I AM WIN ARIAS, A SENIOR
SCIENTIST EMERITUS AT THE
NATIONAL INSTITUTES OF HEALTH IN
BETHESDA, MARYLAND.
AND WITH MY COLLEAGUE, DAN
KASTNER, WHO IS OF THE HUMAN
GENOME RESEARCH INSTITUTE HERE
AT THE NIH, WE WELCOME YOU TO
THE 11TH SESSION OF THE 23RD
YEAR OF A COURSE CALLED
DEMYSTIFYING MEDICINE.
NOW THE GOAL OF THIS COURSE IS
REALLY REPRESENTED BY THE LOGO
IN THE UPPER RIGHT OF MY SLIDE,
WHICH IS, TO MANY OF US IN THE
EASTERN PART OF THE UNITED
STATES, THE MOST FAMOUS BRIDGE
IN THE WORLD, THE BROOKLYN
BRIDGE.
AND IT CONNECTS TWO SHORES:
BROOKLYN AND MANHATTAN.
AND THE TWO CHARACTERS ON THE
BRIDGE CATWALK ARE DISCUSSING AS
IN TODAY'S PRESENTATION THE
STATUS OF REALLY NEUROBIOLOGY
FROM THE LEVEL OF MOLECULES TO
THE LEVEL OF PATIENTS.
THE PURPOSE OF THIS COURSE IS TO
BRING EXCITING DEVELOPMENTS IN
BIOLOGY AND ENGINEERING WITH
MEDICINE.
IT'S AS IF WE ARE ALL LIVING IN
A WORLD OF SILOS, WHERE PEOPLE
ARE EXPERTS IN THEIR OWN AREA
BUT NOT VERY MUCH AWARE, IF AT
ALL AT TIMES, OF WHAT GOES ON,
FOR EXAMPLE, IN A CLINICAL ARENA
OR IN A BASIC LABORATORY.
SO THE GOAL OF THIS COURSE IS TO
EXCITE YOUR INTEREST, NOT TO
OVERWHELM YOU WITH MASSIVE
AMOUNTS OF INFORMATION.
THIS IS NOT LAST WEEK'S RESEARCH
SEMINAR.
FREQUENTLY, WE HAVE LIVE
PATIENTS WHO BEGIN BY TELLING
SOMETHING ABOUT THEIR DISEASE TO
PUT IT IN A CLINICAL FRAMEWORK.
NOW, TODAY'S TOPIC WAS
ORIGINALLY CALLED SOMETHING
SIMPLE.
HOW IS THE BRAIN ORGANIZED AND
HOW DOES IT FUNCTION?
NOW, TODAY, WE'RE NOT GOING TO
ANSWER, OF COURSE, ALL OF THOSE
QUESTIONS, BUT THE IDEA IS TO
STIMULATE YOUR INTEREST AND TO
LET YOU SHARE THE EXTRAORDINARY
EXCITEMENT THAT IS GOING ON IN
TWO SEPARATE BUT RELATED WORLDS
OF UNDERSTANDING BRAIN FUNCTION.
NOW, MANY YEARS AGO, ACTUALLY IN
THE MID 19TH CENTURY, I GUESS,
THE BRAIN WAS STATED BY RAMON
CAJAL, THE NO THE NOBEL LAUREATE
BRAIN IS A WORLD CONSISTING OF A
NUMBER OF UNEXPLORED CONTINENTS
AND GREAT STRETCHES OF UNKNOWN
TERRITORY.
IT IS STILL, TODAY, LARGELY
UNEXPLORED, AND THERE ARE GREAT
STRETCHES OF UNKNOWN TERRITORY
WHICH WE WILL HEAR ABOUT.
NOW, AS A BACKGROUND, PERMIT ME
A VERY BRIEF HISTORY OF
NEUROSCIENCE.
IN ANTIQUITY, THINGS WERE
LIMITED BY THE PRESENCE OF THE
SKULL.
AND ALTHOUGH THERE WERE
OBSERVATIONS AS TO WHAT THE
BRAIN LOOKED LIKE, GROSSLY,
THERE WERE ALSO EVIDENCE FOR
TREPHINING, THAT IS, THE MAKING
OF HOLES IN THE SKULLS TO
RELIEVE PRESSURE.
BUT IT REALLY WASN'T UNTIL THE
19TH AND 20TH CENTURY THAT
NEUROLOGY AS A DISCIPLINE CAME
INTO ITS OWN.
AND THIS WAS DUE TO THE
DESCRIPTION FOR THE FIRST TIME
OF SIGNS, SYMPTOMS, PATHWAYS,
LARGELY DEVELOPED OUT OF AUTOPSY
STUDIES, AND ACTUALLY SOMETIMES
FROM THE LOCALIZATION OF MOTOR
FUNCTIONS BY STIMULATING AREAS
OF THE BROCA REGION, FOR
EXAMPLE, TO ASSOCIATE THOSE
SPECIFIC AREAS WITH SPECIFIC
MOTOR MOVEMENTS IN PARTS OF THE
BODY.
BUT IT WAS CHARCOT IN FRANCE
CONSIDERED THE FATHER OF
CLINICAL NEUROLOGY WHICH FOR
MANY, MANY YEARS WAS ALMOST LIKE
A DETECTIVE STORY, BECAUSE ONE
HAD TO BE COMPETENT IN
NEUROLOGIC EXAMINATION IN ORDER
TO TRY AND DETERMINE WHERE, SAY,
DEFECTS IN ONE OR TWO NEURONAL
PATHWAYS OVERLAPPED, WHICH WOULD
LOCALIZE WHERE PATHOLOGY MIGHT
BE.
IT WAS ALSO THE ERA OF
PSYCHIATRY, AND FREUD, YOU MAY
KNOW, STARTED OUT AS A
NEUROSCIENTIST.
AND IMPORTANTLY, IT WAS THE TIME
WHEN NERVE CONDUCTION STUDIES OF
ISOLATED NERVES OR IN DIFFERENT
SPECIES ESTABLISHED MUCH OF THE
PHYSIOLOGY AND BIOCHEMISTRY.
AND THEN IN THE LATE 20TH
CENTURY, THINGS REALLY CHANGED.
WITH SUDDENLY THE ABILITY TO
VISUALIZE THROUGH THE SKULL,
USING IMAGING TECHNIQUES WHICH
WE WILL HEAR ABOUT TODAY, AND
ALSO THE DEVELOPMENT OF CELL
BIOLOGIC TECHNIQUES, COUPLED
WITH THE DISCOVERY OF
NEUROTRANSMITTERS, THE ROLE OF
GENETICS, CELL-BASED STUDIES,
AND EVENTUALLY DRUGS AND SOME
TREATMENTS THAT EMERGED.
WHAT'S HAPPENING IN THE 21ST
CENTURY?
ONE MIGHT THINK THAT TECHNOLOGY
AND BIOLOGY DEVELOPMENTS WILL
CONTINUE TO INCREASE, MAYBE EVEN
AT A FASTER RATE.
WE NOW HAVE THE IMPACT OF
VARIOUS OMICS.
THE WONDER OF ORGANOIDS, AND
COMPUTER INTERFACING.
NOW DESPITE ALL OF THESE
EXCITING ADVANCES, CONVERTING A
COMPLETELY CLINICAL BEDSIDE
BRANCH OF MEDICINE INTO A HIGHLY
TECHNICAL AND PRECISE DIAGNOSTIC
AND THERAPEUTIC AT TIMES
FEATURE, IT STILL REMAINS THE
BRAVE NEW WORLD, THE GREAT
CHALLENGE, THE LAST FRONTIER.
SO TODAY WE'RE EXTREMELY
FORTUNATE IN HAVING TWO LEADERS
IN DIFFERENT ASPECTS OF
CONTEMPORARY NEUROSCIENCE.
SO OUR FIRST SPEAKER IS GOING TO
BE MARCUS RAICHLE, WHO DID HIS
UNDERGRADUATE AND MEDICAL
TRAINING AT THE UNIVERSITY OF
WASHINGTON, RESIDENCY AT JOHNS
HOPKINS, AND THEN IN NEUROLOGY
AT CORNEL.
AND THEN HE SPENT MANY YEARS AT
WASHINGTON UNIVERSITY IN
ST. LOUIS, WHERE CURRENTLY, HE'S
THE WOLF DISTINGUISHED PROFESSOR
OF MEDICINE, AND ALSO PROFESSOR
OF RADIOLOGY, NEUROLOGY,
NEUROBIOLOGY, AND BIOMEDICAL
ENGINEERING.
HE IS ACKNOWLEDGED TO HAVE
PLAYED A MAJOR ROLE IN THE
DEVELOPMENT OF FUNCTIONAL
IMAGING, PARTICULARLY FUNCTIONAL
MAGNETIC RESONANCE IMAGING,
FMRI, AND POSITRON EMISSION
TOMOGRAPHY, OR PET SCANNING, TO
STUDY THE HUMAN BRAIN
ORGANIZATION AND HOW IT
FUNCTIONS IN HEALTH AND DISEASE.
FOR THESE POWERFUL TOOLS AND THE
DEVELOPMENT OF THEM, HE HAS
RECEIVED A LARGE NUMBER OF
RECOGNITIONS.
FOR EXAMPLE, HE'S A MEMBER OF
THE NATIONAL ACADEMIES OF
SCIENCE, OF MEDICINE, AND THE
ACADEMY OF ARTS AND SCIENCES.
HE'S RECEIVED NUMEROUS
PRESTIGIOUS NATIONAL AND
INTERNATIONAL AWARDS,
HONORARY DEGREES, AND MANY
PRIZES, MAINLY IN NEUROSCIENCE,
AND WAS THE INAUGURAL CARL AND
GERTY CORI AWARD RECIPIENT FOR
FACULTY ACHIEVEMENT AT
WASHINGTON UNIVERSITY.
OUR SECOND SPEAKER IS NELSON
SPRUSTON.
HE DID HIS UNDERGRADUATE WORK IN
PHYSIOLOGY AT THE UNIVERSITY OF
BRITISH COLUMBIA, RECEIVED A
PH.D. IN NEUROSCIENCE AT BAYLOR
COLLEGE OF MEDICINE, FOLLOWED BY
A POSTDOCTORAL FELLOWSHIP IN
HEIDELBERG AT THE MAX PLANCK
INSTITUTE FOR MEDICAL RESEARCH.
FOR THE NEXT 16 YEARS, HE WAS ON
THE FACULTY AT THE NORTHWESTERN
UNIVERSITY SCHOOL OF MEDICINE.
AND IN 2011, WAS RECRUITED TO
THE HOWARD HUGHES MEDICAL
INSTITUTE JANELIA CENTER, WHERE
HE IS SENIOR DIRECTOR OF
SCIENTIFIC PROGRAMS.
HIS MAIN RESEARCH IS ON THE ROLE
OF THE HIPPOCAMPUS AND
MECHANISMS FOR CIRCUIT
FORMATION, WHICH MEDIATE
LEARNING AND MEMORY.
FOR HIS WORK, HE'S RECEIVED A
NATIONAL SCIENCE FOUNDATION
CAREER AWARD, AND A
DISTINGUISHED INVESTIGATOR AWARD
OF THE BRAIN AND BEHAVIOR
FOUNDATION.
WE ARE EXTREMELY PLEASED TO HAVE
BOTH OF YOU GENTLEMEN WITH US
TODAY TO DISCUSS TWO SOMEWHAT
DIFFERENT BUT INTERRELATED
ASPECTS OF THE EXCITING
DEVELOPMENT IN THE FIELD OF
NEUROSCIENCE, WHICH WILL TEACH
US MORE AND MORE ABOUT HOW THE
BRAIN IS ORGANIZED AND HOW IT
WORKS.
SO MARCOS, WOULD YOU PLEASE
BEGIN AS THE FIRST SPEAKER.
MARCUS.
>>I WOULD LIKE TO MAYBE SHARE
YOU A BIT OF HISTORY OF HOW THE
WORLD IN WHICH I LIVE HAS
DEVELOPED OVER TIME AND WHAT
MOTIVATES IT PRESENTLY.
I WOULD SAY THE MOST MOTIVATING
ASPECT OF IT IS APPEARING ON
THIS SLIDE IN FRONT OF YOU NOW.
ON THE LEFT YOU HAVE A PICTURE
OF THE HUMAN BODY FROM THE LEGS
UP WHERE THERE IS A PET SCAN AND
AN MR SCAN SUPERIMPOSED, AND I
THINK IT IS PRETTY OBVIOUS THAT
THE BRAIN STANDS OUT.
AND THIS IS A MEASURE OF ITS
METABOLISM.
IN THIS CASE, ITS METABOLIC RATE
FOR GLUCOSE.
WHILE THE BRAIN IS ONLY 2% OF
THE BODY WEIGHT, IT CONSUMES 20%
OF THE ENERGY BUDGET FOR THE
HUMAN BODY.
SO IT'S 10 TIMES MORE EXPENSIVE
PER UNIT WEIGHT THAN YOU WOULD
HAVE ANTICIPATED.
SO THE ISSUE THAT'S ON THE TABLE
TODAY, AND IT'S ON MY -- AT THE
TOP OF MY LIST, IS TO UNDERSTAND
WHY IS THE BRAIN SO EXPENSIVE?
WHERE IS THE MONEY GOING HERE,
AND HOW SHOULD WE THINK ABOUT
THIS?
SO IF WE CAN HAVE THE NEXT
SLIDE, THIS WAS AN EXPERIMENT
THAT WAS OVERLOOKED FOR A GOOD
BIT OF TIME, BUT IT USES THE
FIRST TECHNIQUE THAT WAS
AVAILABLE WHERE WE COULD
ACTUALLY HAVE A MEASUREMENT OF
THESE METABOLIC STATES OF THE
BRAIN.
IN THIS CASE, IT'S OXYGEN
CONSUMPTION AND IT'S BLOOD FLOW,
AND THIS WAS THE WORK OF SEYMOUR
SAN FRANCISCO KETY AND CARL
SCHMIDT.
IT'S STILL THE PRIMARY MEANS OF
UNARGUABLY MEASURING HOW MUCH
ENERGY IS BEING CONSUMED BY THE
BRAIN.
SO IF I CAN HAVE THE NEXT CLICK
ON THIS SLIDE.
THIS GROUP ASKED THE QUESTION,
WHAT IS THE EFFECT OF AN
EXTREMELY DIFFICULT MENTAL
ARITHMETIC TASK ON THE
CIRCULATION AND METABOLISM OF
THE HUMAN BRAIN.
AND THIS WAS PUBLISHED IN 1955.
IT'S RARELY CITED.
BUT THE SIGNIFICANT FEATURE OF
THIS EXPERIMENT WAS THE FACT
THAT EVEN THOUGH THERE WERE
CHANGES IN THE
ELECTROENCEPHALOGRAM, THERE WERE
CHANGES IN BLOOD PRESSURE, THERE
WERE NO CHANGES FOR THE WHOLE
BRAIN IN ITS BLOOD FLOW AND ITS
OXYGEN CONSUMPTION AND SOME
OTHER THINGS THAT WERE DERIVED
FROM THAT.
GIVEN THE FACT THAT THIS IS SUCH
AN EXPENSIVE ORGAN, ONE MIGHT
WELL HAVE IMAGINED IT WOULD BE
VERY COSTLY DO THE KIND OF
TASKS, BUT IF YOU CAN SHOW THE
NEXT SLIDE, THE COST OF THAT
ADDITIONAL MENTAL ACTIVITY WAS A
TRIVIAL ADDITION.
SO THE QUESTION IS HOW DO WE GET
FROM THIS POINT, THIS SURPRISING
FINDING, TO A BETTER
UNDERSTANDING OF THIS?
AND THE THING THAT WAS SO DEEPLY
IMPORTANT IN THIS THING BOTH
FROM A SCIENTIFIC POINT OF VIEW
AND JUST THE CLINICAL ASPECTS OF
THIS, WAS THE INVENTION OF X-RAY
COMPUTED TOMOGRAPHY, LARGELY BY
GODFREY HOUNSFIELD IN ENGLAND.
THIS WAS IN 1973, AND AS A BODY
NEUROLOGIST WHO HAD TO DEAL WITH
MUCH CRUDER WAYS OF GETTING A
LOOK AT THE BRAIN, THIS WAS
TRULY REVOLUTIONARY FROM A
CLINICAL POINT OF VIEW.
AT ABOUT THE SAME TIME, I HAD
GONE TO ST. LOUIS TO LOOK AT
BRAIN CIRCULATION AND METABOLISM
AT THE INVITATION OF MICHELLE
TERPIGOSIAN, ONE OF THE PIONEERS
IN THE WORLD IN THE USE OF
CYCLOTRON ISOTOPES FOR BIOLOGY
IN MEDICINE AND WAS DEEPLY
INTERESTED IN DEVELOPING
SOMETHING FOR THE BRAIN.
ONE OF THE THINGS THAT ATTRACTED
ME TO ST. LOUIS WAS TH BUILT ME
WHAT THEY CALL A CHICKEN,
RADIOACTIVE DETECTORS SITUATED
AROUND THE HEAD OF A SUBJECT IN
AN ANGIOGRAM SUITE.
FOR PATIENTS THAT WERE HAVING
ANGIOGRAPHY STUDIES DONE, WE
WERE ALLOWED TO INJECT THESE
ISOTOPES AND GET A PICTURE OF
THE BRAIN.
WHAT YOU COULD ONLY IMAGINE HOW
CRUDE SUCH A PICTURE WOULD BE.
BUT THE DEVELOPMENT OF CT WAS AN
UNBELIEVABLE STIMULUS TO MOVE
FORWARD WITH HOW WE DO THIS.
SO THIS 26 PROBE SYSTEM WE HAD,
THE SO-CALLED CHICKEN OVER HERE,
WAS IMMEDIATELY DISASSEMBLED AND
LAID OUT ON A TABLE WHERE YOU
HAVE RADIOACTIVE DETECTORS
CIRCLING AROUND AN OBJECT THAT
WOULD HAVE RADIOACTIVITY IN IT,
AND THE QUESTION WAS, COULD WE
GET A SLICE THROUGH THERE AS YOU
GET WITH CT.
AND GET AN IMAGE OF WHAT'S GOING
ON IN THERE.
SO THIS LED FROM THIS TABLETOP
THING THAT WE CALLED PETT I, OR
PETT II, TO AN ACTUAL TOMORROW
TOMOGRAPHIC SYSTEM BUILT OUTSIDE
MY OFFICE BY THE ENGINEERING
PEOPLE AT THE WASHINGTON
UNIVERSITY CAMPUS.
WE HAD SEVERAL OF THESE UP TO
PETT IV AND PETT VI AND THEY
BECAME EVER MORE VALUABLE.
WHAT IT DID WAS ALLOW US TO DO
FOR THE FIRST TIME EVER
RADIOGRAPHY OF THE HUMAN BRAIN
WITHOUT REMOVING THE BRAIN,
SLICING IT UP AND LAYING IT ON
X-RAY FILMS.
SO THERE WERE A LOT OF THINGS
THAT WERE OF INTEREST TO US.
SO IF I MAY HAVE THE NEXT SLIDE.
THE ISSUE WAS, IF YOU'RE GOING
TO APPROACH THE BRAIN, HOW DO
YOU BEGIN TO INTERROGATE WHAT
IT'S DOING?
AND AT THE INSISTENCE OF A MAJOR
DONOR AT WASHINGTON UNIVERSITY,
JAMES MCDONALD, THE DEVELOPER OF
THE MCDONALD DOUGLAS AIRCRAFT
COMPANY, HE INSISTED IF HE WAS
GOING TO GIVE US SOME MONEY,
THAT WE GET A GOOD PSYCHOLOGIST
INVOLVED IN THIS UNDERTAKING, SO
THAT WE UNDERSTOOD THE BEHAVIOR
WE WERE TRYING TO EXPLAIN SO
MIKE POSNER JOINED THIS GROUP,
WHICH WAS A MAJOR STEP FORWARD
IN HOW WE ACTUALLY DESIGNED
EXPERIMENTS TO LOOK AT HOW THE
BRAIN FUNCTIONS.
