WELCOME TO THE FIRST EVER WORKSHOP ON MRI OF NEUROMODULATION. TARGET ENGAGEMENT, NEUROMECHANISM AND BIOMARKER DEVELOPMENT. I'M FROM BERKELEY AND VERY PROUD TO CO-CHAIR THIS WORKSHOP. THIS WORKSHOP, I'M A SCIENTIST, TO THE BEST OF MY KNOWLEDGE FIRST OF ITS KIND IN HUMAN HISTORY. I THINK IT IS GREAT TO BE SOMETHING, FIRST OFF, IN HUMAN HISTORY, NO MATTER HOW SMALL OR GREAT IT CAN BE. AND I'M ALSO VERY HONORED. THIS WORKSHOP WAS CO-SPONSORED BY ISMRM AND ALSO NIH. NIH IS VERY GENEROUS TO PROVIDE THIS VENUE AND THE MANY SUPPORT. YEAH, SO I WOULD SAY WE CAME A LONG WAY FOR THIS WORKSHOP. IT STARTS WITH GRASSROOTS ACTIVITY. SEVERAL OF US CALLED MEMBERS OF THE ORGANIZING COMMUNITY, WE ORGANIZED SOME MEMBER INITIATIVES WORKSHOP A FEW YEARS AGO FOLLOWED BY OHBM SYMPOSIUM. WE FEEL THERE IS SOME ENERGY IN THE COMMUNITY SO WE DISCUSSED THIS IDEA. THEN WE POST ON SOCIAL MEDIA ON LINKEDIN. WE GOT A LOT OF FANTASTIC ADVICE AND FEEDBACK ESPECIALLY FROM MANY OF YOU GUYS. THAT LEADS TO THIS WORKSHOP AND ORGANIZING COMMUNITIES. MANY PEOPLE CONTRIBUTED, SO THANK YOU. ALSO WE GO THROUGH MANY ITERATIONS WITH ISMRM. SO I WANT TO THANK THE ORGANIZERS, ISMRM ANN MARIE AND RIHANNA. SO WE ALSO SPONSORED BY INDUSTRY. WE HAVE AN R-13 GRANT AND IBIB. AND WE HAVE THREE GENEROUS INDUSTRY SPONSORS, ABBOTT, ROGUE AND MAGVENTURE. I DIDN'T SEE THE SETUP EXHIBITION DESK YET. GO CHECK OUT EVEN IF YOU CANNOT AFFORD TO BUY THIS DEVICE. SO I THINK EVERYBODY HERE ARE PART OF THE COMMUNITY. WE ARE STARTING WITH NEUROMODULATION IMAGES. I WANT TO SEE MORE AMBITIOUS PEOPLE THAN A REGULAR NEUROIMAGE. WE ARE NOT SATISFIED WITH AS A BYSTANDER TO BRAIN ACTIVITY. WE WANT TO ALSO PARTICIPATION. WE ALSO WANT TO DERIVE A CAUSAL RELATIONSHIP. SO THAT IS I THINK WHAT IS TRENDING WITH A RANGE OF NEUROMODULATION TACTICS FROM ELECTRIC MAGNETISM, FROM ULTRASOUND AND OPTICAL IMAGING. SO I THINK THIS IS JUST A CONVERGING FIELD. AND IT ALSO NOT ONLY CROSSES DIFFERENT MODALITIES, BUT CROSSES DIFFERENT LEVELS FROM BASIC SCIENCE TO IMAGING PHYSICS TO NEUROSCIENCE AND EVENTUALLY TO INDUSTRY, TRY TO TRANSLATE COMMERCIALIZATION. I THINK THAT IS WHAT WE ARE STARTING ON, A MULTIDISCIPLINARY CROSS-LEVELS, CROSS-SKILLS. IF YOU LOOK AT THE PUBLICATION, PUTTING PUBMED NEUROMODULATION, IT IS CROSSING TO A THOUSAND PEOPLE PER YEAR. IN 30 YEARS, STARTING FROM THE 1990s AND I THINK THE DROP IS BECAUSE OF COVID, BUT I THINK THE FIELD IS GROWING. I WOULD LIKE TO INVITE PROFESSOR YEN-YU. >>GOOD MORNING, EVERYONE, HERE. AS WE HAVE 30% OF ATTENDEES ONLINE, SO I WOULD JUST LIKE TO SAY GOOD MORNING, GOOD AFTERNOON, AND GOOD EVENING, DEPENDING ON WHERE YOU ARE. I'M YIHONG YANG. AS THE CO-CHAIR OF THE WORKSHOP, ALSO ON BEHALF OF THE NIH HOSTS, I WANT TO WELCOME ALL OF YOU TO THE WORKSHOP. AS YOU KNOW IT IS VERY DIFFICULT TO ORGANIZE SUCH A MEETING DURING THE COVID. WE STARTED LIKE TWO YEARS AGO, GOING THROUGH PROCEDURES AND APPROVALS. FINALLY I WILL GET TO THE POINT WE CAN ALL SIT DOWN AND HAVE THIS WORKSHOP. THE TOPIC OF THIS WORKSHOP IS INTEGRATION OF IMAGING AND NEUROMODULATION. WE BRING THE EXPERTS IN THE FIELD, FROM TECHNICAL DEVELOPMENTS TO NEUROLOGICAL PRESENTATIONS TO COME TOGETHER AND HAVE A DISCUSSION. I HOPE EVERYONE CAN LEARN SOMETHING NEW AND MAKE SOME NEW FRIENDS AND ENJOY THE WORKSHOP IN THE NEXT COUPLE OF DAYS. THANK YOU. [ APPLAUSE ] >>JUST A FEW LOGISTICS. I THINK ONLINE, WE STILL DON'T HAVE THE CHAT. WE'RE STILL TRYING TO PUSH IT. TODAY I THINK BEFORE LUNCH WE WILL TAKE A GROUP PICTURE TOGETHER. >>ALSO ANOTHER QUICK ANNOUNCEMENT. THE KEYNOTE LECTURE WILL START FROM 10:15. SO IT WILL BE 15 MINUTES EARLIER. ALL RIGHT, SO WITHOUT FURTHER ADO, WE CAN START THE FIRST SECTION. >>GOOD MORNING, EVERYONE. I WOULD LIKE TO WELCOME YOU TO THE FIRST SESSION OF THIS WORKSHOP, MRI FOR NEUROPHYSIOLOGICAL USING NEUROMODULATION. I WOULD LIKE TO INTRODUCE YEN-YU SHIH. WELCOME. >>I DO HAVE A CONFLICT OF INTEREST TO DECLARE. I'M CONSULTING WITH -- SO WE WANT TO LINK INFORMATION FROM MOLECULAR AND CELLULAR ASPECTS TO BEHAVIOR. OFTENTIMES THE COMPLEX BEHAVIOR IS NOT DIRECTLY REFLECTED BY MOLECULAR ACTIVITY FROM A SINGLE BRAIN REGION. IN A FORM OF ORCHESTRATED ACTIVITY FROM LARGER SCALES, INCLUDING THE CIRCUIT AND KNELTWORK OBSERVATIONS BY MRI. THERE ARE INCREASING STUDIES TO USE METRICS TO SEE IF THEY SERVE AS A MEDIATOR FOR THIS RELATIONSHIP AT THE BOTTOM. KNOWING THIS IS IMPORTANT BECAUSE WE WAND TO PREDICT BEHAVIOR. TO REACH THAT GOAL, THERE IS A NEED TO BETTER UNDERSTAND HOW FMRI SIGNAL IS FORMED. WHAT NEURAL EVENT IS CONTRIBUTES TO FMRI SIGNALS. WE WOULD LIKE TO READ INFORMATION FROM THE BRAIN THE FMRI. I WILL TOUCH ON ELECTROPHYSIOLOGY, AN ELECTRICAL CHEMICAL. AND YOU CAN GENETICALLY EXPRESS TO ALLOW THE CELLS TO SHINE LIGHTS AND USE MORE OPTICAL FIBER TO PICK UP THOSE SIGNALS. WE ALSO WANT TO BETTER CONTROL THE INFORMATION FLOW BY HAVING THE ABILITY TO WRITE INFORMATION INTO THE BRAIN THIS CAN BE DONE ELECTRICALLY AND GENETICALLY USING OPTICAL OR CHEMICAL APPROACHES. SO WE NEED TO BETTER UNDERSTAND HOW AN F MRI SIGNAL IS FORMED. SPECIFICALLY, THE ASPROECH WE USE IS SPECTRAL PHOTOMETRY. THESE ARE THE WAYS PEOPLE DO FINSER PRINTING, THIS IS THE OPTICAL VERSION OF IT. EACH ONE HAS ITS UNIQUE PATTERN. IF YOU CAN ACQUIRE DATA ACROSS A WIDE RANGE OF SPECTRUM, YOU CAN TRY TOLL ATTACH THE SPECIFIC PROFILE OF THE FINSER PRINT TO EXTRACT THE CO-EFFICIENT OF THE SENSOR ACTIVITIES. THERE ARE A LARGE NUMBER OF SENSORS BEING DEVELOPED. GCAMP, CALCIUM ACTIVITY IN GREEN, JRGECO CALCIUM ACTIVITY IN RED. GLUTAMATE, GABA AND THE VIDEO ON THE RIGHT SHOWS THE SET UP WE HAVE. THE GLUTAMATNERGIC SPECTRUM. IT IS A SINGLE FIBER WE CAN GET INPUT AND OUTPUT ACTIVITY SIMULTANEOUSLY. YOU DON'T HAVE TO USE TWO FLUORESCENT SENSORS. YOU CAN USE THIS TO LOOK AT CUPELING. FOR THIS SETUP WE EXPRESSED GCAMP IN THE CORTEX OF THE RAT AND INJECTED A RED FLUORESCENT DYE. THIS IS A FLUORESCENT DYE THAT WILL CIRCULATE IN YOUR BLOOD STREAM. THOSE FAMILIAR WITH MEASURING BLOOD VOLUME USING MRI, THIS IS CONCEPTUALLY SIMILAR. WE CAN DO AN EXPERIMENT AND GET THIS GCAMP ACTIVITIES, THE PHOTOMERRY AT THE RIGHT VOLUME. SO THIS TYPE OF STUDY OR INFORMATION DOESN'T NECESSARILY HAVE TO COME FROM A STIMULUS EVOKED EVENT. I'M SHOWING YOU EXAMPLES THAT WE CAN ACTUALLY PULL THE INFORMATION OR THE RELATIONSHIP NEURONAL. THIS IS THE RECORDED GCAMP ACTIVITY FROM THE CELLS AND USING THE CBV MEASURE. WE CAN EM PEERICALLY DERIVE A RESPONSE FUNCTION. THIS IS TO CONVOLUTE THIS TO PREDICT THE UNDERLYING CBV CHANGES AND THE MEASURE OF CBV IS SHOWN IN RED. THEY HAVE HIGH CORRELATIONS. THIS APPROACH IS PRETTY ROBUST. THIS VIDEO I'M SHOWING YOU WAS FROM A SINGLE ANIMAL. THE FIBER PLUGGING INTO THE BRAIN AND ACQUIRING THE NEURONAL AND VASCULAR SIGNAL SIMULTANEOUSLY, BUT FEEDING THIS INFORMATION TO THE DECONVOLUTION PIPELINE. BEYOND ONE MINUTE WE CAN GET A STABILIZE HRF PATTERN THAT DESCRIBES THE RELATIONSHIP BETWEEN NEURONAL AND VASCULAR ACTIVITY HERE. WE SCALED THIS UP AND BUILT FOUR CHANNEL SYSTEMS THAT ALLOWS FOUR INDIVIDUAL FIBERS INTO DIFFERENT BRAIN AREAS AND MEASURE THE SIGNAL SIMULTANEOUSLY. IN THIS PARTICULAR EXPERIMENT WE PUT IN THESE CORTICAL REGIONS. YOU CAN SEE THE CONSISTENT PATTERN HERE, WHICH IS GOOD, RIGHT, BECAUSE THAT MEANS FMRI THE WAY WE INTERPRET FMRI DATA HAS A REASONABLY SOLID FOUNDATION. THERE MIGHT ALSO BE SOME EXCEPTIONS WHERE NEUROVASCULAR COUPLING RULES MAY NOT APPLY. WE RAN INTO THIS THROUGH A DEVELOPMENT WITH OUR COLLABORATORS A FEW YEARS AGO TO MAKE FOR STIMULATION RECORDINGS. TO WALK YOU THROUGH THE DEVELOPMENT. WE HAD FLEXIBLE ELECTRODES AND CONTACT LEADS MADE BY GOLD AND COVERED WITH ORIDIUM OXIDES. THIS IS A MINIMUM INTENSITY PROJECTION FROM A 3D SPINNING DATA. THIS WE CAN PASS A QUITE HIGH LEVEL OF THE CURRENTS FOR MULTIPLE TIMES. AND ALSO IN VIVO, WE CAN PUT IT IN ANIMAL BRAINS AND LOOK OVER THE COURSE OF 50 DAYS. THIS PICTURE SHOWS WE ARE USING A FORCEP TO PUT IT ON THE TABLE. IT COMES WITH A BENEFIT TO REDUCE SCARS ONCE YOU IMPLANT THIS INTO THE SUBJECT'S BRAINS. IN A FORM OF MRI COMES WITH AN ADDED EXTRA BENEFIT YOU CAN BEND ELECTRODE AND USE ANY COIL HOUSING TO DO YOUR EXPERIMENT. WE TRIED TO PASS CURRENTS TO DIFFERENT LOCATIONS, DIFFERENT ELECTRODES THAT HAVE BEEN IMPLANTED. THESE CAN CAPTURE BETTER. WHEN WE ARE STIMULATING DIFFERENT PORTION OF THE ELECTRODES WE ARE GOING TO DRIVE DIFFERENT CORTICAL ACTIVATION BECAUSE WE ARE RECRUITING DIFFERENT FIBER GOING TO THE CORTEX. THIS PROVIDES US THE ABILITY TO DO STIMULUS EVOKED FUNCTIONAL ACTIVITIES WITH A REASONABLY HIGH THROUGHPUT COMPARED TO A SINGLE ELECTRODE. THE PROBE CAN BE USED FOR RECORDING. I'M SHOWING YOU A PROFILE FOLLOWING DIFFERENT LAYERS AND INSIDE A MRI TO CAPTURE SINGLE UNIT ACTIVITY. WITH THIS PROBE OUR LAB WAS INTERESTING NO KNOWING WHAT IS THE SPATIAL TEMPORAL PATTERN IN THE BRAIN REGIONS CLINICIANS ARE PICKING TO TREAT PARKINSON'S DISEASE FOR EXAMPLE. WE DID THIS EXPERIMENT AND PUT ELECTRODES IN THE RODENT BRAIN. STM IS A THIN STRUCTURE. THE AREAS ABOVE AND BELOW HAD VERY DIFFERENT FIRING PATTERN. WE CAN USE THIS SAME ELECTRODE TO PICK UP THE LOCATION OF THE STN AND COVER THE SURGERY UP AND COME BACK TO THIS SAME LOCATION AND AS YOU CAN SEE FROM THE PICTURES ON THE RIGHT DERIVE A PATTERN. WE ARE SEEING SOME RESPONSES FROM THE RAPHE, CEREBELLUM AND WE SAW THIS NEGATIVE EVOKED FMRI SPOBSS IN THE STRIDUM AREA. AT THE TIME WE DID NOT HAVE A GOOD WAY TO EXPLAIN THOSE RESULTS. IN A SEPARATE STUDY, INCLUDING SUBSTANTIAL SNR IN THE EXTERNAL GPE. SO KNOWING THAT ELECTRICALLY STIMULATING THOSE REGIONS WILL RECRUIT -- TO FIRE NEURONS WE ARE INTERESTED IN KNOWING WHY DRIVING THIS ACTIVITY WOULD LEAD TO A NEGATIVE FMRI RESPONSES. SO WE WENT ON TO ASK ANOTHER QUESTION? CAN WE PROBE IN THE SOURCE OF THIS NEGATIVE FMRI SIGNAL WITH A CELL TYPE OR PATHWAY SPECIFIC STIMULATION AND IN RODENT MODEL, WE HAVE ACCESS TO A VERY POWERFUL TOOL TO GENETICALLY EXPRESS THIS ON CHANNELS AND SOMETIMES IN THE FORM OF RECEPTORS AND WHEN YOU SHINE THE LIGHT WITH APPROPRIATE WAVELENGTHS, YOU CAN DRAW ACTIVITIES FOR SPECIFIC CELLULAR POPULATION. INSIDE MRI THE SET UP IS STRAIGHT FORWARD. BUILD A COIL. SO WE WENT ON TO INTERROGATE A FEW CIRCUITRIES THAT ARE RELEVANT TO THE STRIATUM, WERE RECRUITING AS YOU CAN SEE FROM THIS RESULT, WE ARE LEARNING THAT FIRING EXCITERY INPUT DOESN'T NECESSARILY ALWAYS LEAD TO A POSITIVE FMRI RESPONSE. IN THIS CASE UNDER OUR EXPERIMENTAL CONDITIONS IT CAN LEAD TO NEGATIVE FMRI SIGNAL. MOVING ON WE ALSO DID THE SAME TO DIRECTLY STIMULATE THE STRIATUM NEURONS. WE STIMULATED THE GCE CELL BODY. BY DOING THIS EXPERIMENT WE REALIZED THAT ACTIVATION OF LOCAL STRIATUM NEURON CANS CAUSE THIS NEGATIVE FMRI RESPONSE. THERE IS ANOTHER INTERESTING FINDING WHEN WE TRY TO TARGET DOPAMINENERGIC NEURONS THAT SENT A LOT TO THE STRIATUM REGION AND SEEING POSITIVE INSTEAD OF NEGATIVE RESPONSES. WE REPORTED THIS BY A PAPER IN 2016, BUT WE ARE NOT THE ONLY GROUP THAT SAW THIS. THERE ARE OTHER PAPERS LISTED HERE SEEING THE SAME THING. WE ARE TRYING TO FIND THE UNDERLYING ACTIVITY. WE ARE TRYING TO MEASURE POTENTIAL AND THE MULTIUNIT ACTIVITY UNDER THE SAME EXPERIMENTAL CONDITIONS WE CREATED A NEGATIVE RESPONSE. INDEED WE ARE SEEING THE INCREASES IN POWER AT A BAND WE MODULATED AND INCREASING IN SPIKING ACTIVITY. WE KNOW THIS VALIDATION IS NOT ENOUGH. WE WANT TO DO MORE THOROUGH INVESTIGATIONS OF THIS. THAT IS THE POINT WE BROUGHT THIS FIBER PHOTOMETRY APPROACH. BY THE TIME WE WERE READY TO LAUNCH THIS EXPERIMENT, THIS IS SHOWING YOU THE CONTROL EXPERIMENTS WHERE WE EXPRESS IN THE PROTEIN INTO THE CORTICAL ACTIVITIES. THIS PROTEIN'S INTENSITY OF LIGHT HAS NOTHING DO WITH THE ACTIVITY. WE ARE STILL SEEING CHANGES, A DECREASE IN THE SIGNAL THAT WE MEASURE BY THIS OPTICAL FIBER. SO WHY? WE WENT ON QUITE A BIT OF A JOURNEY TO FIGURE OUT THE UNDERLYING REASON AND WE FIGURED OUT THIS IS ACTUALLY BECAUSE THE HEMOGLOBIN CHANGES, OR THE CONCENTRATION OR AMOUNT OF HEMOGLOBIN CHANGES. HEMOGLOBIN IS VERY GOOD AT STOPPING THE LIGHT. AS WE ARE OPERATING UNDER THE RULE OF DRIVING ACTIVITIES, FUNCTIONAL HYPER -- THE INCREASE IN HEMOGLOBIN WERE A SIGNATURE CAL THAT CAN HAPPEN IN TWO PHASES. THE LIGHT COMING OUT FROM THE OPTICAL FIBER BEFORE IT REACHES THE TARGETED CELLS AND THE EMISSION LIGHT FROM THE CELLS BEFORE IT GOES BACK TO THE OPTICAL FIBER. WE KNOW THAT WE NEED TO SOLVE THESE ISSUES. AND WE FIGURE OUT A WAY TO ACTUALLY CORRECT THIS TYPE OF CONTAMINATION. I'M NOT GOING TO GO INTO THE DETAIL HERE. THE INFORMATION WAS IN THIS PAPER PUBLISHED BY ZHANG, CELL REPORTS METHODS THIS YEAR. OXY AND DEOXY HEMOGLOBIN OVER TIME USING THE SPECTRAL INFORMATION TO COLLECT THE HEMOGLOBIN AND RESTORE THE NEURAL ACTIVITY TO MAKE A STEP CLOSER TO THE REAL UNDERLYING EVENT. WE NEED TO GET THE ACCURATE NEURONAL ACTIVITY AND TIME SCALE TO MODEL THE RELATIONSHIP. SO MOVING ON, WE DID AN EXPERIMENT BY PUTTING AN ELECTRODE TO STIMULATE THE MULTICORTEX. MULTICORTICAL REGIONS PROVIDE EXCITERY. LATERALLY TO THE STRIATUM. SO THOSE ARE THE TWO LOCATIONS WHERE WE DID THIS FIBER EXPERIMENT, WE PUT IN FIBER TO MEASURE THEIR SIGNALS. BY STIMULATING THE UPSTREAM MOTOR CORTEX WE CAN DETECT THE DOWNSTREAM ACTIVITY SHOWN IN THE PANEL C AND D. YOU CAN SEE FROM THESE TWO REGIONS WE ARE GETTING A SIMILAR PATTERN OF THE CELLULAR CALCIUM EVENTS. THE ACCOMPANYING HEMODIE MA'AMIC RESPONSE IS VERY DIFFERENT. THE NEUROVASCULAR COUPLING SEEMS QUITE SIMILAR ACROSS CORTICAL REASONS, BUT THERE MAY BE DIFFERENCE BETWEEN THE CORTEX AND THE STRIATUM. THAT EXPERIMENT WAS DONE ANIMALS WHO WERE UNDER ANESTHESIA. WE USED THE SAME APPROACH WITH FOOTSHOCK, WHICH WOULD DRIVE THE ACTIVITY AND SAMPLING THE SPONTANEOUS SPIKES FROM THIS STRIATUM NEURONS. WHILE WE HAVE INCREASE IN CALCIUM ACTIVITIES, THERE IS AN ASSOCIATED TIME LOCKED CVV CHANGES MEASURED BY THE FIBER. SO WHAT IS THE MECHANISM? COULD IT BE SOME NEURAL CHEMICAL INFLUENCES TO THESE SIGNALS? TO ADDRESS THIS WE COUPLED FMRI WITH ADDITIONAL NEUROMODULATION APPROACH WITH PHARMACOLOGY THAT ALLOWS US TO INTERROGATE SOME OF THE MECHANISM RESPONSIBLE FOR THIS NEGATIVE RESPONSE. THE SPECIFIC EXPERIMENT WE ARE DOING HERE IS EXPRESSING VIRAL VECTORS AND INJECTING INTO THE DORSAL STRIATUM. INSTEAD OF STIMULATING THE STRIDAL CELL BODIES, WE ARE PUTTING THEM DOWNSTREAM TO ALLOW US TO REKREUTZ AND GO BACK AND FIRE THE STRIADAL CELL BODIES. BY DOING THE EXPERIMENT WE ARE NOT ADJUST AVOIDING THE HEATING ART FACT THAT CAUSED BY THE LIGHT REPORTED BY MANY COLLEAGUES IN THE FIELD WE ARE CREATING EXTRA SPACE TO PUT IN INTRACRANIAL FUSION INTO THE DORSAL STRIATUM. THESE ARE QUITE COMPLICATED EXPERIMENTS. WE STRUGGLE QUITE A BIT TO GET THIS TYPE OF STUDY LAUNCHED. EACH ANIMAL IS SCANNED FOR ABOUT TWO HOURS. DURING THAT PERIOD WE HAVE REPEATED OPTICAL STIMULATION TO SNR TO TRY THE STRIADAL ACTIVITY. THE BLUE IS THE ACTIVITY. THE RESPONSE IS TIME LOCKED TO THAT. THE PINKISH HORIZONTAL BAR AT THE BOTTOM OF EACH GRAPH INDICATES THE FLUIDS OR COMPOUNDS WE ARE INFUSING. YOU CAN SEE FROM PANEL B, INFUSION OF SALINE DOESN'T AFFECT IT. THE STRIADAL RESPONSE, BUT INFUSING LIDOCAINE, WHICH CAN SUPPRESS THE ACTIVITY LOCALLY, WE CAN USE THAT TO KNOCK OFF THE NEGATIVE SIGNALS. WE ALSO USED ACETYLCHOLINING A NIS TO TARGET THE GI COUPLE RECEPTOR HENCE SUPPRESSING THE STRIADAL ACTIVITY. THIS NEGATIVE RESPONSE IS RELATED TO THE LOCAL STRIATUM NEURONS. WE TRIED TO LOOK INTO DIFFERENT TYPE OF NEUROCHEMICAL SIGNAL REPORTED TO BE RELATED TO THE STRIDAL MICROCIRCUITRIES, ACETYLCHOLINE, BRBB, 3226 AND SHARING 22390 AND THESE ARE DOPAMINE D5 AND D1D2ING A NIS COCKTAILS, NONE OF WHICH SUPPRESSED THE NEGATIVE RESPONSE SIGNIFICANTLY. HOWEVER, WHEN WE INFUSE NOR-BNI. WHEN WE CHECKED FOR THE OUTPUT EXPRESSION, WE CAN SEE THE EXPRESSION LOCATED CLOSE BY THE STRIADAL MICROVESSELS. WE TOOK A STEP BACK AND BROUGHT THINGS TO EXVIVO AND LOOKING AT USING A TECHNIQUE MICOSCOPY TO LOOK FOR THE CHANGES DIRECTLY. HERE WE HAD THE STRIDAL BRAIN SLIDES, INFUSE WITH TXA2 AND CSF. TO SEE WHICH BLOOD VESSELS ARE RESPONSIVE. WHEN WE PROFUSE DADLE, A CAFFEINE OPIOID RECEPTORING A NIS, WE CAN FURTHER CONSTRICT VESSELS IN THIS CASE. WHEN WE STOP THIS PER FUSION, THE VESSEL DOESN'T RELAX AS YOU CAN SEE FROM THE PICTURES ON THE RIGHT. THIS INDICATES OPIODNURGIC MAY HAVING SOMETHING TO DO WITH THE VASO CONSTRICTION IN THE AREA. THE POSITIVE RESPONSES. HERE THE PICTURES ON THE LEFT SHOWS A SET UP WE TRIED TO MAKE, ELECTROCHEMICAL MEASURES OF -- USING A FULL SELL SETTING AND FOLLOWED BY IN VIVO EXPERIMENT. THIS CAN BE DONE WITH FMRI, A SIMPLE IDEA WHERE WE INTERWEAVE THE RECORDING TO MAKE IT AWAY FROM THE PULSES OR EPI GRADIENT SWITCHING. WITH THIS APPROACH WE CAME BACK TO OUR QUESTION WHICH IS WHAT IS THE UNDERLYING EVENTS THAT IS HAPPENING WHEN WE DRIVE DOPAENERGIC. YOU CAN SEE IN PANEL C ON THE RIGHT, WE ARE INVOKING THE POSITIVE FMRI RESPONSES THROUGH THIS MANIPULATION AND WHEN WE UNCOUPLE THIS WITH SPECK -- WE ARE SEEING INCREASING IN DOPAMINE. IN THE CASES WE SAW THE NEGATIVE RESPONSES, STIM LATING THE THALAMUS, WE ARE NOT SEEING DOPAMINE CHANGES. THIS HIGHLIGHTS THE POTENTIAL INVOLVEMENT OF THIS NEUROCHEMICAL SIGNALS IN DICTATING THE VASCULAR RESPONSE OUTCOMES. AFTER HAVING THESE FINDINGS WE ARE INTERESTED IN KNOWING IF THERE ARE OTHER NEUROCHEMICALS THAT DISASSOCIATE NEURONAL AND VASCULAR RESPONSES. WE USED A TECHNIQUE HERE SIMILAR, BUT WE CAN EXPRESS THE RECEPTOR OF DESINDER DRUGS, DREADD. THIS RECEPTOR RESPONDS TO A SPECIFIC DREAADD ACTIVATOR. YOU CAN INJECT THE DRUGS AND MODULATE THE CELL ACTIVITY IN THE MORE CHRONIC FASHION. SO WE HAVE ACCESS TO THESE ANIMALS, TRANSGENETIC MOUSE LINES THAT HAS THE DREADD RECEPTORS EXPRESSED IN THE NEURONS RESPONSIBLE FOR THE MAJORITY OF NOREPINEPHRINE IN THE BRAIN. WE KNOW IT IS A NEUROMODULATOR AND A GOOD VASO CONSTRICTOR. WE EXPANDED THIS INTO THREE BANDS. SO IN THE GREEN ZONE WE ARE MEASURING THE NOREPINEPHRINE RELEASE, IN THE RED LOCAL NEURONAL ACTIVITIES, THE GRAY ZONE WE ARE USING A RED DYE TO MEASURE THE VASCULAR ACTIVITY AT THE SAME TIME. THIS EXPERIMENT YOU CAN SEE THE RED VERTICAL BAR IS WHEN WE INJECTED DREADD. SEE INCREASES IN CELL SPIKING ACTIVITIES, CALCIUM ACTIVITIES AND DECREASE IN BLOOD VOLUME. THIS IS A DISASSOCIATION BETWEEN THE NEURONAL ACTIVITY, COMPARED TO THE EXPECTED NEURONAL AND VASCULAR RELATIONSHIPS. SO AGAIN THESE FINDINGS WERE CORROBORATED BY THE FMRI OUTCOMES. I'M NOT GOING TO GO INTO THE DETAIL HERE, BUT THE DREADD MODLATOR CAN SUPPRESS THE CVV CHANGES IN THE BRAIN AND DOWNSTREAM NETWORK MODULATIONS. TO SUM UP, FMRI COUPLED WITH NEURAL STIMULATION AND RECORDING TOOLS IN ANIMALS CAN GIVE US THE OPPORTUNITY TO DO MECHANICISTIC STUDIES DIFFICULT TO IMPLEMENT IN HUMAN SUBJECTS. THE HEMODYNAMIC FUNCTIONS ARE CONSISTENT ACROSS SEVERAL CORTICAL REGIONS, HOWEVER THIS RELATIONSHIP MIGHT NOT HOLD IN SOME BRAIN REGIONS, FOR EXAMPLE THE STRIATUM. WITH THE NEURAL ACTIVITIES IN THE STRIATUM AND DOWNSTREAM OPIODERGIC SIGNALLING RELATED TO NEGATIVE FMRI RESPONSES. NOREPINEPHRINE IS A STRONG MODULATOR AND VASO CONSTRICTOR. DECREASE IN HEMO DYNAMIC FMRI MEASURES DOES NOT NECESSARILY TRANSLATE TO A SUPPRESSION OF NURNL AL -- NEURONAL ACTIVITY. A BETTER UNDERSTANDING OF THE FMRI SIGNAL HAVING THIS READ AND WRITE ABILITY WILL HELP BRIDGE INFORMATION ACROSS TEMPORAL SCALES AND SOMETIMES ACROSS MODALITIES. PEOPLE WHOSE NAMES ARE HIGHLIGHTED DID THE HARD WORK. WE THANK YOU NIH AND WE THANK YOU FOR YOUR ATTENTION. >>ANY QUESTIONS? I GUESS I WILL START. I THINK THAT IS QUITE INTERESTING YOUR RESPONSES IN THE STRIATUM FOR NEUROVASCULAR COUPLING IS DIFFERENT FOR THE CORTEX. DO YOU HAVE ANY IDEA BECAUSE OF THE NEUROTRANSMITTER INVOLVEMENT OR NEUROVASCULAR ANATOMICAL REASON? >>YEAH. SO THE AREA HAVE VERY DIFFERENT ANATOMICAL DISTRIBUTION OF THE CELL TYPES AN DENSITY IN THE CEREBRAL CORTEX. VASCULAR IS A LOT DIFFERENT. THERE IS A LOT OF WORK THAT NEEDS TO BE DONE TO FURTHER DISSECT THE INFORMATION WE HAVE DONE. AGAIN, THIS IS GOING TO BE A LONG JOURNEY TO FIGURE OUT, WE HAVE TO HAVE THE ABILITY TO CONTROL EACH FACTOR. AND PROBABLY TO ASK WHICH IS NECESSITY FOR EACH TO GENERATE A SIGNAL AND THAT IS WHAT WE ARE STILL ACTIVELY PURSUING. >>THAT IS GREAT WORK. OBVIOUSLY, TO LOOK AT THE RELATIONSHIP BETWEEN THE FMRI SIGNAL AND NEUROTRANSMISSION, THAT IS -- FOR UNDERSTANDING OF THE SIGNAL. NOW MOST OF THE WORK IS ON THE SUBJECTS. WHAT IS FOR THE POPULATION, DISEASE POPULATION, WHAT HAPPENED? >>YEAH. WE HAVEN'T HONESTLY GOTTEN INTO THE DISEASE MODEL JUST YET. THERE ARE ALREADY A WHOLE LOT OF THINGS THAT NEED TO BE BROUGHT BACK TO THE FIRST QUESTION, THERE ARE SO MANY THINGS WE NEED TO STUDY IN THE HEALTHY CONDITION. I THINK WE NEED TO TAKE STEP BY STEP AND OBVIOUSLY, THERE ARE MANY DISORDERS WHERE THE OPIOIDERGIC AND DOPAMINEERGIC HAS BEEN AFFECTED. IN SOME OF THE EXPERIMENTS, THE PILOT EXPERIMENT WE DID IN SORT OF PARKINSON'S MIMICRY OF A MOUSE MODEL, WE COULD SEE R VERY, VERY BIG DIFFERENCES IN THE DOPAMINE IN TERMS OF THE RESPONSES. IT IS AN INTERESTING LINE TO PURSUE FURTHER. [ INAUDIBLE ] >>SORRY. I CAN'T HEAR YOU. >>PROBABLY YOU WANT TO USE THE MICROPHONE. >>ARE THESE RESULTS RECORDING RESTING STATE? >>SOME OF THE EXPERIMENTS I SHARE WITH YOU WERE DONE IN THE RESTING STATE SETTING. SOME WERE STIMULUS INVOKED RESPONSES. THIS COULD BE DONE BOTH WAYS. >>AND ALSO FOR THE NEGATIVE RESPONSE, I SAW FOR THE SPATIAL PATTERNS THERE IS SOME POSITIVE RESPONSE VERY CLOSE TO IT. ARE THESE TWO MIGHT BE RELATED? LIKE EXAMINE THE RELATIONSHIP? >>RIGHT. THERE ARE SOME EXPERIMENTS THAT WE, INDEED, SAW THE POSITIVE RESPONSES. OBVIOUSLY, FOR EXAMPLE, WHEN WE TRIED THE DOPAMENERGIC RESPONSES. WE ARE SEEING A POCKET OF RESPONSE IN THIS AREA THAT COMES WITH SURROUNDING NEGATIVE SIGNALS. THAT IS AN INTERESTING PATTERN WE NEED TO STUDY. TO SOME EXTENT WE ARE WORRIED ABOUT POTENTIAL HEAT RELATED COMPOUNDS. WHEN WE DELIVER LIGHT INTO THE LOCAL AREA, MRI IS QUITE SENSITIVE TO THOSE TEMPERATURE RELATED SIGNAL CHANGES THAT COULD CREATE A SIGNALLING PATTERN. WE DON'T KNOW IF THAT IS VASCULAR RELATED. THAT IS WHY WE WENT ON FOR PHOTOMETRY TO CIRCUMVENT PROBLEMS. >>OKAY. THANK YOU. >>ANY OTHER QUESTIONS? OKAY. THANK YOU VERY MUCH. >>YEAH. [ APPLAUSE ] >>ALL RIGHT. THE SECOND SPEAKER OF THE SESSION IS DR. HANBING LU FROM NATIONAL INSTITUTE ON DRUG ABUSE. HE IS TALKING ABOUT FOCAL TMS ON RODENT MODELS. >>GOOD MORNING. GOOD AFTERNOON. SO I GUESS I WOULD LIKE TO START BY THANKING THE ORGANIZERS FOR ORGANIZING THIS WORKSHOP AND FOR THE OPPORTUNITY TO PRESENT OUR WORK. SO MY TALK IS AS FOLLOWS. I WILL GIVE BRIEF BACKGROUND ON TMS AND AN IMPORTANT QUESTION WHICH I THOUGHT WAS IMPORTANT. WHY IS THE EFFICACY OF TMS AND BACK TRANSLATION OF STUDIES. WE WILL TOUCH ON TRANSLATIONAL WORK FOR MECHANICISM AND EFFICACY OF TMS IS THE PURPOSE. THE "NEW YORK TIMES" RAN THIS ARTICLE IN 2018, THE TITLE OF THIS ARTICLE WAS ONE SON, FOUR OVERDOSES, SIX HOURS. THE IMPACT OF ADDICTION TO THE INDIVIDUALS. AND TO FAMILIES. SO CONVENTIONAL ADDICTION TREATMENT IS BASED ON PHARMACO THERAPY. THE NEUROIMAGING FAILED MANY PEOPLE. BRAIN CIRCUITS INDICATED DRUG ADDICTION IN THIS CASE IMPLICATING COCAINE DEPENDENCY THROUGHOUT MODELS. SO WE ARE ASKING WHAT IT CAN DO WITH THIS. USING TMS HAS BEEN APPROVED BY FDA FOR DEPRESSION TREATMENT AND IT IS [INDISCERNIBLE] TMS WORKS BY APPLYING VARIOUS 2,000 VOLTS WHICH WILL GENERATE HIGH MAGNETIC FIELD, 1.5 TESLA OR HIGHER. STIMULATES THE BRAIN. WE ARE HOPING TO -- AND IT FAILED TO APPLY TO ADDICTION TREATMENT. MOST WIDELY USED IS REPETITIVE TMS. IN THIS PROTOCOL FOUR SECOND OR 20 SECOND. DURING THE FOUR SECOND PERIOD TMS IS APPLIED AT 10 HERTZ. THE OTHER ONE IS A TWO SECOND ARM PERIOD. BURSTS OF A PULSE ARE REPEATED. IN THIS CASE EACH BURST CONSISTS OF THREE PULSES, SEPARATED BY 50HERTZ. THE INTERVAL IS 200 MILLISECOND OR 5 HERTZ. THIS IS A FREQUENCY RANGE. # FOR CONVENTIONAL TREATMENT 37.5 MINUTE PR SESSION. [INDISCERNIBLE] SO THIS IS REALLY REMARKABLE TO ME. HOW GOOD ARE EFFICACY? IT IS RELATIVELY MODEST. SUGGESTING THE EMISSION RATE 15% HIGH. AND THE RESPONSE RATE ABOUT 18% HIGHER. ACTIVE V. SHAM RTMS [INDISCERNIBLE] HOW TMS WORKS. WE DON'T KNOW WHY SOME PATIENT RESPOND WELL, SOME PATIENT NOT. THERE COULD BE MANY REASONS. SO I WAS THINKING ABOUT MAYBE WE SHOULD DO SOME ANIMAL WORK TO BACK TRANSLATE USING THE ANIMAL MODEL TO MIMIC TMS CONDITIONS. IN THIS CASE I THOUGHT IT WOULD BE IMPORTANT. THE SECOND WOULD BE [INDISCERNIBLE] THINK ABOUT THE TMS MULTICORTICAL EACH PASS EVOKING A SIGNAL. THE SIZE OF THE COIL TO PRODUCE SINGLE TWITCHES. WAY MUCH DOWN FROM HERE, FROM MONKEY TO RAT BRAIN THERE IS TREMENDOUS DIFFERENCE. SO WE [INDISCERNIBLE] SO ONE QUESTION IS THE RAT BRAIN, A LARGER ONE, REGARD TO BRAIN SIZE. SO THE ANSWER IS NO. 1991 PUBLISHED THIS PAPER. IN THIS PAPER SIMULATE A 5 CENTIMETER COIL AND REDUCED BY 25 TIMES. [INDISCERNIBLE] A TREMENDOUS CHALLENGE IN ELECTROMAGNETIC STRESS. THIS IS STATE OF THE ART. BUT LOOKING HERE, IT IS VERY DIFFICULT TO IMAGINE [INDISCERNIBLE] SO WE WORK ON THIS PROBLEM ON AND OFF FOR QUITE A FEW YEARS AND TRY DIFFERENT METHODS. EVENTUALLY RELATIVELY THE SAME PER METHOD. IN THIS CASE INSTEAD OF MAKING THE COIL PRETTY THIN, WE MADE THE COIL THICK AND THEN WE PUT IT IN MAGNETIC CORE IN THE MIDDLE. THE MAGNETIC CORE CAN ENHANCE, GUIDE, AND FOCUS TO THE BOTTOM REGION HERE. SO THAT IS WAS KIND OF A CONCEPTIONAL IDEA. THIS IS A COIL WE BUILT. THIS IS CORE SIZE DISABILITY MAYBE I CAN SAY. THIS IS FIRST PROTOTYPE COIL WE BUILT. AND WE HAVE BUILT QUITE A FEW AFTERWARDS. SO I WILL SHOW YOU ONE NICE HERE. IN THIS MOUSE, YOU WILL NOTICE THAT TMS -- SO IN THIS CASE TMS CONNECT [INDISCERNIBLE] ANYWAY, IT IS A PROBLEM AND UNFORTUNATELILY I WAITED TOO MUCH TIME HERE. YEAH. ANYWAY, WHAT I CAN SAY IS WHEN TMS IS GIVEN, THIS BODY PART, THIS IDEA. ANYWAY. SO IT IS MORE EXCITING -- THE COIL AND THE POSITION IS CHALLENGING HERE. IN THIS CASE WE COME UP WITH ONE IDEA TO USE HEADPOST ON THE SCALP. THE COIL GUIDE DESIGNED SO WE CAN PUT THE COIL TOWARDS THE TARGETED REGION IN RATS HERE. SO THE COIL GUIDE IS DETACHABLE. AND HERE IS THE COIL HERE. AS YOU CAN IMAGINE, WE CAN THE COIL GUIDE IS THICKER TO WE CAN TARGET THE RIGHT REGIONS. AGAIN, THE TMS CONDITIONS. SO TYPICALLY MULTIVERSION IN [INDISCERNIBLE] YOU INPUT THE ELECTRODES INTO SPECIFIC MUSCLE AND THE RECORDING IS HERE. THIS IS ONE PIECE OF DATA. FROM ONE RAT. [INDISCERNIBLE] WE CAN SAY THE MOTOR EVOKED POTENTIAL IS ONE MILLIMETER IS REDUCED DRAMATICALLY. AND BASED ON THE EVIDENCE WE THINK IS HERE. I WILL GIVE YOU AN EXAMPLE HERE. [INDISCERNIBLE] UNFORTUNATELY, THE SONG IS NOT -- ANYWAY. OKAY. SEW THEN WE ASK THE QUESTION HOW IS IT ACTIVATED BY TMS COIL. IN THIS PART WE KIND OF USE GLUCOSE AS INDICATOR OF WHICH CORTICAL REJOON ACTIVATED BY TMS. WE USED A FLUORESCENT INDICATOR. IN THE IMAGING FIELD, THE 2NBDG WORKS. IN THIS CASE IT IS GLUCOSE REPLACED WITH THE FLUORESCENT HERE. OTHERWISE IT IS METABOLISM. THIS IS FLUORESCENT ASSUMPTION. THIS HAS BEEN APPLIED TO THE MAP [INDISCERNIBLE] INCREASING UPTAKE WHICH YOU HAVE TO BE CAREFUL TO EMPHASIZE HERE. WE USE A PRODUCT CODE DEVELOPED FROM THIS GROUP AND WE DID A HEAD IMPLANTATION, HABITUATION. [INDISCERNIBLE] FOR ABOUT 20 MINUTES. TMS FOR 45 MINUTES AND [INDISCERNIBLE] I CHOSE THIS TO LOOK AT THIS REGION, THE DIFFERENT REGIONS I WILL SHOW YOU LATER. YOU SEE THE ENHANCED REGION IN THIS REGION AND SOME WERE HERE. AND [INDISCERNIBLE] THE SAME MODULE ON TOP. SO THE SAME DATA [INDISCERNIBLE] THIS IS A PRIMARY MOTOR REGION. THIS IS A PRIMARY -- SO IT COVERS THIS MUCH WE CAN CHECK OUT IN THE MAP. WE DID 106% AND 110%. ONE MILLIMETER APART. IT IS SIGNIFICANT HERE, BUT OTHERWISE THERE WAS A MILLIMETERISH ACTIVATION HERE. SO WITH THIS, ONE VERY NICE SIMULATION [INDISCERNIBLE] AND WHAT IN THIS STUDY IS UNIQUE KIND OF CONSTRUCT A MODEL BASED ON NEURONAL ACTIVITIES IN THE CORTEX REGIONS. A NICE DATABASE WITH THIS MODEL. THE CELLS AND CONNECTIONS AND CELL TYPES AND SO ON. WE DID TMS SIMULATION. TMS ACTIVATED WITH LOWEST INTENSITY LAYER 5 PYRAMIDAL CELLS. OUR DATA IS PRETTY MUCH SUPPORTED THE SIMULATIONS. HOWEVER, IN THIS CASE FLUORESCENT DYE AND MICROINJECTION AND [INDISCERNIBLE] TRANSPORTED. IT IS AN IMITATION THE CELL TAKES ON ABOUT 200MICRON BELOW SURFACE. [INDISCERNIBLE] YOU CAN LOOK DEEP ON THE SURFACE. TMS HAS VERY NICE FLUORESCENT RESPONSE, BUT HERE SEEMS NOT. ANYWAY, SOME TECHNICAL QUESTIONS. [INDISCERNIBLE] IN ANY CASE, THERE IS A LONG WAY TO GO TO UNDERSTAND WHAT TMS IS DOING. SO IN CONCLUSION, I HOPE I HAVE GIVEN YOU SOME EVIDENCE TMS COIL WITH RATS [INDISCERNIBLE]. ONE EVIDENCE MEP RECORDING AND GLUCOSE UPTAKE. AND WE FOUND CELLS ACTIVATED BY TMS. [INDISCERNIBLE] >>TREMENDOUS WORK IS NEEDED FOR TMS. OUR RODENT TMS MODEL OFFERS CERTAIN DEGREE OF FACE VALIDITY. I WILL SWITCH TO TALK ABOUT SOME TRANSLATIONAL WORK. IN THIS CASE, WE'LL ASK THE QUESTION, CAN WE ENHANCE THE EFFICACY WHILE MAINTAINED IDENTICAL TIME EFFICIENCY OF TBS? SO EFFICACY IS MODEST. SO THE QUESTION WE ARE TRYING TO ASK, CAN WE ENHANCE THE EFFICACY OF TIME EFFICIENCY TBS. TO ANSWER THIS QUESTION, LET'S TAKE ONE STEP BACK. WE ARE NOW [INDISCERNIBLE] AND 50 HERTZ. SO WE ARE THINKING ABOUT ONE STEP BACK. SO [INDISCERNIBLE] PATTERNED STIMULATION AT THE THETA FREQUENCY IS OPTIMAL FOR INDUCTION OF HIPPOCAMPAL LONG-TERM POTENIATION. THIS GROUP APPLIED FOUR TO FIVE ELECTRICAL PULSES AT 100 HERTZ. SO THESE PULSE PATTERNS. 