>> LET'S RECONVENE FOR THIS MORNING. YESTERDAY WE GOT GREAT BACKGROUND ON THE DEVELOPMENT OF THE BRAIN WITH AN EMPHASIS ON THE MOTOR SYSTEMS. WE LEARNED A LITTLE ABOUT HOW SOME EXTERNAL FACTORS, INSULTS, SOME INJURY, CAN SET THIS OFF COURSE. WE LEARNED ABOUT WAYS OF DIAGNOSING, SUPPORTING AND TREATING KIDS THAT ARE AT RISK AND SOME PERCENTAGE OF THEM WILL END UP WITH SOME SORT OF PERMANENTLY ALTERED SUBSTRATE THAT HAS TO BE DEALT WITH. AND THAT IS WHERE THIS SESSION COMES IN. ONCE THE DIAGNOSIS IS MADE, WHAT STRATEGIES DO WE HAVE FOR STILL DRIVING PLASTICITY, ADAPTATION, COMPENSATION, OR EVEN THE USE OF SOME SORT OF ASSISTIVE TECHNOLOGIES TO HELP KIDS BE EVEN MORE FUNCTIONAL AND TO ATTAIN THE ACTIVITIES THEY WANT TO DO AND SUPPORT THEM IN OTHER THINGS? AND EVEN SOME NOTION OF AVOIDING SECONDARY CONSEQUENCES OF HAVING ALTERED MOTOR FUNCTION. SO WITHOUT FURTHER ADIEU, LET'S JUST LAUNCH INTO IN. OUR FIRST SPEAKER IS TERRY SANGER TALKING ABOUT STRATEGIES FOR PROMOTING CEREBRAL PALSY PLASTICITY AND IMPROVING FUNCTION IN VARIOUS TYPES OF CP CHILDREN. >> THANK YOU. SO THANK YOU RALPH AND JIM FOR INVITING ME. IT'S A PLEASURE TO BE HERE AND I DID SHORTEN THE TITLE A LITTLE BIT. SO I COULD REMEMBER IT. SO, I THINK WHAT I'M TRYING TO FOCUS ON IS HOW DO WE MAKE USE OF THE NEUROSCIENCES? AND PARTICULARLY THE NEUROSCIENCES OF PLASTICITY. IT HAS BEEN STUDIED FOR A LONG TIME. FROM THE NMDA RECEPTORS THROUGH THE VARIOUS MODULATORS OF PLASTICITY AND A LOT IS KNOWN. BUT THE QUESTION IS, HOW DO WE NOW USE THAT? THAT REQUIRES AN UNDERSTANDING OF THE RELATIONSHIP BETWEEN PLASTICITY AT THE CELLULAR LEVEL AND PLASTICITY AT THE BEHAVIORAL LEVEL. I'M GOING TO TALK MORE ABOUT THE BEHAVIORAL LEVEL BECAUSE THAT IS WHERE I COME FROM. SO, YOU COULD COME UP WITH DIFFERENT DEFINITIONS AND THE PROBLEM IS, PEOPLE THAT KNOW ME AND WORKED WITH ME BEFORE, KNOW I CARE A LOT ABOUT WORDS. THE PROBLEM IS YOU USE WORDS LIKE LEARNING AND PLASTICITY AND ADAPTATION ARE NOT ALL WELL DEFINED. THESE ARE THE DEFINITIONS I'M GOING TO USE. PLASTICITY TO INDICATE THE THING THAT MAYBE AT THE CELLULAR LEVEL THAT CHANGES AND REPRESENTS ANY CHANGE IN THE SYSTEM. ANYTIME SYSTEM'S ABILITY TO REMEMBER SOMETHING TO DO SOMETHING DIFFERENT IN THE FUTURE FROM WHAT IT DID IN THE PAST. REMEMBERING THAT THAT IS DIFFERENT FROM DEVELOPMENT WHICH IS THINGS THAT ARE DIFFERENT IN THE FUTURE THAN IN THE PAST BECAUSE YOU HAVE A DEVELOPING BRAIN AND OF COURSE THERE ARE PLASTIC AFFECTS ON DEVELOPMENT AND SO A LITTLE BIT OF CROSSOVER THERE. THE TERMS THAT GET VERY CONFUSING IN MY WORLD AND IN THE WORLD OF MOTOR NEUROSCIENCES ARE ADAPTATION AND LEARNING. AND I'M GOING TO ARGUE THAT THESE THINGS ARE VERY, VERY DIFFERENT. I WON'T BE THE FIRST PERSON TO SAY THIS. THESE THINGS ARE DIFFERENTY WE NEED TO UNDERSTAND THE DIFFERENCE BETWEEN ADAPTATION AND LEARNING BECAUSE IF YOU DON'T YOU MAKE CERTAIN KINDS OF MISTAKES. A COMMON MISTAKE IS THE FEELING YOU CAN USE ADAPTATION AS A WAY OF TEACHING SKILLS AND THE PROBLEM IS THAT THOSE THINGS AT LEAST FROM WHAT WE ARE LEARNING NOW, ADAPTATION AND LEARNING ARE SKILL LEARNING, SEEMS TO OCCUR THROUGH VERY, VERY DIFFERENT MECHANISMS AT VERY DIFFERENT TIME SCALES SO THEY ARE PROBABLY NOT REALLY REALITIED TO EACH OTHER. THIS IS HOW I'M GOING TO THINK ABOUT THESE THINGS. ADAPTATION IS THE THING THAT KIND OF MAINTAINS HOMEOSTASIS. IF YOU ARE WALKING IN SOME WAY AND NOW YOU HAVE SOME PAIN IN A JOINT OR SOMETHING THAT WOULDN'T ORDINARILY PREVENT FROM YOU WALKING, YOU WILL ADAPT YOUR GAIT TO REDUCE THAT PAIN. YOU'RE TRYING TO REDUCE THE AFFECT OF A CHANGE IN ENVIRONMENT. SO A TYPICAL EXAMPLE IN THE WAY IN WHICH ADAPTATION IS STUDIED IN NEUROSCIENCES, THEY ARE MOVING THEIR ARM, THE ENVIRONMENT IS PUSHING THEIR ARM TO ONE SIDE AND AFTER A WHILE THEY WILL LEARN TO MAKE STRAIGHT MOVEMENTS IN A NEW ENVIRONMENT. SO THEY MADE STRAIGHT MOVEMENTS BEFORE NOW THEY ARE LEARNING TO MAKE STRAIGHT MOVEMENTS AFTER EVEN THOUGH THE ENVIRONMENT IS PUSHING THEM IN SOME DIRECTION. ADAPTATION IS THE THING THE BRAIN DOES IS TO GET BACK TO WHERE IT WAS DESPITE PERTUBATION. WHEREAS LEARNING AND I MIGHT TAKE THIS FROM THE SUBMIT DEFINITION OF LEARNING, THE IDEA YOU LEARN SOMETHING NEW. SO NOW IN THE SAME CONTEXT YOU'RE GOING TO DO SOMETHING DIFFERENT. BEFORE, I LEARNED SOMETHING, I WOULD PICK UP THE VIOLIN AND MAKE SOME HORRIBLE SCREECHING NOISE AND NOW I PICK IT UP AND MAKE A LESS HORRIBLE SCREECHING NOTICE NOTICE. SO I'M DOING SOMETHING DIFFERENT -- NOISE. SO THE GOALS ARE VERY, VERY VERY DIFFERENT. AND WHEN YOU THINK ABOUT THESE -- TRYING TO THINK -- MY FAVORITE EXAMPLE OF ADAPTATION -- THE NEUROSCIENTISTS WILL KNOW THIS STUFF. I NEED A VOLUNTEER. MAYBE RALPH. HOW MANY TIMES DO YOU GET TO CHANGE THE BRAIN OF A NEURDIRECTOR AT THE NIH? PUT THESE ON. THESE ARE PRISM GLASSES. THEY ARE MOVING HIS WORLD TO ONE SIDE. SO TAKE THEM OFF FOR A SECOND. HAVE YOU USED THESE THINGS BEFORE? GOOD. THE TASK I WANT YOU TO DO IS MAKE A VERY RAPID OUT AND BACK MOVEMENT OF YOUR FINGER. TO MY FINGER. SO JUST PRACTICE THAT. YOU SHOULD BE ABLE TO HIT IT QUITE RAPIDLY. NOW PUT THE GLASSES ON. TRY THAT A COUPLE OF TIMES. SO, HE'S GOING TO MISS. AND IF I GAVE HIM A CHANCE TO PRACTICE, HE WOULD GET IT RIGHT. BUT NOW SO YOU KNOW YOU'RE MISSING SO THE OBVIOUS STRATEGY IS AIM ABOUT HERE. TRY IT AGAIN. SO NOW HE FIGURED IT OUT. NOW TAKE THEM OFF. NOW DO IT AGAIN. SO THAT IS ADAPTATION. THANK YOU. THANK YOU RALPH. NOW ADAPTATION, YOU THINK OF AS BEING REVERSIBLE. IF YOU DID IT FOR 10 MINUTES, YOUR BRAIN WOULD LEARN THE ABILITY TO ADAPT. SO IF WE TOOK THEM OFF AND PUT THEM BACK ON AND THE SECOND TIME YOU PUT THEM ON THERE WOULD BE SAVINGS AND IT WOULD HAPPEN AGAIN. I JUST MADE A RAPID CHANGE. I WAS JUST DOING THE EQUIVALENT OF MOVING HIS WORLD A LITTLE BIT BUT THAT WILL -- THAT IS PROBABLY THE CEREBELLUM THAT COMPENSATES. BUT TWO STRATEGIES ARE GOING ON. IF YOU JUST PRACTICE AFTER A WHILE, YOUR BRAIN WILL FIGURE OUT THE WORLD ISN'T DOING WHAT YOU THOUGHT IT WAS AND IT WILL SORT OF COMPENSATE AND AFTER A WHILE THIS WILL APPEAR NORMAL. BUT I CAN MAKE IT, BY GIVING A STRATEGY, I CAN FIX IT IMMEDIATELY. IF YOU'RE MOVING TWO INCHES TO THE LEFT, I CAN TELL YOU MOVE TWO INCHES TO THE RIGHT AND YOU'LL FIX IT. THOSE ARE TWO DIFFERENT MECHANISMS. THEY FIGHT EACH OTHER. SO, A EXPERIMENT WHERE THEY DID THIS NOT USING PRISM GLASSES BUT A SIMILAR KIND OF SET UP. AS SOON AS YOU PUT THE GLASSES ON, EFFECTIVELY, YOU START TO MAKE ERRORS. THAT'S WHAT HAPPENED HERE. SO THEY ARE AT ZERO AND THEY START TO MAKE ERRORS RIGHT AWAY. BUT THEN YOU TELL THEM AFTER THE FIRST COUPLE OF ERRORS, JUST AIM A LITTLE BIT TO THE RIGHT. GIVE SOMEBODY A STRATEGY. TEACH THEM THE SKILL AND THEN THEY IMMEDIATELY CORRECT THE ERRORS BACK TO ZERO. BUT, THE BRAIN STILL NOTICES THAT THERE IS A MISMATCH BETWEEN WHAT IT SEES AND WHERE IT THINKS IT'S REMEMBER IS. AND BECAUSE OF THAT MISMATCH, THE BRAIN STARTS TO DO THE ADAPTATION PROCESS WHICH ACTUALLY INCREASES THE ERROR. SO THE ERROR IS INCREASED OVER TIME. AND THE IDEA IS THAT THERE ARE TWO MECHANISMS GOING ON. A LEARNING MECHANISM WHICH IS LIKE HERE IS THE STRATEGY WHICH IS THIS. I WAS TAUGHT WHAT THE ANSWER WAS AND I COULD TURN IT ON AND OFF WHEN I WANTED TO AND THEN THIS GRADUAL PLASTICITY MECHANISM, THE ADAPTATION MECHANISM. I WANT TO POINT OUT THESE THINGS ARE DIFFERENT. ADAPTATION IS TRYING TO MAINTAIN THE WORLD WHERE IT WAS AND WHAT IT REALLY CARES ABOUT IS THE THING THAT HAPPENED WHAT I EXPECTED TO HAPPEN. I SENT MY ARM OUT IN A PARTICULAR DIRECTION, DID IT END UP WHERE I WANTED IT TO END UP? WHEREAS LEARNING IS TRYING TO ACCOMPLISH A GOAL. I WANT TO DO SOMETHING. ONE OF THE THINGS I STUDIED IS THIS QUESTION OF UNDER WHAT CIRCUMSTANCES IS IT HELPFUL TO HELP PEOPLE WITH LEARNING? OUR BRAINS LEARN. WE HAVE THESE SYSTEMS IN PLACE. WE HAVE AN ADAPTATION AND WE HAVE LEARNING. AND THE QUESTIONS ARE, IT IS ONLY USEFUL TO HELP PEOPLE IF THEY NEED HELP. FOR THE MOST PART, IF YOU TAKE SOMEBODY'S BRAIN AND IT'S WORKING OKAY, YOU DON'T NEED HELP THEM. SO THE PRESUMPTION BEHIND EVERYTHING WE DO WHETHER IT IS MEDICATIONS, WHETHER DEVICES, WHETHER REHABILITATION, IS THAT SOMEHOW THE SYSTEM IS NOT ABLE TO GET WHERE IT NEEDS TO ON ITS OWN. SO THE LEARNING MECHANISM IS FAILING. SO I CALL THAT FAILURE OF MOTOR LEARNING. YOU CAN COME UP WITH A NUMBER OF WAYS IN WHICH THIS MIGHT HAPPEN. IF YOU CAN'T SEE YOUR ERRORS YOU WON'T IMPROVE. ONE OF WHICH IS IF YOUR PERFORMANCE IS SO FAR FROM WHERE YOU EVER WANT IT TO BE, THAT YOU PRACTICE THE WRONG THING. YOU'RE TRYING TO DO A BACK FLIP OFF A HIGH DIVE BOARD AND YOU DO A BELLY FLOP AND THEN YOU DO IT AGAIN. AND THEN AFTER A WHILE YOU'RE REALLY GOOD AT BELLY FLOPS. YOUR PRACTICE HAS TO BE DIRECTED AND THEN THE QUESTION OF WHETHER OR NOT LEARNING IS POSSIBLE AT ALL. SO, TYPE I FAILURE. AND THE POINT THE REASON I'M SAYING THIS, I THINK YOU MAY HAVE DIFFERENT TYPES OF FAILURE IN DIFFERENT KIDS. WHEN YOU'RE TRYING TO ENGAGE PLASTICITY TO HELP LEARNING, YOU NEED TO UNDERSTAND WHERE IT FAILED. WHAT WAS THE PROBLEM THAT YOU'RE TRYING TO HELP? BECAUSE THERE MIGHT NOT BE A PROBLEM. SO A PROBLEM MIGHT BE DIFFERENT THAN WHAT YOU THOUGHT. IF YOU CAN'T SEE THE ERRORS, YOU THINK LET'S HELP YOU SEE THE ERRORS BUT WHAT MIGHT BE THE THINGS THAT WOULD STOP YOU FROM SEEING ERRORS? ONE OF WHICH IS YOU DON'T CARE. THAT'S MOTIVATION. WE DID A SURVEY SPECIAL OLYMPICS WAS IN L.A. THIS PAST SUMMER. AND WE SURVEYED PRETTY MUCH ALL THE COACHES OF ALL THE CHILDREN IN THE SPECIAL OLYMPICS AND WE SAID, HOW DO YOU TEACH YOUR CHILDREN SKILLS? WHAT ARE THE IMPORTANT THINGS FOR LEARNING A NEW MOTOR SKILL IN A CHILD WITH DISABILITIES? AND THIS MOTIVATIONA -- THAT WAS NUMBER 1 ON EVERYBODY'S LIST. THIS IS HUGE. OF COURSE MOTIVATION IS HELPFUL FOR LOTS OF DIFFERENT THINGS BUT I'D ALSO SAY YOU HAVE TO PAY ATTENTION. YOU HAVE TO CARE ABOUT YOUR ERRORS. AND SO WE CAN DO THAT. THESE ARE EXAMPLES OF THINGS YOU MIGHT WANT TO DO. CONSTRAINT THERAPY COULD BE CONSIDERED AN EXAMPLE OF THIS WHERE YOU'RE PAYING ATTENTION, TRYING TO CHANGE THE FOCUS OF ATTENTION TO THE IMPAIRED ARM AND THE MORE YOU PAY ATTENTION TO THAT THE MORE YOU WILL LEARN ABOUT THAT. I STUDY OR SPEND A LOT OF TIME LOOKING AT BIOFEEDBACK AND EMG AND THEN QUESTIONS OF SENSORY LEVEL OF FUNCTIONAL ELECTRICAL STIMULATION AND THEN THERE ARE MANY OTHER EXAMPLES. IT'S IMPORTANT TO RECOGNIZE THIS. AND ONE OF THE REASONS I BRING THIS UP, I'M A NEUROSCIENTIST. MOTIVATION FEELS LIKE FUZZY STUFF. BUT THIS IS THE STUFF THAT MATTERS AND SO IN SOME WAYS MAYBE THIS IS ONE OF THE THINGS WE REALLY NEED TO BE LOOKING AT. IT'S NOT LIKE WE DON'T LOOK AT THIS. WE TRY TO BUILD VIDEO GAMES FOR KIDS AND MAKE THESE THINGS ENGAGING BUT RECOGNIZING HOW CENTRAL THIS IS TO THE LEARNING PROCESS. BUT THE OTHER THING CENTRAL TO THE LEARNING PROCESS IS ATTENTION. AND LEARNING DOESN'T HAPPEN WITHOUT ATTENTION AT ALL. THIS IS MY EMG BIOFEEDBACK DEVICE AND I CARRY THESE AROUND JUST IN CASE. AND IT DOESN'T DO MUCH WHEN IT'S NOT TANGLED. IT PICKS UP EMG FROM SOME MUSCLE OR OTHER AND YOU'LL HAVE TO TRUST ME IT IS BUZZING PROPORTIONAL TO THE MUSCLE ACTIVITY. SO IT'S JUST BUZZING. I CAN FEEL A CELL PHONE VIBRATOR IN THERE. AND THE IDEA HERE WAS THAT A LOT OF KIDS WITH CEREBRAL PALSY HAVE DEFICITS IN PERCEPTION AND COULD I SOMEHOW AUGMENT THAT AND GIVE THEM THIS ADDITIONAL SENSORY INFORMATION? AND THE THING WORKED. WE DID THESE TRIALS A COUPLE OF YEARS AGO AND STILL HAVE ONGOING TRIALS. PEOPLE LOVE IT. OUR BIGGEST PROBLEM IS THE PATIENTS DON'T GIVE THEM BACK AT THE END OF THE STUDY BECAUSE THEY USE THEM WHEN THE THERAPIST LOSES THEM AND THEN WE FIND OTHER PATIENTS ARE STILL USING -- OTHER PATIENT THAT WASN'T IN THE STUDY. IT'S LIKE WE LOVE YOUR DICE. HOW DO YOU GET THAT? -- DEVICE -- SO IT WORKS. THE QUESTION IS WHY DOES IT WORK? HERE IS AN EXAMPLE OF THE KIND OF THINGS THAT GOT BETTER. BUT THE POINT IS, INITIALLY WE THOUGHT THIS IS HELPING. IF YOU THINK ABOUT WHAT EMG IS, IT'S THE MUSCLE SIGNAL, ELECTRICAL SIGNAL TURNING ON THE MUSCLE. YOU GENERATED THAT SIGNAL. THAT CAME FROM YOUR BRAIN. THE PROP ACCEPTION WOULD BE WHAT HAPPENED TO THE MUSCLE AFTERWARDS LIKE DID SOMETHING PERTURB IT? YOU DON'T KNOW THAT FROM LOOKING AT EMG. IT'S AN INTERNALLY-GENERATED SIGNAL AND NOT TELLING THE CHILDREN ANYTHING THEY DIDN'T KNOW. BUT YOU'RE CALLING ATTENTION TO IT. SO HOW DO YOU TELL A CHILD, PAY ATTENTION TO YOUR LATERAL DELTOID? IMAGINE TELLING THAT TO A 2-YEAR-OLD. AND EVEN IF YOU COULD EXPLAIN TO THEM WHAT YOU MEANT, EVEN IF YOU COULD EXPLAIN THIS TO A TEENAGER, THEY DON'T REALLY KNOW WHAT IS GOING ON. BUT IF EVERY TIME YOU MOVE YOUR LATERAL DELTOID AND ONLY WHEN YOU MOVE YOUR LATERAL DELTOID YOU FEEL A BUZZING SENSATION NEAR IT, THAT CALLS ATTENTION TO IT THROUGH THE CORRELATION. THAT'S WHAT I THINK IS HAPPENING. I THINK A LOT OF THIS BIOFEEDBACK IS ABOUT FOCUSING ATTENTION ON SPECIFIC PARTS OF THE PROBLEM AND THAT THAT IS WHAT ALLOWS YOU TO LEARN. SO THIS IS MOTIVATION IS KEY. ATTENTION IS KEY. AND FOCUSED ATTENTION. IT'S NOT JUST GENERALIZE ATTENTION OF THE TASK. PAY ATTENTION TO THE THINGS THAT ARE GENERATING THE ERRORS. SO TYPICALLY, THE REASON I TALKED ABOUT LATERAL DELTOID IS THAT MAY BE ONE WHERE THE KIDS HAVE ACCESS MOVEMENT IN THEIR SHOULDERS THEY ARE TRYING TO REACH. SOMETIMES WE'LL GET THAT IN THE SUPER SPENT 8 US AND THEN ANOTHER IS THEY WILL ACTIVATE THE ANTERIOR DELTOID DURING A REACH AND THERE ARE OTHER LIKE INADEQUATE ACTIVATION OF THE WRIST EXSTENSOR MUSCLES. A LOT OF THESE WILL BE MUSCLES FOR UPPER EXTREMITY. AND AGAIN JUST PAY ATTENTION. IF YOU TELL A CHILD WHO HAS FOOT DROP, DON'T DON THAT WHEN YOU WALK, THEY CAN DO IT A LITTLE BIT IF THEY ARE LOOKING AT A MIRROR BUT AFTER A WHILE THEY HAVE NO IDEA BECAUSE THEY ARE TRYING NOT TO FALL. BUT AGAIN YOU PUT BUZZERS ON AND THEY ARE PAYING ATTENTION TO THAT WITH EVERY STEP AND THAT BECOMES THE SALIENT THING IN THEIR WORLD AND THEN LEARNING HAPPENS. SO THINKING ABOUT THE ROLE OF WHAT DO WE KNOW ABOUT THIS? WE KNOW A LOT ABOUT THIS. WE KNOW A IMPORTANT MODULATOR OF THIS SO THIS RAISES QUESTIONS OF WHEN WE ARE USING MEDICATIONS. DO WE HAVE TO BE CAREFUL ABOUT THAT. YOU CAN IMAGINE THE LYNCH BETWEEN WHAT WE SEE AT THE BARREL LEVEL AND WHAT IS KNOWN ABOUT INTENTIONAL MODULATORS OF PLASTICITY AT THE NEURAL LEVEL. SO THAT'S WHAT I CALL THE TYPE I WHERE THERE IS SENSORY STUFF. I THINK A LOT OF SENSORY STUFF IS NOT THAT YOU HAVE A DEFSILT OF SEN CISION, JUST THE DEFICIT OF FOCUS OF SENSATION. TYPE II FAILURE IS WHEN YOU HAVE VERY POOR PERFORMANCE. YOU'RE SO FAR FROM WHAT IT IS THAT YOU'RE TRYING TO DO THAT YOUR PRACTICE IS TEACHING YOU THE WRONG THING. YOU'RE PRACTICING THE WRONG THING OVER AND OVER AGAIN. AND SO, HOW DO WE FIX THIS? SO YOU HAVE TO GET PEOPLE TO PRACTICE THE RIGHT THING AND YOU HAVE TO GUIDE THE PRACTICE IN SOME WAY, SIMPLIFY WHAT THE PRACTICE LOOKS LIKE OR THE SECOND THING, SO RIGHT AFTER MOTIVATION WHEN WE ASKED THE COACHES WHAT DO THEY DO, THE NEXT THING WE GOT WAS VISUALIZATION. THIS CAME LESS FROM THE SPECIAL OLYMPICS COACHES. WE GOT VISUALIZATION FROM THE REGULAR COACHES. WE ASKED THE USC COACHES FOR A VARIETY OF DIFFERENT SPORTS HOW DO YOU TEACH PEOPLE COMPLICATED MOVES? VISUALIZATION. THEY DON'T ALL MEAN THE SAME THING BUT THE WORD KEPT COMING UP. AND SO YOU THINK, WAIT A MINUTE. I'M FOND OF SAYING THIS. I DO MOTOR CONTROL RESEARCH. I HAVE A LABORATORY IN MOTOR CONTROL RESEARCH. NOT ONCE HAS ANY COACH AT USC COME TO ME AND SAID, I KNOW YOU DO MOTOR CONTROL RESEARCH, TEACH ME HOW TO MAKE MY FOOTBALL TEAM BETTER. THEY JUST DON'T ASK ME. THEY JUST DON'T CARE. BECAUSE NOTHING I DO HELPS THEIR ATHLETES. AND THAT IS WHERE I THINK A LOT OF PROBLEM IS HERE. WE NEED TO BE KNOWING ABOUT IT THEIR WAY AND THEN THINKING ABOUT HOW TO TAKE THEIR CONCONCEPTS AND TURN IT INTO NEUROSCIENCES. ONE OF THE AREAS I THINK THAT SHOWS UP IN CEREBRAL PALSY COM COMMONLY. IT SHOWS UP AS A SEPARATE DISORDER OF DYSPRAXIA. PEOPLE ARE OFTEN DOING THINGS -- IT'S A LEARNING DISABILITY FOR MOVEMENT AND THE KIDS ARE VERY FAR FROM THE CORRECT MOVEMENT THEY WILL END UP PRACTICING THE WRONG THING. THIS IS A EXAMPLE OF A TYPE OF IMPAIRMENT WHERE WE REALLY HAVE THIS TYPE II FAILURE. AND IT INTERFERES WITH PERFORMANCE. YOU CAN MAKE LOTS OF VIDEOS OF THESE KIDS. THIS IS A SERIES OF VIDEOS FROM MY CLINIC AND I'M ASKING KIDS TO SORT OF -- HE IS TRYING VERY HARD TO DO HANDGRIPS AND HE IS TRYING TO FIGURE IT OUT AND THEY ARE TRYING TO DO FINGER TAPS. STANDARD THINGS OFF AN CAAM AND THEN I HAVE HER DOING ONE OF THE PINNESS TASKS WHERE YOU HAVE THEM HOLD THEIR FINGERS LIKE THIS. LARGE NUMBER OF KIDS HOLD THEM LIKE THAT. ONE OF THE THINGS THAT SEEMS TO BE COMING UP IS THAT THERE ARE BOTH TYPE I AND TYPE II PROBLEMS GOING ONER - . A LOT OF THE KIDS SIMPLY CAN'T DO IT. THEY JUST DON'T KNOW HOW TO MAKE THESE MOVEMENTS. AND THIS KID IS PARTICULARLY GOOD BECAUSE HIS TRUNKAL CONTROL FALLS APART. HE CAN'T SIMULTANEOUSLY PULL ALL THESE PIECES TOGETHER. HE IS NOT ATAXIC. HE JUST CAN'T FIGURE OUT HOW TO DO EVERYTHING AT THE SAME TIME. SO A LOT OF THAT IS TYPE II. THERE IS TYPE I WHICH IS A LOT OF KIDS CAN'T COPY THE HAND GESTURES. I DO THIS AND THEY DO THAT. I SAY, LOOK CAREFULLY. IS IT RIGHT? AND THEY ARE LIKE, YES. AND SO THEY JUST CAN'T SEE IT. IF YOU CAN'T SEE THE DEMONSTRATION, HOW ARE YOU GOING TO LEARN? SO THAT IS THE PROBLEM. YOU HAVE TO MAKE SURE THE KID CAN SEE WHAT YOU'RE ASKING THEM TO DO OR CAN INTERPRET IT. THINK OF HOW HARD A TASK THAT IS. YOU LOOK AT THE BODY, AT SOMEBODY ELSE'S BODY AND YOU HAVE TO BE ABLE TO TRANSFORM THAT INTO A MOTOR COMMAND FOR YOUR OWN BODY TO MAKE YOU DO THE SAME THING AND YOUR BODY DOESN'T LOOK LIKE THEIRS. YOU SEE YOUR BODY AS FIRST PERSON. SOMEHOW YOU HAVE TO MAKE THESE LINKS. THIS IS HARD. IT'S NOT SURPRISING WITH DIX PACKSIA IS COMMONLY SEEN WITH AUTISTIC FEATURES WHERE THEY HAVE PROBLEMS WITH MIRRORING ANYWAY. ONE OF THE THINGS IS INTERESTING, YOU DON'T HAVE TO HAVE DYSPRAXIA WHEN YOU HAVE A BAD MOVEMENT DISORDER. THESE TWO KIDS HAVE DYT1 DYSTONIA. HE FIGURED OUT BOTH VERY CLEVER WAYS OF MOVING DESPITE THEIR MOVEMENT DISORDER. SO YOU CAN -- IT IS DYSPRAXIA REALLY IS RELATIVE TO THE CONTEXT. AND SO IN THIS CASE, YOU