PATIENTS AND IN CONTRAST WE USED A SMALL SAMPLE OF HIS DATA WITH T1S AND THIS APPROACH AND IT ALMOST LOOKS LIKE AN FMRI OUTPUT WHAT WE'RE FIND FREE RADICALS GENERATED HIS DATA AND MAPPED ON TO DEPRESSION REALLY, REALLY WELL. IN THIS WE SHOULD PICK A TEST CASE VERSUS COGNITION, BUT I'M A COGNITIVE AGING GUY. SO YOU'RE EXACTLY RIGHT. WHAT WE'RE SEEING AS WE ADVANCE AND GET MORE DATA FROM TRIALS, WE ARE STARTING TO SEE THESE PATTERNS THAT LOOK MORE LIKE THE IMAGING PATTERNS WE WOULD EXPECT AND I SHOULD PROBABLY PICK SOMETHING OTHER THAN COGNITION TO STUDY ON THIS. >>I AM LOOKING FORWARD TO THE DATA WHEN YOU BRING IT BACK. >>YEAH, THANKS. >>HEY, ADAM, GREAT WORK. YOUR COGNITIVE TRAINING IS BEING DONE SIMULTANEOUS WITH THE APPLICATION FOR TDCS, IS THAT CORRECT? >>THAT IS CORRECT, THE FIRST TWEBT MENCHUTES OF TRAINING, THE FESTER 20 MACHINEUTES THEY RECEIVE STIMULATION AND THEN THEY CONTINUE DOING TRAINING AFTER 20 MINUTES OF STIMULATION. >>GREAT. SO MY QUESTION IS YOU BUFULLY DESCRIBED HOW 1 MIGHT GO ABOUT INDIVIDUALIZING THE DOSE OF PART OF YOUR INTERVENTION WHICH IS THE TDCS, HOW DO YOU GO INDIVIDUALIZING OR QUANTIFYING THE DOSE OF THE COGNITIVE PART AND HOW THEY--HOW THE 2 INTERACT? >>YEAH, ABSOLUTELY BECAUSE AGAIN IN THE COGNITIVE TRAINING APPROACH WE HAVE A FIXED DOSE OF 3 MONTHS OF TRAINING AT 40 MINS A DAY FOR 5 DAYS A WEEK EMPLOY BUT YOUR QUESTION IS GREAT BECAUSE IT WE CAN GO BACK AND USE THE VARIABILITY OF THE DATA OF WHAT THEY DID RELATIVE TO THEIR RESPONSE TO BASE LINE CHARACTERISTICS RUN THESE SAME TYPE MODELS TO PREDICT TREATMENT RESPONSE AND THE APPROPRIATE DOSING OF TRAINING AND AS THESE LARGER AND LARGER TRIEMS ARE COMPLETED. IN FACT, THERE'S AN ONCATEGORY 7600 PERSON TRIAL CALLED THE PAC TRIAL WHICH WE'RE A PART OF IN OLDER ADULTS THAT WOULD BE DELIVERING DOSING OF ABOUT THE SEAM 3 MONTHS IN VERY SIMILAR COGNITIVE TRAINING APPROACHES THAT UPON WE USED AND THAT SIZE OF DATA WE COULD DO SOME COOL ANALYSIS REGUARDING TREATMENT RESPONSE AND CUSTOMIZING THAT DOSE. AT THIS POINT WE HAVE NOT TRIED TO CUSTOMIZE OR SPECIFICALLY DOSE THE COGNITIVE TRAINING SIDE BUT YOU'RE RIGHT. THAT'S A CERTAIN COMPONENT WE ALSO HAVE TO CONTROL VERSUS SOME OF THESE APPROACHES WHERE TDCS IS THE PRIMARY INTERVENTION LIKE IN DEPRESSION FOR EXAMPLE, OR IN CHRONIC PAIN, WHERE WE WOULD ONLY NEED TO DOSE THAT COMPONENT. YEAH, IT'S A GREAT QUESTION. >>THANK YOU. >>THANK YOU. IF THERE IS NO OTHER QUESTION, WE WILL MOVE ON TO THE IN ACCIDENT SPEAKER, WHICH IS DR. --[ APPLAUSE ] --DR. SILVE NA, HOROVE TZ, FROM THE NATIONAL INNSITUTE OF NEUROLOGICAL DISORDERS AND STROKE. >>HI, GOOD MORNING EVERYBODY. IT'S GREAT TO BE AT HOME IN A MEETING IN PERSON. SO THANK YOU FOR INVITING ME AND LET ME TALK A LITTLE BIT ABOUT OUR WORK ON TMS AND FMRI IN MOVEMENT DISORDERS. I DON'T HAVE ANY CONFLICTS TO DECLARE, SO WHAT I WILL PRESENT TODAY IS WHY WE THINK IT'S IMPORTANT TO COMBINE TMS AND FMRI IN MOVEMENT DISORDERS AND THEN GO THROUGH A FEW WAYS TO COMBINE THAT SOME SOME HAVE BEEN MENTIONED ON OTHER TALKS BUT NOT APPLIED TO MOVEMENT DISORDERS AND I WILL TRY TO GO IN MORE DETAILS. SO YEAH, HOW WE CAN COMBINE THE FMRI AND THE MEDS AND HOW THEY CAN INFORM EACH OTHER. SO WE MOVE, RIGHT? WE TALK AND WE MOVE PARTS OF THE BODY, ANY FUNCTION THAT WE DO, WILL MOVE SOMETHING. SO UNDERSTANDING HOW WE CONTROL THE MOVEMENTS AND WHAT IS EFFECTIVE IN THE DISEASE IS IMPORTANT AND WE CAN--THE WAY THAT WE THINK ABOUT THE MOVEMENTS IS THROUGH THE MOVEMENT, WE THINK ABOUT THE SYSTEM, DIFFERENT PARTS OF THE BRAIN THAT INTERACT THAT WILL PRODUCE THE MOTOR OUTPUT THAT WILL GO TO THE PERIPHERY. SORRY, I'M HAVING ISSUES WITH THE ADVANCE OF THE SLIDES. >>OKAY, SO, SOME OF THESE DISEASES WERE MENTIONED IN THE [INDISCERNIBLE], PARKINSON'S DISEASE, DYSTONIA, SOCIAL TREMOR AND ALL THESE DISORDERS, AND YOU HAVE SOMETHING IN THE BASAL GANGLIA, SOME DEEP STRUCTURES AND SOME CORTICALE AREAS BUT WE KNOW THAT THEIR ARE SYSTEMS THAT INTERACT AND SO THAT'S WHAT WE WANT TO STUDY. HOW THIS DISORDER PRESENT, HOW WE CAN SEE THEM WITH FMRI AND WHAT PART OF THE CIRCUITS ARE AFFECTED OR HOW WE CAN ALTER THEM. SO WHAT WE GAIN FROM COMBINING THE FMRI AND THE TMS, IS THAT WE KNOW THAT FMRI ALLOWS FOR OBSERVATION OF NETWORKS UNDER INTERNATIONS, THAT'S SOMETHING THAT HAVE BEEN A GROWN FIELD IN THE LAST 15 YEARS OR SO. AND WITH TMS, WE HAVE THE CHANCE TO PERTURB THESE NETWORKS AND THEN OBSERVE CONSEQUENCES IN THE SHORT OR LONG-TERM AND THAT'S ALLOWED US TO REALLY STUDY WHAT'S GOING ON IN THE DIFFERENT PARTS OR AT LEAST THE PARTS THAT CAN ACCESS IN THE SYSTEM DOWN STREAM. SO THE FIRST TECHNOLOGY TRANSFER I WANT TO MENTION IS SIMILAR TO THINGS THAT HAVE BEEN PRESENTED IN WAYS THAT WE CAN PROVE WHAT IS OUR SIMULATION IS DOG. SO WE USE FMRI TO OBSERVE, WHAT IS THE MECHANISM BEHIND THE STIMULATION, AND THIS IS THE STUDY THAT WAS [INDISCERNIBLE] AND CENSOR, IN THE GROUP THAT WE WORKED TOGETHER ON AND IN THE STUDY WE HAVE A SEQUENCE WHERE THE SUBJECT NEEDS TO MEMORIZE A TASK. BEFORE THAT DID WE DID A BASE LINE FMRI FOR RESTING STATE ASK THEN WE CAN DO OTHER FMRI RESTING ESTATE AFTER THEY LEARN THESE SEQUENCES AND THEN WE APPLY TMS INTERFERENCE OR [INDISCERNIBLE] AND SUBJECTS GO TO SLEEP AT THEIR HOUSE AND COME BACK, AND THEN WE DO PRERETESTING AND ANOTHER RETEST TRIAL AND ALSO TEST FMRI. SO WHAT WE FIND IS OF COURSE IN BEHAVIOR THAT APPLY THE TMS DURING REACTIVATION, REDOUSES THE LEARNING THAT THEY HAVE, IF YOU LOOK HERE, THE CONTROL IN THE SESSION THAT WILL BE HERE, THERE IS A BIG IMPROVEMENT IN THE PERFORMANCE THAT IS NOT SEEN WHEN AT THE TIME OF REACTIVATION, THE CONSIDERATION TIME THE SUBJECT IS QUESTIONED. THE QUESTION IS WHY DID THIS HAPPEN, THAT IS WE CAN EXPLORE WITH THE FMRI, AND SO WE USE A SEED IN THE MODEL CORTEX AND CAN LOOK AT HOW THE CONNECTIVITY GOES IN THE DIFFERENT CASES AND THE DIFFERENT CONDITIONS AND WAWE SEE IS THAT WHILE SUBJECTS IN THE PREAND POST TESTING BEFORE ANY INTERVENTION IN BOTH GROUP HAVE INTERCONNECTIVITYS BETWEEN THE MOTOR AREA AND THE BASAL GANGLIA, ONCE WE APPLY THE DIFFERENCE AND WE TEST THEM AFTER CONSOLIDATION TIME IN THE SLEEP, THERE IS A DIFFERENCE WHERE THE GROUP IS NOT AFFECTED GETS AN IMPROVEMENT WHILE THE GROUP AFFECTED DOESN'T. SO WHAT FMRI ALLOW US HERE IS UNDERSTANDING WHAT IS BEHIND THE EFFECT THAT WE HAVE IN THE SIMULATION AND WE CAN SEE THAT THE MODIFICATION OF THE MEMORY CORRELATES WITH THESE CHANGES IN CORRELATION, SO IT'S A GOOD EXAMPLE OF HOW WE CAN LOOK AT THE 2 BRAINS. SO THIS IS CONTROLS OF SIMILAR THINGS COULD BE APPLIED IN PATIENTS OF COURSE. ANOTHER STUDY NOW IN PATIENTS, WE TRIED TO SEE, TO UNDERSTAND WHAT IS THE ROLE OF THE [INDISCERNIBLE] FOR DYSTONIA, FOCAL HAND DYSTONIA WAS THE TOPIC OF A HAND YESTERDAY SO THOSE THAT WERE ALREADY HEARD IS--DISEASE WHERE THE PATIENTS HAVE A PROBLEM IN A FINE CONTROL, VERY SPECIFIC FOR EXAMPLE, A PERSON COULD HAVE A DEFICIT IN WRITING THAT'S MORE COMMON, WRITER CRAMPS AND SO ONLY HAVE THESE CO CONTRAKSZ IN THE FINGERS AT THE TIME OF WRITING BUT NOT THAT MATCH ANY OTHER ACTIVITIES. SO THE CONTROL NETWORK THAT WE CALL FOR THESE, WE KNOW IT INVOLVES THE DARSAL AND VENTRAL MOTOR OF THE DORSAL AND INTORIOR INFERIOR PARRY ET AL LOBULE. SO THE LOBULE WILL BE THE 1S AFFECTED SO WE TRIED TO SEE WHETHER WE CAN INTERVENE WITH TMS, SIMULATED DIFFERENT AREAS AND UNDERSTAND WHAT'S HAPPENING IN THESE CONNECTIONS IN THE PATIENT'S DIFFERENT THAN THE CONTROLS. OF COURSE, WE KNOW AND PROBABLY ARE FAMILIAR WITH THAT DEPENDING ON WHERE YOU STIMULATE, IT COULD BE DIFFERENT RESULTS. IT WAS A NICE DEMONSTRATION IN A STUDY BY VERY CLOSE OF THE PARIETAL CORTEX PRODUCE VERY, VERY DIFFERENT RESULTS, SO WE KNOW ALREADY THAT IT IS VERY IMPORTANT AND THIS IS JUST ON A STRUCTURAL T1 SO FOR US IT WAS VERY IMPORTANT TO BE ABLE TO DISTINGUISH THIS SURFACE, THE DORSAL OF THE VENTRAL PATHWAYS IN THE PREMOTOR AND THE PARIETAL CORTEX, SO FOR THAT WE CHOOSE TO USE FMRI AND I KNOW THIS IS A CROWDED SLIDE BUT I MAINLY, THIS IS THE IDEA THAT WE USE FIRST IMANNUALING PARADIGM THAT INCLUDE OTHER THINGS, FOR THIS, BUT WE HAVE RESTING STATE THAT WILL ALLOW US TO STUDY CONNECTIVITY FOR THE FMRI TASK THAT WILL ALLOW US TO IDENTIFY THE DIFFERENT REEJIOKNOWS RELEVANT FOR PERFORMING THE TASK, THE FINE CONTROL TASK AND THEN WE CAN USE THIS INFORMATION FOR THE STUDY, WE SEE WHAT WILL HAPPEN AND WE COULD COMPARE WITH THE TMS RESULTS WITH THE GROUP LEVEL, BUT ALSO WE CAN USE THIS TASK TO LIMITED PARTNERSHIP ABOUT THE SPECIFIC AREA FOR EACH INDIVIDUAL ON HOW TO APPLY THE SIMULATION, SO IF YOU'RE GOINGANNA TOMICALLY, THIS WILL BE THE SEEDS LIKE THESE LITTLE DOTS LIKE WE WOULD PUT THE TMS PROCEED. HOIR WE CAN LEARN MORE AND FOR THE SPECIFIC SUGJECT, THE WAY WE DID WAS TO FIND ANATOMICAL REGIONS THAT THEN LOOK FOR THE VOXEL IN EACH SUBJECT THAT HAD THE HIGHERACIVATION TO SEE THE INTEREST AS YOU CAN SEE HERE THERE ARE SLIGHTLY DIFFERENT THAT ARE FINE BUT THE OTHER REGIONS YOU MAY NOT HAVE THE PEAK AT THE SAME PLACE THAT YOU WILL BE IN ANATOMY AND WE WILL GET BECOME TO THAT IN OTHER STUDIESAs WELL. SO THEN WE CAN USE NAVIGATION BUT PUT THE COIL IN THE RIGHT LOCATION BASED ON THE ACTUAL ACTIVATION FOR THAT TASK FOR THAT PEASHT THAT WILL PROBABLY YIELD THE MORE EFFECTS FOR AFFECTING THAT PARTICULAR TASK SO WHAT WE OBSERVE HERE IS THAT THE PMB TO 1 IS NOT THE REGION AFFECTED AND THE IMBALANCE WAS IN THE PARIETAL REGIONS. SO 1 OF THE THINGS THAT 1 OF THE CONCEPTS THAT THROUGH MANY TMS STUDIES COME REGULARLY IS THE IDEA OF LACK OF SURROUNDING [INDISCERNIBLE] IN THE PATIENTS. THERE IS NO SIGNAL GOING TO BLOCK THE CENTER OF THE FINGER YOU WANT TO USE AND THEN PRESS OUT TO THE NEIGHBOR FINGERS THAT'S WORK IN TMS DONE BY ABOUT THE CONDITIONING AND SO WE WENT OVER OTHER THINGS I WANT TO SHOW IS WE CAN SOMETIMES LEARN SOMETHING ON TMS AND THEN GO TO A VERY DIFFERENT TECHNIQUE AND TRY TO MOVE FORWARD, RIGHT? SO THESE THAT I'M SHOWING HERE IS COMPLIMENTARY INFORMATION TO THAT, BUT THIS IS VASO FMRI AT 7 TESLA, WE DON'T HAVE A SIMULATION HERE BUT WHAT WE CAN DO IS NOW AT A VERY HIGH RESOLUTION AND FMRI TRY TO UNDERSTAND WHAT IS HAPPENING IN THE BRAIN OF THESE PATIENTS, THIS IS DATA FROM PATIENTS BUT WE CAN SEE INDEED THAT THIS IS THE FIGURE REPRESENTATION FOR THE HEALTHY ATMOSHPHERE OR MORE HEALTHY ATMOSPHERE, WE KNOW THERE IS SOME CROSS OVER IN DYSTONIA, BUT WE CAN SAY THAT THIS IS THE HAND THAT IS PROPERLY DISTRIBUTED HOWEVER IN THE PATIENT, IN THE AFFECTED VARIANT, SO IT'S HERE WE DON'T HAVE THE CLEAN REPRESENTATION OF THE FINGER WHICH SUPPORTS THE WHYED THAT WE'RE NOT INHIBITING OR SEPARATING THE ACTIVATION. AND WHEN WE LOOK AT THE LAYERS, WE CAN SEE THAT THEY'RE AFFECTED HERE SHOWN IN GROWN AND THEY'RE AFFECTED IN PLURIBU, THERE IS A BIG DIFFERENCE INTO THE INCREASING THE PATIENTS IN THE SUPERFICIAL LEVELS WHILE DECREASED ACTIVITY IN THE DEEPER LAYERS IN THE BRAIN THAT COULD BE WHAT IS INDEED CAUSING OR THIS LACK OF INHIBITION AROUND AND WE SEE THESE DIFFERENCES IN THE VASOSIGNAL BUT ALSO IN THE [INDISCERNIBLE] FMRI, SO MOVING TO ANOTHER STUDY. WE MENTIONED THAT IN THE PREVIOUS STUDY IS THAT I SHOWED THAT WE CAN USE THE TMS TO LOCALIZE,--I MEAN THE FMRI TO LOCALIZE THE STIMULATION IN PLACE BY DOING ACTEST. BUT SOMETIMES THE DESIRED TARGET IS NOT CORTICALE AND WE KNOW THAT TMS CAN ONLY BE APPLIED TO THE CERTAIN DEPTH OF MANY OF YOU ARE EXPERTS ON THAT OF THE MODELING THAT I'M GETTING INTO BUT WE KNOW WE CAN'T GET IT SO 1 OF THE WAYS THAT WE CAN GO IS BY USING INFORMATION FROM FMRI, AND CONNECTIVITY. SO MAINLY IN THIS CASE, WHAT WE DID IS USING RESTING STATE OF FMRI FOR EACH INDIVIDUAL SUBJECT, AND STRUCTURAL DATA WHERE WE HAD DEFINED ARK MIG DUALA DUALA REGION, EXTRACTED TIMES FROM THE AMYGDALA AND THEN LOOK AT THE FUNCTIONAL CONNECTIVITY AND THEN IF WE HAVE A TARGET AREA IN OUR CASE, THE DORSAL LATERAL PREFRONTAL CORTEX AND WE CAN FIND WHICH AREA WITHIN THE DORSAL LATERAL WE PREFER THE CORTEX AND WE KNOW IT'S A PRETTY LARGENNA TOMICAL REGION IS THE 1 THAT CORRELATES MORE WITH THE AMYGDALA AND WILL GOVERN US A BETTER CHANCE TO MODIFY THE AMYGDALA ACTIVATION. AND AS WE SEE HERE, THIS IS A PILOT STUDY, THIS IS DIFFERENT SECTIONS AND I WILL SHOW YOU THE PARADIGM IN THE NEXT SLIDE BUT WHAT I WANT TO POINT HERE IS THAT WHILE MOST SUBJECT HAVE A VERY CLOSE HIGHER CONNECTIVITY POINT, IT'S NOT EXACTLY THE SAME ON EVERYBODY. AND THEN, OF COURSE 1 IS LOOKING AT THE SUBJECT AND YOU CAN SEE WHETHER THESE ARE THE SAME RESULTS OR NOT BUT MAINLY EVEN WITH THESE LITTLE GROUP FOR DOGS THAT ARE VERY CLOSE TOGETHER, THEY ARE NOT EXACTLY IN THE SAME POINT. SO THE PROGRAM WE HAVE AND THIS WAS PROOF OF CONCEPT TREATMENT IS, WELL, WE FIRST DO THE RESTING STATE, FMRI, TO FIND OUR TARGET REGION AND THEN WE CAN GO THROUGH THE STIMULATION THAT WE DO INTERMITTENT STIMULATION AND WE CAN DO IN THIS TASK, WHEN WE ARE LOOKING THE AMYGDALA HAS HYPER-ACTIVITY IN THE PATIENTS SO WE WANT TO SEE RESPONSES TO FACES AND HAPPY AND POSITIVE AND NEGATIVE BALANCE AND THEN WE CAN SEE WHAT HAPPENED AFTER THESE SERIES OF STIMULATIONS THAT WERE DONE WITH CONSECUTIVE BASE AND WE DO NOT DO TMS IN THE SCANNER THAT'S TECHNOLOGICALLY MORE DEMANDING AND SOMETIMES WITH PATIENTS THAT MOVE AND BECOME VERY TRICKY, RIGHT WHEN TRYING TO BE VERY PRECISE IN THE STIMULATION AND THEN THE SUBJECT WILL MOVE IN THE SCANNER IS SOMETHING THAT REQUIRES ANOTHER LAYER OF CARE. SO ANYWAYS, THIS IS DONE VERY TIMELY WHERE WE HAVE THE BEHAVIORIAL TASK, WE APPLY TMS, WE GO RIGHT TO THE SCANNER, THEN WE DO ANOTHER ITERATION AND WE DO THAT A FEW TIMES. AND WE DO OBSERVE THAT INDEED THROUGH THE DIFFERENT VISITS, OVER ALL CONNECTIVITY BETWEEN THE AMYGDALA AND THE DORSAL PREFRONTAL CORTEX TARGET, CHANGE THE CASE OVER TIME BUT ALSO WE SEE THAT THE BEHAVIOR CHANGE SO NEGATIVE BALANCE DECREASE AND THE POSITIVE BALANCE INCREASE SO IT HAS THE WANTED EEIVET ON THE PATIENTS. SO THESE ARE 1 OF THE TREATMENTS. WE NOW TO MOVE TO DO THAT STUDY AS RUN THE MICE DOUBLE BLIND PATHWAY GIVES SEEB O CONTROL TRIAL, IT'S A SMALL TRIAL WE'RE RUNNING HERE AT NINDS AND I ALSO TRY TO FIND STUDIES FROM OTHER GROUPS OF CLINICAL TRIALS, THERE ARE A LOT MORE IN THE PSYCHIATRIC THAT IN THE NEUROLOGY, ESPECIALLY MOVEMENT DISORDERS, THERE IS ANOTHER STUDY BEING RUP NOW IN CANADA DAILY BASIS AT TITANS AND INTERESTINGLY, THESE 2 STUDIES OF FUNCTIONAL MOVEMENT DISORDERS HAVE DISORDERS, [INDISCERNIBLE] ALSO WITH DISORDERS, RIGHT? THERE ARE OTHER STUDIES FROM THE LITERATURE THAT HAVE DONE TMS AND LOOKING AT DEFECT IN CONNECTIVITY IN PATIENTS WITH DIFFERENT LEVELS OF EFFECT BUT HOWEVER, 1 OF THE TECHNOLOGY TRANSFERS I WANT TO POINT IS LIKE FOR EXAMPLE THESE CEREBELLAR TMS, THAT CHANGE FUNCTIONAL CONNECTIVITY IN CANNED WHAT, SOME STUDIES IN TINITUS, AND STUDIES ON PARKINSONS PATIENTS AND DYSTONIA, ALL THESE STUDIES ARE ABOUT 10 YEARINGS OLD AND DIDN'T MOVE TO CLINIC SO A LOT OF THESE ARE PROOF OF CONCEPT AND VERY HARD TO GET ALL THESE THINGS TOGETHER, IT'S HARD TO SCAN THE PATIENTS, IT'S HARD TO HAVE THE TMSOT PATIENTS AND IT IS EVEN HARDER TO TRY TO DO EVERYTHING WITHIN THE TIME THAT YOU CAN MONITOR THAT THINGS ARE CHANGING. SO I THINK UNTIL WE KNOW FOR EXAMPLE, IF YOU LIKE TMS, HOW LONG THE TREATMENT WILL LAST IS IMPORTANT TO TIME WHEN YOU ARE COLLECTING YOUR FMRI IF YOU ARE TRYING TO SEE WHETHER THERE IS AN EFFECT OR WHAT IS THE MECHANISM OF EFFECT OR THE TMS. SO IN SUMMARY, WE'VE SEEN THAT TMS AND FMRI ARE USED TOGETHER TO GET AN IMPROVEMENT ON HOW WE APPLY TMS AND WHAT WE LEARN ABOUT TMS BY ADDING THE MRI COMPONENT AND THEY CAN HELP US UNDERSTAND MOVEMENT DISORDERS, HOPEFULLY EVENTUALLY BECOME TREATMENT FOR SOME OF THEM. SO WHAT I HAVE SHOWN IS THAT FMRI CAN BE USED TO PROBE TMS, CAN HELP FIND THE LOCATIONS, NOT ONLY BY POINTING TOWARDS THE BEST SPOT CORTEX BUT ALSO BECAUSE WE KNOW THAT THE BRAIN FUNCTION AS NETWORKS AND DEFINITELY MOVEMENT DISORDERS YOU CAN HAVE THIS EFFECT BY HAVING DIFFERENT NODES AFFECTED, FOR EXAMPLE, THERE WAS SOME TALKS YESTERDAY ABOUT DEEP BRAIN STIMULATION AND YOU CAN HAVE THE SAME EFFECT OF DISEASE MODIFYING EFFECTS BY APPLYING STIMULATION IN DIFFERENT PARTS OF THE BRAIN WITH DEEP BRAIN STIMULATION THAT WE HOPE THAT THE SAME COULD BE HAPPENING BY AFFECTING THIS NETWORKS, WITH TMS, SO, CONNECTIVITY COULD BE THE GUIDE TO OUR DOOR TO BE ABLE TO TMS IN AFFECTING DEEP STRUCTURES AND OF COURSE AGGREGATING INFORMATION WOULD IMPROVE OUR KNOWLEDGE. SO WITH THIS, I WOULD LIKE TO ACKNOWLEDGE THE COLLABORATORS IN PARTICULAR, [INDISCERNIBLE] WHO LED MOST OF THESE TMS STUDIES THAT I PRESENTED. AND THE REST OF THE TEAM THAT I WANT TO POINT OUT WERE HERE AT THE NOOH H AND PARTICIPATE INDEED THE STUDIES THAT I'VE SHOWN YOU. THANK YOU. [ APPLAUSE ] >>THANK YOU FOR THE GRAT TALK AND NOW IF THERE'S A FEW QUESTIONS WE HAVE TIME FOR QUESTIONS >>IF YOU ARE RELYING ON ADMISSION FROM THE CORTEX TO THE AMYGDALA DO YOU THINK IT'S ALSO IN THE LOCATION OF OF THE CORTICALE STIMULATION WILL ALSO GIVE YOU A VERY DIFFERENT RESULT IN TERMS OF YOUR THERAPEUTIC EFFECTIVENESS. >>YES. SO YOU NEED TO BE SURE THAT YOU ARE STIMULATING AN AREA THAT WILL BE RELATED TO YOUR TARGET SO THERE ARE WAYS TO DO IT, IT COULD BE STRUCTURAL OR FUNCTIONAL. SO 1 OPTION WOULD BE TO DO DIFFUSION AND FIND OUT WHAT IS THE ACTUAL PATHWAY SO MANY GET IN THE WHITE MATTER STIMULATED CLOSE WHITE MATTER AND GET THAT AND THE OTHER IS LOOKING AT FUNCTIONAL WHERE IT IS STIMULATED IN ANOTHER PLACE IN THE DORSAL POSITIONOLOGICAL FRONTAL CORTEX IT MAY NOT GO TO THE AMYGDALA RIGHT? IT MAY GO TO OTHER REGIONS OF THE DORSAL POSITION AT LATERAL CORTEX CONNECTS WITH ITS HIGH CONNECTIVITY THROUGH THE BRAIN. SO IF YOU DON'T FOCUS ON THAT, YOU MAY OR MAY NOT REACH THE AMYGDALA. >>VERY NICE DATA, INTERESTING THE VASOLAMINA PROFILE YOU SHOWED, SEEMS UNAFFECTED, THAT HAVE NOT AS CLEAN SEPARATION BETWEEN THE DEEP AND SUPERFICIAL LAYERS COMPARED TO THE AFFECT TD [INDISCERNIBLE], THE