IT'S MY DISTINCT PLEASURE TO
WELCOME YOU TO THE 14TH ANNUAL
PHILIP CHEN DISTINGUISHED
LECTURE ON INNOVATION AND
TECHNOLOGY TRANSFER.
ACTUALLY IT'S THE 15TH.
I'M CORRECTED THERE.
I'M AS MANY OF YOU PROBABLY KNOW
MICHAEL GOTTESMAN, THE DEPUTY
DIRECTOR FOR INTRAMURAL RESEARCH
AT THE NIH.
BEFORE I INTRODUCE TODAY'S
SPEAKER, I WANT TO TELL YOU A
LITTLE ABOUT PHIL CHEN, WHOSE
SERVICE TO THE NIH WE HONOR IN
THIS LECTURE SERIES.
PHIL RETIRED 17 YEARS AGO, AFTER
MORE THAN 40 YEARS AT THE NIH.
BUT ENOUGH TIME HAS PASSED THAT
I SUSPECT SOME OF YOU IN THE
AUDIENCE MAY NOT ACTUALLY KNOW
HIM.
AT THE TIME OF HIS RETIREMENT,
PHIL WAS THE ASSOCIATE DIRECTOR
FOR INTRAMURAL RESEARCH, AND HE
WORKED IN MY OFFICE.
THIS WAS CERTAINLY MY GREAT,
GOOD FORTUNE.
PHIL MADE DIVERSE AND CREATIVE
CONTRIBUTIONS TO THE NIH, BOTH
AS A SCIENTIST AND AS AN
ADMINISTRATOR OF MANY IMPORTANT
INNOVATIVE PROGRAMS.
AS A SCIENTIST, PHIL IS THE
AUTHOR OF ONE OF THE MOST HIGHLY
CITED PAPERS IN BIOMEDICAL
LITERATURE, WHICH ESTABLISHES
THE CHEN ANALYSIS FOR PHOSPHATE.
WE USE THIS ALL THE TIME IN MY
OWN LABORATORY, THE CHEN
PHOSPHATE TECHNIQUE, AND I
SUSPECT MANY OF YOU DO AS WELL.
AND PHIL CHEN IS THAT CHEN.
BY THE MIDDLE OF HIS CAREER,
PHIL BEGAN TO TAKE ON MORE AND
MORE ADMINISTRATIVE ROLES,
MOSTLY IN THE OFFICE OF THE
DIRECTOR, AND THEN THE OFFICE OF
INTRAMURAL RESEARCH IN THE
1980s, BEFORE I WAS DEPUTY
DIRECTOR FOR INTRAMURAL
RESEARCH.
PHIL WAS WELL-KNOWN FOR MAKING
THINGS WORK BETTER.
HE WAS BOTH SENSITIVE TO
PEOPLE'S ISSUES AND VERY
PRACTICAL IN HIS SOLUTIONS.
THIS ASPECT OF PHIL WAS
PARTICULARLY INSPIRING FOR ME,
AND I THINK HELPED PAVE THE WAY
FOR WHAT I HOPE HAS BEEN MY
TENURE.
INTRAMURAL SCIENTISTS WOULD COME
TO HIS OFFICE CONCERNED THAT ONE
OR ANOTHER SYSTEM OR PROGRAM
WASN'T SERVING THEM VERY WELL,
AND PHIL WOULD FIX IT.
HE WAS A VERY ACTIVE PARTICIPANT
IN MAKING SURE THAT THE
INTRAMURAL RESEARCH PROGRAM
WHIRLED LIKE A WELL OILED
MACHINE.
FOR EXAMPLE, PHIL CHAMPIONED NEW
PAY AND PERSONNEL SYSTEMS FOR
RESEARCHERS AND HE IMPROVED
PROGRAMS FOR TRAINING SCIENTIST,
PARTICULARLY FOREIGN SCIENTISTS
AT THE NIH.
HE WAS ALSO INVOLVED IN NOVEL
ENDEAVORS SUCH AS HIS LEADING
ROLE IN AN INTERAGENCY PROGRAM
ON ARCTIC RESEARCH.
MOST RELEVANT TO THIS LECTURE
SERIES, PHIL ESTABLISHED IN 1986
THE OFFICE OF TECHNOLOGY
TRANSFER AT THE NIH IN RESPONSE
TO THE NEW FEDERAL TECHNOLOGY
TRANSFER ACT.
HE FORMULATED ALL THE GUIDING
PRINCIPLES THAT LEAD TO
TECHNOLOGY TRANSFER HERE AT NIH,
AND HE ESSENTIALLY INVENTED THE
COOPERATIVE RESEARCH AND
DEVELOPMENT AGREEMENT, OR AS WE
CALL IT, THE CRADA.
THESE ARE PROFOUND
CONTRIBUTIONS, AND WE ARE VERY,
VERY GRATEFUL FOR PHIL'S MAKING
THEM POSSIBLE.
PHIL'S COUNSEL TO ME AND NO
DOUBT ANYONE WHO CAME TO SEE HIM
WAS ALWAYS WISE AND
COMPASSIONATE.
PHIL HAS ATTENDED EACH OF THESE
LECTURES IN HIS NAME, AND HE IS
WITH US TODAY.
HOWEVER, INGER LISE CHEN, HIS
WIFE OF MANY YEARS, PASSED AWAY
LAST SEPTEMBER.
WE MISS HER GREATLY, AND HER
CONSTANT PRESENCE AT PHIL'S
SIDE, AND AT ALL 14 PREVIOUS
CHEN LECTURES.
WE REALLY DO MISS HER, PHIL, AND
WE ARE SAD AT HER DEPARTURE.
PHIL, IF YOU'RE FEELING BRAVE,
PERHAPS TURN ON YOUR CAMERA AND
SAY HI.
I SEE YOU.
YOU WANT TO SAY HELLO?
>> HELLO, EVERYBODY.
I'M GLAD YOU'RE ABLE TO ATTEND
THIS LECTURE TODAY, AND I'M
PROUD TO BE ABLE TO ATTEND
MYSELF.
ALTHOUGH I'M IN TENNESSEE, ABOUT
600 MILES AWAY.
THANK YOU ALL FOR BEING HERE,
AND HOPE TO SEE YOU IN PERSON
SOMETIME.
>> TECHNOLOGY IS WONDERFUL.
PHIL ALSO INVENTED THE INTERNET,
IN CASE YOU'RE INTERESTED.
[LAUGHTER]
IT'S SUCH A PITY THAT WE
COULDN'T HAVE AN IN-PERSON
LECTURE.
OUR LAST CHEN LECTURE WAS IN
2019.
WE POSTPONED THE LECTURE IN
NOVEMBER '20 AND THEN AGAIN IN
'21, BUT WE FELT WE COULDN'T
WAIT ANY LONGER, SO THE REMOTE
LECTURE.
NOW IT'S MY PLEASURE TO
INTRODUCE TODAY'S PHIL CHEN
LECTURER, DR. PETER BASSER, AN
NIH SENIOR INVESTIGATOR AND HEAD
OF THE SECTION ON QUANTITATIVE
IMAGING AND TISSUE SCIENCES AT
THE EUNICE SHRIVER KENNEDY CHILD
HEALTH AND DEVELOPMENT.
PETER STUDIES THE RELATIONSHIP
BETWEEN FUNCTION AND STRUCTURE
IN LIVING TISSUES.
PARTICULARLY HOW THEIR MICRO
STRUCK TEU HIERARCHICAL
ORGANIZATION, COMPOSITION AND
MATERIAL PROPERTIES AFFECT THEIR
FUNCTION OR DYSFUNCTION.
TO DO THIS, HE AND HIS LAB HAVE
DEVELOPED SEVERAL NONINVASIVE
IMAGING METHODS THAT ALLOW THEM
TO OBSERVE AND STUDY VARIOUS
TRANSPORT PHENOMENA IN TISSUES,
WHICH PROVIDE A LINK BETWEEN
STRUCTURE AND FUNCTION.
THE MOST WIDELY USED OF WHICH
PETER IS THE PRINCIPAL INVENTOR
IS DIFFUSION TENSOR MAGNETIC
RESONANCE IMAGING, OR D.T.I.,
AND ANYBODY WHO'S HAD AN IMAGE
REALIZES THAT THIS IS REALLY AN
IMPORTANT CONTRIBUTION, BOTH TO
BASIC RESEARCH AND TO CLINICAL
SCIENCE.
PETER EARNED HIS
UNDERGRADUATE DEGREE IN
ENGINEERING SCIENCES, OR AS WE
USED TO CALL IT, ENGSCI FROM
HARVARD COLLEGE AND HIS PH.D. IN
ENGINEERING MECHANICS FROM
HARVARD UNIVERSITY IN 1986.
IT WAS AT HARVARD THAT HE CAME
TO REALIZE THAT ENGINEERING AND
PHYSICS PRINCIPLES COULD BE
APPLIED TO UNDERSTANDING THE
WORKINGS OF BIOLOGICAL SYSTEMS,
PARTICULARLY IN ELUCIDATING
STRUCTURE FUNCTION
RELATIONSHIPS.
THIS REALIZATION BECAME HIS
PRIMARY RESEARCH FOCUS, AND HIS
MAIN MOTIVATION FOR ACCEPTING A
POSTDOCTORAL FELLOWSHIP IN
BIOMEDICAL ENGINEERING AT THE
NIH.
PETER CAME TO THE NIH AS A
FELLOW IN '86.
HE HELD VARIOUS POSITIONS AT THE
NCRR.
IN 1997, HE BECAME A TENURED
INVESTIGATOR AT NICHD, AND HAS
STAYED THERE EVER SINCE.
PETER PICKED UP NUMEROUS HONORS
ALONG THE WAY.
THESE INCLUDE THE VICTOR
HAUGHTON AWARD FROM THE AMERICAN
SOCIETY OF FUNCTIONAL
NEURORADIOLOGY AND THE
CONSORTIUM AWARD FOR EXCELLENCE
IN TECHNOLOGY TRANSFER.