WOULDN'T BE WORRYING ABOUT THIS ISSUE SO MUCH. SO WAYS OF GUIDING PERFORMANCE. THIS IS ANOTHER WAY OF DEALING WITH TYPE II THINGS. IF YOU HAVE OR A KID ISN'T MOVING WELL CAN WE HELP THEM TO MOVE USING DEVICES IN SOME WAY? I WAS IN THE AIRPORT AND SAW A WHOLE SERIES OF FASHION THINGS ON EXOSKELETON SO I THOUGHT I WOULD PUT THAT UP THERE. I DON'T THINK OF EXOSKELETON AS HIGH FASHION BUT I GUESS WE HAVE TO KEEP UP WITH MILAN. SO BUT I THINK THAT IS EXOSKELETONS CAN BE USED AS ASSISTIVE DEVICE AND TRAINING DEVICE. THEY CAN PROVIDE GUIDED MOVEMENT AND GRADED RESISTANCE AND SO I THINK THERE IS A LOT OF OPPORTUNITY IF ARE THAT. MA NIP LAND UM IS THE FIXED DEVICES. YOU HAVE TO BE CLEVER ABOUT IT. IF YOU DRAG SOMEBODY THROUGH A MOVEMENT IT WON'T HELP THEM. THEY HAVE TO MAKE THE MOVEMENT AGAINST RESISTANCE. FIND WAYS TO GET THEM TO DOT THING YOU WANT THEM TO DO BUT THEY HAVE TO DO IT. YOU CAN NOT FORCE PEOPLE THROUGH THINGS OR THEY WILL RESIST YOU. THAT IS THE NATURAL CONSEQUENCE OF OUR REFLEX SYSTEM AND VISUALIZATION AND VIRTUAL REALITY ENVIRONMENTS CAN BE USED FOR THIS THING AS WELL. SOMETIMES THESE THINGS CAN BE USED TO FOCUS ATTENTION ON PARTICULAR PARTS OF THE TASK. I'M BUILDING EXOSKELETONS. THE IDEA, I TRIED TO FOCUS ON THE THINGS THAT HAVE IMMEDIATE BENEFIT. AND THE IDEA OF BUILDING EXOSKELETONS IS IMMEDIATE. A LOT OF PEOPLE ARE WORKING ON LOWER EXTREMITY. MANY OF THE KIDS ARE WORK WITH ARE VERY, VERY SERIOUSLY IMPAIRED SUCH THAT AMALATION REALLY IS NOT THE PRIMARY GOAL. IT'S MORE MANIPULATION OR COMMUNICATION SO I'M LOOKING AT THESE FLINGS UPPER EXTREMITY. I THINKING OF EXOSKELETON IS SOMETHING THAT COULD BE A PROSTHETIC ESSENTIALLY BUT COULD BE MORE THAN A PROSTHETIC BECAUSE THEY CAN APPLY FORCES. IMAGINE ALL DAY LONG YOU'RE IN YOUR OWN PERSONAL GYM. THIS THING IS ALL DAY LONG PROVIDING YOU WITH INCREASED RESISTANCE, GUIDED RESISTANCE. IT'S DIFFERENT TYPES OF RESISTANCE, VISCOSITY OR SPRING-LIKE AND ESSENTIALLY IS HELPING YOU TO BECOME STRONGER AND TO CONTROL YOUR MOVEMENTS BETTER. SO, THE IDEA IS YOU ALLOW THEM TO PRACTICE DURING CORRECT PERFORMANCE. YOU DON'T KEEP DOING BELLY FLOPS. YOU APPROXIMATE THE CORRECT PERFORMANCE SO URYO CLOSE ENOUGH THE ERRORS START TO BE MEANINGFUL TO YOU AND YOU CAN START TO MAKE IMPROVEMENTS. I MENTIONED THIS ALREADY. AND THE VISUALIZATION. NOW VISUALIZATION IS INTERESTING. BECAUSE WHAT IS VISUALIZATION? I SAID THE COACHES KEEP TALKING ABOUT THIS. WE DON'T KNOW ACTUALLY. FIRST IT'S NOT CLEAR THEY ALL MEAN THE SAME THING BY VISUALIZATION. BUT THERE IS AN ASPECT OF VISUALIZATION THAT WE DO SEE COMING UP ALL OVER THE PLACE. AND THIS IS WHAT I CALL THE EQUIVALENT MECHANICAL SYSTEM. SO, A SWIM COACH WHO WANTS YOU TO REACH IN A CERTAIN WAY WILL OFTEN SAY IMAGINE THERE IS A LARGE RUBBERBAND CONNECTING YOUR RIGHT SHOULDER TO YOUR RIGHT HIP AND PULL AGAINST THAT. YOU IMAGINE THAT. AND THAT MAKES SENSE. YOU KNOW WHAT IT WOULD FEEL LIKE. SO YOU'RE TAKING A PHYSICAL SYSTEM THAT YOU MIGHT HAVE SOME EXPERIENCE WITH, OR YOU CAN IMAGINE IN YOUR HEAD, AND YOU'RE SAYING, THAT IS EQUIVALENT TO THE THING YOU HAVEN'T EXPERIENCED YET AND LET'S USE THE THING YOU KNOW TO TEACH YOU ABOUT THE THING YOU DON'T KNOW. BY TAKING THE PIECES. SO, I THINK THERE IS A REAL ROLE FOR THAT AND WE ARE EXPLORING THIS IN A VARIETY OF DIFFERENT WAYS AS A TRAINING METHODOLOGY. YOU WANT TO MAKE THESE THINGS PRICE AND I THINK YOU CAN. I WANT TO TAKE IT OUT OF THE REALM OF FUZZY TERMINOLOGY AND INTO THE REALM OF SAYING LET'S DO SCIENCE IN THIS. LET'S SEE WHAT THESE THINGS LOOK LIKE. AND THIS IS IMPORTANT. LEARNING. THIS IS WORK WE DID WITH OTHERS AND LEARNING IS MUCH MORE THAN JUST STRATEGY. WHEN YOU LEARN A SKILL YOU HAVE TO REDUCE THE VARIABILITY. YOU HAVE TO FIGURE OUT WHERE YOU'RE GOING TO PUT THE VARIABILITY AND YOU HAVE TO BE FLEXIBLE. YOU HAVE TO BE ABLE TO HIT THAT GOLF BALL NO MATTER WHICH WAY THE WIND IS BLOWING. YOU HAVE TO BE ABLE TO LOOK AT THE SITUATION AND SKILL ISN'T ABOUT JUST DOING THE SAME THING OVER AND OVER AGAIN. SKILL IS ABOUT ACCOMPLISHING THE SAME TASK IN A VARIETY OF DIFFERENT SITUATIONS. TYPE 3 FAILURE. SLOW LEARNING. THIS IS THE SITUATION WHERE THERE MAY BE A PROBLEM AND THERE MAY BE INTERNAL PROBLEM. SOMETIMES YOU CAN FIX THESE THINGS AND SOMETIMES YOU CAN'T. AND SO ONE OF THE THINGS THAT I THINK IS COMMON FOR PEOPLE TO TALK ABOUT IS THE IDEA THAT WE WANT TO ENHANCE PLASTICITY. AND I LIKE TO POINT OUT THAT FASTER LEARNING IS NOT NECESSARILY GOOD. IF YOU LEARN TOO FAST YOU'RE AT RISK FOR DYSTONIA. WE KNOW THIS. IF YOU ARE A COMPUTER OR ROBOT AND YOU LEARN TOO FAST, YOU WILL LEARN THE NOISE AND WON'T LEARN THE UNDERLYING SMOOTH FUNCTION. SO LEARNING RATE IS NOT FASTER IS NOT ALWAYS BETTER. THERE IS A CORRECT LEARNING RATE THAT IS RELEVANT TO THE TASK. THAT IS IMPORTANT TO RECOGNIZE. AND I THINK THE ISSUE WITH LEARNING IF YOU'RE GOING TO USE PLASTICITY, YOU NEED TO GET THE LEARNING RATES RIGHT AND FOCUS IT. YOU DON'T WANT TO JUST INCREASE PLASTICITY IN YOUR WHOLE BRAIN. FOCUS IT. THIS IS THE REASON WHY DEEP BRAIN STIMULATION WORKS. AND I RUN THAT AT CHILDREN'S L.A. IF YOU THINK ABOUT WHAT REPETITIVE STIMULATION DOES, ONE OF THE THINGS WE KNOW IT DOES, LEADS TO DOWNSTREAM LONG TERM DEPRESSION OR LONG TERM POTENTIATION AND BECAUSE WHEN YOU USE THIS FOR KIDS DEFECTS AREN'T IMMEDIATE. SO THAT IS PROBABLY WHAT IS GOING ON. SO THE AFFECTS OF DBS IS NOT IMMEDIATE. REPETITIVE STIMULATION IN PETRE DASHES LEADS TO CHANGES IN SYNAPSES AND WE KNOW THAT WHEN YOU LOOK AT THE DBS SIGNAL, I CAN PICK UP POTENTIALS OF THE CORTEX SO THERE IS PROBABLY SOME KIND OF PLASTIC MECHANISM AT THE CORTEX AND THE DEEP BRAIN STIMULATION IS MODIFYING LONG TERM DEPRESSION AT THE CORTICAL LEVEL. IT IS AN ADAPTATION THAT IS DOING THIS. SO IF YOU TURN THE THING OFF, THEY GET WORSE. IT HAS TO BE THERE THE WHOLE TIME. WE ARE NOT TEACHING THEM ANYTHING. WE ARE JUST CHANGING THE NATURE OF THE SYSTEM TEMPORARILY. BUT NOW IMAGINE SO DBS IS ELECTIVE BRAIN SURGERY. I CAN'T SAY IT WORKS ALL THAT WELL. WE ARE WORKING PRETTY HARD TO FIND NEW TARGETS BUT HERE IS ANOTHER INTERESTING THING THAT COME UP WHICH IS, DBS IS STIMULATING SOME PART OF THE BRAIN. HOW ELSE COULD I STIMULATE PARTS OF YOUR BRAIN? I COULD DO THING TO YOUR SKIN. THIS IS A RECORDING I DID IN A CHILD IN THE VIM NUCLEUS IN THE THALAMUS. THE RED LINES. AND IF YOU STIMULATE ELECTICALLY AT THE WRIST YOU SEE A NICE SIGNAL IN VIM. SO, MAYBE INSTEAD OF PUTTING A WIRE INTO VIM, I JUST PUT AWARE ON YOUR WRIST AND ACCOMPLISH THE SAME THING. SO I THINK THERE IS A ROLE FOR UNDERSTANDING INTERNAL STIMULATION AND EXTERNAL STIMULATION. THE KEY IS IT IS FOCUSED MODULATION OF PLASTICITY. NOT THE WHOLE BRAIN. GO FOR THE AREA WHERE YOU KNOW THE PROBLEM IS AND TRY TO UNDERSTAND THE PROBLEM AND TRY TO FIX IT THERE. SO, IN THE INTEREST OF TIME, I'M GOING TO SUMMARIZE A LITTLE BIT OF THIS. THE GOAL IS LEARNING NOT ADAPTATION. YOU MAY USE ADAPTATION IN CERTAIN CASES TO FACILITATE LEARNING. BUT, RECOGNIZING THESE ARE DIFFERENT MECHANISMS IS VERY, VERY IMPORTANT. BRAINS LEARN BY THEMSELVES. SO THE POINT NEUROREHABILITATION IS PREDICATED ON THE IDEA THAT SOMETHING FAILED. SO FIGURE OUT WHERE THAT FAILURE WAS AND GO FOR THAT. YOU DON'T NEED TO HELP BRAINS DO SOMETHING THEY ALREADY KNOW HOW TO DO. BRAINS LEARN BETTER THAN COMPUTERS AND FOR THE MOST PART AS FAR AS I CAN TELL,EST MONTH OF THE CHILDREN I WORK WITH, THEIR BRAINS LEARN BETTER THAN MINE. YOU HAVE TO RECOGNIZE WHERE THE FAILURE IS AND GO FOR THAT. YOU CAN IDENTIFY IT. YOU CAN CLASSIFY THEM. AND I THINK THIS IDEA OF TARGET SPECIFIC, ANATOMY SPECIFIC, PLASTICITY MODULATION BECAUSE YOU'RE DOING IT THROUGH INTENTIONAL MECHANISMS OR PERIPHERAL STIMULATION OR CENTRAL STIMULATION OR GUIDED PRACTICE. SO WE WERE ASKED TO HAVE TWO SLIDES AT THE END SEAING WHAT THE ARE RESEARCH GAPS. SO THE OBVIOUS ONCE, WHAT IS THE LOCALIZATION? WHY DO PATIENTS REFUSE DOINGS ARE THERE CORRECTABLE DEFICITS? AND WE KNOW THIS. YES, THERE IS LOTS OF RESEARCH GAPS AND LOTS OF THINGS WE NEED TO KNOW ABOUT THIS. IN THE END, I KEEP SAYING THE OVERALL IDEA HERE WHAT I WANT PO FURB FOR IS THE THING THAT I THINK IS UNDER REPRESENTED AMIDST ALL THE INCREDIBLE BASIC SCIENCE WHICH IS ALLOWING US TO MOVE FORWARD AND WHICH WILL BE THE CURES OF THE NEXT FEW DECADES. BUT WHAT DO WE DO RIGHT NOW? AND RIGHT NOW, I THINK WE CAN BUILD THINGS. WE CAN DO TARGETED THERAPEUTIC DEVICES AND COME UP WITH CLINICAL TECHNIQUES AND COME UP WITH MEASUREMENT TOOLS AND FIND THE THINGS THAT HELP INDIVIDUAL CHILDREN. THIS IS NOT SCIENCE. THIS IS ENGINEERING. YOU HAVE ONE CHILD WITH THEIR SERIES OF PROBLEMS. YOU WANT TO FIND THEIR PROBLEMS AND PUT THE DEVICES AND THE THERAPY TECHNIQUES THAT WORK FOR THEM. THIS IS NOT A CLINICAL TRIAL OF 100 PEOPLE DOING THE SAME INTERVENTION. IF YOU'RE DOING CLINICAL TRIAL, IT'S A CLINICAL TRIAL OF A SET OF TECHNIQUES AND METHODS THAT ALLOW YOU TO DEAL WITH THE HETEROGENOUS POPULATION RECOGNIZING THESE STRENGTHS AND DEFICITS AND GOALS ARE DIFFERENT AND HAVE THE TOOLS THAT ALLOW YOU TO INTERVENE. WE NEED TO BUILD THESE TOOLS. THAT'S WHAT I THINK IS THE THING WE NEED. WE NEED THE TOOLS THAT WE CAN BUILD NOW AND FOR ME, THIS IS ALL GOING TO BE DEVICES BECAUSE THESE ARE THE THINGS YOU CAN MAKE QUICKLY. AND YOU WANT TO FOCUS THESE TOOLS ON THE AREAS OF PLASTICITY AND LEARNING THAT ARE GOING TO HAVE THE BIGGEST IMPACT FOR THAT CHILD. SO I WILL STOP THERE WITH THE LIST OF ALL THE PEOPLE WHO REALLY DO THE WORK. SO THANK YOU VERY MUCH. [ APPLAUSE ] >> AS WE PAS THE MICROPHONE TO JEWELS, JEWELS WILL BE TALKING ABOUT MOTOR IMPAIRMENT FACTORS RELATED TO BRAIN INJURY, TIMING AND EARLY HEMIPIECE ICE, IMPLICATIONS FOR REHABILITATION. SO IN OTHER WORDS WHICH STRATEGIES WILL WORK FOR WHICH KIDS CARRYING SOME OF THE THINGS THAT TERRY RAISED AT THE BEHAVIORAL LEVEL. >> WELL, THANK YOU VERY MUCH. JIM AND RALPH FOR INVITING ME TO SPEAK HERE. IT'S REALLY NOOIS TO FOLLOW TERRY. I'M GOING TO TRY TO FOCUS A BIT MORE AND TRY TO USE SOME OF THE THINGS TERRY SAID BUT ALSO MAKE THE CONNECTION WITH SOME OF THE MORE BASIC SCIENCE THAT WE SAW YESTERDAY. AND I'M REALLY GOING TO USE A PORTION OF SEIZ RECALL PALSY AND FOCUS ON A THIRD OF CEREBRAL PALSY CHILDREN NAMELY THOSE WITH EARLY MEMORIESIS. 31% IS THE LATEST NUMBERS. I'M GOING TO FOCUS ON THAT. BASICALLY BE TALKING ABOUT APPROACHES THAT ARE OUT THERE FOR THIS. SO, WHAT DO YOU SEE FOLLOWING HEMIPARESISIS? I'M GOING TO CONCENTRATE ON UPPER EXTREMITY WORK. ONE OF THE THINGS YOU OBSERVE IS WEAKNESS AND YOU SEE POTENTIALLY ABNORMAL STRESS REFLEXES RESULTING IN SPASTICITY, SOMETHING WE TALKED A BIT ABOUT YESTERDAY. I'LL BRING IT UP A BIT NOW AND AT THE END. CHANGES IN MUSCLE PROPERTIES WILL OCCUR AS WELL EVEN IF YOU TRY TO SOLVE THE PROBLEMS IN THE BRAIN, THE MUSCLE PROPERTIES MAY BE SUCH YOU STILL HAVE SIGNIFICANT DEFICITS AND THE SAME THING I'D LIKE TO CONCENTRATE ON TO MAKE THAT LINK BETWEEN WHAT WE HEARD YESTERDAY AND I'LL BE TALKING ABOUT, ABNORMAL DRIVE FROM THE BRAIN THAT RESULTS IN ESSENCE IN THE LOSS OF INDEPENDENT JOINT CONTROL. THE INABILITY TOW DRIVE ONE JOINT WITHOUT CONCURRENTLY DRIVING OTHER JOINTS. SO FOLKS LIKE INDIVIDUALS WITH STROKE AND CERTAIN KIDS WITH HEMIPRETTYIC CEREBRAL PALSY, IF THEY LIFT UP THEIR ARM, THEY CANNOT DO THIS IN ISOLATION. THERE IS A LOSS OF INDEPENDENT JOINT CONTROL. HOW DO WE MEASURE AND TREAT THESE IMPAIRMENTS THAT RESULT IN FUNCTIONAL DEFICITS? WE NEED DIVIDED THAT CAN SENSE THIS, MODIFY ENVIRONMENTS IN WHICH KIDS MOVE AND THEREBY INCREASE OUR UNDERSTANDING OF THE UNDERLYING IMPAIRMENTS AND HOW THAT ULTIMATELY RELATES TO THEIR FUNCTIONAL DEFICITS. SO WHAT IS OUT THERE TODAY? WHAT DO WE HAVE NOW? SO A LOT OF DEVICES THAT WE HAVE REPLICATE PHYSICAL THEY WEREITS DO ALREADY. SO -- THERAPISTS DO ALREADY. THEY ASSIST MOVEMENT AND THAT MAY NOT BE THE RIGHT WAY TO GO. WE WANT THEM TO MOVE NOT A DEVICE TO MOVE FOR THEM. THEY PROMOTE INTERVENTIONS WHICH LACK SOLID LACK OF UNDERPINNING AND EMPHASIZE REPETITION. EVERYBODY TALKS ABOUT REPEATING THINGS BUT NOBODY TALKS ABOUT REPETITION OF WHAT AND WHY. THAT IS SORELY MISSING. PLUS A LOT OF THESE DEVICES WE TALK ABOUT EXOSKELETAL DEVICE, IT'S NICE BUT VERY EXPENSIVE. HOW ARE WE GOING TO BRING THIS INTO PEOPLE'S HOMES? IT IS DIFFICULT. I LIKE TO MAKE A CASE FOR DEVICES THAT WILL BE DEVELOPED IN NOVEL WAYS AND THAT CAN MEASURE IMPAIRMENT AS WELL AS ULTIMATELY BE USED TO COME UP WITH A MORE EFFECTIVE INTERVENTION AS WELL. SO TO ILLUSTRATE THIS, I'LL BE TALKING ABOUT SOME WORK DONE BY ONE OF MY FORMER STUDENTS WHO DID BOTH HER PH.D. IN BIOMEDICAL ENGINEERING AND PHYSICAL THERAPY IN OUR DEPARTMENT. WE COMBINE PH.D.ES IN ENGINEERING WITH DOCTORAL DEGREES IN PHYSICAL ENGINEERING. SHE WAS OUR GUINEA PIG. HAVING THAT DUAL BACKGROUND HELPS A LOT. THE QUESTION HERE S THIS TYPE OF INJURY IMPACT MOTOR IMPAIRMENTS FOUND IN CHILDREN WITH HEMIPRESSIS QUITE EARLY IN LIFE. SO, WHAT THERESA DID IS TRY TO FIND KIDS THAT HAVE CLEAR PRENATAL, PERINATAL OR POSTNATAL INJURIES AND COMPARED THEM TO TYPICALLY DEVELOPING KIDS. YOU HAVE TO LOOK AT 120 KIDS TO MAKE CERTAIN THAT THESE KIDS WERE EITHER PRE, PERRY OR POSTNATAL. NEITHER OF THIS GROUP HAD SIGNIFICANT DIFFERENCES AT THE TIME OF TESTING. UPPER EXTREMITY SCORES, QUEST OR ABIL HAND SCORES EITHER. SO LIKE THE THREE TIMING PERIODS WHICH WE EVALUATED THESE KIDS. PRENATAL, LATE, SECOND TO THIRD TRIMESTER. PERINATAL, LATE THIRD TRIMESTER TO SOON AFTER BIRTH AND POSTNATAL 6 MONTHS TO 10 YEARS OF AGE. SO THAT IS REALLY OUTSIDE OF THE CP RANGE BUT IN THIS CASE, MOST INSIGHTFUL AS I HOPE I WILL BE ABLE TO EXPLAIN TO YOU. SO, WHAT IS UNIQUE? I'M GOING TO BACK TO JACK MARTIN'S TALK OF YESTERDAY ALSO JOHN'S WORK IN KIDS AS WELL. IT'S LIKE IF THE INJURY HAPPENS EARLY IN KIDS THEN MAYBE THESE PROJECTIONS THAT JACK WAS TALKING ABOUT WILL NOT BE PROVEN. THE REST IS COMPETITION BETWEEN LEFT AND RIGHT SIDE OF THE BRAIN. IF THE INJURY HAPPENS EARLY, YOU MAY KEEP THAT AND OF COURSE YOU HAVE THE REGULAR COUNTER LEVEL PROJECTIONS AS WELL. SO YOU GET BILATERAL PROJECTIONS YOU CAN BANK ON. IF YOU COMPARE THAT WITH THE OTHER SIDE OF THE SPECTRUM, KIDS OR ADULTS FOR THAT MATTER, THAT HAD THE INJURIES AFTER BIRTH, THE STORY BECOMES DIFFERENT. NOW YOU HAD HAD THE PRUNING OF THE PROJECTIONS LIKE IN ALL OF US IF YOU HAD A STROKE AS ADULTS, AND WHAT IS YOUR BACKUP SYSTEM NOW IN THE CASE WE HAVE BEEN MAKING IN ADULT STROKE, WHICH WE ARE FINDING IN POSTNATAL KIDS AS WELL. THE ONLY WAY FOR YOU TO ACTIVATE YOUR LIMB IS TO NOT DRIVE IT DIRECTLY BECAUSE YOU DON'T HAVE HIGH RESOLUTION PATHWAYS FROM THE BRAIN BUT YOU GO FROM BRAIN TO FORMATION TO THE CORE. AND THE SPINAL SYSTEM IS GREAT. IT'S A POSSIBLE SYSTEM BUT IT'S NOT VERY SPECIFIC. IT TENDS TO ACTIVATE MUSSELS MULTIPLE JOINTS, CONCURRENTLY AND YOU GET THINGS LIKE DEFLECTION PATTERN IN THE UPPER EXTREMITY. THAT'S THE OTHER PART OF THE STORY. SO LET'S SEE IF THAT STORY, COMING FROM ANIMAL WORK TO HUMAN WORK, IF THAT IS REALLY HAPPENING WHEN WE DO THESE MORE QUANTITATIVE MEASURES THAT I'LL BE SHOWING YOU. SO, ONE THING WE OR THE IMPORTANT THICK WE DID IN THIS INITIAL STUDY WITH THERESA IS ACTUALLY CONTINUE ON SOME THINGS WE HAVE DEVELOPED FOR ADULT STROKE TO MEASURE FORCES AND MOMENTS IN MULTIPLE DEGREES OF FREEDOM AT THE SAME TIME. SO ONE THING, YOU CAN NOT MEASURE FORCE IN ONE DIRECTION. YOU HAVE TO MEASURE IN MULTIPLE DIRECTIONS. BECAUSE THESE KIDS AND ADULTS WITH STROKE COUPLE IN VERY DIFFERENT WAYS. HERE WE HAVE THESE MEASURES AND FORCES IN XYZ DIRECTIONS AND WE MEASURED FORCES IN MOMENTS AND WE CAN BRING IT BACK TO WORKS AT THE SHOULDER AND ELBOW. SO LIFTING UP AND BRINGING DOWN ABDUCTION AND FLEXION AND EXTENSION AND ROTATIONAL TORQUES AND PRO SUPER NATION AT THE ELBOW. ALL MEASURED AT ONCE BY THIS DEVICE. SIMULTANEOUSLY, WE CAN McFORCES AT THE WRIST AND AT THE MCP JOINT LINE SO WE CAN SEE WHAT HAPPENS AT THE WRIST AND FINGERS AT THE SAME TIME. SO WE REALLY MEASURE THE WHOLE LIMB AT THE SAME TIME. SO WHAT DO WE ASK KIDS TO DO? LIFT UP YOUR ARM MAXIMALLY AND I CAN SEE THEIR TORQUES BUT I CAN ALSO SEE CONCURRENTLY WHAT THEY DO WITH OTHER JOINTS. DO THEY FLEX WHEN THEY LIFT UP? DO THEY FLEX AT THE WRIST AND FINGERS OR NOT? I CAN MEASURE IN ONE DIRECTION AT A TIME BUT I CAN SEE WHAT THE COUPLING IS LIKE AT OTHER JOINTS SIMULTANEOUSLY. SO ONE THING WE LOOKED AT IS WEAKNESS. WE SAID WEAKNESS IS ONE OF THE IMPAIRMENTS THAT YOU OBSERVE FOLLOWING BRAIN INJURY. WE LOOKED AT THE TORQUE YOU GENERATE IN THE PREDDIC LIMB MINUS THE PREDDIC DECIDED BY THE SUM OF BOTH. SO THE CLOSER YOU GET TO ONE, THE MORE OR WEAKER THE PA RETTIC LIMB WOULD BE. SO LET ME SHOW WHAT YOU WE GOT IN THE THREE GROUPS. THE PRE, PAREY, POSTNATAL KIDS COMPARED TO TYPICALLY DEVELOPING KIDS. WHAT ARE THE SMALLEST BARS? TYPICALLY DEVELOPING KIDS, YOU CAN SEE THAT BASICALLY A LOT OF WHAT YOU SEE HERE IS AROUND ZERO. MEANING BOTH ARMS ARE EQUALLY STRONG. WHAT ARE THE BIGGEST BARS? WE FIND IN THE POSTNATAL KIDS THEY HAVE THE GREATEST WEAKNESS AND NOT ONLY DO THEY HAVE THE GREATEST WEAKNESS, MORE SO THAN PERRY AND PRENATAL AND ALSO SHOW A DISTINCT ASYMMETRY BETWEEN THE WEAKNESS PROXIMAL VERSUS DISTAL. THE MORE DISTAL YOU GO, THE WEAKER THE PERSON BECOMES. THAT MAKES SENSE BECAUSE CORTICAL SPINAL SYSTEMS ARE PARTICULARLY IMPORTANT FOR THE HANDS AND THAT'S WHERE WE FIND THE GREATEST DEFICIT. YOU CAN SEE THESE LEVELS OF WEAKNESS ARE LESS IN THE PERI AND LESS IN THE PRENATAL KIDS COMPARED TO THE POSTNATALS THAT LOOK VERY SIMILAR TO ADULT STROKE SUBJECTS. SO WEAKNESS PROXIMAL MORE THAN DISTAL AND GREAT NEST POSTNATAL KIDS. WHAT HAPPENS WITH REGARD TO COUPLING WHICH IS SOMETHING WE STUDIED A LOT IN ADULTS. WHAT HAPPENS IN HEMIPRATTIC STROKE CP? THE PATTERNS WE WILL DESCRIBE IN THE 70s AND THE EARLIEST REPORTS DONE BY FIRST AND OTHERS IN THE EARLY 1900s, YOU LIFT UP YOUR LIMB NOT IN ISOLATION BUT FLEX ELBOW, WRIST AND FINGERS. IF YOU PUSH DOWN YOUR ARM, YOU MAY COUPLE THAT EXTENSION AT YOUR ELBOW BUT IF YOU THINK ABOUT ANYTHING FUNCTION WELL YOU DO YOU HAVE TO DEAL WITH THE RATE OF YOUR LIMB TO REACH AND OPEN YOUR HAND. SOEE WE FIND OUT THAT FLEXION TENDS TO BE MORE PREDOMINANT AND IF YOU THINK ABOUT THE FUNCTIONAL IMPACT, THIS HAS A VERY SUBSTANTIAL FUNCTIONAL