>> GOOD AFTERNOON. LET'S SEE. FOR THOSE OF YOU WHO ARE TAKING THIS COURSE FOR CREDIT, SOMETIME NEXT WEEK WE WILL HAVE THE FINAL EXAM POSTED. THIS IS A MULTIPLE CHOICE ELECTRONIC EXAM, YOU NEEDN'T LOSE ANY SLEEP OVER IT. AND YOU CAN TAKE IT AS MANY TIMES AS YOU WANT IF YOU COMPLETE THE STATED NUMBER OF QUESTIONS, YOU'LL GET A CERTIFICATE FOR HAVING PARTICIPATED IN AT LEAST 50% OF THE SESSIONS. THAT'S THE SORT OF A HALLMARK FOR YOUR COMING. NOW NEXT WEEK IS THE LAST SORT OF DOUBLE LECTURE-LIKE SERIES, WHICH IS ON THE MITOCHONDRIAL AND MITOCHONDRIAL DISEASES. THAT WILL BELATER. LYNN WOLF FROM THE LINCOLN CENTER AND JENNIFER LIPPENCOTT SCHWARTZ FROM NICHD. FROM THE VERY LAST SESSION IS THIS MINI SYMPOSIUM ON WHAT DOES THE FUTURE HOLD FOR PH.D. SIGH VERTISES, -- SCIENTISTS. THOSE ARE FOUR OPEN SUBSTITUTE DIRECTORS AND JOHN GALLON WHO IS HEAD OF THE CLINICAL CENTER WHO WILL BRIEFLY DISCUSS WHAT IN THEIR VIEW THE CURRENT SITUATION HOLDS AND WHAT OPPORTUNITIES THERE ARE, AND WHAT EXCITEMENT THERE IS IN THEIR FIELD. AND THE WHOLE THING WILL BE A GENERAL DISCUSSION QUESTIONS AND IT'S USUALLY, THIS IS AN ANNUAL EVENT, WHICH IS NOT ONLY WELL ATTENDED, BUT THERE'S A GREAT DEAL OF INTERVENTION. OKAY. SO TODAY, JEFF. THANKS. OKAY. SO IT'S A LITTLE OVER A YEAR AGO WE HAD A SESSION ON PARKINSON'S DISEASE, AND I RECEIVED A FAIR NUMBER OF E-MAILS SUGGESTING THAT WE HAVE ANOTHER ONE. AND PART OF THE REASONING WAS BECAUSE FROM A CLINICAL STANDPOINT, THE DISEASE ITSELF WAS FASCINATING ENOUGH AND CHALLENGING FOR MANY PEOPLE WHO DIDN'T KNOW MUCH ABOUT IT. AND FROM THE OTHER, FROM THE STANDPOINT OF RESEARCH AND SCIENCE THAT'S GOING ON, IT'S REALLY LIKE AN EXPLOSION OF DIFFERENT MODALITIES THAT ARE BEING BROUGHT TO BEAR. AND PREVIOUSLY WE HAD AN EXTRAORDINARY PRESENTATION, SORT OF NEUROSURGICAL APPROACH TO CONTROL OF TREMORS AND INFLUENCING RIGIDITY. AND SO TODAY, WE'LL HEAR ABOUT ANOTHER EXCITING AVENUE THAT COMES TO BEAR TO DISEASES LIKE PARKINSON'S DISEASE, AND THAT'S REALLY A SOPHISTICATED CELL-BASED NEUROSCIENCE. AND IN THIS CASE, USING A TECHNIQUE CALLED OPTNO GENICS WHICH YOU'LL HEAR ABOUT. SO PARKINSON'S DESCRIBES THIS SHAKING PALSY DISEASE BUT IN HIS DESCRIPTION AND MUCH OF THE LITERATURE, THIS IS PRETTY OVERT. AND YOU'RE GOING TO SEE SOME OF IT ON ONLY MOVIES IN THE MOMENT. BUT I WOULD EMPHASIZE THAT THIS, WELL THAT MAKES IT MUTUAL. I DON'T KNOW WHO YOU ARE. OH, VERY GOOD. I'M THE COURSE DIRECTOR, OKAY. ALL RIGHT. SO AT THE POINT I WISH TO MAKE IS THIS LIKE MANY NEUROLOGICAL DISEASES IS VERY INSIDIOUS IN THE ONSET. AND SOME OF THE PEOPLE IN WHOM IT'S MOST APPARENT WITH THIS INSIDIOUS ONSET ARE PEOPLE WHO DO FINELY TUNED THINGS. LIKE A VIOLINIST OR BEING AN ATHLETE. THE FIRST INDICATION THAT LOU GEHRIG THE FAMOUS BASEBALL PLAYER LATER CAME TO BE CALLED LOU GEHRIG'S DISEASE. HIS BATTING DECLINE BUT HE CONTINUED TO PLAY BALL. HE NOTICED HE WASN'T AS QUICK WITH HIS STEP AND FORCEFUL WITH HIS SERVE AND EVERYTHING ELSE. I LOOKED MUCH MORE CLOSELY AND REALIZE ADD THAT MY GOD SHE HAD EARLY MANIFESTATIONS OF PARKINSON'S DISEASE. SO THIS IS KIND OF AN INTERESTING PARAMETER TO THINK ABOUT. THE EARLIEST PHASE OF THE DISEASE RATHER THAN THE OVERT ONE. I WOULD LIKE TO MAKE MENTION IN THIS CONTEXT A MAN WHOSE NAME HAS SORT OF BEEN LOST A LITTLE BIT IN HISTORY BUT TO ME IS ONE OF THE MEDICAL GIANTS, HE HAPPENED TO BE A FRIEND, GEORGE -- WAS A PHYSICIAN SCIENTIST AT BROOK HAVEN NATIONAL LABORATORY WHO ASKED HIMSELF WHY IS THE BASAL GANGLIA IN THE BRAIN THE SUBSTANTIANIGRA. WHY IS IT BLACK WHEREAS MUCH OF THE OTHER BRAIN OF THE AREA IS WHITE. AND SO HE ISOLATED FROM THAT AREA THE CHEMICAL DOPAMINE. GEORGE DID AN EXPERIMENT WHICH TODAY WOULD BE IMPOSSIBLE, IT WOULD TAKE 20 YEARS BEFORE IT WAS EVER APPROVED AND HE REACHED UP ON THE SHELF AND TOOK SOME V L-DOPA FROM A CHEMICAL VIAL. THEY BROUGHT SOME PATIENTS IN FROM BROOK HAVEN WHO HAD SEVERE PARKINSON'S DISEASE AND HE SORT OF TITRATED THEM AND SHOWED FOR THE FIRST TIME THAT THEIR TREMORS DISAPPEARED. THIS WAS REALLY THE BASIS FOR THE PHARMACOLOGICAL TREATMENT OF PARKINSON'S. SO HE WAS SOMEBODY WHO DISCOVERED SOMETHING AND DID SOMETHING ABOUT IT IN AN ERA WHEN IT WAS POSSIBLE TO. NOW IT'S STILL POSSIBLE BUT IT'S INFINITELY MORE DIFFICULT. SO TODAY WE'RE GOING TO TALK ABOUT PARKINSON'S IN THE GENOMIC, THE NEUROSCIENCE AND THE OPTOGENETIC ERA, WHICH I'M SURE WILL BE VERY EXCITING. SO WE HAVE TWO SPEAKERS AND I'LL BRIEFLY INTRODUCE THEM TO YOU. HE'S KIND ENOUGH TO GO TO BAT FOR MARK HALLETT WHO WAS GOING TO SPEAK TODAY YOU ABOUT HAS BEEN FLOORED BY ONLY INTESTINAL VIRUS. SO -- IS TRAINED AS A NEUROLOGIST, PSYCHOLOGIST AND HAS A DISTINGUISHED RECORD OF BASIC AND TRANSLATIONAL RESEARCH IN CLINICAL TRIALS AND SO FORTH RELATING TO TREMOR DISEASES PARTICULARLY PARKINSON'S. HE'S CHIEF AT THE NATIONAL INSTITUTES OF HEALTH PARKINSON CLINIC ASSISTANT CLINICAL DIRECTOR AT NINDS AND DIRECTOR OF THE -- TOXIC CENTER. WHICH MAYBE SOME OF YOU WISH TO ASK AFTERWARDS AND SOME INFORMATION. OUR SECOND SPEAKER IS A NEWER ARRIVAL AT NIH, ALEXXAL KRAVITZ, WHO OBTAINED HIS PH.D. IN NEUROSCIENCE AT THE UNIVERSITY OF PENNSYLVANIA IN 2009. AND DID A POST DOC DOWN AT THE GRAD STONE INSTITUTE AT UC SAN FRANCISCO. AND CAME HERE IN 2012 TO JOIN NIDDK. ALEXXAL IS INTERESTED IN NEURAL CIRCUITRY AT THE CELLULAR LEVEL, AND HIS WORK CAME TO MY ATTENTION WHEN I SAW IF I THINK IT WAS THE CATALYST, THE CREATION OF AN OPTOGENETIC INTEREST GROUP HERE AT THE NIH. AND KNOWING NEXT TO NOTHING ABOUT OPTOGENETICS I BEGAN TO READ ABOUT IT AND WAS TOTALLY FASCINATED AND PARTICULARLY BY READING SOME OF HIS WORK. SO I THOUGHT IT WOULD BE A VERY, SIGHTING AVENUE FOR ALL OF US TO LEARN. SO THANK YOU BOTH VERY MUCH, AND -- DO YOU WANT TO BEGIN. THANK YOU. CAN EVERYONE HEAR ME OKAY? NO? HOW ABOUT NOW? NO. ALL RIGHT. THANK YOU FOR THE INTRODUCTION. AS I HEARD, I'M A LAST MINUTE SUBSTITUTION, I'M SORRY I KNOW HOW DISAPPOINTING IT IS TO SEE THE UNDER STUDY BUT I WAS TOLD BECAUSE OF THIS THE NEXT LECTURE WILL BE FREE. [LAUGHTER] SO I GAVE A LECTURE ABOUT A YEAR AND-A-HALF AGO AND I THOUGHT IT WAS A GREAT EXPERIENCE. MARK WAS PLANNING TO DO THIS ONE, SO UNFORTUNATELY WE HAVE MUCH OF OF A NOTICE TO CHANGE. THIS AFTERNOON I TRIED TO FRANTICALLY TURN THIS TO MERGE HIS SLIDES AND MINE. I'LL ASK FOR YOUR PATIENCE A LITTLE BIT AS WE GO THROUGH THIS. BUT I THINK IT WILL STILL BE USEFUL INFORMATION. AND HOPEFULLY NICE FOR THE SECOND PART OF THIS LECTURE. I REALIZE JUST NOW THERE'S NO DISCLOSURE SIDES. I HAVE SOME RESEARCH AGREEMENTS BUT NO RELEVANT FINANCIAL DISCLOSURES. STILL HOPING THOUGH. [LAUGHTER] THIS WAS FIRST DESCRIBED BY JAMES PARKINSON IN 1817. IT'S A FASCINATING READ. THE ORIGINAL DESCRIPTION. INCREDIBLE AMOUNT OF INSIGHT, AND YOU CAN STILL READ IT NOW AND STILL DISCOVER NOW HE EVEN KNEW ABOUT THIS. HE MAY NOT HAVE UNDERSTOOD EVERYTHING ABOUT HOW THE DISEASE COMES ABOUT BUT THE DESCRIPTION IS VERY INTERESTING. THE PATHOLOGIC HALLMARK IS THE LEVEE BODY WHICH IS A CYTOPLASTIC INCLUSION THAT OCCURS IN SPECIFIC VULNERABLE NEURONAL POPULATIONS. BY THE WAY, IT'S LEVEE. HE WAS GERMAN, NOT LEVY, I LEARNED THAT RECENTLY. THE GROSS ANATOMY PATHOLOGIC HALLMARK IS THE GENERATION OF THESE PIGMENTED SUBSTANTIAL NIAGRA. THESE ARE PRESENT IN THE NEURON. ON THE LEFT HERE YOU WILL SEE -- I'M SORRY ON THE RIGHT YOU WILL SEE A NORMAL MID BRAIN WITH THIS DARK BAND AND THE SUBSTANTIANIGRA WHICH IS THE MAIN CONCENTRATION OF THE CELLS. ON THE LEFT YOU SEE THE BRAIN OF A PARKINSON