THE STRATEGY THAT DEVELOPED WAS
A KIND OF LEVEL OF
INVESTIGATION.
SO THE FIRST LEVEL, YOU JUST
HAVE SOMEBODY LOOKING AT THE
SCREEN WITH A CROSSHAIR ON IT
AND YOU'D GET A PICTURE OF THAT.
AND THEN WHAT YOU MIGHT DO FOR
THE SECOND LEVEL WAS TO PUT A
WORD ON THE SCREEN AND PEOPLE
JUST LOOKED AT IT AND WE GOT
ANOTHER PICTURE.
THEN WE HAD PEOPLE SAY THE WORD
AND FINALLY WE HAD THEM TO
PROVIDE US WITH A VERB THAT
WORKED FOR THE NOUN.
SO IF YOU SAW A HAMMER, YOU
MIGHT SAY POUND.
WITH EACH INSTANCE OF THIS, WE
SUBTRACTED THE PRECEDING
ACTIVITY FROM THAT, SO WE HAD
KIND OF A STAGED OPERATION HERE
LOOKING AT THIS.
IF YOU CAN SHOW THE NEXT SLIDE,
SOMEHOW OR OTHER, NATURE GOT
WIND OF WHAT WE WERE UP TO AND
ACTUALLY IT'S THE ONLY TIME IN
MY ENTIRE CAREER THAT NATURE HAS
EVER INVITED US TO SUBMIT --
THEY'VE MADE UP FOR THAT BY
REJECTING ME ON A REGULAR BASIS.
BUT THIS APPEARED IN NATURE IN
1988, THE CULMINATION OF THAT
EXPERIMENT, AND IT HAS APPEARED
IN TEXTBOOKS AND SO FORTH.
IT'S A VERY NICE DEMONSTRATION
OF WHAT WE WERE ABLE TO DO.
BUT IT LEFT THE BACKGROUND OF
THIS STUDY COMPLETELY ABSENT
BECAUSE WE WERE VERY CLEVER AT
SUBTRACTING OUT THE DIFFERENCES.
BUT WE SIMPLY DIDN'T CONSIDER
WHAT WAS GOING ON IN THE
BACKGROUND.
BUT AT THAT BECAME MORE
APPARENT, THESE ARE THE UMAGES
IMAGESOF THE FOUR DIFFERENT STAF
BLOOD FLOW TO THE HUMAN BRAIN.
I CHALLENGE YOU TO FIND ANY
SIGNIFICANT DIFFERENCES AS YOU
LOOK AT THE ACTUAL DATA THAT
GENERATED THESE PRECEDING
IMAGES.
THESE ARE THE DIFFERENCE IMAGES,
AND YOU CAN SEE THAT THOSE
DIFFERENCES ARE ACTUALLY QUITE
SMALL.
I'M NOT SOMETHING THEY AREN'T
IMPORTANT, BUT THEY ARE MAKING A
SMALL DIFFERENCE IN THE ACTUAL
OVERALL COST OF RUNNING THE
BRAIN.
SO WE HAVE HIDDEN UNDERNEATH ALL
OF THIS AN ENORMOUS AMOUNT OF
SOMETHING GOING ON AND THE
QUESTION IS, WHAT IS IT, HOW DO
WE THINK ABOUT THIS.
SO THE TAKEAWAY AT THIS POINT IS
HOW INFLUENTIAL ARE CHANGES IN
THE CELLULAR ACTIVITY TO THE
BRAIN'S ENORMOUS ENERGY
CONSUMPTION ONGOING AT ALL
TIMES.
AND THE ANSWER IS VERY LITTLE.
OVERALL.
SO HOW DO WE GO FORWARD WITH
THIS SORT OF PROBLEM?
ONE OF THE ASSUMPTIONS THAT YOU
HAVE IN DOING THIS KIND OF AN
EXPERIMENT IS THAT YOUR CONTROL
STATE IS NOT AFFECTED BY WHAT
YOU ADD IN THE TASK STATE.
THIS IS CALLED THE NOTION OF
PURE INSERTION.
THE QUESTION WAS, HAVE WE MADE
SOME FALSE ASSUMPTION IN HOW ALL
THIS WORKS?
AND SO THE WAY TO CHECK ON THAT
TO FIND OUT WHAT HAPPENS TO THE
BASELINE IF YOU HAD A TASK ON
TOP OF IT, IS YOU JUST REVERSED
THESE SUBTRACTIONS.
AND SEE WHAT HAPPENS.
IF YOU' PURE INSERTION WORKS, YU
SHOULD SEE NOTHING.
BUT THAT IS NOT WHAT HAPPENED.
THESE ARE THE DECREASES THAT
OCCUR ROUTINELY IF YOU DO ANY
EXPERIMENT OF THIS SORT.
AND WHAT WAS SO EERIE ABOUT IT
WAS HOW CONSISTENT THIS WAS.
THERE IS THIS GROUP OF AREAS
THAT ROUTINELY WENT DOWN ANY
TIME WE DID ANY KIND OF AN
EXPERIMENT LIKE THIS.
SO THIS APPEARED IN SEVERAL
PAPERS, SO IF YOU WANT TO CLICK
BELOW THERE.
THE FIRST WAS A COMPREHENSIVE
LOOK ACROSS ALL SORTS OF
DIFFERENT EXPERIMENTS THAT
GORDON SHULMAN PUT TOGETHER FOR
US, AND THE PROBLEM WAS, WHAT
DOES THIS TELL US ABOUT THE
BRAIN FUNCTION?
AND OF COURSE THE SCEP TIPS SKED
HAVE SAID WHEN YOU'RE JUST IN A
CONTROL STATE LOOKING AT A BLANK
SCREEN EU OBVIOUSLY NOT
THINKING, ARE YOU DAYDREAMING
ABOUT WHAT HAPPENED OR
DAYDREAMING ABOUT WHAT YOU DID
YET OR WHAT YOU'LL DO TOMORROW?
SO THIS ISSUE WAS, WHAT IS THE
BASELINE LEVEL OF ACTIVITY IN
THE BRAIN?
AND WE RESORTED IN THIS
ENTERPRISE TO WHAT HAD BEEN
OBSERVED FROM METABOLIC STUDIES
OF THE BRAIN THAT THERE IS A
MARKED RELATIONSHIP IN THE
RESTING BRAIN BETWEEN BLOOD FLOW
AND OXYGEN CONSUMPTION.
SO USING THAT AS THE BASIS FOR A
BASELINE, WE LOOK AT THE BRAIN
AGAIN AND WE WERE ABLE TO
DETERMINE THAT THERE WAS NOTHING
GOING ON IN THE BASELINE THAT
STOOD OUT FROM HIS BACKGROUND.
SO WE CAME ABOUT WITH THE NOTION
THAT THIS ORGANIZATION, WHICH
BECAME THE FOUNDATION OF WORK
GOING FORWARD, WAS ACTUALLY SOME
SORT OF A DEFAULT MODE LARGE
SCALE ORGANIZATION OF THE HUMAN
BRAIN, PROBABLY ANY MAMMALIAN
BRAIN.
SO IF I CAN HAVE THE NEXT SLIDE,
SO THE QUESTION WAS, HOW DO WE
GO FROM HERE?
WHAT DO WE DO ABOUT THIS?
AND THE ANSWER WAS, WELL, ENTER
ANOTHER TECHNOLOGY, AND THAT IS
FUNCTIONAL MAGNETIC RESONANCE
IMAGING, WHICH ITSELF HAS A VERY
INTERESTING HISTORY.
SO I'M GOING TO HAVE THE NEXT
SLIDE.
THE KEY THING TO UNDERSTAND WHEN
YOU LOOK AT WHAT I'M GOING TO
TELL YOU IS WHAT HAPPENS WHEN
THE BRAIN CHANGES ITS
METABOLISM?
IN THE COURSE OF DOING A TASK.
SO LET'S JUST SUPPOSE YOU'RE IN
A SCANNER AND YOU LOOK AT A
BLANK SCREEN AND THEN WE PUT UP
A REVERSING ANNULAR
CHECKERBOARD.
THE COMMON WISDOM WAS THE BLOOD
FLOW WOULD GO UP, OXYGEN
CONSUMPTION WOULD GO UP, GLUCOSE
CONSUMPTION WOULD GO UP.
THAT WAS THE DOGMA.
AND THERE WAS A SMALL AMOUNT OF
EVIDENCE TO SUPPORT THAT WHICH
BOTHERED ME.
MY REACTION TO THIS WAS, WE
BETTER BE DAMN SURE THAT THIS IS
WHAT'S GOING ON HERE.
AND WE WERE DEEPLY SURPRISED AS
WAS THE WORLD WHEN THIS CAME
OUT.
THE BLOOD FLOW WENT UP, THE
GLUCOSE CONSUMPTION WENT UP, BUT
THE OXYGEN UTILIZATION DIDN'T
MATCH THAT CHANGE.
SO WHAT HAPPENED HERE WAS THAT
THE OXYGEN AVAILABILITY TO THE
BRAIN HAD INCREASED.
AND THAT THE ENERGY THAT WAS
REQUIRED FOR THIS PARTICULAR
BRIEF CHANGE WAS BEING PROVIDED
SOLELY BY GLUCOSE OR WHAT WE'VE
COME TO CALL AEROBIC GLYCOLYSIS.
NOW THIS IS IMPORTANT FROM THE
PERSPECTIVE OF FMRI OR MRI.
SO HIT THE BUTTON.
THE ISSUE THAT IS IMPORTANT TO
UNDERSTAND HERE IS THAT THE MR
SIGNALING SYSTEM IS VERY
SENSITIVE TO THE OXYGENATION OF
HEMOGLOBIN, AND MICHAEL FARADAY
FIRST ADDRESSED THIS AS YOU MAY
KNOW, HE WAS INTERESTED IN
ELECTROMAGNETISM AND SO FORTH,
HE LOOKED AT BLOOD AND DIDN'T
SEE ANY DIFFERENCE IN THE
MAGNETIC FIELD, BUT HE'D USED
DRIED BLOOD AND IN HIS
LABORATORY JOURNAL, HE SAID
SHOULD TRY LIQUID BLOOD.
AND IT WAS LINUS PAULING IN 1937
THAT DID PICK UP ON THIS AND DID
FIND OUT THAT DEOXYGENATED
HEMOGLOBIN IS PARAMAGNETIC.
SO IT INTERFERES WITH THE
MAGNETIC FIELD, SO YOU SEE THE
OXYGEN REMOVED HERE, YOU CAN SEE
THESE LITTLE FLUFFY LITTLE LINES
IN THE BACK.
THAT'S DISRUPTION OF THE
MAGNETIC FIELD.
AND IT WAS SEIJI OGAWA AT THE
BELL LABORATORY THAT SAID WHAT
IF I PUT THIS LITTLE RODENT ON
OXYGEN, WHAT HAPPENS.
HERE YOU CAN SEE THE VEINS WHICH
CONTAIN DEOXYGENATED HEMOGLOBIN.
HERE THE OXYGENATION HAS BEEN
REPLACED AND, BINGO, WE HAVE A
MEASURE OF THESE METABOLIC
CHANGES IN TERMS OF OXYGEN
AVAILABILITY.
SO YOU WANT TO HIT THE BUTTON
AGAIN?
OUTCOMES FMRI BOLD SIGNAL WHICH
REALLY REVOLUTIONIZED HOW WE GET
ACCESS TO THIS BUT IT'S
IMPORTANT TO REMEMBER HOW THAT
SIGNAL WORKS.
SO I HOPE YOU KIND OF GRASP THE
SENSE OF IT.
NOW, AN INTERESTING FEATURE OF
THIS SIGNAL IS THAT IT'S NOISY.
IF YOU LOOK AT AN MR SIGNAL AS
IT'S TRACED OUT AND YOU SQUINT
HARD, YOU'LL SEE THERE'S SOME
LITTLE WIGGLES IN IT, SO WE JUST
INCREASED THE SCALE HERE SO YOU
CAN ACTUALLY SEE WHAT IT LOOKS
LIKE.
IT JUST LOOKS LIKE NOISE.
SO THE QUESTION WAS, CAN IT TELL
US ANYTHING ABOUT THE BRAIN'S
BRAIN'SSPONTANEOUS ACTIVITY, ANE
ANSWER IS A RESOUNDING YES.
THIS WAS A GRADUATE STUDENT AT
THE MEDICAL COLLEGE OF WISCONSIN
WORKING UNDER THE GUIDANCE OF
JAMES HYDE, AND HE'D BEEN ASKED
THIS QUESTION, HOW DO WE THINK
ABOUT THE NOISE IN THIS SIGNAL,
AND HIS APPROACH TO THIS PROBLEM
WAS TO LOOK AT THE MOTOR SYSTEM
IN THE BRAIN, AND ON THE LEFT,
YOU CAN SEE THAT IF YOU
STIMULATE ON THE RIGHT-HAND
SIDE, WHICH YOU WILL GET A
SIGNAL AT B, IN THE BRAIN, YOU
GET A MAP OF MOTOR AREA THAT WAS
RESPONSIBLE FOR MOVING THE HAND.
AND YOU CAN DO IT ON BOTH SIDES
AND SO YOU GET AN A AND A B AND
A C IN THE SUPPLEMENTARY MOTOR
AREA.
NOW, IF YOU GO IN AND PUT YOUR
DETECTOR ON B OR A OR C, AND YOU
SAY WHAT IS IT CORRELATED WITH,
IT'S THIS WHOLE COMPLEX.
THEY'RE ALL COORDINATED, THEY'RE
ALL MOVING TOGETHER.
THIS WAS A REMARKABLE
OBSERVATION, OF WHICH THERE WERE
EVIDENCE OF IT LIKELY TO BE THIS
WAY, BUT NOBODY HAD PAID ANY
ATTENTION TO IT UNTIL BHARAT
BISWAL GAVE THIS.
SO OUR INTEREST, ACTUALLY I KNEW
ABOUT THIS, BUT THERE WAS SOME
SKEPTICISM ABOUT THIS WHEN
ANOTHER FRIEND OF MINE, MIKE
GRECIUS AT STANFORD AND HIS
COLLEAGUES DECIDED TO LOOK AT
THIS DEFAULT NETWORK WE TALKED
EARLIER ABOUT AND PUBLISHED ON.
THEY LOOKED AT PLACING A REGION
OF INTEREST EITHER IN THE BACK
OR THE FRONT, WHERE THOSE TWO
THINGS ARE, AND BLOODY WELL,
THEY'RE COORDINATED JUST EXACTLY
THE SAME WAY AS THE MOTOR
SYSTEM.
SO THIS KIND OF LAUNCHED THIS
WHOLE IDEA OF RESTING STATE
FUNCTIONAL CONNECTIVITY IN THE
BRAIN.
AND I THINK A THE BOTTOM OF THE
SCREEN DOESN'T SHOW THE FIGURE,
BUT JUST FOR THE AMUSEMENT SAKE,
I LOOKED AT THE PUBMED AND THE
NATIONATIONAL LIBRARY OF MEDICI,
HOW MANY PAPERS ARE THERE ON
THIS SUBJECT PRESENTLY, AND IT'S
CLOSE TO 250,000 PAPERS, IF YOU
PUT IN AS YOUR SEARCH ITEMS
"BRAIN" AND "FUNCTIONAL MAGNETIC
RESONANCE IMAGING."
IT'S A WORLD ALL OF ITS OWN,
DOING ALL KINDS OF THINGS, SOME
BETTER THAN OTHERS.
SO THIS JUST IS ANOTHER GRAPHIC
ILLUSTRATION OF WHAT THIS KIND
OF LOOKS LIKE IN OPERATIONAL
TERMS.
YOU PUT A REGION OF INTEREST IN
SOME PLACE IN SOMEBODY'S BRAIN
AND YOU FOLLOW THIS THROUGH MANY
ITERATIONS AND YOU GET THIS
SIGNAL.
AND IF YOU HIT THE BUTTON AGAIN,
YOU CAN EASILY REPRODUCE
BHARAT'S OBSERVATION AND
FURTHERMORE, YOU CAN GET THE
FOLLOWING.
YOU GET A WHOLE ARRANGEMENT OF
AREAS THAT FORM NETWORKS WITHIN
THE BRAIN, AND THE ACCOUNT
VARIES SOMEWHAT DEPENDING ON
WHO'S DOING THE STUDY AND
WHATEVER, BUT THERE'S SOMETHING
LIKE 15 TO 20 OF THESE EASILY
REPRODUCIBLE RELATIONSHIPS
WITHIN THE BRAIN.
THAT EXIST ON A FUNCTIONAL
BASIS, AND EASILY DETECTED WITH
FMRI.
SO THE QUESTION, OF COURSE, IS
NEUROPHYSIOLOGICALLY WHAT DOES
THIS RESTING STATE FMRI SIGNAL
REPRESENT?
AND THE ANSWER IS SOMETHING
CALLED INFRA-SLOW ACTIVITY.
THAT IS LESS THAN 1 HERTZ.
IT'S USUALLY AROUND .1 HERTZ.
IF I CAN HAVE THE NEXT SLIDE.
VARIOUS PEOPLE HAVE LOOKED AT
THIS.
THIS IS WORK OUT OF WASHINGTON
UNIVERSITY.
I'M RATHER PROUD OF THIS ONE,
PARTICULARLY BECAUSE IT INVOLVES
SIX DIFFERENT LABORATORIES.
THE RED AUTHORS UP THERE ARE ALL
GRADUATE STUDENTS WHO WORKED ON
THIS PROJECT.
IT WAS ORGANIZED BY ANDREW KRAFT
IN ONE OF THE LABS AND ANISH
MITRA, ONE OF MY STUDENTS THAT'S
NOW AT STANFORD.
WHAT IT IS IS AN INCREDIBLY
COLLABORATIVE LOOK AT A MOUSE
USING CALCIUM HEMOGLOBIN
IMAGING, THE CALCIUM FOR THE
ACTIVITY AND THE HEMOGLOBIN TO
GET IT BACK TOWARDS THE BOLD
SIGNAL ITSELF, AND WE ACTUALLY
USED LAMINAR ELECTROPHYSIOLOGY
AS WELL.
IT WAS JUST VERY HEARTENING TO
SEE HOW YOU CAN GET A VERY
DIVERSE GROUP OF PEOPLE TOGETHER
TO GET SOME ANSWERS AS TO WHAT'S
GOING ON.
AND WE CONCLUDED FROM THIS THAT
THE FMRI WAS A SPECIFIC MARKER
OF THIS INFRA-SLOW ACTIVITY AND
IT TRAVELS THROUGH THE CORTEX IN
A VERY SPECIFIC WAY, AND IT IS
STATES-SPECIFIC.
SO IF YOU LOOK UP ON THE A UP
THERE ON THE SCREEN, YOU CAN
LOOK AT IT IN TWO DIFFERENT
ANESTHETICS HERE, AND YOU'RE
LOOKING AT DELTA ACTIVITY AND
INFRA-SLOW ACTIVITY, AND YOU CAN
SEE THEY'RE RECIPROCALLY MOVING
IN OPPOSITE DIRECTIONS, AND AS
YOU GO FROM THE ANESTHETIZED
STATE TO THE OTHER, THOSE
SIGNALS TRAVEL IN THE OPPOSITE
DIRECTION.
THIS IS PROVEN TO BE VERY, VERY
USEFUL AS YOU BEGIN TO THINK OF
HOW THE BRAIN TALKS TO ITSELF,
HOW ARE THE CONVERSATIONS
ACTUALLY GOING ON IN HERE.
THIS GENERAL IDEA HAS ACTUALLY
BEEN AROUND FOR A WHILE.