100 HERTZ FOUR TO FIVE PULSE/BURST OF ELECTRICAL STIMULATION. TMS GIVEN 50 HERTZ. SO WE -- TO PUT IT THIS WAY, I DO NOT SAY ANY SCIENTIFIC JUSTIFICATION THAT THREE PULSE AT 50 HERTZ IS BEST. YOU CAN INDUCE PLASTICITY. WHAT ABOUT FOUR PLULS, FIVE PULSE, SIX PULSE BURST. WHAT IS GOING TO HAPPEN? WE DEVELOPED A MACHINE THAT CAN DELIVER UP TO SIX PULSE PER PERSON. YOU CAN REACH 4,3500 AMPS AND 2,000 VOLTS. SIX PULSES. WE ARE FIXING AT SIX. WE USE THE SAME [INDISCERNIBLE] IN THIS CASE. WE MEASURE THE POTENTIAL AND CONDITION SO THREE OR FIVE OR FIVE OR SIX PULSE. THE AFTER EFFECTS AT DIFFERENT TIME POINTS. WE WILL COMPARE TO THE RESPONSE UNDER THESE CONDITIONS. AND THE RESULT IS HERE. SO THIS TEST AND COMPARISONS SO WE ARE COMFORTABLE WITH THE FINDINGS HERE. WE FOUND SIX PULSE IS SIGNIFICANT HIGHER PONCE THAN FOUR OR THREE AND FIVE IS SIGNIFICANTLY HIGHER THAN THREE. HOW MUCH? 50%. SO WE ARE VERY EXCITED ABOUT THIS FUNDING. WE ARE HOPING WE CAN APPLY THIS TO HUMANS. AND WITH THAT, I HOPE I CAN CONVINCE -- DELIVER THIS MESSAGE TO YOU. WE DEVELOP A NEW PARADIGM CALLED A HIGH DENSITY TEST, WHICH HAS ENHANCED EFFICACY OF 50%. SO FURTHER STUDY IS NEEDED TO POTENTIAL FOR THIS PARADIGM AND ACTIVELY PURSUE THIS LINE. THESE ARE THE PEOPLE WITH WHICH I COLLABORATED. THIS PROJECT INVOLVED A LOT OF PEOPLE AND I WOULD LIKE TO MENTION THEM. THIS WAS SUPPORTED BY NIDA, IRP. MANY GOOD PROJECTS HAVE A HYPOTHESIS TO START WITH AND NO PRELIMINARY DATA TO START WITH. IT IS VERY DIFFICULT TO GET FUNDED. I REALLY APPRECIATE IT. [INDISCERNIBLE] I HAVE HAD TREMENDOUS SUPPORT. THANK YOU FOR YOUR ATTENTION. [ APPLAUSE ] >>ALL RIGHT. OPEN FOR QUESTIONS. YOU CAN USE THE MICROPHONE OVER THERE. >>I'LL ASK A QUESTION. VERY IMPRESSIVE LATERAL RESOLUTION. DO YOU HAVE ANY IDEA WHAT THE AXIAL RESOLUTION OF YOUR COIL IS? HOW DEEP DOES THE FIELD GO? >>THAT IS A GOOD QUESTION. THAT IS MORE DEPENDING ON HOW MUCH POWER YOU ARE GIVEN. THAT IS VERY TRICKY TO -- IT IS KIND OF VERY HARD QUESTION TO ANSWER. AND WE HAVE SORT OF DATA -- LARGE TECHNIQUE TO METHODS SIMILAR TO MAPPING. [INDISCERNIBLE] YOU COULD GIVE 140% OF POWER YOU COULD REACH [INDISCERNIBLE]. >>OKAY. [INDISCERNIBLE] >>YES. >>WITH THE SIX PULSES, DO YOU THINK THERE COULD BE LIMITATION IN HEATING THE COIL IN HUMAN? >>THAT IS A GOOD QUESTION. [INDISCERNIBLE] PRETTY GOOD. IN OUR ANIMAL STUDIES WE BASICALLY GAVE DRY ICE ON TOP AND -- THE COIL. WHEN THAT IS THE CASE, WE GAVE ONE SESSION -- FOR 200 SECONDS, THERE IS NO PROBLEM. HUMAN TMS, WE WOULD HAVE TO TEST IT. I THINK IT SHOULD WORK. YEAH. THANK YOU. >>THANK YOU FOR YOUR INTERESTING TALK. I HAVE TWO QUESTIONS. ONE IS DOES THE USE OF THIS CORE CHANGE THE DEPTH FOCALITY TRAIT OR THE SAME AS YOU WOULD OTHERWISE SEE FOR A ROUND COIL, JUST THAT IT IS VERY FOCAL? SO WHEN YOU PLOT DEPTH VERSUS FOCALITY, WOULD YOU SEE THE SAME TRAIT WHEN YOU SCALE YOUR IRON CORE? IS IT BETTER OR A VERY FOCAL VERSION OF BOTH? AND THE SECOND QUESTION IS IRON CORES TEND TO SEPARATE FOR VERY HIGH FIELD STRENGTH. DO YOU SEE CHANGES OF THE PULSE SHAPE WHEN YOU GO TO HIGHER INTENSITIES? OF THE ELECTRICAL FIELD OF PULSE SHAPE. >>THIS IS REALLY GOOD, VERY DEEP ENGINEERING AND PHYSICS QUESTIONS. THANK YOU. [INDISCERNIBLE] A CERTAIN RANGE YOU CAN GO. SO, YES, IN OUR CASE, [INDISCERNIBLE] YOU FEEL THE PULSE SHAPE. WHEN WE GIVE VERY HIGH [INDISCERNIBLE] JO THE PULSE PATTERN IS DIFFERENT FROM THE REGULAR ONES. IT IS A MAJOR ISSUE WITH RESULT OF COIL SO THICK. THE TOP -- I DID NOT MENTION THAT. THE COIL -- [INDISCERNIBLE] >>WE CAN DISCUSS MORE. >>THANK YOU. >>THANK YOU. [ APPLAUSE ] >>ALL RIGHT. THANKS, HANBING. OUR NEXT SPEAKER IS JAN KUBANEK FROM THE UNIVERSITY OF UTAH TALKING ABOUT THE MECHANISMS OF TRANSCRANIAL FOCUSED ULTRASOUND. WELCOME. >>I MUCH APPRECIATE THE INVITATION. ABOUT ONE IN THREE PEOPLE WITH MENTAL AND NEUROLOGICAL DISORDERS ARE RESISTANT TO TREATMENTS. AND THAT HAS BEEN A MAJOR ISSUE. WHAT CAN WE DO ABOUT THAT? ONE OF THE KEY CHALLENGES WITH TREATING DISORDERS THAT DON'T RESPOND TO CURRENT TREATMENTS IS THE FACT THAT THESE DISORDERS TYPICALLY INFLUENCE OR AFFECT DEEP BRAIN CIRCUITS. STRUCTURES IN THE LIMBIC AND BASAL GANGLION. IT HAS BEEN DIFFICULT TO MODULATE THESE CIRCUITS WITH THE GOAL TO RETURN THEM BACK TO NORMAL STATE. SO YOU MAY MENTION ONE APPROACH WOULD BE TO IMPLANT STIMULATION ELECTRODES INTO THE STRUCTURES OF BRAIN STIMULATION. THIS HAS BEEN PERFORMED FOR NEUROLOGICAL DISORDERS IN PARTICULAR MOVEMENT DISORDERS QUITE EFFECTIVELY. THE SURGICAL RISKS, THOUGH, ARE QUITE LIMITING IN TERMS OF PERFORMING THESE PROCEDURES FOR TREATMENTS OF MENTAL DISORDERS. THERE IS ONE EXCEPTION FOR OBSESSIVE COMPULSIVE DISORDER. TO COVER COME THESE SURGICAL LIMITATIONS, WE WOULD LIKE TO BE ABLE TO MODULATE THE BRAIN TARGETS, BUT IN A NONINVASIVE WAY WITHOUT THE RISK OF SURGERIES. WE HAVE RECENTLY ACHIEVED NONINVASIVE MODULATION OF THE BRAIN STRUCTURES USING ULTRASONIC WAVES. HERE ULTRA SOUND WAS FOCUSED INTO A DEEP BRAIN OF A PARLIAMENT WITH MAJOR DEPRESSION. THE DELIVERY WAS NONINVASIVE, THE CUPELING TRANSDUCER ARRAY. WE TARGETED THIS BECAUSE THERE IS EVIDENCE FROM DEEP BRAIN STIMULATION FROM CLINICAL TRIALS THAT MAY BE A KEY TARGET IN THE LIMBIC NETWORK THAT IS INVOLVED IN MAJOR DEPRESSION. WE WERE ABLE TO OBSERVE CHANGES IN THE ACTIVITY IN RESPONSE TO BRIEF LOW PULSES OF THE STIMULATION. SO THIS IS VERY EXCITING. THE BRIEF PULSES CAUSED INHIBITION OF THE NEURAL ACTIVITY. HERE IS MORE DETAILED. THESE ARE FLUCTUATION OF THE ACTIVITY, NICELY TIME LOCKED TO THE STIM LACE ONSETS AND OFFSETS. THERE WAS A DECREASE IN ACTIVITY IN RESPONSE TO THE BRIEF PULSES OF THE ULTRASOUND. OF COURSE THIS IS ONE OF THE FIRST APPLICATIONS OF THIS MODEL IN HUMANS. SO WE PERFORM A -- STIMULATION, INSTEAD OF FOCUSING THE ULTRASOUND INTO THE TARGET, WE EMITTED IT AS A BRAIN WAVE. IT WAS THE SAME ENERGY GOING INTO THE BRAIN, INTO THE SUBJECT. NOW IT WAS NOT FOCUSED, IT WAS DILUTED. IT IS A NICE CONDITION BECAUSE WE DELIVER THE SAME ENERGY INTO THE SUBJECT, COUPLING AND OTHER CONDITIONS ARE THE SAME, BUT NOW WE DON'T FOCUS THE ULTRA SOUND. IN THAT CASE WE DID NOT OBSERVE CHANGES IN THE ACTIVITY. TO NAVIGATE YOU THROUGH, THE BLUE IS THE TARGET WE END UP IN OUR TARGETING SYSTEM AND THE RED IS THE ACTUAL ACTIVATION OF THE SIGNATURE CAL. WE HAD A NICE SPATIAL OVERLAP THERE AND THERE WAS A VERY STRONG EFFECT GIVEN THE RELATIVELY WEAK PULSES WE DELIVERED. BECAUSE THE PATIENT HAD A MAJOR DEPRESSION, OUR MAIN TARGET WAS REALLY CLINICAL AND THAT WAS TO IMPROVE THESE SIGNS. IN FACT, WHEN WE DELIVERED ULTRASOUND OF SUBSTANTIAL DURATION, LONGER THAN ABOUT 20 SECONDS, THE PATIENT DID NOTICE CHANGES IN MOOD. THE PATIENT REPORTED IMPROVEMENTS IN THE LEVELS OF DEPRESSION SCALE FROM MINUS 3 TO 3. AND ALSO ANXIETY. ANXIETY IS OFTEN CO-MORBID WITH DEPRESSION. WE PROBED THE GENERAL VALENCE. DOES THE SUBJECT FEEL BETTER. IT WAS THE CASE WHEN WE STIMULATED THE -- BUT NOT WITH THE SHAM STIMULATION, WHICH WAS NOT FOCUSED. THESE EFFECTS WERE SPECIFIC TO THE SUB GENERAL AND INTERESTINGLY BRIEF DURATION DID NOT INDUCE CHANGES IN MOOD. IT HAD TO BE A SUSTAINED STIMULATION LONGER THAN 20 SECONDS TO SHOW AN EFFECT IN A PATIENT. THESE WERE COLLECTED BY BRIAN MICKEY. FOR DEPRESSION THERE ARE INCUMBENTS IMPLICATED IN THIS DISORDER. WE HAVE A TOOL TO NONINVASIVELY MODULATE THESE BRAIN STRUCTURES. THAT IS OUR GOAL IN ONGOING CLINICAL TRIAL. AND, OF COURSE, MANY OTHER DISORDERS ARE ASSOCIATED WITH MULTIFUNCTIONAL BRAIN CIRCUITS, ANXIETY, CENTRALIZED PAIN AND ADDICTION AS WE HEARD IN THE TALK BEFORE. BECAUSE WE HAVE THE ABILITY TO MODULATE DEEP BRAIN STRUCTURES, WE WILL ALSO PURSUE THESE INDICATIONS IN THE FUTURE. SO THIS METHOD AS A TREMENDOUS POTENTIAL. IN THIS TALK, I WILL TALK ABOUT THE KEY FEATURES, THE KEY STRENGTHS OF FOCUSED ULTRASOUND FOR BRAIN DISORDERS, ADDRESS THE MECHANISMS AND DISCUSS THE LIMITING BARRIERS THAT HAVE BEEN HOLDING US BACK AND NEEDED TO BE OVERCOME. SO LET'S START WITH THE KEY STRENGTHS OF ULTRASOUND. IT IS POSSIBLE TO STIMULATE THE BRAIN WITH ELECTRONIC OR MAGNETIC FIELDS. THERE IS HIGH INTENSITY AT THE SOURCE SUCH AS THE ELECTRODES OR THE MAGNETIC COIL. AND THE FIELDS DROP FAIRLY WITH DISTANCE SO WE GET -- LOW WITH DEPTH. ULTRASOUND CAN NOW FOCUS THE ENERGY INTO DEEP BRAIN STRUCTURE OF INTEREST. WE NOW HAVE THE OPPOSITE SITUATION, THE INTENSITY IS LOW AND INTENSITY OF TARGET IS HIGH. THAT IS WHAT WE WOULD LIKE TO HAVE. WHERE DOES THIS DIFFERENCE COME FROM IN TERMS OF PHYSICS. THESE ENERGIES CONSTITUTE FIELDS WHEREAS FOCUS ULTRASOUND IS A SET OF WAVES THAT CAN PROPAGATE THROUGH SPACE AND YOU CAN PLAY SPATIAL TRICKS LIKE THIS TO MAXIMIZE THE ENERGY DELIVERED INTO THE TARGET WHILE MINIMIZING THE ENERGY ELSEWHERE. SO FOCUS ULTRASOUND COMBINES BENEFICIAL TRIAD OF PROPERTIES. IT MAY EMERGE AS AN ALTERNATIVE THAT COMBINES THE STRENGTH OF THE EXISTING MODALITIES. ONE THING THAT IS WORTH NOTING IS THE FLEXIBILITY OF DELIVERY. IT CAN PROPAGATE WITHIN THE TISSUE FAST WITHIN MICK RO SECONDS AND IT IS POSSIBLE TO DEFINE THE TARGET OF THE MODULATION. JUST BY SETTING THE EMISSION PATTERN WITH THE RIGHT TIMING, YOU CAN FOCUS THE ULTRASOUND INTO SPECIFIC TARGETS AS SHOWN IN THE SIMULATION. AND BY CHANGING THE SETTINGS, AGAIN, YOU CAN REACH YET A DISTINCT TARGET. THIS IS A NICE FLEXIBLE WAY TO MODULATE WITH HIGH TEMPORAL PRECISION WHERE THE MRI IS BEING DELIVERED. IT MAY BE HELPFUL TO ELICIT SPECIFIC PATTERNS OF SPATIAL TEMPORAL ACTIVATION FOR DISORDERS THAT ARE CHARACTERIZED BY NONFUNCTIONING TIMING, NOT JUST SPACE. IT HAS BEEN KNOWN FOR QUITE SOME TIME MRI CAN MODULATE EXCITABLE CELLS. IN THE PAST DECADE SEVERAL GROUPS HAVE SHOWN THAT ULTRASOUND IN THE CORTEX OF RODENTS HAVE RESPONDED. THIS HAS BEEN TAKEN INTO THE HUMAN BRAIN AND THERE ARE STUDIES, MAYBE A DOZEN OR MORE, TO BEGIN TO APPLY ULTRASOUND TO THE HUMAN BRAIN. SO LET'S TALK BRIEFLY ABOUT THE MECHANISMS THAT ARE INVOLVED IN THE NEUROMODULATION HERE. WE AND OTHERS HAVE FOUND THAT THE MECHANICAL PRESSURE WAVE ASSOCIATED WITH ULTRASOUND IS ASSOCIATED WITH RADIATION FORCE THAT PUSHES ON MEMBRANES AND TARGET STRUCTURES. IMAGINE A PIECE OF MEMBRANE THAT EXPRESSES ION CHANNEL SUCH AS SODIUM SELECTIVE ION CHANNEL AND THE PIECE OF MEMBRANE IS INFLUENCED OR IMPACTED BY THE MECHANICAL RADIATION FORCE. SO WHAT WE HAVE FOUND IS THE MEMBRANE IS AFFECTED BY THE ONSET AND ALSO THE OFFSET OF THAT PRESSURE PULSE. THE ION CHANNEL OPENS IN RESPONSE TO THESE EVENTS AND CURRENTS FLOW THROUGH. SO THAT HAS BEEN FOUND TO BE THE CASE IN NEURONS BY SEVERAL GROUPS. AND ALSO IN GLIAL CELLS. I WILL TALK ABOUT IT IN JUST A BIT. YOU MIGHT NOW ASK WHAT KINDS OF ION CHANNELS ARE SENSITIVE TO THE ULTRASOUND? HERE IS AN INTRIGUING STUDY THAT SHOWED THERE IS GOING TO BE AN ENTIRE CASCADE OF EVENTS GOING ON. THE ULTRASOUND CAN BE DELIVERED ON TO A CELL MEMBRANE EXPRESSING ION CHANNELS, MAKING ION MECHANICANOSENSITIVE CHANNELS THAT CAN INCREASE IN INTRACELLULAR CALCIUM. WHICH CAN IN TURN AMPLIFY THE RESPONSES OF MANY OTHER ION CHANNELS. SO THERE CAN BE A NUMBER OF EVENTS INVOLVED IN NEUROMODULATION. ONE PARTICULAR EXCITING FINDING IS ULTRASOUND CAN MODULATE GLIAL CELLS. WHICH HAS A MAIN POTENTIAL IN USING NEUROPLASTIC EVENTS, IN PARTICULAR BECAUSE IT HAS BEEN FOUND THAT ULTRASOUND CAN ACTIVATE A CASCADE OF EVENTS LEADING TO AN ACTIVATION OF MDA RECEPTORS. AS YOU ARE AWARE, THAT COULD LEAD TO LONG-TERM POTENTIATION AND DEPRESSION. ONE ION CHANNEL IS A MECHANIC NO SENSITIVE ION CHANNELS THAT RESULTS IN -- RECEPTORS. WHEN WE THINK ABOUT THE EXCITABLE TISSUE AS IN THE MODEL HERE SIMPLIFISIMPLIFIED, ULTRAS ACTIVATE THE CHANNELS IN THAT MODEL. YOU MAY NATURALLY ASK IN THE FOLLOWING WAYS. THE ULTRASOUND PRESSURE WAVE AT SPECIFIC FREQUENCY CAN MODULATE THE DISTANCE OF THE AND THAT CHANGES CAPACITANCE WITH THE SAME FREQUENCY OF MODULATION. IF YOU COMPUTE CURRENT, A DERIVATIVE OF THAT, YOU SEE THAT CHANGES OF CAPACITANCE OVER TIME DO RESULT IN CURRENT FLOWING INTO THE MEMBRANE. THE CHANGE IN CAPACITANCE DUE TO ULTRASOUND LEAD TO MEMBRANE CURRENTS WHICH INCREASE SPIKING ACTIVITY AND FIRING. THAT HAS BEEN MODELLED AS A VERY DETAIL LEVEL. THERE ARE SEVERAL NICE PAPERS AND THERE IS SOME EVIDENCE, SOME EXPERIMENTAL EVIDENCE THAT THIS, INDEED, MAY BE THE CASE. SO TOGETHER ULTRASOUND CAN CHANGE CAPACITANCE OF MEMBRANES. WE SHOULD ASK NOT WHAT IS A MECHANISM UNDERLYING NEUROMODULATION, BUT WHAT MECHANISMS ARE INVOLVED. THERE WILL BE MANY. THE RADIATION FORCES ASSOCIATED WITH THE ULTRASOUND, THE CYCLE BY CYCLE PRESSURES INDUCED BY ULTRASOUND AND HIGH ENOUGH PRESSURES BY HEATING. SO MANY MECHANISMS. SO LET ME BRIEFLY NOW TALK ABOUT THE BARRIERS THAT HAVE BEEN HOLDING US BACK IN DEVELOPING IN LARGE SCALE AND APPLYING TO HUMANS. THE KEY BARRIER HAS BEEN THE SKULL AS WE HAVE ACOUSTICALLY ISOLATED ENVIRONMENT, SO [INDISCERNIBLE] ESPECIALLY AT HIGH FREQUENCIES. WE HAVE MEASURED IN THREE EX VIVO SKULLS. YOU SEE THAT ON AVERAGE ITS MAJOR, FACTOR OF 18 OF ATTENUATION, THAT IS HUGE, AND FOR US THE VARIABILITY IS ENORMOUS WITHIN AND ACROSS INDIVIDUALS. IT IS HARD TO PREDICT BECAUSE OF THAT VARIABILITY HOW MUCH ULTRASOUND IS DELIVERED INTO THE TARGET. SO WE HAVE DONE ANALYSIS IN HUMANS WHERE THOSE MEASUREMENTS AND CONVERTED THE GIVEN INTENSITIES WITH FREE FIELD IN THE SKULL INTO THE INTENSITY DELIVERED TO THE TARGET THROUGH THE SEGMENTS OF THE SKULL AND WE HAVE FOUND THAT THOSE DELIVERED THROUGH THE SKULL WERE QUITE LOW WITH RESPECT TO THE THRESHOLDS WITH NEUROMODULATION SHOWN IN RODENTS. THAT TELLS US THAT NEUROMODULATION SO FAR HAS BEEN QUITE LOW IN HUMANS. YOU MIGHT ACTUALLY ASK, WHY DON'T WE JUST SCALE THE INTENSITIES UP? WE CANNOT QUITE DO THAT. WHEN YOU LOOK AT THE HISTOGRAM, THE LESS ATTENUATION HAPPENS MOST FREQUENTLY. IF WE WERE TO SCALE BY 18, IN MANY CASES WE OVERSHOOT THE ESTIMATED INTENSITY EFFECT AND IT WOULD HURT OR HARM THE SUBJECT. A SIMPLE SCALING IS NOT A SOLUTION. I SHOULD TELL YOU THAT THERE ARE TWO KINDS OF VIBRATIONS BY THE SKULL. THE SKULL SPEEDS UP PROPAGATION OF THE ISSUE TO MAXIMIZE THE INTENSITY THAT ARRIVES AT THE TARGET AT THE SAME TIME. IN FACT, IT HAS BEEN SOLVED MORE OR LESS THIS ISSUE. [INDISCERNIBLE] BASED ON CT SCANS TO ALLOW RESEARCHERS TO FOCUS CONSTRUCTIVELY FOR THE DEPHASING. A MORE IMPORTANT ISSUE ESPECIALLY FOR THESE REVERSIBLE, NONSURGICAL TREATMENTS IS THE ATTENUATION OF ULTRASOUND BY THE SKULL. WE NEED TO DELIVER DETERMINISTIC DOSE INTO SPECIFIC TARGETS BECAUSE WE WOULD LIKE TO INDUCE EFFECTS THAT EXCEED CERTAIN THRESHOLD WHILE THAT STIMULATION BEING SAVED. SO THERE IS A FAIRLY NARROW WINDOW OF INTENSITIES WE WOULD LIKE TO DELIVER. THAT SO FAR HAS NOT BEEN SOLVED. THIS IS A VERY DIFFICULT ISSUE AND IT IS SOMETHING WE HAVE BEEN FOCUSING ON. SO WE HAVE BEEN WORKING ON THIS FOR ALMOST THREE YEARS NOW AND WE HAVE FINALLY BEEN ABLE TO SOLVE THIS ISSUE. WE HAVE DEVELOPED A NEW APPROACH THAT DIRECTLY MEASURES THE ATTENUATION OF ULTRASOUND THROUGH THE HUMAN SKULL AND COMPENSATES FOR IT. THIS IS NO IN REVISION, SO HOPEFULLY YOU WILL BE ABLE TO LEARN THE DETAILS ABOUT THAT METHOD SOON. HERE IS THE RESULT. IN BLACK WE SHOW WHAT WE WOULD LIKE TO DELIVER IN BRAIN TARGETS. EFFECTIVE INTENSITIES. THE SKULL IN FRONT OF THE ULTRASOUND, YOU SEE HOW SEVERITY OF ATTENUATION IS AFFECTED. WE HAVE FOUND JUST LEAVING IT THERE LEAVES TO POOR EFF EFFECTIVE EFFECTIVENESS, NO NEUROMODULATION IN MOST CASES. YET WHEN APPLY THE CORRECTION, WE CAN RESTORE QUITE ACCURATELY IN ALL CASES. THIS WAS KEY TO OBTAIN A RESULT LIKE THIS. THE MODULATION OF THE TARGET IN THIS PATIENT WAS POSSIBLE ONLY WHEN WE APPLIED THE CORRECTION. WITHOUT THAT CORRECTION, WE DON'T SEE STIMULATION EFFECTS. SO THIS IS REALLY KEY MANIPULATION THAT IS NECESSARY. ONE THING I SHOULD ALSO NOTE HERE IS THAT THE SUBJECT, THIS IS OUR FIRST SUBJECT, VERY RECENT, HAD LONG HAIR. AND ACTUALLY, IN PATIENTS WITH MENTAL DISORDERS WE WOULD LIKE NOT TO SHAVE THE HEAD. THAT WOULD BE A MAJOR BARRIER. THAT ALLOWS US TO COMPENSATION FOR HAIR, POTENTIAL BUBBLES IN THE COUPLING AND OTHER BARRIERS. THIS IS EXCITING BECAUSE IT MAKES THAT APPROACH PRACTICAL. TALK ABOUT THE SECOND BARRIER, THAT HAS BEEN THE NEED FOR SUSTAINED EFFECTS OF THE NEUROMODULATION. THE PREVIOUS LITERATURE HAS MOSTLY FOCUSED ON TRANSIENT EFFECTS, A BRIEF PULSE OF ULTRASOUND GOING INTO CORTEX, IMMEDIATE TWITCH AND THE EFFECTS GO AWAY. YET TO TREAT PEOPLE WE NEED TO REWIRE THOSE BRAIN TARGETS. SO HOW DO WE GO ABOUT THAT WITH ULTRASOUND INDUCING CHANGES IN HUMANS IS NOT POSSIBLE IN TEMPERAMENTS OF SAFETY. WE DEVELOPED A NON-HUMAN PRIMATE MODEL. THE' TRANSDUCER IS 256 THE ANIMAL IS AWAKE AND WE CAN ENGAGE THEM IN STANDARD TASKS SUCH AS STANDARD DISCRIMINATION TASKS. WE CAN DELIVER THE ULTRASOUND AND REPEAT IT DAY BY DAY. THE ANIMALS CAN COME BACK NEXT DAY, BE MOUNTED INTO THE SAME LOCATION AND WE CAN DELIVER THE ULTRASOUND. SO WE HAVE DELIVERED THE ULTRASOUND INTO THE LEFT AND RIGHT BECAUSE THOSE ARE THE RELAY NUKELY THAT PASS VISUAL INFORMATION INTO THE BRAIN. SO IN VISUAL TASKS YOU MAY MENTION THIS IS AN IDEAL BRAIN TARGET. WE START WITH 30-SECOND STIMULATION, LOW TO MIDDLE STIMULATION. WE ARE FINDING EFFECTS OF STIMULATION, ALL OUR DATA PUT TOGETHER, 52 SESSIONS, OR 53, DEPENDING IF WE DELIVERED INTO THE LEFT OR THE RIGHT. IT IS QUITE REMARKABLE FOLLOWING THE 30-SECOND SONICATION, THE EFFECTS ARE SUSTAINED UP TO 20 SECONDS AND THEY DEPEND ON WHETHER WE STIMULATED THE LEFT OR THE RIGHT LGN. WE HAVE ALSO FOUND THAT THERE WERE CHANGES IN NEURAL ACTIVITY WHEN WE RECORDED FROM THE IMPLANTED PINS. THERE WAS AN INCREASE IN HIGH GAMMA ACTIVITY THAT HAD GOOD AGREEMENT IN TERMS OF TIME COURSE WITH THOSE BEHAVIORAL EFFECTS. SO THESE SUSTAINED EFFECTS ARE VERY INTERESTING AND HAVE A HIGH POTENTIAL. JUST 30 SECONDS LEADS TO SUSTAINED EFFECTS. IT APPEARS THE ULTRASOUND IS SCULPTING THE SIR CATS AND ACTIVATING THE GLIAL CELLS AND LEADING TO CHANGES. WHAT IS ALSO IMPORTANT IS THE ULTRASOUND, THERE WAS NO MORE SIM LUS. THESE EFFECTS CANNOT BE DUE TO SOME OTHER EFFECTS ASSOCIATED WITH ULTRASOUND. WE ALSO TESTED BRIEFER STIMULI AND WE DIDN'T SEE NOTABLE EFFECTS WHEN THE STIMULI WERE BRIEF. IT WAS NECESSARY TO USE LONGER DURATI DURATIONS. IN OUR RECENT PATIENT, 20 SECONDS OR LESS THERE WERE NO EFFECTS ON MOOD. THEY STARTED TO SHOW ONCE STIMULATION EXCEEDED THAT TIME FRAME, SO LONGER THAN 30 SECONDS, LET'S SAY. AND THERE IS ONE MORE APPROACH THAT CAN BE USED TO HAVE THESE EFFECTS. IT IS AN APPROACH THAT HAVE BEEN WORKED ON. WE WILL HEAR A TALK DEDICATED TO THIS APPROACH. IN THIS APPROACH DRUGS CAN BE ENCAPSULATED I IN CARRIERS THAT ARE BIOCOMPATIBLE. THEY HAVE A RECORDED RESPONSE TO THE ULTRASOUND. IT CAN BE CARBON OR SOME OTHER CHEMICALS. THAT RESPONDS IN RESPONSE TO THE MECHANIC PRESSURE WAVE, THE VIBRATION THAT VIBRATE THE NANO PARTICLES AND YOU GET RELEASE OF THE DRUG ENCAPSULATED. THIS IS AND ATTRACTIVE APPROACH BECAUSE IT ALLOWS TO RELEASE TO SPECIFIC LIMBIC CIRCUITS LOCALLY. IF YOU THINK OF SOMETHING THAT CAUSES NEUROEFFECTS, SYLLISIBEN AND KETAMINE CAN OPEN A NEW AVENUE OF TREATMENT. WE HAVE IMPLANTED PORTS INTO OUR MONKEYS TO TEST THE EFFECTIVENESS AND SAFETY. AS A STARTING POINT, WE ENCAPSULATED INTO -- BECAUSE IT WILL SHOW WHAT SHOULD HAPPEN WHEN PROPOFOL IS RELEASED. WE DELIVERED THE ULTRASOUND INTO THE LEFT AND RIGHT LGN. WE USED RELATIVELY MEDIUM ULTRASOUND, NOT A HIGH PRESSURE, TO RELEASE THE PROPOFOL. AND WE FOUND IT WORKS. THE PROPOFOL WAS ABLE TO MODULATE THE NON-HUMAN PRIMATE BEHAVIOR IN A POLARITY SPECIFIC MANNER. IT DEPENDED IF THE PROPOFOL WAS RELEASED IN THE RIGHT OR LEFT LGN. IT FLIPPED POLARITY IN THAT CASE. AS WE WOULD EXPECT, THE MONKEY SHOWED A BIAS IN HIS BEHAVIOR, CONSISTENT WITH THE LGN CIRCUIT. I SHOULD STRESS THIS IS EXACTLY THE OPPOSITE RESULT THAN WE SAW WHERE THE ULTRASOUND STIMULATION ALONE. THOSE WERE EXCITERY EFFECTS AND THESE ARE INHIBITORY WHICH YOU WOULD EXPECT IF PROPOFOL IS RELEASED. THE TIME IS CONSISTENT WITH THE GENERAL DURATION OF THE INHIBITORY EFFECTS OF ULTRASOUND OF A DOZEN MINUTES OR SO. SO IT IS QUITE EXCITING THAT NONHUMAN PRI MATES ALLOW US TO ASSESS SAFETY. WE DID SEVERAL BLOOD DRAWS IN TWO MONKEYS SO FAR AND WE DIDN'T FIND ANY NOTABLE ISSUES REGARDING THESE CLINICAL TESTS. THERE WAS AN ELEVATED WHITE BLOOD CELL COUNT. FAIRLY CONSISTENTLY ELEVATED FOLLOWING AN INJECTION, BUT IT WAS STILL WITHIN NORMAL VALUES. AND IN A SECOND ANIMAL, THAT WAS LESS PRONOUNCED ELEVATED WHITE BLOOD CELL INCREASE. SO THE MONKEYS ARE ABLE TO PERFORM THE TASK AND THE NEXT DAY WE DON'T DETECT ANY BEHAVIORAL DEFICITS EITHER. IT APPEARS THIS APPROACH WILL BE APPLICABLE TO HUMANS BECAUSE IT APPEARS TO BE SAFE ON NONHUMAN PRIMATES. SO LET ME SUMMARIZE. LOW INTENSITY ULTRASOUND IS IMPORTANT TO MODULATE DEEP BRAIN STRUCTURES NONINVASIVELY. BY VIRTUE OF IT BEING A MECHANICAL WAVE, IT CAN VIBRATE MEMBRANES AND ION CHANNELS AND THIS WAY MEDIATE NEURAL EXCITABILITY. IT MAY MODULATE NOT ONLY NEURONS, BUT GLIAL CELLS. WHICH IS IMPORTANT IF WE START THINKING OF NEUROPLASTIC EFFECTS. THE KEY BARRIER IN TERMS OF APPLYING IN HUMANS IS THE HUMAN SKULL. NOEFL APPROACHES CAN OVERCOME THIS BARRIER. WE CAN THINK OF THIS ISSUE AS BEING SOFT. THE SECOND BARRIER IS TO INDUCE EFFECTS SO SUBJECTS DON'T HAVE TO COME FOR TREATMENT TOO OFTEN. ONE OF THE APPROACHES WE HAVE FOUND IN MONKEY AND HUMANS IS TO DELIVER SUSTAINED MODULATION. NOT MILICMILICLISEMILLISECONDS. BUT UP TO 30 MINUTES OR SO. AN INTRIGUING ADDITIONAL APPROACH WITH SPECIFIC DRUGS THAT CAN INDUCE DURABLE EFFECTS IN THE CIRCUITS. IN THIS MANNER THE DRUG WILL BE DELIVERED ONCE WITH THE HOPES THAT THE EFFECTS WILL OUTLAST THE RELEASE FOR DAYS AND WEEKS AND POTENTIALLY EVEN MONTHS. SO THIS WORK HAS BEEN POSSIBLE DUE TO MANY OUTSTANDING STUDENTS IN MY LABS AND POST DOCS. AND ALSO WITH THE HELP OF COLLABORATING PSYCHIATRIST AND NEUROLOGISTS AND THE SUPPORT OF NIH AND THE FOCUSED ULTRASOUND FOUNDATION. I THANK YOU VERY MUCH FOR YOUR ATTENTION. >>QUESTIONS. >>YEAH. HI. SO STUDIES WITH LOW INTENSITY FOCUS ULTRASOUND TO OPEN UP THE BLOOD/BRAIN BARRIER HAVE SHOWN MICROHEMORRHAGE OR HEATING. IF YOU ARE GOING FOR 30 SECONDS, DO YOU KNOW IF THINGS ARE GETTING HOT? DO YOU KNOW WHETHER THERE IS LONG-TERM DAMAGE? >>THE ULTRASOUND NEUROMODULATION DOES NOT INJEBLT BUBBLES SO IT IS NOT OPENING THE BLOOD/BRAIN BARRIER. YOU CAN DO IT IF YOU WOULD LIKE TO DELIVER LARGE AGENTS, STEM CELLS, GENES, IT IS POSSIBLE TO INJECT MICROBUBBLES INTO THE BLOOD STREAM AND VIBRATIONS OF MICROBUBBLES CAN OPEN THE BLOOD/BRAIN BARRIER. IT IS AN INTRIGUING NEW APPLICATION WHICH I HAVEN'T TALKED ABOUT TODAY. YOU MIGHT BE TALKING -- MAYBE YOU THOUGHT THE NANO PARTICLES. >>I ASKED ABOUT THE TEMPERATURE, THE HEATING. >>THESE ARE LOW INTENSITY LEVELS. WHEN WE MEASURED THE HEATING IT IS BELOW .1 DEGREE CELSIUS, SO IT IS SUB THERMAL. THOSE ARE NOT SURGICAL HIGH INTENSITY TO ABLATE TISSUES. THEY ARE KNOWN FOR REVERSAL SAFE. >>AWESOME WORK. I WANT TO KNOW IF THERE WAS ANY ASSOCIATION IN YOUR MEASURING OF IMAGES YOU FOUND IN VARIOUS BEHAVIORAL SYMPTOMS THAT YOU SAW CHANGES IN? >>MM-HMM. SO YOU MIGHT BE REFERRING TO CHANGES IN FUNCTIONAL CONNECTIVITY. WE ARE LOOKING AT THAT. WE HAVE COLLECTED THESE DATA ABOUT TWO WEEKS AGO, SO WE ARE NOT ANALYZING THEM. SO FAR WE HAVE ONLY LOOKED AT THE IMMEDIATE CHANGES IN THE -- ACTIVITY. WE DO HAVE THE DATA SO WE WILL BE ANALYZING THEM >>ARE ANY OF THE CHANGES IN THE IMMEDIATE BOLD ACTIVITY ASSOCIATED WITH THE CHANGES -- >>GOOD QUESTION. THE BOLD CHANGES ARE FAIRLY IMMEDIATE. THE BEHAVIORAL CHANGES THAT REQUIRED AT LEAST 30 SECONDS OR LONGER STIMULATION. IT APPEARS THE LONGER THE STIMULATION, THE MORE THE SUBJECT FELT POSITIVELY. >>SO YOU SEE THAT AS A TARGET ENGAGEMENT AND THERE IS NO ASSOCIATION WITH CHANGE IN BEHAVIORAL BUT LOOKING INTO THE LONGER BOLD CHANGES? >>SO LIKELY THERE ARE ACUTE EFFECTS OF THE NEUROMODULATION AND SUSTAIN THE STIMULATION BECAUSE SUBJECTS DID MENTION AND THIS IS SUBJECTIVE EVIDENCE THAT SHE FELT BETTER OVER THE WEEKEND WHEN WE STIMULATED ON FRIDAY. THERE MAY BE SOME EFFECTS, WE HAVE TO INVESTIGATE THAT. IN THE MONKEYS WE CAN DO IT AT THE MECHANICISTIC LEVEL TO QUANTIFY AS STIMULATION OF DOSE, DURATION AND ENERGY. IN HUMANS WE CAN AT LEAST COLLECT SO FAR THIS VERBAL EVIDENCE. >>AWESOME. THANK YOU. >>THANK YOU FOR A VERY INTERESTING TALK. >>SPEAK UP, PLEASE. >>I HAVE TWO QUESTIONS. FIRST ONE IS DOSE CORRECTION METHOD. >>AND SPEAK UP EVEN MORE. >>THE FIRST ONE IS ABOUT THE DOSE TRANSMISSION, THE DOSE CORRECTION SCAN OR METHOD BASED ON TRANSMISSION MEASUREMENTS. SO MY FIRST QUESTION WOULD BE IS IT SUITABLE FOR ALL BRAIN REGIONS YOU WANT TO STIMULATE OR ONLY DEEP AREAS WHERE YOU CAN DO THAT? THE SECOND QUESTION IS ESPECIALLY FOR THOSE PATIENTS OR SUBJECTS YOU HAD TO UPSCALE THE INTENSITY A LOT TO REACH EFFECTIVE LEVELS IN THE TARGET. DID YOU THEN HAVE HEATING PROBLEMS IN THE SKULL? >>MM-HMM. TO ANSWER THE FIRST QUESTION, THE DEVICE HAS ABOUT 30 MILLIMETER RADIUS OF TREATMENT. SO IF IT IS POSITIONED IN A CERTAIN LOCATION, ELECTR ELECTRONICALLY, THE TARGET CAN BE STEERED IN THAT RADIUS. IT COULD GO BEYOND BUT YOU WOULD INDUCE SIDE LOBES AND UNDESIRABLE ISSUES, BUT IT IS POSSIBLE TO MOVE THE DEVICE. IF MORE FRONTAL APPLICATIONS ARE DESIRED, YOU CAN SIT MORE IN THE FRONT OR IN THE BACK. SO THAT HOPEFULLY ANSWERS THE FIRST QUESTION. AND THE SECOND QUESTION IS IF WE ARE CORRECTING FOR THE SKULL, THE SKULL CAN BE THICK IN SOME PATIENTS OR ACOUSTICALLY SUBSTANTIAL WHETHER WE WOULD INDUCE HEATING OF THE SKULL? SO THOSE ARE EXPOSURE LEVELS BELOW THE FDA 5-10K RECOMMENDATIONS AND LOW AND CONSERVATIVE. WHEN WE DID CALCULATIONS WHETHER THE INCREASE IN SKULL HEATING WE WERE STILL BELOW SAFE LEVELS BELOW 1 DEGREE CELSIUS. WE HAVE NOT BEEN CONCERNED ABOUT THAT, BUT WE SHOULD MEASURE THAT CAREFULLY. >>THANK YOU. >>THANK YOU. >>I HAVE ONE QUESTION, IF THERE IS TIME. CAN YOU TELL US A LITTLE BIT ABOUT HOW YOU TARGET WITH THAT DEVICE IN THE SCANNER FOR THE HUMANS? >>YES. SO THIS DEVICE IS DESIGNED TO REQUIRE MRI ONCE AND THAT IS REALLY FOR PRACTICAL REASONS, RIGHT? LONG-TERM TRAIN OF STIMULATION WOULD LIMIT THE SUBJECT TO GO INTO MRI EVERY SINGLE TIME. WE HAVE DESIGNED A MASK USED FOR RADIOOLOGICAL TREATMENTS TO FIX THE SUBJECT'S HEAD IN THE SAME LOCATION WITH THE LOCATION OF THE ARRAYS. WE CAN TAKE MRI ONLY ONCE, GET THE BRAIN ANATOMY, GET THE LOCATION OF THE ARRAYS, THEN WE STIMULATE, WE VALIDATE THE TARGET ENGAGEMENT USING BOLD AS WE HAVE SEEN IT AND THE SET UP CAN BE TAKEN OUTSIDE OF MRI. THE SUBJECT IS POSITIONED, THE HEAD IS POSITIONED IN THE SAME LOCATION. WE KNOW WHERE THE MRI SITS. SO IT IS POSSIBLE TO STIMULATE OUTSIDE OF MRI. IN FACT, DURING THE QUANTIFICATION OF THE BEHAVIORAL SIGN AND SYMPTOMS THAT IS EXACTLY WHAT WE DID. THAT WAS DONE OUTSIDE OF MRI. >>ANY OTHER QUESTIONS? MAYBE LAST ONE. >>I JUST HAVE ONE LAST QUESTION. TO SEE THIS AS A DURABLE LONG LASTING THERAPY, DO YOU THINK IT WOULD REQUIRE MULTIPLE SESSIONS OF FOE CUBED ULTRASOUND. IF THAT IS THE CASE, DO YOU THINK IT INCREASES THE BRAIN TISSUE OF INFARCTION SO SAFETY CONCERN THERE? >>IT IS A GOOD QUESTION. REGARDING DURABLE SUSTAINED EFFECTS HOW OFTEN DO THEY NEED TO BE REPEATED? WE THINK OF IT AS TMS, A SINGLE SESSION OF TMS MAY HAVE EFFECTS, BUT NEEDS TO BE REPEATED FOR SEVERAL WEEKS. THAT IS MY EXPECTATION THAT WILL BE THE CASE. WE MAY BE ABLE TO SHORTEN THE TIME. MAYBE IT WILL BE A MATTER OF DAYS INSTEAD OF WEEKS, BUT THI NEEDS TO BE TESTED IN THIS CLINICAL TRIAL. REGARDING SAFETY N THE MONKEYS WE HAVE BEEN REPEATING THESE STIMULATION PROTOCOLS DAILY. AND THEY ARE MEDIUM INTENSITY ULTRASOUNDS. NOW WE ARE EXCEEDING THE FDA RECOMMENDATIONS, OUR PROTOCOL ALLOWS US TO DO THAT AND WE DON'T SEE ANY SAFETY CONCERNS. THE MONKEYS COME BACK THE NEXT DAY AND THE PERFORMANCE GOES UP IN TIME. IF WE ARE DAMAGING THE LGS, IF WE ARE CAUSING DAMAGE, PERFORMANCE WOULD GO DOWN. IF ANYTHING, IT GOES UP OVER TIME AFTER MONTHS AND MONTHS OF STIMULATION. I'M NOT TOO CONCERNED BASED ON THOSE DATA, OBVIOUSLY, WE NEED TO TEST IT AT HUMANS. >>THANK YOU VERY MUCH. WE'LL LEAVE IT THERE. >>THANK YOU. [ APPLAUSE ] >>SO I THINK THAT ENDS THIS FIRST SECTION. TAKE A BREAK AND STRETCH OUT AND COME BACK 10:15. >>I GUESS LET'S GET STARTED FOR A VERY EXCITING KEYNOTE LECTURE. I'M SO DELIGHTED TO INTRODUCE THE KEYNOTE SPEAKER TODAY FOR OUR WORKSHOP. DR. SARAH LISANBY FROM THE NATIONAL INSTITUTE OF MENTAL HEALTH AND FOR MANY OF YOU, I THINK I DON'T REALLY NEED AN INTRODUCTION BECAUSE YOU KNOW HER. SHE IS WELL KNOWN. AND DR. LISANBY IS INTERNATIONALLY RENOWNED INNOVATOR OF NEUROMODULATION TECHNOLOGIES AND IS CURRENTLY SERVING AS DIRECTOR OF THE DIVISION OF TRANSLATIONAL RESEARCH AT THE NIMH. SHE ALSO RUNS THE NONINVASIVE NEUROMODULATION UNIT, KIND OF RESEARCH UNIT AT NIMH, INTRAMURAL RESEARCH PROGRAM. BEFORE COMING TO NIH PROBABLY LIKE FIVE YEARS AGO, SHE WAS THE CHAIR OF THE DUKE UNIVERSITY DEPARTMENTAL PSYCHIATRY, SHE BUILT SPECIALIZING PROGRAMS OF CONVERGENCE OF PSYCHIATRY, NEUROSCIENCE AND ENGINEERING. SHE HAS 280 PAPERS AND HAS RECEIVED NATIONAL AND INTERNATIONAL RECOGNITION EVIDENCED BY NUMEROUS AWARDS. >>THANK YOU FOR THAT VERY KIND INTRODUCTION AND FOR THE OPPORTUNITY TO SPEAK AT THIS REALLY GREAT MOTING ON MRI OF NEUROMODULATION. I WAS ASKED TO GIVE A KIND OF BIG PICK KWHUR -- PICTURE OVERVIEW SO THAT IS WHAT I BROUGHT TODAY. I TOLD YIHONG IF I WASN'T INVITED TO SPEAK, I WOULD WANT TO BE IN THE AUDIENCE BECAUSE IT IS VERY GOOD TALKS. I'M GOING TO START WITH THE BOTTOM LINEUP FRONT. NEUROMODULATION ADDS A LOT TO THE FIELD OF MRI. IN FACT, YOU SAW THAT IN ONE OF THE FIRST TALKS ABOUT HOW READING AND WRITING INTO THE BRAIN CAN HELP UNDERSTAND THE MECHANISMS OF, FOR EXAMPLE, THE BOLD RESPONSE. SO NEUROMODULATION CAN GIVE TO MRI THE ABILITY TO MOVE FROM CORRELATION TO CAUSATION AND ALSO TO TEST THE FUNCTIONAL SIGNIFICANCE OF MRI-DERIVED MEASURES. I WILL GIVE SOME EXAMPLES OF MRI-DERIVED MEASURES OF FUNCTIONAL AND STRUCTURAL CONNECTIVITY. THE FLIP SIDE OF THE COIN IS MRI HAS A LOT TO ADD TO NEUROMODULATION. IT HAS HELPED US IN THE FIELD OF NEUROMODULATION TO UP OUR GAME IN MANY WAYS. FOR EXAMPLE, HAVE TOOLS TO QUANTIFY THE DOSE OF STIMULATION THAT HELPS TO PLAIN VARIABILITY AND RESPONSE ACROSS MODALITIES OF NEUROMODULATION AS WELL AS WITHIN MODALITY ACROSS INDIVIDUALS TO BETTER UNDERSTAND INDIVIDUAL VARIATION AND RESPONSE. MRI HAS TO NEUROMODULATION TO ENHANCE THE SPATIAL PRECISION OF NEXT GENERATION TOOLING TO MAKE THEM MORE FOCAL AND HAVE A BETTER TARGET TO NONTARGET RATIO AND IMPROVE SPES FIS TIS. I IT HELPS UH US MOVE FROM PATIENTS OF SYMPTOM CLUSTERS OF SELF-REPORT TOWARDS GROUPING AT A BRAIN LEVEL USING DATA-DRIVEN MEASURES THAT REFLECT BRAIN ACTIVITY. THIS IS AN APPROACH CALLED BIOTYPING. IT HELPS US TO DEFINE TARGETS, TO DEMONSTRATE WE CAN REACH THE TARGET AND HELPS US VERIFY TARGET ENGAGEMENT, WHETHER THESE ARE SUPERFICIAL TARGETS, DEEP TARGETS OR DISTRIBUTED NETWORKS. IT HELPS US TO ACHIEVE PRECISION TARGETING AT AN INDIVIDUAL LEVEL WHICH IS THE HOLY GRAIL FOR US, IT HAS BEEN FUNDAMENTAL TO TRY TO ACHIEVE THE PRECISION OF NEUROMODULATION FOR BRAIN HEALTH. SO TO SAY THAT ANOTHER WAY, I REALLY THINK OF MRI AND NEUROMODULATION AS TWO SIDES OF THE SAME COIN. ALTHOUGH MY EXAMPLES IN MY TALK WILL BE LARGELY DERIVED FROM TMS AND ECT. OTHER MODALITIES ARE WELL REPRESENTED IN THIS WORKSHOP INCLUDING FOCUS ULTRASOUND AND OTHER TECHNIQUES. ON CAL GENETICS AND OTHER TECHNIQUES. ON THE MRI SIDE THIS IS HELPFUL TO BUILD UPON AND TEST HYPOTHESES BY PROBING THE NETWORK AND CHANGING ACUTELY OR CHRONICALLY IN THE TARGETED NETWORK. IN TERMS OF MOVING FROM CAUSALITY, MRI CAN BE VERY USEFUL FOR INFERRING CAUSALITY IN COMPUTATIONAL APPROACHES TO CAUSAL INFERENCE. WE CAN NAIL DOWN AND VALIDATE THOSE CAUSAL RELATIONSHIPS BY CHANGING ACTIVITY IN THE CIRCUIT WITH STIMULATION. TARGETS CAN BE IDENTIFIED USING IMAGING, BUT WE REALLY WANT TO USE THAT TO DEVELOP TARGETED INTERVENTIONS TO IMPROVE BRAIN HEALTH. AND THEN I MENTIONED INDIVIDUALIZED BIOTYPING WHICH CAN HELP TRANSLATE THOSE MORE BRAIN-BASED CLUSTERING OF PATIENTS INTO PERSONALIZED TREATMENTS SO THAT IS THE CONCEPTUAL LEVEL, SO LET'S NOW DIVE IN. THESE ARE MY TWO CENTS OR YOU CAN THINK OF IT AS TWO SLIDES OF THE SAME COIN. WHAT DOES NEUROMODULATION ADD TO MRI? HOW CAN WE MOVE FROM CORRELATION TO CAUSIZATION? I'M GOING TO GIVE YOU SOME EXAMPLES. THIS IS FROM A METTA ANALYSIS OF MRI STUDIES THAT HAVE IDENTIFIED A FRONTAL PARI ETAL NETWORK CAUSE L IN CERTAIN ASPECT OF COGNITIVE PROCESSING WHICH INVOLVES DECEPTION. DECEPTIVE PROCESSING TASKS. WE WOULD LIKE TO KNOW THIS IS RESPONSIBLE FOR THE COGNITIVE DECEPTION WHICH HAS MANY COMPLEX COMPONENTS. WE APPLIED TMS TO RIGHT AND LEFT PREFRONTAL CORTEX AND WE FOUND WE COULD CHANGE THE PROCESSING TIME IN DECEPTION TASK STIMULATING PRIOR CORTEX NOT FRONTAL CORTEX. IT HAPPENED AT A SFESK LATENCY, 240 MILLISECONDS AFTER THE STIMULUS ONSET. THIS IS WHEN WE WOULD HAVE PREDICTED BASED ON EVENT RELATED STUDIES THAT REGION OF THE BRAIN WOULD BE INVOLVED IN THE PROCESSING THAT THE PROCESS TIME WAS INDICATING. BASICALLY THE TAKE HOME IS, YES, STIMULATING THE PARIATEL NODE WAS CAUSAL, BUT ADDS TO THAT SOME TEMPORAL INFORMATION TO BE HARD TO OBTAIN FROM TYPICAL FMRI SEQUENCES. LE ME DRILL DOWN ON SPECIFICITIES. THIS IS WORK LED BY BRUCE LUBER AT COLUMBIA. BASED ON PAUL'S WORK USING EEG GATED FMRI, THERE WAS A MODEL OF THREE SPATIALLY DISTRIBUTED NETWORKS THAT ARE ACTIVATED IN A TEMPORAL SEQUENCE WHILE SUBJECTS PERFORM A SPECIFIC VISUAL DISCRIMINATION DECISION-MAKING TASK. SO WE WANTED TO STUDY, IS THIS FUNCTIONAL? CAN WE STIMULATE NODES WITHIN THIS NETWORK AND SEE IF WE DISRUPT VISUAL DECISION MAKING IN THE MANNER THIS MODEL WOULD PREDICT? THAT IS WHAT WE DID. WE DELIVERED PRECISELY TIMED TMS TO A PARTICULAR NODE IN THIS NETWORK, LATERAL OCCIPITAL CORTEX HERE, AT A RANGE OF TIMES RELATIVE TO THE STIMULUS ONSET, WHICH IS SHOWN ON THE X AXIS HERE AND WE FOUND WE GOT A PREDICTED SLOWING DOWN OF THE REACTION TIME ON THE VISUAL DECISION MAKING WHEN THE TMS WAS GIVEN AT 400 MILLISECONDS, BUT NOT LATER OR EARLIER, WHICH WOULD HAVE BEEN PREDICTED BY THE MODEL BECAUSE THIS -- OOPS, I'M SORRY, LET ME GO BACK. THE LATE RAL OCCIPITAL NETWORK HAPPENED AT LATER STAGES OF THE PROCESSING. THE TAKE HOME IS WE CAN BASICALLY PROVIDE SOME CAUSAL VERIFICATION OF WHERE AND WHEN PROCESSING HAS OCCURRED AND IS OCCURRING BASED ON FMRI-BASED MODELS. NOW, CAN WE USE NEUROMODULATION TO TEST THE SIGNIFICANCE OF OTHER MRI DERIVED MEASURES AT THE ANATOMICAL LEVEL? I WILL GIVE YOU EXAMPLES OF TESTING FROM DTI OF STRUCTURAL CONNECTIVITY. AND SO THIS IS WORK LED BY BRUCE LUBER AND -- WHO YOU WILD HEAR FROM LATER IN THE WORKSHOP. WE WANTED TO PROVIDE TRANSSYNAPTIC ACCESS SUCH AS THE SUB GENUAL CORTEX SHOWN IN THE RED. USING DTI, WE IDENTIFIED A WHITE MATTER TRACK WITH STRONG CONNECTIVITY FROM THE FRONTAL POLE TO THE SGACC. AND WE WOULD LIKE TO KNOW THAT IS A STRONG, ANATOMICAL CONNECTION, IS IT FUNCTIONAL? IF WE STIMULATE THE FRONTAL POLE CAN WE CHANGE THE SUB GENUAL SINGULATE? THAT IS WHAT WE DID. YOU CAN SEE IN THE IDEAL LOW DOTS THAT IS WHERE THE SCALP LOCATIONS WHERE AND WE PUT THE TMS COIL IN THE FMRI SCANNER TO CONDUCT A CONCURRENT TMS FMRI A TECHNOLOGY YOU WILL HEAR MORE ABOUT IN THIS WORKSHOP. WE WERE ABLE TO DEMONSTRATE THROUGH THIS TMS PULSES WITH THE EK OPLANAR PULSES WE COULD FIND A DOSE DEPENDENT INCREASE ON THE BOLD RESPONSE IN THE SUBG NEXT UAL AN TIERIER SINGULATE. TMS CAN BE USEFUL IN VERIFYING THE FUNCTIONAL SIGNIFICANCE OF STRUCTURAL CONNECTIVITY DERIVED FROM DTI AND ALSO, BY THE WAY, THIS COULD BE A NOVEL APPROACH FOR TARGETING DEEP BRAIN STRUCTURES THROUGH TRANSSYNAPTIC TARGETING. ANOTHER MEASURE NEUROMODULATION CAN BE HELPFUL IN UNPACKING IN HUMANS IS MEASURES OF NETWORK CONTROLLABILITY. AGAIN, STICKING IN THE ANATOMICAL REALM BASED ON DTI. YOU CAN SEE THE MODAL CONTROLLABILITY THAT HAS BEEN BASED ON A GROUP OF SUBJECTS USING DTI. THE CONCEPT IS DIFFERENT ANATOMICAL TARGETS HAVE DIFFERENT DEGREES OF CENTRALITY IN TERMS OF CONNECTION WITH THE REST OF THE THE NETWORK. A PREDICTION IS A BRAIN AREA WITH HIGH DEGREE OF MODAL CONTROLLABILITY SHOULD BE MORE EFFECTIVE TO SHIFT THE BRAIN TO DIFFICULT TO ACHIEVE BRAIN STATES. WE WANTED TO TEST IS THAT THE CASE? LET'S TRY TO SHIFT BRAIN STATE BY STIMULATING DIFFERENT AREAS OF THE BRAIN THAT HAVE DIFFERENT DEGREES OF MODAL CONTROLLABILITY. WE USED A TASK WE KNEW WE COULD MANIPULATE WITH TASK, THIS WAS WORK LED BY BRUCE LUBER AND DANNHAUER AND BEYNEL AND MEMBERS OF OUR TASK FORCE. YOU CAN SEE THE EFFECT WAS SEEN AT THE HARDER VERSION OF THE TASK AND WE ASKED WHETHER THE DEGREE OF BEHAVIORAL CHANGES IN WORKING MEMORY WAS RELATED TO THE MODAL CONTROLLABILITY OF THE TARGET WE STIMULATED? SO HERE YOU SEE WE HAVE STIMULATED THE MODAL CONTROLLABILITY OF WHERE EACH SUBJECT GOT THEIR TMS. AND WE FOUND THAT THE DEGREE OF MODAL CONTROLLABILITY ON THE X AX SITUATION PREDICTED THE BEHAVIORAL EFFECT OF TMS ON THE Y AXIS. SO THE TAKE HOME IS NEUROMODULATION COULD BE USEFUL IN UNDERSTANDING THE FUNCTIONAL SIGNIFICANCE OF DTI-BASED MEASURES OF NETWORK CONTROLLABILITY AND ALSO LED TO LIZZIE ANN HAVING A BRIGHT IDEA WHICH THIS COULD REPRESENT A NOVEL APPROACH TO CONTROLLABILITY BASED TARGETING FOR NONINVASIVE BRAIN STIMULATION. I'M GOING TO LOOK AT THE OTHER SIDE OF THE COIN HERE AND TALK ABOUT WHAT MRI ADDS TO THE FIELD OF NEUROMODULATION. I'M GOING TO CONSTRAIN THIS TO MY ALLOTTED 45 MINUTES. SO DOSE QUANTIFICATION IS REALLY KEY. I'M GOING TO START BY DEFINING WHAT DOSE IS FOR NEUROMODULATION AND GIVE YOU SOME EXAMPLES OF HOW THIS CAN BE USEFUL IN NEUROMODULATION. SO TYPICALLY WE THINK OF THE DOSE OF NEUROMODULATION TO BE THE DOSE OF LITERALLY WHAT WE DIAL ON TO THE BOX OF THE STIMLATOR, THE FREQUENCY PULSE DURATION, INTENSITY. AND/OR THE ELECTRODE POSITION, THEIR SHAPE. THE COIL SHAPE AND ORIENTATION RELATIVE TO THE TARGET BRAIN STRUCTURE. ALL OF THAT CAN BE DESCRIBED AND USUALLY IS DESCRIBED IN METHODS SECTIONS OF PAPERS AND IT CERTAINLY INFLUENCES THE IMPACT OF THE STIMULATION. IT IS ONLY HALF OF THE STORY OR YOU COULD ARGUE LESS THAN HALF. THE REST OF THE STORY IS WHAT HAPPENS AFTER YOU INJECT THAT ENERGY INTO THE HEAD AND IT REACHES THE BRAIN, WHERE IT INDUCES ELECTRICAL FIELDS OR ACOUSTIC WAVES AS YOU HEARD ABOUT WHICH OPEN ION CHANNELS OR YOU ARE DELIVERING A MAGNETIC FIELD INDUCING A FIELD WITH TMS. THAT CHANGES BRAIN ACTIVITY IN SOME WAY. SO THOSE PARTS OF THE RECEIVED DOSE ARE RALLY INFLUENCED DRAMATICALLY BY ANATOMICAL DIFFERENCES, DIFFERENCES IN ANATOMY, THE STRUCTURE OF THE HEAD AND THE BRAIN. PHYSIOLOGICAL DIFFERENCES, NEUROPHYSIOLOGICAL DIFFERENCES AND BRAIN STATE. THESE PARTS ARE NOT USUALLY REPORTED IN METHODS SECTIONS, BUT INCREASINGLY WE ARE SEEING SOME OF THESE BEING MORE STANDARDLY REPORTED, ESPECIALLY THE ELECTRIC FIELD. IF WE FOCUS OUR ATTENTION ON THIS ASPECT OF THE RECEIVED DOSE, YOU CAN SEE HOW MRI