PATIENT WITH PRETTY MUCH NOTHING LEFT THERE. THE MAJOR FEATURES OF PARKINSON DISEASE ARE BRADY KINESIA, RIGIDITY, TRERNL AND POSTURAL INSTABILITY. THEN THERE'S A SCORE OF NON-MOTOR FEATURES. IT'S INTERESTING THAT YOU MENTIONED IN THE INTRODUCTION THERE ARE INSIDIOUS FEATURES VERSUS THE OVERT ONES THAT ARE ACTUALLY SOME THAT FOR A WHILE ARE INVISIBLE ALTHOUGH THE DISEASE IS GOING ON. I'LL TOUCH A LITTLE BIT ON THAT. IN ADDITION TO THESE MOTOR FEATURES THAT HAVE BEEN KNOWN FOR A LONG TIME AND THE MOST VISIBLE ONE, USUALLY THE NON-MOTOR KNEES AS YOU CAN SEE LATER ON CAN PLAY A MAJOR PART AND MOST OF THE DISABLING ONES. WE LIKE TO TALK ABOUT SEVERAL SUBTYPES OF PARKINSON'S. ONE WAY TO SEPARATE IT INTO TWO MAJOR SUBTYPES CLINICALLY WHICH IS IN MOST DOCUMENTED TIME IN WHICH RIGIDITY AND BRADY KINESIA DOMINATES. STATISTICALLY THIS TENDS TO BE MORE SEVERE AND RAPIDLY PROGRESSIVE. AND A TREMOR DOMINANT WHICH TENDS TO BE SLIGHTLY MILDER. THERE'S A CONCEPT NOW THAT CONSIDERING PARKINSON AS ONE DISEASE IS SIMPLY GONE AND IT MIGHT IN FACT WE A CONSTELLATION OF CONDITIONS THAT LOOKS SIMILAR AND HAVE RELATED PATHOGENIC CAUSES THAT REALLY CAN BE VERY DIFFERENT. SHOW A COUPLE VIDEOS OF CLASSIC TAPES. I HAVE TO APOLOGIZE, I DIDN'T REALIZE I NEEDED SOME SORT OF SOFTWARE UPDATE HERE BUT YOU CAN HOPEFULLY STILL SEE THE CLASSIC RESTING TREMOR, IN THIS CASE AFFECTING THE JAW, UPPER EXTREMITIES AND THE LEG. A CHARACTERISTIC THREE TO FIVE HERTZ RATE. IT IS A RESTING TREMOR. IT TENDS TO ALLEVIATE WITH ACTION AND POSTURE, ALTHOUGH THERE'S ACTION AND POSTURAL TREMOR COMPONENT AS WELL. I THINK THESE VIDEOS GO ON FOR QUITE A BIT, SO WE'LL WANT TO SKIP SOME OF THEM IF YOU DON'T MIND. THAT WAS A VERY INTERESTING PHENOMENA. YOU SAW HOW THAT TREMOR STEPS WHEN THE PATIENT MOVES HIS ARMS AND THEN IF YOU WAIT A FEW SECONDS IT COMES BACK TO THE SAME SEVERITY. SO CHARACTERISTICALLY RESTING TREMOR VERSUS AN ACTION TREMOR. THERE ARE OTHER TYPES OF TREMORS THAT ARE MORE PROMINENT WITH ACTION AND POSTURE ESSENTIAL TREMORS AS AN EXAMPLE. AKINESIA, I DON'T LIKE LIKE THIS TERM. IT'S TECHNICALLY MEANS NO MOVEMENT. BRADY KINESIA IS THE PREFERRED TERM WHICH MEANS SLOWED MOVEMENTS OR REDUCED MOVEMENTS. THE MOVEMENTS START WITH A CERTAIN SPEED AND AMPLITUDE AND SLOWLY GETS, THE AMPLITUDE DIMINISHES AND SHE TRIES TO OVERRIDE THAT AND THEN AGAIN THERE'S THIS DIMINISHING FEATURE. AND THEN IT TRANSLATES INTO THE ABILITY TO AMBULATE AND THE ABILITY TO GET UP FROM A CHAIR. THIS IS ANOTHER FEATURE THAT WE SEE. I THINK SHE EVENTUALLY MAKES IT BUT IT TAKES HER MANY ATTEMPTS. THE MASK FACIES -- IN FACT AFFECT THE INTRODUCTION WITH THEIR PHYSICIANS. SOMETIMES IT'S THOUGHT THAT THIS CAN IMPACT THE QUALITY OF CARE THEY GET. BECAUSE AS A PHYSICIAN YOU'RE DEALING WITH A PATIENT THAT'S JUST NOT REACTING, JUST NOT RESPONDING TO THE TREATMENT. AND THAT'S BEEN SHOWN TO NOT ON THE CONSCIOUS LEVEL IMPACT THE RELATIONSHIP THE PATIENT IS HAVING WITH THE PHYSICIAN. IS POSTURAL REFLEXES IS ONE OF THE CHARACTERISTIC FEATURES ALTHOUGH IT TYPICALLY SHOWS UP LATER. AND IT CAN BE FAIRLY DRAMATIC. YOU SEE IT'S A MINOR DISPLACEMENT INSTEAD OF THE PATIENT HAS SOME DIFFICULTIES. SO THERE ARE SEVERAL STEPS COMING BACK TO CATCH HIS BALANCE. AND THAT CAN BE VERY SEVERE AND IN FACT THE PATIENT COULD SOMETIMES JUST FALL IF THE EXAMINER IS NOT THERE. JUST GOES STRAIGHT DOWN. SO YOU CAN SEE THAT THIS IS A MAJOR QUALITY OF LIFE IMPAIRMENT, AND REALLY DANGEROUS BECAUSE PATIENTS START HAVING FALLS AND OTHER COMPLICATIONS. IT'S A FAIRLY CLASSIC PARKINSONIAN WITH NO ARM SWING. TURNING ON BLOCK, THE PATIENT HAS A LOT OF DIFFICULTY TURNING. THE STRIDE IS DIMINISHED AND THE GATE IS SHUFFLED. I THINK WE ALSO MAY VAN EXAMPLE OF FREEZING IN THIS VIDEO. AS YOU CAN SEE THESE ARE VERY OLD TEACHING TAPES. YOU CAN TELL THEY COME FROM VHS. THIS IS AN ILLUSTRATION OF THE POINT I WAS MAKING EARLIER THAT WE MIGHT BE DEALING WITH PARKINSON'S DISEASES. SO FIRST OFF, EVEN IF WE CALL IT, IF WE REFER JUST TO THE CLASSIC IDIOPATHIC SPORADIC DISEASE EVEN THESE ENTITIES THAT ARE SEVERAL SUBTYPES. WE LIKE TO SEPARATE OUT THE SO-CALLED GENETICS. WE CAN THINK ABOUT PRETTY MUCH EVERY DISEASE EXCEPT MAYBE A TOOTH INFECTION EVEN THOUGH YOU CAN DEBATE HAVING A GENETIC COMPONENT. BUT THERE ARE SOME TYPES OF PARKINSON'S THAT HAVE A CLASSIC -- TRANSMISSION. THEY HAVE PATHOGENESIS -- THE MTP IS THE FAMOUS CASE BECAUSE THIS ALSO LED TO THE DEVELOPMENT OF ONE OF THE BOAST KNOWN MODELS OF MARKSONS, THE BASAL GANGLION INJURY. THIS IS A CONTAMINANT AND THOSE PEOPLE DEVELOPED A FORM, A SEVERE FORM OF PARKINSONISM. IT CAN BE SECONDARY TO MULTIPLE -- AND THEN THERE ARE CONDITIONS THAT CAN HAVE PARKINSONISM AND THESE FEATURES AS PART OF THEIR PRESENTATION. BUT IT'S REALLY NOT MARKSONS AND THIS INCLUDES MULTIPLE -- CORTICO BASAL DEGENERATION. AND SOME OF THE SPINAL -- THIS IS A LIST OF THE SO-CALLED MONO GENIC MANDELIAN PARKINSON FORMS. A LOT OF THEM, BEING DISCOVERED UNLESS YOU SEE FOR SOME OF THEM WE DON'T REALLY KNOW EXACTLY WHAT THE GENE IS OR EVEN THE TRANSMISSION IN SOME OF THEM. I ISOLATED FURTHER SOME OF THE MOST, SOME OF THE BEST KNOWN OR MOST COMMON ONES. THE FIRST ONE DESCRIBED WAS THE NEW CREAS -- THIS IS TO BE INVOLVED IN SYNAPTIC TRAFFICKING. YOUNG ONSET RAPID PROGRESSION WITH A HIGH RATE OF DEMENTIA -- WITH SOME PATHOLOGY AS WELL. LARK TWO IS DOMINANT WITH VARIABLE PENETRATION. THIS IS A KINASE INVOLVED IN SIGNALING, AND REALLY IS VERY SIMILAR IN PRESENTATION WITH IDIOPATHIC PARKINSON'S DISEASE AND THE PATHOLOGY IS ALSO VARIABLE SO THAT'S INTERESTING. THE LAST THREE HERE ARE AUTOSOMAL DOMINANT. WE THINK THAT HERE, THE MITOCHONDRIA PATHOLOGY THAT IS PRIMARILY RESPONSIBLE FOR THIS DISEASE COMING ABOUT, THEY HAVE -- TEND TO HAVE, ACTUALLY ALL THREE OF THEM, SLOWER PROGRESSION PRIMARILY MULTIPLE COMPLICATIONS. AND THE PATHOLOGY IS INTERESTING BECAUSE IT SEEMS TO BE ISOLATED THROUGH THE NIAGRA. AND I WILL TALK A BIT MORE ABOUT WHAT HAPPENS IN PATHOLOGY AND IDIOPATHIC PARKINSON'S DISEASE. REALLY MY IDEA IS NOT THE WHOLE STORY BUT REALLY IT'S JUST ONE OF MANY AREAS OF THE BRAIN THAT ARE INVOLVED. ANOTHER INTERESTING THING IS YOU ACTUALLY DO NOT FIND -- IN THESE CONDITIONS SO REALLY WE THINK THERE MIGHT BE SOMETHING RADICALLY DIFFERENT IN THE WAY THESE COME ABOUT. WE DO NOT HAVE A SLIDE WITH THE ACTUAL DIAGNOSTIC CRITERIA. THEY'RE NOT NECESSARILY RELEVANT BUT I WILL JUST SAY THAT THE DIAGNOSIS REMAINS A CLINICAL DIAGNOSIS. AND IN FACT, THE ACCEPTED CLINICAL DIAGNOSTIC CRITERIA GO UP TO TROUBLE PARKINSON DISEASE AND DEFINITE PARKINSON DISEASE REQUIRED PATHOLOGIC INFORMATION. AND OBVIOUSLY THAT'S AN INHERENT LIMITATION FOR MAKING DIAGNOSIS. THERE'S INTERESTING IMAGING IN DEVELOPING IMAGING THAT CAN -- PET SCANNING LOOKING AT THE DOCUMENT TRANSPORTER. THEY ARE NOT DIAGNOSTIC, THEY CAN HELP, THEY CAN HELP CLARIFY BETWEEN DIFFERENT TYPES OF DISEASES WHETHER IT'S PARKINSON'S OR SOMETHING ELSE. THEY REALLY ARE STILL AT THE ANCILLARY TEST NONE OF THEM ARE DIAGNOSTIC. THIS IS AN EXAMPLE OF WHAT DOPA LOOKS LIKE. SO IN A CONTROL YOU SEE A VERY STRONG SIGNAL BILATERALLY. THIS IS A PATIENT WITH PARKINSON AND THIS IS A PRESYMPTOMATIC STAGE AND YOU CAN SEE THE PATHOLOGY IS THERE LONG BEFORE THE PATIENT BECOMES SYMPTOMATIC. IN ADDITION TO THE MANIFESTATIONS THERE ARE A LOT NON-MOTOR FEATURES. IN FACT MANY OF THESE ARE PRESENT LONG BEFORE THE MOTOR FEATURES. AND IT IS FAIRLY CLEAR NOW PARKINSON'S BEGINS IN THE PERIPHERAL NERVOUS SYSTEM LONG BEFORE IT HAPPENS