WHEN I GO TO READ A PAPER THAT
SOMEBODY IS TALKING ABOUT THIS
SORT OF THING, I ALWAYS LOOK FOR
THIS ONE TOP REFERENCE HERE FROM
NINA ALADJALOVA, A RUSSIAN
NEUROPHYSIOLOGIST WHO PUBLISHED
A LETTER TO NATURE IN WHICH SHE
COINED THE TERM INFRA-SLOW
RHYTHMIC OSCILLATIONS.
SHE SUBSEQUENTLY WROTE A BOOK
ABOUT THIS, AND IF YOU'RE AT ALL
INTERESTED IN IT, I VERY MUCH
URGE YOU TO HAVE A LOOK AT THIS.
AND IF YOU WANT TO SEE IT IN A
MORE DETAILED WAY, THESE TWO
PAPERS, ONE IN THE JOURNAL OF
NEUROSCIENCE AND THE OTHER IN
NEUROIMAGING BY THESE GROUPS IN
SCANDINAVIA IN WHICH THEY HAVE
LOOKED AT BOTH THE BEHAVIOR THAT
GOES WITH THIS AND THESE
DIFFERENT FREQUENCIES THAT ARE
PART OF THE SPECTRUM OF
ACTIVITIES WITHIN THE BRAIN.
AND PARTICULARLY THE ROLE OF THE
INFRA-SLOW ACTIVITY, WHICH IS
PICKED UP IN THIS GREY SYMBOL
HERE AND BEHAVIOR, WHICH VARIES
ACCORDINGLY TO THIS, IS ALSO
DEPICTED.
I'M NOT GOING TO GET INTO THE
REAL GRITTY DETAILS OF THIS, BUT
I URGE YOU IF YOU FIND THIS
INTERESTING TO LOOK AT THESE TWO
PAPERS IN PARTICULAR AND OF
COURSE READ NINA'S PIECE IN
NATURE.
IT'S A REMINDER THAT THERE ARE
THESE GEMS OUT THERE THAT NEED
TO BE RECOGNIZED.
SO HOW DO THESE OBSERVATIONS
INFORM A FUNCTIONALLY INTEGRATED
VIEW OF THE BRAIN?
WHAT I WOULD LIKE TO URGE YOU IS
TO THINK ABOUT TIME.
BECAUSE WE'RE SO MUCH INTERESTED
IN WHERE THINGS ARE HAPPENING
AND WHAT THE RELATIONSHIP IS,
BUT WHAT IS THE ROLE OF TIME AND
HOW SHOULD WE BE THINKING ABOUT
THIS?
AND I'M GOING TO TOUCH ON SOME
WORK, AGAIN, BY ONE OF MY
FORMER -- MY LAST GRADUATE
STUDENT.
IN '86, I DECIDED NOT TO TAKE
ANY MORE, BUT HE IS VERY
TALENTED, RYAN RAUT, ALONG WITH
THE REST OF THE TEAM.
SO THE ISSUE OF TIME IS
SOMETHING THAT CAME LARGELY BY
THE WORK OF MY OTHER GRADUATE --
RECENT GRADUATE STUDENT, ANISH
MITRA, WHO IS AT STANFORD, HE
WAS AN UNDERGRADUATE MATHEMATICS
MAJOR AND THEN WENT TO
WASHINGTON UNIVERSITY.
THE IDEA IS IF YOU'RE LOOKING AT
THESE RELATIONSHIPS, SAY THE
DEFAULT NODE NETWORK, THERE IS
THIS CORRELATED RELATIONSHIP
BETWEEN THE COMPONENTS OF THIS
SYSTEM, BUT YOU CAN ACTUALLY
LOOK AT THE TIME DIFFERENCES
BETWEEN TWO POSITIONS.
THERE IS THIS ACTIVITY IS NOT
ONLY SYNCHRONOUS BETWEEN AREAS,
BUT THERE IS A TIME DIFFERENCE
THAT'S HIGHLY REPRODUCIBLE.
SO THE ISSUE AS WE WERE TALKING
ABOUT IS OF PROPAGATING SIGNAL.
SO THERE'S VARIOUS WAYS TO
DEPICT THIS.
HERE'S THE USUAL SORT OF MAPPING
OF NETWORKS IN THE BRAIN, AND
HERE IS THE -- THE TIME
DIFFERENCE IS -- WHEN YOU LOOK
AT IT AND INCLUDE WHO'S EARLY
AND WHO'S LATE IN THESE
RELATIONSHIPS.
BUT OBVIOUSLY WE NEEDED MORE
DETAILS HERE TO THINK ABOUT
THIS.
THIS WAS ONE WHERE I HAD TO
THINK DEEPLY ABOUT HOW TO EVEN
ILLUSTRATE THIS.
IMAGINE FOR MOMENT THAT YOU HAVE
A ROCK AND YOU'RE GOING TO GO
OUT AND THROW THE ROCK INTO A
PUDDLE OF WATER.
YOU'RE GOING TO GET THIS FIGURE
THAT LOOKS LIKE UP HERE AT THE
TOP, THIS SET OF WAVES THAT MOVE
OUT FROM A PARTICULAR LOCATION.
AND THINKING IN THOSE TERMS, YOU
CAN BEGIN TO PARSE OUT HOW TO
THINK ABOUT THESE WAVES AS THEY
PASS THROUGH THE BRAIN, THAT IT
IS, IN FACT, A TRAVELING WAVE,
WHICH REMARKABLY ITS POSITION IS
CORRELATED OR ITS POSITION IN
TIME IS CORRELATED WITH THE PEW
LPUPILLARY DIAMETER.
SO YOU HAVE AREAS THAT ARE --
CAN BE SPACED OUT SUCH THAT IF
THEY'RE ALL ON CIRCLE A, THEY'RE
GOING TO BE SYNCHRONOUS, THERE'S
GOING TO BE ZERO LINE
COMMUNICATION.
THERE CAN BE A LAG, AS YOU CAN
SEE HERE, BUT POSITION VERSUS
THIS MOVING THING, IT BECOMES A
VERY IMPORTANT DETERMINANT OF
HOW YOU THINK ABOUT THIS AND
FINALLY, WHICH CAN EVEN COME
AROUND TO ANTICORRELATIONS,
WHICH WAS ANOTHER SURPRISING
FINDING IN OUR WORK ON THE
BRAIN.
SO THINKING ABOUT THIS IN TIME
ADDS TO THE RICHNESS OF THE
UNDERSTANDING OF WHAT'S GOING ON
HERE, AND OF COURSE YOU IMAGINE
THINKING INTO THE FUTURE THAT
DIFFERENCES IN TIMING WILL HAVE
BHIBEHAVIORAL CONSEQUENCES.
SO IF YOU THINK ABOUT THIS, AND
AS I MENTIONED, IF YOU JUST LOOK
AT THE BRAIN IN TERMS OF LOOKING
FOR CORRELATIONS WITHIN THE
BRAIN, WHAT YOU FIND IS, SAY YOU
HAVE THIS SO-CALLED DEFAULT MODE
NETWORK.
AND YOU ALSO HAVE AREAS OF THE
BRAIN THAT ARE ANTECORRELATED SO
THE BRAIN IS GOING FROM TWO
DIFFERENT STATES AS IT SITS
THERE IN A RESTING FORMATION.
SO THIS IS WHAT'S DEPICTED HERE.
AND WHAT'S SO INTERESTING IS
THAT THIS -- IT'S CUT OFF AT THE
BOTTOM OF MY SCREEN, BUT THIS IS
WORK FROM DAVID MCCORMICK'S
LABORATORY LOOKING AT AROUSAL,
AND LOOKING AT HIPPOCAMPAL
RIPPLE STATE ACTIVITY.
WHAT'S SO REMARKABLE ABOUT THIS
FOR ME, ANYWAY, IS HOW THEY
RESEMBLE THIS STATE CHANGES THAT
ARE ONGOING WITHIN THE BRAIN ON
THESE VERY, VERY LARGE SCALES.
SO YOU MIGHT THINK, WELL, OKAY,
WE'RE MOVING TOWARDS THINKING
ABOUT BRAIN STATES AND THEIR
EFFECT ON BEHAVIOR AND SO FORTH,
AND YOU CAN ALMOST IMAGINE YOU
HAVE AN ALOE CENTRIC, THAT IS,
I'M PAYING ATTENTION TO THE
WORLD AROUND ME, AND EGO
CENTRIC.
THIS IS AN ONGOING CYCLIC
PHENOMENON IN THE NORMAL BRAIN
ACTIVITY AND IS A VERY NICE
EXPLANATION WHERE THE
WELL-DOCUMENTED VARIABILITY IN
BEHAVIOR WHICH HAS BEEN OBSERVED
BY MANY PEOPLE OVER MANY, MANY
YEARS.
THIS IS -- OR THE NEXT THING, IT
PROVIDES KIND OF A UNIFORM
FRAMEWORK FOR INTRINSIC
ACTIVITY.
AND IS A LOGICAL WAY OF THINKING
ABOUT BRAIN STATE DYNAMICS.
IT'S KIND OF A STEPPING STONE IN
A VERY INTRIGUING WAY FORWARD.
NOW THE QUESTION, OF COURSE,
GOING BACK TO THE FMRI SIGNAL
ITSELF, THERE'S A METABOLIC
COMPONENT HERE.
THIS IS NEUROPHYSIOLOGY AND
METABOLISM, SO HOW DO THEY MEET
UP?
ARE THEY RELATED IN SOME WAY,
WHICH COULD BE VERY IMPORTANT.
SO JUST TO REMIND YOU THAT IF
YOU'RE LOOKING AT THE BOTTOM
HERE AND YOU'RE SEEING THIS
WAVING SIGNAL DOWN HERE, WHAT'S
REALLY HAPPENING IS YOU'RE
HAVING CHANGES IN GLYCOLYSIS
THAT ARE GREATER THAN THE
CHANGES IN OXYGEN CONSUMPTION
BETWEEN ACTIVATION AND
DEACTIVATION OR JUST OVER TIME
IN GENERAL.
SO THERE CLEARLY IS A METABOLIC
ACTIVITY ONGOING HERE THAT
INVOLVES THE CIRCULATION AS
WELL.
SO HOW MIGHT WE BEGIN TO IMAGINE
THAT THESE TWO END UP
COORDINATED?
AND I'VE BECOME A VERY BIG FAN
OF THE VIP INTERNEURON AS A
RESULT OF THIS.
SO IF I MAY HAVE THE NEXT SLIDE.
SO WHERE DOES THAT FIT INTO THIS
STORY?
WELL, FROM THE WORK OF PEOPLE
LIKE MIKE STRIKER AND OTHERS,
THE VIP INTERNEURON IS CRITICAL
IN AFFECTING NEURONAL GAIN IN
THE BRAIN.
AND IT DOES SO BY HITTING THE
SOMATOSTATIN INTERNEURON WHICH
DISINHIBITS THE PYRAMIDAL CELL.
WHAT WE TEND TO FORGET HERE IS
HOW THESE INTERNEURONS GOT THEIR
NAME.
VIP IS VASOINTESTINAL
POLYPEPTIDE, AND THIS IS
SOMATOSTA YOU TIN.
SOMATOSTATIN.
THESE ARE BOTH VERY IMPORTANT
PROTEINS.
HIGHLY NEGLECTED.
WHAT DO WE KNOW ABOUT THE OTHER
ARM OF VIP?
SO WHILE IT INCREASES GAIN, IT
INFLUENCES THE ASTROCYTE TO
DEVELOP GLYCOGENOLOSIS, DEEPLY
IMPORTANT WORK OVER TIME IS THAT
A ACUTE CHANGE IN NEURONAL
ACTIVITY IS LARGELY FUELED BY
LACTATE AND THE ATP PRODUCED.
WHICH GOES BACK TO THE WHOLE
STORY THAT I TALKED ABOUT IN THE
CONTEXT OF THE DEVELOPMENT OF
FMRI, BUT IT HAS BIOLOGICAL
CONSEQUENCES AS WELL.
BUT THIS IS A BEAUTIFUL
DEMONSTRATION OF PROVIDING THE
NECESSARY FUEL FOR A SUDDEN
CHANGE IN ACTIVITY THAT IS
LIKELY TO BE CONSEQUENCES OF A
CHANGE IN THE GAIN OF A
PYRAMIDAL CELL.
AND I THINK IT ILLUSTRATES HOW
WE WOULD BEGIN TO THINK ABOUT
THESE RELATIONSHIPS AS BOTH
METABOLIC AND
NEUROPHYSIOLOGICAL, AND THEY
HAVE TO BE ADDRESSED TOGETHER TO
MAKE THIS THING WORK RIGHT.
THE OTHER THING THAT I THINK IS
DEEPLY IMPORTANT HERE IS THAT
THE BRAIN ISN'T ALONE IN THIS
JOB, THAT WHAT IS GOING ON HERE
METABOLICALLY AND HORMONALLY AND
OTHERWISE IS RELATED TO THIS
WHOLE ISSUE OF AROUSAL, WHETHER
IT FIGHT OR FLIGHT OR REST AND
DIGESTION.
AND I THINK THE THING THAT HAS
CAPTURED THIS BETTER THAN
ANYTHING I KNOW IS THE WHOLE
NOTION OF AL ALLOSTASIS, WHICH A
BRAIN CENTERED PREDICTIVE MODE
OF PHYSIOLOGICAL REGULATION,
FIRST PUT FORWARD BY PETER
STERLING.
THE BRAIN HAS TO OPERATE IN AN
ENVIRONMENT IN WHICH IT HAS TO
ANTICIPATE CHANGING CONDITIONS
AND ADJUST ITSELF FOR THAT.
AND THIS IS A MAJOR TALK OF ITS
OWN, SO I'M NOT GOING TO BELABOR
THIS POINT, BUT AS WE THINK OF
THE BRAIN AND ITS DEALING WITH
THE WORLD IN WHICH WE LIVE, AND
PROVIDING THE ADEQUATE ENERGY TO
ACCOMPLISH WHAT NEEDS TO BE
ACCOMPLISHED, IT IS A BRAIN BODY
PROBLEM THAT INVOLVES METABOLISM
AS WELL AS NEUROPHYSIOLOGY, AND
IS A VERY IMPORTANT AREA OF
FUTURE RESEARCH.
WE MIGHT SAY A LITTLE BIT ABOUT
DISEASE OR MUCH THAT COULD BE
SAID, MUCH THAT HAS BEEN
WRITTEN, BUT I WOULD JUST LIKE
TO GIVE A QUICK EXAMPLE OF ONE
CONDITION IN WHICH IF YOU PUT IT
IN THE FRAMEWORK OF MUCH OF WHAT
I'VE SAID, YOU FIND THAT YOUR
PERSPECTIVE IS ENLARGED AS YOU
THINK ABOUT IT THIS WAY.
SO WE HAVE, IN ACTIVITY
DECREASES AND SPONTANEOUS
ACTIVITY, WE SEE IT HAS ELEVATED
GLYCOLYSIS, THIS IS THIS SO CA
CALLED DEFAULT NETWORK.
IF YOU LOOK AT THE DISEASE, YOU
SEE THE REMARKABLE
REPRESENTATION OF THE AMYLOID
DEPOSITS, THE DECREASE IN
METABOLISM AND THE ATROPHY IS
THE SAME.
AND I THINK WHAT THIS DOES, IT
SAYS, OKAY, WE HAVE A PROBLEM
HERE, A MEMORY DISORDER
INVOLVING THE DEFAULT NETWORK,
WHICH IS INCLUDED WITH THE
HIPPOCAMPUS IN A SO-CALLED
HIPPOCAMPAL CORTICAL MEMORY
SYSTEM, BUT WE KNEW A LOT ABOUT
THAT FROM THE NEUROPHYSIOLOGY
HERE THAT WOULD, I THINK, HELP
US A GREAT DEAL IN UNDERSTANDING
THE NUMBER OF POSSIBILITIES THAT
HAVE GONE WRONG IN THIS
BEAUTIFUL RELATIONSHIP INVOLVING
THE NEUROPHYSIOLOGY OF THE
MEMORY SYSTEM AND THE METABOLISM
THAT SUPPORTS IT, AND THE ROLE
OF THINGS LIKE AMYLOID AND TAU,
THESE PROTEINS THAT ARE CRITICAL
TO THIS.
I'M LEAVING A SUBJECT THAT
OBVIOUSLY COULD BE A LECTURE AND
A HALF, BUT I THINK IT ALLOWS US
TO FRAME WITH THIS INCREASED
KNOWLEDGE OF HOW THE BRAIN IS
ORGANIZED FUNCTIONALLY AND
METABOLICALLY, IT OPENS
OPPORTUNITIES FOR US TO BE MORE
SOPHISTICATED IN HOW WE
UNDERSTAND THEM.
SO FINAL SLIDE, I THINK.
I JUST LOVE THIS COMMENT BY
RODOLFO LLINAS WHEN HE SAID IN
HIS BOOK, THE SIGNIFICANCE OF
INCOMING SENSORY INFORMATION
DEPENDS ON THE PRE-EXISTING
DISPOSITION OF THE BRAIN, IS A
FAR DEEPER ISSUE THAN ONE
GATHERS AT FIRST GLANCE,
PARTICULARLY WHEN WE LOOK INTO
THE QUESTION OF SELF.
THANK YOU VERY MUCH.
>>OKAY.
THANK YOU VERY, VERY MUCH FOR AN
INTRODUCTION FOO THE EXCITING
WORLD IN WHICH YOU SPEND YOUR
CAREER.
SO NOW WE WANT TO TURN MORE TO
OUR CELLS AND MOLECULES.
AND NELSON, WOULD YOU PLEASE
BEGIN?
>>YES, THANK YOU VERY MUCH FOR
THE INVITATION TO BE HERE THIS
AFTERNOON.
AND ADDRESS THE SIMPLE QUESTION,
HOW DO THE BRAIN WORK?
I'M GOING TO DO MY BEST TO TELL
YOU A LITTLE BIT ABOUT WHAT WE
KNOW ABOUT HOW THE BRAIN WORKS.
AND NOT KNOWING THE AUDIENCE
VERY WELL, IT'S DIFFICULT TO
GAUGE WHAT KIND OF A LEVEL I
SHOULD BE SPEAKING AT, SO I'M
GOING TO TRY TO COVER A BUNCH OF
GROUND HERE AND LOOK FORWARD TO
THE QUESTION AND ANSWER.
SO I WAS ASKED TO PROVIDE THESE
DISCLOSURES, I DON'T HAVE ANY
SIGNIFICANT CONFLICTS OF
INTEREST.
LEARNING OBJECTIVES IS TO
ACHIEVE A BASIC UNDERSTANDING OF
THE COMPOSITION AND FUNCTION OF
THE NERVOUS SYSTEM AND THE
DESCRIPTION OF MODERN APPROACHES
TO STUDYING THE BRAIN AT THE
CELLULAR, SYNAPTIC AND CIRCUIT
LEVELS.
SO I GOT INTERESTED IN
NEUROSCIENCE AS AN UNDERGRADUATE
LARGELY BECAUSE I WAS FASCINATED
WITH THE CONCEPT OF MEMORY, THAT
SOMETHING COULD HAPPEN TO US ONE
TIME AND WE COULD REMEMBER IT
YEARS LATER.
I NOW REALIZE THAT MEMORY IS
EVEN MORE FASCINATING BECAUSE
THE OLDER I GET, THE LONGER I
CAN STORE THOSE MEMORIES AND
REALIZE THAT I CAN REMEMBER
THINGS THAT HAPPENED TO ME
DECADES AGO.
AND I'VE THOUGHT IT WAS A
FASCINATING QUESTION HOW DOES
THIS STUFF INSIDE OF OUR SKULL
MAKE THIS POSSIBLE.