AFFECTED [INDISCERNIBLE] WAS CLEANER ACTUALLY. >>YES. SO THE NONAFFECTED PROFILE, THIS IS ONLY DATA FROM 4 SUBJEKS THAT WE COLLECTED HERE BEFORE THE SCANNER WAS SWAPPED BUT THERE'S A LOT OF DATA COLLECTED FROM THE SAME SCANNER WITH SAME SEQUENCE WITH HEALTHY VOLUNTEERS. WHAT WE SEE IN THE NONAFFECT SIDE WHAT YOU EXPECT. YOU EXPECT A BUMP IN THE UPPER LAYERS AND A LITTLE BUMP IN THE LOWER, DEEPER LAYERS BUT THEY SHOULD HAVE SIMILAR PATTERN, RIGHT? IN THE PATIENTS WE HAVE MORE OF AN IMBALANCE OF AN INCREASE IN THE SUPERFICIAL LAYERS AND THE DECREASE, THAT'S WHY--I MEAN THERE'S DIFFERENCES IN BOTH SIDES. THAT'S WHAT MAKES IT KIND OF MORE LIKE MUCH DIFFERENT BECAUSE 1 IS DECREASED AND THE OTHER IS DECREASED FROM THE MIDDLE THAT ARE TIERS IN THE CONTRA LATERAL ATMOSPHERE SEEN IN THE PATIENTS. >>THANK YOU VERY MUCH. NOW WE CAN MOVE TO THE NEXT SPEAKER. THANK YOU VERY MUCH. [ APPLAUSE ] OUR SPEAKER WILL BE DR. LI-MIN CHEN TALKING ABOUT MRI GUIDED FOCUS ULTRASOUND FROM VANDERBILT UNIVERSITY. >>THANK YOU FOR INVITINGITOUS PARTICIPATE IN IF WORKSHOP AND THANK YOU FOR THE OPPORTUNITY TO SHARE OUR DATA, I WILL TALK ABOUT MRI GUIDED FOCUS ON ULTRASOUND STIMULATION, AND I HAVE NO FINE ASH INTEREST TO DECLARE AND FOR BY NOW, SO WE PROBABLY HEARD A LOT ABOUT, YOU KNOW THE ADVANTAGES OR THE BENEFITS OF USING ULTRASOUND AS A STIMULATION TOOL AND WE'RE MOTIVATED TO COMBINE IMAGING MI WITH NEURAL, WITH FOCUSED ULTRASOUND SO WE HAVE BEEN WORKING ON A FEW ASPECT. AND 1 IS A REALTIME VERIFICATION OF THE THE ULTRASOUND BEAM LOCATION WITH MRI ARFI, SO AS YOU PROBABLY HEARD THE FUNCTIONAL IMAGING PROVIDE US A TOOL TO REALLY MONITORING THE ULTRASOUND MODULATION EFFECTS. I KNOW WE GAIN MECHANISTIC UNDERSTANDING OF THE NEURAL MODULATION AND MOST IMPORTANTLY, NOT JUST AT THE TARGETED BRAIN REGION, AND ALSO OFFTARGET IN THE ENTIRE NETWORKS, SO, I PROBABLY WILL TOUCH ON SEVERAL--FROM SEVERAL ASPECT, WOKNOW IS WE WILL SHOW THE BRAIN STAY DEPENDENT BY DIRECTIONAL STIMULATION OF THE ULTRASOUND AND WE LOOK AT THE FIRST DOSE RESPONSE AND I WILL ALSO SHOW YOU SOME OF THE EXAMPLES WE HAVE BEEN STUDYING THAT'S THE SENSORY INDEPENDENT NETWORK IN NONHUMAN PRIMATE MODEL AND IN THE END, I WILL SHOW YOU SOME OF OUR NEWER DATA SUGGEST THE MODERATOR--THE ULTRASOUND CAN ALTER THAT WILL AMILLIOEC CONNECTING NETWORK AND RESTING STATE NETWORK. SO IN THE END I WILL ALSO TOUCH ON 2 OF THE FACTORS, THAT ARE RELEVANT TO ULTRASOUND STIMULATION, 1 IS THE TEMPERATURE CONFOUND SO WE DEVELOP A NEW METHOD TO LOOK AT TEMPERATURE MONITORING USING MRI DATA AND IN THE END I WILL TOUCH ON SOME OF OUR DATA TO MONITOR THE SAFETY OF THE ULTRASOUND. SO OUR OVERALL APPROACH IS USED COMBINED IMAGING AT THE 7 T OR 3 T, I HAVE DATA FROM BOTH SCANNERS IN A MA CABBING MONKEY. AND WE ALSO COLLECT DATA WITH A SINGLE TRANSDUCER ULTRA SOUND AND 128 CHANNEL TRANSDUCER. SO THIS IS OUR OVERALL DATA STRATEGY. SO WE HAVE 6 MONKEYS, BEFORE WE DO ANY ULTRASOUND STIMULATION, WE USUALLY REQUIRE AC1 IS HIGH RESOLUTION, T1 WEIGHTED STRUCTURE IMAGE THAT WILL ALLOW US TO ALIGN FUNCTIONAL DATA TO THE MA CABBING ATLAS AND WE ALSO APPLY FUNCTIONAL DATA TO EITHER TACTILE STIMULATION OF THE HAND OR HEAT STIMULATION OF THE HAND TO IDENTIFY BRAIN REGIONS THAT WE CAN TARGET FOR ULTRASOUND NEUROMODDULATION. SO WHERE YOU DO FUNCTIONAL MRI AS A LOCALIZER TO IDENTIFY THE REGION AND ONCE WE HAVE THOSE DATA, AND WE FIRST OF ALL ACQUIRE T1 WEIGHTED. THIS IS 1 SCAN, AND LASTS ABOUT 7 HOURS AND WE FIRST OF ALL ACQUIRE T1 IMAGE AND SIMI RESOLUTION IMAGE AND THEN RESTING STATE FMRI AND THEN FOR 7 HOURS WE OOH QUIRE FUNCTIONAL MRI DATA AND WE PRODUCE A POSITIVE OR ACTIVE CONTROL BY USING EITHER TACTILE STIMULATION OR HEAT STIMULATION. NOW AFTER THE SESSION, WE ALSO APPLY A RESTING STATE MRI DATA DP IN THE END WE WILL ACQUIRE SAFETY MRI DATA. AND HERE'S THE DETAILS OF THE DATA. SO, I WANT TO POINT OUT IS THE ANIMALS UNDERLIGHT ANESTHESIA, AND WE USE EITHER A SINGLE SURFACE COIL AT THE 70 OR A PAIR OF FLEX COIL AT THE 3 T FOR IMAGING DATA OPTIMIZATION AND EACH IMAGING RUN IS ABOUT 10 MINUTES AND OVER 300 VOLUME. WE DO STANDARD MRI ANALYSIS. SO FIRST OF ALL I WANT TO SHOW YOU OUR EFFORT TO TRY TO OPTIMIZE THE RF AND THE REDUCE THE TIME AND OUR ARFI IS OPTICAL TRACKING TBIEDED IS SIMILAR TO NEURAL NAVIGATION AND THIS IS THE WORK DONE BY [INDISCERNIBLE] GROUP. SO YOU CAN SEE THIS IS THE MARKERS, AND WE--THIS IS THE MONKEY STILL TEXT BEING FRAME, THIS IS THE TRANSDUCER, AND WE HAVE THIS MARKER WE CAN USE THAT FOR OPTICAL TRACKING AND THIS IS THE ILLUSTRATION. SO WHEN WE HAVE THE MONKEY HERE, AND YOU CAN SEE HERE, THIS IS MONKEY BRAIN WITH THE MI DATA AND THEN THIS OPTICAL SIMULATED TRANSLATIONAL RESEARCH JUDGE ECTOMYOSINRY OF THE ULTRASOUND THEME. I FORGOT TO MENTION 1 THING IS BEFORE EACH ANIMAL ENTER ULTRASOUND STIMULATION, WE WILL ALSO REQUIRE SAFETY DATA AND SO CHARLES' GROUP COMBINED THIS FOR THE TRAJECTORY FOR THE TARGETING. SO THIS IS OPTICAL TRACKING TRAJECTORY. AND THIS IS JUST SHOWING YOU, WE HAVE SUCCESSFULLY TARGETED, THIS IS THE AREA, AND YOU CAN SEE WHEN WE INCREASE THE PRESSURE AND THEN THE TRANSDUCER INTRODUCED THE DISPLACEMENT, ALSO INCREASE, THIS IS A DOSE RESPONSE TO SHOWING METHOD TO DETECT THE PULSES EMPLOY AND IMAGE, I SHOW YOU AND WHY OPTICAL TRACK SUGGEST IMPORTANT BECAUSE OPTICAL IMAGESERAL TRACKING ALLOW US TO DO REDUCE THE ARFI AND THAT CAN SAVE TIME AND ALSO MINIMIZE THE ULTRASOUND EXPOSURE AND WE HAVE RECENTLY DEVELOPED A NEW METHOD, THIS IS BY WILL GRIS ORDER OF MICRONS' GROUP AND BY GRADUATE STUDENT LAURA AND SHE DESEENED THIS METHOD, CAN YOU DO REDUCED FIELD OF VIEW ARFI AND FOR VERY HIGH RESOLUTION IT'S ABOUT 2-MILLIMETER CUBIC SIZE BUT IN 2 MINUTES. SOPHISTICATED THIS IS A VERY FAST ARFI IMAGE AND HERE THE IDEA IS WE ARE TRYING TO MEN MYSELF ARFI EXPOSURE AND THE PAPER JUST PUBLISHED IF YOU ARE INTERESTED, YOU CAN TAKE A LOOK AND THEN, WE WENT OUT, SO WHEN WE KNOW ARFI BY WHEN WE USE ARFI TO VERIFY THE TARGET IS AT OUR INTENDED LOCATION AND THEN WE WILL DO FUNCTIONAL MRI EXPERIMENTS. SO OUR FUNCTIONAL MRI EXPERIMENT IS INTERLINKED EXPERIMENT CONDITION, SO WHAT DO I MEAN BY THAT? SO WE USUALLY ALWAYS HAVE A BUILDING FUNCTIONAL, LIKE POSITIVE CONTROL. SO IN THIS CASE WE HAVE A TACTILE STIMMULES OF THE MONKEY HAND AND THEN WE INTRODUCE ULTRASOUND STIMULATION SO WE HAVE AN INTERLEAVED SESSION, WE HAVE A TACTILE, PLUS ULTRASOUND. AND THE TRACKING THE TRAJECTORY, AND THIS IS THE ARFI DATA SO THEY ALIGNED PRETTY WELL AND SO HERE BOTTOM SHOWING YOU, THIS IS THE FUNCTIONAL MRI MAP, INTRODUCED BY TACTILE STIMULATION AND YOU CAN SEE THE C, THIS IS THE C WITH FUNCTIONAL ADENTIFIED SO WE WERE ABLE TO OVERLAY THE ARFI, THE ULTRASOUND BEAM AFTER THE TARGET VERIFIED BOY ARFI. AND AND SO WHAT WE SEE, WITH THIS DATA, SO HERE YOU CAN SEE THE TOP 1 WHEN WE DELIVERED A TACTILE STIMULATION TO THE HAND, WE SEE ACTIVATION IN THAT AREA WE EXPECT. FOR EXAMPLE, THE SENSORY SYSTEM, THE MEDIAL PC C AREA IN THE CORTEX AND WHEN WE DELIVER THE FIRST STIMULATION AT THE C, THIS IS AREA 3 A, 3 B, EQUIVALENT TO THE MONKEY--I'M SORRY THE RODENT PRIMARY SENSORY CORTEX. AND YOU CAN SEE, WE SEE SIMILAR ACTIVATION AND WHEN WE LOOK AT THE TIME COURSE, YOU CAN SEE THE FIRST IS THE BLUE TIME COURSE, THE BACKGROUND IS THE STIMULUS ON AND OFF BOX DESIGN AND USING THE 2 KILOPACIFIC AT STIMULATION, IT LOOKED QUITE COMPARABLE BOTH SIGNAL CHANGE WITHIN THE SENSORY SYSTEM IN THE ON TARGET AND OFF TARGET REGION AND HERE'S SHOWING YOU THE TIME COURSE, CAN YOU SEE THE TIME COURSE, THIS IS OUR TARGET, OFFTARGET REGION, PRETTY ROBUST SIGNAL CHANGE. AND THEN WHAT WE DID NEXT IS WE BASED ON THE SIMULATION AND THEN WHEN WE LOWER THE THRESHOLD BUT WHY LOWER INTENSITY TO THE [INDISCERNIBLE]. SO THE SEE THE TACTILE SIMULATION ALONE AND THIS IS THE WHOLE NETWORK SLIDING UP AND WHEN WE HAVE A MODERATING TEST SOWBD AND YOU ALSO SEE ACTIVATION, AND SBA IS THIS 1, SO WHEN WE HAVE COMBINED THE TACTILE WITH THE MODERN INTENSITY ULTRASOUND AND YOU CAN SEE THE AGHTIVATION PRETTY MUCH SIGNIFICANTLY REDUCED AND WE HAVE--I GENERATE CONTRAST MAP, THE CONTRAST MAP IS THE 1 CONDITION SUBTRACT ANOTHER CONDITION SO THE PLURIBU VOXELS BASICALLY TELLS YOU WHERE WHICH REGIONS HAVE BEEN SUPPRESSED AND TO SUPPORT THIS SO THIS IS TIME FOR ANALYSIS, YOU CAN SEE HERE, THE BLUE IS COMBINED TACTILE WITH MODERATE ULTRASOUND IS PRETTY MUCH SUPPRESSED NOT ONLY AT THE TARGET BUT ALSO THE OFF TARGET RENALLION. WE HAVE A CONTROL ROI, THIS IS THE WHITE MATTER YOU DON'T SEE THAT MUCH SIGNAL CHANGE. SO AND THEN, WE--NOW WE HAVE 1 HIGH TEST, LOW IPT GREATER TENSITY RANGE AND WE LOOK AT, WE HAVE ACTIVATION WITH 2-5 AND WE HAVE SUPPRESSION WITH THE 425 AND THEN WE SAY WHAT IS THE DOSE RESPONSE? CAN WE LEARN ANYTHING BY LOOKING AT THE DOSE RESPONSE? I WANT YOU TO LOOK AT OUR DESIGN. WE HAVE ULTRASOUND WITH 3 DIFFERENT DOSES AND THEN WE HAVE A TACTILE ACTIVATION, TACTILE CONTROL. SO WHAT DO WE SEE HERE, I WANT TO YOU LOOK AT THIS MAP. OKAY, SO, HERE, THIS IS OUR TARGET. BASICALLY WHEN WE LOWER INTENSITY OF THE ULTRASOUND BEAM AND THEN AS YOU EXPECTED THE PERCENTAGES BOTH SIGNAL CHANGE IN DECREASES AS IT'S A LINEAR DEKREEZING AND THIS IS THE TARGET AND THIS IS THE WHOLE TIME COURSE AND THEN, THIS OTHER AREAS ARE INTERCONNECTED, BRAIN REGIONS TO THIS AREA, 3 A AND 3 B MONKEYS. AND WHAT'S INTERESTING IS THIS 1. SO WHEN WE COMBINE THE FIRST WITH TACTILE TOGETHER AND COMPARE WITH TACTILE ALONE AND THEN, YOU CAN SEE AT THE TARGET, THE RESPONSE DIFFERED HERE. HIGH INTENSITY IS NO EFFECT ON THE TACTILE RESPONSE BUT THE MODERATOR AS WE SHUOF THE SHOWED YOU BUT WE HAVE SUPPRESSION, WE LOWER INTENSITY TO 200 KILOPACIFICCAL INTENSITY AND WE SEE EVEN LESS, LESS INHIBITION, SO IT'S NOW SHOWING A [INDISCERNIBLE]. SO HERE GIVE YOU A BETTER IDEA. SO, THE LINE DOSE CONDITION, THE 3 DOSES, THEN THE GREEN LIGHT THIS IS THE V-SHAPE AND WHEN WE HAVE THE ULTRASOUND PLUS DACTILE STIMULATION, SO THE WHYEDS WE'RE TRYING TO USE ULTRASOUND TO MODULATE THE TACTILE RESPONSE AND SO YOU CAN SEE WHEN THE BRAIN IS IN DIFFERENT STATE. WHAT DO I MEAN BY STATE. SO THE BRAIN IS NOT ENGEAJING ANY TASK AND WHEN WE REDUCE THE INTENSITY OF THE FIRST AND THE BOLD SIGNAL DECREASES. WHEN WE HAVE THE AREAS ACTIVATED BY TACTILE STIMULATION, NOW THE CONCURRENT DELIVERY NOW HAVE INTRODUCED THE VERY BEST RESPONSE FUNCTION. IT'S A VSHAPE. IT'S SIGNIFICANTLY REDUCED AT THE MODERATE THE INTENSITY. IF YOU LOOK AT OFFTARGET REGIONS, HOW THEY ARE FOLLOWING WHAT'S CHANGING AT THE TARGET SO WE DID A VERY SIMPLE CORRELATION ANALYSIS AND HERE YOU CAN SEE AT THE RESTING STATE, THE TOP 1S FIRST ALONE AND THEN THE CORRELATION IS PRETTY AND THEN OFFTARGET REGION. IN OTHER WORDS RESTING STATE OFFTARGET RATE FOLLOW WHAT HAPPENED WITH THE TARGETED STIMULATED AREA BUT INTERESTING IS THIS FINDING SO WHEN WE HAVE ULTRASOUND INTERACTING WITH THE ACTIVATED BRAIN WHERE THE NEURON IS WORKING HARD AND THEN WE SEE DIFFERENCES BETWEEN CORTICALE REGIONS AND THEN THE THALAMUS REGION SO YOU SEE THERE'S ACTUALLY NEGATIVE CORRELATION TO THE VPL NUCLEI OF THE THALAMUS. SO OUR DATA INDICATE ACTUALLY. THE ULTRASOUND INTERACTING THE CORTEX, THE INTERACTION SEEMS VARIED BETWEEN CORTICALE, CORTICALE CONNECTIONS VERSUS CORTICALE THALAMIC CONNECTIONS AND WEB CONNECTED HAVE A HYPOTHESIS WE THINK IS PROBABLY REAL RELATED TO THE FEET FORWARD AND FEEDBACK CONNECTIONS SPRINTS BETWEEN DIFFERENT AREA, THAT'S OUR HYPOTHESIS. AND THEN I WANT TO MOVE ON TO INTRODUCE SO NOW WE HAVE THE ARFI IN PLACE, SO WE WANT TO EXTEND THE ABILITY FOR APPLICATION IN MUSEUM MAN, IS IF IN CASE THE ULTRASOUND BEAM IS OFF TARGET LIPID, CAN WE USE ELECTRICAL STEERING ABILITY AND TRY TO MOVE IT BACK. SO THIS IS WHAT WE TRIED WITH THE 128 ELEMENTS OF FIRST ARRAY. SO HERE I'M SHOWING YOU, WE CAN USE ELECTRIC STEERING TO MOVE THE TARGET FROM THE THALAMUS TARGET TO THE INSULAR CORTEX AND AND HAVE THIS DOWN RANGE ABOUT 2 SEBT METERS SO THAT COVERED A PRETTY GOOD RANGE AND WHAT WE CAN DO. AND HERE WE HAVE 1 PROJECT SUPPORTED BY HEAL INITIATIVE, SO THE IDEA IS DEVELOP THIS MRI GUIDED SYSTEM THAT WILL ALLOW US TO INTRODUCE PAIN RELIEVE IN CHRONIC PAIN PATIENTS. AND CAN WE INTRODUCE ANY SUPPRESSIVE EFFECT WITH ULTRASOUND. SO BASED ON THE DATA WE HAVE, NOW WE DESIGN THIS EXPERIMENT TO LOOK AT 3 DIFFERENT BRAIN REGIONS HAS BEEN TARGETED IN DBS STUDIES FOR PAIN RELIEF, SO THESE ARE 3 AREAS WE DESIGN, 1 ISAN TERIOR SINGULAR CORTEX AND THE OTHER IS WE LOOK AT THALAMUS AND ALSO THE PARADACTYL GRAY. SO THESE 3 AREAS ARE REP ARE SENTATIVE IN TERMS OF THEIR LOCATION IN THE BRAIN, IT'S SUPERFICIAL IN THE DEEPER IN THE BRAIN AND SO, HERE, WE'RE SHOWING OUR ARFI DATA SO YOU CAN SEE, WE CAN RELIABLY TARGET THIS AREA WITH NO PROBLEM WITH THE CHANNEL ARRAY. SO I'M GOING TO SHOW YOU SOME OF OUR FUNCTIONAL DATA FROM THE THALAMUS STIMULATION. SO AND HERE AGAIN, WE TRY TO USE THE MODERATE PHOTON TO SUPPRESS THE HEAT RESPONSE, THE IDEA IS MAYBE IT CAN REDUCE PAIN. SO THIS 1 IS WHEN WE STIMULATE WITH HEAT WITH A TEMPERATURE THAT CAN ELICIT BURNING SENSATION IN HUMANS WE CAN LIGHT UP THE ENTIRE NETWORK AND THIS IS VERY CONSISTENT OR SIMILAR TO WHAT WE REPORT IN A HUMAN LITULATURE WHEN YOU GIVE THE SAME STIMULUS TO THE HUMANS AND THIS IS SHOWING ACTIVATIONOT INFLATE OF THE BRAIN. SO MEN WITH HIGHER WE HAVE THE FIRST ADDED TO THE HEAT STIMULATION, AT THE THALAMUS NUCLEUS, AND SOME AREAS INHIBITED, THIS IS THE LIST OF AREA BEING SUPPRESSED BUT INTERESTINGLY WE ALSO HAVE THE AREA ACTUALLY GETTINGS ADDITIONAL RESPONSE, WE CALL IT EXCITED, SO, WE DON'T KNOW WHY IS THIS CASE, SO THIS IS OUR OBSERVATION. SO HERE'S SHOWING YOU THE CONCOURSE. SO THE RED IS THE HEAT RESPONSE AT EACH INDIVIDUAL ROI WAS SELECTED FOR THIS ANALYSIS AND THE BLUE CURVE IS THE HEAT PLASMAS AND DELIVERED AT THE THALAMUS, SO GENERALLY YOU CAN SEE, WE SEE DRASTIC SIGNIFICANT REDUCTION IN THE PERCENTAGE BOLT SIGNAL CHANGE AT EACH FMRI, I DO WANT TO TELL YOU WE DO SEE SOME AREAS ACTUAL RESPONSE GET ENHANCED BUT I'M NOT SHOWING THE TIME COURSE HERE. THE NEXT AS WE PROBABLY APPRECIATE FOR CHRONIC PAIN NETWORK SO IT'S PROBABLY A CIRCUIT PROBLEM, 1 IDEA IS TO UNDERSTAND ULTRASOUND MECHANISM, WE WANT TO ELECTRIC AT WITH WE SUPPRESS THE THALAMUS RESPONSE, YOU KNOW WHETHER WHAT IT DOES TO THE ENTIRE--SO THE ANALYSIS WE COME UP TO LOOK AT IS WE CALLED EFFECTIVE CONNECTIVITY ANALYSIS, THE PSYCHOPHYSIOLOGICAL ACTION ANALYSIS. SO ANALYSIS ALLOW US TO LOOK AT THE TASK OF SPECIFIC INTERACTION TBEEN BRAIN REGIONS ARE INVOLVED IN THE SAME TASK, SO HERE, WE FOCUSED ON THALAMUS BECAUSE THIS IS WHERE WE'RE PERTURBATING AND HAD IS DURING THE HEAT STIMULATION AND THEN WE IDENTIFIED THIS AND WE EXTRACTED THE BOLD SIGNAL AND WE USE THIS SIGNAL AS A REPRESSOR TO FIND WHERE IN THE BRAIN THOSE AREA ACTUALLY--STRONGLY CONNECTED TO THIS THALAMUS NUCLIER DOING THE PAINFUL STIMULATION PROCESSING. SO WE CALLED IT THE THALAMUS EFFECTIVE CONNECTIVE FOAT WORK. SO WHAT HAPPENS? SO HERE IS THE THALAMUS PET NETWORK SO THIS IS DIFFERENT THAN WHAT WE HAVE JUST SEEN THE NATURAL PAIN NETWORK THIS IS THE SIDE VIEW AND CENTER VIEW AND THIS IS ALL AREAS CONNECTED AND PART OF THE PAIN NETWORK FOR EXAMPLE, THE MOTOR CORTEX AND THE SENSORY CORTEX AND WHEN WE HAVE THE THALAMUS MODULATED BY FIRST AND PROBABLY YOU CAN SEE SOME OF THE AREAS HAVE MORE CHANGES THAN OTHER AND FOR EXAMPLE, THE POSTERIOR INSULAR CORTEX RESPONSE IS NOW SHOWING UP WHEN WE WHEN WE PERTURBATED OUR RESPONSE. AND SO, THAT'S THE MAP AND THEN WE DID PAIR WISE, THE RI BASED ANALYSIS, SO THIS IS THE METRIC SHOWING YOU ALL THE RIs HAVE A STRONG CONNECTION TO THE THALAMUS NUCLEAR AND THEN IN 2 CONDITION, HERE LEFT METRICS, THIS IS THE HEAT PLOT FIRST, THE FIRST IS INTRODUCED TO SUPPRESS THE THALAMUS RESPONSE AND PROBABLY YOU CAN PROASHT AFTER THE THALAMUS SUPPRESSION, THE OVERALL CONNECTIVITY PATH AND CHANGE. AND ALSO SOME OF THE AREAS ARE SIGNIFICANTLY SUPPRESSED. SO THE STAR, YOU SEE HERE THAT THOSE ARE SIGNIFICANTLY CHANGED THE PAIRS. AND THIS IS THE BETA CO EFFICIENT IN BETWEEN THE THALAMUS SEED AND THE ROI WE CHOOSE TO PLOT HERE. SO THE MESSAGE IS, WHEN WE SUPPRESS THE THALAMUS HEAT RESPONSE REGION, THE CONNECTION BETWEEN OTHER AREAS FOR THE CONNECTION SAMPLES ALSO MOST OF THEM ARE SUPPRESSED. AND WE ALSO PERFORMED THE HIERARCHICAL CLUSTER ANALYSIS, THE WHYED IS WHEN WE SUPPRESS THE NUCLEAR PAIN RESPONSE, WHAT HAPPENED TO THE NETWORK OPTIMIZATION, AND WHAT WE FOUND IS, THIS IS THE HEAT NETWORK, THOSE ARE THE AREAS ARE INVOLVED AND WHEN WE DO HIERARCHICAL ANALYSIS, CAN YOU SEE SOME AREAS ARE CLUSTERED TOGETHER AND MEANS THEY'RE FUNCTIONALLY MORE SYNCHRONIZED AND THEN WE SAY WE HAVE A PLURIBU NETWORK AND HAVE A RED SUBNETWORK. WHEN WE HAVE THE ULTRASOUND SUPPRESSED, THE THALAMUS PAIN RESPONSE AND YOU CAN SEE, THE ORGANIZATION CHANGE, SO, AFTER THE EXPOSURE, THE NETWORK REORGANIZED. AND SO NOW WE LOOK AT WHEN WE--WE INTERESTINGLY, WHEN WE INTRODUCE THE SAME ULTRASOUND THEME TO THE ACCAND 2 OF THE PVG, WE SEE ALSO REPRESSIVE EFFECT SO THAT'S THE AREA WE'RE SHOWING SO THE PARAMETER SEEMS TO BE WORKING IN OUR EFFORT TO SUPPRESS HEAT INDUCED RESPONSE. SO THE NEXT 1 I WANT TO SHOW YOU, RESTING STATE IS ALSO ANOTHER MEASUREMENTS MIGHT TELL US ABOUT THE POST ULTRASOUND EFFECT SO AS A THERAPY WE WANT TO KNOW, WHAT--HOW LONG THE--YOU KNOW THE PROTURBATION OR MODULATION LASTS, SO THE 1 WAY WE TRY TO ELECTRIC AT IT IS WE ARE LOOKING AT THE RESTING STATE NETWORK CHANGE BEFORE AND AFTER ULTRASOUND EXPOSURE AND THIS IS THE MAP AND SO THIS 1 IS THE BEFORE ULTRASOUND EXPOSURE, SO THIS IS THE--THIS IS THE NETWORK DEFINED BY RESPONSE TO THE ENHANCED STIMULATION, WE CALL IT THE NETWORK. AND AFTER THE ULTRASOUND SUPPRESSED THALAMUS AND YOU CAN SEE, IT'S MUCH COOLER IN A TEMPERATURE, THAT MEANS OVERALL, OVERALL THE CONNECTIVITY IS DECREASED, THIS IS AFTER THE ULTRASOUND EXPOSURE. BUT SOME OF THE AREAS, YOU CAN SEE, IT