SPARC Strategic Planning Workshop: Biology & Technology (Day 1)

SPARC Strategic Planning Workshop: Biology & Technology (Day 1)


I’D LIKE TO INTRODUCE DR. JAMES M. ANDERSON, WHO IS THE DIRECTOR OF THE DIVISION OF PROGRAM COORDINATION, PLANNING AND STRATEGIC INITIATIVES, KNOWN FONDLY AS DPCPSI HERE’S JIM.>>MY CHARGE WAS TO GIVE YOU A HEARTY WELCOME SO GOOD MORNING. I’M WELCOMING YOU ON BEHALF OF THE NIH STAFF INVOLVED IN DEVELOPING THIS PROGRAM, AND WELCOME TO BETHESDA. THIS IS GOING TO BE A REALLY FUN COUPLE OF DAYS HERE. LET ME BEGIN BY GIVING A LITTLE BACKGROUND BECAUSE THIS PROGRAM HAS BEEN A LITTLE DIFFERENT. CAPTIONS RESUME IN A FEW
MINUTES WHICH WAS FIRST REPORTED A COUPLE OF YEARS IN 2012, WITH THE FIRST PERSON TO HAVE BEEN TREATED IN THIS FASHION AND REMARKABLE IMPROVEMENT THAT SURPRISED EVEN THE INVESTIGATORS, THE PRIMARY INVESTIGATORS OF THE STUDY, REGGIE EDGERTON AND SUSAN HARKIMO WERE SURPRISED THAT THIS INDIVIDUAL TREATED WITH THE EXPECTATION OF HIM BEING ABLE TO SIMPLY HOLD UP HIS POSTURE AS HE WAS ABLE TO STAND, THEY WERE ABLE TO STAND HIM UP, OBSERVE THAT HE REGAINED SOME VOLUNTARY LEG CONTROL, AND YOU’LL HEAR FROM HIM, WE HAVE A VIDEO AT THE VERY END, BUT ALSO REGAINED BLADDER, BOWEL AND SEXUAL FUNCTION. THIS MADE A TRE MEN DID DUS DIFFERENCTREMENDOUSDIFFERENCE IN
HIS QUALI
TY OF LIFE. IT WAS A SURPRISE TO EVERYONE. THAT WAS REPEATED IN THREE ADDITIONAL PATIENTS AND REPORTED A LITTLE LESS THAN A YEAR AGO AS YOU CAN SEE HERE IN “BRAIN” THAT OFFERING SPINAL CORD EXCITABILITY ENABLES VOLUNTARY MOTION AFTER COMPLETE PARALYSIS, IT WAS NOT ONLY VOLUNTARY BUT INVOLUNTARY, AS YOU’LL HEAR FROM ROB SOMERS, WITH DRAMATIC IMPROVEMENTS IN THE AUTONOMIC NERVOUS SYSTEM. FLANKING HIM ON BOTH SIDES. RECEIVED TREMENDOUS PRESS. AS YOU CAN SEE HERE, THIS IS JUST A FEW OF THE PUBLICATIONS AND COVERAGE IN THE MEDIA THAT WAS OBSERVED, INCLUDING AN ABOVE THE FOLD FIRST PAGE REPORT IN “U.S.A. TODAY,” AND THERE’S A VARIETY OF PUBLICATIONS FROM AROUND THE WORLD. SO HERE I’D LIKE FOR YOU TO TAKE — THIS IS ABOUT 3 1/2 MINUTES OR SO. LISTEN TO THIS FIRST PERSON’S ACCOUNT OF WHAT HAPPENED WHEN HE WAS STIMULATED WITH THESE ELECTRODES, SURGICALLY IMPLANTED IN HIS LUMBAR SPINE JUST ABOVE THE EPIDURAL, WITH SUFFICIENT ELECTRICAL STIMULATION TO MODULATE THE EXCITABILITY OF THE SPINAL CORD, BUT NOT AT THE LEVEL TO STIMULATE ANY SORT OF MUSCLE CONTRACTION. I WANT TO MAKE THAT A POINT. THIS WAS DONE IN A CONTROL PANEL, IT’S STILL BEING STUDIED, BUT IF YOU LISTEN TO HIM, YOU’LL HEAR ABOUT HIS JOURNEY AND THE DISCOVERIES THAT WERE BEING MADE BY THIS TEAM WITH THIS PARTICULAR APPROACH, AND SPECIFICALLY HEAR ABOUT THE AUTONOMIC SYSTEM AND THE SURPRISES THAT WERE TO COME WITH THIS PARTICULAR TREATMENT AS REGARDS THE AUTONOMIC CYST IT TEM. CYST TE.>>ON THE THIRD DAY OF THE EXPERIMENT — experiment — experiment — THAT WAS THE BEGINNING OF THE BEN THE FIT. THE FIRST THING I STARTED TO NOTICE WAS AN INCREASE IN SENSATION THROUGHOUT MY ENTIRE BODY WHEN THE STIMULATOR WAS TURNED OFF THE. THIS WAS GREAT, NOW I COULD FEEL WHEN I WAS UNCOMFORTABLE, I WAS ABLE TO ADJUST MY SE MYSELF. THIS MADE SURE THAT I WASN’T GOING TO GET ANY PRESSURE SORES OR SKIN BREAK DOWNS, WHICH ARE A HUGE RISK FOR PEOPLE WHO LIVE WITH PARALYSIS. THE INCREASED SENSATIONS ALSO MADE ME REALIZE THAT MY OVERALL CIRCULATION HAD IMPROVED WHILE THE STIMULATION WAS TURNED OFF. I HAD NOTICED THIS BECAUSE MY SKIN STARTED TO CLEAR UP AND REGAIN THE HEALTHY COLOR AS OPPOSED TO A GRAYISH PALE COLOR. WITH THE INCREASED CIRCULATION, I ALSO REGAINED THE ABILITY TO — THIS ALLOWED ME TO STAY OUT IN THE — LONGER AND KEEP MY BODY COOL, WHEREAS BEFORE, I COULD ONLY SPEND NO LONGER THAN 30 MINUTES OUT THE IN THE SUN ON A HOT DAY. NOW THAT I’M ABLE TO SWEAT NORMALLY, I CAN GET BACK OUTSIDE AND DO THE THINGS I LOVE SUCH AS BASEBALL AND HELPING OUT WITH YOUTH ORGANIZATIONS. THE ELECTROSTIMULATION HAS ALSO HELPED MY LUNG FUNCTION. I’VE BEEN ABLE TO TAKE LONGER, DEEPER BREATHS WHILE WORKING OUT. I’VE BEEN ABLE TO TALK WITHOUT ANY ASSISTANCE, WHICH AGAIN SOUNDS UNUSUAL, BUT AS A — I DIDN’T HAVE THE LUNG ABDOMINAL STRENGTH TO TALK WITHOUT HELP. SO BETTER LUNG FUNCTION HELPS ME IN MANY ASPECTS OF SOMEONE WITH PARALYSIS. BETTER BREATHING, BEING ABLE TO TALK, ALLOWS ME TO BREAK UP THE STUFF IN MY LUNGS — SOME OF THE BIGGEST THINGS I NOTICED THAT CAME BACK WERE THE BLADDER AND BOWEL FUNCTION. THIS HAS GIVEN ME THE ABILITY AND FREEDOM TO GO AND DO THINGS, I CAN GO OUT IN PUBLIC, GO ON LONG PLANE RIDES AND NOT HAVE TO WORRY ABOUT BATHROOM ISSUES OR UNACCESSIBILITY ISSUES. IF YOU WERE TO ASK ANYONE LIVING WITH PARALYSIS ON A DAILY BASIS WHAT THE ONE THING IS THEY’D WANT TO GET BACK, THE NUMBER ONE THING THEY WOULD ALL TELL YOU IS BLADDER AND BOWEL FUNCTION, SO THEY COULD BE MORE INDEPENDENT WITHOUT HAVING TO RELY ON OTHER PEOPLE FOR THOSE TYPES OF ISSUES. I’VE ALSO REGAINED SEXUAL FUNCTION WITHOUT USING MEDICATION OR ANY OTHER — THIS IS VERY IMPORTANT TO PEOPLE LIVING WITH PARALYSIS, ESPECIALLY THOSE IT — LIVING A NORMAL LIFE. ALL OF THESE HAVE COME BACK WHILE THE EPIDURAL STIMULATION IS TURNED OFF. WHEN THE STIMULATOR IS TURNED ON, I HAVE THE ABILITY TO STAND WITHOUT — HELP AND I CAN — ALL ON COMMAND, WHICH IS HUGE IN TAKING THE NEXT STEP. EACH ONE OF THESE I’VE GAINED BACK OR OBTAINED GREAT — EACH ONE OF THESE THINGS I’VE SEEN A GREAT IMPROVEMENT ON IS GREAT BY ITSELF, BUT WHEN YOU PUT THEM ALL TOGETHER, IT’S UNBELIEVABLE. IT HAS COMPLETELY CHANGED MY LIFE FROM WHERE I WAS FIVE YEARS AGO. IT HAS ALLOWED ME TO BE INDEPENDENT AGAIN BUT MORE THAN ANYTHING, IT’S GIVEN ME MY — BACK. I’D LIKE TO AGAIN THANK THE NIB FOR EVERYTHING THEY DO AND CONTINUE TO PLEASE FUND ALL THESE GREAT THINGS SO OVER THE NEXT 10 YEARS, MY STORY WILL JUST BE ANOTHER REGULAR STORY. THANK YOU VERY MUCH. [APPLAUSE]>>I THINK IT WAS OBVIOUS BUT I NEGLECTED TO UNDERSCR THAT HE HAD A HIGH LEVEL CERVICAL SPINE INJURY AND WAS A QUADRIPLEGIC FOR FOUR YEARS AFTER HIS INJURY, AND WHAT HE WAS RECOUNTING WAS AFTER THE STIMULATION AND AFTER HIS COMPLETE PARALYSIS. SO THE OVERARCHING WORKSHOP GOAL IS TO IDENTIFY STRATEGIC AREAS FOR NIH TO INVEST IN TO CATALYZE THIS NEUROMODULATION RESEARCH. THERE HAS BEEN CONSIDERABLE PLANNING THAT HAS GONE INTO ESTABLISHING AND ORGANIZING THIS WORKSHOP. THERE WAS A BIOELECTRIC MEDICINE SUMMIT MEETING THAT WAS CO-HELD BY THE NIH WITH A NUMBER OF INDUSTRIAL COLLEAGUES AND THEN THE DATES THAT YOU SEE THERE, WHERE THE IDEA WAS BRINGING THE RESEARCH COMMUNITY, THE GLOBAL RESEARCH COMMUNITY TOGETHER. THE NIH HAS ESTABLISHED THE COMMON FUND WORKING GROUP, YOU’VE HEARD ABOUT THIS, IN A GENERAL SENSE WITH QUITE A NUMBER OF NIH INSTITUTES PARTICIPATING IN THIS, WHICH IS TYPICAL OF COMMON FUND ACTIVITIES AS YOU HEARD FROM JIM JIM, TRANS-NIH ACTIVITIES THAT SUPPORT THE RESEARCH AND THE MISSIONS OF MULTIPLE INSTITUTES ACROSS NIH, AND YOU CAN SEE ALL OF THEM INVOLVED IN THIS PARTICULAR EFFORT. WE’VE CONTINUED TO HAVE CONVERSATIONS, AGAIN, WITH THE COMMUNITY INSIDE AND OUTSIDE WITHIN THE GOVERNMENT AND OUTSIDE THE GOVERNMENT AS YOU CAN SEE THERE. AND INDEED AS IS COMMON PRACTICE FOR US IT NIH TO RECEIVE BROADER COMMUNITY WITH A SEARS OF R FAs, RFIs, I’M SORRY, IS LISTED THERE, ONE FOCUSING ON INPUT REGARDING THE USE AND POTENTIAL UTILITY OF DEVICES THAT ALREADY HAVE RECEIVED MARKET APPROVAL BUT FOR OTHER APPLICATIONS AND HAVING THOSE POTENTIALLY ADAPTED FOR THIS PURPOSE, INFORMATION ON ADDRESSING THE MECHANISMS THAT UNDERLIE NEUROMODULATION, AND THE THIRD ONE, DEVELOPING TECHNOLOGIES THAT WOULD BE NEEDED TO TAKE ADVANTAGE OF THIS UNDERSTANDING THAT WOULD BE ATTAINED IN OUR APPROACH AS REQUESTED IN THE MIDDLE RFI. THE GOAL OF THIS PARTICULAR WORKSHOP IN BROAD STROKES IS QUITE STRAIGHTFORWARD. IT REALLY IS TO LISTEN TO ALL OF YOU, BOTH IN THIS ROOM AND THOSE THAT ARE LISTENING BY WAY OF THE WEBCAST, TO INFORM US IN OUR DECISION-MAKING PROCESS AND TO HELP WITH PLANNING THE NEXT STEPS FOR THIS PARTICULAR INITIATIVE STIMULATING PERIPHERAL ACTIVITY TO RELIEVE MEDICAL CONDITIONS, OR SIMPLY, SPARC. SO WITH THAT, AS WAY OF INTRODUCTION, I’LL TURN THIS OVER TO MY COLLEAGUES TO FOLLOW. ALAN WILLARD AND CRAIG GERMINO. GREG GERMINO.>>GOOD MORNING. I’M GOING TO GIVE YOU A VERY BRIEF UPDATE ON THE STATUS OF WHAT WE’VE BEEN DOING HERE WITHIN NIH TO GET THIS SPARC INITIATIVE MOVING. JUST TO REMIND YOU OF THE OPPORTUNITY AND THE CHALLENGE AND DRAMATIC STORIES SUCH AS THE ONE THAT DR. PETTIGREW JUST SHARED WITH YOU, WE ARE AWARE THAT THERE ARE THESE INCREDIBLE OPPORTUNITIES TO E TO ENHANCE
END ORGAN FUNCTION BY VARIOUS FORMS OF STIMULATION. AT THE MOMENT, WE HAVE THESE INTERESTING OBSERVATIONS, BUT WE DON’T IT HAVE GOOD UNDERSTANDINGS OF THE MECHANISMS OF ACTION. SO THE REAL CHALLENGE FOR US IS TO BE ABLE TO GET FROM CASES WHERE WE HAVE SPECTACULARLY SURPRISINGLY GOOD RESULTS TO ONES WHERE WE HAVE A GOOD RESULT AND WE’RE NOT SURPRISED AND WE WERE EXPECTING IT TO HAPPEN AS A RESULT OF THE TREATMENTS THAT WE DO. SO OUR CHALLENGE HERE IS TO USE THE AMAZING TECHNOLOGICAL ADVANCES THAT HAVE HAPPENED TO HELP US UNDERSTAND THE BIOLOGY, TO USE THE DISCOVERIES IN BIOLOGY TO REVERSE ENGINEER AND REVERSE TRANSLATE AND MOVE BACK TO THE TECHNOLOGY AND TO GET THROUGH THIS ITERATIVE PROCESS TO COME UP WITH NEW THERAPIES. JUST AS A REMINDER FOR THOSE OF YOU WHO HAVEN’T THOUGHT ABOUT PERIPHERAL NERVOUS SYSTEM AND SOME PERIOD OF TIME, WE HAVE OUTLINED HERE THE MAJOR ELEMENTS OF THE AUTONOMIC PARASYMPATHETIC AND SYMPATHETIC NERVOUS SYSTEMS. ABC ONE WHO USED TO WORK ON THE ENTERIC NERVOUS SYSTEM, ENORMOUS NUMBER OF CELLS WITHIN THE LINING OF THE INTESTINE, IN FACT, IF I DO IT HERE, I THINK PEOPLE WHO SEE THE SCREEN CAN GET IT, AS MANY NEURONS IN THE EP TAIRK NERVOUS SYSTEM AS THERE ARE IN THE SPINAL CORD. SO SOMEWHAT DIFFERENT DENSITY BUT LOTS OF THEM THERE. SO IF WE LOOK AT THIS AMAZING NEUROANATOMY, THERE ARE INCREDIBLE OPPORTUNITIES, AND THE CHALLENGE FOR US IS HOW TO TAKE ADVANTAGE OF THEM. SO IF WE THINK ABOUT WHAT WE NEED TO BE ABLE TO REALLY UNDERSTAND IT, WE NEED DETAILED KNOWLEDGE OF THE PHYSIOLOGY AND NEUROPHYSIOLOGY OF THESE VARIOUS VISCERAL ORGAN SYSTEMS, WE ALSO REALLY NEED TO UNDERSTAND WHAT IS THE EXTENT OF INDIVIDUAL VARIATION, BOTH BETWEEN INDIVIDUALS WITHIN THE SPECIES AND ALSO VARIATION BETWEEN SPECIES IF WE’RE GOING TO TAKE GOOD ADVANTAGE OF VARIOUS ANIMAL MODELS. SO AS ONE WHO SPENT THE EARLY PART OF HIS CAREER WORKING ON THE PERIPHERAL NERVOUS SYSTEM, IT’S INCREDIBLY EXCITING TO ME TO SEE WHERE WE ARE TODAY AND TO SEE THIS FOCUS AND INTEREST IN REALLY GETTING INTO THE PERIPHERAL NERVOUS SYSTEM AND UNDERSTANDING HOW TO USE IT TO HELP IMPROVE ATHE LOT OF PATIENTS WITH A VARIETY OF CONDITIONS. SO WHAT ARE WE THINKING ABOUT NOW? AS DR. ANDERSON SAID, WHEN YOU THINK COMMON FUND, YOU THINK BIG AND BOLD, BUT YOU ALSO DON’T THINK FOREVER, SO HERE ORDER OF MAGNITUDE, WE’RE THINKING SOMETHING ON THE ORDER OF $2,200,000,000 OVER SEVEN YEARS. THESE THINGS CAN VARY ACCORDING TO OPPORTUNITIES, AND THE TEAMS WORKING ON SPARC CAN BE IT DIVIDEDIVIDEDINTO FOUR GROUPS. THE BIOLOGY TEAM WHERE WE’RE REALLY INTERESTED IN GETTING THE KINDS OF DETAILED ANATOMIC AND FUNCTIONAL MAPPING THAT WE NEED TO REALLY STAND HOW THESE SYSTEMS WORK, THE TECHNOLOGY DEVELOPMENT TEAM THAT WILL HELP US GET THE NEXT GENERATION TOOLS, GETTING THE BETTER NEUROMODULATION SYSTEMS, REALLY UNDERSTANDING HOW TO USE NEW TECHNOLOGIES IN THE PERIPHERAL NERVOUS SYSTEM. WE’RE AWARE OF AMAZING THINGS GOING ON IN OPTIGENETICS, WE’RE HEARING ABOUT THIS EVERY DAY IN THE NIH, BRAIN INITIATIVE FOR ALL THESE TECHNOLOGIES BEING DEVELOPED FOR STUDIES IN THE CENTRAL NERVOUS SYSTEM. MANY OF THEM WILL BE WONDERFULLY APPLICABLE TO MAKING ADVANCES IN THE PERIPHERAL NERVOUS CYST IT TEM AS WELL. THESE KIND OF DEVELOPMENTS AREN’T GOING TO IT HAPPEN JUST IN ACADEMIC AND MEDICAL INS TUESDAYS, WE’RE GOING TO NEED VERY THOUGHTFUL PARTNERSHIPS WITH INDUSTRY AND WITH FDA, ALL OF THESE VARIOUS TYPES OF DEVICES WHICH CAN HAVE BOTH SHORT TERM AND POTENTIALLY LONG TERM PLASTICITY MEDIATED EFFECTS, REALLY NEED TO BE THOUGHT ABOUT VERY CAREFULLY AND SO THERE’S PROBABLY GOING TO BE SOME INTERESTING ACTION IN THE REGULATORY SPACE AS WELL AS WE MOVE FORWARD THAN THESE. FINALLY, IT IF WE’RE REALLY GOING TO MAKE ADVANCE ON THE AGGRESSIVE TIME LINES THAT JIM TALKED ABOUT, WE’RE REALLY TRYING TO MAKE A BIG DIFFERENCE, A CATALYTIC DIFFERENCE IN FIVE TO 10 YEARS, WE NEED TO BE SHARING DATA VERY EFFECTIVELY AND SO WE HAVE TO BE THINKING ABOUT HOW TO GET THIS DATA INTO A PUBLICLY AVAILABLE RESOURCE AND HOW TO REALLY USE GOOD MODERN MODELING AND THEORETICAL METHODS TO BE ABLE TO TAKE ADVANTAGE OF THE DATA TO MAKE THAT MOVE BETWEEN BIOLOGY AND FUNCTION AND THERAPY. SO A LOT OF INTERESTING CHALLENGES, AND I KNOW DURING THE COURSE OF THE NEXT TWO DAYS, WE’RE GOING TO IT HEAR ABOUT A LOT OF INTERESTING OPPORTUNITIES AND ADDITIONAL CHALLENGES. WE HAVE RELEASED THE FIRST FUNDING OPPORTUNITY ANNOUNCEMENT FOR THE SPARC PROGRAM. THIS ONE IS AN EXPLORATORY ONE FOCUSED ON DEVELOPING TOOLS FOR THE DISCOVERY OF MECHANISMS. FOR THOSE OF YOU WHO DO BUSINESS REGULARLY WITH NIH, THE U18 IS PROBABLY NOT A FAMILIAR MECHANISM. YOU CAN THINK OF IT AS AN R21, SO IT’S A TWO-YEAR GRANT WITH A MODEST BUDGET BUT THE U MEANS IT’S A COUP OFTIVE AGREEMENT AND THAT THERE’S MORE PARTNERSHIP WITH NIH AND A BIT MORE MANAGEMENT. THE MOST IMPORTANT POINT ON THIS SLIDE IS THAT FOR ANYONE INTERESTED, THERE’S A PREAPPLICATION INFORMATIONAL IT TELECONFERENCE ON MARCH 5TH FROM 3:30 TO 43 4:30. I WOULD ALSO POINT OUT THAT THE CONTACT PERSON HERE IS DR. GRACE PENG, WHO IS AT THE TABLE, AND I’LL SHOW YOU A PICTURE OF HER FOR THOSE OF YOU IN A MINUTE SO IF YOU HAVE QUESTIONS FOR HER, YOU CAN TALK TO HER DURING THE COURSE OF THE MEETING. JUST A COUPLE OF POINTS ABOUT THIS FUNDING OPPORTUNITY ANNOUNCEMENT, IT’S REALLY HEAVILY FOCUSED ON IDENTIFYING TECHNOLOGIES THAT WILL ENABLE US TO HAVE END ORGAN CONTROL, NEURAL CONTROL OF END ORGAN FUNCTION. SO IT’S NOT JUST TECHNOLOGY FOR TECHNOLOGY’S SAKE. WE REALLY WANT TO HAVE THIS END GOAL IN MIND. AGAIN, THIS IS PART OF THE COMMON FUND WHERE WE’VE GOT A BIG PICTURE GOAL HERE, SO IN THESABLECATIONS, PEOPLE REALLY NEED TO BE DESCRIBING ON THE PROPOSED TECHNOLOGY IS GOING TO BE TAILORED TO ENABLE US TO UNDERSTAND HOW TO ACHIEVE END ORGAN CONTROL — PEOPLE NEED TO DEFINE APPROPRIATE TECHNOLOGY CHALLENGES LIKE ARE R21s, THERE’S NO PRELIMINARY DATA EXPECTED OR REQUIRED BUT YOU SHOULD HAVE SOME REASONABLY SOUND THEORETICAL RATIONALE FOR WHY YOU WANT TO DEVELOP OR IMOF PROVE THE TECHNOLOGY THAT YOU’RE THINKING ABOUT. THERE IS A SPARC WEBSITE AND ON THE SPARC WEBSITE FUNDING OPPORTUNITY ANNOUNCEMENTS LIKE THIS ONE WILL BE DESCRIBED. HERE I’LL SHOW YOU THE ACTUAL URL, BUT IT IF YOU’RE LIKE ME AND YOU DON’T REMEMBER URLs, GOOGLE CAN ALWAYS FIND IT. GOOGLE IS ESPECIALLY GOOD AT FINDING NIH SITES, NIH SPARC. I DON’T THINK IT’S JUST BIG BROTHER FOLLOWING ME, BUT ANYTHING THAT I WANT TO FIND LIKE THIS, USUALLY THE TOP HITS ARE UP THERE. AND SO THIS WEBSITE WILL HAVE LINKS TO REQUEST FOR INFORMATION, FUNDING OPPORTUNITY ANNOUNCEMENTS, WORKSHOPS AND, VERY IMPORTANTLY, THAT MARCH 5TH WEBINAR. SO NOW AS PROMISED, I HAVE PICTURES OF THE MEMBERS OF THE TEAM WHO I ENCOURAGE YOU TO INTERACT WITH TODAY, SO HERE’S GRACE PENG, WHO IS THE LEAD FOR THE FUNDING OPPORTUNITY ANNOUNCEMENT, RIGHT BESIDE HER IS JILL CARRINGTON, WHO’S LEAD OF THE BIOLOGY TEAM, I THOUGHT I SAW VINAY HERE. RAISE YOUR HAND — NOT IN THE ROOM, I GUESS, WORK WOULDING ON DATA COORDINATION. I KNOW DAN, AND THEN MARY PERRY, WHO HELPS DEMISTIFY COMMON FUND, HSHE HAS SEVERAL ADVANCED DETBREE DEGREESIN CAT HERDING. SHE CAN CONSULT WITH YOU ON THAT ALONG WITH MANY OTHER THINGS. I’M GOING TO TURN IT OVER TO GREG GERMINO WHO WILL GIVE YOU YOUR MARCHING ORDERS FOR THE REST OF THE MEETING.>>GOOD MORNING. YOU’VE HEARD FROM OUR PREVIOUS SPEAKERS THE GREAT OPPORTUNITIES THAT LIE AHEAD. I THINK PARTICULARLY MANY OF THE ORGAN SYSTEMS THAT WE AT NIDDK ARE RESPONSIBLE FOR IS A REALLY UNTAPPED POTENTIAL, SO WE’RE EXCITED ABOUT PARTICIPATING IN THIS INITIATIVE. AS YOU’VE HEARD, THE GOAL OF OUR SPARC PROGRAM, IT’S A BILL DETAILED, INTEGRATED, FUNCTIONAL AND ANATOMICAL NEURAL CIRCUIT MAPS IN MULTIPLE ORGANS IN HUMANS SUITABLE FOR GUIDING THERAPEUTIC APPROACHES IN THE FUTURE. IN ORDER TO ACHIEVE THIS AMBITIOUS GOAL, WE WILL REQUIRE THE CLOSE COOPERATION OF DIVERSE GROUPS OF INVESTIGATORS AND KRI NICHES WHCLINICIANS WHO ARE NOT