AND THIS LED ME TO STUDY THE
HIPPOCAMPUS BECAUSE THERE ARE
MANY PATIENTS THAT HAVE SUFFERED
DAMAGE TO THE HIPPOCAMPUS
BILATERALLY AND HAVE VERY
INTERESTING IMPAIRMENTS OF THEIR
MEMORY, SPECIFICALLY IMPAIRMENTS
OF THE TYPES OF MEMORIES THAT
THEY CAN TALK ABOUT CALLED
EPISODIC MEMORIES.
AND THOSE DEFICITS INCLUDE
LARGELY AN INABILITY TO FORM NEW
MEMORIES, YET AN ABILITY TO
RECALL SOME OF THEIR OLDER
MEMORIES.
AND THE REASON FOR THIS IS THE
GENERAL THINKING HERE IS THAT
THERE ARE COMPLIMENTARY LEARNING
SYSTEMS.
THE HIPPOCAMPUS IS A FAST
LEARNING SYSTEM WHICH CAPTURES
OUR EXPERIENCES RIGHT AWAY, AND
THEN OVER TIME, THOSE
EXPERIENCES ARE REPLAYED AND
LEARNED OR STORED IN THIS LARGER
OVERLYING NEOCORTEX THAT YOU SEE
HERE IN THE HUMAN BRAIN.
SO THE INTERESTING QUESTION FOR
ME IS, HOW DOES THIS -- HOW DO
MEMORIES GET CAPTURED BY THE
HIPPOCAMPUS AND HOW DOES THIS
REPLAY SYSTEM ALLOW THE
NEOCORTEX TO LEARN FROM THOSE
STORED MEMORIES AND HIPPOCAMPUS.
AND EARLY ON IN MY TRAINING, I
BECAME FASCINATED WITH THE
STRUCTURE OF NEURONS, AND IT
BECAME APPARENT TO ME THAT A KEY
TO UNDERSTANDING THIS QUESTION
OF HOW DOES THE BRAIN WORK OR
HOW ARE MEMORIES STORED IS TO
UNDERSTAND SOMETHING ABOUT THE
RELATIONSHIP BETWEEN THE
STRUCTURE AND THE FUNCTION OF
NEURONS.
THESE ARE JUST SOME EXAMPLES,
BEAUTIFUL DRAWINGS MADE BY
SANTIAGO CAJAL ABOUT A HUNDRED
YEARS AGO SHOWING NEURONS IN
DIFFERENT PARTS OF THE BRAIN,
AND YOU CAN SEE THAT THEY HAVE
TWO REALLY STRIKING FEATURES.
ONE IS A VERY LARGE ELABORATED
DENDRITIC TREE.
YOU CAN THINK OF DENDRITIC TREES
AS PART OF THE NEURON THAT
RECEIVES INPUT FROM OTHER
NEURONS, AND THEN THE AXON,
WHICH USUALLY EMERGES FROM THE
CELL BODY HERE, AND THE AXON,
YOU CAN THINK OF AS THE
STRUCTURE THAT PROVIDES OUTPUT
FROM THE NEURON, AND
COMMUNICATES WITH OTHER NEURONS
IN THE BRAIN.
THIS IS ANOTHER BEAUTIFUL SLIDE.
THIS WAS ASSEMBLED BY ONE OF MY
COLLEAGUES, BARTLETT MEL AT USC.
HE COLLECTED DRAWINGS OF THE
DENDRITIC TREE OF MANY DIFFERENT
NEURONS AND FROM VARIOUS
PUBLICATIONS AND HIS GOAL WAS TO
SORT OF ILLUSTRATE HOW DIVERSE
THE DENDRITIC TREES ARE OF
DIFFERENT TYPES OF NEURONS.
IT TURNS OUT THAT WE KNOW THAT
ALONG WITH THE COMPLEXITY AND
DIVERSITY OF THE MORPHOLOGY OF
NEURONS AS DEPICTED HERE,
THERE'S A COMPLEMENTARY
DIVERSITY IN THE MOLECULAR
COMPOSITION AND THE
PHYSIOLOGICAL PROPERTIES OF
THESE DIFFERENT TYPES OF
NEURONS.
SO ONE OF THE KEYS, I THINK, TO
UNDERSTANDING HOW THE BRAIN
WORKS IS TO UNDERSTAND WHAT KIND
OF COMPUTATIONS ARE BEING
PERFORMED PHYSIOLOGICALLY BY
THESE NEURONS THAT HAVE THESE
AMAZING STRUCTURES?
AND DENDRITES PLAY A SUPER
IMPORTANT ROLE IN THAT PROCESS
WHICH IS WHY FOR A COUPLE OF
DECADES, I STUDIED DENDRITES
INTENSIVELY IN MY OWN LAB.
HERE'S A PICTURE FROM SOME WORK
WE PUBLISHED SEVERAL YEARS AGO
NOW FROM MY OWN LAB.
THIS IS A NUMBER OF PYRAMIDAL
NEAR ONS IN HIPPOCAMPUS, WHICH
ARE SHOWN HERE IN GREEN, AND
THEN THERE ARE SOME AXONS OF
INHIBITORY INTERNEURONS SHOWN
HERE IN RED, AND I THINK THIS
NICELY DEPICTS THE STRUCTURAL
COMPLEXITY OF NEURONS IN THE
HIPPOCAMPUS AND DR. REICHLE
REFERRED TO VIP INTERNEURONS.
THEY'RE ONE OF MANY DIFFERENT
TYPES OF INHIBITORY INTERNEURONS
THROUGHOUT THE BRAIN, EVEN IN
THE HIPPOCAMPUS, THERE ARE
THOUGHT TO BE AT LEAST A COUPLE
DOZEN DIFFERENT TYPES OF
INHIBITORY INTERNEURONS.
I WANT TO TURN TO THE AXON,
BECAUSE A LOT OF WHAT WE'VE SEEN
OF PICTURES OF NEURONS FOCUSES
ON DENDRITES, BUT ACTUALLY AXONS
ARE QUITE FASCINATING.
AND THIS WAS A VIDEO THAT WAS
PUT TOGETHER BY THE MOUSELIGHT
PROJECT TEAM HERE AT JE KNEEL YA
-- ATJANELIA WHERE I WORK, ANDS
IS A PROJECT THAT USED A NEW
MICROSCOPE THAT INVOLVED
CLEARING, STAINING A FEW NEURONS
IN THE BRAIN AND THEN CLEARING
THE TISSUE TO MAKE IT AS CLEAR
AS POSSIBLE AND IMAGING IT WITH
A 2 PHOTON MICROSCOPE THAT
IMAGES THE SURFACE OF THE TISSUE
AND THEN SECTIONED IT AWAY,
IMAGED THE SURFACE OF THE TISSUE
AGAIN, AND SO ON THROUGH THE
ENTIRE VOLUME OF THE BRAIN.
AND THEN COMPUTATIONAL METHODS
WERE USED TO STITCH TOGETHER THE
MANY IMAGES THAT WERE COLLECTED
FROM THIS APPROACH, AND A
RECONSTRUCTION EFFORT WAS
UNDERTAKEN TO RECONSTRUCT AXONS
OF MANY DIFFERENT NEURONS.
SO NOW WHAT YOU'RE SEEING RIGHT
NOW IS AN AXON OF A SINGLE
NEURON THAT'S BEEN RECONSTRUCTED
THROUGH YON THE MOUSE BRAIN AND
THE REST OF THE VIDEO WHICH WILL
GO ON FOR ANOTHER MINUTE OR TWO
WILL SHOW YOU MANY OTHER
EXAMPLES OF NEURONS AND I'LL
POINT TO SOME OF THE FEATURES AS
IT PLAYS.
WE'RE GOING TO NEXT LOOK AT SOME
NEURONS IN THE SOMATOMOTOR AREA.
THIS IS ALL DONE IN THE MOUSE
BRAIN.
SO MUCH OF WHAT WE KNOW ABOUT
THE BASIC PHYSIOLOGY IS STUDIED
IN MICE AND RATS AS WELL AS
OTHER ORGANISMS LIKE FISH AND
FLIES.
THESE ARE JUST THREE NEURONS,
AND YOU CAN SEE THE AMAZING
ELABORATION OF THE AXON
ARBORIZATIONS OF THESE THREE
NEURONS, SO JUST THREE NEURONS
IN THE MOUSE BRAIN CONSTITUTE
OVER A METER OF AXON THAT'S
CONTAINED WITHIN THE SKULL OF
THIS ANIMAL.
THESE ARE JUST A HANDFUL OF
NEURONS.
EACH MOUSE BRAIN CONTAINS
70 MILLION NEURONS.
HUMAN BRAIN CONTAINS 80 OR
90 BILLION NEURONS.
AND SO YOU CAN BEGIN TO
APPRECIATE THE INCREDIBLE
COMPLEXITY, EVEN OF A MOUSE
BRAIN, WHEN YOU REALIZE THEY'RE
LOOKING AT A TINY FRACTION IN
EACH OF THESE IMAGES, A TINY
FRACTION OF THE TOTAL NUMBER OF
NEURONS IN THE BRAIN.
AND EACH ONE OF THESE NEURONS IS
SENDING INFORMATION TO THOUSANDS
OF TARGET NEURONS IN OTHER PARTS
OF THE BRAIN AND ALSO RECEIVING
INFORMATION SIMILARLY FROM
THOUSANDS OF OTHER NEURONS IN
DIFFERENT PARTS OF THE BRAIN.
THIS IS A PYRAMIDAL
NEURON OF THE HIPPOCAMPUS, AND
WE'RE MEASURING MEMBRANE
POTENTIAL, SO TRANSMEMBRANE
POTENTIAL WHICH NORMALLY HAS A
RESTING VALUE OF AROUND MINUS 7,
AND THEN THERE'S A THRESHOLD FOR
ACTION POTENTIAL GENERATION OF
ABOUT MINUS 50 MILLIVOLTS, AND
FOR REFERENCE, I PUT ANOTHER
LINE HERE AT ZERO MILL BOLTS.
SO NOW LET'S SUPPOSE THERE'S A
SINGLE SYNAPTIC INPUT INTO THE
DENDRITIC TREE OF THIS NEWER ON.
WHAT WILL HAPPEN IS A SMALL
DEPOLARIZATION OF THE MEMBRANE
POTENTIAL FROM ITS NORMAL
RESTING LEVEL TOWARDS THE
THRESHOLD.
THEN IF A SECOND -- WE CALL THIS
AN EPSP FOR EXCITATORY POST
SYNAPTIC POTENTIAL.
SO THE SECOND NEURON, SECOND
SYNAPSE IS ACTIVATED WITH A
BRIEF DELAY.
THIS INCREASES THE SIZE OF THE
RESPONSE.
THIRD NEURON WOULD INCREASE THE
SIZE OF THE RESPONSE EVEN
FURTHER.
AND A FOURTH NEURON WOULD
INCREASE THE SIZE OF THE
RESPONSE TO DRIVE THE MEMBRANE
POTENTIAL ABOVE THE THRESHOLD
FOR GENERATION OF AN ACTION
POTENTIAL.
NOW, I WANT TO POINT OUT SOME
REALLY GROSS OVERSIMPLIFICATIONS
HERE.
SO FIRST OF ALL, IN A NEURON
LIKE THIS, A PYRAMIDAL NEURON,
FOUR EXCITATORY SIN A SYNAPSES D
ALMOST CERTAINLY NOT BE ENOUGH
TO DRIVE POTENTIAL FIRING IN
THIS NEWER ON.
IT WOULD REQUIRE MORE LIKE 40 OR
MAYBE EVEN A HUNDRED SYNAPTIC
INPUTS, EXCITATORY SYNAPTIC
INPUTS TO PRODUCE AN ACTION
POTENTIAL.
NEVERTHELESS CONCEPTUALLY IT'S
THE SAME IDEA, YOU NEED
SUMMATION OF THE MEMBRANE
POTENTIAL CHANGES CAUSED BY EACH
INPUT IN ORDER TO REACH
THRESHOLD.
NOW, THIS LINE HERE THAT I ADDED
TO THE DIAGRAM IS INTENDED TO
DEPICT THE AXON, AND THE ACTION
POTENTIAL IS ACTUALLY GENERATED
IN THE AXON WHEN THE MEMBRANE
POTENTIAL HITS THRESHOLD, AND
THEN THE ACTION POTENTIAL
PROPAGATES ALONG THE AXON TOWARD
THE NERVE ENDINGS OF THE AXON
ARBORIZATION.
YOU SAW WHAT SOME OF THOSE AXON
ARBORIZATIONS LOOKED LIKE IN THE
MOVIE THAT I SHOWED YOU.
IF WE CONSIDER THEN ONE OTHER
IMPORTANT FEATURE HERE, WHICH IS
INHIBITION, SO IMAGINE WE HAVE A
SINGLE INHIBITORY INTERNEURON
HERE SHOWN IN RED, FORMING A
SYNAPSE ON THIS CELL, IF
ACTIVATED ON ITS OWN, IT WOULD
ACTUALLY HYPERPOLARIZE THE
MEMBRANE, THAT IS, MOVE IT AWAY
FROM THE RESTING POTENTIAL.
WE CALL THIS AN INHIBITORY POST
SYNAPTIC POTENTIAL OR IPSP, AND
IF THE INHIBITORY INPUT IS
ACTIVATED TOGETHER WITH THE
EXCITATORY INPUTS, THAT CAN BE
ENOUGH TO PREVENT THOSE
EXCITATORY INPUTS FROM REACHING
THRESHOLD AND DRIVING IN ACTION
POTENTIAL.
SO ONE OF THE KEY THINGS, EVERY
NEURON INTEGRATES SYNAPTIC INPUT
FROM BOTH EXCITATORY AND
INHIBITORY SYNAPTIC INPUTS, AND
AT ANY GIVEN MOMENT, WHETHER THE
CELL IS FIRING AN ACTION
POTENTIAL OR NOT IS DETERMINED
LARGELY BY WHETHER SYNAPTIC
INPUTS ARE SUFFICIENT TO DRIVE
THE MEMBRANE POTENTIAL IN THE
AXON TO THAT THRESHOLD FOR
FIRING.
NOW THERE ARE MANY, MANY OTHER
FACTORS THAT INFLUENCE THIS
INPUT/OUTPUT RELATIONSHIP, SO
FOR EXAMPLE, WE AND MANY OTHERS
HAVE SHOWN THAT THE DENDRITIC
TREES OF THESE NEURONS CONTAIN
MANY DIFFERENT TYPES OF ION
CHANNELS THAT CAN ALSO INFLUENCE
THE WAY SYNAPTIC INPUTS ARE
INTEGRATED BY THESE NEURONS.
THE STRUCTURE OF THE DENDRITIC
TREE IS ALSO AN IMPORTANT
FACTOR, AND AS I SHOWED YOU,
DENDRITIC STRUCTURE IS HIGHLY
VARIABLE ACROSS DIFFERENT
NEURONS AND DIFFERENT PARTS OF
THE BRAIN, AND EVEN WITHIN THE
SAME PART OF THE BRAIN, YOU CAN
FIND NEURONS WITH VARYING
DENDRITIC STRUCTURES.
SO WE BELIEVE THAT THE
COMPUTATION THAT IS PERFORMED,
THE INPUT/OUTPUT COMPUTATION
THAT'S PERFORMED BY EACH NEURON
DEPENDS ON THOSE FACTORS, THINGS
LIKE THE STRUCTURE OF THE
DENDRITES, PROPERTIES OF THE
SYNAPSES, THE TYPES OF SYNAPSES
THAT ARE ACTIVATED AND THE TYPES
OF LI LIGAND AND VOLTAGE GATED
CHANNELS IN THE MEMBRANE THAT
ARE ACTIVATED WHEN THESE
PROCESSES ARE OCCURRING.
SO WHAT HAPPENS WHEN THAT ACTION
POTENTIAL GETS TO THE END OF THE
AXON OR ALONG THE AXON, THERE
ARE THOUSANDS OF TERMINALS
CHEMICAL SYNAPTIC TRANSMISSION
IS OCCURRING WITH THE TARGET
NEURONS.
THIS IS KIND OF A FANCY PICTURE
I FOUND ON THE WEB THAT SHOWS
HOW CHEMICAL SYNAPTIC
TRANSMISSION WORKS.
YOU HAVE A PRESYNAPTIC TERMINAL
RELEASING MOLECULES ON TO THE
POST SYNAPTIC NEURON, AND THAT
CHEMICAL SYNAPTIC TRANSMISSION
TURNS AN ACTION POTENTIAL ON THE
PRESYNAPTIC SIDE INTO AN EPSP OR
IPSP LIKE THE ONES I JUST SHOWED
YOU ON THE POST SYNAPTIC SIDE.
FREQUENTLY, YOU CAN SEE NEURAL
CIRCUITS DEPICTED AS THESE VERY
SIMPLE DRAWINGS WHERE EXCITATORY
AND INHIBITORY SYNAPSES ARE
DEPICTED IN A CARTOON-LIKE
FASHION DESCRIBING SOME OF THE
CIRCUITRY THAT CAN BE FOUND IN
THE NERVOUS SYSTEM OF MANY
DIFFERENT TYPES OF ANIMALS, BUT
OBVIOUSLY WHAT WE WANT IS A MORE
SOPHISTICATED UNDERSTANDING OF
SYNAPSES AND CIRCUITS AND
NEURONS THAN IS REVEALED BY
SIMPLE DIAGRAMS LIKE THIS.
NOW ONE WAY OF THINKING ABOUT
WHAT OUR GOAL IS IN TERMS OF
UNDERSTANDING HOW THE BRAIN
WORKS IS TO THINK ABOUT
ARTIFICIAL NEURAL NETWORKS.
WE'RE ALL PROBABLY VERY FAMILIAR
WITH ARTIFICIAL NEURAL NETWORKS
THESE DAYS, READING THE NEWS
ABOUT CHAT GPT AND PLAY PLAIINGH
CHAT GPT OR WATCHING THE MOVIE
ALPHA GO, WHICH IF YOU HAVEN'T
SEEN IT I'D HIGHLY RECOMMEND IT.
IT'S A DESCRIPTION ABOUT HOW 10
YEARS AGO THE DEEP MIND TEAM WAS
ABLE TO DEVELOP AN ARTIFICIAL
NEURAL NETWORK THAT BEAT THE
BEST PLAYERS IN THE WORLD AT THE
GAME OF GO.
THIS IS ALL DONE WITH VERY, VERY
LARGE BUT -- YOU KNOW, AT THE
CORE, RELATIVELY SIMPLE NEURAL
NETWORK ARCHITECTURE.
SO THIS IS A PARTICULARLY SIMPLE
NEURAL NETWORK THAT'S DEPICTED
HERE.
THIS IS A FEED FORWARD NETWORK.
IT HAS AN INPUT LAYER, AN OUTPUT
LAYER, AND IN BETWEEN, A BUNCH
OF HIDDEN LAYERS.
AND MOST OF THESE ARTIFICIAL
UNUSUAL NETWORKS ARE, IN FACT,
INSPIRED BY THE PROPERTIES OF
REAL NEURAL NETWORKS.
FOR EXAMPLE, INDIVIDUAL
ELEMENTS, WE CAN THINK OF AS
NEURONS.
THE CONNECTIONS BETWEEN THEM AS
MEDIATED BY AXONS, AND SYNAPSES,
AND REALLY IMPORTANTLY, THESE
SYNAPSES HAVE ADJUSTABLE
WEIGHTS.
AND THE KEY TO LEARNING IN THESE
ARTIFICIAL SYSTEMS IS SIMPLY
ADJUSTING THE WEIGHTS OF EACH OF
THESE CONNECTIONS WITHIN THESE
SYSTEMS AND DOING THAT IN A WAY
THAT HELPS ACHIEVE THE TARGET.