HE HAS THE UNIQUE DISTINCTION OF
BEING THE ONLY CURRENT NIH P.I.
ELECTED TO THE NATIONAL ACADEMY
OF ENGINEERING.
IN FACT, WE HAD TO MAKE A
SPECIAL PAGE FOR HIM FOR THE
NATIONAL ACADEMY OF ENGINEERING
SINCE THE ONLY IRP WEBSITE WE
HAD INCLUDED ONLY NIS AND NIM
MEMBERS.
HOPEFULLY WITH OUR NEW EMPHASIS
ON CREATION OF A BIOENGINEERING
CENTER AT THE NIH, HE WILL BE
THE FIRST OF MANY ON THIS LIST.
PETER'S TALK TODAY IS TITLED
USING WATER MIGRATION TO PROBE
BRAIN STRUCTURE AND
ARCHITECTURE.
PETER, THANK YOU SO MUCH FOR
JOINING US TODAY.
THE MIC IS YOURS.
>> THANK YOU, MICHAEL, SO MUCH.
AND THANK YOU TOO FOR INVITING
ME TO GIVE THIS PHILIP CHEN
DISTINGUISHED LECTURE ON
INNOVATION AND TECHNOLOGY
TRANSFER.
SO MICHAEL STOLE SOME OF MY
THUNDER, BUT I DID WANT TO SHARE
ONE BRIEF ANECDOTE ABOUT PHIL
AND HOW IMPORTANT HIS WORK WAS
IN CHANGING THE INTELLECTUAL
PROPERTY LANDSCAPE.
WHEN I ACTUALLY ARRIVED AT NIH,
IT WAS IN 1987, IN THE SPRING,
AND BEING A SERIAL INVENTOR, I
SOON HAD TO HAVE MEETINGS WITH
THE NIH PATENT COUNSEL, AND IT
WAS A LOVELY ELDERLY GENTLEMAN
WHO USED TO BE PART OF THE
WASHINGTON PATENT BAR WHO
RETIRED AND CAME TO THE NIH.
I'M SORRY I DON'T REMEMBER HIS
NAME.
BUT HE HAD AN ASSISTANT, AND ONE
PERSON COVERED ALL OF THE
INTRAMURAL PROGRAM'S I.P., IF
YOU CAN BELIEVE THAT.
AND WITHIN ABOUT A YEAR, THE
WHOLE LANDSCAPE CHANGED.
THERE WAS AN OFFICE OF
TECHNOLOGY TRANSFER, AND
CRADAs BEGAN TO COME INTO
EXISTENCE.
THIS WAS ALL DUE TO PHIL'S
EFFORTS, AND IT REALLY CHANGED
THE OPPORTUNITIES FOR INVENTOR
SCIENTISTS AND SCIENTIST
INVENTORS ON THE NIH GROUNDS.
SO I'M VERY GRATEFUL TO HIM.
SO IN TALKING ABOUT ELUCIDATING
BRAIN MICROSTRUCTURE
ARCHITECTURE ORGANIZATION, I
THINK OF THE WORK BY JEFF
LICHTMAN'S GROUP AT HARVARD.
THIS IS A SECTION OF HUMAN BRAIN
CORTICAL TISSUE, THESE
PIE-SHAPED PIECES WERE REMOVED
FROM THE BRAIN OF A SUBJECT
UNDERGOING A NEUROSURGERY
PROCEDURE
SO IN TERMS OF ELUCIDATING BRAIN
MICROSTRUCTURE AND ARCHITECTURE,
THIS IMAGE FROM JEFF LICHTMAN'S
GROUP SHOWS QUITE CLEARLY WHAT
WE HAVE IN MIND IN TERMS OF
COMPLETE PARCELLATION AND
ANALYSIS OF TISSUES OF INTEREST.
THIS SHOWS SMOOTH NEURONS,
ASTROCYTES, MICROGLIA, AXONS
THAT GO FROM THE SUBCORTICAL
WHITE MATTER ON THE LOWER LEFT
TO THE PERIPHERY TO THE CORTEX
ON THE RIGHT.
AND REALLY THIS IS A MAGNIFICENT
SORT OF STRUCTURAL
DECONSTRUCTION OF WHAT'S IN THE
BRAIN.
THE PROBLEM IS, THIS IS DONE
OVER MANY MONTHS WITH VERY HIGH
RESOLUTION NANOMETER SLICES OF
BRAIN TISSUE, AND A WHOLE FARM
OF -- TO DO THIS KIND OF
ANALYSIS, AND REALLY TO BE ABLE
TO DO THIS INA VERY V IN VIVO AND
NON-INVASIVELY, SO IT'S A BIG
TASK.
I WILL TELL YOU THAT WE WILL
CERTAINLY MAKE AN EFFORT AND
YOU'LL SEE -- THERE'S SOME GOOD
RESULTS ABOUT IT.
SO HOW DO WE DO NONINVASIVE IN
VIVO MICROSTRUCTURE ELUCIDATION?
WE USE WATER MIGRATION AND WATER
DIFFUSION AS A MEANS TO PROBE
TISSUE MICROSTRUCTURE USING
MAGNETIC RESONANCE IMAGING.
FOR THOSE OF YOU WHO DON'T KNOW,
DIFFUSION IS A TRANSPORT
MECHANISM THAT INVOLVES MIXING
COMPONENTS OF MOLECULES, ATOMS,
PARTICLES, PRIMARILY THROUGH
THERMAL AGITATION OR THERMAL
COLLISIONS AMONG THEM.
AND THE BEAUTY IS THAT IT'S
SENSITIVE TO LOCAL
MICROSTRUCTURE BECAUSE IT CAN BE
USED IN A WAY TO PALPATE THE
LOCAL STRUCTURES' MEMBRANES,
MOLECULES, SO YOU CAN SEE
SOMEWHAT BY WATCHING
PARTICULARLY WATER DIFFUSION,
YOU CAN SEE FEATURES OF THE
LOCAL MICROSTRUCTURE IN WHICH
THOSE WATER MOLECULES ARE -- SO
THIS IS AN EXAMPLE OF FICKIAN
DIFFUSION WHERE YOU HAVE
PARTICLES CONFINED IN A CERTAIN
POINT IN A SPACE, LET'S SAY IN A
LIQUID BATH, AND THEN YOU LET
THEM -- EXCUSE ME.
THERE WE GO.
YOU LET THEM DIFFUSE, YOU LET
THEM -- YOU RELEASE THEM AND
THEY START TO COLLIDE WITH ONE
ANOTHER, AND THEY START TO
SPREAD OUT.
AND EVENTUALLY, IF YOU WAIT
ENOUGH TIME, THE CONCENTRATION
WILL BE UNIFORM.
THIS IS DESCRIBED BY FICK'S LAW,
WHICH IS RELATIONSHIP BETWEEN
THE FLUX OF THE PARTICLES AND
THE CONCENTRATION DIFFERENCE OR
GRADIENT, AND THE COEFFICIENT
THAT RELATES TO THEM IS CALLED A
DIFFUSIVITY OR DIFFUSION
CONSTANT.
IN 1827, ROBERT BROWN OBSERVED
UNDER A MICRO SCOPE THAT HIS --
THAT PARTICLES THAT WERE VISIBLE
WERE MOVING IN A RA A RANDOM WAY.
I REFER TO THIS AS DANCING.
HE THOUGHT MAYBE IT WAS A LIFE
FORCE INITIALLY, BUT EVENTUALLY
HE DISABUSED HIMSELF OF THAT
NOTION WHEN HE USED COAL DUST
AND OTHER KINDS OF INERT
MATERIALS, AND RECOGNIZED THAT
IT WAS A PROPERTY OF MANY
PARTICLE SYSTEMS.
BUT DIDN'T HAVE AN EXPLANATION
FOR WHAT WAS GOING ON.
AND IT WAS REALLY EINSTEIN IN
1905 WHO SYNTHESIZED THE FICKIAN
AND THE BROWNIAN VIEW OF DI
VEUTION, AND WAS ABLE TO
DESCRIBE THEM USING A NET
DISPLACEMENT DISTRIBUTION, A
PROBABILITY DISTRIBUTION THAT
DESCRIBED THE PROBABILITY OF
FINDING A PARTICLE AT ONE POINT,
AT ONE TIME, GIVEN THAT IT WAS
RELEASED AT ANOTHER POINT, AT
ANOTHER TIME.
SO IT WAS A DISPLACEMENT
DISTRIBUTION.
THIS WAS PART OF HIS -- THE
MIRACLE YEAR, THE ONUS
MIRABOLIS, CITED IN HIS NOBEL
PRIZE AS ONE OF HIS GREAT
CONTRIBUTIONS TO SCIENCE.
IF YOU GO AHEAD ABOUT 50 YEARS
TO THE WORK OF ED PURCELL AND
HERMAN CARR, THEY USED NMR
METHODS TO ACTUALLY MEASURE
EINSTEIN'S DISPLACEMENT
DISTRIBUTION, AND ACTUALLY FOR
THAT, PURCELL WON A NOBEL PRIZE.
AND THIS MEASUREMENT WAS
DESCRIBED AS A GOLD STANDARD,
AND AN INTERESTING POINT THAT
CARR AND PURCELL MADE IN THEIR
CLASSIC PAPER WAS THAT A MORE
INNOCUOUS LABEL WOULD BE
DIFFICULT TO IMAGINE.
THE NMR EXPERIMENT DOESN'T
REQUIRE INTRODUCING A DYE OR A
CONTRAST AGENT OR ALTER THE
WATER MOLECULES AT ALL.
IT JUST PERTURBS THE
MAGNETIZATION, WHICH IS REALLY
AN INNOCUOUS LABEL IF YOU COULD
THINK OF ANOTHER ONE, I WOULD
LIKE TO HEAR IT.
SO HOW DOES THIS MEASUREMENT
WORK?