IMPACT IN YOUR ABILITY TO REACH AND OPEN AND GRASP. SO WHAT WE DID HERE IS WE LOOKED AT THE TORNS LIFTING UP, AND WHILE A PERSON LIFTS MAXIMALLY, I'LL SHOW YOU RAW DATA. THE PERSON IS LIFTING UP MAXIMALLY IN THE SHOULDER ABDUCTION. WE LOOK AT WHAT HAPPENS AT THE ELBOW, WRIST AND THE FINGERS. SO WE CAN SEE HOW KIDS COUPLE DEPENDING ON WHETHER THEY ARE TYPICALLY DEVELOPING, PRE, PERI OR POSTNATAL. AS WE OBSERVED AS WE LIFT UP A LOT, THERE IS DEFINITELY SOME FLEXION AT THE ELBOW POTENTIALLY DUE TO THE FACT THAT THE BICEP MUSCLE IS ACTION WITH THE SHOULDER SO YOU HAVE TO DIVE UP THE BICEPS AND YOU SEE INFLECTION HAPPENING TO THE ELBOW BUT WRIST AND FINGER ACTIVITY IS A LOT LESS IN TYPICALLY DEVELOPING KIDS. NOW WE COMPARE PRE, PERI AND POST, WHERE DO I HAVE THE BIGGEST BAR? THE POSTNATAL KIDS. WHEN THEY LIFT UP THEY FLEX BIG TIME WITH ELBOW FLEXION. ABOUT 80-90% OF ELBOW FLEXION. BUT ALSO CONCURRENTLY FLEX WITH WRIST AND FINGERS. SO LIFT UP, NOT JUST ELBOW FLEXION. THERE IS SUBSTANTIAL TORQUE GENERATED AT THE WRIST AND FINGERS AT THE SAME TIME. IF YOU LOOK AT PERI AND PRE, PERI IS IN THE MIDDLE AND PRE, AT THE WRIST. NOT SO MUCH COUPLING HAPPENING WITH THEM AT ALL IN THE PRENATAL KIDS. IT'S LESS OF AN ISSUE OF COUPLING. SO, TO RECAP QUICKLY, WE HAVE SEEN THE WEAKNESS WAS HOW MUCH MORE PROFOUND IN POSTNATAL THAN IN PRENATAL KIDS. WE ALSO FOUND OUT THAT THE ABNORMAL COUPLING WAS MUCH MORE SEVERE IN POSTNATAL AND PRENATAL KIDS AS WELL. AND THE REASON FOR THAT, AND I'M KIND OF GOING BACK TO JACK'S STORY OF YESTERDAY AND OUR FINDING IS, THAT POTENTIALLY THE PRENATAL KIDS STILL HAVE THE PRESERVEDIPS LAT CALL CORTICAL SPINAL PROJECTION SO THE COUPLING IS NOT ADD BAD BECAUSE THEY DON'T NEED TO RELY ON THE SPINAL SYSTEM AS MUCH. WHAT HAPPENS BETWEEN LIMBS? BECAUSE WE HAVE DEFINITELY PRENATAL CASE, WE HAVE ONE BRAIN HEMISPHERE CONTROLLING BOTH UPPER EXTREMITIES. HERE WHAT TREES DID IS COMPARE BASICALLY -- THERESA -- WHAT HAPPENS WHEN THE NONPA RETTIC LIMB OR DOMINANT LIMB IS BEING MOVED IN FLEXION EXTENSION WITH VARIOUS LEVELS OF RESISTANCE AND WHAT TORQUES WOULD BE GENERATED CONCURRENTLY AT THE SHOULDER AND ELBOW? AND TO SHOW YOU WHAT HAPPENS IN A TYPICALLY DEVELOPING KID, AS THEY ARE DOING INFLECTION AND EXTENSION, HERE WE SEE THE EXTENSION FOLLOWED BY FLEXION IN THE DOMINANT LIMB THAT THE NONDOMINANT LIMB DOES NOT GENERATE TORQUE. IT IS TOTALLY RELAXED. WHEN WE DO THIS IN A PRENATAL KID HOWEVER, YOU CAN SEE THAT WHILE THEY ARE EXTENDING OR WHILE THEY ARE FLEXING, THERE IS A LOT OF MIRROR MOVEMENT, MIRROR TORQUES GENERATED IN THE PA RELATIC LIMB. EVEN IF YOU TRY TO THEY'LL THEM TO KEEP THE LIMB RELAXED THEY CAN'T. IT MAKES SENSE BECAUSE YOU'RE DRIVING BOTH UPPER LEAMS FROM THE UPPER HEMISPHERE. AND SUBSEQUENTLY YOU MAY HAVE LESS SYNERGIES, LESS WEAKNESS, BUT YOU DO HAVE A LOT MORE MIRROR MOVEMENT THAN IN THE OTHER GROUPS AND YOU CAN SEE THAT THE DIFFERENCES ARE PRETTY ASTOUNDING PARTICULARLY IF YOU PROVIDE SIGNIFICANT RESISTANCE HERE. LET'S CONCENTRATE ON THIS FOR INTEREST OF TIME. YOU CAN SEE PRENATAL KIDS HAVE MASSIVE AMOUNT OF TORQUES THEY GENERATE WITH THEIR PA RETTIC LIMB. 50%. A BIT LESS IN THE PERI BUT HARDLY ANYTHING IN THE PRENATALS. THE PRENATALS HAVE NO SIGNIFICANT COUPLING AT ALL. NO COUPLING. SO ON THE ONE HAND THEY ARE WORSE OFF WITH REGARD TO BEING WORKER AND HAVING MORE SYNERGIES BUT THEY DON'T ACCEPT THESE MIRROR ACTIVATIONS AT ALL. SO I TALKED ABOUT THIS ALREADY. SO, WHERE DOES THIS LEAVE US? I'M GOING SWITCH A BIT TO ADULT STROKE BECAUSE WE HAVE STARTED THIS IN CEREBRAL PALSY AND IN THE INTEREST OF THE WORKSHOP, IT'S GOOD TO SAY WHAT THE NEXT STEP MAY BE. THIS IS THE NEXT STEP THAT WOULD MAKE SENSE FOR ALL THREE POPULATIONS BUT MORE SO FOR THE POSTNATAL KIDS GIVEN THE COUPLING. SO HERE WE ARE USING A DEVICE. WE ARE USING ROBOTIC DEVICE. NOT A EXOSKELETAL SYSTEM. IT'S A ROBOT THAT HAS AGAIN THIS LOAD CELL YOU HAVE SEEN BEFORE IN THE MEASURE OF FORCES AND MOMENTS IN ALL DIRECTIONS AND IT HAS A GAMBOL AND POSITION SENTENCERS AND A SIMPLE -- SLAP THE ARM ON IT AND STRAP THE PERSON DOWN TO IT AND THIS ROBOT HAS A PARTICULAR TYPE OF CONTROL THAT WE ACTUALLY BORROWED FROM FLIGHT STIMULATORS. ENGINEERING AND CONTROL ENGINEERS USED THIS A LOT AND THESE ARE ROBOTS THAT SENSE FORCES. SO, IF YOU WANT TO KEEP THE FORCE SMALL, YOU PROGRAM IT THAT WAY. SO YOU MOVE YOUR ARM AND BARELY KNOW YOU'RE ATTACHED TO A ROBOT. BUT YOU CAN CREATE ANY ENVIRONMENT YOU WANTED. SO CREATE A HEP TICK TABLE OVER WHICH YOU SLIDE THE ARM BUT THE TABLE SELL FRICTIONLESS SO SLIDE OVER IT LIKE A PIECE OF ICE. OR, YOU CAN DECIDE TO SUPPORT HALF OF THE WEIGHT OF THE LIMB WHILE THE KID MOVES THE ARM. OR YOU CAN GO BEYOND THE WEIGHT OF THE LIMB WHICH IS WHAT YOU HAPPEN IF YOU OPEN UP THE FRIDGE IN THE MORNING AND TAKE OUT THE CARTON OF MILK. YOU'RE NOT DEALING WITHUST JUDGE THE WEIGHTED LIMB, YOU'RE ALSO HAVING TO DEAL WITH THE WEIGHT OF THE CARTON OF MILK AND YOU MAY HAVE TO DRIVE YOUR SHOULDERS MORE. SO THIS IS A GREAT IN WHICH TO STUDY THESE ENVIRONMENTS -- GREAT ENVIRONMENT. AND YOU CAN START TO DEVELOP VERY TARGETED INTERVENTIONS AS WELL. SO HERE WE HAVE A MODERATE TO SERIOUSLY IMPAIRED STROKE. WE FOCUS ON THOSE REALLY MORE IMPAIRED PEOPLE THAT REALLY ARE NOT HELD BY CURRENT THERAPIES. AND WE'LL HAVE THIS PERSON MAKE LARGE REACHING RANGE THEY CAN. WE'LL DO THIS FULLY SUPPORTED AND AS WE MAKE THE LIMB HEAVIER AND THE ROBOT BASICALLY CREATES THE ENVIRONMENT IN WHICH THIS CAN HAPPEN. SO HERE YOU SEE THE PURPOSE MOVING AND YOU CAN SEE HIM SLIDING OVER THE HOSPITALLIC TABLE, AND THE #RED BAND IS AS FAR AS THIS PERSON CAN MOVE BASED ON THE LENGTH OF HIS OR HER ARM. YOU CAN SEE THIS VERY WELL. HE IS MODERATE TO SERIOUSLY IMPAIRED BUT HE CAN REACH OUT LIKE YOU AND I. HE DOES A NICE JOB. NOW HIS ARM IS WEIGHT LESS BIKE BEING IN SPACE. YOU CAN SEE THIS ABOUT AS WELL. HE CAN REACH OUT REAL, REAL WELL AND WHY? BECAUSE I'M SUPPORTING THE WEIGHT OF HIS LIMB. HE DOESN'T NEED TO DRIVE THE ABDUCTOR MUSCLES. SO, 0% SUPPORT BY THE SUBJECT. THE ROBOT DOES ALL THE WORK. YOU CAN SEE A FEW TIMES THAT MAYBE DOESN'T GET AS FAR BUT PRETTY CLOSE TO IT. NOW HE NEEDS TO DEAL WITH THE TOTAL WEIGHT OF HIS LIMB AND HE IS FIGHTING TO GET HIS ARM OUT THERE. HE IS REALLY FIGHTING TO GET HIS HAND OUT THERE. SO BASICALLY, WHAT DO WE SEE? WE BASICALLY SEE IF I DO THIS IN A NONPA RETTIC LIMB AND GO FROM TABLE TO FLOATING TO TWO TIMES LIMB WEIGHT TO EMULATE WHAT HAPPENS IF YOU MOVE OBJECT IN THE WORKSPACE. IT MAKES NO DIFFERENCE. I CAN MAKE YOUR ARM 5 TIMES HEAVIER. YOU STILL CAN REACH JUST FINE. BUT THIS IS WHAT YOU SEE IN THE ADULTS WITH STROKES AND IN SOME OF OUR EARLY RESULTS IN POSTNATAL KIDS AS YOU MAKE THE LIMB HEAVIER, THE WORKSPACE GETS SMALLER. SO TWO TIMES LIMB WEIGHT CAN BERYLY GET THEIR ARM AWAY FROM THEIR BODY ANYMORE. THEY BECOME DISABLED. ARE THEY WEAKER IN THE PA RETTIC LIG? WEAK ENOUGH TO EXPLAIN THIS? NO IT'S BETWEEN DRIVING OB DUCTORS AND WRIST AND FINGER FLEXORS THAT CREATES THIS PROBLEM. SO AGAIN, WE TESTED THE WRIST AND FINGER AND LIKE WE SEEN ON THE CASE AS YOU REACH YOU GET MUCH MORE ACTIVITY AT WRIST AND FINGER IN THE PA RETTIC LIMB AS WELL. SO TRY TO MAKE THE LINK OF WHAT HAPPENED YESTERDAY. WHAT HAPPENS AT THE BRAIN WHEN WE PLAY THESE GAMES? SO DOING FMRI IS SOMETHING WE DO A LOT. HARD TO DO WITH THESE ROBOTS. SO WE USE FOR THIS SOME REALLY COOL NEW FORMS OF HIGH DENSITY EEG AND WE USE BASICALLY EEG ELECTRODES WHERE YOU HAVE THEM BUILT INTO THE ELECTRODES SO RIGHT CLOSE TO THE SCALP AND WE USE MR BECAUSE WE USE MR TO BUILD HEAD MODELS. SO THAT MEANS EVERY SUBJECT THAT PARTICIPATES, WE DID BUILD VERY SPECIFIC HEAD MODEL. WE PLACED THE ELECTRODES ON THE HEAD AND DIGITIZED THE LOCATION WHICH YOU CAN DO NOW WITH THE CAMERA WALKING AROUND THE PERSON ONE TIME, ALL THE ELECTRODES LOCATIONS ARE BASICALLY IN MEMORY OF OUR COMPUTERS. WE DON'T HAVE TO GO ONE AT A TIME WHICH FOR KIDS WOULD BE IMPOSSIBLE. WE WANT TO DO THESE THINGS QUICK. SO WE MAY GO UP TO 128 ELECTRODES AS OPPOSED TO 60 OR MORE AND SPECIFIC HATS FROM WHICH WE BUILD MODELS WHICH HAVE THE SKIN, THE SKULL AND YOUR BRAIN. SO IF YOU MOVE YOUR RIGHT ARM, LEFT BRAIN BECOMES ACTIVE. YOU GO THROUGH THE FLUID AROUND YOUR BRAIN, SKULL AND SKIN BY THE TIME YOU PICK IT UP AT LEVEL OF SCALP. THAT MEANS YOU END UP WITH LOW RESOLUTION PICTURE FROM BRAIN ACTIVATION. HOWEVER, KNOWING THE SHAPE OF THE BRAIN AND THE PROPERTIES OF TISSUES, I CAN DO AN INVERSE SOLUTION. I CAN GO FROM THE LOUSY SIGNAL ON THE SCALP TO A MUCH HIGHER RESOLUTION ON THE CORTEX. AND THE RESOLUTION I'LL HAVE WHICH IS WORK WE HAVE DONE IS IN THE ORDER OF 3-5 MILLIMETERS. SO, THE COOL THING ABOUT THIS IS, WE HAVE SMALL SPACIAL RESOLUTION, NOT NEARLY AS GOOD AS THE WORK WAS SHOWN YESTERDAY IN MR BUT PRETTY GOOD NONETHELESS AND MUCH BETTER TIME RESOLUTION. NO RESPONSE THAT TAKES 4-6 SECONDS. I HAVE RESOLUTION OF ONE MILLISECOND. SO I CAN LOOK AT WHAT THE BRAIN IS DOING RIGHT BEFORE A PERSON STARTS TO MOVE. SO I GOT AN IDEA ABOUT THE SIGNALS THE BRAIN SENDS TO THE SPINAL CORD. BOTH WHEN THE ARM IS SUPPORTED AND AS WELL AS WHAT WE MAKE THE LIMB HEAVIER AND SEE WHAT HAPPENS. AND THAT IS WHAT WE DID. AND THIS IS WORK DONE BY A MAN WHO CAME TO ME AT THE OLD AGENCY OF 20 WITH A BACHELOR'S AND MASTERS IN ELECTRICAL ENGINEERING FROM STAMFORD AND WE FOUND OUT THAT COMBINING THE TWO THINGS WOULD BE A REALLY GOOD THING MEANING ROBOTICS AND IMAGING AND THE PERSON WOULD REACH THROUGH A SINGLE TARGET THREE DIFFERENT CONDITIONS, SUPPORTED ON THE TEP TICK TABLE, FLOATING MOVING TO THE SPOT, LIFTING UP AT 25% OF THE MAXIMUM ABILITY MOVE TO THE SAME TARGET IN SPACE. SO WE CHANGE THE ABDUCTION LOADING. SO HERE YOU CAN SEE IN STROKE AS WE MAKE THE LIMB HEAVIER REACHING THE DISTANCE BECOME LESS AND SEEING THE SAME IN POSTNATAL KIDS. THE OTHER GROUPS WE HAVEN'T STUDIED YET. THEN WE LOOKED AT INDEXES AND WHAT IS THE ACTIVITY? AND THE MORE WE GO TO ONE, THE MORE IT IS COUNTER LATERAL AND THE CLOSER TO ZERO THE MORE IT IS BILATERAL. SO WHAT YOU OBSERVE IN YOU OR ME? BEING ON THE TABLE FLOATING OR LIFTING UP TO 25%, THE BLUE BARS, WE ALL BIGGER THAN ZERO. WE HAVE MORE COUNTER LEVEL THANIPS LA ACTIVATION. WHAT WE FOUND IN STROKE AND EARLY ACTIVATION AS I MAKE THE LIMB HEAVIER, FOLKS USE MORE THEIR IPSILATERAL CORTEX. SO THEY START TO BORROW THE IPSILATERAL CORTEX AND USE IT MORE AND NOT ONLY THAT, IT SEEMS TO BE DIRECTLY RELATED TO THE LEVEL OF IMPAIRMENT. PEOPLE THAT ARE MORE IMPAIRED START TO DO SWITCH OVER MORE QUICKLY THAN THE PEOPLE THAT ARE NOT SO IMPAIRED. SO BOTH KIDS AND ADULTS SHALLY RESULTS AND RESULTS IN ADULTS SEEM TO INDICATE THIS. BASICALLY WHAT DOES THIS MEAN? WELL, IF YOU HAVE A LESION, AS AN EXAMPLE OR CORTICAL LESION THAT AFFECTS MOTOR CORE TICKSES DO YOU LOSE ALL YOUR SPINAL PROJECTIONS IN NO. YOU STILL HAVE FIBERS LEFT. BUT AS YOU MAKE A LIMB HEAVIER YOU MAY LEAVE RESOURCE TO DRIVE THE LIMB. INSTEAD OF BEING ABLE TO USE YOUR CORTICAL SPINAL PROJECTION,Y WE THINK YOU WILL START USING PROJECTIONS FROM YOUR IPSILATERAL HEMISPHERE. WE THINK YOU'RE DRIVING THIS SPINAL PATHWAYS AND THE REASON WHY WE THINK THAT IS COMING FROM ANIMAL WORK BY JOHN BUFORD IN COLUMBUS. IF YOU STIMULATE THE IPSILATERAL SIDE YOU GET ACTIVATION OF ABDUCTEDDORS OF ELBOW, WRIST AND FINGER FLEXORS WHAT WE SOARING IN ADULT WITH STROKE AND SOME AM OUR HEMIPRATTIC KIDS AS WELL. WE CAN DO DTI AND SEE THE LOSSES AND BUILD PREDICTIVE MODELS OF THIS ASK SO THAT IS WHAT I MEAN BY HAVING GOOD PERIPHERAL QUANT FATIVE MEASURES. YOU CAN GO A VERY LONG WAY AND START TO CHANGE THINGS. SO WE WERE TALKING YESTERDAY ABOUT WHETHER WHAT TIME YOU NEED TO INTERVENE? I'M LOOKING AT FOLKS OLDER THAN I AM. I'M CLOSE TO 60. I HATE TO TELL YOU BUT BASICALLY WE HAVE FOLKS THAT ARE OLDER THAN I AM THAT GO THROUGH THESE INTERVENTIONS. MIKE HAS BEEN RUNNING THIS AND WE HAVE PEOPLE MOVE THROUGH ONE OF 5 TARGETS AND WE MAKE THE LIMB SO HEAVY THEY CAN ONLY MOVE HALF THE DISTANCE AND THEN TRAIN THEM 3 TIMES A WEEK FOR 8 WEEKS FOR AN HOUR AT A TIME. IF THEY CAN DO 80% OF THE DISTANCE, THEN WE MAKE THE LIMB HEAVIER AGAIN. SO THE PROGRESSION OF MAKING LIMB HEAVIER BASED ON REACHING ABILITIES. SO GETTING OUT OF THEIR WAY. THE ONLY PARAMETER I'M CHANGING IS THE WEIGHT OF THE LIMB USING ROBOTICS. SO OUR EFFORTS RESULT WORK AREAS BEFORE THE INTERVENTION, WORK AREAS AFTER THE INTERESTS VENTION, THESE ARE PEOPLE WITH STROKES 5, 10, 15 YEARS AGO AND THEY BASICALLY INCREASED WORKSPACE BY AN AREA OF AT LEAST 8 BY 11 PIECE OF PAPER IF NOT MORE. SO THIS IS VERY SPECIFIC AND WORKS IN OUR MORE IMPAIRED INDIVIDUALS. I HAVE TREMBLY THIS WILL WORK WAY BETTER IN OUR KIDS WHERE THE BRAINS ARE MORE PLASTIC THAN IN PEOPLE THAT ARE 60 AND OLDER. HERE ARE THE RESULTS. YOU CAN SEE ONLY IN THE FOLKS WHO MAKE THE LIMB HEAVIER DID WE GET IMPROVEMENTS NOT IN THE FOLKS WHERE WE DID NOT CHANGE ABDUCTION LOADING. SO ESSENTIAL IN GREED GENT THAT. WE SHOW YOU THESE BEAUTIFUL ROW DOTS JERRY TALKED ABOUT BUT THESE DEVICES ARE VERY EXPENSIVE. ONCE YOU KNOW WHAT YOU'RE DOING YOU CAN SIMPLIFY. HERE THE DEVICE WHERE WE HAVE A PATENT PENDING AND IT CAN MAKE A LIMB HEAVIER AND LIGHTER AS WELL. BUT YOU CAN ATTACH TO YOUR NIGHTSTAND, ATTACH TO KITCHEN TABLE AND YOU CAN USE IT IN DAY REHAB ET CETERA. THESE ARE DEVICES THAT ARE A FRACTION OF THE COST AS WHAT IS ON THE MARKET RIGHT NOW BUT BASED ON SCIENCE. AND I THINK THAT IS THE WAY TO MOVE FORWARD. SO, THE LAST TWO SLIDES. I'M GETTING THERE. SO, BASICALLY WE DO NOT UNDERSTAND WHAT LOSSES OF NEUROCIRCUITRY DRIVE MOTOR IMPAIRMENTS FOLLOWING CP AND WHY. THAT'S WHAT WE NEED TO REALLY BE EFFECTIVE IN INTERVENTION. I FIRMLY BELIEVE THAT. WE NEED TO DETERMINE THE DEVELOPMENT RELATED CHANGES IN NEURAL PATHWAYS. WE TALKED ABOUT IMAGING. WHAT HAPPENS TO CORTICAL PATHWAYS? WE SAW GREAT, GREAT RESULTS FROM YOU YESTERDAY OF THE WHOLE BRAIN BUT MAYBE WE NEED TO BE A BIT MORE SPECIFIC IF WE KNOW WHAT WE ARE AFTER IN LOOKING AT CHANGES IN DESCENDING PATHWAYS FOR INSTANCE. AND WE NEED TO KNOW WHAT THE NORMAL DEVELOPMENT IS AS WE LEARNED YESTERDAY BEFORE WE KNOW THAT THINGS ARE OUTSIDE THE NORM. NOT ONLY DO WE NEED TO LOOK AT THE BRAIN, WE NEED TO UNDERSTAND HOW MUSCLE PROPERTIES CHANGE. HAVEN'T HAD TIME TO GO INTO THIS BUT I HAVE A BIG GRANT LOOKING AT ADULTS WITH STROKE AND I'M GOING TO TELL YOU SMALL THING IF I MAY AND THAT IS, IF I LOOK AT THE CHANGE IN MOST PROPERTIES IN FALLING STROKE, THE SHORTENING OF LENGTH AND THE LOSS IN CROSS SECTIONAL AREA AND I BASICALLY ON MY COMPUTER USING MUSCLE SKELETAL MODELS DRIVE THE SYSTEM. NORMALLY I FOUND OUT THESE FOLKS EVEN IF I AM ABLE TO SOLVE THINGS WITH STEM-CELL RESEARCH THEY WOULD STILL HAVE DIFFICULTIES MOVING NORMALLY BECAUSE THE SYSTEM CHANGES SO MUCH. THE PERIPHERY CHANGES SO MUCH. THIS IS ADULTS. IT'S ONLY WORSE IN KIDS. SO WE NEED TO BE VERY COGNIZANT OF CHANGE IN MUSCLE AND WANTS HOW TO PREVENT OR REDUCE AS MUCH AS POSSIBLE. CURRENTLY THERE IS A LACK OF SCIENCE IN THE DEVICES. LOTS OF DEVICE BUS REALLY VERY LITTLE SCIENCE AND THE VERY EXORB DEPUTY AMOUNT OF MONEY. IT'S NOT HELPING OUR KIDS. SO MOVING FORWARD. WHAT DO WE NEED TO DO? WE NEED TO DEVELOP MODELS BASED ON LOSS CIRCUITRY. IMAGING IS CRUCIAL HERE. AND I'M FIRMLY BELIEVE THAT IS THE WORK WE ARE DOING IN ADULTS THEY CAN PREDICT THE DEFICITS THEY GET QUANTITATIVELY IN ADULTS AND HOPE TO BE ABLE TO DO THIS IN KIDS AS WELL, TO SEE WHAT IS HAPPEN THINK. SO IN OTHER WORDS IF YOU HAVE LOST 50% OF THE YOUR CORTICAL SPINAL SYSTEM, THIS IS THE DEFICIT IN YOUR ABILITY TO OPEN YOUR HAND. SO THAT HELPS BECAUSE YOU HAVE AN IDEA OF WHAT YOU'RE TARGETING IN YOUR REHAPPEN REHAB. WE SAY WORK HARD AND YOU'LL GET IT BACK. BUT WE DON'T KNOW. THESE ARE THE DIRECTIONS WE NEED TO GO. WE NEED TO IMPLEMENT EFFECTIVE NONINVASIVE IMAGING AND MECHANICAL MEASURES TO STUDY CHANGE IN MUSCLE PROPERTIES. IT CAN BE DONE. YOU CAN USE RESULT SOUND TO CAN LOOT STIFF INNOCENCE MUSSELS. YOU DON'T ALWAYS INDIVIDUAL TO PUT PEOPLE ON ROBOTS. SO A LOT OF APPROACHES THERE AND NEED TO GO TO MORE BASIC SCIENCE IN OUR COLLEAGUES ARE DOING. WE NEED THAT TYPE OF WORK WELL. SO WHETHER I CHANGE THE MUSCLE FLAPS MAY BE GENETICALLY DRIVEN AS WELL. THE NERVOUS SYSTEM TALKS TO THE NERVOUS SYSTEM AND IT TALKS BACK. NOT LIKE THE BRAIN DOMINATES EVERYTHING. WE DON'T UNDERSTAND THESE THINGS VERY WELL BUT I SUBMIT TO YOU RESPECTFULLY IF CHANGE IN MUSCLE HAVE CHANGED, NOT TOO EASY TO TURN THE WAY BACK. TRY TO PREVENT IN THE FIRST PLACE IS VERY IMPORTANT. SO NEUROMECHANISMS ARE UNDERSTOOD AND THEN WE NEED TO DEVELOP MORE EFFECTIVE DEVICES THAT NOT ONLY MEASURE IMPAIRMENT AND USED AS INTERVENTION TOOL. THAT'S WHAT WE ARE DOING. THE DEVICE WEIS ARE BUILDING NOW WE HAVE PEOPLE FLOW FRISBEES THROUGH THE SEARS TOWER. KIDS ARE VERY, VERY SOPHISTICATED USERS. MUCH MORE THAN ADULTS. WHEN I SHOW A VIRTUAL ARM ON THE SCREEN TO SOMEBODY MY AGE, THEY SAY WOW, THIS IS COOL. KID SAYS IT'S JUST A GAME. I HATE IT. WE NEED TO BE MUCH MORE SOPHISTICATED. NEEDS TO BE FUN. THEY PLAY A VIDEO GAME. ATTACHED TO A DEVICE AND THEY DON'T EVEN KNOW THEY ARE HAVING THERAPY. THAT'S WHERE WE WE NEED TO GO. IF NOT THEY WILL NOT DO IT AND ALL THIS WORK WILL BE FOR NOTHING. SO SCIENTIFICALLY UNDERPINNED DEVICES NEED TO BE SIMPLIFIED AS WELL. TO INTRODUCE THEM INTO THE CLINIC TO ALLOW FOR INTUITIVE USE BY THERAPISTS AND BY OUR CLIENTS, THE KIDS. THEY ARE SMART. THEY CAN PUT THEIR OWN ARM ON THE DEVICE AND PLAY A GAME. AND THEREFORE REDUCE COST SIGNIFICANTLY. NOW, THESE DEVICES WITHOUT SAYING NAMES ARE 60,000 DOLLARS AND UP. I'M TALKING 300. IF YOU TALK LOWER EXTREMITY DEVICES. 