ON THE INPUT LAYER YOU MIGHT
HAVE A PICTURE OF AN ANIMAL, ON
THE OUTPUT LAYER, THE
INFORMATION WOULD THEN GET
MATCHED TO A DOG OR CAT OR
WHATEVER KIND OF ANIMAL WAS BEST
MATCHED BY THE INPUT.
OKAY.
SO ONE WAY OF TRYING TO
UNDERSTAND ON BRAIN FUNCTION IS,
HOW DO REAL BRAINS DIFFER FROM
THESE ARTIFICIAL NEURAL
NETWORKS?
WE KNOW NOW THAT ARTIFICIAL
NEURAL NETWORKS CAN SURPASS THE
PERFORMANCE OF HUMANS IN MANY
NARROW DOMAINS OF INTEREST, FOR
EXAMPLE, PLAYING THE GAME OF GO,
BUT THEY TEND TO FAIL WHEN
PITTED AGAINST HUMANS ON THINGS
THAT REQUIRE MORE GENERAL
INTELLIGENCE.
SO WHAT IS IT ABOUT THE BRAIN
THAT MAKES GENERAL INTELLIGENCE
IN HUMANS AND OTHER ANIMALS
POSSIBLE THAT IS NOT YET
CAPTURED BY THESE RELATIVELY
SIMPLE AI SYSTEMS?
WELL, THIS WAY OF THINKING ABOUT
NEURAL NETWORKS AS CONNECTIONIST
ARCHITECTURE REDUCES THE
CONNECTIVITY OF THE BRAIN DOWN
TO SIMPLY A SERIES OF MI TRI MAI
SEES OR WEIGHTS THAT CONNECT
DIFFERENT NEURONS WITHIN THE
NEURAL NETWORK.
WHEN IN FACT, WE KNOW THAT --
AND THEN THE FUNCTION THAT'S
PERFORMED BY EACH ONE OF THESE
NEURONS IS AN INPUT/OUTPUT
FUNCTION THAT LOOKS SOMETHING
LIKE THIS ONE.
THIS IS CALLED THE RECTIFIED
LINEAR UNIT.
IT MEANS IF THE INPUTS ARE BELOW
THRESHOLD, THE OUTPUT IS ZERO,
BUT IF THE INPUT IS ABOVE
THRESHOLD, THE OUTPUT IS
PROPORTIONAL TO THE SIZE OF THAT
ABOVE-THRESHOLD INPUT.
SO HOW IS IT THAT REAL NEURONS
SURPASS OR ALLOW US HUMANS AND
OTHER ANIMALS TO SURPASS THE
PERFORMANCE OF ARTIFICIAL
SYSTEMS?
WELL, WE KNOW, FOR INSTANCE,
THAT REAL BIOLOGY IS MUCH, MUCH
MORE COMPLICATED THAN THAT
SIMPLE PICTURE OF AN ARTIFICIAL
NEURAL NETWORK THAT I DESCRIBED.
FOR EXAMPLE, AT THE CHEMICAL
SYNAPSE, THERE ARE MOLECULAR
MACHINES ON BOTH THE PRE AND
POST SYNAPTIC SIDE THAT INVOLVE
HUNDREDS OF MOLECULES THAT
ORGANIZE STRAIGHT A REALLY
PRECISE PROCESS THAT ALLOWS, FOR
EXAMPLE, NEUROTRANSMITTERS TO BE
PACKAGED INTO VESICLES AND AXON
LOU TONS AND RESPONSE TO ACTION
POTENTIAL FIRING DEPICTED BY
THESE YELLOW FLASHES CAUSE THESE
NEUROTRANSMITTER CONTAINING
VESICLES TO FUSE WITH THE
PRESYNAPTIC MEMBRANE AND RELEASE
TRANSMITTER THAT THEN BINDS TO
ION CHANNELS ON THE POST
SYNAPTIC SIDE ALLOWING IONS TO
FLOW INTO THE POST SYNAPTIC CELL
AND PRODUCE EXCITATORY OR
INHIBITORY POST SYNAPTIC
POTENTIALS.
THEN THERE ARE ALSO GLIAL CELLS
THAT REGULATE THIS PROCESS IN
PART BY TAKING UP THE
NEUROTRANSMITTERS FROM THE
SYNAPTIC CLEFT AND DOING MANY
OTHER THINGS TO ENSURE THAT THIS
PROCESS OF SN SYNAPTIC TRANSMISN
IS ROBUST, FAST AND RELIABLE.
I'M GOING TO SHOW YOU THIS
MOVIE.
THIS COMES FROM A PUBLICATION
FROM HELM, ET AL., AND IT IS A
BEAUTIFUL STUDY THAT LOOKED AT
THE MOLECULAR COMPOSITION OF
THOUSANDS OF DENDRITIC SPINES,
AND THIS IS ONE DENDRITIC SPINE
THAT IS DEPICTED HERE, IS THE
POST SYNAPTIC SITE OF CONTACT ON
A DENDRITE.
THIS IS ABOUT A MICRON-LONG
STRUCTURE, AND INSIDE OF IT,
THERE ARE HUNDREDS OF PROTEINS,
POSSIBLY EVEN THOUSANDS OF
PROTEINS CONTRIBUTING TO THIS
PROCESS OF SYNAPTIC
TRANSMISSION.
AND THE MOVIE JUST KIND OF GOES
THROUGH AND SHOWS YOU BASED ON A
RECONSTRUCTION OF SINGLE SPINES
AND HUNDREDS OF MOLECULES HOW
INCREDIBLY COMPLEX THIS
STRUCTURE IS, JUST ONE SIDE OF
THE SYNAPSE, AND YOU'RE LOOKING
AT VARIOUS TYPES OF PROTEINS
DEPICTED INSIDE OF THE SYNAPSE.
AND ALL OF THIS MOLECULAR
MACHINERY ALLOWS THE CELL NOT
ONLY TO RESPOND TO THOSE
PRESYNAPTIC CHEMICALS THAT ARE
RELEASED ON TO THE POST SYNAPTIC
SPINE, BUT ALSO TO ENGAGE IN
BIOCHEMICAL REACTIONS THAT ALLOW
THE WEIGHT OF THAT SYNAPTIC
CONNECTION TO BE CHANGED AS A
FUNCTION OF EXPERIENCE.
AND THIS CONCEPT OF CHANGING
SYNAPTIC WEIGHTS IS A FUNCTION
OF EXPERIENCE IS BELIEVED TO BE
REALLY CENTRAL TO THE CONCEPT OF
LEARNING AND HOW MEMORIES ARE
FORMED.
SO WE CAN THINK ABOUT MEMORIES
ESSENTIALLY AS CHANGES IN THE
WEIGHTS OF SYNAPSES THAT ALTER
ACTIVITY IN THE BRAIN AND ALLOW
THE BRAIN TO RESPOND TO INCOMING
SENSORY INFORMATION AND INTERNAL
INFORMATION COMING FROM OUR
BODIES TO PRODUCE UNIQUE TYPES
OF CONSCIOUS EXPERIENCES WHEN
THOSE THINGS HAPPEN.
SO AGAIN, THE GOAL IS TO
UNDERSTAND HOW THE BRAIN WORKS,
WHICH MEANS UNDERSTANDING HOW
PROTEINS, WHICH WE CAN MEASURE
ON THE SCALE OF NANOMETERS, AND
ORGANELLES AND CELLS WHICH ARE
MEASURED ON THE SCALE OF
MICRONS, INFLUENCE THE FUNCTION
OF ORGANS, LIKE BRAINS ON THE
SCALE OF MILLIMETERS AND EVEN IN
WHOLE ANIMALS ON THE SCALE OF
COUNCILMEM --OF CENTIMETERS AND.
SO THIS IS THE GOAL OF MANY
STUDYING THE FUND MENTAL BIOLOGY
OF THE NERVOUS SYSTEM AND IT'S
HARD, IT REQUIRES THAT MANY
PEOPLE DO STUDIES AT THESE
DIFFERENT LEVELS AND TRY TO
UNDERSTAND MECHANISTIC
RELATIONSHIPS BETWEEN THESE
DIFFERENT LEVELS OF
UNDERSTANDING HOW THE NERVOUS
SYSTEM FUNCTIONS.
AND I THINK THIS IS REALLY THE
ANSWER TO THE QUESTION HOW THE
BRAIN WORKS WILL REALLY BE
ANSWERS TO MANY, MANY QUESTIONS
ABOUT THE FUNCTIONAL
RELATIONSHIPS BETWEEN THESE
DIFFERENT STRUCTURES THAT WE
STUDY AT DIFFERENT LEVELS --
SIZE LEVELS AND ORGANIZATIONAL
LEVELS IN NERVOUS SYSTEMS.
TO GIVE YOU AN APPRECIATION FOR
THAT, I'M GOING TO SHOW YOU
ANOTHER MOVIE.
THIS IS PROVIDED GENEROUSLY BY
JEFF LICTHMAN FROM HARVARD
UNIVERSITY.
HE AND HIS GROUP OBTAINED FROM A
PATIENT WHO HAD TISSUE RESECTED
FOR EPILEPSY SOME OF THE
UNDAMAGED TISSUE THAT HAD TO BE
REMOVED ALONG WITH THE EPILEPTIC
SEIZURE FOCUS.
THIS IS FROM THE NEOCORTEX, WAS
THEN PRESERVED AN IMAGE USING
SERIAL ELECTRON MICROSCOPY, AND
THEN IN COLLABORATION WITH
GOOGLE, THEIR TEAM RECONSTRUCTED
EVERY SINGLE STRUCTURE INSIDE
THIS RELATIVELY LARGE PIECE OF
HUMAN CORTEX.
AND THE MOVIE SORT OF ZOOMS IN
TO THE EXTREMELY HIGH RESOLUTION
VIEW PROVIDED BY THE ELECTRON
MICROSCOPE.
AND IN THESE HIGH RESOLUTION
VIEW, YOU CAN SEE THINGS LIKE
CELL BODY, DENDRITES, AXONS AND
SYNAPSES, AND EVERY SINGLE ONE
OF THOSE STRUCTURES IN THIS
VOLUME HAS BEEN RECONSTRUCTED
FOR FURTHER ANALYSIS.
AND THIS IS ONE OF THE GREAT
CHALLENGES, IS TO IMAGE LARGE
VOLUMES OF TISSUE AT HIGH
RESOLUTION.
I SHOWED YOU ONE EXAMPLE OF THAT
IN THAT MOVIE FROM THE
MOUSELIGHT TEAM HERE AT JANELIA.
THIS IS ANOTHER EXAMPLE OF USING
VERY HIGH RESOLUTION FORM OF
MICROSCOPY TO STUDY LARGE
VOLUMES OF TISSUE.
IT INVOLVES NOT ONLY THE
TECHNOLOGY OF THE MICROSCOPY,
BUT ALSO THE COMPUTATIONAL
TECHNOLOGY REQUIRED TO STITCH
ALL THESE IMAGES TOGETHER AND
THEN RECONSTRUCT THOUSANDS OF
NEURONS AND TENS OR HUNDREDS OF
THOUSANDS OF SYNAPTIC
CONNECTIONS BETWEEN THESE
NEURONS.
AND THIS HAS BEEN DONE, FOR
EXAMPLE, HERE AT JANELIA FOR THE
DROSOPHILA FRUIT FLY BRAIN, AND
THE TEAM IS WELL ON THEIR WAY OF
HAVING THE ENTIRE FRUIT FLY
BRAIN IMAGED AND THEN
RECONSTRUCTED SO THAT EVERY
SINGLE NEURON AND EVERY SINGLE
CONNECTION BETWEEN ALL THOSE
NEURONS CAN BE DESCRIBED IN
DETAIL.
THIS HAS PROVEN TO BE REALLY
INCREDIBLY ENABLING FOR THE
PEOPLE WHO ARE STUDYING THE
RELATIONSHIP BETWEEN NEURONS AND
THE FUNCTION OF THE ANIMAL.
NOW COMING BACK TO JEFF LICHTMAN
AND HIS TEAM'S WORK AT HARVARD,
HERE'S FROM THAT VOLUME THAT I
JUST SHOWED YOU SINGLE PYRAMIDAL
CELL SHOWN IN BLUE, YOU CAN SEE
THE DENDRITIC SPINES.
THESE ARE PROTRUSIONS FROM THE
DENDRITES THAT ARE THE POST
SYNAPTIC SITES OF CONTACT OF
PRESYNAPTIC AXONS.
SO THE PRESYNAPTIC AXONS ARE NOT
SHOWN HERE, BUT EACH ONE OF
THOSE DENDRITIC SPINES WOULD
RECEIVE SYNAPTIC INPUT FROM THE
PRESYNAPTIC AXON OF ANOTHER
NEURON.
HERE'S ANOTHER DEPICTION, YOU
CAN GET AN APPRECIATION FOR HOW
INCREDIBLY COMPLICATED THE
CONNECTIVITY OF THE NERVOUS
SYSTEM IS BY LOOKING AT THESE
BEAUTIFUL IMAGES.
AND ZOOMING IN TO EVEN HIGHER
RESOLUTION, ON THE LEFT YOU CAN
SEE A SINGLE SMALL PIECE OF THIS
LARGE VOLUME ELECTRON
MICROSCOPY, YOU CAN SEE THE
PRESYNAPTIC TERMINAL HIGHLIGHTED
HERE IN BLUE, THE POST SYNAPTIC
DENDRITE AND DENDRITIC SPINE.
THE MAGENTA, YOU CAN EVEN SEE
THE VESICLES AND THE PRESYNAPTIC
TERMINAL.
THOSE ARE THE NEUROTRANSMITTER
CONTAINING VESICLES THAT WOULD
RELEASE CHEMICAL TRANSMITTERS ON
TO THE POST SYNAPTIC DENDRITE
AND PRODUCE A RESPONSE IN THE
POST SYNAPTIC NEURON.
AGAIN, SINCE EACH OF THESE
NEURONS IS RECEIVING THOUSANDS
OF THESE SYNAPTIC INPUTS, MANY
OF THEM HAVE TO BE ACTIVATED IN
CLOSE TEMPORAL PROXIMITY IN
ORDER FOR THE CELL TO GENERATE A
RESPONSE.
AND LICHTMAN WITH HIS TEAM ALONG
WITH MANY OTHER PEOPLE USING
COMPLEMENTARY APPROACHES ARE
TRYING TO USE THIS VERY, VERY
DETAILED STRUCTURAL INFORMATION
TO GAIN A BETTER UNDERSTANDING
OF HOW THE CONNECTIVITY OF THE
NERVOUS SYSTEM WILL INFLUENCE
ITS FUNCTION.
NOW ULTIMATELY, AGAIN, WE WANT
TO GO FROM THESE HIGH RESOLUTION
VIEWS OF CELLS AND SUBCELLULAR
ORGANS AND EVEN PROTEINS INTO
HOW THE NERVOUS SYSTEM GUIDES
THE FUNCTION OF ENTIRE ANIMALS.
AND TO DO THAT, MANY GROUPS ARE
NOW DOING THESE KINDS OF STUDIES
IN VIVO, IN BEHAVING ANIMALS.
MY GROUP IS WORKING AS MANY
PEOPLE ARE WITH MICE, AND USING
MICROSCOPY TO STUDY THE ACTIVITY
OF THESE -- OF NEURONS IN THE
BRAIN AT THE CELLULAR LEVEL
WHILE WE CHALLENGE THE ANIMALS
TO LEARN TO DO TASKS IN A
VIRTUAL REALITY ENVIRONMENT.
SO ANIMAL IS SITTING ON A LARGE
SPHERICAL STYROFOAM BALL WHICH
IS FLOATING ON A CUSHION OF AIR.
THE ANIMALS ARE HEAD-FIX SOD WE
CAN USE A MICROSCOPE TO IMAGE
ACTIVITY IN THE BRAIN, AND I
THINK -- IT CHANGES THE VIEW ON
THESE SCREENS AROUND THEM TO
PRODUCE THE ILLUSION OF
NAVIGATING IN VIRTUAL REALITY.
THIS IS WHAT IT LOOKS LIKE
PHOTOGRAPHICALLY.
HERE'S THIS LARGE SPHERICAL
TREADMILL, HERE'S THE MOUSE, AND
HERE'S THIS OBJECTIVE FROM THIS
MICROSCOPE THAT WAS DESIGNED AND
BUILT HERE AT JANELIA, AND IT
ALLOWS US TO IMAGE THE ACTIVITY
OF INDIVIDUAL NEURONS, THOUSANDS
OF INDIVIDUAL NEURONS IN THE
HIPPOCAMPUS, WHILE THE ANIMAL IS
RUBBING AND LEARNING AND
PERFORMING A TASK.
AND WE CAN NOW IMAGE 5 TO 10,000
HIPPO CAM PAL NEURONS EVERY DAY
FOR WEEKS AS WE TRAIN ANIMALS TO
DO TASKS, AND THAT'S GIVING US
SOME INSIGHT INTO HOW NEURAL
ACTIVITY CHANGES AS THE ANIMAL
LESHES LEARNS AND FORMS MEMORIE.
THIS IS ONLY POSSIBLE BECAUSE
EACH IS EXPRESSING A PROTEIN
CALLED GKAMP THAT IS SENSITIVE
TO CALCIUM.
SO EACH TIME AN ACTION POTENTIAL
FIRES IN THESE NEURONS, CALCIUM
ENTERS THE CELL AND CAUSES AN
INCREASE IN FLUORESCENCE
SUBMITTED BY THE MOLECULES
EXPRESSED IN THESE NEURONS, AND
THAT'S A CELLULAR RESOLUTION
MEASUREMENT OF NEURAL ACTIVITY
IN THESE ANIMALS.
AND AGAIN, BY DOING THIS EVERY
DAY AND ALIGNING THE DATA FROM
ACROSS DAYS AND WATCHING HOW
THINGS CHANGE AS THE ANIMAL
LEARNS, IT GIVES US SOME INSIGHT
INTO HOW MEMORIES ARE FORMED AND
HOW THEY'RE STORED IN THE
HIPPOCAMPUS.
SO ANOTHER WAY OF MEASURING
NEURAL ACTIVITY IN BEHAVING
ANIMALS IS TO USE ELECTRODES,
AND AT JANELIA, WE RECENTLY
DEVELOPED A NEW TYPE OF PROBES
CALLED NEUROPIXEL PROBES, AND
THESE ARE HIGH SITE COUNT PROBES
THAT ARE FABRICATED AT A
NANOFABRICATION FACILITY IN
BELGIUM, PROBABLY THE ONLY
FACILITY IN THE WORLD THAT CAN
BUILD THESE STATE OF THE ART
PROBES BECAUSE IT'S A RESEARCH
FACILITY AS OPPOSED TO A
COMMERCIAL FACILITY OR IN
ADDITION TO BEING A COMMERCIAL
FACILITY.
AND THESE PROBES NOW ARE REALLY
IMPROVING THE WAY THAT
NEUROSCIENTISTS CAN MEASURE
NEURAL ACTIVITY IN THE BRAINS OF
BEHAVING ANIMALS, WHETHER THAT
BE MICE OR RATS OR NON-HUMAN
PRIMATES, AND THE NEURAL
ACTIVITY THAT CAN BE MEASURED IN
MANY DIFFERENT BRAIN REGIONS
SIMULTANEOUSLY FROM HUNDREDS OR
EVEN THOUSANDS OF NEURONS,
AGAIN, AS ANIMALS ARE PERFORMING
INTERESTING TASKS.
ANOTHER REALLY IMPORTANT
APPROACH THAT HAS REVOLUTIONIZED
THE FIELD IS CALLED
TRANSCRIPTOMICS, THE ABILITY TO
DETERMINE WHICH GENES ARE
EXPRESSED IN INDIVIDUAL CELLS.
THIS IMAGE YOU'RE LOOKING AT ON
THE LEFT IS FROM A RECENT
PUBLICATION WHERE A SINGLE CELL
ANALYSIS WAS DONE FOR ABOUT
1.7 MILLION NEURONS IN THE MOUSE
BRAIN.