GENERALLY ACCUSTOMED TO WORKING WITH EACH OTHER. THIS WILL REQUIRE THE IN PUT OF NEUROSCIENTISTS, OF PHYSIOLOGISTS, ELECTRICAL ENGINEERS, BIOENGINEER, SURGEONS, COMPUTATIONAL AND DATABASE EXPERTS, AND SPECIALISTS FROM A VARIETY OF OTHER MEDICAL DISCIPLINES WILL ALL PARTICIPATE IN THIS ENDEAVOR. WE WILL NEED TO DRAW ON EXPERTISE FROM ACADEMIA, GOVERNMENT, INDUSTRY, RESEARCH INSTITUTES, AND RECRUITING THEIR PARTICIPATION IN BUILDING NEW TEAMS THAT CAN WORK IN AN ITERATIVE TRANSFORMATIVE FASHION. TODAY’S WORKSHOP IS AN IMPORTANT STEP IN THIS PROCESS. WE HAVE THREE OVERARCHING GOALS FOR THIS WORKSHOP. THE FIRST BIG QUESTION IS WHAT INFORMATION IS REQUIRED TO BUILD MAPS THAT ARE SUITABLE FOR GUIDING SAFE AND EFFECTIVE NEUROMODULATION THERAPIES. SPECIFICALLY, WHAT PARAMETERS OF THE NERVOUS SYSTEM MUST BE DEFINED? WE OBVIOUSLY EXPECT DETAILED KNOWLEDGE OF THE NEUROANATOMY, FIBER SIZES, NEUROTRANSMITTERS, BUT ARE THERE ANY OTHERS THAT ARE MISSING THAT WE SHOULD NEED TO THINK ABOUT? WHAT PARAMETERS OF THE TARGET ORGANS ALSO NEED TO BE DEFINED AND UNDERSTOOD? WHAT ASSAYS DO WE NEED TO DEVELOP FOR MEASURING RESPONSE? AND MORE IMPORTANTLY, FOR BEING ABLE TO MEASURE EFFECTIVENESS OF OUR INTERVENTIONS. HOW CAN WE LEVERAGE THE ANIMAL AND HUMAN DATA TO BUILD BETTER FUNCTIONAL HUMAN MAPS? THE SECOND BIG QUESTION THAT WE NEED TO ADDRESS DURING THIS WORKSHOP IS WHAT TECHNOLOGIES DO WE CURRENTLY HAVE THAT WE CAN APPLY WITH MAPPING EFFORTS, AND AT LEAST AS IMPORTANT IS WHAT TECHNOLOGIES DO WE NEED TO DEVELOP TO HELP PROMOTE THE SCIENCE AND PROMOTE OUR MAPPING EFFORTS. AND FINALLY, WHAT TYPES OF DATA DO WITH WE EXPECT TO GENERATE AND HOW WILL WE CAPTURE THIS INFORMATION AND SHARE THIS IN A WAY THAT IS MOST USEFUL TO THE BROADER COMMUNITY? WE WANT TO CONSIDER THIS ISSUE PROSPECTIVELY, BUILDING THINGS AND THEN LATER ON TRYING TO FIGURE OUT HOW TO CONNECT THINGS UP, SO THIS IS REALLY A VERY PROACTIVE STEP THAT’S GOING TO FOLLOW AND GO ALONG IN PARALLEL WITH ALL OF OUR MAPPING EFFORTS. OUR ORGANIZERS HAVE CAREFULLY STRUCTURED THE WORKSHOP TO BEGIN WITH AN OVERVIEW OF CURRENT APPROACHES AND CHALLENGES IN NEUROMODULATION THERAPY, AND A REVIEW ON THE AUTONOMIC NERVOUS SYSTEM. THIS FOLLOWED BY A SERIES OF SESSIONS AT FUTURE PAREN FAITION FOR BOTH A BIOLOGICAL AND TECH TECHNOLOGICAL PERSPECTIVE ON A NUMBER OF ORGAN SYSTEMS. THEY’VE INTENTIONALLY SELECTED A REASONABLY SIMPLE AND WELL UNDERSTOOD SYSTEM, BLADDER CONTROL, AS THE FIRST, AND THEN OVER THE NEXT COUPLE OF SESSIONS, OVER THE NEXT DAY AND A HALF, THE WORKSHOP WILL INCREASINGLY LOOK INTO MORE COMPLEX SYSTEMS THAT ARE LESS WELL CHARACTERIZED. PLEASE BE ASSURED THAT THE ORGAN SYSTEMS THAT WERE SELECTED ARE SIMPLY JUST EXAMPLES, MODELS, AND WE ENCOURAGE YOU TO THINK BROADLY ABOUT WHERE WE CAN HAVE THE BEST IMPACT, THE GREATEST NEED AND GREATEST OPPORTUNITY. THEY’VE INCLUDED ADDITIONAL SESSIONS THAT ADDRESS THREE OTHER MAIN THEMES. ONE ADDRESSES A DATA ISSUE, FEATURING CASE STUDIES AND HOW DIVERSE DATASETS MIGHT BE COORDINATED AND ASSEMBLED INTO A COMPREHENSIVE SEARCHABLE DATABASE AVAILABLE TO OTHERS, TO EVERYONE. ANOTHER LOOKS AT HOW WE MIGHT USE STUDIES IN BOTH HUMANS AND AN WILL MALL MODELS TO BUILD HUMAN RELEVANT MAPS AND TOOLS. FINALLY A SESSION THAT REVIEWS PARALLEL EFFORTS BY OTHERS TO DEVELOP NEUROMODULATION THERAPISTS AND APPROACHES FOR THE PRIF LAL NERVOUS SYSTEM. EACH SPEAKER HAS BEEN ASKED TO ADDRESS A COMMON SET OF QUESTIONS THAT HAVE BEEN SELECTED TO HELP FRAME SUBSEQUENT DISCUSSIONS. THE INTENT IS TO FOCUS ON BOTH OPPORTUNITIES AND CHALLENGES, AND OF COURSE THE ENTIRE WORKSHOP IS SPRINKLED LIBERALLY WITH OPPORTUNITY FOR DISCUSSIONS. WE WANT YOU TO ENGAGE IN DISCUSSIONS AS WE ADDRESS THESE THREE OVERARCHING — OUR LEADERS WILL USE TOMORROW TO SPARK, THIS IS INTENTIONALLY A BAD PUN, OUR FINAL DISCUSSIONS TOMORROW AFTERNOON BEFORE WE CLOSE. FINALLY, ON BEHALF OF MY CO-DIRECTORS, I WANT TO THANK MARY PERRY, CHRISTINE, OUR CO-LEADS, OUR PROGRAM STAFF WHO HAVE ALSO WORKED TO HELP DEVELOP THIS AGENDA, AND FINALLY OUR EXTRAMURAL INVESTIGATORS WHO HAVE BEEN HELPING US VERY GREATLY ON DEVELOPING THIS, FOR TAKING OUR BIG PLAN, HAVE A WORKSHOP, SOMEHOW KICK OFF THIS VERY AMBITIOUS INITIATIVE AND TRANSFORMING THIS INTO AN INCREDIBLE ONE AND A HALF DAY FUSION OF BIOLOGY, TECHNOLOGY, AND THE SCIENCE AND INFORMATION MANAGEMENT. THANK YOU.>>WE’D LIKE TO THANK THE STAFF FOR WHAT THEY’VE PUT TOGETHER HERE THIS MORNING. WE REALLY APPRECIATE IT. THE NEXT HOUR IS DEVOTED TO THREE SESSIONS WHICH WILL GIVE AN OVERVIEW, THE FIRST IS AN OVERVIEW OF CURRENT — [INAUDIBLE]>>GOOD MORNING, EVERYONE, INCREDIBLY EXCITED TO BE HERE. AS A BRIEF RIDER BEFORE I GIVE THE TALK, PRIOR TO COMING TO THE NIH, I WAS A RESEARCH SCIENTIST AT CB IM., A COMPANY THAT CAN DID NEUROMODULATION FOR END ORGAN FUNCTION, HYPERTENSION AND/OR HEART FAILURE, SO I’M GOING TO GIVE AN OVERVIEW OF WHAT’S ALREADY OUT THERE IN INDUSTRY IN THIS SPACE, A LOT MORE THAN YOU MIGHT THINK, THEN I’M GOING TO TALK ABOUT MY SPECIFIC EXPERIENCES IN DESIGNING A NEXT GENERATION THERAPY FOR THE COMPANY AND HOW THE LEVEL OF BUOLOGY THAT WE OF
BIOLOGY TH
AT WE NEEDED WASN’T QUITE THERE. I THINK THERE’S A PERFECT STORM OF TECHNOLOGY HERE, GIVEN WHAT’S BEEN DEMONSTRATED IN THE BRAIN, ET CETERA, AND APPLY IT TO THIS TO REALLY CREATE AN ORDER OF MAGNITUDE DIFFERENCE IN OUR UNDERSTANDING OF THESE THERAPIES AND HOW EFFECTIVE THEY ARE. SO AS ROD SAID, THIS IS NOT AN OLD IDEA. THIS IS ACTUALLY A PICTURE FROM — A PAPER FROM BRUMWALD IN THE 1970s WHERE HE WAS STIMULATING THE CAROTID SINUS NERVES IN PATIENTS FOR ANGINA. THESE ACTUALLY WERE A SERIES OF STUDIES DONE FROM THE 60s AND 70s. THESE WERE ACTUALLY QUITE EFFECT ITTIVE, I MIGHT ADD. THERE WERE SOME — THE REASON THIS DIDN’T GO INTO A REGULAR THERAPY WERE A COUPLE OF REASONS. ONE, THERE WAS CONCERN ABOUT NOT JUST STIM IT LATING WHAT YOU WANT BUT STIMULATING WHAT YOU DON’T WANT ON KA RO TICK SINUS NERVE. THE TECHNOLOGY WAS A LITTLE BULKY AND THERE WERE SOME CONCERNS ABOUT DAMAGE OF THE KA CAROTID — THERE WERE A LOT OF ADVANCES IN DRUGS AT THAT TIME AND THEY THOUGHT THEY WERE GOING TO SOLVE A LOT OF THESE PROBLEMS. AND WHAT TURNED OUT IS THEY DIDN’T SOLVE THESE PROBLEMS. BUT EVEN BEFORE THAT, IF YOU’RE LOOKING AT WORK FOR VAGAL STIM TO IMPACT THE SPLEEN, THAT GOES BACK TO THE 1870s AND 1880s. THIS IS NOT ONLY NOT A NEW IDEA, IT’S A VERY OLD IDEA. BUT THAT BEING SAID, THERE’S BEEN A LOT OF RECENT SUCCESS SHOWING THE PROMISE OF NEUROMODULATION OF END ORGAN FUNCTION. THIS IS THE INSPIRE SYSTEM. RECENTLY IT GOT A PMA AND THE INSPIRE SYSTEM IS FOR SLEEP APNEA TO STIMULATE THE HYPOGLOSSAL NERVE. THIS IS A CLOSED LOOP SYSTEM, WHEN IT SENSES BREATHING ABNORMALITY OR OBSTRUCTION, THEY KNOW HOW TO STIMULATE. THIS IS THE ENTEROMEDIC SYSTEM, STIMULATES THE ABDOMINAL VEGAS. IT IS A BLOCKING SYSTEM FOR OBESITY THAT BLOCKS THE SIGNAL THAT TELLS HAW IT YOU’RE HUNGRY. THIS IS THE CVRX NEOSYSTEM WHICH STIMULATES THE CAROTID VAIR OWE CENTERS FOR HYPERTENSION. IT GOT WHAT’S CALLED A HUMANITARIAN DEVICE EXEMPTION AS THEIR COMMERCIAL APPROVAL QUITE RECENTLY FOR INTRACTABLE HYPERTENSIVE WHO WERE RESPONSIVE IN THEIR ORIGINAL TRIAL. AND THEN THERE ARE SOME OLDER DEVICES AS WELL THAT HAVE FDA APPROVAL SUCH AS THE MEDTRONIC INTERSTIM DI VICE, IT’S A SACRAL NEVER SIMULATOR FOR URINARY AND FECAL INCONTINENCE. THIS FOR SPINAL CORD INJURY IS THE FINE TECH BRINLY SYSTEM. THIS GOT AN HDE IN 1997. THIS IS REALLY INTERESTING WHEN YOU START TALKING ABOUT THE SMALL MARKET INDICATIONS AS WELL BECAUSE I BELIEVE THEY TOOK IT OFF THE MARKET IN 2007 BECAUSE COMMERCIAL SUSTAINABILITY BECAME AN ISSUE. THIS IS ANOTHER ONE I WANT TO MENTION, WHICH IS ARGUABLY END ORGAN FUNCTION, THAT I THINK IS REALLY IMPORTANT. THIS JUST GOT A 510K, BASED OR A PREDICATE DEVICE, THEY IT DID NOT HAVE TO DO A SHAM CONTROLLED STUDY AND SHOW EFFECT, BUT WHAT IT IS IS A SPINAL CORD STIMULATOR FOR PAIN WHICH HAS BEEN ON THE MARKET FOR YEARS, BUT IT’S WIRELESS. THERE’S NO BATTERY. THEY JUST IMPLANT THE ELECTRODES. THAT’S THE SORT OF TECHNOLOGY THAT IS COMING ONLINE NOW, THAT MAKES THESE SYSTEMS POTENTIALLY VERY MINIMALLY INVASIVE, VERY MINIMAL RISK AS PART OF THE SURGICAL PROCEDURE. I COULD ALSO TALK A LITTLE BIT ABOUT NOT NEUROMODULATION OF END ORGAN SYSTEMS AND MEN TOUR NEUROPASE OR SECOND SITE. THAT’S A RETINAL PROSTHETIC FOR PEOPLE WITH RET NIG RETINITIS PIGMENTOSA. BOTTOM LINE, IN MANY OF THE DRUG AND BIOLOGICS COMPANIES ARE HAVING DIFFICULTIES SHOWING SUCCESS IN GETTING FDA APPROVALS IN THESE LARGE CLINICAL TRIALS. WE HAVE SUCCESS IN HUMANS AND IN MANY CASES IT’S PHENOMENONOLOGY, WE DON’T KNOW EXACTLY HOW IT WORKS. IF YOU LOOK IN EUROPE OR OTHER COUNTRIES, NEUROMODULATION OF END ORGAN SYSTEMS IS MUCH MORE COMMON IN TERMS OF CLINICAL PRACTICE. SO FOR HEART FAILURE, THERE ARE TWO SYSTEMS THAT HAVE CE MARK, WHICH IS AVAILABLE FOR SALE IN EUROPE, I’LL TALK A LITTLE MORE ABOUT THAT, THE BIO CONTROLS CARDIOFIT SYSTEM, WHICH STIMULATES THE VAGUS, CYBERONICS SUBMITTED IN DECEMBER, HE’LL GIVE THE TALK AS A FORMER EMPLOYEE AND NOW INDEPENDENT CONTRACTOR, I BELIEVE, FOR HYPERTENSION, ALSO THE NEO SYSTEM, SEVERAL COMPANIES HAVE — MEDTRONIC, ST. JUDE, COINDIVIDUALIAN, WHICH IS INTERESTING BECAUSE MEDTRONIC DID AN — THE RECOR SYSTEM. ALSO THE MEDICARE DIAMOND SYSTEM WHICH STIMULATES THE STOMACH MUSCLES FOR OBESITY AND TYPE 2 DIABETES. SO THESE ARE IN HUMAN BEINGS. THESE ARE SHOWING EFFECT SOMETIMES IN SHAM CONTROLLED STUDIES, SOMETIMES NOT IN SHAM CONTROLLED STUDIES BUT THEY’RE IN HUMAN PATIENTS RIGHT NOW. THIS IS MUCH MORE ADVANCED THAN YOU THINK IN TERMS OF CLINICAL PRACTICE, AND IT’S AMAZING HOW MUCH IS BASED OFF OF PHENOMONOLOGY. WE STICK IN AN ELECTRODE AND SEE AN EFFECT. I’D LOVE TO SAY THIS WAS SCIENTIFIC, THAT I WENT TO CLINICALTRIALS.GOV, ET CETERA. THESE ARE CLINICAL STUDIES WHERE THEY’RE STIMULATING THE VAGUS THAT I’M AWARE OF OFF THE TOP OF MY HEAD. I ONLY MADE ONE OF THESE UP. [LAUGHTER] AND I REALLY HAVE FOUR POINTS FOR THIS SLIDE. FIRST IS THAT THEY’RE STIMULATING THE VAGUS, IN MANY CASES THEY’RE STIMULATING IT IN VERY SIMILAR WAYS. THIS TO LAYMEN OR THOSE WHO AREN’T IN THE SPACE SOUNDS TOO GOOD TO BE TRUE, AND THAT DOESN’T MEAN THERE’S NOT A LOT OF PROMISE HERE. IN FACT, MANY OF THESE HAVE A LOT OF COMPELLING OPEN LABEL DATA THAT’S QUITE FRANKLY PROBABLY BETTER THAN THE AN WILL MALL DATA YOU HAVE TANIMALDATA
YOU HAVE TO
SUPPORT A LOT OF THINGS, BUT WHAT THIS REALLY MEANS IS IF YOU’RE IN THIS FIELD, YOU HAVE TO BE REALLY SCIENTIFICALLY METICULOUS IN HOW YOU DO YOUR STUDIES AND HOW YOU CONVEY THEM BECAUSE YOU’RE FIGHTING KNEE JERK SKEPTICISM. SO IT’S NOT JUST FOR YOUR PARTICULAR AREA OR INTEREST FOR TREATMENT THAT YOU HAVE TO DO THIS, BUT IT’S FOR ALL THE OTHER ONES. BECAUSE IF YOU OVERSELL VAGAL NERVE STIMULATION AND THE DATA IT TO SUPPORT IT, YOU’RE BRINGING SKEPTICISM FOR ALL THESE THINGS THAT ACTUALLY DO HAVE GREAT PROMISE. SECONDLY, SO THERE’S A LOT OF SAFETY DATA ON VAGAL NEVER NERVE STIMULATION, BUT TYPICALLY THEY’RE NOT LOOKING FOR SIDE EFFECTS TO THIS LEVEL OF DETAIL. SO IF YOU’RE THINKING THERE’S SOME PROMISE IN ALL THESE INDICATIONS, THE QUESTION IS, WHAT ARE YOU DOING LONG TERM WHEN YOU’RE STIMULATING, ESPECIALLY WHEN MANY OF THESE, YOU’RE STIMULATING IN THE EXACT SAME LOCATION IN A VERY SIMILAR FASHION, AND MANY OF THE EFFECTS ARE PURPORTED TO BE PLASTICITY-MEDIATED. WHICH MEANS IF YOU’RE NOT LOOKING FOR THEM, YOU’RE NOT GOING TO FIND THEM. THE OTHER THING THAT’S REALLY WORTH MENTIONING, ESPECIALLY THE ACADEMICS, I’M VERY HAPPY TO SEE A LOT OF INDUSTRY REPRESENTATION, A LOT OF THE DATA THAT’S OUT THERE FOR THESE TRIALS DOESN’T COME IN THE WAY THAT YOU’RE USED TO IT. IT DOESN’T COME IN PAPERS. THERE ARE PMA SUMMARIES THAT TELL YOU NOT JUST THE EFFECTS, THE SIDE EFFECTS, THE UNPUBLISHED PRECLINICAL DATA, ET CETERA. AND IF YOU’RE LOOKING AT VAGAL NERVE STIMULATION FOR HYPERTENSION OR FOR HEART FAILURE, YOU REALLY SHOULD BE LOOKING AT VAGAL NERVE STIMULATION FOR EVERYTHING TO UNDERSTAND THAT SYSTEM VERY WELL. AND REALLY, THE FOURTH POINT I WANTED TO MAKE IS THAT I’M A BIT OF A SMART ASS. NOW, THIS ALL SOUNDS REALLY PROMISING, BUT THERE’S A CAVEAT. SO THERE ARE SEVERAL NEUROMODULATION RCTs. THESE ARE DOUBLE BLINDED SHAM CONTROLLED CLINICAL TRIALS THAT DIDN’T MEET THE PRIMARY EFFICACY MARK OR THE PRIMARY EFFICACY POINT IN THE U.S. AFTER DOING AN OPEN LABEL STUDY IN EUROPE TO GET THEIR CE MARK. WHAT OPEN LABEL STUDY MEANS TYPICALLY IS YOU’RE NOT BLINDED, NOT ALWAYS BUT OFTEN, YOU’RE NOT NECESSARILY RANDOMIZED. PRETTY MUCH EVERYBODY KNOWS WHO’S ON. SO FOR THE ENTAROT MEDICS AND POWER SYSTEM, THEY GOT THEIR CE MARK, THEY CAME TO THE U.S., THEY DID THEIR RCT, AND THEY’RE STIMULATING FOR WEIGHT LOSS. THE GREAT THING IS YOU CAN IMPLANT IT AND NOT TURN IT ON. SO THAT’S CALLED A SHAM ARM. SO THEY ACTUALLY HAD A LARGE PERCENTAGE EXCESS WEIGHT LOSS IN THESE PATIENTS IN THE SHAM ARM WITHOUT STIMULATING. THEY WERE LOOKING FOR A PRIMARY END POINT IT DIFFERENCE OF 10% BETWEEN THE ON AND OFF ARM, THEY GOT ROUGHLY AN 8% DIFFERENCE. THIS WAS ENOUGH TO GET THEM A PANEL DECISION, AND THE PANEL DECISION WAS VERY INTERESTING AS WELL. THIS WAS STATISTICALLY SIGNIFICANT, SO THIS IS SCIENTIFICALLY RIGOROUS DATA, BUT IT’S NOT QUITE THE EFFECT THEY WERE HOPING FOR. THEY GOT AN 8-1 DECISION ON SAFETY, A 4 TO 5 DECISION ON EFFICACY AND A 6 TO 2 FOR APPROVAL AND EVENTUALLY THEY GOT THEIR PMA. CMA REIMBURSEMENT, ET CETERA, IS GOING TO BE A DIFFERENT STORY THAT THEY’RE GOING TO HAVE TO FIGHT WITH. MEDTRONIC SIMPLICITY, THIS IS THE RENAL DENERVATION IN THEIR OPEN LABEL TRIALS IN EUROPE, I WANT TO SAY THEY ARE ROUGHLY A 28-MILLIMETER DROP. THEY CAME TO THE U.S., HAD A SHAM ARM, THEY HAD A LARGE DROP IN THEIR SHAM ARM. BOSTON JUST HAD THEIR TRIAL FOR CARDIAC — WELL, FOR HEART FAILURE, AND THEY SHOWED CARDIAC REMODELING, OPEN LABEL, THEY SHOWED WHEN THEY DID A SHAM CONTROLLED STUDY, THEY SHOWED NO DIFFERENCE BETWEEN THE TWO ARMS. THIS IS A WIDER PHENOMENON, NOT JUST STIMULATION OF END ORGAN FUNCTION. THERE’S SIMILAR DATA FROM DEPRESSION AND FOR EPILEPSY FROM THE SANTE TRIAL. I WANT TO TALK A LITTLE ABOUT MY PERSONAL EXPERIENCE AND RELATE IT TO THE BIOLOGY. I COME FROM CVRX, I NO LONGER GET MONEY FROM CVRX RIGHT NOW. WHAT WE DID IS STEM LATED THE BARO RECEPTORS AND IMPLANTED A GLOVE ON BOTH SIDES OF THE CAROTID SINUS, WRAPPED IT AROUND THE CAROTID SINUS. THIS IS A FAIRLY EXTENSIVE SURGERY. THE GLOVE IS ALSO INSULATION THAT DIRECTS THE CURRENT, WHERE YOU WANT IT TO GO. WE IT DID THE OPEN LABEL TRIAL IN EUROPE, GOT A VERY GOOD BLOOD PRESSURE DROP, THEN WE IT DID A SHAM CONTROLLED STUDY WHERE AT SIX MONTHS, WE ONLY HAD ONE-THIRD — OR TWO THIRDS OF THE PATIENTS ON, ONE-THIRD OFF. WE DIDN’T GET THE RESULT WE WERE LOOKING FOR. FIRST WE FAILED OUR SAFETY END POINT. WE WANTED AN 82% COMPLICATION FREE RATE, WE GOT A 74.8% BECAUSE WE WERE DOING — YOU CAUSE A LOT OF NERVE DAMAGE WHEN YOU DO IT. WE ALSO FAILED OUR — WHAT’S CALLED ACUTE EFFICACY, WHICH IS THE PERCENTAGE OF PATIENTS WITH A 10-MILLIMETER DROP IN BOTH ARMS. AND WHAT YOU’LL SEE IS, WE GOT A REALLY LARGE PERCENTAGE WITH A 10-MILLIMETER DROP IN OUR OFF ARM. SO WE WERE LOOKING FOR PERCENTAGE OF PATIENTS WITH A SMALL DROP AS OUR PRIMARY EFFICACY END POINT. AS A PRESPECIFIED ANCILLARY EFFICACY END POINT, WE LOOKED AT PEOPLE WHO HAD COMPLETELY CONTROLLED HYPERTENSION. WHAT WE SAW WAS A STA TIS TI CLICK SIGNIFICANT DIFFERENCE. 42% AFTER SIX MONTHS IT COMPLETELY CONTROLLED HYPERTENSION, ON AN AVERAGE OF SIX MEDICATIONS, MANY AS MANY AS 15. WE’RE DOING A PRETTY GOOD JOB. IT WAS 24% IN THE OFF ARM. THEN YOU TURN EVERYBODY ON, AND IT WAS IANDIT WAS 50% OF