300,000 DOLLARS AND UP. THAT'S CRAZY. THANK YOU VERY MUCH. [ APPLAUSE ] >> SO NOW DIANE IS GOING TO MAKE SOME WRAP UP COMMENTS AND I'M ALSO GOING TO COME BACK AND HEAR HAHNS AS WE COME BACK TO GENETIC PONTS AND GENOMIC FACTORS OF INFLUENCE AFTER DIANE SPEAKS. >> GOOD MORNING. TRUTH BE TOLD, I SHOULDN'T BE UP HERE BECAUSE I'M NOT A BASIC SCIENTIST. I DECIDED I WOULD TALK ABOUT SOME THOUGHTS AND PERSPECTIVES AND HOPEFULLY DISCUSSION POINTS AROUND THIS IDEA OF TRANSLATION FROM THE PERSPECTIVE OF CLINICAL RESEARCHER. SO ONE OF THE THINGS THAT IS ALWAYS AMAZED AND FRUSTRATED ME IS THIS QUESTION. WHY IS EARLY INTERVENTION NOT MORE EFFECTIVE? HOW CAN THIS BE? WE HEAR AND MORE MORE ABOUT WHAT IS POSSIBLE THERE IS PLASTICITY IS TREMENDOUSALLY RAMPANT ESPECIALLY WHEN YOU'RE YOUNG AND THE BRAIN CAN CHANGE SO MUCH. WHY ARE THESE -- WHY IS THIS NOT SHOWING UP IN CLINICAL STUDIES? JUST TO GIVE YOU SOME OF THE RECENT DATA, THIS WAS A REVIEW ARTICLE ON LOOKING AT EARLY INTERVENTION. WE HAVE LOTS OF GOOD STUDIES, LOTS OF NICE RANDOMIZED TRIALS AND POSITIVE AFFECTS THAT WE CAN FACILITATE COGNITIVE AND MOTOR DEVELOPMENT BUT ABSOLUTELY NO AFFECT ON THE RATE OF CP IN THESE STUDIES OR THE SEVERITY OF CP. SO WE ARE NOT DOING ANY REPAIR. AND THEN IF YOU LOOK AT ALL THE SYSTEMATIC REVIEWS ON EARLY INTERVENTION IN CP, WE KNOW THAT THERE IS NO DATA SHOWING THAT WE CAN ALTER MOTOR PROGNOSIS. SO WHAT ARE WE MISSING? SO THE POSSIBILITY EXPLANATIONS WE ARE OBVIOUSLY MAYBE WE ARE NOT STARTING EARLY ENOUGH. MAYBE WE ARE NOT PROVIDING THE RIGHT INTERVENTIONS. MAYBE THE DOSE, MAYBE WE ARE DOING THE RIGHT THINGS BUT IT'S NOT ENOUGH AND THEN THE WHOLE ISSUE WE ARE COMBINING MANY TYPES OF KIDS. MANY OF OUR STUDIES SINCE WE DON'T DIAGNOSIS CP, INCLUDE PRETERMS AND THEY HAVE A VERY DIFFERENTIAL RESPONSE IF YOU LOOK AT THESE STUDIES TO THESE INTERVENTIONS IN CHILDREN WITH CP. AND THIS IS NOT EVEN GETTING TO THE ISSUE THAT CHILDREN WITH CP CAN BE VERY DIFFERENT. SO I'M GOING TO TALK ABOUT THESE OPPORTUNITIES AND GAPS AND TRANSLATE THE BASIC SCIENCE TO CLINICAL INTERVENTIONS AND WE ARE TALKING ABOUT PROMOTING PLASTICITY IN LEARNING IN CHILDREN THAT HAVE A DIAGNOSIS OF CP. AND I'M GOING TO TALK ABOUT WHEN TO INTERVENE AND INSIGHTS INTO WHAT WE SHOULD BE DOING HOW MUCH AND WHO BENEFITS FROM WHAT. SO WHEN? THIS QUESTION I'M SITTING HERE LISTENING YESTERDAY, IS REPAIR ONLY POSSIBLE EARLY IN DEVELOPMENT? AND IS REPAIR POSSIBLE? I THINK THAT WE SAW SOME NICE DATA THAT IT IS POSSIBLE. AND IF SO, WHEN DOES THAT WINDOW OPEN AND WHEN DOES DOES IT CLOSE? HOW CAN WE RELATE THE TIME LINES WE LEARNED IN ANIMALS TO HUMANS? HOW DO WE APPLY THIS INFORMATION? AND THEN LOOKING AT THE MORE LEARNING AND PLASTICITY, ARE THERE AGES WHEN ABILITY TO LEARN CERTAIN SKILLS IS MORE PRONOUNCED? SO, WE HEARD FROM JACK MARTIN YESTERDAY AND THIS IS A WONDERFUL STUDY GIVING US INSIGHTS INTO WHEN. THIS IS PRETTY FRIGHTENING TO ME BECAUSE THEY HAVE A UNILATERAL KITTEN MODEL AND TALK ABOUT RECOVERY FROM BEING ABLE TO RECOVER FROM THAT AND WHAT HE WAS TALKING ABOUT YESTERDAY WAS A SPINAL CORD NEURONS AND THERE IS PLASTICITY THROUGHOUT THE CORTICAL SPINAL SYSTEM BUT THEY HAVE THAT EARLIEST WINDOW. AND THE ARTICLE THAT THEY PUBLISHED SAID THAT WINDOW IS 3-6 MONTHS POSSIBLY OF INFANT AGE. WE ARE NOT EVEN DIAGNOSING KIDS BY THIS POINT AND CHILDREN HAVE VERY FEW MOTOR CAPABILITIES. HOW CAN WE REALLY CHANGE WHAT A CHILD ZERO-6 MONTHS IS DOING TO TRY TO ACCESS SOME OF THIS? SO WHAT ABOUT WHAT? WHAT SHOULD WE BE DOING? WE HEAR A LOT OF CONTROVERSY I'M THE PHYSICAL THERAPIST AND INTERESTING IN ACTIVITY-BASED TRAINING. FOR REPAIR, IS MOTOR TRAINING ALONE SUFFICIENT? WE ARE GETTING SUGGESTIONS THERE PROBABLY HAS TO BE SOME TYPE OF DRUG OR STEM CELLS THAT ALSO HAVE TO BE COMBINED WITH MOTOR TRAINING. COULD THOSE THERAPEUTICS INCLUDE NEUROMODULATION AS BERNADETTE BROUGHT UP YESTERDAY OR ELECTRICAL STIMULATION AS KATHLEEN AND JACK HAVE DONE. WHAT ARE THE OPTIMAL INTERVENTIONS TO FACILITATE PLATISSITY AND LEARNING AND WHAT ARE WE MISSING IN ANIMAL STUDIES? WHAT DON'T THEY TELL US WE NEED TO BE PAYING ATTENTION TO THAT IS DIFFERENT IN HUMANS? SO WE DO HAVE DATA. THIS IS REVIEW THAT WE SLOWED IN THE CLINICAL COURSEWORK UP WE HAD AND WHAT YOU SEE HERE, WHAT WE HAVE LEARNED IN ACTIVITY BASED INTERVENTIONS IS THAT THE THINGS THAT WORK IN THESE GREEN BUBBLES ALL REQUIRE ACTIVITY-BASED CHILDREN HAS TO BE ENGAGE. THEY HAVE TO EXERT THE EFFORT AND THEN THE THINGS IN THE RED BUBBLES WHICH MEANS DON'T DO IT, ARE THINGS DONE PASSIVELY TO THE CHILD. SO WE KNOW ACTIVITY IS CLEARLY IMPORTANT. WE ALSO KNOW THAT PLASTICITY CAN BE ADAPTIVE OR MALADAPTIVE. ONE OF THE THINGS THAT CONCERNS ME, THE CHILDREN, THEY ARE PROVIDING INPUT TO THEIR NERVOUS SYSTEM. THE NERVOUS SYSTEM IS CHANGING. IF THAT INPUT IS ABNORMAL, HOW DO WE STOP THAT? BECAUSE WE KNOW THAT IS MAKING CHANGES. THAT IS REORGANIZING THE BRAIN THAT WE DON'T WANT THAT WON'T FACILITATE FUTURE DEVELOPMENT. HOW DO WE PREVENT THOSE THINGS FROM HAPPENING? SO I FEEL LIKE I NEED TO REPRESENT THE MUSCLE PEOPLE AS WELL BECAUSE ONE OF THE THINGS THAT DIDN'T GET ON THIS SCHEDULE WAS LOOKING AT MUSCLE AND THE BASIC SCIENCE OF MUSSEL. BUT THIS IS A BIG DIFFERENCE. WE APPLY A LOT OF ANIMAL MODELS TO HUMANS BECAUSE THE UNIQUE THING ABOUT MOVEMENTS AND MOTOR IMMATURITY THE. NOT JUST DUE TO BRAIN MATURATION BUT CLEARLY DUE TO MUSSEL DEVELOPMENT. WE KNOW MUSCLE CELLS MATURE AT BIRTH. THEY ARE WAT REAND HAVE SMALL NUCLEI. WE KNOW WHAT IS CHANGING THE BRAIN, THE MUSCLES ARE PRODUCING MOVEMENT AND GOING INTO THE BRAIN. SO THAT IS THE CENTURY INPUT INTO THE BRAIN TO CHANGE SOME OF THE PATHWAYS. SO, WE KNOW THAT MUSCLE ACTIVATION HAS FAR-REACHING AFFECTS ON THE BRAIN. IT RELEASES NERVE GROWTH FACTORS AND ONE OF THE THINGS WE REALIZED AFTER MANY YEARS OF WONDERING WHY CHILDREN WITH CP WERE SMALL IS THAT MUSCLE ACTIVITY SIGNALS THE BRAIN TO GROW. WE KNOW THAT ANTI-GRAPHITY STRENGTH IS IMPORTANT IN THE DEVELOPMENT OF UPRIGHT MOBILITY. AND A GREAT EXAMPLE OF THAT IS THAT WE HAVE NOW CHANGED OUR CULTURAL PRACTICES WITH THE BACK TO SLEEP. AND WHAT HAS HAPPENED TO MOTOR DEVELOPMENT SINCE WE CHANGED THAT? IS IT CHILDREN ARE NOW WALKING AT A LATER AGE. MANY CHILDREN NOW NOT CRAWLING BECAUSE OF THIS. WE HAVE DRAMATICALLY CHANGED MILESTONES IN HEALTHY KIDS JUST BY HOW WE ARE TREATING THEIR ANTI-GRAPHITY STIMULATION. THIS IS INTERESTING BASIC SCIENCE AGAIN TRYING TO SIMULATE MOTOR IMMATURITY. THEY SEND RODENTS IN SPACE AND SHOWED THAT MUSSEL DEVELOPMENT WAS IMPAIRED AND THESE RODENTS UP IN SPACE. AND WHAT THEY WERE TRYING TO SIMULATE IS THE INNER UTERINE -- WHAT HAPPENS WHEN YOU DON'T HAVE THE INNER UTERINE ENVIRONMENT FOR PREMA FUR INFANTS. THEY CONCLUDED THAT PREMATURE BABIES ARE PUSHING AGAINST THE UTERINE WALL AND DOING RESISTANT EXERCISES. AND WE SEE THE PREEMIES, THEY ARE LAYING THERE NOT MOVING VERY MUCH. THEY LOOK VERY WEAK. THEY HAVEN'T HAD THE NORMAL STIMULATION THEY WOULD HAVE HAD. THESE ARE DATA FROM ONE OF MY POSTDOC WHOSE WENT ON TO DO WORK LOOKING AT MUSCLE ULTRASOUND AND WHAT CAN YOU SEE HERE ON THE FAR HAS TWO CHILDREN OF THE SAME GESTATIONAL AGE AND THIS IS A TERM INFANT AT 6 WEEKS. AND THIS IS A MEDEIO GHAST ROCK THICKNESS. YOU CAN SEE THAT MUSCLE LOOKS DIFFERENT IN THAT BABY. IN THE PRETERM INFANTS IT'S SMALLER AND THINNER. THEY WERE 57% SMALLER AT 6 WEEKS OF GESTATION. DRAMATIC CHANGES IN THE MUSCLES VERY EARLY ON. BACK TO THE NEURAL RECOVERY. WHAT ARE WE LEARNING? ANOTHER THING WE LEARNED IS BY BRIAN WHERE HE HAS DONE BOTH UNILATERAL AND BILATERAL LESIONS IN NEONATAL RATS AND FOUND THEY WILL RECOVER SOMEWHAT ON THEIR OWN WITH DEFICITS BUT THEY CAN GET NEAR FULL RECOVERY WITH TACTILE STIMULATION AND THIS SILENT SCHEDULE THEY USED. AND THEY FOUND THAT THE MECHANISM WAS UPREGULATION OF FIBROBLAST GROWTH FACTOR TWO IN THE SKIN AND BRAIN AND INJECTED THIS FACTOR INTO THE BRAINS AND FOUND SOME RECOVERY BUT NOT AS GOOD SO THAT IS A KEY HINT FROM BASIC SCIENCE. ANOTHER BIG THING IS ENVIRONMENTAL ENRICHMENT. THIS IS HUGE IN THE BRAIN INJURY WORLD AND TBI AS WELL. WHAT WE KNOW IS THAT THESE ARE JUST BELLS AND WHITELS AND READING SHAKESPEARE. THERE IS A COMPLEX MOTOR ENVIRONMENT AND THEY ARE GOING THROUGH TUNNELS AND MAZES AND THEY ARE CHANGING OVER TIME AND CHALLENGING THEM. THIS ACTIVITY AND THIS SELF-ENGAGED ACTIVITY IS KEY. HOW DOES THAT APPLY TO BASIC SCIENCE? TO CLINICAL SCIENCE? THIS IS REVIEW OF THE ARTICLES ENVIRONMENTAL ENRICHMENT IN INFANTS AND THIS IS BASICALLY THE AFFECT SIZE AND ANYTHING TO THE RIGHT OF THE LINE ON YOUR VEST A POSITIVE AFFECT. SO IT SHOWS THAT THERE IS CLEARLY A CONSISTENT POSITIVE AFFECT IN INFANTS FROM ENVIRONMENTAL ENRICHMENT. SO AGAIN, SOMETHING THAT WE ARE LEARNING VERY CLEARLY THROUGH BASIC SCIENCE WE SHOULD BE DOING. HOW MUCH? WE DON'T KNOW THE MINIMAL DOSE THAT PRODUCES A MEANINGFUL BEHAVIORAL OUTCOME. WE DON'T KNOW THE AMOUNT BEYOND WHICH WE SHOULD JUST STOP DOING SOMETHING. WHEN DO WE STOP TRAINING? HOW DO WE STRUCTURE DOSING TO OPTIMIZE? HOW TRANSLATABLE ARE DOSAGE DATA FROM ANIMALS TO NUMEROUS WE DON'T KNOW THAT EITHER. THE FINAL THING I WANT TO TALK ABOUT IS THIS IDEA OF WHO AND HUNS WILL GO INTO THIS MORE. BUT WHICH TYPES OF CHILDREN ARE MOST LIKELY TO BENEFIT FROM WHICH THERAPIES AND THEN WHY DO EVEN VERY SIMILAR CHILDREN HAVE DIFFERENT RESPONSES TO THE SAME INTERVENTION? THIS GETS INTO THE THING THAT WAS MENTIONED MANY TIMES HERE. THIS IDEA OF PERSONALIZED NEUROREHABILITATION. WE KNOW THE CS A GROUP OF DISORDERS. WE KNOW THAT THE BEST EARLY DIAGNOSTICS AND BEST INTERVENTIONS ARE VERY LIKELY TO DIFFER FOR THESE DIFFERENT GROUPS OF CHILDREN. BUT THE REAL ISSUE TO ME IS AGAIN ONE OF THE THINGS THAT FRUSTRATES ME AS A SCIENTIST, THIS RESPONSE VARIABILITY. WE DO TRIALS AND WE HAVE IN THE SAME INTERVENTION, THAT THESE CHILDREN RESPOND VERY, VERY DIFFERENTLY AND IT HAPPENS IN EVERY INTERVENTION WE DO. SO WE ARE LOO CANNING AT KIDS -- LOOKING AT KIDS AT THE MEAN GROUP LEVEL BUT NOT UNDERLYING RESPONSES IN THESE INDIVIDUALS AND THAT IS REALLY WHERE THE INFORMATION, I THINK. AND THIS CARTOON SHOWS US ONE JACKET IS THE MEAN JACKET SIZE FOR THESE THREE PEOPLE AND IT DOESN'T FIT ANY OF THEM. SO THESE ARE DATA FROM A RECENT TRIAL WE COMPLETED AT NINETY FIVE. WE DID A LOCALO MOTOR TRAINING STUDY KIDS ALL HAD BY WILL THE RECALL C. AND HAD TO BE BORN BEFORE 34 WEEKS AND DIFFUSE WHITE MATTER INJURY. YOU THINK THEY WILL HAVE THE SAME RESPONSE. WHAT WE SEE HERE IN THE CIRCLE IS A THIRD OF THE CHILDREN HAD A VERY GOOD OUTCOME IN THEIR GAIT SPEED. THEY WALKED BETTER AFTER THE TRIAL. ANOTHER THIRD HAD LITTLE CHANGES AND ANOTHER THIRD GOT WORSE. SO I WAS FRUSTRATED BY THIS AND THOUGHT MAYBE MY INTERVENTION IS BAD. IF YOU LOOK AT CONSTRAINT INDUCED MOVEMENT THERAPY, LOOK AT THEIR DATA. THEY HAVE THIS SAME SPREAD WHERE IT SHIFTS MORE POSITIVELY BUT A THIRD DO WELL AND A THIRD DON'T MAKE MUCH CHANGE AND A THIRD HAVE WORSE OUT COMES MOTOR TRAINING. HOW DO YOU HAVE WORSE OUTCOMES IN THIS IS WHAT HAPPENS. SO THESE ARE THINGS WE NEED TO UNDERSTAND AND THAT BRINGS US TO THE IDEA OF GENETICS AND EPIGENETICS AND CP. AND THIS DIDN'T GET ON AS A BULLET ITEM BUT DID IS SOMETHING VERY IMPORTANT. FOR DECADES, WE USED TO PUT IN BRANTS AND THOUGHT THIS ISN'T GENETICS, WE WON'T GET THIS FUNDED BECAUSE THAT WAS THE BIG THING. AND THEN WE STARTED TO REALIZE THERE IS THINGS IN CP THAT ARE MASQUERADERS AND THEY HAVE GENETIC CAUSES. WHAT REALLY STARTED STIMULATING US WHEN THIS CAME OUT IN THIS ARTICLE, CP MAY BE LIKE AUTISM AND THEY SITED THIS SWEDISH STUDY WHERE THEY FOUND THAT 60% OF -- BASICALLY HAD SOME KIND OF GENETIC BASIS. THIS IS CAN SHOWING NEWS TO PEOPLE THAT THOUGHT THIS IS NOT A JETTYNETIC DISEASE. WE KNOW COPY NUMBER VARIATIONS ARE BEING REPORTED AS HIGH AS 10% OF KIDS WITH CP AND THEN WE HAVEN'T EVEN TALKED ABOUT EPIGENETICS FACT ORGANIZATIONS, MATERNAL CARE, HOSTILE NEONATAL ENVIRONMENTS AND THESE ALL TREMENDOUSLY CAN AFFECT OUTCOME. AND THEN FINALLY, INDIVIDUALS OWN GENE RISK CAN AFFECT THE RISK OF CP, THEIR RECOVERY, THEIR PLASTICITY AND THEIR RESPONSE TO MOTOR TRAINING AND THAT IS WHAT HAHNS WILL FOCUS ON. JUST QUICKLY, JUST ONE -- TERRY MADE THE QUICK COMMENT THAT HYPERPLASTICITY IN DYSPHONIA IS GENETICALLY RELATED. WE KNOW THAT GENES ARE RELATED TO PLASTICITY. BUT THIS IS ANOTHER STUDY PUBLISHED LOOKING AT IDENTICAL AND FRATERNAL TWINS. THEY DID A PAIRED ASSOCIATIVE STIMULATION AND THEN MEASURED THEIR POTENTIALS AFTER THAT. AND WHAT THEY FOUND IS THAT CHILDREN THAT WERE THE IDENTICAL TWINS HAD TWICE AS MUCH SIMULATOR NETHEIR RESPONSES. SO HAY SHOWED A STRONG HERITABILITY NEPLASTICITY AND NOW WE HAD MANY ACTIVITY PLASTICITY GENES HAVE BEEN IDENTIFIED. SO THAT IS ALL I HAVE. [ APPLAUSE ] >> LET ME INVITE UP HAHNS TO TALK ABOUT GENETIC AND GENOMIC FACTORS WE HAVE BEEN ALLUDING TO. >>> SO THANK YOU AGAIN FOR INVITING ME HERE TO THIS WONDERFUL COUNTRY AND TO THIS WONDERFUL CONFERENCE AS I SAID YESTERDAY. WE DO NOT HAVE THIS SIMILAR REALLY FOCUSED WORKSHOPS WHERE WE ARE DISCUSSING WITH FOUNDERS WHAT WOULD BE THE RIGHT AREA TO GO. SO, WHAT I WILL DO IS BRING UP A NEW AREA WHICH WE HAVE NOT DISCUSSED SO MUCH AND WHAT THE THREE OTHERS HAVE MADE A GOOD BASE FOR. AND I GO DIRECTLY TO ONE OF THE SLIDES DIANE HAD NAMELY, WHAT WE DO TODAY ARE ACTIVE INTERVENTIONS. AND THAT IS THE AUSTRALIAN GROUP. AND ALL THE GREEN INTERVENTIONS ARE BASED ON THE INDIVIDUAL THAT IS ACTIVE. THERE IS NO PASSIVE TREATMENT THAT HAS BEEN SHOWING TO IMPROVE FUNCTION. SO THAT IS THE BASE. AND IT IS ALSO IMPORTANT TO SEE THAT WE ARE NOT SO MUCH DEALING WITH THE RECOVERY OR REPAIR. WHAT WE ARE FOCUSING ON IS THE PART OF THE BRAIN WHICH REMAINS AND HOW CAN WE MAXIMIZE THE CAPACITY OF THAT PART OF THE BRAIN? AND THEN WE ARE COMING INTO MOTOR LEARNING OR ADAPTATION OR MOTOR TRAINING AND I THINK IT IS IMPORTANT TO HAVE THE DISTINCTION BUT MAYBE THEY GO INTO AT LEAST WHEN WE COME DOWN TO MOLECULAR LEVEL. SO MOTOR LEARNING. WHAT -- IT IS QUITE CHARACTERISTIC. IN THIS CASE, IT IS SEQUENCE MOTOR LEARNING WHILE YOU -- WHY YOU LEARN CERTAIN SEQUENCES WITH FINGER. IN THIS CASE, IT IS CONSORTIUM AND YOU HAVE EARLY PHASE WHERE YOU RAPIDLY IMPROVE YOUR FUNCTION AND THEN YOU HAVE CONSOLIDATION PHASE WHERE IT PLATEAUS. IN THIS CASE, IT TAKES MINUTES AND IT TAKES MONTHS BUT IT SEEMS TO BE THE SAME UNDERLYING SHAPE. FROM THE SAME REVIEW HERE, THEY HAVE BEEN LOOKING ON MULTIPLE FMRI STUDIES TO SEE WHAT IS HAPPENING DURING THE TRAININGS. SO YOU HAVE ONE MOTOR PARADIGM YOU DO BEFORE TRAINING. YOU DO IT EARLY DURING TRAINING OR LATE DURING TRAINING. AND THE FMRI TELLS US IF THERE IS INCREASE IF THERE IS INCREASED ACTIVITY. AND IF YOU LOOK HERE ON THE CONTRALATERAL SIDE, YOU HAVE THIS SUPPLEMENTIARY MORTUARY AND THE PRIMARY MORTUARY AND THE OTHER SECONDARY MORTUARIES WHO ARE MOSTLY UP BUT DOWN REGULATED. BUT LOOK ALSO HERE. THIS IS A DORSAL MEDIAL WHICH TELLS US WE ARE NOW DEALING WITH CIRCUITS. IT'S NOT JUST CORTEX IT'S A CIRCUIT. AND YOU CAN ALSO SEE THE CEREBELLUM WHERE YOU HAVE UPREGULATION. SO OBVIOUSLY IT IS IMPORTANT THAT WE HAVE THE CIRCUITS, THE WHITE MATTER IS COMMUNICATING PROPERLY. THESE ARE DURING ART I - - DURING EARLY PHASE. IF YOU LOOK LATE PHASE, MUCH DISAPPEARS. THERE ARE SOME SMALL DIFFERENCES BUT MOST TELLS US IT'S A DYNAMIC PROCESS WHAT IS HAPPENING HERE. BUT WE KNOW ALSO THAT IT IS A LONG AFFECT BECAUSE IN THIS CASE THEY ARE LOOKING AT THE GRAY MATTER AND IF BEFORE AND AFTER THEY LEARNED THESE THREE AND IN THIS AREAS THERE IS INCREASED IN GRAY MATTER VOLUME IN THESE AREAS SO THAT MEANS THERE ARE LONG SUSTAINABLE CHANGES AFTER A TRAINING. AND SIMILARLY, AND THIS IS OUR OWN STUDY WHERE WE WERE LOOKING ON PROFESSIONAL CONCERT PENISTS AND IT IS LOOKING AT THE INTEGRITY OF THE PATHWAYS AND WHERE WE CAPSULAR ANTENNA COULD SEE YOU HAD AYER FRACTIONAL BETTER INTEGRITY IN THE PROFESSIONAL PIANISTS. WHEN WE THEN MADE A REVIEW BACK HOW MUCH DID YOU TRAIN, WE COULD THEN SEE A CLEAR RELATION HOW MUCH THE PIANIST HAD BEEN TRAINING BEFORE 11 YEARS OF AGE. AND THAT ACTUALLY WAS ALSO IN THE CAPSULE ANTENNA. THAT TELLS US EARLY TRAINING OF FINGER MOVEMENTS -- AND THESE ARE ADULTS. THAT IS ACTUALLY GIVING LONG LIFE CHANGES IN BODY STRUCTURE IN THIS CASE. NOW WE ARE COMING INTO THE GENETIC AREA. SO IN THIS CASE, THEY WERE LOOKING ON A MOTOR SIMULATION. AND WE ARE LOOKING AT SPECIFIC GENE. BDNF GENE. AND YOU HAVE THERE POLYMORPHISM WHICH IS THE VAL MET AND YOU HAVE THE ORDINARY WHICH IS THE VAL VAL. AND WHAT YOU THEN SEE IS THE VAL VAL, THEY LEARN MUCH QUICKER BECAUSE THIS IS TIME THAN THE VAL MET. AND WHEN YOU DO THE FMRI YOU CAN ALSO SEE THAT THE VAL VAL HAS MUCH LARGER AREAS OF ACTIVITY COMPARED TO THE VAL MET AND ALSO THEY HAVE MORE INCREASE THERE. SO THAT TELLS US THERE IS SOME OF THE MECHANISM PROBABLY THEN DEPENDING ON THE BDNF IN THE BRAIN. I WILL DROP THAT AND I CAN COME BACK BECAUSE I THINK THIS IS A VERY IMPORTANT BUT I WILL INSTEAD FOCUS ON WHAT WE HAVE BEEN DOING FOCUSING ON DOPAMINE SYSTEM. MANY OF YOU KNOW OF COURSE EVERYTHING OF THE DOMA MEAN SYSTEM. -- TOPA MEAN SYSTEM. SO TAKE IT FROM THE BEGINNING SO YOU CAN FOLLOW HERE. WE HAVE THE DOPAMINE NEURONS LOCATED IN THE MID BRAIN AND YOU HAVE TWO DOPAMINE SYSTEMS. ONE IS GOING TO THE BASAL GANGLIA. AND THAT IS WHAT IS HAPPENING IN PARKINSON'S FOR EXAMPLE. THEN YOU ALSO HAVE THE AREA PREACTING TO THE FRONTAL LOBE WHERE YOU HAVE THE MOTOR CORTEX AND OTHER MORTUARIES. AND WHEN WE LOOK NOW ON THIS IS A PRESYNAPTIC NEURON WHERE YOU HAVE THE DOPAMINE WHICH IS FORMED IN THE PRESYNAPTIC NEURON T IS RELEASED IN THE SYNAPTIC CLEFT. I DON'T THINK YOU CAN SEE MY POINTER ANY LONGER. AND THEN IT IS GOING TO THE D1 RECEPTORS OR THE D2 CLASS RECEPTORS AND THEN THEY ARE ACTIVATING THE POST SNATTIC CELL. BUT THEN TO CLEAR DOPA EN MOO, YOU HAVE DOPAMINE TRANSPORTER SUCKING IT BACK IN AND THAT IS WHAT YOU ARE BLOCKING IN ADHD WITH AMPHETAMINE. SO YET YOU GET INCREASED DOPAMINE. BUT YOU ALSO HAVE THE ENZYME BREAKING DOWN OF THE SO THAT MEANS THESE PROTEINS, THEY ARE NOW CONTROLLING HOW MUCH DOPAMINE WILL BE IN THE SYNAPTIC CLEFT. SO, INTERESTING IN KRAMER'S GROUP, THEY NOW TOOK AGAIN POLYMORPHISM IN DIFFERENT DOPAMINE MARKERS. IT IS THE DOPAMINE D1 AND D2 OR THEN THE RECEPTORS. IT IS THE CONT BREAKING DOWN AND THE DOPAMINE TRANSPORTER. WHAT THEY DID, THEY COULDN'T FIND ANYTHING IF THEY DID IT INDIVIDUALLY. BUT WHEN THEY ADDED THESE POLYMORPHISMS TOGETHER, THEY COULD SEE ONE POLYMORPHISM GIVES A LOT OF DOPAMINE. THE OTHER LESS. WHAT THEY COULD FIND IF YOU HAVE THE GENE SCORE YOU COULD HAVE ZERO, ALL DOWN OR YOU COULD HAVE 5 ALL OF THEM WERE UP. AND IF YOU LOOK ON THE RED SPOTS, IT'S VERY CLEAR RELATION BETWEEN THE GENOTYPE AND HOW MUCH OR HOW GOOD THEY LEARNED. SO HIGHER DOPAMINE SCORE THE BETTER THEY LEARNED. WHEN THEY GETEL DOPA, INCREASING DOPAMINE, YOU SEE