OVER ON THE RIGHT SIDE, YOU CAN
SEE CLASSIFICATION OF THOSE
NEURONS INTO DIFFERENT TYPES,
AND IT TURNS OUT THAT THE
DIVERSITY OF NEURONS IN THE
MOUSE BRAIN IS MUCH, MUCH
GREATER THAN WE HAD EVER BEFORE
APPRECIATED JUST BY LOOKING AT
MORPHOLOGIES.
WHEN YOU START LOOKING AT GENE
EXPRESSION ACROSS THE BRAIN, YOU
SEE THAT THERE ARE MANY, MANY
DIFFERENT TYPES OF CELLS IN
TERMS OF THE COMPLEMENT OF GENES
THAT THEY EXPRESS AND EVEN IF
YOU ZOOM IN ON ONE PARTICULAR
BRAIN REGION OR THE CA1 THAT MY
LAB STUDIES EXTENSIVELY, YOU SEE
THAT CELLS THAT WE USED TO THINK
OF AS A MONOLITHIC POPULATION OF
NEURONS ACTUALLY CAN CONSIST OF
MANY DIFFERENT TYPES THAT DIFFER
VERY SUBTLELY IN TERMS OF GENE
EXPRESSION, AND THEN WHEN YOU
LOOK, YOU FIND THAT STRUCTURAL
AND FUNCTIONAL DIFFERENCES
CORRELATE WITH THOSE DIFFERENCES
IN GENE EXPRESSION AS WELL.
SO ONE OF THE GREAT CHALLENGES
FOR NEUROSCIENCE GOING FORWARD
IS TO DETERMINE ESSENTIALLY AN
ATLAS OF THE CELL TYPES THAT ARE
FOUND IN THE BRAINS OF DIFFERENT
TYPES OF ANIMALS, AND THEN
TRYING TO RELATE THE ATLAS OF
CELL TYPES TO FUNCTION.
NOW, TRANSCRIPTOMICS GIVES YOU
OWL CRUDE RESOLUTION IN TERMS OF
SPATIAL LOCATION OF THE
DIFFERENT TYPES OF NEURONS
BECAUSE THEY'RE USUALLY SMALL
PARTS OF THE BRAIN ARE DISSECTED
AND THEN THE CELLS ARE
DISASSOCIATED AND GENE
EXPRESSION IS DETERMINED, BUT
THE LEVEL OF RESOLUTION ABOUT
WHERE THOSE CELLS CAME FROM,
WHERE THEY'RE LOCATED IN THE
BRAIN IS LIMITED TO HOW SMALL
PIECES OF TISSUE CAN BE
DISSECTED OUT.
SO THERE'S A BIG, BIG PUSH IN
THE FIELD TO DO WHAT'S CALLED
SPATIAL TRANSCRIPTOMIC, WHICH
IS -- AND THIS IS FROM ANOTHER
RECENT PAPER THAT APPEARED AS A
PRE-PRINT LAST MONTH.
AGAIN SHOWING -- THIS IS A
REPRESENTATION OF ALL THE GENES
EXPRESSED IN HUNDREDS OF
THOUSANDS OF CELLS, AND THEN A
VARIETY OF METHODS HAVE BEEN
DEVELOPED THAT ALLOW THE
COLLECTION OF GENES THAT
DESCRIBE THESE DIFFERENT TYPES
OF CELLS TO BE MAPPED ON TO
THEIR LOCATION IN THE MOUSE
BRAIN.
AND THIS IS -- REALLY THIS
APPROACH, SPATIAL
TRANSCRIPTOMICS, COMBINED WITH
SISINGLE CELL -- IT'S A REVOLUTN
THAT'S LIKELY TO BE EXTENDED
INTO MANY OTHER TYPES OF
ANIMALS, INCLUDING HUMANS AS WE
NOW SEE MORE AND MORE PEOPLE
DOING TRANSCRIPTOMICS AND
SPATIAL TRANSCRIPTOMICS ON HUMAN
AS WELL AS MOUSE TISSUE.
SO FINALLY, WHAT DO WE DO THIS
WITH INFORMATION, ONCE WE HAVE
THIS ATLAS OF CELL TYPES?
ONE OF THE THINGS WE CAN DO IS
I -- THERE ARE VARIOUS FORMS
THAT HAVE BEEN ENGINEERED TO
ALLOW US TO STIM LAY NEURON, SO
INSTEAD OF USING A MORE
TRADITIONAL APPROACH OF USING
LEK TRAL STIMULATION WHICH WOULD
STIMULATE ANY NEURON IN THE
VICINITY OF THE ELECTRICAL
STIMULATING ELECTRODE, TO
EXPRESS TRANSGENICICALLY THESE
LIGHT SENSITIVE PROTEINS THAT
HAVE BEEN EXCITED -- WHEN AN
APPROPRIATE WAVELENGTH OF LIGHT
IS SHOWN ON TO THEM.
SO THE IDEA IS YOU CAN TAKE
ADVANTAGE OF OUR KNOWLEDGE OF
GENE EXPRESSION TO EXPRESS THESE
TRANS GENES IN A SINGLE CELL
TYPE, AND THEN EITHER ACTIVATE
OR INHIBIT THAT CELL TYPE USING
LIGHT, AS ANIMALS ARE PERFORMING
TASKS.
YOU CAN DO THIS IN INTACT
BEHAVING ANIMALS.
OVER THE PAST DECADE OR MORE, A
LARGE NUMBER OF STUDIES HAVE
BEGUN TO USE OPTOGENETICS TO
EXPLORE THE FUNCTION OF
DIFFERENT TYPES OF NEURONS AND
DIFFERENT TYPES OF -- AND
DIFFERENT PARTS OF THE BRAIN AND
LOOK NOT ONLY AT HOW THAT
AFFECTS THE BEHAVIOR OF THE
ANIMAL, BUT HOW IT AFFECTS THE
ACTIVITY OF NEURONS THROUGHOUT
THE BRAIN.
SO WITH THAT, I THINK I'LL STOP
AND TRY TO LEAVE SOME TIME FOR
DISCUSSION.
I HOPE THAT WHIRLWIND TOUR OF
THE BRAIN HAS GIVEN YOU SOME
INSIGHT INTO HOW MODERN
NEUROSCIENCE IS DEVELOPING SOME
INCREDIBLE NEW TECHNIQUES AND
MAKING PROGRESS TOWARDS
ACHIEVING A BETTER UNDERSTANDING
OF THE FUNDAMENTAL PHYSIOLOGY OF
THE BRAIN AND HOW IT ENABLES THE
AMAZING THINGS THAT WE AND OTHER
ANIMALS CAN DO.
THANK YOU.
>>WELL, I WANT TO THANK YOU
BOTH FOR AN INCREDIBLY EXCITING
INSIGHTS INTO AREAS THAT MOST OF
US KNEW VERY LITTLE ABOUT, BUT
VERY SUPERFICIALLY, PERHAPS.
WE HAVE A WHOLE SERIES OF
QUESTIONS.
SOME OF THEM HAVE TO DO MORE
SPECIFICALLY WITH THE
HIPPOCAMPUS, AND WITH YOUR WORK,
NELSON, IN REGARD TO DIFFERENT
FORMS OF MEMORY AND SO FORTH.
SO EVEN THOUGH YOU DIDN'T DWELL
ON YOUR PARTICULAR RESEARCH OR
ON THE HIPPOCAMPUS IN
PARTICULAR, PERHAPS WE COULD
CONSIDER SOME OF THOSE QUESTIONS
BECAUSE PEOPLE KNEW ENOUGH TO
ASK ABOUT IT.
LET ME GIVE YOU A FEW OF THEM
AND SEE HOW YOU FEEL, AND MAYBE
MARCUS WOULD FEEL THEY WOULD
WANT TO RESPOND TO THEM.
OKAY.
SO ONE IS, WHAT HAS IMAGING
REVEALED ABOUT UNCONSCIOUS
LEARNING AND UNCONSCIOUS
MEMORIES?
AND I SUPPOSE WE COULD ADD ON TO
THAT, SLEEP.
SO MAYBE -- MARCUS, DO YOU WANT
TO COMMENT ABOUT THAT FROM THE
STANDPOINT OF IMAGING?
>>THERE'S ONE THAT CAME FROM
DAVID -- SEVERAL THINGS COME TO
MIND BUT ONE WAS HOW MUCH
INFORMATION COMES FROM THE
OUTSIDE WORLD FOR US TO PROCESS
IN THE FIRST PLACE?
SO YOU CAN FIGURE THAT THE
RETINA RECEIVES A FAIR AMOUNT OF
INFORMATION ALL THE TIME, AND
THE QUESTION IS FIRST OFF, HOW
MUCH OF THAT ACTUALLY GETS TO
THE VISUAL CORTEX?
IT'S ORDERS OF MAGNITUDE, LIKE
SIX ORDERS OF MAG TEUT LESS THAS
THAN THE INFORMATION THAT GETS
TO THE RETINA IN THE FIRST
PLACE.
SO YOU HAVE TO IMAGINE WITH OUR
ELEGANT VIEW OF THE WORLD AS WE
SEE IT, THAT THE BRAIN MUST BE
FILLING IN A LOT, BASED ON
EXPERIENCE, VARIOUS PEOPLE HAVE
TALKED ABOUT THIS, VERNON AND
OTHERS, BUT I THINK WE TEND TO
OVERLOOK THIS ENORMOUS AMOUNT OF
WHAT HAS TO BE A LARGE AMOUNT OF
NON-CONSCIOUS ACTIVITY BECAUSE
THE BANDWIDTH OF CONSCIOUSNESS
IS ACTUALLY NOT AS BIG AS YOU
MIGHT IMAGINE.
WHICH LEAVES FOR THE NERVOUS
SYSTEM A MAJOR ROLE OF
CONSTRUCTING OUR CONCEPT OF THE
WORLD AROUND US.
SO THAT WHEN WE, FOR EXAMPLE,
DECIDE TO GO BUY A CAR, AND WE
BUY THE RED CAR, YOU'D SAY,
WELL, WHY DEPARTMENT YOU B -- WY
DIDN'T YOU BUY THE RED FORD
INSTEAD OF THE BLUE CHEVROLET?
PEOPLE CAN COME UP WITH ALL
SORTS OF EXPLANATIONS BUT MY
GUESS WOULD BE THERE'S CERTAIN
INTUITIVE PROPERTIES OF THE
BRAIN THAT BIAS OUR JUDGMENTS,
AND MOST OF THAT IS
NON-CONSCIOUS.
JUST OUT OF THE PRACTICAL
NECESSITY OF IT BEING SO.
SO JUST A SMALL PART OF THIS,
BUT MY GUESS WOULD BE BUT
DAVID'S WORK -- IT WAS SO
ASTONISHING, THE BANDWIDTH OF
THE ACTUAL CONSCIOUSNESS IS NOT
VERY LARGE, RELATIVE TO THE
OVERALL COMPLEXITY OF THE
SYSTEM.
SO JUST A PASSING THOUGHT THAT
OCCURRED TO ME.
>>THAT'S INTERESTING.
SO NELSON, DO YOU WANT TO
COMMENT ABOUT THIS?
I SUPPOSE ONE OF THE QUESTIONS
THAT CAME UP WHEN YOU SHOWED THE
MOUSE STUDIES, HAVE YOU OR YOUR
COLLEAGUES OR OTHERS IN THE
FIELD USED SUCH AN EXPERIMENTAL
MODEL TO OBSERVE EFFECTS IN THE
PARAMETERS THAT YOU MENTIONED
WITH REGARD TO SLEEP OR
ANESTHESIA IN THE ANIMAL?
>>LET ME COMMENT ON THAT IN A
FEW DIFFERENT WAYS.
FIRST I WOULD SAY THE KIND OF
IMAGE STUDIES THAT I SHOWED YOU
ARE REALLY STILL IN THEIR
INFANCY AT THE MOMENT.
BUT ONE OF THE BIG ADVANTAGES IS
THE LARGE NUMBER OF NEURONS THAT
WE CAN RECORD FROM AND OUR
ABILITY TO GO BACK AND ASSESS
THE SAME NEURONS EVERY SINGLE
DAY.
BUT THIS WAS BUILDING ON A HUGE
BODY OF WORK OVER THE PAST
SEVERAL DECADES DONE BY A NUMBER
OF LABS WHO, INSTEAD OF USING
IMAGING, HAVE USED ELECTRODES
AND PLANTED IN THE BRAINS OF
MICE AND RATS, MOSTLY RATS
ACTUALLY HISTORICALLY, THAT HAVE
REVEALED A LOT ABOUT WHAT THE
HIPPOCAMPUS IS DOING NOT ONLY IN
THE WAKE ANIMAL BUT ALSO DURING
SLEEP.
SO TO TRY TO SUMMARIZE THE
EMERGING VIEW OF WHAT HAS COME
OUT OF THAT VERY LARGE BODY OF
WORK FROM SEVERAL LABORATORIES
ACROSS DECADES, THE BASIC IDEA
IS THAT THE HIPPOCAMPUS IS
INTERPRETING THE SENSORY
INFORMATION THAT'S COMING IN IN
THE CONTEXT OF WHAT THE ARN MALL
ANIMALIS DOING AND WHERE THE ANS
LOCATED.
SO THE EARLIEST VIEW OF WHAT THE
HIPPOCAMPUS WAS DOING IS IT WAS
PRODUCING A COGNITIVE MAP OF OUR
ENVIRONMENT, SO LITERALLY
MAPPING OUT THE PHYSICAL SPACES
THAT WE EXPLORE IN, AND THAT
IDEA HAS REALLY SURVIVED THE
TEST OF TIME.
MANY OF THE CELLS IN THE
HIPPOCAMPUS RESPOND BEST WHEN
THE ANIMAL IS IN A SPECIFIC
PLACE IN THE ENVIRONMENT.
IN ADDITION, THOUGH, A NEW IDEA,
A NEWER IDEA, STILL NOT THAT
NEW, CLOSE TO A COUPLE DECADES
OLD AT THIS POINT, IS THE IDEA
THAT CELLS WILL -- IN
HIPPOCAMPUS WILL RESPOND NOT
ONLY WHEN THE ANIMAL IS IN A
POSITION BUT ALSO IN CONTACT, SO
FOR EXAMPLE, IF IT'S MOVING IN A
CERTAIN DIRECTION OR IN IT'S
COMI --IF IT'S COMING FROM PLACO
PLACE B, THE CELL WILL RESPOND,
WHEREAS IF IT'S COMING FROM
PLACE C TO PLACE B, THE CELL
WILL NOT RESPOND IN LOCATION B.
SO THERE'S A LOT OF WORK THAT IS
SUGGESTING THAT THERE'S THIS
COGNITIVE MAP NOT ONLY OF THE
ENVIRONMENT BUT ALSO OF THE
ANIMAL'S BEHAVIOR AND THE
CONTEXT WITHIN WHICH THE ANIMAL
IS EXPERIENCING THAT ENVIRON
ENVIRONMENT.
THAT DOES NOT EXIST WHEN THE
ANIMAL IS BORN.
THE HIPPOCAMPUS IS BUILT TO
ALLOW THE FLEXIBILITY TO ALLOW
AN ANIMAL TO BUILD THOSE
COGNITIVE MAPS IN ANY KIND OF
ENVIRONMENT, NO MATTER WHAT IT
HAPPENS TO ENCOUNTER IN THE
COURSE OF THE SLIDE.
SO OBVIOUSLY THERE ARE SERB
THARE CERTAINTHINGS THAT ARE WIR
DEVELOPMENT AND WHAT WE WOULD
CONSIDER TO BE HARD WIRED
CIRCUITS TO DRIVE INNATE
BEHAVIORS.
MAKING MAPS OF ENVIRONMENTS IS
JUST NOT ONE OF THOSE THINGS
BECAUSE ENVIRONMENTS ARE FAR,
FAR TOO DIVERSE, THERE'S FAR TOO
MANY DIFFERENT TYPES OF
ENVIRONMENTS AN ANIMAL CAN
ENCOUNTER IN ITS LIFETIME AND
THEY'RE CONSTANTLY CHANGING.
SO THE HIPPOCAMPUS HAS THE
FLEXIBILITY TO BUILD THESE MAPS
OF OUR ENVIRONMENTS AND OUR
BEHAVIOR WITHIN THOSE
ENVIRONMENTS ON THE BASIS OF
EXPERIENCE.
AND ALL OF THAT, OF COURSE,
HAPPENS WHEN THE ANIMAL IS AWAKE
AND WHEN IT'S EXPLORING AND WHEN
IT GOES TO SLEEP, THERE'S
SOMETHING CALLED MEMORY
CONSOLIDATION THAT HAPPENS.
MEMORY CONSOLIDATION IS BUILT IN
LARGE MEASURE OR THE
CONVENTIONAL WISDOM IS IT'S
BUILT IN LARGE MEASURE ON REPLAY
OF NEURAL ACTIVITY THAT HAPPENED
WHILE THE ANIMAL WAS AWAKE WHILE
THE ANIMAL IS ASLEEP.
AND THAT REPLAYED ACTIVITY
ALLOWS FOR ACTIVITY DEPENDENT
SYNAPTIC PLASTICITY TO CHANGE
THE WEIGHTS OF THE NETWORKS IN
THE BRAIN IN A WAY THAT
REINFORCES OR STORES THOSE
COGNITIVE MAPS THAT ARE
BEGINNING TO BE FORMED DURING
THE ANIMAL'S AWAKE EXPERIENCES.
THAT'S A HUGE AREA OF INTEREST
IN THE FIELD, UNDERSTANDING HOW
REPLAY OF NEURAL ACTIVITY DRIVES
THE STABILIZATION OF MEMORIES
THAT IS NECESSARY FOR COGNITIVE
MAPS TO BE FORMED, IT'S A BIT OF
A CHALLENGE WITH IMAGING BECAUSE
THE LIMITATION OF THE TRANSGENIC
PROBES I DESCRIBED CALLED G CAMP
IS THEY'RE MEASURING CALCIUM
INSTEAD OF ELECTRICAL ACTIVITY,
THEY'RE INHERENTLY SLOWER AND
SOME OF THE REPLAYED NEURAL
ACTIVITY IS VERY, VERY FAST, AND
MUCH MORE DIFFICULT TO IDENTIFY
SEQUENCES OF SPIKES IN
POPULATIONS OF NEURONS FROM
IMAGING THAN FROM ELECTRODES.
NEVERTHELESS, WE AND OTHERS CAN
SEE INDICATIONS OF REPLAYED
ACTIVITY WHILE THE ANIMAL IS
EITHER RESTING OR SLEEPING, SO
WE ACTUALLY HAVE NOT DONE IT
WHETHER THE ANIMAL IS ASLEEP,
BUT WE CAN SEE IT WHEN THE
ANIMAL STOPS RUNNING AND IT
PAUSES AND IT'S IN THE DARK AND
IT'S RESTING, YOU CAN SEE THIS
REPLAYED ACTIVITY AS WELLMENT SO
THE LAST THING I WANT TO HIT ON
IS THIS WHOLE QUESTION OF
CONSCIOUSNESS.
I STUDY MICE SO I DON'T KNOW HOW
TO MEASURE CONSCIOUSNESS IN
MICE.
I CAN'T ASK THEM ABOUT THEIR
CONSCIOUS EXPERIENCES.
SO BY AND LARGE, WE ASSUME -- WE
ASSUME THAT MICE ARE CONSCIOUS,
BUT -- AND SOME OF THE PROCESSES
THAT WE'RE MEASURING REFLECT
CONSCIOUS ACTIVITY IN THE ANIMAL
BUT WE DON'T KNOW HOW TO DRAW
THAT LINE FROM NEURAL ACTIVITY
TO CONSCIOUSNESS BECAUSE IT'S SO
HARD TO MEASURE THE LATTER.