IS KEY IN UNDERSTANDING THIS. WHAT DO I MEAN BY THAT? SO WE WANT TO QUANTIFY THE ELECTRIC FIELD. WE CAN USE STRUCTURAL MRI TO SIMULATE THE BRAIN. IT CAN ALLOW US TO DEMONSTRATE WHETHER OUR STIMULATION PARADIGM IS ABLE TO REACH THE TARGET BRAIN AREA AT A DOSE THAT IS ABOVE THRESHOLD FOR INDUCING NEURONAL DEPOT LARIZATION OR CHANGING NEURONAL ACTIVITY. AND ALLOWS TO IDENTIFY THE DEGREE OF THE TARGET VERSUS NONTARGET STIMULATION. SO CROWE MIGHT BY ABLE TO REACH A DEEP BRAIN TARGET WITH A REALLY BIG TMS COIL, BUT YOU ARE NOT DOING THAT SELECTIVELY. PHYSICS EXPLAINS THAT. AS YOU SEE HERE, THE DEPTH FOCALITY TRADEOFF, WE HAVE MODELLED MANY DIFFERENT TMS COILS IN THE NUMBERED CIRCLES AND ON THE X AXIS IS THE DEPTH AND Y IS DEGREE OF SPREAD. THE DEEPER YOU GO, THE LESS FOCAL YOU ARE. THAT IS IMPORTANT TO KNOW WHEN YOU ARE TRYING TO REPORT THE RESULTS OF YOUR EXPERIMENTS TO KNOW THAT, YEAH, MAYBE YOU WERE ABLE TO REACH THE INSULA, BUT YOU WEREN'T ONLY STIMULATING THE INSULA, AT LEAST IN THE CASE OF TMS. WHAT ABOUT NEURONAL ACTIVITY? MRI CAN HELP US THERE AS WELL, FMRI OR OTHER MEASURES, ARTERIAL SPIN LABELING, MRSPECTROSCOPY, THIS CAN HELP QUANTIFY THE STATE OF BRAIN AT THE TIME OF STIMULATION WHICH INFLUENCES RESPONSE TO STIMULATION. WHEN WE PUT THE TMS COIL IN THE SCANNER AND DO CONCURRENT TMS MRI, WE CAN MUSH R MEASURE ACUTE RESPONSE TO THE STIMULATION. I SHOWED YOU AN EXAMPLE, STIMULATED THE FRONTAL POLE AND GETTING A RESPONSE. AND WITH PRE-POST PARADIGMS, SUB ACUTE AND COURSES OF STIMULATION TO UNDERSTAND HOW THEY WORK AT A BRAIN LEFT. SO MRI IS REALLY BIG AND CENTRAL TO ALL OF THESE ASPECTS OF QUANTIFYING DOSE AND UNDERSTANDING DOSE. SO LET'S TALK ABOUT HOW WE CAN USE THESE TOOLS OF DOSE QUANTIFICATION TO BETTER UNDERSTAND AND DEVELOP NEXT GENERATION NEUROMODULATION TECHNOLOGIES. SO THESE TOOLS CAN HELP US UNDERSTAND VARIATION IN RESPONSE TO STIMULATION ACROSS DIFFERENT MODALITIES. I'M GOING TO GIVE YOU AN EXAMPLE FROM ECT, RIGHT UNILATERAL PLACEMENT WHERE THE RIGHT HEMISPHERE OR BILATERAL ECT WHERE YOU HAVE ONE ELECTRODE ON EACH SIDE OFD THE HEM FEAR. THESE DIFFER DRAMATICALLY IN COGNITIVE SIDE EFFECTS. SIGNIFICANT AMNESIA WITH BILATERAL COME BARED TO THE YUP LATERAL. WHY IS THAT? WHY IS THIS SUCH A DRAMATIC DIFFERENCE. YOU CAN SEE RIGHT OFF THE BAT, THERE ARE TREMENDOUS DIFFERENCES IN THE DISTRIBUTION OF ELECTRIC FIELD AND THIS MIGHT GIVE US CLUES AS TO WHY THESE MODALITIES DIFFER SO SIGNIFICANTLY IN TERMS OF SIDE EFFECTS. NOW, IF WE STICK WITHIN ONE MODALITY, WE HAVE THE PROBLEM WITH INDIVIDUAL VARIATION BETWEEN PEOPLE. EFIELD MODELING CAN HELP US THERE. YOU WILL HEAR MORE FROM E ZHENG. THIS IS THE SAME DOSE GIVEN TO PATIENTS WITH DEPRESSION. THE E FIELD STRENGTH ACROSS INDIVIDUALS. XI SHOWED ON THE X AXIS IS THE HIPPOCAMPUS AND THE Y AXIS COGNITIVE CORRELATION, MORE COGNITIVE IMPAIRMENT. REALLY IMPORTANT IF WE SEEK TO UNDERSTAND WHY SOME PATIENTS ARE MORE SUSCEPTIBLE TO THIS COGNITIVE SIDE EFFECT THAN OTHERS AND MAY GIVE US CLUES TO DEVELOP NEXT GENERATION TECHNOLOGIES TO BE SAFER FOR PATIENTS. SO -- ON THAT POINT, HOW CAN WE USE THIS TO INFORM THE DEVELOPMENT OF NEW THERAPIES THAT WOULD BE SAFER? HERE I'M SHOWING YOU THE ELECTRIC FIELD STIMULATION OF THE THREE CONVENTIONAL ELECTROPLACEMENTS, BILATERAL, BF AND RUL. THE AQUA COLOR IS AT THRESHOLD FOR NEURONAL DEPOT LARIZATION. ALL THE ENTIRE BRAIN WITH ALL THREE OF THESE ELECTRODE PLACEMENTS IS AT THRESHOLD OR HIGHER. THE RED AREAS ARE THREEFOLD ABOVE THRESHOLD OR HIGHER. IT IS WHOLE BRAIN STIMULATION. SO WE CAN USE THESE INSIGHTS TO DEVELOP NOVEL ELECTROPLACEMENTS TO TRY TO MINIMIZE THIS. I'M SHOWING YOU THREE EXPERIMENTAL FORMS OF SEIZURE THERAPY. YOU CAN SEE THESE THREE EXPERIMENTAL PLACEMENTS ARE ABLE TO REDUCE THE VOLUME OF TOTAL BRAIN STIMULATED ABOVE THRESHOLD AND IN THE CASE OF THE MAGNETIC SEIZURE THERAPY ON THE FAR RIGHT IT IS MINIMIZED AND LIMITED TO SUPERFICIAL CORTEX. WE HAVE SHOWN YOU CAN DRAW REGIONS OF INTEREST AROUND THE HIPPOCAMPUS AND YOU CAN SEE HERE THAT THE EXPERIMENTAL ECT ELECTRODE PLACEMENTS REDUCE THE E-FIELD IN THE HIPPOCAMPUS COMPARED TO CONVENTIONAL ELECTRODE PLACEMENT, BUT STILL AT THRESHOLD. THE BLUE BAR IS MAGNETIC SEIZURE THERAPY. NOW WE CAN INDUCE SEIZURES WITHOUT GETTING HIPPOCAMPUS FROM E-FIELD EXPOSURE. THIS IS IMPORTANT FOR SAFETY. FROM HUMAN DATA THE SPEED OF REORIENTATION CORRELATED WITH RETROGADE AMNESIA AND ECT AND THE RED BARS MST IN THE BLUE BARS. MINIMIZING E-FIELD EXPOSURE, WE ARE ABLE TO INDUCE SEIZIERS WITH MINIMAL COGNITIVE SIDE EFFECTS. ANOTHER THING THAT MRI CAN ADD TO NEUROMODULATION IS A NEW WAY OF UNDERSTANDING HETEROGENERALITY IN PATIENT GROUPS CALL BIOTYPING. IF WE CLUSTER PATIENTS USING PSYCHIATRIC DIAGNOSIS, BASED ON SYMPTOM SELF-REPORT, AN APPROACH THROUGH THE DSM, CLASSICAL CLASSIFICATION. A GROUP OF PATIENTS WITH DEPRESSION, A GROUP WITH ANXIETY AND A GROUP WITH SKITS FRE -- SCHIZOPHRENIA. THE CONCEPT HERE IS WE COULD USE OBJECTIVE MEASURES OF BRAIN FUNCTION LIKE MRI MAYBE COUPLE THAT WITH OTHER MEASURES OF NEUROPHYSIOLOGY AND ON THE BRAIN BASIS, RESORT THOSE PATIENTS INTO DATA-DRIVEN BIOTYPES. GROUPS OF PATIENTS MORE SIMILAR TO EACH OTHER AT THE LEVEL OF OBJECTIVELY MEASURED BRAIN STRUCTURE, FUNCTION OR ACTIVITY. THIS BIOTYPING APPROACH CAN BE USEFUL IN TERMS OF SELECTING TREATMENTS THAT ARE RIGHT FOR EACH PATIENT. THIS WAS SHOWN BY DRYSDALE AND LISTON AND COLLEAGUES THAT TOOK A GROUP OF PATIENTS WITH DEPRESSION AND USED RESTING STATE FUNCTION CONNECTIVITY MRI TO DERIVE FOUR BIOTYPES, THOSE SIGNIFICANTLY PREDICTED THE LIKELIHOOD OF PATIENTS RESPONDING TO TMS FOR DEPRESSION. THE BLUE ARE PATIENTS MORE LIKELY TO RESPOND TO TMS. THIS APPROACH CAN BE USEFUL UNDERSTANDING HETEROGENERALITY AS WELL AS FOR SELECTING PATIENTS WHO MAY OR MAY NOT RESPOND TO A STANDARD THERAPY. WHAT WE WOULD LIKE TO DO IS HAVE A THERAPY FOR EACH PATIENT. WE WANT TO BE ABLE TO USE THIS BRAIN INFORMATION TO INDIVIDUALIZE THE TREATMENT SO THAT THE PATIENT IN FRONT OF YOU COULD RESPOND. AND PART OF THAT IS ABOUT FINDING THE RIGHT TARGET FOR EACH PATIENT. MRI REALLY CAN HELP US WITH TARGETING, WHETHER STRUCTURAL OR FUNCTIONAL, MRI OR CONNECTIVITY. OSCILLATIONS, THESE ARE DIFFERENT LEVELS OF ANALYSIS TO SEARCH FOR TARGETS AND THEY ARE NOT MUTUALLY EXCLUSIVE BECAUSE THEY ARE ALL GOING ON IN YOUR BRAIN AT THE SAME TIME. WHEN WE THINK ABOUT STRUCTURAL OR FUNCTIONAL TAR AL TARGETING LOOKING FOR THE PLACE TO PUT THE COIL. WE ARE THINKING ABOUT HOW TO CONTROL THIS NETWORK, THIS DISTRIBUTED NETWORK AS YOUR TARGET AND IN TERMS OF NEUROOSCILLATIONS, NEURODYNAMICS SO TARGETING IN THE TEMPORAL DOMAIN. WHEN YOU ARE TRYING TO FIND SIGH SITES, YOU ARE TRYING TO TARGET CIRCUITS ARE TRANSSYNAPTIC TARGETING. I SHOWED YOU THAT. WHEN WE ARE TARGETING NEURODYNAMICS WE ARE TRYING TO TARGET THE TEMPORAL DOMAIN SO I CALL THAT TEMPORAL TUNING. THESE APPROACHES CAN BE COMBINED TO TRY TO FIND WHERE AND WHEN AND HOW TO STIMULATE FOR EACH PATIENT. NOW, I GAVE YOU ONE EXAMPLE ALREADY OF TRYING TO ACCESS A DEEP TARGET. USING STRUCTURAL CONNECTIVITY. I'M GOING TO GIVE YOU A DIFFERENT EXAMPLE THAT COMES FROM WORK FROM LIZZIE ANN BEYNAL. SHE WANTED TO TARGET THE AMYGDALA. SHE WANTED TO HAVE PRECORTEX STRONG FUNCTION CONNECTIVITY WITH THE AMYGDALA. SHE IDENTIFIED OF REGIONS OF THE BRAIN THAT HAS CONNECTION WITH THE AMYGDALA. SHE TOOK THAT INFORMATION INTO THE LAB, USED NEURONAVIGATION, STRUCTURAL AND FUNCTIONAL MRI TO NAVIGATE THE COIL TO THIS TARGET IN EACH SUBJECT AND STIMULATE WITH TMS. WHAT SHE FOUND WAS A SIGNIFICANT INCREASE IN THE CHANGE IN THE AMYGDALA ACTIVATION OF THE TASK-BASED FMRI WITH ACTIVE TMS IN THE BLUE COMPARED TO SHAM IN THE RED. THIS IS AN EXAMPLE OF USING FUNCTIONAL CONNECTIVITY TO REACH A DEEP BRAIN TARGET. I MENTIONED STRUCTURAL AND FUNCTIONAL CONNECTIVE TARGETING, WHICH IS BETTER OR MAYBE WE SHOULD BE USING BOTH. HERE IS AN EXAMPLE FROM THE FIRST STUDY FROM BRUCE LUBER WHERE WE USED STRUCTURAL CONNECTIVITY TO TARGET. SO THE STRUCTURAL CONNECTIVITY, HERE WERE SCALP LOCATIONS FOR THE FRONTAL POLE. IN THE SAME PATIENTS WE HAD RESTING STATE FUNCTIONAL MRI. WE COMPUTED WHERE THE FUNCTIONAL TARGET WOULD HAVE BEEN. THAT IS ON THE RIGHT. THOSE ARE THOSE BLUE DOTS. WHAT WE FOUND IS THE EFFECT OF OUR STRUCTURALLY TARGETED TMS HAD -- WAS IN THE ACC WAS NEGATIVELY CORRELATED WITH THE DISTANCE OF OUR COIL LOCATION FROM THE FUNCTIONAL TARGET. SO WE DON'T KNOW IF PUTTING THE COIL ON THE FUNCTIONAL TARGET WOULD HAVE BEEN BETTER, BUT IT DOES SUGGEST TARGETING COULD BE IMPROVED BY INCORPORATING INFORMATION FROM STRUCTURAL AND FUNCTIONAL CONNECTIVITY. ONCE YOU HAVE IDENTIFIED YOUR TARGET AND SHOWN YOU CAN REACH IT WITH YOUR INTERVENTION, YOU WANT TO KNOW IF YOU CAN ENGAGE IT. HAVE YOU CHANGED ACTIVITY IN THAT SITE OR NETWORK THAT CONTINUES AFTER YOU STOP STIMULATING? HERE I'M USING AN EXAMPLE AGAIN FROM BRUCE LUBER. WE USED A TMS NEURONAVIGATED TO INDIVIDUAL SITES THAT WERE ACTIVATED USING A PRIMING TASK. THIS IS PATIENTS WITH DEPRESSION WHO WERE RECEIVING SIMULTANEOUS COGNITIVE BEHAVIORAL THERAPY AND TMS FOR DEPRESSION. WE DID FMRI BEFORE AND AFTER THE COURSE OF TREATMENT. FOLLOWING TREATMENT, THE PATIENT SHOWED SIGNIFICANT REDUCTION IN DEPRESSION SCORES SHOWN ON THIS HAMILTON RATING SCALE. THE IMPORTANT PART IS THE PRE/POST MRI SHOWS PRE-TMS IN THE DARK BLUE TO POST-TMS IN THE LIGHT BLUE AN INCREASE IN THE TARGET. THIS DEMONSTRATED WE WERE ABLE TO ENGAGE THIS LIMBIC CIRCUIT FOLLOWING A COURSE OF CHRONIC TMS. WE ARE DOING THE RANDOMIZED CONTROL TRIAL CURRENTLY WHERE OUR OUTCOME MEASURE IS NOT DEPRESSION SCORES BUT CHANGE IN CIRCUIT EXPRESSION. WE ARE TRYING TO DETERMINE WHETHER WE ARE ABLE TO ENGAGE THE TARGET AND IF WHEN WE DO ENGAGE THE TARGET DOES THE PATIENT'S DEPRESSION GET BETTER? THIS BLINDED TRIAL IS BEING LED BY LIZZIE ANN BEYNEL. IT IS AN EXAMPLE OF INDIVIDUAL TARGETING BECAUSE WE ARE PUTTING ALL PATIENTS THROUGH THE SCANNER. SO THAT LEADS ME TO THE PART ON PRECISION TARGETING. WE WOULD LIKE TO DEVELOP TOOLS AND PRACTICAL PIPELINES TO DISSEMINATE THE ABILITY TO DO THIS TARGETING ACROSS LABS AND ACROSS CLINICS, ULTIMATELY. PERSON SELK TARGETING OF NEUROMODULATION. USE IMAGING TO IDENTIFY THE PERSON'S SPECIFIC COIL PLACEMENT AND ORIENTATION AND ACHIEVE THE DESIRED E-FIELD IN THE TARGET OR TARGETED NETWORK. HERE IS ONE EXAMPLE OF ONE SUCH PIPELINE LIZZIE ANN USED IN HER WORK. THIS INCORPORATES STRUCTURAL AND FUNCTIONAL IMAGING, E-FIELD MODELS AND DIFFERENT LOCATIONS TO OPTIMIZE THE COIL PLACEMENT AND/OR ORIENTATION. THIS IS WORK FROM STANHAUR, TAP. WHAT CROWE ARE SEEING HERE IS THE HIGH-LEVEL WORK. IT INCORPORATES STRUCTURAL AND FUNCTIONAL IMAGING, INTEROPERABILITY WITH SIM LIBS. IT IS ENHANCING COIL PLACEMENT FOR EXPERIMENTS. AS THESE PIPELINES BECOME DISSEMINATED IT ALLOWS TO INCREASE RIGOR AND TO SEE IF WE CAN REPLICATE THE SAME EXPERIMENT AND GET THE SAME RESULTS RATHER THAN HAVING EVERYONE REINVENT THEIR OWN WHEEL. COULD THIS BE USEFUL? THE STANFORD NEUROMODULATION THEORY FOR TREATMENT OF DEPRESSION USED RESTING STATE MRI TO TARGET TMS IN PATIENTS WITH DEPRESSION. THEY WERE TARGETED PREFRONTAL CORTEX -- IT IS SO IMPORTANT FOR DEPRESSION. THEY GIVE PATIENTS 10 TREATMENTS A DAY FOR FIVE DAYS WITH THETA BURST. YOU HEARD ABOUT THAT IN AN EARLIER TALK. ENSIVE STIMULATION IN A SHORT PERIOD OF TIME. THEY REPORTED IN THE RANDOMIZED SHAM CONTROLLED TRIAL IS THIS POTENT ANTI-DEPRESSION RESPONSE WITH THE ACTIVE SAINT COMPARED TO SHAM ON THE OPEN CIRCLES ON THE MADRAS, WHICH IS A MEASURE OF DEPRESSION. SCORES 52% WITH ACTIVE AND 11% WITH SHAM. IT IS A BIG EFFECT SIZE AND RAPID. CONVENTIONAL TMS PROTOCOLS REQUIRE FOUR TO SIX WEEKS TO SHOW THERAPEUTIC BENEFIT. WE NEED STUDIES TO UNPACK WAS IT THE INDIVIDUALIZED TARGETING, THE INTENSE OF TREATMENT SCHEDULE OR BOTH THAT LED TO THIS IMPRESSIVE THERAPEUTIC OUTCOME? YOU ARE PROBABLY THINKING WHEN IS MRI GOING TO GET APPROVED FOR TMS AND DEPRESSION? I'M GLAD YOU ASKED BECAUSE IT IS ALREADY IS. I'M GETTING CHOKED UP, BUT I'M ACTUALLY COUGHING. IT IS ALREADY ON LABEL. IT HAPPENED LAST MONTH. THE SAME APPROACH RECEIVED FIVE-10K APPROVAL IN THE U.S. FOR SUBSTANTIAL EQUIVALENCY TO OVER TMS DEVICES FOR TREATMENT OF DEPRESSION. MRI INFORMED TARGETING FOR TMS DEPRESSION IS A PRESENT DAY REALITY, ACCORDING TO THE FDA. AS EXCITING AS THAT IS, THAT IS JUST THE BEGINNING. WE NEED MORE RESEARCH TO UNDERSTAND THE TEST RELIABILITY NOW THAT MRI-BASED TARGETING IS FDA APPROVED, WE NEED TO KNOW WE CAN DO THIS RELIABLY AND UNDERSTAND HOW TO IMPLEMENT THIS. WE NEED TO UNDERSTAND THIS SCALEABILITY OF THIS APPROACH ACROSS LABS, ACROSS CLINICS. CLINICIANS ARE GOING TO WANT TO USE TOOLS THAT ARE MORE EFFECTIVE THAN EXISTING TOOLS. WE WANT TO UNDERSTAND WHAT EVIDENCE IS REQUIRED FOR PAIRS TO COMPENSATE FOR THE MRI PART OF THIS TARGETING SO IT CAN GET PAID FOR. OF COURSE, INSURANCE APPROVAL IS IMPORTANT FOR CLINICAL ADOPTION. AND WE NEED THOSE UNPACKING STUDIES TO UNDERSTAND WHETHER IT IS THE MRI INFORMED TARGETING OR TENSIVE TBS THAT WERE IMPRESSIVE IN THE RESULTS. I TALKED ABOUT ADULT APPLICATIONS. MRI CAN HELP US UNDERSTAND HOW TO TAILOR NEUROMODULATION TOOLS FOR THE DEVELOPING BRAIN SO THAT WE CAN ADVANCE IN TERMS OF CHILD AND ADOLESCENT BRAIN HEALTH AND ALSO TO HELP US UNDERSTAND CONDITIONS THAT HAVE A HIGH DEGREE OF INDIVIDUAL VARIATION AT THE BRAIN LEVEL SUCH AS AUTISM SPECTRUM DISORDERS FOR EXAMPLE. YOU MIGHT BE WONDERING, THOSE ARE GREAT RESEARCH GOALS. WHERE ARE WE GOING TO GET FUNDED DO DO THAT RESEARCH? I'M GLAD YOU ASKED. WE HAVE A SUITE OF OPPORTUNITIES AT THE NIH THAT SUPPORT ALL PHASES OF THE DEVICE DEVELOPMENT LIFE CYCLE. FOR EXAMPLE, AT THE LEVEL OF NIMH AS WELL AS BRAIN INITIATIVE AND COMMON FUND FUNDING OPPORTUNITIES THAT FUND STAGES OF DEVICE DEVELOPMENT TO FUND STUDIES THAT EXAMINE MECHANISMS AND TARGET DISCOVERY. ALSO THE LEVEL OF CLINICAL TRIALS OF NOVEL DEVICES. I ONLY HAVE TIME TO HIGHLIGHT ONE OF THESE. THE BLUEPRINT MED TECH FUNDING OPPORTUNITY. BLUEPRINT MEDTECH SUPPORTS THE DEVELOPMENT OF HUMAN GRAY PROTOTYPES BY GIVING RESEARCHERS ACCESS TO TRANSLATIONAL RESOURCES AND EXPERTISE. I'M SHOWING YOU THE TYPING OF RESOURCES NIH IS PROVIDING TO INVESTIGATORS. RESOURCES FOR DEVICE PROTOTYPE AND BENCH TESTING, BUSINESS DEVELOPMENT, INDUSTRY EXPERTS, REGULATORY COMPLIANTS, BY COMPATIBILITY, ANIMAL STUDIES, FIRST IN HUMAN AND CLINICAL TESTING. A WHOLE SUITE OF SUPPORT THAT MOST DEVELOPERS OR INNOVATORS AT UNIVERSITIES MAY NOT HAVE ACCESS TO. WE WANT TO PROVIDE WRAP AROUND SERVICES TO ENABLE YOUR GREAT NEW IDEAS TO GO THROUGH THESE DIFFERENT TRANSLATIONAL STAGES. WE HAVE DR. LIZZIE AN CODAVICH. SHE DIRECTS THIS PROGRAM ON NEUROMODULATION. THE GOAL IS TO DEVELOP AND REFINE MULTIMODAL COMBINATION MODULATION WITH AN ETCH SIS ON SYNERGI SYNERGISTIC. REACH OUT TO LIZZIE TO LEARN MORE ABOUT THAT PROGRAM. WE ARE HIRING IF YOU WOULD LIKE TO LEAD CUTTING-EDGE FUNDING PROGRAMS. I'M HIRING FOR TWO PROGRAM OFFICERS AND ANY PSYCHIATRY RESIDENTS GETS EXPERIENCE WITH THESE THERAPIES COME SEE ME BECAUSE WE ARE RECRUITING FOR A CLINICAL FELLOW. HERE ARE CONTACTS FOR LIZZIE AND OTHERS WHO LEAD OUR PROGRAMS WITH DEVICE DEVELOPMENT AND NEUROMODULATION. AND TO CONCLUDE WHERE I STARTED. NEUROMODULATION ADDS TO MRI THE ABILITY TO MOVE BEYOND CORRELATION TOWARDS CAUSATION AND TEST FUNCTIONAL SIGNIFICANCE OF MRI-DERIVED AMERICAN YOURS AND I SHOWED YOU SOME EXAMPLES. MRI ADDS TO NEUROMODULATION THE ABILITY TO QUANTIFY THE DOSE AND EXPLAIN ACROSS MODALITIES AND ACROSS INDIVIDUALS. IT HELPS US TO UNDERSTAND THE SPATIAL PERFORMANCE OF NEUROMODULATION TOOLS TO MOVE BEYOND SIMPLE GROUPINGS IN PSYCHIATRY TO HELP US BETTER SELECT THE RIGHT PATIENT FOR THE RIGHT TREATMENT AS WELL AS TO CONSTRAIN HEAT ROGENE IFRKS TY. IT HELPS DEFINE AND REACH TARGETS AND ACHIEVE THIS VISION OF NEUROMODULATION AND TARGETING AT THIS LEVEL. AND IT IS ON LABEL TODAY FOR DEPRESSION. I WANT TO RECOGNIZE THE MEMBERS OF THE NIMH NEUROMODULATION UNIT MANY OF WHOM ARE HERE IN ATTENDANCE TODAY AND I'M HAPPY TO TAKE YOUR QUESTIONS. THANK YOU. >>THANKS SO MUCH. VERY NICE, ALL OF YOU AND VERY USEFUL INFORMATION FOR THE GRANTS. QUESTIONS? PLEASE GO TO THE MICROPHONE. >>HI. SO THANK YOU. YOU ARE VERY INSPIRATIONAL. SO YOU LOOKED AT THE LONG-TERM EFFECTS OF TMS USING FUNCTIONAL MRI AND THROUGH ACT VASE. HAVE YOU LOOKED AT IT IN TERMS OF CONNECTIVITY? DOES IT LOOK LIKE THE DIFFUSION TENSOR WEIGHTED DIFFERENT AFTER AND BEFORE TMS? >>YEAH. I DID NOT SHOW YOU DTI POST TMS. THERE ARE STUDIES THAT DO LOOK AT WHETHER TMS OR OTHER FORMS OF INTERVENTION LIKE ECT CAN CHANGE DTI MEASURES. I DON'T PERSONALLY HAVE DATA ON THAT. I KNOW SOME STUDIES HAVE LOOKED AT THAT. I THINK MUCH OF THE FOCUS HAS BEEN ON THE FUNCTIONAL MEASURES AND A PARTICULAR CHANGE IN THE RESTING STATE CONNECTIVITY AND SEEING IF THOSE TRACK WITH CLINICAL RESPONSE. WHAT I SHOWED YOU WAS A TASK-BASED FMRI NOT RESTING STATE CONNECTIVITY. I THINK YOU ARE HEARING MORE, PERHAPS IN THE SESSION THAT FOLLOWED. >>THANK YOU VERY MUCH. SUCH A NICE PRESENTATION AND SIN INSPIRING AS ALWAYS. I WAS WONDERING THE RECENT FDA APPROVAL. IN MY UNDERSTANDING THIS IS THE FIRST TIME WE HAVE SORT OF A PROTOCOL, A FAMOUS PROTOCOL THAT RECEIVES APPROVAL FOR PSYCHIATRIC DISORDER IN COMBINATION WITH FMRI. WHAT ARE THE POTENTIAL CHALLENGES HAVING THE PROTOCALS BY UNIVERSITIES? THE FUTURE ASPECTS OF MRI AND NEUROMODULATION IN THAT DIRECTION? >>SO, THERE IS A TENSION HERE, ISN'T THERE? TO BE A GOING CONCERN TO BRING TOOLS TO THE CLINIC, YOU NEED A COMPANY THAT MAKES THE TOOL THAT BRINGS THE TOOL TO THE CLINIC. INTELLECTUAL PROPERTY IS A KEY ELEMENT THAT ENABLES COMPANIES TO FUND RAISE AND TO DEVELOP TECHNOLOGIES TO GET THEM TO THE CLINIC. AND SO PATENTS ARE A MAJOR PART OF HOW ALL OF THE TOOLS WE USE TODAY IN IMAGES AND NEUROMODULATION GOT THERE. THE PART OF THAT TENSION IS ALSO THE DESIRE TO HAVE OPEN SOURCE ACCESS SO THAT WE CAN VERIFY AND REPLICATE. AND SO THERE'S -- I THINK YOU ARE REFERRING TO THE ALGORITHM THAT IS USED FOR TARGETING. WE WOULD REALLY LIKE TO BE ABLE TO HAVE OPEN-SOURCE ALGORITHMS SO THE ACADEMIC COMMUNITY CAN REPLICATE AND UNDERSTAND AND IMPROVE UPON. SO I THINK THAT IS A FUTURE CHALLENGE FOR THE FIELD TO GRAPPLE WITH. HOW BEST TO DO THAT IN A WAY THAT ALLOWS THE TECH SPACE TO ADVANCE. SO THAT WE WILL HAVE INDUSTRY PARTNERS TO HAVE THE THINGS WE NEED TO DO RESEARCH AND HAVE CLINICAL WORK. I WILL PUT A PLUG FOR ACADEMIC PUBLICATIONS. IT IS REALLY USEFUL TO SCIENCE TO REPORT AS MUCH AS ONE CAN ABOUT WHAT YOU ACTUALLY DID, INCLUDING THE ALGORITHM. YOU KNOW, OPEN SOURCE, NOT JUST HERE IS YOUR DATA THAT IS AVAILABLE, BUT HERE IS YOUR PIPELINE OF HOW YOU ANALYZED WHAT WAS YOUR ALGORITHM FOR TARGETS? HERE IS YOUR GETHUB LINK. HERE IS WHERE WE CAN FIND OPEN SOURCE AND TAKE YOUR DATA AND REPRODUCE YOUR ALGORITHM AND GET THE SAME RESULT AS WELL AS TAKE THE ALGORITHM WITH OUR DATA AND SEE IF WE GET THE SAME RESULT. THAT IS SORT OF OPEN SOURCE ENVIRONMENT CAN ACCELERATE DISCOVERY. SO DOES THAT -- I WOULD LOVE TO HEAR YOUR ANSWER TO THAT QUESTION? >>THAT IS THE CHALLENGE WE HAVE IN OUR TEAM RIGHT NOW, IN TERMS OF HOW MUCH TRANSPARENCY YOU HAVE FOR THE ALGORITHMS WE ARE DEVELOPING AND HOW MUCH WE NEED TO GO TOWARDS THAT DIRECTION OF MAKING PATENTS. THAT IS ALWAYS A TENSION BETWEEN ACADEMIC MIND AND INDUSTRIAL SORT OF ASPECTS OF THAT. THANK YOU FOR YOUR INPUT. I THINK THAT WILL BE AN INTERESTING DISCUSSION WITHIN THE COMMUNITY THAT WE HAVE. PROBABLY SEEING WHETHER WE HAVE THE BEST WAY TO PROMOTE SCIENCE IN THAT DIRECTION. THANK YOU. >>ALL RIGHT. THANKS AGAIN. >>YEAH. THANK YOU. >>DUE TO THE TIME, WE HAVE TO MOVE TO THE NEXT SECTION. >>ALL RIGHT. THE NEXT SESSION MRI IN TMS. THIS IS A TOPIC VERY NEAR AND DEAR TO MY HEART. I WANT TO SAY IT IS WONDERFUL TO BE DOING THIS RESEARCH IN AN ERA WHERE HOLLY LISANBY IS AT NIH, ALL OF US IN THE U.S. ARE BENEFITING FROM HER LEADERSHIP. THANKS FOR THAT. OLIVIER, I WILL LET YOU GO. >>I DON'T HAVE ANY FINANCIAL INTERESTS TO DISCLOSE. SO I'M NOT FROM THE U.S. I'M FROM EUROPE. AND I WOULD LIKE TO POINT OUT WE ARE ALSO GOING IN THE SAME DIRECTION, TRYING TO PROMOTE OPEN SCIENCE, REPRODUCEABLE RESEARCH. AND I WOULD LIKE TO SHOW THE EXAMPLE OF THAT PARTICULAR PLATFORM, THE HUMAN NEUROSCIENCE PLATFORM. WE ARE NOT ACADEMICS, BUT WE ARE STAFF WHO SUPPORTS ACADEMICS OR ANYONE, COULD BE INDUSTRY, TO DO HUMAN NEUROSCIENCE. WE HAVE ALL THESE DIFFERENT PLATFORMS AT OUR DISPOSAL OPEN TO EVERYONE. WE HAVE THE EXPERTISE AN EQUIPMENT THEY CAN USE. IT HAS BEEN VERY BENEFICIAL, IN PARTICULAR, FOR EVERYTHING THAT IS MULTIMODEL BECAUSE WE ARE ON THE SAME. AND PEOPLE ARE COMBINING ALL OF THESE TOGETHER. WE DID VIRTUAL REALITY WHILE DOING TMS, TEMPORAL INFERENCE INSIDE THE MRI, CONCURRENT MRI WHICH THIS TALK IS GOING TO FOCUS ON. OUTLINE OF THE PRESENTATION. THE DIFFERENT CHALLENGES OF CONCURRENT MRI. YOU HAVE SEEN THE BIG PICTURE. NOW WE WILL DEVIL HOW OWE DO CONCURRENT TMS-MRI. AND WHAT IS LEFT TO SOLVE. OKAY. SO THERE ARE DIFFERENT WAYS TO COMBINE MRI AND TMS, BUT YOU CAN CATEGORIZE THEM INTO THE OFFLINE APPROACH WHERE YOU WOULD FIRST DO AN MRI SCAN TO DERIVE SOME PARTICULAR TYPE OF METRICS AND DO TMS AND THEN AFTER THAT YOU WOULD DO ANOTHER MRI SCAN. AND IN THAT CASE, YOU DO CONVENTIONAL TMS AND MRI. THERE IS NO INTERACTION. THIS IS, I WOULD NOT SAY EASY, BECAUSE YOU KNOW IF YOU WORK IN THE FIELD YOU KNOW THE TRICKS. IF YOU WANT TO DO ONLINE TMS, WHILE THE SUBJECT IS INSIDE MRI THIS IS WHERE THINGS GET TRICKY OR INTERESTING. THAT IS A TYPICAL TMS EXPERIMENT SET UP. TMS, TMS HOLDER, CHAIR FOR THE SUBJECT, NAVIGATION CRITICAL TO TARGET PROPER AREA AND SOME KIND OF TMS CONTROLLED DEVICE. YOU MIGHT WANT TO RECORD SOME MUSCULAR RESPONSE. THAT IS THE TYPICAL SET UP. YOU HAVE A VERY STRONG MAGNETIC FIELD AND ALSO YOU HAVE A VERY TIGHT SPACE. VERY RESTRICTED SPACE INSIDE THE MRI. AND THESE ARE THE MAJOR CONSTRAINTS. BASED ON THIS, THE DIFFERENT CHALLENGES ARE THE FOLLOWING. WE ARE GOING TO GO THROUGH THE LIST TOGETHER. BASICALLY NAVIGATION IN THE MRI. ARE WE TARGETING THE PROPER AREA. DOES THE QUESTION OF THE MRI COIL AND WHETHER IT IS COMPATIBLE WITH TMS. THE QUESTION OF THE TMS COIL, WHICH IS AS IMPORTANT. HOW DO YOU PERFORM SHAM OR CONTROL EXPERIENCE INSIDE THE MRI? WHAT IS THE DIFFERENCE BETWEEN SIMULTANEOUS AND CONCURRENT USE OF TMS AND MRI AND HOW YOU DO IT. HOW DO YOU CONTROL TMS CONTROL SYNCHRONIZATION AND PROPER QUALITY OR CO-REGISTRATION OF DATA? SO WE'VE SEEN THAT WITH NEW NAVIGATION, YOU CAN ACTUALLY TRY TO DEFINE YOUR TARGET, EITHER BASED ON STRUCTURAL DATA, T1, 122, TRACTOGRAPHY OR FUNCTIONAL. YOU GET THE SOFTWARE AND ACTIVATION LAB TO YOUR FAVORITE NEURONAVIGATION SOFTWARE. YOU DEFINE YOUR TARGET. NOW, TO DO IT INSIDE THE MRI IS TRICKY. THERE ARE BASICALLY TWO WAYS TO DO IT. YOU CAN DO IT RETROSPECTIVELY, WHICH MEANS YOU WILL FIND OUT AFTERWARDS IF YOU WERE ACTUALLY TARGETING THE PROPER AREA, WHICH COULD EXPLAIN WHETHER YOUR DATA MADE SENSE OR NOT. WHAT YOU NEED TO DO IS PUT MARKERS ON YOUR TMS COILS SO YOU CAN SEE IN THE MRI IMAGES WHERE IT IS LOCATED. THERE IS VARIOUS WAYS TO GO ABOUT IT. THE TYPE OF MARKERS YOU CAN USE. SOME PEOPLE HAVE BEEN USING MUSTARD AS WELL AS THE COMMERCIAL MARKERS AND YOU CAN SEE IN THESE EXAMPLES ON T2 WEIGHTED IMAGE HOW YOU CAN LATER FIND OUT WHERE YOUR COIL WAS. THIS IS CHEAP AND EASY TO IMPLEMENT. YOU NEED THOSE LABELS. YOU MIGHT WANT TO 3-D PRINT SOMETHING, BUT YOU ARE SENSITIVE TO ANY MOTION THE SUBJECT MIGHT MOVE. SO IT REQUIRES A LOT OF SKILLS TO PUT IT RIGHT AT THE BEGINNING OF THE SESSIONS AND IN CASE THE SUBJECT MOVES, IT TAKES TIME TO READJUST. THE OTHER SOLUTION IS CONTINUOUS MONITORING. IN THAT CASE IT IS AN ACTUAL CONTINUOUS REAL TIME NEURONAVIGATION SO YOU NEED MOTION TRACKERS ON THE TMS AND THE SUBJECT, JUST LIKE YOU WOULD DO ON THE REGULAR TMS EXPERIMENT. THAT IS TRICKY BECAUSE OF THIS PACE. YOU CAN SEE HERE A COUPLE OF EXAMPLES WHERE YOU HAVE THE CAMERA WHICH IS LOCATED ON THE FAR SIDE OF THE MRI BED AND THEN HERE THE DIFFERENT TRACKERS, ONE ON THE FOREHEAD, ONE OF THE TMS COIL AND YOU TRY TO HAVE THIS LINE OF SIGHT BETWEEN THE TWO. THIS IS ANOTHER EXAMPLE HERE. SO THE PROS. THIS CONTINUES. IT IS A FEEDBACK THAT IS POSSIBLE IF THE SUBJECT IS MOVING. YOU CAN FEED HIM SOME KIND OF TARGET THE SAME WAY WHEN WE DO NAVIGATION. SUBJECT IS ACTIVELY INVOLVED IN THE POSITION. THIS IS NOT EASY. YOU NEED CAMERA ROD AND SEDUP AND KEEP THE LINE OF SIGHT ALWAYS AVAILABLE IS TRICKY AS SOON AS YOU WANT TO DO A VISUAL STIMULUS, THE SUBJECT IS LOOKING AT SOMETHING IT BECOMES REALLY COME POLITIC -- COMPLICATED. THERE IS AT THE MOMENT NO REAL, I WOULD SAY, APPROPRIATE SOLUTION. EVEN THE COMMERCIAL ONE ARE NOT OPTIMAL. YOU NEED TO TRAIN YOUR PATIENTS THAT IS VERY WELL BEHAVE. IT WOULD BE INTERESTING, ACTUALLY, TO MAYBE CONSIDER DIFFERENT WAYS OF DEVELOPING THIS TECHNOLOGY. MAYBE HAVING SOME KIND OF MULTICOIL CAPABILITY SO EVEN IF THE SUBJECT IS MOVING YOU CAN TRY TO DEFINE THE TARGET WHEN THE SUGGEST IS STILL INSIDE THE MRI. HERE I THINK THE COMMUNITY REALLY NEEDS TO MAKE AN EFFORT INTO FINDING A PROPER SOLUTION BECAUSE THIS IS A BIG PROBLEM WITH CONCURRENT TMS-MRI. THE TMS COILS ARE LARGE. SO IF YOU WANT TO USE A CONVENTIONAL MRI COIL BASICALLY YOU ARE LEFT WITH THE ONLY OPTION WHICH IS BIRD CAGE COIL. IT MEANS THAT POTENTIALLY YOU HAVE POOR MRI SIGNAL AND NO MULTIBAND CAPABILITY. AND THAT IS A PROBLEM WHEN YOU WANT TO DO FMRI. ALSO YOU MIGHT HAVE LESS FLEXIBILITY IN COIL POSITIONS BECAUSE THE BIRD CAGE IS STILL RESTRICTED ON THE SIDE, THE SPACE THAT YOU HAVE. SO FOR THAT REASON SOME DEDICATED MRI SURFACE COILS HAVE BEEN DEVELOPED AND THEY LOOK LIKE THIS. SO IN WHITE IS YOUR TMS COIL SO YOU CAN STIMULATE INSIDE THE MRI IN BLUE IS THE MRI COIL. ONE OF THEM IS DIRECTLY CLIPPED INSIDE THE TMS COIL SO YOU HAVE A GOOD SIGNAL AT THE AREA YOU ARE PRIMARILY TARGETING. YOU CAN SEE IN THIS DPLAMPL IS A SECOND BLUE ONE THERE BASICALLY TO MAKE SURE YOU HAVE MRI SIGNAL ON THE OTHER SIDE OF THE BRAIN. I DON'T WANT TO SAY BIRD CAGE COILS. I USE THAT WITH WHOLE BRAIN IMAGING. IF YOU ARE INTERESTED IN DOING INDIRECT STIMULATION, STIMULATE ON CORTEX BUT INTERESTED IN SOMETHING DEEP IN THE BRAIN AND YOU WANT INFORMATION THERE, KEEP IN MIND SPACE IS VERY LIMITED SO YOUR TYPICAL TARGETS FOR TMS WOULD BE M1 OR SMA. ON THE OTHER HAND, FOR THE SURFACE COILS IT IS ADVANTAGEOUS TO DETECT TMS ACTIVITY NEAR THE COILS TO SOW HAVE SIMILAR TO BIRD CAGE AND MORE VERSATILE IN TERMS OF GEOMETRY AND TARGETS. IF YOU WANT MULTIBAND CONNECTIVES, YOU NEED TO COMBINE COILS TOGETHER AND IN THAT CASE YOU HAVE A MUCH BETTER SMA IN HALF OF THE BRAIN. THIS IS THE SOLUTION THAT WE ARE CONSIDERING IN OUR LAB AND THIS IS WHAT A TYPICAL SET UP IS LIKE. YOU CAN SEE HERE, THIS IS THE TMS COIL, ONE MRI COIL CLIPPED TO IT AND THERE IS ANOTHER ONE HERE. HERE WE WOULD BE STIMULATING, FOR EXAMPLE, VRKSZ 5 IN THAT PARTICULAR EXAMPLE. FOR THE TMS COIL, OF COURSE, IT MUST CONTAIN NO -- MATERIAL. THE STRONG STATIC BE ZERO AND THE DYNAMIC MAGNETIC FIELD DUE TO RAPID SWITCHING OF THE GRADE YENS WHEN FUNCTIONAL MRI. IT IS IMPORTANT TO USE A COIL WHICH IS MORE COMPATIBLE BECAUSE THE OTHER ONES CAN MOVE OR BREAK/EXPLODE. SO YOU REALLY DO WANT THAT. IN TERMS OF PULSES -- PULSES HAVE A LOWER TMS CODE. THIS IS ACTUALLY BENEFICIAL. IN TERMS OF VERY CONCRETE ASPECTS YOU ALWAYS NEED A WAVE GUIDE AND LOW-PASS FILTER TO REMOVE WITH THE EQUIPMENT. SOMETHING THAT NEEDS TO BE TAKEN INTO ACCOUNT IS TO WORK ON THESE DIFFERENT FILTERS. A LOT OF TMS COILS HAVE COUNTERS. IT IS EASY TO DEPLETE THESE TMS COILS RUNNING AN MRI EXPERIMENT. WE LEARN ON THAT AND WORKED WITH MANUFACTURERS SO THIS PROBLEM DOESN'T ARISE ANYMORE. IN PRACTICE, THOSE COILS EXIST. THEY ARE COMMERCIALLY AVAILABLE WITH FDA APPROVAL, BUT THEY ARE AVAILABLE, IT DOESN'T MEAN THEY ARE PERFECT. WHEN YOU DISCHARGE THE TMS COIL INSIDE THE MRI YOU INDUCE A BIG FORCE. SOME OF THE LORENTZ FORCE COMPENSATE, NEVERTHELESS, THERE IS A LOT OF STRESS ON THE COILS WHICH IS WHY YOU NEED TO SEND THEM BACK TO BE REFURBISHED AFTER A FEW THOUSAND PULSES. WHICH MEANS YOU NEED TO DESIGN YOUR EXPERIMENTS PROPERLY SO THAT IN PRACTICE YOU CAN DO IT WITH A SINGLE COIL OR AT LEAST TAKE INTO ACCOUNT WHEN YOU ARE RECRUITING A SUBJECT YOU MIGHT HAVE SOME DOWN TIME. TMS COILS MUST BE COOLED DOWN SO YOU MUST HAVE ACCESS TO COMPRESS SOR OR COOLER. SOMETHING THAT IS EXTREMELY IMPORTANT IS TMS COILS INSIDE THE MRI ARE LESS STRONG THAN OUTSIDE. SO TYPICALLY YOU CANNOT REACH THIS 140% OF MOTOR THRESHOLD LIKE YOU WOULD BE ABLE TO IN THE REST OF THE EXPERIMENT. YOU NEED TO PAY ATTENTION TO THE EXPERIMENTAL DESIGN. THERE ARE DIFFERENT REASONS FOR THAT. BASICALLY THERE IS, IF YOU ARE USING THESE DEDICATED MRI COILS, YOU INTRODUCE AN EXTRA DISTANCE BETWEEN THE TMS COIL AND THE BRAIN. SO YOU LOSE POWER THERE. YOU WOULD HAVE A LONGER CABLE BETWEEN THE TMS COIL AND THE STIMLATOR. THE TMS STIMLATOR LOCATED OUTSIDE OF THE MRI ROOM. THIS EXTRA DISTANCE DECREASES THE POWER. AND JUST THE FACT OF BEING IN A STRONG MAGNETIC FIELD DECREASES. I WOULD ENCOURAGE THOSE ASKING FOR THE MORE POWERFUL VERSION OF THE STIMLATOR WHEN YOU ARE PARTICIPA PARTICIPATING. COIL HOLDER IS NECESSARY BECAUSE THEY ARE HEAVY. NOT FOR V1 OR V5 BECAUSE YOU ARE LYING ON IT. THIS IS WHAT A TYPICAL COIL HOLDER WOULD LOOK LIKE HERE. THE WAY THEY ARE DESIGNED TO HAVE ALL ACCESS OF FREEDOM SO IN THEORY YOU CAN HOLD THE TMS IN WHATEVER POSITION YOU LIKE. IN PRACTICE IT IS DIFFICULT TO USE. THE SUBJECT MOVES ONLY A LITTLE, YOU NEED TO ROTATE THREE OR FOUR OF THE DIFFERENT KNOBS TO GO BACK TO A PROPER POSITION. WE HAVE SOME WORK TO DO THERE. AND IN THE MEANTIME, IT REQUIRES A LOT OF SKILL TO BE ABLE TO DO IT PROPERLY. WHICH IS ALSO SOMETIMES GOOD THAT WE HAVE A PLATFORM SO THAT WE MAKE SURE IT STAYS WITH US AND DOESN'T LEAVE WITH THE PH.D. STUDENTS OR POST DOC. IN TERMS OF SHAM CONTROL, WELL, THIS IS A POPULAR PROBLEM FOR TMS. TMS STIMULATES A LOT OF NOISE. THESE ARE ALL AMPLIFIED INSIDE THE MRI. SHAM COILS CANNOT BE USED SO THERE ARE DIFFERENT SOLUTIONS. BASICALLY EACH GROUP HAS ITS PREFERRED TECHNIQUE. SO SOME LIKE AN ACTIVE CONTROL SITE, FOR EXAMPLE, THE VERTEX. SOME DO THE SAME TMS PROTOCOL UNDER A DIFFERENT MRI TASK. COMPARING HIGH AND LOW INTENSITY TMS TO HOPE LOW INTENSITY PROFINDS THE SAME CONFOUNDS. IF YOU RETATE YOU NEED TO TAKE THE SUBJECT OUT AND DO MANIPULATION OR INTRODUCE PLASTIC AS AN EXTRA DISTANCE. TO HAVE SOME OF THE COMPOUNDS AT LEAST SIMILAR. SO ALL OF THESE HAVE BEEN CONSIDERED. THERE'S NOT A CLEAR WINNER, TO MY KNOWLEDGE HERE. AND IN MY DEFENSE, ON THE PARTICULAR APPLICATIONS THAT YOU ARE DOING. NOW, I WANT TO MENTION ABOUT SIMULTANEOUS TMS FOR MRI. IF YOU ARE REALLY SIMULTANEOUS, BASICALLY, YOU WON'T GET ANY MRI SIGNAL. THE PMS TMS REDUCES YOUR MRI SIGNAL TO 0, DEPENDING ON WHEN YOU ARE PULSING IN THE SPACE. WE INTRODUCED A SMALL GAP BETWEEN THE TMS AND THE NEXT VOLUMES. IT HAS BEEN DONE AND VERIFIED BY A FEW GROUPS. 