IN THE BRAIN. THERE'S SOME RESEARCH COMING OUT IN TERMS OF FINDING A MARKER OF PRESYMPTOMATIC DISEASE. AND ALPHA NUCLEUS STAINING ON COLONIC BIOPSY SAMPLES FROM PATIENTS JUST GETTING ROUTINE COLONOSCOPIES, 100% OF THE PEOPLE WITH PARKINSON'S WERE HAVING POSITIVE OUTCOME IN NUCLEAR STAINING. THAT'S INTERESTING. WE'RE TALKING -- BEFORE THE MANIFESTATION. THAT'S WORK IN PROGRESS AND WE'RE VERY INTERESTED TO SEE WHERE THIS IS GOING TO LEAD. THIS IS NOT AN EXHAUSTIVE LIST, AND THESE CAN BE VERY DISABLING MANIFESTATIONS. AND GOING A BIT MORE INTO DETAIL HERE, THIS IS FIVE YEARS DURATION PRETTY MUCH 100% OF PATIENTS HAVE A LOT OF NON-MOTOR MANIFESTATIONS. IN FACT I STRONGLY BELIEVE I'M NOT ALONE IN THIS THAT IF YOU DON'T FIND NORMAL MANIFESTATIONS BY THE TIME SOMEBODY HAS MOTOR MANIFESTATIONS YOU JUST DIDN'T LOOK HARD ENOUGH BECAUSE THEY ARE GOING TO BE THERE. AND THINGS LIKE FATIGUE, ANXIETY, PAIN, WE NOW KNOW PAIN IS PART OF PARKINSON'S AND SOMETIMES WITH RESPONSE TO THE -- MEDICATION AND A NUMBER OF OTHER THINGS -- DYSFUNCTION IS NOW CONSIDERED ALMOST A SPECIFIC MANIFESTATION FOR PARKINSON'S SO MUCH SO IF WE SEE SOMEBODY WHO LOOKS LIKE THEY HAVE PARKINSON BUT THEIR SENSE OF SMELL IS NORMAL WE QUESTION THE DIAGNOSIS. WE'RE LOOKING AT ABOUT 15-20 YEARS OF DISEASE. REALLY, MOST OF THE COMPLAINTS AT THIS STAGE ARE NON-MOTOR. THIS IS PRESENT IN ALL THE PATIENTS, FALSE DEMENTIA, FREEZING. SO YOU SEE A NUMBER OF VERY DISABLING MANIFESTATIONS, AND SINCE THAT TIME WHEN THE DOCUMENT WAS DISCOVERED, WE'VE BECOME QUITE GOOD AT CONTROLLING MANIFESTATIONS OF THE DISEASE WITH DON'T MEAN. WE'VE DEVELOPED A LOT OF VERY INTERESTING DRUGS TREATING THE MOTOR MANIFESTATIONS. WE'RE STILL REALLY LAGGING BEHIND WHEN IT COMES TO THE NON-MOTOR MANIFESTATIONS. SO TALK LITTLE BIT ABOUT THE BASAL GANGLIA. SO WE PUT THIS IN CONTEXT OF WHAT THESE STRUCTURES ARE. I'LL POINT OUT THE MAJOR PLAYERS. THESE THE SUBSTANTIANIGRA -- AL STAINING IN THE -- NUCLEUS. AND THEN THE POLY -- AND THE CONTAINMENT IS HERE AND THE -- AND THE CODDATE, YOU SEE THE HEAD HERE AND SOME I THINK ARE LABELED ON THIS END, SORT OF THE LOOPING STRUCTURE. SO THAT'S WHAT IT LOOKS LIKE ANATOMICALLY. SCHEMATICALLY, THIS IS A SIMPLIFIED VIEW OF WHAT THIS LOOKS LIKE. THIS IS AGAIN, IT'S A SIMPLIFIED MODEL AND ALL MODELS ARE FLAWED. SO KEEP THAT IN MIND. I WILL TAKE YOU THROUGH THE SUR SUR-- CIRCUITS HERE VERY STRICTLY. THE DIRECT PATHWAY GOES FROM THE CONTAINMENT TO THE GPI AND THEN TO THE THALAMUS. THE INDIRECT PATHWAY HAS -- SUBATOM ANYTHING NUCLEUS. A SIMPLE WAY IS TO SKIP TO THE END WHERE WE HAVE ATOMIC NUCLEI THAT ARE CONSIDERED TO PROVIDE A TONE TO THE CEREBRAL CORTEX. THESE ARE STIMULATING -- BLACK ONES BEING INHIBITION. THIS IS A STIMULATING TONE FACILITATING MOVEMENT. HERE'S YOUR SUBSTANTIANIGRA THAT STARTS THE CIRCUIT F WE GO OVER WHAT HAPPENS IN PARKINSON'S, YOU DON'T HAVE NERVE DOCUMENT HERE. YOU WILL SEE THAT DOPAMINE HAS TWO DIFFERENT ACTIONS IN THE CONTAINMENT. THERE'S AN EXCITATORY PATHWAY AND AN INHIBITORY PATHWAY. THE NET RESULT YOU CAN IN YOUR TIME DO THE NICE MATH OF INHIBITION AND I THINK -- EXCITATION, SO ON AND SO FORTH. THE NET RESULT THROUGH BOTH OF THESE PATHWAYS IS AN INCREASED INHIBITORY OUTPUT FROM THE PAL DOME THAT INHIBITS THIS FROM THE THALAMUS TO THE CORTEX RESULTING IN DIMINUTION OF MOVEMENT. SO THIS EXPLAINS TO SOME EXTENT THE RIGIDITY AND THE BRADY KINESIA. IT DOES NOT EXPLAIN THE TREMOR. AND THIS PICTURE HERE SORT OF CONNECTS THE ANATOMIC VIEW SO THIS IS THE PATH FROM THE NIAGRA -- IT'S INTERESTING HOW TREMOR COMES ABOUT BECAUSE IT DOESN'T REALLY QUITE FIT WITH THIS PICTURE. THIS IS FROM A VERY ELEGANT STUDY FROM 2011. THE CURRENT THINKING IS THAT THERE'S A SEPARATE CEREBELLA CORTICO CIRCUIT THAT IS RESPONSIBLE FOR GENERATION OF TREMOR. AND IT IS CONNECTED WITH THIS BASAL GANGLIA CIRCUIT BETWEEN THE GPI AND THE -- VIM REGION OF THE THALAMUS. AND THE DISEASE BASAL GANGLIA CIRCUIT DRIVES THE CEREBELLA CIRCUIT INTO TREMOR CAUSING THE PARKINSONAL TREMOR. WE'LL START AT THE END WHERE THE FINAL RESULT IS CELL DEATH. YOU'LL SEE THAT MITOCHONDRIAL DYSFUNCTION FEATURES PROMINENTLY HERE. WE THINK THAT THAT IS CENTRAL IN THE PATHOGENESIS IN PARKINSON'S. SO THE AUTOSOMAL RECESSIVE MUTATIONS I HAVE POINTED OUT -- THEY CAUSE DIRECTLY MIGHT CHONDRAL DYSFUNCTION WHICH IN TURN RESULTS IN OXIDATIVE STRESS THAT FEEDS ADDITIONAL PATHWAYS. LOOKING SEPARATELY AT PARKEN, THIS IS SORT OF THAT ROLE EXPLODED. THAT'S THROUGH AN INTERMEDIARY HERE AND THIS MOLECULE DID YOU SEE ONE ALPHA HAS BEEN REFERRED TO AS THE MASTER REGULATOR OF MITOCHONDRIAL SURVIVAL. SO THIS IS JUST AN OUTLINE OF HOW THAT HAPPENS. THE OTHER SIDE OF THIS SPECULATION -- IS SUPPOSED TO BE CENTRAL IN CELL DEATH. AND ALSO IN TURN DRIVES ADDITIONAL MITOCHONDRIAL DYSFUNCTION CREATING A PATHOLOGIC FEET FORWARD LOOP. IT'S A BROAD OUTLINE AND -- TALK ABOUT GENE THERAPY AND POSSIBLE GENE THERAPY TARGETS. I'LL GET TO THAT JUST BRIEFLY LATER ON. IN TERMS OF STAGING OF THE DISEASE AND THIS IS A TOPIC I LIKE TO EMPHASIZE BECAUSE IT REALLY REFLECTS THE WHOLE IDEA OF MANIFESTATIONS THAT YOU SEE AND SOME THAT ARE INSIDIOUS. SO THE FIRST TWO STAGES OF PARKINSON'S, THIS IS A PATHOLOGIC POST MORTEM STUDY LOOKING AT PATIENTS WITH PARKINSON'S WHO HAS DIED AT DIFFERENT STAGES. THE FIRST COUPLE OF STAGES DO NOT EVEN REACH THE SUBSTANTIANIGRA THAT CAUSES THE MOTOR MANIFESTATIONS. THEY REACHED THE DORSAL NUCLEUS OF THE VAGAL. THEN ONLY IN STAGES THREE AND FOUR IS THE NIAGRA INVOLVED, AND THIS IS WHEN YOU START HAVING MOTOR MANIFESTATIONS. AND THEN IN THE LATER STAGES THE ENTIRE BRAIN IS INVOLVED INCLUDING THE CORTEX CAUSING THE DIMENSION AND OTHER PROBLEMS. SO WHAT DOES THIS DO ON A CLINICAL STAGE? WELL, THERE IS A PRESYMPTOMATIC PHASE, THIS IS NOT TO SCALE IN TERMS OF TIME. SO THERE'S A PRESYMPTOMATIC STAGES YOU CAN SEE, I'M SORRY I LOST MY POINTER HERE. THERE WE GO. BY THE TIME WE HAVE MOTOR MANIFESTATIONS, WE THINK THAT ABOUT 80% OF THE NIAGRA ALREADY DIED -- WE REALLY NEED TO FIGURE OUT WHEN THIS DISEASE STARTS WAY BEFORE IT ACTUALLY MANIFESTS. THIS IS USUALLY WHEN THE PATIENTS ARE PRESCRIBING MEDICATION. THERE'S A HONEYMOON PERIOD WHEN THE MEDICATION WORKS SUPERBLY, AND THEN THERE'S A MOTOR COMPILATION PERIOD THEN THE SYMPTOMS TEND TO BECOME RESISTENT AND THEN WE HAVE A DECLINE AND A PERIOD OF COMPILATIONS. A BRIEF OVERVIEW OF THE TREATMENT. UNFORTUNATELY I'M AFRAID THAT THAT PICTURE DOESN'T QUITE SHOW UP. SO I WILL JUST POINT OUT LEFT OWE DOPA IS THE PRECURSOR OF DOPAMINE. THIS IS THE NEURON. IN COMBINATION WITH -- THIS PROVIDES THE MISSING DOCUMENT. WE GIVE A PRECURSOR -- SOME PERIPHERAL EFFECTS INCLUDING NAUSEA. THIS IS DOWN HERE SO THEY'RE NOT DOPAMINE BUT THEY PLAY THE DISEASE SHALL WE SAY. THEY HAVE THE SAME THING, THE SAME EFFECT AT THE RECEPTORS. THEY HAVE A DIFFERENT SET OF SIDE EFFECTS BECAUSE THEY ACT ON THE SAME RECEPTORS BUT THEIR FUNCTION SEEMS TO BE A LITTLE BIT DIFFERENT. THEY HAVE A HIGHER INCIDENCE OF PSYCHIATRIC SIDE EFFECTS, HIGHER INCIDENCE OF DRUGS AND SLEEP PROBLEMS. ANTI-COLLIN ENERGETICS -- THEY HAVE UNPLEASANT SIDE EFFECTS. INHIBITORS IS AN INTERESTING CLASS. THEY DO NOT DOPAMINE FROM OUT SIDE BUT THEY PREVENT THE BREAK DOWN OF DOPAMINE INSIDE THE CENTRAL NERVOUS SYSTEM. THEY HAVE INTEREST BECAUSE SOME ARE STUDY FOR DISEASE MODIFYING EFFECT -- WE THINK THIS HAS AN -- COGNITIVE SIDE EFFECTS. L-DOPA IS, REMAINS THE MAIN STAY OF SYMPTOMATIC TREATMENT AND THE MOST POWERFUL MEDICATION. ITS SIDE EFFECTS