GETS ENHANCED. AND THIS IS OUR PLOT, SO THE BLUE, THAT'S THE HEAT ALONE, AND THE RED, THIS IS HEAT, PLUS ULTRASOUND PLUS SUPPRESSION, SO YOU CAN SEE THE ORE ALL CORRELATION, THE OVERALL INTENSITY DECREASED BUT 1 VERY INTERESTING FINDING IS--I'M SORRY, SOMEHOW--OH, GO BACK? SORRY. I APOLOGIZE. THIS 1 IS SOMEHOW, THIS--THIS 1 DIDN'T WORK AND WE HAVE ALSO TRIED THE SAME NETWORK BUT WHEN WE SUPPRESS THE PVG, AND THEN PVG HAS A VERY DIFFERENT EFFECT, I'M SORRY THE PVG ALSO INDUCED SAME SUPPRESSION, SO IN WORTH ORDERS IF WE SHUT DOWN THE THALAMUS OR THE PVG ACCIDENT THE RESTING STATE PAIN NETWORK IS THE CONNECTIVITY STRENGTHS ARE REDUCED. AND. >>YOU HAVE 2 MINUTES. >>SO THE TEMPERATURE MONITORING IS ANOTHER CONFOUND FOR AWLT RASOUND STIMULATION SO IESM SHOWING YOU THE 1 METHOD WE DEVELOPED ACTUALLY WE'RE USING WITHOUT APPLY ANYMORE DATA USING FUNCTIONAL IMAGINGA TO MEASURE THE PAPER. SO THIS IS A NEW PAPER PUBLISHED LAST MONTH AND IF YOU'RE INTERESTED YOU CAN LOOK THE THIS WORK BY [INDISCERNIBLE] AND HIS STUDENTS AND WE'RE USING FUNCTIONAL DATA TO MEASURE THE TEMPERATURE AND I'M JUST SHOWING YOU 1 DATA HERE AND THIS IS IN A PUBLICATION IF YOU'RE INTERESTED, WE HAVE A BETTER CONTROLLED OPTICAL IMAGES O GENETICS STUDY MODEL AND WE'RE USING LASER TO DHAIMPLEG AND STIMULATE AND HERE SHOWING YOU WE CAN--WE CAN MEASURE THE TEMPERATURE CHANGE AT THE PROBE, AT THE TIP OF THE PROBE AND WITH THE ACBEERACY OF .02-DEGREES. SO IT'S VERY SENSITIVE TOGETHER. I WOULD RECOMMEND IF YOU'RE INTERESTED TO MONITOR, AND THEN IN THE END, AS YOU SAY THE SAFETY IS ALWAYS A CONCERN SO WE ARE DEVELOPED THE PIPELINE TO LOOK AT USING THE BEST IMAGING TO MONITORING THE MI SAFETY, SO HERE IS ALL THE METHOD AND JUST SHOWING YOU SOME OF THE DATA WE ACQUIRED AT THE END OF EACH SESSION, TAKES ABOUT 30 MINUTES AND WE--WE DO MAKE IT MORE SENSITIVE AND HERE I GIVE AN EXAMPLE, IF WE DO BBB OPENING WE CAN DETECT THE SIGNAL AT THE TARGETING SYSTEM THEET YEAH, SO THIS IS JUST SUMMARIZE WHAT I JUST DESCRIBED, YES, THANK YOU SO MUCH AND THIS IS OUR--THIS IS REALLY A MULTIDISCIPLINED TEAM WORK AND 3 OF US AND OUR COLLABORATOR, OUR DIRECTOR, LEADER ISSUES EVERYONE IT'S REALLY TEAM WORK ANDIME HONORED TO BE PART OF IT. THANK YOU VERY MUCH. AND ALSO THANK YOU FOR THE FUNDING. [ APPLAUSE ] >>WE CAN TAKE 1 OR 2 QUESTIONS. >>BEAUTIFUL TALK, VERY ROBUST EFFECTS. SO YOU IMAGE UP TO 7 HOURS, DO YOU HAVE A SENSE OF HOW LONG THESE CHANGES IF FUNCTIONAL CONNECTIVITY LAST? HOW LONG WAS IT PERFORMED AFTER THE ULTRASOUND? >>YEAH, SO OUR MEASUREMENTS BASICALLY TELL US LIKE 2 OR 3 HOURS AND WE,--YEAH, BASED ON THE FULL DURATION HOW MUCH EACH SESSION TAKES. >>SO THAT BY ITSELF COULD BE USED AS A NEW TOOL FOR DIAGNOSTIC APPLICATIONS WITH SUCH A HIGH SPATIAL PRECISION. >>MM-HMM. >>VERY EXCITING. >>THANK YOU. THANK YOU. >>SO AT THE END DID THE TEMPERATURE GO UP OR DOES THE TEMPERATURE NOT GO UP? >>SO FOR THE ANSWERS, THE TEMPERATURE DID NOT GO UP. SO THE IDEA IS I SHOW YOU DATA WITH OPTICAL IMAGES O GENETIC BECAUSE WE CAN REALLY RAMP UP THE TEMPERATURE TO SEE, YOU KNOW WHAT IS THE DETECTION THRESHOLD AND WE CAN DETECT ROBUST SIGNAL CHANGE ABOUT OUR OR 5-DEGREES, SEE WITH HIGH INTENSITY WITH THE LASER STIMULATION BUT FOR THE ULTRASOUNDS, THE INTENSITY FOR VERY LOW OPTICAL IMAGES O GENETIC LASER, THERE'S NO TEMPERATURE CHANGE, WE HAVE AN ACRAZZY OF A POINT OR 2 FOR DEGREES. >>THANK YOU VERY MUCH. >>[ APPLAUSE ] SO NOW AS PART OF THE ORAL SESSION, FIRST SPEAKER WILL BE DR. KRISHNAMURTHY FROM EMORY UNIVERSITY. >>GOOD MORNING. I WOULD LIKE TO THANK THE ORGANIZING COMMITTEE FOR THE OPPORTUNITY. SO I HAVE--LET'S SEE. I HAVE NOTHING TO DISCLOSE. >>ALL RIGHT, SO, MY STUDIES FOCUSED ON STROKE INDUCED ASFACIA, PEOPLE THINK OF APHASIA AS JUST A LANGUAGE DISORDER BUT IT'S A COMMUNICATION DISORDER AND IT PRESENTS IN UP TO 38% OF ACUTE STROKE PATIENTS AND IT PERSISTS EVEN IN CHRONIC STAGE WHICH IS GREATER THAN 6 MONTHS AND UP TO 60% OF THE PARTICIPANTS. SO IT'S NOT JUST AGAIN LIKE I SAID LANGUAGE, IT AFFECTS SPEAKING, SPEECH PRODUCTION, COMP REHENGSZ WHICH IS UNDERSTANDING AND ALSO READING AND WRITING. SO IT'S PRETTY DEBILITATING. ALL RIGHT. SO LET'S LOOK AT TDCS EVENTS IN PATIENTS WITH APHASIA, THIS WAS AN EARLY STUDY IN 2010, IT WAS JUST 10 PARTICIPANTS AND I THINK YOU FOUND IN SOMETHING IN HUMANS AND INSPIRE HIM TO DO A LARGER CLINICAL TRIAL AND THIS 1'S PUBLISHED IN GERMANY IN 2018. AND THIS 1 FOR THE ANALYSIS AND AND THIS 1 IS TCS AS AN ADJUVANT FOR SPEECH THIR ACTIVITIES AND PROJECTS THAT'S ARE QUIRING MUCH PROMISING RESULTS. AND THEN THERE WAS ANOTHER PAPER IN 2019 ON BRAIN STIMULATION WHERE THEY ACTUALLY I THINK ON THE SAME COHORT, 74% OF CHRONIC APHASIA, SHOWED THAT TDCS, LEFT TEMPERRAL LOCAL HAS SUPERIORITY COMPARED TO THE SHAM. SO AT THE END WOE DON'T HAVE RANDOMIZED STUDIES OR TRIALS, IT'S JUST MIXED RESULTS SO THAT LEADS TO WHAT IS THE TDCS MECHANISM WHICH IS STILL TRYING TO UNDERSTAND. WELL 1 CONCERNED WITH THE REHABILITATION IS WE DO A PRE POST DESIGN, BEHAVIORIAL, POINT MEASURES, THEY'RE NOISY AND THE PRE/POST DESIGN DOES NONAPOPTOTIC THE CAPTURE THE TIME. AND ALSO WITH THE TDCS INTERVENTION IS 20 MINUTES PER DAY BUT THE PARTICIPANTS ARE ACTIVELY DOING LANGUAGE IN 8 OR 9 HOURS SO THEY'RE DOING A LOT OF DIFFERENT THINGS SO WE CAN'T TRULY TELL WHAT IS THE TDCS EFFECT. SO 1 WAY THAT PEOPLE USE AND NEUROIMAGING TO UNDERSTAND MECHANISMS BUT WE KNOW THAT BOLD IS NOT JUST [INDISCERNIBLE]. AND THE BIG QUESTION IS HOW DOES THIS MONITOR EFFECTS IN BRAIN PHYSIOLOGY INCLUDING NEUROVASCULAR DISEASE WHICH IS STROKE. SO THE OBJECTIVE IS TO INVESTIGATE THE MECHANISM AND TARGETED ENGEAJMENT FOR STIMULATION SITE AND THE VASCULAR BIOMARKER IN POST CHRONIC PATIENTS. WE MONITOR EFFECTS, THE TARGET ENGAGEMENT HERE FOR US WAS TO UNDERSTAND WHEN WE HAVE A FIXED STIMULATION SITE, AND WHEN THE LESION IS HOW PROXIMAL IS THE LESION AND HOW DOES IT IMPACT THE MONITORED OUTCOMES AND FINALLY PROGNOSTIC BIOMARKER CAN BE USED CONCURRENT FMRIs FOR DIAGNOSTIC BIOMARKERS FOR PREDICTION, RIGHT? SO THIS WAS, YOU KNOW AS YOU CAN SEE-- >>RECORDING: PRESS YES. >>I'M GOING THE WRONG WAY. THE POINTER IS NOT WORKING, SO HERE YOU CAN SEE WE HAVE NOW THE PARTIC PLAN TO ANALYZE BY AGE LYING IN THE SCANNER, WE HAVE THE PHOTO BOX INSIDE, IN HERE WE DESIGN A TRAPEZOIDAL TO THE PARADIGM, WE STIMULATED F7, F8, THE FRONTAL GYRUS, THIS IS THE SYSTEM, AND HERE IS OUR PROTOCOL GENERAL STUDY DESIGN AND WE HAD CROSS OVER, THE SAME DISCIPLINE CAME ON 2 DIFFERENT DAYS AND IT WAS PLIENDED, RANDOMIZED AND COUNTER BALANCED ACROSS THE PARTICIPANTS. RIGHT? SO WE DID AUDITORY DECISION TASK, THIS IS VERY IMPORTANT FOR THE SPOKEN WORD COMP REHENGSZ WHICH IS VERY IMPORTANT IN TERMS OF LANGUAGE GAINS, OR TREATMENT GAINS IN THESE PARTICIPANTS AND OF COURSE WITH APHASIA AND I JUST WANT TO PLAY A QUICK 30-SECOND VIDEO HERE SO THAT YOU GUYS CAN SEE HOW THE TASK WENT. OKAY, HERE WE GO. SO I CAN EXPLAIN, THIS IS A DECISION AUDITORY TASK, IT'S THE SOUND TO PRACTICE THE INDEX FINGER IF THEY RECOGNIZE A REAL WORLD AND WE OF COURSE HAVE PSEUDOWORDS, AND WE KEEP SEEING THE + SIGN AND KEEP THEIR EYES OPEN IN THE CONDITION IN TERMS OF STATE AND FOR THE PROPERTIES THEIR VOICE WAS RECORDED WITH THE FEMALE VOICE AND VERY NEUTRAL MIDWEST ACCENT. ALL RIGHT, SO LET'S JUST KEEP MOVING. NOW LET'S LOOK AT PARTICIPANTS. OUR FIRST GUY IS 66 YEAR-OLD LESION IN THE FRONTAL GYRUS, 14 MONTHS AFTER STROKE AND RELATIVELY I WOULD SAY HI, MODERATE APHASE IMRA SEVERITY, DISP IF YOU LOOK AT THIS GUY, HOW DID HE DO, FOR WORDS, AS YOU CAN SEE HERE, THIS IS IN SCANNER BEHAVIORIAL PERFORMANCE WITH THE ACTIVE STIMULATION JUST OVER THE LESION, THERE'S IMPROVED ACRAZZY AND ALSO THE REACTION TIME IS NOT THAT DIFFERENT COMPARED TO SHAM BUT STILL IT'S BETTER. IN TERPS OF THE TASK ACTIVITY WE SEE REALLY SUPPRESSED TASK ACTIVITY, WE SEE INTERESTING LANGUAGE AREAS, LEFT AND RIGHT, AND BUT ANYWAY, SO, BUT IF YOU LOOK AT VASCULAR AND NEURO, YOU THIS DISPORTIONATE OF ACTORS SO WE SEE THE CHANGES BUT MORE IMPORTANTLY THE AREA IN THE CURVE THAT IS THE BRAIN ENERGETICS SO WE CAN SEE THAT IS A SIGNIFICANT CHANGE FROM ACTIVE TO SHAM, SO THE CONTRAST HERE IS ACTIVE FOR SHAM FOR THE WORD CONDITIONS. WHAT ABOUT NONWORDS. AGAIN, SAME GOI, PHYSIOLOGY IS THE SAME BUT IN TERMS OF BEHAVIORIAL PERFORMANCE WITH THIS GUY, THE ACCURACY WAS NOT THAT DIFFERENT DURING ACTIVE STIMULATION BUT REACTION TIME SIGNIFICANTLY DECREASED. OKAY, THEN WE TOOK, WE DID THE RESTING STATE. WE SEE THAT F7, F8 WHICH IS THE ELECTORATE PLACEMENT AND ALSO AS YOU TOOK THE GUY FROM THE PREVIOUS 1, THE SIGNIFICANT LANGUAGE ACTIVATION AREAS FROM THE TASK AND WE TOOK THOSE SEED AREAS WHERE WE SEEDED FROM THAT, THOSE SEEDS AND THEN WE DID THE CONNECTIVITY ANALYSIS, AGAIN, YOU SEE THAT WE SEA SUPPRESS CONNECTIVITY ESPECIALLY WHEN YOU'RE STIMULATING RIGHT OVER THE LESION. OKAY? SO NOW LET'S LOOK AT A DIFFERENT PARTICIPANT, THIS GUY IS 59 YEAR-OLD NOW THE LESION IS STILL IN FRONTAL BUT IT'S MORE IN THE PRESENTERAL GYRUS, A BIT MORE ANTERIOR, 13 MONTHS AFTER STROKE BUT HE'S A REALLY HIGH FUNCTIONING GUY, HE IS REALLY HIGH FUNCTIONING. SO IF WE LOOK AT THIS GUY, WE LOOK AT THE BEHAVIORIAL PERFORMANCE THE REACTION TIME TO BE ACCURATE TO RESPONSE NOT THAT DIFFERENT BUT IN THE ACCURACY, TOO, IN TERMS OF THE PAST ACTIVITY, AGAIN IT'S SUPPRESSED DUE TO ACTIVE TDCS, BUT IF YOU LOOK AT THE HEMODISCIPLINARY MEDICARE AND MEDICAIDIC RESPONSE, THERE'S A SIGNIFICANT CHANGE IN THE DISTORTION, THE [INDISCERNIBLE], YOU CAN CLEARLY SEE HERE IN THE, IN HERE, TOO, JUST BECOMING PRETTY FAST. IF YOU LOOK AT THE NONWORDS FOR THE SAME GUY IN TERMS OF PHYSIOLOGY AGAIN IT'S THE FIRST ACTIVITY FOR TASK, WE CAN SEE THE LESION HERE BUT THEN AGAIN THE FULL MAX MA, AGAIN IS A SIGNIFICANT DECREASED WHICH IS A DISPERSION PARAMETER BUT THE KEY THING IS PETRESSABLE HAIEVERRIALLY, THE ACCURACY IS MORER LEFT THE SAME BUT THE REACTION TIME IS REALLY GOING DOWN IN RESPONSE TO THE ACTIVE TDCS. ALL RIGHT, SO IN THE END WE DID THE SAME THINK THIS FOR RESTING STATE CONNECTIVITY FROM F7, F8 AND LANGUAGE AREAS HERE WE SEE INCREASED CONNECTIVITY WHICH WE HAD SEEN BEFORE AND PREVIOUS WORKS, TOO, WE EXPECT THAT WITH ACTIVE TDCS INERTIA PRIME THE NETWORK FOR THE TASK, BUT THE INTERESTING PART IS THE TASK ACTIVITY WAS SUPPRESSED IN RESPONSE TO ACTIVE TDCS, BUT THERE IS RESTING STATE ACTUALLY INCREASED; OKAY, NOW MY LAST PARTICIPANT HE HAD LESION IN THE TEMPORAL GYRUS, 55 YEAR-OLD BUT THIS GUY'S A LITTLE BIT ON THE LOWER END OF THE MODERATE SIDE OF THE EFFICIENT SEVERITY SO HE'S HIGH FUNCTIONING, SO IF YOU LOOK AT THIS GUY, WHEN WE STIMULATE THE SAME F7, F8, NOW THERE'S NOT MUCH DIFFERENCE IN TERMS OF BEHAVIORIAL ACCURACY OF THE REACTION TIME BUT THERE'S A HUGE RESPONSE ACTIVITY IN RESPONSE TO THE ACTIVE TRKTS DCS, AND YOU CAN CLEARLY THAT THE DIFFERENCE BUT THE VASCULAR SIDE IS NOT CHANGING THAT MUCH. OKAY, AND THE SAME GUY FOR THE NONWORDS THE PHYSIOLOGY IS THE SAME, PHYSIOLOGICAL RESPONSE, ACTIVITY, AGAIN THE AREA UNDER THE CURVE IS SIGNIFICANTLY CHANGING NOT THE VASCULAR SIDE BUT THE INTERESTING PART IS THAT THE BEHAVIORIAL SIDE, NOT MUCH DIFFERENCE MAYBE THE SHAM WAS BETTER FOR ACCURACY BUT NONVERSUS HARDER SO HE TOOK LONGER TIME TO GET C-TYPE LECTINS ANDERATE RESPONSE ESPECIALLY UNDER ACTIVE TDCS. AND IF YOU LOOK AT THE RESTING STATE, AGAIN WITH THIS GUY, WHERE THE LESION WAS DISSAL FROM THE STIMULATION SITE, AGAIN WE SEE THESE INCREASED CONNECTIVITY IN THE RESPONSE TO THE F7, F8 STIMULATION. SO, THEN YOU WANTED TO LOOK AT THE STATE IN ORDER OF EFFECT. SO AGAIN, I'M KIND OF GOING BACK TO OUR SET UP HERE, OUR STUDY DESIGN SO WE HAD RESTING STATE WITH NO TDCS, THE TDCS OFF ON BOTH DAYS AND THEN WE HAD THE RESTING STATE DURING TDCS, WHEN WE WAS ON SHAM SO WE WANT TO LOOK AT THE INTERCESSION AND INTRA SESSION DIFFERENCES SO BASICALLY HERE I'M SHOWING THE ORDER, AND WE HAD 1 WITH SHAM, WE HAD S3 WAS ACTIVE FOLLOWED BY SHAM. THE DAYS APART MAKERS AND A NOTE THAT IT WAS ONLY 3 DAYS, SO WAWE SEE HERE IS THAT MORE OR LESS, I MEAN IT'S S2 AND S3, PROBABLY S2, THERE'S NO SIGNIFICANCE BUT WE SAW SIGNIFICANT DIFFERENCE FOR S1 DURING THE-- >>MAYBE 2 MINUTES. >>OKAY, AND AND S3, SO IF YOU LOOK AT THAT, SHOW OTHER DIFFERENCES, SO WHAT WERE THE SUMMARY OBSERVATIONS IN TERMS OF MECHANISMS WE SEE THAT ACUTE REALTIME TDCS STIMULATION DOES NODULATE NEURAL AND VASCULAR SIDE. THE TYPE DOES INFLUENCE THE TDCS EFFECTS BOTH IN PHYSIOLOGY AND BEHAVIOR, WHAT WE ALSO SAW WHAT WAS ORDER OF STIMULATION BETWEEN ACTIVE AND SHAM AND BRAIN STATE, DOESN'T GO WITH THE ACUTE TDCS MODALATORY RESTING STATE. IN TERMS OF TARGETING ENGAGEMENT, PARTICULARLY FROM S1, WE--YOU SAY THAT YOU KNOW STIMULATING OVER THE LESION, IT MIGHT BE BENEFICIAL ON MONDAY DOCTOR [INDISCERNIBLE] SHOWED THAT WITHLET DIFFERENT MODALITY WHICH IS TMS, WHICH TOLD US THE TIGR MRI, THIS IS THE PREKAFITATIONAL AREAS, YOU KNOW WE MAY NOT WANT TO ABOUT THE TISSUE IN THE LESION, BUT THIS LESION BASED ON BASE LINE CHARACTERISTICS, SO IN TERMS OF BIOMARKER DEVELOPMENT WE SEE DISPERSION IN THE AREA WHICH OCCUR PARAMETERS ARE PRETTY SENSITIVE AND OF COURSE RESTING STATE, TOO. SO, MY LAST SLIDE. WHAT ARE THE LIMITATIONS AND OUR FUTURE WORK, SO THIS WAS A PILOT AS YOU SAW, BUT THE APPROACH IS PRETTY INFORMAIVE IT TOWARDS PERSONALIZED APPROACH WHICH IS VERY BIG IN STROKE REHABILITATION. THERE WAS JUST 3 DAYS IN BETWEEN ACTIVE AND SHAM, PROCEEDING SHAM IT MAY HAVE IT CLEARED OVER PHYSIOLOGICAL EFFECTS DUE TO POST INAPTAMERRIC INTEGRATION TAKES TIME, AND MAYBE THAT'S WHY YOU KNOW SOME OF THE STATE EFFECTS THAT YOU SAW IN S3 COULD BE COMING FROM THAT. IN TERMS OF, YOU KNOW THE NEWER METABOLITES, YOU KNOW WE PUBLISHED EARLIER THIS SUMMER IN AGINGSINGS THAT GABBA DPLIEWT MATE HAS A STRONG INFLUENZ ON THE NEURAL VASCULAR EFFECTS, OF TASK, SO I THINK TESTIMONY BE VERY INTERESTING TO LOOK AT THAT, IN APHASIA AND ALSO IN RESPONSE TO TDCS, PARTICULARLY TDCS, AND OUR ELECTRODES WERE PRETTY SUFFICIENT, AND I WILL ALWAYS SHAMS AND ALSO THE TISSUE WITHIN THE TISSUE AND I MENTIONED THAT AND MAYBE DEVELOP MORE SENSITIVE BIOMARKERS FOR ACCOUNTING FOR EFFECTS. OKAY. WITH THAT I THANK YOU FOR YOUR ATTENTION AND OUR FUNDING SOURCE. THANK YOU VERY MUCH. >>[ APPLAUSE ] WHY CAN TAKE 1 QUESTION. >>DPRAIT TALK, IN OTHER MODELS I'M SEEING IN STROKE, THE TIME WHEN IS YOU DO THE STIMULATION RELATIVE TO THE INJURY AND WONDERING IF YOU HAVE EXPLORED THAT TIME PARAMETER FROM A BASIC SCIENCE TIME POINT PLASTICITY VERY SPECIFIC WHEN IT OPENS UP POST INJURY SO LOOKING AT THAT COULD HELP WITH AUG. METROPOLITANNING THAT RESPONSE? >>I AGREE WITH YOU AND PARTICULARLY IN CHRONIC PHASE, IT'S TYPICALLY CONSIDERED THE WINDOW AND SMALL AND WE DID RECORD HOW MANY MONTHS POST STROKE, WE JUST HAVE TO CODE IT OUT AND SEE HOW THE EFFECTS HAVE CHANGED BUT THAT'S A REALLY GOOD POINT. >>GOOD, NOW WE CAN MOVE--THANK YOU VERY MUCH. [ APPLAUSE ] OUR NEXT SPEAKER IS GOING TO BE DR. LIPENG, NING, FROM HARVARD. >>THANK YOU FOR THE INTRODUCTION. I HAVE NOTHING TO DISCLOSE. I THINK WE HAVE MANY PEOPLE TALK ABOUT RTMS FOR DEPRESSION. FMRI IS THE BASED WITH RESTING STATE AND HAD BEEN USED FOR FINDING TARGET FOR RTMS TREATMENT. CAN YOU SELECT ROI, OF THE SINGULATE OR LABEL FOR A NETWORK TO DEFUND THE FC MAP, THEN THE BRAIN REGION, LIKE THE DLPFC, WHICH IS IN THE NETWORK IS FINDING THE TARGET. THE TARGET FOUND THE GROUP [INDISCERNIBLE]. THE UNDERLYING IDEA THAT THIS CAN BE A WINDOW TO THE UNDERLYING DEEP BRAIN REGION FOR THE UNDERLYING NETWORK, BUT THEN THE NEUTRAL PATHWAY HAS BEEN [INDISCERNIBLE] NOT REAL LEGAL WELL UNDERSTOOD. SO WE LOOK INTO THIS PROBLEM WITH THE WORK TRYING TO UNDERSTAND THE STRUCTURE AMILLIO POSSIBILITIES UNDERLYING GREATER THAN THE RTMS ESTIMATION, SO WITH [INDISCERNIBLE] BUNDLE THAT CONNECT THE LATERAL PFC AND ENTER MEDIAL PFC FOR THE [INDISCERNIBLE] REGION, [INDISCERNIBLE] AND THE FAB RIDICULOUS GOES THROUGH THE OTHER BRAIN [INDISCERNIBLE] AND ALSO CONNECTION TO [INDISCERNIBLE] SINGULATE. I THINK THE LAST IS NOT REALLY [INDISCERNIBLE] BUT THE LAST 1 THIS 1'S PRETTY INTERESTING. AS CAN YOU SEE THERE'S NO CONNECTION FROM THE DLPFC EVEN THOUGH THERE'S STRONG FUNCTIONAL CONNECTIVITY. AND WE LOOKED AT THESE IN A LOT OF DATA IN THE HIGH QUALITY NECKANISM DATA, [INDISCERNIBLE] AND THEN WE LOOK INTO THE LITERATURE ABOUT TODAYS AND THEY INJECT INTO THIS REGION AS A SINGULAR SUBJECT UNIT. AND WE STUDY [INDISCERNIBLE] DATA AND BEFORE RTMS DATA FOR ENTIRE SESSIONS AND I THINK IN THE [INDISCERNIBLE]. I THINK THE MAJOR CHANGES ALL CONNECT TO THE INTERMEDIATE PFC. SO I THINK IT INCREASED CONNECTION IN THESE CONNECTIONS TO THE PFC AND ALSO INN CREASE THAT WAY INTO MULTIPLE FIBERS AND ALSO REDUCE THE [INDISCERNIBLE]. SO AS INDICATE THAD MAYBE THE PERIVASCULAR SPACE INCREASE FOR THE [INDISCERNIBLE] THAT WAS TALKED YESTERDAY AND MAYBE FIBER INTEGRATED MEANS IT'S MAYBE OR [INDISCERNIBLE] LEAD TO THE INCREASE IN THE [INDISCERNIBLE]. AND ALSO WE FOUND THAT EVEN THOUGH THE LATERAL CONNECTION, IS LESS SIGNIFICANT CHANGES, BUT THE CHANGES MORE RELEVANT TO CLINICAL OUTCOME, IT MEANS THAT MORE IMPROVEMENT IN THE LATERAL CONNECTION TO LATERAL PFC INDICATES BETTER TREATMENT AND OUTCOME AND ALSO MORE REDUCTIONS IN THE [INDISCERNIBLE]. SO THIS IS REALLY INTERESTING BUT STILL NOT ANSWER THE QUESTION FROM A CLINICAL PRACTICAL POINT. SO WE TARGET WHICH PATHWAY WOULD WE USE AS A TARGET? SO I THINK THIS STUDY, SO WE LOOKED FURTHER INTO THE DATA USING THE ELECTROFIELD MODELING, SO THIS IS MORE DETAILS ABOUT THE DATA APPLICATION, SO WE HAVE 21 PATIENT WHO SUBMIT WITH THE OTHER AND THEY'RE ALSO WITH THE FOOD SESSION 36 SESSION WITH THE HIGH FREQUENCY TO THE LEFT AND USING SUBJECT SPECIFIC ACTUALLY USING SUBJECT WITH THIS, SO THIS JUST INDICATES THAT THE REGION, AND ALSO THIS IS SHOWING THE WAY WE [INDISCERNIBLE] SIMILAR TO [INDISCERNIBLE] PROPOSE THE METHOD AND FUND TARGET FOR [INDISCERNIBLE] SUBJECT. THE BUT THE TARGET FOR THAT MAY NOT BE THE TARGET THAT WE ACTUALLY STIMULATE BECAUSE THE DIFFERENT DISTRIBUTION FIELD TO UNDERSTAND THE EFFECTIVE TARGET THAT WE HAVE SO WE APPLY SIM NIB TO SIMULATE ELECTRICAL FIELD BASE EDUCATIONAL ON THE MRI, AND THEN WE LOCALIZE THE ROSENT WITH [INDISCERNIBLE] OF THE FIELD, THAT'S CONSIDERED EFFECTIVE SUBMISSION TARGET. USING THE ALGORITHM WE CAN MAP ALL THE TARGET THE SAME AND OVERLAY ON TOP OF THE [INDISCERNIBLE] AREA WHERE WE SHOW THE DISTRIBUTION OF TARGET. YOU CAN SEE THAT MULTIPLE TARGET IS AROUND THE [INDISCERNIBLE], THAT IS THE TRADITIONAL RPFC REGION BUT SOME TARGETS WILL BE FURTHER AWAY BECAUSE THE INTERSUBJECT WHERE WE HAVE [INDISCERNIBLE] THAT. SO WE ALSO DISTRIBUTION OF THE TARGETS FOR SOME OF THE ADVANCE IN THE ISOTOPIC WALL HAVE EQUAL DISTANCE TO THE FIBER, TO THE TARGET. SO THEN WE CALCULATED THE CORRELATION FROM THE DISTANT OF THE FIBERS [INDISCERNIBLE]. SO THIS IS THE MAIN RESUMMIT. WE FOUND THAT SHOULDER DISTANCE TO THE CONNECTION TO SUBUNIT SINGULAR RUNNING 9, SO IT'S BASICALLY TO THE MEDIAL PART AND YOU GET BETTER THAN OTHERS SO THE WAY WE DID IT IS USING HIERARCHICAL ANALYSIS AND FORCED TO A PORTION FROM THE SEVENTH MAJOR FIBER BUNDLE AND DO THAT TO THE SMALLER FIBER BUNDLE TO LOCALIZE MORE SPECIAL FIBER, BECAUSE THERE'S SO MANY OF THESE, I THINK THE [INDISCERNIBLE] IS INTERESTING BUT NOT SIGNIFICANT ENOUGH TO CLAIM IT TO SLIDE [INDISCERNIBLE] BUT IT'S STILL INTERESTING PERMITTING AND ALSO I THINK SOME OF YOU MAY BE INTERESTED IF THERE ARE SIGNIFICANT CULTURE WITH IN FIELD INTENSITY [INDISCERNIBLE] WE DIDN'T FIND ANY INFORMATION WITH THE INTENSITY SO WE CALCULATE THE INTENSITY OF THE FIBER BUNDLES AND ALSO AROUND THE REGION BUT WE DIDN'T SPEND ANY OR DATA AND SO THIS IS JUST 1 EXAMPLE OF HOW THIS CONNECTION LOOKS LIKE FOR 1 SUBJECT. I THINK THAT'S OUR MAJOR RESULT SO BASICALLY WE DISCUSS ULTIMATELY FUTURES IN MULTIPLE FIBER PATHWAYS AND ALSO IF YOU'RE MODELING AND WITH THE TARGET. AND THE TARGET, I THINK--SO BEASKLY THE RESULTS FROM OUR STUDY TO THE MEDIAL PART OF [INDISCERNIBLE] BUT TALK THAT DR. ELIZABETH PRESENTED ON MONDAY THAT'S CONNECTION BETWEEN SGC KD--SALLY BA AND SO THAT'S FROM THIS PAPER, THIS IS JUST THE COMPARISON BETWEEN THE 2 FIBERS SO THEY ARE REALLY RELATED SO FOR 9 AND 10, NEXT TO EACH OTHER AND ALSO CONNECTION TO THE INTERMEDIAL PART. AND ALSO WE LOOK INTO THE MONKEY LITERATURE THAT THIS STUDY THAT INJECT [INDISCERNIBLE] FROM EITHER 9 OR 10, THEY OFFER TO [INDISCERNIBLE] 25 SO I THINK IT'S VERY INTERESTING. BUT I THINK ALSO WE NEED TO RETHINK THAT WE CLARIFY THE FIBER BASED ON THE CENTRAL ARCHITECTURAL STRUCTURE OF THE REGION BUT MAYBE IF THEY BELONG TO THE SAME FUNCTION, THEY HAVE THE SAME FUNCTIONAL, MAYBE CAN YOU BE AT THE GROUP TARGET. SO, BUT ALSO OUR STUDY IS ALSO IMAGED BY THE NUMBER OF SUBJECTS. WE ARE LOOKING FOR MOST DATA, I THINK MOST LIKELY KNOW IF WE HAVE ANY DATA RELATED AND ALSO, I THINK FROM THIS I SAW MANY TALKS USING FMR, AND TO A LIST OF [INDISCERNIBLE] FM R STUDY BECAUSE IT DOES PROVIDE DIFFERENT INFORMATION TO UNDERSTAND UNDERLYING NETWORK. THAT'S ALL FOR MY TALK. CAN YOU E-MAIL ME IF YOU HAVE ANYY REQUESTS. THANK YOU. [ APPLAUSE ] >>THANK YOU VERY MUCH, WE CAN TAKE 1, 2 QUESTIONS. IF THERE IS A QUESTION. >>OH, SORRY GO AHEAD. >>VERY NICE WORK OF COURSE THE IT'S A VERY DIFFICULT PROBLEM. WE CAN ALWAYS RELAX THE FIBER PARAMETERS AND GET ARE DIRECT CONNECTIONS ABOUT YOU DOESN'T MEAN THERE'S ACTUALLY CONNECTIONOT OTHER END YOU COULD NOT FIND THOSE CONNECTIONS THAT ALSO DOESN'T MEAN THAT THERE AREN'T CONNECTIONS BUT YOU ALSO WITH NEUROANATOMY SO WHAT IS THEIR EXPECTATION? DO THEY EXPECT A DIRECT CONNECTION AS A POSSIBILITY? SO IS THERE A LIKE A SEARCH ACTUALLY TFERREDS THE DIRECTION ALSO? OR I MEAN LIKE A--IS [INDISCERNIBLE] VALUABLE TO ACTUALLY SPECULATE THAT THAT COULD BE A DIRECT PATHWAY ALSO? WHAT'S YOUR OPINION? >>YOU MEAN THE DIRECT CONNECTION FROM THE [INDISCERNIBLE] TO SUBJECT STIMULI? >>YEAH. >>OUR DATA WE DIDN'T FIND THAT. REALLY HIGH RESOLUTION MR AND ALSO THE MONKEY LITERATURE, FOR 1 CITATION, THEY INJECT FROM THE [INDISCERNIBLE] PROGRAM FOR THIS AND DIDN'T GO TO [INDISCERNIBLE] SO I THINK THAT'S VERY CONSISTENT TO OUR RESULTS. SO THESE ARE THE CONNECTIONS, INDIRECT CONNECTION FROM OTHER PATHWAYS OR FROM OTHER CORTICALE TO CORTICALE PATHWAY THAT CAN NOT BE [INDISCERNIBLE]. SO WE ALSO WORKING ON HIGH RESOLUTION AND SUPER OFFICIAL BUT TRACKING SO WE GET MORE DETAILS NETWORK STRUCTURE FOR THAT RETURN. >>OKAY, THANK YOU. >>MAYBE IF I CAN JUST ADD 1 COMMENT. WHEN WE DO FOCUS ULTRASOUND IMAGING IN THE INTERNAL CAPSULE, WE DO ACTUALLY GET THE SAME FIBERS YOU'RE GETTING TO 9 AND 10 EMPLOY I GUESS MOST PAPERS ARE PREDICTING THE IMPROVEMENT. SO LESIONING THE FIBERS GO IN THERE ALSO WORKS, --I GUESS. >>THANKS. OKAY. >>THANK YOU AGAIN FOR THE NICE TALK. >>[ APPLAUSE ] AND THEN THE LAST SPEAKER WILL BE DR. ZHAI FROM THE NATIONAL INNSITUTE ON DRUG ABUSE. YOU CAN STARLIGHT THE VIDEO. >>I HAVE NOTHING TO DISCLOSE FOR MY TALK TODAY, HELLO I'M TIANYE, ZHAI FROM THE NATIONAL EN--STRATEGIESITUTE ON DRUG ABUSE AND MY TALK TODAY IS NEUROIMAGING BASED TARGET PRESCREENING FOR TARGET DESIGN, BASED ON YEARS OF HUMAN RESEARCH ON THE HUMAN BRAIN, OR SO CALLED READING FROM THE BRAIN, WE ARE NOW ENTERING AN ERA OF BACK TRANSTHRAIGZ TO THE HUMAN BRAIN OR WRITING TO THE BRAIN WITH A AID OF LIST OF TRANSCRANIAL STIMULATION TECHNIQUES SUCH AS THE TMS, TDCS, TACS, TAUS, ET CETERA THAT WE HAVE BEEN TALKING ABOUT OVER THE PAST FEW DAYS. THE NAWP INVASIVE NATURE OF THESE TECHNIQUES MADE THEM PROMISING TOOLS TO TACKLE WITH DIFFICULTIES IN A TREATMENT OF A WIDE RANGE OF NEUROSICKIATRIC DECS SUCH AS MAJOR DEPRESSIVE DISORDER, OBSESSIVE COMPULSIVE DISORDER AND SUBSTANCE USE DISORDER. DUE TO THE OVERARCHING WROAL ROLE IN GOVERNING MANY COGNITIVE AND EFFECTIVE PROCESSES, THE PRECORTEX, SUCH AS THE PFC, AND THE OFC AND THE VFC HAS GAINED ATTENTION AS TARGETS OF THE HOW HOWEVER, LIKE THE HUMAN OFC, THESE ARE USUALLY ANATOMICALLY LARGE AND FUNCTIONALLY HETEROGONEIOUS, THIS MEANS IF YOU STIMULATE DIFFERENT REASON YOJS, YOU'RE LIKELY TO,A CHIEF DIFFERENT THINGS, ALTHOUGH THEY'RE ALL CALLED OFC STIMULATION. IT HAS BEEN DEMONSTRATE THAD EACH WITHIN THE CONCEPT OF DFLCSOMULATIONS, DIFFERENT ACTIONS WERE ASSOCIATED WITH EFFICACY FOR DEPRESSION. AND WE KNOW THAT IN NONEVASIVE STIMULATION, IT'S A CRUCIAL DETERMINANT FOR THE TREATMENT AND EFFECTIVENESS AMOUNT OF PRIMER TO SPACE, BUT MANY NEUROMODDULATION BASE AND CLINICAL STUDIES LACK COMPELLING JUSTIFICATIONS IN SELECTING THE ACTUAL LOCUS OF A REGION FOR THE STIMULATION TARGET. WE HAVE 3 FOR THE DLPFC, AND DRIVING FROM THE CLASSICAL 1020 SYSTEM OR SOMETIMES IT CAN BE EVEN SIMPLER THAN THAT JUST TO USE COORDINATES FROM A PREVIOUS PUBLISHED LITERATURE. IN SEARCHING FOR THE EFFECTIVE TREATMENT TARGETS OF A SPECIFIC DISORDER, THE MOST INTUITIVE WAY IS TO SEARCH WITHIN INTERESTED AREA DIRECTLY WITH THE CLINICAL TRIALS IN THIS CASE, SAY WE HAVE DIFFERENT BRAIN SIDES TO BE TESTED FOR EFFICACY. EACH SIDE REQUIRES A CLEANICAL TRIAL WITHIN PARTICIPANTS, THAT IS A TOTAL OF PARTICIPANTS NEEDED TO EVALUATE THE TREATMENT'VE CASSIE UNDER CLINICAL SETTING. PLUS THE OTHER FACTORS IN HUGE PRIMARY SPACE, THIS DIRECT STRATEGY IS FINANCIALLY COSTLY AND TIME CONSUMING TO AN EXTENT OF BEING VIRTUALLY IMPOSSIBLE. IT IS HOWEVER POSSIBLE TO USE THE FUNCTIONAL IMAGING SUCH AS FMRI TO CHARACTERIZE FUNCTIONAL FEATURES OF MULTIPLE RIs TO IDENTIFY LOCI AND FUNCTIONAL SUCKERITS THAT ARE MOST RELEVANT TO DISEASE RECOVER EXPE TREATMENT, AND MIGHT BE PRIORITIZED IN TESTING EFFICACY IN CLIN CAM SETTINGS AS A STIMULATION TARGET. THEREFORE WE PROPOSE THE 2 STAGE APPROACH FOR NEURAL MODULATION BASED ON TRIM AND DEVELOPMENT, A STAGE 1 THAT INVOLVES THE EXPLORING RIs FOR THEIR RELEVANCE TO A SPECIFIC DISEASE. AND A STAGE 2 OF TESTING ONLY A FEW. MOST RELEVANT BRAIN LOCATIONS WITH A CLINICAL TRIALS FOR EFFICACY. THIS WILL GREATLY REDUCE THE TIME AND EFFORT NEEDED FOR TARGET OPTIMIZATION, IN NEUROMODDULATION BASED CLINICAL INVESTIGATIONS TO A FEASIBLE LEVEL. SO NEXT I WILL BE FOCUSING ON DEMONSTRATING THE NEUROIMAGING BASE TO STAGE 1 WITH THE EXEMPLAR OF THE OFC STIMULATION FOR COCAINE DISORDER. THE COCAINE USE DISORDER HAS MANY OTHER FORMS OF ARK DICTION IS A HIGHLY REFRACTORY PSYCHIATRIC DISEASE WITH A HIGHER LAPSE RATE POST TREATMENT EACH FOR THE TREATMENT SEEKING PATIENTS, THEREFORE OUR STAGE GOAL HERE IS TO IDENTIFY LOW C 1 THE ROI THAT COVERS THE ENTIRE OFC THAT RELATE THE MOST TO COCAINE RELAPSE. IN ORDER TO DO SO, 2 COHORTS WERE INVOLVED COHORT 1 DISCOVERED AS A RESTING DATA FROM 43 TREATMENT SEEKING CUD PATIENTS WERE SCANNEDDA THE END OF A 30 DAY PATIENTS SOCIAL TREATMENT PROGRAM AND FOLLOWED UP FOR UP TO 6 MONTHS. ALSO INVOLVE SUGGEST A COHORT 2 OR INDEPENDENT VALIDATION COHORT, SIMILARLY, THIS COHORT OF A 36 PARTICIPANTS WERE SCANNED AT THE END OF 2-4 WEEK IN PATIENT TREATMENT PROGRAM FOR RESTING STATE FMRI AND FOLLOWED FOR UP TO 90 DAYS POST TREATMENT FOR COCAINE RELAPSE. REGARDLESS OF THE TECHNICAL DETAILS GENERALLY WHAT WE DO IS FOR EACH OF THE ROIs, WE COMBINE WHOLE BRAIN FUNCTIONAL CONNECTIVITY AND RELAPSED DATA WITH THE MODELING TO GENERATE PREDICTION MODELS, SIFORT WE PREDICT ANALYSIS ON COHORT 1, ON THE CROSS VALIDATION LOOP AND THEN WE USE COHORT 2 BEFORE EXTERNAL FOUNDATION. THE ANALYSIS CONDUCTED FOR ALL 20 ROIs, FOR MEDIA TO BILATERALLY. TWO OUT OF THE 20 RIs WE TESTED WERE IDENTIFY AS SIGNIFICANTLY COCAINE RELAPSE WITHOUT THEIR FUNCTIONAL CIRCUITS. BOTH ON THE LEFT LATERAL SIDE OF THE OFC. THESE ARE REFERRED TO AS PREDICTIVE ROI 1 APPROXIMATE 2 HERE AND AFTER. AFTER EACH OF THE ROIs, 2 SETS OF FUNCTIONAL CIRCUITS THAT UNIQUELY CONTINUED TO COCAINE RELAPSE WERE ALSO IDENTIFIED, A SET OF PROTECTIVE CIRCUITS WHICH MEANS THE STRONGER FUNCTIONAL CONNECTIVITY AND THE LESS LIKELIHOOD OVERLAPS AND A SET OF RISK CIRC ARE UTRS WHICH MEANS THE STRONGER FUNCTIONAL CONNECTIVITY, THE HIGHER LIKELIHOOD OF RELAPSE, DURING THE FOLLOW UP, BUT IN ORDER TO MINIMIZE THE OVERLAPPED VARIANCE EXPLAINED BETWEEN PREDICTION MODELS FROM THE 2 ROIs, WE COMBOYNE THOSE FROM THE ROIs AND SELECTING TERMS IN THE COMBINATION AND BUILD THE FINAL PREDICTION MODEL THAT INCLUDE THE RISK INDEX OF THE REDICTIVE RO-1 AND THE BRO DICTIVE INDEX OF ROIs 2 OF 91.4%. WE THEN APPLY OUR REFINED FINAL PREDICTION MODEL ON COHORT 2 FOR INDEPENDENT VALIDATION WHICH YIELDED REASONABLY ACCURATE PREDICTION OF RELAPSE AT 75.9% ACCURACY. FINALLY WE ALSO CONDUCTED A POST HOC ANALYSIS BY COMBINING ALL DATA FROM 2 COHORTS AND CLUSTERING THEM ON THE PROTECTIVE RISK PLAYING FROM THE FINAL PREDICTION MODEL. SIX TYPES WERE IDENTIFIED. FOR EXAMPLE, CLUSTER 1 AND 2 ON THE LOWER CORNER AND HIGH PROTECT AND I HAVE LOWER RISK INDICES, WHICH IS THE LONGEST BASE FOR RELAPSE AS SHOWNOT BAR PLOT ON THE RIGHT. FOR QUICK DISCUSSION USING FMRI AND COST REGRESSION BASED PREDICTION MODELS WE WERE ABLE TO IGENETICALLYIFY 2 OUT OF HUMAN, ROIs THAT ARE HIGHLY RELEVANT TO COCAINE RELAPSE, WITH THE FUNCTIONAL CIRCUIT. THESE COULD BE TREATED AS POTENTIAL STIMULATION TARGETS TO BE FURTHER TESTED WITH CLINICAL TRIALS. THE IDENTIFIED FUCHGZAL CIRCUITS SERVING RISK FACTORS WAS RELAPSED NOT ONLY PROVIDE A SYSTEM LEVEL NEURAL MECHANISM FOR THEIR RELEVANCE TO COCAINE RELAPSE BUT MAY ALSO SERVE AS A POTENTIAL UNDERLYING MECHANISM NEAR NEURAL MODULATION TREATMENT TO TAKE EFFECT. ONE THING THAT GAVE US MORE CONFIDENCE IN THIS IS OUR PREVIOUS STUDY USE UTILIZING A SIMILAR MODELING TECHNIQUE INVESTIGATED [INDISCERNIBLE] AND IDENTIFIED AS 3 HIGHLY RED ROIs, AND THE 1 ON THE LEFT IS VIRTUALLY THE SAME AS THE ACTUAL RTMS SIMULATION TARGET THAT SHOWED PROMISING TREATMENT IN THE ADVOCACY IN AN OPEN LABEL PILOT STUDY TREATING COCAINE ADDICTION, THIS IS THE PERFECT EXAMPLE OF THE POTENTIAL APPLICATION IN THE MODELING APPROACH IN THE FIRST STAGE FOR TARGET PRESCREENING WHICH CAN BE USED TO GUIDE EXPERIMENTAL DESIGNS IN THE SECOND STAGE FOR VALIDATION WITH CLINICAL TRIALS. AWLTS POTENTIAL SUBSTIEPS OF DEC CAN BE CHARACTERIZED WHICH COULD BE UNDERLYING A CALMLY OBSERVED VARIANCE IN INDIVIDUAL RESPONSIVENESS TO NEUROMODDULATION TREATMENT. THIS INFORMATION OF POTENTIAL SUBTYPES COULD ALSO BE USED TO GUIDE THE DESIGN EVER PERSONALIZED TREATMENT FOR EXAMPLE, TO PROMOTE THE PROTECTIVE CIRCUITS FOR PARTICIPANTS WITH A HIGHER RISK OF CIRCUIT BUT WITHOUT THE BALANCE OF THE PROTECTIVE CIRCUIT LIKE CLUSTER 5 AT TOP LEFT CORNER SHOWS. SO TO SUM UP HERE WE PROMOZ A 2 STAGE TARGET PRESCREENING ANDEM DIDON STRAIGHTED THE STAGE 1 IN DETAILS THAT INVOLVES SYSTEMATIC LOAMACYY COMPREHENSIVELY EXPLORING ROIs FOR A SPECIFIC DISEASE, THE INCOME STEP WOULD BE TESTING THESE POTENTIAL TACKERETS WITH CLINICAL TRIALS FOR TARGET ENGAGEMENT AND TREATMENT ADVOCACY. EXAMPLES ARE 2 ONGOING CLINICAL STUDIES HERE AT NIDA, BASED ON THE INVOLVED MENTION SIMILAR WORK ON THE HUMAN DLPC, 1 IS A CONCURRENT STUDY LEAD BY DR. [INDISCERNIBLE] STUDYING TARGET ENGAGEMENT AND ACCURATE EFFECT ON THE DPLC, WITH THE HEALTHY PARTICIPANTS THE OTHER IS AN OFFLINING EYE TBS TREATMENT STUDY BY DR. [INDISCERNIBLE], STUDYING TREATMENT EFFICACY OF THE DLFPC STIMULATION FOR TREATMENT FROM SEEKING COCAINE USERS. THIS IS ALL I WOULD LIKE TO ACKNOWLEDGE MY SUPER VISOR COLLEAGUES AND COLLABORATE OARS AND MY INSTITUTE FOR MAKING THIS STUDY POSSIBLE. AND LAST BUT NOT LEAST DEPENDING ON THE SET UP, I MAY OR MAY NOT BE ABLE TO ANSWER YOUR QUESTIONS BUT PLEASE FEEL FREE TO REACH OUT TO ME SHOULD SHOULD YOU HAVE ANY. THANKS IF ARE YOUR ATTENTION. [ APPLAUSE ] , OKAY, THANK YOU VERY MUCH FOR ATTENDING THIS SESSION. WE ARE A LITTLE BIT BEHIND THE SCHEDULE SO IT WOULD BE NICE IF YOU CAN BE BACK IN 15 MINUTES TO START THE NEXT SESSION. SO LET'S START WITH THE FIRST SPEAKER, DR. DESMOND OATHES, FROM THE UNIVERSITY OF PENNSYLVANIA. >>THANK YOU FOR STICKING AROUND AND LISTENING TO ME SHARE MY WORK AND THE FOR THE INVITATION. THIS IS A SUBTITLE FOR MY TALKS TITLED THE ORIGINAL TITLE BUILDINGA I DISCOVERY PIPELINE AND HOPEFULLY I HAVE FLESHED OUT AND PIQUED YOUR INTEREST. I DON'T HAVE ANY DISCLOSURES, SO THIS WAS MENTIONED ACTUALLY IN THE LAST TALK ABOUT THE PATH TO FINDING NEW TARGETS AND TESTING THEM AND SLOW AND ARDUOUS AND TRYING TO FIGURE OUT WAYS OF SPEEDING UP THAT PROCESS WOULD BE VERY WORTH WHILE SEE, LIKE THE TYPICAL OLD STYLE OF DOING OUR TREATMENT OR DEPRESSION TAKES QUITE A WHILE, LIKE 4 TO 6 WEEKS, OF DAILY TREATMENT, IT COSTS A LOT. THERE'S A BIG BURDEN ON PROVIDERS AND THE RESEARCHERS, THE PATIENTS HAVE TO WAIT A REALLY LONG TIME, NOT CLEAR WHAT TO DO WITH THEM WHEN THEY DON'T RESPOND. WE FIND THAT IT DOES WORK ON AVERAGE, WE DON'T KNOW WHY TYPICALLY, YOU DON'T HAVE A BRAIN RESPONSE OR ANYTHING THAT YOU MEASURE, ASIDE FROM SYMPTOMS, YOU JUST KIND OF FIGURED THAT YOU CHANGED SOMETHING AND THEN YOU HELP WITH THE SYMPTOMS AND THAT'S ALL YOU KNOW. YOU DON'T KNOW WHY, WHAT PART OF YOUR PROTOCOL REALLY WAS THE MOST EFFECTIVE, THE DOSE TIMING, THE TARGET, THERE'S USUALLY SO MANY UNKNOWNS THAT COME OUT EVEN WHEN THE CLINICAL EFFECT GOES. WHY SHOULD YOU CARE WHY IT WORKS, IF IT, WOS THEN JUST DO IT, RIGHT? BUT IF YOU UNDERSTAND A LITTLE BIT MORE ABOUT WHY IT WORKS, THERE'S THE PERSPECTIVE OF UNDERSTANDING, LEARNING A LITTLE BIT MORE MENTAL ILLNESS ISSUES ET CETERA, THAT'S BEEN IN A LOT OF OUR IMAGING GRANTS FOR MANY DECADES AND UNFORTUNATELY IT HASN'T TRANSLATED INTO MUCH OF A CLINICAL BENEFIT BUT I STILL THINK UNDERSTANDING IS IMPORTANT BUT MAYBE MORE DIRECTLY APPLICABLE AND PRAGMATIC IS TO FURTHER OPTIMIZE WHAT THEY'RE DOING AND MAKE THE TARGETS AND TREATMENT PROTOCOLS EVEN BETTER. SO YOU GET THESE SITUATIONS WHERE A SIMULATION PROTOCOL WORKS FOR SOME PEOPLE AND IT DOESN'T WORK FOR OTHER PATES. YOU HAVE A PATIENT THAT COMES IN DISTRESSED ON THE LEFT SIDE, YOU APPLY TMS SOMEWHERE, USUALLY DLPFC AND SOME PEOPLE GET BETTER, SOME PEOPLE DON'T HAVE ANY CHANGE, OTHER PEOPLE GET A LITTLE WORSE. WE HAVE NO IDEA, WHY, RIGHT? AND ESPECIALLY FOR THESE POOR FOLKS WHO ARE NOT RESPONDERS, YOU PROBABLY HAD 1 MAIN TREATMENT AND IT DIDN'T WORK FOR THOSE GUYS AND NOW YOU WASTED A LOT OF TIME AND YOU DON'T KNOW WHAT TO DO WITH THE PATIENT. SO IN MY LAB WE DO A LOT OF TMS/FMRI, SO WE ISSUE BRAIN RESPONSES. ONE OF THE CONVENIENT THINGS ABOUT THAT IS THE BOLD RESPONSE IS SLOW SO CAN YOU PING A CIRCUIT AND YOU CAN CAPTURE THE DOWN STREAM EFFECTS CAUSED BY THE STIMULATION THROUGHOUT THE BRAIN, CAN YOU MEASURE THESE RESPONSES AND YOU AVERAGE THEM FOR MANY TRIALS JUST LIKE ANY OTHER EVENT RELATED FNRI DESIGN AND YOU CAN SEE WHERE DOES THE COMMUNICATION GO WHEN YOU STIMULATE A PARTICULAR CIRCUIT. AND SO WE'RE VERY INTERESTED IN MY LAB AND I BE THIS IS CONSISTENT WITH WHAT A LOT OF YOU GUYS ARE DOING IN DEVELOPING A NEUROMODDULATION DISCOVERY PIPELINE, USING TMS FMRI, MAYBE WE CAN USE IT IN A WAY THAT WILL SPEED UP THE PROCESS, TEST HYPOTHESIS ABOUT BRAIN CIRCUITRY AND HOW RESPONSIVE IT IS TO STIMULATION AND MAYBE EVEN IN SOME WAYS RESCUE NEUROIMAGING FOR THE USE IN PSYCHIATRY EVEN WHEN THERE ARE THESE COUNTER EXAMPLES OUT IN THE LITERATURE THAT PEOPLE ARE VERY CONCERNED WITH TRYING TO DETECT ABNORMALITIES, ET CETERA. SO THE FIRST THING YOU CAN DO IS YOU START WITH IN THE PIPELINE MAKING A NEW TARGET. THIS IS YOUR HYPOTHESIS, YOU SAY, HEY, I THINK I HAVE A NEW CLEVER WAY OF MEASURING BRAIN AND I WANT TO AND I WANT TO TRY STIMULATING THAT PATHWAY AND SEE WHAT IT DOES, AND IT DOESN'T HAVE TO BE CONFINED TO 1 PARTICULAR KIND OF THEORETICAL BEND IN WHAT YOU THINK IS THE BEST WAY TO TARGET, YOU CAN TEST THEM ALL. SO IF YOU HAVE 1 BASED ON METE YORK DISCIPLINARY AM NAICS OR THEORY, GRAFT THEORY BASED ON DTI, IN EFIELDS, COMBINE THIS THEM HOWEVER YOU WANT TO THESE ARE ALL PROMISING THINGS WE SHOULD BE TRYING IN VARIOUS WAYS. BUT THE NEXT STEP IS A