75 TO 100 GAP. YOU RECOVER MAGNETICIZATION AND WHAT WE DO IN PRACTICE IS WE DO EVERYTHING WE CAN WITH YOUR USUAL 64, 32 CHANNEL MRI COIL AND YOU ONLY CHANGE THE SETUP FOR THE FMRI PART. AND MAYBE SOME ADDITIONAL SCANS TO DO COIL DEMONSTRATION. FOR THE SEQUENCE YOU MIGHT DEPEND ON THE PROTOCOL YOU WANT TO DO. YOU NEED TO INTRODUCE GAP BETWEEN MRI VOLUMES. DEPENDING ON THE FREQUENCY, YOU CAN DO DIFFERENT THINGS. WE HAVE SEEN SOME NICE EXAMPLES IN THE PREVIOUS PRESENTATION. A NICE BOLD ACTIVATION TO SEE THE RESPONSE WHEN WE DO TMS. IN TERMS OF METHODS, IT IS NICE MOST PRODUCT SEQUENCE FROM THE MANUFACTURERS ARE CAPABLE OF INTERLEAVING. LEAVING A GAP BETWEEN VOLUMES OR SEGMENTS OF SLIDES SO IT IS POSSIBLE FOR US WITH A GOOD SIN K SYNCHRONIZIZATION. THERE IS NO MEASURE FOR WHERE THE TMS IS TARGETING WHICH IS WHY WE NEED TO USE NEURONAVIGATION. BECAUSE THE TMS KILLS ALL THE SIGNAL THAT IS EVERYWHERE, THAT IS DIFFICULT TO DO. IT WOULD BE GREAT IF SOMEONE CAME UP WITH A GENIUS IDEA TO GO AROUND THIS PARTICULAR PROBLEM. THERE IS ONE FOR TDCS AND I THINK WE HAVE A TALK LATER ON THIS PARTICULAR TOPIC. SYNCHRONIZIZATION IS NOT A PROBLEM. THERE ARE TOOL BOXES AND OPEN ACCESS. MANY OF THEM SO WE CAN EASILY CONTROL THE TMS AND HAVE A VERY GOOD SYNCHRO NISZ -- SYNCHRONIZATION. YOU WANT TO TRIGGER FAST, YOU GET VERY GOOD SYNCHRONIZATION. THE DIFFERENT SETUPS. ON THE LEFT TMS ON M1, THE SUBJECT IS FULLY INSTALLED. THERE IS AN ADDITIONAL MRI COIL TO RECOVER THE SIGNIFICANT AT THE SPINE LEVEL. THIS IS TMS PERFORMED ON V5. HERE THE OTHER COIL WAS PUT ON THE VERTEX. THE MRI RECEIVED COIL IS DIFFERENT, TWO BIG LOOPS, ONE OF THE LEFT, ONE OF THE RIGHT AND PUT YOUR FIGURE 8 COIL ON THE TOP. THIS IS GOOD FOR SOME APPLICATIONS, LIKE I SAID, BUT MAYBE NOT ALL OF THEM. ANOTHER FEW SLIDES BEFORE THE SUBJECT ARRIVES, IT LOOKS LIKE A MESS. WHEN THE SUBJECT IS INSTALLED, NO NAVIGATION, NO MARKERS. WHEN THE SUBJECT IS FULLY IN PLACE THIS IS HOW IT WOULD LOOK. IF YOU LOOK AT THE CONSULT ROOM YOU SEE BECAUSE WE TRY TO REDUCE CABLE LEJTS, THE MRI IS IN THE ROOM JUST BEHIND. WE HAVE THE STIMLATOR KIND OF IN FRONT OF THE -- SORRY, OF THE CONSOLE, OF THE MRI CONSOLE AND THE CONNECTION IS SIMPLY A FEW CABLES THERE. NOW, IN TERMS OF QUALITY, BASICALLY FOR EVERYTHING WHICH IS STRUCTURAL YOU HAVE THE SAME MRI QUALITY YOU ARE USED TO BECAUSE YOUD ARE USING THE SAME MRI COIL YOU ARE USED TO AND YOU ONLY USE YOUR DEDICATED SETUP FOR FMRI AND A BIT FOR DEMONSTRATION. THIS IS HOW IT LOOKS FOR A SINGLE VOLUME WHEN YOU ARE USING THIS DID KATED TMS COILS. YOU CAN SEE WE HAVE THE MARKERS TO CHECK THE POSITION RESPECTIVELY AND THE ACTIVATION WORKS PRETTY WELL. WE DO ALTERNATING PHASE TO ACCOUNT FOR THE DISTORTIONS. LIKE ANY MRI PROTOCOL, REALLY. WE HAVE A STUDY THAT SHOWS IT WORKS REALLY WELL. IT IS SIDE DEPENDENT AND POWER DEPEND AND WE GET GOOD RESULTS WITH OUR USUAL METHODS. I JUST WANT TO MENTION THIS POINT. IT WAS A PROBLEM, BUT IT IS ONE THAT IT IS EASY TO GO AND SOLVE FOR. IT IS TYPICALLY DIFFICULT TO TMS MRI DATA ACQUIRED WITH A DIFFERENT COIL BECAUSE YOU HAVE A DIFFERENT CONTRAST AND A DIFFERENT B1 COVERAGE. YOU OMITTED ONE STEP WITH DIFFERENT CONTRACT WITH THE SAME B1 COVERAGE. IN THAT CASE THIS IS YOUR FMRI IMAGE. YOU WOULD REQUIRE A STRUCTURAL SCAN. SO VERY SMI EFFICIENT WITH THE SAME COIL SO THEY ARE CO-REGISTERED TOGETHER. THE SUBJECT IS WITH THE SAME MRI COIL AND YOU CHANGE THE SOFTWARE AND USE THE BODY COIL INTEGRATED WITH THE SCANNER GIVING YOU DIFFERENT B1. AND YOU CAN EASILY CO-REJ TER TOGETHER AND USE THIS ONE AS AN INTERMITTENT STEP. SO I THINK THIS IS A VERY EXCITING TIME TO DO RESEARCH IN THIS FIELD. THERE HAVE BEEN RECENT ADVANCES IN TERMS OF NEW TECHNOLOGY AVAILABLE AND SOMETHING WE HAVE NOT MENTIONED, ALL THESE DIFFERENT LEARNING ALGORITHM IMPACTING THE FIELD OF MRI AND IT IS UNCLEAR HOW WE CAN BENEFIT FROM THEM IN THIS FIELD. ALL OF THIS TECHNOLOGY IS NOW AVAILABLE WITH CLINICAL GRADE AND THE TYPE THAT PLATFORMS ALSO EXISTING PERMIT TO MAKE THEM AVAILABLE TO POTENTIALLY A LARGER COMMUNITY, WHICH DO NOT HAVE NECESSARILY ACCESS TO AFFORD THIS EXPENSIVE MACHINE, BUT YOU CAN DO YOUR OWN EXPERIMENTS LIKE THIS. SO THERE ARE STILL AREAS OF IMPROVEMENT AND OPEN QUESTION I MENTIONED IN PRACTICAL ABILITY AND HOW DO DO A GOOD SHAM DESIGN. WE HAVE SEEN THIS IN THE PREVIOUS TALK. THERE IS A LOTS OF WORK GOING ON RIGHT NOW AND THIS IS GREAT AND WE NEED TO TWO FURTHER AND REACH CONSENSUS. SAME THING FOR THE STIMULATION OF DEEP BRAIN STRUCTURE. WHAT IS MORE APPROPRIATE? STRUCTURAL, FUNCTIONAL, MAYBE A COMBINATION OF BOTH. ALSO MAYBE -- IT IS INTERESTING TO GO TO HIGHER FIELD STRENGTH IF YOU ARE LOOKING AT TMS AND SEE HOW WE CAN HAVE AN INDIVIDUAL BRAIN ACTIVITY, WHICH IT GIVES US IN TERMS OF FMRI. IT IS VISIBLE ON A SINGLE SUBJECT. IN THAT CASE, THE TMS TECHNOLOGY IS DIFFICULT TO DIVIDE UP SO THESE ARE ALL INTERESTING TOPICS. I'M ALSO GLAD TO SEE THAT THERE IS THIS WORKSHOP. THERE IS ANOTHER ONE THAT HAS BEEN CREATED ON CONCURRENT TMS-FMRI WHICH IS GOING TO BE RENEWED EVERY YEAR. THIS COMMUNITY CAN EXCHANGE SEVERAL TIMES A YEAR AND TRY TO PROGRESS AS FAST AS POSSIBLE. SO THANK YOU FOR YOUR ATTENTION. [ APPLAUSE ] >>THERE IS ALSO A SLACK WORKSPACE FOR THAT GROUP THAT PEOPLE ARE WELCOME TO JOIN. SO ANYBODY WHO IS ACTUALLY DOING TMS-MRI AND WANTS TO BE ON THE SLACK, I WILL BE HAPPY TO INVITE YOU IF ANYBODY WANTS TO JOIN. ANY QUESTIONS? >>I'M A NEUROLOGIST IN MED OFFICE FOR FDA. JUST CO-MODERATING. I HAVE A QUICK QUESTION ABOUT THE SURFACE COIL. DOES IT HAVE ANY ADVANTAGE OF PREVENTING THE SPREAD OF CURRENT STIMULATION? AND THE OTHER IS CAN IT BE USED FOR ALL THE TMS, LIKE ITBS. >>WHICH COIL, SORRY? >>THE SURFACE COIL. >>THE SURFACE COIL. >>YEAH. >>I DON'T THINK THEY ARE VERY EFFICIENT, THIS TYPE OF COIL. SO IN THEORY, IT GIVES YOU FLEXIBILITY IN TERMS OF WHAT YOU CAN DO BECAUSE THEY ARE VERY VERSATILE. BUT I WOULD GO FOR THIS DEDICATED MRI COILS, I THINK, IF I WANT TO HAVE -- I MEAN, IF WE ARE TRYING TO DEVELOP THIS TECHNOLOGY, I THINK WE WANT TO HAVE THE BEST TOOL AT EACH PLACE AND THESE WERE NOT DEVELOPED ESPECIALLY FOR THIS, YOU ARE LACKING A BIT OF SIGNAL COMPARED TO THESE OTHER NEW TOOLS SO WE SHOULD REALLY GO FOR THAT. >>THANK YOU. >>I WOULD SAY, IT DOESN'T HAVE TO DO WITH THE SURFACE COIL, BUT THE TMS DEVICE ITSELF IS CAPABLE OF RTMS. THERE IS AN AIR COOLED VERSION OF THE TMS COIL SO YOU CAN RUN RTMS SESSIONS WITH IT. IT IS UNRELATED TO THE MRI SURFACE COIL. >>THANKS. >>NO QUESTIONS. OKAY. THANKS VERY MUCH. >>THANK YOU. [ APPLAUSE ] >>BARAN IS COMING UP AND GETTING SET UP, WE ARE A CLOSE-KNIT COMMUNITY. THE GROUP IN CYPRUS, A BUNCH OF PEOPLE WERE ABLE TO ATTEND. I HIGHLY ENCOURAGE YOU TO ATTEND IF YOU CAN, A BEACH RESORT, A BEAUTIFUL PLACE, IF YOU ARE UP FOR THAT, WE WOULD LOVE TO SEE YOU. BARAN AYDOGAN. >>THANK YOU. I'M HAPPY TO BE HERE IN PERSON. I'M DOING RESEARCH FELLOW AT THE A.I.VIRTANEN INSTITUTE FOR MOLECULAR SCIENCES AT THE UNIVERSITY OF EASTERN FINLAND. WE ORIGINALLY THIS SLOT TO BE PRESENTED BY HIM AND HE GLADLY ACCEPTED. HE WANTED TO BE WITH US IN HERE TODAY, BUT UNFORTUNATELY, HE HAD TO CANCEL. BECAUSE HE WAS ASKED TO SPEAK IN A GRANT PANEL IN BRUSSELS. WE AGREED THAT I WILL TRY TO MAKE A PRESENTATION WHERE THE WORK HE HAS BEEN LEADING AT AALTO OVER THE YEARS AND OUR JOINT WORK IN THE MOST RECENT YEARS. SO THE FIRST HALF OF THE PRESENTATION WILL BE MAINLY ABOUT HIS CONTRIBUTION AND THE TEAM AT AALTO. I DON'T HAVE ANYTHING TO DECLARE. SO THIS TALK A GENERAL ASPECT. I NEED TO THANK THE KEYNOTE SPEAKER. MAYBE FROM THE POINT OF THE RESEARCH DONE IN FINLAND. I DIVIDED IT INTO THREE WHERE I WILL MENTION ANALYSIS PERSPECTIVE, MRI IS UTILITY AND TARGETING PERSPECTIVE AND JOINT PERSPEC PERSPECTIVE. SO LET'S GET STARTED. ANALYSIS. AS WE HEARD ALREADY IN THE MORNING, TMS AFFECTS THE BRAIN IN COMPLICATED WAYS. EXACT IS MULTIDIMENSIONAL, LET'S SAY. IF YOU ARE CURIOUS ABOUT WHAT IS BEING STIMULATED, I HIGHLY RECOMMEND THIS PAPER RECENTLY PUBLISHED ON THIS. ONE IMPORTANT THING TO HIGHLIGHT IS THAT TMS CAUSED STIMULATION, AUDITORY AND SENSORY. NEVERTHELESS, WE HAVE A GENERAL UNDERSTANDING OF WHAT IS HAPPENING. WE BASICALLY RUN A LARGE AMOUNT OF CURRENT IN A COIL. THIS IS, OF COURSE, TRACE A MAGNETIC FIELD THAT LEADS TO E FIELD, ELECTRIC CURRENT IN THE TISSUE, CHANNELS TO OPEN AND ACTION POTENTIALS. THESE PROPAGATE THROUGHOUT THE BRAIN AND THROUGH SYNAPTIC ACTIVATIONS. THROUGHOUT THE PROCESS WE HAVE POST SYNAPTIC -- BECAUSE WE CAN DETECT. SO THE MEASUREMENT OF EEG WITH CONCURRENT TMS HAS BEEN LEAD IN THE 1990s ACTUALLY. THIS IS WHAT A TMS-EEG SETUP LOOKS LIKE. THE VALUE IS WE WILL HAVE HIGH TEMPORAL DYNAMICS MEASURED BY EEG. OF COURSE, EEG DOESN'T LIKE TMS MUCH. WE HAVE ARTIFACTS. THERE ARE GOOD ALGORITHMS TO CLEAR UP THESE ARTIFACTS. ALREADY IN THOSE TIMES, THE UTILITY OF MRI WAS CLEAR IN 1990s BASED ON THE DATA COLLECTED IN THIS STUDY. THE SOURCES ACTIVATED IN THE BRAIN WERE MEASURED USING NEUROESTIMATE. SO THIS SLIDE WILL BE VERY CROWDED AND I WILL STEP OUT OF WHAT IS BEING DONE OUTSIDE BECAUSE THESE ARE QUITE EXCITING DEVELOPMENTS IN OUR FIELD NOWADAYS. WHAT EXCITED ME ARE BIOPHYSICAL BASED SIMULATIONS WHICH WE HEARD IN THE MORNING. THESE WANT TO GO TO CELLULAR LEVEL MECHANISMS OF HOW TMS AFFECTS THE BRAIN AND THEY HAVE POTENTIAL TO INFORM US MORE PRECISELY ABOUT WHAT IS GOING ON AND DEVELOP NEW TREATMENT OPPORTUNITIES. AS SOMEONE WHO IS HEAVILY INVOLVED IN THE MRI RESEARCH, I'M VERY INTERESTED TO FOLLOW WHERE THIS RESEARCH WILL GO BECAUSE THERE ARE A LOT OF PARALLEL DEVELOPMENTS WHICH COULD HELP THIS TYPE OF RESEARCH. IN THE DIFFUSION MRI COMMUNITY WE HAVE BIOPHYSICALLY MICROSTRUCTURE MODELS COMING. IN THIS PAPER, THE MODEL IS ABLE TO INFORM US ABOUT THE CORTICAL SITE OF ARCHITECTURE TELLING US ABOUT THE SOMA AND NEURIT DENSITY. THIS COULD BE TIED TO CELLULAR PROFILING AND HEAVILY USED IN BIOPHYSICAL AS WELL. WE HAVE AN INCREASING STRENGTH IN OUR SCANNERS. THE DEVELOPMENT LEADING TO HIGHER B VALUES IN DIFFUSION SCANNERS. THESE ARE ABLE TO PROVIDE FINER AND FINER MICROSTRUCTURE INFORMATION. THE AXON DIAMETER G RATIOS COULD BE IN THE FUTURE POSSIBLE TO BE MEASURED BECAUSE THEY ARE CLOSED TYPE CONDUCTION. ON A HIGHER LEVEL WE ARE SEEING TOOLS FOR CIRCUIT AND MASS MODELING. FOR EXAMPLE THIS TOOL, STEPHANIE JONES IS DEVELOPING OR REALLY LOOKING AT THIS CIRCUIT LEVEL ACTIVITIES, WHICH ALSO TIES TO SYSTEM LEVEL OPERATION OF THE BRAIN, WHICH WE CAN LEVERAGE MRI INFORMATION, FOR EXAMPLE. THESE STRUCTURE CIRCUITS, A DIVISION OF MRI TRACT. WE WILL HERE MORE DOWN TO MOLECULAR. WE WILL HAVE IMAGING WHICH ARE EXCITING TO FOLLOW. I WOULD LIKE TO TALK ABOUT THE TARGETING PERSPECTIVE, NAVIGATED TMS APPROACH. FOR EXAMPLE, MANY THIS CASE WE HAVE STRUCTURAL MRI AND THE TMS AND THE PATIENT'S HEAD. AND WE CAN ACTUALLY SEE WHERE THE TMS COIL IS LOCATED WITH RESPECT TO THE SUBJECT'S BRAIN. THIS IS USED FOR PRESURGICAL LOCALIZATION FOR PREFRONTAL CORTEX. THIS IS FDA APPROVED. AND HERE ARE SOME RESULTS FROM CORTICAL MAPPING. WE CAN SEE HERE ON THE LEFT NAVIGATED TMS MAPPING, WHICH IS NONINVASIVE, SOME MUSCLES AND WE CAN SEE ON THE RIGHT THE CRANIOTOMY, THERE IS A GOOD MATCH BETWEEN THE TWO. WE MAYBE CAN DO BETTER. NOW WE ARE DEVELOPING ALGORITHMS IN OUR HARDWARES, WE CAN DO MODELING USING REALISTIC HEAD MODELS. THIS COULD BE VERY USEFUL TO HAVE IN YOUR NEURAL NAVIGATION SYSTEMS FOR BETTER TARGETING. I WITHOUT LIKE TO SPEND A FEW WORDS ABOUT WHAT WE CAN DO BEFORE THIS. BECAUSE THESE E-FIELD MODELING ARE BASED ON CORE GEOMETRY, WHICH MAY NOT BE ENOUGH AS THE PREVIOUS SPEAKER MENTIONED, PUT TMS COILS INSIDE MRI AND THE VIBRATIONS. SO IT MIGHT BE VALUABLE TO HAVE EXPERIMENTAL WAYS OF MEASURING THE E-FIELD. AND IN THIS STUDY, AN APPARATUS TO MEASURE THE E-FIELD BY TMS COIL IS SUGGESTED. THESE TOOLS ARE ALSO USEFUL, FOR EXAMPLE, TO MAKE THIS MULTILOCAL TRANSCRIPTION STIMULATION SYSTEMS. IN THIS CASE WE ARE LOOKING AT A FIVE-COIL ARRANGEMENT. EACH OF THESE COILS ARE ACTUALLY ABLE TO CREATE THEIR OWN E-FIELD PROFILES. WHEN YOU STACK ALL OF THESE ON TOP OF EACH OTHER AND RUN DIFFERENT CURRENT COMBINATIONS, IT IS POSSIBLE TO MOVE THE EFIELDS ELECTRICALLY. WHEN AFFIXED ON A CERTAIN PART OF THE HEAD, WE ARE ABLE TO MOVE THIS E-FIELD MAXIMUM BY RUNNING DIFFERENT CURRENTS THROUGH THIS COIL. HERE THEY ARE. AGAIN, PREVIOUSLY MENTIONED, THESE SET UPS CAN BE QUITE HEAVY TO HANDLE, EVEN OUTSIDE THE TMS. SO THERE'S EFFORTS TOWARDS A ROBOTIC SYSTEM TO HOLD THESE COILS TOGETHER. AS YOU CAN SEE HERE, WE ALSO HAVE BEEN PUTTING SOME EFFORT ON THE ROBOTIC PART. WE CAN SEE REAL TIME COMPUTED FIBER TRACKS. I WOULD LIKE TO SPEND A FEW MINUTES TO TALK ABOUT THAT. I HAVE A BETTER VIDEO FOR IT. SO HERE WE SEE THE OPERATOR HOLDING THE TMS COIL AND THE SUBJECT'S HEAD IS REGISTERED WITH THE MRI AS WELL. SO CONVENTIONAL NAVIGATION SYSTEMS ARE CAPABLE OF SHOWS THIS. BUT THE DTI INFORMATION IS COMING RATHER NEW. WE ARE ABLE TO COMPUTE THE TRACKS REAL TIME WHILE THE NAVIGATION INTERFACE IS RUNNING. BECAUSE THIS IS NOT THAT WELL KNOWN AND NOT STUDIED BY MANY GROUPS AND I HAVE BEEN THE MAIN PERSON RESPONSIBLE FOR DOING THIS, I WOULD LIKE TO SPEND A FEW MINUTES TO DESCRIBE HOW WE ARE DOING IT. WE ARE USING OUR OWN FIBER TRACKING ALGORITHM. AND FOR THAT, WE HAVE DEVELOPED A SOFTWARE CALLED TRACKER. THIS IS A GENERAL PURPOSE DIFFUSION MRI-BASED TRACK TOOL. IT IS WRITTEN IN CC LGBTQIA+. IT HAS A PYTHON AND IS INTENTED SO PEOPLE CAN DEVELOP THEIR OWN DEVICE. TREKKER HAS NO DEPENDENCIES. IT RUNS ON COMPUTER CLUSTERS TO RUN ON BIG DATA. THERE IS A WEBSITE FOR IT. THE REASON WE MADE OUR OWN TRACKING ALGORITHM, WAS NOT TO MAKE IT FAST, BUT THE REASON WAS TO MAKE IT GOOD SO WE CAN HAVE BETTER AND MORE ACCURATE REPRESENTATION OF THE BRAIN. TREKKER HAS BEEN IN ALL COMP TIGS SINCE 2017. IN LAST YEAR THE TOP THREE TEAMS ALL USED TREKKER AND WE WERE ONLY LUCKY TO WIN IT. WE HAD SAUL NUANCES IN OUR ROBOT. BUT THE -- I HAVE BEEN WORKING ON TREKKER SINCE 2015. THIS MAKES IN OUR CASE THE REAL TIME. IT IS LARGELY A SOFTWARE PROJECT. SO I MENTIONED THAT WE MADE THIS SO PEOPLE CAN DO THEIR OWN TRACTOGRAPHY. I WOULD LIKE A QUICK DEMONSTRATION. YOU JUST IMPORT A TRACKER PACKAGE, UPLOAD FOD, INPUT AND JUST RUN. SIX LINES OF CODE. [INDISCERNIBLE] IN THE NAVIGATION SITE, WE JUST GET THESE DIE NAM CLICK FROM THE NAVIGATION SYSTEM AND VISUALIZE. OF COURSE, IT IS EASY FOR ME TO SAY BECAUSE WE HAVE A NAVIGATION SOFTWARE EFFORT GOING ON AT AALTO. SOME OF THE FEATURES OF THIS REAL TIME TRACTOGRAPHY IS NAVIGATION. SO WE ARE ABLE TO CREATE THOUSANDS OF STREAMLINES IN A FEW SECONDS. THIS IS IN THE C PLUS PLUS VERSION IN PYTHON. IT IS A LITTLE SLOWER, TO BE HONEST, BUT MOST IMPORTANTLY, YOU MAY WONDER IF THE QUALITY IS LOWER BECAUSE WE ARE DOING IT IN REAL TIME. ACTUALLY, QUALITY IS NOT LOW WHEN YOU COMPARE TO THE STATE OF OFFLINE PIPELINES BECAUSE WE USE EXACTLY THE SAME PROTOCOL. NOTHING IS DIFFERENT. IT IS THE SAME QUALITY. WE ACTUALLY LEVERAGE ANATOMICAL CONSTRAINTS SO THERE IS REALLY NO LOSS. OFFLINE, OF COURSE, CAN PROVIDE SOME COMPLEMENTARY INFORMATION FOR CONNECTIVITY OF OTHERS, FOR EXAMPLE, BUT WE HAVEN'T TESTED THAT. IN DIFFERENT WAYS IT IS BETTER THAN STATE OF THE ART OFFLINE. BECAUSE WE CAN CHANGE THE PARAMETERS IN REAL TIME. THIS MIGHT BE USEFUL IN CERTAIN APPLICATIONS, FOR THOSE WHO ARE FAMILIAR WITH TRACTOGRAPHY MAY UNDERSTAND THIS. THIS IS AN INTERESTING FEATURE. THE OTHER FEATURE IS MORE INTERESTING BECAUSE OF THE WAY WE ARE VISUALIZING DYNAMICALLY THIS ACTUALLY COMES WITH CERTAIN DIFFERENT OPPORTUNITIES FOR EXAMPLE WE DO VISUALIZATION TO -- STREAMLINES ARE MORE LIKELY TO BE POSITIVE --. IN THE FINAL PART I WOULD LIKE TO TALK ABOUT ANALYSIS AND TARGETING. THESE ARE GENERALING ILY ABOUT FUTURE PLANS, ACTUALLY. IN THE PREVIOUS PART I TALKED ABOUT THE STRUCTURAL IMAGES AND E-FIELD. THERE IS A DOWN SIDE IN THEIR STUDY AND THEY ARE REQUIRED BEFORE THE EXPERIMENT. SO, OF COURSE, THERE IS TO BE VALUABLE IF WE CAN SEE ACTIVATION WHERE WE ARE HITTING OR WHICH CIRCUITS ARE WE TARGETING DURING THE EXPERIMENT. SO THE MEASUREMENTS WITH FMRI COULD BE HIGHLY USEFUL CONCURRENTLY. WE WOULD ACTUALLY LIKE TO INCLUDE FEEDBACK FROM FMRI. WHICH THE ESPECIALLY YOU MIGHT APPRECIATE IT IS A QUITE CHALLENGING SET UP TO PUT EVERYTHING IN THE SCANNER, BUT THIS APPROACH COULD ENABLE THIS IN THE FUTURE. SO THE IDEA HERE IS TO USE FMRI FEEDBACK AND LOOK AT THE ACTIVATION AND CHANGE THE TARGET LOCATION. SO THIS IS MAYBE TO SET TARGET. BUT, OERNN THE OTHER HAND, AS T KEYNOTE SPEAKER MENTIONED, WE HAVE TIME. THERE IS ANOTHER ROLE WITH THE TARGETING. ALTHOUGH WE MAY BE AFFECTING IN THE E-FIELD A SIMILAR NEURONAL POPULATION, BUT MIGHT BE ACTIVATING DIFFERENT CIRCUITS OR DIFFERENT CELLS OR DIFFERENT WAY. SO THIS STUDY SHOWS THERE IS THIS KIND OF DEPENDENCY, TIME DEPENDENCY BASED ON TMS TRIGGER. SO WE WOULD LIKE TO CLOSE THE LOOP ON THIS SIDE. THIS BRINGS US TO TWO LOOPS. WE NAMED THIS DUAL CLOSED LOOP APPROACH. I GUESS THERE MIGHT BE OTHER PEOPLE WHO AIM FOR THIS PURPOSE. THIS IS WHAT WE CALL IT. IN THE GUIDANCE TMS PROJECT WHICH JUST RECENTLY STARTED, THIS WILL BE TRIED IN THE NEXT FIVE YEARS. AND WE ARE TRYING TO MAKE THIS SETUP DUAL APPROACH TO HELP TREAT DEPRESSION. BECAUSE THAT IS AN IMPORTANT DISEASE AND THERE ARE REALLY STRONG HYPOTHESIS OF THE STIMULATION OF SINGLE PORTALS THAT COULD BE MAYBE HELPFUL. IN THE GUY-IN TMS PROJECT IS INDIVIDUALIZED. YES. AND, OF COURSE, WHAT WE STARTED WITH WAS THE HARD PROBLEM HERE, WHICH IS THE CLOSE-LOOP EEG. BECAUSE THE OTHER PART, THE CLOSED LOOP FMRI IS A HARDER PROBLEM. WHAT WE DID WAS START WITH A CAR BIN WIRE LOOP WITH SIMULTANEOUS EEG RECORDING THIS WAS MOSTLY DONE BY -- HE IS A BACHELOR'S DEGREE WITH THIS WORK. WE CAN SEE EEG RECORDING SIMULTANEOUS WITH MRI. WHICH ARE [INDISCERNIBLE] AND HERE WE SEE THE GRADING ART FACT IN BLUE AND BLACK IS THE REFERENCE SIGNAL. THEN WE CAN SEE THE ALPHA PEAK POWER QUITE CLEARLY. HE MEASURED THE EEG PHASE AND IN THE COMING CONFERENCE IN PORTUGAL HE IS GOING TO PRESENT HIS RESULTS. SUFFICE TO SAY IT IS POSSIBLE TO DO FACE, EEG FACE TRIGGERS. WE HAD THE TRIGGERS COMING FROM THE CLOSED UP DEVICE. SO WITH THAT, I WOULD LIKE TO END AND I THANKS MY GRANT AGENCIES AND CLABTORS AND ESPECIALLY DOCTOR ILMONIEMI FOR LEADING THIS WORK AND THE TEAM AT ACTION ALTO AS WELL. WE HAVE BEEN DOING A LOT OF WORK WITH THE EXPERIMENTS. AND WE WORK WITH MANY CENTERS FOR CLOSED LOOP EEG SITE AND THE FMRI SITE AND THESE PEOPLE HAVE BEEN INSTRUMENTAL FOR RUNNING OUR EXPERIMENTS AND THANK YOU FOR YOUR ATTENTION. [ APPLAUSE ] >>SO WITH THE TREKKER SOFTWARE, IF THERE IS SOME WAY OF BALANCING FOR EXAMPLE THE QUALITY OF THE IMAGING DATA THE USER UPLOADS WITH HOW ROBUST THE TRACKS ARE IN NORMATIVE SPACE. IF IT IS A BIG, WELL KNOWN TRACK. IF THE IMAGING DATA ARE BETTER YOU WOULD HAVE MORE CONFIDENCES. IS THERE SOME WAY OF BALANCING THOSE? >>THAT IS A VERY GOOD QUESTION AND, OF COURSE, TREKKER HAS A LOT OF PROBLEMS. I THINK I ALWAYS TRY TO CONVINCE PEOPLE THEY REALLY NEED TO HAVE SOMEONE WHO KNOWS THE LIMITATIONS OF TRACKTOGRAPHY. IF YOU ARE NOT SURE WHAT YOU ARE LOOKING AT, IT IS EASY TO BE CONVINCED THEY ARE RIGHT. THIS IS NOT A PROBLEM FOR NEUROSURGEONS BECAUSE THEY KNOW -- WHEN THEY LOOK AT TRACTOGRAPHS, THEY AUTOMATICALLY KNOW WHICH ONES TO BE WRONG. YOUR QUESTION IS VERY RELEVANT BECAUSE IT IS NOT KNOWN TO MANY PEOPLE. SO I SUGGEST A TRAINING OR COLLABORATING WITH PEOPLE WHO ARE TRAINED. >>THANKS. ANOTHER QUESTION? >>YES. I MIGHT HAVE A QUESTION. DOES YOUR TRACTOGRAPHY, YOUR REAL TIME NAVIGATION TAKE INTO ACCOUNT COIL ORIENTATION? >>I'M SORRY. COIL ORIENTATION, IS THAT TAKEN INTO ACCOUNT? >>WE ARE EDITING E-FIELD, THE RESULTS I SHOW DON'T TAKE INTO ACCOUNT THAT. >>ALL RIGHT. WONDERFUL. THANKS VERY MUCH. >>THANK YOU. >> [ APPLAUSE ] . >>WE ARE TELLING YOU ABOUT ALL KINDS OF IMAGING. >>THANK YOU FOR THE NICE INTRODUCTION. THESE ARE MY AREAS OF INTEREST. I HAVE A LICENSED AGREEMENT WITH DSMI. THIS IS THE OUTLINE OF MY PRESENTATION, BUT BEFORE I GO INTO MY PRESENTATION, THE FIRST THING I WANT TO DISCUSS IS WHY WE WANT TO COMBINE TMS MRI AND EEG AND WHY IT IS IMPORTANT FOR BASIC NEUROSCIENCE. I WILL TALK ABOUT THE FUTURE IMPROVEMENTS OF TMS/FMRI EXPERIMENT. THIS IS THE WORK I HAVE BEEN DOING. THESE ARE TWO PROJECTS, MULTICHALLENGE -- TOWARDS THE END OF THE PRESENTATION I WILL SWITCH GEARS AND TALK ABOUT INTERACTIONS BETWEEN THE SYSTEMS AND HOW THEY AFFECT THE IMAGE QUALITY AND THE SAFETY. SO COMBINING TMS WITH FMRI HAS THE POTENTIAL TO INCREASE OUR UNDERSTANDING OF THE RELATIONSHIPS BETWEEN BRAIN NODES AND WHY IS THIS? WE KNOW FMRI IS A PERFECT TOOL TO KEEP TRACK OF BRAIN ACTIVITY. IT HAS A HIGH SPECIAL RESOLUTION TO KNOW WHERE THE ACTIVATION COMES FROM. EEG IS GREAT TO KEEP TRACK OF THE BRAIN ACTIVATION BASED ON THE NEURAL RESPONSE, IT IS CAPABLE TO KEEP TRACK OF THE TIMING. IT HAS A GREAT HIGH TEMPORAL RESOLUTION. IT IS DIFFERENT TO KNOW WHERE THE ACTIVATION COMES FROM. THE LOCALIZATION IS VERY DIFFICULT. LUCKILY WE HAVE TMS. BEFORE THIS, I WANT TO SAY THESE TWO, THE EEG AND FMRI ARE VERY COMPLEMENTARY. AND IMAGING METHODS. WE HAVE TMS THAT CAN ACTIVATE IN A NONINVASIVE WAYS IN VERY WELL DEFINED TIME POINTS. IT CAN ADD A FACTOR TO THE EEG AND FMRI. I THINK ADDING IT CAN BRING EVERYTHING TOGETHER TO FINALLY A BLAINING TOOL. -- A BRAIN MAPPING TOOL. THIS IS GREAT FOR NEUROSCIENCE. CLINICAL REV LANCE FOR THE CLINICAL APPLICATION OF TMS. WE KNOW 20% OF AMERICANS SUFFER FROM MENTAL HEALTH DISORDERS. ANXIETY DISORDERS ARE MOST COMMON. MAJOR DEPRESSION AFFECTS MORE THAN 17 MILLION OF PEOPLE IN AMERICA AND IN THE REST OF THE WORLD, OF COURSE. WE HAVE HEARD THE TREATMENTS ARE USUALLY MEDICATIONS AND THEY CAN HAVE SEVERE EFFECTS ON THE PATIENT'S LIFE. THERE ARE MANY PATIENTS THAT DON'T FIND ANY RESPONSE TO THESE MEDICATIONS. SO LUCKILY, THE FDA HAS APPROVED THE BRAIN STIMULATION TREAT THESE MENTAL HEALTH PROBLEMS. THERE IS A LOT OF EVIDENCE THAT SAYS THE EFFICACY OF THESE TREATMENTS DEPEND WHERE WE HAVE STIMULATED. AND WHEN WE ARE STIMULATION. WHEN WE ARE APPLYING THE STIMULATION, THE BRAIN STATE WHEN APPLYING THE STIMULATION. TO ENHANCE THE EFFICACY OF THE TREATMENTS WE HAVE TO COMBINE THE SPECIAL NFLGS WITH THE APPLICATION OF THE TMS. AS I SAID BEFORE, I THINK THE BIGGEST CHALLENGE COMBINING TMS AND FMRI IS THE LACK OF DEDICATED INSTRUMENTATION. IF YOU SEE AVAILABLE SETUPS THAT WERE AVAILABLE BEFORE 2015, YOU HAVE 32 CHANNEL CORD. AND UNFORTUNATELY THESE 32 CHANNEL COILS, WHICH MOVE FMRI TO A NEW LEVEL OF SIGNIFICANCE, THEY CANNOT BE USED WITH THE TMS BECAUSE THERE IS A LACK OF SPACE FOR THE TMS. WE KNOW THEY ARE GREAT FOR FULL HEAD COVERAGE. THEY OFFER THE IMAGES THAT REALLY HAVE IMPROVED THE TIME RESOLUTION OF THE FMRI. SO THE COILS WE WERE ABLE TO USE THE SIX CHANNEL COIL AND BIRD CAGE COIL. IT IS VERY TRICKY BECAUSE YOU HAVE TO KNOW WHERE YOU ARE STIMULATING DURING THESE EXPERIMENTS. FRMPL, THE BIRD CAGE COIL DID NOT ALLOW ANY PARALLEL IMAGING CAPABILITIES. FOR MY PH.D. I DEVELOPED A COIL PLACED UNDER THE TMS AND ON TOP OF THE SUBJECT. WE SOLVED MOST OF THE PROBLEMS. WE ENABLED FOR THE FIRST TIME THIS TYPE OF IMAGES. OUR WORK WAS PRESENTED IN OUR PUBLICATION IN 2015 AND WE WERE ABLE TO SHOW WE ACHIEVED FIVE TIMES MORE SNR THREE CENTIMETERS TO THE COIL COMPARED TO THE BIRD CAGE COIL. WE WERE ABLE TO SHOW 42% OF THE BRAIN IS IMAGED WITH THE SAME SNR AS THE BIRD CAGE COIL. WE DID AN ASSESSMENT OF THE -- WHEN WE ACCELERATE IMAGES WE LOSE SNR. THE QUARTER ROOT OF R, WE CANNOT GET RID OF THAT. THERE IS THE GEOMETRICAL FACTOR THAT IS AN INDICATOR FOR THE FEASIBILITY OF REDUCING ACQUISITION TIME BY R. WE STUDIED G FACTOR OF OUR COIL. WE PLACED THE COIL HERE AND CALCULATED THE G FACTOR AND WE SAW THE ACCELERATION FACTOR 2. WE DID NOT HAVE AN INCREASE IN THE G FACTOR AND WE DID NOT SEE ANY REDUCED SNR IN THE IMAGES ANY OF THE 3, 4, OR 5 CENTIMETERS AWAY FROM THE COIL. HOWEVER, FOR THE ACTIVATION FACTOR THREE, WE SAW -- AT 4CENTIMETERS. THESE HERE YOU CAN SEE ARE ACTIVATION MAPS OF OUR RESULTS. I THINK THE MOST IMPORTANT PERMANENT RESULT THAT WE GOT WAS THE FULL RESPONSE WAS CORRELATED TO THE TMS INTENSITY. SORRY, I FORGOT TO SAY WE USE FOUR INTENSITIES IN THIS STUDY. TWO WERE OTHER THRESHOLD, ONE AT THRESHOLD AND ONE UNDER TLOESH HOLD. -- THRESHOLD. NOW WE CAN SAY THERE IS A NEW STATE OF THE ART. YOU CAN USE TWO COILS TO HAVE ONE WITH STIMULATION AND ONE ON THE OTHER PART. SO IT IS THEE AXIS TMS COIL BECAUSE IT CONSISTS OF THREE COIL, X, THE Y AND THE Z. # HERE YOU SEE THE AIR COOLING TUBES, EVERYTHING IS EMBED AND ATTACHED TO A TUBE THAT IS GOING BE USED FOR FIXATION. THEN WE WE USE A SAFETY NET. THIS COIL HAS BEEN DESIGNED AND DEVELOPED BY US AND TRISTAN TECHNOLOGIES AND THE OVERVIEW OF THE SYSTEM IS PRESENTED HERE. THE ARROWS FOR THE MULTICHANNEL TMS SYSTEM AND THE WITHHOLD HEAD. SO IN THE LEFT PART OF THE IMAGE, YOU SEE ALL THREE OF WHAT THE RF COIL LOOKS LIKE. THE DESIGN WAS TO HAVE HOLES SO WE COULD REPLACE THE TMS COILS DIRECTLY ON THE HEAD. SO WE NEEDED TO HAVE A VERY COMPACT MODEL. SLIGHT INCLINATION OF THE HEAD TO PLACE ELEMENTS ON THE POST STIMULATION OF THE HEAD. FOR THE COIL, WE ARE REPLACING ALL ELECTRONICS SO DWOENT HAVE ANY CABLES AROUND TO MESS UP WITH THE MULTICHANNEL DMS. THEN WE PLACE THE PREAMPLIFIERS ON THE SIDE OF THE COIL AND THE REAR PART. SO WE HAVE DONE A PERFORMANCE. WE DID -- WE HAVE CALCULATED THE SNR PERFORMANCE AND COMPARED THEM WITH A 32-CHANNEL WITH TWO COMMERCIAL COILS, 32-CHANNEL COIL AND 20-CHANNEL COIL AND WE CAN SEE HERE, I'M SHOWING YOU THE VALUES FOR THESE SLIDES. WE ARE CLOSER TO THE PERFORMANCE OF THE 20-CHANNEL COIL AND 32-CHANNEL COIL BECAUSE WE HAVE SEEN SOME CASE IN THE SNR WHERE WE HAVE THE TMS COILS. I JUST WANT TO POINT OUT WE HAVE DONE ALL THESE MEASUREMENTS WITH THE TMS UNITS HERE WHICH ARE ONLY C COILS. HERE YOU HAVE THE PILOT IMAGING CAPABILITIES COMPARED TO THE 32 CHANNEL AND 20 CHANNEL. WE HAVE SHOWN WE CAN SEE THAT IT IS VERY SIMILAR TO THE 32 CHANNEL. MUCH BETTER THAN THE 20 CHANNEL COIL. WE CAN USE TWO, THREE, AND FOUR WITH TWO BY TWO AND THREE BY THREE WITHOUT THE SNR SIGNAL. TO SUM UP THIS MULTICHANNEL TMS PROJECT, WE SAID IT IS VERY DIFFICULT TO ENSURE THE SAME TARGET. IT IS GREAT WORK WITH MULTICHANNEL TMS IN THE SCANNER. FOR THAT, WE HAVE BUILT THE TMS MR COIL. IT WILL ACHIEVE THE FULL BRAIN COVERAGE THAT WE NEED AND PERFORMS CLOSE TO 20-CHAN RECEIVE ARRAY IT WILL HAVE THE CAPACITY TO USE HIGH ACCELERATION FACTORS TO HAVE A MULTICHANNEL TMS TO USE WITHOUT MOVEMENT. SO NOW I'M GOING TALK ABOUT THE SECOND PROJECT. SO NOW THERE IS A LOT OF DEVELOPMENT IN FLEXIBLE COILS, THE IDEA IS TO HAVE JUST A CAP TO ALLOW TO USE THE TMS TOGETHER. IT IS A CAP. IT BECOMES EASY TO ADD THE EEG. THAT IS WHAT WE THOUGHT AND WE PROPOSED THAT AND IT HAS BEEN THE RF EEG CAP IS SHOWN IN BLUE. IT WILL BE ATTACHED TO A EEG CAP. WE WILL HAVE 24 CHANNELS. THINK KNOW KNOW. >>HOWEVER, YOU'VE SEEN THE STANDARD FMRI MESSAGE, WE WERE ABLE TO PERSIST OR TO GET RID OF THIS ARTIFACTS AND I WANT TO TELL YOU HOW CLOSE TO THE TELOMERE THEY WERE CAPTURED AND ALSO IN THE SIGNAL METHODS THAT WE USE, SO IN CONCLUSION WE DID NOT SEE A DEGRADATION OF THE EEG DATA CAUSED BY [INDISCERNIBLE]. WE ALSO DID AN ASSESSMENT OF THE QUIEWLT OF THE IMAGE, AND THIS IS THE CHANNEL, THAT'S WHY YOU DON'T HAVE FULL BRAIN COVERAGE YET AND THEN WE PLACE THE ELECTRODES COMPARED TO HOW WE DHAINCH TO THE ORIGINAL SNR MAP AND WE DIDN'T SEE A DIFFERENCE WHEN WE PLACED THEM HERE. WE HAVE REPORTED IN 2020 THE P1 EFFECT THAT I WILL TALK ABOUT THE AT END OF THE PRESENTATION BUT WE DID NOT SEE ANY NEW EFFECTS FROM THE--WE DIDN'T SEE ANY EFFECT SAYS OF THE QUALITY OF IMAGE. SO TO SUM UP WHAT WE WANTED TO,A CHIEF, WE THOUGHT THE RPG CAPITAL THAT WE WANT TO,A CHIEF IS HAVE A FULL HEAD COVERAGE, HIGH VALUE IMAGE FACTORS WITH LOW DEFECTORS, WE WANT TO HAVE MORE FLEXIBILITY FOR THIS FMRI AND EXPERIENCE. AND WE WANTED TO HAVE THIS INTERNATIONAL CLASSIFICATIONICATION WITH EEG. SO OUR RESULTS HAVE SHOWN THAT WE DID NOT SEE ANY DETERIORATING EFFECTS AND WE PLACED THEM ON THE RF ELEMENTS. WE DID NOT SEE ANY EFFECTS ON THE EGFR SIGNAL AND WE DIDN'T SEE NEW EFFECTS ON THE MR IMAGING SO WE DO BELIEVE THAT THE RFEG CAP IS THE SOLUTION TO OPTIMIZE COMPARING TMS FMRI AND ELECTROPHYSIOLOGICAL DAT A. SO NOW LET ME CHANGE A BIT OF THE TOPICS AND I WANT TO DISCUSS A BIT INTERACTIONS BETWEEN THE SYSTEM SYSTEM. SO I'M JUST GOING TO TALK ABOUT TMSRA AND WE HAVE 2 VERY STRONG FACTORS THAT IS THE TMS AND THE MR, WE ARE PUTTING THEM TOGETHER IS THEY HAVE TO BE PART OF THE SAME GROUP. SO AS YOU KNOW TMS PRODUCES HIGH FER ENSEL IN SHORT TIMES AND IT PRODUCES FIELDS UP TO TESLA RANGES AND THESE ARE GOING TO LIVE INSIDE OF THE 3 TESLA FIELD OF THE MR SYSTEM. THIS IS GOING TO HAVE AFFECT ON THE OTHER SYSTEMS BECAUSE THEY ARE BOTH VERY SENSITIVE TO ANY MAGNETIC FIELD. SO THIS IS A SUMMARY OF THESE INTERACTIONS, I HAVE DIVIDED THEM WITH RESPECT TO WHICH PART OF THE SYSTEM OF THE MR SYSTEM IS INTERACTING AND WHICH IS THE CONSEQUENCE OF THIS INTERACTION OF THE IMAGE EFFECT OR SPECIFICITY CONCERN. SO I'M GOING TO GO INTO DETAILS, ALL OF THIS. SO BASICALLY THE EFFECTS, THE EEIVETS THAT HAVE AN IMPLICATIONS IN THE IMAGING QUALITY. SO AS I SAID BEFORE, WE HAVE MODULATING SO WE WILL HAVE BIG GEOMETRICAL DISTORTIONS, WE KNOW THIS CAN BE CORRECTED BUT UP TO A CERTAIN DEGREE AND THIS IS ALWAYS A BIT OF THE QUALITY OF THE SYNAPSE, HOWEVER IF THESE DISTORTIONS ARE SO HUGE AND WE HAVE SIGNATURES NILE VIRUS DROP OFFS THERE'S NO WAY TO RECOVER THEM. SO THE ONLY THANS WE HAVE IS AUXILIARY IMAGING, WE HAVE TO USE THE SPACING SO THAT THE DISTANCE OR THE FACING OF THIS IS MINIMIZED FOR BOXES FOR NEIGHBORING BOXES IN THE DIRECTION. THE ONLY PROBLEM IS THE FASTER PRECISION METHODS OF COURSE REQUIRES VERY HIGH SNR. SO WE HAVE WHAT WE NEED TO SPECIALIZE OUR--TO BE ABLE TO ACQUIRE THE SIGNAL FASTER. DID EMPLOY NOW, I WANT TO TALK A LITTLE BIT ABOUT THE TORQUES THAT WE APPLIED IN THE SCANNER, THE TMS WILL TRY TO ALIGN TO THE BUZZIER FIELD AND THIS IS DUE TO STRONG LARGE FORCES. WE HAVE A HUGE TORQUE SO WE NEED TO FIXATE IT OTHERWISE IT'S GOING TO VIBRATE OR IT CAN BE A SAFETY ISSUE. RESPIRATORY SO WE HAVE SOLUTIONS OUT THERE BY VENDORS AND 1 OF THE CONSEQUENCES OF THIS VIBRATION IS THIS HUGE SOUND THAT IT PRODUCES. SO BECAUSE THE SOUND IS ALSO PRODUCED INSIDE THE BOARD, THE BIEWRD ACTS LIKE A SPEAKER SO THE PRACTICAL RECOMMENDATION IS SOME NOISE ABSORBING MATERIAL LINING FOR THE TORQUE. AND WE HAVE THE MOTOR INTERACTION AND THIS WILL HAVE OF COURSE AN EFFECT ON IMAGING, RIGHT? SO THERE IS THIS PAPER, THIS SEMINOLE PAPER, WE CAN TALK ABOUT IT FROM 2003 BUT I REALLY RECOMMEND YOU TO KNOW WHEN YOU ARE PLACING YOUR PULSES, SO WE DID THIS WORK WITH THE ISOMERS AND WE PLACED THE PROCESS IN DIFFERENT MOMENTS IN THE SEQUENCE, SO HERE, WE PLACE IT AT 0, JUST AFTER THE TRIGGER, 20 AND DWNCHT POINTS AND THE MOMENT I WANT TO CLOSE TO THE RF POLICIES OF THE IMAGING GRADIENTS, THEN WE HAVE MADE SIGNAL DROPS, THIS IS A MULTIBAND ACQUISITION SO WE YOU HAVE EFFECTS ON BOTH THE SLICES THAT ARE APPLIED BUT AS I SAY THAT RECOMMENDATION, YOU HAVE TO KNOW WHEN YOU ARE PLACING YOUR TMS PULSES, YOU HAVE TO KNOW WHAT IS HAPPENING IN YOUR SEQUENCE. THEN I WENT TO REPORT THIS EFFECT ON THE B1 PLAOF THE AS DISCUSSED BEFORE, SO BECAUSE WE ARE THIS HUGE VOLTAGE PULSES RF PULSES, THIS IS GOING TO INDUCE A RECURRENCE ON OVER TMS. AND SO EVEN THOUGH WE MIGHT BE VERY NICE FOR THE VOLUME CORD, THESE ARE GOING TO PRODUCE ANOTHER FIELD WHICH WILL BE SUPER IMPOSED TO THE B1 PLAZ MIDS MID. SO WE'RE GOING TO HAVE ENHANCEMENTS IN THE CASE OF THE FIELD, WHICH MEANS WE WILL HAVE LESS SIGNAL OR LESS ON THESE REGIONS, THE GOOD NEWS IS THIS EFFECT IS PRETTY CHAL O, IN IS VERY FAST WITH RESISTANCE, BUT IT'S IMPORTANT TO KEEP IT IN MIND OF COURSE WE ARE THINKING THIS, WE THINK OF THE EQUAL CHANGES. THE GOOD NEWS IS THIS IS THE INFORMATION THAT WE REPORTED THIS IN 2020, THE GOOD NEWS IS THIS IS NOT THE CASE, WE ARE NOT CHANGING THE DISTRIBUTION SIGNIFICANTLY, WE SHOWED THAT ONLY--LESS THAN 1 [INDISCERNIBLE] WAS CHANGED WHEN THE PLACED THE TMS IN THE VOLUME. AND FINALLY--SO THE REFERENCE ROLE IS JUST A LOOP, IT IS ALWAYS THE SAME DISTANCE WHICH CHANGES THE TMS LOOP FROM 1 TO EACH OTHER. WE ALSO DID SOME MEASUREMENTS OF THE NORMALIZED CCNR, WE TOOK OUT THE BAY 1 SPECIFIC SO THERE'S OTHER SEARCH SIMULATIONS ARE HEAR FOR MEASUREMENTS SO WE SAW A SIGNIFICANT DROP HERE IN THE MIDDLE OF THE COIL, THIS IS LIKE [INDISCERNIBLE] FROM THE MSR CORONAL SLICES SO WE HAVE IMPORTANT DROPS HERE AND 10 WE SAW THEM THE SAME MEASUREMENTS. SO WHAT WE SEE IS THAT THE EFFECTS OF THIS HAS DEGREES, INCREASES WHEN THE TMS IS FARTHER FROM THE [INDISCERNIBLE]. SO OVERALL EXPLANATION FOR THESE EFFECTS IS THAT IT SAYS THE MRSENIOR PRODUCES THE CURRENTOT DMS AND THESE ARE SUPER IMPOSING THOSE FOR THE WORK AND WHY WE SEE THESE EFFECTS. SO WE WANT TO SHOW YOU WHAT WE FIND, WE HAD SIMILAR EFFECTS FROM THE MEASUREMENTS AND THE SIMULATIONS AND WE CAN SEE THAT BEFORE THE MEASUREMENTS, 1 CENTIMETER AWAY FROM THE TMS GROUP. WE HAVE CHANGES OF ABOUT 15--LESS THAN 15% HOWEVER THE SIMULATIONS GAVE US HIGH SNR DROPS SO WE HAVE TO CLASSIFY WHERE THESE COME FRU BUT IT IS STILL INTERESTING. SO I TALK ABOUT THE SPECIALIZATION HOW WE SAID THEM, HOW WE ENABLE THE IMAGING, AND WITH THE ACTIVATION FACTOR 2 I HAVE FOUND THE WORK THAT WE ARE DOING HERE AT THE CENTER, WE ARE TRYING TO ACHIEVE FULL COVERAGE AND WE WANT TO,A LOW FINALLY THE TRACKING OF THE HOT SPOTS IN CASE THE MOVE SAYS AND SO THIS IS A MULTIINTEGRATED SYSTEM AND THEN I HAVE PREPERRED THE RFEG CAP WHICH WILL DO TD FULL COVERAGE AND ENHANCE THE FLEXIBILITY OF THE EXPERIMENTS AND INTEGRATE EEG AND OF COURSE IF IT'S MULTITALENTED EMS FOR--FOR EQUAL USE THAT ARE FOCUSING OF THE HOT SPOT IN CASE OF A PATIENT MOVEMENT AND THEN I DISCUSSED THE INTERACTIONS, I WANT YOU TO TAKE THEM INTO CONSIDERATION, THERE IS WORK TO BE DONE AND BE ANALYZED IT WILL BE GREAT IF WE KEEP WORKING IN THIS FIELD. AND WITH SLIDE I WANT TO THANK MY COLLABORATORS, OUR TEAMERS, OUR INDUSTRIAL COLLABORATORS AND I'M THANK YOU FOR YOUR ATTENTION AND I AM HAPPY TO ANSWER YOUR QUESTIONS. [ APPLAUSE ] >>I MIGHT HAVE A QUICK SILLY QUESTION, BUT THANK YOU IT WAS INFORNLAATIVE FOR ME, SO THE PURPOSE OF THE INTEGRATION OF EEG IS IT FOR THE NEUROFEEDBACK PURPOSE OR TO DETECT OR TO DETECT-- >>IT'S NOT LIKE THE CLOSED LOOP DIRECTION, LIKE WHAT WE WERE TALKING ABOUT THE CLOSED LOOP, DUAL CLOSED LOOP DIRECTION SO WHAT WE WANT TO DO IS WITH THE EEG, KNOW WHEN WE HAVE APPLY THE TMS AND EVERYTHING WE WANT TO DO EVERYTHING WITH THE SCANNER, SO WE WANT TO KNOW WHERE WE ARE APPLYING THE TMS, AND WITH THE FMRI AND WITH THE EEG ACCIDENT WE WANT TO FIGURE WHEN THE TMS PULSES AND WE WENT ON TO SEE IF THERE'S A DIFFERENCE, BASED ON FMRI ACCURACYS THAT WE OBTAIN. >>IS IT CONVENTIONAL EEG? >>WELL IT'S CONVENTIONAL, COMPATIBLE EEG, BUT YES, THE WHYED IS TO DO THIS FOR ALL THESE ARTIFACTS AND REMOVE EVERYTHING ONLINE, AND GIVE IT THE FACE WITH--WHATEVER FEATURE WE WANT TO DEFINE, IT'S GOING TO BE USED TO TRACK OR TO TRIGGER THE TMS AND THEN SEE IF WE CAN SEE DIFFERENCES. >>THANK YOU. >>YES. NYES, SO I HAVE--DO YOU PLAN ON FOR THE RFEEG HEAD CAP HAVING SHIMMING CAPABILITIES TO TRY TO HELP SOME OF THE [INDISCERNIBLE] IN HOMOGENERATED AITY ISSUES? FOR EXAMPLE, THOSE COIL VS A UNINTERRUPTED PATH FOR DC CURRENTS SO I WONDERING IF YOU HAVE-- >>NO, WE HAVE NOT PLANNED THEM WITH THIS, WE HAVE NOT PLANNED THEM WITH THIS, THANK YOU. >>VERY IMPRESSIVE. CAN YOU ELABORATE A LITTLE BIT ABOUT [INDISCERNIBLE], CHANNEL, IT LOOKS LIKE MAYBE HOW MANY? NWE WILL HAVE 60 ELEMENTS AND EACH OF THESE COILS ARE 3 COILS WHICH ARE THESE 3 ACCESSING TO THE COILS, I WENT FAST THROUGH EVERYTHING, IT'S A LOT OF INFORMATION AT ONCE BUT EVERY STIMULATION UNIT, I WANT TO CALL IT LIKE THAT BECAUSE OTHERWISE WE HAVE TOO MANY COILS AND THEY ARE 16 OF THEM ALL OVER THE HEAD, I CAN SHOW YOU THE FIGURES. >>CAN YOU STEER THEM? LIKE STEER THE STIMULATION-- >>WHAT WE WANT TO STEER IS THE INDUCING FEED, WE DON'T WANT TO MOVE THEM IN THE SCANNER. YEAH, WHAT WE ARE GOING TO CHANGE IS THE CURRENTS THAT WE ARE PASSING THROUGH THE ELEMENTS. THAT'S WHAT WE ARE GOING TO STEER BUT WE DON'T WANT TO MOVE THEM. >>HERE THAT'S THE BEST SHOT. THESE ARE THE STIMULATION UNITS. HERE WE ARE JUST PLACING SOME PLACE HOLDERS, THESE ARE ALL SEQUENCED TO DO THE PERFORMANCE. WE REALIZE THAT PLACING THE ACCESS COILS DELIVERS THE SAME INFORMATION FOR THE SNR PERFORMANCE. THAT'S WAWE DID BUT THE FINAL SYSTEM IS GOING TO LOOK LIKE THIS. HERE IT IS. THERE ARE 16 OF THEM, THAT'S WHY THERE ARE 16 HOLES AND YES, THE ELEMENTS GO THROUGH IT. THROUGH THE RF HOLES ARE REALLY SURROUNDING THEM. DO YOU NEED AN INDIVIDUAL TMS CAPACITIOR FOR EACH CHANNEL, EACH 1 HAS A STIMULATOR, IT'S A 48 SIMULATOR RUN, THAT'S TRUE. WE SIT EVERY SINGLE 1, IT'S A HUGE SYSTEM, YEAH. >>THANKS. >>I KNOW WE'RE RUNNING A BIT LATE SO WE CAN APPROACH THE SPEAKER AFTERWARDS BUT I DON'T KNOW THE FORMAT OF THE PROFFERED PAPERS BUT WE'RE OVER TIME LUCIA, THANK YOU VERY MUCH. [ APPLAUSE ] ALL RIGHT AS JULIAN GETS SET UP HERE ON THE TALK TWISTED PAIR RECEIVER COILS FOR A COMBINED TMS/EEG/FMRI SYSTEM. >>THANK YOU FOR THE INTRODUCTION. TODAY I WILL TALK ABOUT THE WORK