>>SO MARCUS, DO YOU SEE SOME
CONNECTION BETWEEN WHAT NELSON
HAS BEEN SPEAKING ABOUT AND YOUR
INTERESTS IN BIG QUESTIONS LIKE
CONSCIOUSNESS AND MEMORY, BOTH
IN HEALTH AND IN DISEASE?
DO YOU WANT TO COMMENT ABOUT
THAT?
>>WELL, I WAS ACTUALLY THINKING
ABOUT A QUESTION I HAVE FOR
NELSON.
IT RELATES TO SOMETHING, MAYBE
I'M DODGING THE ANSWER TO YOUR
QUESTION, BUT ONE OF THE THINGS
THAT IS VERY INTERESTING IS THIS
VARIATION IN BEHAVIOR THAT HAS
BEEN WELL DOCUMENTED FOR
DECADES.
THAT IS IF YOU ASK SOMEBODY TO
DO A VERY, VERY -- SAY JUST
PRESS A LITTLE BUTTON AND YOU
RECORD THE WEIGHT OF YOUR
PRESSURE, IT VARIES.
AND THE INTERESTING THING IS, IT
VARIES ROUGHLY AT THE RATE OF
INFRA-SLOW ACTIVITY.
NOW, THE QUESTION IS, WHAT'S THE
ADVANTAGE?
WHY ARE WE -- WHY ARE WE NOT
JUST CONSISTENT ALL THE TIME?
AND AS NELSON WAS JUST TALKING
ABOUT, THERE ARE THESE TWO
STATES OF THE HIPPOCAMPUS, THE
THI TA THETASTATE AND SHARP WAVE
STATE.
OFTEN ONE THINKS ABOUT THIS IN
THE CONTEXT OF SLOW WAVE SLEEP
AND IN PARTICULAR, WHERE YOU
REVERSE THESE STATES, PRESUMABLY
AS YOU ELOQUENTLY DESCRIBED A
MOMENT AGO.
BUT WE HAVE THIS VARIABILITY
GOING ON ALMOST AS IF YOU'RE
VARYING N IN AROUSAL STATE WHILE
YOU'RE AWAKE.
THE QUESTION THAT'S OCCURRED TO
ME IS, ARE WE GOING THROUGH THAT
SHARP WAVE RIPPLE STATE VERSUS
THETA STATE ALL THE TIME WHEN
WE'RE AWAKE?
AND THIS KIND OF COMES OUT OF
THAT SLIDE I SHOWED OF DAVID
MCCORMICK'S WORK WHERE IT WAS
TUCKED IN A CORNER, BUT IT'S
ALWAYS STRUCK ME THAT IF I'M
GOING TO REMEMBER SOMETHING, I
WANT TO RECORD IT FAIRLY
IMMEDIATELY.
I DON'T WANT TO HAVE TO GO TO
BED TONIGHT TO HOPE THAT I CAN
REMEMBER A DAY'S WORTH, HOW
ABOUT DOING IT SEVERAL TIMES A
MINUTE?
WE DON'T HAVE DIRECT DATA THAT
WOULD SPEAK TO THAT AT THE
MOMENT, BUT I WOULD THINK MAYBE,
NELSON, YOU'VE EITHER THOUGHT
ABOUT THIS OR NOT.
I'M JUST ASKING FOR MY OWN
EDIFICATION HERE, IS THAT THE
VARIABILITY IN HUMAN BEHAVIOR,
WHICH HAS BEEN DOCUMENTED FOR
DECADES, SUBTLE AS IT MAY BE,
IT'S THE PRICE WE PAY FOR
ENHANCING THE MEMORY OF THE
MOMENT.
IF YOU WILL.
>>YEAH, I MEAN IT'S DEFINITELY
TRUE THAT SHARP WAVE EVENTS,
WHICH ARE THE EVENTS THAT HAPPEN
WHEN THE ANIMAL IS SLEEPING ALSO
HAPPEN WHEN THE ANIMAL IS AWAKE
BUT IN A LESS AROUSED STATE.
SO TYPICALLY MICE, WHEN THEY'RE
RUNNING, FOR EXAMPLE, AND
THEY'RE MOVING AROUND AND
EXPLORING THEIR ENVIRONMENT,
THEY DO NOT EXHIBIT SHARP WAVE
RIPPLES, BUT WHEN THEY STOP AND
PAUSE, THERE ARE SOMETHING
CALLED AWAKE SHARP WAVE RIPPLES.
SO IT DOES HAPPEN DURING THE
ANIMAL'S AWAKE STATE WHILE IT'S
EXPLORING, USUALLY IN A SLIGHTLY
LESS AROUSED STATE THAN WHEN
THEY'RE ACTUALLY RUNNING AND
EXPLORING.
AND IT HAS BEEN SHOWN BY LAUREN
FRANK'S LAB AT UCSF THAT IF YOU
INTERFERE WITH THOSE SHARP WAVE
RIPPLES IN THE AWAKE STATE, THAT
IT INTERFERES WITH THE ANIMAL'S
ABILITY TO FORM MEMORIES.
SO THERE'S DEFINITELY AN
INTERPLAY.
IT'S ALSO BEEN SHOWN THAT
INTERFERING WITH SHARP WAVE
RIPPLES DURING SLEEP INTERFERES
WITH MEMORY, SO THERE'S AN
INTERPLAY BETWEEN THOSE TWO
THINGS.
IT SEEMS LIKE A GOOD HYPOTHESIS
IS THAT SHARP WAVE RIPPLES SORT
OF LABEL POPULATIONS OF NEURONS
AND SYNAPSES FOR SYNAPTIC
PLASTICITY, THE PROCESS GETS
STARTED AND THEN IT GETS
REINFORCED AT NIGHT IN THOSE
SAME POPULATIONS OF CELLS.
OR DURING SLEEP.
>>THAT'S VERY INTERESTING.
YOU KNOW, ONE OF THE SURPRISING
FINDINGS THAT WE HAD EARLY ON IN
ALL THIS IMAGING WORK WERE THESE
ANTICORRELATIONS, AND THERE WAS
A BIG FUSS ABOUT WHETHER THEY
WERE ARTIFACT OR THEY WEREN'T,
BUT THEY INVOLVE NOT THE PRIMARY
SENSORY MOTOR CORTICES, BUT THEY
INVOLVE THINGS LIKE THE
ANTERIOR -- OR THE ATTENTION
NETWORKS, THERE'S TWO OF THEM,
AND THIS HI HIPPOCAMPAL CORTICAL
MEMORY SYSTEM AND THEY'RE
ALTERNATING ALL THE TIME.
AND THE QUESTION IS, AGAIN, WHY
IS THIS AN EFFICIENT WAY OF, IF
YOU WILL, KEEPING TRACK OF
WHAT'S GOING ON AS YOU NAVIGATE
THE DAY YOU'RE UNDERTAKING.
BECAUSE WE'RE PAYING A PRICE FOR
IT, OBVIOUSLY.
WE'RE NOT TOTALLY CONSISTENT IN,
AND THERE HAS TO BE SOME SORT OF
A REASONING FOR THAT BEING BUILT
INTO THE SYSTEM.
IN ALZHEIMER'S DISEASE, THIS
WHOLE PROCESS HAS RADICALLY
CHANGED.
SO THAT YOU HAVE THESE ONSET AND
OFFSET CON ASSISTANTS HAVING TO
DO WITH DEPRESSION OF THE
DEFAULT MODE NETWORK, AND YOU
HAVE -- IN ALZHEIMER'S, YOU HAVE
AN ONSET AND IT NEVER GOES DOWN.
YOU NEVER TRANSITION FROM THESE
ONE STATE TO THE OTHER.
IT'S COMPLETELY BOLIXED UP.
WHICH MIGHT BE PART OF THE
MEMORY PROCESS.
>>I THINK BEHAVIORAL
CONSISTENCY IS NOT NECESSARILY
THE GOAL EITHER, BECAUSE IF
YOU'RE TRYING TO LEARN FROM YOUR
EXPERIENCES, YOU WANT TO TRY
SOME THINGS OUT.
AND SO WE'VE SEEN INDICATIONS OF
THAT IN MOUSE BEHAVIOR ALSO,
THAT THEY'LL SETTLE INTO A
PATTERN OF DOING THE SAME THING
OVER AND OVER AGAIN, WHEN THAT
THING THAT THEY'RE DOING IS
ACTUALLY NOT THE MOST EFFICIENT
THING THEY COULD BE DOING, AND
THEN THEY SOMEHOW MANAGE TO
BREAK OUT OF THAT.
AND THEY'RE ONLY ABLE TO BREAK
OUT OF THAT BECAUSE THEY VARY
THEIR OWN BEHAVIOR AND THEY
EXPLORE A LITTLE BIT AND THEN
THEY REALIZE, THROUGH
EXPLORATION, THAT, OH, THERE'S
MAYBE A MORE EFFICIENT APPROACH
TO DOING THIS BEHAVIOR.
AND THAT'S ONE OF THE REALLY
REMARKABLE THINGS TO ME, THIS
DATES ALL THE WAY BACK TO PEOPLE
STUDYING RODENTS, YOU KNOW, BACK
IN THE 20s AND 30s AND
TOLLMAN IN THE 40s, THAT THEY
OBSERVE PERSEVERATION OF ANIMALS
IN A RELATIVELY INEFFICIENT
BEHAVIORAL MODE, AND THEN AFTER
TIME, THEY'LL BREAK OUT OF THAT.
AND THEY'LL START PERFORMING
MORE EFFICIENTLY.
AGAIN, THEY WOULDN'T BE ABLE TO
DO THAT IF THEY DIDN'T VARY
THEIR BEHAVIOR.
>>I THINK, YEAH, THESE
VARIABILITIES ARE TREATED AS
KIND OF A NUISANCE, AND YOU
KNOW, WHY WOULD YOU DESIGN
SOMETHING, LEAVES ME WITH THE
FEELING THAT THEY'RE VERY
PURPOSEFUL.
THERE IS SOMETHING THAT IS
FUNDAMENTALLY A PROPERTY OF THIS
SYSTEM THAT HAS TO CALL TIME OUT
PERIODICALLY TO GET SOMETHING
RIGHT.
AND SO THIS IS WHERE YOUR LEVEL
OF INVESTIGATION COULD FILL IN A
BIG GAP BETWEEN WHAT WE LOOK AT
IN A VERY LARGE GROSS LEVEL,
PROBABLY HAS SOME VERY DETAILED
SPECIFIC ISSUES THAT FIT RIGHT
INTO YOUR GLOVE BOX.
>>TRADITIONALLY IN BEHAVIORAL
NEUROSCIENCE, PEOPLE WILL HAVE
ANIMALS PERFORM TASKS AND
THEY'LL CLASSIFY BEHAVIOR AS
CORRECT OR INCORRECT, AND YOU
HAVE TO SOMETIMES QUESTION
WHETHER INCORRECT IS THE RIGHT
WORD TO DESCRIBE THEIR BEHAVIOR,
IF THEY'RE, IN FACT, EXPLORING.
SO I REMEMBER THE COLLEAGUE
ANDRE FENTON AT NYU DESCRIBING
AN EXPERIMENT WHERE THE RATS HAD
TO MOVE AROUND IN A CERTAIN WAY
TO AVOID GETTING SHOCKED, AND
THEN EVERY NOW AND THEN, THEY
WOULD APPROACH THE SHOCK ZONE
AND TEST IT AND SEE IF THEY
WOULD STILL GET SHOCKED BECAUSE
THEY HAD TO DO SO MUCH WORK TO
AVOID THE SHOCK ZONE THAT THEY
THOUGHT IT SEEMED -- MAYBE
SEEMED WORTH TO CHECK ONCE AND A
WHILE IF THEY STILL REALLY
NEEDED TO DO ALL THAT WORK.
SO YOU KNOW, THAT'S NOT
NECESSARILY A MISTAKE ON THE
PART OF THE ANIMAL, IT'S JUST
EXPLORATION.
>>YES.
THIS IS VERY, VERY INTERESTING.
I MUST SAY, THIS IS WHERE GOING
BACK AND LOOK AT SOME OF THIS
EARLY WORK, GOING BACK AND
READING ON INFRASLOW
FLUCTUATIONS.
THE INSIGHT IN SOME OF THIS WORK
IS REALLY REMARKABLE, AND YET IT
JUST KIND OF GOT LOST IN THE
DUST BIN OF HISTORY.
>>IT REALLY IS, IT'S
INCREDIBLE, WHAT PEOPLE HAVE
BEEN ABLE TO -- WERE ABLE TO DO
MANY DECADES AGO WITH, YOU KNOW,
VERY RUDIMENTARY TOOLS.
>>YES.
>>AND NOW, YOU KNOW, HERE WE
ARE AT THIS POINT IN TIME IN
NEUROSCIENCE WHERE THE TOOLS ARE
INCREDIBLE.
THE TOOLS THAT YOU TALKED ABOUT,
THAT ALLOW US TO, YOU KNOW,
INTERROGATE HUMANS WITHOUT DOING
ANYTHING DISRUPTIVE AT ALL TO
THE BRAIN, TO DETAILED
ANATOMICAL PHYSIOLOGICAL AND
PERTURBATIONS THAT WE CAN MAKE
IN ANIMALS LIKE MICE AND FLIES
AND FISH.
IT'S EXTRAORDINARY, WHAT WE CAN
DO NOW.
AND I WANT TO EMPHASIZE ONE
OTHER THING WHICH SORT OF
APPROACHES -- IS COMPUTATION AND
THEORY.
ANSWERING THIS QUESTION, AGAIN,
HOW DOES THE BRAIN WORK MEANS WE
HAVE TO COLLECT INFORMATION FROM
A VAST NUMBER OF STUDIES AND
BRING IT TOGETHER SOMEHOW IN A
MEANINGFUL WAY, AND I THINK THAT
HAVING COMPUTATIONAL MODELS OF
SYSTEMS AND USING THOSE MODELS
TO MAKE EXPERIMENTALLY TESTABLE
PREDICTIONS AND USING THE MODELS
ESSENTIALLY TO ASK OURSELVES,
WELL, DO WE REALLY UNDERSTAND
THIS SYSTEM AS WELL AS WE THINK
WE DO, IS A SUPER IMPORTANT
APPROACH, AND THEN THEORY, YOU
KNOW, I NOTICED IN THE CHAT,
THERE WAS SOME COMMENTS ABOUT
THE THEORY OF RELATIVITY AND I
DON'T KNOW EXACTLY HOW THAT
RELATES TO NEUROSCIENCE, BUT YOU
KNOW, THE IDEA IN PHYSICS IS
THAT IF THEORY REPRESENTS OUR
UNDERSTANDING OF THE WORLD, IF
WE HAVE A THEORY, THEN THAT'S
SORT OF OUR BEST CASE
UNDERSTANDING OR CURRENT
UNDERSTANDING OF THE WORLD WE
WANT TO UNDERSTAND OR THE SYSTEM
WE WANT TO UNDERSTAND.
AND NEUROSCIENCE, I THINK, NEEDS
MORE OF THAT.
THERE'S A LOT OF --
>>I'M GETTING AN EDUCATION
ALONG THIS LINE IN THAT MY LAST
GRADUATE STUDENT RYAN RAUT IS AT
THE ALLEN INSTITUTE IT THE
UNIVERSITY OF WASHINGTON IN A
COMBINED PROGRAM ON THEORETICAL
NEUROBIOLOGY.
LARGE SYSTEM COMPLEXITY.
AND WE HAVE LUNCH, NOW I'M THE
STUDENT AND HE IS THE TEACHER.
BUT I THINK IT'S DEEPLY
PROMISING, WHEN YOU THINK OF
THESE VERY LARGE COMPLEX
SYSTEMS, HOW YOU BEGIN TO THINK
ABOUT THEM, AND PEOPLE HAVE BEEN
THINKING ABOUT THIS KIND OF
THING AND GETTING IT FOCUSED ON
THE BRAIN, I THINK, IS A VERY
IMPORTANT AVENUE GOING FORWARD
HERE.
>>LET ME INTERJECT FOR A MINUTE
HERE.
WE HAVE A COUPLE OF QUESTIONS
THAT ARE MORE -- THAT HAVE BEEN
SUBMITTED.
FOR EXAMPLE, NELSON, BOB ASKS,
YOU SHOWED AN ARTIFICIAL NEURAL
NETWORK WITH A SIMPLE LINEAR
NODAL FUNCTION.
HAVE ARTIFICIAL NEURAL NETWORKS
WITH NON-LINEAR NODAL FUNCTIONS
BEEN SHOWN TO PRODUCE MORE
REALISTIC RESPONSES?
>>YEAH, I SAW THAT QUESTION.
SO ACTUALLY, MOST NEURAL
NETWORKS DO CONTAIN
NON-LINEARITIES.
THERE WAS THIS CONCEPT I SHOWED
CALLED THE RECTIFYING LINEAR
UNIT, AND THAT IS FUNDAMENTALLY
A NON-LINEARITY BECAUSE THERE'S
A THRESHOLD, BUT IT IS LINEAR
ABOVE THRESHOLD.
SO THERE ARE LOTS OF DIFFERENT
VARIATIONS ON THE RECTIFYING
LINEAR UNIT THAT HAVE BEEN
INCORPORATED INTO ARTIFICIAL
NEURAL NETWORKS.
IT DOES AFFECT THE WAY A.I.
SYSTEMS PERFORM.
I WOULD HESITATE TO SAY WHETHER
THAT MEANS THEY PRODUCE MORE
REALISTIC RESPONSES.
IT JUST MEANS THAT THERE ARE
COMPUTATIONAL TRICKS THAT CAN BE
USED IN A.I. SYSTEMS TO IMPROVE
THEIR PERFORMANCE.
NOW, YOU KNOW, AN EXAMPLE OF
THAT, IS THERE SOMETHING -- A
CONCEPT CALLED A REGULARIZATION.
AND REGULARIZATIONS ARE
ESSENTIALLY NOISE THAT
INTRODUCED PERIODICALLY INTO THE
SYSTEM.
AND THE REASON FOR THAT IS,
ESSENTIALLY ARTIFICIAL NEURAL
NETWORKS ARE GIGANTIC FITTING
FUNCTIONS, AND THOSE FITTING
FUNCTIONS WILL FIND LOCAL MINIMA
AND GET STUCK IN THEM, SO ONE
WAY OF IMPROVING THE FUNCTION OF
A NEURAL NETWORK IS TO PUSH IT
OUT OF LOCAL MINIMA BY
INTRODUCING NOISE ONCE IN A
WHILE.
SO THESE ARE -- THESE KINDS OF
VARIATIONS ON ARTIFICIAL NEURAL
NETWORKS HAVE BEEN EXPLORED
EXTENSIVELY BY THE FIELD, AND IN
FACT, ARE IN LARGE MEASURE
RESPONSIBLE FOR SOME OF THE
IMPROVEMENTS THAT WE SEE
HAPPENING VERY RAPIDLY IN THE
LAST FEW YEARS.
THE OTHER THING THAT HAS LED TO
THE RAPID IMPROVEMENT, IT'S JUST
MASSIVE SCALING UP OF THESE
SYSTEMS.
SO I THINK THAT WHAT BOB'S
QUESTION MAY BE GETTING AT IS,
ARE THERE SORT OF ON A LARGER,
MORE BROAD LEVEL IS, ARE THERE
THINGS THAT WE CAN LEARN FROM
STUDYING BIOLOGICAL NEURAL
NETWORKS THAT WILL GIVE US SOME
CLUES ABOUT HOW WE CAN MAKE
ARTIFICIAL NEURAL NETWORKS MORE
EFFICIENT AND EFFICIENCY, I
THINK, IS KEY, AND I THINK THE
ANSWER IS PROBABLY YES.