ARE DIS KINESIA -- ABOUT ONE THIRD TO HALF OF THE PATIENTS START HAVING DYSKINESIA -- ON DOPAMINE IS WORKING TO OFF AND HAD HE STARTED HAVE DYSKINESIA. I KNOW WE WERE DELAYED A BIT BUT WE WANT FIVE, TEN MINUTES. KEEP GOING, ALL RIGHT. THIS IS A SLIDE LOOKING AT NON-DOPAMINERGIC -- THEY'RE CONCENTRATED IN THE NEURONS WHICH ARE THE NEURONS ON WHICH THE DOPAMINEERGIC -- IN ADDITION TO THAT THERE ARE DRUGS BEING STUDY FROM THE -- AND OTHERS. I WON'T GO INTO A LOT OF DETAIL FOR THE SAKE OF TIME. STIMULATION HAS BEEN AROUND FOR WHILE AND IT'S AN INTERESTING AND WHEN APPLIED CORRECTLY, VERY SATISFACTORY METHOD OF TREATMENT. SO SIMPLY PUT IT'S A PACEMAKER FOR THE BRAIN. IT DOES NOT INTERFERE WITH DOPAMINE BUT IT INTERFERES WITH THE CONSEQUENCES OF PARKINSON'S SO IT NORMALIZES THE NORMAL ELECTRICAL SIGNALS IN THE BRAIN. THIS IS A SCHEMATIC OF WHAT IT LOOKS LIKE. THEY ARE PLACED -- CAN HAVE AN ENTIRELY DIFFERENT LECTURE ON THAT. LET ME GO BACK TO THE SCHEMATIC THAT I SHOWED YOU. SO THERE ARE A COUPLE OF OBVIOUS TARGETS. IF ULTIMATELY THE RESULT OF DOPAMINE NOT REALLY WORKING IS THAT YOU HAVE A HYPER ACTIVE SUB-- DRIVING THIS WHOLE DOWN STREAM PATHWAY INHIBITION. IF YOU INTERFERE WITH THEM HERE THEN YOU MIGHT HELP THE SYMPTOMS. AND THESE ARE INDEED THE MAIN TARGETS OF THE BRAIN STIMULATION. I DON'T HAVE TIME TO GO INTO DETAILS OF HOW THE BRAIN STIMULATION WORKS. THE SHORT ANSWER IS WE DON'T KNOW BUT WE KNOW IT WORKS THE LONGER ANSWER IS AT THE VERY LEAST IT'S NOT DIRECTING THE CONDEX. IT'S NOT THE SAME AS KNOCKING OUT THESE STRUCTURES. IT'S MORE COMPLEX THAN THAT AND WE CAN TALK MORE ABOUT THIS WHEN WE HAVE TIME FOR QUESTIONS AND ANSWERS. THIS SINCE I SHOWED YOU THE SCHEMATIC FOR TREMOR, THIS WILL OBVIOUSLY BE AN OBVIOUS TARGET FOR INTERFERING WITH TREMOR, RIGHT? IT CAN IMPROVE THE ON TIME WITHOUT DYSKINESIA. IF SOMEBODY HAS FLUCTUATIONS THAT'S WHAT WE TARGET. IT GENERALLY DOESN'T DO BETTER THAN MEDICATION. SO THE GOAL HERE IS TO DO AS GOOD AS MEDICATION CAN BUT WITHOUT THE FLUCTUATIONS AND SIDE EFFECTS. A LOT OF DATA IS COMING OUT NOW SHOWING THE EARLIER YOU DO THE STIMULATION THE BETTER YOU MIGHT BE. YOU DON'T GO TO THAT FIRST BUT THE AREA IN TRIAL IS THE LATER THING SHOWING THE EARLIER IT IS THE BETTER IT IS. GOING A BIT MORE INTO THE WHOLE IDEA THAT IT'S NOT JUST THE DOPAMINERGIC NOWRNZ. THE FALLING AND FREEZING PORTIONS I TALKED ABOUT -- ARE MOSTLY RESPONSIBLE FOR THAT. AND BASED ON THAT, THOSE STUDIES, THIS IS AN INTERESTING STUDY LOOKING AT IMAGING DATES. SO ESSENTIALLY VIRTUAL GATE. THE SAME AREA IN FUNCTIONAL MRI ACT AS THEY WOULD AN ACTUAL GATE. THIS HIGHLIGHTED THIS AREA OF THE MID BRAIN. AND THIS IS PATHOLOGIC DATA, THIS IS A CONTROL. PATIENTS WITH PARKINSON'S WHO DO NOT HAVE PROMINENT FALLING AND GATE IMPAIRMENT, THERE ARE PATIENTS WITH PARKINSON'S WHO DID HAVE A PROMINENT GATE IMPAIRMENT. IT HOOVES THE POINT ALL PARKINSON'S IS NOT THE SAME. THERE'S A SUBCATEGORY OF PATIENTS THAT HAVE MORE DIFFICULTY ARE WALKING. THIS LED INTO THE WHOLE PROCESS TARGETING THE AREA IN PARKINSON'S DISEASE. AND WE ARE ACTUALLY WE HAVE A STUDY THAT WE HOPE WE'RE GOING TO START SOON LOOKING AT PRIMARILY AT THE PHYSIOLOGY BUT ALSO AT THE EFFICACY. SO HAVING TOWARDS THE END I JUST WANT TO MENTION THE VIRAL VECTOR GENE THERAPY. THIS IS A VERY INTERESTING AREA THAT HOLDS A LOT OF HOPE WE THINK. BECAUSE ESSENTIALLY IT HAS, IT ALLOWS US TO DELIVER GENETIC CONSTRUCT SURGICALLY FOR THE FIRST TIME GO TO THE SOURCE OF THE PROBLEM RATHER THAN JUST TREAT IT SYMPTOMATICALLY. SO YOU CREATE THESE CONTRACTS WHERE YOU HAVE A HELPER PACKAGING CONSTRUCT THAT IS VITAL GENES FROM AN INACTIVATED VIRUS AND THE WHOLE GENE TURNS INTO A MEDICATION FACTORY WITH THESE GENE PRODUCTS. THERE ARE A NUMBER OF RELEVANT PATHWAYS YOU CAN TARGET HERE. THIS IS A DIFFERENT SCHEMATIC OF THE SAME THING. SHOW ON THIS AREA, YOU CAN SEE HOW YOU CAN DELIVER SYMPTOMATIC THERAPY IN A MUCH MORE EFFICIENT WAY. FOR EXAMPLE, THIS IS THE ENZYME THAT DIFFERS -- THIS IS THE TARGET ASSOCIATED VIRUS TWO TARGET THAT DELIVERS THIS GENE. YOU TAKE THE NEURONS THAT ARE STILL THERE AND YOU TURN THEM INTO FACILITATED ACTIVITIES OF DOPAMINE. THESE ARE ALL STUDIES THAT ARE EITHER ONGOING OR IN DIFFERENT STAGES. IS FOR EXAMPLE GOING INTO THE -- NUCLEUS, THAT WAS THE STIMULATING MATT WAY IN THE SCHEMATIC I SHOWED YOU. AND IF YOU DELIVER THIS ENZYME GAV, YOU CAN TURN GLUTAMATE WHICH IS A TRANSMITTER INTO GABA WHICH IS AN INHIBITOR NEUROTRANSMITTER. ESSENTIALLY YOU PUT THE DIAL IN THERE TO DIAL DOWN THE EXCITATORY OUTPUT. THE MOST INTERESTING ONE IS THIS. IT'S FEATURED HERE -- IS IN THE SAME PATHWAY AND I'LL SEGUE INTO THAT. WHICH ARE NEUROTROPIC FACTORS THAT ARE SUPPOSED TO ARREST THE NEURONS OR PROMOTE SURVIVAL. AND THIS WOULD IN FACT GO TO THE SOURCE OF THE DISEASE. SO INSTEAD OF JUST READING THE SYMPTOMS IT MAY REVERSE THE NON-PATHOGENIC PROBLEMS. THIS IS ONE OF THE NEUROTROPIC FACTORS. IT WAS ISOLATED BASED ON DISCOVERY THAT IT PROMOTES SURVIVAL OF THE -- NEURONS. SO THEN LOGICALLY THE NEXT STEP WAS TO SEE IF IT HAS NEUROPROTECTIVE OR NEURORESTORATIVE THERAPY. YOU MAY HAVE HEARD ABOUT BOTH OF THESE. THEY'RE BOTH OUT THERE IN TRIALS. THERE ARE A NUMBER OF TOPICS ON THIS PATHWAY. THESE ONLY ACT PERIPHERALLY. THESE ARE THE TWO THAT ACT IN THE CENTRAL NERVOUS SYSTEM -- OF NEURONAL POPULATIONS. THE PRECLINICAL DATA LOOKED VERY ENCOURAGING. THIS IS DATA FROM PRIMATE STUDIES. THIS IS AN AGED PRIMATE MODEL UNILATERAL INJECTION. YOU SEE THE SUCCESSFUL EXPRESSION HERE. AND WHAT YOU SEE FURTHER DOWN, THIS IS STAINING WITH NEUROMELANIN WHICH MARKS THOSE SURVIVING NEURONS, I'M SORRY, I'M GETTING MY STRIPES CONFUSED HERE. IT'S ACTUALLY THIS SHOWS EXPRESSION OF DOPAMINE AFTER THE INJECTION OF THE VIRAL VECTOR. SO THE AGE PRIMATE MODEL IS PROBABLY AS CLOSE WE CAN GET TO A PARKINSON'S MODEL. BECAUSE IT'S NOT THE -- PROGRESSIVE GENERATION LIKE WE HAVE IN HUMANS. AND BASED ON THAT, THERE HAVE BEEN A COUPLE TRIALS. THE LATEST ONE TO COME OUT I THINK JUST ANNOUNCED THE PRELIMINARY RESULTS OF THEIR TRIAL AND IT DID NOT MEET EFFICACY CRITERIA, BUT IT MET SOME SECONDARY END POINTS AND IT WAS TO BE SAFE. WE HAVE A STUDY WE HAVE JUST STARTED AT THE NIH USING GDNF AND WE JUST ENROLLED OUR FIRST PATIENT. THE FIRST SURGERY HAS YET TO TAKE PLACE. THIS IS A DOSE FINDING STUDY SAFELY IN THE EFFICACY OF THE SECONDARY OUTCOMES SO WE'RE PRETTY EXCITED ABOUT THAT. AND THIS BRINGS ME TO THE END WHERE THE TAKE-HOME POINTS, WE HAVE SOME CLASSIC FEATURES IN PARKINSON'S BUT A NUMBER OF NON-MODEL FEATURES THAT CAN WE JUST AS OR MORE DISABLING THAN THE MOTOR ONES. WE'RE DOING A LOT OF WORK IN UNDERSTANDING THE ETIOLOGY AND HOW THIS DISEASE COMES ABOUT. WE HAVE A NUMBER OF MEDICATIONS AND FOR NUMBER OF YEARS WE CAN DO VERY WELL. THE BRAIN STIMULATION DEFINITELY HAS A MAJOR ROLE IN INCREASE IS QUALITY OF LIFE AND EXTENDING THE WINDOW OF EFFICIENT THERAPY. I WOULD SAY THE FUTURE IS BRIGHT SO HOPEFULLY I WILL BE GIVING THE SAME LECTURE TEN YEARS FROM NOW IN THE EXACT SAME PLACE BUT I DON'T THINK WE WILL BE. THANK YOU. [APPLAUSE] >> I THINK WE HAVE TIME FOR QUESTIONS? >> [INDISCERNIBLE] >> THAT'S TWO DIFFERENT QUESTIONS. SO IT DOES IDIOPATHIC PARKINSON DISEASE PROBABLY IN THE -- 60 AND 70'S. THE PATHOGENIC PROCESS STARTED EARLIER THAN THAT AS WE NOW KNOW. JUVENILE PARKINSONISM IS A DIFFERENT TYPE AND IT IS MOST OFTEN ASSOCIATED WITH ONE OF THOSE GENETIC CAUSES SOMETIMES WITH UNKNOWN GENETIC CAUSES. AND IN FACT -- WHO IS A NEUROLOGIST IN THE