THAT IN THIS CASE, YOU HAD INCREASE. YOU COULD IMPROVE THE MOTOR LEARNING. BUT WHAT HAPPENED OF THESE WITH HIGH SCORE? AND NOW I THINK WE ARE COMING INTO WHAT DIANE HAD IN ONE OF HER SLIDES. WE SEE A DIFFERENCE. SOME OF THEM ARE THEN LEARNING WELL. OTHERS ARE NOT AND WE CAN SEE THAT IF WE NOW BOOST THES IS, THEY RESPOND DIFFERENTLY. AND WHY IS THAT? HOW CAN THAT BE POSSIBLE? ISN'T DOPAMINE GOOD? UP TO THE SKY? BUT THEN WE NOTICE IN RESEARCH 10-15 YEARS BACK, THAT IT IS NOT A LINEAR RELATION. IT'S NOT MORE AND MORE DOPAMINE THE BETTER YOU'RE GOING. WE HAVE WHAT IS CALLED INVERTED U SHAPE. SO THAT MEANS THERE IS AN OPTIMAL LEVEL. THIS IS WHERE YOU SHOULD BE. IF YOU HAVE TOO LOW DOPAMINE, THEN YOU WILL BECOME BETTER IF YOU GET BOOSTED BUT IF YOU'RE ON THE TOP, YOU WILL LOSE. SO, NOW TO COME DEEPER INTO THIS, WE HAVE STARTED TO LOOK -- AND I HOPE TERRY AGREES THIS IS A MOTOR LEARNING PARADIGM. WE CAN DISCUSS THAT LATER. WHAT IS LEARNING AND TRAINING. SO, WE ARE USING RODENTS AND THEY ARE THEN REACHING THROUGH A SLOT IN A PLEXIBAR AND THEY ARE THEN GRASPING WITH THEIR DIGITS, SMALL SMALL PALLETS. AND YOU SEE IT IS VERY SIMILAR TO WHEN WE ARE REACHING IN HERE. AND THIS IS JUST TO SHOW YOU WHAT IT LOOKS LIKE. NOW WE MUST BE VERY OBSERVANT. LOOK NOW. THAT WAS QUITE GOOD. THIS IS A SCALED RAT. YOU WILL SEE, HER COMING BACK -- NOW SHE TRIED TOO FAST. WE HAVE TO GO ALL THE WAY BACK. AND THEN PALLET AND YOU SEE THE SLOT? SHE HAS TO MOVE THROUGH THE SLOT, TURN TO THE -- WHATEVER. THERE YOU SAW IT. SO, NOW I SHOULD SHOW YOU AN UNSKILLED RAT IN THIS CASE. SO HERE IT TOOK FOUR TIMES. WHAT WE ARE NOW COUNTING IS HOW MANY TIMES DOES IT TAKE TO DO THIS? AND THIS WAS NOT OUR -- THIS IS AN ESTABLISHED PARADIGM. SO THE FIRST STUDY WE DID WAS ACTUALLY ON SPONTANEOUS HYPERTENSIVE RAT WHICH IS AN ADHD MODEL. AND WHICH IS KNOWN TO BE HYPERACTIVE AND HAVE PROBLEM IN ATTENTION BUT WE NOW WANTED TO STUDY MOTOR BECAUSE IN ADHD, ABOUT HALF OF THE POPULATION ALSO HAD MOTOR PROBLEMS. AND VERY CLEARLY, THIS IS WILDTYPE AND THIS IS SHR. TELLING US THAT THIS RAT HAS PROBLEMS IN MOTOR LEARNING. AND AS YOU KNOW, ADHD IS VERY MUCH A DISEASE OF DOPAMINE OR MONOAMINE TRANSMISSION. SO THEREFORE I THINK THIS STUDY IS VERY IMPORTANT. SO WHAT THEY WERE DOING, THEY WERE USING SIX HYDROXY DOPAMINE, A TOXIC SUBSTANCE WHICH KILLS THE DOPAMINE NEURONS. SO THEY WERE INJECTING THIS HERE. AND THAT IS THE RED ONE. SO THIS IS THE WILDTYPE. YOU SEE ORDINARY LEARNING CURVE. DO YOU IT BEFORE TRAINING AND THEY DO NOT LEARN. SO IN THIS WAY, YOU CAN BLOCK IT. THE NEXT THING THEY DID WAS THEY TRAINED THE ANIMAL, OBVIOUSLY THEY HAVE REACHED THE PLATEAU. THEY INJECTED THIS AND DID NOT LOSE THE PERFORMANCE. AND THIS IS VERY IMPORTANT. THAT MEANS THE DOPAMINE IS REQUIRED DURING LEARNING BUT WHEN YOU HAVE ACQUIRED THE SKILL, THEN YOU DON'T NEED IT ANY LONGER. SO OBVIOUSLY DOPAMINE IS ONE OF THESE PLASTICITY GENES. SO THEN WE NEED TO GO THROUGH THE DOPAMINE SYSTEM A BIT MORE. THIS ONE YOU ALREADY KNEW. YOU WANT TO SEE IT IN MID BRAIN PROJECTING. I ALSO SHOWED YOU THIS ONE. PRESYNAPTIC SIGNALING TO THE POST SYNAPTIC. BUT THE KEY HERE AS WE THINK IS ACTUALLY THE POST SYNAPTIC NEURON AND NOW IT IS GETTING DIFFICULT. SO YOU WILL NOT UNDERSTAND THE DETAILS BUT I THINK YOU WILL UNDERSTAND THE WAY OF THINKING. BECAUSE DOPAMINE IS MODULATOR. IT'S A NEURAL MODULATOR. AND IT CHANGES NOW AS YOU SEE THROUGH SECOND MESSENGERS T CHANGES THE RECEPTORS. IT CHANGED THE ION CHANNELS, ION PUMPS AND ALSO THE TRANSCRIPTION OF FACTORS. AND THE HUB OF THIS IS ACTUALLY A PROTEIN, THE DOPE 32. WHICH IS ACTIVATED THROUGH CYCLIC AMPPK IN WHICH DOWNSTREAM COMPLETELY CHANGED THE PROPERTY OF THE POST SYNAPTIC NEURONS. THIS IS WHAT WE DID. WE WERE LOOKING ON A SPECIFIC STRAIN WHICH HAS A LOT OF DOPAMINE. ABOUT 30-40% MORE DOPAMINE. IT'S A POOR LEARNER. WHEN WE LOOK NOW ON THE ARK, AN ARK IS AN EARLY GENE ACTIVATED WHEN YOU'RE ACTIVE. YOU CAN SEE IT AS AN FMRI AND WHAT YOU SEE NOW IS THAT YOU HAVE INCREASED ACTIVITY IN THE EARLY PHASE NOT IN THE LATE AND YOU HAVE IT IN THE M1 BUT YOU ALSO HAVE IT IN THE DORSAL MEDIA. DO YOU REMEMBER THE HUMAN? IF WE WANT TO TRANSLATE SO IT IS THE SAME AREAS AS YOU SAW WITH THAT FMRI THAT ARE ACTIVATED. WHEN WE LOOK ON THE EXPRESSION OF THESE DOPAMINE MARKERS. FOR EXAMPLE WE SEE NOW THERE IS INCREASE IN THE -- HIGHER IN THE NORMAL THAN IN THE C. WHEN WE DO THE CORRELATION, THERE IS VERY CLEAR ASSOCIATION BETWEEN IN THIS CASE, IN DOPE 32 -- AND IT IS VERY STRONG BETWEEN BALB32 BUT ALSO IN DOPAMINE. SO THE FINAL SERIES IS, WE COOK CAPTURE THE CHANGE OF THE GENES DURING TRAINING PHASE? WE ARE LOOKING AT THE EARLY PHASE AND AT THE LATE PHASE. AND WHAT WE SEE IS NOW IN THE DORSAL MEDIA 3 AND OTHERS, IN EARLY PHASE, YOU HAVE DOWNREGULATION NOW IN THE TRAINED ANIMALS. NOT SO MUCH IN THE LATE PHASE. WE CAN SEE THE 32 IS INCREASED IN TRAINING SO EXPRESSING MORE 32. NOW, GETTING EVEN MORE. IT'S THE PHOSPHORYLATION OF THIS PROTEIN WHICH IS SENDING SIGNALS DOWNSTREAM AND WHAT WE CAN SEE IS THAT THE PHOSPHORYLATION IS INCREASED EARLY DURING TRAINING. AND EVENTUALLY NOW YOU USE A TRANSGENIC MICE WHICH WE GOT FROM PAUL GREEN, WE CAN NOW BLOCK THE SITE AND WHAT YOU SEE IS THEY HAVE A POOR TRAINING. SO I THINK THIS ACTUALLY TELLS US THAT WE HAVE CHANGE IN THE DOPAMINE D1, IN THE DOPE 32 AND IN THE DOWNSTREAMS AND THAT WE ALSO CAN BLOCK IT. SO, THESE ARE MY FINAL SLIDES. HOW CAN WE RELATE TO HUMANS? THESE ARE FROM CHRISTINE IN MY GROUP WHO DID THE FIRST STUDIES IN CEREBRAL PALSY AND AFTER THAT HAVE DONE A LOT OF STUDIES WHERE WE HAVE BEEN SHOWING IN PARTICULAR AT THE MOMENT. AND WHAT WE HAVE SEEN IS EXACTLY WHAT DIANE SAID. THERE IS A WHOLE RANGE OF RESPONSES. SOME RESPOND VERY WELL AND OTHERS NOT. SO WHAT WE NOW ARE DOING, WE ARE TAKING IN ALL OF THESE KIDS BECAUSE THE GENE IS NOT CHANGING. IT'S EXPRESSION IS. AND WHAT WE HAVE DONE, WE USED THE SAME GENE SCORE AND USING THE OUTCOME MEASURES AND GATHERING ABOUT 60 OF THESE AND THIS IS HALFTIME. AND I WOULD SAY IT IS VERY ENCOURAGING. BECAUSE OBVIOUSLY THOSE WHO ARE THE REALLY POOR LEARNERS, THEY ALSO HAVE A LOW DOPAMINE SCORE. WHILE THOSE WHO ARE THE GOOD LEARNERS, THEY HAVE A GOOD ONE. THIS IS NOT THE WHOLE STORY. WE HAVE -- THERE ARE MANY OTHER POSITIVES. MY LAST CONCLUSION THEN. WHAT WE HAVE SHOWN IS THE SCALED MOTOR LEARNING IS ASSOCIATED WITH POLYMORPHISMS. THAT IF YOU NOW DISTURB THE PROJECTION TO THE FRONTAL CORTEX, YOU CAN BLOCK IT. WE HAVE SHOWN NOW YOU HAVE ASSOCIATION BETWEEN HOW THE OUTCOME AND THE THEN THE DOPAMINE SIGNALING. WE CAN INTERACT. THE QUESTION IS, CAN WE NOW USE THESE PATHWAYS? SO THESE ARE THE LAST STUD EASED I HAVE BEEN DOING. BD NF IS VERY INTERESTING. I WOULD LIKE TO SAY WELCOME TO THIS MEETING WHICH WE HAVE IN STOCKHOLM IN A FEW MONTHS. UNFORTUNATELY IT'S ALMOST FULL SO IF YOU WANT TO COME, I THINK YOU HAVE TO GO IN DURING THIS WEEKEND AM WE STILL HAVE MAYBE 100 OR 50 LEFT OF 1300 SLOTS. THANK YOU VERY MUCH. [ APPLAUSE ] >> [ OFF MIC ] SO I POINTED OUT WE WENT THROUGH A TREMENDOUS AMOUNT OF INFORMATION AT THE BEHAVIORAL LEVEL, THE STRUCTURAL LEVEL IN TERMS OF THE PATHWAYS AND EVEN THE NEUROTRANSMITTER LEVEL TO REFINE THE DIFFERENCES OF CP CHILDREN, HOW THIS HAS DIRECT IMPLICATIONS FOR TREATMENT. LET'S START WITH QUESTIONS. PEOPLE WANT TO START? ANY QUESTIONS TO THE MIC? >> JUST TO STIMULATE THE TALK HERE. I JUST COME FROM CLINICAL TRIALS. I WANT TO KNOW WHAT CONCEPTS ARE ABOUT INTRODUCING ANY NEW THING AS A CLINICAL TRIAL, RANDOMIZING PATIENTS. BECAUSE I KNOW THE -- ALL OF US WANT THE BEST THING FOR OUR CHILDREN, FOR OURSELVES BUT WE KNOW THE HISTORY OF MEDICINE IS REPLETE WITH ATTEMPTS TO DO SOMETHING THAT REALLY DON'T DO. SO UNLESS THE FAMOUS WORDS OF THOMAS RANDOMIZE THE FIRST PATIENT. SO THAT WAS MANY, MANY YEARS AGO. JUST WANT TO LEAVE IT THERE. >> CLINICAL TRIAL DESIGN A VERY BROAD TOPIC. ANYBODY WANT TO MAKE A SPECIFIC COMMENT ABOUT OPTIMIZING DESIGN AND TARGETING INTERVENTIONS IN. >> WE HAVE A REAL PROBLEM WHEN WE DEAL WITH CP BECAUSE IT'S A IN HOMOGENEOUS POPULATION AND THE BASIC IDEA BEHIND RANDOMIZATION IS THAT THE RANDOMIZATION WILL REMOVE ALL OF THE OTHER AFFECTS OTHER THAN YOUR IN TINNEDDED TREATMENT AFFECT AND THEIR YOU CAN DRAW CONCLUSIONS ABOUT THE TREATMENT AFFECT. BUT THAT ASSUMES THERE IS ENOUGH OF A POPULATION IN THE TWO DIFFERENT ARMS OF YOUR STUDY THAT THESE NOW BECOME COMPARABLE. AND THE PROBLEMS WHEN YOU'RE DEALING WITH A MULTIFACTORIAL DISEASE THAT IS EXTREMELY UNLIKELY. AND SO, THE CLASSIC DESIGNS OF RANDOMIZED TRIALS WILL GENERALLY FAIL. EVEN IF -- AND FAIL JUST BECAUSE OF SITUATIONS LIKE THIS NOW YOU THINK ABOUT OTHER TRIAL DESIGNS ACROSS OVER DESIGNS AND THINGS WHERE YOU CAN ESSENTIALLY DO WITHIN SUBJECTS COMPARISONS OVER THE GROUP. AND THEN YOU CAN COME UP WITH REASONABLE DESIGNS. SO, WITHOUT GOING INTO ALL OF THE DETAILS OF STUDY DESIGN I WOULD SAY RECOGNITION THAT IT IS A SPECIAL PROBLEM AND THAT COMING UP WITH GENERALIZABLE SCIENTIFIC RESULTS THINGS THAT WILL PREDICT THE OUTCOME OVER A GROUP, WHEN YOU'RE DEALING WITH CP, REQUIRES PARTICULAR ATTENTION TO THIS GROUP AND YOU CAN NOT USE THE STANDARD THINKING WITHOUT REALLY BEING QUITE AWARE OF THAT. THERE IS A SEPARATE QUESTION AS WELL OF HOW CAN YOU MAKE THE RESULTS OF A TRIAL AFFECT A PARTICULAR CHILD. WE ARE ALL FULLY AWARE OF THE SITUATION YOU'RE FACED WITH A CHILD IN YOUR CLINIC AND THEY SAY, YES, WE UNDERSTAND BUT THE TRIALS WORKS BUT WILL IT WORK FOR ME? WHAT IS THE PROBABILITY AT THE WILL WORK FOR ME? THE ANSWER IS IT'S EITHER ZERO OR 100%. I JUST DON'T KNOW WHICH, RIGHT? SO, I THINK THAT ONE OF THE THINGS THERE THAT BECOMES VERY IMPORTANT AND I EMPHASIZED THIS A LOT, IS THE ROLE OF MEASUREMENT AND CLASSIFICATION. THIS IS SOMETHING THAT HAHNS WAS TALKING ABOUT AS WELL. IF YOU CAN IDENTIFY THE SUBGROUPS AS CAREFULLY AS POSSIBLE AND FIGURE OUT AND THEN A LINK BETWEEN THE SUBGROUP AND THE MECHANISM AND THE INTERVENTION, THEN YOU CAN TARGET INTERVENTIONS OF INDIVIDUAL CHILDREN AND THEN YOU IF YOU THINK ABOUT A DESIGN OF A TRIAL IN THAT SITUATION, YOU'RE TRYING A METHOD THAT SORT OF SAYS, I'M GOING TO GO FROM ASSESSMENT AND MEASUREMENT TO TARGETED INTERVENTION AND THAT WHOLE PROCESS IS THE THING THAT I'M ATTEMPTING TO DO. AND AGAIN, I THINK THESE ARE JUST THE REQUIREMENTS OF IN HOMOGENEOUS POPULATIONS AND COMPLEX DISORDERS. >> SO I'M NEITHER STATISTICIAN OR EXPERT IN CP BUT I'M BRINGING IT UP BECAUSE YOU WANT TO GENERALIZE YOUR APPROACH AFTER YOU DO INTERVENTION, GENERALIZABLE DATA WHAT YOU'RE TALKING ABOUT. AND DEFINITELY THAT NEEDS TO BE TALKED ABOUT. AND AVOIDING INTERVENTION BY -- ALL OF US HAVE BIAS THAT OUR INTERVENTION HAS BENEFIT. SO -- >> THIS IS A VERY RICH DISCUSSION BUT I WANT TO GET ON TO OTHER QUESTIONS. JEWELS DO YOU HAVE ANOTHER QUICK COMMENT? >> JUST TO CONTINUE, YOU REALLY NEEDED TO SUBDIVIDE CP AND SECTIONS WHERE YOU KNOW WHAT YOU'RE AFTER. SO FOR INSTANCE THE STUDY I SHOWED YOU IS IT TERPS OUT THERE ARE THREE SUBGROUPS DEPENDING ON THE LOSSES THATTURE CAN. WE NEED TO THINK THAT WAY AND NOT COME UP WITH A -- RESOLUTION TO EVERYTHING. IT MAY WORK FOR SOME BUT NOT FOR OTHERS. SO THAT IS WHAT WE NEED TO ACKNOWLEDGE AND MOVE ON FROM THERE [ OFF MIC ] HI, I'M DIE APP FROM NEMOUR'S HOSPITAL FOR CHILDREN IN DELAWARE. MY QUESTION IS FOR HAHNS. I WAS REALLY FASCINATED BY THE DIFFERENT RESPONSE THAT YOU SHOWED WITH THE LOW DOPAMINE TO HIGH DOPAMINE GROUP AND YOU SAID THAT THAT WOULD BE A WAY THAT YOU COULD KNOW WHO WOULDN'T RESPOND. BUT AS A PHARMACOLOGIST, I IMMEDIATELY THINK WHAT KIND OF PHARMACOLOGICAL INTERVENTION YOU COULD DO TOGETHER WITH THE TREATMENT TO IMPROVE THE RESPONSE IN THAT GROUP. THAT'S MY FIRST QUESTION. I HAVE A SECOND COMMENT. WE JUST COMPLETED A TRIAL OF ABUSE BORN IN CHILDREN OF AUTISM IN WHICH THE LOW DOSE IMPROVED ON STEREOTYPE BEHAVIOR WHEREAS WITH HIGH DOSE THEY DID NOT. SO THIS IDEA OF FINDINGS THE RIGHT DOSE IN THE USHAPED CURVE IS VERY IMPORTANT -- BUSPIRONE. BUT I WANT TO HEAR YOUR RESPONSE TO THE FIRST PART FIRST. >> THANK YOU. I THINK THE FIRST EASY ONE IS TO JUST USE THE PSYCHOSTIMULANTS TO INCREASE THINGS LIKE -- BUT THEY HAVE VERY BROAD AFFECTS. SO I THINK IF WE COULD FIND TARGETS IN THIS INTRACELLULAR PATHWAYS, I THINK THAT THAT WOULD BE IMPROVEMENT AND THERE IS QUITE A LOT OF RESEARCH IN OTHER MEMORY SYSTEMS WHERE THEY ARE LOOKING FOR TARGETS. SO I THINK IT EVENTUALLY WE WILL BE ABLE TO -- I HAVE A NEW ONE I CAN TELL YOU ABOUT LATER. >> JOHN, I THINK YOU WERE NEXT AND THEN WE'LL GO BACK TO THE OTHER SIDE. >> THAT WAS A REALLY GREAT SESSION. TWO VERY QUICK COMMENTS AND A QUESTION. COMMENT PERTAINING TO SOMETHING THAT CAME ACROSS A COUPLE OF TALKS. OUR STUDY WITH KATHLEEN FIELDS SHOWED THAT CONSTRAINT INDUCED MOVEMENT THERAPY ALONE DIDN'T BOOST THE SPINAL INTERNEURONS. SO THAT SURPRISED US. SO THAT REALLY POINTS TO ENGAGEMENT BECAUSE ONLY WHEN THE ANIMALS WERE KNOW GAUGED IN REACH TRAINING THERE WAS IMPROVEMENT IN THE CORTICAL MAP -- ENGAGED - WELL - REGARDING PERSONALIZED REHABILITATION, ONE THING WE HAVE BEEN PLAYI ENGAGED - WELL - REGARDING PERSONALIZED REHABILITATION, ONE THING WE HAVE BEEN PLAYING WITH OUR ENGINEERING COLLEAGUES, IS USING FINITE ELEMENT MODELING, METHOD MODELING TO IDENTIFY WHERE CURRENTS ARE FLOWING IN NEUROMODULATORY PARAISMS DO. THEY ARE DOING THIS A LOT IN ADULT STROKE WHERE YOU CAN TUNE IN THE POSITION OF TRANSCRANIAL DIRECT CURRENT ELECTRODES TO HAVE CURRENTS GOING TO THE REGIONS. THE QUESTION IS, FOR ALL OF YOU, IN TERMS OF THE BROAD PLASTICITY STRATEGIES AND LEARNING STRATEGIES THAT YOU DESCRIBE, WHAT IS YOUR FEELING ABOUT PERSISTENCE OF SOME OF THESE CHANGES? TMS FOR EXAMPLE AND DC MODULATION PRODUCES NICE SHORT-TERM AFFECTS. THE STUDIES OFTEN DON'T GO ON VERY LONG AND IF THEY DID, THEY PROBABLY WOULDN'T SHOW MUCH. DO YOU HAVE A SENSE OF A DURABLE PLASTICITY? >> YES. SO I LIKE TO RESPOND TO THAT. WE HAVE DONE THINGS LIKE TD CS FOR STIMULATING HEMISPHERE AND IMPROVEMENT IN REACHING WHICH YOU POINTED OUT SHORT-TERM. IF YOU DO THESE INTERVENTIONS I SHOW ROBOTICS AND BASICALLY PROMOTE FOLKS TO REACH MORE AS YOU INCREASE THEIR ABDUCTION LOADS, WE SEE THEY HAVE CARRYOVER FOR MONTHS AND MONTHS SO THESE ARE RESULTS THAT JUST CAME OUT OF MY COLLEAGUE MICHAELIS WHO RUNS THIS WORK, HAS BEEN FINDING THIS. HE CREATES MUCH MORE LONG TERM CHANGES. ANOTHER THING I HAVEN'T TALKED ABOUT BUT GO MORE ALONG THE LINES OF HAHNS AND WE TALKED ABOUT THIS YESTERDAY EVENING, THERE ARE WAYS TO INTERVENE PHARMACOLOGICALLY AS WELL. IF THE INTICULAR SPINAL SYSTEM IS HEMIPRATTIC BECOMES A BACKUP SYSTEM AND TO FORCE THEM TO GO BACK TO WHAT THEY STILL HAVE IS TO INHIBIT THE RETICULAR SPINAL SYSTEM. WE HAVE EARLY RESULTS WHERE WE SEE THAT THAT SILENT CASE. SO IF YOU INHIBIT THE SPINAL SYSTEM AT THE LEVEL OF THE BRAINSTEM, YOU SEE IMMEDIATE IMPROVEMENT IN REACHING. WE HAVEN'T SHOWN THE CHANGES AT THE BRAIN YET ALTHOUGH WE KNOW THAT WHEN YOU TRAIN PEOPLE AND YOU SEE IMPROVING REACHING, REALLY WHAT YOU SEE IS START TO USE LESS OF THE HEMISPHERE AND GO BACK TO WHAT THEY HAVE GOT. THAT IS DATA WE ALREADY HAVE. SO WE ARE NOT REBUILDING THINGS AND I THINK YOU BROUGHT UP SOMETHING YESTERDAY ABOUT THE IDEAL TIME TO INTERVENE THAT MAY HAVE TO BE EARLY. YOU ARE MORE THE EXPERT ON THAT THAN I AM WITH REGARD TO SPINAL DEVELOPMENTS WHICH MAY BE EXTENDED OVER A LONG PERIOD OF TIME WITH REGARD TO MILE ENIZATION BUT THE FIBERS ARE ALREADY THERE. SO, I THINK THAT A LOT OF WHAT WE DO IS START TO OPTIMIZE WHAT WE STILL HAVE GOT IN A MORE EFFICIENT MANNER AND THE BEST APPROACHES ARE THINGS WE ARE WORKING ON BECAUSE YOU CAN COME UP WITH 100 EXERCISES BUT WHAT WE SHOWED IS INCREASED ABDUCTION IS WHAT SEEMS TO BE IMPORTANT IN THIS SEGMENT OF CEREBRAL PALSY. >> LET'S GO TO THE NEXT QUESTION. >> THANK YOU FOR A WONDERFUL SESSION. SO BETWEEN JACK MARTIN'S THOUGHT PROVOKING TALK YESTERDAY AND THE SESSIONS TODAY, I THINK YOU'RE BRINGING OUT THE FACT THAT WE ALSO NEED TO FOCUS A LOT ON THE MUSCLE NEUROMUSCULAR JUNCTION AND SPINAL CORD AND CEREBELLUM -- CEREBELLUM AND THIS TIDES BACK BECAUSE IT IS IMPORTANT FOR LEARNING, FOR PROPERTY INCEPTION, SENSORY PATHWAY AND THE AUTONOMIC SYSTEM ANOTHER PIECE WHICH IS AFFECTED IN CHILDREN WITH CP THAT WE HAVEN'T TALKED ABOUT. SO, MY QUESTIONS I HAVE A COUPLE OF QUESTIONS BASED ON THIS. WOULD YOU SAY WE HAVE PROBABLY A MUCH BROADER WINDOW OF OPPORTUNITY TO INTERVENE WHERE WE PROBABLY HAVE A REASONABLY BROAD WINDOW FOR THE BRAIN, FOR THE CORTICAL ASPECTS AND MAYBE EVEN BROADER TIME PERIOD FOR THE PERIPHERAL SYSTEM? AND MY SECOND QUESTION IS, DO YOU HAVE ANY SUGGESTIONED OR THOUGHTS ABOUT OTHER PHARMACOLOGIC THERAPIES THAT MIGHT ENHANCE THE PLASTICITY? >> VERY CRUCIAL QUESTION. WHO WANTS TO TAKE A SHOT AT THAT? >> CERTAINLY I'LL TRY TO ADDRESS A LITTLE BIT OF THE FIRST ONE BUT I THINK IT'S A VERY BROAD QUESTION. BUT I'M GOING TO TAKE A LITTLE BIT TO THE SIDE WHEN IS TO SAY THAT I THINK THE RECOVERY PROCESS NORMAL FUNCTION AS WELL AS RECOVERY PROCESS INVOLVES INTERACTION BETWEEN THE NEURAL CONTROL AND THE MECHANICAL SYSTEM. AND SO, UNDERSTANDING HOW THESE THINGS INTERACT IS VERY IMPORTANT AT A CLINICAL LEVEL WE ALL UNDERSTAND THAT ONE OF THE AFFECTS OF PLASTICITY CAN LEAD TO CONTRACTORS AND THAT'S ORTHOPAEDIC SURGICAL INTERVENTIONS CAN FACILITATE RELEARNING OF GAIT FOR INSTANCE, SO THERE IS A CLOSE LINK BETWEEN MECHANICAL AND NEUROLOGICAL. RESEARCH IN THIS AREA IS JUST STARTING. STEVE SCOTT MADE A BIG POINT ABOUT THIS IN AND THERE IS UPON OTHERS WHO ARE TRY TOCK LOOK AT THAT INTERACTION IN A DEEP WAY. AND I THINK THE ISSUE TO ME IS LESS FOCUSING ON SPECIFIC ASPECTED OF MUSALLY ALTHOUGH THAT IS IMPORTANT BUT ALSO WRECKINIZING INTERACTION BETWEEN THE CHANGE THAT IS HAPPEN IN THE JOINTS AND MECHANICAL SYSTEM. AND THE NEURAL CONTROL THAT IS TRYING TO BOTH COMPENSATE FOR THIS AND ALSO MAY BE PARTIALLY RESPONSIBLE FOR DEFICITS. >> ANY PANEL VISITED COMMENTS ABOUT THE PHARMACOLOGICAL ADJUNCTS? >> YES, BUT SO WE ARE REALLY NOW STARTING MORE ON THE PLASTICITY AND I WE KNOW THERE ARE MANY OTHER DRUGS WHO CAN INFERENCE PLASTICITY. AND FROM THE VISUAL SYSTEM, I THINK WE ARE ALL AWARE OF THE EXPERIMENTS WHERE YOU HAVE THE WINDOW CLOSING NOW YOU CAN AFFECTIONATELY