I'M NOT GOING TO GO INTO
EXPLAINING THE DETAILS OF THE
PULSE SEQUENCES AT THE TOP OF
THE PAGE, BUT I WILL TELL YOU
THAT THE GENIUS OF THE CARR AND
PURCELL EXPERIMENT IS THAT IT
ESSENTIALLY EMBODIES THE
DISPLACEMENT DISTRIBUTION
MEASUREMENT THAT EINSTEIN WAS
REFERRING TO.
SO IN THAT FIRST PULSE, THE
SPINS GET A PHASE AND IN THE
SECOND PULSE, THEY GET A PHASE
REVERSAL.
AND IF THEY'VE MOVED DURING THAT
PERIOD OF TIME, THEY'LL ACQUIRE
A NET PHASE, AND THAT NET PHASE
IS PROPORTIONAL TO THE NET
DISPLACEMENT.
SO IN OTHER WORDS, THIS
MEASUREMENT ALLOWS YOU TO
MEASURE IN A VOLUME, AN EXCITED
VOLUME, THE DISPLACEMENT
VARIATION OR THE DISPLACEMENT
DISTRIBUTION, THE SAME THING
THAT EINSTEIN HAD MENTIONED, BUT
IT'S DONE THROUGH THE
MAGNETIZATION, AND IT'S NOT A
DIRECT MEASUREMENT OF
DISPLACEMENT BUT EVEN FURTHER
DISPLACEMENT FROM IT.
SKIPPING AHEAD TO 1973, PAUL
LAUTERBUR IS THE PERSON CREDITED
WITH INVENTING MRI BUT HE ALSO
CONCEIVED OF SOMETHING WE CALL
NOW DIFFUSION MRI, AND HE
BASICALLY SAID THAT WHEN YOU
MAKE THE MAGNETIC RESONANCE
IMAGING MEASUREMENTS, YOU CAN IN
EACH VOXEL OR PIXEL IN WHICH
YOU, LET'S SAY, MEASURE THE
PROTON DENSITY OF THE WATER
CONCENTRATION, YOU CAN COMBINE
THAT WITH THE MEASUREMENT OF
CHEMICAL COMPOSITIONS, AND HE
MENTIONED SPECIFICALLY DIFFUSION
COEFFICIENTS AND OTHER
PROPERTIES OF OBJECTS MEASURABLE
BY NMR SPECTROSCOPIC TECHNIQUES.
SO IN OTHER WORDS, HE'S SAYING
THAT YOU CAN COMBINE MRI WITH
THE EXPERIMENTS THAT CARR AND
PURCELL HAD CONCEIVED OF AND
DID, AND SOME OF THE OTHER
SUBSEQUENT DIFFUSION EXPERIMENTS
THAT HAD TAKEN PLACE SINCE.
SO TWO PROPERTY OF DIFFUSION
THAT YOU NEED TO KNOW ABOUT IS
ISOTROPY AND ANISOTROPY.
IN A JAR OF WATER IF YOU'RE
WATCHING PARTICLES RELEASED FROM
A SINGLE POINT AND YOU KEEP
DOING THAT EXPERIMENT MANY
TIMES, THEY WON'T GO TO THE SAME
PLACE EACH TIME, BUT OVER TIME,
THEY'LL EXPLORE THE SPACE AND IF
YOU WAIT A CERTAIN DIFFUSION
TIME AND YOU SEE WHERE THEY
WENT, YOU CAN PRODUCE A FIGURE
THAT LOOKS LIKE THIS.
THESE ARE EINSTEIN'S SURFACES OF
CONSTANT DISPLACEMENT, AND IN A
WATER JAR, THESE WOULD BE
SPHERES THAT ARE CONCENTRIC,
BECAUSE THE PROBABILITY OF
FINDING A PARTICLE IN ONE
DIRECTION -- GOING IN ONE
DIRECTION WOULD BE THE SAME AS
IN ANY OTHER DIRECTION.
BUT IN A LOT OF BIOLOGICAL
MEDIA, LIKE NERVES, SKELETAL
MUSCLE, AXONS THAT RUN IN THE
BRAIN, THAT ISN'T THE CASE.
THERE IS A DIRECTIONAL BIAS, AND
IF YOU RELEASE PARTICLES, LET'S
SAY, IN SKELETAL MUSCLE OR IN
WHITE MATTER, YOU'LL FIND THAT
PARTICLES TEND TO MIGRATE IN
SOME DIRECTIONS MORE RAPIDLY
THAN IN OTHERS.
AND THESE SURFACES OF CONSTANT
DISPLACEMENT OR PROBABILITY ARE
ELLIPSES IN 2D AND ELIPSOIDS IN
2 DIMENSIONS.
THAT'S SOMETHING WE'LL GET TO
SHORTLY.
SO MIKE MOSELY WAS THE FIRST
PERSON TO DO DIFFUSION, TO
DEMONSTRATE DIFFUSION IMAGING IN
1991 AND SHOWED THAT THERE ARE
CERTAIN TISSUE TYPES IN BRAIN
THAT WERE ISOTROPIC AND CERTAIN
TISSUE TYPES THAT WERE
ANISOTROPIC.
SO FOR INSTANCE, IF YOU LOOK IN
THE TOP RIGHT IMAGE WITH THE X
UNDERNEATH, IF YOU LOOK AT THE
CORTEX, THE SURFACE OF THE
BRAIN, YOU'LL SEE THAT THE
CONTRAST, THE INTENSITIES ARE
PRETTY MUCH THE SAME WHEN YOU
LOOK AT DISPLACEMENTS IN THE X,
Y OR Z DIRECTION, IN THE THREE
OORTHOGONAL DIRECTIONS.
BUT I DON'T KNOW IF YOU CAN SEE
MY CURSOR, BUT IF YOU LOOK AT
THIS, THAT BLACK STRIPE IN THE
MIDDLE, IN THE UPPER RIGHT
FIGURE, THAT'S THE CORPUS
CALLOSUM.
IN THAT FIGURE, IT'S DARK, BUT
IF YOU LOOK AT THE Z AND THE Y
FIGURES AT THE BOTTOM RIGHT AND
THE BOTTOM LEFT, IT'S BRIGHT.
SO WHEN YOU'RE LOOKING AT
DISPLACEMENTS IN THE X, Y AND Z
DIRECTION IN THE WHITE MATTER
AND THE CORPUS CALLOSUM, THOSE
SIGNAL DIFFERENCES INDICATE THAT
THAT'S ANISOTROPIC.
MIKE UNDERSTOOD THAT BUT HE
DIDN'T REALLY KNOW WHAT TO DO
WITH IT FROM A MEASUREMENT
PERSPECTIVE.
SO I DIDN'T KNOW ABOUT REALLY
ANY OF THIS STUFF WHEN I
STUMBLED UPON DOUEK'S POSTER AT
AN NIH RESEARCH FESTIVAL IN
1991.
IT WAS AT THE END OF THE DAY AND
I DECIDED TO GO INTO THE BACK
TENT AS I HADN'T DONE MY DUE
DILIGENCE, AND I THOUGHT THAT
THIS POSTER WAS STAGGERING TO
ME.
FIRST, I FOUND OUT THAT
DIFFUSION WAS HETEROGENEOUS IN
THE BRAIN, THAT IT COULD BE
MEASURED BY NMR OR MRI, AND THAT
SOME TISSUES, LIKE THE WHITE
MATTER, WAS ANISOTROPIC, AND
ANOTHER THING THAT WAS CLEAR TO
ME WAS THAT THE METHODOLOGY THAT
THEY WERE USING WASN'T REALLY
ADD THE QUESTION TO CHARACTERIZE
THE ANISOTROPIC DIFFUSION
PROCESS.
THEY WERE USING SCALER
DIFFUSIVITIES WHEN THEY REALLY
SHOULD HAVE BEEN USING TENSORS.
AND I STARTED TO IMAGINE WHAT WE
COULD DO WITH THIS INFORMATION,
IF YOU STARTED TO USE A FULL
TENSOR MODEL TO DESCRIBE THIS
ANASEISOTROPY.
YOU COULD PRODUCE EINSTEIN'S
DIFFUSION ELLIPSOIDS BECAUSE YOU
COULD MEASURE THE WHOLE
DISPLACEMENT DISTRIBUTION, YOU
COULD DO TRACTOGRAPHY, YOU COULD
FOLLOW STREAMLINES, MAXIMUM
DIFFUSIVITY.
YOU COULD CHARACTERIZE THE
FRAMES OF REFERENCE IN WHICH THE
DIFFUSION PROCESS IS THE
SIMPLEST, SO EACH CHUNK OF
TISSUE HAS ITS OWN INHERENT
FIBER COORDINATE SYSTEM WHICH
YOU COULD DISCOVER WITH THAT
QUANTITY, AND YOU COULD ALSO
PRODUCE VARIOUS KINDS OF STAINS,
SO-CALLED SCALER INVARIANTS THAT
WOULD TELL YOU OF NEW FEATURES
ABOUT THE TISSUE, SUCH AS
THE DEGREE OF ANISOPRO PEE.
ISOTROPY.
SO I BEGAN DRAFTING A MEMO AND A
FEW WEEKS LATER, I GOT THE
GUMPTION TO PRESENT TO PHILIP
DOUEK, MY COLLEAGUE, BOB TURNER,
BRAD ROTH, KIND OF OUTLINING A
RESEARCH PROPOSAL THAT WE COULD
ALL WORK ON TOGETHER.
AND THIS IS IN DERRICK JONES'
BOOK, THESE LAB NOTEBOOK PAGES
THAT ARE REPRODUCED, BUT THE
TENSOR CAN BE DESCRIBED BY THIS
3 BY 3 MATRIX THAT HAS THREE
ROWS, THREE COLUMNS, AND FROM
IT, YOU CAN CALCULATE MANY
USEFUL FEATURES.