LITTLE TRICKIER WITH TARGET ENGAGEMENT. YOU DO A LITTLE RTMS ON A DEPRESSED PATIENT AND THEY DON'T SAY THAT FEEL BETTER AND THEY SAY OW, THAT HURTS, AND YOU SAY YOU NEED TO COME BACK FOR A LOT OF SESSIONS BEFORE WE SEE ANYTHING CONCONVENIENT. SO IT WOULD BE CONCONVENIENT AND USEFUL IF YOU CAN SHOW THEM SOME WAY TO ENGEAJ THEM AS A CIRCUIT AS A PROOF THAT YOU'RE AIMING FOR SOMETHING AND TMS CAN ACTUALLY DO SOMETHING TO THAT CIRCUIT. SO IF YOU THROW IN THE TMS FMRI, YOU CAN STIMULATE THESE CIRCUITS, MULTIPLE PLACES AND YOU CAN GET A RESPONSE IN THE PLACE I WAS TRYING TO GET AN EVOKED RESPONSE ISSUES YOU GET A LOT OF MAP OUT SO YOU GET A LOT OF INFORMATION FOR DOING THIS AND YOU DO ENGAGEMENTS. ALL RIGHT SO IN MY LAB WE DO SOMETHING LIKE THIS. THESE ARE THE LITTLE BLUE ARE THE SPECIFIC TRs, AND YOU GET A RESPONSE FROM AND SO, WE HAD GAPS, ACTUALLY BETWEEN EACH TR AND THE NEXT IN WHICH WE APPLY A SIPPINGLE PULSE TMS, SO IT'S NOT NEUROMODDULATION, IT'S PROBING, MAPPING, ENGAGE BEING CIRCUITS. AND THROUGH THAT WE DEVELOPED THIS CAUSAL MAP. STIMULATE HERE WHERE DOES THE ACTIVITY PROP GATE? ON THE TIME SCALE OF AN FMRI RESPONSE, RADIOIT? AND SO WE'VE BEEN DOING THIS FOR A VERY LONG TIME AND WE START WIDE CONONICLE RESTING STATE NEST WORKS AND HEALTHY CONTROLS AND WE CAN ENGAGE NETWORKS BY STIMULATING NOTE NODES ON THE NETWORK AND USING THE READ OUT OF FMRI TO TELL YOU THAT YES INDEED, YOU FOCUSED ON A SPECIFIC NETWORK, YOU PING IT, WITH THE SINGLE PULSES AND YOU CAPTURE AN EVOKED RESPONSE IN THE BRAIN NETWORK AND SAY, OKAY, WE'RE ON TO SOMETHING, I THINK WITH THIS PROBING ENGAGEMENT STUFF, LET'S KEEP GOING WITH IT. SO I DID THIS WITH USING RESTING FMRI TO PERSONALIZE TARGETING OF TMS, SO COLLECT A BASE LINE SESSION, RESTING FMRI, BASIC BASE CONNECKATIVITY, LOOK FOR HOT SPOTS ON THE SURFACE OF THE BRAIN, STIMULATE THEM FOR AN AMIC DUALA TARGET AND A SINGULAR TARGET RELATIVE TO ANXIOUS AND DEPRESSION AND SAY, WHEN CAN CAN WE ENGAGE THESE CIRCUITS? LET'S TRY THESE CIRCUITS. THEY'RE REMOTE PRESIDENT CIRCUITS OF BRAIN AND IF WE CAN ENGAGE THEM, THEY WOULD BE USEFUL AND THEY'RE INTERESTING FOR WHAT TARGET YOU ARE CHASING AND WHAT BRAIN REGION YOU'RE STIMULATING SO THERE WAS DISCUSSION EARLIER ABOUT AMIG DUALA TIEWLA PATHWAYS, DIRECT, INDIRECT, THIS IS A WAY OF SHOWING THAT ENGAGING THE CIRCUIT CAN BE DONE IF IT'S INTERACTING AND IN OUR INITIAL FORAY INTO THESE CIRCUITS WE FOUND THAT LOOKING AT FUNCTIONAL PEAKS THIS FOR MATTER, IT DIDN'T MATTER WHAT YOU WERE STIMMULING AS LONG AS IT'S A HIGH CONNECTING. SO THE AMYGDALA IT SEEMED TO MACK A DIFFERENCE IN THE EVOKED RESPONSE. SO THE DLCP, THEY TENDED TO SHOW A POSITIVE EVOKED RESPONSE WHEREAS MOTOR CORTEX AND DLPFC HAD A NEGATIVE INVOKED RESPONSE WHICH WE ARE THINKING MAYBE THE DIRECTION THAT WE WANT SO THE SINGULATE WE REPLICATED A MUCH LARGER SAMPLE AND SHOWED WE GET CONSISTENT EVOKED RESPONSES IN THE NEGATIVE DIRECTION WHICH IS DIFFERENT ACTUALLY THAN THE PAPER THAT WAS MENTIONED EARLIER FROM BRUCE AND HOLLY, THEY'RE SHOWING A POSITIVE EVOKED RESPONSE SO IT'S NICE THAT THERE'S ACTUALLY DIFFERENT CIRCUITS THAT CAN BE--THAT CAN ENGAGE THE DOWN STREAM BRAIN AREA, DIFFERENTIALLY EMPLOY SO WE DID OUR SIMILAR DESIGN PAIR WITH THE INTERLEAVE AND IT ALSO MATTERED SO THIS IS A MUCH BIGGER SAMPLE, 78 HEALTHY CONTROL ASKS WHEN WE ELECTRIC AT ANTICORRELATED LIKE THE POPULAR 1, VERSUS POSITIVATIVELY CORRELATED SPOTS AND HEALTHY CONTROLS, BOTH OF THEM DID PRETTY WELL. THEY ENGAGED THE CIRCUIT AND SHOWED A NEGATIVE EVOKED RESPONSE BUT ACTUALLY IN THE PATIENT, SOMETHING DIFFERENT HAPPENED, THE ANTICORRELATED DID ENGAGE THE CIRCUIT, BUT THE POSITIVELY CORRELATED SPOTS ACTUALLY ENGAGED IT BETTER. SO IF WHAT WE'RE REALLY TRYING TO DO IS ENGAGE WITH THAT CIRCUIT AND IT'S MECHANISTICALLY IMPORTANT FOR DEPRESSION TREATMENT, WE MIGHT TRY THE POSITIVELY CORRELATED SPOTS IF THAT'S REALLY--IF WE'RE REALLY UNDERSTANDING THE MECHANISM WE'RE AIMING FOR. ALSO THERE WAS DISCUSSION OF AMYGDALA EVOKED RESPONSE SO I SHOW THAT SMALL STUDY INITIALLY AND WE ACTUALLY REPLICATED THAT EFFECT IN A MUCH LARGER COHORT, AND SHOWED A CONSISTENT ARK MIG DUALA DUALA EVOKED RESPONSE THROUGH VLPC PATHWAYS, SO VPLC, AND SO WAS COMPLETELY CONSISTENT WITH OUR SMALLER PILOT STUDY, WE ALSO DID DTI AT BASE LINE AND LOOKED TO SEE IF WE DID [INDISCERNIBLE] THROUGH PUTATIVE PATHWAY, CONNECTING THE VLPFC TO THE AMYGDALA NETWORK AND FOUND THERE IS AN ASSOCIATION BETWEEN THE AMYGDALA EVOKED RESPONSE AND FIBER DENSITY IN THAT AMYGDALA PATHWAY SO WE KNOW TMS LIKES TO FOLLOW WHITE PARTY PATHWAYS, THIS IS KIND OF REASONABLE BUT AGAIN MORE SUPPORT FOR THE EVOKED RESPONSES TELLING US SOMETHING INTERESTING ABOUT THE CIRCUIT. BACK TO THIS PIPELINE. WE SHOWED EVIDENCE OF MAKING A TARGET, ENGAGING THE TARGET, THOSE THINGS SEEM TO BE WORKING, NEXT WE WANT TO SEE, OKAY, WELL, ENGAGING CIRCUITS THAT'S INTERESTING BUT IS IT AT ALL RELEVANT TO ACTUALLY BEHAVIORIAL CHANGES YOU WOULD SEE WITH REPETITIVE TMS, SO WE DESIGN THIS AND CAPTURE AND SPEED UP THE PROCESS OF TESTING CIRCUITS AND THE MODULATION, TRYING TO SAY WHAT IS KIND OF THE MINIMAL DOSE WHERE WE PRETTY CONSISTENTLY IN THE LITERATURE SEE RTMS INDUCED DEPRESSION CHANGES. SO IT'S SOMEWHERE AROUND THIS TIME PERIOD OF TROUGH--TROJANOWSKIITATIONAL PROTOCOL AFTER A COUPLE WEEKS AND SEWE SAID, OKAY, WE'LL MAKE THIS DOSE ABOUT THAT BIG AND WE THINK WE WILL MOVE DEPRESSION AND WE'LL LOOK AT THE BRAIN RESPONSES TO TMS FMRI AND SEE IF THERE'S RELEVANCE THERE, AGAIN NOT TRYING TO MOVE THAT THIS IS TRYING TO QUICKLY ITERATE THROUGH SHORT DIRECTION KIND OF SMALL INTERVENTIONS WE THINK ARE ENOUGH TO MOVE SYMPTOMS, MOVE THE CIRCUIT AND DEMONSTRATE THE RELEVANCE OF TMS THERE. SO NEXT WE WANT TO MAKERS AND SURE WE MODULATE THE TARGETTINGLY SENGULATE RELATED TMS FMRI AND MAPPING BEFORE HAND AND THEN WE HAVE THIS 3 DAY MINIINTERVENTION AND THEN DO THE PING OF THE CIRCUIT AGAIN AND SEE WHAT CHANGED. THIS IS OUR SCAN PROTOCOL SO WE WERE DOING A BASE LINE TO DETERMINE THE CONNECTIVITY TARGETS BUT THEN WHEN WE DO THE TMS FMRI SESSION WE DID THE PROBE INTERLEAVE AND AROUND, SHORT ROUND OF DATA BURST IN THE SCANNER. WHEN THEY'RE OUTSIDE OF THE SCANNER GETTING OUR INTERVENTION THEY COME BACK FOR 3 DAYS, THEY GET 2400 PULSE TRIPLETS OF ITBS THROUGH THEIR [INDISCERNIBLE] PATHWAY, AND INDEED WE FOUND THERE WAS A CHANGE IN THE VERSUS POST TMIs AND WE GOT SOMETHING STRONGER IN RESPONSE TO THE DEMONSTRATION. SOPHISTICATEDY WE DEMONSTRATED TARGET, ENGAGEMENT MODULATION, SO FAR SO GOOD. WHAT YOU REALLY WANT KNOW IS WHAT THAT RELEVANT TO THEIR SYMPTOM CHANGES, FERS IT RELATED DID ANYTHING HAPPEN TO THE CIRCUIT THAT SHOWS THE ASSOCIATION. WE REALLY WANT THAT TO HAPPEN PROBABLY WOULDN'T BE STANDING HERE TALKING ABOUT THE WORK BUT THIS IS THE PING OF THE CIRCUIT BEFORE IT, SO YOU SAY ALL RIGHT, IS A MEASURE OF THE CIRCUMSTANCE UTR'S INTEGRITY THE EVOKED RESPONSE DOWN STREAM ACTUALLY TELL YOU ANYTHING ABOUT HOW WELL THE INTERVENTION THROUGH THAT SAME PATHWAY WILL WORK AND IT LOOKS LIKE IT DID SO IF YOU HAVE A STRONGER ESCROAKED RESPONSE IN YOUR SUBGENERATEDDULE TO THAT PLACE WHERE WE WILL DO THE INTERVENTION, YOU WILL EXPERIENCE MORE BENEFIT, FROM THE INTERVENTION THROUGH THAT SAME PATHWAY. ALL RIGHT, SO, WE ALSO FOUND--SO WE FOUND THIS TARGET ENGAGEMENT, RIGHT. IT'S RELATED TO SYMPTOM CHANGE. TMS, FMRI TELLS YOU SOMETHING. THAT'S GREAT. ANOTHER PIECE IS THAT--SORRY HPV-YOU MAY ALSO WANT TO KNOW WELL WHAT DID THE PING LOOK LIKE DIFFERENT, DIFFERENTLY FROM THE PRETO POST INTERVENTION. SO THERE'S A CHARGE IN THE CIRCUIT ON AVERAGE IT BECOMES NEGATIVE, BUT ACTUALLY TO THE DEGREE THAT IT SHIFTS IN THE OTHER DIRECTION, TOWARDS POSITIVE DIRECTION IT SHOWS AN ASSOCIATION WITH BETTER RESPONSE TO THE INTERVENTION. SO YOU SAY, AH, THAT'S REALLY INTERESTING, CAN WE THROW A DIFFERENT KIND OF RTMS PROTOCOL AT THEM. TO RELIABLE PUSH THAT IN THE OTHER DIRECTION, IT HOPES UP A BUNCH OF NEW THINGS TO POTENTIALLY TEST. BUT WE'RE ESTABLISHING LONG ALONG THE WAY LIKE THIS PIPELINE ENGAGING THE TARGET, MAKING YOUR TARGET, MODULATING IT, SHOWING IT WITH ASSOCIATION OF SYMPTOMS, KIND OF BRINGING EVERYTHING ALL TOGETHER BUT SINCE WE COLLECTED THIS RICH DATA SO, THERE ARE MORE TECHNOLOGY TRANSFERS WE CAN LOOK AT SO STIMULATING MULTIPLE PATHWAYS HOW IMPORTANT IS THAT PATHWAY, THE EVOKED RESPONSE THROUGH THIS SPOT VERSUS ANOTHER LIKE ACTIVE CONTROL SITE. DOES IT MATTER, THAT THIS IS THE SAME SAME 1 YOU DID THE INTERVENTION ON VERSUS THE EVOKED RESPONSE IN THE DOWN STREAM AREA BUT THROUGH THE PATHWAY WE DIDN'T APPLY THE INTERVENTION TO. SO WE LOOKED AT THAT AND FOUND THAT OHM THROUGH THE PATHWAY THAT WE STIMULATED, THERE'S A RELIABLE ASSOCIATION WITH DEPRESSION CHANGE AND THAT IT'S SPECIFIC TO DEPRESSION AND NOT TO ANXIETY ON THE DES21. SO WE ARE INTRIGUED BY THIS, MAYBE THIS IS HIGHLY RELEVANT TO DEPRESSION, MAYBE LESS REEL KEEPSAKES VABT TO ANXIETY AND THERE'S ALSO THE FC STORY THAT'S OUT THERE, RIGHT WITH THE ANTICORRELATION AND WHAT WE FOUND IS ACTUALLY THE BASE LINE SESSION WE COLLECTED ON AVERAGE 10 DAYS BEFORE THE INTERVENTION STARTED WAS NOT A PREDICTOR OF HOW WELL PEOPLE ARE GOING TO RESPOND TO THE STIMULATION PROVIDED. BUT IF YOU COLLECT FC CLOSER TO IN TIME TO THE INTERVENTION WE DID ISSUES ISSUES THIS WAS A PREDICTOR AND NOT ASSOCIATION OF THE LITERATURE ISSUES THE IN THE POSITIVELY CORRELATED SPOT, THE STRONGER THE POSITIVE CORRELATION, THE BETTER THE PATIENTS RESPONDED TO TREATMENT SO IT THROWS UP A WHOLE BUNCH OF NEW THINGS, A LITTLE LIKE--A LITTLE ROCK IN THE RENCH OF GEARS OF SAYING, OKAY BEING WE HAVE IT ALL FIGURED OUT NOW WHAT THE BEST PATHWAY IS, AND RETREATING PATIENTS, MAYBE NOT, BUT LEARNING FROM IMAGING AND THERE'S MORE DATA SO AS I MENTIONED WE COLLECT THE WHOLE BRAIN DATA AND WE WANT TO KNOW IS THERE ANYTHING ELSE INTERESTING IN THERE AND HERE'S ANOTHER PIECE OF THE EXTRAS THAT COULD FEED THE NEXT PLANNED TARGET. AND SO WE LOOK AT WHAT OTHER AREA IN THE BRAIN DO WE SEE THE CHANGE FROM THE EVOKED RESPONSE FROM PRE TO POST THAT ARE ASSOCIATE WIDE SYMPTOM IMPROVEMENT AND THE THIS POPPED UP AS A WITHIN THE WHOLE BRAIN KIND OF APPROACH AS A PLACE THAT RESPONDED WELL ASSOCIATED WITH THE OUTCOME BUT THERE ARE A BUNCH OF OTHER SPOTS, TOO, PERIHIPPO CHAMPAL GYRUS AND POSTERIOR SINGULATE, AND ANXIETY DID IMPROVE THROUGH THE CIRCUIT IT WAS JUST NOT RELATED TO THE GENERAL EVOKED RESPONSE. WHAT ARE THE PLACES THAT ANXIETY IS SOCKED WITH CHANGE IN COMMUNICATION THROUGH THE CIRCUIT. AND THERE ARE AREAS, SO THERE'S A NEARBY REGION AT THE MPSC, THE 1 IN THE AMYGDALA SUGGESTING THAT MAYBE FUNCTIONAL CONNECTIVITY THORS THOSE IF THEY CANNOT RESPOND TO ANXIETY OR ANXIETY IS THE PRIMARY SYMPTOM YOU WILL TRY TO SHOOT FOR. SO THAT'S PART OF FEEDING THE NEXT PIPELINE AND THE EVOKED RESPONSE WITH IMAGING MODALITY IT'S A RESPONSE TO TMS, DIRECT RESPONSE TO TMS, SO YOU SAY, OKAY IF YOU WANT TO ENGAGE A CIRCUIT WITH TMS, YOU CAN DO THIS TMS FMRI IT'S ESPECIALLY RELEVANT TO WHETHER THE NEUROMODDULATION PROTOCOL THROUGH THAT CIRCUIT WILL BE THERE. OTHER THINGS WE CAN DO POTENTIALLY, IN THE FUTURE IS WHAT IF YOU MULTIPLE THEORIES ABOUT HOW TO PROPERLY TARGET A SPECIFIC PATHWAY. I WILL USE THIS ATLAS, I WILL USE THIS PARTIAL SCHEME, I WILL USE DTI, I WILL USE MULTIECHO RESTING STATE, WHATEVER YOU WANT, RIGHT? YOU CAN GENERATE MULTIPLE TARGETS FROM ANY BISE LINE SESSION YOU WANT AND YOU CAN PING EACH 1 OF THOSE AND SAY, WHAT I CARE ABOUT IS THE CANNED WHAT OR AMYGDALA OR THE NETWORK AND YOU CAN PING IT IN THE SCANNER, PING MULTIPLE SPOTS AND SAY WHEN 1 OF THESE ACTUALLY GIVES YOU THE BEST INVOKED RESPONSE IN THAT NETWORK OR REGION OF INTEREST FOR THAT PATIENT THROUGH THAT TARGET. AND WE THINK BASED ON THIS ACCUMULATING EVIDENCE, RIGHT? THAT YOU CAN USE THAT CLINICALLY TO SAY, FOR THIS PATIENT SHOULD BE HERE, FOR THIS PATIENT IT SHOULD BE THERE. AND HOPEFULLY WE WILL SPEED UP THE RESPONSIVENESS TO TREATMENT AND LEAD TO NEW CONSTANT TARGETS. SO QUESTION IS, ARE WE MAKING PROGRESS THEN KNOWING WHAT IN THE WORLD IS HAPPENING IN RESPONSE TO TMS WHEN WE APPLY IT TO VARIOUS PLACES ON THE SCALP AND NOT KNOWING EXACTLY WHAT'S HAPPENING UNDERNEATH? WE THINK THAT HOPEFULLY, WE ARE START NOTHING THAT DIRECTION. AND CONSISTENT WITH THIS PIPELINE, WE MADE A TARGET, 2 DIFFERENT TARGETS, THEY SEEM TO ENGAGE THE CIRCUIT, WE DEMONSTRATED THE ENGAGEMENT OF THE CIRCUIT WITH THE SINGLE PULSES. WE DID A BRIEF INTERVENTION PROTOCOL TO SHOW WE CAN MODULATE THESE THINGS, WE SAW A CHANGE IN THEM, SIGNIFICANT CHANGE AND WE BUILT THE ASSOCIATION BETWEEN THOSE PINGS TO MEASURES BEFORE THE TREATMENT, AND IN RESPONSE TO THE INTERVENTION RELATED TO THE SYMPTOM CHANGE AND THEN THROWING IN EXTRAS, WE'RE NOT DONE INTEGGIC--STRATEGICIGATING THE DATA SET, THERE ARE OTHER THINGS WE CAN EXPLORE. SO SO IN THE FUTURE, I MENTION THIS BEFORE, BUT YOU CAN USE OTHER IMAGING MODALITIES, OTHER APPROACHES TO DECIDE WHAT THE BEST TARGET IS AND TEST THEM. ALSO OF COURSE, WE WANT TO TAKE THE MOST PROMISING 1S AND MOVE THEM INTO A LONGER OR HIGHER DOSE STIMULATION PROTOCOL AND SAY, ARE THESE STILL LIKE THE MOST EFFECTIVE THINGS WE CAN BE DOING, SHAM CONTROL, THIS IS PART OF THE PROCESS OF REALLY LAUNCHING A NEW--MAKING A CLAIM THAT YOU HAVE A NEW TREATMENT TARGET, RIGHT? THAT'S ESSENTIAL WORK. THE PIPELINE GETS YOU THERE, BUT THEN YOU REALLY HAVE TO VALIDATE THAT THIS IS, YOU KNOW COULD BE BE SHAM AND THERE'S OTHER WORK IN MY LAB WHERE WE'RE TRYING TO UNDERSTAND BETTER THE TMS REVOKED RESPONSE, HOW TO OOH QUIRE THE DATA BETTER AND ANALYZE IT BETTER AND I HAVE A WONDERFUL TEAM OF COLLABORATORS AND FOLKS IN THE LAB FUNDING AGENCIES HAVE BEEN VERY GENEROUS TO US, ESPECIALLY AT NIH. AND AND THANK YOU FOR YOUR ATTENTION. I HAD A QUESTION, SO THE DATA YOU ARE SHOWING IS DIFFERENT THAN THE OTHER CORRELATION, SO I TEND TO BELIEVE ALL DATA AGNOSTICALLY THAT I'M NOT SAYING 1 IS WRITE OR WRONG BUT WHAT MAKES THE DIFFERENCE? THE OTHERS THAT ARE FINDING ANTICORRELATION, WHERE ARE THEY FINDING THE OPPOSITE AND SOME OF THE THINGS I'VE THOUGHT ABOUT IN TERMS OF VARIABILITY AND DATA AND/OR DATA ANALYSIS MIGHT HAVE TO DO WITH HOW DATA IS BEING PROCESSED. YOU KNOW I KNOW THERE'S THIS GLOBAL REGRESSION DEBATE AND WHETHER IT WANTS YOU TO TAKE THAT OUT OR NOT, AND ALSO DIFFERENCES RELATED TO AGE, RELATED TO SYMPTOM PRESENTATION. YOU KNOW MAYBE IT'S BEST FOR--THIS 1 IS GOOD FOR ANADONNIC DEPRESSION, THIS IS BEST FOR SOME OTHER FORM OR FLAVOR AND SO, I GUESS JUST YOUR THOUGHTS IN TERMS OF WHAT IS DRIVING THE DIFFERENCES AND THE FINDINGS AND I GUESS, MY THOUGHT IS IT'S PERHAPS BOTH BUT FOR DIFFERENT PEOPLE OR DIFFERENT WAYS YOU ANALYZE IT OR I DON'T KNOW WHAT'S YOUR THOUGHT ON THAT? >>EXACTLY THE SAME QUESTION. I FOUND YOUR BRAIN BEHAVIOR CORRELATION TO BE THE MOST IMPRESSIVE. MY QUESTION--LET ME KEEP IT SHORT. SUPPOSE YOU CHANGE THE FMRI REPROCESSING PIPELINE, RIGHT, DO A DIFFERENT SET OF PARAMETERS, DOES THAT CORRELATION CHANGE. HAVE YOU LOOKED INTO HA? >>I HAVE ONLY PLAYED AROUND WITH GLOBAL WITH THE RESPONSE STAYING CONSISTENT. SO AS TO THE BROADER KEOF WHY DOEUR DATA LOOK LOOK THEY MIGHT BE INCONSISTENT, THERE ARE A LOT OF ANSWERS TO THAT. ONE EVER THEM, I THINK THE EASIEST 1 IS TO SAY THAT OTHER FOLKS HAVEN'T LOOKED WIDELY ENOUGH WITHIN FC, IF YOU SEE THE RANGES WHEN THERE'S ASSOCIATION WITH OUTCOME BETWEEN THE ANTICORRELATION AND THE OUTCOME, THEY'RE USUALLY VERY LIMITED ON THE SIDE OF POSITIVE CONNECTIVITY. I THINK IT HASN'T BEEN EXAMINED CLOSELY ENOUGH. I WILL ALSO SAY THAT IN OUR DATA IT DIDN'T LOOK LIKE THE ANTICORRELATED SPOT DIDN'T ENGAGE THE SUBGENERATEDDULE, IT LOOKED LIKE IN PATIENTS WHO ARE UNMEDICATED IN MY CASE, ANOTHER VARIABLE, RIGHT, THE POSITIVELY CORRELATED SPOT JUST BETTER AT ENGAGING THE SUBGANNAULE, SO IF YOU DID A TREATMENT THROUGH THE ANTICORRELATED SPOT, MAYBE IT WOULD WORK IF WE ASSUME THAT SUBGRANNULES IS WHAT YOU'RE AFTER BUT MAYBE IT WOULD BE FASTER AND BESTER IF YOU WENT THROUGH POSITIVE LOW CORRELATED SPOTS SO WHAT HAPPENS IF YOU GO OVER A INTENSIVE PROTOCOL THROUGH MANY, MANY SESSIONS THAT PERHAPS WEEKER ENGAGED ANTICORRELATED TARGET. IT MAY BE THE CLINICAL EFFECT IS STILL PRETTY ROBUST TO THAT EVEN THOUGH IT'S A BIT WEEKER BUT MAYBE LIKE IT COULD BE FASTER OR MORE ROBUST OR LAST LONGER IF WE ABOUT THROUGH THE POSITIVELY CORRELATED SPOT. WE DON'T KNOW. WE JUST INVITE ALL OF THOSE SUGGESTIONS AS TO PEOPLE'S IDEAS AND I THINK WORTH PURSUING THEM, I'M HOPING TO SHIFT PEOPLE'S CONSCIOUSNESS OFF OF THE IDEA THAT WE HAVE IT FIGURED OUT, THAT THE CORRELATED SPOT IS IT, THEREFORE DONE, WE KNOW HOW TO FIX IT, JUST INVITE MORE KIND OF FOLKS TRYING OUT OTHER TYPES. >>SORRY, JUST IT FOLLOW UP ON THAT HOW FAR AWAY IN BRAIN GEOGRAPHY IS THE ANTICORRELATED TO THE POSITIVELY CORRELATED ARE WE TALKING ABOUT A PRETTY DARN CLOSE SPOT THAT IF YOU WITH A NORMAL COIL, SOMEONE NOT SUPER PRECISE THAT YOU WOULD HIT BOTH OR EITHER OR EITHER OR HOW FAR AWAY ARE THESE SPOTS FROM EACH OTHER TYPICALLY. >>SO THE WAY WE TARGET OUR SPOT SYSTEM TO FIND HIGHLY HOMOGENOUS REGIONS FOR AT LEFT A COUPLE CENTIMETERS IN ALL DIRECTIONS THERE'S ALSO NOT A HIGH NEGATIVE PEAK BECAUSE WE'RE TRYING TO SUPPORT THE IDEA THAT THE POSITIVE PEOPLE WORK BUT IF YOU LOOK JUST ON MMNI SPACE ACROSS ALL THE PLACES WE STIMULATE THEY DON'T LOOK VERY DIFFERENT FROM THE ANTICORRELATED SPOT FIST YOU DO THE SAME THING BUT AT THE INDIVIDUAL SUBJECT LEVEL, RIGHT, THERE ARE THESE BEAUTIFUL ISLANDS OF POSITIVE CORRELATION THAT ARE ROBUSTLY THERE IN DLPFCKISH TERRITORY FOR EVERY PATIENT WE LOOKED AT, EVERY HEALTHY SUBSCRECT WE LOOKED AT. THEY'RE CONSISTENTLY THERE. IF YOU ELECTRIC AT THE AVERAGE THEY WASH OUT OF IT AND THERE'S NOT MUCH GOING ON OZATIVELY BUT AT THE INDIVIDUAL LEVEL, THEY'RE VERY, VERY CLEANLY THERE, AND EVERYBODY THAT WE'VE LOOKED AT SO FAR. >>OKAY, THANK YOU. [ APPLAUSE ] >>SO THE NEXT