PATIENTS IN BOTH ARMS HAD TREATED HYPERTENSION. SO THIS IS EFFECT IN HUMANS, STATISTICALLY SIGNIFICANT AND A ROARANDOMIZED STUDY. IF YOU’RE CVRX, WHAT DO YOU DO? YOU TRY TO DEVELOP A MINIMALLY INVASIVE SYSTEM, AND YOU HIRE SOMEBODY FRESH FROM GRAD SCHOOL TO DEVELOP THE MINIMALLY INVASIVE INTERFACE. AND SO THAT WAS MY JOB. THIS IS ACTUALLY THE NEXT GENERATION SYSTEM THAT HAS SHOWN SIMILAR EFFECTS TO GET A CE MARK IN EUROPE AND IS NOW IN PIVOTAL TRIALS IN THE UNITED STATES. AND WHAT I WANTED TO TALK ABOUT IS AS THE PERSON DESIGNING THIS ELECTRODE INTERFACE, ALL THE STUFF I DIDN’T KNOW ABOUT THE BIOLOGY THAT REALLY WOULD HAVE HELPED ME DESIGN THIS DEVICE, AND IT’S ONE OF THE REASONS I ABSOLUTELY HATE THIS PICTURE. THIS PICTURE GIVES YOU AN IDEA THAT YOU KNOW WHERE THE BARO RECEPTORS ARE. WE KNOW THEY’RE ON THE MEDIA — BORDER, WE HAVE NO IDEA OF THEIR DISTRIBUTION, WE HAVE NO IDEA OF THE VARIANCE FROM PATIENT TO PATIENT, BUT IT’S WORSE THAN THAT. WE DIDN’T KNOW WE WERE STIMULATING THE BORO RECEPTORS. WE COULD HAVE BEEN STIMULATING THEM, THE SIZ IS A SPIKE INITIATING ZONE, WE COULD HAVE BEEN STIMULATING PROXIMAL AFFERENTS, WE COULD HAVE BEEN STIMULATING THE CAROTID SINUS NERVE THAT BRAUNWALD WAS DOING IN THE 60s AND 70s. WE DIDN’T KNOW WHAT WE WERE STIMULATING FOR SIDE EFFECTS. MOST WAS PAIN, WHICH LIMITED THE THERAPY. WE DEFINITELY DEPARTMENT KNOW THE MINIMAL FUNCTIONAL UNIT TO CREATE THESE EFFECTS. THIS IS REALLY IMPORTANT. IF YOU’RE GOING TO MAKE A REALLY SMALL ELECTRODE, YOU NEED TO FIGURE OUT WHAT THE SMALLEST VOLUME YOU CAN STIMULATE THAT CREATES THE EFFECT YOU WANT AND THE SIDE EFFECTS THAT YOU DON’T WANT. WE CERTAINLY DIDN’T KNOW THE LOCATIONS AND DENSITIES OF ANY OF THIS NEUROMAPPING IN THE CANINES WHICH WERE THE COMMON MODEL WE WERE USING, OR IN THE HUMAN BEINGS CERTAINLY WE DIDN’T KNOW. THIS IS IMPORTANT IN TERMS OF THE MAPPING WE’RE TALKING ABOUT. WE DIDN’T KNOW THE LOCATION OF VASCULAR POINTS ACCESS. WHAT MOST ACADEMICS DON’T REALIZE IS THE HOLY GRAIL IS ESSENTIALLY TO HAVE AN IMPLANT THROUGH THE VENUS SYSTEM, SO IT’S NOT JUST WHERE THERE’S NEUROBIOLOGY THAT CREATES THE EFFECT, IT’S WHERE THERE’S ACCESS POINTS, SO KNOWING WHERE THERE’S HIGHWAYS IS IMPORTANT. WE DIDN’T KNOW THE VARIANCE OF ATHE NAT MEE FROM SUBJECT TO SUBJECT. CERTAINLY THAT’S AN INCREDIBLY IMPORTANT POINT FOR PHYSIOLOGICAL MAPPING. ANCHORING TECHNIQUES TO PREVENT ELECTRODE MOVEMENT, I’LL TALK A LITTLE ABOUT THAT IN A SECOND SO I WON’T GO INTO IT. THIS IS INCREDIBLY IMPORTANT. ANIMAL DATA DID NOT RECAPITULATE THE EFFECTIVENESS GIVEN MULTIPLE MEDICATIONS AND MULTIPLE DIFFERENT PATHOLOGIES. THERE’S PROBABLY 40 DIFFERENT REASONS YOU COULD BE HYPER10 SI. WE DID OUR STUDIES IN A NORMOTENSIVE OROBEES MODEL. THEN FOR ALL OF THIS, WE REALLY DON’T UNDERSTAND THE LONG TERM IMPACT OF ADAPTATION. A LOT OF THESE ARE, EVEN IF YOU’RE DOING CHRONIC STU DIRKS YOU STIMULATE FOR THREE WEEKS, YOU IMPLANT FOR A YEAR. YOU’RE NOT LOOKING AT STIMULATING FOR A YEAR OR TWO, AND WHAT SORT OF ADAPTATION DEVELOPS FOR THE SYSTEM. YOU MIGHT ASK ME CAN’T I JUST CREATE ELECTRODES AND TRY THEM IN THE ANIMAL MODEL? I’M NOT GOING TO GO INTO TOO MUCH DETAIL BECAUSE I’M LIMITED ON TIME, BUT WHAT I WANT TO STRESS IS THAT ELECTRIC FIELDS FALL OFF REALLY QUICKLY FROM AN ELECTRODE, AND IT DEPENDS ON THE SIZE. IT IF YOU HAVE A FIELD OF STRENGTH OF 10-MICRONS, IT’S ONE FOURTH STRENGTH AT 20-MICRONS, 116TH AT 40 MICRONS. EDGE EFFECTS, DIFFICULTIES WITH INSULATION STEERING CURRENT. BOTTOM LINE, THE CURRENT GOING TO YOUR NERVES IS DIFFERENT THAN YOU THOUGHT. OTHER PROBLEM IS THE NERVES ARE DIFFERENT THAN YOU THOUGHT. THE WAY NERVES ARE ACTIVATED DEPEND ON THEIR SIZE, THEIR DEGREE OF MYELINATION, THEIR ORIENTATION. ALL OF THAT CHANGES IN AN ANIMAL MODEL IN A NON-LINEAR WAY THAT’S DIFFICULT TO PREDICT. THERE ARE FUNDAMENTAL DIFFERENCES IN PHYSIOLOGY. MANY PEOPLE AREN’T AWAY THERE ARE DIFFERENT VAGAL AFFERANTS IN THE CANINE MODEL THAN IN HUMANS. THE SIDE EFFECTS ARE ALMOST IMPOSSIBLE TO EFFECT IN ANIMAL MODELS. WHEN I FIRST TURNED UP A PATIENT TOO HIGH IN THE CLINIC, IT HURT HIM AND HE THREATENED TO BEAT ME UP. THAT DOESN’T HAPPEN IN THE ANIMAL MODEL. AND THEN, OF COURSE, THERE’S A RANGE OF PATHOLOGIES THAT CAUSE THE SAME SYMPTOMS, AND THERE’S DRUG INTERACTIONS THAT IT THESE DON’T RECAPITULATE. SO THE OTHER QUESTION IS, DO WE NEED KNOW THE MAPS A AHEAD OF TIME IF WE CAN DO SURGICAL MAPPING, IF WE CAN JUST TRY IT IN SURGERY? IF YOU’VE EVER BEEN PART OF THESE SURGICAL PROCEDURES, YOU’LL REALIZE THESE ARE MUCH MORE ART THAN SCIENCE. A LOT OF TIMES YOU CAN’T SEE WHAT YOU’RE LIGHTING UP WITH THESE ELECTRODES. AND YOU’RE USING SURROGATE BIOMARKERS FOR EFFECT. IT IF YOU’RE USING BLOOD PRESSURE OR HEART RATE, THEY HAVE HIGH VARIANCE IN A PROCEDURE, ANESTHESIA AFFECTS THESE PLUS THEY AFFECT CIRCUIT FUNCTION, AND THE OTHER THING FROM A NEURAL INTERFACE POINT OF VIEW, THE FIELD IS A BLOODY MESS. CURRENT GOES IN A LOT OF PLACES THAT THEY’RE NOT GOING TO GO CHRONICALLY. SO MAPPING ISN’T THE WAY TO DO THIS SORT OF PHYSIOLOGY THAT YOU NEED TO KNOW. THERE’S A LOT OF TECHNIQUES POST — WHERE PEOPLE HIGH POT SIZE IF I’M NOT IN THE RIGHT LOCATION, YOU I CAN USE DIFFERENT STIMULATION IDEAS TO STIMULATE WHAT I WANT OR NOT STIMULATE WHAT I DON’T WANT TO STIMULATE. THERE’S SEVERAL OF THESE, WHETHER IT’S TO ACTIVATE BY FIBER TYPE, TO ACTIVATE BY LOCATION, THERE’S BLOCKING CURRENTS YOU CAN DO OR YOU COULD PUT ELECTRODE TO BLOCK WHAT YOU DON’T WANT TO STIMULATE. MOST OF THESE TECHNIQUES HAVE NEVER BEEN VALIDATED IN A CHRONIC SITUATION. MOSTLY MODELING OF WHICH THE ASSUMPTIONS ON CONDUCTIVITY ARE QUESTIONABLE, MOSTLY ACUTE DEMONSTRATIONS, VERY LITTLE PUBLISHED CHRONIC VALIDATION THAT THESE TECHNIQUES GET THE SPECIFICITY YOU WANT, BUT MOST IMPORTANTLY, EVEN IF YOU TAKE THEM TO WORK AS WELL AS YOU POSSIBLY HOPED, THEY CHANGED THE THRESHOLD DIFFERENCES BETWEEN NERVE TYPES ROUGHLY ONE FIFTH TO 5X. THIS MEANS IT FALLS OFF MUCH FASTER THAN THAT. IT MEANS THE DOMINANT EFFECT WILL ALWAYS BE HOW CLOSE YOU ARE TO WHAT YOU WANT TO STIMULATE, AND HOW FAR AWAY YOU ARE FROM WHAT YOU DON’T WANT TO STIMULATE. THERE’S ONE CAVEAT TO THIS, AND I’M GOING TO GIVE A SHOUT OUT TO MY COLLEAGUES, MILTON MORRIS, HE TALKED ABOUT THE NEURAL LANGUAGE OF LOVE. IVE OFTEN WITH WE DO CONTINUE WITH WITH US STIMULATION, WHICH IS NOT REALLY THE WAY THESE THINGS ARE ENCODED. THERE MAY BE SOME ABILITY TO DIFFERENTIATE EFFECT BY KNOWING HOW THE BODY ENCODES THINGS SO YOU ONLY SEND THE MESSAGE TO THE BRAIN OR THE MESSAGE TO THE END ORGAN SYSTEM THAT YOU WANT, AND NOT TO THE THINGS YOU DON’T WANT. I JUST LIKE THE PHRASE NEURAL LANGUAGE OF LOVE. SO REALLY, THE QUESTION IS — AND I’LL GO THROUGH THIS QUICKLY IT — WHY WEREN’T THESE BIOLOGICAL UNKNOWNS THAT I REALLY NEEDED TO DESIGN A MINIMALLY INVASIVE SYSTEM AND THERAPY AND STIMULATION PROTOCOL KNOWN? THE TOOLTS DIDN’THE TOOLS DIDN’T
EXIST. THERE WERE NO STAINS FOR BARE ROW REACCEP RECEPTORS SPECIFIC. YOU HAD TO MAKE GUESSES TO WHAT THE SIDE EFFECTS WERE IN THE ANIMAL MODEL. WE HAD NO WAY TO DETERMINE THE EXTENT OF RECRUITMENT, THE MINIMUM FUNCTIONAL UNIT WE NEEDED TO CREATE THE EFFECT WE WANTED OR THE SIDE EFFECTS WE DIDN’T. WE HAD NO TOOLS TO MODULATE WITH CELL TYPE SPECIFICITY OR — WHERE THERE’S A LASER WHERE I KNOW WHAT’S BEING ACTIVATED PRIMARILY, TO A CERTAIN EXTENT. FUNCTIONAL ANATOMICAL MAPS DIDN’T EXIST IN ANIMALS AND IT DOESN’T EXIST IN HUMAN BEINGS THIS IS INCREDIBLY IMPORTANT, I THINK, FOR SPARC GOING FORWARD. THERE WERE LIMITED OPPORTUNITIES TO ESTABLISH THE ANIMAL RELEVANCE WITH HUMAN DATA. MANY OF THESE COMPANIES ARE MAKING A BET ON A DEVICE DESIGN IN ANIMAL MODELS AND THEN PUSHING IT TO APPROVAL AS FAST AS THEY CAN. THE TRUTH IS, THE LEAP TO HUMAN BEINGS IS HUGE. WE SAW GROSS DIFFERENCES IN THE OBVIOUS RESPONDERS IN STIMULATION PARAMETERS, FREQUENCY, IN THE HUMAN DATA, FROM THE ANIMAL MODELS. WE’RE REALLY GOING TO NEED TO TIE THAT REVERSE TRANSLATION, ESTABLISH THE CLINICAL RELEVANCE OF THESE MODELS. THERE’S LIMITATIONS TO WHAT YOU CAN DO HUMANS BUT THAT’S GOING TO BE INCREDIBLY IMPORTANT FOR SPARC GOING FORWARD. THE GREAT THING IS, THOUGH, I DO THINK OF THIS AS A PERFECT STORM OF OPPORTUNITY. ALL OF THESE THINGS I MENTIONED, THERE ARE NEW TOOLS THAT HAVE BEEN DEVELOPED IN THE BRAIN AND NEW OPPORTUNITIES THAT CAN BE APPLIED TO THE PERIPHERAL NERVOUS SYSTEM. THESE ARE TRACTABLE SOLUTIONS. WE’RE NOT GOING TO SOLVE EVERYTHING, PU IF W BUT IF WITH
WE DO THIS, OUR THERAPIES, I GUARANTEE YOU, WILL GET AN ORDER OF MAGNITUDE BETTER. QUESTIONS? AND I WENT OVER ON TIME SO LIMITED TIME FOR QUESTIONS.>>THE CAROTID SINUS IS INNOVATED BY BARE OWE RECEPTORS AND CHEMO RECEPTORS IN ANIMALS. DO WE KNOW ANYTHING ABOUT IN THE MODEL THAT YOU USED THE SIZE OF THE AXONS, THE THRESHOLD FOR THOSE TWO TYPES OF — AND CAN YOU STIMULATE BARORECEPTORS IN ISOLATION FROM CHEMO RECEPTORS BECAUSE THAT OFTEN RAISES BLOOD PRESSURE OR ACTIVATE SYMPATHETIC NEVERS, WHEREAS BARORECEPTORS INHIBIT –>>SO THE TRUTH OF THE MATTER IS, YOU’RE DEAD RIGHT, AND THE IDEA WAS THAT WHEN YOU STIMULATE THE CAROTID SINUS NERVE WHICH HAS MORE CHEMO RECEPTORS, THAT’S EVEN MORE OF A PROBLEM, THE BARORECEPTORS WOULD BE MORE ISOLATED BUT NOT PERFECTLY. BUT THE TRUTH OF THE MATTER IS, NO, WE CAN’T STIMULATE THAT SPECIFICALLY. WE’RE ACTIVATING PROBABLY EVERYTHING THAT IS ON THE ARTERIAL WALL TO SOME EXTENT, AND WE CAN’T VISUALIZE WHAT WE’RE ACTIVATING. THOSE ARE ARE INCREDIBLY IMPORTANT TOOLS TO HAVE TO REALLY UNDERSTAND HOW THESE THERAPIES WORK.>>AND ACTIVATION OF ONE IT — TURN OFF THE EFFECT OF THE OTHER –>>AND BECAUSE OF THE SIZING DIFFERENCE AND DENSITY DIFFERENCES, YOU ALSO SEE VERY DIFFERENT — ALL YOU’RE REALLY DOING IS MEASURING BLOOD PRESSURE EFFECTS OR NOREPINEPHRINE SPILLOVER, ET CETERA. IN HUMAN BEINGS, YOU ACTUALLY SAW VERY DIFFERENT TIME COURSES IN THE EFFECT AS WELL, WHICH SUGGESTED YOU MAY BE STIMULATING DIFFERENT THINGS TO CREATE YOUR EFFECT. SO I SAW ONE MORE QUESTION. ALL RIGHT. THANK YOU VERY MUCH. [APPLAUSE]>>WHILE DR. MORRIS IS BEING INTRODUCED AND COMING UP TO THE MICROPHONE, I’LL MENTION THAT I AM THE STAFF MEMBER WHO HAD GIVEN THIS CHARGE TO KEEP PEOPLE ON TIME. SO FAR WE’RE 10 MINUTES OFF. AND IT WAS TIME WELL INVESTED. BUT I WILL GIVE YOU THE SIGN WHEN THERE ARE 5 MINUTES LEFT AND WHEN THERE ARE 2 MINUTES LEFT, AND AFTER THAT, WE’LL INSTITUTE A BELL SYSTEM, I UNDERSTAND. SO TRY TO AVOID THAT. IT WILL BE LIKE THIS, 5 MINUTES AND 2 MINUTES. AND WE NEED TO ASK EVERYONE TO USE MICROPHONES, EVEN YOU, EVEN THE CHAIR NEEDS TO GO TO THE MICROPHONE BECAUSE PEOPLE CAN’T HEAR ON THE — AND I’M NOT USING MY MICROPHONE WHEN I USE THAT — PEOPLE CAN’T HEAR ON THE VIDEOCAST OTHERWISE.>>SORRY ABOUT THAT LACK OF MICROPHONE. SO THE SECOND SPEAKER IN THE ORIENTATION SESSION THEN IS DR. MILTON MORRIS, LONG TIME WITH CYBERONICS AS WE ALL KNOW, SHORT TIME OF — BIOMEDICAL, WHICH HE MIGHT BE TELLING US ABOUT.>>THANK YOU. I HAVE NO PLANS ON TELLING YOU ABOUT MEH BIOMEDICAL, I WON’T BORE YOU WITH THAT STORY. I HAVE SPENT THE MAJORITY OF MY TIME IN THE MEDICAL DEVICE SPACE, ABOUT 23 YEARS. THE LATEST OF WHICH WAS SENIOR VICE PRESIDENT RESEARCH AND DEVELOPMENT AT CYBERONICS. I DO WANT TO FOCUS A LITTLE BIT OUR ATTENTION ON SOME OF THE CHALLENGES THAT WE HAD. IT’S GOOD TO BE TRANSITIONING OUT OF THE COMPANY, I CAN NOW EXPLAIN TO YOU SOME OF THE FRUSTRATIONS WE’VE HAD AS AN ENGINEERING ORGANIZATION TO THIS POINT. HOPEFULLY THIS WILL BE AN OPPORTUNITY TO CATCH UP. THE PREVIOUS SPEERKS HAVE ACTUALLY HIT A LOT OF THE SALIENT POINTS I CHOSE TO FOCUS ON. THIS IS JUST OUR NEUROMODULATION PERSON T THERE ARE A LOT OF OPPORTUNITIES TO PLUG IN TO THE NEURAL ANATOMY, TO PROVIDE THERAPEUTIC BENEFITS. SOME HAVE ALREADY REACHED FDA APPROVAL. THERE ARE AR A FEW ALSO OFF INTO THE FUTURE THAT I DO WANT TO TOUCH UPON, SPECIFICALLY HEART FAILURE. I WON’T BE MAKING ANY ANNOUNCEMENTS ABOUT THE APPROVAL STATUS FOR THE AID MISSION FOR CYBERONGS TODAY BUT I’M HOPING THAT CAN BE DISCUSSED OR TALKED IN THE NOT TOO DISTANT FUTURE. WE DO LIKE TO TALK ABOUT NUMBERS. WE LIKE HEALTHY, LARGE PROBLEMS TO SOLVE. ON THE EPILEPSY SIZE, FAIRLY LARGE COHORT FOR VAGUS NERVE OF STIMULATION THERAPY. FOR INTRACTABLE EPILEPSY, PATIENTS THAT ARE DRUG REFRACTORY. AS IT TURNS OUT, IT IF YOU FAILED TWO DRUGS, ANTIEPILEPTIC DRUGS, YOU HAVE LESS THAN A 3% CHANCE OF EVER REACHING SEIZURE FREEDOM, WHICH GIVES AN OPPORTUNITY FOR NEURAL MODULATION TO STEP IN OR SOME SORT OF AN ALTERNATIVE THERAPY FOR TREATING THESE PATIENTS. EPILEPSY IS AN IMPORTANT PATHOLOGY, NOT THAT ALL PATHOLOGIES ARE DEFINED BY WHETHER OR NOT IT CAN BE MORTAL FOR YOU, BUT THERE IS A 25 TO 40 TIMES INCREASE OR FOLD INCREASE IN THE MORTALITY RATE OF PATIENTS SUFFERING WITH EPILEPSY. AND IT IS A FAIRLY COSTLY BURDEN TO OUR HEALTHCARE SYSTEM HERE IN THE UNITED STATES. THERE ARE FDA APPROVED THERAPIES THERAPIES, AS WELL AS THE WHOLLY IN THE SKULL TECHNOLOGY OR SYSTEM FOR TREATING EPILEPSY, AND THERE IS FAVORABLE COVERAGE FOR THE VEGA VAGUS NERVE
STIMULATION OF THIS THERAPY. DEPRESSION IS ALSO A LARGE MARKETPLACE. I’M GOING TO TALK A LITTLE BIT ABOUT THIS BECAUSE OF THE IMPORTANCE THAT CLINICAL TRIALS PLAY IN THE ABILITY TO TREAT PATIENTS WITH NEUROMODULATION THERAPY. SOME 4 MILLION PATIENTS STRUGGLING IN THE U.S. WITH DEPRESSION, SOME 25% OF THOSE ARE DRUG REFRACTORY. AGAIN, THOSE ARE THE — THAT IS A PATIENT POPULATION THAT IS FOR INDICATION FOR NEUROMODULATION. SOME 39,000 PATIENTS ARE SUICIDAL, ARE MOVING TOWARD — OR WILL MOVE TOWARDS SUICIDE ATTEMPTS. MANY OF THOSE WILL BE SUCCESSFUL. GREATER THAN $43 BILLION OF COST, DIRECT AND INDIRECT, MOSTLY REA LATE RELATED TO PRO
DUCK ITTIVITY OR LESS PRODUCTIVITY IN THE WORKPLACE. AGAIN I’LL COME BACK TO DEPRESSION WHEN WE TALK ABOUT CLINICAL TRIALS. FDA APPROVED FOR THERAPY ON THE VNS SIDE, NON-FAVORABLE COVERAGE RECOMMENDATION, WHICH WE’VE TALKED ABOUT AS A COMPANY PUBLICLY, AND HAS ACTUALLY VERY MUCH LIMITED THE ABILITY TO GET THIS THERAPY INTO THE HANDS OF PATIENTS WHO NEED IT. WHAT WAS INTERESTING IN BOTH THE EEPILEPSY AND DEPRESSION PIVOTAL CLINICAL TRIALS, AND WHAT WE’RE FINDING IN SOME OF THE HEART FAILURE PATIENTS FEEL BETTER ON THIS THERAPY. IT LED US TO DOING THE DEPRESSION TRIALS. HEART FAILURE IS SOMETHING KIP TALKED ABOUT JUST A MOMENT AGO. IT IS AN EMERGING THERAPY, SOME 700,000 NEW DIAGNOSED CASES ANNUALLY. IT DOES HAVE A 5-YEAR, 50% MORTALITY RATE. AND IT’S A HUGE BURDEN TO THE HEALTHCARE SYSTEM IN THE UNITED STATES. AT THE FIVE-YEAR MARK, YOU DO HAVE A NUMBER OF PATIENTS WHO WILL HAVE PASSED AWAY IN MANY CASES DUE TO SOME SORT OF DEATH CAUSING OR SUDDEN DEATH CAUSING ARRHYTHMIA, WE’LL TALK MORE ABOUT ARRHYTHMIA LATER ON IN THIS WORKSHOP. WE ARE IN PIVOTAL PILOT TRIALS HERE. THEY HAVE BEEN A LITTLE BIT INCONSISTENT. WE’VE BEEN SUCCESSFUL ON THE CYBERONICSES SIDE, WE’VE SEEN A LITTLE BIT OF STRUBL ON THE — FROM BOSTON SCIENTIFIC, THOUGH I BELIEVE THEY’RE LOOKING FOR LONGER TERM FOLLOW-UPS TO FINALLY UNDERSTAND HOW THEIR APPROACH TO NEUROMODULATION FOR HEART FAILURE WILL WORK. I WON’T BELABOR THE INITIAL POINT HERE, WITH WHICH I THINK THE PREVIOUS SPEAKERS TALKED ABOUT VERY WELL. IT IS VERY DIFFICULT TO FASHION A HUMAN CLINICAL TRIAL IN NEUROMODULATION IF YOU’RE NOT FULLY AWARE OF THE PHYSIOLOGY AND THE CAUSE AND EFFECT OF YOUR STIMULATION. IS IT IS THE CASE SHAM CONTROL TRIALS ARE DIFFICULT TO RUN. WE DO SEE A LOT OF MOVEMENT IN WHAT WE WOULD CALL AN UNDERDOSED POPULATION OR WOULD THINK OR REFER TO AS AN UNDERDOSED POPULATION IN OUR DEPRESSION TRIAL FOR CYBERONICSES, WEONICS,
WE STIMULATED WA WE THOUGHT WAS AN UNDER DIDDOSED OUTPUT, TURNED OUT THOSE PATIENTS FELT BETTER. COULD BE PLACEBO, COULD BE THE CASE THAT THOSE LOW DOSES ARE ACTUALLY EFFICACIOUS. THE PROBLEM HERE THAT I’M TRYING TO ARTICULATE IS, WE DON’T KNOW. SO I THINK WE NEED TO GET THAT UNDERSTOOD A LITTLE BIT BETTER. THE CAUSE OR THE INDIRECT IMPACT OF CHALLENGES ASSOCIATED WITH CLINICAL TRIALS IS THAT IT DAMPENS THE ENTHUSIASM FOR INVESTMENT AND INNOVATION, SO COMING TO THE SPARC WORKSHOP AND SEEING BOTH INDUSTRY AND GOVERNMENT AGENCIES WORKING TOGETHER IS ACTUALLY FANTASTIC, AND I WANT TO THANK THE ORGANIZERS FOR DOING THAT. REIMBURSEMENT CHALLENGES, THE FDA APPROVALS DO NOT SUGGEST THAT YOU WILL GET C MSM S OR MEDICARE FAVORABLE — FOR REIMBURSEMENT AND THAT IN ITSELF CAN SHUT DOWN A THERAPY AS WE SAW WITH VNS FOR DEPRESSION. LOOKING TOWARD THE CLINICAL TRIALS OR MAKING TALKING A A LITTLE MORE ABOUT THE SPECIFICS THAT CAN CURTAIL RESULTS, FAVORABLE RESULTS IN CLINICAL TRIALS, MODULATION THERAPIES ARE PARTICULARLY INDICATED FOR TREATMENT RESISTANT PATIENTS. WE SAVE THE WORST OF THE WORST FOR NEUROMODULATION. SO WE KNOW THERE ARE GOING TO BE SOME DIFFICULT TIMES AHEAD FOR ANY NEUROMODULATION APPROACH AS IT RELATES TO HUMAN CLINICAL TRIALS BECAUSE ONLY THE MOST DIFFICULT OR MOST CHALLENGED PATIENTS ARE GOING TO BE INCLUDED OR BE MOVED TO AN INVASIVE THERAPY LIKE MANY OF THE NEUROMODULATION APPROACHES. WE TALKED ABOUT CONTROL GROUPS PERCEIVING LOW LEVELS OF STIMULATION, ACCENTUATING ANY PLACEBO EFFECT, POTENTIALLY ACCENTUATING ANY PLACEBO EFFECT, BUT ALSO LOW LEVEL STIMULATIONS COULD BE EFFICACIOUS. WE DON’T KNOW. NOT ALWAYS OBVIOUS WHAT THE TREATMENT EFFECT MAY BE, AND IN MANY CASES, IT TAKES MONTHS COMING BACK TO PLASTICITY BEFORE YOU’LL ACTUALLY SEE OR KNOW WHAT THAT END RESULT WILL BE FOR THE PATIENT THAT YOU’RE TRYING TO TREAT. WE WITH SAW IN SOME OF OUR STUDIES PATIENT BENEFITS INCREASING OUT TO SIX MONTHS BEFORE THEY START TO PLATEAU. SO THAT IS SOMETHING THAT NEEDS TO BE CONSIDERED WHEN DESIGNING CLINICAL TRIALS. NO QUANTITATIVE END POINTS ARE KNOWN AVAILABLE, SO WITH DEPRESSION, VERY MUCH A QUESTIONNAIRE-DRIVEN END POINT. WITH EPILEPSY, WE CHOSE VERY ARBITRARILY — I’M NOT SURE I COULD USE THE TERM “WE” GIVEN THAT IT WAS SO LONG AGO, BUT A 50% REDUCTION IN SEIZURE FREQUENCY WAS A STAKE PUT IT IN THE GROUND AS A DEFINITION FOR RESPONSE. SO IF YOU WERE A PATIENT WHO RECEIVED GREATER THAN 50% REDUCTION IN YOUR SEIZURES DURING THE COURSE OF TREATMENT AND YOU’RE PLACED IN THE RESPONDER BUCKET AND THE THERAPY WAS SAID TO HAVE RESPONDED. INTERESTING, NOT SURE THERE’S A LOT OF SCIENCE OR DATA BEHIND THAT. IT DOES TURN OUT TO BE THE CASE THAT THESE BATTERY OPERATED IMPLANTS HAVE TO BE REPLACED. IF ONLY 50% OF THE POPULATION OR 40% OF THE POPULATION WAS RECEIVING A 50% OR GREATER BENEFIT, THEN YOU WOULD EXPECT THAT ONLY 43% OF THE POPULATION AS THE PIVOTAL TRIAL INDICATED WOULD GET A REPLACEMENT DEVICE. WE ACTUALLY SEE THOSE RACE UPWARDS OF 90% WITH CYBERONICSES. SO I THINK THERE IS MORE THAN JUST THE DEFINITION AS IT RELATES TO WHETHER OR NOT A PATIENT IS DERIVING BENEFIT. AND KIP REALLY HAMMERED HOME MODELS FOR TRANSLATION, A LOT OF ANIMAL MODELS OUT THERE AND THEY DON’T ALL TRANSLATE VERY WELL TO HUMANS. THE HUMAN CONDITION PARTICULARLY IN THE REFRACTORY POPULATION, THERE ARE MANY CO-MORBID CONDITIONS, MANY PATHWAYS OF HOW THEY GOT TO EPILEPSY OR DEPRESSION OR HEART FAILURE, AND TEASING THEM ALL OUT IS A LARGE TASK. AND UNDERSTANDING HOW ANIMAL MODELS CAN BE BEST AUGMENTED TO REFLECT THAT CONDITION IS ALSO A BIT OF A CHALLENGE. SO STEPPING FORWARD INTO THE TECHNOLOGY SCIENCE OF PHYSIOLOGY, THERE ARE LIMITATIONS IN THIS SPACE, WELL, SURPRISE, SURPRISE. IMPRECISE TARGETING. I THINK KIP KIND OF HAMMERED THIS ONE AGAIN. WE STIMULATE WHERE WE CAN PLACE THE ELECTRODES AND WHETHER THERE’S A NERVE THERE THAT WILL GO TO THE END ORGAN THAT WE’RE TRYING TO EFFECT OR NOT. WE USE BASIC PHYSIOLOGY TO HELP US UNDERSTAND THAT, BUT IT IS THE CASE THAT THERE IS A LOT OF COLLATERAL STIMULATION THAT CAN OCCUR AS WELL. POSSIBLE STIMULATION PARAMETERS FOR ANY INDIVIDUAL PATIENT THAT’S BEING TREATED, THERE ARE SOME 7,000 PARAMETER SETS IN A STANDARD PULSE GENERATOR AND FIGURING OUT WHICH ONES ARE THE MOST EFFICACIOUS HAS BEEN THE LOT OF MANY PHYSICIAN HE’ LIVES FOR 10 OR SO YEARS. MAY NOT BE — WE TALK ABOUT THERAPEUTIC RYE SPONS MA