UNDIAGNOSED DISEASE PROGRAM HAS BEEN KIND ENOUGH TO INVOLVE ME IN SOME OF THEIR PARKINSONIAN PATIENTS. SO WE'VE SEEN SOME VERY INTERESTING EARLY PARKINSON'S PATIENTS AND IN SOME OF THEM WE DID NOT KNOW HOW IT COMES B THE INFLAMMATION QUESTION IS DEFINITELY AN INTERESTING TOPIC, ONE THAT'S GENERATED A LOT OF INTEREST IN SOME DEVELOPING THERAPIES UNDERSTANDING THE PATHOGENESIS. WE KNOW THAT OXIDATIVE STRESS AND INFLAMMATION PLAYS A ROLE. WE DO NOT HAVE LINEAR CONNECTION. WE DON'T THINK IT'S A PRIMARY INFLAMMATORY DISEASE THAT THEN CAUSES PARKINSON'S. THE INFORMATION PROBABLY PLAYS A ROLE WE'RE STILL IN THE PROCESS OF DEFINING WHAT THAT ROLE IS. >> YES. >> [INDISCERNIBLE] >> THE QUESTION IS YOU PUT THE GENE CONSTRUCTS IN THERE WHAT HAPPENS BECAUSE THAT WILL JUST KEEP GOING INDEED. FOR SOMETHING LIKE GDNF, IF THE TARGET THAT WE HAVE IS TO PROMOTE SURVIVAL OF THE REMAINING NEURONS, LOGICALLY WE SAY YES, LET THIS GO FOREVER. I KNOW ONE OF THEM IS OFF. FOR ONE OF THE OTHER SYMPTOMATIC FOCUSED THARYMSZ WHERE YOU START EXPRESSING THE PRODUCT, IT MAY HAVE AN ADVERSE EFFECT THAT YOU REALLY HAVE NO WAY OF TURNING IT OFF. THE CONSTRUCT THAT HAVE BEEN USED IN CLINIC DO NOT AN OFF SWITCH OR SOMETHING LIKE THAT SO IT HAS BEEN AN ISSUE IN SOME OF THE INITIAL TRIALS WHERE THEY HAVE INTRACT KNOWLEDGE DYSKINESIA. IT'S A REASONABLE CONCERN FOR THE NEUROPROTECTIVE GENE THERAPY APPROACHES THE PRELIMINARY DATA THE PRIMARY DATA AND THE PRELIMINARY HUMAN SAFETY DATA INDICATES IT'S NOT LIKELY TO BE A CONCERN. >> I WAS WONDERING IF THE EARLY PARKINSON'S HAS THE SAME SYMPTOMS. >> IT DEPENDS ON WHAT TYPE OF EARLY PARKINSON'S. YOU CAN GET EARLIER PARKINSON'S MANIFESTATION AND IT CAN LOOK JUST THE SAME FOR THE OLDER PATIENTS. FOR THE MOST PART, NO. SO DEFINITELY THE ONE THAT STARTS VERY EARLY IN LIFE TENDS TO BE DIFFERENT. GENERALLY THE PATTERN, I'M GOING TOLY ASIDE HERE THE JUVENILE PARKINSON'S FROM CHILDHOOD BECAUSE THAT'S DIFFERENT. THE ONE THAT HAPPENS IN THE 20'S AND 30'S AND FOR EXAMPLE THE PINK ONE PARKEN MITOCHONDRIA LINK SO-CALLED PARKINSONISM -- THEY APPEAR TO HAVE THE MANIFESTATIONS WITHOUT THE NORMAL MANIFESTATIONS. THE EASY ANSWER IS YES. >> I SEEM TO RECALL THAT PARKINSON'S IS TYPIFIED BY THESE PYRAMIDAL CELLS WHICH ALZHEIMER'S HAS. IS THAT TRUE AND IF IT IS, WHAT DOES THIS TYPE OF CELL TELL US ABOUT THESE DISEASES? >> THE EXTRA PYRAMIDAL TERM REFERS TO THE ENTIRE CIRCUITRY. I DON'T THINK THERE'S A CELL, IT'S AN OLD TERM WE DON'T NECESSARILY LIKE A LOT. THE IDEA WAS THERE'S THE PYRAMIDAL CORTICO NEURONS THAT ARE LAID IN THE CORACO SPINAL PATHWAY. THERE'S A GLOBAL UMBRELLA APPLIED TO ALL THE MOTOR PATHWAYS THAT WERE EXTRA PYRAMIDAL. AND THAT'S THE PATHWAY THAT INVOLVES IN PARKINSON. BUT THERE ISN'T AN EXTRA PYRAMIDAL CELL TYPE POPULATION. >> IS THE -- BODY THE CAUSE OF OR THE RESULT OF. >> EXCELLENT QUESTION. YES. THAT'S REALLY AN IMPORTANT QUESTION BECAUSE WE REALLY DON'T KNOW IF THE LEVEE BODIES ARE THERE AND THEN THE DISEASE HAPPENS OR MAYBE THEY ARE SURVIVAL MECHANISM THAT THE CELL BUILDS UP. MAYBE THEY ARE SEPARATE CONSEQUENCES FROM THE DISEASE. AND YOU CAN HEAR AS MANY POWERFUL ARGUMENTS FOR EACH OF THESE THEORIES ACTUALLY RIGHT NOW. >> REGARDING THE VECTOR THERAPY HOW DO YOU TITRATE THOSE AND [INDISCERNIBLE] >> SO HOW DO YOU DETERMINE? f: ONE. >> [INDISCERNIBLE] >> THERE ARE SEVERAL OUTCOMES THAT WE'RE LOOKING FOR. SAFETY IS ONE BECAUSE OF THE FIRST OBLIGATION IN THIS FORM. WE ARE LOOKING FOR -- MOTOR SYMPTOMS AND THEN AMONG SECONDARY OUTCOMES THERE'S A PATH, AN IMAGING MARKER OF SORTS LOOKING AT THE AMOUNT OF DOPAMINE. THANK YOU. >> ONE ANOTHER QUICK QUESTION. IN THE IMPLICATION OF SOME OF THE THERAPEUTICS, PARTICULARLY OF MORE RECENT ONES THAT THEY REALLY SHOULD BE GIVEN EARLY IN THE COURSE OF THE DISEASE. AND SO MY QUESTION IS, IF IT'S EARLY IN THE COURSE OF THE DISEASE AND THE SYMPTOMS OF THE VERY EARLY DISEASE ARE SYMPTOMS WHICH OCCUR WITH A GREAT VARIETY OF OTHER KINDS OF ILLNESSES AND THE DIAGNOSIS IS BASED PREDOMINANTLY ON CLINICAL SYMPTOMATOLOGY, YOU IMPLIED THAT THE SCANNING CAN BE HELPFUL BUT NOT DIAGNOSTIC, HOW DO YOU RESOLVE THAT DILEMMA. >> I THINK YOU JUST OUTLINED A MAJOR REASON WHY A LOT OF RESEARCH EFFORT IS WITHIN WHICH IS THE EARLY DIAGNOSTIC QUESTION WHAT YOU'RE GETTING AT. WE DO NOT HAVE A GOOD EARLY ARE DIAGNOSTIC SOLUTION. THERE'S A LOT OF WORK BEING PUT INTO THIS. TREATMENT ACTUALLY, THE ONLY REASON TO GIVE TREATMENT EARLY IS THE QUALITY OF LIFE AND TO TREAT SYMPTOMS. IF WE HAD A NEURO PROTECTOR TREATMENT THAT'S WHERE THIS QUESTION BECOMES MAJOR. AS OF NOW WE DO NOT HAVE A PROVEN NEURO PROTECTIVE TREATMENT. WHICH IS UNFORTUNATE BUT WE ALL HOPE ONE WILL COME ABOUT. BUT THEN THE QUESTION OF EARLY DIAGNOSIS WILL BECOME EVEN MORE ACUTE SO WE'RE HOPING TO DEFINE WAYS TO MAKE THE DIAGNOSIS EARLY BEFORE WE ACTUALLY HAVE THAT. >> IN MANY MITOCHONDRIAL DISEASES WHICH WEALTHY HEAR NEXT WEEK THE IMPLICATION IS THERE'S REACTIVE OXIDATIVE SPECIES AND SO FORTH WHICH IS A DRIVING FORCE OF MUCH OF THE PATHOLOGY. THE CLINICAL TRIALS ARE DONE WITH LARGE DOSES OF ANTI-OXIDANTS AND VITAMIN E AND FISH OIL AND ALL OF THAT. THERE'S SOME EVIDENCE IN SOME OF THOSE DISEASES OF IMPROVEMENT. IF THAT'S THE COMMON MECHANISM AS PROPOSED IN YOUR PATHWAY, IS THAT NOT A -- >> YES, AND THAT'S BEEN OF COURSE RESEARCH WENT THERE. THE MITOCHONDRIAL PATHWAYS ARE DEFINITELY INVOLVED. HOWEVER SO FAR ALL OF THAT -- ONE WAY OR THE OTHER THEY HAVE PRETTY MUCH FAILED. SOME OF THEM STILL HAVE SOME HOPE THAT MAYBE THERE WILL BE SOME INFLUENCE ON THE PATHWAY BUT NOTHING'S BEEN A GAME CHANGER. AS OF NOW AS FAR AS WE KNOW THERE'S NO NEUROPROTECTORS IN PARKINSON'S. >> THIS IS MITOCHONDRIA IN NEURONS. >> YES. >> WE HAVE TIME FOR QUESTIONS AND COMMENTS AFTERWARDS. >> THANK YOU VERY MUCH. >> THANK YOU. >> CAN YOU GUYS HEAR ME? I WANT TO THANK YOU FOR INVITING ME TO SPEAK AND ALL OF YOU FOR COMING. WHAT I WANT TO TALK ABOUT IS A LITTLE BIT DIFFERENT IT'S GOING TO BE MOUSE WORK, TALKING ABOUT -- TRYING TO GET US THINKING OF THINGS OF WHAT MAY BE POSSIBLE IN PEOPLE AT SOME POINT OR MAY INFORM HUMAN THERAPIES. AND THE TITLE OF MY TALK IS CALLED OPTOGENETIC CONTROL OF BASAL GANGLIA CIRCUITRY. I'M GOING TO HAVE TWO MAIN POINTS. THE FIRST WILL BE THE OPTOGENETIC CIRCUITRY AND THEN I'LL GO INTO A PARKINSON'S MODEL AND TALK ABOUT HOW CAN THIS WORK, TELL US SOMETHING ABOUT PARKINSON'S DISEASE. AND HOPEFULLY BY THE END I'LL LEAVE YOU WITH A MESSAGE THERE ARE TWO BASAL GANGLIA CIRCUITS THE DIRECT EXPOIN DIRECT PATHWAY THAT HAVE CONTROL OVER MOTOR OUTMOVEMENT WE WENT THROUGH IN THAT DIAGRAM. I'LL GET PRETTY EXPLICIT ON THE OPPOSING CONTROL. AND EACH ONE MAY REPRESENT A THERAPEUTIC TARGET FOR TREATING PARKINSON'S DISEASE MAYBE WITH THE NEW VECTOR THERAPY OR SOME WAY OF MODULATING THE ACTIVITY OF EACH. SO TO TALK YOU THROUGH THE CIRCUITRY, THIS IS A BASAL GANGLIA. AGAIN IT'S A VERY SIMPLIFIED MODEL. THE STRIATUM ALSO REFERRED TO IN PRIMATES -- IN MICE WE LUMP IT TOGETHER TO BE ONE STRUCTURE CALLED THE STRIATUM. IT'S THE INPUT NUCLEUS OF THE BASAL GANGLIA. IT RECEIVES INPUT FROM CORTICAL -- STRUCTURES THERE'S TWO MAIN OUT PUT GROUPS. THESE ARE THE DIRECT EXPOIN DIRECT PATHWAYS I MENTIONED BEFORE. I'M GOING TO REFER TO THESE AS THE G1 PATHWAY AND G2 PATHWAY WHICH REFERS TO A DOPAMINE RECEPTOR THAT'S EXPRESSED DIFFERENTIALLY ON EACH ONE. IF WE FOCUS ON THIS D1 PATHWAY OR DIRECT PATHWAY, THIS HAS OUR INHIBITORY CELLS. IT HAS AN INHIBITORY CONTROL OVER THE SUBSTANTIANIGRA