I'VE DONE WITH THE RECEIVER COILS THAT CAN HOPEFULLY BE USED FOR SUCH A COMBINED SYSTEM. SO HERE ARE MY DECLARATIONS. SO AS MULTIMODAL IMAGING TECHNIQUES BECOME MORE COMMON AS WE'VE SEEN IN MANY OF THE PREVIOUS TALKS, THE GET FILLED WITH LESS AND LESS SPACE FOR LARGE SCALE RECEIVER RATES BUT THERE'S A CLEAR NEED TO HAVE THIN AND FLEXIBLE CLEAR ELEMENTS AS YOU BUILD THOSE LARGE RECEIVER COILS IN THESE VERY TIGHT FITTING AREAS. SO FOR EXAMPLE WHEN YOU WANT TO COMBINE EMS WITH EEG/FMRI, BECAUSE AS WE'VE SEEN WE'VE USED THIS PICTURE, IT'S LIMITING WHEN YOU HAVE THIS BIG BULKY COMMERCIAL COIL AND WITH SOMETHING LIKE A CONFIRMAL HEAD KOIM, YOU CAN UNLOCK THE FULL POTENTIAL OF RANGE OF MOTION OR THAT TMS COIL. AND 1 OF THE ADDED BENEFIT SYSTEM THAT BECAUSE WE TRY TO MAXIMIZE FOR THE PROXIMITY OF THE MAXIMIZE THE PLACEMENT OF THE TMS COIL, WE ALSO GET SNR BENEFITS BECAUSE AS RECEIVER COILS GET CLOSER TO THE BODY, YOU DO GAIN SNR AND THAT MIGHT BE BENEFICIAL IN THE SENSE THAT YOU GAIN BETTER DIAGNOSTIC QUALITY IMAGES BY JUST INCREASING--ESSENTIALLY GETTING CLOSER TO THE IMAGING AREA YOU WANT TO IMAGE. AND I WANT TO SHINE SOME LIGHT ON SOME OF THE PREVIOUS WORK THAT'S BEEN DONE IN COILS SO HERE YOU SEE SOME SCREEN PRINTED RECEIVER COILS THAT HAVE A LOT OF BENEFIT AND A LOT OF IMPROVEMENTS FOR PEDIATRIC IMAGING. THERE'S ALSO BEEN A LOT OF GREAT WORK IN ESSENTIALLY USING IT ON ELASTIC TUBES TO BUILD THESE VERY THIN STRETCHABLE AND ELASTIC RECEIVER COILS OR LASTING BENEFIT OR ANYTHING OF JOINTS. AS WE'VE SEEN IN THE PREVIOUS TALK, THERE'S ALSO BEEN A LOT OF WORK ON THESE COAXIAL COILS THAT USE THIS COAXIAL TRANSMISSION LINE THAT'S FLEXIBILITY TO ESSENTIALLY ACHIEVE A VERY FIN AND FLICKSIBLE RECEIVER COIL AND THEY'VE BEEN SHOWN FOR HANDLING THE GLOVER AWAY AND RF/EEG CAP EVEN WITH ALL THE INTERFACE ELECTRONICS. AND THERE'S ALSO THE EEG AIR COILS THAT USE THESE INTEGRATED CAPACITIVE WIRES AND [INDISCERNIBLE] AMPLIFIERS TO ACHIEVE A VERY THIN AND FLEXIBILITY RECEIVER COIL THAT ALSO HAS VERY ADEQUATE FINE TUNING PERFORMANCE. SO KIND OF TAKING INSPIRATION FROM THE COAXIAL COILS AND THE AIR COIL, I ESSENTIALLY DESIGNED A TWISTED PAIR RECEIVER COIL THAT IS VERY THIN AND FLEXIBILITY CAN AND HAS THE IMAGING TO BE USED IN THIS SYSTEM. SO IN WORK I AIM TO COMPARE THE TWISTED PAIR COIL TO A COAXIAL AND STANDARD COIL IN TERMS OF IMAGING PERFORMANCE AND ALSO IN TERMS OF SAFETY TO INSURE THAT WE CAN ACTUALLY PLACE THIS COIL IN YOUR PATIENT AND AFTER A VERIFYING ITS PERFORMANCE AND SAFETY, PROCEEDED TO BUILD A 15 CHANNEL HEAD ARRAY THAT HAS FULL COVERAGE OF THE BRAIN AND CAN EVENTUALLY BE MODIFIED TO THE ELECTRODES AND BE COMBINED IN A SYSTEM, BUT TO GET TO A SPECIFIC COIL, YOU NEED TO START WITH PTFD TWISTED WIRE. SO IF YOU KNOW A LITTLE BIT ABOUT ELECTRICAL ENGINEERING IF YOU HAVE TBO PLATES AND PUT A DIALETTIC BETWEEN THEM, YOU GET A CAPACITY, IF YOU DID IT WITH A WIRE, YOU GET A FLEXIBLE CAPACITIOR AND THEN YOU CAN FORM IT INTO A LOOP AND TURN IT INTO A CANNED WHAT AND YOU MAKE 1 CUT WHERE YOU INTERACT THE COIL WITH THE SCANNER AND ADD THE INTERFACE ELECTRONICS AND ANOTHER GAP AND OPPOSING WIRE AND THIS ALLOWS IT TO BECOME RESIDENT AND SENSITIVE TO THE MOTOR INDUCED SIGNALS CAUSED BY THE SPINS. WITH ALL THESE ELEMENTS, POTENTIALLY ONLY TAKE UP 1 PBT 28-MILLIMETERS OF SPACE, WE STILL HAVE WORK TO DO TO GET THE ELECTRONICS TO GET A LITTLE BIT THINNER. SO HOW ABOUT SNR PERFORMANCE, DO THESE COILS PRODUCE WELL, 1 METRIC WIEWSED TO USE TO SEE IF IT WORKED WELL, WAS THE RATIO QUALITY FACTOR WHEN THE COIL IS LOADED AND UNLOADED AND WE WANT THIS RATIO TO BE I GREATER THAN 2 AS THAT KIND OF SHOWS THAT THE SIGNAL THAT WE RECEIVE IS BODY NOISE DOMINANT. SO THE RATIO IS LOTS GREATER THAN 2, THAT MEANS MOST OF THEM IN THE SIGNAL IS COMING FROM THE BODY, AS YOU SEE HERE THE TWISTED PAIR RECEIVER COIL BECAUSE OF IT'S LOW DIALECT RICK, RECEIVES A LOADED TO KEY LOADED RATIO THAT'S GREATER THAN THAT OF A COAXIAL COIL DUE TO HAVING INS TRINSIC LOSS. SO HERE WE TAKE A SINGLE COIL IMAGE AND WE TACK A PROFILE AND LOOK AT THE SNR AND WE SEE THAT THE TWEOF THED COIL CAN FORM VERY WELL COMPARED TO CONTROL COIL AND WE SEE A LITTLE BIT OF REDUCTION IS NSNR PERFORMANCE DUE TO ADDED LOSSES AND WHAT ABOUT THE FULL SAFETY, DOES IT COIL--CAN YOU PUT THIS NEAR A PATIENT WELL, YOU CAN, SO HERE WE SO THAT THE TUNING PERFORMANCE HAD IS DONE BY ACTIVELY TUNING, FROM THE 2 STAINS WE SEE AT LEAST 30 DB ISOLATION AND THIS COULD BE BETTER BUT WHEN WE LOOK AT D1 MAPS WE SEE THAT A COIL ON A PHANTOM WE DO SEE ANY VERYIATION IN THE CLIPPING. AND WHAT ABOUT HEELTING SO THESE GET HOT, WELL WE PUT 15 OF THEM IN AN ARRAY AND THEN WE RAN A HEAT SEQUENCE UNDER THE SCANNER AND WE DID NOT SEE ANY SIGNIFICANCE OR HEAT SPOTS EVEN AFTER THIS VERY INTENSE OF HEAT SEQUENCE. SO WITH ALL THAT IN COMBINATION, WE DECIDED TO PUT SOME OF THESE TWISTED PAIR ELEMENTS ON A NOMEX SKITTOMA CAP TO FORM THIS 15 CHANNEL HEAD ARK RAY. AND IF YOU CAN SEE HERE ON A PERSON IT FITS COMFORTABLE, VERY THIN BUT YOU SLEEP APNEA AND OBESITYY A POTENTIAL PROBLEM HERE, THERE'S ALL THIS WIRING HERE SO WITH THIS CURRENT INTEGRATION, WE CAN'T PASS A COIL OVER IT BUT IF YOU WRAP THE COILS MORE LIKE BRAIDS INSTEAD OF A PONY TAIL, CAN YOU GET THE FULL RANGE OF MOTION FOR THE TMS COIL. HERE WE LOOK AT SNR DATA SO THE 15 CHANNEL ARRAY, CAN YOU SEE HAS A 2 TIMES SNR GAIN AT THE PERIPHERIES AND WE SEE IT HAS A NOISE CORRELATION THAT'S BETTER THAN THE E, G HEAD COIL AND WE WERE ABLE TO ACHIEVE THIS REALLY GOOD NOISE CORRELATION WITHOUT HAVING TO PUT THE AMPLIFIER SO CLOSE TO THE ACTUAL COIL. AND HERE ARE SOME 3D T1 IMAGES WE TOOK ON THE SCANNER WITH WITH 2 BY 2 ACCELERATIONING LEADING TO 2 MINUTES AND 40 SECONDS. SO TO CONCLUDE FUTURE WORK, JUST 15 CHANNEL ARRAY IN SNR AND SNR AND ALSO TAKEN--THEY TAKE THE MAPS THAT THE COIL WILL MAINTAIN SNR EVEN UNDER ACCELERATED CONDITIONS. WE ALSO HOPE TO INTERFERON-GAMMA T-CELLUALLY IMPLEMENT THE ELECTRODES OF THIS,A RAY AND DO FEASIBILITY AND SAFETY TESTING WITH EMS AND EEG TO INSURE PROPER SAFETY. SO I WOULD LIKE TO ACKNOWLEDGE MY ADVISORS, MY MENTORS AND MY UNDERGRADUATE STUDENTS WHO HAVE BEEN EXTREMELY VITAL IN THIS WORK. THANK YOU. [ APPLAUSE ] >>ALL RIGHT, LET'S LIMIT IT TO 1 QUESTION PERSPEAKER SINCE WE'RE WAY OVER TIME PLEASE? >>ONE QUESTION, ACTUALLY DID YOU HAVE A TO INVESTIGATE OR CONFIRM THE PRANCE OF THIS COIL IN EMERGING ITS OF MUTUAL OR DECOUPLING. JUST BY USING MORE NOISE AMPLIFIERS OR MECHANICAL ARRAY OR DID YOU HAVE A CHANCE TO COMPARE YOUR COIL WITH THE COAXIAL COILS. >>THAT'S A GOOD QUESTION, AND I HAVE A ABSTRACT FROM THE [INDISCERNIBLE] AND WHAT I SHOWED IS AT LEAST IF YOU USE THE SAME WORK AND THE SAME AMPLIFIER I DID NOT SEE A DIFFERENCE IN THE DECOUPLING PERFORMANCE BETWEEN THE TWISTED PAIR AND THE COAXIAL. >>THANK YOU. >>THANK YOU. NEXT SPEAKER READY? [ APPLAUSE ] >>ALL RIGHT, THANKS EVERYONE. I HAVE NOTHING TO DECLARE, SO STROKE IS THE LEADING CAUSE OF ADULT DISABILITY AND THE RECOVERY OF MOTOR FUNCTION IS IMPORTANT FOR GETTING BACK TO ACTIVITIES OF DAILY LIVING BUT PREDICTING MOTOR STROKE RECOVERY IS ACTUALLY REALLY, REALLY DIFFICULT FOR AN INDIVIDUALIZED PARTICIPANT AND ACCURATE ROGINOSEIS WOULD ENABLE FOR THE REALISTIC GOAL SETTING AS WELL AS MORE EFFICIENT ALLOCATION OF CLINICAL RESOURCES. SO IN ORDER TO SORT OF ADDRESS THIS, CATHY AND WINSTON IN 2012 CAME UP WITH THE PREP ALGORITHM WHICH PREDICTS THE POTENTIAL FOR UPPER EMILY MOTOR RECOVERY SO THEY FIRST TOOKA A BEHAVIORIAL SCORE AND IF THAT PARTICIPANT GOT ABOVE A CERTAIN THRESHOLD THEY PREDICTED A COMPLETE POTENTIAL FOR UPPER LIMB RECOVERY. IF THEY WERE BELOW A CERTAIN BEHAVIORIAL THRESHOLD THEY WENT TO TRANSCRANIAL MAGNETIC STIMULATION TO SEE IF THEY COULD ELICIT A MOTOR EVOKED POTENTIAL. AND IF THEY WERE ABLE TO, THEY PREDICTED THERE WOULD BE A NOTABLE UPPER LIMB RECOVERY AND IF THE MEP WAS ABSENT, THEY WENT TO MRI AND PREDICTED EITHER LIMITED OR NO RECOVERY. BUT WHAT IF, THE APPARENT ABSENCE OF AN MEP DOES NOT MEAN THEREYA A LACK OF REHABILITATION PROTENTIA AND COUPLED WITH THAT BECAUSE WE'RE TALKING ABOUT CHRONIC STROKE AND LESIONS, WHAT IF THE CHRONIC STROKE LESION IS NOT HOMOGEANIOUS AND THERE IS IN FACT TISSUE THERE THAT WE CAN STIMULATE? SO I WILL SHOW YOU A CASE REPORT STUDY WHERE WE DEMONSTRATE THAT NEURAL SUBSTRATES OF REHABILITATION DO EXIST IN THE MEP AND IN THE ABSENCE OF A SIGNAL AND 1 WEIGHTED T-IMAGE. SO HERE'S MY CASE REPORT ON 55 YEAR-OLD MALE POST STROKE AND PRESENTED WITH AFACIA AND UPPER AND LOWER MOTOR EXTREMITY PIM PAIRMENT. HERE YOU CAN SEE THE LESION ON THE T21 AND THE T28 IMAGES BUT BEFORE I GO INTO THE CASE STUDY REPORT, I WOULD LIKE TO TELL YOU ABOUT TIGER MRI, IT'S A NEW WAY TO LOOK AT CHRONIC STROKE LESIONS CROSS LINKING IF YOU LOOK AT THE T1 WAVE IMAGE, THE LESION IS MAINLY DARK AND IN THE IMAGE FOR YOU BUT IF YOU IF YOU CONTRAST BETWEEN THESE IMAGES YOU GET THIS TIGER SCORE AND I WILL ORIENT YOU AND I WILL CALL KAFITATION SO THESE ARE CSF FILLED SPACES THOSE ARE BOTH DAMAGED TISSUES SO THERE'S NO REAL ISSUE THERE. SO I WANT TO ORIENT YOU TO THESE BLUE AND GREEN REGIONS THAT I WILL CALL KAFITATIONAL AND I WILL DEFINE THOSE AS DAMAGE TISSUE WITHIN THE LESION BUT THEY MAY STILL CONTAIN LIVING CELL BODIES AND THOSE ARE THE AREAS THAT I THINK WE CAN TRY TO STIMULATE WITH TMS AND OTHER NEUROMODLATTORY TECHNIQUES, EVEN IN THE CHRONIC STROKE LESION TO TRY AND ILLICIT A RESPONSE AND LET'S SEE WHAT UPONS. SO IF WE COME BACK TO THE CASE REPORT STUDY YOU CAN SEE IN THE T1 WEIGHTED IMAGE IT'S VERY DARK AND INSIDE THERE IS QUITE A BIT OF KAFITATION IN THIS PARTICIPANT BUT THERE ARE ISLANDS OF POTENTIAL TISSUE RIGHT SO IF WE ZOOM IN ON THE SAGITTAL AND I WILL BASICALLY DO TMS ASSESSMENTS SO I WILL TARGET THE M1 AREA. AND YOU CAN SEE HERE THAT M1 AREA WOULD BE KIND OF IN HERE, THERE'S NOT MUCH OF ANY SIGNAL THERE ON THAT T1. IF YOU LOOK AT THE TARGET IMAGES, YOU CAN SEE THIS LITTLE HOOK. THAT'S WE WILL TRY TO TARGET DP IF WE LOOK AT PROFUSION IMAGING THAT IS INDEED PROFUSED. SO WE ARE GOING TO COLLECT TMS DATA BOTH SINGLE AND PAIR PULSEMENT AND WE WILL CONTRACT THAT DURING LIPSE AND [INDISCERNIBLE]. SO WE WILL DO THAT DURING THE ENGAGEMENT OF THE HAND SO EVEN THOUGH THEY HAD A CHRONIC STROKE LESION WITHIN M1, THEY WERE ABLE TO GRAB THE HAND, IT WAS DIFFICULT, WE HAD TO TAKE SEVERAL BREAKS BUT WE DID IT FROM THE LESS AFFECTED AND AFFECTED HANDS. SO LET'S FIRST LOOK AT THE NONLESIONED HEMISPHERE. SO IF WE STIMULATE ON THE NONLESION HEMISPHERE WITH THE SINGLE PULSE, WE WILL SEE A NICE BIG MEP AND THAT'S WHAT WE GET AND I WILL MARK THE AMPLITUDE BASED WITH THESE RED BARS. SO IF WE THEN CONDITION THAT MEP FROM A PULSE FROM THE LESIONED HEMISPHERE, WE DO STILL GET THE REDUCTION OF MEP AMPLITUDE AND IF WE DO WITH A LEAKY EXPERIENCE, EVEN GREATER REDUCTION, AND IF WE KIND OF DISPLAY THAT GRAPHICALLY, HERE'S SINGLE PULSE, AND WE OBSERVE THAT THE LESIONED HEMISPHERE ON TO THE NONLESIONED HEMISPHERE DOES REDUCE THE HEMISPHERE AND WE WILL INTERPRET THAT IS FROM THE LESIONED HEMISPHERE TO THE NONLESIONED HEMISPHERE. SO SOMETHING STILL EXISTS. NOW IN YOUR MIND SWAP THAT TMS CONFIGURURATION, NOW WE WILL TRY TO STIMULATEOT LESIONED HEMISPHERE, WE WILL TRY TO CONDITION FROM THE NONLESIONED HEMISPHERE, ALL RIGHT, SO, IF WE--IF THERE WERE AN INTACT BRAIN, WE WOULD EXPECT A NICE BIG MEP RESPONSE RIGHT HERE, WE DON'T SEE IT, RIGHT? BUT I WOULD ARGUE THAT WE ACTUALLY DO NOT SEE A COHERENT MEP AND IN FACT IF WE PULL THIS APART, TRIAL BY TRIAL YOU CAN SEE THAT THERE'S POTENTIALLY A VOLLEY OF MEPs THAT ARE NOT LINING UP IN TIME, LIKE WE WOULD EXPECT IN A NORMAL HEALTHY PARTICIPANT. SO COULD THAT VOLLEY OF MEPs REALLY INDICATE THAT THEREY A DNCH CONTRIBUTION FROM DIFFERENT MOTOR UNITS THAT HAVE DIFFERENT ARK MOUNTS OF DAMAGE. POTENTIALLY. SO IF WE THENNADAD IN A CONDITIONING PULSE FROM THE NONLESIONED HEMISPHERE INTO THE MIX, CAN YOU SEE ACTUALLY NOW THOSE MEPS ARE STARTING TO LINE UP SO CAN YOU START TO SEE SOME SORT OF AVERAGE MEP RESOLVE, AS WELL AS A SILENT PERIOD. AND IF WE DO THAT SO IF WE PULL THAT APART, YOU CAN SEE THAT THOSE MEPs, THAT VOLLEY OF MEPs THAT WERE ALL OVER THE PLACE IN TIME, NOW KIND OF START TO LINE UP AND THEY'RE FOLLOWED BY A SILENT PERIOD BUT WE STILL KIND OF HAVE THAT VOLUME OF MEPs AS WE GO THROUGH TIME AND THE SAME THING HAPPENS WITH LIHI, AGAIN WE GET THE AVERAGE MEP AND POTENTIALLY A LONGER SILENT PERIOD. AND IF WE PULL THAT APART, SAME STORY, WE HAVE THE MEPs NOW LYNNING UP BUT STILL A VOLLEY OF MEPs AS WE GO THROUGH TIME. SO OUR OBSERVATION IS THAT THAT CONDITIONING PULSE FROM THE NONLESIONED HEMISPHERE CAUSES AN MEP AND THE SILENT PERIOD TO BE DETECTED FROM THE LESION HEMISPHERE, AND WE'RE GOING TO INTERPRET THAT AS THERE'S INHIB THORS THORY PROJECTIONS FROM THE CONTRACT TO THE HEMISPHERE, THERE'S INHIBITORY PROJECTIONS FROM BOTH HEMISPHERES EVEN IN THE PRESCRIBING ENCYCLOPEDIAS OF THAT LESION, SO WE WENT TO RESTING STATE TO REALLY SEE, CAN WE LOOK AT THIS SYSTEM, EVEN THOUGH IT'S BROKEN. AND ON THE BOTTOM HERE IS THE--WE SEE IT FROM THE SAME REGIONS THAT WE DID THE TMS STIMULATION AND ON THE BOTTOM HERE IS THAT IS A COHORT OF 17 HEALTHY OLDER ADULTS AND YOU CAN SEE IF YOU SEE FROM IPSE, YOU GET A NICE HOMOLOG FROM THE OTHER HEMISPHERE, SAME WITH CONTRA. WE DO NOT SEE THAT IN THE CASE STUDY REPORT. RIGHT? SO THAT EXPECTED M1 TO M1 CONNECTIVITY IS NOT THERE EVEN THOUGH WE'RE GETTING THAT TMS INHIBITORY RESPONSE WITH THE PARAPULSE EXPERIMENT. HOWEVER, WE ALSO SEE THAT EACH SEED IS CONNECTED TO--WE THEN GET BACK A SIGNIFICANT TOPIC ACTIVITY SO THE WAY WE WILL INRETINAL LOCATION THIS IS THAT THE M1 SMA M1 FUNCTIONAL CONNECTIT IS PROBABLY AS ALTERNATE ROUTE FOR THAT INHIBITORY PROJECTION THAT WE'RE SEEING IN THE TMS EXPERIMENTS. SO IN SUMMARY I HOPE I CONVINCED YOU IT IS FEASIBLE TO APPLY TMS OVER THE CHRONIC STROKE LESION, THAT MRI CAN GUIDE THE LOCUST OF STIMULATION USING TARGET AND BLOOD FLOW MAPS. IN THIS CASE STUDY REPORT WE SHOWED BI-DIRECTIONAL INHIBITORY PROJECTIONS BETWEEN NONLESION M1 AND EVEN THOUGH THE PARTICIPANTS DO NOT HAVE A DETECTABLE COHERENT MEP IN THE PRESENCE A CONDITIONING STIMULUS,A A COHERENT PERIOD FOLLOWED BY ANOTHER COULD BE DETECTED AND FINALLY RESTING STATE FMRI DETERMINED THAT THE M1-M1 FUNCTIONAL CONNECTIVITY IS LIKELY ROUTED THROUGH SMA AND THANK YOU FOR YOUR ATTENTION AND I'M HAPPY TO TAKE ANYY REQUESTS. [ APPLAUSE ] >>VERY INTERESTING TALK CAN YOU TALK MORE ABOUT HOW THE TIGR WAS CALCULATED? >>YEAH, SURE IT IS, I CAN SHOW YOU IN THE BREAK, WE HAVE AN ENTIRE PAPER ON THAT BUT IT'S LITERALLY A DIVISION OF TQ DIVIDED BY T1. SO INSTEAD OF THE MILEIN MAPS THAT THEY'VE BEEN DOING WHICH IS T1 DIVIDED BY T2, WE'RE DOING T2 OVER T1 AND JUST LOOKING AT TD LESION AREA AND YEAH, HAPPY TO DISCUSS MORE. >>AWESOME THANK YOU, WE CAN ONLY DO 1 QUESTION, WE'RE WAY OVER TIME. SORRY, PLEASE APPROACH THE SPEAKERS AFTER. NEXT WE HAVE DR. FEI DU FROM HARVARD MED ON MOLECULAR MECHANISMS UNDERLYING DISRUPTED BRAIN CIRCUITS, MULTIMODAL NEUROIMAGING AND BRAIN STIMULATION APPROACHES. >>HELLO EVERYBODY, I NO FINANCIAL ISSUES TO REPORT SO HERE IS MY TITLE: MOLECULAR MECHANISMS UNDERLYING DISRUPTED BRAIN CIRCUITS MULTIMODAL NEUROIMAGING AND BRAIN STIMULATION APPROACHES. EACH PART HAS ITS OWN FUNCTION IT'S ALSO DEEP LINE OF WORK, WE WORKED TOGETHER WE COULD START BY STRUCTURAL MG OR [INDISCERNIBLE] FOR COLLECTIVE DNS. REALLY THIS BRAIN SECLUDED PROGRAM HAS BEEN A LOT OF NEUROBRAIN DISORDERS BUT [INDISCERNIBLE], HOW CAN WE TREAT THIS? THIS IS MY IMPORTANT PRESENTATION TO DATE. SO HERE I GIVE AN EXAMPLE, 2 NETWORK, 1 IS DESIGN NETWORK AND 1 IS [INDISCERNIBLE] NETWORK WE JUST PROCEED FOR THE WHOLE BRAIN MAPPING YOU CAN SEE 1 COLOR THAT WENT FROM [INDISCERNIBLE] AND THE OTHER COLOR IS THE WORK. SO THIS IS [INDISCERNIBLE] AND WE CALL THIS THE ANTICORRELATION, BUT THIS IS A LOT OF NEURAL DISORDERS, ANTICORRELATION IS CLEAR AND BY DISORDER REALLY YOU CAN FIND THE ADR RESEARCH, TOO, THIS IS WHAT WE CALL CANNED WHAT, ANOTHER IS THE TEST FOR [INDISCERNIBLE] HERE, WE CO ACTIVATION AND DEACTIVATION, CANNED WHAT FOR WORK IN MEMORY BECAUSE WE ARE VERY INTERESTED IN A [INDISCERNIBLE] BRAIN DISORDERS. YOU CAN SEE THERE HAS BEEN FOR MY SUMMARY [INDISCERNIBLE] COLOR THAT'S WHY THE--ACTUALLY THAT'S FROM THE [INDISCERNIBLE], AND SOME REGION EXCITED, ACTUALLY [INDISCERNIBLE] LIKE HERE, LIKE REALLY, WE TALK ABOUT THIS AND DIVISION, DEACTIVATION WHEN WE [INDISCERNIBLE] STARTING, USE HERE OR PEOPLE JUST USE [INDISCERNIBLE]. THAT'S [INDISCERNIBLE], PEOPLE, PEOPLE WILL GET THIS ACTIVITY AND [INDISCERNIBLE], SO HERE WE HAVE THESE MDR RECEPTOR ANTAGONIST SO THIS NEUROTRANSMITTER [INDISCERNIBLE] SOMETHING IN THIS CASE, SO THIS IS THE PICTURE HERE IS BASED ON MOLECULAR [INDISCERNIBLE] RESK OF PATIENT. SO IT'S REALLY COMPLICATED STORY BUT PEOPLE DON'T KNOW EXACTLY THE MECHANISM BUT BASE CAN BE DISFUNCTIONING AND MDR HYPER FUNCTION [INDISCERNIBLE] AND RESEARCH NEEDED TO [INDISCERNIBLE] SYNAPSE HERE. SO HERE JUST RUNS THE SPECTROSCOPY, WE CAN SEE [INDISCERNIBLE] BUT USUALLY THIS DOSE METER KD--SALLY IS DIFFICULT TO MEASURE BECAUSE OF THE SENSITIVITY ISSUE, SO HERE I SHOW YOU JUST CHOOSE 2, 1 IS [INDISCERNIBLE], MPFC AND ANOTHER EXAMPLE IS DLPFC, AS SHOWN HERE. SO HERE YOU SEE AN INTERESTING ANOMALY, [INDISCERNIBLE] THAT'S IN THE SAME REGION, YOU KNOW SAME REGION, THIS IS THE CITATION, SO THEY CAN SAY IT HAS A HIGHER FUNCTION HERE, BUT THE VERY INTERESTING HERE, WITH THE ASSOCIATE INVITED FOR LONG DISTANCE BETWEEN [INDISCERNIBLE] BECAUSE THIS LOCAL THEN PROJECT TO ANOTHER [INDISCERNIBLE] HERE. BUT INTERESTINGLY, CAN YOU SAY THIS PATIENT, THIS RELATIONSHIP CORRELATION BY THE MPFC, AND DLPFC, THIS [INDISCERNIBLE] HERE. SO NOW, YOU KNOW PEOPLE KNOW BRAIN [INDISCERNIBLE] BROKEN, WE WANT TO RECOMPUTE THIS COLLECTION, BUT REALLY WE MEASURE ABOUT WHICH TARGET FOR 1 STABILIZE AND WHAT'S IT IT'S WORK IS IT CITATION, WHATEVER, SO QUICKLY I MENTION, FOR THIS PEOPLE WE JUST THOUGHT ABOUT IT, IT'S PURE, IT'S THE RIGHT COLOR BUT FULL UP, YOU WILL SEE THIS IS APPROACHING AND AM CAN BACK, THIS IS VERY INTERESTED IN THE [INDISCERNIBLE] BASE LINE, GABBA IS THE LAST COMPARED TO [INDISCERNIBLE], CAN IT COMES BACK, TOO, THIS IS 1 DOSE METER AND ANOTHER WITH MOW STIMULATION, YOU SAY, OH IT'S CITATION DURING--MAYBE SOME REGION IS SLEEPY, HE'S QUITE DEPRESSED WE CALCULATE, WE THINK IT WOULD HELP AN ENERGY SYSTEM BECAUSE WE OTHER [INDISCERNIBLE]. THIS PAPER PUBLISHED MANY YEARS AGO, YOU KNOW WE HAVE VALIDATED [INDISCERNIBLE] STRONG WITH NEUROACTIVITY AND ADDED A VERY, VERY DEEP CORRELATION, IT ALMOST REDUCED 50%, THAT MEANS 50% IN THE SUPPORT SYSTEM LIKE THAT, RIGHT? SO THEN, I WILL TALK QUICKLY, WE REALLY HAVE SOME [INDISCERNIBLE], TRANSFER, WE CAN [INDISCERNIBLE], AND ALL THIS ACTIVITY WITH THE SLIDE, YEAH, I WILL NOT HAVE TOO MUCH TIME FOR THIS DETAIL, BUT REALLY WE COME IN AND WE MEASURE THE COUNTER FUNCTION [INDISCERNIBLE]. HERE, PATIENT WE SOON FOUND THAT THE [INDISCERNIBLE] ACTIVITY IS [INDISCERNIBLE]. SO NOW WE WANT TO LOOK AT HOW ENERGY WITH FUNCTION SO HERE ON TOP OF ENERGY MEASUREMENTS IS MP REGION BUT WE FIRST LOOK AT CONNECTIVITY IN THE SAME WAY AS MP DID, AND WITH SOME OTHER WORK, DEFENDING OUR WORK, CAN YOU SEE, [INDISCERNIBLE] HAS A VERY VERY CERTAIN CIRCUITRY WITH [INDISCERNIBLE] WITH SLIDE BUT IN PATIENT, CAN YOU SAY THIS PATIENT IS COMPROMISED OR BIPOLAR DISORDER. YES, WE HOPE THIS SORT OF [INDISCERNIBLE] WORK BUT VERY INTERESTING, [INDISCERNIBLE] WORK, THIS IS STILL THERE BUT IT'S COMPLEMENTING THIS PATIENT. BASED ON THIS RESEARCH WE BELIEVE ENERGY DEMAND AND LARGE SCALE BRAIN WORK, THERE YOU CAN SIMPLY PLACE TOGETHER AND MAKE BREAK FUNCTION WORK COGNITIVE FUNCTION IN A VERY EXACT FUNCTION. SO NOW, OF COURSE, WE CAN HAVE FIBERS AND DO ORIENTATION, LIKE [INDISCERNIBLE] SO NOW I TAKE [INDISCERNIBLE] AS WELL. AND WE QUALIFY [INDISCERNIBLE] AND WITH PATIENT PSYCHEOSEIS, THEN WE FOUND THE MEASURE HAS A VERY GOOD MEASURE FOR EACH OTHER AND WITH THE PATIENT WHICH INDICATES THE LOWER ENERGY GENERATION RATES WITH DECREASED NEUROTRANSMISSION MIGHT DISRUPT THE LONG DISTANCE AND LARGE SCALE NEURONAL COMMUNICATIONS. AND THEN OUR STUDY REVEALED THE GENERAL PRINCIPLE OF BRAIN ENERGY ACTIVITY, ORGANIZATION AND SUGGESTS THAT THE METABOLISM, THAT'S IT AND THANK YOU SO MUCH FOR YOUR ATTENTION. [ APPLAUSE ] THAT WAS AMAZING AMOUNT OF INFORMATION CONDENSED INTO A VERY SHORT PERIOD, IF THERE ARE ANY--ANYBODY WHO'S NOT SO STUNNED AND STILL PROCESSING IF THEY HAVE A QUESTION? THAT WAS REALLY FANTASTIC. OKAY, IF THERE ARE NO QUESTIONS, I THINK THE NEXT TECHNOLOGY TRANSFER ON THE DOCKET IS A LUNCH AND A GROUP PICTURE, IF YOU DIDN'T BRING HALLOWEEN COSTUME, YOU WILL BE FITTED WITH 1 AND THAT'S ALL THE NEWS I HAVE >>WELCOME BACK FROM LUNCH. I'M WYNN LEGON FROM VIRGINIA TECH, TALK ABOUT THE LOW INTENSITY EFFECTS OF ULTRASOUND AND USE WITH MRI IMAGING. THIS IS WORK DONE AT HARVARD WELL THEY BUILT A DECRANE UTILIZED RABBIT MODEL AND THEY SHOWED THEY COULD INDUCE A MOTOR RESPONSE IN THE MOTE OR CORTEX WHERE THEY WERE DIRECTING THE FOCUS BEAM AND YOU CAN SEE HERE FROM THE HUMAN DYNAMIC RESPONSE FUNCTION, YOU GOT A NICE SET OF RESPONSE FUNCTION, THIS IS INDEPENDENT OF INTENSITY, SO DOUBLING THE INTENSITY DID NOT DOUBLE THE EFFECT SIZE. WORK FROM LEMAN CHEN'S GROUP AND I THINK SHE'S HERE AND ALSO CHARLES CASKY'S GROUP AT VANDERBILT ABOUT WORK IN THE NONHUMAN PRIMATE, IN THIS CASE THEY WERE TARGETING SOMAT O SENSORY AREAS AND PULLING AREAS. EVEN THE DIAGRAMOT TOP WAS SHOWING AREAS THAT WOULD RESPOND TO THE FINGER TOUCH, ON THE BOTTOM IS WHEN THEY DELIVERED ULTRASOUND TO THE SAME AREA AND SHOWED A SIMILAR BOLD PATTERN AND YOU CAN SEE DOWN THERE IN IMAGE D, WE HAVE A NICE HEMODYNAMIC RESPONSE FUNCTION TO THE ON OFF OF THE ULTRA SOWBD IN THE PINK LINES, VERSUS THE GREEN LINES. SO MY LAB HAS DONE A BIT OF WORK EXAMINING THE EFFECT OF LIFU AND FMRI BOLD HUMANS, WE DELIVERED THE ULTRASOUND TO THE FINGER TO SEE IF WOULD GET A PULSE RESPONSE. WE DELIVERED 2 DIFFERENT WAVE FORMS, SO PUNS IN THIS CASE MEANS PERIPHERAL ULTRASOUND AND M WAS INDUCE THE MECHANICAL STIMULATION AND T WAS A TECHNICAL GENERATION AND PEEZ WERE ABLE TO GENERATE THESE RESPONSES IN THESE HIERARCHICAL AREAS TO DIFFERENT PERIPHERAL SENSATIONS. SO THIS IS THE EARLY WORK TO SEE IF CAN THE EFFECT OF BOLD ACTIVITY DIRECT ACTIVITY THROUGH TRANSCRANEIO APPLICATION ULTRASOUND. AND SO WE DID A LOT OF WORK IN THE EARLY DAYS WITH COMMERCIAL TRANSDUCERS TRYING TO PAIR THIS TO 3 T MRI AND WE CAN SEE WE'RE HAVING DIFFICULTIES, SO, OUR INITIAL TRANSDUCERS THAT DO HAVE 3 T CONTRAST AND IT DID PRODUCE QUITE A BIT OF ARTIFACT AND SO, THERE IS 1 KIND OF STORY HERE OR MESSAGE THAT IN THE EARLY DAYS WHEN YOU COULD BUY A COMMERCIAL TRANSDUCERS THAT THEY WERE NR SAFE BUT WHAT THEY WEREN'T WAS MR COMPATIBLE SO WE HAD RAY LOT OF ARTIFACT ISSUES. SO THESE WERE SOME OF OUR EARLY--SHOWS 3 SUBJECTS HERE WHERE WE DID HAVE HINTS OF BOLDER RESPONSES BUT I DID HAVE SUBJECTS WHERE WE WERE NOT ABLE TO GET A ROBUST RELIABLE BOLD SIGNAL. BUT WE'VE BEEN WORKING ON THIS AND 1 OF THE ISSUES TO REMOVE THE ARTIFACT FROM A TRANSDUCER IN THE HEAD COIL, YOU CAN SEE FROM THE PHOTOGRAPHS ON THE LEFT THAT WHAT WE ENDED UP DOING IS WE ENDED UP SEEING WHAT COMPONENTS OF THE TRANSDUCERS LED TO THE ARTIFACTS SO HOW DID WE ELIMINATE SOME OF THIS, SO CAN YOU SEE THE TRANSDUCER IN THE HEAD IN THE BOTTOM AND HOW WE CAN FIT IT IN THE HEAD ON THE PHOTO ON THE TOP LEFT. WE DID A LOT OF EXPERIMENTS AND WE WE CAN GET CERAMICS AND GET IT FROM THE PET, AND DIFFERENT LENGTHS THEN IT'S NOT JUST THE PZT ELEMENT THAT HAS ARTIFACTUAL ISSUES AND SOMETIMES THE EPOXYS AND THE PLASTICS HAVE THIS THESE ISSUES. SO YOU DO HAVE SOME SUCCESS, YOU CAN SHOW HAD SOME OF THESE ARTIFACTS BUT FROM ALL OF THESE STUDIES, WE WERE HAPPY TO SAY WE WERE ABLE TO PRODUCE OUR OWN TRANSDUCERS THAT DID HAVE VERY LITTLE ARTIFACT AND WE'RE SHOWING DATA FROM A 70S GROUP. YOU CAN SEE THE SEQUENCES ARE QUITE NICE NOW SO THESE ARE IMAGING TAKEN WITH OUR CUSTOM HOM MADE TRANSDUCE THEY'RE IS 3 TN17 COMPATIBLE. IN THIS CASE, THE STUDY WE'RE NOT INTERESTED IN INDUCING A BOLDER RESPONSE, WE WERE INTERESTED IN SEEING WHAT AN ULTRASOUND DID TO A PREVIOUS ULTRASOUND RESPONSE, SO IF YOU DID IT WITH A FINGER YOU COULD GET A NICE BOLDER RESPONSE. SO IN THIS STUDY WE HAD PARTICIPANTS MOVE MIDDLE FINGER, INDEX FINGER, RING FINGER AND IF WE AFFECTED THOSE COULD WE GET NEUROMODDULATION, SO I'M SOING THE DISPLACEMENT FROM THE FINGER REPRESENTATIONS AND THE SPOINT THAT LOW INTENSITY FOCUSED URLT RASOUND OF 500 K HERTZ DOES CONFIRM THE SPATIAL RESOLUTIONS, IN THIS CASE, THE DATA ON THE RIGHT IS FROM 5 SUBJECTS AND WE DID NOT SEE AN INCREASE OR DECREASE IN THE HEMODYNAMIC AGNITUDE BUT WE DID SEE A CHANGE IN THE VOLUME OF THAT EFFECT AND THAL CASE, THIS IS THE DATA FROM THE INDEX FINGER AND THEN THAT DATA, THAT AFFECT DID NOT TRANSLATE TO THE INDEX, TO THE MIDDLE FINGER OR TO THE RING FINGER. AND SO THIS IS A BIT OF A BACKGROUND, IT'S LED TO OUR STUDIES NOW WHERE WE'RE REALLY INTERESTED IN,A PLYING SOWBD FOR PAIN INDICATION SO INSTEAD OF LOOKINGA THE PRIMARY MOTOR CORTEX, WE WERE INTERESTED IN LOOK BEING AT THE ANCILLARY CORTEX, SO HERE'S THE CORTEX AS PICTURED HERE, IT'S DEEP THROUGH THE CORTICALE SURFACE IT'S COVERED BY THE PERIPHERAL LOBE, SO IT'S QUITE DIFFICULT TO ACCESS NONINVASIVELY, I THINK WE'VE SEEN A LOT OF WORK HERE TODAY ABOUT THE LIMITATIONS OF TMS FOR DEATH PENETRATION AND SO 1 OF THE VALUE PROPOSITIONS, BENEFIT OF ULTRASOUND IS THAT IT DOES HAVE DEPTH PENETRATION AND YOU CAN MODIFY THE RESOLUTION OF IT TO TARGET AN AREA LIKE THE INSIEWLA, SO THERE'S SEVERAL DATA POINT SUGGESTING IT IS THE PAIN PROCESSING HERE, CAN YOU SEE ON THE LEFT THAT THE MAJORITY OF THE DISCIPLINARY SYNAPTIC PROJECTIONS FROM THE LATERAL SPINE INFLAMMATORY TRACT DO TERMINATE THE ENSUE LA SO THIS IS A TARGET AREA. SO THESE--THE COLOR--SORRY I'M LEARNING HOW TO USE THIS THING. IT CAN BE DIVIDED BROADLY INTO AN ANTER ANTERIOR AND POSTERIO. SO WE WANTED TO TRY BOTH TO SEE IF WE WOULD GET DIFFERENT EFFECTS WITH ULTRASOUND. AND SO JUST TO CONFIRM THAT YOU CANNOT TARGET THE INSULIN VERY WELL WITH TMS OR TDCS, THIS IS WORK I'M DOING IN COLLABORATION WITH ALEX AT THE UNIVERSITY OF MINNESOTA. THE TOP ROW IS AN EFIELD FOR A TYPICAL 8 COIL TARGETING THE INSIEWLA SO ALEX HAS A NICE PIPELINE TO ITERATE THROUGH SEVERAL DIFFERENT LOCATIONS OF THE TMS COIL OR THE ELECTRODES TO TRY TO OPTIMIZE A TARGET LOCATION AND YOU CAN SEE FROM BOTH THE TMS AND THE TDCS DATAOT BOTTOM, THESE WERE THE BEST CONFIGURURATIONS FOR THESE 2 METHODOLOGIES TO TARGET THE INSULA, AND YOU SEE THAT THE FIELD DID SNOT REACH THE INSU LA AT ALL. THIS IS DIFFICULT TO DO WITH MAGNETIC STIMULATION AND WE THINK WE HAVE A NICE OPPORTUNITY TO SEE IF THE ULTRASOUND WILL AVENGHT THE PAIN PROCESSING. SO HERE'S SOME ACOUSTIC MODELS THAT WE DO IN OUR LAB, SHOWING SPATIAL SPECIFICITY OF ULTRASOUND, I APOLOGIZE IF THE IMAGES ON THE LEFT, IT'S HARD TO SEE THE BEAM SO CAN YOU NOTICE THAT IF YOU LOOK AT THE CALIFORNIAOR BAR AND THE IMAGES ON THE LEFT, WE'RE DELIVERING WHAT 70-PASCAL OUTSIDE THE HEAD AND THEN IF YOU LOOK AT THE IMAGE ON THE RIGHT, THE MODEL'S PREDICT PROBABLY ABOUT A 4 FOLD LOSS OF ENERGY GETTING INTO THE HEAD. SO THIS IMAGE ON THE RIGHT HERE IS THE IMAGE FROM THIS CUT THROUGH THIS LINE HERE ON THIS TRANSVERSE IMAGE OR CORONA IMAGE AND THIS IS THE IMRKS Y IMAGE AND YOU CAN SEE LIFE DOES CONFER, THE SPATIAL SELECTATIVITY TO INDIVIDUALLY TARGET GIRI WITHIN THE INSULA. SO HERE WE'RE TARGETING THE INFERIOR INSULA, AND THE POSTERIOR INSIEWLA LANGUAGE PATHOLOGISTS THIS YEAR, AGAIN THIS IS THE IMAGE TAKEN HERE IN THIS TRANSVERSE SLICE AND CORONAL SLICE AND YOU CAN SEE HERE WE'RE TARGETING THE JOINT GYRUS AND THE INSULA, AND I WILL TALK MORE ABOUT THIS, THERE IS B MEMBER IDENTIFICATION IN THIS CASE, SO YEN IN HIS EARLIER TALK, THIS IS A MAJOR ISSUE FIDUCIARY ULTRASOUND TRANSCRANIALLY, SO IT DOES ATTENUATE THE BEAM AND I WILL TALK A BIT ABOUT HOW WE CAN MITIGATE THESE THINGS. YES, OKAY, SO THIS IS THE PROBLEM WITH THE SKULL. SO THIS IS WORK DONE WE'RE LEGALLY INTERESTED IN SEEING IF WE COULD USE ULTRASOUND TO TARGET THE CEREBELLUM. AND SO HERE WE HAVE A MODEL WITH SAGITTAL SLICE SHOWING THAT YES, WE HIT THIS PRETTY DEFINED THEME, TARGET THE CEREBELLUM, EVERYTHING LOOKS NICE AND FINE AND DANDY BUT WHEN YOU LOOK AT THE TRANSVERSE SLICE, CAN YOU SEE HOW THE MORPHOLOGY CAN REALLY MISDIRECT THE BEAM, SO IN THE LIFE OR WORLD WE HAVE TO COMPENSATE FOR NOT ONLY THE ATTENUATION OF THE SKULL, BUT ALSO THE MORPHOLOGY OF THE SKULL TO MISDIRECT THE BEAM. SO BACK TO THE PAIN STUDIES, SO THIS WAS A GENERAL METHODOLOGY. THIS IS KIND OF A 2 PART STUDY. WE HAD RESTING STATE CONDITION IN THE YELLOW AND MY STUDENT ANDREW WILL TALK MORE ABOUT THE RESTING STATE DATA LATER AND I WILL TALK ABOUT THE EVENT RELATED DATA RIGHT NOW, AND SO THIS IS A HEAT RELATED STUDY SO THIS IS A DEVICEOT LEFT TO DELIVER A PAINFUL STIMULUS TO THE DORSAL OF THE HAND WHERE THE SUBJECT HAD TO RATE IT ON A BUTTON BOX. SO THEY WOULD DO THIS BEFORE ULTRASOUND AND THEN WE WILL DELIVER ULTRASOUND AND SO THIS IS A BIT DIFFERENT THAN THE CONCURRENT LIFE THAT I SHOWED EARLIER, WE'RE NOT DELIVERING ULTRASOUND DURING POLED ACQUISITION, THIS IS MORE--THIS IS A PREPOST DESIGN. AND SO IN THIS CASE, WE DELIVERED A HUNDRED STIMULATIONS OF LIVE FLOW AT AN INTERVAL OF 5-SECONDS AND THEN WE DID THE PAIN TESTING AGAIN AFTERWARDS AND WE HAD 3 CONDITIONS, WE HAD AN ACT OF [INDISCERNIBLE] CONDITION WHERE WE DELIVER IT TO THE VORTEX, AND IN THIS CASE WE DELIVER IT AT THE DORSAL AND WE DELIVERED IT AT 2 DIFFERENT INTENSITIES. AND OF COURSE, WE USE MRI GUIDED STEREO TAXIC NAVIGATION SO THIS IS THE EXACT SYSTEM YOU WOULD USE FOR A TMS STUDY AND IT'S EASILY RETROFITTED TO AN ULTRASOUND TRANSDUCER. THE ONLY THING YOU HAVE TO DO IS CHANGE THE Z-OFFSET IN THESE SYSTEMS AND SO IT'S--IT PAIRS REALLY EASILY HERE'S AN EXAMPLE OF A CORTICALE TRANSDUCER AND YOU CAN SEE HOW WE'RE USING A TRADITIONAL TMS STEREOTYPE IN THE NAVIGATION SYSTEM, TO DO ONLINE TESTING AND SEE EACH UBIQUITINNATION IS JECT WILL HAVE THEIR OWN CT AND MR WILL IDENTIFY THE INTERIOR INSULA, WILL KNOW THE DEPTH OF IT, THE DEPTH OF THE TRANSDUCER AND THIS IS HOW THE GENERAL TARGETING STRATEGY WORKS. OKAY, THESE ARE SOME OF OUR EARLIER RESULTS HOT OFF THE PRESSES, AND SO THIS IS SOME DATA BEFORE LIFU. AND SO WHEN YOU DELIVER A HEAT PAIN STIMULUS TO THE HAND, YOU WILL ACTIVATE THIS HIERARCHICAL NO SUSCEPTIVE SOPHISTICATED MAT O SENSORY NETWORK AND YOU CAN GET S1, SOPHISTICATED MAT O SENSORY CORTEX, WE DO GET CONTRA LATERAL AND IPSA LATERAL INSULA, THALAMUS AND ACC, SO WHAT I'M SHOWING ON THE RIGHT. ON THE TOP THIS IS THE RAW DATA, BOLD DATA FROM THE LEFT INSULA, HIGHLIGHTED HERE IN THE WHITE CIRCLE, AND EVERY TIME THE STIMULUS, STIMULUS IS REPRESENTED, THE STIMULUS STORYOT HAND IS REPRESENTED BY EACH 1 OF THOSE RED VERTICLE LINES AND THEN THE TRACE BELOW IS THE AVERAGE HEMODYNAMIC RESPONSE FOR THE LEFT INSULA. SO WHEN YOU DIRECT TO THE DIRECT INSULA, WHAT HAPPENS? THIS HAPPENS. WE HAD MASSIVE SIGNAL ATTENUATION AND YOU CAN SEE FROM A--FROM THE RAW DATA AND ALSO FROM THE AVERAGE TRACE THAT WE DO GET A MASSIVE INHIBITION AND THAL CASE, IN THIS SUBJECT. SO THE OTHER THING WE'RE INTERESTED IN IS DOES THIS HAVE BEHAVIORIAL RELEVANCE. SO THE 2 BARS ON THE LEFT, THIS IS THE AVERAGE PAIN RATING ON THE LEFT AND THEN AFTER THE INTERVENTION ON THE RIGHT AND WE HAVE A SLIGHT DECREASE IN THE PAIN RATING IS WHAT WE'RE REALLY INTERESTED IN DOING NOW IS LOOKING AT HOW DOES THE BEHAVIORIAL DATA RELATE TO THE BOLD DATA AND SO THAT'S WAWE'RE SHOWING HERE AS THIS IS THE RAW DATA FROM THE LEFT ANTERIOR INSULA, SO THIS IS A SMALL RI SPHERE AND THAT'S THE RAW BOLD DATA IN BLACK AND THIS IS THE BEHAVIOR DATA, THE BUTTON PROCESS FROM AFTER EACH STIMULUS, SO, IT'S NOT CONCLUSIVE IF THERE'S ANY STRONG RELATIONSHIP BETWEEN THE BEHAVIORIAL RESULTS AND THE RAW BOLD DATA FOR EITHER THE INSULA OR THE PRIMARY SOPHISTICATED MAT O SENSORY CORTEXAS BUT WE'RE LOOKING AT DIFFERENT WAYS TO LOOK AT THIS DAT AND POTENTIALLY USING THE DEHAIEVERRIAL DAT AS 1 OF OUR REGRESSORS TO TEASE A BIT OF THIS OUT. SO THE OTHER THING WE'RE INTERESTED IN S&P LOOKING AT CORRELATION BETWEEN THESE AREAS AND THESE TASK POSITIVE AREAS IN THE SOPHISTICATED MAT O SENSORY HIERARCHY, WHAT IS IT DOING NOT ONLY TO ACTIVITY AND THE ANTERIOR INSULA BUT ALSO IN THESE RELATED CONNECTED AREAS, SO THIS IS A CORRELATION MATRIX OF SOME OF OUR TASK POSITIVE AREAS WE'RE INTERESTED IN, AND SO WE HAVE BEFORE ULTRASOUND ON THE LEFT, AND THEN POST ULTRA SOUND IN THE MIDDLE AND THEN THERE'S THE DIFFERENCE PLOT ON THE RIGHT AND I THINK WHAT'S INTERESTING IS THAT THE BIGGEST DIFFERENCE BETWEEN PREAND POST WITH THIS SUBJECT WAS FOR LEFT INSULA CONNECTIVITY AND OHM IN THE LEFT INSULA CONNECTIVITY, WHERE WE DELIVER DIFFERENCES IN CONNECTIVITY WITH THE PRIMARY SOPHISTICATED MAT O SENSORY CORTEX AND THE ANTERIOR SING LATTERY CORTEX. THIS IS DATA FROM ANOTHER SUBJECT. IT'S BEFORE LIFE, ON THE LEFT AND THEN AFTER, A LIFU ON THE RIGHT AND ONCE WITH AGAIN CAN YOU SEE THAT THE STIMULUS DOES RECRUIT THE INSULA AND IN THIS CASE IT'S HEAVILY RECRUITED THE AMYGDALA IN THIS SUBJECT AND THEN AFTER ULTRASOUND, IF THE INSULAR ACTIVITY HAS BEEN ATTENUATE AND THEN THERE'S SOME CHANGES, SLIGHT ATTENUATION OF THE AMYGDALA AND OTHER NETWORKS SUGGIEST THAGOREAN LIFU MIGHT HAVE AN INHIBITORY EFFECT ON THIS NETWORK. THAL CASE, WE DID NOT SEE THE DIFFERENCE FOR THE PAIN RATING AND WE'RE CURRENTLY, LOOKING AT THE RELATIONSHIP OF THE PAIN RATING WITH THE RAW DATA TO SEE WHAT THE RELATIONSHIP IS IF ANY. SO, I'VE KEPT ALL MY DATA HERE TO WHAT WE'VE DONE IN ULTRASOUND WITH BOLD IMAGING AND WE HAVE, 2 SUBJECTS NOW, WHAT WE HAVE OVER 30 SUBJECTS NOW THAT I'VE DONE EEG AND I DON'T HAVE THAT DATA NOW BUT WE DO HAVE VERY ROBUST BEHAVIORIAL EFFECTS IN THE GROUP LEVEL AND EEG DATA I'M ONLY SHOWING YOU A COUPLE SUBJECTS HERE AND HOPEFULLY HAVE THAT RELATIONSHIP WITH OUR BOLD DATA AS WELL. AND SO THE OTHER THING WE'RE INTERESTED IN, AND I THINK YAN POINTED THIS OUT