RESPONSE MAY NOT
BE IMMEDIATE OR OBVIOUS, WON’T BELABOR THAT POINT. ALSO TALK A LITTLE BIT ABOUT BIOMARKERS. IT IS NICE TO BE ABLE TO MEASURE BIOMARKERS AT THE 3 AND THE 6 MONTH TIME STAMPS, IT WOULD BE MUCH NICER IF WE WERE ABLE TO DO THAT IN REALTIME AND PROVIDE SOME SORT OF A CLOSED LOOP SYSTEM. AND OF THE ABILITY TO STEER OUR STIMULATION IN A QUANTIFIABLE WAY. RESPONSE PREDICTION IS ALSO AN IMPORTANT THING. WE SEEM TO HAVE ABOUT A 33% PROBLEM, WHICH ABOUT 33% OF OUR PATIENTS DON’T SEEM TO RESPOND AS FAVORABLY AS WE WOULD LIKE. AND WE NEED TO UNDERSTAND THE PHYSIOLOGY AND WHY THAT WOULD BE THE CASE. WE BELIEVE THAT IF WE HAD BETTER RESPONSE PREDICTION LEADING INTO A THERAPY THAT PATIENTS AND PHYSICIANS WOULD STEP INTO THAT THERAPY WITH GREATER CON FI DENSE. SO THAT IS AN IMPORTANT ASPECT OF THIS. I THINK WE’VE ALL TALKED ABOUT THE INCOMPLETE KNOWLEDGE OF MECHANISMS OF ACTION. BUT I DID WANT TO TOUCH A LITTLE BIT UPON WHY THAT WOULD BE A CHALLENGING AREA AND WHY WE MIGHT STILL HAVE A LACK OF UNDERSTANDING. WELL, IF YOU LOOK AT JUST THE HUMAN VAGUS NERVE WHICH HAS BEEN THE FOCUS OF OUR ATTENTION AT CYBERONICS, THERE ARE OVER — UNMYELINATED, LARGE, 20% A FIBERS AND B FIBERS. WHICH FIBERS ARE RESPONSIBLE FOR THE THERAPEUTIC EFFECT? IT DEPENDS ON ORGAN THAT YOU’RE TRYING TO HIT. THERE ARE SOME HYPOTHESES IN GOOD SCIENCE TO DEPICT WHICH FIBERS ARE THE TARGET FIBERS. ONCE YOU WRAP AN ELECTRODE AROUND THE NAY VALENTINE’S DAY
VAGUS NERVE
AND DELIVER STIMULATION TO IT — WHERE DO THESE FIBERS PROJECT INTO THE CNS PRI PERIPHERALLY? WHAT SYSTEMS ARE MODERATED OR INHIBITED? I LIKE TO SHOW THIS GRAPHIC JUST BECAUSE IT GIVES YOU THE SENSE THAT WE ACTUALLY MIGHT KNOW WHERE THE VAGUS NERVE GOES INTO THE BRAIN. WE THINK IT INNERVATES THE — AND HITS VERY IMPORTANT CENTERS OF THE BRAIN LIKE THE LOCUS COERULEUS, WE CAN SEE WHERE IT WOULD DRIVE A LACK OF EXCITABILITY IN THE EPILEPTIC PATIENT AND WHERE SEROTONIN MIGHT ACTUALLY DRIVE SOME MOOD IMPROVEMENT IN THE DEPRESSED PATIENT. WHAT ISN’T SHOWN HERE, WHICH WE’VE HAD TO LEARN OVER TIME, IS THAT BEFORE YOU CAN GET TO THIS NUCLEUS TRACTUS SOLITARIUS, YOU ENCOUNTER SOMETHING CALLED THE NODO GANGLIA, IT HAS A FUNNY WAY OF FILL IT TERRING OUT THE STIM LEATION YOU TRY TO PROVIDE. I’VE GOT ONE MINUTE TO WRAP THIS UP SO I’M GOING TO SPEED THIS ALONG. BOTTOM LINE ON THAT LAST SLIDE IS, JUST WHEN YOU THINK YOU UNDERSTAND THE ANATOMICAL LAYOUT AND WHERE THINGS GO, AND WE DO HAVE GOOD SCIENCE TO DEMONSTRATE THAT THE PROJECTIONS IN THE BRAIN DO HIT THOSE CENTERS, THERE ARE THINGS ALONG THE WAY THAT YOU DIDN’T ACCOUNT FOR THAT MIGHT ACTUALLY INHIBIT YOUR AIN’T TO DRIVE A ONE TO ONE EFFECT. A ONE TO ONE CAUSE AND EFFECT RELATIONSHIP BETWEEN THE STIMULATION SITE AND THE TARGET END ORGAN THAT YOU’RE TRYING TO EFFECT. THIS IS JUST A QUICK SLIDE THAT TALKS A LITTLE BIT ABOUT A FINITE ELEMENT ANALYSIS THAT WAS DONE IN COLLABORATION WITH HELMERS, ET AL., WHICH SHOWS AN ELECTRODE ENCOMPASSING ABOUT 270 DEGREES OF VAGUS NERVE AND AT VARIOUS OUTPUTS, BOTH IN THE ACUTE SETTING AND IN THE CHRONIC SETTING. THAT PLASTICITY AND ALSO FIBER END GROWTH CAN HAVE AN EFFECT ON HOW YOU STIMULATE. SO CHANGING STIMULATION OUTPUTS, IT IS VERY DIFFICULT TO USE THE ACUTE SETTINGS AND EXPECT THAT THEY WILL HAVE THE SAME LEVEL OF EFFECT IN THE CHRONIC SETTING JUST BECAUSE YOU’VE GOT A CHANGING TISSUE ELECTRODE INTERFACE, AND FIBROTIC TISSUE THAT IS CAUSING THE ELECTRICAL FIELDS TO CHANGE LOCALLY. SO HOW BEST YOU ACTIVATE THE RIGHT FIBER GROUPS BUT MINIMIZE ADVERSE EVENTS, WE’VE TALKED ABOUT THAT. LAST SLIDE HERE, I WANTED TO END ON SOMETHING THAT WAS A BIT OF A POSITIVE UPSWING WE’VE BEEN TALKING ABOUT CHALLENGES AND BELABORING THOSE A LITTLE BIT. I DO BELIEVE IN THE NEURAL CODE, I WATERED IT DOWN A LITTLE BIT, I DIDN’T THINK YOU GUYS WERE READY FOR THE LOVE LANGUAGE OF THE VAGUS NERVE SO WE TALK ABOUT IT IN TERMS OF THE NEURAL CODE. IF YOU THINK ABOUT THE AMOUNT OF MONEY, TIME AND ENERGY THAT WAS SPENT IN DECODING THE HUMAN GENOME, I’M NOT SUGGESTING WE HAVE TO GET TO THAT LEVEL TO UNDERSTAND OR TO PROVIDE BENEFICIAL THERAPY FOR PATIENTS THROUGH NEUROMODULATION, BUT WE COULD STAND TO UNDERSTAND THE BASIC PHYSIOLOGY AND THE MECHANISMS OF ACTION A LOT MORE THAN WE DO TODAY, AND I DO THINK THAT WE’RE IN THE BEST POSITION EVER TO DO THAT WITH SOME OF THE NOVEL TECHNOLOGIES AND TOOLS THAT ARE COMING OUT. YOU’LL SEE THOSE TOOLS ON THE RIGHT SIDE JUST FOR THE PEOPLE WHO ARE REMOTE, ADVANCED BRAIN IMAGING TECHNOLOGIES, FMRI, SOME OF THESE IMAGING TECHNIQUES ARE ALLOWING US TO UNDERSTAND WHERE CEREBRAL BLOOD FLOW IS OCCURRING AND IN CONJUNCTION WITH STIMULATION AND HELPING US TO FEEL MORE BULLISH THAT WE’RE GETTING THE END RESULT OR AT LEAST TOUCHING CERTAIN AN ANATOMICAL LOCATIONS IN A RELIABLE WAY. OPTIGENETICS AS IT RELATES TO DIAGNOSTICS AND UNDERSTANDING CAUSE AND EFFECT. THE PROMISE OF BIG DATA, WE’LL GET TO THAT LATER IN THE WORKSHOP, NANOTECHNOLOGIES, AND SINGLE — OUTPUTS AND ALGORITHMS THAT CAN BE USED AND BROUGHT TO BEAR JUST UNDERSTANDING IN A MORE FULL CONTEXT THE EVOKED POTENTIAL THAT IS THE RESULT OF STIMULATION. I THINK WITH THAT, I’LL JUST CALL IT. THANK YOU FOR YOUR TIME. [APPLAUSE]>>MILTON, VERY NICE PRESENTATION ABOUT WHERE WE ARE. I’M GOING TO TALK BRIEFLY IN MY PRESENTATION ON — DEPENDING ON THE TIME. THE ONLY POINT I WANT TO MAKE THE COMMENT TO THIS GROUP IS THAT SOME OF THESE TRIALS THAT FAILED, PRESUMABLY FAILED, SHOULD BE USED AS AN OPPORTUNITY TO LEARN RATHER THAN TO DEFEAT ITS PURPOSE OF WHAT WE’RE TRYING TO DO.>>CORRECT.>>ALSO WITH REGARD TO KIP’S COMMENT ON ANIMAL MODELS, I AGREE THAT IT’S NOT ALWAYS TRANSLATABLE TO THE HUMAN. BUT DEPENDING ON THE MODEL, AND DEPENDING ON HOW IT’S BEING USED, AND DEPENDING ON THE ABILITY TO REPLICATE THE HUMAN CONDITION IN TERMS OF BACKGROUND THERAPY AND WHAT YOU HAVE, ONE CAN GET CLOSER TO WHAT IT MIGHT TURN OUT TO BE.>>YES.>>IN THE END, WE HAVE NO CHOICE, WE CANNOT USE THE HUMAN AS THE — FOR THE ANIMAL. JUST SO THAT WE ARE ALL ON THE SAME PAGE.>>AND I AGREE WITH THOSE POINTS 100%, AND IF YOU LOOK AT MY OLD COMPANY, CYBERONICS, WE CONTINUE TO MOVE FORWARD WITH THE HEART FAILURE TRIAL, ANTHEM IS NOW MOVING INTO ENCORE, WHERE WE’VE STARTED A PRESERVED EJECTION FRACTION PATIENT POPULATION AS WELL, AND ARE NOT DISSUADED BY THE RESULTS OF NECTAR. WE DO THINK THAT HAS A LOT MORE TO DO WITH THE STUDY DESIGN AND WE’LL LOOK FORWARD TO THEIR 12 AND 18 MONTH RESULTS AS WELL.>>THE ANIMAL MODEL, YOU DON’T HAVE TO WORRY SO MUCH ABOUT THE PLACEBO EFFECT WITH THE ANIMAL MODEL. DR. — OF UCLA IS GOING TO TAKE THE DAUNTING TASK OF TELLING US ABOUT THE AUTO MO NICK NERVOUS SYSTEM, BRINGING US UP TO SPEED ON IT IN 15 MINUTES. OR 20.>>10 MINUTES NOW. SO I WOULD LIKE TO THANK THE ORGANIZERS FOR INVITING ME TO GIVE THIS OVERVIEW. SO WHICH IS QUITE A DAUNTING TASK INDEED. SO IF WE GO BACK TO THE TERM OF AUTONOMIC NERVOUS SYSTEM THAT WAS COINED IN BY LANGLEY IN 1898 TO DESCRIBE THE SYMPATHETIC SYSTEM AND THE ALLIED NERVOUS SYSTEM OF THE CRANIAL AND SACRAL NERVES AND THE LOCAL SYSTEM OF THE GUT. SO THE AUTONOMIC NERVOUS SYSTEM ENCOMPASSES THE SYMPATHETIC DIVISION, THE PARASYMPATHETIC DIVISION AND THE ASSOCIATED VISCERAL AFFERENT NEURONS AND THE ENT TAIRK DIVISION, WHICH IS THE LARGEST — WITH 200 TO 600 MILLION NEURONS. THESE ENTERIC DIVISIONS ACTUALLY IS ORGANIZED IN — BETWEEN THE SECULAR AND LONGITUDINAL MUSCLE AND THE SUBMUCOSAL PLEXUS, WHICH IS NEAR THE MUCOSA — ABOVE THE — MUCOSA. THE — WAS EXTENSIVELY DID DESCRIBED IN A SINGLE — 600 PAGES THAT I RECOMMEND YOU TO READ TO GET MORE INSIGHT, WHICH I APOLOGIZE WE DON’T HAVE THE TIME TO DO IT AS I WAS PREPARING FOR THAT TALK, SO BUT WHAT WE COULD SAY IS THAT ALMOST ALL BODILY FUNCTIONS ARE UNDER OF THE CONTROL OF THE AUTO NO MIC NERVOUS SYSTEM WHICH ACTUALLY ADJUSTS THE ACTIVITIES OF ORGANS OR TISSUES NOT UNDER OVERT VOLUNTARY CONTROL. WHICH IS A KEY POINT. AND THERE IS A LOT OF EXAMPLES THAT YOU WILL HEAR THROUGHOUT THE WORKSHOP — CARDIOVASCULAR SYSTEM AND THE GASTROINTESTINAL SYSTEM. THERE WAS SOME DEBATE ABOUT WHETHER TO CLASSIFY SOME NEURON THAT CARRIES THE AFTE AFFERENT INFORMATION TO THE BRAIN WERE AUTO NAUTONOMIC — FROM THE
VISCERA OF THE DIGESTIVE TRACT AND WE ARE NOT REALLY CLASSIFIED AS AUTONOMIC AFFERENT AND THE NAME OF VISCERAL AFFERENT IS MORE LARGELY USED FOR THIS TYPE OF AFFERENT — SENDING INFORMATION TO THE BRAIN. THIS IS A LONG GOING LIST OF MAJOR FUNCTIONS WHICH ARE UNDER THE CONTROL OF THE AUTONOMIC NERVOUS SYSTEM, WHICH GO FROM THE HEART RATE, FORCE AND CONDUCTION, ARTERIAL DIAMETER, THE MESENTERIC VENUS CAPACITY, THE PEUP LEAR DIAMETER, ACCOMMODATION OF LENS, EXOCRINE GLAND SECRETION, INCLUDING LACK RI MALL, SALIVARY, GASTRIC, EXOCRINE PANCREATIC, SWEAT GLANDS, GLANDS OF GENITAL ORGANS, ENDOCRINE GLANDS INCLUDING THE PANCREAS, ADRENAL GLAND AND LIVER, SECRETION INTO ORGAN LIKE INTESTINAL WATER OR ELECTROLYTE SECRETIONS, THE ACTIVITY OF THE GASTROINTESTINAL TRACT, THE GALLBLADDER AND BILIARY TRACT, THE REGULATION OF THE BLADDER THAT YOU WILL HEAR IN THE NEXT WORK SHOP, AND THE CONTROL OF MIC TOUR ITION, TRAIL YAK AND BRONCHIAL DIAMETER, CONTRACTION OF VAS DEFERENS, VAGINA AND OTHER INTERNAL GENITALIA, MOBILIZATION OF ENERGY STORES — THIS REALLY SHOWS THE IMPORTANCE OF THE AUTONOMIC SYSTEM WITH A LOT OF FUNCTIONS. WHAT’S IMPORTANT FROM AN ANATOMICAL POINT OF VIEW IS THAT THERE IS A LOT OF DIFFERENCE BETWEEN THE SYMPATHETIC AND PARASYMPATHETIC SYSTEM, AND IT MUST BE SAID THAT WHILE THEY HAVE BEEN NAMED AS OPPOSITE SYSTEMS, BASED ON THE EARLY DEMONSTRATIONS THAT THE — WAS — CARDIOVAST GAR FUNCTION, IS NO LONGER — ACTUALLY BOTH SYMPATHETIC AND PARASYMPATHETIC PARASYMPATHETIC — SO HOWEVER — VERY MUCH DIFFERENCE IN THEIR ORIGIN, WHEREBY THE SYMPATHETIC NERVES ARE ORIGINALLY ORNLG RATING FROM IT THE THORACOLUMBAR PART OF THE SEGMENT OF THE SPINAL CORD, FROM THE CRANIAL — THERE IS ALSO DIFFERENCE IN THE LOCATION OF THE BEGAN DPLE OF
THE GANGLIA. OBVIOUSLY THIS LEADS TO VERY MUCH DIFFERENTIAL LENGTH IN THE POST — FIBER WHEREBY THE SYMPATHETIC LONG FIBER AND PARASYMPATHETIC ARE SHORT. ONE EXCEPTION IN SYMPATHETIC INNERVATION OF THE ADRENAL MEDULLA, THEREFORE WE COULD LOOK AT THIS ACTIVITY IN THIS NERVE AS A REFLECT OF PREGANGLIONIC OUTFLOW. INTERESTING WORK DONE IN GERMANY CLEARLY ESTABLISHED THAT THE MED MEDULLA GLANDS — IT ACTUALLY INTERACT WITH THE ADRENAL CORTEX THAT — WHEREBY THE ACTIVITY OF THE CELL IN THE MEDULLA PROMOTES PROMOTES — SHOWING A VERY STRONG INTERACTION BETWEEN THE SYMPATHETIC OUTFLOW AND THE ENDOCRINE RESPONSE OF THE ADRENAL CORTEX, AND — IN MANY WAYS ARE — WORKING TOGETHER AND SHOULD BE CONSIDERED AS AN IMPORTANT FUNCTION TO REGULATE MOST OF THE VISCERA. SO THIS IS LIKE AN OVERVIEW SLIDE THAT WILL BE MOST LEA MORE DETAILED BY EACH SPEAKER AS THEY GO ALONG WITH THE SPECIFIC TARGET ORGAN FROM THE BLADDER TO THE CARDIOVASCULAR SYSTEM, THE LUNGS AND THE GI TRACT, BUT IT JUST OUTLINES MORE CLEARLY THE SYMPATHETIC AND AUTONOMIC PATHWAY IN RELATIONSHIP WITH — SYMPATHETIC NEURONS WHICH ARE ALONG THE THORACOLUMBAR — PROJECTIONS THAT GO INTO THE DIFFERENT SIM PA THEY IT TICK TRACT — GANGLIA AND THE PREDICTIONS THAT GO — THAT GO ALONG THE — GANGLIA, WHICH COMPOSES — AND THEIR PROJECTION TO TARGET ORGAN. WHILE THE PARASIM PA THEY IT TICK ORIGINATES FROM THE CRANIAL NERVE AND THE SACRAL PARASYMPATHETIC NERVE — AND MOSTLY INNERVATES THE LOWER GI TRACT AS THE BLADDER AND THE REPRODUCTIVE ORGANS. SOME DETAILED INFORMATION WILL BE GIVEN, BUT WHAT IT SHOWS, HOW MUCH NERVE THERE IS IN TERMS OF MODULATING THE END POINT ORGANS IN EACH PART, AND ALSO A VERY NICE SET OF — THAT COME FROM — AND GOING EITHER THROUGH THE SPINAL CORD OR THROUGH THE — GOING TO THE — SO NOW I WILL SWITCH — RELATIONSHIP WITH TARGETING SPECIFIC ORGAN, FOR WHICH THERE IS A LARGE NUMBER OF NEWER OWNS AS I HAVE MENTIONED, MILLIONS OF ENTERIC — AND THERE IS A LOT OF INFORMATION THAT HAS BEEN ACQUIRED IN RELATIONSHIP WITH WITH THE INNERVATION OF THE GASTROINTESTINAL TRACT. A GROUP OF DR. – DR. FURNESS —
THAT COULD SENSE THE INFORMATION COMING FROM THE — AND DO A REFLEX ARC WITHIN THE G.I. TRACT. — ESTABLISHED THESE INTESTINAL AFFERENT NEURONS THAT EITHER GO TO THE SYMPATHETIC PATHWAY OR TO OTHER TARGET ORGAN INCLUDING THE PANCREAS OF THE AIRWAY AND THIS SHOWS THERE IS THE POSSIBILITY OF INTERACTION BETWEEN ORGAN TO ORGAN IN RELATIONSHIP WITH THIS COMMUNICATION OF THE GUT INNERVATION TO ALSO TARGET ORGAN FROM THE PANCREAS, GALLBLADDER OR AIRWAYS. THERE IS THE AFFIRMATION ABOUT THEIR FUNCTION AND — ACTION IT’S — WELL ESTABLISHED BR — IMPORTANT TO — ACTIVITY OF THE G.I. TRACT IN CONNECTION WITH OTHER ORGANS. THERE IS ALSO A NUMBER OF — PARASYMPATHETIC EITHER AS THE LEVEL OF THE VAGAL OR LUMBOSACRAL AND SYMPATHETIC PATHWAY, SO THIS SHOWS THAT IT — INTESTINAL SYSTEM IS EXTREMELY WELL INNERVATED AT THE DIFFERENT REFLEX ARC THAT STILL NEED TO BE — WE HAVE TALKED A LOT ALREADY ABOUT THE VAGUS SO THAT HAS BEEN A SUBJECT OF INTERESTING RESEARCH FOR MANY YEARS, AND THERE IS NOW CLEAR EVIDENCE THAT THE — MOTOR NEURON — THE VAGUS — WHICH INNERVATES EITHER THE LIVER OR THE — WHICH IS A LIVER — THERE IS A GASTRIC — WHICH MOSTLY INNERVATES THE STOMACH AND THE — BRANCH WHICH MOST LIE INNERVATES MOST OF THE INTESTINE. AND THIS — THERE IS ALSO THE NUCLEUS — MOTOR NEURON THAT ALSO GO BACK TO THE VAGAL TRUNK AND INNERVATES EITHER THE LUNG, THE — AND THE LARYNX, FAIRNS, PHARYNX — ONLY 20% OF THE CYBERARE E — THE ORIGINAL DOGMA WAS THAT THERE IS THIS EV RENT PATHWAY GOING TO THE GUT RELATED TO THIS — NEURON I MENTIONED PREVIOUSLY AS THE ONE COMMON NEURON THAT TRANSMITS THE INFORMATION ON OTHER NEURONS NEURONS. — CLEARLY IT ESTABLISHED THAT VAGAL — EXTENSIVELY CONTACTING LARGE NUMBER OF GAS TRICK — NEURON, ON — ILLUSTRATE HERE, THIS TEM STRAITS HOW MUC
DEMONSTRATES — A
SSIGNED MAPPING TECHNIQUE, YOU COULD GO FROM ONE CONCEPT TO ANOTHER, AND COMPLETELY CHANGE THE OVERALL UNDERSTANDING THE WAY THAT THE VAGAL INNERVATIONS MODULATE THE ENTERIC NERVOUS SYSTEM. SO WE HAVE BEEN INTERESTED BECAUSE OF THE FACT THAT THIS — MOTOR NEURON ARE SO IMPORTANT TO REGULATE GASTRIC AND INTESTINAL MOTOR FUNCTIONS THROUGH THE PROJECTION, WE HAVE TRIED TO ESTABLISH WHAT IS THE OVERALL MECHANISM — AND WE WERE ABLE IT TO SHOW THAT THIS THREE AMINO ACID PEPTIDE — FACTOR WHICH IS LOCATED IN THE — OF THE PEPTIDE AND ALSO — VERY RICH EXPRESSION OF — WHEN WITH WE USE THIS PEPTIDE INJECTED INTO THIS KNEWLY EYE, WE WERE VAST ARRAY OF RESPONSE IN RELATIONSHIP WITH INCREASED — THAT LEAD TO INCREASE IN — GROWTH, BLOOD FOE — IN THE STOMACH AND — WHAT WAS INTERESTING IS THE FACT THAT THE — OF THE ENDOCRINE GLAND OF THE STOMACH, INCLUDING RELEASE OF — AND SEROTONIN AND GHRELIN, ALSO WE DEMONSTRATE AN ANTI-INFLAMMATORY EFFECT OF THIS ACTIVATION OF THIS CHOLINERGIC PATHWAY IT — WITH THE EARLY IT — DEMONSTRATION BY DID DR. TRACY. THE PANCREATIC EXOCRINE AND END DRIN KRIN IS ALSO STIMULATED, INTESTINAL MOTILITY AND SECRETION, SHOWING HOW MUCH THIS VAGAL ACTIVITY COULD CONTRIBUTE TO THE HOST OF CHANGE IN MODULATING THE GASTROINTESTINAL FUNCTION, BUT MORE IMPORTANTLY WAS THE FACT THAT BY IDENTIFYING THIS — STIMULANT OF THE VAGUS DURING THE — PHASE, WE WERE ABLE TO INJECT THIS PEPTIDE AT DIFFERENT DOZDOSE TO MODULATE