AS I SAID, THE COORDINATE
SYSTEM, YOU CAN GO FROM THE
LABORATORY COORDINATE SYSTEM TO
THIS PREFERRED PRINCIPLE
COORDINATE SYSTEM, YOU CAN FIND
THE PRINCIPLE DIFFUSIVITIES.
THIS IS A CARTOON OF THE
TRACTOGRAPHY IDEA FOLLOWING THE
DIRECTION OF MAXIMUM DIFFUSIVITY
ALONG THESE STREAMLINES, AND THE
MATHEMATICS TO PRODUCE THESE
DIFFUSION ELLIPSOIDS AS I SAID
REPRESENTS EINSTEIN'S
DISPLACEMENT DISTRIBUTION, AND
THE SIZE AND SHAPE AND
ORIENTATION TELL YOU A LOT ABOUT
THE LOCAL MICROSTRUCTURE AND
DIFFUSION PROCESS.
AND THEN SOME PARAMETERS THAT
YOU GET FOR FREE THAT ARE
INTRINSIC TO THE TISSUE AND
DON'T DEPEND ON THE SPECIFICS OF
THE MEASUREMENT.
SO HE TURNED TO ME AND SAID YOU
KNOW, IN A VERY STRONG FRENCH
ACCENT, HE SAID THIS IS ALL VERY
INTERESTING, HE SAID, BUT NOBODY
KNOWS HOW TO MEASURE A DIFFUSION
TENSOR.
THAT WAS AN ASSUMPTION I MADE
AND IT WAS AN INCORRECT ONE WHEN
I VISITED HIS POSTERMENT SO I'M
GLAD THAT I HAD THE PRESENCE OF
MIND TO TURN AROUND WHEN I WAS
LEAVING THE ROOM AND ASK BOB
TURNER AND DENIS, I SAID IF I
REALLY WANTED TO LEARN HOW TO DO
THIS MYSELF, WHAT DO I NEED TO
KNOW, WHAT ARTICLES DO I NEED TO
READ?
AND THEY BOTH SUGGESTED READING
WORK BY STEJSKAL AND TANNER.
SO I STARTED TO DO THAT.
I WENT TO THE LIBRARY AND AT
THAT TIME, ALL OF THE JOURNALS
WERE IN STACKS IN THE BASEMENT,
AND ONCE WE FOUND ONE, WE WOULD
LINE UP AND GET THEM MIMEOGRAPHS
OR XEROXED, AND WE HOPED THAT
THE XEROX MACHINE DIDN'T GET
JAMMED OR FAIL WHILE WE WERE
DOING THAT.
AND I STARTED TO READ PAPERS BY
STEJSKAL AND TANNER AND FRANKLY
I COULDN'T REALLY UNDERSTAND
THEM THAT WELL, BUT I NOTICED IN
THE BIBLIOGRAPHY THERE WERE
PAPERS BY ERWIN HAHN, NICHOLAS
BLUMBURG, ED PURCELL AND OTHER
PEOPLE AND I STARTED READING
THOSE PAPERS AND I CAME BACK TO
THE STEJSKAL AND TANNER PAPERS
AND I STARTED TO UNDERSTAND THEM
BETTER.
I ACTUALLY HIT GOLD WHEN I READ
ONE OF THE PAPERS ABOUT THE
ANISOTROPIC DIFFUSION AND I WAS
ABLE TO REFORMULATE THE MODEL
AND EXTEND IT AND APPLY TO
IMAGING, AND CREATE A
RELATIONSHIP BETWEEN THE SIGNAL
ATTENUATION, THE SAME SIGNALS
THAT MIKE MOSTLY SHOWE MOSLEY SHOWED IN TH AT
FIGURE OF THE CAT BRAIN I SHOWED
YOU A FEW MOMENTS AGO, AND THE
DIFFUSION TENSOR.
I ALSO FIGURED OUT A WAY TO
MEASURE THE DIFFUSION TENSOR
FROM A MULTIPLICITY OF THOSE
IMAGES.
SO THAT WAS THE SECOND, I GUESS,
EUREKA MOMENT, THAT WAS THE WAY
IN WHICH WE COULD ACTUALLY MAKE
THIS PHYSICAL MEASUREMENT.
THEN FAST FORWARD A FEW -- ABOUT
A MONTH OR SO, JIM MAT TIELO,
ANOTHER POSTDOC IN THE GROUP IN
THE BIOMEDICAL ENGINEERING
PROGRAM WANTED TO WORK WITH ME
ON THIS, AND HE COLLECTED SOME
OF THE DATA HERE.
THIS IS THAT MATRIX THAT YOU SEE
ON THE LEFT COLUMN, THAT'S THE
FIRST DIFFUSION TENSOR THAT I'M
AWARE OF THAT WAS EVER MEASURED
WITH NMR METHODS.
THIS WAS MADE OF WATER, AND IT'S
SUPPOSED TO HAVE DIAGONAL
ELEMENTS THAT ARE ALL EQUAL AND
ABOUT .00025, BUT THEY'RE NOT
QUITE, AND THE OFF DIAGONAL
ELEMENTS ARE ALSO SUPPOSED TO BE
PRETTY CLOSE TO ZERO.
THEY'RE MUCH SMALL THEARN THE
DIAGONAL ELEMENTS BUT THEY'RE
STILL NOT, YOU KNOW, WITHIN
STATISTICAL SIGNIFICANCE ZERO.
SO THAT BOTHERED ME ACTUALLY
QUITE A BIT, BECAUSE I WAS
THINKING IF WE CAN'T MEASURE
WATER DIFFUSION TENSORS IN
WATER, HOW ARE WE SUPPOSED TO
MAKE CREDIBLE ESTIMATES IN WHITE
MATTER OR IN OTHER BIOLOGICAL
TISSUE?
BUT WE FIGURED THAT OUT TO SOME
EXTENT, AND IT CAME TIME TO
SUBMIT THIS TO THE ISM -- IT WAS
THE SOCIETY OF MAGNETIC
RESONANCE IN MEDICINE, AND YOU
DON'T HAVE TO GO THROUGH THIS,
BUT THE POSTER OR THE ABSTRACT
ON THE LEFT IS THE MEASUREMENT
THAT DESCRIBES HOW YOU ACTUALLY
MEASURE THE DIFFUSION TENSOR
FROM DIFFUSION-WEIGHTED SIGNALS
AND EXAMPLES IN WATER AND IN
SKELETAL MUSCLE, AND THE
ABSTRACT ON THE RIGHT BASICALLY
IS A RE-DO OF THE MEMORANDUM
THAT YOU SAW EARLIER WITH SOME
ADDITIONAL DIFFUSION ELLIPSOIDS
OF SKELETAL MUSCLE THAT WAS
ORIENTED INITIALLY IN THE Z
DIRECTION IN THE MAGNET AND THEN
ROTATED.
YOU CAN SEE THAT ELLIPSOID GETS
ROTATED AS THE TISSUE GETS
ROTATED, INDICATING THAT IT'S AN
INTRINSIC PROPERTY OF THE
TISSUE, AND DOESN'T FOLLOW THE
LABORATORY COORDINATE SYSTEM.
SO THIS ENDED UP BEING ACTUALLY
RELEGATED TO THE CORNER OF THE
ISMRM DIMENSION CENTER, AND I
THINK ONLY ABOUT FIVE PEOPLE
SHOWED UP AND ASKED ME QUESTIONS
ABOUT IT.
SO IT WASN'T A HIGH POINT BUT,
YOU KNOW, I THINK THIS IS THE
KEY THING, YOU JUST HAVE TO
PERSIST.
SO THE NEXT STEP WAS TO COMBINE
THE NMR EXPERIMENT WITH IMAGING,
AND THIS IS WHAT WE CALL
DIFFUSION TENSOR IMAGING NOW.
THIS IS ONE OF THE WAYS IN WHICH
WE WOULD CALIBRATE THE SYSTEM,
WE WOULD PUT JUGS OF WATER IN
THE MAGNET AND WE WOULD MEASURE
THE DIAGONAL ELEMENTS THAT WOULD
BE AT THE TOP ROW AND THE
OFF-DIAGONAL ELEMENTS WHICH
WOULD BE CLOSE TO ZERO IN THE
BOTTOM ROW, AND THIS WOULD BE A
WAY FOR US TO SEE WHETHER THERE
ARE ANY ARTIFACTS AND WHETHER
OUR PIPELINE WAS WORKING.
AND THIS IS SOMETHING THAT WAS
AN IMPORTANT INNOVATION, THE
COMBINATION OF THE DIFFUSION
TENSOR NMR EXPERIMENT AND WHAT
BOB TURNER DEVELOPED AT THE NIH
CALLED ECHO PLANAR IMAGING.
HERE THESE ARE DIFFUSION
ELLIPSOIDS OF WATER WITH THE HE
COPLANAECHO PLANAR IMAGING, THERE ARE
NO BIASES ACCORDING TO WHERE
THOSE ELLIPSOIDS ARE IN THE
IMAGING VOLUME SO THAT WE'RE CON
CONFIDENT THAT THERE AREN'T ANY
IMAGING ARTIFACTS EITHER.
THIS IS THE FIRST MEAN
DIFFUSIVITY OR TRACE MAP, AND
THIS WAS IN VIVO CAT BRAIN, AND
THIS IS AN IMPORTANT QUANTITY AS
WE'LL SEE IN A MOMENT.
THE STRIATIONS OR STRIPES, TO ME
NOW WITH WHAT I KNOW, ARE
ARTIFACTS ASSOCIATED WITH GIBBS
RINGING, BUT GENERALLY THE
SIGNAL IS UNIFORM IN THE BRAIN
EXCEPT FOR THOSE BRIGHT POCKETS
THAT ARE CEREBROSPINAL FILLED,
THEY'RE ALMOST LIKE --
INCLUSIONS IN THE BRAIN THAT
HAVE A HIGHER DIFFUSIVITY.