CALLED THE REPARTICULAR LIE TAU AND THIS IS MOTOR OUTPUT. IF YOU THINK THROUGH THE DOUBLE NEGATIVE YOU COME TO THE IDEA THE -- IT WILL RELEASE THE MOTOR OUTPUT FROM INHIBITION FROM THE NIAGRA AND THE D1 PATHWAY CAN FACILITATE MOVEMENT. IF WE BRING BACK THE D2 PATHWAY HERE WE HAVE THE SAME INHIBITION PHENOMENA -- THE NIAGRA, SO IN THIS WAY WHEN D2 CELLS FIRE THE NIGRA -- THE BLACK AREA IN THE BRAINS THAT WE SAW. THOSE ARE THE DOPAMINE NEURONS THEMSELVES. THEY LIVE IN THE NIGRA, THEY POSSESS -- AND BECAUSE THESE TWO POPULATIONS OF -- THE RECEPTORS ARE INHIBITORY SO DOPAMINE CAN INHIBIT THE INHIBITORY PATHWAY AND FACILITATE MOVEMENT IN THAT WAY TOO. SO TWO INDEPENDENT PATHWAYS, THE EFFECT OF DOPAMINE ON BOTH OF THEM IF IT FACILITATES MOVEMENT. THE REST OF THIS TALK, I'M GOING TO GIVE YOU ANN'T SIMPLIFIED, MORE SIMPLIFIED MODEL. THE TWO THINGS I WANT YOU TO REMEMBER I'M GOING THROUGH THERE ARE TWO PATHWAYS, D1 AND D2 PATHWAY, DIRECT OR INDIRECT PATHWAY HAVE CONTROL OF THE OUTMOOT AND THE DOPAMINE CAN HAVE A DIFFERENT EFFECT BECAUSE THESE PATHWAYS HAVE DIFFERENT DOPAMINE RECEPTORS. WHEN I STARTED INVESTIGATING THESE ABOUT FOUR YEARS AGO, THIS IS A MODEL AND A LOT OF EVIDENCE IN SUPPORT OF IT BUT IT'S NOT BEEN EMPIRICALLY TESTED IN A DIRECT WAY. AND THE REASON WAS, THE TECHNOLOGY DIDN'T EXIST. BUT UNFORTUNATELY UNLIKE THE SCHEMATIC I SHOWED -- AND THE D2 CELLS ON THE OTHER IN REAL LIFE THEY ARE MIXED UP IN THE STRIATUM -- AND ASIDE FROM THE STRIATUM YOU SEE THEY'RE ALL MIXED IN TOGETHER AND THIS IS TRUE THROUGHOUT THE STRIATUM. IF YOU TAKE THE ELECTRICAL STIMULATION AND YOU STIMULATE THE STRIATUM -- NOT MEMO WITH -- CALLED OPTOGENETICS -- IN THE NERVOUS SYSTEM IN THE MOST WIDELY APPLIED AND HAS ALSO BEEN APPLIED OUTSIDE OF THE NERVOUS SYSTEM. THE MAIN PROTEIN I'M GOING TO TALK ABOUT, THIS LIGHT ACTIVATED PROTEIN, IT CHANNELS -- SO THIS IS A LIGHT ACTIVATED ION CHANNEL. IT SITS ON THE MEMBRANE OF A NEURON AND IT'S ACTIVATED BY BLUE SLIGHT AND IT WILL HOPE LIKE A RECEPTOR, DEPOLARIZE THE CELL AND CAUSE IT TO SPIKE. HERE'S AN EXAMPLE OF THE SCHEMATIC. THIS IS A PATCH RECORDING OF A STRIATAL CELL -- I'LL SHOW YOU A VIDEO OF THIS. THERE ARE THREE DIFFERENT TRACES AT THREE DIFFERENT FREQUENCIES. I'LL SHOW YOU A VIDEO IN AN AWAKE MOUSE. THIS IS A SINGLE D1 PATHWAY FROM THE STRIATUM FIRING. THIS HAS A RECORDING ARRAY OF ELECTRODES INTO THE STRIATUM -- IT'S GOING TO ACTIVATE THE CHANNEL IN THESE D1 CELLS. WE'RE GOING TO LISTEN TO THE INCREASE IN FIRING. YOU PROBABLY GET THE IDEA. SO WE HAVE THESE CELLS WE CAN SELECTIVELY ACTIVATE THEM IN AWAKE MICE. WHAT THIS ALLOWS ONE OF THE REALLY STRONG BENEFITS OF OPTOGENETIC OVER OTHER TECHNIQUES LIKE ELECTRICAL STIMULATION IS THE CELL SPECIFIC CONTROL. WE'RE IN A STRUCTURE THAT CONTAINS DIRECT PATHWAY AND INDIRECT PATHWAY CELLS. WE COME IN WITH THE FIBER OPTIC AND WE CAN SELECTIVELY ACTIVATE ONE OR THE OTHER DEPENDING WHICH ONE WE CHANNELED TO. FOR COMPLETENESS I WILL JUST MENTION THERE'S AL, SO YOU CAN CHANGE THE PROTEIN ITSELF. SO INSTEAD OF -- YOU USE SOME OTHER PROTEINS THAT HAVE INHIBITORY EFFECTS ON THE CELL. AND THEN YOU CAN DO CELL TEST SPECIFIC OPTICAL INHIBITION AS WELL. WITH A PREPARATION LIKE THIS, WE I TAKE YOU THROUGH -- WE USE A SYSTEM THAT RELIES ON -- A LOT IS GENERATED BY A PROJECT COMBINED WITH NIH AND ROCKEFELLER UNIVERSITY. THIS IS A MOUSE THAT EXPRESSES A PROTEIN KNOWN AS -- IN THESE CELLS. WIRE LOOKING AT A CORONAL SECTION OF A MOUSE SCREEN HERE. THE STRIATUM IS THIS BIG AREA IN THE MOUSE THAT'S LIT UP IN BROWN. AND IF WE COULD SEE A LITTLE BIT MORE CLOSELY WE SEE ONLY HALF THE CELLS ARE ACTUALLY -- EXPRESS THE DEED RECEPTOR WHICH IS THE D2 MOUSE. THIS IS A VIRUS THAT WILL INFECT ALL THE CELLS AND BECOME ACTIVE IN THOSE THAT EXPRESS. ALSO IN D1 AND D2 -- TARGETS THE TWO PATHWAYS I'M GOING TO SHOW YOU A LITTLE BIT OF HISTOLOGY. THIS IS WORK THAT WAS DONE I DID THIS WITH TWO VERY TAPTD GRADUATE STUDENTS TUDENTS BEAN FREEZE AND -- LOOKING AT IT FROM THE SIDE AND WE'RE SEEING THE THREE MAJOR THE STRIATUM AND THE TWO MAIN TARGETS. THE -- NEXT DOOR -- AND ALL THE WAY ACROSS THE BRAIN IT'S ALMOST A CENTIMETER SCIENCE THE FIBER THE D1 CELLS NEURONS AND FIBERS TO SIGNALS IN THE NIGRA. WE LOOKED AT HISTOLOGY NOW WE'RE LOOKING AT THE SAME VIEW SAGITTAL VIEW AND THIS IS THE STRIATUM HERE. AND THE FIBERS COME UP ALL THE WAY. WE PUT THE SAME VIRUS INTO THE D2 MOUSE WE GET AGAIN THE FIBER THE CELLAR BODIES IN THE TRITAL AND THE FIBERS TERMINATE RIGHT NEXT DOOR IN THE PALLITUS THERE. NOW WE CAN DO AN EXPERIMENT AND TEST HOW THE STIMULATION OF THESE PATHWAYS AFFECT MOVEMENT. I'M GOING TO SHOW YOU A VIDEO AND WE'RE GOING TO ILLUMINATE THE D2 CELLS AND THE HYPOTHESES IS THAT THE INHIBIT MOVEMENT WHICH IN FACT YOU'LL SEE IT DOES. THE WORD LAYERS WILL APPEAR STIMULATING THE D2 CELLS AND THE EFFECT WILL BE PRETTY OBVIOUS. THIS IS RAPIDLY REVERSIBLE. THE MOUSE RECOVERED PRETTY MUCH IMMEDIATELY. THIS IS FROZEN. YOU'LL SEE THIS TWO MORE TIMES. THIS LASTS ABOUT 15 SECONDS. I'VE DONE THESE OUT FOUR OR FIVE MINUTES FOR VARIOUS BEHAVIORAL REASONS AND THEY REALLY STAY FROZE I. YOU CAN THINK BACK TO THE VIDEOS WE SAW IN THE PREVIOUS TALK THE FREEZING AND POSSIBLY IT MAY BE KIND OF MAKING A CONJECTURE THAT THESE PARKINSON PATIENTS MAY BE EXPERIENCING THIS BECAUSE THE INDIRECT PATHWAY IS STUCK ON. I QUANTIFY THIS A FEW WAYS. THIS IS A SUMMARY. WHAT WE'RE LOOKING AT NOW ARE THREE BARS. THREE REFERS TO 30 SECONDS BEFORE THE LASER. LASER IT'S A 30 SECOND LASER PULSE AND THIS IS RIGHT AFTER 30 SECONDS. THIS IS JUST SPLITTING UP THE TOTAL TIME INTO THREE CATEGORIES. FREEZING IS LIKE WE SAW IN THE VIDEO. I GUESS FROM THE PIXEL CHANGES UNDER THE VIDEO, IT'S REALLY THE VIDEO FRAME IS NOT CHANGING. WALKING IS WHEN THE MOUSE IS MOVING FROM PLACE TO PLACE AND DO A LOT OF OTHER THINGS THEY'RE STAYING IN PLACE GROOMING SNIFFING THINGS HARDER TO TEASE APART. I'M LUMPING THEM TOGETHER. AS YOU SAW IN THE VIDEO FREEZING WENT WAY UP. IT WAS FIVE FOLD MORE FREEZING IN THESE ANIMALS WHEN THE LASER IS AND IT COVERS AS SOON AS THE LASER'S OFF. WHEN THE LASER'S ON THEY DON'T GO ANYWHERE. FINE MOTOR DROPS A LOT OF BECAUSE THEY SPENT FROZEN SO MUCH TIME. I'LL SHOW YOU THE SAME SLOT IN THE D1 AND NOW WE HAVE THE OPPOSITE EFFECT WHERE FREEZING IS PRETTY MUCH AT ZERO. D1 IS REALLY NOT FROZEN. THEY SPENT A LOT OF TIME WALKING AROUND, RUNNING AROUND THE ARENA AND THE TIME MOVEMENT IS ALSO REDUCED BECAUSE THEY'RE SPENDING SO MUCH TIME RUNNING AROUND. I BROUGHT THIS UP A LITTLE BIT FINER IN THESE SLOTS. NOW WE'RE LOOKING AT EVERY TIME THEY MOVE THEY'RE ATTRACTED BY VIDEO. WE PULL OUT THINGS HOW MANY TIMES DO THEY MOVE, HOW LONG, HOW FAST IS THE MOVEMENT. THE ONE ON THE LEFT IS HOW MANY TIMES DO THEY MOVE AND WE'RE STILL IN THAT SAME. HERE WE'RE LOOKING AGAIN BEFORE THE LASER, DURING THE LASER AND AFTER. WE CAN SEE FOR THE D2 STIMULATION THEY MOVED LESS FREQUENTLY WHEN THEY MOVED THE MOVEMENTS ARE SHORTER AND THE MOVEMENTS ARE SLOWER LIKE THE KINESIA WE SAW IN THE PARKINSON'S PATIENTS. IF WE LOOK AT THE D1 WE GET THE OPPOSITE EFFECT. IF THEY MOVE MORE FREQUENTLY, WHEN THEY MOVE THESE MOVEMENTS ARE LONGER AND THEY'RE OF THE SAME SPEEDS. THERE'S NO DIFFERENCES IN THE MOVEMENT OF THE D1 STIMULATION. THE MOUSE SPENDS TIME FROZEN WITH THE D2 STIMULATION AND WE CAN ASK QUESTIONS DOES HE FREEZE LONGER. IT'S A LITTLE MORE OFTEN BUT THE FIGURE EFFECT WHEN HE FREEZES HE JUST DOESN'T START AGAIN. HE STAYS FROZEN. WE ALSO LOOKED AT FINE