EFFERENT ACTIVITY OF THE VAGUS, AND THERE WE WERE ABLE TO DEMONSTRATE THE VARIOUS — DIFFERENT EFFECT OPPOSITE ACTION DEPENDING IF YOU HAVE A LOW STIMULATION OR HIGH STIMULATION. ON THE LOW STIMULATION, NOT IN THE STOMACH, YOU INCREASE AS THE OVERALL DIFFERENCES MECHANISM OF THE GASTRIC MUCOSA, WHICH PROTECT AGAINST AGENT AND THIS WAS MORE ABOUT THE INCREASE IN BLOOD FLOW — TO INCREASE THE BLOOD FLOW, AND ALSO BY — THE EFFERENT FUNCTION OF — PEPTIDE WHICH — THE BLOOD FLOW. WHEN WE HAVE MAXIMAL STIMULATION — ONE HOUR LEAD TO GASTRIC EROSION SO IT SHOWS WE WOULD REALLY — MAP OF THE OVERALL IMPACT OF DIFFERENT LEVEL OF ACTIVATION ON THE — FUNCTION USING — STIMULANT OF — MOTOR NEURONS. NOW WHEN WE — AS ANOTHER EXAMPLE, OUR — TO RECORD BOTH AFFERENT AND EFFERENT SIGNALING IN THIS REFLEX, THIS IS ILLUSTRATED BY THE — WORK DONE BY — AT UCLA WHERE HE WAS ABLE TO — FROM THE DISTAL GASTRIC — BRANCH AND THE PROXIMAL, WHICH ARE DEPICTED HERE FROM THE BEAUTIFUL AFTER RANS TRACING DONE BY — SO HE WAS ABLE TO REGARD FROM THOSE TWO BRANCHES AT THE SAME TIME AS RECORDING CHANGE IN OVERALL — PRESSURE IN THE STOMACH, AND WHAT’S VERY INTERESTING IS THAT WHEN WE USE A — STIMULANT OF GA TRICK VAGAL AFTER RANT DEMONSTRATED BY ELLEN RYE BOLD EARLY ON, WHICH SHOWS THE ACTIVATION OF VAGAL — WHEN WITH WE LOOK AT THE — WHEN YOU GO IN ONE PATH OF THE STOMACH, YOU HAVE AN INCREASE IN VAGAL EFFERENT ACTIVITY, WHICH WILL — GAS TRICK ACCOMMODATIONS, BUT IN THE DISTAL PATH, YOU — THE VAGAL OUTFLOW TO THE — STOMACH WHICH HAS A — ACTION TO PROPEL THE COMPOUND INTO THE — SO YOU ACHIEVE WA WE CALL — KNOWN FOR WHICH IS TO — AND RELAX THE STOMACH AND ALSO INDUCE — SO THIS OUTLYING THE IMPORTANCE TO BE ABLE TO RECORD AT THE DIFFERENT PATH OF THE TERMINAL OF THOSE VAGAL EFFERENCE — UNDERSTANDING OF THE REFLAX ART. ANOTHER — WHICH HAS BEEN RECENTLY ESTABLISHED BY THE GROUP OF IT DR. LITTLE AT — UNIVERSITY IN RELATIONSHIP WITH ALL THIS SENSORY SIGNALING COMING TO THE GUT IS AN IMPORTANT ASPECT WHICH IS RELATED TO HOW THE ENDOCRINE CELL, WHICH ARE ALL ALONG THE OVERALL GASTROENTESSAL TRACT THAT — GUT PEPTIDE SENDING SIGNALING INFORMATION TO THE BRAIN OR SAMPLING THE — OF THE BACTERIA, WHICH ARE IN THE LUMEN OF THE G.I. TRACT, AND WHAT WAS THE PREVIOUS UNDERSTANDING WHAT ACTUALLY — WHEN YOU ACTIVATE THOSE CELL, REALLY THEIR COUNTDOWN COULD BE PEPTIDE — BY — MECHANISM — ENTERIC NEURON ARE GOING TO — USING VERY — MICE ALONG WITH VERY — MAPPING STUDY, ESTABLISH ACTUALLY THAT THIS ENDOCRINE CELL FORM WHAT WE CALL NEURO — THIS — NEURON — LOW TO ESTABLISH SOME KIND OF — CONTACT BETWEEN NERVES. IT’S STILL NOT CLEAR WINNER OF COULD BE — IF SYNAPTIC CONTENT IS WITH EE FERNT OR AFTER NARNT — IMPORTANT FIELD THAT NEEDS TO BE FURTHER DEVELOPED, BECAUSE THIS WILL — TO REALLY WHAT WE CALL A — SIZE TOPOGRAPHICAL — AND ALSO THE POTENTIAL OF HAVING VIRUSES IN THE LUMEN TO THE GUT AND GAIN ACCESS TO THE PERIPHERAL OR CENTRAL NERVOUS SYSTEM. THERE’S IS A — DISEASE THAT STARTS IN THE GUT AND MOVES ITS WAY INTO THE NUCLEUS, WHICH IS WHY YOU HAVE CONSTIPATION FOR FIVE OR 10 YEARS BEFORE THE MODEL SYMPTOMS SIMENTS. SO THIS CHANGE IN THE OVERALL ARTICULATION OF THIS IT — ENDOCRINE SYSTEM IN RELATIONSHIP WITH SAMPLING WHAT’S HAPPENING IN THE LUMEN, UNDER PATHOLOGICAL CONDITION COULD BE — IMPORTANT TO UNDERSTAND . SO I THINK I WOULD LIKE TO MENTION ANOTHER EXAMPLE FOR WHICH — IMPORTANCE THE VAGAL SYSTEM AND THIS WILL BE PROBABLY WELL DETAILED BY TRACY, WHO HAS — THIS NEW CONCEPT. THE SAMPLE — OF THE VAGUS AS A — INFLAMMATORY REGULATOR, AND THIS IS BROUGHT ABOUT — FLAM TRI CYTOKINE THAT COULD INTERACT WITH VAI TBA ALL THROUGH THE
GANGLIA THAT CONTAINS THE CELL — OF VAGAL AFTER RANS THAT PROJECTS BOTH TO THE STOMACH AND TO THE BRAIN, AND THIS ACTIVATION BY THE CYTOKINE IS — TO MODULATE THE — ACTIVITY OF THE VAGUS, LEADING TO CHOLINERGIC PATHWAY AND DID — CHOLINERGIC RECEPTOR, MODULATE THE OVERALL REACTIONS OF THE INFLAMMATORY CELL. THERE IS ALSO A LOT OF WORK THAT NEEDS TO BE DONE TO UNDERSTAND THIS COMMUNICATION BETWEEN THE VA TBUS AND THE SYMPATHETIC GANGLIA, SHOWING THAT MAYBE — COULD BE A MIXED GANGLIA SYMPATHETIC AND PARASYMPATHETIC. STO IN CLOSING, THIS WAS A QUICK SURVEY WITH WITH DIFFERENT ASPECT THAT I WANTED TO OUTLINE, BUT I THINK AT THE — LEVEL, IT’S CLEAR THAT WE NEED A MORE DETAILED MAP TO DRIVE THIS HIGH RESOLUTION TRACING OF AFTER RAPT AND EFFERENT — AT VARIOUS LEVEL OF TARGET AND ALSO THE DIFFERENCES AND REALLY HIGHLIGHTED BY THE WORK OF DR. — BY THIS NEW APPROACH OF — WAS ABLE TO COMPLETELY REVERSE THE PREVIOUS — UNDERSTANDING OF THE ARTICULATION BETWEEN THE VAGUS AND ENTERIC NERVOUS SYSTEM, SO THIS NEEDS TO BE MORE DEVELOPED IN DIFFERENT TARGET ORGAN. AT THE FUNCTIONAL LEVEL, I THINK IT WILL BE VERY IMPORTANT TO GENERATE — RECORDING OF NEURONAL SIGNAL AND ORGAN FUNCTION, AND TO ASSOCIATE WHAT WE CALL END ORGAN — IN RESPONSE TO — STIMULUS SO WE HAVE A BETTER UNDERSTANDING OF OUR NEURAL SIGNAL TARGET — THE NEURAL SIGNAL AND — TO MODULATE END ORGANS AND WHAT ARE THE BIOMARKERS — SIGNALING OF THE NEURONAL ACTIVATION. WE NEED TO — FOR WHICH — NERVOUS SYSTEM — SIGNALING — CHANGE OF ORGAN FUNCTION USING AS I HAVE MENTIONED MAYBE SOME SPECIFIC — THAT ARE TARGETING SPECIFIC NEURON OF THOSE — NERVES SO WE HAVE A BETTER UNDERSTANDING OF DIFFERENT INTENSITY OF NERVE STIMULATION — IN TRANSLATING TO CHANGE IN THE END ORGANS — IT NEUROCHEMICAL AND THE APPLICATION OF THE ORGAN. ALSO — FROM CHANGE AT TARGET ORGAN TRANSFER TO DIFFERENT AUTO NO MIC REFERENCE LOCALLY, WE — CONNECTED ORGAN — INTEGRATION OF THE IT — AND THIS IS REALLY HIGHLIGHTED BY THIS INTERACTION BETWEEN THE — CELL AND THE NERVES THAT ARE NOW — COULD BE A MIXED — NEURONAL INTERACTION AS I HAVE MENTIONED. SO I THINK SOME OF THE WORK I HAVE MENTIONED HAS BEEN SUPPORTED BY THE NIH AND I THANK YOU FOR YOUR ATTENTION. [APPLAUSE]>>WE HAVE TIME FOR ONE QUESTION.>> — FROM BOSTON SCIENTIFIC. THANK YOU FOR A VERY NICE REVIEW. ONE QUESTION THAT I HAVE, YOU MADE AN IMPORTANT POINT ON ANATOMICAL DIFFERENCE BETWEEN THE SYMPATHETIC AND PARASYMPATHETIC NERVOUS SYSTEM WHERE THE SYMPATHETIC HAS SHORT — AND LONG — NEURONS AND THE PARASYMPATHETIC HAS LONG — AND VERY SHORT — LONG — AND SHORT — KIP MADE AN IMPORTANT POINT ABOUT AN IMPORTANT ISSUE WHEN YOU’RE TARGETING NEURONAL TARGETS WITH NEUROMODULATION, HOW CLOSE YOUR ELECTRODE IS TO YOUR TARGET. THE SECOND IMPORTANT ELEMENT IS HOW BIG YOUR AXON IS IN TERMS OF DIAMETER OF. THE DOGMA IS THAT PRE — NEURONS HAVE LARGER DIAMETERS THAN — NEURONS. IS THAT THE CURRENT BELIEF, IS THAT WHAT WE THINK IS HAPPENING WITH ALL OF THESE SYSTEMS, THAT WILL HAVE VERY IMPORTANT IMPLICATIONS FOR HOW WE DESIGN OUR SYSTEMS AND WHICH TARGET DO WE GO FOR.>>YEAH, THINK IT’S A VERY IMPORTANT POINT. I DON’T KNOW IF DR. POLLEL HAS MORE INSIGHT INTO IT THIS, BUT FROM YOUR TRACING STUDY THAT YOU HAVE DONE DONE?>>[INAUDIBLE]>>SO IT IS TIME FOR A BREAK.>>IT’S A PLEASURE TO BE HERE AND TO CHAIR THE NEXT SESSION, WHICH IS ENTITLED “NEUROCIRCUITS AND ORGANS AND DISEASE, OPPORTUNITIES FOR NEUROMODULATION IN THE LOWER URINARY TRACT.” MY NAME IS HELEN FROM THE SCHOOL OF VETERINARY MEDICINE. I’VE LONG BEEN INTERESTED IN THE AUTONOMIC NERVOUS SYSTEM, WHEN I FIRST MET CHET AT THE UNIVERSITY PITTSBURGH HE CERTAINLY HAS INSPIRED MANY YOUNG SCIENTISTS LIKE MYSELF AT THAT TIME TO COME INTO THIS FIELD. SO IT’S A PLEASURE TO INTRODUCE THE FIRST SPEAKER, WHO’S GOING TO TALK ABOUT NEURAL CONTROL AND NEUROMODULATION OF LOWER URINARY TRACT FUNCTION. WHAT WE WOULD LIKE TO DO, AS HE IS GOING TO TALK ABOUT THE BIOLOGY AND THE SECOND IT TWO SPEAKERS ARE GOING TO TALK A LITTLE MORE ABOUT SOME OF THE BIOENGINEERING ISSUES THAT WE WOULD HAVE A SHORT PERIOD OF TIME FOR DISCUSSION AFTER DR. DEGROTE’S TALK, MOVE ON TO THE TECHNOLOGY AND THEN HAVE AN INTEGRATED DISCUSSION AT THE END OF THE SESSION AFTER THE LAST SPEAKER.>>THANK YOU, HELEN. THE MIC IS NOT WORKING SO I’LL TRY TO TALK INTO THIS. I’M GOING TO HAVE A TOPIC INITIALLY DESCRIBED AS BEING SIMPLE. I’D LIKE TO RESPECTIVELY DISAGREE WITH DR. JE GERMINO. I THINK IT’S ACTUALLY MORE COMPLICATED THAN SOME OTHER FUNCTIONS IN THE BODY, BECAUSE IN CONTRAST TO AUTONOMIC CONTROL OF THE CARDIOVASCULAR SYSTEM, THIS IS UNDER VOLUNTARY CONTROL AS WELL AS AUTONOMIC CONTROL. SO AT ANY RATE, I WILL DISCUSS A NUMBER OF DIFFERENT TOPICS. ANATOMY AND FUNCTIONS, CENTRAL NEURAL CONTROL DYSFUNCTION, TREATMENT OF DYSFUNCTION WITH NEUROMODULATION AND RESEARCH OPPORTUNITIES. SO I AGREE THE FUNCTIONS ARE RELATIVELY SIMPLE. THERE ARE JUST TWO. IT STORE URINE AND RELEASES URINE. THAT’S THE LOWER URINARY TRACT. AND THERE’S A RESERVOIR, WHETHER YOU’RE — THE BLADDER, THE OUTLET, TH THE URETHRA, WHERE
URINE IS RELEASED. INTEREST IS A NECESSARY INTEGRATION BETWEEN SMOOTH AND STRIDED MUSCLE, WHICH AGAIN MAKES IT A LITTLE MORE COMPLICATED THAN MANY OTHER VISCERAL FUNCTIONS WHERE THERE’S PURELY SMOOTH MUSCLE. THESE FUNCTIONS ARE CONTROLLED BY THE CENTRAL NERVOUS SYSTEM. SO THE GUT AND THE HEART CAN REALLY FUNCTION QUITE WELL WITHOUT CENTRAL CONTROL. THIS DEPENDS ON CENTRAL NERVOUS SYSTEM CONTROL. YOU CAN’T EMPTY YOUR BLADDER WITHOUT THE CNS BRAIN AND SPINAL CORD PLAYING A ROLE. THE OTHER THING THAT YOU SHOULD RECOGNIZE, THAT THERE ARE DIFFERENT TYPES OF VOIDING. THERE IS INVOLUNTARY VOIDING IN INFANTS AND EVEN IN THE FEE IT TUS, AND THAIN THE FETUS,THAT
GOES ON FOR
SEVERAL YEARS AFTER BIRTH, AND EVENTUALLY WE BRING THAT INVOLUNTARY CONTROL UNDER VOLUNTARY REGULATION BY THE BRAIN WITH MATURATION OF THE NERVOUS SYSTEM. SO THERE’S A LOT OF INTERESTING ISSUES RELATED TO THE DEVELOPMENT OF VOLUNTARY CONTROL. IF WE’RE FORTUNATE, IT REMAINS THAT WAY THRAWOUT ADULT LIFE. IF YOU’RE UNFORTUNATE AND ENCOUNTER PARKINSON’S DISEASE OR MULTIPLE SCLEROSIS, STROKE, BRAIN TUMOR, SPINAL CORD INJURY, ET CETERA, YOU CAN LOSE VOLUNTARY CONTROL AND CYCLE BACK SOMEWHAT TO WHAT YOU WERE WHEN YOU WERE FIRST BORN. REFLEX CONTROL EMERGES AND THE GOALS OF THERAPY ARE TO REMOVE OR ELIMINATE REFLEX CONTROL, RE-ESTABLISH NORMAL VOLUNTARY CONTROL, AND NEUROMODULATION CAN BE EFFECTIVE AND DRUGS CAN AS WELL IN PROMOTING THAT CHANGE. SO THE URINARY TRACT IS INNERVATED AS THE VET SAID BY SYMPATHETIC AND PARASYMPATHETIC NERVES, AND ALSO BY SOMATIC NERVES. SO YOU HAVE THE BLADDER INNERVATED BY PARASYMPATHETIC WHICH RELEASES — EXCITING CHOLINERGIC RECEPTORS THAT CAUSE THE BLADDER TO CONTRACT, INNERVATED BY SYMPATHETIC NERVES, WHICH CAN ACTIVATE BETA 3 RECEPTORS AND TURN THE BLADDER CONTRACTION OFF. THE SYMPATHETIC PATHWAY CAN ALSO INNERVATE ALPHA RECEPTORS IN THE URETHRA BECAUSYOU’RE EETURETHRA,
AND THE P
UDENDAL NERVES AND OTHERS THAT ARISE FROM THE LUMBOSACRAL CORD CAN INNERVATE THE PELVIC FLOOR MUSCLES AS WELL AS THE EXTERNAL URETHRAL SPHINCTER. NOW WE SHOULD RECOGNIZE THAT THIS IS A TEXTBOOK PICTURE. THIS IS A TRADITIONAL VIEW. AND AS EE VET POINTED OUT, THERE ARE AUTONOMIC GANGLIA INTERVENING BETWEEN THE SPINAL CORD AND THE END ORGAN ITSELF. WE REALLY DON’T KNOW VERY MUCH ABOUT THE FUNCTION OF THE GANGLIA WHICH ARE INVOLVED IN BLADDER CONTROL IN HUMAN, BUT IN ANIMALS, THESE GANGLIA CAN BE QUITE COMPLEX. THEY CAN MODULATE IN VERY COMPLEX WAYS THE SIGNALS COMING FROM THE SPINAL CORD OUT SO THE END ORGAN. IN ADDITION, THIS IS A VERY SIMPLIFIED VERSION OF THE INNERVATION BECAUSE THE SYMPATHETIC AND PARASYMPATHETIC NERVES CAN INTERACT, AND WE PROBABLY WILL HEAR SOMETHING ABOUT THIS IN THE HEART. BUT ONE TRANSMITTER CAN ACT ON THE PRESYNAPTIC POST GANGLIONIC TERMINALS AND EFFECT TRANSMITTER RELEASE. IN ADDITION, IN THE GANGLIA, NOT SHOWN HERE, THE SYMPATHETICS CAN ALSO MODULATE PARASYMPATHETIC BEGAN GLEEONICS TRANSMISSION. NOTHING IS KNOWN ABOUT THIS IN HUMANS, SO THIS IS AN AREA THAT SHOULD BE STUDIED. SO WE HAVE OVER HERE THE BRAIN, NECESSARY FOR VOLUNTARY VOIDING, SENDING INFORMATION DOWN TO THE SPINAL CORD, AND GOING OUT TO THE LOWER URINARY TRACT THROUGH THE THREE SETS OF NERVES, HYPOGAS TRICK SAME PATHETIC, AND SOMATIC NERVES GOING OUT TO THE STRIDED MUSCLE, THE SPHRINGTER
SPHINGTER AND THE VICK FLOOR. SO THE THE BRAIN’S FUNCTION IS TO COORDINATE THE THREE ORGANS AND THREE NERVE SUPPLIES TO THOSE ORGANS. SO YOU SHOULD ALSO ALREADY AS EVETTE POINTED TOUT THAT AUTONOMIC NEVERS CONTAIN AFTER RANT AS WELL AS EFFERENT NERVES, SO THERE ARE MOTOR PATHWAYS MEDIATED BY E IF FFRENS — AND IN THE VISCERA, THERE ARE GENERALLY TWO TYPES OF AFFERENTS, SMALL MYELINATED A DELTA FIBERS AND UNMYELINATED C FIBERS. THIS IS SIMILAR FOR BLADDER AND FOR BOWEL IN TERMS OF THE LUMBOSACRAL INNERVATION. WE BELIEVE BASED ON ANIMAL WORK THAT THE — ARE MECCA KNOW SENSITIVE AND TELL YOU THAT YOUR BLADDER IS BEING FILLED AND INDUCES SENSATIONS OF FULLNESS AND OVERACTIVITY. THE C FIBERS ARE THOUGHT TO BE INCANO INSENSITIVE AT LEAST IN SOME ANIMALS AND MAY PRESENT IN THIS WAY IN HUMANS. THESE CAN BE ACTIVATED BY — LIKE BLADDER INFECTION OR CHEMICAL IRRITATIONS IN THE URINE, AND TRIGGER URGENCY FREQUENCY AND INCONTINENCE AND PAIN. SO THE C FIBER SYSTEM IS OFTEN LINKED WITH PATHOLOGY. BY THAT MEANS THEN IS A TARGET FOR VARIOUS TYPES OF DRUGS AND FOR NEUROMODULATION. SO THE IMPORTANT TAKE HOME MESSAGE IN TERMS OF AFFERENS IS THIS IS PATHOLOGICAL INDUCED ACTIVITY, THIS IS NORMAL MECHANICAL INDUCED ACTIVITY. SO THERE ARE A COUPLE OF INTERESTING UNUSUAL CHARACTERISTICS OF THE AFTER RANS TO THE LOWER URINARY TRACT. ONE IS THAT THE C FIBERS CAN ACTUALLY RECEIVE INFORMATION FROM THE PEP THEEL YAL LINING OF THE BLADDER BY THE RELEASE OF CHEMICAL MESSENGERS. THIS IS SIMILAR TO WHAT EVETTE TALKED ABOUT IN THE GUT, WHERE THERE MAY BE EPITHELIAL CELLS THAT COMMUNICATE WITH AFTER RENTS AND TELL YOU SOMETHING ABOUT THE COMPOSITION OF THE FOOD, WE’LL PROBABLY HEAR THAT THIS MAY HAPPEN IN THE LUNG AS WELL. SO THE C FIBERS ARE ABLE TO RECEIVE INFORMATION ABOUT THE CONTENTS OF THE BLADDER LUMEN THROUGH — SIGNALING. THE BLADDER URITHELIUM — WHICH PREVENT THE IT DIFFUSION OF SUBSTANCES FROM THE URINE INTO THE BLADDER. AND SO THIS IS A WELL-KNOWN BARRIER FUNCTION. BUT THE — ALSO RECEIVED AN AFFERENT INNERVATION AND THIS INNERVATION THEN CAN BE SUBJECTED TO A VARIETY OF CHEMICAL MODULATIONS. AND THIS JUST SHOWS YOU SOME EXAMPLES. HERE’S THE UROTHEEL YUM, HERE’S THE MUSCLE DOWN HERE. THE YOU’RE THEEL CELLS CAN RELEASE ETP, AND CAN RELEASE THOSE IN RESPONSE TO VARIOUS STIMULI LIKE CHANGES IN MECHANICAL STRETCH, ACID CONDITIONS IN THE URINE, CAPSAICIN OR TEMPERATURE CHANGES IN THE BLADDER. SO THE UROTHELIAL YUM, AS I SAID BEFORE, CAN SEND SIGNALS TO AFFERENT NERVES THROUGH CHEMICAL MESSAGES. IN ADDITION, THE AFFERENT NERVES CAN RELEASE CHEMICALS AND EFFERENT NERVES CAN RELEASE CHEMICALS, WHICH MAY ACTUALLY REACT — TO CHANGE UROTHELIAL YAL PROPERTIES. SO I THINK WE WANT TO EMPHASIZE THAT THERE’S A BUY DIRECTION ITAL COMMUNICATION BETWEEN AFFERENCE, EV RENS, AND THE UROTHELIAL YUM, AND THIS MAY BE PLAYING A VERY IMPORTANT ROLE IN DER SENSATIONS, PARTICULARLY IN PATHOLOGY. THIS IS SOMETHING THAT COULD BE PURSUED IT FURTHER IN HUMANS TO DETERMINE THE IMPORTANT ROLE IN THIS BOTH IN PHYSIOLOGY AND PATHOPHYSIOLOGY. SO THERE’S ANOTHER INTERESTING ASPECT OF THE AFFERENCE, THAT IS FROM THE ADJACENT PELVIC ORGANS CAN SEND SIGNALS TO THE SAME POPULATION OF SECOND AUTO NEURONS IN THE SPINAL CORD. THEREFORE SOMETHING THA THAT HAPPENS IN ONE ORGAN MAY AFFECT THE PROCESS OF SENSORY OUTPUT COMING FROM ANOTHER ORGAN, AND THIS COULD BE CALLED CONVERGENCE. THERE’S A RELATIVELY SMALL AREA OF THE SPINAL CORD, JUST A FEW SEGMENTS, THAT RECEIVE INPUT FROM THESE VARIOUS PELVIC ORGANS AND THERE’S A LOT OF OVERLAP WITH THAT TYPE OF SENSORY INPUT. SO THE OTHER IS DICHOTOMIZING AFTER RENS, AND THIS HAS BEEN RECOGNIZED IN THE LAST FEW YEARS THAT — IN THE DORSAL ROOT GANGLIA CAN INNERVATE MORE THAN ONE ORGAN. SO THE BLADDER AND THE COLON MAY RECEIVE INPUTS FROM ONE SENSORY NEURON. AND WE’LL HEAR MORE WITH ABOUT THIS FROM JAY PASHRIKA, I BELIEVE TOMORROW, WHERE THE PANCREAS AND THE INTESTINE MAY INTERACT OR COMMUNICATE VIA THESE DICHOTOMIZING AFFERENTS. AND SO SOME POINT ALONG THE PATHWAY, THERE’S A BRANCH POINT AND NERVES GO TO TWO DIFFERENT STRUCTURES. WHETHER THIS HAPPENS IN HUMANS, NOT KNOWN. IT’S BEEN STUDIED MAINLY IN CATS. THE OTHER THING IS RECENTLY COLLEAGUES IN PITTSBURGH HAVE SHOWN THAT VIRUSES INJECTED INTO ONE ORGAN CAN TRANSPORT BACK UP TO THE DORSAL GANGLIA, COME BACK DOWN AGAIN AND GO TO THE OTHER ORGAN AND INFECT THE EPITHELIAL CELLS. SO THIS RAISES THE POSSIBILITY THAT YOU COULD HAVE COINFECTION OF DIFFERENT ORGANS THRAW THIS DICHOTOMIZING AFFERENT SYSTEM. AS A MATTER OF FACT, CONVERGENCE MAY CONTRIBUTE TO VISCERAL REFERRED PAIN THAT, IS THE INTESTINAL AFFERENT SHOWN HERE, THEY CONVERGE ON THE SAME POPULATION OF NEURONS THAT ARE INNERVATED BY SKIN. PAIN IN THE INTESTINE CAN INFLUENCE THE PROCESSING OF INPUT FROM THE SKIN AND, THEREFORE, INDUCE REFERRED PAIN. SO THIS SYSTEM CAN BE VERY IMPORTANT AND OBVIOUSLY IF WE’RE TRYING TO TREAT PATHOLOGICAL CONDITIONS WITH NEUROMODULATION, IT’S A ANATOMICAL SYSTEM THAT NEEDS TO BE TAKEN INTO ACCOUNT. CAN YOU HEAR ME BACK THERE? AM I CLOSE ENOUGH TO THIS? OKAY. ALL RIGHT. SO LET’S GO TO THE CENTRAL NERVOUS SYSTEM. AND TRY TO UNDERSTAND IN A VERY GENERAL WAY HOW THE CNS CONTROLS LOWER URINARY TRACT FUNCTION. SO AS I SAID, THE FUNCTIONS ARE SIMPLE. STORAGE AND RELEASE. WE CAN GO FROM STORAGE OF URINE TO RELEASE OF URINE, IN A VERY RAPID FASHION. SO I’VE OFTEN PROANSED AND LIKE TO THINK THAT THIS WORKS LIKE THE SWITCH, THE SWITCH ON THIS POINTER, ON OR OFF. SO IT’S NOT A GRADUAL CONTROL OF BLOOD PRESSURE RAISED AT 10 MILLIMETERS OF MERCURY AS KIP TOLD US OR LOWERED IT A LITTLE BIT. THIS WAS AN ALL OR NONE SWITCH AND THAT’S THE WAY IT NORMALLY WORKED. SO YOU HAVE VARIOUS ELEMENTS OF THAT SWITCHING CIRCUIT, AND FOR YEARS WE’VE BEEN INTERESTING IN DEFINING ANATOMICAL AND FUNCTIONAL PROPERTIES OF THAT CIRCUIT. SO YOU HAVE THE ORGANS THEMSELVES, THE RESERVOIR OR THE OUTLET, YOU HAVE AFFERENT — TO THAT SWITCH AND THAT LEVEL OF INPUT DETERMINES HOW THAT SWITCH IS THROWN, OR ALSO HOW IT’S CONTROLLED AND HOW IT PROVIDES INFORMATION BACK TO THE ORGANS. WITH A LOW LEVEL OF AFFERENT ACTIVITY IN THE HUMAN INFANT AS THE BLADDER IS FILLING, THE AFFERENTS DRIVE THE SWITCH INTO A STORAGE MODE. STORAGE IS ON, ELIMINATION IS OFF. AS THE BLADDER FILLS UP FURTHER, THE AFFERENT ACTIVITY INCREASES AND EVENTUALLY REACHES THE LEVEL OF THE THRESHOLD FOR THE SWITCH, TURNS THE STORAGE OFF, TURNS THE ELIMINATION ON, AND URINE M COMES OUT AND THEN IT STARTS TO FILL AGAIN. SO MIC TRITION SWITCH IS A LARGE CHALLENGE TO UNDERSTAND HOW THE LOWER URINARY TRACT FUNCTIONS. THE SWITCHES ARE SHOWN IN THE VERY GENERAL WAY IN THIS WAY. IT TURNS OUT THAT STORAGE REFLEXES AND VOIDING REFLEXES ARE ORGANIZED DIFFERENTLY IN THE CENTRAL NERVOUS CYST IT TEM. STORAGE REFLECTED ARE ORGANIZED IN THE SPINAL CORD AS SEGMENTAL AND DRIVEN ALL BY BLADDER MECCA KNOW SENSITIVE — WHEN IT’S FILLING, IT DRIVES THE NERVE TO CAUSE THE SPHINCTER TO CONTRACT. THIS IS CALLED THE GUARDING REFLEX, AND IT ALSO GENERATES AN INTERSEGMENTAL REFLEX FROM SACRAL CORD TO LUMBAR CORD THAT ACTIVATES THE HYPE GAS FRICK