THIS WAS THE FIRST HUMAN
DIFFUSION ELLIPSE VERSION WE
PRODUCED.
YOU CAN'T SEE IT SO WELL HERE,
BUT ON THE TOP LEFT AND TOP
RIGHT, THOSE ARE SCREEN ROW
SPINAARE CEREBROSPINALFLUID FILLED ELLIPSE S THAT ARE
LARGELY CIRCULAR BUT THEY'RE A
LITTLE BIT SQUASHED.
IN THAT DARKER RIM AREA BELOW,
YOU CAN SEE ELLIPSES THAT ARE
ORIENTED ALONG THE DIRECTION OF
WHAT IS THE CORPUS CALLOSUM, AND
YOU'LL SEE BETTER EXAMPLES OF
THIS LATER ON.
AND IF YOU LOOK AT JIM MAT
TIELLO'S AND MY NOTEBOOKS,
YOU'LL SEE EXAMPLES OF MISOTROPY
YOU'LL SEE SOME IN SUBSEQUENT
SLIDES.
THIS IS PROBABLY THE -- AND
MAYBE THIS IS THE ONLY EQUATION
I'M SHOWING, THIS IS SOMETHING
CALLED THE FRACTIONAL
ANISOTROPY, MEASURES THE DEGREE
OF PRO LATENESS OF EINSTEIN'S
ELLIPSOID, AND YOU CAN USE THAT
AS WE'LL SEE AS A MEASURE OF
MICROSTRUCTURE AND A STAIN FOR
WHITE MATTER IN THE BRAIN.
SO CARLO PIERPAOLI AND I STARTED
WORKING TOGETHER, AND HE DECIDED
TO APPLY HIMSELF TO DEVELOP
CLINICALLY VIABLE WAY TO PRODUCE
HIGH QUALITY RADIOLOGICALLY
ACCEPTABLE D.T.I. DATA, AND THIS
IS A BEAUTIFUL EXAMPLE OF AXIAL
SLICES OF DIFFUSION TENSOR DATA,
THE TOP ROW SHOWS THE DIAGONAL
ELEMENTS, THE BOTTOM, THE
OFF-DIAGONAL ELEMENTS, AND YOU
CAN DERIVE FROM THEM THESE
PRINCIPLE DIFFUSIVITIES, THE
DIFFUSIVITIES ALONG THE AXES OF
THE ELLIPSOID THAT I MENTIONED
BEFORE.
THESE ARE -- THE MIDDLE MAP HERE
ARE DIFFUSION ANISOTROPY
MEASURES LIKE THE FA, THE
FRACTIONAL ANISOTROPY, AND YOU
CAN SEE THE REGIONS THAT ARE
WHITE ARE BRIGHT MATTER AND THE
REGIONS THAT ARE DARK ARE
CEREBROSPINAL AND DARK MATTER,
THIS IS REALLY LIKE A STAIN FOR
WHITE MATTER, AND THE TRACE
RELATED TO THE AVERAGE
DIFFUSIVITY IS VERY UNIFORM IN
THE PARENCHYMA, EXCEPT IN THE
CEREBROSPINAL FLUID POCKETS, THE
VENTRICLES, WHERE THE
DIFFUSIVITY IS THE SAME AS FREE
WATER AT BODY TEMPERATURE.
THIS IS A LOVELY IMAGE THAT
SHOWS THAT SAME AREA IN THE
CORPUS CALLOSUM, YOU SEE THE
LATERAL VENTRICLE, THEY LOOK
LIKE THE ROUND COTTON BALLS, AND
YOU CAN SEE NOW THE CORPUS
CALLOSUM COURSING THROUGH
UNDERNEATH THOSE FLUID-FILLED
POCKETS, AND NOW YOU CAN SEE THE
ANGULAR CHANGES IN THE DIFFUSION
ELLIPSOIDS CLEARLY, AND YOU CAN
SEE SMALLER SPHERICAL ELLIPSOIDS
THAT CORRESPOND TO GREY MATTER.
THEY'RTHERE THE DIFFUSIVITY IS LOWER
THAN IN THE CEREBROSPINAL FLUID,
BUT THERE'S NO ORIENTATIONAL
DEPENDENCE THE WAY THERE IS IN
THE WHITE MATTER.
AND HERE ON THE RIGHT IS THE
FRACTIONAL ANISOTROPY MAP, A
GOOD STAIN FOR WHITE MATTER IN
THE BRAIN.
THESE ARE DIRECTION MAPS.
THEY SHOW YOU THE ORIENTATIONS
OF THOSE WHITE MATTER PATHWAYS,
AND WE'LL BE TRACKING THOSE IN A
SECOND.
AND THIS IS A METHOD THAT CARLO
AND PAJEVIC PIONEERED,
COLOR-CODED MAPPING.
YOU TAKE THE MAP I SHOWED YOU
BEFORE THAT TELLS YOU WHERE THE
WHITE MATTER IS AND YOU SUPER
IMPOSE ON IT A COLOR THAT'S
RELATED TO THE ORIENTATION OF
THE FIBER.
SO THAT COLOR WHEEL ON THE
BOTTOM RIGHT TELLS YOU -- IT'S A
LEGEND FOR DIRECTIONALITY OF THE
FIBER PATHWAY.
THIS IS REALLY NOVEL INFORMATION
THAT WAS NEVER AVAILABLE BEFORE.
AND THIS IS, I THINK, STILL A
STUNNING IMAGE.
IT'S A CORONAL SLICE SHOWING
WHITE MATTER PATHWAYS WITH THE
COLOR MAPPING, AND FOR THE FIRST
TIME, YOU REALLY SEE THESE
DIFFERENT DISTINCT WHITE MATTER
PATHWAYS THAT POP OUT, AND YOU
CAN SEE NEARBY PATHWAYS LIKE
THIS CINGULUM BUNDLE IN THE
UPPER LEFT.
THESE ARE FIBERS THAT GO ACROSS
THE TOP OF THE CORPUS CALLOSUM.
YOU CAN SEE THEY HAVE A
DIFFERENT COLOR GREEN THRAN THE THAN THE
CORPUS CALLOSUM THAT RUNS
UNDERNEATH THEM THAT'S RED.
SO FOR THE FIRST TIME, YOU CAN
REALLY SEE THESE DISTINCT
PATHWAYS, EVEN ONES THAT RUN
CLOSE TO ONE ANOTHER WITH THIS
CONSTRUCTION.
AND CARLO SHOWED ALSO WITH
SINESHA THAT THESE T2 WEIGHTED
IMAGES WHICH ARE KIND OF
STANDARD CONVENTIONAL IMAGES ARE
REALLY NOT VERY ELOQUENT WHEN IT
COMES TO LOOKING AT WHITE
MATTER.
IF YOU LOOK AT THESE COLOR MAP,
THE SAME REGION IN THE PONS,
NEAR THE BRAINSTEM, YOU CAN SEE
WHITE MATTER FIBERS, THE MOTOR
FIBERS, SENSORY FIBERS AND THESE
FIBERS THAT RUN LEFT AND RIGHT,
THE TRANSVERSE PONTINE FIBERS
ARE VERY APPARENT.
AND THEY'RE NOT VISIBLE AT ALL
IN CONVENTIONAL IMAGING.
SO WHAT ARE SOME OF THE CLINICAL
AAPPLICATIONS OF THIS TECHNOLOGY?
WELL, MIKE MOSELY, AGAIN, WAS
RESPONSIBLE FOR SHOWING THAT IN
ISCHEMIA, WHEN THERE'S A LOSS
OF -- PERCENT, AND THIS ISCHEMIA
AND STROKE WERE REALLY AN
INVISIBLE CONDITION TO
RADIOLOGISTS BECAUSE THERE WERE
NO MR METHODS OR CT METHODS THAT
REALLY ALLOWED YOU TO SEE A
STROKE IN PROGRESS LIKE THIS IN
THE PARENCHYMA, IN THE BRAIN
TISSUE.
THIS WAS A REAL BREAKTHROUGH.
BUT THERE WAS A PROBLEM, WHICH
WAS THAT DEPENDING ON WHICH
DIRECTION YOU APPLIED YOUR
GRADIENTS, WHICH DIRECTION YOU
ARE LOOKING AT DIFFUSION, YOU
WOULD GET DIFFERENT AREAS THAT
WERE BRIGHT AND DARK, VERY MUCH
LIKE HIS PREVIOUS PAPER THAT I
SHOWED YOU FROM 1991.
SO THIS IS AN EXAMPLE OF THIS
THAT'S MORE PALPABLE, THIS IS A
CAT BRAIN, THIS IS AN ISCHEMIA
THAT WAS IP DUED, AN INDUCED, AND YOU CAN
SEE IN DIFFERENT AREAS, THE
DIFFUSION COEFFICIENTS ARE
BRIGHT AND DARK, AND THE FIRST
ONE ON THE LEFT, IT LOOKS LIKE
IT COULD BE DARK ON BOTH SIDES.
ON THE ONE IN THE MIDDLE, IT'S
DARKER ON THE LEFT SIDE, BUT
THEN THERE ARE STRIPES AND AREAS
THAT ARE MUCH DARKER THAN IN ANY
OF THE OTHER IMAGES, AND SO
FORTH, FOR THE DXX COMPONENT.
IT TURNS OUT THAT WHEN YOU PLOT
ONE OF THESE DIFFUSION TENSOR
DERIVED QUANTITIES, THE AVERAGE
DIFFUSIVITY, IT WIPES AWAY THE
ARTIFACT OF ANISOTROPY, THE
STRIPES THAT YOU SEE IN
DIFFERENT DIRECTIONS THAT MIKE
MOSELY HAD ALREADY IDENTIFIED,
AND WHAT YOU'RE LEFT WITH IS A
REGION ON THE LEFT WHICH IS
CLEARLY IDENTIFIED AS THE
ISCHEMIC REGION AND THE REST OF
THE BRAIN LOOKS OKAY.