QUITE WELL IS THE MAJOR BARRIER TO ULTRASOUND IS THE SKULL. SO WE'RE VERY INTERESTED IN I THINK SOME OF THESE OTHER NEUROMODLATTORY TECHNIQUES ARE ALSO UNDERSTANDING THE DOSING AND HOW MUCH ENERGY IS NEEDED TO GET THESE TYPES OF EFFECTS. AND SO WE'RE REALLY INTERESTED IN LOOKING AT METRICS OF THE SKULL TO HELP US INDICATE HOW MUCH ENERGY IS GETTING IN THERE AND WHERE THE ENERGY IS GOING. SO WE COLLECT CTs AND MR IMAGING ON ALL OUR SUBJECTS SO WHAT WE'RE ABLE TO DO IS WE'RE ABLE TO IMAGE THE BONE QUITE WELL AND WE CAN PARSE IT INTO THE CORTICALE AND FOLLICULAR LAYERS AND THEN WHAT WE CAN DO IS DRIVE THIS SKULL DENSITY RATIO METRIC AND SO, THE METRIC IS USED WITH HIGH INTENSITY PROTOCOLS TO INDICATE WHETHER THE SUBJECT IS APPROPRIATE FOR LIFU ISHT VENTION BECAUSE IF YOU ARE--IF YOU'RE SKULL DENSITY RATIO IS AN APPROPRIATE, CAN YOU GET INCREASED HEATING FROM HIGH ENERGY AND SO THAT'S NOT CONDUCIVE, IT'S NOT CONDUCIVE TO SAFE INTERVENTIONS, AND SO WE'RE CURRENTLY LOOKING AT WHAT ARE THE SKULL DENSITY RATIOS OF OUR PARTICIPANTS? WHAT IS THE RELATIONSHIP OF THAT TO HOW MUCH DOSING IS GETTING IN AND WHETHER IT'S HAVING A BOLD EFFECT OR A BEHAVIORIAL EFFECT? AND ALSO INTERESTED IN THE THICKNESS OF THE BONE, BUT WE'VE PREVIOUSLY SHOWN THAT THICKNESS ALONE DOES NOT ACCOUNT FOR THE PRESSURE IN THE HEAD OR SOME OF THESE BOLD RESPONSES BECAUSE BONES NOT HOMOGEANIOUS SO THE THICKNESS IS NOT A GOOD PREDICTOR OF THE NG THAT'S GETTING IN THE HEAD. SO CAN YOU SEE HERE FROM SOME OF OUR MODELS, I'M POINTING OUT TO HOW MUCH PREDICTED LOSS CAN YOU GET. SO WE'RE DELIVERING 700-PASCALS OUTSIDE THE HEAD, AND I THINK THE CURRENT STATE OF THE FIELD, I'M HAPPY TO DEBATE THIS WITH ANYONE WHO MAY OR MAY NOT KNOW, BUT WE DON'T ACTUALLY KNOW WHAT PRESSURE IS TOO LOW OR WHAT IS OPTIMAL DOSING FOR ULTRASOUND YET SO THESE ARE THINGS WE'RE TRYING TO FIGURE OUT RIGHT NEW IS HOW MUCH PRESSURE IN THE HEAD DO WE NEED TO GET THE SUSTAINED ROBUST RELIABLE EFFECTS. AND WITH THAT I WOULD LIKE TO THANK MY LAB, PAST AND PRESENT AND ALSO THE INSTITUTIONS THAT I'VE COLLABORATED WITH AND SOME OF MY FUNDING PARTNERS AND I'M HAPPY TO ANSWER ANY QUESTIONS. [ APPLAUSE ] >>QUESTIONS FOR WYNN? >>ALL RIGHT, YAN, HIT ME. >>I HIT THE CHANGES IN FUNCTIONAL CONNECTIVITY INTRIGUING, WERE THEY OBSERVED ALSO IN THE SECOND SUBJECT? >>YES, BUT IN DIFFERENT AREAS AND SO THAT SUBJECT HAD A DIFFERENT KIND OF LIFU PROAND I THINK THIS WAS BROUGHT UP IN THE ISSUE OF NEUROMOD, IS WHAT IS THE CURRENT STATE OF THE SUBJECT OR HOW WOULD THE RECEPTOR [INDISCERNIBLE] INTERVENTION OR TESTING AND SO IN THAT CASE WE DID NOT SEE A SIMILAR RELATIONSHIP. WE DID SEE CHANGES AFTER LIFU BUT IT WAS BT SPECIFIC TO THAT INSULA ACC, AND IT THEY HAD A LOT MORE CONNECTIVITY IN THE AMYGDALA AND THAT SHOWED DIFFERENTIAL RESULTS SO I THINK WE'RE REALLY INTERESTED ON THE SINGLE SUBJECT EFFECTS AND HOW THEY CONTRIBUTE TO GROUP EFFECTS. BUT AS I THINK EVERYONE KNOWS THESE SINGLE SUBJECTS ARE DIFFERENT. AT LEAST BETWEEN THOSE 2 SUBJECTS NOW, WASN'T THE SAME. >>DR. CHEN? NGREAT TALK. THANK YOU SO MUCH. I HAVE 2 QUESTIONS, YOU MENTIONED THE BEHAVIOR SO CAN YOU JUST PLEASE TELL A BIT MORE, DID YOU GET THAT BEHAVIOR READ OUT BEFORE OR WITH THE MAGNET OR-- >>INSIDE THE MAGNET DURING THE SCAN SO PULSE DELIVERED ON THE HAND AND THEN A CERTAIN WINDOW TO RESPOND AFTERWARDS. >>AND THE SECOND QUESTION IS HAVE YOU LOOKED AT YOU KNOW AFTER THE FIRST OF THE INSULA, YOU SEE THE DECREASING MEDULLAR, AND HAVE YOU LOOKED AT THE CONNECTIVITY CHANGE AFTER? >>YEAH, SO MY STUDENT ANDREW WILL PRESENT A LOT OF THE CONNECTIVITY DATA TO THAT SHORTLY TODAY. >>THANK YOU. >>HI, JUST QUICK QUESTION, DID YOU SAY THAT THERE WAS TO YOUR TASTE NOT A GOOD COMMERCIAL SOLUTION FOR MR COMPATIBLE [INDISCERNIBLE] AND THEN YOU HAD TO BUILD YOUR OWN? >>SO I DIDN'T--I MISSED THAT. >>IS THERE TO DATE AN MR-COMPATIBLE [INDISCERNIBLE] OR YOU HAVE TO BUILD YOUR OWN IF YOU REALLY WANT TO BE--COMPATIBLE? >>THIS DATA IS FROM A COMMERCIAL TRANSDUCER AND SO WE DID NOT DELIVER ULTRASOUND WHILE THEY WERE IN THE SCANNER, SO THIS DAT IS NOT CONCURRENT, BUT YES, OUR PAST DATA WE ENDED UP MAKING OUR OWN TRANSDUCERS THAT WERE MR COMPATIBLE SO IF WE WANT TO DO CONCURRENT FMRI, WE JUST FOUND THAT SOME COMMERCIAL TRANSDUCERS, NOT ALL, I KNOW THERE'S SOME THAT WORK BUT, WHEN THEY SELL YOU AN MR COMPATIBLE TRANSDUCER, IT IS MR SAVE BUT THEY DON'T HAVE ANY ANY IN WHETHER IT HAS ARTIFACT OR NOT. SO WE FOUND A LOT OF THESE MR SAFE TRANSDUCERS, DO HAVE A LOT OF ARTIFACT AND SO WE ENDED UP JUST BUILDING OUR OWN. >>ONE MORE QUESTION. WOULD YOU EXPECT THAT THE HIGHLY FOCAL STIMULATION OF A SUBPORTION OF INSULA WOULD HAVE A MAJOR IMPACT ON THE PERCEPTION? IT'S QUITE IMPRESSIVE TO SEE SOME IN SUBJECT NUMBER 1. WHERE I AM AIMING TO--HAVE YOU CONSIDERED STIMULATING MULTIPLE OF THESE TARGETS, MAYBE LARGER PORTION, MAYBE BILATERAL AND MAYBE THE FELLOW [INDISCERNIBLE] TO REALLY-- >>I THINK IT'S A GOOD POINT WE ALWAYS TALK ABOUT THE VALUE OF LIFE IS HOW SPECIFIC IT IS BUT IT'S QUITE A POSSIBILITY THAT IT'S TOO SPECIFIC SO IT DOES LEAVE TO YOU SOME TARGETING ISSUES AND SO, YES, WE FIRST THOUGHT CAN WE GET A DIFFERENTIAL EFFECT BETWEEN AMPI, BUT BILATERAL MIGHT BE BETTER BUT IN THIS CASE, THIS S THE FIRST FORAY INTO THAT BUT YES, I WOULD BE INTERESTED IN SEEING THAT AS MORE IS BETTER THAT KIND OF THING. >>LET'S THANK DR. LEGON. >>THANK YOU. >>[ APPLAUSE ] >>OUR NEXT SPEAKER IS DR. JACEK, DMOCHOWSKI, FROM THE CITY COLLEGE OF NEW YORK. HE'S CURRENTLY AN ASSOCIATE PROFESSOR AND TODAY HE WILL TALK TO US ABOUT THE MRI OF NEAR-INFRARED OPTICAL MODULATION. >>THANK YOU YAN, I'M JACEK, I'M AT THE CITY COLLEGE OF NEW YORK AND TODAY I WILL TALK ABOUT A TYPE OF BRAIN SIMULATION THAT I DON'T THINK WE'VE HEARD ABOUT YET TODAY. OPTICAL MODULATION IS ACTUALLY NOT THE PREFERRED NOMENCLATURE BUT IT IS THE TITLE OF THIS TALK. UNFORTUNATELY FOR ME I DON'T HAVE ANY DISCLOSURES. SO WHAT IS PHOTO BIOMODDULATION? SO FIRST OF ALL, THIS USED TO BE CALLED LOW LEVEL LASER THERAPY, SO ALSO HAS BEEN REFERRED TO AS COLD LACER. PHOTO BIOMODDULATION IS NOW I'VE HEARD, THERE WAS LIKE A GROUP OF EXPERTS IN THIS FIELD THAT ALL DECIDED TO COME TOGETHER 1 DAY AND DECIDE ON THIS BEING THE HOPEFUL ULTIMATE NAME OF THIS TECHNOLOGY SO AS WITH MANY THINGS IN MEDICINE, IT WAS DISCOVERED ACCIDENTALLY IN THE 60S. A HUNGARIAN PHYSICIAN HAD AN IDEA THAT HE COULD CURE CANCER WITH RAISER RADIATION. AND SO HE ASKED HIS PHYSICIST, THIS WAS IN HUNGARY, I BELIEVE, ASKED HIS PHYSICIST COLLEAGUE TO BUILD HIM A LASER SPECIFYING SOME INTENSITY THAT HE WANTED TO WORK WITH. UNFOR THEINATELY, AND THEY ONLY DISCOVERED THIS AFTER THE FACT, THAT THE LASER HE GOT FROM HIS COLLEAGUE HAD A MUCH LOWER INTENSITY THAN HE HAD INTENDED TO USE. AND HE DID NOT, SO, YOU KNOW THE EXPERIMENT WAS VERY STRAIGHT FORWARD, IT WAS 2 GROUPS OF MICE, HALF GOT THE LASER THERAPY, THE OTHER HALF DIDN'T AND THERE WAS NO EFFECT ON THE CANCER PROGRESSION, BUT HE DID NOTICE THAT THE MICE THAT GOT TREATED WITH THE LASER, THEIR HAIR WOULD GROW BACK MORE QUICKLY. YOU KNOW THE MICE HAD TO BE SHAVED FOR THESE EXPERIMENTS AND SO THAT WAS KIND OF THE GENESIS OF PHOTO BIOMODDULATION. AND UNFORTUNATELY AS WITH MANY FIELDS THAT HAVE A LOW BARRIER TO ENTRY, THERE HAVE BEEN MANY, WELL WHAT I'M CALLING HERE IS LESS THAN RIGOROUS REPORTS IN THIS FIELD, SO THIS IS NOT A FIELD THAT YOU WANT TO GET INTO FOR THE PRESTIGE BECAUSE THERE ARE SOME PRETTY YEAH, PRETTY PSEUDOSCIENTIFIC REPORTS OUT THERE. BELIEVE IT OR NOT OUT OF ALL THOSE PICTURES I BELIEVE THAT THE ONLY 1 OF THESE PICTURES THAT IS ACTUALLY FDA APPROVED IS THE BASEBALL CAP. THAT IS--IT'S AN FDA APPROVED TREATMENT FOR MALE PATTERN BALDNESS. BUT WHAT I'M TRYING TO SAY HERE IS THAT, THIS IS AN AREA, PHOTO MODULATION IS NOT JUST ABOVE THE BRAIN, I'LL BE TALKING TO YOU ABOUT THE SUBSET OF THIS THAT IS DIRECTED AT THE BRAIN, BUT THAT FACET, THAT I'M INTERESTED IN, IS VERY RECENT. SO, REALLY JUST IN THE LAST 10, 15 YEARS HAS PHOTO BIO MODULATION BEEN SERIOUSLY INVESTIGATED IN THE CONTEXT OF COGNITIVE FUNCTION, PSYCHIATRIC APPLICATION. SO TRANSFERRING OF PHOTO BIOMODDULATION, YOU KNOW THE DEFINITION, IT'S HARD TO EVEN COME UP WITH A VERY SPECIFIC DEFINITION. I DEFINE IT HERE AS THE NONINVASIVE APPLICATION OF LOW LEVELS OF NEAR INFRARED LIGHT THROUGH THE BRAIN. SO WHAT IS LOW LEVEL? SO IF YOU'RE FAMILIAR WITH POWER, YOU KNOW POWER MEASUREMENTS AND BRAIN STIMULATION, THE POWER OF THITE LIGHT COMING OUT OF THAT LASER IS GENERALLY A COUPLE HUNDRED MILLI WATTS AND THE PERCENTAGE OF THAT THAT ACTUALLY PENETRATES TOWARDS THE BRAIN SURFACE, DEPENDS BUT IT'S IN THE ORDER OF A FEW%, AND SO IF YOU SHINE 300 MILLI WATTS AT THE HEAD, YOU WILL GET 3-6 MILLI WATTS IN THE BRAIN. SO THAT'S A GOOD WAY OF DEFINING LOW LEVEL HERE IS IT'S AN INTENSITY THAT DOESN'T HEAT THE BRAIN OR HOPEFULLY DOESN'T HEAT THE BRAIN AND IT CAN BE DOABLE WITH LASERS OR LIGHT EMITTING DIODES, THE ONLY ADVANTAGE OF THE LASER, THERE'S NOTHING SPECIAL ABOUT COHERENT LIGHT, IN THIS SENSE, CAN YOU DO EVERYTHING THAT IS DONE WITH LASERS WITH LEDs, IT'S JUST HARDER TO GET 300 MILLI WATTS OUT OF AN LED, THAN IT IS WITH A MONOCHROMEATIC LASER. SO THE REASON PEOPLE USE LASERS HERE IS JUST A CONVENIENCE OF DELIVERING THAT MUCH LIGHT, YOU KNOW, EFFICIENTLY. SO I THINK IF THERE'S 1 THING THAT YOU REMEMBER FROM THIS TALK IS THAT PHOTO MODULATION IS DIFFERENT THAN TMS AND TDCS AND ALL THOSE ASSETS. IT'S NOT TRYING TO MAKE NEURONS FIRE AT ALL OR NOT DIRECTLY AT LEAST. IT'S TARGETING THE BI ONY ENERGETIC PATHWAYS, PATHWAYS. AND SO, THE TARGET HERE IS NOT MEMBRANE POTENTIAL, BUT IT'S HOW MUCH ENERGY, ATP NEURONS HAVE AT THEIR DISPOSAL. SO I'M IN THE A BIOLOGIST SO I'M PROBABLY NOT THE BEST PERSON TO TRY TO EXPLAIN TO YOU THE BIOPHYSICS OF PHOTO BIOMODDULATION BUT THE KEY MOLECULE, THE KEY ABSORBER HERE AND AGAIN, THIS IS BACKED BY A LOT OF GOOD--ACTUALLY EXPERIMENTS, HOWEVER, YOU'RE STILL A LOT OF DEBATE HERE AS TO WHAT THE PRECISE MECHANISM IS, LIGHT, THE INTERACTION BETWEEN LIGHT AND BIOLOGICAL TISSUE IS ALWAYS SUPER COMPLICATED AND IT'S VERY HARD TO GET STRAIGHT ANSWERS BUT CYTOCHROME C-OX DACE IS AN ENZYME IN THE ELECTRON TRANSPORT CHAIN OF THE MITOCHONDRIAL RESPIRATION CYCLE. SO IT'S THE THEORY IS THAT PHOTONS IN THE INFRARED LIGHT HAVE THE RIGHT ENERGY LEVEL TO BE ABSORBED BY CCO AND THAT BASICALLY SPEEDS UP THAT CELLULAR RESPIRATION PROCESS, IT SPEEDS UP, YOU KNOW THE CHEMICAL REACTIONS THAT ARE ULTIMATELY PRODUCING ATP WHICH IS A GOOD THING. ESPECIALLY IF, THERE IS AN IMBALANCE IN ATP. THERE ARE OTHER HYPOTHESIS OUT THERE, 1 IS THAT, NITRIC OXIDE IS ASSOCIATED AND THAT CAN BE--THAT CONTRIBUTOR OF BASAL DILATION, SO THERE'S THE BLOOD FLOW HYPOTHESIS IS STILL OUT THERE. IT'S STILL A POTENTIAL WAY THAT PHOTO BIOMODDULATION EXERTS WHATEVER EFFECTS IT DOES EXERT. BUT THERE IS A LOT OF EVIDENCE THAT SHINING THE INFRARED LIGHT ON CELLS, BASICALLY INCREASES THE COMSUMPTION OFOX GENERATED AND AS A RESULT, GLUCOSE METABOLISM AND THERE'S LOTS OF INVITRO, AND ANIMAL WORK THAT DOCUMENTING THE INCREASED PRODUCTION OF ATP, WITH PHOTO BIOMODDULATION. AGAIN, I JUST WANT TO MAKE IT CLEAR THAT KIND OF THE BASIC SCIENCE STUDIES HERE ARE ACTUALLY PRETTY SOUND. IT'S MORE ON THE APPLICATION SIDE THAT I THINK THERE'S A LOT OF, SOME, YEAH, LESS THAN RIGOROUS INVESTIGATION REPORTS OUT THERE. SO 1 THING ABOUT THIS FIELD THAT'S INTERESTING IS THAT A LOT OF THE PHYSIOLOGICAL EFFECTS THAT HAVE BEEN DOCUMENTED HAVE BEEN DONE IN MICE, AND SO THIS IS A--I GENERAL TREND IN NEUROMODDULATION THAT GETTING EFFECTS, SHOWING EFFECTS, IS A LOT EASIER IN THE RODENT AND I THINK THAT'S PRIMARILY BECAUSE OF THE--JUST THE ANATOMY DOESN'T SCALE UNIFORMLY FROM RODENT TO HUMAN. IT'S JUST, YOU KNOW IF YOU NEED 300 MILLI WATTS TO REACH THE HUMAN BRAIN, THEN AND THE HUMAN BRAIN IS LET'S SAY, I DON'T KNOW 10 TIMES BIGGER THAN THE MOUSE BRAIN, YOU WILL NEED LESS THAN 30 MILL WATTS TO REACH THE MOUSE BRAIN, THE ANATOMY IS MORE FAVORABLE AND SO THERE MAY BE OTHER REASONS WHY, AND SO SHOWING THESE KINDS OF EFFECTS IN HUMANS HAS BEEN MORE CHALLENGING. I MEAN, EVEN JUST BECAUSE IT'S NOT EASY TO MEASURE CEREBRAL BLOOD FLOW OR ATP PRODUCTION IN THE HUMAN BRAIN. SO THATIA KIND OF THE MOTIVATION FOR OUR WORK. AND SO, MY VIEW HERE IS THAT MRI CAN BE VERY VALUABLE FOR FULL BRAIN STIMULATION IN THIS CASE, FOR PHOTO BIOMODDULATION AND THE REASON IS THAT MRI, ALLOWS US TO ACTUALLY SEE WHAT'S GOING ON WHEN YOU STIMULATE THE BRAIN WITH LIGHT. SO IT PERMITS A NONINVASIVE SPATIALLY RESOLVED READ OUT OF THE ACUTE AND ALSO THE AFTER EFFECT OF THE HUMAN BRAIN TO FET O BIOMODDULATION AND SO,--PHOTO BIOMODDULATION AND HERE'S THE PICTURE OF WHAT MOST OF OUR EXPERIMENTS HAVE LOOKED LIKE. WE GENERALLY HAVE BEEN SIMULATING HEALTHY HUMAN PARTICIPANTS AT REST AND MOST OFTEN THE MOST RIGHT FRONTAL POLE. I DON'T HAVE GREAT EXPLANATION FOR WHY WE CHOSE THE RIGHT FRONTAL POLE, THE FOREHEAD IS MOSTLY BECAUSE THERE'S NO HAIR THERE SO THERE'S 1 LESS POTENTIAL SOURCE OF VARIABILITY BECAUSE YOU DON'T HAVE THE SCATTERING AND THE RIGHT SIDE, THERE'S REALLY NO REASON. WE COULD HAVE GONE WITH THE LEFT BUT YOU WOULD NEED TWICE AS MANY SUBJECTS IF YOU WANTED TO RANDOMIZE THE HEMISPHERE THAT YOU'RE TARGETING. YOU KNOW I'VE NEVER SEEN ANY EVIDENCE FOR LIKE A HEMISPHERIC IN THE RESPONSE TO THIS TYPE OF STIMULATION. SO THE QUESTIONS THAT WE'VE BEEN TRYING TO ANSWER FOR THE LAST 2 YEARS, ON NUMBER 1 IS CAN YOU MODULATE FUNCTIONAL CONNECTIVITY WITH PBM AND TO ANSWER THAT WE'VE BEEN USING MULTIECHO BOLD SEQUENCES. ALSO MR GIVES US THE OPPORTUNITY TO DO THERMOGENESIS ORDER OF MICRONSETRY WHICH IS REALLY NICE AND WE'VE USED THAT TO ANSWER THE REQUESTY OF WHETHER PHOTO BIOMODDULATION INCREASES BRAIN TEMPERATURE AND MOST RECENTLY, WE'VE BEEN USING SPECROSCOPY, SO PHOSPHOROUS MAGNETIC RESONANCE SPECROSCOPY TO TRY TO ANSWER THE KEY QUESTION HERE WHICH IS ARE YOU ACTUALLY MODULATING ATP IN THE HUMAN BRAIN WITH THIS. >>ALL RIGHT, LOOKS LIKE I HAVE 8 MINUTES SOPHISTICATED I HAVE TO--HERE'S A--I DON'T WANT TO ALL TOO MUCH ON THE APPROACH BUT JUST SO YOU UNDERSTAND WHAT ARE--HOW OUR EXPERIMENTS ARE CONDUCTED. THEY'RE ALMOST ALWAYS LIKE THIS, BEFORE, DURING AND AFTER. WHERE BEFORE AND AFTER THERE'S NO STIMULATION AND DURING THERE IS, WELL, THIS IS FOR THE--THIS IS OUR EXPERIMENTAL TIMING DIAGRAM FOR THE FMRI STUDIES THAT WE DID, SO BASICALLY A VERY LONG BOLD SCAN, WE'RE IN THE MIDDLE OF THAT SCAN, WE STIMULATE THE PATIENTS WITH THE LASER, AND THE READ OUT HERE IS FUNCTIONAL CONNECTIVITY WHICH IS JUST CORRELATION, ACTUALLY, IT'S CORRELATION BETWEEN DIFFERENT PARTS OF THE BRAIN, AND THERE'S LOTS OF EVIDENCE, A TON OF EVIDENCE, ACTUALLY THAT THIS IS AN IMPORTANT THING TO STUDY. INFORMATION PROCESSING IS DISTRIBUTED AND YOU KNOW BRAIN STATE AND PATTERN OF CONNECTIVITY, YOU KNOW THEY'RE ALMOST 1 AND THE SAME, THERE'S JUST A PROBLEM WITH A LOT OF EVIDENCE TO SUGGEST THAT A LOT OF YOUR EXPERIENCE IS ROOTED IN JUST WHICH PARTS OF THE BRAIN ARE RIGHT NOW COMMUNICATING WITH EACH OTHER, SO, THIS WAS A NATURAL PLACE TO LOOK FOR EFFECTS. SO WHAT I'M GOING TO SHOW YOU HERE, YOU WILL SEE A BUNCH OF INFLATED COTTERISS AND THE COLOR YOU WILL SEE ON THE CORTEX WILL TELL YOU HOW STRONGLY THAT PART OF THE BRAIN IS CONNEBTED TO THE RIGHT FRONTAL POLE WHICH IS WHAT WE'RE STIMULATING. SO CONNECTIVITY IS KIND OF HARD TO SHOW. SO THIS IS BEFORE STIMULATION, SO AGAIN, WE'RE STIMULATING THE RIGHT FRONTAL POLE AND THE COLOR HERE, THE MORE YELLOW, THE MORE CONNECTED, THE REGION IS, AND THEN THIS IS--THAT WAS BEFORE, THERE IS DURING, CAN YOU SEE HOPEFULLY, IF YOU AGREE WITH ME, THAT IT'S BRIGHTER AND THEN THIS IS AFTER. SO, IT'S NOT--NOT QUITE AS BRIGHT, BUT THERE'S STILL SOMEWHAT BEEN AFFECTED AND THIS IS NOW THE RIGHT HEMISPHERE. SO I'LL SHOW YOU ON THE NEXT SLIDE, KIND OF THE WHOLE BRAIN VIEW OF THIS PREDICTURE. IN A COLOR MATRIX, SO ESSENTIALLY WHAT'S HAPPENING IS THAT THERE'S THE CONNECTIVITY WITH THE REGION THAT HAS BEEN STIMULATE SIDE GOING UP. ESPECIALLY DURING ILLUMINATION AND IT DOESN'T SEEM TO BE, IT SEEMS TO BE RATHER GLOBAL, SO HERE, NOW, THESE ARE THE CONNECTIVITY MATRIXES, SO QUADRABBITS ARE HEMISPHERES, THE MORE RED THE MORE CONNECTIVITY. WE PARCELLATE THE BRAIN HERE INTO 150 REGIONS OF INTEREST AND WE LOOK AT CONNECTIVITY MEASURED BEFORE DURING AND AFTER ILLUMINATION SO, I WILL CUT TO THE CHASE, IT DOESN'T LOOK LIKE ACTUALLY IN THE A, B, C, AND DOESN'T LOOK LIKE THERE'S MUCH GOING ON IF YOU DO A SUBTRACTION, YOU SUBJECT THESE, YOU DO SEE AN INCREASE AND WHAT'S REASSURING RATHER IS THAT THE QUADRANT THERE AND PANEL THAT HAS THE LEAST RED IS THE CONNECTIONS BETWEEN THE LEFT HEMISPHERE AND THESE ARE THE CONNECTIONS WITHIN THE NONSIMMULATED HEMISPHERE, SO THAT'S SOMEWHAT OF A VALIDATION AND YOU SEE THE EFFECTS IS LARGELY GONE AFTERWARDS, SO IT DOES SEEM, THIS INCREASE IN CONNECTIVITY DOES SEEM TO BE MOSTLY AN ACUTE PHENOMENON, IN TERMS OF TIME COURSE, SO I DON'T HAVE TIME TO GET INTO WHY WE DID MULTIPLE ECHOES, BUT WE DID DO MULTIPLE ECHOES, MOST TO TRY TO DISAMBIGUATE BLOOD FLOW ANDOX GENERATEDDATION WHICH IS MUCH HARDER THAN WE THOUGHT IT WOULD BE, BUT ECHO 3 HERE IF YOU LOOK AT THE TIME COURSE, THE VERT AXIS IS CONNECTIVITY, HORIZONTAL ACCESS IS TIME AND HOPEFULLY YOU WILL AGREE WITH ME THAT SOMETHING IS HAPPENING AT THE TIME OF STIMULATION WHICH HERE IS AT THE 5 MINUTE MARK. THERE'S ACTUALLY A SHARP DECLINE RIGHT WHEN YOU TURN ON THE LASER AND THEN, A RAPID ASCENT TO HIGHER BASE LINE LEVEL. SO IT DOES SEEM TO BE LARGELY WITH THIS EFFECT, I APPROXIMATE UTR IT IN QUOTATIONS THERE BECAUSE BOLD IS SLOW. WHEN I SAW THIS, THIS MADE ME BELIEVE THAT THERE IS ACTUALLY SOMETHING REAL HERE WE ALSO HAVE THERAPY AND MOMETRY, I WILL REALLY CUT TO THE PUNCH LINE HERE WE HAD A PHASE DIFFERENT SEQUENCE, BASICALLY LOOKS AT THE TEMPERATURE FREQUENT, TEMPERATURE DEPENDENT ATOM AND WE DIDN'T SEE ANY DIFFERENCE. WE DID A SHAM CONDITION HERE, BUT WE DIDN'T SEE ANY DIFFERENCE IN THE TEMPERATURE OF THE SIMULATOR REGION OR ANYWHERE ELSE IN THE BRAIN AT ALL. AND SO, THIS WAS AGAIN REALLY MOSTLY A VALIDATION OF THE FACT THAT THE AMOUNT OF LIGHT THAT WE'RE PUTTING INTO THE BRAIN IS NOT ENOUGH TO PRODUCE A RESOLVABLE INCREASE IN TEMPERATURE. OORK AND THE MOST RECENT STUDY THAT STILL ISN'T PUBLISHED BUT HOPEFULLY NEXT TIME WE GIVE THIS TALK WILL BE, USING PHOSPHOROUS MRS AND I WAS THINKING HOW DO I EXPLAIN THIS BAZ THE PHYSIC SYSTEM NOT STRAIGHT FORWARD BUT I CAME UP WITH THIS SEQUENCE AND ENERGY METABOLITES CONTAIN PHOSPHOROUS AND THE PHOSPHOROUS HAS A SPIN, THIS ISOTOPE HAS A SPIN AND SO IT'S ACCESSIBLE TO MR, AND SPECIFICALLY PHOSPHOROUS MRS IS WOQUANTIFYING DIFFERENT MOLECULES THAT CONTAIN PHOSPHOROUS AND SO FOSTER NURSED FOCUSED ON KRE TINSA TIEN AND ATP ARE REALLY IMPORTANT FOR ENERGY AND METABOLISM AND WITH MRS WE'RE ABLE TO MEASURE THOSE AND OBVIOUS EXPERIMENT IS TO DO THIS BEFORE, DURING AND AFTER PHOTO BIOMODDULATION, SO HERE ARE SOME PICTURES IN THE SCANNER, WE DO WHOLE BRAIN MRS, THE VOXELS ARE BIG, 1 AND HALF CENTIMETERS, AND THE PICTURE ON THE RIGHT IS A PICTURE OF A SPECTRUM, SO THE HEIGHT HEIGHT OF THE PEEK SYSTEM THE HIGHER THE CONCENTRATION, SO WE WANT TO CARE ABOUT THE RELATIVE, BASICALLY WE CARE ABOUT THE 3 PIECES ON THE RIGHT, THOSE ARE THE ATP GROUPS AND THE BIG PEEK IN THE MIDDLE, THAT'S PC R, BASED ON THE REFERENCE, LIKE A STORAGE, OF ENERGY, SO WE'RE LOOKING TO SEE WHETHER THESE PEEK HEIGHTS ARE MODULATED BY PHOTO BIOMODDULATION, SO THE EXPERIMENT WAS SAME AS BEFORE. THE ONLY DIFFERENCE IS THAT IT TAKES 10 MINUTES TO COME UP WITH 1 OF THESE SPECTRA, SO WE DID 10 MINUTES BEFORE AND 10 MINUTES DURING AND 10 MINUTES AFTER. SO FOR EVERY SUBJECT WE HAVE AND EVERY VOXEL WE HAVE 3 OF THESE SPECTRA AND WE LOOK AT DUE TO HEIGHTS OF THOSE PEAKS DIFFER. BECAUSE THIS ACTIVITIES AND PROJECTED, COVID TOTALLY KILLED--TRIED TO KILL THIS PROJECT SO WE HAD TIME TO DO SOMETHING THAT DIDN'T REQUIRE US GOING INTO THE CAMPUS SO WE DID SOME MODELING AND THE 1 THINK THIS I WAS ABLE TO DO WAS FINALLY FIGURE OUT WHAT IS--WHEN YOU STIMULATE WHAT WE THOUGHT WAS THE RIGHT FRONTAL POLE WHERE DOES THE LIGHT ACTUALLY GET ABSORBED. WELL IT TURNS OUT IF YOU BELIEVE MCX WHICH IS A GREAT TOOL, THAT THE MOST OF THE ABSORPTION IS ACTUALLY HAPPENING IN THE ORBITAL GYRUS AND I THINK THE REASON IS THE FOREHEAD ON MOST PEOPLE'S ACTUALLY SLOPED SO WHEN YOU PUT SOMETHING KIND OF NORMAL TO THE SURFACE, IT'S ACTUALLY ALREADY IN A MORE DOWNWARDS AND IT'S A LOT OF IT GOES RIGHT ABOVE THE EYE. SO THAT BECAME KIND OF OUR ROI. AND WE WERE ABLE TO DO THIS BECAUSE WE WERE STUCK AT HOME WITH SOMETHING TBU SOFTWARE. ALL RIGHT. BECAUSE I DON'T WANT TO GO OVER TIME, WHAT I WILL SAY IS, YES I THINK THERE'S AN EFFECT, NO I DON'T THINK IT'S A SLAM DID YOU THINK BUT I DEFINITELY DO WHEN I LOOKED AT, SO THE AXIS ON THE LEFT RESHAM AND POST, PRESTEM AND POST, AND THE VERTICALAXIS HERE IS THE RATIO OF ATP. IF THE RATIO GOES DOWN, ATP'S GOING UP AND THE IMPORTANT LOT IS THE SECOND PLOT THERE, WHAT YOU SEE HERE IS THAT BASICALLY ALL THE SUBJECTS, GYRATIONS GOING DOWN DURING AND AFTER, ACTIVE STIMULATION, COMPARED TO SHAM. SO IT'S--YOU KNOW IT'S A MODULATION OF THE DYNAMICS OF ATP. THAT WE SAW IN OUR COHORT. WE DID NOT SEE THIS AND I'M SHOWING YOU 1 OFFTARGET REGION HERE, THIS IS JUST ILLUSTRATED. THIS IS THE LEFT INTRA PARIETAL SULKUS FOR EXAMPLE. SO YES THERE WAS AN EFFECT, SO SIGNIFICANT EFFECT ON ATP, BUT IT'S--IT'S--YOU NEED TO COMPARE IT THE SHAM CONDITION CONNECKATIVITY INCREASED BY 1 PERCENT, AND THIS CONSIDERED THIS TO BE A BRAIN WIDE EFFECT IN TERMS OF HOW THIS HAPPENS AND THIS OCCURRED TO ME THAT ALL BRAIN STIMULATION, AT THE END ADDING ENERGY AND THE BRAIN LIGHTER OR MECHANICAL STIMULATION, IT'S ENERGY AND THE DIFFERENCE IS HOW IT'S TRANSDUCED, THIS IS JUST ANOTHER SUBSTANTIATION OF THAT, WE'RE GIVING THE BRAIN MORE ENERGY AND THE HYPOTHESIS HERE IS THAT THAT ENERGY IS BEING USED TO BRING THE PATTERN OF CONNECTIVITY CLOSER TO WHATEVER THE BRAIN WANTS, WE DO HAVE THEFS IS CHANGING ATP CONCENTRATION--THOSE 2 SYSTEMS HAVE TONS OF FEEDBACK, IT'S A PESSIMISTIC BULLET BUT P31 MRS WHICH I STILL THINK IS AN AMAZING TOOL THAT YOU CAN MEASURE ATP IN THE BRAIN, BUT I WILL SAY IT'S SLOW, IT'S NEARBY, AND IT HAS LOW SNR, OTHER THAN THAT IT'S GREAT. THANK YOU. BIG SHOUT OUT TO DUKE [INDISCERNIBLE] AND RYAN AND TAUGHT ME HOW TO DO ALL THIS MRI SEQUENCES. THANK YOU. [ APPLAUSE ] >>THANK YOU. THAT WAS VERY ENTERTAINING. JUST A SUGGESTION, I THINK YOU'VE BEEN LOOKING IN HEGHTY HUMAN BRAINS, IT'S INTERESTING BECAUSE THE MECHANISM THAT YOU'RE LOOKING AT IS BIOENERGETICS AND 1 SUGGESTION WOULD BE IF YOU APPLY THIS IN A CLINICAL STUDY, PARKINSONS IS A DISEASE WHERE IT'S IMPORTANT, I KNOW YOU MENTIONED RODENT MODELS, SO IN PARKINSON'S DISEASE, ABNORMALITY HAS BEEN SHOWN IN MITOCHONDRIA, THEY'VE BEEN SHOWN TO BE CHANGES IN THE ATP AND THE REGION YOU'RE TARGETING WHICH IS THE FRONTAL POLE IS THE ORBITAL IS THE AREA THAT IS RELEVANT IN PARKINSONS SO THIS COULD BE CLINICALLY APLIBLABLE. MORE SPECIFICALLY ABOUT QUESTIONS ON THE SITE, I'M JUST WONDERING HOW LONG DO YOU EXPECT THESE EFFECTS TO LAST FOR, I KNOW IMMEDIATELY YOU WERE SAYING 22ndS BUT BIOLOGICALLY ? >>I CAN'T KEEP THEM IN THE SCANNER MORE THAN 6 OR 8 MINUTES. HONESTLY, I THINK THAT THE ATP EFFECT LASTED AT LEAST 10 MINUTES AFTERWARDS. I CAN'T ANSWER YOU WITH ANY DATA, IT'S A CRITICAL QUESTION, WHAT I ALWAYS SAY IS THE LIKELIHOOD OF GETTING LASTING EFFECTS WILL GO UP WITH REPEATED APPLICATION, RIGHT? AND SO I'M NOT A BIG BELIEVER THAT 1 SHOT BRAIN STIMULATION WILL INCREASE YOUR MOOD FOR A MONTH LIKE SOME PEOPLE HAVE CLAIMED, BUT BUT I THINK THAT--I THINK THAT THE CIRCUITRY IS THERE TO PRODUCE A PLASTIC EFFECT BUT I IMAGINE THAT WE WILL HAVE TO REPEAT THE STIMULATIONS FOCUSED ON GET IT. >>GREAT, THANKS. >>THANK YOU. >>LET'S THANK DR. DMOCHOWSKI, AGAIN. OUR NEXT SPEAKER IS DR. KIM BUTTS PAULEY, SHE'S A PROFESSOR IN RADIO LOGICAL SCIENCES AT STANFORD UNIVERSITY AND SHE WILL BE TALKING ABOUT MRI BASED VERIFICATION OF TRANSCRANIAL ULTRASOUND STIMULATION TARGETING WITH 2 SPECIFIC TARGETS. >>THANK YOU CROSS LINKING I WANT TO TALK ABOUT HOW WE USE TRANSCRANIAL SIMULATION TO HUMANS. -SORRY, THE FLUORESCENCE MOVES AROUND WITH A FOCUS INTERESTING, ANYWAY, LET ME GET PAST THAT AND TALK ABOUT THE MRI. OKAY, SO YAN AND WYNN, SET UP VERY NICELY 1 OF THE BIGGEST PROBLEMS FOR US WHICH IS THE CULL. SO IF YOU HAVE A THIN AND HOMOGEANIOUS SKULL, THEN MAYBE YOU GET ABOUT HALF THE INTENSITY ACROSS THE SKULL. YOU COULD HAVE A LESS GOOD SCENARIO HERE WHERE YOU HAVE A THICK AND HOMOGEANIOUS AND YOU WILL AND CORTICALE BONE AND YOU GET MAYBE LIKE 20% OF THE INTENSITY SCROOSES THE SKULL BUT THERE COULD ACTUALLY BE MORE COMPLICATED CASES SO THESE ARE--I'M SHOWING YOU IMAGES HERE THAT ARE CT IMAGES HERE OF DIFFERENT SUBJECTS THAT ARE TREATED FOR ESSENTIAL TREMOR FOR ULTRASOUND AND IF YOU LOOK AT THESE SKULLS THERE'S A LOT OF HETEROGENERATED AITY IN THE THICKNESSS, AS WELL AS THE COMPOSITION, AND FOR EXAMPLE, LIKE I--I MIGHT ASK YOU WELL WHICH 1 YOU THINK IS THE LEAST TRANSMISSIVE TO ULTRASOUND, AND YOUR EYE IS PROBABLY DRAWN TO THIS 1 OVER HERE, AND PARTLY BECAUSE IT'S VERY THICK BONE, BUT ALSO BECAUSE I SHOWED IT ON THE LAST SLIDE BUT IT TURNS OUT THAT THIS 1 UP HERE IS ACTUALLY 50% LESS THAN MISSIVE AND IT'S BECAUSE IT HAS ALL THAT BONE, WHICH IS WHAT WYNN WAS ALLUDING TO IS IN PRESENTATION, WHEN YOU HAVE A LOT OF BONE, IT'S NOT TRANSMISSIVE. SO THESE REALLY SHOW YOU THE VARIATIONS BETWEEN SUBJECTS IN THE CT PICTURES BUT I SORT OF MISLED YOU A LITTLE BIT WHEN I SAID I WAS SHOWING YOU ALL THESE CT PICTURES BUT IT ACTUALLY TURNS OUT THAT 1 OF THESE ROWS IS MRI PICTURES OF SKULLS, SO NOW I MIGHT ASK YOU WHICH ROW DO YOU THINK THAT IS, BUT RATHER THAN GIVE YOU A QUIZ BECAUSE I DON'T HAVE THAT MUCH TIME AND I HAVE A LOT I WANT TO COVER, I WILL TELL YOU IT'S THE LAST ROW, AND SO THESE ARE UTE IMAGES OF DIFFERENT SKULLS AND IN CASE YOU DON'T BELIEVE ME, THERE'S THE ACTUAL IMAGES, A LITTLE BIT OF VARIATION WAS USED, I DON'T REALLY GO INTO THAT. BUT MRI PICTURES OF THE SKULL ARE GETTING BETTER AND BETTER ALL THE TIME. THERE WERE BEAUTIFUL PICTURES AND THIS SET RIGHT HERE SHOW YOU, YOU CAN ALSO USE THOSE FOR LOOKING FOR CALCIFICATIONS WHICH COULD BE VERY USEFUL TO US. OKAY, SO WHAT DO WE WANT TO DO WITH THOSE? ONE OF THE THINGS WE HAVE TO DO IS ASSESS THE ATTENUATION AND BASE ABERRATIONS CORRECTIONS WHICH WAS ALLUDED TO EARLIER, SO I HAVE A COUPLE OF ANIMATIONS HERE THAT SHOW YOU WHAT THE ISSUE IS, SO IF WHAT YOU HAVE IS YOUR BEAM GOING THROUGH HOMOGENERATED YIEWS SKULL, THEN YOU SEE THE OTHER SIDE IS THAT THE WAVE FRONTS ARE ALL IN FACE AND THAT'S IN CONTRAST TO THE SITUATION NOW WHERE IF YOU HAVE YOUR WAVE FRONTS COMING THROUGH, A SKULL THAT IS VARIABLE THICKNESS, SO IT'S NOW GOING TO HIT THE SKULL, THOSE WAVE FRONTS WILL SPEED UP AS THEY GO THROUGH THE SKULL BECAUSE IT'S VARIABLE THICKNESS THEY COME OUT ON DIFFERENT PHASES ON THE OTHER SIDE. SO NOW WE HAVE THE SITUATION WHERE OUR BEAM WAS--I DIDN'T MEANINAR TO PLAY AGAIN WAS INITIALLY END FACE AND THEN, IT WAS COHERENT AND THEN IN THE END IT WAS INCOHERENT OR OUT OF FACE SO IF YOU LOOK OVER HERE YOU CAN SEE IT'S A HIGH PRESSURE POINT AND A LOW PRESSURE POINT AND WHAT DOES THAT DO, SO IF YOU HAVE A BEAM WHICH IS NOT ABNORMALITIESERATED AND MORE AND MORE ABERRATION LOOKS LIKE THAT. AND SO WHAT IF YOU SAY THESE SKULLS OVER HERE YOU MIGHT HAVE SIGNS THAT ARE A LITTLE BIT ABNORMALITIESERATED AND OVER HERE VERY ABNORMALITIESERATED THIS IS AGAIN WHAT WYNN MENTIONED AND THIS IS AN INTERESTING CASE BECAUSE IT MAY NOT BE VERY ABNORMALITIESERATED BUT IT WOULD BE REFRACTED MEANING IT WON'T BE WHERE YOU THINK IT IS. SO MY POINT HERE WAS THAT MRI CAN DO A GOOD JOB OF DIAGONALLING YOU NOT JUST ABOUT THE ABSORPTION OF THE ATTENUATION BUT ALSO THE ABERRATION CORRECTIONS AND THE IDEA HERE IS THAT IF YOU CAN CALCULATE WHAT THE PHASES SHOULD BE THROUGH ANY PORTION OF SKULL, CAN YOU PREPHASE THE ELEMENTS IN ORDER TO MAKE SURE THE BEAM IS COHERENT AT THE FOCUS. OKAY, SO TO PROVE THAT POINT, MY STUDENT STEVE YOUNG DID THIS WITH THE INSIGHT TRANSDUCER, HE HAD 3 DIFFERENT SKULLS AND HE DID THIS VERY CAREFUL SET UP WHERE HE PUT THE SKULLS IN THE TRANSDUCER AND HE HAS A HYDROPHONE RIGHT HERE AND HE CAN TURN THE TRANSDUCER ON AND GET A PICTURE OF THE FOCAL SPOT AND IN THE ABSENCE OF ANY PHASE CORRECTION, YOU SEE SOMETHING THAT LOOKS LIKE THAT SO THE INTENSITY IS A BIT LOW AND ON AVERAGE IT'S A BIT LOW COMPARED TO THE SITUATION WHERE YOU WERE TO DO THE BEST CORRECTION YOU COULD THAT MEANS YOU WOULD CALCULATE THE PHASES WITH THAT HYDROCONE AS YOU TURN ON 1 ELEMENT OF A TIME, YOU COULD CYCLE THROUGH ALL THE ELEMENTS AND CALCULATE THOSE PHASES ARE AND YOU CORRECT FOR THAT AND THAT'S THE BEST YOU CAN DO AND SO, THAT'S WHAT I'M GOING TO GIVE OVER HERE WITH A NORMALIZED TO THAT 1 SO IT'S A VALUE OF 1. OKAY, WHERE AM I GOING WITH THIS? I WANTED TO TELL YOU ABOUT MRI VERSUS CT. SO THE IDEA NOW IS IF YOU TAKE YOUR MRI PICTURE OF THE SKULL AND SAY LET'S CALCULATE WHAT THAT PHASE TERM SHOULD BE, YOU DO THAT FOR THE PATHS AND YOU THEN YOU GET A PICTURE OF THE FOCAL SPOT AS MEASURED AND YOU CAN DO THAT WITH CT AS WELL AND HOW DO THEY COMPARE, OOPS, SORRY ABOUT THAT, NIGH NEED TO GO BACKWARDS. AND THEN WHAT YOU SEE, THE COMPARISON IS THAT ACROSS THE 3 OTHER SKULLS ON AVERAGE THEY ARE EQUIVALENT. THEY GIVE YOU AN EQUIVALENT OF FOCAL SPOT, AT THE--THIS WAS JUST 1 OF THOSE 3 SKULLS BUT ON AVERAGE ACROSS THE 3, THEY'RE EQUIVALENT SO MRI CAN BE USE INDEED PLACE OF CT. OKAY, SO THAT'S 1 PLACE, 1 OF THE 3-POINTS I WANTED TO DISCUSS. THE SECOND 1 IS CAN MRI BE USED TO MAKE A MEASUREMENT. SO, WE TALKED A BIT ABOUT WELL, YOU COULD CALCULATE WITH THE PHASE IS, YOU COULD DO A BEAM SIMULATION BUT COULD YOU MAKE A MEASUREMENT OF WHAT ACTUALLY REACHES THE BRAIN AND THEN WHAT CAN THAT TELL US. SO, WE DID A STUDY, LARGE ANIMAL STUDY, WITH THE FRY BROTHERS DID BACK IN THE 1950SALY WE DID IT ACROSS THE INTACT SKULL IN THE SHEEP AND WE SONICATED LGN WHILE THERE WERE FLASHING LIGHTS ON THE SHEEP MODEL HERE. WE DID THIS WITH THE INSIDE TRANSFACIC TRANSDUCER, 500 KILOHERTZ WHICH IS GREAT, NOT SUITABLE FOR HUMAN USE BUT WE WERE ABLE TO USE IT FOR THIS STUDY. THE SHEEP MODEL AGAIN HAS A THIN AND HOMOGEANIOUS SKULL AND WE AFFIXED THE TRANSDUCER TO THE TOP OF THE MR HEAD COIL. WE HAD TO USE THE HEAD COIL BECAUSE IT WOULD ACCOMMODATE THE SHEEP NOSE AND YOU CAN SEE THE LED FLASHING LIGHTS HERE ON THE SHEEP. OKAY, SO WE PUT THEM IN THE MR UNDERANESTHESSIA AND FIGURED OUT WHERE THE LGN WAS AND WE COULDN'T FIND THE RIGHT CLAIM IN ORDER TO DO THAT STUDY SO WE REFER TODAY BACK TO PUTTING ELECTRODES BACK ON THE SUBCUTANEOUSLY OVER THE VISUAL CORTEX AS WELL AS FRONTAL PART OF THE BRAIN AND THEN OUR PARADIGM WENT LIKE THIS, SOPHISTICATEDY THEY WERE AN THESAURUS THISITIZED DOING THE E, G AS WE FLASHING LIGHTS IN ORDER TO MEASURE THE POTENTIAL WHICH WOULD BE 240 MINUTES PERIOD FOLLOWED BY 2-3 MIN PERIODS OF SONIC CONTROL LOCATION SO WE HAD AN ACTIVE CONTROL, DURING THAT PERIOD THERE WAS 1 THAT WAS ONLY LIGHT ONLY AND 1 THAT WAS ULTRASOUND ONLY, BUT I WILL SHOW YOU THE RESULTS FROM THE LIGHT ONLY. AND SO THAT MEANS IT'S A BIT MORE LIKE AN OFFLINE PROTOCOL IN THAT THE ULTRASOUND HAD BEEN ON DURING OTHER--ANOTHER 152nd PERIOD BUT WE WEREN'T LOOKING RIGHT AFTER THE ULTRASOUND. AND THE HEART RATE AND TEMPERATURE MAINTAINED CONSTANT WHICH IS SORT OF LIGHTENING UP. SOPHISTICATED OKAY, SO THIS LOOKS AS IF OUR FOCAL SPOT LOOKED LIKE AND WE DID THE SIMULATIONS AND THEN WE DID AN PICTURE SO WE'RE ABLE TO GET A PATIENTS IN THE CLINIC UPPER OF THE FOCAL SPOT SO I WANT TO TAKE TIME TELLING YOU ABOUT MRRP, AND THE WAY WE USE IT AT THE TIME WAS SORT OF VERIFYING OUR TARGET, WELL 2 THINGS FIRST OF ALL WAS THE EQUIPMENT WORKING, THAT WAS IMPORTANT TO KNOW. YES WE GOT AN ULTRASOUND INTO THE BRAIN AND IS IT WHERE WE PRESCRIBED IT TO BE? BECAUSE IT'S ENTIRELY POSSIBLE IN A SKULL THAT WASN'T THIN AND HOMOGEANIOUS IT MAY HAVE BEEN DISPLACED AS I MENTIONED BEFORE BUT HERE IT GAVE US THE LOCATION WHERE WE WANTED IT SO THAT WAS GREAT. SO JUST A BIT OF A DIGRESSION AS TO HOW THIS WORKS. WHEN YOU TURN ULTRASOUND ON, THERE WILL BE ABSORPTION OF MOMENTUM, YOU LOOK AT THE FOCUS, THEY WILL ABSORB AND THEN I WILL DISPLACE AS CAN YOU SEE THERE, SO WITH MRI WHAT HAPPENS IS THAT WE TURN THE ULTRASOUND ON, DURING THE APPLICATION OF A MAGNETIC FIELD GRADIENT. SO WHEN WE DO THAT NOW, WE THINK ABOUT PROTONS, SPINS ABOVE PROTONS THEY WILL MOVE TO A HIGHER MAGNETIC FIELD, THEY WILL ACCUMULATE PHASE DEPENDING ON THE DISTANCE THAT THEY MOVED AND NOW WHAT WE'VE DONE IS WE ENCODED INTO THE PHASE WHAT THAT DISPLACEMENT WAS. IN OTHER WORDS WE ENCODED TO THE FACE WHAT THE INTENSITY OF THE ULTRASOUND IS. SO THIS WAS SORT OF A SIMPLE IMPLEMENTATION, WE DON'T USE SOMETHING WIGHT THAT SIMPLE. WE USE SOMETHING QUITE LIKE THIS, IT HAS A LOWER B-VALUE SO WE HAD BETTER SIGNAL TO NOISE. THAT'S WHAT OUR EXVIVO PICTURE LOOKED LIKE AND THEN FOR ANY PARTICULAR SET UP, AS YOU INCREASE THE POWER ON THE TRANSDUCER, THEN YOU GET MORE DISPLACEMENT AND SO, THIS IS JUST SAYING AS WE HAVE MORE INTENSITY, AND WE TURNED IT UP, THE POWER AND WE GET MORE DISPLACEMENT. SO THE REQUESTY IS, CAN WE MEASURE DISPLACEMENT AND BACK OUT THE INTENSITY OR EFFECT? SO THE EFFECT WE WERE LOOKING AT WAS IN THE SHEEP. WE WERE LOOKING AT REDUCTION IN THE VISUALLY EVOKED POTENTIAL SO THIS IS THE ANIMALS, THIS IS JUST 1 OF THEM SHOWING YOU THE TRACE THERE, SO THE BASE LINE IS IN BLUE, WE WERE LOOKING AT THE DIFFERENCE BETWEEN THE N70 AND THE P100 PEAKS AND SEEING WHEN WE WERE SONICATING LGN THAT WAS REDUCED. JUST LOOKING OVER A NUMBER OF ANIMALS, HERE'S THE SHAM ANIMALS AND ON AVERAGE THERE'S NO DIFFERENCE AND IN THE 1S WE WERE SONICATING, THERE WAS A REDUCTION AND WE WERE SONICATING IT AT ACTIVE CONTROL AND THIS IS JUST IN THE BAR GRAPH OF THAT SAME DATA AS WELL AND THESE 2 LGN TIME POINTINGS TOGETHER IN THE 3 CONTROLS THERE. OKAY, SO WE SEE A REDUCTION AND DOES THE MRR, TELL US ABOUT THE REDUCTION? IN THIS PLOT WE HAVE THE REDUCTION IN THE VISUALLY