BUT WE DON'T KNOW YET WHAT
THAT'S GOING TO BE.
>>SOMEWHAT ALIGNED TO THAT IS
ANOTHER QUESTION THAT HAS TO DO
WITH, ON ONE HAND, WHAT DO YOU
THINK OF THE IMPACT OF THE
UPCOMING QUANTUM PARTICULARLY
NOT JUST QUANTUM BIOLOGY AND
MECHANICS BUT OTHER ASPECTS OF
QUANTUM BIOLOGY GOING BACK TO
THE CONCEPT OF PHYSICISTS THAT
SPACE IS SORT OF ALMOST A MENTAL
CONSTRUCT THAT MAKES OUR
SURROUNDING REALITIES
UNDERSTANDABLE.
SO THE QUESTION THAT BOB ASKED
IS, DO NEUROSCIENTISTS USE THESE
KIND OF IMPLICATIONS IN TRYING
TO UNDERSTAND HOW THE BRAIN
CONSTRUCTS THE WORLD AROUND US?
AND I ADDED THE QUANTUM ASPECT
TO IT, BECAUSE THAT'S SOMETHING
THAT IS RAPIDLY EVOLVING AND TO
WHAT EXTENT HAS THAT IMPACTED
NEUROSCIENCE?
>>YEAH, I MEAN, PERSONALLY I
DON'T THINK QUANTUM PHYSICS HAS
HAD MUCH OF AN IMPACT ON
NEUROSCIENCE AT ALL.
MAYBE THERE'S SOMETHING THAT I'M
NOT AWARE.
I DO THINK THE QUESTION IS
INTERESTING ABOUT WHETHER, YOU
KNOW, SPACE IS REAL OR IF IT'S A
MENTAL CONSTRUCT, VERY DIFFICULT
QUESTION TO ANSWER, I THINK, BUT
I DO DEFINITELY THINK THAT, YOU
KNOW, WE FORM -- ONE OF THE
MAJOR THINGS THAT THE BRAIN DOES
IS IT FORMS AN INTERNAL MODEL OF
THE WORLD.
THAT'S WHAT OUR EXPERIENCES AND
OUR MEMORIES DO, IS THEY PRODUCE
AN INTERNAL MODEL OF THE WORLD
THAT ALLOWS US TO MAKE
PREDICTIONS.
IF I TRY TO JUMP FROM ONE ROCK
TO ANOTHER ROCK, I'M PRETTY SURE
I CAN MAKE IT, YOU KNOW, BECAUSE
I HAVE THIS MODEL OF HOW FAR I
CAN JUMP AND HOW BIG THAT GAP IS
AND WHETHER I'M GOING TO MAKE IT
OVER THERE OR WHETHER I'M NOT
GOING TO MAKE IT AND I'M GOING
TO FALL TO MY DEATH.
I MEAN, WE HAVE TO MAKE THOSE
KINDS OF PREDICTIONS ALL THE
TIME, AND WE WOULDN'T BE ABLE TO
DO THAT IF WE DIDN'T HAVE A
MENTAL MODEL OF THE WORLD THAT
WAS BUILT UP FROM OUR OWN
EXPERIENCES.
AND THAT MENTAL MODEL OF THE
WORLD STRONGLY INFLUENCES HOW WE
PERCEIVE EVERYTHING AROUND US.
WE'RE NOT SIMPLE MACHINES THAT
ARE JUST, LIKE, MEASURING THE
WAVELENGTH OF LIGHT THAT'S
COMING FROM THE PLANTS OUTSIDE
MY WINDOW.
YOU KNOW, WE'RE INTERPRETING
THOSE COLORS IN THE CONTEXT OF
THE SHAPE AND THE SHADING AND
THE OTHER THINGS AROUND THEM TO
KNOW THAT IT'S A PLANT AND NOT
JUST A GREEN THING.
SO WHAT'S REALITY, WHAT'S NOT
REALITY, THAT'S A HARD QUESTION
TO ANSWER, BUT THERE'S NO DOUBT
THAT EVERYTHING WE PERCEIVE IS
INFLUENCED BY OUR PAST
EXPERIENCES AND OUR INTERNAL
MODELS OF THE WORLD.
>>MARCUS, DO YOU WANT TO
COMMENT ABOUT THAT?
>>ALL I CAN THINK ABOUT WAS A
ONE-PAGER I WROTE FOR SCIENCE
SEVERAL YEARS AGO CALLED THE
BRAIN'S DARK ENERGY.
IN OTHER WORDS -- AND THE
RESPONSE TO THAT -- I GOT AN
EMAIL AND I'M -- I THINK I
STEPPED ON A PHYSICIST'S FOOT OR
SOMETHING OR TOE AND I GOT THIS
EMAIL THAT SAID -- HE SAID, DARK
MATTER, JEEEEEZ, LIKE, STAY OUT
OF THERE.
BUT WHEN YOU THINK ABOUT IT, YOU
KNOW, THE BRAIN IS DEVOTING AN
ENORMOUS AMOUNT OF RELATIVE
ENERGY TO ITS ONGOING STATE THAT
DIRECTLY HAS NOTHING TO DO WITH
MY MOVEMENT OF MY HAND OR MY
SPEAKING TO YOU, BUT PROVIDES
THE CONTEXT IN WHICH THAT IS
OCCURRING.
WHICH IN ORDER TO ACHIEVE WHAT
NELSON JUST TALKED ABOUT IS A
VERY EXPENSIVE BUSINESS OF
HAVING SOMETHING THAT HAS THIS
MODEL OF THE WORLD THAT IS
FLEXIBLE, ADAPTABLE AND
APPLIABLE, AND IT DOES SO AT
GREAT EXPENSE TO MAINTAIN IT
PROPERLY AND ADJUST IT ON THE
RUN.
ONLINE.
SOMETHING LIKE THAT.
AND THAT ACCOUNTS FOR WHAT I
WOULD CALL THE BRAIN'S DARK
ENERGY.
SO THAT'S A LITTLE PHYSICS.
>>ARE MEMORIES -- DO EITHER OF
YOU HAVE -- WE HAVE A QUESTION
HERE, WHY MEMORIES DURING
CHILDHOOD O -- ARE LONGER LASTIG
THAN MEMORIES IN ADULTHOOD?
DO WE HAVE ANY IDEAS ABOUT THAT,
MARCUS?
THAT MAY BE -- ARE THERE ANY
STUDIES, MAYBE WE CAN PUT THIS
IN A BROADER CONTEXT.
COULD YOU BRIEFLY SUMMARIZE THE
STATUS OF IMAGING APPROACHES TO
UNDERSTANDING OR PREDICTING
NEURODEGENERATIVE DISEASES,
INTELLIGENCE, ALL SORT OF
BEHAVIORAL TYPE OF THINGS, DO
PEOPLE WHO CAN MEMORIZE A POEM
BUT CAN'T MEMORIZE THE MUSIC OF
A CONCERT OR REVERSE, ARE THOSE
DIFFERENCES THAT YOU CAN DETECT
BY IMAGING?
>>I DON'T THINK I CAN ANSWER
THAT QUESTION DIRECTLY, BUT AS
OUR BRAIN AGES -- WELL, FIRST
OFF, IF YOU LOOK AT THE BRAIN
METABOLICALLY, IT'S NOT UNIFORM
TO BEGIN WITH.
AND ONE OF THE THINGS THAT HAS
GREATLY INTERESTED US OVER THE
YEARS WHEN WE CAME ACROSS THIS
IDEA THAT GLYCOLYSIS WHICH ONLY
PRODUCES A SMALL AATP, SO TO
SPEAK, BUT IT DOES IT IN A
VARIETY OF IMPORTANT WAYS, IS
NOT UNIFORM THROUGHOUT THE
BRAIN.
AND IN FACT, IT IS QUITE
SPECIFICALLY DEVOTED TO AREAS
THAT GENETICALLY ARE FOCUSED ON
NEONATUS GENES, IN OTHER WORDS
THINGS INVOLVED IN SYNAPTIC
PLASTICITY.
NOW GIVEN THAT RELATIONSHIP,
THIS HAS ALL BEEN PUBLISHED IF
SOMEBODY IS INTERESTED, BUT
WHAT'S VERY INTERESTING IS, AS
WE AGE, THIS DIFFERENCE IN
METABOLISM AND PARTICULARLY
AEROBIC GLYCOLYSIS DECREASES
WITH AGE.
NOW, LINKING THAT DIRECTLY TO
CHANGES IN SOMETHING LIKE MEMORY
HAS NOT BEEN DONE, BUT IF IT'S A
KEY TO THE GENETIC COMPOSITION
OF TISSUES THAT OBVIOUSLY HAVE
A DEGREE OF PLASTICITY THAT'S
DIFFERENT THAN OTHER AREAS, THIS
COULD EASILY HAVE AN EFFECT.
AND THE OTHER INTERESTING THING
IS THAT IT IS GENDER -- THERE IS
A GENDER DIFFERENCE AS TO
SECOND -- WE PUBLISHED A YEAR OR
TWO AGO, THAT WOMEN TEND TO
MAINTAIN THE AEROBIC GLYCOLYSIS
LONGER THAN MEN.
SO THE THREE OF US ARE DOOMED TO
BECOME MORE FORGETFUL THAN SOME
OF OUR FEMALE COMPANIONS.
MAYBE.
I DON'T KNOW.
BUT THE METABOLISM OF THIS AND
THE GENETICS BEHIND THE
METABOLISM DOES HAVE A LINK TO
THE MEMORY PROCESSES THEMSELVES,
AND OVER TIME, AND MAYBE
INDIVIDUALLY, THERE ARE
DIFFERENCES AS WELL.
BUT IT'S AN AVENUE THAT
CERTAINLY IS WORTH PURSUING.
>>WE HAVE A QUESTION ABOUT TWO
OTHER HUGE TOPICS.
ONE IS, WHAT DO YOU -- DO YOU
SEE A SIGNIFICANT IMPACT ON
ARTIFICIAL INTELLIGENCE ON THE
SYSTEMS THAT YOU BOTH WORK WITH,
AND THE OTHER IS, THERE SEEMS TO
BE INCREASING STUDIES LINKING
COMPUTER DRIVEN NEURAL FUNCTI
FUNCTIONS.
DO YOU WANT TO COMMENT ABOUT
EITHER OR BOTH OF THOSE FIELDS
WHICH ARE PRETTY NEBULOUS, I
AGREE, BUT YOU KNOW, IF WE'RE
SPECULATING A BIT, FEEL FREE.
>>MY LAB AND ME, WE ARE
ACTIVELY -- WE'RE VERY
INTERESTED IN ACTIVELY WORKING
ON UNDERSTANDING, YOU KNOW, THE
DIFFERENCES BETWEEN BIOLOGICAL
NETWORKS AND ARTIFICIAL
NETWORKS, AND I THINK THERE'S A
POTENTIAL THAT WHAT WE DISCOVER
AS BIOLOGISTS WILL HAVE
IMPLICATIONS FOR ARTIFICIAL
INTELLIGENCE.
IT'S ALSO TRUE THAT, YOU KNOW,
ARTIFICIAL INTELLIGENCE OR
MACHINE LEARNING HAS REALLY BEEN
ENABLING IN TERMS OF TRYING TO
UNDERSTAND LARGE DATASETS.
SO THERE'S A HUGE EMPHASIS IN
BIOLOGY THESE DAYS ON USING
MACHINE LEARNING TOOLS TO
CLASSIFY BEHAVIORS, FOR EXAMPLE,
TO RECOGNIZE PATTERNS IN THINGS
LIKE NEURAL ACTIVITY.
SO I THINK AS A TOOL, IT'S VERY
POWERFUL FOR BIOLOGISTS, AND
THEN AS A SYSTEM, A COMPLEX
SYSTEM THAT HAS AT LEAST SOME
PROPERTIES IN COMMON WITH
BIOLOGICAL NEURAL NETWORKS, THAT
COMPARISON THERE IS LIKELY, I
THINK, TO BE A VERY, VERY
IMPORTANT ONE.
AND FOR THAT REASON, I THINK WE
SEE BIOLOGY DEPARTMENTS AROUND
THE WORLD NOW INVESTING QUITE A
LOT IN HIRING PEOPLE THAT HAVE
THIS KIND OF EXPERTISE.
AND IT'S AN EXCITE TIME IN THAT
REGARD, AND WHO KNOWS WHAT'S
AROUND THE NEXT CORNER BECAUSE
THAT FIELD IS MOVING SO FAST,
IT'S ALMOST SCARY.
>>I GUESS I WOULD SECOND YOUR
ENTHUSIASM FOR SURE.
BECAUSE THE DATA THAT WE'RE
DEALING WITH, AND I TALKED ABOUT
IT IN A FAIRLY SIMPLISTIC WAY,
BUT WHETHER YOU GET INTO THESE
SYSTEMS AND YOU HAVE NEURAL
MODULATORS AND YOU HAVE ALL
THESE DIFFERENT CELL TYPES AND
ALL THESE DIFFERENCES IN
METABOLISM AND SO FORTH, AND HOW
YOU BEGIN TO SYNTHESIZE THAT
FROM THE DATASETS, IS A
CHALLENGE TO BEGIN WITH.
AND THE OTHER THING IS THAT IT'S
BECOME VERY APPARENT THAT FOR US
TO USE OUR DATA, PARTICULARLY AT
AN INDIVIDUAL LEVEL, WE NEED A
LOT OF IT.
SO YOU GET THESE MASSIVE
DATASETS WITH ALL THIS MATERIAL
IN IT, AND HAVING MORE
SOPHISTICATED CONCEPTS FROM A
SYSTEMS LEVEL, AND ALSO THE
TOOLS THAT -- COMPUTATIONAL
TOOLS THAT WOULD ALLOW US TO
LOOK FOR INCREDIBLY SUBTLE
DIFFERENCES.
I MEAN, FOR EXAMPLE, THERE WAS A
STUDY I WAS BRIEFLY INVOLVES IN
IN THE MCARTHUR NETWORK ON
NEUROSCIENCE IN THE COURTROOM.
AND THE REASON I ENDED UP ON
THIS PANEL WAS THE FACT THAT
IMAGING IS ENDING UP IN COURT
CASES.
PEOPLE WILL SHOW IMAGES AND THEY
SAY, WELL, HE DID IT BECAUSE OF
WHATEVER, BECAUSE HIS BRAIN
WASN'T WORKING RIGHT.
AND WE HAD THE OPPORTUNITY
THERE, THIS GROUP, TO LOOK AT
DATA OBTAINED IN THE NEW MEXICO
PRISON SYSTEM ON INCARCERATED
JUVENILES, AND SO THE COMMITTEE
AS WE DISCUSSED IT AND I SAID
WELL FOR PETE'S SAKE, YOU'VE GOT
TO GET RESTING STATE DATA.
LET'S JUST LOOK AT THE BRAIN AS
IT'S SITTING THERE.
SO THIS WAS DONE, AND ALSO THERE
WERE DETAILED BEHAVIORAL
STUDIES.
AND THE BIGGEST QUESTION ON THE
TABLE WAS IMPULSIVITY.
SO WE HAD JUST DEVELOPED AN
ALGORITHM FOR ANALYZING CERTAIN
ASPECTS OF DATA, AND I WON'T
BURDEN YOU WITH THE DETAILS OF
IT, BUT WE POSED A QUESTION OF
THIS RATHER LARGE -- IT WAS 107
JUVENILES HERE THAT HAD
DIFFERENT LEVELS OF IMPULSIVITY
BASED ON STANDARD WAYS OF
MEASURING THAT, AND WHAT WAS SO
STUNNING ABOUT IT WAS THE
RESULTS THAT CAME OUT OF IT AND
HOW SPECIFIC THEY WERE AND HOW
SPECIFIC THEY COULD BE
PREDICTIVE.
SO YOU TAKE 107 PEOPLE AND YOU
TAKE ONE PERSON OUT AND YOU
RECOMPUTE THE MODEL AND THEN YOU
CAN PREDICT WITH INCREDIBLE
ACCURACY.
SO WHAT DID WE FIND?
IT WAS A SUBTLE DIFFERENCE
BETWEEN TWO NETWORKS IN THE
BRAIN, PARTICULARLY THE
OPPONENTS OF THESE CORRELATIONS
BUT IT WAS A VERY SUBTLE CHANGE
IN THE BALANCE BETWEEN NETWORKS.
AND WHILE YOU COULD ARGUE, WELL,
IS THAT -- HOW GOOD A STUDY WAS
THAT, 107, SOME PEOPLE THINK YOU
HAVE TO HAVE A THOUSAND PEOPLE
AND WHATEVER.
BUT IT SUGGESTED TO ME THAT AS
WE LOOK FOR THESE CRITICAL
DIFFERENCES IN HUMAN BEHAVIOR,
THEY'RE GOING TO AMOUNT TO, IN
SOME INSTANCES, VERY SUBTLE
DIFFERENCES BETWEEN THE
PROPERTIES OF DIFFERENT AREAS OF
THE BRAIN AS THEY INTERACT AS A
COMMUNITY.
AND I THINK HAVING COMPUTATIONAL
TOOLS THAT CAN GO IN AND EXPLORE
THIS, IT JUST STRIKES ME AS
ALMOST -- AS A BYSTANDER -- NO
ARTIFICIAL INTELLIGENCE GUIDE,
BUT WE'RE GOING TO NEED THOSE
KIND OF TOOLS TO BEGIN TO SORT
IT OUT, AND AS I LOOK AT THE
BEAUTIFUL PICTURES, NELSON, THAT
YOU HAD, THE COMPLEXITY OF THE
ISSUES THAT ARE INVOLVED HERE
ARE ALMOST OVERWHELMING, AS YOU
LOOK AT THESE POPULATIONS OF
CELLS AND HOW DO YOU PULL OUT
THAT TREND IN THERE SOME WAY.
BUT THE OTHER THING THAT
PROBABLY OUGHT TO COME TO THE
FOREFRONT HERE IS, HOW WE
STIMULATE THE BRAIN NOW, THE USE
OF THINGS LIKE TRANSCRANIAL
MAGNETIC STIMULATION, HOW ARE WE
AFFECTING THESE SUBTLE
DIFFERENCES IN THE WAY THE WHOLE
SYSTEM IS BALANCED, AND I THINK
WE'RE HEADED IN A DIRECTION THAT
IS REALLY EXCITING AS WE THINK
ABOUT IT, BUT UNDERSTANDING WHAT
WE'RE ACTUALLY DOING IS GOING TO
BE ABSOLUTELY CRITICAL TO THIS.
ANYWAY, ENOUGH RAMBLING.
>>I REGRET THAT WE HAVE HIT OUR
TIME LIMIT WITH THE HOURS AT THE
NIH.
SO LISTEN, PERMIT ME ON BEHALF,
I'M SURE OF THE HUNDREDS IF NOT
THOUSANDS OF PEOPLE WHO ENJOYED
THIS PRESENTATION AND YOUR
DISCUSSION OF THE STATE OF THE
ART AND THE INCREDIBLE
EXCITEMENT THAT THE FUTURE PO
PORTENDS, AND THE GREAT
OPPORTUNITIES FOR YOUNG PEOPLE
WHO ARE INTERESTED IN THIS HUGE
PROBLEM OF HOW THE BRAIN WORKS.
ON BEHALF OF EVERYONE, WE WANT
TO THANK YOU FOR TAKING YOUR
TIME AND PARTICIPATING.
IF THERE ARE ANY ADDITIONAL LATE
QUESTIONS, WE'LL SEND THEM OFF
TO YOU AND IF POSSIBLE, YOU MAY
CHOOSE TO ANSWER.
BUT THANK YOU, THANK YOU VERY
MUCH, AND WE ALL LOOK FORWARD
THAT WE MAY HAVE ANOTHER SESSION
IN 10 YEARS TO CATCH UP.
THANK YOU.
>>YOU'RE WELCOME.