SPEAKER IS ANDY HORN FROM HARVARD. MANY OF YOU COURSE KNOW THESE VIDEOS CAN BE HIGHLY EFKEASHES IN SOME PATIENTS WE ALL KNOW THAT. IN THIS PATIENT FOR EXAMPLE IT IS WITHOUT [INDISCERNIBLE], WE SEE MARKED DIFFERENCE BETWEEN SAME TIME, SAME DAY STIMULATION VERSUS OFF VERSUS OFF ON THE AND OFF ON THE LEFT AND ON ON THE RIGHT, BUT AS MANY YOU KNOW THE TREATMENT OUTCOME IS NOT ALWAYS AS OPTIMAL. ONE KEY QUESTION IS TARGETING AND WE I THINK BY NOW ALL AGREE THAT OPTIMAL BRAIN CIRCUITS NEED TO BE MODULATED BY DEEP BRAIN STIMULATION. SO FIRST OF ALL THE QUESTION IS WHICH ARE THE OPTIMAL BRAIN CIRCUITS AND HOW TO BEST TARGET AND ENGAGE THEM. THE SAME APPLIES TO TRANSCRANIAL MAGNETIC STIMULATION AS WELL SO AGAIN WE ARE LOOKING AT DEFINING OPTIMAL BRAIN CIRCUITS AND THEN USING TMS TO TREAT THEM. SO THE QUESTION IS HOW DO WE DEFINE THESE CIRCUITS, RIGHT? OF COURSE THERE ARE ANIMAL MODELS WITH THE TRANSLATIONAL VALUE MODEL REMAINS UNCLEAR AND THEN OF COURSE FUNCTIONAL MRI OR FUNCTIONAL IMAGING, WE COULD LACK AT PASHTS AND COMPARED FOR EXAMPLE, PATIENTS OR TASKS VERSUS HEALTHY CONTROLS AND TASKS AND WE SEE NETWORKS BUT THE QUESTION IS ALWAYS A THERAPEUTIC NETWORK WE'RE SEEING OR COMPENSATORY NETWORK AND THE SAM WITH ELECTROPHYSIOLOGY, THE QUESTION WILL REMAIN IS IT CAUSAL TO TREATMENT? SO AT THE CENTER OF BRAIN CIRCUIT THERAPEUTICS WHEN WORKING RIGHT NOW IN BOSTON, WE CAME UP WITH A DIFFERENT TECHNIQUE TO REVERSE THE QUESTION AND WE ALSO USE BRAIN LESIONS TO INFORM THE OPTIMAL BRAIN SUCKER UTR SO WE WANT TO USE THESE CAUSAL INTERVENTIONS TO THE BRAIN TO DEFEIGN THE OPTIMAL BRAIN CIRCUITS AND THEN THE DEEP BRAIN STIMULATION, THE QUESTION IS SIMPLE WHICH CONNECTION IS OPTIMAL, WHICH TARGET DO WE NEED TO STIMULATE. WE CAN LOOK AT THAT BY USING THE VARIANTS IN THREEMENT AND IN ELECTROPLACEMENT AND LOOKING AT WHICH CIRCUITS WERE ENGAGED BY THE PATIENTS THAT DID REALLY WELL VERSUS THE 1S THAT DID NOT DO REALLY WELL. WE'VE DONE THIS IN MANY INDICATIONS BY NOW, AND I WANT TO TALK ABOUT THIS FOR OCD, BECAUSE START WITH THIS SLIDE BECAUSE THIS IS AN ONGOING PROJECT IN MY LAB WHERE WE LOOK AT DBS IN 4 DIFFERENT DISEASES THAT INVOLVES A LOT OF COLLABORATIONS WITH A LOT OF CENTERS. WHERE WE LOOK AT WHICH TRACTS WERE IN EACH OF THESE DISEASES, ASSOCIATED WITH OPTIMAL RESPONSE, AS YOU KNOW THE SUBTHALAMIC SKULL KUS HAS A BROAD AREA AREA IN THE FRONTAL CORTEX SO WE SEE HERE THAT IN OCD, THERE'S MORE A TRACT THAT SEEMS CRITICAL VERSUS IN DYSTONIA WITH MORE SENSORY AND SENSORY MOTOR TRACK FOR DREADS DISEASE AND PARKINSON'S DISEASE. SO AS I MENTIONED, I WANT TO FOCUS ON THIS SPECIFIC TRACT HERE WE FIRST DISCOVERED IN 2019 WORK BY [INDISCERNIBLE], THIS WAS TAKEN UP BY NING FEI, LI IN MY TRACK, SO THE KEY THING IS THAT ALL OF YOU KNOW IS WE HAVE MULTIPLE TARGETS TO MULTIPLE TARGETS THAT SEEM TO BE PROMISING INCLUDING THE BCBS REGION, SO THE VENTRAL CAPSULE TRIAT UMKC, WHICH HAS DIFFERENT TARGETS INCLUDED LIKE THE DID YOU KUS CUM BENS PROPER, THE VENTRAL [INDISCERNIBLE]. AND THEN WE HAVE THE REACH AND THE 4 BRAIN BUNDLE TARGET IS CLOSE BY. SO WE WERE SUPER FORTUNATE TO BE COLLABORATING WITH [INDISCERNIBLE] LED BY [INDISCERNIBLE] AND SPEARHEADED BI CAD BI--BY [INDISCERNIBLE], AND THENLESS ALSO SPEARHEADED BY MIRCEA POLOSAN, AND ASTROORK D KIBLEUR, AND IF YOU ELECTRIC AT THE SCIENCE SHOWN IN GREEN, WE GET DIFFERENT RESULTS RIGHT SO THE STN AS YOU'VE SEEN BEFORE OF COURSE CONNECTED TO A LOT OF FRONT CORTEX IS OF COURSE THIS IS A DIFFERENT CONNECTIVITY AS WELL BUT WE IF USE STATISTICS AND USE THESE BUNDLES WE SEE BY THEIR ABILITY TO ABILITY DISCRIMINATE OPTIMAL RESPONDING PATIENTS AND NONOPTIMAL RESPONDING PATIENTS WE FIND A SIMILAR TRACT IN BOTH OF THESE TARGETS, RIGHT? SO YOU SEE HERE THAT THE STAIM TRACT JUST CALCULATED ON THE PEASHS EMERGES AS THE 1 CALCULATED FROM THE STN PATIENTS THAT I'VE SHOWN YOU ALSO BEFORE. SO WE WERE SUPER EXCITED BY THIS BECAUSE THAT WAS THE FIRST TIME WE COULD LINK DIFFERENT SURGICAL TARGETS FOR THE SAME INDICATION TO A COMMON TRACT TARGET. AND WE THOUGHT, OKAY, CAN WE NOW CLALCULATE THIS TRACT ON THE ALICK PATIENTS AND OVERLAY THE STN OF THE COHORT, SOME OF THESE STIMULATIONS WOULD REACH THE TRACT MORE STRONGLY, OTHERS WOULD MISS THE AND WE USE THAT TO CROSS ESTIMATE SO TO ESTIMATE THE OUTCOMES, AGAIN THAT WAS CALCULATED ONLY ON THE COHORT AND THEN THE AIM WAS TO PREDICT THE OUTCOMES OR THE RANKS OF THE OUTCOMES IN THE STN PATIENTS SO YOU SEE THESE 2 EXAMPLES HERE, DID NOT REACH THE TRACT MATCH, HAD A LOW FIBER SCORE WE CALL IT AND THEN THIS HAD A VERY HIGH FIBER SCORE, YOU KNOW HIT THE TRACK QUITE RECISELY. AND THAT CORRELATED WITH CLINICAL IMPROVEMENT YOU CAN ALSO DO IT THE OTHER WAY AROUND. THIS TIME WE ONLY CALCULATE BASED ON STN WE SEE NONESSENTIALICAL CLAYINGS HERE THAT ARE NOT IMPORTANT AND WE OVERLAY THE COHORTS AND SOME HIT THE TRACK AND MISS THE TRACK, SAME THING HERE, THIS FEATURE COMPLETELY MISSED THE TRACT, HAD A POOR RESPONSE, THIS DID PARTIALLY CAPTURE THE TRACT AND HAS ADEQUATE GOOD RESPONSE. LOOKING AT OTHER INDICATIONS FROM THE LITERATURE, YOU SEE THAT THESE SEEM AROUND THE TRACT SO THESE TARPGETS STICK UP THAT'S WHY THEY ARE A BIT MORE VENTRAL TO THIS AND WE COULD EVEN CALCULATE THE DISTANCE BETWEEN THE TARGET SIDES WITH THE TRACT AND CORRELATE THAT WITH THE REPORTED AVERAGE OUTCOME IN EACH OF THESE STUDIES SHOWING THAT AGAIN, THIS WAS A CLEAR RELATIONSHIP, THE CLOSER YOU WERE, THE TARGET WAS TO THAT TRACT, THE BETTER THE OWM COME AND THE STUDY. SO WE PRESENTED THIS WORK AT CONFERENCES AND WE'RE QUITE FORTUNATE THAT THE T-FROM LONDON AND THE TEAM FROM MADRID PITCHED IN TO ADD ADDITIONAL DATA TO THIS, TO VALIDATE IT FURTHER SOPHISTICATEDY WE ADD 2 MORE CORHOTTERS, THIS TIME CALCULATE THE TRACT BASED ON THE FIRST 2 COHORTS AND THE SAME THING EMERGES NOW A BIT MORE CRYSTAL CLEAR, A PRECISE AND WE AGAIN NOW OVERLAY THE SIMULATION VOLUMES FROM THE OTHER 2 COHORTS AND THE MORE THEY HIT THE RED TRACK, THE BETTER WAS THE IMPROVEMENT, A VERY SIGNIFICANT CORRELATION AND THIS WAS REALLY I REPRINT WITH THE 2 COHORTS AND WE FINE GOT THE LAST COHORTS SO WE GOT THEM ONCE THE TRACT WAS ESTABLISHED. SO THAT WAS SUPER REWARDING TO SEE THIS CHECKS OUT IN UNDEAN DATA AS WELL, BUT WHAT WAS MORE EXCITING IS THAT OTHER PEOPLE HAVE REPLICATE THE FIEBDINGS WELL, WE PUBLISHED WITHIN GBS THAT'S OPEN AND AVAILABLE, EVERYBODY CAN DOWNLOAD THE EXACT TRACT DEFINITION AND AT THE MT. SINAI GROUP OF HELEN AND [INDISCERNIBLE] DID SO AND THEY DID OVERLAY THE VOLUMES OF THEIREN IT PATIENTS AND AGAIN THE MORE TRACT WAS MODULATED, THE BETTER THESE PATIENTS DID. IN FACT 4 TOTAL REPLICATIONS CAME WITHIN THE FIRST 6 MONTHS. SO THERE'S THE PAPER I JUST MENTIONED MY SMITH ET ALAND THERE WAS ANOTHER REPLICATION IN [INDISCERNIBLE] WITH 8 PATIENTS SHOWING THE SAME TRACT VERY CLEAR CORRELATION WITH OVERLAPS AND THEN THERE WAS A STUDY FROM [INDISCERNIBLE] IN BRISBANE, AND YOU SEE THIS TRACT EMERGE HERE AND THE OVERLAP WITH OUR PUBLISHED TRACK WAS NOT SIGNATURESSATIVE CANT BUT WAS ASSOCIATE WIDE OUTCOMES AND FINALLY WHAT I FIND MOST INTERESTING IS THAT KAREN JOHNSON, [INDISCERNIBLE] LOOKED AT 28 PEASHTS WITH 5 CENTERS WITH TOURETS SYNDROME BUT WITH OCD IN THE GPIs TO GET ANOTHER TARGET AND THE OUR TRACT WAS MODULATED AT THE BETTER IMPROVEMENT SIGNIFICANTLY IN THESE TOWERET PATIENTS IN THE OBSESSIVE COMPULSIVE BEHAVIOR. SO THIS IS GREAT. NEXT STEPS TO FURTHER VALIDATE IS TO DO IT BLINDEDLY. SO I WAS QUITE EXCITED THAT SAMIR, [INDISCERNIBLE] WAS OPEN FOR SUCH A COLLABORATION AT PAY LORA RODRIGUEZ UNIVERSITY. SO THEY HAVE 10 ADDITIONAL PATIENTS NONAPOPTOTIC THE SEEN AT ALL BY NOW FROM THIS PROJECT AND THEY SENT US THE NEUROIMANNUALING AND SIMULATION PARAMETERS IN A PLIENDED PACKAGE. WE DID NOT KNOW HOW THESE PATIENTS DID, ALL WE HAVE THE IMAGING AND WE RAN THEM THROUGH THE TRACK MODEL AND PREDICKED THE CLINICAL OUTCOMES AND WE SENT BACK THE PREDICTIONS, AND THEN, SMIR'S TEAM KNEW THE ACTUAL CLINICAL OUTCOMES AND COULD CORRELATE THE 2 AND VOILĖ, IT IS REALLY EXCITING THAT THIS WORKED, RIGHT? THIS WAS REALLY PLIENDED. WE HAD TO PUT OUR NICKEL DOWN, WE HAD TO SEND OUR PREDICTIONS TO PAY LORA RODRIGUEZ AND IT DID WORK. HE USED THEIR PATIENTS, THIS IS OUR TRACT AND YOU REPLICATE THE SAME WITH THE 10 NEW PATIENTS FROM BAYLOR, YOU GET EXACTLY THE SAME TRACT AGAIN WITH THE SAME METHOD. WE ALSO LOOKED AT FUNCTIONAL CONNECTIONS LOOKINGA THE MORE SYNAPTIC NETWORKS WITH THE SAME TECHNIQUE USING FUNCTIONAL CONNECT OMES, NOW AND CONNECTED IN THE OCDDBS, AND THAT COULD BE CRUCIAL FOR TRANSLATING FINDINGS INTO THE NONINVASIVE STIMULATION AROUND WHICH HAS BEEN SUCCESSFULLY DONE IN GBS FOR DEPRESSION AND TMS FOR DEPRESSION AND BUT NOT YET FOR OCD. WE WROTE A REVIEW ON THIS ASK LOOKED AT ALL THE DATA THAT IS OUT THERE AND ATOMICAL ADULTS IN NEUROMODDULATION AND FORMS, IT TURNS OUT THAT THIS TRACT SEEMS TO LINK DIFFERENT THERAPIES THAT WE KNOW LIKE CAPSULEOT ME, AND TMS, AND SO THIS SEEMS TO BE A UNIFYING STRATEGIC BUNDLE THAT IS HELPFUL. AS NEXT STEPS THIS IS ONGOING WORK NOW, QUITE PRELIMINARY AND THIS IS WORK BY BARBARA [INDISCERNIBLE] WHO IS A ROCK STAR Ph.D. STUDENT IN MY LAB IN BERLIN. I WANT ON TO BRIEFLY SHOW IT. WE EXTENDED TO COHORT, THERE ARE SO MANY GREAT COLLEAGUES THAT HELP WITH THIS I DID NOT HAVE THE SPACE TO PUT PICTURES OF EVERYBODY ON HERE BUT THIS IS A GREAT COLLABORATIVE EFFORT BETWEEN OUR MUCH BIGGER COLLABORATION. AND WE HAVE THE ELECTRODES LOCALIZATIONS AND DIFFERENT TARGETS NOW WITH THE A MUCH BIGGER POWER HERE, THESE ARE THE DIFFERENT COHORTS WE'RE INCLUDING AND THESE ARE THE ACTIVE SIMULATION SIDES, AND NOW THE IDEA IS TO SEGREGATE THIS TRACT INTO SPECIFIC SYMPTOMS, RIGHT? THE IDEA IS TO LOOK AT--JUST THE GENERAL WIDE BOX TRACK BUT IF WE LOOK AT SPECIFIC SYSTEMS CAN WE FIND SPECIFIC CONDITIONS, ANXIETY, DEPRESSION, GLOBAL FUNCTIONING, SO HERE IT DOES BETTER DEGRADATION GREEN CELLS GET--I SO WE FIND DIFFERENT PARTS OF IT TO RESPOND BET TORE DIFFERENT SUBSYMPTOMS OF A OCD. IT HAS SPECIFIC NETWORKING FOR SUCCESSION ARE KIND OF LINING WITH THE ORIGINAL TRACT WHILE OBSESSION SEEM TO BE A BIT MORE DAUNTLY CONNECTED AND THEN WE DO SEE IN DEPRESSION, CRITICALLY ALSO THE PROPER MEDIA FOREBRAIN BUNDLE AND ALSO A BIT OR VENTAL SESSIONS AND PLOABAL FUNCTIONING IN GENERAL BEING THE MOST VENTRAL CONNECTION HERE. SO THE NEXT STEPS WILL NOW BE TO USE IN INFORMATION TO PERSONALIZE DEEP BRAIN STIMULATION, RIGHT? WE WANT TO DEFINE AND VALIDATE THESE SYMPTOM NETWORKS THAT I'VE SHOWN YOU FURTHER, ONCE WE HAVE THEM, WE HAVE--WE HAVE ESSENTIALLY A LIBRARY OF THESE METE YORKS IN THE TEMPLATE SPACE AND IF A NEW PATIENT COMES IN, THIS IS A SLIDE FOR PARKINSON'S DISOAZ WHERE WE ARE ALSO DOING THE SAME THING, THAT PATIENT COULD HAVE DIFFERENT SYMPTOM INTENSITIES IN THIS CASE, [INDISCERNIBLE], CAN YOU THINK OF OCD OF COURSE, SOMEBODY WITH A LOT OF ANXIOUS AND A LOT OF OBSESSIONS BUT MAYBE NO COMPULSES OR SIMILAR DISTRIBUTIONS OF SIM TOMS, WE CAN ALSO ASK THE PATIENT, WHAT IS THE MOST ANNOYING SYMPTOM, PARKINSON THAT IS EASIER, THERE ARE SOMETIMES PATES THAT WOULD CLEARLY SAY MY TREMOR IS LEADING TO THE MOST BURDEN FOR ME VERSUS YOU KNOW I CAN LIVE WITH [INDISCERNIBLE] KINNIESIA AND WE CAN MULTIPLY AND GET TO A FUNCTION OF TARGETS WHICH CIRCUITS WE WANT TO MODULATE MOST. NOW WE CAN AGGREGATE THESE NETWORKS FOR EACH SYMPTOM FOR THE PASHT AND PROJECT THEM TO THEIR BRAIN AS A STEP IN BETWEEN, WE CAN EVEN USE THE PROFUSION DATA OF THAT PATIENT, TO REFINE, YOU KNOW THE PERSONALIZED TRACTS IN THAT PATIENT'S BRAIN AND NOW WE CAN SEE ONCE THE ELECTRODE IS IMPLANTED WHICH CONTACTS AUTOMATICALLY TO ENGAGE THE BEST SYMPTOM SPECIFIC NETWORK FOR THAT PATIENT. WE CAN DO THE SAME WITH FMRI AS WELL AND OF COURSE IT'S ALSO USED EVEN TO IMFORP AND GUIDE TARGETING TO REALLY DERIVE AT A PERSONALIZED DEEP BRAIN STIMULATION FOR EACH PATIENT DEPENDING ON THEIR SYMPTOMS. SO I WANT TO CONCLUDE AND I WILL SAY THAT THE BRAIN NETWORKING MAPPING CAN BEY PREDICTIVE OF THE DBS OUTCOME AND I'VE SHOWN THAT ACROSS MODELS AND OUTCOMES AND TARGETS AND CENTERS. IT CANNOT BE USED TO SEGGREGATE THE HUMAN CHRONIC [INDISCERNIBLE]. SO THE FIRST SLIDE I SHOWED USING DBS ACROSS DIFFERENT DISEASES AND DIFFERENT TRACTS, I THINK IS ALSO JUST FROM A BASIC SCIENCE PERSPECTIVE, WITH GREAT TECHNIQUE THAT CAN HELP US UNDERSTAND THE BRAIN BETTER, AND THEN, LAST I SHOWED THAT SYMPTOM NETWORK PLENDING COULD BE USED TO PERSONALIZE DEEP BRAIN STIMULATION. AND MY PERSONAL AIM IS REALLY TO LOOK CLIN CAM TRANSLATIONS, I THINK ESPECIALLY THE WIDE BOX TRACK, I THINK THE IT HAS BEEN REPLICATED SO OFTEN NOW THAT IT WOULD BE GREAT TO GO PROSPECTIVE AND USE IT FOR SURGICAL PLANNING TO TENTIALLY OR FOR REPROGRAMMING TRIALS, SO, IF THERE IS INTEREST THERE, PLEASE DO REACH OUT. I WOULD LOVE TO BE INVOLVED IN SUCH A PROJECT AND WITH THAT I WANT TO END. THIS IS MY GROUP. MY LABORATORY IS SPLIT BETWEEN BERLIN AND BOSTON WITH, THIS IS THE BOSTON TEAM AND THE BERLIN TEAM WHILE [INDISCERNIBLE], THE TEAM MOVE WITH ME, AND THERE'S IF YOU ARE INTERESTED IN THESE THINGS, THERE'S A NEW BOOK OUT CALLED CONNECT TELOMERIC DEEP BRAIN STIMULATION WITH ALL OF THE METHODS WE USE FOR THIS GREAT COLLABORATIVE EFFORT THAT I HAD THE JOY OF EDITING. THANK YOU SO MUCH FOR YOUR ATTENTION. I THINK THERE WILL BE NO ROOM FOR QUESTIONS UNFORTUNATELY BUT FEEL FREE TO REACH OUT VIA E-MAIL OR TWITTER AND THANK YOU VERY MUCH FOR YOUR ATTENTION. [ APPLAUSE ] >>[INDISCERNIBLE] TALKING ABOUT CONCURRENT TMS AND MI IN DRUG ADDICTION APPLICATIONS. NTHANKS. >>THANKS ALL FOR STICK TO THE LAST TALK. I KNOW IT'S A LONG WORKSHOP. HOPEFULLY, PEOPLE WOULD ENJOY MOST OF THAT. SO, YEAH, JUST KIND OF FOLLOWING THE PREVENTIVUOUS 2 SPEAKERS ABOUT THE PACKET IDENTIFICATION AND HERE I'M GOING TO TALK ABOUT, THE IDENTIFYING THE TARGETS IN SUBSTANCE USE DISORDER OR ADDICTION, OKAY, OKAY GREAT. SO SUD FROM NEUROCIRCUITRY PERSPECTIVE IT'S REALLY A DISRUPTION OF MULTIPLE BRAIN CIRCUITS OR NETWORKS UNDERLYING THE VERY COMPLEX ADDITIONAL BEHAVIORS AND THE ANIMAL MODEL ALSO OFFERS A LOT OF OPPORTUNITY TO UNDERSTAND THE DISEASE. BECAUSE, FOR EXAMPLE, RATS HAVE VERY ANALOGOUS BRAIN CIRCUITS, BRAIN REGIONS. AND ALSO FROM A LITTLE BIT OF A MORE BROADER PERSPECTIVE S. U. D. INVOLVES IN MULTIPLE STAGES AND SUCH AS PINCHING, INTOXICATION, WITHDRAWAL AND EFFECTIVE NEGATIVE EFFECT AND PREOCCUPATION AND ANTICIPATION. SO IT'S VERY TRICKY FOR THE TREATMENT NEUROMODDULATION BASED TREATMENT. SO FIRST WHERE TO STIMULATE AND AT WHAT STAGE FOR EXAMPLE? SO, THE TREATMENT FOR THE S. U. D IS VERY CHALLENGING AS SHOWN HERE, FOR THE PSYCHOSOCIAL INTERVENTIONS. YOU CAN SAY FOR DIFFERENT TYPE OF SUDs, THE DROP OUT IS VERY HIGH, 35% AND THE RELAPSE RATE AFTER TREATMENT RESULTS VERY HIGH, LIKE 70%. SO, SO AS WE SEE IN THIS WORKSHOP SEVERAL NEUROMODDULATION APPROACH BEING DEVELOPED AND IN PARTICULAR TMS HAS BEEN APPROVED BY FDA FOR THE DEPRESSION XREEMENT AND FOR OCD TREATMENT. SO STILL A CHALLENGE IN THE TMS BASED TREATMENT FOR SUD AS I MENTIONED, YEAH, SO 1 IS WHERE, WHERE TO FIND THE OTHER TARGETS IN THE BRAIN BECAUSE THERE'S NUMEROUS POTENTIAL REGIONS SUCH AS DLPC, MEDIAL PFC, OFC INSULAR AND SO ON, ALSO VERY IMPORTANT IN EACH OF THOSE REGIONS, THE HETEROGENERATED AITY IS PRETTY HIGH. SO I WILL SHOW YOU A LITTLE BIT IN A LATER SLIDES. AND ANOTHER CHALLENGE IS IN THE TMS SPACE, THERE ARE SO MANY PARAMETERS SUCH AS FREQUENCY, INTENSITY, DURATION, TEMPORAL PATTERNS, AND SO ON. AND ALSO AS I BRIEFLY MENTIONED, WHERE TO STIMULATE, YOU KNOW DURING THE DIFFERENT BRAIN STATES. SO IN THE SUD, THERE ARE AT LEAST 3 STAGES IN THE CYCLE SO WHERE TO STIMULATE IS VERY IMPORTANT. SO, YE, WITH THOSE KIND OF BACKGROUND, SO I JUST WANT TO TELL YOU OUR RECENT EFFORTS IN THIS DIRECTION AND SOME ARE BEING PUBLISHED, SOME ARE STILL ONGOING, SO THE FIRST 1 IERK DENTIFY TARGETS BASED ON NEUROIMAGING AND DISEASE RELATE TD BEHAVIOR, IN THIS CASE, DRUG RELAPSE. SO AS WE KNOW, THIS IS A STUDY IN DEPRESSION AND WE KNOW THAT EVEN WITH THE DLPC FR EXAMPLE, THE TREATMENT IS HETEROGEANIOUS, AS THE PREVIOUS SPEAKER MENTIONED, THE ANTICORRELATION WITH [INDISCERNIBLE] INDICATES SOME TREATMENT EFFICACY IN DEPRESSION. SO, YEAH, DEPRESSION IS RELATIVELY KNOWN FOR SOME REGIONS, BUT FOR SUD IT'S MUCH LESS NOW. SO WHERE TO STIMULATE? IF WEB CONNECTED DO A VERY SYSTEMATIC SEARCH, FOR OPTIMAL TARGETS WOULD IT BE FINANCIALLY COSTLY. LIKE SAY IF IT'S A HUNDRED POTENTIAL SITES IT'S ALMOST IMPOSSIBLE TO DO THAT SO WE PROPOSE A 2 STAGE APPROACH. THE FIRST STAGE WE SYSTEMATICALLY OR COMPREHENSIVE EXPLORATION FOR THE REGION FOR INSURANCE AND RELATED TO THE DISEASE AND SECOND STAGE HOPEFULLY WE CAN NAIL DOWN ONLY A FEW POTENTIAL TARGETS. SOPHISTICATED THAT'S THE STRATEGY WE ARE USING. SO THIS STUDY ALREADY PUB LESHED SO THIS--THIS WAY IS A FOCUSING ON A DPLC, AND BASICALLY, THE--THERE'S A COHORT OF COCAINE TREATMENTS, YOU KNOW SEEKING COCAINE USERS. SO AFTER A FEW WEEKS OF PSYCHOSOCIAL TREATMENT, DID FMRI AND THEN FOLLOW UP ABOUT 24 WEEKS FOR THE RELAPSE. SO JUST KEEPING IN MIND THERE'S NO TMS HERE, IT'S JUST MORE CONVENTIONAL PSYCHOSOCIAL TREATMENT. BUT WHAT WE TRY TO DID IS FIND THE CIRCUITS AND TREME THEM AS OUTCOME AND USE THEM AS TARGET FOR THE TREATMENT. SO AS CAN YOU SEE FROM THIS SURVE BASICALLY IS A REMAINING [INDISCERNIBLE] AFTER THE TREATMENT SO YOU CAN SEE FOLLOWING ABOUT 24 WEEKS AND THEY ARE DROPPING TO ABOUT LEAK ABOUT 20% REMAINING, SO YOU CAN VIEW THIS AS KIND OF A SURVIVE CURVE IN CLINICAL SETTINGS. SO, THEN, BASED ON THAT, WE CAN--WE DEVELOPED A MODEL LOOKING AT TO LINK THE FUNCTIONAL CONNECTIVITY AND THE TREATMENT OUTCOME. SO IN THIS CASE, WE ARE USING THE REGRESSION MODEL WHICH IS A REVENTIVE TR THE SURVIVAL BEHAVIOR, SO,--SO, HERE, NOW, WE--WE PUT IT, IT SEEMS WE DON'T KNOW WHERE IN THE DPLC WOULD BE OPTIMAL FOR SUD TREATMENT, SO WE PUT IT ABOUT A HUNDRED REGION WE CHOSE OVER THERE AND WE