REVOKED POTENTIAL SO HERE WE SEE THE SITUATION WHERE THERE'S LOWER SKULL ATTENUATION, THERE'S MORE DISPLAYMENT AT THE FOCUS AND THAT'S WHERE WE HAD A BIGGER REDUCTION IN THE VISUALLY EVOKED TO PENTINE REGIMENNIAL, OVER HERE THERE'S HIGHER SKULL ATTENUATION, LESS DISPLACEMENT AND LESS OF A REDUCTION, SO THIS IS REALLY NICE BECAUSE NOT ONLY WOULD IT TELL US, YES, IT'S WORKING AND THE SPOT IS WHERE WE THINK IT SHOULD BE, BUT IT ALSO TELLS US HOW MUCH INTENSITY WE'RE ACTUALLY GETTING INTO THE SKULL AS OPPOSED TO KIND OF SIMULATING JUST ENOUGH. AND THEN THEREFORE, HOW MUCH OF A MODLATTORY EFFECT DO YOU THINK WE'RE GOING TO GET. OKAY, SO THE THIRD THING I WANT TO TALK ABOUT TODAY IS A BIT ON THE AUDITORY COMPOUND AND THEN MRI WILL PLAY A ROLE HERE TWICE SO THE STORY HERE IS THAT FIRST OF ALL IT'S BEEN A COUPLE YEARS SINCE WE WERE SORT OF REAWAKENED TO THE ISSUE THAT ULTRASOUND CAN BE HEARD. AND SO, IF YOU HAVE AN ULTRASOUND ENVELOPE THAT LOOKS LIKE THIS WITH A RECK TANGLE THEN IT'S A RECENT PUBLICATIONS, SHOWED THAT IN RODENTS, THAT COULD BE HEARD AND THEN WE FOLLOWED UP WITH A PUBLICATION THAT SHOWED IF YOU SMOOTH YOUR WAVE FORMS, AND YOU DON'T HAVE FREQUENCY, IMPLEMENTS THAT OVERLAP IN THE HOUSE HEARING RANGE THEN IT DOESN'T INVOLVE THE PERIPHERAL AUDITORY SYSTEM, OKAY, SO NOW, IN 2022, WE 2 WEEKS AGO HAD THE FOCUS ULTRASOUND MODULATION CONFERENCE AND THERE'S A FAIR AMOUNT OF FOCUS ON THE ISSUE OF THE AUDITORY COMPOUND IN HUMANS SO 2 OF THE LABS THERE, LEONARD AND [INDISCERNIBLE] WERE BOTH SHOWING THAT IF YOU USED A WAVE FORM THAT HAS THESE SQUARE COMPONENTS, THEN IT'S GOING TO AFFECT AN ONLINE TASK THAT HAS ATTENTION EFFECT. AND THEN ALSO THE IMPLICATION IS THAT IF THERE'S GOING TO BE A TREATMENT THAT WILL HAVE A PLACEBO EFFECT THEN THAT COULD BE EFFECTIVE AS WELL. ALL RIGHT, SO, WHEN I WAS ON SEBATICLE THIS SUMMER I SPENT A MONTH WITH [INDISCERNIBLE] AND WE DID A PILOT STUDY AND IN THIS STUDY WE STUDIED 7 SUBJECTS WHERE WE,A PLIED A RECTANGULAR WAVE FORM LIKE THIS, THAT WAS 20-SECONDS LONG AND THIS 1 LOOKED RAMPED UP AND THIS IS WHAT THE POWER SPECTRA LOOKS LIKE. SO IN THE RECTANGULAR WAVE FORM THERE'S PREQUENCY COMPONENTS ACROSS THE HEARING RANGE, HEARING IS DEFINED AS 32-HERTZ, 2/16 KILOHERTS. SO WE HAVE A REDUCTION HERE IN THE FREQUENCY COMPONENTS THAT HUGH MANS ARE MOST SENSITIVE TO FROM 1 TO 41 KILL HERTZ TO 1 KILL HERTZ AND THERE'S REDUCTION OF MAGNITUDE IN THE POWER SPECTRUM SO WHAT HAPPENED WITH OUR SUBJECTS. AS I MENTIONED WE HAD 7 SUBJECTS AND WE WOULD INCREASE, WE INTERSPERSED THESE TO IN A RANDOM ORDER AND WE INCREASE INDEED LOWERED THE PRESSER LEVEL AND ASKED THEM WHEN WHO RAISED THEIR HAND WHEN THEY HEARD SOMETHING AND HERE WE'RE PLOTTING THE DETECTION THRESHOLD SO THIS IS FOR THE RECTANGULAR PULSES SHOWN HERE WITH ALL THE FREQUENCY COMPONENTS HERE SAYS KROO THE RAIRVELG SO YOU SEE THE DETECTION THRESHOLD IS A LOW PRESSURE, AND THEN WITH THE SMOOTHED WAVE FORM IT INCREASES ON AVERAGE THE DETECTION THRESHOLD WITH PRESSURE. SO THAT WAS REALLY GREAT SAYING THAT YOU KNOW THIS CAN REALLY REDUCE THE AUDITORY COMPOUND IF YOU SMOOTH THE FORM IN RODENTS, THE SAME THING HAPPENS FOR HUMANS AS WELL. SO THAT'S REALLY GREAT. I DO WANT TO POINT OUT THE FACT THAT WHILE MRI IS VERY USEFUL, CAN BE USED FOR LOTS OF THINGS, IF, MRI, FOR EXAMPLE, THAT I JUST MENTIONED, THAT THIS AUDITORY ISSUE IS VERY PROBLEMATIC FOR MRI, IT'S ALREADY A LOUD ENVIRONMENT AND THEN WE'RE TALKING ABOUT APPLYING ULTRASOUND WHICH CAN BE HEARD ESPECIALLY IF YOU DO SOMETHING LIKE A 1 KILOHERTZ RECTANGULAR PULSE LINGS THAT ARE INCREDIBLE LOAMACYY LOUD AND TO TOP IT ALL OFF, IT'S ESPECIALLY PROBLEMATIC BECAUSE IF YOU WEAR EAR PLUGS THE CONDUCTED SOUND IS A THOUSAND TIMES LOUDER, SO IT'S VERY PROBLEMATIC FOR MRI IN TERMS OF SAFETY. IT'S ALSO ANOTHER POINT I WANTED TO POINT OUT HERE IS THAT IT'S ACTUALLY VERY INTERESTING, SO THIS PARTICULAR WAVE FORM WAS A LITTLE BIT COMPLEX, IT SOUNDED MORE LIKE A--ACTUALLY PLAYED 3 IN A ROW, 2 OR 300 MILLISECONDS APART SO IT SOUNDED LIKE TSH-TSH-TSH. SO THIS JUST RESULTED IN A VERY HIGH PITCH. HIGHER PITCH THAN THE ENVELOPE OF THAT WAVE FORM WOULD HAVE SUGGESTED BUT THAT IS WELL CORROBORATED WITH THE LITERATURE THAT THERE IS A FREQUENTLY HIPITCH. AND WE LOOK AT THIS DATA OVER HERE, IT WAS VERY INTERESTING BECAUSE AGAIN, THE SUBJECTS REPORTED THIS HIGH PITCH AND ALL OF THESE SUBJECTS, WELL I SHOULD SAY, 6 OUT OF THE 7 WERE WERE TESTED AND HAD NORMAL HEARING AND THE PURPOSE WHO HAD THE BEST HEARING WAS THE LIGHT PLURIBU AND THEN THEY COULD NOT HEAR THAT HIGH PITCH. SO THERE'S A LOT OF VARIABILITY IN TERMS OF COULD HEAR WHAT. AND THEN, LASTLY IT WAS VERY INTERESTING BECAUSE I WAS ABLE TO LOOK BACK, 5 OF THE 7 SUBJECTS HAD BONE MRIs AND I WAS ABLE TO LOOK BACK AND SEE HOW THORS THRESHOLD DETECTION RELATED TO SKULL THICKNESS AND YOU CAN SEE THAT THE DETECTION THRESHOLD WAS HIGHER WHEN THEY HAD A THICKER SKULL. SO MOST LIKELY THAT'S TELLING US THAT WELL, THERE'S 2 POSSIBILITIES, EITHER THE THICKER SKULL DIDN'T SORT OF RESONATE TO THE ULTRASOUND IN THE SAME WAY OR THAT WHAT THEY HEAR WITH THAT HIGH PITCH IS BECAUSE THE ULTRASOUND IS GETTING THROUGH AND THEN IT'S SORT OF VIBRATING THE TISSUES AND THAT'S GOING IN VIA TISSUES MAYBE THROUGH THE INTURNOVERRAL AUDITORY CANAL BUT THERE'S I LITTLE HERE WE HAVE STOCK EXCHANGE STUDY AND IN TERMS OF BONE CONDUCTION AND WILL END UP BEING VERY INTEREST. OKAY, SO I WOULD LIKE TO CONCLUDE NOW. MR SKULL IMAGING CAN BE EQUIVALENT TO CT, WITH THE GOOD PICTURES WE'RE SEEING, IT COULD BE USED TO SCREEN FOR KAGZ ESKSS, MRR FEE WILL BE A VERY IMPORTANT TECHNIQUE TO ASSESS LOCATION AND ALSO PROVIDE A MEANS TO ELECTRIC AT THE DOSE ACTUALLY DREVERRED INTO THE BRAIN IN ORDER TO GET A SENSE OF THE DOSE RESPONSE AND THEN LASTLY, NOT LISTED HERE, WE DO NEED TO BE CAREFUL OF THE AUDITORY COMPOUND, NOT JUST FOR THE COMPOUND FOR THE TASK BUT ALSO IN TERMS OF SAFETY AND THE AUDITORY EFFECTS WITH ULTRA SOUND COULD BYE-BYE A SAFETY ISSUE. --BECOME A SAFETY ISSUE. I THINK I'M OUT OF TIME. DO WANT TO ADVERTISE THE FOCUS ULTRASOUND MODULATION CONFERENCE IN 2023. WE AS A MULTIDISCIPLINARY CONFERENCE FOCUSING ON MECHANISMS, NEUROSCIENCE AND CLINICAL APPLICATIONS AND TECHNICAL ADVANCEMENTS. I WOULD LIKE TO ACKNOWLEDGE MY GROUP, FUNDING AND MY CENTERS. THANK YOU IF YOU HAVE QUESTIONS, I AM HAPPY TO ANSWER THEM AT THIS TIME. >>[ APPLAUSE ] >>QUESTIONS FOR DR. PUTTS PAULEY. >>GREAT TALK. DID YOU--HOW WELL DO YOUR DISPLACEMENT MEASUREMENTS CORRELATE WITH ATTENUATION MEASUREMENTS FROM ANY KIND OF ACOUSTIC MODELS WHETHER THEY CORRELATE THAT WAS 1 WAY TO MEASURE IT, SO HOW WELL DID THOSE WORK? >>THEERGT OF THEM CORRELATED WITH IT EITHER, SO SINCE THERE WAS A GOOD CORRELATION BETWEEN THE DISPLACEMENT, YOU BELIEVE THOSE MORE THAN WE BELIEVE THE OTHER 2 METRICS. ANOTHER QUESTION? >>HOW WELL DO YOU THINK IF YOU DID AN OFFLINE ULTRA ULTRASOUND MAKE GET THE PREDATORY ISSUES? >>HOW MUCH OFFLINE DO YOU THINK I WOULD RSKT AFFECTED FOR IT. >>YEAH. >>I'M NOT SURE, THAT MIGHT BE SOMETHING FOR THE CLINICAL SCIENTISTS TO FIGURE OUT. I THINK IT WOULD BE INTERESTING TO FIND OUT. , THANK YOU. >>GREAT. TALK I HAVE A QUESTION ABOUT YOUR AUDITORY CONFOUND. IF YOU LOOKED AT THE AUDITORY CORTICALE RESPONSE AND HOW THAT MAYBE CORRELATE TO THE DETECTION? OR ANY WAY AND THAT GIVES TOO ABOUT WHETHER THAT'S LIKE BONE? >>SO WE HAVEN'T DONE THAT IN HUMANS, WE HAVE DONE SOME WORK IN THE MOUSE WITH THE CALCIUM I WAS TELLING YOU THERE AND WOOF BEEN MAINLY LOOKING AT THE SMOOTH WAVE FORMS BECAUSE WE WANT TO TO STAY AWAY FROM THE AUDITORY CONFOUNDS, WE HAVE DONE JUST A TOKEN NUMBER WITH A RECTANGULAR WAVE FORM IS IT SEEMS SORT OF ON THE SURFACE AND QUANTITATE THAT AND THAT THE FLUORESCENCE RESPONSE WE SEE IS VERY HIGHLY CORRELATED TO THE PRESSURE TIMES THE SQUARE ROOT OF THE DURATION OF THE PULSE, AND SO THAT HOLDS FOR BOTH WHEN YOU LOOK AT THE LOCUST. >>YOU SAW MAYBE REDUCTION OF THE VP, STRONGER EFFECT FOR THE STRONGER DISPLACEMENT, THAT IS QUITE IMPRESSIVE TO ME AND 1 THING THAT WE CAN OBSERVE ACROSS THE 3 TALKS TODAY, AT LEAST BECOME AN OBSERVATION TO ME WAS THE INHIBITION IN RESPONSE TO THE ULTRASOUND. SO, WE MIGHT START THINKING OF WHY WE SEE THESE INHIBITORY EFFECTS IN THESE CASES, AND YOU HAVE ANY THOUGHTS ON THAT. >>YEAH, THERE'S A FAIR AMOUNT OF WORK GOING ON RIGHT NOW, LOOKING AT RODESSENTS WITH THE CALCRUM IMAGING OF WHERE THEY MAKE A GCAMP MODIFICATION, I SHOULD SAY ME AND OTHERS ARE ON EXCITATORY CELLS AND INHIBITORY CELLS AND IT'S ACTUALLY VERY INTERESTING THAT IT SORT OF A RESPONSE DEPENDS ON THE MAKE UP OF THE CELLS IN DIFFERENT PARTS OF THE BRAIN. SO THE CORTEX FOR EXAMPLE WHERE HAVE YOU BOTH AND YOU SEE A BIG RESPONSE AND YOU POLIT IT OUT, IT SEEPS LIKE THE INHIBITORY CELLS HAVE SORT OF A DECREASE AND MAYBE THE INTERPRETATION THEN IS THAT THE INHIBITORY CELLS ARE SHUTTING DOWN, THE EXCITATORY CELLS, HAVE A BIG RESPONSE, SO I THINK A LOT OF IT HAS TO DO WITH THE CELL MAKE UP, IN THAT WHEN WE THINK ABOUT IF SOMETHING'S EXCITATORY OR INHIBITOR, WE HAVEN'T TAKEN THAT INTO ACCOUNT AND I THINK WE THINK BACK ON THEKS SIGHTATTORY AND INHIB THORS ORT WE SHOULD PROBABLY TRITE TO DISAMBIGUATE THAT BEFORE WE MAKE CONCLUSIONS. MAYBE WE SHOULD REINREPRESENTATION AT THE TIME OUR LITERATURE. >>ADDITIONAL QUESTIONS FOR DR. BUTTS-P A ULY? ALL RIGHT. GREAT LETS THANK THE DOCTOR AGAIN. [ APPLAUSE ] >>ALL RIGHT, I'M BASTIAN AND I WILL START THE PROFFERED PAPERS ORAL SESSION. I WOULD LIKE TO REMIND THE SPEAKERS TO USE THIS SLIDE, IF YOU DON'T HAVE THE SLIDE, SAY IT OUT LOUD. AND FINALLY IF AURORE NIEWENHUYS, IF YOU ARE HERE PLEASE UPLOAD YOUR PAPER IF YOU ARE NOT HERE WE WILL MOVE ON. AND RIGHT NOW WE WILL HEAR FROM HARRIET LEA-BANKS AND SHE WILL TALK ABOUT MRI-GUIDED TRANSCRANIAL FOCUSED ULTRASOUND FOR ANESTHETIC DELIVERY IN THE BRAIN. >>HELLO, DISCLAIMER AND PROFESSORS THOSE THAT ARE USED IN THIS WORK. THIS IS A REAL COLLABORATIVE EFFORT BETWEEN A GROUP OF SCIENTIST DEPARTMENT AND SUNNY BROOK AND THE ALSO THE DIVISION OF NEUROSURGERY AND OUR COLLEAGUES IN NEUROSURGERY ARE ABSOLUTE EXPERTS IN DEEP BRAIN STIMULATION BUT ARE NOW LOOKING FOR A NONINVEIGHS ALTERNATIVE METHOD TO EITHER EXCITE OR INHIBIT SPECIFIC PARTS OF THE BRAIN AND WORK WE'VE BEEN INVOLVED IN LOOKS AT USING NANO PARTICLES TO DELIVER ANESTHETIC AGENTS IN SPECIFIC REGIONS OF BRAIN GUIDED AND TARGETED WITH MRI GUIDED TRANSCAIN ARIAL FOCUSED ULTRASOUND. AS WE'VE HEARD ALREADY TODAY, MANY TIMES FOCUSED ULTRASOUND ALONE IS ABLE TO MODULATE NEURONAL ACTIVITY. BUT PREVIOUSLY, WE'VE SHOWN THAT YOU CAN USE ULTRASOUND TO TRIGGER THE RELEASE OF ANESTHETICS IN THE BRAIN, IN PARTICULAR, WE'VE BEEN LOOKINGA THE ANESTHETIC AGENT PENTIUM BARB TOLL-LIKE RECEPTOR WHEN LOOEDED INTO THE DROPLETS, THESE LIQUID FILLED NANO DROPLETS, THEY UNDERGO VAPORIZATION, THEY TRANSFORM FROM A LIQUID NANO PARTICLE INTO A GASEOUS MICROBUBBLE. AND AS THEY UNDERGO THIS PROCESS, NOT ONLY DO THEY EMIT UNIQUE ACOUSTIC EMISSIONS WE CAN DETECT IN REALTIME THEY ALSO OFFLOAD ANY DRUG THEY MIGHT BE CARRYING IN THEIR SHELL FOR EXAMPLE, FOR EXAMPLE AN ANESTHETIC AGENT. AND WE'VE BEEN ACIAL TO SHOW IF WE TRIGGER THIS MOTORIZATION, IN 1 HALF OF THE MOTOR CORTEX, WE CAN SEE A ROBUST AND SUSTAINED MOTOR SENSORY DEFICIT WHICH LASTS UP TO 2 HOURS AFTER TREATMENT AND THIS IS PERHAPS THE BEGENERATEDDING OF COMPATTING THOSE LIMITATIONS AROUND USING FOCUS ULTRASOUND FOR NEUROMODDULATION AND TYPICALLY THOSE TRANSIENT EFFECTS PERHAPS BY USING ULTRASOUND TO DELIVER AN AGENT THAT HAS A LONGER LASTING EFFECT, WE CAN SUSTAIN AND ENHANCE THE PERSISTENCE OF ULTRASOUND FOR NEUROMODDULATION. TO GIVE YOU A BIT OF BACKGROUND ABOUT THESE NANO DROPLETS, THEY'RE RELATIVELY TIGHTLY SIZE DISTRIBUTED WITH A DIAMETER OF 200 NONE O METERS BUT WHEN THEY UNDERGO VAPORIZATION THEY TRANSFORM INTO 1 MICRON SIZED MICROBUBBLES. THIS IS OF A TYPICAL SIZE AT LEAST BOTH IN CLINICAL DIAGNOSTIC IMAGING AND FOR BLOOD BRAIN BARRIER IMAGING, WE SEE THAT THIS VAIBORRIZATION PROCESS IS PRESSURE DEPENDENT AND DEPENDING ON THE FORMULATION OFLET DROPMENTS AND THE FREQUENCY WE USE AS WE RAMP UP THE ULTRASOUND PRESSURE, WE SEE THIS DISTINCT THRESHOLD BY THOSE DROPLETS VAIBORRIZE, THEY EMIT THESE EMISSIONS AND ALSO WE FIND THOSE ACOUSTIC EMISSIONS MAP TO THE EXTENT OF DRUG RELEASES THAT'S OCCURRING. AS I MENTIONED THIS VAPORIZATION THRESHOLD IS ALSO RELATIVE AND ALSO DEPENDENT ON FREQUENCY. WE FIND THAT HIGHER FREQUENCIES, TYPICALLY FOR THIS FORMULATION REQUIRE HIGHER ULTRASOUND PRESSURES. SO HOW DO WE ACHIEVE THIS IN VIVO, WELL WE'RE USING THIS MRI GUIDED TRANSCRANIAL AND SINGLE METROPOLITAN TRANSDUCER WHICH WE'RE DRIVING THIRD HARMONIC FREQUENCY AND IN THE CENTER OF THERE IS A HYDROPHONE, A SECOND TRANSDUCER THAT'S LISTENING BACK TO ANY EMITTED ACOUSTIC FROM THAT FOCAL REGION. THE RAT HERE IS PLACED AND THE HEAD IS--SO YOU CAN SEE HERE THAT THE CENTRAL LOCATION OF THAT MR IMAGE WAS CO REGISTERED TO THE WELLICATION OF THE ULTRASOUND FOCUS, WE'RE ABLE TO GET ACCURATE TARGETING OF OUR ULTRASOUND FOCUS WITHIN THE BRAIN. IN TERMS OF TREATMENT, WE'RE USING A SIMPLE ULTRASOUND PULSING SCHEME, 10 MILLI SECOND BURSTS, PULSE EVERY SECOND FOR A DURATION OF 5 MINUTES. DISP THOSE DROPLETS ARE DELIVERED THROUGH IV. PREVIOUSLY THE WORK I'VE SHOWN YOU HAS BEEN WITH THE INTACT BLOOD BRAIN BARRIER, NOTHING HAS CHANGED IN TERMS OF THE COMPETITION OF THE BRAIN. WE'VE BEEN USING SMALL LIP OPHILIC AGENTS THAT ARE ABLE TO CROSS THE BLOOD-BRAIN BARRIER SO RECENTLY WE DELIVERED CO DELIVERING MICROBUBBLES ALONGSIDE NANO DROPLETS TO SEE IF THIS EFFECT COULD BE ENHANCED AND SUSTAINED FURTHER. SO IN THIS SCHEMATICIME SHOWING YOU 4 SEQUENTIAL EEVENLGT EVENTS THAT HAPPEN DURING OUR PROTOCOL. SO FFORTLY WE'RE INJECTING MICROBUBBLES AND NANO DROPLETS TOGETHER IN THE RAPS, WE THEN VERIFIED THAT WE'RE ABLE TO ACHIEVE BLOOD BRAIN BARRIER OPENING, SO HERE YOU CAN SEE SOME OF THOSE UNIQUE AKOWOF THETIC EMISSIONS THAT WE ONLY DETECT WHEN WE HAVE DOUBLES PRESENT, HARMONIC FREQUENCIES WITHIN ULTRASOUND SPECTRA, BUBBLES RESPOND AT MUCH LOWER PRESSURES THAN NANO DROPLETS, SO LEER WE'RE USING A LOW PRESSURE ULTRASOUND SONICATION, SO YOU EXCITE THE MICROBUBBLES, THE DYNAMICALLY RESPONDING IN SIZE AND THEY'RE OPENING UP THOSE TIGHT JUNCTIONS INCREASING THE PERMIABILITY OF THE BLOOD BRAIN BARRIER. WE VERIFIED THE BLOOD BRAIN BIRRIER SURFACESSIER HAS BEEN CHANGED IN SOME WAY BOTH THROUGH MRI CONTRAST ENHANCED IMPEDIMENTSAGING, THIS IS AN AGENT WE INJECT OR THROUGH EVANS BLUE FOR HISTOLOGICAL APPROACH, BOTH OF THESE ARE 2 DYES WITH AN INTACT BRAIN BEAR AREA WOULD NOT BE SEEN IN THE BRAIN TISSUE. THIRDLY WE WAIT FOR THOSE MICROBUBBLES TO WASH OUT. TYPICALLY THIS ONLY TAKES A MINUTE BUT TO BE SAFE WE'RE USING A 20 MINUTE DURATION TO INSURE THOSE MICROBUBBLES ARE WASHED OUT IN CIRCULATION. WE APPLY A SECOND LOW PRESSURE SONICATION TO VERIFY THAT THAT'S HAPPENED AND YOU CAN SEE HERE THAT WE'RE ONLY SEEINGA I REFLECTION OF THE FUNDAMENTAL THERE, NONE OF THOSE EXCITING HARMONIC EMISSIONS, 30 MINUTES LATER WE WANT TO SEE HAVE WE THEREFORED NANO DROPLETS INTO THE BRAIN TISSUE, IS ANYTHING STILL ACOUSTICALLY ACTIVE IN THAT REGION. NOW AT THIS TIME POINT IF WE SONICATE THE OTHER HEMISPHERE, A MEMORY RESPONSEIS FEAR THAT HASN'T BEEN OPENED WE DON'T SEE CEREBELLUMS SIGHTING ACOUSTIC EMISSIONS, HOWEVER WHEN WE SONICATE AT A HIGHER PRESSURE, REQUIRED FOR VAPORIZATION, THAT OPEN BRAIN REGION WE SEE THIS REAPPEARANCE OF THE HARMONIC EMISSIONS LETTING US KNOW ACTIVITY IS OCCURRING. HOWEVER IS ANY DRUG BEING RELEASED OR ANY AMOUNT OF DRUG BEING RELEASED IN THE BRAIN REGION. BEFORE I GOET TO THAT ISSUES LET ME RECAP THE WAYS IN WHICH WE'RE USING MRI IN THIS STUDY FOR TARGETING FOR TREATMENT MAPPING TO VERIFY THAT WE ARE INCREASING THE PERMIABILITY OF THE BLOOD BRAIN BARRIER AND FOR SAFETY ASSESSMENT AND OF COURSE WE FOLLOW THAT UP WITH VARIOUS HISTOLOGICAL STUDIES. AT THE CELLULAR LEVEL WHAT'S GOING ON THEN WHEN WE DELIVER THIS ANESTHETIC INTO THE BRAIN, USING CFOSTER NURSED EXPRESSION WE'RE ABLE TO MAP WHETHER THE NEURONAL FIRING IS TAKING PLACE AND HAS IT CHANGED AT ALL RELATIVE TO UNSONICATED REGIONS. AND WE FIND WHEN WE DON'T HAVE THE DRUG ON BOARD IN THOSE NANO DROPLETS AT LEAST IN THE MOTOR CORTEX WE SEE ANP CRISE IN CFOSTER NURSED EXPRESSION IN THAT REGION. HOWEVER WHEN WE SUCCESSFULLY DELIVER THE PENTINE REGIMEN O BARBIT OL, WE UNDERSTAND SOMETHING'S HAPPENING AT A CELLULAR LEVEL BUT WHAT ABOUT AT A BEHAVIORIAL LEVEL? WELL WE'RE USING RATS, PAINTING THEIR FEET AND HAVE THEM WALK ALONG AN ENCLOSER, WHILE IT'S A SIMPLE TEST, IT'S A SENSITIVE WAY OF DETECTING CHANGES IN SENSORY MOTOR BEHAVIOR AND WE CAN SEE, THAT AFTER SUCCESSFULLY DELIVERING PENTINE REGIMEN O BARBITAL TO 1 HALF OF THE MOTOR CORTEX WE SEE AN INREECE IN THE ASYMMETRIC MOTOR FUNCTION. HOWEVER THE TAKE HOME MESSAGE I WOULD LIKE TO SHARE WITH YOU HERE IS IN THE CASE OF THE OPEN BLOOD BRAIN BARRIER, WE'RE ABLE TO ACHIEVE AN EQUIVALENT LEVEL OF SENSORY MOTOR DEFICIT BUT WITHOUT A THIRD OF THE DRUG DOSE. SO BY HAVING THE BLOOD BRAIN BARRIER OPEN DURING THIS PROCEDURE, WE'RE ABLE TO CUT DOWN ON THE AMOUNT OF ANESTHETIC REQUIRED TO ACHIEVE THIS MOTOR DEFICIT BY A THIRD MPLET SO IN CONCLUSION WE'RE EXPLORING HOW THESE ULTRASOUND NANO DROPLETS MIGHT BE A WAY TO ADAPT A NEUROMODDULATION TOOL WITH MRI GUIDED ACHIEVED ULTD RASOUND AND ACHIEVING THROUGH THIS SMALL 18thS. WE'VE SHOWN THAT THIS VAPORIZATION SHOWS THE RELEASE OF THE DRUG AND ALSO AN EMISSION OF UNIQUE ACOUSTICS WHICH WE CAN DETECT IN REALTIME AS A WAY BOTH TO LOOK AT--SORRY TREATMENT EFFICACY AND ALSO TREATMENT SAFETY. AND THE OPEN THE BLOOD BRAIN BARRIER WITH THE MICROSOUND AND MICROBUBBLES WITH THE POTENTIAL STRATEGY TO DELIVER THESE DROPLETS INTO THE BRAIN WHERE THEY SEEM TO REMAIN AKOWOF THEICALLY ACTIVE FOR AT LEAST 30 MINUTES AFTER INJECTION. SO IN THE FUTURE I'M LEARNING MRI TECHNIQUES, BUT WE MAY INVESTIGATE INVOLVING IN THIS WORK, I LOOK FORWARD TO LEARNING MORE FOR THE NEXT COUPLE OF DAYS AND WE'RE LOOKING FORWARD TO THE FEATURE WHERE WE'RE ALREADY STARTING TO APPLY THIS PLATFORM TO SERL NEUROLOGICAL AND PSYCHIATRIC DISORDERS WITH OUR MARTENERS IN NEUROSURGERY. THANK YOU VERY MUCH FOR LISTENING. AND THANK ALL THOSE INVOLVED IN THIS WORK. >>HI, THANK YOU FOR THE TALK. I WAS WONDERING, ARE YOU LIMITED IN THE SIZE OF THE DROPLETS, THAT YOU COULD USE FOR THIS TECHNIQUE? >>SO SORRY FROM TERMS OF FABRICATION BY TUNING THE RATIO OF THE SHELL MATERIAL TO THE CORE MATERIAL WE DO HAVE QUITE A LARGE RANGE OF DROPLETS THAT CAN BE FABRICATED HOWEVER, IN TERMS OF SAFETY, WE ARE AWARE THAT YOU GET THIS 5 TIMES EXPANSION IN DIAMETER IF WE'RE INJECTING THESE AGENTS INTO THE VASCULATURE, WE WANT TO INSURE IT THAT THEIR RESULT IN SIZE WILL NOT BE CAUSING ANY DAMAGE IN TERMS OF GASEOUS VOLUME. SO WE HAVE SETTLED ON THE SIZE OF 200-NANOMETERS IN DIAMETER BECAUSE IT'S COMPARABLE TO THE MICROBUBBLE SIZE WE USE CLINICALLY. >>THE EXCITATION GIVEN THE EMPTY NANO PARTICLES IS QUITE INTRIGUING TO ME, WHAT DO YOU THINK IS HAPPENING? >>YEAH, IT'S AN EXCELLENT QUESTION. MICROBUBBLES HAVE HAD THE SAME EFFECT, WE THINK AS PROFESSOR CANNED WHAT WAS TALKING DIFFERENT REGIONS OF THE BRAIN WE KNOW ARE GOING TO HAVE DIFFERENT RESPONSE DEPENDING ON THEIR NEURONAL COMPOSITION WE SEE DIFFERENT EFFECTS WHEN WE SEE CENTRAL BRAIN REGIONS BUT I WOULD SUGGEST IT'S A MECHANICAL EFFECT AS THAT VAPORIZATION PROCESS IS HAPPENING WITH THE MICROBUBBLES, THEY UNDERGO THIS VOLUMETRIC EXPANSION, WHICH CAN PULL AND PRESSURE ON THIS. >>DO YOU THINK IT'S PUSHING ON THE ENDOTHELIAL WALL OR SOME KIND OF WAVE LOCALLY INTO THE BRAIN? >>VERY INTERESTING QUESTION. I THINK PROBABLY THE MECHANICAL EFFECTS ARE DOMINATING IN THAT SCENARIO, WE ALSO KNOW THAT FLUID EFFECTS AROUND THAT VOLUMETRICALLY ARE CHANGING CAN BE VERY STRONG THE VELOCITIES IN THE FLUID AROUND BUT SECONDARY RADIATION FORCES MAY ALSO BE COMING INTO PLAY, THAT WAS AN INTERESTING POINT. THANK YOU. >>CAN YOU TALK A LITTLE BIT ABOUT HUMAN TRANSLATION, IT SEEMS SUPER SMART TO TALK ABOUT MICROBUBBLES. I MEAN DO YOU THINK IT'S SOMETHING THAT COULD BE USED RELATIVELY SOON IN HUMANS? WHAT ARE THE MAIN BARRIERS? CAN YOU SPEAK ON THAT? >>YEAH, THANK YOU. I'VE BEEN--BUILDING ON SOME OF THE REALLY EXCELLENT WORK THAT MANY OF YOU PARTICULARLY DR. [INDISCERNIBLE] THERE, DOING MANY OF THESE NEW NOW PHASE 1 PHASE 2 CLINICAL TRIALS USING MICROBUBBLES FOR BLOOD BRAIN BIRRIER SURFACESSIER OPENING WE KNOW THAT THAT PORTION OF THE WORK IS BEING REALLY WELL CLINICALLY USED AND CLINICALLY TOLERATED WITH NO ADVERSE SIDE EFFECTS. THE INFUSION GROUP WOULD BE VERY SIMILAR, THE COMPETITION OF NANO DROPLET SYSTEM ALMOST IDENTICAL, THEY'RE JUST IN A LIQUID STATE RATHER THAN A GAS STATE SO WE IMAGINE THINGS LOAMACYIC REGULATORY APPROVAL WOULD PROBABLY BE RELATIVELY SIMPLE. YES, I THINK THERE'S CERTAINLY POTENTIAL FOR THIS AND I THINK THE SYSTEMS ARE THERE AND READY TO BE USED FOR THESE PLATFORMS. >>GREAT. LET'S THANK THE SPEAKER AGAIN. COMPREHEND. >>THE NEXT SPEAKER IS ANDREW STROHMAN, HE WILL TALK ABOUT LOW INTENSITY FOCUSED ULTRASOUND TO THE LEFT HUMAN DORSAL ANTERIOR INSULA ALTERED SALIVA--SALIVAIENCE NOTEBOOK WORK BOLD SIGNALS DURING RESTING AND PAIN CERTAINLY--CERTAINLY VOAKED STATES IN AN INTENSITY DEPENDENT FASHION. >>HELLO, EVERYBODY MY NAME IS ANDREW STROHMAN AT THE FRALIN BIOMEDICAL RESEARCH INSTITUTE AT VTC IN VIRGINIA, WE WILL LOOK AT THE ABILITY TO ALTER NETWORK FUNCTIONAL CONNECTIVITY AND INTENSITY DEPENDENT FASHION AND I HAVE NO FINANCIAL CONFLICTS OF INTEREST. QUICKLY WE WILL TALK ABOUT BRIEFLY REITERATING THE ROLE OF INSULA IS PAIN, GOING OVER THE PROTOCOLS AND METHODS AND THE RESULTS OF 2 OF THESE ARE ROI CONNECTIVITY ANALYSIS AND VOXEL AND FINALLY [INDISCERNIBLE]. SO YOU SAW THIS SLIDE EARLIER. JUST TO RITY IT CAN BE SUBDIVIDED INTO ANTERIOR AND AND INTERIOR SECTIONS, IT INTEGRATES THESE BOTTOM UP SIGNALS WITH TOP DOWN COGNITIVE EMOTIONAL PAIN SIGNALS THROUGH A COMMUNICATION WITH A VARIETY OF STRUCTURES NOTABLY THE HYPOTHALAMUS AND THE AMYGDALA. AS YOU SAW PREVENTIVELY FROM SOME OF THE MODELING WE'VE DONE HERE, CAN YOU SEE FREE WATER TANK DATA LAID OVER TO SCALE ON A STRUCTURAL MRI SHOWING WE HAVE SINGLE GYRATE ISOLATION WITH LIFU. ON THE SIM NOLL IS ITED ON THE SIGNATURE OF PHYSICAL PAIN, THE AUTHORS IDENTIFIED POORLY AND ANTICORRELATED REGIONS WITH TRANSIENT HEAT PAIN. NOTABLYTHEY SAW THAT THE ANTERIOR INSULA AND SINGULATE HAD HIGH INTENSITY TO HEAT PAIN VERSUS OTHER NONPAINFUL STIMULATIONS. AN ADDED FEATURE OF THE DORSAL ANTERIOR INSULA AND THE ANTERIOR SINGULATE IS THAT THEY SERVE AS CORD NOTES IN THE RESPONSE, WHICH IS IMPORTANT FOR SWITCHING WITH THE DEFAULT NET,OT LEFT AND THE CORTEX AS WELL AS THE EXECUTIVE NETWORKOT RIGHT WITH THE POSTERIOR GIVING--YOUERAL AND LATERAL CORTEX. IT'S A FURTHER NONAPOPTOTICET THAT THESE NETWORK RESPOND DYNAMICALLY TO PAIN. PREVIOUSLY, IN NONHUMAN PRIMATES, SUCH AS LEONARD HAGUEIN HAVE SHOWN IN NONHUMAN PRIMATES THAT THE RESTING STATE FUNCTIONAL CONNECTIVITY CAN BE ALTERED WITH LIFU APPLICATION, SO YOU CAN SEE HERE, THEY APPLIED LIFU TO THE SINGULAR, OR THE AMYGDALAs A THE SEED REGIONS OF INTEREST SHOWING THEY ARE ABLE TO ALTER RESTING FUNCTIONAL CONNECT AND THAT LEADS US TO THE NEXT QUESTION IS LIFU, TO THE LEFT DAI, MODULATE THESE RESTING STATE FUNCTIONAL CONNECTIVITY METRICS IN REASON YOJS TO THE FMRI NEURAL PAIN BASED SIGNATURES. SO FOR ROI-ROI ANALYSIS WE WANTED TO SEE IF IT WOULD DECREASE SALIVA--SALIVAIENCE FUNCTIONAL NETWORK CONNECTIVITY AND AS WELL AS SEEING RESTING STATE SALIENCE CONNECTIVITY WITH THE AMYGDALA AND THE HYPOTHALAMUS. NEXT WE WANT TO SEE IF THERE WAS ANY CHANGES IN THE INTRA PLAY BETWEEN THOSE 3 NETWORKS WE SAW EARLIER SO WE HYPOTH CISED THAT IT WILL DECREASE NETWORK CONNECTIVITY AND THESE 2 REGIONS OF INTEREST ISSUES AS WELL AS THE COG 95ATIVE EXECUTIVE NOTEBOOK WORK AGAIN USE THE BILATERAL AND LATERAL PREFRONTAL CORTEXS, FINALLY FOR THE FOURTH HYPOTH THAT WE HAVE VARYING INTENSITIES, WE WILL ALTER THE RESTING STATE NETWORK FUNCTIONAL CONNECKIVITYITY. WE FOLLOW THIS UP, WITH THE VENTURES BEING THE LEFT DORSAL INSULA AND HYPOTHESIS THAT WE DECREASE THESE ASSOCIATE WIDE THE FMRI SIGNATURE. FOR PROTOCOLS AND POETIC RAM TERS THIS FOCUSED TRANSDUCER TO THE LEFT EAI, USING OUR NAVIGATION SYSTEM AND USED THE REGISTERS AND CTs ARE THE PURPOSE OF OUR MODELING. RIGHT HERE, HERE THE PARAMETERS FOR THE STUDY, THESE HAVE BEEN USED SERL TIMES AND CONSISTENTLY SHOWN TO PRODUCE ACTIVITY, THAT VERGES ON INHIBITION. I WILL USE AGAIN I SAW THE SLIDE AND DR. LIGON'S TALK, THIS IS THE BASIC OUTLINE FOR OUR FMRI STUDY, HE LOOKEDDA THE HEAT EVOKED STIMULI AND THE COUNTER BALANCE RESTING STATE SCANS WE DID ON EITHER SIDE OF OUR PREPOST LIFE DESIGN AND AGAIN OUR RESTING STATE FUNCTIONAL CONNECTIVITY WITH THE REGIONS OF INTEREST THAT WE JUST DEFINED. SO, FOR OUR ROI TO ROI NETWORK FUNCTIONAL CONNECTIT ANALYSIS WE RESULTS HERE WITH THE MAP, LOOKINGA THE FIRST HYPOTHESIS OF DECREASING SALIENCE IN THE NETWORK, CAN YOU SEE HERE THAT WHEN YOU GROAP BOTH TOGETHER, WE CAN SEE THAT CONTRARY TO WHAT WE WOULD ASSUME, WE WILL SEE DECREASED CONNECKATIVITY OF THE THE ACCWITH THE BI LAT AMYGDALA AND THE HYPOTHALAMUS. FOLLOWING UP YOU CAN SEE THAT THESE NETWORKS ARE IN GREEN AND OTHERS IN BLUE AND YOU CAN SEE WE HAVE DECREASED FRONTAL CORTEX AND INCREASES IN THE FRONTAL CORTEX NODE WITH THE BILATERAL AMIC DUALA AND THE HYPOTHALAMUS. ALL OF THESE DIFFERENT INTENSITIES, ATTRIBUTING TO THE EFFECTS AND WE FOLLOW THIS UP BY TAKING THE EXACT SAME ANALYSIS AND STRATIFYING IT BASED ON INTENSITY. SO LOOK AGAIN REVISITING THE FIRST HYPOTHESIS WITH THE RESTING ESTATE CONNECTIVITY. YOU CAN SEE AT THE LOWER INTENSITY WE DO SEE DECREASED CONNECTIVITY BETWEEN THE LEFT AI AND THE RIGHT AI AND THIS IS NOT SEEN IN THE HIGHER INTENSITY. LOOKING AGAIN WITH THE SECOND HYPOTHESIS, IT'S THE OPPOSITE, IT'S LOWER INTENSITY WE DID NOT SEE THE EFFECTS AT THE HIGH EXPOSURE TO RADIATION WE DID SEE THE INCREASE BETWEEN THE ACCAND REGIONS OF INTEREST. AND LOOKING AT THE INTERPLAY TWEEZE THEEN NETWORKS WE SEE THAT THE HIGHER INTENSITY WE HAVE THE DECREASED INTENSITY WITH WHERE THIS IS NOT SEEN AT THE LOWER IPT GREATER TENSITY. --LOWER INTENSITY. FINALLY, THE LEFT REGION OF INTEREST AND WE SAW DECREASED CREATIVITY WITH THE PREKUHNIOUS, AND LOOKING BACK ON THE SIGNATURE OF PAIN, THE LEFT PREKUHNIOUS IS 1 OF THE ANTICORRELATED REGIONS WITH THESE TRANSIENT HEAT STIMULI. AND SO CONCLUSIONS, FOR ROI-ROI ANALYSIS WE SHOW THAT THE LEFT AI DECREASES FUNCTIONAL CONTHECTATIVITY WITH THE RIGHT AI, AND DECREASES FUNCTIONAL CONNECTIVITY BETWEEN THE RADIOIT AND LEFT PREFRONTAL CORTEXS. TO THE LEFT AI THIS IS INCREASES FUNCTIONAL CONNECTIVITY OF THE ACCAND MEDIATE PREFONTAL CORTEX WITH THE HYPOTHALAMUS AND THE BILATERAL AMYGDALA AND FINALLY BOTH INTENSITIES SLEEP APNEA AND OBESITYEM TO CONTRIBUTE TO THE OBSERVED WHOLE GROUP EFFECTS. FINALLY, LIFU TO LEFT DAI INCREASES FUNCTIONAL CONTECTATIVITY OF THE ACCAND BOTH INTENSITIES DIFFERENTIALLY CONTRIBUTE TO THE OBSERVED WHOLE GROUP. AND DECREASES CONNECTIVITY WITH THE LEFT PREKUHNIOUS. THANK YOU SO MUCH, THANK YOU TO EVERYONE WHO WORKED ON THIS AND I WILL TAKE QUESTIONS. >>[ APPLAUSE ] >>QUESTIONS? WHEN YOU DID YOUR ROI ANALYSIS WAS THIS OVER SINGERLE SUBJECTS OR AVERAGED OVER THE 8 SUBJECTS. >>AVERAGED. >>ROI AND AVERAGE, AND YOU DIDN'T SHOW, THERE WERE NO LINES BETWEEN SOME OF THE ROIs IS THAT BECAUSE YOU SAW NOTHING OR BECAUSE YOU--IT WAS NOT SIGNIFICANT WITH THE SIGNIFICANT CHANGE? >>YEAH, YOU DIDN'T SEE THEM BECAUSE THEY WERE NOT SIGNIFICANT. >>OKAY. ALL RIGHT IF THERE ARE NO OTHER QUESTIONS, LET'S THANK THE SPEAKER AGAIN.. [ APPLAUSE ] SO FINALLY IS AURORE HERE? YEAH? SURE. OKAY, GO AHEAD. >>GOOD AFTERNOON, EVERYONE. SO, I AM PASCAL [INDISCERNIBLE] BASED OUT OF BELGIUM, THIS PROJECT IS FINANCED BY THE REGION SO THAT'S FOR DISCLOSURE, IN BELGIUM WE MAKE CHOCOLATE, WE MAKE BEER BUT WE ALSO BUILD NEUROSTIMMULATORS AND THAL CASE, IT'S A NOCT URNAL STIMULATOR AND IT IS DESIGNED FOR ACTIVE STIMULATION AND STIMULATION DURING MRI AND FMRI. FOR THOSE WHO DON'T KNOW WHAT IT IS OR SMALL REMINDER OF A NEUROSTIMMULATOR AT LEAST, IN THIS CASE, IT'S AN IMPLANTABLE NEUROSTIMMULATOR. SO IT'S BASICALLY VERY SIMILAR TO WHERE BASE MAKER EXCEPT THAT'S STIMULATING SO THEY ARE ALMOST ALL BUILT IN THE SAME WAY WHERE YOUR ELECTRONICS AND BATTERY ARE INSIDE. YOU HAVE WIRES, COMING OUT OF THE TITANIUM CASING AND THEY GO TO AN CERTAINLY--CERTAINLY LECT RODE AND THE ELECTRODE IS NEXT 1 OR BRAIN TISSUE. AND ALL THIS METASELL A PROBLEM, IT'S A PROBLEM, IT'S A RISK WHEN YOU GO TO MRI. YOU CAN HAVE IMPLANT MOVEMENT AND ON THE IMAGE YOU CAN SEE THAT YOU HAVE THE MAGNET OF THE COCHLEAR IMPLANT WHICH IS RIPPED OFF BY ITSELF, CAN YOU HAVE IMPLANTING, IT CAN BE HEATING, CAN YOU HAVE BURN DURING AN MRI SECTION, CAN YOU HAVE IMPLANT MALFUNCTION DUE TO MAGNETIC FIELD OR INTERACTION AND MRI IMAGE ARTIFACT GAVES VERY POOR IMAGE. IF YOU WANT TO PLACE A NEUROSTIMMULATOR ON THE MARKET, YOU NEED TO ASSESS ITS MRI SAFETY. AND YOU DO THAT USING SPECIFIC STANDARD AND AFTER TESTING THE MRI CONDITIONS THAT DURING RADIOLOGISTS HAS TO APPLY TO BE SAFE. AND UNDER THESE CONDITIONS, THEY ARE RELATED TO BODY REGIONS THAT ARE [INDISCERNIBLE], THEY RELATED TO THE FACT THAT THEY HAVE TO BE SWITCHED OFFER DURING THE MRI SESSION, THE REACT TO THE FACT THAT THE SCAN DURATION MIGHT BE LIMITED, OR MIGHT BE LIMITED AND CHANGING SOIN CREASE THE TIME OF THE PEOPLE THERE AND THE RADIOLOGISTS AND YOU ALSO HAVE PATIENTS AT RISK AND MOST OF THE TIME MOST PEOPLE WHO ARE NOT UNIVERSITY STUDENTS, REGULAR PATIENTS THEY DON'T WANT TO MAKE MRI WITH SOMEONE WITH AN IMPLANT. SO WE WANTED TO CHANGE TAKEN--THEY FACT. AND AS I SAID, METEDDAL IS THE PROBLEM, SO THE IDEAS ARE EASY, METAL IS THE PROBLEM SO LET'S REMOVE THE METAL. IT WAS NOT THAT EASY, WE A LOT OF RECOMMEND, WE HAVE A GREAT TEAM AND WE SUCCEEDED TO DO SO AND I WILL PRESENT YOU WITH THAT NEUROSTIMMULATOR THAT WE ATTRIBUTED AND THE 1 YOU SEE ON THE SLIDE IS THE NEUROSTIMMULATOR THAT IS SUPPLIED FOR VAGUS STIMULATION, AND YOU IMPLANT IT IN THE CHEST REGION AND THEN YOU HAVE TO LEAD THAT GOING TO THE ELECTRODE AND THE ELECTRODE IS WRAPPED ARK ROUND IN THIS CASE, THE AND THIS SEIZURE EFFECT, THAT WILL BE FEPILEPSY TREATMENT. AND IT IS A NEUROSTIMMULATOR SO YOU DON'T SEE ANY TITANIUM CASING ANYWHERE, SO THE ELECTRONIC IS INSIDE GLASS INCAP SURVEYSALATION, WE REPLACE THE WIRES CAN OPTICAL FIBERS AND CUSTOM OPTICAL FIBERS WE BUILT THEM FROM SCRATCH TO BE COMPATIBLE TO BE FIT FOR IMPLANTATION AND THE NEUROSENSORS, SO SENDING THOSE UP TO THE ELECTRODE. IN THIS CASE, WE STILL STIMENTULATING QUICKER WAYS OR WE HAVE TO CONVERT BACK TO THE OPTICAL PARALYSIS TO ANOTHER [INDISCERNIBLE] AND WE DO THAT WITH [INDISCERNIBLE] CELL THAT IS CONVERTING THE OPTICAL ENERGY TO [INDISCERNIBLE]. AND THEN WE ASSESSED THAT EVENT FOR MRI SAFETY BECAUSE WE WANT TO PLACE IT ON THE MARKET. AND WE FOUND THAT WE GOT NO [INDISCERNIBLE] DUE TO THE CANNED WHAT ELEBT RODE WE HAVE NO AMOUNT OF FUNCTION AND THE GENERATORS AND DURING ANY KIND OF MRI SEQUENCES MEANING IT IS FRUITFUL WITH FMRI AND BIG RISK IS EATING AND IN THIS CASE, WE HAVE NO MORE THAN 2-DEGREES EVERYWHERE FOR THE IMPLANTABLE PATH, TO THE DEGREE SO 3.60 RISK FAHRENHEIT AND EVEN THE ELEBT RODE WHICH IS THE MOST SENSITIVE PART, EVEN IF EATING IS NEGLIGIBLE. TALKING ABOUT [INDISCERNIBLE] QUALITIES, WE STILL HAVE SOME METAL PARTS, SO WE HAVE THAT DID YOU THE DEFECT IS QUITE LIMITED AND THE BRAIN IMAGING CAN BE PERFECT. AND AS A RESEARCHER WE HAVE CONDITION THAT NEED TO BE APPLIED SO AT 1.5, THERE'S NO SCAN TRANSMISSION, NO CHANGE, NO TIME LIMITATION, NO LIMIT AITIONZOT MODE OR BODY SCAN AND WE HAVE NO LEAD FOR THIS WITHY NEED TO THIS FOR THE TERM WHERE THIS CASE CAN BE THE PROBLEM AND IN THIS CASE, THERE WILL BE THERE AND THERE IS NO PROBLEM. AND AS A CONCLUSION, WHAT WE DID WAS TO BUILD THE NEUROSTIMMULATOR, WE BUILD IT FOR VAGUS STIMULATION BUT THE TECHNOLOGY PLATFORM, IT CAN BE APPLIED TO ANY KIND OF NEUROSTIMMULATION PIECE, ESPECIALLY DEEP BRAIN STIMULATION IN THIS CASE, WHERE IT'S A BIG ADVABTAGE BUT ALSO WE REMOVED THE INTAKE CELLS, WE HAVE AN IMPLANT QUICKLY READY FOR OPTICAL IMAGES O GENETICS AND IN THE NEAR DISTANT FUTURE, ALSO DIRECTOR OF THE [INDISCERNIBLE] STIMULATION. AND @ MOMENT WE ARE STUDYING THE POTENTIAL BY O MARKERS FOR STIMULATION. AND THERE IT IS. AND THAT WAS OF COURSE DUE TO A GREAT TEAM WHERE SOME OF THEM ARE PRESENT HERE AND I WANT TO THANK YOU FOR ALL THE WORK THAT DID FOR THE PAST 6 YEARS. THANK YOU. [ APPLAUSE ] MCAN YOU HAVE IT ON DURING MRI. WOULD MRI IMPACT THE EFFICIENCY OF THE THERAPY? >>SO THAT'S THE WHYED, WE GO TO MRI, WE SIMULATE AND AT THE SAME TIME CAN YOU SEE WHAT'S HAPPENING IN THE BRAIN. >>SO THE IPG IS IMPLANT IN THE BODY. >>IT IS IMPLANTED THERE. >>IT CAN HAVE IT ON. >>IN THE CHEST. >>YEAH. >>AND YOU GO TO EXTERNAL SYSTEM WHICH IS BASICALLY [INDISCERNIBLE] OPTICS AS WELL GOING OUT OF THE MRI OR KD--SALLY LAWEDDER DALE. >>JUST CURIOUS LIKE RF FIELD, GRADIENT FIELDS FROM THE MRI, WITH THAT IMPACT OF FUNCTIONALITY OF THE IPG. I KNOW IT'S A SAFE, BUT I WAS WONDERING DOES IT IMPACT ANY THERAPY? FUNCTIONAL-- >>FUNCTIONALLY [INDISCERNIBLE]. SO THAT'S STANDARD WE NEED TO FOLLOW. IT'S A NICE STANDARD FOR THAT, IT'S GOOD GUIDANCE, IT'S PROVIDING ANY KIND OF AREA [INDISCERNIBLE] WORST CASE MRI SEQUENCES AND EACH 1 FOR THE FUNCTIONAL, WITHOUT ANY PROBLEM. AND WHAT WE DID IS TO BE OF COURSE THE EXTERNAL SYSTEM TO COMMUNICATE OUTSIDE THE MRI RULE AND WE STIMULATE AT THE SAME TIME YOU CAN RECORD THE MRI SEQUENCES. >>THANK YOU. >>I THINK I MAY HAVE MISSED IT, I'M CONFUSED. WHAT IS THE MECHANISM OF ACTION HERE, LOOK ARE YOU TALKING ABOUT OPTICAL IMAGES O GENETICS? SO IS THIS SOMETHING THAT INVOLVES INJECTION OF A DRUG TO PENTACLIALLY GENETIC ALTERATION OR THIS IS LIKE GENETIC-- >>THIS THE 1 I PRESENTED TO YOU IS NORMAL STIMULATION, WE--WE REGULARLY STIMULATE THE NERVE BUT WHAT I WAS SAYING ON THE PLATFORMS WE CAN REMOVE, WHEAR I SAID WHICH IS ON TOP OF GH1, AND WE WANT TO IMPLANT TO DELIVER A PARTICULAR PROCESS THAT OR