HYPOGASTRIC NERVE — AND THIS PROMOTES URINE STORAGE. WHETHER THIS OCCURS IN HUMANS IS NOT KNOWN, SO THIS IS DEFINITELY SOMETHING THAT SHOULD BE STUDIED IN THE FUTURE. THERE IS A AREA IN THE CAT CALLED THE PONTINE STORAGE CENTER, WHICH FACILITATES THESE SPINAL REFLEXES. NOW, IN THE INFANT AS AFFERENT ACTIVITY INCREASES FURTHER, MORE INFORMATION IS SENT UP TO THE BRAINSTEM. TO THE PERI AQUA DUCT AL — IT TURNS ON THE DESCENDING PATHWAY TO THE CORD, IT TURNS OFF THE SYMPATHETIC AND — INPUT, TURNS OFF THE PUDENDAL SOMATIC INPUT TO THE SPHINCTER AND TURNS ON THE INPUT TO THE BLADDER TO CAUSE THE BLADDER TO CONTRACT, AND THAT IS THE SUPRASPINAL VOIDING REFLEX. IN ANIMALS, YOU CAN REMOVE EVERYTHING ABOVE THE PERIAQUEDUCTAL GRAY. THAT SWITCH IS FUNCTIONAL. YOU CUT THE SPINAL COUR SPINAL
CORD AT ANY POINT BELOW THE LEVEL OF THE PONS AND THAT SWITCH FAILS. SPINAL CORD INJURY HAS AN IMPORTANT DOWNSIDE AND THAT’S LOSS OF BLADDER FUNCTION. SO VOLUNTARY CONTROL NOW IS BUILT BY HIGHER CENTERS WHICH IMPINGE UPON AND CONTROL THOSE IT BASIC SWITCHES, AND THIS IS A — BASED ON A SERIES OF STUDIES USED IN FUNCTIONAL MAGNETIC RESONANCE IMAGING. THIS SLIDE WAS PREPARED BY MY COLLEAGUE, CLAIRE FALLARD, WHICH SHOWS THE MICTURITION CENTER AND HOW AFFERENT ACTIVITY IS INCREASING AS THE BLADDER FILLS, AS RECEIVED BY THESE AREAS UP IN THE BRAIN. THESE AREAS IN THE BRAIN ARE IN TURN CONTROLLED BY FOUR BRAIN STRUCTURES, PREFRONTAL CORTEX, WHICH IT DURING URINE STORAGE AUTOMATICALLY SENDS INHIBITORY SIGNALS BACK TO THESE REFLEX CENTERS TO KEEP THEM SIGH LEAPT. SO THAT’S WHAT’S HAPPENING IN THEORY DURING URINE STORAGE AND DURING VOIDING THAT — IS TURNED OFF AND VOLUNTARILY EXCITATION IS TURNED ON, SENDS — SIGNALS TO THESE STRUCTURES, AND THEN THOSE SIGNALS ARE SENT BACK DOWN TO THE SPINAL CORD AND COORDINATE BLADDER CONTRACTION AND URETHRAL RELAXATION AND VOIDING. SO THIS WOULD BE THE BASIC CENTRAL CIRCUITRY WHICH REGULATES LOWER URINARY TRACT FUNCTION. AND THE CIRCUITS — I’M GOING TO RUN OUT OF TIME SO I’LL JUST SAY A NUMB W NUMBER OF DIFFERENT
CIRCUITS HAVE BEEN IDENTIFIED. THALAMUS AND — ARE VISCERAL SENSORY RECEIVING AREAS, WHICH THEN IMPINGE UPON THE MEDIAL PREFRONTAL CORTEX WHICH THEN FEEDS INFORMATION BACK TO THESE CIRCUITS IN THE PHA AND PMC, AND THEN THE DUSH AND YOUR — CORTEX AND SUPPLEMENTAL AREA PROVIDE MOTOR CONTROL THAT REGULATES THE VOIDING FUNCTION. SO PATHOPHYSIOLOGY IN THEORY, AT LEAST, AND HERE’S WHERE WE REALLY ARE WEAK, WE DON’T REALLY UNDERSTAND THE ETIOLOGY OF OVERACTIVE BLADDER OR EVEN THE ETIOLOGY OF MULTIPLE SCLEROSIS OR PARKINSONS DISEASE. BUT IN THEORY, YOU COULD HAVE MULTIPLE FACTORS THAT CONTRIBUTE TO OVERACTIVE BLADDER. ONE, THE SMOOTH MUSCLE CAN BE OVERACTIVE ITSELF WHICH THEN ACTIVATES SENSORY INPUT. SENSORY INPUT CAN ENHANCE — TRANSMISSION IN THE CNS OR IT CAN REDUCE CNS INHIBITION. IN ADDITION TO SOMETHING HAPPENING IN THE PERIPHERY, CAN BE PURELY CENTRAL, IN PARKINSON’S DISEASE, MS, YOU CAN REMOVE CENTRAL INHIBITION AND MAKE THE BLADDER STORAGE MECHANISMS DECLINED, MAKE BLADDER VOIDING MECHANISMS INCREASE, AND PRODUCE INCONTINENCE AS WELL AS URGENCY AND FREQUENCY OF URINATION. SO AS THE BLADDER FILLS, THESE CENTRAL PROCESSES WITHIN THE BRAIN AND SPINAL CORD ARE RECEIVING EXCESSIVE AFFERENT ACTIVITY AND THE BLADDER REFLEX BECOMES ENHANCED. SO HIGH LEVEL OF AFFERENT ACTIVITY COULD IMPINGE UPON THE SWITCH AND THAT IN TURN COULD BE MODULATED BY ELECTRICAL STIMULATION OF NERVES. SO AFFERENT NERVE STIMULATION EITHER SACRAL ROOT STIMULATION CALLED INTERSTEM STIMULATION OF THE TIBIAL NERVE, THE PUDENDAL NERVE, THE SKIN OF THE PAIR OWE NEEM, THE VAGINA, THE URETHRA, THE PENIS, ALL OF THESE AFFERENT STIMULATIONS HAVE BEEN USED EXPERIMENTALLY AND CLINICALLY TO TRY TO MODULATE THAT SWITCH. WE KNOW AT LEAST WITH SACRAL NERVE MODULATION AND TIBIAL STIMULATION THAT THE SENSATIONS OF SURGE SEE AND THE OVERACTIVITY OF THE BLADDER CAN BE DOWNREGULATED, BUT THE VOIDING EFFICIENCY IS NOT CHANGED. SO TO UNDERSTAND NEUROMODULATION, WE HAVE TO UNDERSTAND HOW IT CAN CHANGE THE AFFERENT OR SENSORY LIMB WITHOUT AFFECTING THE EFFERENT LYMPH MICTURITION REFLEX, ANOTHER CHALLENGE FOR THE FUTURE. SO AT ANY RATE, JUST EMPHASIZING THAT MANY DIFFERENT AFFERENT INPUTS ARE PLAYING A ROLE IN NEUROMODULATION OF THE CNS SWITCH. SO INTERSTIM OR SACRAL NERVE MODULATIONS — APPROVED THERAPY URINARY URGENCY INCONTINENCE, FREQUENCY — FECAL INCONTINENCE, AND EXPERIMENTALLY FOR BLADDER PAIN INTERSTITIAL CYSTITIS OR BLADDER PAIN. CATCH THE UNUSUAL PARADOX HERE. THE SAME STIMULATION WITH THE SAME FREQUENCIES, THE SAME NERVE, CAN PROMOTE STORAGE FOR CONTINENCE AND CAN PROMOTE VOIDING. A REAL CHALLENGE TO UNDERSTAND HOW YOU CAN TREAT TWO DIFFERENT DIE MET RICKLY OPPOSED FUNCTIONS WITH THE SAME STIMULATION. THERE ARE SPECULATIONS ABOUT HOW THAT CAN OCCUR. SO WHAT ARE WE STIMULATING? WITH INTERSTEM, WE’RE STIMULATING AFFERENT NERVES IN THE SPINAL ROOTS. THOSE AFFERENT NERVES CARRY INFORMATION INTO THE SPINAL CORD, AND THERE THEY RELEASE NEUROTRANSMITTERS AND THAT LEADS TO MODULATION OF CENTRAL NERVOUS SYSTEM FUNCTION. WHEN THESE STIMULATIONS WERE FIRST STUDIED, THEY THOUGHT MAYBE IT WAS ACTIVATION OF THE EFFERENT OUTFLOW TO THE SPHRINGTER. NOW IT’S PRETTY CLEAR THAT IT’S AFFERENTS WHICH ARE BEING TARGETED. JUST AS KIP TALKED ABOUT THE, THE SIZES OF THE AFFERENTS ARE VERY IMPORTANT. WE’RE STIMULATING ADDED INTENSITY WHICH DOES NOT PRODUCE PAIN, SO WE PROBABLY ARE NOT ACTIVATING VISCERAL, WE’RE ACTIVATING LARGE MYELINATED AFFERENTS WHICH CAN MODULATE VISCERAL FUNCTION. SO THOSE THEN CAN RELEASE TRANSMITTERS AND PRODUCE SOMETHING IN THE CNS WHICH REALLY DEPENDS IN PART ON THE ACTIVATION OF INTACT PATHWAYS. UNLESS WE’RE TREATING PATHOLOGY IT AND THERE WE CAN HAVE PATHWAYS WHICH ARE NORMALLY NOT PRESENT WHICH ARE BEING ACTIVATED WHICH MAY BE SUPER SENSITIVE TO THE EFFECTS OF THIS STIMULATION. SO SACRAL NEUROMODULATION IS APPLIED HERE, TIBIAL NERVE STIMULATION IS APPLIED MORE INTO THE PERIPHERY IN THE NERVES THAT INNERVATE THE LOWER LEG AND FOOT, AND PUDENDAL STIMULATION INNERVATING THE PATHWAYS TO THE URETHRA TO THE PERINEUM TO THE PENIS TO THE VAGINA. I’M JUST GOING TO TELL BUT THESE TWO AND WHAT LITTLE BIT WE KNOW FROM ANIMAL MODELS ABOUT THE MECHANISMS OF ACTION. YOU’VE HEARD ONE OF THE TOP PRIORITIES IS TO UNDERSTAND HOW DOES NEUROMODULATION WORK. I THINK THE FIRST APPROACH IS TO USE ANIMAL MODELS TO SEE IF WE CAN WORK THAT OUT AND THEN SEE IF WE CAN DO THIS SAME KIND OF EXPERIMENT IN HUMANS. SO QUESTIONS ABOUT NEUROMODULATION. WHAT TYPES OF AXONS ARE ACTIVATED? WE TOUCHED A BIT ON THAT. WHAT TRANSMITTERS ARE RELEASED? I’LL TELL YOU ABOUT THAT IN THE REMAINING TWO MINUTES. WHAT TRANSMITTER RECEPTORS ARE ACTIVATED, WHERE DOES NEUROMODULATION OCCUR? IN THE PERIPHERY, THE URINARY BLADDER, IN THE SPINAL CORD, IN THE BRAIN, SENSORY PATHWAY, MOTOR PATHWAYS, THE DIFFERENT TYPES OF NEUROMODULATION ACT BY THE SAME MECHANISM. SO HERE’S A WHOLE LIST OF EXPERIMENTS AND QUESTIONS THAT CAN BE EXPLORED IN THE SPARC PROGRAM. SO VERY QUICKLY, PUDENDAL NERVE MODULATION STUDIED IN CATS BY THE PITTSBURGH GROUP SHOWS AT LEAST IN PART THE SITE OF ACTION IS IN THE SPINAL CORD. PUDENDAL NERVE STIMULATION SENDS INPUT TO THE LUMBOSACRAL CORD. ONE IN THE CAT IT ACTIVATES — TO THE BLADDER AND IT ALSO INHIBITS THE ASCENDING PATHWAY TO THE PONS. AND FINALLY, IT INHIBITS THE DESCENDING INPUT COMING DOWN FROM THE PONS TO THE BLADDER. THE ACT MECHANISM IN PART IS GABAERGIC INHIBITION AND ACTIVATION OF PI HYPOGASTRIC INHIBITORY PATHWAY TO THE BLADDER. STIMULATION IS EFFECTIVE OVER A NARROW RANGE OF FREQUENCIES, 3 TO 10 HERTZ, AND EFFECTS REQUIRE CONTINUOUS STIMULATION. EFFECTS ARE RAPID IN ONSET, AND RECOVER OR ARE ELIMINATED VERY SOON AFTER YOU TURN THE STIMULATION OFF. IN CONTRAST, STUDIES IN CATS SHOW — BY ACTION IN THE BRAINSTEM. YOU STIB LAT STIMULATE TIBIAL
NERVE HERE BUT — HERE IN THIS HE REFLEX CIRCLE. THIS IS A MECHANISM THAT’S DEPENDENT UPON OPIOID RECEPTORS AND ENKEPHALINERGIC INHIBITION. STIMULATION EFFECTIVE OVER A WIDE RANGE OF FREQUENCIES, 3 TO 30 HERTZ, AND PERSISTS FOR AT LEAST TWO HOURS AFTER THE TERMINATION OF STIMULATION. SO VERY DIFFERENT MECHANISMS AND PROPERTIES. THIS FITS WITH THE FDA APPROVED THERAPY WHERE YOU HAVE 30 MINUTES OF THERAPY AD
ADMINISTERED EVERY WEEK FOR 12 WEEKS AND THEN BOOSTER TREATMENTS OVER A MONTH. SO CLINICALLY, TIBIAL NERVE STIMULATION CAN LAST FOR A LONG TIME. PUDENDAL NERVE STIMULATION DOESN’T. I’M GOING TO SKIP SPINAL CORD INJURY. WITH SPINAL CORD INJURY, YOU HAVE THE BLADDER UNABLE TO STORE AND IT DOESN’T EMPTY WELL, AND WE CAN TALK ABOUT HOW NEUROMODULATION CAN AFFECT THIS AND HOW PATHOLOGY INDUCES THE EMERGENCE OF THESE DEFECTS AFTER SPINAL CORD INJURY. THEN FINALLY, WE WILL TALK ABOUT RESEARCH OPPORTUNITIES AT SOME POINT DURING THE GENERAL DISCUSSION. SORRY FOR RUNNING OVER. THANK YOU. [APPLAUSE]>>WE DO HAVE TIME, I THINK, FOR A FEW QUESTIONS.>>YOU WANTED TO KNOW ABOUT THE LOWER URINARY TRACT.>>CAN I ASK ONE QUESTION? MY NAME IS STEFFAN — FROM THE UNIVERSITY OF MIAMI. I’M HERE TO THINK ABOUT DATA INTEGRATION AND HOW TO BRING ALL THE DIFFERENT TYPES OF DATA TOGETHER. NOT REALLY KNOWING MUCH ABOUT THIS, IT MAY NOT BE A VERY SMART QUESTION. MY QUESTION IS, SO THOSE FANTASTIC DIAGRAMS THAT YOU SHOWED, THOSE MODELS — TO EXPLAIN THE VARIOUS TYPES OF FUNCTIONS AND HOW THEY INTERACT, HOW MUCH OF THAT IS SOMEHOW FORMALLY MODELED OR AVAILABLE IN SOME KIND OF INFORMATION SYSTEM VERSUS JUST IN THE PICTURE OR IN SOME HUMAN’S MIND OR BRAIN? [LAUGHTER]>>ACTUALLY, I CAME UP — OLD AGE IS AFFECTING — ACTUALLY I’VE BEEN FASCINATED BY HOW ONE WOULD MODEL A SWITCH, A NEURONAL SWITCH, SO RECENTLY WE’VE COLLECTED AND OTHERS HAVE COLLECTED ENOUGH INFORMATION, ESPECIALLY ABOUT THE — MICTURITION CENTER AND THE PAG, THAT WE’VE BEEN ABLE TO PUT AN EXCITATORY AND INHIBITORY PO MODEL TOGETHER. WE PUBLISHED THAT A YEAR AGO. WHEN WE FILL THE BLAH IT DER, IT FUNCTIONS VERY CLOSELY TO WHAT WE SEE IN THE NORMAL ANIMAL AND IN THE HUMAN. IT STORES EURNG, AND THEN IT REACHES A CRITICAL LEVEL OF BLADDER DISTENTION AND IT TRIGGERS AN ALL OR NONE RESPONSE TO INDUCE VOIDING. SO WHETHER THAT IS A REALISTIC MODEL, I DON’T KNOW. SOME OF THIS IS BASED ON ELECTROPHYSIOLOGY, SOME ON BRAIN IMAGING, ET CETERA. SO AT LEAST WE’VE REACHED A STAGE WHERE WE CAN MODEL THE SWITCH.>>I’M ASKING THIS MORE LIKE TO, PERHAPS, YOU KNOW, THINK A LITTLE BIT ABOUT THAT PROBLEM, HOW TO STORE THE DATA, HOW TO MODEL ALL THE DATA. BECAUSE IT’S LIKE ALL CONNECTED, FAIRLY COMPLEX.>>YOU CAN’T BUILD A MODEL WITHOUT HAVING DATA. SO THE DATA HAS BEEN COLLECTED BY SINGLE UNIT RECORDING OR INTRACELLULAR RECORDING, AND PHARMACOLOGICAL DATA. WE KNOW THAT IF WE INJECT CHEMICALS WHICH CAN MODIFY SYNAPTIC TRANSMISSION, IN THE PONTINE MICTURITION CENTER, WE CAN DO SOMETHING LIKE NEUROMODULATION. WE CAN MAKE THE BLADDER STORE MORE URINE, EMPTY WELL, WE CAN NOW INJECT OTHER AGENTS WHICH MAKES THE BLADDER LESS STORAGE, AND WILL STILL EMPTY WE. SO BY MA ANYBODY LATING THE CIRCUITS WITHIN THE BRAINSTEM, WE CAN IN AN ALL OR NONE FASHION CHANGE THE VOIDING PROPERTIES OF THE LOWER URINARY –>>THANK YOU.>>YOU SHOW THAT THE BLADDER AFFERENT FIBER, THE MYELINATED A DELTA FIBERS, HAVE AT LEAST THREE ROLES. ONE, THEY SEEM TO TRIGGER MICTURITION, THEY ALSO SEEM TO ACTIVATE SYMPATHETIC PATHWAYS, THEY ALSO SEEM TO ACTIVATE THE SPHRING TER MOTOR NEURONS. IS THERE ANY EVIDENCE OF WHETHER OR NOT THERE’S THE SAME POPULATION PERFORMING ALL THREE OF THOSE FUNCTIONS IN COORDINATION, AND WHAT HAPPENS TO THE MYELINATED A DELTA FIBERS THAT ACTIVATE THE FIBER PATHWAYS WHEN THE CORD IS CUT? DO THEY LOSE THAT ABILITY COMPLETELY OR ARE THEY JUST HANGING OUT THERE LOOKING FOR SOMETHING TO DO?>>SO WE DON’T KNOW WHETHER THESE MYELINATED FIBERS ARE MADE UP OF DIFFERENT POPULATIONS. IT SEEMS THAT THE SPINAL STORAGE REFLEXES WHICH ARE DRIVEN BY THEM ALL SEEM IT TO BE DRIVEN BY THE SAME POPULATION THAT IS THE CONDUCTION VELOCITY AND ELECTRICAL THRESHOLDS. IT SEEMS LIKE THE POPULATION THAT GOES UP TO THE BRAINSTEM TO TRIGGER VOIDING ALSO HAS THE SAME ELECTRICAL THRESHOLDS. BUT WE CAN’T EXCLUDE THE POSSIBILITY THAT THERE ARE DIFFERENT POPULATIONS DISTRIBUTED AT DIFFERENT SITES WITHIN THE BLADDER WALL. WHEN WE CUT THE SPINAL CORD, WITH WHICH IS SHOWN ON THAT SLIDE THAT I ELIMINATED, WE HAVE THE SPINAL STORAGE REFLEXES MAINTAINED. AND SO THE BLADDER DOESN’T EMPTY WELL BECAUSE THOSE AFFERENTS ARE STILL FUNCTIONING. BUT THE VOIDING RESPONSE IS COMPLETELY ELIMINATED BECAUSE THAT’S DEPENDENT ON STRUCTURES IN THE — ABOVE THE SPINAL CORDS. THE MICTURITION IN THE SPINAL CORD INJURED ANIMAL IS DRIVEN BY C FIBER AFTER RENTS AFFERENTS,
WHICH DON’T SEEM TO PLAY A ROLE IN NOR HALL VOIDING BUT — NAWR OWE TROA PICK FACTORS AFTER SPINAL CORD INJURY. THAT’S SOMETHING WE CAN TALK ABOUT A BIT LATER. SO NEUROPLASTICITY IS PLAYING A KEY ROLE IN THE EMERGENCE OF MICTURITION RESPONSES AFTER SPINAL CORD INJURIES.>>>> — FROM BRIGHAM WOMEN’S. I HAVE A GENERAL QUESTION ABOUT WHAT IS KNOWN OF THE EFFECT OF AGING ON THE URINARY TRACT REFLEX.>>>>MOST PEOPLE BELIEVE AGING IS SOMETHING THAT’S OCCURRING INDEPENDENT OF DISEASE, AND IF YOU’RE GOING TO EVALUATE THE EFFECT OF URGING, YOU HAVE TO SEPARATE DISEASE FROM THE BASIC PROPERTIES OF AGING ITSELF. IT SEEMS LIKE IN ANIMAL MODELS, THAT THIS ARE CHANGES IN THE PERIPHERAL NERVOUS SYSTEM. A GROUP IN WALES STUDIED THIS A NUMBER OF YEARS — IN RATS AND FOUND THAT THE NUMBER OF NEURONS IN THE MAJOR PELVIC GANGLIA WAS REDUCED IN AGED ANIMALS. THEN THERE IS ALSO CHANGE IN THE PROPERTIES OF THE EPITHELIUM, AND THAT MAY LEAD TO CHANGES IN EPITHELIUM AFFERENT SIGNAL. THERE ARE CHANGES ALSO IN — AT LEAST IN SOME STUDIES IN THE ABILITY OF THE EFFERENT SYSTEM TO CONTRIBUTE THE BLADDER MUSCLE, IN OTHER STUDIES THAT SEEMS LIKE THE CONTRACTION IS QUITE NORMAL. THE CENTRAL PATHWAYS WHICH ARE INVOLVED IN THE SWITCHING FUNCTION HAVE REALLY NOT BEEN STUDIED AS FAR AS I KNOW IN AGED ANIMALS. THERE IS ANOTHER POINT, I GUESS, I SHOULD MENTION, THAT AGING IS ASSOCIATED WITH ANOTHER CONDITION I DIDN’T EVEN MENTION, AND THAT’S CALLED THE UNDERACTIVE BLADDER. AND THAT’S RECEIVING A LOT MORE ATTENTION RECENTLY WHERE OLDER PEOPLE JUST CANNOT EMPTY THEIR BLADDER. THEY CAN’T CONTRACT IT A LONG ENOUGH TIME SO THAT THEY GET URINARY RETENTION, AND THIS IS A MAJOR ISSUE AND PEOPLE IN NURSING HOMES AND — NOTHING IS KNOWN ABOUT THE PATHOLOGY –>>CAN I SUGGEST THAT YOU HOLD YOUR QUESTION FOR MORE GENERAL DISCUSSION AFTER WE’VE HEARD SOMETHING FROM THE TECHNOLOGY FOLKS. SO IT’S MEE PLEASURE TO INTRODUCE DR. GRAHAM CREASEY FROM STANFORD UNIVERSITY, A SURGEON WHO HAS STRONG INTEREST IN SPINAL CORD INJURY AND BIOMEDICAL APPROACHES AND BIOENGINEERING APPROACHES IN THAT DISEASE.>>THANK YOU. AS HELEN SAID, SINCE I’M A SURGEON, I LOOK FORWARD TO LEARNING A LOT MORE ABOUT TECHNOLOGY AT THIS WORKSHOP FROM SOME REAL ENGINEERS. AND SINCE IT THIS IS THE FIRST TECHNOLOGY RESPONSE OF THE WORKSHOP, I’LL MENTION A FEW GENERAL PRINCIPLES. THEN THEN TRY TO ILLUSTRATE HOW THESE HAVE BEEN APPLIED OR MIGHT BE APPLIED IN THE LOWER URINARY TRACT. I’VE TAKEN THE TITLE OF THIS INITIATIVE TO INDICATE THAT WE’RE INTERESTED IN STIMULATING PERIPHERALLY, AS OPPOSED TO STIMULATING THE BRAIN AND SPINAL CORD WHICH HAVE BEEN MENTIONED EARLIER, BUT ALSO THAT WE’RE INTEREST ITED IN PERIPHERAL ACTIVITY IN THE PERIPHERAL NERVES AND ORGANS WHICH IMPORTANTLY INCLUDES SOMATIC AS WELL AS AUTONOMIC IN SOME CASES, BUT OBVIOUSLY WE HAVE TO CONSIDER THIS IN THE CONTEXT OF ALL THE CONTROL AND ACTIVITY HAPPENING IN THE CENTRAL NERVOUS CYST TELL, EVEN THOUGH IN SOME CONDITIONS LIKE SPINAL CORD INJURY, THERE MAY BE SUBSTANTIAL DISCONNECT BETWEEN THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM WHICH MAKES IT SUCH A DIFFICULT PROBLEM TO SOLVE PARTICULARLY FOR RESTORING BLADDER EMPTYING. I’M CONSCIOUS ALSO THAT AT NIH, THERE IS A LONG HISTORY OF ELECTRICAL INTERACTION WITH THE NERVOUS SYSTEM, CAME BACK AT LEAST HALF A CENTURY TO THE NEUROPROSTHESIS PROGRAM, CURRENTLY THE NEURO — PROGRAM. AND I THINK THIS ACTIVITY HERE AND THROUGHOUT THE WORLD HAS LED TO TWO MAIN APPROACHES TO THESE USES OF ELECTRICAL STIMULATION, WHICH I THINK IT’S USEFUL OH IT DRAW THE DISTINCTION BETWEEN PARTLY DISTINCTIONS OF SCALE IN THAT NEURAL CONTROL ACTIVITIES HAVE BEEN MAINLY CONCERNED WITH UNDERSTANDING AND CONTROLLING MOLECULAR MECHANISMS LIKE VOLTAGE SENSITIVE EY ION