JUST GONE THROUGH THIS AND WITH VERY STATISTICAL CORRECTIONS FOR THE MULTIPLE COMPARISON AND WE FOUND ONLY 3 OUT OF A HUNDRED REGIONS SHOWING SIGNIFICANT PREDICTION FOR THE RELAPSE AND THEN WE LOOK AT 1 REGION ACTUALLY ON THE LEFT SIDE OF THE DPLC, AND WE CHECK THE LITERATURE AND FIND IT VERY INTERESTING THIS SIDE, AND THIS AREA OF INTEREST, IMAIF USA I LET OF CONFIDENCE THAT THIS METHOD MAY WORK. ANDY SHOWED A LOT ON THE RIGHT SIDE OF DPLC, WHICH WE SEARCH LITERATURE NEVER BEEN USED FOR THE ADDICTION SO IT COULD BE POETIC TEBTIAL SITES FOR THE TREATMENT. SO IF WE WANT TO GO LOOK IN DETAIL, WHAT'S--WHAT KIND OF BRAIN CIRCUITS INVOLVED IN THIS FIRST AREA OF INTEREST, BASICALLY, THEY WOULD SHOW PROTECTIVE CIRCUITS AND THE RISKS CIRCUITS PROTECTIVE MEANS STRONGER CONNECTIVITY, IT WOULD HAVE, IT WOULD HAVE A LONGER I MEEP ABSTINENCE TIME AND RISK CIRCUITS WILL BE UP THE OTHER WAY,A ROUND SO THE PROTECTIVE SECOND QUARTER UTRS BASICALLY INVOLVED IN THIS EXECUTED CONTROL NETWORK, WHICH WE BELIEVE IS INVOLVED IN CONNECTIVE CONTROL AND THE RISKS CIRCUITS IS MORE INVOLVED IN THE INFORMAL NETWORK, AND WE BELIEVE THAT'S PROBABLY SERVING AS THE KIND OF DRIVE CIRCUITS, DRIVE FOR THE [INDISCERNIBLE]. SO, YEAH, WE ARE--WE ARE STILL WORKING ON THAT, AS YOU SEE IN A PREVIOUS TALK, I THINK THE TALK IN THE PREVENTIVE YOIS SESSION WE MOVED THIS TO OTHER BRAIN REGIONS LIKE OFC AND OTHER INSULAR OR SOME OTHER REGIONS. SO SECOND PROJECT WE ARE DOING IS, THIS IS NOT NOT BEEN PUBLISHED YET, I JUST WANT TO SHOW YOU SOME--YEAH, SO THIS IS--THIS IS BASED ON THE META-ANALYSIS, SO THE CONCEPT IS TO TARGETING THE ENTIRE PATHOLOGICAL NETWORK, SO, FROM A--FROM A MECHANISM, TYPICALLY YOU SEE A SET OF BRAIN REGIONS, IT'S ALTERED FROM THE HEALTHY CONTROL OR SOMETHING LIKE THAT, SO, HOW CAN YOU TAKE CARE OF THIS MULTIPLE REGIONS INTO YOU KNOW YOUR TARGET IDENTIFICATION. SO HERE, I JUST GIVE YOU EXAMPLE. THIS IS THE META-ANALYSIS FOR DEPRESSION AND IT'S SHOWING MULTIPLE REGIONS, YOU KNOW, HYPER OR HYPOACTIVATED. SO THEN THE GOAL IS TO FIND A SO CALLED MODLATTORY NETWORK. SO HERE JUST GIVE YOU EXAMPLE, HOW DO WE DERIVE THIS AND DEFINE THIS MODLATTORY NETWORK. SO FOR EXAMPLE, YOU PUT A TMS COIL SOMEWHERE HERE AND WITH POSITIONING AND ORIENTATION, AND WE CAN SIMULATE THE EFIELD AND HOW DO YOU FEEL WILL GENERALLY EFFECTS PROPAGATE TO THE WHOLE BRAIN, AND ANAPOISE THIS STIMULATION NETWORK. SO THIS IS A LOT OF WAYS TO DO, AND WE CAN USE FOR EXAMPLE, STRUCTURAL CONNECTIVITY, AND WE CAN USE FUNCTIONAL CONNECTIVITY AND WE CAN USE INDIVIDUALIZED CONNECTIVITY OR WE CAN USE GROUP CONNECTIVITY, RIGHT? SO, IT JUST AS A FIRST STAGE, WE JUST USED A GROUP LEVEL RESTING STAGE FUNCTIONAL CONNECTIVITY AS ESTIMATE FOR THIS PROPAGATION NETWORK. SO 1--SORRY, SO ONCE WE HAVE THESE 2 NETWORKS PATHODPLOJ LOGICAL NETWORK AND MODLATTORY NETWORK, THEN WE--OUR NETWORK OF TARGETING IS BASKLY TO LET THE MODLATTORY NETWORK KIND OF COMPARE ON THE PATHOLOGICAL NETWORK, SO FOR EXAMPLE, A PATHOLOGICAL NETWORK IF IT'S HYPER ACTIVATED WE BRING TO BING IT DOWN, SO IF IT'S HYPOWE TRY TO BRING IT UP, SO THAT IS A MATHEMATICAL MODEL FOR THAT SO I WON'T GO THROUGH THAT. SOPHISTICATED WITH THAT METHOD, CAN YOU IMAGINE JUST ON A COHORT OF SUBJEKS, THE WAYS TMS FOR EXAMPLE, TMS TREATMENT AT DIFFERENT LOCATIONS, YOU WILL SEE, THEY WILL GENERATE DIFFERENT MODLATTORY NETWORK AND THEY WOULD END UP WITH DIFFERENT EFFICACYS IN THE TREATMENT. AND SO, IN THIS CASE, YOU KNOW HOPEFULLY, WE WILL ANAPOISE THIS KIND OF SITUATION SO WE HAVE THIS SO CALLED NETWORK OF TRACKING ACCURACY BASICALLY IT'S JUST A DEGREE OF MODLATTORY NETWORK OF CONTACTS ON A PATHOLOGICAL NETWORK. SO HOPEFULLY THIS NETWORK OF TARGETING ACCURACY WOULD BE CORRELATED WITH A CLINICAL TREATMENT AND EFFICACY HERE. SO THIS IS JUST ALL HYPOTHESIS OR MODELING, RIGHT? SO THEN WE JUST MOVE ON TO GET US ON EXISTING DATA SO WE--YEAH, WE FOUND 1 PAPER FROM A FRENCH GROUP, THEY NICELY, THEY HAVE THE TREATMENT, TMS TREATMENT AND THEY HAVE FOR INDIVIDUAL SUBJECTS, THEY HAVE A LOCATION, AND ORIENTATION AND SO ON, IT'S EVERYTHING. SO THIS IS THE PERFECT PLACE TO KIND OF TEST OUT THIS METHOD. SOPHISTICATEDY IN THIS CASE, WE HAVE TWEIVE SUBJECTS AND AS I MENTIONED DIFFERENT LOCATIONS AND DIFFERENT ORIENTATION FOR THE TMS COIL. SO THEN WE JUST, YOU KNOW PUT IT OUT VARIOUS INFORMATION IN THE MODEL AND WE SEE CORRELATED BUT SPECIFICALLY EXPLAIN THE VARIANTS SO IT'S SOMETHING THERE, RIGHT? THEN WE--WE TRIED TO DO ANOTHER DAT SITE, THE SAME GROUP IN THE FRENCH GROUP, THEY DID THE TMS TREATMENT ON THE AUDITORY ON THE HALLUCINATION PATIENT, THE SCHIZOPHRENIA PATIENTS, AUDITORY HALLUCINATION, SO THEY HAVE A 15 SUBJECT, AGAIN THEY HAVE THE LOCATION, AND ORIENTATION OF THE TMS COILS AND WE PLUG INTO OUR MODEL AND WE FOUND THAL CASE, EXPLAINS EVEN MORE VARIANTS ABOUT 30% OF THE VARIANTS. SO I THINK IT'S ENCOURAGING AND IF WE HAVE A LARGER DATA SET AND WE WILL BE--WE WILL BE VERY HAPPY TO TEST THIS OUT TO SEE HOW THIS MODEL WORKS. ADDITIONALLY, YEAH, THIS MODEL CAN ALSO PREDICT IN THIS HALLUCINATION PATIENTS WE CAN PETITION THE BEHAVIOR, IN THESE PATIENTS. SO YEAH, THIS IS THE ONGOING AND NOT PUBLISHING YET, WE'RE STILL WORKING ON THAT AND THE OTHER PROJECT I WANT TALK ALSO IS AN ONGOING PROJECT. SO THIS IS TO IDENTIFY THE NEW MODULATION SITES BASED ON ANNUAL MODELS, YOU WANT TO SAY ARE YOU A LITTLE BIT CRAZY ABOUT THIS BECAUSE WE'RE WORKING ON HUMANS BUT ANIMAL MODELS, THE RAT MODELS CAN GET A PRETTY GOOD BEHAVIOR FEATURES OF THE DISEASE AND ALSO HAVE VERY [INDISCERNIBLE] BRAIN REGIONS AND CIRCUITS SO I THINK IT'S NOT TOO CRAZY TO DO THIS. SO 1 WAY TO DO THIS IS AS YOU KNOW THE SUD INVOLVES KEY FEATURES AND ARK DICTION IS COMPULSIVE DRUG TAKING, SO WE PUBLISHED A PAPER BY USING ANIMAL MODEL TO MIMIC THISY ABOUT HAIEVER, COMPULSIVE DRUG BEHAVIOR, SO HERE WE HAVE RATS AND WE TRAIN THEM TO ADMINISTRATE DRUG AND THEN AFTERWARDS WE GIVE THEM PUNISHMENT, IN THIS CASE, INCREASE THE CURRENT OF THE FOOT SHOCK, SO, NOW WE--WE WILL SEE BEHAVIOR WISE, AND WHEN YOU TRAIN THEM TO DO SELF-NUTRITION, SO THEY ARE TAKING DRUG MORE AND MORE BUT GETTING TO STATUS STATE AND THEN YOU GIVE THEM FOOT SHOCK AND ALSO INCREASE THE STRENGTHS. SO YOU WILL SEE OVERALL, THEY WERE REDUCED THE DRUG TAKING AND FROM THIS CURVE WE CAN DEFINE THE SO CALLED COMPULSIVITY INDEX. SO BASICALLY JUST THE DRUG TAKING IN THE END OF THE PUNISHMENT PHASE NORMALIZED BY THE DRUG TAKING IN THE END OF THE SELF-ADMINISTRATION PHASE, SO IT'S VERY SIMPLE INDEX, FOR THIS INDEX, YOU SEE, FOR RATS, WITH THE HIGH COMPULSIVITY THEY WILL HAVE HIGH CI, BASICALLY. SO, OKAY, SO, THIS IS JUST AVERAGE CURVE FOR A GROUP OF RATS BUT IF WE LOOK AT CAREFULLY, WE KIND 2 SUBGROUPS HERE SOY 1 GROUP IS RESISTANT OF THE FOOT SHOCK SO EVEN THOUGH THEY FACE PUNISH AM, THEY KEEP TAKING DRUG, THIS IS THE ORANGE GROUP, THE OTHER GROUP IS THE BLUE GROUP. SO THEY JUST GIVE UP TAKING DRUGS. YES, TO THE PUNISHMENT, SO WE LOOK AT THE BRAIN CIRCUITS, WE DID FMRI ON THESE RATS AND LOOK AT BRAIN CIRCUITS AND WE FUNDED BASICALLY 2 CIRCUITS, 1 IS CALLED GOLD CIRCUITS IT'S FROM OFC TO THE STRIATAL, SO BASICALLY THEY ARE INCREASING, THE CONNECTIVITY IS INCREASING AFTER SELF-ADMACHINEISTRATION AND SLIGHTLY DECREASED AFTER PUNISHMENT BUT NOT MUCH DIFFERENCE BETWEEN THESE 2 GROUPS. THE OTHER CIRCUMSTANCE UTRS WOULD CALL THE STOP CIRCUITS OR KIND OF A CONTROL CIRCUITS IT'S FROM A PRELIMBIC TO STRIATAL. SO THESE 2 CIRCUITS DECREASED DECREASED AFTER CONNECTIVITY OF THIS CIRC UT DECREASED AFTER SELF-ADMINISTRATION TRAIPING BUT YOU KNOW, INTERESTINGLY, AFTER THE PUNISHMENT, THE RESISTANT GROUP IS KEEPING DECREASING BUT THE SENSITIVE GROUP COMES BACK A LITTLEIT SO WE CAN ALSO PUT THEM TOGETHER TO LOOK AT THE BALANCE OF THESE 2 CIRCUITS SO WE SEE AGAIN, THESE 2 RATS COMPARED TO THE SALIENT GROUP THAT DEVIATED QUITE A BIT AFTER SELF-ADMINISTRATION BUT AFTER THE PUNISHMENT, THE RESISTANT GROUP JUST KEEP THE SAME, KEEP DEVIATED BUT THE SENSITIVE GROUP IS KIND OF COMING BACK A LITTLE BIT. ALSO, WE CAN LOOK AT THE BEHAVIOR WISE, AS I MENTIONED, WE DEVELOPED A SO CALLED COMPULSIVITY INDEX, CI, SO, ONLY THIS RESISTANT GROUP THE IMAGING CORRELATED WITH THE BEHAVIOR, NOT THE SENSITIVE GROUP. SO I THINK THIS IS A NICE MODEL AND SPEAKS TO THE INDIVIDUAL DIFFERENCES, IN DRUG ADDICTION. AND THEN, SO, JUST BACK TO THE MODULATION, SO HOW DO WE DO THIS, WITH GO IN WITH STOP CIRCUITS. AND 1 WAY WE CAN DO IT IS WE'RE USING CHEMO GENETIC OR OPTICAL IMAGES O GENETIC STIMULATION AND WE TRY TO UNDERSTAND A MORE KIND OF CELLULAR MECHANISM. IN THIS CASE I GIVE EXAMPLE USING CHEMO GENETICS AND SO WE CAN TRY TO ENACTIVATE THIS ORC CIRCUITS BUT KIND OF SUPPRESS THE ORC CIRCUITS BUT BRING UP THE PRELIMBIC CIRCUITS IF WE CAN DO THAT. SO THEN WE CAN ASK SOME QUESTIONS HERE SO WE CAN ALTER THE CIRCUITS BE RESTORED AFTER THIS NEUROMODDULATION, CAN THE BEHAVIOR, WITH THE DRUG TAKING BEHAVIOR BE ELIMINATED AND IF, OH YES, THEN WHAT IS OPTIMAL NEURAL MODULATION PROT COLFOR THE TREATMENT. SO, AS YOU SEE IN THE FIRST DAY [INDISCERNIBLE] SHOWED A VERY NICE DEVELOPMENT OF THE FOCUS TMS ON RAT BRAIN SO THE NEXT STEP, OBVIOUSLY, WE WILL MOVE TO MORE KIND OF TRANSLATIONAL NEUROMODDULATION. OBVIOUSLY THE CHEMO GENETIC BE DIFFICULT TO DO ON HUMANS SO WE TRY TO USE TMS, FOCAL TMS AND TRY TO ANSWER THE SAME QUESTIONS, HERE. AND THAT'S--ALSO THE ONGOING, IT'S NOT PUBLISHED YET. SO IT'S JUST BRIEFLY SUMMARIZE, SO I THINK I IDENTIFY THE NEW INSIGHT SYSTEM VERY IMPORTANT STEP FOR THE SUCCESS OF THE TREATMENT IN THE SECOND OF--FOR PSYCHIATRIC DISORDERS INCLUDING ADDICTION AND JUST FOR SOME DISEASE WITH VERY LIMITED KNOWLEDGE OF THE TARGETS, SUCH AS ARK DICTION, SO WE PROPOSE SOME STRATEGIES TO FIND A POTENTIAL TARGETS ON THAT. SO JUST SUMMARIZED HERE THE FIRST IS TO USE NEUROIMAGING AND A DISEASE-RELEVANT SYMPTOMS OR BEHAVIOR. THE SECOND IS TARGETING THE ENTIRE PATHOLOGICAL NETWORK FROM BASED ON THE META-ANALYSIS, AND THE THIRD 1 IS ANIMAL MODELS WITH TRANSLATIONAL POTENTIALS. THAT'S ALL I HAVE. THANK YOU VERY MUCH. [ APPLAUSE ] NTHAT WAS REALLY INTERESTING. YOU KNOW, CAN YOU SAY ANYTHING MORE ABOUT THE PUNISHMENT RESISTANT TYPE AS WELL IS SOMETHING YOU CAN USE AS A PREDICTOR OR IS THERE EVIDENCE THAT THEY DON'T FEEL THE STIMULUS AS WELL? ANYTHING MORE TO UNPACK IN TERMS OF WHICH ANIMALS ARE FALLING INTO THAT CATEGORY? >>SORRY. SORRY SOME ECHOES WOULD YOU REPEAT THE LITTLE BIT YOUR QUESTION? >>SURE. I WAS JUST WONDERING IF THERE'S SOMETHING SPECIAL ABOUT THE RATS THAT ARE RESISTANT TO PUNISHMENT? >>YEAH. WE DON'T KNOW WHY, THEY ARE JUST COUSINS, THEY ARE SHOWING QUITE DIFFERENT BEHAVIORS AND THAT IS PRETTY WELL TO HUMANS ABOUT MAYBE 20% OF THE PEOPLE USING DRUG END UP DEVELOPED INTO DEPENDENCE OF DRUG. SO, YEAH, WE REALLY DON'T KNOW THE CAUSE OF THAT, BUT YEAH, WE FOUND--WE FOUND THIS KIND OF SUBGROUPS, SO IT DEPENDS ON MANIPULATIONS FOR EXAMPLE, YOU CAN MANIPULATE THE STRENGTH OF THE CURRENT FOR THE FULL SHOCK AND YOU CAN--CAN YOU HAVE 20% OR 80%, YOU CAN HAVE 50%, SO, BUT I THINK INTERESTINGLY, THEY--YEAH, LOOKS LIKE BESIDES THE BRAIN DEHAIEVER DISRCHES THEY'RE ALSO SHOWING BRAIN CIRCUIT CONNECTIVITY DIFFERENCE. SO YEAH, THAT'S SOMETHING VERY INTERESTING FOR US AND ALSO MIGHT BE USEFUL TO GUIDE THIS TREATMENT. FOR EXAMPLE, THE TREATMENT SEEKING PATIENT COMES INTO THE CLINIC IF WE CAN MEASURE THEIR CONNECTIVITY OR SOME TASK OR WHATEVER, THEN IF WE HAVE CAREER IF AN IDEA CAN SEPARATE THE PATIENTS INTO SUBGROUPS. ONE GROUP SUCH AS MAYBE NOT A GOOD CANDIDATE FOR SOME TREATMENT, BUT IT COULD BE GOOD FOR OTHER TREATMENT, FOR EXAMPLE IN YOUR CASE, YOU FIND [INDISCERNIBLE] AMYGDALA, SMAIB SOME PATIENTS WOULD BE JUST GOOD FOR 1 OF THEM. >>YEAH, YEAH. >>SO, IT'S OBVIOUSLY IT'S A LONG WAY FOR PARTICULAR ANIMAL MODELS, IT'S A LONG WAY TO GETTING TO KREK THE SITUATION. >>AWESOME, THANK YOU. >>THAT'S GREAT, SO I HAVE A GENERAL QUESTION, SO YOU PRESENTED THE VERY NORMAL WAY TO IDENTIFY THOSE THERAPEUTIC TARGETS. AND YOU KNOW FROM THE PATIENT PERSPECTIVE, FROM THE ANIMAL, MY QUESTION IS WHAT IS YOUR IDEA ABOUT HOW YOU CAN EPITHELIAL GREAT ALL THE INFORMATION AND YOU KNOW FROM DIFFERENT LEVEL AND THEN BECAUSE IF YOU WANT TO, LIKE EACH PATHWAY OR EACH--IT'S GOING TO INVOLVE A LOT OF WORK SO AND FROM YOUR POINT OF VIEW, HOW YOU CAN BRING THE ANIMAL DATA TO HELP WITH THE CLINICAL OR HOW YOU INTEGRATE ALL THE INFORMATION. >>YEAH, YEAH, THANKS. YEAH. >>YEAH, SIMILARLY, AS--IT'S ALONG WAY TO GO, ANIMAL MODELS, WE USE THE [INDISCERNIBLE], I'M NOT ANIMAL MODEL GUY, BUT NIDA HAS SOME VERY GREAT ANIMAL BEHAVIOR MODEL GUY. SO ALAN [INDISCERNIBLE] IS NOW ANIMAL MODEL IS PERFECT. CANNED WHAT AND THAT'S TYPICALLY TALK ABOUT HIM. SO YEAH, ANIMAL MODELS, I THINK TYPICALLY TO MIMIC THE IMPORTANT HUMAN DISEASE BEHAVIOR, RIGHT? SO IN THIS CASE FOR EXAMPLE, IT'S COMPULSIVE DRUG TAKING BEHAVIOR, SO WE ARE USE ALSO USING OTHER MODELS IF ARE EXAMPLE, THE RELAPSE MODELS TO MIMIC THE RELAPSE BEHAVIOR. SO, YEAH, IT'S A--TO BE HONEST, I ALSO STUDIED THIS A FEWIERS AGO, BUT --I THINK IT'S PRETTY PROMISING AT LEAST YOU KNOW CURRENT PROGRESS. BUT I THINK IT'S STILL, IT'S A LONG WAY TO GO FROM RODENTS TO HUMANS AND PROBABLY IF POSSIBLE, WE COULD DO SOME MONKEYS, YOU KNOW BETWEEN AND KIND OF GRADUALLY TRANSLATE THIS KNOWLEDGE INTO THE [INDISCERNIBLE]. SO THE CHALLENGE FOR SOME DISEASE, LIKE ADDICTION OR MAYBE SOME OTHERS, YOU DON'T HAVE ANY IDEA, YOU KNOW WHERE, OR HOW TO DO THIS MODULATION, PEOPLE JUST LIKE TO TRIAL AND ERROR AND HEY, SOMETIMES THEY'RE LUCKY ENOUGH TO BE VERY SUCCESSFUL, BUT A LOT OF UNSUCCESSFUL PEOPLE DO STUDIES THAT PROBABLY NOT PUBLISHED. SO YEAH, SO, YEAH I DON'T KNOW IF I ANSWER YOUR QUESTION BUT I THINK, YEAH, IT'S A LONG WAY BUT HOPEFULLY WE ARE MOVING TOWARDS THAT. >>OKAY, SO NOW WE END THE PANEL DISCUSSION SESSION. CAN THE PANELISTS COME TO THE PODIUM, DR. WOODS, DR. [INDISCERNIBLE] AND 2 INDUSTRY REPRESENTATIVE AND ALSO NIH [INDISCERNIBLE]. >>I THINK WE HEARD A LOT OF DEVELOPMENT IN ACADEMIA, AS I THINK WE WILL HAVE 2 REPRESENTATIVES HERE FROM INDUSTRY, [INDISCERNIBLE]. AND NIH DR. [INDISCERNIBLE]. OKAY, AND THAT'S IT AND THERE ARE [INDISCERNIBLE] SO I THINK WE WILL START WITH NIH PERSPECTIVE BECAUSE YOU KNOW I THINK NE H HAS A LOT OF RFAs THAT EVERYBODY'S VERY INTERESTED. >>ACTUALLY DOCTOR [INDISCERNIBLE] SHE'S THE P. O. SHE'S THE BOSS OF ALL THE NEUROEMAGING PROGRAMS, YEAH IT WAS WONDERFUL TO HEAR YOU TALK. CAN YOU OFFERER SPECTIVE? >>YEAH, SO I WOULD WOULD SAY IT WAS LONG BUT I DO HAVE A COUPLE OF IDEAS ABOUT SOME REALLY RELEVANT PROGRAMS FOR THIS SPACE IN TERMS OF NIMH PROGRAM, WE JUST LAUNCHED A NEW PROGRAM THAT I'M RUNNING CALLED THE MULTIMODAL NEURAL THERAPIES PROGRAM THAT WAS JUDGE UOF THE LAUNCHED THIS SPRING AND I THINK IT'S REALLY RELEVANT FOR A LOT OF WHAT'S BEEN DISCUSSED TODAY INCLUDING DEVICE SPACE INTERVENTIONS IN COMBINATION WITH IMAGING MODALITIES AND JUST APPROXIMATE MULTIPLE POETIC DALLASCOWBOYS.COMITYS IN COMBINATION AND IN ORDER TO UNDERSTAND VARIOUS SORTS OF POSITIVE SYNERGYS THAT CAN HAPPEN ACROSS MODALITIES IN TERMS OF STIMULATION BUT ALSO IN TERMS OF BIOMARKER DEVELOPMENT ISSUE UNDERSTANDING HOW WE CAN ENGAGE THE TARGET MORE RECISELY AND UNDERSTAND TARGET ENGAGEMENT IN NEW WAYS. THE OTHER THING I WANT TO TALK ABOUT IS, I DID NOTICE THAT THERE WAS SOME REALLY INTERESTING WORK HERE LOOKING AT IMAGING IN COMBINATION WITH INVASIVE STIMULATION MODALITIES, WE ALSO HAVE A NEW FUNDING OPPORTUNITY THROUGH THE BRAIN INITIATIVE CALLED BRAIN BEHAVIOR QUANTIFICATION AND AND I'M ALSO FAMOUS FOR THAT PROGRAM AND WHAT WE'RE LOOKING TO DO THERE IS USE MULTIMODAL COMBINATIONS TO REALLY CAPTURE BEHAVIOR AND LINK IT SIMULTANEOUSLY TO LINK IT TO BRAINS IN HUMANS AND THAT IS NOT NIMH SPECIFIC THAT CAN BE IN ANY DISEASE POPULATION AND A RANGE OF PATIENTS ACROSS HEALTH STATES. IT IS LASTER TECHNOLOGY ORGANIZATION I WANT TO MENTION, DISCIPLINARY NOTICE THAT THERE WERE MANY ENGINEERING REORIENTED TALKS HERE AND IN TERMS OF DEVICE DEVELOPMENT, I JUST WANTED TO PLUG OUR NEWLY LAUNCHED BLUE MED TECH PROGRAM, THIS IS ALSO A TRANSNIH EFFORT. THE GOAL HERE IS TO TAKE A NEWLY DEVELOPED TECHNOLOGIES AND ADVANCE THEM OREAC CELLERATE THEM INTO A PROGRAM INTO FIRST AND HUMAN NEWS TRANSLATION AND GOING FROM PROTOTYPES ALL THE WAY UP INTO FIRST IN HUMAN TRANSLATION AND THERE ARE A NUMBER OF NUMBER OF ICs CURRENTLY FOUND IN THAT SPACE INCLUDING NIMH BUT ALSO NIDA, NIBIB, NICHD, AMONG OTHERS, SO REALLY EXCITING STUFF, I'M ALSO CURRENTLY SERVING AS THE INTERIM CONTACT FOR THE BLUEPRINT MED TECH PROGRAM, ANY FOLKS HERE WHO ARE INTERESTED IN ANY OF THESE PROGRAMS PLEASE REACH OUT TO ME I DON'T HAVE A CARD WITH ME BUT YOU CAN FIND MY NAME IN THE PROGRAM AND JUST GOOGLE AND IT YOU WILL SEE--YOU WILL FIND ME BECAUSE MY NAME IS PRETTY DISTINCT. THANK YOU. >>[INDISCERNIBLE]--HOW DO YOU START WHICH 1 MOST PROMISE TO TRANSLATE, I KNOW TO TRANSLATE FROM DBS, TO SURE, SO THE WAY I THINK ABOUT IT, WELL, MAYBE A LITTLE BIT INTRODUCTION WAS ALSO GIVEN BACKGROUND, I GOT MY PPh.D., PENN STATE, I AM PART OF THE COMMUNITY BUT AFTER THAT I JOINED MED TRONNIC TO WORK ON MI --SO ABOUT 3 YEARS AGO JOINED ABNORMALITIES SOT BUT DOING THE SAME TECHNOLOGY TRANSFER BUT MORE ON THE MANAGEMENT SIDE NOW, SO THAT'S A LITTLE BACKGROUND. THIS IS REALLY 2 ROIs IN THE SCIENTIFIC COMMUNITY WE TALK ABOUT WHICH 1 I WANT TO TARGET FOR THIS DISEASE, RIGHT AND THEN THERE'S ALSO ROI FOR BUSINESS WHICH IS RETURN ON INVESTMENT RIGHT? FROM PRETTY MUCH ALL COMPANIES THAT'S A BIG ROIs, OKAY, SO BUSINESSES HAVE TO HAVE THE MONEY TO SURVIVE, RIGHT, SO WHEN WE HAVE THESE 2 ROI OVERLAP AS MUCH AS POSSIBLE, THAT'S THAT'S WHERE THE OPPORTUNITY ARE. SO THINK ABOUT HOW FOR EXAMPLE,--IF THEY DON'T HAVE INVESTED IN THAT NEW DEVICE IT'S JUST FOR EXAMPLE, IF WE TAKE EXISTING DEVISITING, JUST MOVE TO A SLIGHTLY DIFFERENT TARGET. THAT PHYSICIAN