OPEN UP THIS WINDOW AGAIN IN OTHER ANIMALS SO THAT MEANS YOU CAN NOW HAVE NEW PRO ACTIONS GO INTO THE VISUAL CORTEX. SO I THINK WE ARE JUST IN THE BEGINNING. NOTHING HAS BEEN INTRODUCED IN THE CLINIC. BUT I KNOW IN SOME STROKE STUDIES GOING ON WHERE THEY ARE GIVING SEROTONIN UPTAKE BLOCKERS. ALSO IN REGARD TO JACK'S QUESTION ABOUT THE STIMULATION, ELECTRICAL STIMULATION, WE DON'T REALLY KNOW WHAT IS HAPPENING. EITHER IF YOU HAVE THE DIRECT STIMULATION OR IF YOU HAVE THE RTMS. BUT THERE ARE NOW A LOT OF SUGGESTIONS ANYWAY THAT IT IS BDNF SYSTEM AND THAT IS KNOWN THAT IT HAS LONG TERM CHANGES. AND WE KNOW FROM OTHERS WHEN YOU HAVE USED STIMULATION FOR OTHER DISORDERS, FOR EXAMPLE, FOR DEPRESSION OR FOR -- WE KNOW THERE IS REALLY A LONG PERIOD YOU HAVE AN AFFECT AFTER THE IMMEDIATE. SO SOMEHOW YOU ARE MODULATING THE CIRCUITS, WHICH STAY FOR QUITE A LOPPING TIME. >> THANK YOU. >> SUE? >> I HAVE BEEN USING A LOT OF MY BRAIN TRYING TO FIGURE OUT HOW TO MAKE OR DISGUISE MY COMMENT AS A QUESTION. I SPENT 30 YEARS AS THE MOTHER OF A MAN WITH PROFOUND DISABILITIES. HE STARTED OUT AS A BABY AND BECAME A CHILD. HE WAS A TEEN ANALLER AND GREW INTO A MAN. HE DIED WHEN HE WAS 30. LOTS OF THERAPIES. I HAPPEN TO BE TRAINED IN PHILOSOPHIES SO RALPH KNOWS I WITHOUT FROM THE CONFLICT OF THE FACULTIES THAT THAT THE DISCIPLINE THAT IS CLOSEST TO THE HUMAN IS THE MOST IMPORTANT DISCIPLINE IN THE UNIVERSITY. AND I THINK WHAT YOU'RE DOING IS VERY CLOSE TO THE HUMAN, BUT I HAVEN'T QUITE HEARD IT HERE THAT WHAT YOU'RE TRYING TO DO IS EMPOWER THE AGENCY OF THE CHILD AND HIS PARENT. AND SO, SINCE I THINK BASIC SCIENCE IS A HUMANISM THAT LEADS ME TO QUESTION HOW IS YOUR OWN AGENCY AS SCIENTISTS CONNECTED TO THE HUMAN OF THE CHILD? AND I JUST WANT TO COMMENT THAT I KNOW THE DEFINITION OF TRANSLATIONAL RESEARCH IS VERY MURKY. BUT MY COMMENT WOULD BE THAT IT SEEMS TO ME THAT YOUR HUMANISM BEING CONNECTED TO THE CHILD'S HUMANISM IS A REALLY IMPORTANT PIECE OF THAT NOTION OF TRANSLATIONAL RESEARCH. AND I JUST HAVEN'T HEARD IT REALLY DEEPLY. UPON I HAVE MANY, MANY ADULT FRIENDS WITH CP. ONE OF WHOM POSTEDDA FACEBOOK LAST NIGHT. GOD, PLEASE DON'T CURE ME, THIS IS YOU HO I MAKE MY LIVING. THERE IS A VALUE OF HAVING CP TOO AND WE CAN'T JUST TEACH CHILDREN AND FAMILIES THAT WE ARE WILLING TO SPEND 30 MILLION DOLLARS TO TRY TO MAKE THEIR CP GO AWAY BUT WE ARE NOST WILLING TO SPEND ANYTHING TO ACCOMMODATE THEM OR RECOGNIZE THEM AS HUMAN BEINGS. SO THAT'S JUST -- I DON'T THINK IT WAS A QUESTION. >> I THINK IN FAIRNESS TO THEIR PANELIST HAVE MORE SYMPATHY TO WHAT YOU'RE SAYING. >> I UNDERSTAND THAT. JUST NEXT TIME, I SAW A NOD OVER HERE ONE NOD ANYWAY. >> FROM MY EXPERIENCE, I HAVE A 3-YEAR-OLD CHILD THAT IS SEVERELY AFFECTED BY CP AND THE OCEAN OF THERAPIES AVAILABLE AND THE CARTE BLANCHE APPROACH TO WHAT WE ARE PRESENTED WITH AND THE GUILT THAT YOU BEAR AS A PARENT FOR NOT BEING ABLE TO DO ALL OF IT IS INCREDIBLY DAUNTING. FOR EXAMPLE, AND WE ALL KNOW THAT YOU CAN DO A THERAPY, CAN HAVE ABSOLUTELY NO BENEFIT IF YOU'RE NOT VERY DILIGENT AFTERWARDS AND BOTOX IS A PERFECT EXAMPLE OF THAT. YOU CAN DO BO TOXIN JECTION AND SEE NO BENEFIT IF YOU DON'T DO STRETCHES ALL DAY EVERY DAY FOR THE NEXT SIX WEEKS. SO, I THINK FROM MY PERSPECTIVE, WHAT I WOULD LIKE TO SEE HAPPEN HERE IN THE ROOM IS THOSE OF YOU THAT ARE MORE FOCUSED AT THE MUSCULAR LEVEL AND THE APPLICATION AND LEARNING LEVEL JOIN FORCES WITH THOSE OF YOU THAT ARE MORE IN THE CLINICAL LABORATORY SETTINGS WHERE YOU'RE TESTING THE AFFECTS OF CERTAIN STIMULUS ON BRAINS AND YOU'RE LOOKING AT THAT IN AN IMAGING -- IF THE TWO WORLDS ARE SEPARATE, IT DOESN'T HELP THE CHILD. SO, IT'S NOT A QUESTION. IT'S JUST A COMMENT OF SOMETHING I HAVE OBSERVED HERE IN THE ROOM. IT NEEDS TO BE WHAT THIS PANEL IS DOING AND WHAT THE SPEAKERS FROM YESTERDAY ARE DOING, NEED TO BE INTEGRATED AND IT HAS TO BE A REQUIREMENT OF GRANT FUNDING THAT THAT PRACTICAL APPLICATION IN GETTING TO INDIVIDUALIZED THERAPIES, WHICH EVERYONE HAS AS A -- IN THEIR MIND, THEIR MANIFESTO. BUT IF IT'S NOT PART OF THE STUDY THE PARENTS ARE STILL GOING TO BE OVERWHELMED. >> AND YOU'RE RIGHT. IT'S PART OF THE CREATIVE -- I DON'T WANT TO GET INTO PHILOSOPHICAL DISCUSSION. IT'S PART OF THE CREATIVE TENSION THAT IS PART OF SCIENCE AND THE WAY WE DOE RESEARCH. WE ARE FORCED TO BE REDUCTIONIST IN THE WAY WE PRESENT THINGS BUT I THINK THESE PEOPLE ARE VERY INTEGRATED IN THEIR APPROACH. WE ASKED THEM TO FOCUS SPECIFICALLY -- WE COULD HAVE HAD WEEKS OF DISCUSSION ON CP. WE HAVE COME UP WITH AN AGENDA TO BE CONVERGE ENT. I DON'T WANT TO GET OFF INTO A -- >> [ OFF MIC ] >> BUT I APPRECIATE IT. THAT IS WHY WE INVITE YOU HERE TO KEEP US GROUNDED AND KEEP FAITH WITH WHAT YOU'RE FRYING TO DO. I THINK WE ARE TRYING TO RESPECT THAT. GO AHEAD. >> YES, XINA. IT WAS A GREAT SESSION. VERY INTERESTING. I HAVE TWO QUESTIONS. ONE IS I UNDERSTAND HOW DIFFICULT IT IS TO BUILD A DEVICE WHICH WILL ALLOW SUCH TUNEABLE RESPONSES. SO MY QUESTION IS, I JUST RECENTLY READ ABOUT A SMALL COMPANY, HOLLAND NEUROSCIENCESES IN THE BAY AREA, SAN FRANCISCO AREA AND WHAT THEY DID IS THEY CREATED A DEVICE LOOK LIKE HEADPHONES FOR BRAIN STIMULATION, GENTLE THEY SAY, AND THEY KIND OF TARGETED TO THE SPORTS AUDIENCE ADULTS AND KIDS. AND SO TO ME, I IMMEDIATELY HAD LIKE MANY, MANY QUESTIONS ABOUT IT. BUT MY QUESTION IS, SHOULD IT BE EXPLORED THAT THE DEVICES THAT THEY BUILD OUTSIDE OF ACADEMIA CAN BE USEFUL IN SOME WAY SINCE THEY EXIST? BECAUSE IT SEEMS TO BE CREDIBLE ET CETERA. THIS IS MY FIRST QUESTION. WHAT ARE YOUR THOUGHTS OR WE JUST WANT TO BE VERY RIGOROUS AND STRICT WITH WHAT THE COMMUNITY -- >> I THINK WE USE ANY DEVICE THAT LOOKS LIKE IT IS PROMISING TO BE TESTED. I THINK CERTAINLY WHEN THESE THINGS BECOME AVAILABLE THAT'S AN EXCELLENT AND VERY RAPID ROUTE TO DOING THESE THINGS. UNFORTUNATELY A LOT OF DEVICES ARE BUILT FOR COMMERCIAL MARKET ARE NOT TARGETED FOR REHABILITATION AND UNTARGETED FOR CHILDREN. SO NOW YOU'RE FACED WITH SOMETHING THAT IS ALMOST WHAT YOU WANT BUT NOT QUITE AND THE DIFFICULTY TAKING SOMETHING THAT IS ALMOST RIGHT AND FIXING IT IS HUGE. >> I LIKE TO CONTINUE TO THAT THEME. THE ROBOTICS I SHOWED FAIRLY NOVEL. SO WE CAN START DOING THINGS NOW THAT EVEN 10 YEARS AGO WE COULDN'T HAVE DONE. THE EEG ANOTHER EXAMPLE. THESE ARE APPROACHES THAT HAVE BEEN AROUND BUT NOW SO MUCH MORE SOPHISTICATED AND QUICKER TO APPLY TO DO FOR RESEARCH PURPOSES BUT TEARY IS RIGHT. 95% OF WHAT IS OUT THERE IS NOT SCIENTIFICALLY INDEPENDENT SO NOT OPTIMIZING INTERVENTION OF THE KIDS. AND THAT IS WHAT WE NEED TO DO. I DON'T THINK THERE IS A SHORTCUT THERE. WE HAVE TO DO THE WORK TO PROVE WHAT IS BEST AND WE NEED YOUR HELP AND BECAUSE I'M DOING THESE EXPERIMENTS BUT I HAVE TO TELL YOU, IT'S REALLY DIFFICULT FOR ME TO RUN THEM. YOU KNOW WHY? FOR KIDS TO PARTICIPATE. I SPEND 200,000 DOLLARS IN DONATIONS TO BUILD THIS BIG REGISTRY AND EVEN THOUGH I HAVE OVER 1000 KIDS IN THAT, I HAVE SUCH A HARD TIME TO HAVE KIDS TO COME TO MY LAB TO HELP EVERYBODY OUT. IT'S REALLY BEEN DIFFICULT. AND I DO ADULT STROKE WORK AND IT'S EASY. THEY ARE KNOCKING ON MY DOOR. CAN I PARTICIPATE TOMORROW? I HAVE NOTHING TO DO. I UNDERSTAND THE REASONS WHY. IT'S HARD TO MAKE PROGRESS. I'M ENER JET ECK TO HAVE PARENTS HERE. WE NEED YOUR HELP TO MAKE PROGRESS. IT'S HARD WORK. WE NEED TO DEVELOP DEVICES THAT ARE VERY EFFICIENT, CHEAP, EASY TO USE BUT HAVE SCIENTIFIC UNDERPINNING. >> I KNOW IT WAS A NAIVE QUESTION BUT KIND OF EXCITING THERE ARE OTHER OPPORTUNITIES AS WELL. AND MY SECOND QUESTION -- >> MAKE IT QUICK. I WANT TO GET TO THESE LAST TWO COMMENTS. >> I THINK IT IS JUST IMPORTANT TARGETS. A TOPIC IMMUNOSYSTEM -- IMMUNE SYSTEM DURING REHABILITATION PROCESS THERE IS LITERATURE IN STROKE, ADULT STROKE AS YOU KNOW THAT ALL THIS ISOLATION OF THE PATIENTS AND SUCCESS OF REHABILITATION SOMEHOW LINKED TO THE STATUS OF THE IMMUNE SYSTEM. SO IN YOUR STUDIES, OR IN OTHERS LABORATORIES, IS IT BEING INCORPORATED DURING THE REHABILITATION PROCESS? ARE THERE ANY LINKS BEING MADE? I'M NOT VERY FAMILIAR WITH THE LITERATURE. >> NEUROIMMUNOLOGY IS A RAPIDLY CHANGING FIELD. BUT I THINK IT IS NOT NEARLY UNDERSTOOD TO THE LEVEL THAT WE NEED TO UNDERSTAND IT TO BE ABLE TO ANSWER YOUR QUESTION. >> LET'S GET IN THESE TWO QUICK 90s A COMMENT TO WHAT HAHNS MENTIONED ABOUT BDNF BEING REGULATED IN TRAINING PROGRAMS. WITH BRAIN STIMULATION WE HAVE BEEN LOOKING AT CHANGES IN GENE REGULATION AND THE KINDS OF GENES THAT ARE TURNED ON WITH HIGH FREQUENCY BRAIN STIMULATION THAT PRODUCES SPROUTING ARE THE SAME KINDS OF GENES THAT ARE IMPORTANT LET'S SAY IN AXON REGENERATION. SO THE M TORE PATHWAY GETS TURNED ON AND THE JACK STAB PATH WAY GETS TURNED ON AND IT COMES DOWN TO BASELINE AFTER STIMULATION. SO IT IS LIKE ELECTROSUED CALL APPROACH. >> HI. SO, MY QUESTION HAS TO DO WITH SOME OF THE WORK THAT DR.S MARTIN, FREELY, STOUT HAVE DONE THAT SHOWS THAT FOR EVERY GAIN THAT WE MAKE IN PLASTICITY, IT USUALLY IS AT THE EXPENSE OF SOMETHING ELSE LIKE SPEED OR SOME OF THE OTHER THINGS YOU HAVE MENTIONED. SO, IN ALL THE TRIALS THAT YOU DESIGN AND THE RESULTS THAT YOU REPORT, IS THERE ALWAYS THE POSSIBLE TRADE OFF THAT YOU CAN GET FROM LEARNING, FROM PLASTICITY? DO YOU ALWAYS REPORT THOSE? AND HOW DO YOU THINK THAT WILL INFLUENCE THE DESIGN OF FUTURE CLINICAL TRIALS? >> I THINK YOU ALWAYS LOOK FOR -- THERE IS THE ADVERSE EVENTS AND THEN THERE ARE SORT OF THE SUBTLE WORSENING. AND WE LIKE TO BELIEVE THAT YOU CAN LEARN ONE THING WITHOUT FORGETTING ANOTHER THING. AND I THINK THAT MAY WELL BE TRUE WITHIN HEALTHY POPULATION AND I DON'T KNOW IF IT IS ALWAYS TRUE IN A CHILD WHO IS REALLY STRUGGLING TO DO THE TASKS THAT WE ARE GIVING THEM. WHAT I HAVE GENERALLY ADVOCATED WHEN YOU LOOK AT OUTCOME MEASURES FOR CLINICAL TRIALS IN THIS TYPE OF POPULATION, YOU HAVA YOUR PRIMARY OUTCOME MEASURE, THE THING YOU'RE MEASURING AND ALSO SOME KIND OF QUALITY OF LIFE SCALE SO THAT CAPTURES THE BROAD IDEA OF OVER ALL DID THIS MAKE YOU BETTER? EVEN IF SOME THINGS GOT BETTER AND SOME THINGS GOT WORSE, OVER ALL WAS IT WORTH DOING? THAT IS A WAY TO APPROACH THIS, RECOGNIZING THERE ARE SOMETIMES TRADE OFFS AND EVERYTHING EVERY DEVICE, EVERY MEDICINE HAS SIDE EFFECTS AND RISKS ASSOCIATED WITH IT. AND YOU HAVE TO BALANCE THOSE AGAINST THE POTENTIAL BENEFITS AND SAY, DID IT HELP? >> ONE MORE COMMENT. >> IF YOU GO TO THE IPSILATERAL BILATERAL PATHWAYS, IT IS ONE OF THE COFACTORS WE HAVE TO STUDY IF IT INFLUENCE. SO I MEAN THAT WAS FIRST QUESTION ACTUALLY ON THIS. CP IS NOT ONE. WE HAVE TO FIND DIFFERENT GROUPS AND SEE WHAT IS IMPORTANT IN DIFFERENT FUNCTIONS. IN THIS CASE, WE ACTUALLY FROM THE SAME STUDY, WE WERE LOOKING NOW ON THE FAITH WAYS BECAUSE WE THAWED MAYBE THEY COULD INFLUENCE IF THEY ARE GOOD OR POOR LEARNERS. BUT IT GO NOT HAVE AFFECT. A GROUP SPECULATED THAT THERE ARE WOULD BE POOR LEARNERS IF YOU HAVE A BILATERAL OR IPSILATERAL BUT WE COULDN'T CONFIRM THAT. >> WE GOT PERMISSION FOR FINAL TOL COMMENTS BEFORE WE GO TO BREAK. SO KEEP IT CONCISE. >> I WAS SUPPOSED TO SPEAK AFTER SUE'S COMMENTS ON HUMANANISM AND I NEED TO -- I NEED TO ECHO WHAT WAS SAID SO THIS IS UNDERSTOOD. THE HUMANIST IN ME AS A CLINICIAN AND WE HAVE GONE DOWN THIS PATH IN NEONATOLOGY FOR YEARS. WE HAVE TRIED EVERY SINGLE THERAPY AT THE BABY'S BEDSIDE BASED ON THIS HUMANISM CONCEPT OF DOING SOMETHING. RIGHT? AND FOR 30 YEARSUNETOLOGY HAS DONE A LOT OF HARM BY DOING FOLLOWING THIS -- ALL OF THESE UNNECESSARY USELESS THERAPIES AND WE HAVE ONLY TWO OR THREE THERAPIES WHICH HAVE SHOWN SCIENTIFIC BENEFIT WITH RIGOR. AND THIS IS THE LESSON WHICH I HAVE LEARNED PERSONALLY ALSO AS WELL AS THROUGH THE TREVORS, BECAUSE USING HUMANISM WE ARE SOMEWHAT BIASED. WE WANT THE CHILD TO IMPROVE. AND WE HAVE BEEN PRACTICING THERAPIES AFTER THERAPIES WHICH ARE SORT OF USELESS AND NOT BENEFICIAL. SO I THINK THE KEY QUESTION IN THIS CONFERENCE IS ACTUALLY FROM A PARENT'S POINT OF VIEW, BEING A PARENT MYSELF, IS I WANT TO KNOW WHAT THERAPIES ARE USELESS? WHAT THERAPIES ARE USELESS FOR ME OR MY CHILD? BECAUSE THAT IS MOST IMPORTANT. WE NEED TO SEPARATE THE USELESS ONES FIRST. I MEAN, TO THE PARENT, I THINK THE CLASSICAL PROBLEM RIGHT NOW IS, THEY ARE FACED WITH ALL THIS INFORMATION WHICH IS, THEY GET THESE BITS ON THE INTERNET THAT SAY THIS GROUP IS INTERESTED IN THIS. BUT THEY DON'T KNOW WHETHER THIS IS SCIENTIFIC -- AND WE KNOW IN THE TRENCHES WE KNOW IT USELESS. TERRY KNOWS CERTAIN THINGS ARE USELESS BUT TERRY DOESN'T BROADCAST IT. AND YOU KNOW, WE DON'T BROADCAST OUR NEGATIVE INFORMATION. >> I THINK THAT HAS BEEN DRIVING A LOT OF THE MEETINGS IS THE PARENTS -- >> AND MY FINAL POINT IS BECAUSE OF THE USHAPED CURVE, I THINK IT BECOMES IMPORTANT WE DO NEED TO HAVE RIGOR. WE DO NEED TO RANDOMIZE AND DO NEED TO KNOW WHICH OF THE THERAPIES -- >> WHICH WORK FOR WHICH CHILDREN. >> MORE IMPORTANTLY WHICH DON'T WORK. AND FOR LIKE CLASSICAL NEWBORN INFANT, THERE ARE CERTAIN STIMULATION, YOU CAN OVER STIMULATE AND DRIVE THEBA TOBE HAVE COMP PENS TORY VIGOROUS RESPONSES AND ACTUALLY MAKE THEM WORSE. AND THIS IS IMPORTANT FOR US BEFORE WE EMBARK ON THE OVER STIMULATION AND THINGS LIKE THAT. SO I THINK MY PLEA IS, I THINK WE DO NEED TO HAVE SCIENTIFIC RIGOR AND WE DO NEED TO RANDOMIZE. WE NEED TO HAVE SOME SORT OF STANDARDIZATION TO SHOW WHETHER OR NOT THINGS WORK OR DO NOT WORK. >> AND I THINK CP IS A CLASSIC -- BECAUSE OF THE PARENTS INVOLVEMENT, AND BLESS THE PARENTS FOR WANTING TO BE THAT INVOLVED. HETEROGENEITY OF IT. THE MARKETERS OUT THERE. CP IS THE CLASSIC EXAMPLE OF THAT VERY DISCUSSION. ABSOLUTELY. FINAL POINT. >> TWO VERY QUICK COMMENTS. FIRST IS, I REALLY ENJOYED THIS TALK, THIS SESSION. AND I ACTUALLY FELT THAT THERE IS AN ATTEMPT BEING MADE TO CLASSIFY QUANTIFY, LOOK WHAT THE IS WORKING. THE CHART CAME UP A COUPLE OF TIMES AND WE ARE REALLY TRYING TO DO IT AND MANIFEST THE BIGGER SCIENCE IN TERMS OF WHAT WORKS. I'M NOT GETTING INTO THE LINGUISTIC THING BUT WE ARE DEALING WITH THE BRAIN THAT OPERATES A BODY. AND THERE IS DIFFERENT LANGUAGE FOR BOTH OF THOSE AND TO UNDERSTAND HOW TOUGH THAT IS, IS TO ALSO LOOK AT TECHNOLOGY WHICH DOES WORK LIKE THE BRAIN AND THE BODY AND GOOD CODERS DON'T UNDERSTAND THE USER EXPERIENCE. AND PEOPLE WHO UNDERSTAND HOW TO USE SOMETHING IN A GREAT USER EXPERIENCE, DON'T KNOW HOW TO CODE. SO BRINGING THESE TWO DISCIPLINES TOGETHER IS REALLY IMPORTANT AND I FEEL A LOT OF PROGRESS. THE OTHER POINT I WANT TO MAKE IS THAT AS THIS IS A MEETING TRYING TO UNDERSTAND A STRATEGIC DIRECTION, IS THAT WHAT CAME OUT OF A LOT OF WHAT YOU'RE TALKING ABOUT ARE DELIVERABLE PRODUCTS THAT ARE EXCITING AND INTERESTING, AND THAT ARE ECONOMICALLY NOT FEASIBLE BECAUSE THEY ARE HARD TO DO FOR PEOPLE AND YOU NEED TO BUILD THAT. 2% OF THE TWO BILLION DOLLARS BEING SPENT HERE MUST GO TO SBARs AND STTRs AND I HAVE BEEN A BENFICIARY OF THAT. I KNOW MANY PEOPLE WHO HAVE DONE GREAT WORK THERE. WHAT IS BEING BUILT HERE HAS INNOVATION, SCIENTIFIC UNDERPINNING AND IF THIS GROUP GETS TOGETHER AND GETS SOME OF THAT EVIDENCE-BASED STUFF WITH SOME OF THE WORK YOU'RE DOING, THERE IS 40 MILLION DOLLARS OUT THERE AND CP IS AN EXTRAORDINARILY FERTILE AREA FOR SBIR AND STTR. I WOULD ASK PEOPLE TO REALLY THINK ABOUT THAT AS YOU'RE LOOKING AT R01S. >> THE POINT IS A LOT OF RESEARCH BECAUSE THERE IS TECHNOLOGY DRIVEN, WE CAN SUPPORT IT THROUGH THE SMALL BUSINESS INVESTIGATOR INITIATED PROPOSALS AND SO ON. IT IS VERY RIPE FOR THAT. I THINK THIS WAS A GREAT DISCUSSION. I WANT TO THANK OUR PANELIST AND THE AUDIENCE FOR A VERY ENGAGING DISCUSSION. GIVE YOURSELF A BIG HAND. [ APPLAUSE ] WE ARE GOING TO TAKE A BREAK AND THEN JIM WILL MAKE A FEW COMMENTS. AFTER THE BREAK, WE WILL REORGANIZE AND START TO DO SOME OF THE FORWARD THINKING FROM THIS MEETING. >> THANK YOU. THAT WAS TERRIFIC. WONDERFUL MORN. >> THANK YOU. THAT WAS TERRIFIC. WONDERFUL MORNING. THANK YOU, EVERYBODY. SO I HAVE THREE THINGS THAT I WANT TO SAY AT THIS PARTICULAR POINT. ONE HAS TO DO WITH THE BREAKOUTS AND OUR SCHEDULE GOING FORWARD. THE FIRST THING IS, I WANT TOLY MIND YOU ALL IF YOU NEED A TAXI, TALK TO IDA AND THE FOLKS FROM PLAYEDIAN BACK AT THE TABLE AND GET ON THE LIST. THEY'LL ARRANGE A TAXI FOR YOU IF YOU NEED TO GO TO THE DIFFERENT AIRPORTS THIS AFTERNOON. URGE YOU TO DO THAT. I ALSO WANT TO THANK OUR COLLEAGUES FROM PALADIUM THAT HAVE BEEN SO WONDERFUL AND HELPING LIKE IDA AND -- I'D LIKE TO GIVE THEM A ROUND OF APPLAUSE. [ APPLAUSE ] THEY DID A LO DOT HO HELP ME AND RALPH AND DEBORAH AND PAUL AND THEY ARE BEHIND-THE-SCENES. AND THEY NEED TO BE ACKNOWLEDGED. THE OTHER THING, WE ARE SUPPOSED TO GO TO A BREAK. WE ARE ABOUT 10 OR 15 MINUTES BEHIND SCHEDULE. SO HERE IS WHAT I'D LIKE TO SUGGEST. I'D LIKE TO SUGGEST THAT WE TAKE A 15 MINUTE BREAK AND AT THE END OF THAT 15 MINUTE BREAK, WE GO TO OUR BREAKOUT ROOMS AND SO, THE BREAKOUT ROOMS ARE THE FOLLOWING. IF YOU'RE INTERESTED IN TALKING ABOUT THE RECOMMENDATIONS THAT CAME FROM SESSION ONE AND ALL OF THE SPEAKERS FOR SESSION ONE, SHOULD GO TO ROOM A WHICH IS ACROSS THE OTHER SIDE OF THE LOBBY. ANYBODY THAT IS INTERESTED IN SESSION TWO SHOULD GO TO ROOM B, AND THAT IS ALSO ON THE OTHER SIDE OF THE LOBBY. THE SESSION 3 SPEAKERS AND DISCUSSANTS AND ANYBODY INTERESTED IN THAT SHOULD STAY IN THIS SIDE OF THE ROOM AND SESSION 4 FOLKS AND ANYBODY WANTS TO TALK ABOUT THOSE RECOMMENDATIONS, GO TO THE LEFT SIDE OF THE ROOM. SO, WHAT WE ARE LOOKING FOR IN THIS PARTICULAR PIECE OF THE ACTIVITY, THIS IS THE REAL TAKEHOME PIECE. THIS IS THE THING THAT HAS LEGS AND HAS TRACTION FOR US AT NINETY FIVE. WHAT WE WANT TO DO IN THE COURSE OF THESE BREAKOUTS IS FOR YOU ALL TO COME UP WITH A SET OF RECOMMENDATIONS FROM THE SCIENCE THAT WAS PRESENTED IN EACH ONE OF THE SESSIONS. TWO SPECIFIC RECOMMENDATIONS AT MOST 3 OF THE THINGS THAT ARE THE LARGEST RESEARCH GAPS, THE LARGEST IMPEDIMENTS AND THE THINGS THAT WOULD HAVE THE MOST IMPACT IF THEY WERE SOLVED. THAT IS ITEM NUMBER 1. SO WE WANT ONE SLIDE WITH THOSE TWO OR THREE POINTS LISTED ON IT THAT WILL SHOW. THE SECOND THING THAT WE WANT IS A STRATEGY OVER THE SHORT-TERM, MIDTERM AND THE LONG TERM TO TRY AND RESOLVE THOSE PARTICULAR GAPS IN THOSE PARTICULAR ISSUES. KEEP IT SHORT, KEEP