CHANNELS IN THE CELL MEMBRANES OF NERVES AND MUSCLE CELLS, AND THEN CONTROLLING THESE AND USE THEM TO GENERATE OR PREVENT THE GENERATION OF ACTION POTENTIALS IAND THEIR PROPAGATION. SO THIS HAS LED TO SOME USEFUL PRODUCTS, USUALLY KNOWN AT NEUROPROSTHESES, OF COURSE THE CARDIAC PACEMAKER IS A PROTOTYPE OF THESE BUT ALSO MOTOR PROS KNEE THEE SEES FOR STIMULATING THE FRE NICK NERVE OF TO THE DIAPHRAGM AND GETTING PEOPLE OFF VENTILATORS. THE SYSTEM MENTIONED EARLIER FOR BLADDER AND BOWEL CONTROL AND FOR LIMBS, PARTICULARLY PARALYZED AFTER CORD INJURY. THE AUDITORY PROSTHESIS. SO THIS APPROACH IS REALLY FOCUSED ON CONTROL OR RESTORATION OF SPECIFIC FUNCTIONS, AND IT WAS DESCRIBED BY TOM MORTIMER OF THE LAB IN CLEVELAND AS CONTROLLED AND TARGETED RELEASES NEUROTRANSMITTERS. AND IT’S LARGELY BEEN DRIVEN BY BIOENGINEERS WHO HAVE FOCUSED ON THIS VERY SPECIFIC UNDERSTANDING OF MECHANISM. BY CONTRAST, A LOT OF NEUROMODULATION WORK HAS BEEN DRIVEN BY — WHO ARE INTERESTED IN A BENEFICIAL EFFECT FOR A PATIENT EVEN IF WE DON’T UNDERSTAND THE MECHANISM. AND THIS I THINK HAS TYPICALLY BEEN OPERATING MONSIGNOR AT A
MORE AT A SY
STEM LEVEL AND THE DEVICES THAT ARE OUT THERE AS WE BELIEVE PROBABLY THEIR MECHANISM IS MAINLY BY STIMULATING AFFERENT FIBERS TO PRODUCE STIMULATION OR INHIBITORY REFLEXES. IT MAY WELL BE THAT — WE DON’T KNOW WHAT EFFECT THAT’S HAVING BUT IT DOES INJECT SIGNALS INTO THESE NEURAL NETWORKS, AND PROBABLY — NETWORK ACTIVITY. SO VERY OFTEN THIS VIEW OF NEUROMODULATION IS THE EFFECTS ARE MORE CYST ST SYSTEMIC AND
THEREFORE SOMEWHAT ANALOGOUS TO CHEMICAL MODULATION WHICH WE CARRY OUT WITH DRUGS AND FAR
PHARMACEUTICALS. THE NORTH AMERICAN NEUROMODULATION SOCIETY ASSIGNS IT AS THE THIRD — ALTERATION OF ACTIVITY. SO CLEARLY A MUCH LARGER SCALE AND COMPLEX TO UNDERSTAND IN TERMS OF ELECTRICAL OR NEURAL NETWORKS. THE TWO MAIN DEVICES THAT HAVE BEEN APPLIED TO THE LOWER URINARY TRACT HAVE BEEN REALLY FALLING INTO THESE TWO CATEGORIES. FOR EMPTYING THE SPINAL CORD INJURY BLADDER — SHOWN ON THE LEFT, THE — IMPROVING STORAGE AND OVERACTIVE BLAH IT DER, THE MEDTRONIC — SHOWN ON THE RIGHT. THE FINE TECH — RECEIVED FDA APPROVAL IN THIS COUNTRY IN 1998 AND THERE’S NO LONGER PROMOTION AVAILABLE IN THIS COUNTRY ALTHOUGH THERE IS IN ABOUT 20 OTHER COUNTRIES. — WAS FIRST APPROVED IN 1997 AND HAS HAD SUBSEQUENT INDICATIONS SINCE. SO THESE ARE ABLE TO PRODUCE BLADDER EMPTYING IN SPINAL CORD INJURY IN ADDITION TO — AND PENILE ERECTION AND TO INDUCE OR IMPROVE STORAGE OF THE OVERACTIVE BLADDER. IT’S A DID DIFFERENT QUESTION TRYING TO PRODUCE STORAGE OR IMPROVE IT AFTER SPINAL CORD INJURY AND TRYING OH TO IMPROVE EMPTYING WITH THE — DEVICE. SOME PATIENTS MAY NOT NEED EMPTYING BUT AS DR. DEGROAT MENTIONED — IT MAY BE THAT THE MECHANISM HERE IS REDUCING OVERACTIVITY OF THE SPHINCTER AS OPPOSED TO THE USUAL USE FOR REDUCING OVERACTIVITY OF THE BLAH IT DER. BUT THE REAL CHALLENGE IN RESTORING FUNCTION TO THE LOWER URINARY TRACT IS BEING ABLE TO PRODUCE BOTH EMPTYING AND STORAGE. IN THE SAME PATIENT AND PREFERABLY WITH THE SAME DEVICE. PARTICULARLY A PROBLEM AFTER SPINAL CORD INJURY. SO HOW CAN WE ADVANCE THE FIELD PARTICULARLY TAKING ADVANTAGE OF THE KIND OF MAPPING THAT DR. DEGROAT HAS DESCRIBED AND STUDIED SO THOROUGHLY? I’VE SIMPLIFIED SOME OF THESE THINGS DOWN TO A VERY SIMPLIFIED CIRCUIT AT THE SACRAL SEGMENTAL LEVEL AND LUMPED ALL THE AFFERENTS TOGETHER IN ONE COLOR THERE AND MAINTAINED THE SAME COLOR CODING THAT DR. DE GROAT USED FOR THE — THAT FORCED CONTRACTION OF THE SMOOTH MUSCLE OF THE BLADDER, AND THE SOMATIC EFFERENTS THAT CAUSE CONTRACTION OF THE EXTERNAL URETHRAL SPINGT TER. SPHINGT TER. I HAVEN’T ATTEMPTED TO INCLUDE — AND THE NEUROCONTROL APPROACH WAS INITIATED BY BRINDLEY IN BRITTON IN THE 70s WITH — WITH WHICH ADMITTEDLY STIMULATES BOTH THE EFFERENT FIBERS TO THE BLADDER AND TO THE — SPHINCTER. HE WAS NEVERTHELESS ABLE TO INDUCE EFFECTIVE AND SAFE VOIDING BY USING INTER — STIMULATION WHICH SUSTAINED THE PRESSURE OF THE BLADDER WHILE ALLOWING INTIMATE RELAXATION OF THE SPHINCTER AND INTERMITT TENT ELIMINATION OF URINE, NOT HOW HUMANS USUALLY VOID BUT HOW SOME SPECIES VOID AND IT PROVED TO BE SAFE AND EFFECTIVE. WE DID TRY SOME OTHER TECHNIQUES IN THE 90s, WHICH I’LL MENTION LATER, TO TRY TO PRODUCE ISOLATED CONTRACTION OF THE BLADDER, AND IT WAS POSSIBLE, BUT IT DIDN’T PROVE REALLY TO BE NECESSARY — STIMULATION AND — VOIDING WAS ADEQUATE. IT WAS NOT SUFFICIENT TO DEAL WITH THE OTHER PROBLEM, MAINLY, STORAGE. AND IN THE 80s, A GERMAN UROLOGIST INTRODUCED POSTERIOR — TO INTERRUPT THE SAY CALORIE FLEXES PRIMARILY FOR THE PURPOSE OF REDUCING THE OVERACTIVITY HYPERREFLEX YA OF THE — MUSCLE OF THE BLADDER, WHICH ARE IS AN IMPORTANT PROBLEM THAT NOT ONLY CAUSES REFLEX INCONTINENCE BUT CAUSES — AND KIDNEY DAMAGE. AND THIS WAS VERY EFFECTIVE IN IMPROVING CONTINENCE AND PROTECTING THE KIDNEYS, HOWEVER, IT HAD THE DISADVANTAGE OF INTERRUPTING DESIRABLE REFLEXES LIKE PENILE ERECTION AND EJACULATION. EVEN THOUGH THE DEVICE ITSELF COULD RESTORE ERECTION — PRODUCING EJACULATION. SO THE GOAL HAS BEEN TO SEE IF WE CAN GET RID OF CUTTING THESE NERVES, PARTICULARLY IN AN ERA WHEN PATIENTS ARE HOPEFUL THAT STEM CELLS MAY BECOME AVAILABLE TO THEM. AND ONE TECHNIQUE THAT IS POTENTIALLY PROMISING HAS BEEN DEVELOPED BY KEVIN KILGORE IN CLEVELAND, WHO WILL BE SPEAKING AT THIS WORKSHOP USING KILOHERTZ FREQUENCY ALTERNATING CURRENT BLOCK TO PREVENT TRANSMISSION OR PROPAGATION OF ACTION POTENTIALS. AND THIS HAS BEEN SLOAN B HAS
BEEN SHOWN B
Y HIM AND HIS COLLEAGUE WHEN APPLIED TO THE PUDENDAL NERVE TO PREVENT EXTERNAL SPHINCTER CONTRACTION AND IN CONJUNCTION WITH ANTIROOT STIMULATION TO BE ABLE TO PRODUCE VERY EFFECTIVE VOIDING IN ANIMALS WITH CHRONIC SPINAL CORD INJURY WHO ARE AWAKE AND BEHAVING. IF THE AFFERENTS ARE MAINTAINED INTACT, THAT ALSO PROVIDES THE OPPORTUNITY TO APPLY NEUROMODULATION TO THEM, IF WE FIND THE APPROPRIATE MECHANISM PATHWAY AND PARAMETERS FOR THAT KIND OF NEUROMODULATION AND THERE D BY POTENTIALLY TO BE ABLE TO USE NEUROMODULATION FOR CONTINENCE AND BLOCK — STIMULATION THEREBY TO PRODUCE BOTH STORAGE AND EMPTYING AFTER SPINAL CORD INJURY, WE’RE STARTING A PHASE ONE CLINICAL TRIAL TO TEST THAT IN HUMANS AT THIS TIME. NEUROMODULATION HAS BEEN TRADITIONALLY APPLIED TO THE SACRAL NERVES AS YOU’VE HEARD, BUT IT’S BEGINNING TO BE APPLIED MORE TO THE PUDENDAL NERVES USING SIMILAR ELECTRODES. WARREN GRILL, WHEN HE WAS IN CLEVELAND, BECAME INTERESTED IN INTERACTIONS WITH THE PUDENDAL NERVES AND PARTICULARLY THE DIFFERENT COMPONENTS OF THE PUDENDAL NERVES WHICH MAY PROVIDE AFFERENTS FROM DIFFERENT PART OF THE LOWER URINARY TRACT, SUCH AS THE PROXIMAL AND DISTAL URETHRA AND THE BLADDER NECK. AND IT APPEARED THAT CERTAIN DIFFERENT PARTS OF THE URETHRA IN PARTICULAR EVOKE IT DIFFERENT MECHANISMS FOR GUARDING AND CONTINENCE AND POTENTIALLY EVEN REFLEX ACTIVATION OF THE BLADDER. SO BY BEING ABLE TO — THE HOPE WAS THAT BY USING CUFF ELECTRODES WITH MULTIPLE CONTACTS PLACED AROUND THE NERVE, IT WOULD BE POSSIBLE TO ACTIVATE CERTAIN COULD BE TACTS
CONTACTS A
ND NOT OTHERS, PERHAPS TO PURSUE MORE SELECTIVE PARTS OF THE NERVE. THIS ALSO TOOK ADVANTAGE OF THE FACT THAT THE FREQUENCY OF STIMULATION APPEARED TO HAVE AN INFLUENCE, THE LOWER FREQUENCIES BEING MORE EFFECTIVE IN INHIBITING THE BLADDER AND HIGHER FREQUENCIES SOMETIMES PRODUCING REFLEX CONTRACTION OF THE BLADDER. ALSO DEPENDING ON THE STATE OF FULLNESS OF THE BLADDER. SO PROBABLY INVOLVING AFTER RENS FROAFFERENTSFROM THE BLADDER
WITH THIS NEUROMODULATION. THERE IS STILL SOMETHING OF AN OPEN QUESTION WHETHER WE CAN GET ADEQUATE REFLEX INHIBITION OF THE SPHINCTER BY NEUROMODULATION BUT WE DO STILL HAVE THE HIGH FREQUENCY BLOCK POTENTIAL. SO THIS IS ANOTHER POTENTIAL AVENUE FOR STORING AND EMPTYING BY MODULATION. SO LOOKING TO THE FUTURE, WHAT DO WE NEED TO ADVANCE THE FIELD? I THINK AS SOMEBODY ELSE MENTIONED, WE NEED BETTER TARGETING, BETTER SELECTIVE, WHRR IT’S THE LEVEL OF THE NERVE OR EVEN INDIVIDUAL AXONS. FOR THE NERVE, OF COURSE, WE CAN PUT CUFF ELECTRODES ON MANY OF THESE BRANCHES BUT TOO MANY ELECTRODES MEANS TOO MANY WIRES, INCREASED DPLEXITY OF TECHNOLOGY, INCREASED RISK OF INFECTION, AND SO ONE APPROACH IS TO MOVE PROXIMAL AND PUT ON THESE MULTI-CONTACT SELECTORS IN AN ATTEMPT TO ACTIVATE DIFFERENT FAST KELS WITHIN A LARGER NERVE TRUNK. THIS IS A IT DIAGRAM FROM CLEVELAND SHOWING DIFFERENT FRAT GEES FOR ACTIVATING THESE FASCICLES EITHER WITH A CYLINDRICAL CUFF — IF THE NERVE IS FLAT OR FLATTENED. ULTIMATELY GETTING AT TH — SO
THERE ARE COMMERCIALLY ELECTRODES SUCH AS THIS, FLAT INTERFACE NERVE ELECTRODE, OTHER SIMILAR TECHNIQUES FOR GETTING AT INDIVIDUAL AXONS. BUT I SUGGEST THAT WHILE IT THIS KIND OF TECH IT NOLG MAY BE USEFUL FOR MAPPING AND ELECTROPHYSIOLOGICAL RESEARCH, IT’S OFTEN NOT WHAT WE NEED FOR RESTORING FUNCTION OR RELIEVING CONDITIONS. SUCH AS, FOR EXAMPLE, DISTINGUISHING THE PARASYMPATHETIC — FIBERS IN THE SOMATIC E FOR RENT SIDE TO THE SPHINCTER. NORMALLY YOU TURN UP — IT’S POSSIBLE TO REVERSE THAT RECRUIT BY USING A — BLOCK AND WE APPLIED THIS TO THE SACRAL ANTERIOR ROOTS TO ACTIVATE THE BLADDER BY IT SELF, WE ALSO — THIS IS JUST AN ILLUSTRATION OF THE TRI POLAR CONFIGURATION USED TO OBTAIN THAT, LARGE AND SMALL FIBERS. WE ALSO COULD MAKE THE ELECTRODE ASYMMETRICAL AND PRODUCE EUN DIRECTIONAL PROPAGATION AND, THEREFORE, APPLY THIS TO THE PUDENDAL NERVE — TO THE IT SPHINCTER. THERE MAY BE OTHER APPROACHES THAT ENHANCE OUR REPERTOIRE, PARTICULARLY USE OF OPTIGENETICS — DIFFERENT POPULATIONS OF NERVES AND STIMULATE THEM WITH DIFFERENT WAVELENGTHS OF LIGHT. SO BACK IN ABOUT 2008, I SUGGESTED THIS TO — AT STANFORD WHO HAD LARGELY BEEN WORKING IN THE CENTRAL NERVOUS SYSTEM THAT WE SHOULD APPLY THIS TO PERIPHERAL NERVES, TO BE MORE SELECTIVE WITH SPHINCTER AND BLADDER. IT THERE ARE — AND SO — TIME SCALES, SO WE MIGHT BE ABLE TO SWITCH OFF THE SPINNING TER FOR SHORT PERIODS OF VOIDING AND THE BLADDER FOR LONGER PERIODS FOR STORAGE. WORKING QUITE HARD, SEVERAL YEARS NOW, SO FAR FOUND IT DIFFICULT TO GET ADEQUATE GENE TRANSPORT BY THE VIRAL VECTORS AND ADEQUATE GENE EXPRESSION. SO IT REMAINS TO BE SEEN WHETHER THIS CAN BE MADE TO WORK IN THESE PERIPHERAL NERVES IN THE LOWER URINARY TRACT. NOT ONLY, THOUGH, HOW MUCH SELECTIVE — IS POSSIBLE TECHNICALLY BUT HOW MUCH DO WE ACTUALLY NEED? IN THE CASE OF NEUROCONTROL, WE MAY WANT VERY SELECTIVE ACTIVATION FOR RESEARCH AS WELL AS FOR RELIEVING CONDITIONS. IN NEUROMODULATION, WE MAY WANT TO ACTIVATE LARGE POPULATIONS OF NERVES TO GET THE LARGEST EFFECT. A FEW OTHER PRIORITIES TO TOUCH ON BRIEFLY. WE’VE TALKED ABOUT STIMULATING PERIPHERAL ACTIVITY IT, I WOULD ARGUE IT’S IMPORTANT — THE SPHINCTER AND BLAT DER, THERE ARE WAYS WE TOUCHED ON FOR DOING THAT BY BLOCK, OR BY INHIBITING ACTIVITY. WHETHER AT THE BLADDER OR THE SPHINCTER. AND I MENTIONED OPTOGENETICS HAS WAYS OF STOP ITING PERIPHERAL NERVE ACTIVITY AS WELL. THIS MAY, OF COURSE, ALSO RELATE TO PAIN, SPASTICITY AND OTHER ISSUES WE WANT TO CONTROL. THE OTHER — EXISTING DEVICES TEND TO HAVE BEEN DEVELOPED FOR A PARTICULAR SINGLE APPLICATION AND MAY NOT BE COMPATIBLE OR USABLE FOR OTHER APPLICATIONS, AND I THINK IN THE FUTURE, WE NEED TO THINK OF MONSIGNOR MODULAMORE MODULARSYSTEMS WHICH
CAN FUNCTI
ON IN THE BODY AND WITHOUT, WHETHER THE PATIENT GETS BETTER OR WORSE OR WHETHER THE TECHNOLOGY ADVANCES, AND CAN BE ADAPTABLE TO DIFFERENT NEED AND APPLICATIONS. THAT — SEXUAL FUNCTION BUT OTHER APPLICATIONS WE’VE MENTIONED BEFORE, AND THE SYSTEM BEING DEVELOPED IN CLEVELAND IS A POTENTIAL EXAMPLE OF THIS THAT MAY ALSO SOLVE SOME OF THE — TECHNOLOGY PROBLEMS. DR. RIJKHOFF WILL SAY MORE ABOUT SENSING, ELECTRONEUROGRAM MORE DIFFERENT, I THINK INTEREST RIJKHOFF KNOWS MORE ABOUT THAT, BUT OF COURSE WE HAVE A BURGEONING WORLD OF SENSORS, DEVICE BEING DEVELOPED IN CLEVELAND SHOWN HERE, ANOTHER ONE BEING EVALUATED IN NORWAY, SHOWN HERE, AND WE MAY WANT SENSORS FOR OTHER ISSUES IN THE BLADDER AS WELL. ALLOWING US TO THEN APPLY OUR NEUROMODULATION INITIALLY AND NOT CONTINUOUSLY WHICH IS USUALLY DONE AT PRESENCE. FINALLY, WE SHOULD THINK ABOUT SYNERGY WITH DRUG IT DELIVERY. AFTER ALL, THE BODY USES BOTH ELECTRICAL AND CHEMICAL CONTROL SYSTEMS. AND WE HAVE HAD A LOT LONGER IN THE PHARMACEUTICAL INDUSTRY THAN WE HAVE HAD IN THE ELECTRONIC — IN THE ELECTROSUIT CAL INDUSTRY OH IT APPLY TO THIS. SO GIVEN SIMILAR TIME IN THE ELECTRONIC INDUSTRY, IT WILL BE INTERESTING TO SEE HOW FAR WE CAN TAKE THIS KIND OF SYNERGIES. THAT BRINGS ME BACK TO CONTROL AND TARGETED — OF TRANSMISSION. FINALLY, SMALLER, SMARTER IMPLANTS, BATTERY POWERED IMPLANTS HAVE OFTEN BY — PARTICULARLY BY THE SIZE OF THE BLADDER T HAS TO BE REPLACED SO YOU WANT A LARGE BATTERY THAT DOESN’T HAVE TO BE REPLACED SO OFTEN. NOW WE HAVE MORE RECHARGEABLE BA TREES BUT THEY STILL HAVE A LIMITED NUMBER OF CHARGE CYCLES. THEY MAY BE LIMITED BY THE SIZE OF THE ANTENNA, IN THIS CASE, THE — RECEIVING ANTENNAS OF THIS SIZE JUST OVER A COUNCILMEMBER, THE SAME SIZE AS TRANSMITTING IT OUTSIDE THE BODY. THE — REQUIRED VERY LARGE TRABS MITTING ANTENNAS TO GET THE ENERGY AND LI. LIMITED EFFICIENCY. THERE’S A PROTOTYPE BEING DEVELOPED AT STANFORD WHICH USES VERY SMALL RECEIVING ANTENNAS, AND THEN USES A HIGH CARRY — FREQUENCY WHICH ALLOWS — BEAM WITHIN THE IT TISSUES AND TO STEER THIS TO TARGET VERY SMALL IMPLANTS SUCH AS THIS SHOWN HERE. SO IN SUMMARY. THOSE ARE SOME OF THE TECHNOLOGICAL NEEDS I IT THINK WE MIGHT APPLY — BUT I HOPE TO OTHER SYSTEMS LIKE THE BOWEL AND OTHER PARTS OF THE AUTONOMIC — NERVOUS SYSTEMS. THANK YOU.>>THANK YOU VERY MUCH. WE’LL MOVE RIGHT ALONG TO THE NEXT SPEAKER. DR. NICO RIJKHOFF IS GOING TO TALK ABOUT HIS WORK.>>THANK YOU VERY MUCHMENT AS A FEW OF THE EARLIER SPEAKERS, I WANT TO SPEND A FEW SLIDES OFF IT DIFFERENCES BETWEEN HUMAN AND ANIMAL WORK. A LOT OF GROUPS HAVE TRIED IN ANIMALS TO OPTIMIZE CURRENT TREATMENTS, AND I THINK THIS IS VERY DIFFICULT AND VERY — THE RESULTS ARE VERY LIMITED OF USE. THIS GROUP IN GERMANY, THEY — IN — THEY IRRITATED THE BLADDER TO GENERATE BLADDER CONTRACTIONS AND YOU CAN SEE HERE THE NUMBER OF CONTRACTIONS PER MINUTE, WHICH IS ACTUALLY RATHER HIGH, WE HAVE DIFFERENT ANIMAL NUMBERS, THIS IS OUR SIX ANIMALS IN TOTAL, AND THEN THEY PLACED — AROUND THE DORSAL SACRAL ROOTS AND STIMULATED IT, AND STIMULATED ONE E ELECTRODE
OR BILATERAL STIMULATED — STIMULATION AND SAW THAT UPON STIMULATION, THE NUMBER OF CON TRACKS WAS REDUCED AND WITH — STIMULATION, THE REDUCTION WAS LARGER THAN WITH UNILATERAL STIMULATION. FROM THAT, THEY CONCLUDED THAT BUY LOT RAL SACRABILATERAL
SACRAL STIMULAT