SURGEON STILL FEEL VERY COMFORTABLE TO DO, SO YOU DON'T HAVE TO CHANGE THE DEVISITING, YOU DON'T HAVE THE CHANGE THE PROCEDURE THAT DRASTICALLY BUT YOU CAN TREAT A BIG DISEASE FOR EXAMPLE, DEPRESSION, YOU KNOW, BACK IF THEY HAVE TO CHANGE IF THEY FIND A GREAT TARGET BUT THEN, YOU HAVE TO CHANGE SAY PROCEDURE, IMPLANT PROCEDURE OR YOU HAVE TO CHANGE IT TO HARDWARE, RIGHT THE SYSTEM ON OR SOFTWARE THEN THE COSTS BECOME MORE TO RETURN, YOU KNOW ON THE INVESTMENT IS A LITTLE BIT LESS. SO, WHEN YOU GUYS DO, WHEN THE COMMUNITY ESPECIALLY LIKE MED TECH, IT IS PROBABLY HELPFUL TO THINK ABOUT 2 IOIs. I KNOW YOU ARE REALLY GOOD AT YOU KNOW FIRST ROI, BUT ALSO THINK ABOUT FROM THE BUSINESS POINT YOUR ROI THAT'S GOING TO HELP MAYBE, I DON'T KNOW, MAYBE EVEN HELP YOU SELECT ALL THESE DIFFERENT TARGETS, NETWORKS. >>HOW CAN YOU--YOU GUYS THOUGHT OR HAVE ACADEMICS CALL YOU SAY, I HAVE A GREAT TARGET, A GREAT TRIAL. >>COULD YOU PLEASE IDENTIFY YOURSELF BY NAME AFTER YOU SPEAK, THERE'S NO NAME TITLES OR ANYTHING HERE. >>HMM? >>CAN YOU IESHES DENTIFY YOURSELF BY NAME WHEN YOU SPEAK. >>YEAH, SORRY. >>YEAH,. >>MY MAIM IS [INDISCERNIBLE]. SO I'M SENIOR R&D MANAGER WITH THE ABBOT NEUROMODDULATION. >>[INDISCERNIBLE] SCOTT, TARGET ACADEMIC PROPOSE TO YOU, YOU SHOULD TRANSLATE THIS. >>PROBABLY WOULD START WITH THE MARKET SIZE, RIGHT IF YOU TALK ABOUT DEPRESSION OR TALK ABOUT IF IT'S A VERY SMALL OFTEN DISEASE, PROBABLY COMPANIES WOULD BT EVEN LOOK AT IT. IF THE MARKET IS BIG ENOUGH, THEN SAY, OKAY, WHERE ARE YOU AT? RIGHT? IF IT'S STILL IN THE LAB TESTING, THAT'S A HARD FOR COMPANY TO SPONSOR. IF HEY, I HAVE A SMALL VISIBILITY STUDY IN HAD YOU MANS, THE RESULTS REAL PROMISING, THEN, THAT'S PROBABLY WORTH THE TALK START THEN COME DOWN TO OKAY, HOW MUCH MONEY YOU NEED, WHAT KIND OF OUTCOME, HOW LONG IT'S GOING TO TAKE, IT ALWAYS HELPS TO HAVE SOMEBODY IN THE COMPANY THAT YOU KNOW, RIGHT? LIKE IF I DON'T KNOW YOU, THEN OF COURSE I PROBABLY WON'T BE ABLE TO SIT HERE, RIGHT SO HUMAN CONNECTION WITHIN THE COMPANY, ALWAYS HELP. SO IT'S NOT INDUSTRY IS NOT YOU KNOW JUST BLACK BOXES. COME DOWN DEPENDING ON EACH INDIVIDUAL COMPANY AND THEIR STRATEGY AND KNOWING SOMEBODY INSIDE ALWAYS HELPS. NTHANK YOU, DO YOU WANT TO COMMENT BECAUSE YOU ARE MORE IN BETWEEN, RIGHT? YOU ARE MORE THE RESEARCH PRODUCTS? >>THAT'S RIGHT. YEAH, SO OUR COLLEAGUES AT ABBOT ARE KIND OF COVERING THIS SPACE AND I AM HENRY-- >>YOU NEED TO TURN ON. >>SO, SORRY. >>HELLO. YEAH, SO OOM HENRY I'M THE SCIENTIFIC DIRECTOR FOR ROGUE RESEARCH. MANY OF YOU KNOW US AS SORT OF A COMPANY THAT BUILDS TOOLS FOR THOSE INVOLVED IN NONENVASIVE BRAIN STIMULATION, WE'RE BASED IN MONTREAL, SORT OF A SPINOFF OF THE MONTREAL NEUROLOGICAL INNSITUTE AND THE FUNDAMENTALS OF COMPANY SPEAK TO YOUR QUESTION WHEN YOU SPEAK TO TARGETING ENGAGEMENT SORE SELECTING WHAT PATHWAYS TO PURSUE COMMERCIALLY. OUR METHODOLOGY HAS BEEN TO BUILD TOOLEDS IN CONJUNCTION WITH RESEARCHERS, EVERYTHING WE DO IS A REQUEST BY A RESEARCHER OR REQUEST BY THE FIELD AT LARGE AND THEN AS THOSE TOOLS MATURE SO DOES OUR OUTLOOK, OUR TECHNOLOGY AND OUR DIRECTION. SO, HISTORICALLY, WE'VE ALSO PROVIDED PROVIDED RESEARCH TOOLS BECAUSE THE FIELD WAS PERHAPS NOT SET ON THE TARGET AND THE METHODOLOGY AND WE PREFER NOT TO GET YOU TO THE WRONG PLACE CONSISTENTLY EVERY TIME, THAT WOULD BE SORT OF ILL USE OF THE TOOLS. NOW, AS THE FIELD HAS MATURED AND THINGS LIKE RESTING STATE MRI CONNECTIVITY ANALYSIS, HAVE SORT OF PROVIDED UTILITY FOR CLINICAL APPLICATIONS, NOW WE'RE DEVELOPING THE TOOLS, AND YOU KNOW FOLLOWING THE FIELD, FOLLOWING OUR CUSTOMERS THAT WE WELCOMERRED WITH ALL THIS TIME, TO YOU KNOW WE'RE THE SIDE THAT DEVELOPS THE TOOLS, SO, IN TERMS OF RESTING STATE MRI, DEVELOPING SORT OF A CLINICAL ORIENTATION WHERE PEOPLE CAN MAKE USE OF THAT INFORMATION, SEND THAT INFORMATION IN TERMS OF MULTISITE STUDIES DOING EVERYTHING THAT WE CAN TO REDUCE VARIABILITY ACROSS STUDIES WHICH SEEMS TO BE, YOU KNOW 1 THING CAN AFFECT THINGS QUITE I BIT. SO, YOU KNOW, BUILDING A ROBOTIC HOLDER FOR FOCUSED ULTRASOUND OR FOR TMS TO REDUCE SORT OF OPERATOR VARIABILITY, PARTNERING WITH COLUMBIA DUKE UNIVERSITY PRODUCE NEXT GENERATION TMS DEVICE THAT CONTROLS FOR PARAMETER THAT VARIES ACROSS DEVICES, THE PULSE SHAPE AND THE PULSE WHIP. AND YOU KNOW THE MULTIMODAL APPROACH WE'VE SEEN HERE WITH PEOPLE INTEGRATING EEG, ET CETERA WE'RE AWZ WORRY BODY NEURONAVIGATION AND TMS, NOW NEXT GENERATION MAY INTEGRATE EEG CHANNELS, WE'RE NOT AN E, G COMPANY BUT THE RESEARCH HAS PUSHED US TOWARD THE APPROACH SO I THINK IT'S JUST IMPORTANT FOR US TO HAVE AN EAR ON THE GROUND TAKEN--THEY TO BE VERY TIED TO THE RESEARCHERS TO UNDERSTAND WHAT TOOLS THAT I NEED AND TO UNDERSTAND THAT WHERE THEY ARE IN THAT SORT OF RESEARCH TO CLINICAL TRANSLATION PATHWAY. WE ALSO HAVE A VETERINARY SIDE OF THE COMPANY WHERE WE PAIK USE OF THESE KIND EVER TRANSLATION COMOPPOSITE BEHAVIORIAL PHENOTYPENTS AND IF WE TELL WHERE OUR CUSTOMERS ARE IN THEIR RESEARCH AND UNDERSTANDING THEN WE CAN PROVIDE THE BEST RESEARCH TOOLS OR MAKE THAT LEAP WITH THEM TO THE CLINICAL SPACE TOGETHER. >>YOU ARE MORE FLEXIBLE, YOU ARE WILLING TO SERVE THE SMALLER COMMUNITY? >>YEAH THAT'S RIGHT. THAT'S WHAT I MEAN BY OUR WHY COMPANY, THE REASON FOR EXISTING IS TO DO COOL NEUROSCIENCE TO HELP OUR CUSTOMERS, ACCOMPLISH THEIR GOALS, TO HAVE A GOOD TIME SOLVING THESE COMPLEX AND INTERESTING PROBLEMS SO WE DON'T REALLY SEE OURSELVES AS A NEURONAVIGATION OR TMS COMPANY, WE TRY TO BE FLEXIBILITY AS THE RESEARCHERS ARE FLEXIBLE, AS OPPORTUNITIES RISE OR FALL AS MODALITIES MAKE THEMSELVES MORE USEFUL, PARTICULARLY IN THE SPACE OF BIOMARKER IDENT ISKSZ AND PERHAPS SOFTWARE TOOLS WE CAN BE FLEXIBLE FOR WHAT'S SERVING THE RESEARCHER THE MOST. SO THAT KIND OF FLEXIMENT, WILLINGNESS TO MOVE QUICKLY. THERE ARE BUSINESS DECISIONS THAT GO INTO THAT FOR EXAMPLE, KEEPING OUR RESEARCH AND SORT OF THE CLINICAL ASSPIRRATION SEPARATE WE FOUND THAT WHEN COMPANIES IN THE NONINVASIVE SPHERE MAY LEAN HEAVILY CLINICALLY, THE RESOURCES BECOME DIVERTED FROM RESEARCH AND THE INFORMATION THEY'RE GATHERING FROM THERE. SO FROM A BUSINESS PERSPECTIVE WE MAKE A DECISION TO SILO THOSE OFF TOW WE CAN REMAIN FLEXIBILITY FROM THE RESEARCH SIDE WHILE CREATING THE CLINICAL TOOLS THAT OUR CUSTOMERS FEEL ARE READY FOR DEPLOYMENT AND READY FOR PRIME TIME. >>AUDIENCE WANTS TO ASK THE PANEL SOME QUESTIONS. >>HI, I WAS WONDERING IF FOLKS ON THE PANEL THOUGHT WHAT WE SHOULD BE CHASING FOR NEURAL MODULATION TO REALLY OPTIMIZE OUR OUTCOMES? SO WHAT IF IT'S THE CASE THAT THERE'S NOT GOING TO BE A REALLY CLEAN BIOMARKER FOR SOMETHING, AN ABNORMALITY THAT WE CAN DETECT AT THE INDIVIDUAL LEVEL BUT NEVERTHELESS WE'RE BUILDING UP NEUROMODDULATION EVIDENCE THAT CERTAIN SYMPTOMS MOVE AND WE THINK WE HAVE TRACTABLE TARGETS FOR THAT SIMILAR TO WHAT ANDY WAS SUGGESTING IN HIS TALK THAT MAYBE YOU START WITH ASKING THE PATIENT, YOU SAY WHAT DO YOU THINK IS BOTHERING YOU THE MOST AND IF WE HAVE EVIDENCE FOR MODULATING THAT, THAT'S WHAT WE SHOULD FOLLOW INSTEAD OF KEEPING, CHASING THESE BIOMARKERS THAT ARE JUST SO ELUSIVE BUT, AS ALL OF US ARE WORKING ON NEUROMODDULATION, EVEN IF IT'S AN ANIMAL MODEL OR FOR A DIFFERENT DISORDER AND YOU SAY OOH, WE'RE TRYING TO STIMULATE HERE FOR PARKINS SONS AND WE SHIFTED MOOD, LET'S TRY THAT NOW, IF WE'RE A MOOD SORT OF TARGET, DO YOU GUYS THINK THAT THAT'S MORE TRACTABLE AND SHOULD BE OUR FOCUS OR ARE WE JUST NEEDING TO REFINE AND FURTHER IMPROVE AND SUBTYPE AND FURTHER CHASE IMAGING BASED ABNORMALITY? >>SURE. I'LL GO FIRST. I THINK IT'S A PHENOMENAL QUESTION AND I DON'T THINK WE HAVE A CLUE WHAT WE'RE CHASING RIGHT NOW IF I'M BEING HONEST. I THINK WE'RE ALL TAKING STABS IN THE DARK AND I THINK DR. YANG SAID WE'RE FIRING OFF RANDOMLY ATTEMPTING TO FIND SOMETHING THAT WORKS. AND WHEN FACED WITH THAT I THINK IT'S NOT GOING TO BE A MAGIC BULLET, IT WON'T BE 1 THING, WE ULTIMATELY KNOW IT WILL NOT BE 1 MARKER TO RULE THEM ALL. I THINK WE NEED TO HAVE ROBUST APPROACHES AND I ALSO THINK WE NEED TO HAVE BETTER DAILY BASIS THEA SHARING APPROACHES. WE STRUGGLE WHERE WE CAN RUN A TRIAL, IT CAN TAKE US 5 YEARS TO FINISH THAT TRIAL ASK THEN SOMEONE ELSE RUNS A TRIAL BUT WE CAN'T ACCESS THE DATA AND YET WE COULD ANSWER ALL THESE QUESTIONS CAN NOT WASTE ANOTHER $10 MILLION ON THAT TRIAL IF 5 YEARS IF WE COULD ONLY ACCESS THE T1, OUTCOMES, ET CETERA. SO EFFORTS ACROSS FIELDS TO CREATE UNIFIED FIELD DATA SHARING SO WORK LIKE THIS IS HAPPENING IN THE ENIGMA WORKING GROUPS BUT IT'S VERY INFANTILE IN THE PROGRESSION AND BETTER SUPPORT FROM NIH, INDUSTRY AND ARES FOR THESE KINDS OF APPROACHES, I THINK WILL HELP US IESHES DENTIFY WHAT THE BEST TARGET IS SOY DON'T KNOW THAT WE ACTUALLY KNOW IN ANY TARGET AT THIS POINT. WE HAVE GOOD HINTS, BUT WE NEED MORE SCIENCE AND WE NEED MORE DATA. JUST MY OPINION. >>IS THIS ON? OKAY, SO, I WANT TO GIVE SOME PERSPECTIVE WORKING ANN ENGINEER IN SOLVING ANY PROBLEM. I THINK THE GOAL HERE IS TO UNDERSTAND BRAIN AND PATHOPHYSIOLOGY AND FROM THE ENGINEER'S PERSPECTIVE WE DON'T UNDERSTAND SOMETHING UNLESS WE CAN BUILD IT. AND SO, YOU KNOW IT'S ALWAYS BEEN MY DREAM TO BUILD A MODEL OF THE BRAIN, EITHER HARDWARE OR SOFTWARE AND BE ABLE TO SIMULATE THESE DIFFERENT CONDITIONS, SIMULATE DIFFERENT STIMULATION CONDITIONS ON TOP OF A HEALTHY OR PATHOLOGICAL BRAIN. AND WE'RE NOT THERES ARE YET, WE'RE NOT EVEN CLOSE TO HAVING A VERY REALISTIC MODEL OF THE BRAIN ON A NEURON LEVEL BUT THERE ARE ONGOING EFFORTS. FOR EXAMPLE, FROM THE CELL ATLAS PROJECTS AND THE ALAN EN--STRATEGIESITUTE IS PUTTING TOGETHER AND CATALOGING ALL OF THE CELL TYPES IN THE BRAIN TO SOME OF THE EUROPEAN BRAIP PROJECTS THAT ARE TRYING TO USE FUNCTIONAL DATA USING STRUCTURAL DATA TO INFORM A VIRTUAL BRAIN MODEL. THIS IS THE VIRTUAL BRAIN PROJECT THAT THE EUROPEAN, SOME OF THE INITIATIVES THERE IS STARTING. AND SO, FOR ME, I'M INTERESTED IN SHIFTING AT LEAST OUR RESEARCH IN THAT DIRECTION IS BEING ABLE TO BUILD A BRAIN AND MANIPULATE IT STARTING WITH SIMULATIONS. >>WELL I WILL JUST SAY VERY BRIEFLY, IS THIS ON, IS THIS, I WILL SAY BREFLY THAT OUR ULTRASOUND BEING SORT OF THE NEW KID ON THE PLOK HERE THAT IN MANY WAYS IT'S EASIER FOR US WATCHING THE OTHER MODALITIES AND LEARNING AND SEEING WHERE DO WE NEED TO GO, BUT IN MANY WAYS - IT IS HARDER FOR US BECAUSE WE NEED TO IDENTIFY WHAT'S OUR ADDED VALUE THAT, IS NEW OVER THE OTHER MODALITIES SO I THINK THAT'S PRETTY IMPORTANT FOR US WHERE WE NEED TO GO. >>FOLLOWING THE DISCUSSION THAT YOU ALREADY HAVE, I THINK THAT WE ALL HERE ARE LOOKING FOR THE SAME BASICALLY QUESTION AND THAT WE ARE TRYING TO SEE, WHATEE CAN DO AND EACH OF US IN OUR LABS, WE ARE TRYING TO FIND KIND OF TARGETS AND WE ARE TRYING TO VALIDATE THEM, BUT THE QUESTION I HAVE IS BEYOND WHAT WE ARE DOING BEYOND WHAT WE ARE DOING IN OUR INDIVIDUAL LAB, THE QUESTION IS HOW CAN WE DO SOMETHING ON AT THE COMMUNITY LEVEL. THIS IS WHAT WE TRY TO DO TOGETHER, THE LAST 3 DAYS, GETTING TGHTS, DISCUSSING WHAT OTHER DIFFERENT LABS ARE DOING AND THE REQUESTY IS WHAT IS GOING TO HAPPEN AFTER THIS MEETING? WHAT ARE THE POTENTIAL KIND OF BENEFITS WE CAN MAKE FROM THESE NETWORKING ACTIVITIES THAT WE ARE DOING HERE? I WILL ASK A QUESTION FROM PEOPLE HERE, HOW MANY OF YOU WOULD BE INTERESTED TO ATTEND THIS MEETING IN 2 YEARS SAME TIME, HERE IN NIH? JUST RAISE YOUR HANDS. SO, SO THAT IS KIND OF AN ONGOING DISCUSSION NERMALS OF--AND COMPARED TO MANY OTHER MEETINGS WE ATTENDED IN THE LAST COUPLE OF YEARS, I THINK THAT KIND OF THE UNIQUE FEATURE OF THIS MEETING THAT WE HAVE ALWAYS BEEN DISCUSSING ABOUT THE CENTRAL CORE OF BASICALLY MRI, AS BEING IN THE CENTER OF THE DISCUSSIONS, AND DIFFERENT MODALITIES AROUND MRI TRYING TO SEE HOW WE CAN LEARN FROM EACH OTHER, AS KIM MENTIONED HOW WE CAN LEARN FROM OTHER MODALITIES. WHAT PEOPLEY IN OTHER MODALITIES ARE DOING AND THE REQUESTY IS OKAY, HOW WE CAN GO BEYOND THAT? IS THERE ANY CHANCE WE CAN CONTINUE THE DISCUSSION, IS THERE ANY CHANCE WE CAN START TO EVEN WRITE PAPERS, MAKE NOTES ABOUT THE TAXONOMY, ABOUT THE TERMINOLOGIES THAT YOU HAVE BEEN DISCUSSING ABOUT CURING LAST COUPLE OF DAYS WE HAVE BEEN DISCUSSING ABOUT THOSE DOSE RESPONSE RELATIONSHIP. BUT WE HAVE DIFFERENT MEANINGS FOR WHAT WE CALL DOSE AND WHAT WE CALL RESPONSE AND IS THERE ANY CHANCE WE CAN GET TOGETHER IS KIND OF DEFINE THE SPACE AROUND DOSE RESPONSE OR OTHER TECHNICAL DETAILS WE ARE INTERESTED. WHAT ARE THE KIND OF CROSS TALKS BETWEEN DIFFERENT MODALITIES THAT WE HAVE IN A FEW YEARS FOCUS ULTRASOUND BUT WE HAVE IN TMS HOW WE CAN LEARN FROM EACH OTHER AND CAN WE CONTINUE DISCUSSION BEYOND WHAT WE ARE DOING HERE AND THAT IS SOMETHING INTERESTING TO SEE HOW WE CAN GO BEYOND THAT. >>THAT'S EXACTLY THE NEXT STEP WE WANT TO TALK ABOUT, DO WE WANT TO CONTINUE THIS MOMENTUM TO HAVE THIS MEETING LIKE EVERY OTHER YEAR, NOT EVERY OTHER DAY, BUT THE TOPIC CAN BE CHANGED SLIGHTLY ALONG THE DEVELOPMENT OF THE FIELD, BUT IN GENERAL, I THINK IMAGING NEUROMODDULATION AND TECHNICAL DEVELOPMENT AND CLINICAL APPLICATION, THOSE ARE THE KEY WORDS, YEAH, I'M, YEAH. A LOT OF WORK I'M PRETTY SURE. IF SOMEONE WANTS TO TACK A LEADER FOR IT, BUT I'M HAPPY TO, IF NOBODY WANTS TO, I AM HAPPY TO DO IT AGAIN, BUT YEAH, YEAH, I THINK THAT'S SOMETHING WE SHOULD THINK ABOUT. >>SO WE WILL-- >>FOR PEOPLE IN AUDIENCE,. >>HI, SO I JUST WANTED TO ADD TO THAT I THINK THERE HAS BEEN SIMILAR KIND OF CONFERENCES THAT START WITH AN IDEA AND BUILD, AND SO JUST TO KIND OF GIVE A PARALLEL EXAMPLE, I THINK THE DBS THINK TANK SORT OF STARTED THIS WAY WHERE THERE WERE A GROUP OF PEOPLE WITH A SPECIFIC NICHE INTERESTED IN DEVELOPING TARGETS AND THEY GOT TOGETHER AT OAKINS UNIVERSITY OF FLORIDA AND EVENTUALLY THEY CERTAINLY--CERTAINLY VOLVED THAT FROM EACH MEETING AND EACH ADVANCEMENT, THEY WOULD PUB LESH A GROUP PAPER ON WHAT IS THE MOST UPDATED INFORMATION THAT PEOPLE IN THE COMMUNITY COULD USE. SO JUST THINKING SIMILARLY, EITHER A COMMUNITY SO GROUP CONFERENCE PAPER TO SAY THIS IS WHAT WE ARE ACHIEVINGAs A FIELD AT THIS TIME VERSUS AN OPEN PLATFORM AS STEVE WAS SUGGESTING WHERE WE ARE CONTRIBUTING COLLECTIVELY TO AN AREA WHERE WE CAN COLLECTIVELY PUT THE TAGHTA TOGETHER WHETHER POSITIVE FINDINGS OR NEGATIVE SO WE DON'T, YOU KNOW WASTE MONEY OVER AND OVER AGAIN AND I THINK AS COME OUT AS SAYING WE'RE ALL DOING A VERY SIMILAR THING AND LEARNING FROM EACH OTHER AND SO PROBLEM SOLVING PROBLEMS A LOT EASIER WHEN WE ACROSS DISEASES ARE ASKING SIMILAR APPROACHES AND CAN COME UP WITH A MORE UNIFORM PIPELINE TO OPTIMIZE AND IMPROVE EFFICIENCY, REALLY IN ADVANCING DISEASES. SO, JUST THINKING ABOUT HOW TO BUILD BETWEEN CONFERENCES. >>SORRY, THAT'S EXACTLY WHAT ANDY HAVE BEEN THINKING ABOUT, TALKING ABOUT, IS THE 1 POSSIBILITY IS TO FORM A STUDY GROUP FOR EXAMPLE IN ISMRM, IT HAS SEVERAL STUDY SITE GROUPS AND THAT'S 1 POSSIBILITY, ANOTHER IS TO PROPOSE SYMPOSIUMS IN CONFERENCES, IN OHPM, ISMRM, OR BRAIN STIMULATION AND SO ON. SO, YOU KNOW PAST COUPLE YEARS, DANNY AND I PROPOSED A COUPLE IN OHPM AND ISMRM BUT WE WILL BE HAPPY TO DO IT AGAIN, I GUESS. YEAH, SO THOSE ARE THE THINKINGS THAT WE HAVE. >>SO I THINK WE SEND OUT AURE VEY, TOGETHER WITH THE NICE GROUP PICTURE WE TOOK ON MONDAY. YOU WILL RECEIVE A SURVEY TO BRAINSTORM IDEAS WE WANT TO HEAR BACK FROM THEM, YEAH, IT'S A COMMUNITY EFFORT. YEAH, OKAY. >>I JUST WANT TO COMMENT ON YOUR PREVIOUS QUESTION, I REALLY LIKE YOUR BLACK BOX DIAGRAM. I THINK TRIAL AND ERROR, THAT'S HOW HUMANS LEARN, RIGHT? WE HAVE--WE CAN TAKE LIKE A DIFFERENT TIERS TO ME IS HOW I THINK ABOUT RIGHT, THE KEY ARE THESE FOR BUSINESS? CAN YOU PROVE IT WORKS, RIGHT? IF YOU CAN, IT WORKS, THEN YOU CAN HAND IT TO BUSINESS, GO MAKE IT, MAKE A PRODUCT. I KNOW IT WORKS, NOW YOU GO MAE IT, RIGHT? BUT THEN YOU GO INTO THE BLACK BOX AND YOU ASK ALL THE WHYs, SO IT'S VERY IMPORTANT FOR RESEARCH AND THEN ONCE THEY ANSWER ALL THE WHYs YOU DO NEXT GENERATION OR BRAND NEW STEPS BUT FIRST STEP IF IT COMES FROM WORK, THAT'S HOW DBS, NOW 99% SURE IT'S GOING TO WORK, THEN THAT'S BASICALLY, YOU'VE DONE MOST HEAVY LEFTINGS' DONE THEN THE TREY, ASSUME MARKET IS BIG ENOUGH THEN I'M SURE INDUSTRY, COMPANIES THE FIND A WAY TO MAKE IT INTO PRODUCT. >>OKAY, WE HAVE THE LAST ITEM. PANEL PLEASE STAY, I THINK WE HAVE,A WARDS CEREMONY? YOU GUYS [INDISCERNIBLE] TO HAVE YOU HERE. SO WE HAVE 3 AWARDS TO GIVE TO THE OTHER PRESENTATIONS, IT COMES OUT VERY COMPETITIVE, VERY, YEAH, [INDISCERNIBLE] >>I WOULD LIKE TO SAY A FEW WORDS ABOUT THE AWARDS FIRST OF ALL THANK YOU VERY MUCH FOR PRESENTATIONS. I LEARNED A LOT, I HOPE YOU ALSO LEARNED AND ENJOYED THE WORKSHOP. THIS WAS SO HARD, ALL THE PRESENTATIONS ARE VERY GOOD. I JUST WANT TO SAY THAT INNOVATION, SCIENTIFIC QUALITY AND PRESENTATION, AND MAYBE WE CAN ANNOUNCE THE WINNERS. >>YOU CAN. >>ALL RIGHT. ALL RIGHT. SO WE HAVE LI-PANG NI, COMPUTER MODELING MY IEE, AUDIENCE DENTIFY TARGET FIST ARE ATTENT DEPRESS ANT RTMS. [ APPLAUSE ] >>PLEASE POSE FOR A PICTURE. [LAUGHTER] >>[ APPLAUSE ] >>SECOND PLACE WE HAVE [INDISCERNIBLE] MR DUST IMPLANTABLE NEUROINTERFACE WITH DATA COMMUNICATION VIA MRI. [ APPLAUSE ] [ APPLAUSE ] >>AND NUMBER 1 AREA BANKS MRI FOCUSED CIRCUITRY FOR ANESTHETICS IN THE BRAIN. [ APPLAUSE ] [ APPLAUSE ] [LAUGHTER] YEAH, SO THANK YOU ALL FOR STAY SO LONG. WE ARE REALEE GLAD TO BRING TOGETHER EVERYBODY AND HOPEFULLY THIS IS A START. >>YEAH, I JUST WANT TO THANK DANNY AND [INDISCERNIBLE] FOR HAVING ME HERE. I KNOW--E-MAILED ME PROBABLY IN THE MIDDLE OF THE PANDEMIC ABOUT A YEAR AND HALF AGO. >>YEAH, IT TOOK A LONG TIME IT'S A GRASS ROOTS. IT'S A TRULY GRASS ROOT ACTIVITY. >>THIS IS THE FIRST 1. >>IT'S ALWAYS HARDER. >>IT TURNED INTO A MOVEMENT. >>YEAH. >>JUST REALLY APPRECIATE A LOT OF HARD WORK INVOEVERLED. >>THANK YOU. LOOK FORWARD IT SEEING YOU IN THE FUTURE AND WE WILL SEND YOU SURSURVEYS TO LOOK FOR IT IN YOUR E-MAIL. [APPLAUSE ]