SO THIS WAS AN IMPORTANT
INNOVATION, AND IT ALLOWED
RADIOLOGISTS TO MAKE BETTER
DETERMINATIONS ABOUT WHERE
STROKE WAS OCCURRING.
THE DTI DATA IS ALSO VERY WIDELY
USED IN BRAIN TUMOR ASSESSMENT
AND DIAGNOSIS, AND HERE, FOR
INSTANCE, THIS IS PRETTY EARLY
WORK BY AARON FIELD AND ANDY
ALEXANDER, AND IT SHOWS TUMOR
AND THE BRAIN, IT'S A BRIGHTER
AREA ON THE ADC MAP, AND THE
FRACTIONAL ANISOTROPY, WHITE
MATTER STAIN IS ALL BUT ABSENT
IN THE AREA THAT'S AFFECTED BY
THE TUMOR, LOOKS LIKE AN
INFILTRATING TUMOR.
AND YOU CAN SEE IN THIS
DISTRIBUTION OF THE FRACTIONAL
ANISOTROPY VERSUS THE APPARENT
DIFFUSION COEFFICIENT 2 TENSOR
DERIVED PROPERTIES, YOU CAN VERY
CLEANLY SEPARATE THE TUMOR
TISSUE FROM THE NORMAL TISSUE.
ANOTHER WAY IN WHICH DIFFUSION
TENSOR INFORMATION IS USED IN
THE CANCER DIAGNOSIS FIELD IS TO
ASSESS HOW WELL A SUBJECT -- A
PATIENT IS DOING ONCE
CHEMOTHERAPY OR RADIATION HAS
BEEN GIVEN.
SO THESE FIGURES ON THE BOTTOM
SHOW THE PROGRESSION OF THE
APPARENT DIFFUSION COEFFICIENT,
AND INITIALLY, THE YELL LOW
AREAYELLOW AREASSHOW WHERE THE CANCER IS, AND
WHERE THE RESOLUTION OCCURS,
THEY BECOME MORE AND MORE RED.
THIS IS A FUNCTIONAL METHOD THAT
THEY PROPOSE.
BUT BASICALLY IT'S AN ADC
MEASURE.
AND AS THE AD SEA CHANGE, IT ADC CHANGES, IT SHOWS
RESPONSE.
WEEK 3, WEEK 10 UNCHANGED
BECAUSE OF RESPONSE TO THE DRUG
THERAPY.
SO I WANTED TO CUT BACK TO TRACT
TRACTOGRAPHY AND TRACKING
BECAUSE THAT'S BECOME REALLY A
FIELD IN ITSELF.
ONE OF THOSE ABSTRACTS I SHOWED
YOU IN 1992, I INCLUDED A
SENTENCE THAT I WANTED TO READ
OUT LOUD, WHICH IS, ONE COULD
ENVISION 3D FIBER MAPS OR
DIFFUSION ELLIPSOIDS DISPLAYED
IN EACH VOXEL, CONNECTED LIKE
LINK SAUSAGES THAT FOLLOW FIBER
TRACTS.
SO HERE'S A CHEF HOLDING LINKED
SAUSAGES, FOR THOSE WHO DON'T
KNOW WHAT A LINKED SAUSAGE IS,
AND THE IDEA I HAD THERE WAS
THAT YOU COULD SOMEHOW STRING
TOGETHER THESE ELLIPSOIDS, AND
TURN THEM INTO INTO CONTINUOUS
PATHWAYS.
I USED TO GIVE LECTURES AND SAY
YOU CAN LOOK AT THE ELLIPSOIDS
AND YOU CAN CONTINUE THEM AROUND
AND I WOULD SAY IT'S LIKE A
POINTLESS PAINTING IF YOU STAND
IN THE BACK OF THE ROOM AND YOU
SQUINT, YOU CAN KIND OF MAKE OUT
AN ARC THAT ELABORATES A
PATHWAY.
BUT IT TURNS OUT FROM A
MATHEMATICAL STANDPOINT, IT'S
NOT THAT EASY TO COME UP WITH
LINKED SAUSAGE TRACTOGRAPHY
ALGORITHMS.
AN EASIER THING TO DO WAS TO CUT
BACK TO THE STREAMLINE ALGORITHM
AND BEING AN OLD FLUID
MECHANICIAN, IT WASN'T SO
DIFFICULT TO FIGURE OUT HOW TO
DO THAT.
SO IN 1997, I PROPOSED THIS SET
OF EQUATIONS.
YOU DON'T HAVE TO -- I DON'T
HAVE TO REALLY EXPLAIN THEM
MATHEMATICALLY, BUT THE BASIC
IDEA IS THAT THE TRACT IS
DESCRIBED AS A SPACE CURVE, A
CURVE THAT GOES THROUGH THE
IMAGING VOLUME, AND AT EVERY
POINT ON THAT CURVE, THE SLOPE
OF THAT CURVE IS THE DIRECTION
ASSOCIATED WITH THE LARGEST
DIFFUSIVITY.
SO YOU'RE ALWAYS MOVING ALONG
THE DIRECTION OF MAXIMUM
DIFFUSIVITY, AND YOU JUST KEEP
CHUGGING ALONG AND SOLVING THAT
EQUATION AND SEEING WHERE THAT
FIBER TRACT TAKES YOU.
AND THIS IS KIND OF AN ANIMATION
THAT'THAT SEEDPOINT MADE FOR ME MANY
YEARS AGO, AND I IT SHOWS HOW YOU
MIGHT DO THIS EXPERIMENT.
YOU LAUNCH A FIBER FROM THE C .,
YOU FIND OUT WHAT AS THE MAXIMUM
DIRECTION OF DIFFUSIVITY, YOU
STOP AND EVENTUALLY YOU MIGHT
GET TO THE END OF THE TRACT.
YOU DON'T WANT TO GO THROUGH THE
SKULL, YOU DON'T WANT TO GO
THROUGH THE CORTEX, YOU DON'T
WANT TO CHANGE DIRECTIONS TOO
RAPIDLY SO THERE ARE ALL KINDS
OF CRITERIA FOR STOPPING, BUT
THAT'S BASICALLY HOW YOU MAKE
YOUR PATHWAY, YOUR TRACT.
AND THIS IS FIBER TRACKING, THE
MOVIE.
THIS WAS ALSO AN ORIGINAL.
YOU START AT A POINT ON THE
CORPUS CALLOSUM, YOU TRACE IT
AROUND AND FIND YOURSELF AT A
POINT IN THE CORTEX ON THE OTHER
SIDE OF THE BRAIN AND YOU STOP.
SO THEY ALSO DEVELOPED
ALGORITHMS TO GENERATE THE FIRST
DEPICTION OF THE CORPUS CALLOSUM
ACTUALLY WITH D.T.I. DATA.
HE STARTED WITH A SLICE DOWN THE
INTERHEMISPHERIC PLANE, THAT'S
THIS KIND OF CUT.
THIS IS LIKE THE MACH BET MC BETH CUT,
YOU CUT THE BRAIN AT THIS
ORIENTATION.
HE STARTED IN A REGION WHERE HE
KNEW THERE WAS WHITE MATTER AND
HE JUST BASICALLY RELEASED --
FROM THOSE SEED POINTS, HE
RELEASED TRACTS ON BOTH SIDES
AND WAS ABLE TO ELABORATE THE
ENTIRE CORPUS CALLOSUM AND SOME
OF THE OTHER TRACTS.
AND THIS WAS ACTUALLY USED AS A
POSTER FOR THE D.T.I. CLOAK QEEM COLLOQUIU M
AT THE NIH WE ORGANIZED IN THE
EARLY 2000s.
MY POSTDOC WHO'S NOW IN WALES
RUNNING A LARGE BRAIN IMAGE
CENTER, DERRIC DEREK JONES, MADE THIS
CONSTRUCTION OF TRACTS USING
STREAMTUBES WHICH IS A VERY
EFFECTIVE MEANS OF DISPLAYING
THESE.
IN TERMS OF APPLICATIONS OF
TRACTOGRAPHY, A VERY IMPORTANT
ONE IS, IN NEUROSCIENCE, AS
WE'RE TRYING TO UNDERSTAND HOW
THE BRAIN WORKS, WE LOOK AT
DIFFERENT KINDS OF CONNECTIVITY.
SO FUNCTIONAL IMAGING PEOPLE
LOOK AT TIME SERIES OF AREAS OF
THE BRAIN THAT ARE TURNING ON
AND TURNING OFF, AND THOSE ARE
PRESUMABLY CONNECTED THROUGH
WHITE MATTER PATHWAYS.
SO ANATOMICAL CONNECTIVITY AND
FUNCTIONAL CONNECTIVITY ARE USED
TOGETHER A LOT TO TRY TO
UNDERSTAND HOW BRAINNET WORKS
BEHAVE AND FUNCTION.
AND THIS IS A WHOLE BRAIN TRACT
MAP THAT IS ON THE DANA
FOUNDATION WEBSITE.
CHALEZ, A WONDERFUL MAN AND
GREAT RADIOLOGIST, HAS A CENTER
NAMED AFTER HIM FOLLOWING HIS
DEATH, AND HERE, THIS DISPLAYS A
NEUROSURGICAL PLANNING SOFTWARE
THAT THEY MAKE
AVAILABLE AND IT SHOWS HOW
YOU CAN USE TRACTS TO IDENTIFY
PARTS OF THE BRAIN AND ALSO
DISPLAY ELOQUENT AREAS THAT YOU DON'T
WANT TO TRANSECT IF YOU'RE
CUTTING OUT TUMORS OR DOING
OTHER KINDS OF BRAIN SURGERY.
THERE ARE COMMERCIAL -- YOU
KNOW, THERE'S THIS STEALTH VIZ
D.T.I. MODULE SOLD BY MEDTRONIC
TO HELP SURGEONS SEE WHERE WHITE
MATTER PATHWAYS ARE IN RELATION
TO TUMORS THAT THEY'RE TRYING TO
RESECT.