ION WAS BETTER — AND I THINK THIS CONCLUSION CANNOT BE MADE AT ALL FROM THIS EXPERIMENTS. THIS IS AN INFLAMMATION MODEL, THIS IS NOT AN OVERACTIVE BLADDER. WE’RE LOOKING AT AN ACUTE EFFECT WHILE USUALLY EFFECTS IN THE PATIENT OF — RELATION COMES ON AFTER TIME, RELYING ON — AND ALSO THE STIMULATION AMPLITUDES THAT ARE USED HERE IS TOO HIGH TO BE USED IN PATIENTS. AND NOT APPLICABLE IN PATIENTS. THIS IS FROM MR. TYE FROM THE PITTSBURGH GROUP. THEY LOOKED AT TIBIAL NERVE STIMULATION AND THEY ALSO HAVE RHYTHMIC CONTRACTIONS HERE AND APPLY DIFFERENT STIMULATION AMPLITUDES TO THE TIR YAB NERVE OF, TWO-TIME MOTOR HOLDS, THEN YOU SEE THAT SOME OF THESE CONTRACTIONS ARE IB HIBTED FOR A WHILE AND THEN IT STARTS AGAIN. AND WITH INCREASING AMPLITUDES, THESE CONTRACTIONS ARE GONE. NOW WE HAVE DONE SOMETHING SIMILAR ACTUALLY EARLIER IN MS PATIENTS, AND THIS ACUTE EFFECT WAS NOT SEEN IN MS PATIENTS. SO HERE WE HAVE EIGHT PATIENTS AND WE FILL THE BLADDER AND EACH TIME AT THE ONSET OF A CONTRACTION, WE STARTED STIMULATION ON THE TIB IT YAL NERVE WITH AN AMPLITUDE AS HIGH AS POSSIBLE SO THAT PATIENTS WERE JUST ABLE TO TOLERATE AND NO EFFECT WAS SEEN ON BLADDER PRESSURE IN NONE OF THESE PATIENTS. HOWEVER, ALL THESE PATIENTS RESPONDED VERY WELL TO GENITAL SISTER OF STIMULATION. SO IT’S NOT THAT MS DISEASE IN THESE PATIENTS CAUSED DAMAGE TO THEIR PERIPHERAL NERVES. SO AGAIN TIBIAL NERVE OF, TRYING IT TO OPTIMIZE THERAPY OUTCOME MAY BE VERY LIMITED BECAUSE TIBIAL NERVE STIMULATION ACUTE EFFECTS ARE NOT SEEN IN PATIENTS. AT LEAST NOT WITH THE AMPLITUDES THAT CAN BE USED. SO TO SUM THIS UP, IT IS VERY DIFFICULT TO CREATE AN ANIMAL MODEL WITH A RELEVANT DISEASE, WE DON’T REALLY KNOW WHAT IT IS. IT IS SYMPTOMS. NEUROMODULATION MAY AFFECT EXTENSIVE NETWORKS, BUT THESE NETWORKS ARE NOT NECESSARILY THE SAME IN ANIMALS. SO IN PATIENTS, AS HAS BEEN SAID BEFORE, THE EFFECTS THAT COME ON AFTER SOME TIME RELY ON PLASTICITY WHILE MOST OF THE ANIMAL WORK, WE’RE LOOKING AT ACUTE EFFECTS. IN ADDITION, RESULTS CAN BE OBTAINED IN ANIMALS WITH STIMULATION PARAMETERS NOT POSSIBLE TO BE USED IN PATIENTS BECAUSE THEY WILL CAUSE PAIN OR OTHER SIDE EFFECTS. SO I THEREFORE THINK THAT WHERE POSSIBLE, WE SHOULD USE HUMAN EXPERIMENTS. IT THIS IS POSSIBLE IN PATIENTS WITH UROLOGICAL PROBLEMS. ANIMALS, OF COURSE, CAN CERTAINLY BE USED TO LOOK AT MORE — THE EFFECTS OF — BLOCK, THE EFFECTS OF HIGH FREQUENCY STIMULATION, BEFORE WE GO INTO THE HUMAN. BUT ALSO THEIR SIMPLE EFFECTS ARE NOT ALWAYS REP LICKABLE IN PATIENTS BECAUSE — PARAMETERS MAY BE VERY DIFFERENT. WE HAVE HEARD ABOUT SOME OF THESE DEVICES THAT ARE AVAILABLE IN THE CLINIC FOR CURES DISORDERS. WE HAVE THIS — USED FOR BOTH OVERACTIVE BLADDER AND RETENTION, AND — YOU COULD READ 60 TO 80% OF THE PATIENTS THAT RESPOND SUCCESSFULLY T HOWEVER, WHAT IS THE DEFINITION OF A SUCCESSFUL RESPONDER, THAT IS THAT THEY HAVE A LARGER THAN 50 PERCENT IMPROVEMENT. SO IF THIS PATIENT HAS 10 — AND GOES DOWN TO FOUR, THIS IS SUCK SUCCESSFUL. ONLY 10 TO 20% OF THESE PATIENTS IMPLANTED ARE ACTUALLY SYMPTOM-FREE. BUT THEN YOU ALSO NEED TO REALIZE THAT THESE NUMBERS ARE AFTER A TEST. ALL THESE PATIENTS THAT HAVE BEEN TESTED, THEY ARE — IN THE SYSTEM ARE STIMULATED FOR A COUPLE OF WEEKS. IT IF THEY RESPOND, THEN THEY RECEIVE AN IMPLANT. SO THESE NUMBERS ARE NOT BASED ON THE NUMBER OF PATIENTS WHERE YOU HAVE THE INTENTION TO TREAT. THESE NUMBERS ARE — BETTER FOR FECAL INKOP INCONTINENCE AND
ALSO FOR RETENTION. WE ALSO HAVE THE URGENT PC FOR OVERACTIVE BLADDER WITH I IS BASICALLY STIMULATION OF THE OF THE — NERVE IN A REPEATED FASHION AND THE OUTCOME IS SOMEWHAT SIMILAR. SO HOW COULD WE DO BETTER? BECAUSE I THINK WE REALLY NEED TO DO BETTER. MORE PATIENTS NEED TO BE CURED. NEED TO BE SYMPTOM-FREE. WELL, ONE POSSIBILITY IS TO — ON DEMAND GENITAL NERVE STIMULATION. WHAT HAPPENS IF WE STIMULATE THE DORSAL NERVE — OF THE PEW DEN IT DAPUDENDALNERVE, BUT THEN WE
— REVOKE THAT ITS PRESENCE IN ALL OF US AND IS ACTIVE DURING SEXUAL ACTIVITY. DURING SEXUAL ACTIVITY, THE DORSAL GENITAL NERVE IS ACTIVATED AND INHIBITS THE BLADDER, BECAUSE DURING SEXUAL INTERCOURSE, YOU DON’T WANT TO LOSE URINE. BECAUSE URINE KILLS SPERM CELLS. SO DURING SEXUAL ACTIVITY, THE BLADDER IS INHIBITED. THIS IS SOMETHING THAT WE CAN USE IN A SYSTEM. SO WE CAN STIMULATE THIS DORSAL GENITAL NERVE, THIS TRAFFIC WILL GO UP TO THE CORD AND THEN IN RETURN, IT WILL GO DOWN TO THE BLADDER TO SUPPRESS IT. THIS IS SOMETHING NA W THAT WE
CAN DO ON THE — SO HERE WE HAVE BLADDER TRACE, THESE SPIKES ARE BLADDER PRESSURE, THESE BARS HERE ARE THAT WHEN THE STIMULATION IS ON. SO WHAT HAPPENS IS STIMULATION STARTS TO RISE, WE SWITCH ON STIMULATION AND IN RESPONSE, IMMEDIATELY DEPRESS YOUR FULL — AND THIS CAN BE REPEATED AND HERE WE CAN SEE THE INCREASE IN BLADDER VOLUME, INDICATING THAT WE CAN INCREASE BLADDER VOLUME AND, THEREFORE, PREVENT THE THE INCONTINENCE. ONLY IN THE END, NO LONGER ABLE TO SUPPRESS THE CONTRACTIONS AND LEAKAGE WILL OCCUR. BESIDES — WE ALSO CAN SUPPRESS URGENCY. IN THIS WAY, WE CAN FULLY RESTORE THE INCONTINENCE BECAUSE WE CAN WARN THE PATIENT AFTER A FEW CONTRACTIONS OR AFTER FIRST CONTRACTION AND TELL THEM, NOW IT’S TIME TO FIND THE BATHROOM OR THE TOILET, AND IN THAT WAY, YOU CAN PREVENT THAT THE BLADDER BECOMES TOO FULL AND, THEREBY, THE PATIENT WILL BE CONTINENT. THIS ALSO WILL PREVENT HABIT WAITION — FURTHER STIMULATION. SO WE HAVE A KIND OF CLOSED LOOP SYSTEM AS DEPICTED HERE. WE NEED TO WAIT FOR INCREASING PRESSURE IN THE BLADDER THAT NEEDS TO BE DETECTED, DURING RESPONSE WE CAN SWITCH ON STIMULATION WHICH WILL LEAD TO INHIBITION, THE PRESSURE WILL DROP AGAIN, STIMULATION WILL BE TURNED OFF, AND JUST WAIT FOR THE NEXT CONTRACTION. THIS IS SOMETHING THAT WE TRIED IN — FIRST IN SPINAL CORD INJURED PATIENTS WITH AN EXTERNAL SYSTEM HERE RECORDED BLADDER PRESSURES AND WE FILLED THE BLADDER AND THEN — THE EXTERNAL SYSTEM TO RECORD THESE PRESSURES AND AFTER CERTAIN PRESSURE SWITCH ON STIMULATION HERE ON THE DORSUM OF THE PEE NUSPENISOVER THE DORSAL GENITAL
NERVE. HERE WE SEE WHAT HAPPENS IN A PARTICULAR PATIENT, WHEN THE SYSTEM IS OFF, SEE HERE THIS IS THE SPIKES BLADDER PRESSURE, LINE HERE IS BLADDER VOLUME. THRAWS A SPIKE IN PRESSURE, THERE’S ACTUALLY LEAKAGE WAWS VOLUME DROPS AND STARTS TO INCREASE AGAIN. SO CONTRACTIONS — IN THIS CONTRACTION, THERE IS LEAKAGE. YOU SEE HERE THERE’S ONLY 15 MINUTES OF FILLING BEFORE WE HAVE A CONTRACTION. NOW HERE, WE SWITCHED ON THE DEVICE AND YOU CAN SEE THERE IS NO LEAKAGE WHATSOEVER. THERE ARE MANY SMALL CONTRACTIONS BUT EACH IS DETECTED, IT STIMULATION IS SWITCHED ON AND THE PRESSURE GOES DOWN AGAIN. YOU’LL SEE INSTEAD OF 50 MINUTES FILLING THIS PATIENT CAN GO FOR ABOUT 50 MINUTES BEFORE THERE’S LEAKAGE. SUMMARIZED HERE, 13 PATIENTS, WE SEE IN EACH PATIENT AN INCREASE IN BLADDER CAPACITY. COMPARED TO WITHOUT STIMULATION. SO THIS IDEA WORKS. BUT — THEY CAUSE PROBLEMS SO WE NEED — ELECTRODES OF. THIS IS RATHER SIMPLE, ALTHOUGH THIS MAY BE IN A SENSITIVE AREA AND IS ALSO ADIPOSE TISSUE WHERE WE NEED TO PLACE AN ELECTRODE, BUT THIS CAN BE DONE AND WE HAVE ALREADY IMPLANTED ELECTRODES FOR UP OH TO TWO WEEK TO TWO WEEKS
IN PATIENTS
. THE SECOND THING IS LONG TERM PRESSURE RECORDING IS NOT POSSIBLE. SO WE NEED SOME OTHER WAY OF SENSING, AND WE CAN DO THIS BY SACRAL ROOT, ARTIFICIAL SENSORS OR WE CAN ALSO USE PATIENT CONTROLS. NOW, WE ACTUALLY DID SIX PATIENTS WHERE WE INVESTIGATED WHERE THESE SIGNALS ARE AVAILABLE. THERE’S ANIMAL WORK, WHICH — RECORDINGS FROM INDIVIDUAL SENSORY — WHICH INDICATED UPON BLADDER FILLING THERE IS AN INCREASE IN NEURAL — BUT IF — FROM THE SACRAL ROOTS, POTENTIALLY WE ALSO HAVE A PROBLEM WITH NOISE FROM OTHER SOURCES FROM THE SKIN, THE GENITALS, THE RECTUM, BECAUSE ALL THESE FIBERS CONVERGE INTO THE SA SACRAL ROOTS AND WE MAY
HAVE A PROBLEM WITH SELECTIVE. WE RECORD SOMETHING BUT HOW DO WE KNOW THAT IS IT FROM THE BLADDER. I’LL SKIP THIS ONE. SO WHEN WE FILL THE BLADDER WITHOUT DOING ANY OTHER STIMULATION, WE COULD SEE HERE IN A PATIENT THAT’S UPON IMPLEASING BLADDER PRESSURE, THERE WAS ALSO INCREASE IN THE SIGNAL, BUT THE SIGNAL WAS VERY, VERY SMALL. WE CONCLUDED IT IS POSSIBLE TO RECORD — FROM THE BLADDER — BUT IT’S VERY, VERY SMALL, AND THE — NOISE RATIO IS ALSO VERY SMALL, SO WE NEED TO IMPROVE UPON THE — THAT THEY USED. HOW CAN WE DO THIS? WELL, PERHAPS A SMALLER CUFF ON INTRADURAL ROOTS, THEN WE HAVE A SMALLER DIAMETER THAT WOULD PHILIPPOUSSIS BOOST THE SIGNAL, BUT IT IS VERY INVASIVE TO DO SO. WE CAN RECORD FROM THE DORSAL BEGAN DPLEE ON, WE CAN RECORD WITH — ELECTRODES, WE CAN ALSO USE A MULTI-CUFF ELECTRODES. I UNFORTUNATELY — NO TIME TO GO INTO THIS, BUT THIS CONFIGURATION WE COULD IN PRINCIPLE RECORD FROM ALL DIFFERENT FIBER DIAMETERS SIMULTANEOUSLY ALSO IN DIFFERENT DIRECTIONS. THIS IS A SENSOR THAT WE HAVE USED, THERE’S ANOTHER THING — THESE PATIENTS COULD ALSO CONTROL IT THEMSELVES BECAUSE A LOT OF THESE PATIENTS CAN ACTUALLY FEEL THERE’S A CONTRACTION COMING AND THEY COULD ACTIVATE A SYSTEM THEMSELVES. BUT FAST — IS IMPORTANT. SO THE SUMMARY LIMITED ANIMAL WORK FOR THERAPY OPTIMIZATION — OF THE DGN MAY FULL EYE LI RESTORE CONTINENCE IN THESE PATIENTS WHO ARE –. MOST SIMPLE WOULD BE PATIENT CONTROLS. BUT I THINK AUTOMATIC CONTROL IS MOST LIKELY PREFERRED BUT REQUIRES A SENSOR GENERAL — IN ORDER TO MAKE THIS PRODUCT FLY, IT NEEDS TO BE AS LESS INVASIVE AS POSSIBLE, ALSO THE COMPLEXITY NEEDS TO BE AS LOW AS POSSIBLE, AND USER INTERACTION IS FOBL SHOULD NOT BE THERE. SHOULD BE AUTOMATIC. THANK YOU VERY MUCH. [APPLAUSE]>>SO WE’LL HAVE 10 MINUTES OF GENERAL DISCUSSION. SO I’D LIKE TO ASK THE TWO OTHER SPEAKERS, MAYBE TO COME TO IT THE FRONT SO THAT YOU CAN — WE CAN HAVE A DISCUSSION DISCUSSION. WE HAVE A QUESTION FROM THE VIDEOCAST WEBSITE. THE QUESTION IS FROM DR. SUSAN HARKIMA FROM UNIVERSITY OF LOUISVILLE, THE SUBJECT IS COLLABORATION FOR BLADDER NEUROMODULATION. THE MESSAGE IS, THE SEAMED CONTRADICTION OF MODULATING TWO OPPOSING MECHANISTIC CONTROL OF THE BLADDER MAY BE EXPLAINED BY COMPLEX PROCESSING WITHIN SPINAL CORD INTERNEURONS. ALL INFORMATION SUCH AS STATE OF BLADDER FILL, NEUROMUSCULAR ACTIVITY SUCH AS WHETHER YOU ARE STANDING OR WALKING VERSUS SITTING, THE STATE OF SPHINCTER ACTIVITY AND OTHERS IS INTERPRETED, AND THEN A NETWORK OF INTERNEURONS THEN EXECUTE BLADDER EMPTYING. THIS MAY BE SUPPORTED BY THE PRELIMINARY EFFORTS WE ARE OBSERVING IN EPIDURAL STIMULATION WITH BLADDER CHANGES IN VOIDING EFFICIENCY, WITH EPIDURAL STIMULATION AND CHANGES IN RECOGNITION OF FULLNESS OF BLADDER AND CONTROL WITH THOSE CHRONICALLY IMPLANTED WITH EPIDURAL STIMULATORS EVEN WHEN THE STIMULATOR IS OFF WITH MOTOR COMPLETE SPINAL CORD INJURY. IT MAY BE AN ADVANTAGE TO FORM COLLABORATIVE GROUPS FROM MULTIPLE DISEASE STATES AND APPROACHES TO STIMULATION TO COLLATE THE INFORMATION TO BETTER MOVE TOWARDS UNDERSTANDING OF THE UNDERLYING MECHANISMS.>>I DON’T KNOW IF ANY OF OUR SPEAKERS WOULD LIKE TO ADDRESS THAT.>>WELL, I DEFINITELY THINK INTERNEURONAL CIRCUITRY IN THE SPINAL CORD IS AN IMPORTANT TARGET FOR VARIOUS TYPES OF NEUROMODULATION. IN CONTRAST TO WHAT GRAHAM SAID SAID — MOST RECENT SPECULATION ABOUT THE EFFECTIVENESS OF SACRAL KNEW OWE MODULATION IN THE TREATMENT OF FOWLER’S SYNDROME, IDIOPATHIC URINARY RETENTION, IS THAT IT INTERCEPTS THE SPHINCTER AFFERENT ENTERING THE CORD AND INHIBITING BLADDER SENSORY PATHWAYS. AND THAT NEUROMODULATION TURNS OFF THAT INHIBITION, SO ESSENTIALLY IT’S DISINHIBITION. IN FOWLER’S SYNDROME, THERE IS PROBABLY A — CONNECTIONS BETWEEN THE VIED MUSCLE CELLS AND THAT ACTIVITY IS MAINTAINED EVEN DURING NEUROMODULATION. BUT THAT CONTRACT TILE ACTIVITY OF THE STRIDED MUSCLE ACTIVATES AFTER RENS, WHICAFFERENTS, WHICH
GOES INTO
THE SPINAL CORD AND TURNS ON THE SENSORY PATHWAY. SO THESE PEOPLE WITH FOWLER’S SYNDROME NOT ONLY CAN’T EMPTY THEIR BLADDER BUT THEY DON’T HAVE THE FEELING OF BLADDER FULLNESS. — RESTORES THAT ALONG WITH THE ABILITY TO EMPTY THE BLADDER. SO INTERNEURONS ARE PROBABLY A KEY SITE, WHERE ONE INPUT INTERRUPTS THE INHIBITORY INTERNEURONAL PATHWAY FROM ANOTHER TYPE OF AFFERENT INPUT.>>I’D LIKE TO IT — THE CONCEPT THAT PERIPHERAL GANGLIA ALSO HAVE INCREDIBLE CAPABILITIES FOR REFLEX PROCESSING. MY SPECIFIC QUESTION — IN TERMS OF YOU TALKED ABOUT DIFFERENT TYPES OF STIMULATION, ONE HAD MEMORY, ONE IT DIDN’T, IN TERMS OF THE TIME AFTER EFFECT AFTERWARDS. WHAT DID YOU FIND — WITH LONG TERM STIMULATION YOU ACTUALLY CHANGED THE DYNAMICS OF THE PROCESSING BETWEEN CENTRAL AND PERIPHERAL IN TERMS OF EFFICACY FOR MAINTAINING EFFECTIVENESS WITH YOUR BLADDER CONTROL? YOU ALREADY SHOWED ONE THING, YOU TURNED IT OFF, ONLY HAD TO HAVE IT ON FOR A SHORT PERIOD. YOU LOST EFFECTIVENESS AS SOON AS YOU TURNED OFF STIMULATION. OART ONE LASTED FOR A VERY LONG PERIOD OF TIME. OR DID I MISINTERPRET WHAT YOU’RE SAYING?>>I THOUGHT YOU WERE TALKING –>>GO AHEAD.>>BASICALLY — BETWEEN STIMULATION TWO OF YOUR PERIPHERAL NERVES, ONE, YOU LOST EFFECTIVENESS IMMEDIATELY AFTER TURNING IT OFF FOR A LONG TIME. MY QUESTION IS, EFFICACY WITH LONG TERM STIMULATION REORGANIZATION IN THAT CIRCUITRY. DID YOU LOOK AT THAT?>>YEAH, I THINK THAT THE TIBIAL NIR ONERVE STIMULATION LONG TERM EFFECT IS MEDIATED BY SOMETHING THAT’S HAPPENING IN THE BRAIN AND THAT REQUIRES A MORE PROLONGED STIMULATION, ABOUT 30 MINUTES IS NECESSARY TO DRIVE THIS. WHEREAS THE PUDENDAL INHIBITION IS A SPINAL REFLEX MECHANISM MEDIATED BY FAST INHIBITORY TRANSMISSION THROUGH GABA RELEASE AND ACTIVATION OF GABA RECEPTORS, AND WITHIN 20 OR 30 SECONDS AFTER YOU TURN THAT STIMULUS OFF, THE HYPERACTIVITY OF THE BLADDER IS BACK. SO I THINK DEPENDING ON THE SITE, YOU HAVE DIFFERENT TYPES OF INHIBITORY CIRCUITS. THESE BRAIN CIRCUITS ARE — THAT’S INDUCED BY HIGH FREQUENCY, PROLONGED STIMULATION. I AGREE WITH NIKO THAT THE ACUTE EFFECT TIB LAL NERVE STIMULATION IS RELATIVELY A SMALL EFFECT IN COMPARISON TO THE MORE PROLONGED OR PERSISTENT EFFECT OF TIBIAL NERVE STIMULATION. SO WE DON’T KNOW ANYTHING ABOUT THE NEUROPLASTICITY OR WHAT WE WOULD CALL POST PANIC INHIBITION OR THE HIGH FREQUENCY STIMULATION INDUCING CHANGES IN SYNAPTIC EFFICIENCY, WE DON’T KNOW ANYTHING ABOUT THOSE MECHANISMS.>>[INAUDIBLE]>>CAN YOU USE THE MICROPHONE, PLEASE?>>THE REASON I BRING THIS UP IS BECAUSE WHEN WE’VE USED VAGAL STIMULATION OR SPINAL CORD STIMULATION AT LEAST FOR CARDIAC CONTROL, THREE MINUTES OF NEUROMODULATION CAN OBSERVE PROTECTIVE EFFECTS FOR 30 MINUTES TO AN HOUR AFTERWARDS. WE THINK A LARGE PART OF THIS HAS TO DO WITH CHANGES IN PROCESSING WITHIN THE PERIPHERAL GANGLIA WITH OBVIOUSLY SOME INFLUENCES AT THE END ORGAN ITSELF.>>YEAH, AND THIS IS IN THE AUTONOMIC GANGLIA, NOT — BECAUSE SOMEONE MENTIONED THIS MORNING ABOUT HOW CHANGES IN THE TORE SAL ROUTE GANGLIA MY ALTER THE RESPONSE TO VAGAL STIMULATION. I FORGOT WHO IT WAS THAT MENTIONED THAT, AND THAT’S SOMETHING THAT WE SHOULD PURSUE FURTHER IN DISCUSSIONS LATER IN THE MEETING. BUT THE EFFECTS ON AUTONOMIC GANGLIA OF HYPOGASTRIC ACTIVATION ARE SOMETHING THAT OCCUR FOR A RELATIVELY SHORT PERIOD. THEY’RE REVERSIBLE BUT MAYBE IN THE CARDIAC GANGLIA, THIS IS SOMETHING THAT’S LONGER LASTING.>>MARCO KUTZA, NEPHROLOGIST FROM THE UNIVERSITY OF VIRGINIA. MY QUESTION IS, IT RELATES TO DR. RIKHOFF’S PRESENTATION IN WHICH HE TALKED ABOUT ANIMAL AND HUE MABS AND MENTIONED THAT WE SHOULD STICK WITH SIMPLE EXPERIMENTS FOR ANIMALS AND THEN MOVE TO HUMANS. I GUESS WHAT I WOULD LIKE TO KNOW FROM ANYBODY IS THAT HOW DO WE MOVE FROM ANIMAL STU IT DIS TO HUMAN STUDIES, HOW DO WE TRANSITION FROM THESE MECHANISTIC STUDIES? DO WE USE LARGE ANIMALS, OR WHICH LARGE ANIMALS ARE MORE REPRESENTATIVE OF HUMANS?>>I THINK THIS IS VERY DIFFICULT TO ANSWER. IF YOU HAVE DEVELOPED ELECTRODES AN YOU WANT TO STIMULATE STRUCTURES, THEN YOU WOULD LIKE TO STIMULATE STRUCTURES THAT HAVE SIMILAR SIZE THAN IN HUMANS. SO FOR THAT REASON, WE WORK A LOT WITH PIGS. BUT HOW WE MOVE FROM THE PIG TO THE HUMAN, WE USE IT FOR SAFETY, SOMETIMES DEMONSTRATION OF PRINCIPLE WHEN IT WORKS, IT MAY WORK SOMEWHAT, I DON’T THINK WE SHOULD USE THE PIG MODEL FOR OPTIMIZATION OF STIMULATION PARAMETERS, BECAUSE IT COULD BE VERY DIFFERENT IN THE PATIENT. SO AS SOON AS IT WORKS, I’D RATHER GO FOR A PATIENT TO SEE IF WE CAN GET THE SAME EFFECT.>>IF WE ASSUME THAT NEUROMODULATION IS MEDIATED AT LEAST IN PART BY A CHEMICAL PROCESS THAT IS RELEASE OF NEUROTRANSMITTERS AND ACTIVATION OF THOSE RECEPTORS IN THE CENTRAL NERVOUS SYSTEM, THEN WE HAVE DRUGS WHICH ARE AVAILABLE TO EITHER ENHANCE THAT CHEMICAL PROCESS OR BLOCK THAT CHEMICAL PROCESS, SO THOSE DRUGS IN SOME CASES LIKE — BLOCKING OPIATE RECEPTORS ARE OFTEN USED IN HUMANS, SO WE COULD ACTUALLY EVALUATE THE CHEMISTRY OF NEUROMODULATION IN HUMANS USING DRUGS WHICH ARE CURRENTLY AVAILABLE. I MIGHT WANT TO MENTION THAT IF WE THINK THAT A GABA RECEPTOR INHIBITION IS IMPORTANT FOR PUDENDAL NERVE STIMULATION INHIBITION, THERE ARE AGENTS NOT NECESSARILY TO BLOCK THE GA BA
BA RECEPTORS LIKE WE DID IN AN INTERNATIONAL FALLS, BUT TO MODULATE GABAURGENT — WE KNOW VARIOUS LIKE DIAZEPAM AND ALCOHOL, VARIOUS OTHER SYNTHETIC DRUGS CAN ALTER GABA INHIBITION AND ALTER IT IN EITHER AN UP OR DOWN DIRECTION, SO YOU CAN USE THIS CHEMISTRY THAT IS PHARMACOLOGY PLUS NEUROMODULATION TO EVALUATE THE SIMILARITIES AND DIFFERENCES BETWEEN ANIMALS. THE OTHER THING WE’RE CONSIDERING IS YOU MIGHT WANT TO CONSIDER IN THE FUTURE USING DRUG COMBINATION WITH NEUROMODULATION. IF YOU KNOW THAT X TRANSMITTER IS INVOLVED IN INDUCING BENEFICIAL EFFECTS EU THE DRUGS WHICH ENHANCES THE ACTION OF THE X TRANSMITTER AND, THEREFORE, YOU MIGHT INCREASE THE EFFICIENCY OF NEUROMODULATION, ALONG WITH DETERMINING THE MECHANISM BY WHICH IT WORKS. FINALLY THEN, IT IF WE THINK NEUROMODULATION TARGETS PATHOPHYSIOLOGY, WHICH I DEALLY WOULD BE THE RIGHT WAY TO GO, WE DON’T WANT TO AFFECT NORMAL FUNCTION, WE WANT TO AFFECT PATH LOGICAPATHOD LOGICAL FUNCTION,
THAT KIND OF STUDY MIGHT GIVE US INSIGHTS OF THE ETIOLOGY OF VARIOUS TYPE OF BLADDER DISEASES.>>I’VE BEEN TOLD WE HAVE TO WRAP UP THE DISCUSSION. THE THREE PEOPLE WHO STILL HAVE REMAINING QUESTIONS, CAN YOU COME AND SEE ME AND I WILL NOTE DOWN YOUR QUESTIONS SO THAT WHEN WE COME UP FOR THE FINAL DISCUSSION, I CAN MAKE SURE THAT YOUR POINTS ARE REFLECTED. THANK YOU VERY MUCH TO THE SPEAK RS AND THE DISCUSSANTS.>>OKAY. IT’S TIME FOR LUNCH BREAK.

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