MOVEMENT. I REACHED THIS IS KIND OF AN AGGREGATE OF A LOT OF DIFFERENT BEHAVIOR WE WE STILL LOOK STENO POINT OF THE MOUSE. THE MOVEMENT IS ALSO SLOWER. THAT'S KIND OF REMINISCENT OF THE BRADY KINESIA IN THE PARKINSON'S PATIENTS. THIS IS KIND OF THE MOST OBVIOUS THING BY EYE. WHEN THEY FREEZE THE MOUSE KIND OF WALKS AND FREEZES AND STOPS HERE AND THEN. WHEN THE LASER'S ON THE D1 MICE, EVERY TIME THEY START THEY START AGAIN. ALSO WE FOUND THE D1'S THEY'RE GROOMING AND SNIFFING AND THING WAS MORE VIGOROUS AND EVIDENCE THAT THEY HAVE A FASTER FINE MOVEMENT SPEED. IN CONTRAST TO LOCOMOTION SPEED. THE FINAL THING BEFORE WE GET INTO THE PARKINSON'S MODEL IS WE ALSO LOOKED AT GREAT. WE CALLED THAT PARKINSON'S PATIENT BUT THEY HAVE A STEREOTYPED GAIT. WE TRIED TO ANALYZE THIS ON A TREADMILL. WE CAN SEE ALL THE -- SOFTWARE CAN PULL OUT THE PAUSE AND CAN GIVE YOU METRICS LIKE HOW LONG ARE THE STRIDE, HOW WIDE IS THE STANCE, WHAT ARE THE ANGLES OF THE BECAUSE. IS THERE VARIANCE IN THE STEP WITH IT ON OR OFF. AND THIS IS A BIG NEGATIVE RESULT. WHEN THE LASER'S ON. THESE MICE WALK NORMALLY ON THE TREADMILL. I THINK AT THE TIME I WAS KIND OF SURPRISED BUT SPEAKING MORE -- PROBABLY SOMETHING I HAD DONE EARLIER PARKINSON'S PATIENTS CAN WALK ON A TREADMILL. AND THE GAIT PROBLEMS MAY BE MORE PRONOUNCED IN NATURAL WALKING. SO KEEP IN MIND WE DIDN'T HAVE THIS ANY GAIT DIFFERENCES WITH THE LASER ON OR OFF. I'M SORRY, THESE BARS ARE REPRESENTING THE PERCENT CHANGE LASER ON TO OFF. SO A HUNDRED PERCENT IS NO CHANGE WITH THE D1 ON OR THE D2 ON. AND NOTHING WAS SIGNIFICANT THERE. BUT THIS IS KIND OF A FORCED MOTION THAT MAYBE IF WE HAD A MORE VOLUNTARY MOTION WITH ENOUGH JUST -- WE MAY HAVE FOUND DIFFERENCES IN GATE. IN CONCLUSION FOR THIS FIRST PART THE D1 PATHWAY INCREASES THE FREQUENCY AND DURATION OF THE MOVEMENT -- DECREASE THE FREQUENCY AND DURATION OF MOVEMENT. WE DID HAVE SOME SMALLER CHANGES IN THE MECHANICS OF LOCOMOTION. THE BIG EFFECTS WERE ON THE INITIATION, ON WHEN THEY MAKE MOVEMENTS, HOW MANY MOVEMENTS DO THEY MAKE. I'M NOT GOING TO MOVE TO PARKINSON'S MODEL AND TALK ABOUT WHAT THIS CAN TELL US ABOUT PARKINSON'S DISEASE. IF YOU GO BACK TO THE SIMPLER MODEL I MADE WHERE WE'RE LOOKING AT THE STRIATUM AND. EFFECTS OF THE D1 AND D2 PATHWAYS POSITIVE AND NEGATIVE ON MOTOR OUTPUT. WE CAN TURN THIS INTO A PARKINSON'S MODEL PRETTY EASILY BY THESE CELLS THAT MAKE DOPAMINE. THEY DIE. SO THEY LOSE THEIR DOPAMINE INPUT. A PREDICTION BASED ON THE EXCITATORY EFFECT OF D1 RECEPTORS AND INHIBITORY EFFECT OF D2 RECEPTORS THAT WE SHOULD LOSE EXCITATORY TONE IN THE D1 PATHWAY AND HAVE OVER ACTIVE D2 PATHWAYS. AND TWO QUESTIONS THAT CAME FROM THIS. ONE IS WOULD INHIBITING THE PATHWAY IMPROVE PARKINSONIAN SYMPTOMS. THE SECOND IS WOULD ACTIVATING THE DIRECT PATHWAY. I'M NOT GOING TO TALK ABOUT THIS QUESTION. THIS IN FACT APPEARS TO BE TRUE INHIBITING THE INDIRECT PATHWAY DOES IMPROVE PARKINSONIAN SYMPTOMS SEEMS TO BE THE MECHANISTIC EFFECT OF DEEP BRAIN STIMULATION. THESE ARE IN TURNING OFF INDIRECT PATHWAY STRUCTURES. BUT THIS OTHER IDEA COULD YOU ACTIVATE THE DIRECT PATHWAY COULD REALLY ONLY BE DONE IN THE STRIATUM TO THE MONO SYNAPTIC ACTION FROM THE STRIATUM TO THE NIGRA. THERE'S NO OTHER PLACE IN THE CIRCUIT YOU COULD ACTIVATE JUST THE DIRECT PATHWAY. YOU CAN ONLY BE DONE IN A ANIMAL SITUATION LIKE THIS AT THIS POINT. NOT TOO MUCH -- THE MODEL THAT WE USED WAS THE TOXIN MODEL. SO THIS IS VERY DIFFERENT THAN THE GENETICS AND THE HUMAN CONDITION. IT'S REALLY A MODEL OF DOPAMINE CELL DEATH. LOOKING AT THE CHEMICAL STRUCTURE HERE OF DOPAMINE AND A TOXIN CALLED SIX HYDROXY DOPAMINE WHICH REFERS TO THE HYDROXYL GROUP THIS TIME IT'S CARBON. BECAUSE IT'S DOPAMINE IT'S TAKEN UP BY DOPAMINE CELLS AND WILL END UP CAUSING OXIDATIVE STRESS AND KILLING THOSE CELLS. KEEP IN MINUS A MODEL OF DOPAMINE CELL DEATHS BUT IT'S PROBABLY RELEVANT TO SORT OF THE DOPAMINERGIC CELL DEATH AT THE END STAGE PARKINSON. TO SHOW YOU WHAT THIS DOES TO THE STRIATUM. THIS IS A CONTROLLED STRAIN FOR -- HYDROXASE -- SO DOPE MAN CELLS EXPRESS THIS ENZYME. WE SEE THE STRIATUM HERE LIT UP STRONGLY IN RED. THAT'S WHERE MOST OF THE DOPAMINE TERMINALS ARE IN THE BRAIN. WE INVENTORY INJECT THE HYDROXY HOPE MEAN. YOU CAN SEE A LITTLE BIT OF DAMAGE IN THIS SECTION AND WE INJECTED IT DIRECTLY INTO THE STRIATUM. SO WHERE THE TOXIN WENT THOSE DOPAMINE TERMINALS TOOK UP THE TOXIN AND THEY DIE -- THE OPTOGENETIC RELIES ON THE UPIC AND THE LIGHT DOESN'T GO VERY FAR. WE GO THROUGH THE SAME -- THIS IS IN D1 CELLS WE'RE GOING TO TEST ACTIVATING D1 CELLS IN PARKINSON'S MODEL. WE CAN EXPRESS IT THROUGH THE SAME CAN YEW LAW IN THE SAME REGION. WE ONLY HAVE CONTROL OF A SMALL PIECE OF TISSUE WHO MAY NOT GET ANY BENEFICIAL EFFECT. HERE WE'RE CONTROLLING THE SAME PIECE OF TISSUE THAT'S MISSING THE DOPAMINE AND HAS HYPO ACTIVE D1 EXPRESSING NEURONS. SO THIS IS THE CONDITION OF THE SIMPLIFIED MODEL OF PARKINSON'S DISEASE BUT THESE HYPO ACTIVE D1 CELLS. WHAT YOU WANT TO KNOW IS CAN WE TURN ON THE LASER, STIMULATE THESE CELLS AND RESTORE MOTOR OUTPUT. I'LL SHOW YOU A VIDEO. AGAIN YOU'LL SEE THE WORD LASER. IN THIS VIDEO YOU'RE SEE A MOUSE WALKING AROUND. IF YOU THINK BACK TO THE OTHER VIDEO OR BECOME APPARENT THIS LESION THAT WE DID THE STRIATUM IS NOT VERY ROBUST. IT'S SORT OF A MODERATE PARKINSON IS LESION. IT'S ONLY REMOVING DOPAMINE IN THAT AREA OF THE STRIATUM. THIS MOUSE MOVES AROUND OKAY. HE'S A LITTLE BIT SLOW. ONE NOTABLE THING IS THESE MICE DON'T REAR. THEY KIND OF DO THESE SLOW BEHAVIORS ON THE BOTTOM. HE BECOMES PRETTY MUCH EXPLORATORY KIND OF EXCITED MOUSE. WE'LL SEE HIS BEHAVIOR TURNED OFF AND RETURNED TO THE PARKINSON'S. HE'S RAPIDLY BACK I'M GOING TO SHOW THE SAME QUANTIFICATION. THE FIRST BAR IS THE EFFECT OF THE LESION. WE TEST EVERY MOUSE BEFORE THE LESION TO GET AN IDEA OF THE BASELINE ANYTHING WANTING WITH FINE MOVEMENT. WE'RE LOOKING AT THE PRELASER PERIOD THE EFFECT OF THE LESION. THEY FREEZE MORE WALK LESS. THESE MICE CAN EAT DRINK AND MAINTAIN THEIR WEIGHT. WE TURNED ON THE LASER NOW WE'RE SEEING THE LARTZ AND THE SEEING THE LASER AND THIS IS PRETTY MUCH TO THE PRELESION LEVELS WHICH I FOUND A LITTLE SURPRISING. I WAS SOMEWHAT WORRIED ABOUT GETTING TOO MUCH MOVEMENT OR SOME OF THE THINGS WE TALKED ABOUT, THE DYSKINESIAS WITH TOO MUCH MEDICATION. I TRIED CRANKING THE LASER HIGHER IN THINGS. IT SEEMS LIKE YOU CAN DRIVE THESE CELLS AS MUCH AS POSSIBLE. I HAVE NOT SEEN DYSKINETIC. YOU CAN SEE THE INITIATION, THE DURATION OF EACH MOVEMENT -- THIS IS NOW THE NICE LESION AND EVERYTHING NORMALIZED TO THAT. SO THE EFFECT OF THE LATION WAS TO RULES THE FREQUENCY. NOT THE DURATION OR THE SPEED. SO THESE MICE TEND TO DO NORMAL SEEMING MOVEMENTS BASED ON THESE TWO PARAMETERS. WHEN THE LASER'S ON THIS FREQUENTLY CAME RIGHT BACK TO PREVIOUS NOT AN OVERSHOOT. WHEN WE LOOKED AT FREEZING AND FINE MOVEMENTS THIS WAS THE ONLY OVERSHOOT WE HAD WAS IN FREEZING BOTH THE FREQUENCY AND THE DURATION OF FREEZING WAS HIGHER IN THE PARKINSON'S ANIMAL. THEY FREEZE LESS FREQUENCY BUT THE DURATION IS AGAIN A RESTORED WHERE TO WHERE IT WAS. AND THE SAME THING WITH THE FINE MOVEMENTS THAT THESE MICE WERE A LITTLE BIT SLOWER WITH DEFINED MOVEMENTS AGAIN LIKE A BRADY KINESIA AND THIS WAS RESTORED TO THAT SAME LEVEL. I'M GOING TO ADD TO THIS FINDINGS THAT I FEEL LIKE I SKIPPED A SLIDE EARLIER. THE MAIN FINDINGS OF THE -- DIRECT ACTIVATION INCREASES MOVEMENT THE INDIRECT PATHWAYS DECREASE IT. I'M GOING TO ADD TO IT