A PARTICULAR OBSERVATION THAT WE CAN QUICKLY DO [INDISCERNIBLE] NEUROSIMMULATOR TO NEUROSCIENCE. >>OKAY, VERY GOOD. >>YOUR IPG I THOUGHT WAS QUITE SMALL. IS THERE ANY KIND OF BATTERY SORT OF INNOVATION GOING ON HERE. >>JPG IS SMALL, AND I WOULD LIKE IT TO BE EVEN SMALLER AND EFFECTIVELY IT'S SMALL BECAUSE THE BATTERY IS ALSO SMALL, BUT IT'S A RECHARGEABLE BATTERY. AND THE IDEA WE TALKED ABOUT THERE IS THAT, WE WANT TO BE ABLE TO MAKE THE ALGORITHMIC SIDE FOR SENSING INSIDE AS COMPLEX AS WE WERE, SO WE DON'T WANT OUR LIMITATION TO LIMIT THE FUNCTIONALITY OF THE DEVICE. >>LOOK FORWARD TO UPDATES. >>OKAY, WELL, THEN,-- >>SORRY. >>[INAUDIBLE ] >>IF YOU HAVE PUT A TYPE ON YOUR ROOF, BASICALLY YOU GET SUN LIGHT, AND YOU CONVERT ABOUT MAX NULL TWEBT PERSON, MEANING THAT INSIDE [INDISCERNIBLE] EACH PERSON WILL [INDISCERNIBLE]. IF YOU DO THAT, BASICALLY YOU HAVE THE SAME--AND THE OPTICAL GO TO THE [INDISCERNIBLE] OF COURSE AND THAT 1 IS SMALLER, IT'S VERY, VERY SMALLER. BUT IT'S NOT LIKE UPON WE HAVE RANKED [INDISCERNIBLE] OTHER PHOTO ITSELF AND WE GOT AROUND 60 PERSON OF CONVERSION. WE STILL HAVE ABOUT 40 PERSON OF THAT [INDISCERNIBLE] WHICH IS CONVERTED TO [INDISCERNIBLE] BUT IT'S VERY LIMITED, IT'S ONLY THE [INDISCERNIBLE] STIMULATION, I HAVE DONE IT A FEW TIMES. OKAY. >>ALL RIGHT. THANK YOU VERY MUCH. THANK YOU FOR SUCH A GREAT SESSION. [ APPLAUSE ] >>SO WE RESUME AT 4:30 >>WELCOME TO THE FOURTH AND LAST SESSION FOR TODAY. THIS WILL BE THE ORWILLA PRESENTATION OF ABSTRACTS. WE WILL HAVE A LINE UP OF 5 SPEAKERS. AND OUR FIRST SPEAKER IS MATTHIEU, DAGOMMER, WHO WILL TALK ABOUT HIS OPTICAL IMAGES MIATION OF DEEP LEARNING STRATEGY FOR ESTIMATION OF CORTICAL PORS ONITY MAP FROM MRI T1-WEIGHTED IMAGES. >>SO I HAVE NOTHING TO DECLARE. SO AS YOU KNOW, TRANSCRANIAL ULTRASOUND IS A PROMISING NEUROSTIMMULATION TECHNIQUE, IT'S NONINVASIVE, IT REACHES DEEP IN THE BRAIN AND HAS BEEN DEVELOPED AND VALIDATED IN ANIMAL STUDIES. HOWEVER, TRANSLATION TO HUMANS IS STILL DIFFICULT BECAUSE OF SCATTERING AND OBSTRUCTION BY THE SKULL. SO HERE'S AN EXAMPLE OF THE SIMULATION IN ORDER TO, YOU HAVE A DUCER--SO, ACOUSTIC [INDISCERNIBLE], PEEK INTENSITY FALLS INSIDE TARGET OF INTEREST, NOW, IF PEOPLE SCHEDULE BETWEEN THOSE IN AND THE TARGET, YOU SEE THE STRONG LEAD, AND ATTENUATE, SO, SO TAKING INTO,A COUNT IS CRITICAL FOR THOSE ACCURATE, HOWEVER, A MAIORITY OF ONGOING CLINICAL STUDIES STILL DO NOT MODEL THIS CAUSE, SO HERE'S AN EXAMPLE OF THAT ONGOING MGH STUDY, OR GETTING THE RIGHTS WITH THE ENVELOPE USING THE TARGET LINE UP STRATEGY SO THESE ARE SIMULATIONS PERFORMED RETROSPECTIVELY ON THE SUBJECTS AND AS YOU CAN SEE HERE ON THIS MAP, WE HAVE BLACK CIRCLE REPRESENTING THE AMYGDALA AND WE CAN SEE THAT WE'RE ABLE TO REACH THE TARGET, HOWEVER, FOR OTHER SUBJECTS, WE MISS TARGETS. AND WE REALIZE, IF WE HIT THE TARGET, WE ONLY GET 30% OF MEASHTS. THE THING IS FORTUNATELY WE HAVE WELL ESTABLISHED METHODS, NUMERICAL METHODS TO TAKE INTO ACCOUNT THIS CAUSE AND THOSE STIMULATIONS RELYOT MAPS AND THIS IS THE TYPICAL WORK FLOW TO PERFORMANCE SIMULATIONS: FIRST WE PERFORM A CT SCAN, WE THEN EXTRACT THE MAP, WE DERIVE ACOUSTIC PARAMETERS AND THEN WE FEED THESE ACOUSTIC PARAMETERS TO THE SIMULATION, THE PROBLEM OF THE FLOW CHART IS THAT CT SCAN EXPOSES THE SCAN THROUGH IONIZING RADIATION AND THE THING WE CARE ABOUT IN THE END IS THE PERS ONITY MAP SO HOW CAN WE OBLIGATIONS STAIN THE MAP IN A DIFFERENT WAY. WELL IN THIS STUDY, WE WANT TO DEVELOP A TOOL TO ESTIMATE, VELOCITY FROM MRI, SO YOU'RE LOOKING AT A PATIENT, AND THIS IS THE EQUIVALENT PORS ONITY MAP. NOW LET'S LOOK AT THE MRI. AS CAN YOU SEE THERE IS VERY LITTLE CONTRAST AROUND THE SKULL. HOWEVER, IF WE CHANGE THE SATURATION, WE CAN SEE CLEARLY THAT THE INFORMATION ABOUT POROSITY IS THERE, SO WHAT WE NEED IS AN IMAGE TO IMAGE TO IMAGE TRANSLATION METHOD AND WE KNOW THAT DEEP LEARNING IS WELL SUITED FOR THIS SO WE PROPOSED A APPROACH TO GO OVER THE PROBLEM AND WE WERE INSPIRED BY OTHER SIMILAR STUDIES. SO BEFORE I DIVE INTO DEEP LEARNING, I WILL TALK ABOUT POROSITY, IT IS AT PLACENTAS BASED SO IT CONSISTS IN AVERAGING MRI CT PAIRS FOR FOR MULTIPLE SUBECTOMYOSIN JUDGES. AS YOU CAN SEE ON THE IMAGE THE POROSITY, 1 PART IS VERY BLURRY SO THE POROSITY IS VERY QUITE DIRT EXPE WE LOST INFORMATION BECAUSE OF THE AVERAGING PROCESS. IN THIS STUDY WE USED POROSITY AS A CONFIRMATION FOR OUR METHOD BUT WE DID NOT USE IT DIRECTLY. SO NOW LET'S TALK ABOUT DEEP LEARNING SO WHAT WE WANT TO DO IS TO CREATE A GENERATOR THAT'S TAKES AND INPUTS AN MRI MESSAGE AND THE MAP. HOW TO--SO THE WAY TO DELIVER THIS TO TRAIN THAT KIND OF MODEL IS TO COMPARE THE GENERATED POROSITY WITH THE ACTUAL POROSITY MAP AND TO GIVE FEEDBACK TO THE GENERATOR TO TRAIN IT. SO THIS IS THE VERY SIMPLE, SIMPLEST GENERATED MODEL WE CAN HAVE. IF WE REFINE A LITTLE BIT, WE CAN ADD DISCRIMINATOR WHICH IS A TYPE OF NETWORK, THAT'S ABLE TO TELL THE DIFFERENCE BETWEEN GENERATED AND THE REAL POROSITY MAPS AND THIS ALLOWS TO GIVE MORE REFINED FEEDBACK TO THE GENERATOR. NOW STARTING FROM THIS ARCHITECTURE, WE CAN TRY TO CHANGE THE TARGETS, SO WAWE TRY TO DO WAS REPLACING THE POROSITY BY THE SQUARE ROOT OF POROSITY IN ORDER TO BOOST THE POROSITY CONTRAST. WE ALSO TRIED DIFFERENT TYPES OF GENERATOR. WE TRIED TO USE DIFFERENT LOSS FUNCTIONS AND WE TRY TO CHANGE THE INPUT SO, 1 THING WE DID WAS TO STACK THE IMAGE WITH WHAT I STALK BODY A FEW SLIDES BEFORE AND CREATE A 2 CHANNEL IMAGE. WE ALSO TRIED DIFFERENT PROTEIN STRATEGIES USING 3D BATCHES, THE IDEA REMAINS THE SAME. THE IDEA IS TO INCREASE THE SIZE OF THE DATA SET AND TO INCREASE THE MEMBER OF WEIGHT OF THE MODEL. FINALLY, SO ANOTHER METHOD WE USED WAS CALLED [INDISCERNIBLE] MASK AND THE IDEA WAS TO MASK OUTPUTS FROM THE GENERATOR IN ORDER TO FORCE THE GENERATOR TO RESTRICT THE LEARNING OF THE MODEL TO PIXELS INSIDE THE SKULL MASK THROUGH A--YEAH,--NOW LET'S TALK ABOUT ANOTHER METHOD WE USE WITH THE MODEL, IT CONSISTS IN DAISY CHAINING THE SIMILAR MODELS IN A ROPE AND ANY MODEL IN THIS SERIES, THE PREVIOUS OUTPUT, THE OUTPUT OF THE PREVIOUS MODEL. SO QUICK WORD ABOUT THE DATA WE USED WE HAD 1 MILLIMETER IOWAS O TROPIC MRI OBTAINED WITH MP RED SEQUENCE, WE HAD CLINICAL STEMS, WE HAD A TOTAL OF 15 SUBJEKS, TO REGISTERED [INDISCERNIBLE], WE USED 13 SUBJECTS FOR TRAINING, 1 FOR VALIDATION AND 1 FOR TEST, SO NOW LET'S TALK ABOUT THE RESULTS SO WHAT YOU SEE HERE, S&P OUR VALIDATION, SO THE ERROR, MODELS ON VALIDATION SETS, AND ON THE Y-AXIS YOU HAVE THE ABSOLUTE ERROR AND THE RESPONSE TO THE AVERAGE RAB ABSOLUTE PIXEL ERROR AND ON THE X-AXIS YOU HAVE THE RESPONSE THAT RESPONDS TO DEEP LEARNING MODEL ITERATIONS. AS YOU CAN SEE THE 2 CURVES CONVERSE TOGETHER SO THERE IS NOT A BIG GROUP BETWEEN THIS PORS ONITY AND THE POROSITY TARGET. NOW WE TROO TO USE THE GENERATORS AND TRY TO TYPES OF INPUT. MRI OR MRI COMPIN ONS WITH SPECIFICITY. SO WE HAD 4 CONFIGURURATIONS IN TOTAL. WE CONCLUDED THAT THE BEST CONFIGURURATION WAS TO USE RESNET AND NO PC T. WE ALSO TRIED DIFFERENT COMBINATIONS AND IT TURNED OUT THAT THE BEST CONFIGURURATION WAS TO USE L1 PRESENTER FOR LOSS FUNCTION. NOW, CHARGING THE INPUT SIZE HAS DRAMATIC IMPACT ON THE PERFORMANCES AS WE CAN SEE, THE 3D CROPPINGS, YIELDED THE BEST RESULTS. SO WE USED 3 CROPPINGS. THREE PATCHES. REGARDING THE OTHER CONTEXT MODEL, WE CONCLUDED THERE WAS LITTLE PERFORMANCE INCREASE, HOWEVER, IT DID NOT OUTWEIGH THE COMPUTATIONAL COST OF TRAINING SELF-MODELING IN A ROW SO WE DID NOT CURE IT IN THE FINAL MODEL. NOW, THE PROPAGATION IN THE MASK IS A METHOD THAT YIELDED BETTER RESULTS IN 2 D MODELS AND 3D MODELS. SO WE DID IT IN THE FINAL MODEL. SO THE PROPOSED MODEL INN CLUEDS A GENERATOR, 3D PATCHES, THE TARGET IS THE POROSITY, IT'S STRAINED USING [INDISCERNIBLE] AND [INDISCERNIBLE], AS YOU CAN SEE ON THESE BAR PLOT, THE PERFORMANCE OF THE PC T ONLY WAS 12%, THE [INDISCERNIBLE] WHICH WAS THE STANDARD IMAGE TO IMAGE ALGORITHM PERFORMED SLIGHTLY BETTER BELOW 12% AND OUR MODEL RETURNS AN ERROR SO ON THE TEST, SORRY, OF 5.8% OF THE POROSITY. SO WE HAVE A SIGNIFICANT IMPROVEMENT WITH RESPECT TO THE REFERENCE METHODS. SO FOR NOW LET'S TACK A LOOK AT THE OUTPUTS FROM OUR MODEL. SO WHAT YOU HAVE HERE IS THE MRI AND THEN THE PIXTOP IX AND THE ERROR OF THE MODEL IS LOWER ON THIS SLIDES. SO THIS IS ANOTHER VIEW ON THE SLICE WITH THE SAME CONCLUSION AND ON THE SAGITTAL SLICE AGAIN WITH THE SAME CONCLUSION. SO TO SUM UP, WE OPTIMIZED A DEEP LEARNING METHOD FOR MRI TO PROVIDE THE ESTIMATION, THE PURPOSE INCLUDES THE RESONATE GENERATOR, 3D BATCHES, TARGET THE POROSITY AND USES 1% TO LOSS AND BIM. OUR PROPOSED APPROACH HAS LESS THAN 6% ERROR, AND IT'S A 2 TIMES PERFORMANCE IMPROVEMENT COMPARED TO PC T AND THE STANDARD DEEP LEARNING ALGORITHM AND FINALLY THIS ENABLES FAST SIMULATIONS FOR TFUS NAVIGATION. THANK YOU VERY MUCH FOR YOUR ATTENTION AND I'M HAPPY TO TAKE ANY QUESTIONINGS. [ APPLAUSE ] >>ANY QUESTIONS? >>THANK YOU VERY MUCH FOR THE PRESENTATION, WE KNOW THAT L1 AND L2 NORMS PROVIDE YOU SOME INSIGHT INTO THE LOSS FUNCTIONS AND ABOUT THE PERFORMANCE OF YOUR MATING, MY QUESTION IS DID YOU HAVE A CHANCE TO COMPARE YOUR FINDINGS WITH THE GROUP FOR FUTURE SIMILARITIES IN THE INDEX MATRIX, SO DID YOU CHECK THAT PARAMETERS IN PROCESSING PARAMETERS? >>WE DID CHECK THOSE METRICS, I ASSUME WE'RE TALKING ABOUT STRUCTURAL SIMILARITY, RIGHT? WE DID USE IT. BUT WE DECIDED TO STICK TO ABSOLUTE HERROR, YOU KNOW IN AN EFFORT TO REALLY FOCUS ON THE PIXEL ERROR. >>IN TERMS OF LOSS FUNCTIONS L1 AND L2 ARE KIND OF GROUND ROOTS IN THE IMAGE PROCESSING SITE BUT ONCE YOU COMPETED YOUR PREDICTIONS, DID YOU HAVE A CHANCE TO COME PAIR YOUR PREDICTIONS AND THE GRANT ROOTS IN TERMS OF SSIM OR FSIM? DO YOU HAVE FOR EXAMPLE, 90% OF SIMILARITY THROUGH [INDISCERNIBLE] OR 95% OF SIMILARITY TO [INDISCERNIBLE] >>SO, FROM MEMORY, I THINK THE SSEM WAS AROUND 1997%, SOMETHING LIKE THAT. THANK YOU. >>WELCOME. >>ALL RIGHT, THANK YOU VERY MUCH MATTHIEU. >>OUR NEXT SPEAKER IS DR. NOREEN BUKHARI-P A RLAKTURK, SHE WILL TALK ABOUT ENGAGEMENT TO DEEP BRAIN NETWORK AS A PREDICTOR BIOMARKER FOR CLINICAL PRESPONSE TO TMS. >>GOOD AFTERNOON, CAN EVERYBODY HEAR ME. I'M FROM DUKE UNIVERSITY. I'VE HAD A GOOD TIME AT THIS CONFERENCE SO FAR, IT'S BEEN FOCUSED MOSTLY ON THE TECHNOLOGICAL DEVELOPMENT I'M A NEUROLOGIST AND SCIENTIST SO I WILL DISCUSS SPECIFICALLY ABOUT THE APPLICATION OF TMS AND FUNCTIONAL MRI TO ADVANCE THERAPY FOR PATIENTS WITH NURRA O LODGE CALIFORNIA DISORDERS DEBINNING WITH FOCAL HAND DYSTONIA. I HAVE NO CONFLICTS OF INTEREST OR DISCLOSURES. DYSTONIA IS AN INVOLUNTARY GESTURE, IT CAN INVOLVE THE WHOLE BODY OR IT CAN BE FOCAL TO A LIMB SUCH AS THE HAND. PATIENT WHO ARE GENERALIZED ARE WHEELCHAIR BOUND AND BED BOUND AND OVERALL VERY DEBILITATING. THERE ARE CURRENTLY NO DISEASE MODIFYING THERAPY FIST ANY MOVEMENT DISORDERS, SPECIFICALLY DYSTONIA HERE, AND SYMPTOMS VARY FROM PATIENT TO PATE. WE KNOW FROM KRINICAL AND PRECLINICAL STUDIES IN THIS DISORDER THAT THE PROBLEM WITH DYSTONIA IS A PROBLEM OF BRAIN CIRCUITRY, AND SPECIFICALLY OF BRAIN CONNECTIVITY. THEREFORE TMS, TRANSCRANEIO MAGNETIC STIMULATION KNOWN TO PLAY A ROLE IN MODIFYING BRAIN CIRCUITRY AND BRAIN PLASTICITY BECOMES AN IDEAL APPROACH TO TRY TO DEVELOP NEW THERAPY FOR THESE PATIENTS. ONE OF THE KEY LIMITATIONS OF TMS THOUGH, IS IT ONLY ACTIVATES AND MODIFYS NEURONS THAT ARE LESS THAN 1 CENTIMETER. NOW THERE HAVE BEEN PRIOR STUDIES OF TMS, TMS STUDIES IN PATIENTS WITH FOCAL HAND DISTONE RAW DATA AND THEY HAVE SHOWN SOME TRANSIENT BENEFIT, SO WHAT CAN WE LEARN FROM THESE INITIAL 7 STUDIES. THERE ARE 5 OF THE STUDIES THAT SHOWED THAT MULTIPLE SESSIONS OF REPETITIVE TMS IN PATIENTS WITH FOCAL HAND DYSTONIA, LED TO CLINICAL IMPROVEMENT AFTER TMS WAS APPLIED AT THE PREMOTOR CORTEX. WITH THE STUDY THAT SHOWED THE LONGEST EFFECT WAS 2-3 WEEKS AND THAT WAS SHOWN WHEN TMS WAS APPLIED AT THE PRIMARY SO MAT O SENSORY CORTEX. AND SO, THUS FAR WHEN WE KNOW IS THAT TMS ISSUE, REPETITIVE TMS APPLICATION AND FOCAL DYSTONIA DOES SHOW A TRANSIENT BENEFIT AFTER APPLICATION AT THE PREMOTOR AND SOPHISTICATED MAT O SENSORY CORTEX. BUT HOW DO WE PROLONG THIS EFFECT. HOW DO WE DEVELOP A LONG LASTING THERAPY, A QUESTION THAT IS APPLICABLE IN THE NEUROLOGICAL BUT ALL THE CLINICAL DISEASE MODELS. SO WORK BY OTHERS IN ANOTHER DISEASE MODEL IS HAS ACTUALLY LED US TO AN ADVANCEMENT, SPECIFICALLY JOEL VOSS' GROUP HAS SHOWN THAT WHEN TMS IS SAW PLIED AT THE SUPERIOR PARIETAL CORTEX IT LEAD TO DEEP BRAIN MODIFICATION OF THE HIPPOCAMPUS. THEY SHOWED THAT CHANGES IN FUNCTIONAL BRAIN CONNECTIVITY CAN LEAD TO IMPROVEMENT IN MEMORY SO THIS LED US TO ASK THE QUESTION THAT WHAT IS THE KEY DIFFERENCE, WHAT IS THE KEY DEEP BRAIN NEST WORK TO TARGET PATIENTS WITH DYSTONIA AND SO MULTIPLE GROUPS HAVE ACTUALLY SHOWN THAT BASAL GANGLIA IS A KEY DEEP BRAIN REGION THAT IS ABNORMALITIES SNRORMAL IN PATIENTS WITH FOCAL DYSTONIA. THIS IS A SEMINOLE PAPER FROM JOEL PEARL MATTERS GROUP AT WASH U. AND THAT I HAVE SHOWN SEVERAL PATIENTS SHOW A KEY DEFACT IN THE KEY REGION OF THE BASAL GANGLIA. AND SPECIFICALLY IT'S A DEE CREASE IN BASAL GANGLIA ACTIVITY AND FUNCTIONAL MRI. OUR GROUP HAS ALSO SHOWN, THAT THE ABNORMALITY IN PATIENTS WITH FULL DYSTONIA ALSO OCCURS PRIMARILY AT THE BASAL GANG LIAISON AWHAT WE'RE SHOWING ADDITIONALLY IS THAT ACTIFORT, THE FUNCTIONAL BRAIN ACTIVITY IS STAYED DEPENDENT AND IT CHANGES DEPENDING ON WHETHER THE ACTIVITY OCCURS ON THE ON BLOCK OF WRITING OR THE OFF BLOCK. DETAILTHIS STUDY WILL BE DISCUSSED TOMORROW BY DR. ANDREW MICHAEL, BUT THIS FINDING BY OUR GROUP AND OTHERS ACTUALLY FORM THE FUNDAMENTAL BASES FOR OUR HYPOTHESIS WHICH WAS WHICH BASAL AREA WILL HELP PATIENTS WITH DYSTONIA AND OUR HOPE IS THAT BY MODIFYING THE BASAL GANG LIAISON A WE CAN DEVELOP A LONG LASTER THERAPY. SO WE'VE HOPE TO BE ABLE TO DELIVER TMS AND WE FOCUS ON THE PREMOTOR CORTEX AND THE PRIMARY SOPHISTICATED MAT O SENSORY CORTEX, HYPOTHESISSING THAT THE TRANSIENT BENEFIT MAY HAVE BEEN DUE TO SOME MODIFICATION OF THIS DEEP BRAIN REGION SO WE APPLY 10 MRTMS, AND WE PATIENT WITH FOCAL HAND DYSTONIA AT THE PREMOTOR CORTEX OF THE PRIMARY SOPHISTICATED MAT O SENSORY CORTEX. WE ALSO DELIVERED [INDISCERNIBLE] AT THE PREMOTE CORCORTEX IN THESE PATIENTS. OUR STUDY WAS DOUBLE BLINDED AND SHAM CONTROLLED AND IMPORTANTLY WE DID A RANDOMIZED ORDER OF TMS DELIVERY WHERE ALL SUBJECTS RECEIVED ALL 3 TMS CONDITIONS IN A CROSS OVER DESIGN. NOW THE TMS IN ORDER TO MEASURE THE EFFECT OF THIS TMS STUDY, WE ACTUALLY TOOK BEHAVIORIAL MEASUREMENTS AT BASE LINE, AND THEN IMMEDIATELY AFTER THE TMS SESSION, WE ALSO TO LOOK AT THE BASAL GANGLIA ACTIVITY WE PERFORMED TASK FUNCTIONAL MRI. NOW IN ORDER TO INSURE THAT WE WERE TARGETING A REGION OF INTEREST, WHICH IS PRIMARILY THE MOTOR NETWORK WE USE AN APPROACH CALLED THE MOTOR TEST SYNCHRONIZED TMS DELIVERY WHICH MEANS WE DELIVERED TMS IN 4 BLOCKS OF SIM USE, ALTERNATED BY 4 BLOCKS OF A TASK THAT WAS REEL KEEPSAKES VABT TO PATIENTS WITH DYSTONIA, WHICH IS A MOTE OAR LEARNED TASK SUCH AS WRITING. AND SO 1 OF THE CHALLENGE I DON'T NEED TO TELL THIS GROUP IS THE TECHNICAL VARIABLE, BIOLOGICAL VARIABILITY. SO TO ASK A BIOLOGICAL QUESTION, WE WANTED TO OPTIMIZE THE TECHNICAL DELIVERY OF TMS. SO WE WORK WITH OUR COLLEAGUES IN FUNCTIONAL MRI AND OUR COLLEAGUES IN TMS ENGINEERING TO OPTIMIZE AND REALLY INSURE MORE PRECISE DELIVERY OF THIS TMS. SO WE BEGAN BY GETTING A FUNCTIONAL MRI ON PATIENTS WITH FOCAL HAND DYSTONIA AS A BASE LINE TO DEVELOP OUR BRAIN LINE TARGETING. SO SPECIFICALLY SUBJECTS COMPLETED A T1 MRI. AND THIS KNOW THEY COMPLETED A TASK FMRI TO THE WRITING TASK TO IDENTIFY FUNCTIONAL BRAIN ACTIVITY. WE THEN OVERLAY THE MNIAT LAS PINTAS FOR THE PREMOTOR TEXT AND ULTIMATELY WE IDENTIFIEDED HIGHEST WE HAVE SCORE WITHIN THE FORMULA METER TO LESS THAN 1 CENTIMETER DANCE FROM THE SUPERFICIAL CORTEX. WHICH ALLOWED US TO DEVELOP A SMALL 2 VOXEL MASK, WE THEN TOOK THE FUNCTIONAL BRAIN TARGETED MASK AND WE WORK OUR COLLEAGUES IN ENGINEERING, PARTICULARLY DR. PETER [INDISCERNIBLE] GROUP, HIS GROUP HAS SHOWN THAT TO OPTIMIZE AND MAXIMIZE THE ELECTRIC FIELD AT THE CORTICALE GYRUS OF INTEREST, YOU WANT TO DELIVER TMS COIL IN AN ORIENTATION THAT MACK MYSELFS THE LANGUAGE FIELD TANGENTIAL TO THE COTTERICALLY GYRUS. SO USING THAT PRINCIPLE WE WORK TOGETHER TO BASICALLY DEVELOP A TMS TARGETED ANALYSIS PIPELINE. AND THE GOAL WAS TO ABLE TO RUN A COMPUTATIONAL SIMULATION IN SOFTWARE THAT ALLOWED US TO DETERMINE WHICH IS THE OPTIMAL COIL ORIENTATION ON THE SCALP THAT COULD MASS MIKES THE ELECTRIC AT FIELD AT THE CORTICALE GYRUS SO THE ULTIMATE GOAL AND OUTPUT WAS BASIC LE A SCALP TARGETING THAT ALLOWED US TO BE ABLE TO MAXIMIZE ELECTRIC FIELD AT THE CORTICALE GYRUS, THAT DATA WAS THEN INPUT AND ON THE DAY, 1 MORE THING IS THAT ON THE DAY OF THE TMS STIMULATION, WE THEN ADJUST THAD SCALP TARGETING BASED ON THE HAIR THICKNESS OF THE SUBJECT. AND THIS INFORMATION WAS PUT INTO A NEURONAVIGATION SOFTWARE AND THEN COMPLETED THE STUDY, AND THE FIRST QUESTION WE WANTED TO KNOW WAS HOW WELL DID WE DO IN THE RECEIVED ELECTRIC FIELD AT THE CORTICO GYRUS OF INTEREST IN ORDER TO ANSWER THE QUESTION BIOLOGICALLY, WE NEED TO BE ABLE TO DELIVER EQUAL AMOUNTS OF ELECTRIC FIELD ACROSS BOTH ACTIVE CORTICALE TARGETS AND SO WE LOOKEDDA THE THAT AND IN FACT WE HAVE NO DIFFERENCE IN THE RECEIVED ELECTRIC FIELD AT THE PRIMARY SOPHISTICATED MAT O SENSORY OR PRO MOTOR CORTEX IN PATIENTS WITH FOCAL HAND DYSTONIA, SO THEN WE ASKED THE QUESTION, WELL HOW DID OUR PATIENTS DO BEHAVIORIALLY AFTER 1 SESSION OF REPETITIVE TMS. AND WHAT WE SAW WAS THAT TMS DELIVERED IN A SINGLE SESSION ACTUALLY LED TO A SIGNIFICANT REDUCTION IN BEHAVIOR OF DYSTONIA, IN PATIENTS WHO RECEIVED ACTIVE TMS OR PREMOTOR PRIMARY SOPHISTICATED MATE O SENSORY TORTEX AND WE ASKED HOW DO WE DO IN TERMS OF FUNCTIONAL BRAIN ACTIVITY, DO WE MODIFY THE BASAL GANGLIA AND IT WAS A SURPRISE TO US AS WELL AS HOW MUCH BENEFIT WE ACTUALLY DELIVERED, WE SAW THAT PATIENT WHO IS HAVE TMS DELIVERED AT THE SOPHISTICATED MAT O SENSORY CORTEX SO A INCREASE WITH BOLD ACTIVITY IN THE PATIENTS COMPARED TO THOSE WHO RECEIVE ACTIVE TMS AS A PREMOTOR OR SHAM. SO IN CONCLUSION I'VE SHOWN YOU THAT REPETITIVE TAMERICA S CAN ALLOW FOR MODIFICATION OF DEEP BRAIN NETWORK AND THAT RTMS AND THE PRIMARY SENSORY CORTEX IMPROVE DISTONNIC BEHAVIOR BUT IT'S SPECIFICALLY THE 10-HERTZ, A CONCEPT WE CAN SAY IS TARGET ENGAMEMENT AND FUTURE STUDIES ARE NEEDED TO SELECTIVE ENGAGEMENT OF BASE AT GANGLIA COULD SERVE AS A PREDICTIVE BIOMARKER BUT CLINICAL RESPONSE TO OUR TMS AND THEREFORE ALLOW US TO DEVELOP A TARGETED THERAPY THAT WOULD BE LONG LASTING IN THESE PATIENTS AND FIEBDING FROM THE STUDY COULD OVERALL INFORM THE DESIGN AND DEVELOPMENT OF NONINVASIVE NEUROMODDULATION WITH PATIENTS WITH DYSTONIA, WITH THAT I AM HAPPY TO TAKE ANY QUESTIONS, I WORK WITH A LARGE GROUP OF PEOPLE AND FORTUNATE TO HAVE TECHNICAL EXPERTS TO COLLABORATE WITH SO THANK YOU VERY MUCH. >>DO WE HAVE ANY QUESTIONS? STHRKS YOU TALKED SO FAST I MIGHT HAVE MISSED IT. SO DID YOU END UP GETTING A LASTING IMPROVEMENT IN THE PATIENTS WITH DYSTONIA. >>YES, SO THE BENEFIT I WAS SHOWING IN THE BEHAVIOR SIDE WAS MEASURED IMMEDIATELYOT DAY OF, HOWEVER, WE ACTUALLY WERE ASKING OUR PATIENTS THE SAME QUESTION, WHAT WAS SURPRISING IS HOW LONG THEY WERE REPORTING THE BENEFITS SO OUR PATIENTS REPORTED BENEFITS THAT LASTED UP TO A MONTH AND 1 PATIENT SAID IT NEVER REOCCURRED. SO WE'VE HAD TO DO ADVANCED ANALYSIS TO SEE WHAT WAS CONSISTENT WAS THAT PATIENTS WHO HAD LONG LASTING BENEFIT ENDED UP HAVING AT THIS TIME AT THE PRIMARY SOPHISTICATED MAT O SENSORY CORTEX, ENDED UP RECEIVING TMS AT THE CORTEX, SUGGESTING THAT MAYBE ACTIVATION OF DIFFERENT TYPES OF PLASTICITY RESPONSES, WHEREAS TMS AT THE ACTIVE PRIMARY SOPHISTICATED MAT O SENSORY CORTEX MAY BE ACTIVATING A LONG-TERM PLASTICITY RESPONSE COMPARED TO THOSE WHO WERE RECEIVING, THE TMS CONDITION AT THE PREMOTOR CORTEX. THANK YOU VERY MUCH DR. BUKHARI. [ APPLAUSE ] >>NEXT UP, DR. DEBILY FROM THE UNIVERSITY OF HOSPITAL OF STRASBOURG. >>THANK YOU CAN YOU HEAR ME? I AM A PSYCHIATRIC DOCTOR IN THE CENTER HOSPITALLIER UNIVERSITY DESTRASBOURG, IN FRANCE, I WANT TO TALK ABOUT THE VALIDATION OF A BIOMARKER IN THE DIAGNOSIS OF PERIODIC CATATONYA, I HAVE NO DECLARATIONS. SO FIRST WHAT ARE WE TALKING ABOUT WE ARE TALKING ABOUT A SUBTYPE OF SCHIZOPHRENIA, WHICH IS WITH THE PATIENT AND HAS RECEIVED [INDISCERNIBLE] WITH ACCLIMATION OF THE RESIDUAL SYMPTOMS, IT'S A POLYMORPHIC PRESENTATION AND THESE 2-POINTS WILL BE VERY IMPORTANT LATER. AND ALL RIGHT BEEN BY 2 TEEMSOT FMRI, TO WONDER WHAT ARE THE ORIGIN EVER THE BRAIN WHICH CAUSES THE SYMPTOMS. BUT THIS GROUP EFFECT AND WE WANTED TO MAKE A TODAY ABOUT SINGLE PATIENT IMAGES. SO WE WROTE A PROTOCOL WITH ACQUISITION OF [INDISCERNIBLE] CONTRAST. EVERY PATIENT HAS A 3 SCAN WITH 2 MEASURE, 1 WAS AT TEOF 9.7 MILLI SECONDS AND 1 WAS 21 MILLI SECONDS. WE FOCUSED ON THE SAME 2 ORIGINS OF INTEREST, L-PMAND L-SMA AND EACH PATIENT HAD IT'S OWN MRI COMPARED TO IT, AND THE DAILY BASIS THEA BASE OF CONTROLLED SUBJECT TO MAKE [INDISCERNIBLE] THE BRAIN [INDISCERNIBLE]. >>WE USE THE BIOSCAN MODEL WHICH ALLOW US TO MAKE MODULARIZATION OF THE SENSITIVITY AND SPECIFICITY. AND WE--WHICH ALLOWS A POSSIBILITY TO MAKE THE [INDISCERNIBLE] UPDATES FOR THE [INDISCERNIBLE] EVERY TIME WE RECRUIT A NEW [INDISCERNIBLE]. WE USE PRIOR DATA AND IT GIVES YOU MORE REPRESENTATIVE OF THE RESULT, WITH THE BELIEF OF THE SENSITIVITY AND THE HER EDITTITY OF THIS VALUE IS A TRUE 1. WE MADE THE FIRST PROOF OF CONCEPT 2 D WITH A SAMPLE. OUR METHOD OF ACQUISITION HAS HAD HIGH ACRASESY AND HIGH KD--SALLY WHICH MADE IT REALLY RELIABLE MEASUREMENT. THE FIRST 1 IS PRIOR CATATONYA 23, AND 26 PATIENTS WITH NOVEL OR PHENOTYPE OF MENTAL DISEASES, WE HAD A SENSITIVITY OF 98% AND A SPECIFICITY OF 8% WITH A NORMATIVE PRIOR. THIS FIRST PROOF OF CONCEPT, WE LEARNED 2 THINGS. FIRST, OUR WORK SEEMS TO BE SPECIFIC, BECAUSE THE OTHER PATIENT WITH ANOTHER FORM OF [INDISCERNIBLE] SEEMS TO HAVE IT. ALSO, OUR BIOMARKERS SEEMED TO BE SENSITIVE TO A PATIENT WITH A MOTOR IMPAIRMENT INCLUDING THE REQUIRED MOTOR IMPAIRMENT LIKE MULTIPLE SCLEROSIS OR LEG INJURIES. WE DECIDED TO USE OUR DATA WITH ANOTHER EXAMPLE, THE DATA WAS WEIGHTED INDEX AND WE INCLUDED 13 PATIENT [INDISCERNIBLE] AND A PATIENT WITH ANOTHER PHENOTYPE. WE THEN HAD A SENSITIVITY OF 77 PERSON AND A PATIENT WITH 78%. PATIENTS WITH MORE UNCLEAR DIAGNOSIS AND DIAGNOSTIC CORRECTIONS, THEY MAKE ALLOW US TO MAKE A CORRECTION OF THE DIAGNOSIS. WE DECIDED TO MAKE AN UPDATE OF THE ABILITY OF OUR BIOMARKER EXCLUDING THE PATIENT WITH MOTOR IMPAIRMENT AND TAKING A FULL DATA SET WITH THE [INDISCERNIBLE] PRIOR, AND THEN WE THEN HAD SENSITIVITY OF 82% AND SPECIFICITY OF 98%. SO, WE HAVE INCENTIVE AND SPECIFIC BIOMARKER. COMBINED WITH THE CLINICAL EXAM NATION, IT HAS A GOOD [INDISCERNIBLE], AND A GOOD PARTICIPATORY [INDISCERNIBLE], SO FOR EXAMPLE, IF YOU TAKE THE PATE WITH THE SSD DIAGNOSIS, WITHOUT BIOMARKER THEY HAVE PROBABILITY OF 14% TO HAVE PERIODIC CATATONIA, IF THEY HAVE A POSITIVE BIOMARKER THEY HAVE A PROBABILITY OF 73% TO HAVE A CATATONYA, AND IF THEY HAVE A NEGATIVE BIOMARKER, THE PROBABILITY HOLDS TO 3%. WE WILL NOW REPLICATE OUR FURTHER STUDY INCLUDING MORE PHENOTYPES OF MENTAL INJURY, AND WE CAN NOW IN OUR MODEL, ALLOW US TO MAKE [INDISCERNIBLE] THAT,A LOW US TO WEIGH THE DATA FOR EACH PROTOCOL. WE ARE NOW MAKING DIAGNOSIS FOR [INDISCERNIBLE] - AS I SAID IT'S A MOLECULAR PRESENTATION OF THE SYMPTOMS SO IT'S A HUGE AREA FOR PATIENTS WITH THE MORE SYMPTOMS, THERE IS NO ACHE, OR STRATEGY WITH THE FOLLOW UP OF THE [INDISCERNIBLE] AND WE ARE NOT ABLE TO MAKE BETTER RESEARCH ON THE CATATONYA, FOR EXAMPLE, WE ACTUALLY CORTICALE USING THIS BIOMARKER ON THE TARGET FOR THE TMS STIMULATION, AND WE OBTAINED A HUGE EVALUATION OF THE PATIENTS MORE THAT WE COULD HOPE WITH ONLY A PHARMAICOLOGGIC TREATMENT AND STIEMENTS BETTER BY [INDISCERNIBLE]. WE WILL NOW USE THE BIOMARKER TO REDEFINE THE PHENOTYPE OF THE CATATONYA. USING A RIGOROUS APPROACH, YOU USE THE BIOMARKER FOR THE PATIENT WITH A MORE BOUNDARY PATIENT WITH EARLY ONSET, DIAGNOSIS, I DON'T HAVE THE SAME CLINICAL PRESENTATION OF THE OTHER AND WE CAN WITH THE TECHNOLOGY AND OUR BIOMARKER, REDEFINE THIS PHENOTYPES AND CONFIRM IT WITH ANATOMY [INDISCERNIBLE]. I WOULD REALLY LIKE TO THANK THE [INDISCERNIBLE] TEAM WITHOUT WHOM I WOULD NOT BE ABLE TO MAKE THIS PRESENTATION ESPECIALENTIALLY [INDISCERNIBLE]. AND ALSO THE TEAM OF THE STRASBOURG, AND THE NEUROMODDULATION CENTER. THANK YOU FOR YOUR ATTENTION. [ APPLAUSE ] >>HI, NICE PRESENTATION. WHY WAS THE--WAS THE LONG TE NEEDED? YOU SHOWED THERE WAS A CORRELATION BETWEEN THE 2 ISL, WAS IT NEEDED AFTER LONG T? >>THREE? >>ARE WHY DO YOU NEED 2? >>ONE IS MORE IMPORTANT THAN THE OTHER AND THE OTHER IS SPECIFIC. IN THE 1970S LIKE THE [INDISCERNIBLE] ACQUISITION, BUT THE 21 SIGNAL IS NOR SENSITIVE AND WE HAVE BIOMARKERS WITH THE A COMBINATION OF THE BOTH, TO THE TARGET SO THE CONTEXT AND [INDISCERNIBLE] IN THE 2 ACQUISITION, AND THE COMPOSITION OF THE 4 FACAS RAM TERS MADE THE BY O MARKER, THE POSITIVITY OF THE BIOMARKER. >>ARE THERE ANY OTHER QUESTIONS? IF NOT WE WILL MOVE TO THE NEXT SPEAKER. THANK YOU VERY MUCH. [ APPLAUSE ] DR. JEANJEAN FROM THE UNIVERSITY HOSPITAL OF STRASBOURG. >>HELLO EVERYBODY, MY NAME IS LUDOVIC, DORMEGNY-JEANJEAN, AND I WILL TALK TO YOU ABOUT OUR WORK ON PERSONALIZING TARGETING IN RTMS USING ASL IN DEPRESSION, AND IT'S APPLICATION TO THE DEPRESSIVE DISORDER. SO I WILL NOW SAY A SENTENCE NOW [INDISCERNIBLE] WE NEED TO REFINE OUR EQUIPMENT [INDISCERNIBLE]. IN THE FIELD OF TMS, IN THIS WAY WE CAN [INDISCERNIBLE] THE ONE-SIZE-FITS-ALL APPROACHES AND IMPROVE EFFICACY. WE DO THAT BECAUSE OF BIRTH AS ANNOT ME OF FUNCTION AND VIABILITY OF THE BRAIN BUT PATHOPHYSIOLOGICAL HETEROGENERATED AITY OF DEPRESSION AND THE OTHER CIRCUITRY DISORDERS. WE PROPOSE TO USE TMS TARGETING TO RUES IT FOR ROBUSTNESS AND [INDISCERNIBLE] BETWEEN THESE. AND WE USE FOR THESE TODAY, VERY CLOSE WITH THE 1 PRESENTED BY [INDISCERNIBLE] AND USE IT TO DEFINE ANOMALY AND A SET OF CONTROL--ABNORMALITIES VERSUS CONTROLS AND ALSO PERSONALIZE THAT WITH THE REBALANCE PERFUSION ABNORMALITIES AND THEN THERE IS A PARTICULAR BIOMARKER, IF WE,A ASSESSES IT [INDISCERNIBLE], WOO CAN USE IT AS IT MAY NOT COME AND READY WITH YOUR [INDISCERNIBLE].--WE SEEM TO BE LESS NEUROLOGIC FUNCTION [INDISCERNIBLE] WE WE ARE ALSO DIFFERENT TO THE WORK ABOUT REBALANCING [INDISCERNIBLE] BECAUSE WE USE MORE ACCURATE AND MORE REPRODUCIBLE MEANS AND WE--WE ARE NOT LIMITED TO A SINGLE PURPOSE THAT [INDISCERNIBLE] DEFICIT TARGET. WE CONDUCTED A PILOT STUDY WITH THE COURSE OF A DESIGN WITH EQUIPMENT TMS, CLASSIC TMS, TARGETING THE DORSAL [INDISCERNIBLE]. AND POST CONNECTOR STIMULATION. FOR [INDISCERNIBLE] WE USE STIMULATION OF ACTIVATION AND LOOK FOR CONSISTENCY WITHIN THE BRAIN AND WE USE [INDISCERNIBLE] POSITIONING. THERE IS A CHANGE OF DEFINITION IN [INDISCERNIBLE] AND [INDISCERNIBLE], DEVELOP WELL AND [INDISCERNIBLE] BECAUSE OF THE 2 SHORT AREA, THE THRESHOLD BETWEEN THOSE 2. JUST A LITTLE BIT MORE ABOUT THE DATA PROCESSING WE USE, THE [INDISCERNIBLE] CONTRAST FOR EACH EQUIPMENT AND THEN COMPARE EACH OF THIS INTEREST, WE'VE [INDISCERNIBLE] WITH THOSE [INDISCERNIBLE]. THIS WAY, WE KIND HAVE BEEN SPECIFIC TYPE OF SPECIFIC OF EQUIPMENT FOLLOWING [INDISCERNIBLE] OF THIS CONTRAST. WE USE THE [INDISCERNIBLE] BETWEEN THE 2 MOBILITYS OF THESE AND BETWEEN THE [INDISCERNIBLE]. AND WE INCLUDED 22 PATIENTS [INDISCERNIBLE] AND WE HAVE EFFUSION [INDISCERNIBLE] WITH MANY POSSIBILITY OF TARGETING AND THANKS TO THE ROBOTIC PLACEMENT WE WERE ABOUT TO REACH UP TO 18 TARGET SECTION. IN THIS CASE, WE HAVE THE NUMBER OF [INDISCERNIBLE] BETWEEN TARGETS AND THE NUMBER OF [INDISCERNIBLE] BETWEEN SESSIONS. TMS INDUCED SPECIFIC LOCALIZED DECREASED SDF IN THE BRAIN HEMISPHERE, IT WAS THE EARLY TREATMENT TO INDUCE THIS TYPE OF [INDISCERNIBLE] PROPHETIC. AND IT WAS IN [INDISCERNIBLE] INVOLVED IN [INDISCERNIBLE] PROCESSES. AND TO CONCLUDE IMAGING INN DUCED SPECIFIC EFFECT ON THE RCBF, WHICH IS RTMS OR TDCS, [INDISCERNIBLE] AND THAT FURTHER WORK FOR INTERPRETATION AND [INDISCERNIBLE]. THIS IS AN ALTERNATIVE WAY TO PERSONALIZE THE RTMS, DIFFERENT TO CONNECTIVITY BASED ON [INDISCERNIBLE] BUT NOT MANDATORY [INDISCERNIBLE]. AND [INDISCERNIBLE] TODAY AND WAS NOT SIGNIFICANT IN OUR STUDY BECAUSE IT WAS [INDISCERNIBLE]. BUT THE NEXT DAY, IT WOULD BE TO [INDISCERNIBLE] STUDY WITH BETTER DESIGN TO THANK [INDISCERNIBLE] CORRELATES OF [INDISCERNIBLE] METRIC AND WE SHOULD PAY PARTICULAR ATTENTION TO PATIENT WITH A REEMINENT [INDISCERNIBLE] PROCESS [INDISCERNIBLE]. I WANT TO THANK OUR TEAM WE ARE LUCKY TO WORK WITH [INDISCERNIBLE] AND I THANK YOU IF ARE YOUR ATTENTION. [ APPLAUSE ] >>ARE THERE ANY WEB CONNECTEDS FOR THE SPEAKER? I HAVE A QUESTION. SO THE ASL MEASUREMENTS ARE THEY GIVING YOU THE TARGETS FOR TMS? >>YES. >>DO HAVE YOU AN EXPLANATION FOR THE MECHANISM, WHAT BY? >>WE DO NOT TAKE [INDISCERNIBLE] ABOUT UNDERLYING MECHANISM BECAUSE WE MADE AS FEW ASSUMPTION AS POSSIBLE ABOUT MECHANISM BUT JUST, SEEKING TO REBALANCE OKAY, THANK YOU. ANY OTHER WEB CONNECTEDS. ANY OTHER QUESTIONS, OKAY, IF NOT WE WILL MOVE TO THE NEXT SPEAKER. THANK YOU. [ APPLAUSE ] NEXT UP WE HAVE HONG MING LI FROM THE UNIVERSITY OF PENNSYLVANIA. >>GOOD AFTERNOON EVERYONE, UNFORTUNATELY HONG MING LI WAS NOT ABLE TO JOIN THIS MEETING SO I WILL MAKE THIS PRESENTATION. SO WE WILL START WITH THE SLIDES SHE PROVIDED TO SPEED UP THE PLACEMENT OF ELECTRONIC FIELD. I HAVE NO CHRIS DISCLOSURES. SO FOR ELECTRIC FIELD MODELING, WHAT MATTERS IS THE LEARNING FOR FAST OPTICAL IMAGES MIEDZATION FOR TMS COIL PLACEMENT, SO RELATIVELY FASTER OF OPTIMIZATION FOR PLACEMENT. IN RECENT YEARS, [INDISCERNIBLE] HAVE SPEED UP THE DEEP FIELD MODELING, SO INCLUDING NASA TO HELP SIMPLIFY THIS, BUT PARTICULARLY DEEP LEARNING HAVE DEMONSTRATED THAT [INDISCERNIBLE] PERFORMANCE TO SPEED UP THE OPTIMIZATION, SO THIS CAN GENERATE SOLUTIONS BY DIRECT LEARNING FROM ELECTRONIC FIELD THAT GENERATED BY OTHER TYPES OF MEDICINE LIKE FEM, HOWEVER THIS METHOD KIND OF TO PROVIDE DEEP LEARNING MASS WERE NOT DESIGNED FOR DIRECT STARTS, THE POSITIVE DECREASED IN THE DEEP FIELD MODELING. SO GET THIS STARTED WITH THE PROVIDE THE DEEP LEARNING METHOD TO DIRECT [INDISCERNIBLE]--CAN GENERATE AN ELECTRONIC FIELD THAT'S LOOSE AND USING ANY REASON. THIS IS SELF-CONTAINED, KD--SALLY WADIFFERENT FROM THIS, IN, AND DEEP LEARNING MASS, THAT HAVE TO USE ALL THE TYPES OF [INDISCERNIBLE] TO GENERATE DATA OF ELECTRONIC FIELD. SO THIS IS OVER THE FRAMEWORK OF THE [INDISCERNIBLE], GIVEN ANY INPUT CONSISTENT E-FIELD MODEL AND EFIELD GENERATED BY MASK COIL. OUR MASK IS APPLIED TO AUTOMYSELF DEEP LEARNING NEURAL NETWORK TO GENERATE ELECTRONIC SCALE UP TO MINIMIZE LOST PARTS AND ON THE MODEL YOU DON'T OPTIMIZE IT, THE MODEL CAN DIRECTLY APPLY TO NEW DATA TO GENERATE ELECTRONIC FIELD OF THESE EVENTS THERE FOR THE [INDISCERNIBLE]. >>OR UPON THAT, THE STANDARD UNIT, NETWORK ARCHITECTURE TO USE IT AND THE NETWORKS THAT COMPUTERS ARE ELECTRONIC FIELD SO BASICALLY WE WANT INPUT AND CONDUCTING AND PRIME THE FIELD THAT OUR METHOD CAN DIRECTLY GENERATE THAT ELECTRONIC POTENTIAL AND THE CAN ALSO COMPUTE GRADIENT OF THIS POTENTIAL TO GENERATE THE ELECTRONIC FIELD. WE HAVE [INDISCERNIBLE] METHOD ON OUR [INDISCERNIBLE] WITH 100 IMAGE OR THE HIGH QUALITY [INDISCERNIBLE] TO THE MRI IMAGE, THUS WE DON'T HAVE [INDISCERNIBLE] FOR THE FIELD SO WE COMPARED OUR FEM SOLUTIONS IS USING THE SAME NAMES. SO THE MODEL ON THE 100 SUBJECTS AND THE VARIED MODEL TO THE 25 SUBSETS. SO 1 IS VERY DIFFERENT SETTINGS OF [INDISCERNIBLE] PLACEMENT. BECAUSE FIRST EVALUATE THE MASS FOR THE COIL PLACE AT A LOCATION [INDISCERNIBLE]. THE RIGHT FIGURE SHOWS SOLUTION GENERATED BY FEM AND THE DEEP LEARNING MASK FOR DIFFERENT SUBSET. THIS RESULTS INDICATES THAT THOSE ARE GENERATED SIMILAR ELECTRONIC FIELDS. IS A SMALL DIFFERENCE, THE SPEED OF OUR [INDISCERNIBLE] DEPEND ON THE SPECIAL AND HEAD MODEL. THE HEAD MODEL WAS A CUBIC [INDISCERNIBLE] AND WE WERE ASKED DO CONSIDER ELECTRONIC FIELD FOR 25-SECONDS. SO WE ALSO TEST THE MODEL ON THAT DATA WITH COIL PLACED AT THE SAME PLACE BUT INDIFFERENT DIRECTION. WE ALSO UPON [INDISCERNIBLE] MODEL WITH THE PLACEMENT WITH A DIFFERENT DIRECTION AND MOUNT FOR DIFFERENT PLACE. SO ALL THOSE RESULTS, EXPERIMENTS HAVE [INDISCERNIBLE] DEMONSTRATED THAT DEEP LEARNING MASK CAN GENERATE ELECTRONIC FIELD COMPARABLE TO FEM SOLUTIONS. HOOVER, THIS, IS THE COMMITTEE WERE A RESULTS FOR THE COMPARISON BETWEEN FEM SOLUTIONS IS THE DEEP LEARNING SOLUTIONS. ON THE GRAY MATTER, THE PLAQUE MATTER, READINGS, THE CORRELATION BETWEEN THOSE 2, THE 2 SOLUTIONS WERE UP FOR 4984, AND THE DIFFERENCE, WAS AS SMALL AS A POINTER 0, OF COURSE, THE PERFORMANCE WAS DIFFERENT AT DIFFERENT SETTINGS OF THE COIL PLACEMENT, BUT ALL THIS METHODS, ALL THESE RESULTS HAVE DEMONSTRATED THAT THE DEEP LEARNING MASS CAN GENERATE IT, SOLUTIONS TO COMPARABLE TO THE FEM'S MASTER, WE KNOW THE FEM SOLUTIONS ARE NOT [INDISCERNIBLE] AND THE SUBSET TO CERTAIN AREAS SO WE ALSO COMPARED IT TO THE DEEP LEARNING MASS TO THESE FEM BASED ON SEVERITY MODEL. THESE RESULT INDICATORS THAT THE DEEP LEARNING ACTUALLY CAN ATTENUATE SLIGHT BETTER ACCURACY THAN THE STANDARD FEM. SO, IN SUMMARY OUR STUDY SHOWS THAT THE STEPS PROVIDED CAN GENERATE A ELECTRONIC FIELD COMPARABLE TO FEM MASS, HOWEVER, ONGOING RESEARCH FOCUS ON MODEL OPTIMIZATION, INCLUDING TRAINING MODEL ON THE LARGER BETA SAMPLE AND AUTOMYSELF THE [INDISCERNIBLE], AND OPTIMIZATION [INDISCERNIBLE]. THANK YOU FOR YOUR ATTENTION. [ APPLAUSE ] >>THERE ARE ANY QUESTIONS? OKAY, I HAVE A QUICK, QUESTION, SO HOW LONG DOES IT TAKE TO OPTIMIZE WITH CNIBS? >>I'M SORRY? >>HOW LONG DOES IT TAKE TO OPTIMIZE FOR CNIPS, YOU SAID WITH DEEP LEARNING IT TAKES A SECOND? >>DEPENDS ON YOUR USE, IT TAKES ABOUT 10-SECONDS. HOWEVER, THERE ARE IMPAIRMENTS. >>OKAY. ANY QUESTIONS? OKAY, IF NOT, I THINK WRAPPING UP THE SESSION, THANK YOU ALL FOR ALL THE SPEAKERS. [ APPLAUSE ]