IT BRIEF. BUT BE VERY IMPACTFUL. THINK ABOUT THE THINGS THAT YOU NEED TO REALLY MOVE THE FIELD FORWARD. SO WHEN WE DO THE REPORT OUT AT 1:00, EACH GROUP, AND THERE WILL BE A SPEAKER FROM EACH ONE OF THOSE GROUPS THAT SHOWS THE SLIDES AND GOES OVER THE POINTS VERY BRIEFLY AND WE'LL OPEN IT UP FOR DISCUSSION AFTER EACH ONE OF THOSE AND THAT WILL KIND OF BE THE WRAP UP FOR THE ENTIRE MEETING. SO, LET'S TAKE ABOUT A 15 MINUTE BREAK. BE AT YOUR BREAKOUT ROOMS AROUND 11ISH OR SO. A LITTLE BIT BEFORE WOULD BE GOOD AND WE'LL GO FROM THERE. >>> LET'S GO AHEAD AND GET STARTED SO WE CAN STAY ON TIME. I NEED TO MAKE EVERYBODY AWARE OF ONE SMALL LOGISTICAL ISSUE. I DON'T KNOW HOW MANY OF YOU ARE TAKING METRO GOING TO THE AIRPORT. BUT I JUST HEARD THAT THERE WAS A FIRE ON ONE OF THE LINES. IT DOESN'T APPEAR TO BE THE ONE THAT IS GOING TO THE AIRPORT OR THE TWO THAT ARE GOING TO THE AIRPORT. YOU HAVE TO TAKE RED FROM HERE TO YELLOW. BUT IT MIGHT IMPACT YOUR COMMUTE TIME SO BE AWARE OF THAT. KEEP IT IN THE BACK OF YOUR HYPED JUST IN CASE. SO, HOPEFULLY THAT WON'T BE TOO MUCH OF AN ISSUE FOR ANYBODY. SO, OKAY, LET'S GO AHEAD AND START THE BREAKOUT REPORTS AND AGAIN, THE WHOLE IDEA HERE IS TO GENERATE THE RECOMMENDATIONS FROM THE SCIENCE THAT WE TALKED ABOUT FOR THE LAST DAY AND A HALF AND HOW WE CAN MELIORATE SOME OF THE GAPS IN THE SCIENCE THAT HAS BEEN IDENTIFIED. SO WE'LL GO AHEAD AND START WITH -- TALKIN G ABOUT THE OUTPUT FROM THE SESSION 1 FOLKS. >> HI. I'M FROM HOPKINS. SO I'M GOING TO SUMMARIZE WHAT WE DISCUSSED DURING THE FIRST SESSION. WE HAVE DISTILLED IT DOWN TO JUST A COUPLE OF POINTS BECAUSE WE THINK IT PRETTY MUCH EN COMPASSES MOST OF WHAT CAME UP. SO ONE OF THE BIGGEST KNOWLEDGE GAPS THAT WE FELT RELATED TO ANIMAL MODELS AND USING THAT FOR TRANSLATION IS LEARNING ABOUT CP RELEVANT CIRCUITRY, PRETTY MUCH EVERYTHING FROM THE CORTEX TO THE MUSCLE WITH SPECIAL ATTENTION TO THE SPINAL CORD TO MUSCLE CIRCUIT, WHICH REALLY HAS NOT BEEN STUDIED WELL IN ANIMAL MODELS BEFORE. AND THE OTHER GAP WHICH WE FELT WAS PRETTY SIGNIFICANT IS LOOKING AT THE DISEASE PHASES ESPECIALLY INVESTIGATION OF THE PATHOPHYSIOLOGY INVOLVED IN THE CHRONIC PHASE. AND THIS IS TO LOOK AT IT AS A CONTINUUM FROM THE ACUTE TO THE CHRONIC WITH A FOCUS ON THE CHRONIC PHASE. SO, THE STRATEGIES THAT WOULD HELP TO ADDRESS THESE GAPS ARE THE SHORT-TERM STRATEGIES WOULD BE TO HAVE COMMON DATA ELEMENTS FROM MULTIPLE ANIMAL MODELS AND BOTH GENETIC AND ENVIRONMENTAL MODELS AND COMPILE THIS AND WORK ON THIS TOGETHER. THAT WOULD BE A SHORT-TERM GOAL. A MIDTERM GOAL WOULD BE THE NEXT STEP TO BE EVALUATE DIFFERENT KINDS OF ANIMAL MODELS BECAUSE DIFFERENT ANIMAL MODELS MAY BE MORE RELEVANT FOR CERTAIN MECHANISTIC ASPECTS OF CP AND TO USE ALL OF THEM TO UNDERSTAND THE CHRONIC PHASE BETTER AND TAKING THIS ALL THE WAY FROM USING MAYBE SPECIFIC ANIMAL MODELS FOR LEARNING ABOUT PLACENTA VERSUS SOME FOR UNDERSTANDING THE CIRCUITRY BETTER. AND TO USE THESE TO THE NEXT OR FINAL STEP WOULD BE TO USE THIS INFORMATION TO DOUBLE UP THERAPEUTICS AND TO BASE THIS ON THE GOALS ON WHAT WE LEARNED FROM STEP ONE AND STEP TWO. AND THE DETAILS ARE SUMMARIZED OVER HERE AND THESE ARE THE DETAILED DISCUSSIONS. THANK YOU. >> OFF MIKE [ OFF MIC ] >> THANK YOU. SO, LET'S MOVE ON TO SESSION TWO AND SUNNY JEWEL IS GOING TO PRESENT THE RECOMMENDATIONS FROM SESSION TWO. >> THANK YOU. WE HAD A GREAT DISCUSSION AND I THINK THAT WHAT WE ENDED UP SETTLING ON IS FOR THE KNOWLEDGE GAPS LOOKING AT NEUROPROTECTION, WE WANTED TO KNOW WHAT ARE THE AFFECTS OF COMBINED THERAPIES AND CO-TREATMENTS, AND IF YOU SEQUENTIALLY IMPLEMENT TREATMENTS, HOW DOES THAT AFFECT OUTCOME? SO, THAT INVOLVES LEARNING A LOT MORE ABOUT WINDOWS OF THERAPEUTIC OPPORTUNITY AND MECHANISMS OF REPAIR AND HOW YOU BEST IMPLEMENT DIFFERENT THERAPIES AT DIFFERENT TIMES. A GREAT EXAMPLE WAS GIVING A GROWTH FACTOR WITH STEM CELLS TO IMPROVE THE OUTCOME. SO, WE ALSO FELT THERE WAS A REAL NEED FOR BIOMARKERS THAT WOULD GIVE US LONGITUDINAL MEASURES TO IDENTIFY BOTH SUSCEPTIBILITY AND ALSO DIFFERENTIAL THERAPEUTIC RESPONSE OF THE WE HEARD A LOT ABOUT HOW CP IS NOT A SINGLE DISEASE. THAT THERE IS REAL HETEROGENEITY AMONG CHILDREN WHO HAVE CP. AND SO TO BETTER DEFINE WHO WOULD BEST RESPOND TO WHICH THERAPY. AND THEN, TALKING ABOUT CELL-BASED THERAPIES, THERE WAS A LOT OF INFORMATION THAT WAS STILL NEEDED. SO, THAT INCLUDES LOCATION OF ADMINISTRATION, ADDED GROWTH FACTORS, WHICH GROWTH FACTORS, WHAT IS THE OPTIMAL CELL TYPE? WHAT IS THE BEST TIMING OF ADMINISTRATION? AND LEARNING MORE ABOUT MECHANISMS OF REPAIR. FOR RESEARCH STRATEGIES, FOR OUR SHORT-TERM STRATEGIES WE THOUGHT THAT WE COULD REALLY BUILD UPON KNOWLEDGE THAT REALLY EXISTS ALREADY BUT MAYBE WE HAVEN'T CAPTURED WELL ENOUGH. SO FOR EXAMPLE, AN IVH STUDY WHERE A LOT OF GENETIC INFORMATION WAS COLLECTED AND ALSO OUTCOME DATA SO WE COULD LOOK THAT AND SAY, OUT OF THOSE CHILDREN WHO HAD CP AND WHAT IS THE GENETIC PHENOTYPE OF THAT POPULATION? AND THERE IS OTHER STUDIES LIKE THAT. WE HAVE DONE THE SAME THING WITH PEANUT STUDY. WE HAVE GOT CELL PALLETS WE COULD QUERY. SO, LEVERAGING EXPERTISE ACROSS SPECIALTIES AND FIELDS. WE THOUGHT WOULD BE BENEFICIAL. THERE IS A LOT OF WORK THAT HAS BEEN DONE IN THE ADULT STROKE COMMUNITY THAT WOULD BE BENEFICIAL FOR US NEONATOLOGISTS AND NEONATAL SCIENTISTS TO BENEFIT FROM AND WE DON'T ALWAYS DO THAT VERY EFFECTIVELY. AND THEN TO SHARE DATABASES THAT ALREADY EXIST OR ARE BEING BUILT SO DATABASES THAT CONTAIN BOTH BASIC AND TRANSLATIONAL DATA. FOR MIDTERM STRATEGIES, WE THOUGHT FUNDING ANIMAL STUDIES TO BETTER DEFINE CELL-BASED THERAPY RISKS AND BENEFITS ACROSS DEVELOPMENT, AND AGAIN DEVELOPMENT KEEPS COMING UP BECAUSE IT'S SO IMPORTANT IN CP STUDIES. AND THEN ALSO ALONG WITH THAT, THE NEED FOR APPROPRIATE ANIMAL MODELS. WE THOUGHT HAVING A CELL-BASED THERAPY WORKSHOP THAT DELVED INTO THE DIFFERENT FACTORS YOU HAVE TO THINK ABOUT, INCLUDING ETHICS AND REGULATORY MEASURES AS WELL AS MECHANISTICS WOULD BE GREAT TO GET THE COMMUNITY OF PEOPLE THAT APPROACH CELL-BASED THERAPIES FROM DIFFERENT ANGLES TOGETHER AND THAT WOULD REALLY SYNERGIZE THE GROUP. AND THEN, UTILIZING UPCOMING TRIALS TO MAXIMIZE DATA COLLECTED. SO FOR EXAMPLE, THE HEEL TRIAL WE'LL LOOK AT BIOMARKERS TO BETTER IDENTIFY THE EVOLUTION OF DISEASE AND JUST TO LEARN MORE ABOUT IT. SO THERE IS SEVERAL TRIALS THAT WE COULD UTILIZE TO REALLY MAXIMIZE THE INFORMATION WE GAIN. COLLECTING EPIDEMIOLOGIC DATA AND CORRELATE THAT WITH OUTCOMES BECAUSE I THINK WE STILL DON'T HAVE ENOUGH INFORMATION IN THAT REGARD. AND THEN TO ACCELERATE BENCH TO BEDSIDE STRATEGIES AND PERHAPS DOING THAT BY UTILIZING LARGE ANIMAL MODELS MORE OR USING OR -- AND/OR USING BIOMARKERS TO ACCELERATE THE PROCESS. SO IF YOU HAVE GOOD BIOMARKERS YOU CAN DO PHASE II TRIALS AND GET A LOT MORE INFORMATION ABOUT WHAT MIGHT BE A PROMISING PHASE III TRIAL. AND THEN LONG TERM, WE THOUGHT IT WAS REALLY IMPORTANT TO TRAIN THE NEXT GENERATION OF SCIENTISTS. I THINK WE ARE ALL WORRIED ABOUT WHAT IS GOING TO HAPPEN IN THE FUTURE. AND THEN SUPPORTING MORE PHASE III CLINICAL TRIALS. WE ASKED HOW MUCH WAS TREATMENT VERSUS PROPHYLAXIS WITH CELL-BASED THERAPIES AND WE DIDN'T GET INTO THAT SO MUCH IN THIS DISCUSSION. I THINK THERE IS SO MUCH BASIC INFORMATION THAT IS STILL NEEDED. I THINK THAT WOULD BE INCLUDED, THOUGH. WE WERE TALKING ABOUT CORD BLOOD TRAPS FUSIONS. >> DID YOU GET INTO ANY DEPTH OF THE TYPES OF EPIDEMIOLOGIC DATA? >> WE HAD A FAIR AMOUNT OF DISCUSSION ABOUT THAT. BUT, NOTHING SPECIFIC THAT I CAN SHARE. GO AHEAD. >> I WANT TO ADD ONE OF THE THINGS WE STRESSED WAS WITH THE COLLECTION OF GENETIC DATA ON ALL SUBJECTS IN STUDIES THAT IT WOULD BE SO CRITICAL TO HAVE VERY EXPLICIT PHENOTYPIC DATA THAT GOES ALONG WITH ALL OF THOSE AT THE SAME TIME. SO WE COULD MAKE SENSE OUT OF IT. >> YES, I THINK COLLECTING THINGS LIKE, WHAT TREATMENTS CHILDREN ARE GETTING AND WHAT THE OUTCOMES ARE AND DETAILS ABOUT BIRTH SITUATION. SO THERE IS A LOT OF DEMOGRAPHIC AND ALSO TREATMENT DATA THAT IS REQUIRED. >> ANY OTHER QUESTIONS? THANK YOU. SO THE THIRD GROUP TO REPORT OUT IS ALLEN SONG AND CHRIS. ARE YOU HELPING? >> THANK YOU. SO THE IMAGING GROUP HAD A HEATED DISCUSSION. SO I THINK WE HAD A LIST OF ALL THE THINGS WE WISHED WE WOULD HAVE AT THIS POINT BUT WE ALSO TRY TO SAY WHAT WE CAN DEVELOP AS A GROUP IN THE FUTURE. SO, AGAIN AS YOU CAN SEE, THESE ARE THE THINGS THAT ARE NEEDED THAT WOULD BE REPRESENTING OUR KNOWLEDGE GAPS. I'M TRYING TO DO A SUMMARY TO TRY TO EXTRACT THREE KEY POINTS FROM ALL OF THESE IMPORTANT THINGS THAT WE TALKED ABOUT. I THINK FIRST WE NEED A CREDIBLE IMAGING -- I ALSO HAVE TO APOLOGIZE THAT MI IS MEANT TO BE IMAGING. NOT THE ONLY IMAGING MODALITY WE TALKED ABOUT. WHAT WE WANT IMAGING TO BE, THE FIRST THING WE WANT IS A CREDIBLE MICROCOPPIC IMAGING BIOMARKER TO DETECT THE DISEASE ONSET AND ALSO ALLOW TO UNDERSTAND THE MECHANISMS OF THE TREATMENT, FOR EXAMPLE IF YOU GO TO STEM CELLS THERAPY YOU WANT TO SEE WHAT IS REPAIR OR WHAT IS DUE TO PLASTICITY. THESE ARE IMPORTANT THINGS TO NOTE. AND THE SECOND POINT IS THAT WE NEED TO REACH CELLULAR AND MOLECULAR RESOLUTION TO UNDERSTAND HOW THE NEURONAL FUNCTIONS ARE IMPAIRED IN THE DISEASE. AND THAT INCLUDES A MYRIAD OF ANALYSIS TOOLS, MULTIDIMENSIONAL ANALYSIS COMBINING BEHAVIORAL MEASURES AND CLINICAL OUTCOME TO HAVE A PHENOTYPICAL UNDERSTANDING THAT MIGHT ALLOW US TO CLASSIFY DIFFERENT SUBTYPES OF CP AND THEN ALLOW US TO DISGUISE STRATEGIES TO TREAT THEM. AND I THINK THE LAST IMPORTANT POINT IS TO DEVELOP A HOLISTIC IMAGING APPROACH TO UNDERSTAND THE WHOLE MOTOR SYSTEM. NOT JUST TO LOOK AT THE BRAIN. NOT JUST TO LOOK AT CEREBELLUM. -- IT IS A BULLET HERE BECAUSE ONE ADVOCATE REALLY WANTED TO STUDY CEREBELLUM AND WE ALL AGREE. SO AND ALSO NEUROMUSCULAR SYSTEMS AS A WHOLE. SO I THINK WITH THESE THINGS, WE CAN DO A LOT MORE USING IMAGING. SO HAVING SAID ALL OF THE GAPS, I'M GOING TO MOVE ON TO THE APPROACHES OR STRATEGIES TO ADDRESS THESE GAPS. SO FOR THE IMAGING BIOMARKER, I THINK ESSENTIAL RELIANCE IS ON IMAGING TECHNOLOGY. IF WE CAN DEVELOP TECHNOLOGIES THAT CAN EXTRACT INFORMATION FROM MAXIMAL STANDPOINTS, WE CAN DO A LOT MORE SO THAT INCLUDES SPEED ACQUISITION, DECREASE OF IMAGING NOISE, INCLUDING PATIENT COMFORT. GET TO A CELLULAR MOLECULAR LEVELS. ALL OF THESE ARE RELYING ON TECHNOLOGY ADVANCEMENT. WE SHOULD DO THAT TO ALLOW US TO ESTABLISH CREDIBLE IMAGING BIOMARKER. AND AGAIN, SECOND POINT IS ON THE SO-CALLED WHOLE SYSTEM IMAGING AND THAT APPLIES NOT ONLY JUST TO SAY WITHIN THE HUMAN BODY WE GO FROM BRAIN, CEREBELLUM TO NEUROMUSCULAR SYSTEMS AND ALSO LOOK AT PERCENT IMAGING FOR EXAMPLE, IN THAT SOMETIMES INFORMATION FROM PERCENT CAN GUIDE US TO SEE WHETHER WE SHOULD START IMAGING AS EARLY AS FETAL STAGES. SO THESE ARE AGAIN HOLISTIC IMAGING BUT NOT NECESSARILY WITHIN THE HUMOR WITHIN THE BODY AFTER WE ARE BORN BUT DOING IT LONGITUDINALLY AS WELL ON THE WHOLE TIME COURSE AND THAT ALSO INCLUDES IMPROVED COMMUNICATION AMONG DIFFERENT DISCIPLINES OF PHYSICIANS, ADVOCATES AND PARENTS. SO, NEUROLOGISTS CAN ACTUALLY GET-TOGETHER TO STUDY THE LATEST ADVANCES IN NEUROIMAGING, WE CAN ACTUALLY GET TO THE DISEASE MECHANISM MUCH BETTER THAN IF WE DO IT BY OURSELVES. THE FINAL STRATEGY IS TO ALLOW NEUROIMAGING TO BE APPLIED MORE WIDELY AND MORE ACCESSIBLE TO PEOPLE THAT MAY NOT HAVE THE RESOURCES TO GET ACCESS TO IMAGING MODALITIES. SO THAT WAS THE POINT THAT IS EMPHASIZED BY OUR ADVOCATES IN THE COMMUNITY. CHRIS, YOU HAVE ANYTHING TO ADD? >> SINCE WE TRIED TO BREAK THIS DOWN INTO SHORT-TERM, MIDTERM AND LONG TERM TYPES OF SOLUTIONS, HOW WOULD YOU PUT TEMPORAL RELATIONSHIPS TO THESE? >> SO, SHORT-TERM SOLUTION I THINK HOLISTIC WHOLE BODY IMAGING -- BECAUSE WE HAVE EXCELLENCE IN NEUROIMAGING AND NEUROMUSCULAR SKELETAL IMAGING. SOME PEOPLE IN THIS GROUP ALREADY ARE DOING MUSCULOSKELETAL IMAGING. WE CAN COMBINE THEM IN VERY SHORT-TERM. THE LONG-TERM WILL BE GETTING TO THE CELLULAR, MOLECULAR LEVELS. I THINK THAT WOULD TAKE SOME TIME FOR US TO USE NONINVASIVE IMAGING TOOLS TO LOOK AT HUMAN BODY, FOR EXAMPLE, AT THAT LEVEL N ANIMAL STUDIES WE CAN GET TO THAT ALREADY. I'M TALKING ABOUT MORE ON THE HUMAN SIDE. THE MIDTERM WILL BE TO COMBINE SOME OF THE IMAGING MODALITIES THAT WE ACTUALLY DON'T USE VERY OFTEN, FOR EXAMPLE, I GUESS I PERSONALLY ONLY DO MRI. I KNOW THERE ARE IMAGING ADVANCES USING MULTIMODAL APPROACH LIKE TMS OR TDCS, THESE CAN BE COMBINED IN CONJUNCTION WITH FUNCTIONAL OUTCOME MEASURES, DYNAMIC MEASURES AT MULTIPLE TIME POINTS FOR US TO COME UP WITH UNDERSTANDING OF DISEASE AND MECHANISMS AND TRAJECTORY OF THE DISEASE PROGRESSION AND THEN RESPONSE TO THE TREATMENT. I THINK THOSE ARE THINGS TO DO IN THE NEXT 10 YEARS. SO THAT WOULD BE MY MIDTERM. BUT IN THE END, I FEEL LIKE EVERYTHING HAS TO COME TOGETHER. IT TAKES A WHOLE VILLAGE AND ALL OF US TO DO IT WELL. >> SO I JUST WANT -- A GREAT JOB OF SUMMARIZING OUR GROUP. REALLY A HEATED DISCUSSION. >> ONLY 5 MINUTES TO LOOK AT IT. >> GREAT JOB. I WANT TO BRING THE PERSPECTIVE OF THE HUMAN ENTERPRISE MENTIONED. I THINK IF MAJORITY OF THE -- LARGE CHUNK OF THOSE COME FROM DEVELOPMENTAL ORIGINS, OR DEVELOPMENTAL TIME SPAN, WE HAVE 270 DAYS FOR SOME TIME DURING THAT TIME OR BEFORE THAT DAMAGE TO TAKE PLACE. SO THEREFORE, WHEN WE WANT TO EXTEND -- IF YOU WANT TO EXTEND THE FETAL IMAGING AS A MARKER AS SOMETHING IS WRONG WITH THE BABY AND THE FETUS AND WANT TO TREAT SOMETHING, SO THERE HAS TO BE A MARKER AND THAT MARKER WHAT WE ARE TRYING TO SAY IF WE CAN CONNECT THE HUMAN PLACENTAL RESEARCHERS DOING HUMAN IMAGING, WHICH ALREADY NOW STIMULATED AT NICHD WITH THE NEUROSCIENTISTS AND OTHER IMAGING EXPERTS, THEN PROBABLY OUTPATIENT ADAPTED IN THE CLINIC HAPPENS TO LOOK OR EXAMINE A PREGNANT WOMAN AND SAY THERE IS SOMETHING WRONG IN THIS FUNCTION, EXCHANGE FUNCTION. NOT SIMPLY BLOOD FLOW. THIS IS AN ACCIDENT JEN EXCHANGE PROBLEM. A NUTRIENT EXIT. THAT MAY BE THE TIME FOR THE NEUROIMAGING FOLKS TO COME IN AND GIVE MORE SOPHISTICATED ANALYSIS OF THE BRAIN AND IF IS THERE A TIME TO INTERVENE, THAT MAY BE THE BEST TIME TO DO IT. OTHERWISE JUST TAKING AN IMAGE ON ONE DAY OF THE FETUS NEXT DAY IF THERE IS DAMAGE, YOU ALREADY MISSED THE POINT AND SO, THIS IS HOW WE WERE THINKING ABOUT AND DISCUSSING THAT. >> THANK YOU. >> A LOT OF THINGS UNDER BIOMARKERS AND IT IS PROBABLY BURIED IN THERE SOMEWHERE. ONE THING I SUGGEST IS HAVING -- IT WOULD BE GREAT IF WE HAD A NEUROIMAGING-BASED BIOMARKER FOR PEOPLE WHO RESPOND AND DON'T RESPOND AND THE STATE OF NEUROPLASTTISSITY. FUNCTIONAL CONNECTIVITY. WHATEVER THINGS AND WE MIGHT NOT BE THERE YET BUT IT SOMEBODY SOMETHING WE SHOULD BE ABLE TO DO IN THE FUTURE MAINLY BECAUSE OF THE ADVANTAGE OF HAVING A NONINVASIVE WAY OF LOOKING AT IT AND THEN THAT WAY WE DON'T HAVE THE SAME PROBLEMS OF HETEROGENOUS GROUPS AND STARTING WITH PEOPLE WHO ARE AT THE SAME LEVEL IN THE BRAIN. >> GREAT. THAT SORT OF IMPLIED IN MY MULTIDIMENSIONAL ANALYSIS TRYING TO CLASSIFY GROUPS IN CP USING NEUROIMAGING BIOMARKERS. >> WE HAVEN'T SAID THE WORDS YET BUT METABOLOMICS IS KEY AND THAT IS A WAY YOU COULD LOOK AT THE METABOLOMIC OR FINGERPRINT IF YOU WILL, IN RESPONSE TO THERAPEUTIC HYPOTHERMIA AND GO ON AND LOOK AT IT EVER AWARDS TO SEE WHO IS A RESPONDER AND WHO IS NOT. >> YES. GREAT. >> SO GREAT JOB. VERY BROAD. I LIKE TO MAKE A SUGGESTION OF BEING SLIGHTLY MORE FOCUSED AND NOT ONLY LOOKING AT THE BRAIN WHICH YOU CAN DO VERY WELL AS I SEEN YESTERDAY BUT ALSO LOOK AT WHAT MAY HAPPEN IN THE PERIPHERY A BIT MORE. SO LOAD CELLS WE PUT IN MR THAT ARE MR COMPATIBLE TO SEE WHAT THE BRAIN DOES UNDER VERY CONTROLLED SITUATIONS AND I THINK IT WOULD BE MORE SPECIFIC. I KNOW YOU TRIED TO INCLUDE EVERYTHING BUT I THINK THERE IS MAYBE LOWER HANGING FRUIT SO IF BEING MORE SPECIFIC AND USE YOUR CONSIDERABLE POWER IN THIS AREA TO LOOK AT PARTICULAR CIRCUITS AND PARTICULAR PATHWAYS AND WHATEVER AND PULL THINGS TOGETHER. SO NOT LOOK AT THE BRAIN IN ISOLATION BUT LOOK AT THE BRAIN DURING BEHAVIOR THAT IS VERY WELL QUANTIFIED. >> YES. GREAT. SO THE GROUP FOR BAKE OUT WILL BE PRESENTED BY BERNADETTE. >> THANK YOU. SO, GROUP 4 WAS PROMOTING NEUROPLASTICITY AND ADAPTATION SO IT REALLY GETS INTO TRANSLATIONAL ASPECTS. WE HAD A VIBRANT DISCUSSION OF 35 PEOPLE AND SO I'M SEEING NOW WITHIN THE PREVIOUS THREE GROUPS THERE ARE A LOT OF COMMON THEMES THAT ARE REALLY STRONG. SO WE WILL START A LITTLE GENERAL AND GET MORE SPECIFIC IN TERMS OF WHAT WE IDENTIFIED. WE IDENTIFIED THE MOST IMPORTANT GAPS HERE AS FIRST IDENTIFYING THE MECHANISTIC BASIS OF GENETIC, STRUCTURAL AND FUNCTIONAL FACTORS THAT DRIVE IMPAIRMENT AND RECOVERY OF FUNCTION IN CEREBRAL PALSY OF THE THE SECOND WAS CREATE AN INTERDISCIPLINARY COLLABORATIONS TO PROMOTE RESEARCH-CLINICAL-TECHNOLOGY-CON SUMER INTERFACES FOR RAPID DEVELOPMENT OF THERAPIES. THIRD WAS TO ADOPT DYNAMIC PRECISION MEDICINE STRATEGIES IN CP ACROSS THE LIFESPAN, A LARGE THEME, USING LARGE DATA REPOSITORIES OF CLINICAL AND BIOLOGICAL DATA WITH RESEARCH FINDINGS. SO FOR EXAMPLE, CLASSIFICATIONS AND QUANTITATIVE ASSESSMENTS. AND THE FOURTH WAS TO TRANSLATE THERAPIES DEVELOPMENT THROUGH RESEARCH INTO LOCAL AND GLOBAL CLINICAL PRACTICE AND TO THE LAY PUBLIC AND FAMILIES. AGAIN BROAD BUT MORE SPECIFICALLY, SHORT-TERM MIDTERM AND LONG TERM RESPONSES TO THOSE IDENTIFIED GAPS. THE SHORT-TERM IS TO EXPAND CP SPECIFIC STUDY SECTIONS THAT INCLUDE PEDIATRIC AND CLINICAL REHABILITATION EXPERTS ALONG WITH THE EXISTING ADULT AND BASIC SCIENCE EXPERTS. MIDTERM THAT WE CAME UP WITH WAS TO SPONSOR WORKSHOPS TO IDENTIFY SPECIFIC AREAS COMMON ACROSS DISCIPLINES TO DESIGN NEW APPROACHES RAPIDLY. SO, EARLY MOTOR LEARNING AND REPAIR INTERVENTIONS, GENETIC BASIS RESPONSE TO TREATMENT, NEURAL SUBSTRATES OF IMPAIRMENT, AND THEN ALSO TO INCENTIVIZE TRANSLATION THROUGH DIFFERENT TYPES OF RFAs THAT ARE SPECIFIC TO CP. SO U, P, NON-BUSINESS TECHNOLOGY, EDUCATION TRANSLATION AND TRAINING. AND THE LONG TERM WAS TO DEVELOP LARGE COMMUNICATION NETWORKS AND REPOSITORIES WHICH REQUIRES COMBINATION OF PUBLIC AND PRIVATE FUNDING. ANY QUESTIONS OR COMMENTS FROM OUR GROUP? >> GO AHEAD. >> WELL WITH 35 PEOPLE, THAT'S PRETTY WILD WHAT YOU DID IN