AND THIS IS ANOTHER VIEW OF A
NEUROLOGICAL VISUALIZATION
METHOD THAT THEY OFFER TO BE
ABLE TO IDENTIFY TRACTS AND SEE
MAYBE HOW THEY MOVED OR HAVE
BEEN DISPLACED BY TUMORS.
IN RADIOTHERAPY PLANNING, IT'S
VERY SIMILAR, THE TRACTS ARE
AVOIDED TO THE BEST EXTENT BY
USING DIFFUSION -- OR
TRACTOGRAPHY SO YOU CAN PLAN
YOUR DELIVERY OF YOUR RADIO
LOGIC COMPOUND OR YOUR X-RAYS
ESSENTIALLY, AND YOU CAN AVOID
THE DAMAGING WHITE MATTER
PATHWAYS AND REDUCE THE DOSAGE
OF THE RADIATION THAT IS
EXPERIENCED IN DIFFERENT PARTS
OF THE BRAIN BY INCLUDING A
TRACT INFORMATION IN YOUR
PLANNING PROCESS.
NOW, THIS TYPE OF DATA IS ALSO
USED TO STIMULATE OUR
IMAGINATION WITH REGARD TO
VARIOUS NIH FUNDED PROJECTS, THE
HUMAN CONNECTOME PROJECT WAS
STARTED, I GUESS ABOUT 15 YEARS
AGO, MAYBE MORE RECENTLY, AND
THE IDEA WAS TO TRY TO DEVELOP
THE TECHNIQUES AND METHODS FOR
ESTABLISHING CONNECTIONS BETWEEN
DIFFERENT BRAIN AREAS, AND
TRACTOGRAPHY WAS A VERY
IMPORTANT PART, AND THIS IS
ALMOST AN ADVERTISE M FOMENT FOR THAT
PROGRAM AT HUMANCONNECT
TOMORROW.ORG.
ANOME.ORG.THIS WEBSITE IS ACTUALLY STILL
ACTIVE.
YOU CAN SEE A WHOLE BRAIN
TRACTOGRAPHY MAP, AND WHY IS THE
BRAIN INITIATIVE NEEDED?
BECAUSE WE WANT TO UNDERSTAND
THESE CONNECTIONS, AND HOW THEY
ARE FUNCTIONALLY OPERATING IN
THE BRAIN AND HOW WE CAN USE
THEM TO GET A DEEPER INSIGHT
INTO DISEASE, VARIOUS
PSYCHIATRIC CONDITIONS,
DEVELOPMENT, AGING PROCESSES
THAT GO ON IN THE BRAIN.
AND ANOTHER PAGE FROM THE BRAIN
INITIATIVE ALSO SHOWS THESE
TRACTS FROM MAGNETIC RESONANCE
DIFFUSION METHODS, YOU KNOW,
THAT EXPLAIN THE RATIONALE IN
THE WAY FOR DOING THESE
MULTI-INSTITUTE INITIATIVES TO
SUPPORT BRAIN RESEARCH.
IN TERMS OF MEDICAL EDUCATION,
IN TRAINING AND ACIN ADDITION
MEEAMATTANATOMY, THEYWOULD USE THESE TO ID ENTIFY
NERVES AND MUSCLES AND OTHER
STRUCTURE, PARTICULARLY IN THE
BRAIN.
NOW IF YOU LOOK AT GRAY'S
ANATOMY, YOU'LL SEE THE SHORT
AND LONG CONNECTIONS OF THE HAND
REACH IN THE HUMAN BRAIN, WHICH
ARE TRACTOGRAPHY MODELS THAT
WERE OBTAINED BY MARCOUX KATANI
AND FLAVIO DELAQUA AND USED ON
THE COVER OF GRAY'S ANATOMY.
SO IT LOOKS LIKE THESE KIND OF
APPROACHES ARE BECOMING PART OF
THE WAY NEUROANATOMY IS TAUGHT
IN MEDICAL SCHOOL.
AND THIS IS ANOTHER
NEUROANATOMY, NEUROSCIENCE
TEXTBOOK THAT SHOWS A WHOLE
BRAIN TRACTOGRAPHY ON THE COVER.
IT SHOWS THE WHITE MATTER
PATHWAYS, CORTICAL SPINAL TRACTS
IN BLUE COMING DOWN, THE CORPUS
CALLOSUM COMING OUT TO THE TOP
OF THE BRAIN AND THEN FANNING
OUT.
YOU CAN SEE THE PONS AT THE
BOTTOM, THAT BASKET THAT'S
HOLDING THE CORTICAL SPINAL
TRACT.
IT REALLY QUITE BEAUTIFUL, BUT
ACTUALLY THERE ARE A LOT OF
FIBERS THAT THAT LOOK SPURIOUS
TO ME.
SO I DON'T KNOW HOW MUCH EDITING
WAS DONE.
IN TERMS OF POPULAR CULTURE, I
FOUND THIS ON ONE OF MY FAVORITE
WEBSITES, THE CEREBRANAUTS,
SCIENCE FICTION.
I HAVEN'T READ IT BUT YOU CAN
SEE THERE'S A TRACTOGRAPHY MODEL
OF THE BRAIN AND IT LOOKS LIKE A
SCIENCE FICTION THRILLER THAT
I'LL HAVE TO READ THIS SUMMER.
AND THERE ARE EVEN T-SHIRTS YOU
CAN BUY NOW THAT ARE D.T.I.
FIBER TRACTS OF THE BRAIN.
THERE'S A WOMAN'S SIZE AND A
CHILDREN'S SIZE HERE.
THEY'RE NOT THAT INEXPENSIVE.
AND IF YOU GO TO THE BEACH THIS
SUMMER AND YOU SEE SOMEBODY
CARRYING A TOTE BAG, IT MIGHT BE
A D.T.I. TRACTOGRAPHY TOTE BAG.
SO THIS IS KIND OF A MOVEMENT --
BEDSIDE AND BEYOND.
I THINK WHAT'S INTERESTING IS
THAT MANY DIFFERENT TYPES OF
TISSUE HAVE STILL BEEN
UNEXPLORED IN TERMS OF THESE
KINDS OF APPROACHES.
EVEN 30 YEARS AFTER THE FACT.
SPINAL CORD PERIPHERAL NERVES,
VARIOUS MUSCLES, CARDIAC MUSCLES
JUST BECOMING IMAGEABLE WITH
D.T.I. BECAUSE THE HEART IS
MOVING SO MUCH.
IT VERY DIFFICULT TO FREEZE THE
MOTION AND MEASURE DIFFUSION.
AT
THE SAME TIME THE HEART IS
CONTRACTING AND SQUEEZING.
BUT THERE ARE A LOT OF
POSSIBILITIES FOR WHOLE BODY
IMAGING THAT I THINK STILL CAN
BE EXPLORED AND WILL BE
EXPLORED.
SO BASICALLY THE D.T.I. PIPELINE
IS LARGELY UNCHANGED SINCE THE
BEGINNING, WHEN I WAS THINKING
ABOUT IT.
YOU START WITH DIFFUSION WAITED
IMAGING DATA.
WEIGHTED IMAGING DATA.
YOU START WITH THIS WORK AND USE
DATA THAT YOU ACQUIRE THAT'S,
QUOTE, DIFFUSION WEIGHTED TO
ESTIMATE THE DIFFUSION TENSOR
THAT'S SHOWN ON THE BOTTOM LEFT.
AND THEN YOU CAN CALCULATE MANY
DIFFUSION-WEIGHTED AND DIFFUSION
TENSOR DERIVED STAINS OR
CONTRASTS, THE PRINCIPLE
DIFFUSIVITY, EINSTEIN'S
DIFFUSION ELLIPSOID, AND THE NEW
COORDINATE SYSTEM IN WHICH
DIFFUSION BECOMES SIMPLE AND
UNCORRELATED, MEAN DIFFUSIVITY
STAINS OF WHITE MATTER, THE DEK
MAN.
YOU CAN MAKE MAPS OF THE
ELLIPSOIDS AND YOU CAN MAKE
FIBER TRACTS.
AND THAT'S A PRETTY
COMPREHENSIVE SUMMARY.
IN TERMS OF ELUCIDATING BRAIN
MICROSTRUCTURE AND ARCHITECTURE,
THIS STILL REPRESENTS GOLD FOR
ME, BUT WE'RE ACTUALLY GETTING A
LITTLE BIT BETTER AT GETTING
THESE KINDS OF IMAGES OURSELVES
WITH MRI.
THIS IS A MACAQUE BRAIN, AND
VARIOUS STAINS OF CORTICAL
ARCHITECTURE THAT WE USE AND
JUXTAPOSED WITH THEM ARE MR DATA
THAT WE'VE ACQUIRED THAT SHOW
THAT CORTICAL LAYERS ONE THROUGH
SIX, THE WHITE LAYER THAT'S
BELOW LAYER SIX, THE SO-CALLED
SUBCORTICAL WHITE MATTER, AND
THEY MATCH UP QUITE WELL WITH
HISTOLOGICAL STAINS THAT ARE
OBTAINED ON THE SAME SPECIMEN.
AND HERE IS A GOOD EXAMPLE,
WE'RE STARTING TO BE ABLE TO SEE
MICROSTRUCTURE AND ORGANIZATION
IN THE CORTEX REALLY IN AN
UNPRECEDENTED LEVEL WITH MRI.
AND WE'RE HOPING TO CONTINUE TO
DEVELOP THIS AND MAKE IT MORE
CLINICALLY ACCESSIBLE AND
ACCESSIBLE TO NEUROSCIENTISTS,
SO THEY CAN UNDERSTAND STRUCTURE
AND FUNCTION RELATIONSHIPS AND
UNDERSTAND DISEASE PROCESSES OF
THE BRAIN IN A WAY THAT WE
HAVEN'T BEEN ABLE TO PREVIOUSLY.