THIS DIRECT PAT ACTIVATION IS THERAPEUTIC IN THIS MOUSE MODEL OF PARKINSON'S DISEASE. I'M GOING TO END WITH ONE FINAL THOUGHT WHAT DOES THIS MEAN FOR PATIENTS. IS THIS SOMETHING WE'RE GOING TO SEE AT SOME POINT. AND I THINK ABOUT, I DON'T KNOW, ABOUT TWO YEARS AGO I ACTUALLY HAD THIS SLIDE AND MY MOMENT WAS THAT THIS IS ACTUALLY NOT, THIS IS KIND OF A BETTER RESEARCH TOOL AND THERE'S SO MANY TECHNICAL HURDLES TO USE THIS IN PEOPLE QUESTIONING THE VIRAL DELIVERY OF A PROTEIN YOU NEED TO GET THE OPTOGENETIC STIMULATION INTO PEOPLE. I REALLY THOUGHT THIS IS A RESEARCH TOOL. YOU CAN USE IT FOR LEARNING SOMETHING ABOUT THE SYSTEM AND THEN USE SOME TRADITIONAL WAYS TO FIND OTHER WAYS TO STIMULATE THE D1 CELLS. MAYBE PHARMACOLOGICAL OR IDENTIFYING IT AS A TARGET. I THINK IN THE LAST YEAR OR SO I FELT LESS SECURE IN THE IDEA THAT THIS IS NOT GOING TO HAPPEN IN PEOPLE. I MET PEOPLE THAT ARE DESIGNING AND HAVE PATENTS. WE HEAR TALKS LIKE THIS THAT GENE THERAPY IS REALLY COMING ALONG. THERE'S NO INHERENT REASON WHY SOMETHING LIKE THIS COULDN'T BE APPLIED IN PEOPLE. I WOULD LIKE TO ACKNOWLEDGE THE LAB WHERE THIS DATA WAS COLLECTED. THIS WAS DURING MY POST DOC AT -- AND I MENTIONED A FEW PEOPLE THAT CONTRIBUTED DIRECTLY TO THE DATA THAT I'VE SHOWN. AND I'LL END WITH THE CONCLUSION THAT I HOPE I'VE CONVINCED YOU THERE ARE TWO BASAL GANGLIA THAT HAVE OPPOSING CONTROL OVER MOTOR OUTPUT A HAVE A TARGET FOR TREATING MARKSONS MARKSONS -- PARKINSON'S DISEASE. THANK YOU VERY MUCH. THIS IS MY E-MAIL ADDRESS, FEEL FREE TO DROP ME A LINE. THANK YOU. [APPLAUSE] >> THANK YOU FASCINATING FANTASTIC WORK. FIRST I JUST WANT TO SAY I'M USUALLY A PESSIMIST BUT I REMEMBER READING YOUR 2010 PAPER AND I DIDN'T KNOW YOU WERE A PESSIMIST THEN BECAUSE WHEN I READ IT THEN I THOUGHT THIS SHOULD GO THROUGH THERAPY AT SOME POINT. I'M CURIOUS IF YOU HAVE COMBINED THIS WITH ELECTROPHYSIOLOGY. I THOUGHT THAT WAS WHERE AT SOME POINT YOUR LECTURE WAS GOING BECAUSE I WOULD BE VERY CURIOUS TO KNOW WHAT HAPPENS TO THE -- AND ALL THOSE THINGS WHEN YOU TURN THESE ON AND OFF. >> THE QUESTION IS WHETHER THESE CAN COMBINE WITH ELECTROPHYSIOLOGY TO RECORD FROM THESE CELLS. I SHOWED AN EXAMPLE, THIS GUY WE CAN IDENTIFY THE CELLS AND THEN YOU CAN TRACK THEM THROUGH A PARK ZONIAN MANIPULATION. YOU HAVE THAT ACTUALLY IN SUBMISSION AND I CAN TALK TO YOU ABOUT THAT LATER. I DON'T KNOW IF I CAN GET INTO DETAIL ABOUT THAT. >> ARE THERE NEURONS THAT ARE BOTH DOPAMINERGIC -- HOW CAN THAT INFLUENCE. >> WE MENTIONED THAT THIS BLAWTLE IS EXTREMELY SIMPLIFIED AND ONE OF THE, IF WE KEEP ASKING QUESTIONS WE'LL LEARN BUT ONE OF THE SIMPLIFICATIONS IS THESE ACTIONS SECRETE GLUTAMATE AT WELL OR THE SIDE OF THEM RELEASE GLUTAMATE. THEY ALSO RELEASE GABA. SO IT'S TRICKIER THAN JUST THEM RELEASING DOPAMINE AND EXCITING THE DIRECT PATHWAY INHIBITING. I DON'T KNOW IF ANYONE KNOWS HOW TRICKLY IT GETS BUT THEY DO KNOW THAT THE CELLS RELEASE GOOT MATE. >> I HAVE A QUESTION FOR YOUR BEHAVIOR. IS IT OBJECTIVE OR NOT OBJECTIVE BECAUSE YOU CAN SEE THE LASER'S ON IF YOU'RE LOOKING AT THE MOUSE. HOW DO YOU AVOID BIAS BY THE OBSERVER. >> WE USE COMPUTERS TO VIEW I. THE VIDEO DOES KNOW WHEN THE LASER'S ON. >> WHAT ARE YOU WORKING ON HERE AT THE NIH. >> TAKING THE SAME SYSTEM AND RESEARCHING OBESITY IN FOOD ADDICTION. MY BACKGROUND WAS IN ADDICTION AND I LEARNED ABOUT THIS CIRCUITRY IN COMBINATION WITH ADDICTION IT'S THE SAME CIRCUITRY AND THE SAME CELLS AND SAME ADAPTATIONS IN THE STRIATUM. SO KIND OF GOING BACK TOAT BUT INSTEAD OF LOOKING AT THE ABUSE LOOKING AT DIFFERENT DIETS AND HOW THEY MAY SHARE PROPERTIES BECAUSE OF ABUSE IN TERMS OF CHANGING THE CIRCUIT IN ADDICTIVE WAYS. >> YOU HAVE A DOUBLE PRODUCT. I MEAN YOU COULD BOTH WITH OPTOGENETICS YOU COULD BOTH INHIBIT AND EXCITE DIFFERENT NEURONS. DID YOU MANAGE TO DO THE DOUBLE -- >> TO ALSO INHIBIT THEM. >> AT THE SAME TIME WITH THE SAME LASER BOUT. >> NOT AT THE SAME TIME. LET'S SEE IF I HAVE. I DON'T HAVE THIS DATA HERE. I'LL ANSWER YOUR QUESTION IN TWO WAYS. ONE IS YOU CAN PUT BOTH AN INHIBITORY AND EXCITATORY -- IN PRACTICE THAT'S BEEN, CAN BE DIRTIER BECAUSE NOW YOU HAVE TWO IN THE MEMBRANE. I'VE DONE IT SEPARATELY USING THE SAME SYSTEM BUT PUTTING AN INHIBITORY PROTEIN JUST INTO THESE CELLS ACTUALLY. I HAVEN'T DONE IT IN THE D1. AND WE GOT, THEY MOVED MORE IF YOU INHIBIT THEM. THE EFFECTS ARE NOT NEARLY AS ROBUST AS EXCITING THEM. YOU SAW IN THE VIDEO WHERE THE MOUSE JUST FREEZES. WHEN YOU INHIBIT THEM THEY MOVE 20% MORE. YOU NEED TO DO THE VIDEO ANALYSIS AND TEASE OUT THAT THEY'RE MOVING MORE. >> THE IDEA I WAS GOING FOR IS THAT IMITATING EXACTLY THE -- >> PUT ONE IN EACH. >> EXACTLY. >> I HAVEN'T DONE THAT. THERE'S NO -- >> AND THEN THE CROSS OVER WHICH WOULD BE THE EFFECTIVE TREATMENT EVENTUALLY. >> YES. I HAVEN'T DONE THAT. THERE'S NO TECHNICAL LIMITATIONS WHY THAT COULDN'T BE DONE. >> FOR SURE. >> WE ASK YOU SPEAK IN THE MICROPHONE BECAUSE THERE ARE MANY PEOPLE ON-LINE AND THEY CAN'T HEAR THE QUESTION. >> YOU HAD MENTIONED THAT YOU MODULATED THE INTENSITY OF THE LASER. DID YOU FIND THERE WAS A THRESHOLD EFFECT IN THE MOTIONS, THAT IS IS THIS A SYSTEM WHICH IS PROPORTIONAL CONTROL OR IS THERE A NON-LINEAR THRESHOLD IN THE RESPONSES? >> IT'S PRETTY LINEAR ACTUALLY THERE WAS A ROTATION TEST WHERE -- THE MOUSE ROTATES. IT'S EASY TO QUANTIFY. THAT WENT UP LINEAR WITH THE INTENSITY OF THE LASER. GETTING DOWN TO PRETTY LOW LEVELS GETTING DOWN TO ABOUT A 20TH OF WHAT WE SAW IN THE -- IT'S TOO MUCH, IN THIS VIDEO. SO THAT WAS, THAT'S ONE TO REFERENCE LASER POINTERS ARE USUALLY ABOUT ONE TO THREE. THAT'S ONE OFF AND I'VE GONE DOWN TO .50 MILL WATTS. YOU CAN STILL GET SOME BIAS AND ROTATIONS AND IT GOES UP WITH THE INTENSITY OF THE LIGHT. >> SO WHAT IS THE DEPTH OF PENETRATION IT WOULD REACH OF THE LASER. WHAT HAVE YOU TRIED AND WHAT IS THE MAXIMUM YOU COULD REACH. >> SO THE QUESTION IS WHAT IS THE DEPTH OF THE PENETRATION. AND IT DEPENDS, THE DEPTH WITH THIS PROTEIN THAT RESPONDS TO BLUE LIGHT YOU USE THE BLUE LIGHT TO ACTIVATE IT. IT'S ABOUT A MILLIMETER AND-A-HALF. IF IT WAS INFRARED LASER YOU COULD PENETRATE FURTHER BUT YOU NEED TO MODIFY THE -- TO RESPOND TO INFRARED. PEOPLE HAVE BEEN DOING THAT AND SHOWN SOME SUCCESS BUT NOT SUCCESS IN TERMS OF MODULATING GOOD BEHAVIOR. >> DOES MOON LIGHT PENETRATE THROUGH THE SKULL. >> NOT VERY WELL. BLUE LIGHT IS THE WORST. IT SCATTERS THE MOST. >> THE REASON I ASK IS BECAUSE YEARS AGO WE HOPED TO DEVELOP A TECHNIQUE FOR TREATING CHILDREN WITH PROLONGED UNCONJUGATED HYPEREMIA. THIS IS -- WHICH TODAY NEWBORN KIDS WITH MARKED JAUNDICE ARE PUT UNDER THE LIGHTS. BUT SOME OF THESE MET A GENETIC DEFECT WHERE THEY HAVE LIGHTS ON -- THEY'RE UNDER THE BLUE LIGHTS FOR MORE THAN 12 HOURS A DAY FOR YEARS. AND THEY OFTEN HAVE NEUROLOGICAL FINDINGS WHICH ARE ASCRIBED TO SOMETHING CALLED -- WHICH IS A TOXIC MANIFESTATION OF BILIRUBIN IN THE SAME AREA OF THE BRAIN, THE BASAL GANGLIA. AND I WONDER IN THE LIGHT OF WHAT YOU'RE TELLING US SOME OF THOSE MANIFESTATIONS MAY NOT HAVE BEEN THE RESULT OF PROLONGED PHOTO THERAPY. THIS IS OF GREAT PRACTICAL IMPORTANCE BECAUSE PATIENTS WIND UP HAVING LIVER TRANSPLANTS TO RESTORE THE ENZYMATIC DEFECT. IS THAT POSSIBLE? >> I WANT TO SAY IT'S NOT POSSIBLE THAT WAY. IT MAY BE RETINAL AND THERE ARE -- >> THESE ARE NEWBORN INFANTS. MANY OF THEM ARE PREMIES. >> OKAY. IF THERE ARE NO OTHER QUESTIONS I WANT TO THANK YOU BOTH FOR A REALLY VERY EXCITING PRESENTATION. THANK YOU ALL FOR BEING HERE.