GROUP 4 AND SHOWS CONNECTIONS TO THE THE EARLIER GROUPS. THE ONLY THING I CHALLENGE OR LIKE TO HEAR YOUR THINKING, YOU'RE THE ONLY GROUP THAT BROUGHT UP THE NEED FOR IMPLEMENTATION SCIENCE, WHICH IS ON THE TRANSLATIONAL CONTINUUM. IT'S A FORMAL BRANCH OF SCIENCE. IT'S VERY NEW. BUT YOU DO RANDOMIZED TRIALS, FOR EXAMPLE, OF WHICH TECHNIQUES LEAD TO HIGH FIDELITY, EQUITABLE, RAPID, AND EFFECTIVE ADOPTION OF THINGS AFTER THEY HAVE BEEN REPEATEDLY PROVEN AND ARE JUDGED TO BE READY TO BE ADOPTED IN THE COMMUNITY. I WONDERED WHY THEN IN YOUR STRATEGIES YOU PUT, AS LONG TERM DEVELOPING THE COMMUNICATION NETWORKS AND REPOSITORIES. WHY SHOULDN'T WE START THAT NOW SO AS MORE COMES IN FROM SOME OF THE ONGOING NEUROPROTECTIVE AND OTHER TRIALS, WE ARE GOOD TO GO? WE HAVE ALREADY GOT NINETY FIVE SAYS 17-YEAR GAP. YOU LOOK AT THE ANALYSIS IT IS OFTEN 25-35 YEARS WITH VERY INCOMPLETE PENETRANTS OF FINDINGS IN COMMUNITY PRACTICE. SO I JUST WONDER WHY THAT IS LONG TERM. >> I THINK THAT THROUGH OUR DISCUSSIONS, I DON'T THINK WE PRECLUDED IN ANY WAY A MORE SHORT-TERM ADOPTION OF THAT. I THINK WE WERE THINKING MORE ALONG THE LINES AND THOSE WHO ARE IN THAT SECTION CAN ALSO BACK THIS UP, IN TERMS OF WHAT IT WOULD TAKE TO DEVELOP THAT LARGE TYPE OF DATABASE. SO THAT WAS THE LONG TERM THINKING IN TERMS OF PRACTICALITY HOW COULD WE DO THAT AND PULL IT TOGETHER. BUT I AGREE WITH YOU AND I THINK I REPRESENT MANY IN THAT GROUP TO SAY ADOPTING THAT IN EARLY FASHION MIGHT BE MORE EFFICACIOUS. >> I THINK WE CAN DO THE LONG TERM THING NOW. >> YOU'RE ON RECORD. AND YOU'RE BEING RECORDED. ANY OTHER COMMENTS FROM THOSE IN OUR GROUP? ANYTHING WE DIDN'TITERATE BETTER? >> THANK YOU. SO THANK YOU TO ALL OF THOSE RECOMMENDATIONS. THEY ARE TERRIFIC. I WANT TO THANK YOU ALL FOR GENERATING SUCH WONDERFUL LIST OF IDEAS THAT WE CAN UTILIZE GOING FORWARD. I WANT TO COME BACK TO NUMBER 1 HERE ON THIS LIST. BECAUSE I THINK IT IS SOMETHING THAT CUTS ACROSS EVERYTHING THAT WE HAVE TALKED ABOUT FOR THE LAST DAY AND A HALF. I MEAN THE IDEA THAT THERE NEEDS TO BE SOME MECHANISTIC BASIS FOR GENETIC AND STRUCTURAL AND FUNCTIONAL FACTORS IS SOMETHING THAT I THINK MANY OF US TOUCHED ON IN THE COURSE OF THE CONVERSATIONS THAT WE HAD. AND THIS SEEMS TO BE A THEME THAT REQUIRES ADDITIONAL EDUCATION, INFORMATION AND INVESTIGATION FROM MANY OF US IN THIS ROOM AND MANY FOLKS THAT ARE NOT IN THE ROOM. SO, I REALLY APPLAUD GROUP 4 FOR PUTTING THIS SO SUCCINCTLY AND CLEARLY. SO, WITH THAT SAID, I THINK THAT WE ARE RAPIDLY APPROACHING THE END OF THE WORKSHOP. I WANT TO THE THROW IT OPEN FOR ANY OTHER GENERAL CONVERSATION OR DISCUSSION THAT ANYBODY MIGHT WANT TO BRING UP. IS THIS ANYTHING THAT IS ON YOUR MIND THAT HASN'T BEEN SAID OVER THE COURSE OF THE LAST DAY AND A HALF THAT MAYBE SHOULD BE SAID AT LEAST AT THIS PARTICULAR JUNGURE? HEARING NONE, AND NOBODY MOVING TOWARDS THE MICROPHONE, LET ME GO AHEAD AND INTRODUCE THE DIRECTOR OF THE NINDS, WALTER KOROSHETZ AND WALTER IS KIND ENOUGH TO TAKE TIME OUT OF HIS SCHEDULE THE LAST COUPLE OF DAYS TO BE WITH US AND HE IS GOING TO OFFER SOME CLOSING THOUGHTS. WALTER? >> IT'S A PLEASURE TO BE HERE. I THINK TRUTH OF THE MATTER IS, EVERYBODY AT NINETY FIVE IS WORKING TO TRY TO GET GROUPS LIKE THIS TO MAKE PROGRESS FASTER, MAKE LARGER PROGRESS. SO TO SEE THE GROUP COME IN LIKE THIS WITH THE KIND OF DEDICATION AND HARD WORK YOU PUT IN THE LAST COUPLE OF DAYS, IT'S KIND OF WHY WE GO TO WORK. AND SO THANK YOU FOR COMING IN AND I ALSO WANT TO THANK THE CEREBRAL PALSY FOUNDATION FOR THE COFFEE AND FOOD BECAUSE IT'S HARD TO RUN MEETINGS WITHOUT COFFEE. AND EVERYBODY STAYED AWAKE. I WAS WATCHING. I DIDN'T SEE ANYBODY SLEEPING. THAT WAS GREAT. SO, AND AS JIM SAID AND RALPH WILL ALSO CHIME IN, THAT WE AT NINETY FIVE ARE TRYING TO MOVE THE SCIENCE FORWARD AND WE DON'T KNOW THE ANSWERS AND SO WE REALLY GET A LOT OUT OF THESE KIND OF MEETINGS. THEY HELP US DO OUR PLANNING AT ALL DIFFERENT LEVELS. YOU CAN'T IMAGINE THE NUMBER OF DECISIONS THESE PEOPLE ARE MAKING ON A REGULAR BASIS. SO THIS KIND OF INFORMATION, GETTING INFORMATION AND KNOWING WHERE THE FIELD IS INCREDIBLY IMPORTANT FOR THE FOLKS AND DIRECTOR. SO, THANK YOU AGAIN FOR THAT. I THINK JUST A COUPLE OF COMMENTS. AN APOLOGY FIRST OF ALL TO THE PARENTS OF KIDS WITH CEREBRAL PALSY. WE DON'T HAVE THE ANSWERS THAT WE NEED. AND I MEAN, I THINK EVERYBODY IN THE ROOM FEELS BAD ABOUT IT. AND THE QUESTION IS, HOW TO MOVE FORWARD AND AS I MENTIONED YESTERDAY, I THINK YOU HAVE TO HAVE A DIVERSE PORTFOLIO. YOU WANT A MAGIC BULLET BUT YOU HAVE TO ALSO MAYBE TAKE SHOTS ON GO FOR A MAGIC BULLET BUT THE HISTORY IS THAT THERE ARE VERY FEW MANAGE IIC BULL EIGHTS OUT THERE -- MAGIC BULLETS. PROGRESS IS STEP-BY-STEP AND THEN MAYBE GET TO THE POINT WHERE SOMETHING REALLY BIG HAPPENS. CLEARLY, IN ANY KIND OF PUBLIC HEALTH AND NINETY FIVE IS ABOUT THE PUBLIC HEALTH. THE BIGGEST IMPACT IS AT THE PREVENTION STAGE. SO PREVENTING THE EVENTS THAT CAUSE CEREBRAL PALSY WILL HAVE THE GREATEST IMPACT ON PUBLIC HEALTH. IT MAY NOT HELP THE PEOPLE WHO HAVE IT NOW BUT THAT'S CLEARLY THE SOLUTION IN THE LONG TERM. SO THE WORK YOU TALKED ABOUT AND THE PROTECTION AND THINGS WE ARE FUNDING, I THINK THERE HAS BEEN PROGRESS IF YOU LOOK AT OUTCOMES IN PREEMIES WITH GREATER NEONATAL CARE. THERE IS A LOT OF PEOPLE LIVING WHO WOULDN'T HAVE BEEN LIVING WITHOUT THOSE KIND OF ADVANCES THAT HAPPENED. AND SOME OF IT ARE FUNDED AT NINETY FIVE AND SOME OF IT IS RELATED TO DOCS LEARNING HOW TO DO BETTER. PREVENTION IS CLEARLY THE KEY THING. THE REHAB PIECE, I WOULD MAKE ONE COMMENT THAT SOMEONE MENTIONED YOU CAN LEARN A LOT FROM THE ADULTS. I'M NOT SURE ABOUT THAT. THE ADULTERY HAB WORLD IS STILL MIRED IN VERY HARD TO MOVE FORWARD IN. SO THE REASON I WAS UP AND DOWN, WE WERE DISCUSSING OUR REHAB PORTFOLIO AND WE BASICALLY COMING TO THE POINT WHERE WE HAVE TO RE-THINK THE WHOLE THING. THE RESEARCH THAT WE FUNDED, PARTICULARLY IN THE STROKE REHAB AREA, IT'S NOT CLEAR THAT IT HAD MAJOR IMPACT. THE QUESTION ABOUT HOW THE BRAIN RECOVERS FROM INJURY IS INCREDIBLY COMPLICATED. AND EVEN IN AN ADULT, IT'S VERY HARD TO UNDERSTAND WHAT THE PROCESS ARE AND HOW TO MANIPULATE THOSE PROCESSES. AND A CHILD YOU HAVE THE ADDED ISSUE THAT THE BRAIN IS DEVELOPING SO YOU ARE LOOKING AT A MOVING TARGET AND SO IT IS DIFFICULT BUT POTENTIALLY MAYBE THE CHILD IS GOING TO HAVE BETTER RESILIENCE ON THAT PATHWAY TO RECOVERY THAN AN ADULT MIGHT HAVE. SO YOU MAY BE IN A BETTER POSITION THAN THE ADULT FOLKS. WITH THAT BEING SAID, I WANT TO MENTION A COUPLE OF THINGS. SO THE POINT IS, THIS IS A HARD PROBLEM. WE HAVE TO REALIZE IT'S A HARD PROBLEM AND THE COMMUNITY THAT IS ASSEMBLED HERE IS THE COMMUNITY THAT IS TAKING THE PROBLEM UNDER THEIR WING AND TRYING TO MOVE IT FORWARD AND SO YOU HAVE TO FEEL THAT SENSE OF COMMUNITY. YOU HAVE TO FEEL PROUD OF WHAT YOU'RE DOING. AND YOU HAVE TO PERSIST AND REALIZE IT'S A HARD PROBLEM. FAILURE IS PART OF THE GAME. AND YOU JUST TO KEEP PUSHING FORWARD TRYING TO BUILD A COMMUNITY IS IMPORTANT, PARTICULARLY TRYING TO GET NEW YOUNG PEOPLE INTO THE FIELD. BECAUSE THOSE ARE OFTENTIMES WHERE A NEW LOOK REALLY CHANGES THE GAME. SO TO PUT EMPHASIS, PARTICULARLY WE HAVE DONE A LOT TO TRY AND GET TRAINING, PARTICULARLY IN THE NEUROSPACE SO, WE HAVE TRAINING PROGRAMS NOW FOR RESIDENTS TO TRY TO GET THEM INTO RESEARCH. WE HAVE A NEW PROGRAM FOR PEDIATRIC NEUROLOGISTS, A NATIONAL PROGRAM THAT ANYBODY CAN APPLY FOR FROM ANY UNIVERSITY. THEY GET CHOSEN AND GET MENTORED NATIONALLY SO AT NINETY FIVE WE CAN'T GO OUT AND SAY WE WANT YOU TO BE A CEREBRAL PALSY RESEARCHER OR A DYSTONIA RESEARCHER. THAT COMES TO US. BUT THE ADVOCACY ORGANIZATIONS THEY CAN DO THAT. YOU CAN REACH INTO THE DEPARTMENTS AND GO TO DONNA'S DID DEPARTMENT AND TALK TO THE RESIDENTS AND TELL THEM HOW CP REACH IS AND PROBABLY HOOK PEOPLE. SO I WOULD ENCOURAGE PEOPLE TO DO THOSE KIND OF OUTREACH INTO THIS YOUNGER POOL. SO I WANT TO JUST CLOSE ON TELLING YOU A COUPLE OF THINGS THAT ARE GOING ON THAT I DON'T THINK ARE GOING TO BE SHORT-TERM ANSWERS BUT YOU NEVER KNOW. AND THAT IS OUTSIDE OF THE CEREBRAL PALSY AREA IS A LOT OF RESEARCH THAT IS PROBABLY GOING TO BE VERY RELEVANT TO THE THINGS THAT YOU TALKED ABOUT TODAY. THE ONE THING I WOULD MENTION IS WHAT IS CALLED THE BRAIN INITIATIVE. SO THAT IS NOW 150 MILLION DOLLAR A YEAR PROJECT AND THE PURPOSE OF THE BRAIN INITIATIVE IS TO DEVELOP TOOLS THAT WILL ALLOW US TO IN TEAR GATE AND MODULATE CIRCUITS IN THE BRAIN AND THE SPINAL CORD. SO, YOU'RE TALKING ABOUT SEIZAL PALSY, THAT'S WHAT YOU WANT TO DO -- CEREBRAL PALSY. WHAT YOU WANT TO KNOW IS WHAT IS WRONG WITH THE CIRCUITS AND HOW CAN YOU MODULATE THEM? AND THERE ARE INSTANCES, DBS FOR PARKINSON'S IS AN EXAMPLE WHERE IT TURNS OUT TO BE A MIRACLE THAT YOU UNDERSTAND WHAT THE CIRCUIT ABNORMALITY IS. YOU INJECT CURRENT AND THE PATIENT'S MOTOR SYMPTOMS GO AWAY. SO IT'S NOT WITHIN -- THERE ARE PRECEDENTS THAT ONE COULD HOLD ON TO. SO THINKING ABOUT IF THOSE TOOLS FOLLOWING THOSE TOOLS, AND APPLYING THEM TO CEREBRAL PALSY, YOU MAY GET THE ABILITY TO LISTEN TO CIRCUIT ACTIVITY WHICH IS AT THE BASE OF THE PROBLEM, AND THEN USE THAT AS YOUR MARKER, BIOMARKER OR THE THING YOU WANT TO NORMALIZE TO GET BETTER FUNCTION IN THE PERSON. THE OTHER ONE WHICH I AM NOT SURE PEOPLE -- HPP. PEOPLE USE THE WORD HPP. WHAT DID THAT MEMBERSHIP? [ OFF MIC ] >> HUMAN PLACENTA PROJECT. THERE IS ANOTHER HUMAN BRAIN PROJECT CALLED THE HUMAN CONNECTOME PROJECT. SO THE CONNECTOME PROJECT IS A REALLY BIG EFFORT ACROSS ALL THE NEUROSCIENCES INSTITUTES TO COLLECT FUNCTIONAL AND STRUCTURAL IMAGING IN PEOPLE ACROSS THE LIFESPAN SO THEY ARE GOING FROM BABIES UP TO 69-YEAR-OLDS AND THE LEVEL OF 1500 PEOPLE. SO THAT PROVIDES YOU WITH NORMATIVE DATABASE THAT YOU CAN THEN, IF YOU USE THE SAME ACQUISITION PARAMETERS THAT THEY USE, YOU CAN COMPARE YOUR RESULTS TO THEIR RESULTS AND REALLY KNOW WHAT IS THE DIFFERENCES AS OPPOSED TO TRYING TO DEVELOP YOUR OWN COHORTS AND THEY ARE ALWAYS TOO SMALL AND YOU FIND DIFFERENCES BY CHANCE BUT YOU DON'T KNOW THAT. SO I WOULD SAY THAT IS ANOTHER OPPORTUNITY TO TAP INTO. WITH REGARD TO MRI SCANNING BECOMING MORE CHEAP, WELL, WE DON'T KNOW IT IS GOING TO WORK BUT WE DID INVEST WITH GE IN DEVELOPING A HEAD-ONLY 3T-MRI SCANNER THAT CAN DO KIDS WITHOUT A PROBLEM. IT'S HEAD-ONLY. WE TRIED TO MAKE IT SO IT WOULDN'T HAVE HELIUM AND THE COST COULD COME DOWN BELOW A MILLION DOLLARS. IT'S CURRENTLY BEING TESTED OUT AT MAYO CLINIC. I'M HOPEFUL THERE WILL BE NEW IMAGING TECHNOLOGIES THAT WILL BE PORTABLE AND ACCESSIBLE. THE BRAIN INITIATIVE THERE IS A WHOLE PROGRAM OF WHAT IS CALLED NEXT PHASE NEUROIMAGING WHICH IS TRYING TO DEVELOP NEW DEVICES, AGAIN SOME OF THESE ARE WEARABLE PET SCAN TYPE DEVICES. SO, THINGS THAT COULD REALLY BE APPLIED TO CHILDREN MAYBE EVEN BETTER THAN ADULTS. SO THE POINT IS THAT THERE IS THIS COMMUNITY HERE AND THEN THERE IS A BIGGER SCIENCE COMMUNITY OUTSIDE. I THINK EVERYBODY IS MARCHING FORWARD AND EVERYBODY HEADS THEIR PROBLEMS BUT THERE ARE DEFINITE BREAKS IN THE CLOUDS WHERE IT LOOKS LIKE SUN COULD COME THROUGH SO I URGE PEOPLE TO JUST PERSIST, PERSIST, PERSIST. THANK YOU VERY MUCH FOR THE MEETING. [ APPLAUSE ] >> AND NOW FOR A FEW CLOSING THOUGHTS FROM NICHD AND RALPH NITKIN. >> SO I ACTUALLY GET TO COME BEFORE YOU AS NOT ONLY REPRESENTING NI WHY. HD BUT ALSO ONE OF THE ORGANIZERS OF THIS MEETING ALONG WITH JIM AND SOME OF OUR COLLEAGUES, AND ALSO AS A PARTICIPANT IN THE MEETING. SO FIRST OF ALL AS FAR ADDS NICHD, WE ARE VERY COMMITTED TO THE GOALS OF THIS MEETING WHERE THE CHILD HEALTH INSTITUTE. WE HAVE THE PREGNANCY BRACH, INTELLECTUAL ABILITIES BRANCH. CHILD DEVELOPMENT BEHAVIOR BRANCH AND THE MEDICAL FOR REHABILITATION. IT PLAYS TO OUR INTEREST AS WELL AS OUR COLLEAGUES AT NINDS. SO I WANT TO REAFFIRM THAT. AND SECOND, AS BEING INVOLVED AS AN ORGANIZER OF THIS MEETING, YOU TRY TO SET UP AN AGENDA AND BRING THE RIGHT PEOPLE AND YOU NEVER REALLY SURE HOW IT WILL WORK OUT AND I THINK JIM AND I WERE VERY EXCITED ABOUT THE TYPE OF DISCUSSION WE HAD, THE BREATH OF TOPICS WE TALKED ABOUT ACROSS THIS ENTIRE MEETING AND YET, IT WAS VERY MUCH CONVERGENT. THERE WAS A TREMENDOUS AMOUNT OF COLLEGIALITY AND YOU ACTUALLY GAVE US A LOT OF VERY USEFUL INFORMATION ABOUT OPPORTUNITIES IN THESE REHABILITATION. SO, I THINK WE ARE HAVE ARE EXCITED ABOUT HOW SUCCESSFUL THIS MEETING WAS. THIS IS NOT JUST A MEETING OF A POINT IN TIME AND THAT'S IT. I THINK IT'S SOMETHING WHERE WE WANT TO INSPIRE YOU TO GO BACK AND KEEP DOING WHAT YOU DO AS FAR FAR AS RESEARCHERS AND ADVOCATES AND SUPPORTERS. I THINK THIS IS OPENING SOMETHING UP. IT'S NOT THE END OF THE DISCUSSION BUT THE BEGINNING OF A DISCUSSION. AND THEN AS A CONSUMER, I JUST REALLY -- IT WAS REALLY INTERESTING TWO DAYS. I VERY MUCH APPRECIATED HEARING IT. VERY USEFUL TO ME AS A PROGRAM OFFICIAL TO HEAR ALL THIS KNOWLEDGE AND ESPECIALLY HEARING YOUR INSIDE PERSPECTIVES FOR THE NEEDS OF THE CADES AND WHAT YOU'RE TRYING TO DO AS A CLINICIAN AND THE FIGHTS YOU'RE HAVING AS FAR AS GETTING YOUR RESEARCH FUNDED -- NEEDS OF THE KIDS -- I WANT TO FINISH UP WITH SOME OF THOSE POINTS. AND IT IS GOOD NEWS AND BAD NEWS. I THINK THAT CP IS ACTUALLY, THERE IS A LOT OF VERY IMPORTANT CLINICAL ISSUES AND NOT ONLY THAT, BUT IT INTERSECTS WITH A LOT OF INTERESTING AND COMPELLING INTELLECTUAL, EXCITING RESEARCH QUESTIONS SO I THINK THAT IS SUCH A SWEET SPOT THAT WE HAVE FOR RESEARCH. IT'S SUCH A GREAT OPPORTUNITY. PARTLY YOU JUST HAVE TO WRITE MORE GRANT APPLICATIONS. WE ARE THERE TO HELP YOU. IT'S A VERY TOUGH TIME. HAVE YOU TOUR PERSISTENT BUT PLEASE TALK TO US. WE ARE GOING TO DO WHAT WE CAN TO KEEP INCENTIVIZING WHAT YOU'RE DOING WELL BUT YOU GOT TO KEEP PLAYING. YOU GO TO THE KEEP PUTTING THOSE IN. GRABBING OTHER COLLEAGUES AND GETTING THEM EXCITED. YOU HAVE TO PUT IN THE APPLICATIONS AND PARTICULARLY GOOD TIME -- LET ME SPEAK AS A REPRESENTATIVE OF THE NATIONAL CENTER FOR MEDICAL REHAB. WE ARE CHARGED WITH FUNCTION WITHIN NICHD AND THE COORDINATING RESEARCH ACROSS NINETY FIVE. OUR COLLEAGUES AT NINDS HAVE BEEN SHARING THE BURDEN. NIH -- IT'S A PRIME-TIME FOR YOU FOLKS AND FOR NEW INVESTIGATORS AS WELL. TAKE VALUE OF THAT. AND SINCE WALTER MADE MORE SOME OPPORTUNITIES, I WANT TO HIGHLIGHT A INFRASTRUCTURE PROGRAM. WE ASKED OR SOLICIT APPLICATIONS OVER THE YEARS FOR CENTERS TO TAKE SOME AREAS, SOME DOMAIN TA IS KEY TO REHABILITATION AND MAKE A CAKE CASE THAT THEY ARE EXPERTS AND IT IS TEACHABLE. AND OVER THE YEARS, WE HAD A PROGRAM OF MAYBE HALF A DOZEN CENTERS OR SO THAT HAS DONE A NICE JOB OF SUPPORTING REHABILITATION AND NINDS AND NIBAB HELPED US IN SUPPORTING THESE CENTERS. AND I WAS THINKING TOO, THE CURRENT EVOLUTION OF THAT PROGRAM, THE SIX CENTERS NOW OUT THERE AND I REALIZE EACH OF THOSE SIX CENTERS REALLY HAS A CONNECTION TOCK WHAT WE ARE DOING IN REHABILITATION. SO, FOR EXAMPLE, WE HAVE ONE CENTER SUPPORTING REGENITIVE MEDICINE, THE IDEA OF USING REHABILITATIVE APPROACHES TO SUPPORT THE CELLULAR AND MOLECULAR BIOLOGY OF BRINGING IN STEM CELLS AND OTHER EXTRACELLULAR MATRIX FACTORS TO SUPPORT REGENERATION. WE HAVE THAT CENTER. WE HAVE ANOTHER CENTER ON STIMULATION AND NEUROMODULATION. THAT ALSO IS VERY RELEVANT TO SOME OF THE DISCUSSION WE HAD. ANOTHER CENTER ON MODELING OF MOVEMENT. THAT IS ALSO RELEVANT. WE HAVE A CENTER ON KLINE CALL TRIAL DESIGN. WE DISCUSSED HOW CP HAS A TREMENDOUS RICHNESS BUT IT'S ALSO A LITTLE BIT OF A RESEARCH ISSUE ABOUT HOW TO YOU GET ACROSS THE IMPORTANCE OF UNDERSTANDING THE HETEROGENEITY AND WHAT IS DRIVING DIFFERENT CP POPULATIONS AND WHAT IS GOING TO BE OPTIMAL FOR WHICH KIDS AND ALSO WHICH ADULTS. SO THE CLINICAL TRIALS DESIGN. WE HAVE ANOTHER CENTER THAT FOCUSES ON ANALYSIS OF LARGE DATASETS, THE INTERSECTION OF HEALTH SERVICES RESEARCH. AND FINALLY WE HAVE A CENTER THAT HELPS PEOPLE WITH TRANSLATIONAL RESEARCH AND COMMERCIALIZATION. HOW DO YOU BRING THINGS, DECISES AND ACTIVITIES TO THE MARKET? HOW DO YOU UNDERSTAND F DA REGULATIONS AND SO ON? I WAS REALIZING HOW BECAUSE OF THE RICHNESS OF DISCUSSION, HOW IT PLAYS TO THOSE SIX DOMAINS. I WANTED TO HIGHLIGHT THAT AS WELL. AND SO, I JUST WANT TO FINISH OFF BY SAYING IT'S BEEN A TREMENDOUSLY INTERESTING TWO DAYS. I WANT TO VERY MUCH THANK THE PEOPLE THAT PRESENTED, ALL THE WORK THAT WENT INTO MAKING THOSE AND PUTTING TOGETHER THAT INFORMATION AND CERTAINLY THE PEOPLE THAT PRESENTED DID A GREAT JOB OF NOT JUST PRESENTING THEIR OWN RESEARCH BUT REALLY TAKING A LOT OF RESEARCH FROM THEIR COLLEAGUES AS WELL. I WANT TO APPRECIATE THE AUDIENCE WHO EACH OF YOU HAVE YOUR OWN COMMITMENTS AND CONNECTIONS TO THE FIELD. I WANT TO APPRECIATE WHAT BROUGHT YOU TO THIS MEETING AND ALSO THE COMMITMENT EACH OF YOU HAD DURING THE TWO DAYS. WE HAD GREAT COLLEGIAL DISCUSSIONS. I HOPE THAT YOU CONTINUE TO TAKE THAT BACK TO YOUR COMMUNITIES AND TAKE WHAT HAPPENED HERE, IT'S VIDEOTAPED. AND TO KEEP THAT DISCUSSION GOING. SO WITH THAT, LET ME AGAIN THANK JIM. DO YOU HAVE ANY CLOSING COMMENTS YOU WANT TO MAKE? [ APPLAUSE ] >> SO I JUST WANT TO ADD MY THANKS TO THE SPEAKERS AND THE DISCUSSANTS. DEBORAH? [ OFF MIC ] >> YES. THE VIDEOTAPE WILL BE ARCHIVED SO YOUR COLLEAGUES WILL BE ABLE TO TAKE A LOOK AT IT AT THEIR LEISURE. IT WILL BE ON THE NINDS WEBSITE. I WANT TO SAY THANK YOU TO ALL OF THE SPEAKERS AND THE DISCUSSANTS. YOUR PRESENTATIONS WERE PHENOMENAL, INFORMATIVE. CONCISE AND CLEAR AND THEY REALLY HELPED BRING OUT THE MAJOR ISSUES AND THE STATE OF THE FIELD. I ALSO WANT TO THANK EVERYBODY IN THE AUDIENCE FOR COMING. ESPECIALLY THE PARENTS OF CHILDREN WITH CP. I THINK IT WAS VERY IMPORTANT FOR YOU ALL TO BE HERE AND TO HELP US AS INVESTIGATORS REALLY HAVE A GREATER APPRECIATION FOR SOME OF THE THINGS THAT YOU EXPERIENCED ON A DAY IN AND DAY OUT BASIS AND I THINK THAT IS A CRITICAL ELEMENT THAT SOMETIMES GETS OVERLOOKED AND NEEDS TO. AND LAST, I WANT TO WISH YOU ALL A WONDERFUL WEEKEND. I HOPE YOU HAVE SAFE TRAVELS. THANK YOU VERY MUCH FOR COMING. AND AS RALPH SAID SO ELOQUENTLY, THIS IS THE BEGINNING OF THE CONVERSATION AND NOT THE END. SO HOPEFULLY I LOOK FORWARD TO SEEING YOU IN THE FUTURE AT ADDITIONAL WORKSHOPS. THANK YOU AGAIN FOR COMING. [ APPLAUSE ]