SO I'D LIKE TO THANK AND LIST
PEOPLE WHO WORKED WITH ME OVER
THE YEARS ON DIFFUSION TENSOR
IMAGING.
SADLY MAT TIELLO PASSED AWAY I
THINK IN 2017 AND WE'R 2017 AND SHRAGER, B UT
WE'RE GETTING ALONG WELL AND I'D
LIKE TO THANK PHIL BECAUSE
WITHOUT SOME OF THESE
INTELLECTUAL PROPERTY STRUCTURES
THAT HE PUT IN PLACE LIKE
CRADAs AND THE OFFICE OF
TECHNOLOGY TRANSFER, THIS
PROBABLY WOULD HAVE BEEN SITTING
IN SOME LIBRARY SOMEWHERE AND
NEVER BEING USED, AND NOW A LOT
OF PEOPLE CAN REALLY BENEFIT
FROM IT AND CONTINUE TO DEVELOP
IT.
SO THANK YOU, PHIL, AND THANK
YOU ALL FOR ATTENDING.
>> PETER, THANK YOU FOR A REALLY
FASCINATING INTELLECTUAL ODD
SIGH.
ODYSSEY.
I HAVE TO SAY I DIDN'T KNOW THE
COMPLETE STORY OF HOW DIFFUSION
TENSOR IMAGING CAME TO HE BE.
STARTINBE.STARTING WITH A POSTER SESSION,
A REMINDER TO US THAT IN-PERSON
MEETINGS ACTUALLY RESULT IN
CONVERSATIONS THAT CAN LEAD TO
GREAT INTELLECTUAL DEVELOPMENTS
AND THE WHOLE TEAM SCIENCE THAT
WE WERE DOING AT NIH TO DEVELOP
SOME OF THIS TECHNOLOGY.
IT JUST A WONDERFUL, WONDERFUL
STORY, AND I THINK A GOOD
TESTAMENT TO THE SUPPORT THAT
PHIL'S WORK HAS GIVEN US IN
COMMERCIALIZING AND MAKING
USEFUL SOME OF THE IDEAS THAT
HAVE COME OUT OF NIH.
ALSO I HAD MENTIONED
BIOENGINEERING AT NIH, AND IT'S
A GREAT EXAMPLE OF HOW
BIOENGINEERS AND BIOLOGISTS NEED
TO WORK TOGETHER.
LET ME START WITH A QUESTION,
AND LET ME FIRST REMIND PEOPLE
THAT IF THEY HAVE QUESTIONS,
THAT THEY CAN LOOK ON YOUR
VIDEOCAST.
THERE'S A BUTTON CALLED SEND
LIVE FEEDBACK TOWARDS THE BOTTOM
OF YOUR SCREEN, AND IF YOU CLICK
ON THAT, YOU CAN DIRECTLY ASK A
QUESTION AND IT WILL EVENTUALLY
MAKITY WAY TO MMAKE ITS WAY TO ME AND I'LL PASS
IT ALONG TO PETER.
SO I HAVE A QUESTION WHICH IS
PROBABLY SOMEWHAT NIGH EE NAIVE.
THE EINSTEIN TENSOR ELLIPSOID
WHICH IS A MATHEMATICAL FEATURE
OF THE ANALYSIS THAT YOU DO, IS
THAT IN ITSELF AN ADVANTAGE IN
TERMS OF THE WAY IN WHICH THE
IMAGES ARE ANALYZED, OR IS IT A
DISADVANTAGE?
IF THE MATH WERE DIFFERENT, THIS
IS KIND OF A VERY THEORETICAL
QUESTION, WOULD THAT BE BETTER
OR IS HAVING THE ELLIPSOID A
SPECIFIC ELEMENT THAT MAKES IT
POSSIBLE TO DO EVERYTHING THAT
YOU CAN DO?
>> WELL, THAT'S A GOOD QUESTION.
WELL, FIRST OF ALL, YOU KNOW, IN
THE INTEREST OF FULL DISCLOSURE,
I JUST READ EINSTEIN'S PAPER
AGAIN YESTERDAY TO RELOAD, AND
HE NEVER TALKED ABOUT AN
ELLIPSOID OR EVEN THESE SURFACES
OF CONSTANT CONCENTRATION.
HE DID MENTION DIFFUSION IN
THREE DIRECTIONS, AND THE FACT
THAT THE DIFFUSIVITY, THE
EQUATIONS CHANGE WHEN YOU'RE
CONSIDERING DIFFUSION IN THREE
DIRECTIONS OR IN 3D AS OPPOSED
TO 1D.
THE FACT THAT THE ELLIPSOIDS
HAVE STRUCTURE OR PRO LATE OR
OBLATE REALLY GIVE YOU A LOT OF
INFORMATION ABOUT THE
MICROSTRUCTURE.
IF THEY'RE SPHERICAL, THEY'RE
NOT AT HELPFUL TO YOU.
THERE'S NO PARTICULAR COORDINATE
SYSTEM THAT IS BETTER THAN
ANOTHER TO DESCRIBE THEM.
AND THERE ISN'T ANYTHING USEFUL
REALLY THAT YOU CAN EXTRACT FROM
THE DIFFUSION TENSOR THAT YOU
CAN'T GET FROM JUST A SCALER
MEASUREMENT.
SO THE FEATURES OF THE ELLIPSOID
ACTUALLY GIVE YOU THE
INFORMATION ABOUT THE PREFERRED
COORDINATE SYSTEM, AND ALL OF
THE PARAMETERS THAT TELL YOU HOW
THE DIFFUSION PROCESS DEVIATES
FROM ISOTROPIC OR SPHERICAL
ELLIPSOID DIFFUSION PROCESS, SO
I WOULD SAY I LIKE ELLIPSOIDS AS
OPPOSED TO SPHERE, AND THEY DO
GIVE US A LOT OF ADDITIONAL
INFORMATION.
NOW WE HAVE DRILLED INTO THE
FOXHOLE QUITE A BIT OVER THE --
YOU KNOW, A LOT OF THIS
DIFFUSION TENSOR STUFF IS A
NUMBER OF YEARS OLD.
SO SINCE MAYBE 2000, WE'VE BEEN
LOOKING AT DIFFUSION PROCESSES
ON A MUCH FINER LINK SCALE, AND
EVEN THOUGH THINGS MIGHT BE
ISOTROPIC OR SPHERICAL ON THE
VOXEL LEVEL, YOU STILL MIGHT
HAVE A LOT OF ANISOTROPIC --
RANDOMLY ORGANIZED MICRO
SCOPICALLY THAT PRODUCE AT
MACROSCOPIC SPHERE.
SO WE'RE STARTING TO DRILL INTO
THOSE SPHERES AND PULL OUT
INFORMATION ABOUT MICROSTRUCTURE
THAT IS KIND OF BELIED BY THE
SPHERICAL DIFFUSION TENSOR IN
THOSE TISSUES.
LIKE GRAY MATTER.
YOU KNOW IT'S NOT LIKE GELATIN
OR WATER, IT HAS A LOT OF FIBERS
AND -- IN IT.
SO THAT IS AN ACTIVITY OF OURS.
IT'S A GOOD QUESTION, AND YOU
GOT ME STARTED.
SORRY.
>> WELL, I'M GLAD TO HEAR.
I THINK PEOPLE AS DIVERSE AS
KEPPLER AND MILLIONS OF FOOTBALL
FANS ALSO APPRECIATE ELLIPSOIDS.
WE HAVE A QUESTION FROM ROLAND
OWENS.
DO YOU NEED TO COMPENSATE FOR
GRAVITY IN THE DIFFUSION
IMAGING?
IF SO, COULD YOU GET MORE
ACCURATE IMAGES IN A
MICROGRAVITY ENVIRONMENT?
>> WELL, THAT'S VERY
INTERESTING.
YOU KNOW, LIKE EINSTEIN REALLY
SPECIFICALLY IGNORED GRAVITY,
AND I THINK THAT IT BECAUSE THE
EFFECTS ARE VERY, VERY LIMITED.
I MEAN, WE'RE NOT LIVING IN AN
ULTRA CENTRIFEUJ WHERE YOU WOULDCENTRIFUGE WHERE YOU WOULD
HAVE TO REALLY INCLUDE IT.
BUT DIFFUSION DOES FIGHT AGAINST
GRAVITY.
AND IF YOU THINK ABOUT GAS
MOLECULES THAT ARE SURROUNDING
US, THEY'RE DIFFUSING AND MIXING
AND TRYING TO GET AS FAR FROM
EACH OTHER AS POSSIBLE BUT ARE
ALSO BEING PULLED DOWN BY
GRAVITY.
THEY CREATE A CONCENTRATION
VARIATION THAT'S NOT VERY
SIGNIFICANT BUT IT'S MEASURABLE.
SO TO FIRST -- EINSTEIN IGNORED
IT.
I'M NOT GOING TO SAY JUST
BECAUSE HE DID IT THAT IT'S
RIGHT, BUT FOR THE MOST PART, IT
DOESN'T ENTER INTO OUR
CALCULATIONS.
WE'RE NOT NEARLY SENSITIVE
ENOUGH TO BE ABLE TO MEASURE
THESE MINUTE DIFFERENCES THAT
YOU MIGHT EXPECT TO SEE, BUT YOU
KNOW, MAYBE LET'S FLY UP IN A
SPACE SHUTTLE AND CHECK IT OUT.
>> OKAY.
I'M SURE WE CAN FIND SOME
VOLUNTEERS.
SO ANOTHER QUESTION FROM
MUSTAFASBURARA.
QUICK QUESTION.
CROSSING FIBERS ARE AN ISSUE IN
MR DIFFUSION-TYPE MEASUREMENTS,
WHICH MAY BIAS RESULTS
INTERPRETATION, INCLUDING IN
TRACTOGRAPHY.
A FEW TECHNIQUES HAVE BEEN BEEN
SUGGESTED BUT MOST OF THE TIME
ARE NOT VERIFIED.
IN YOUR OPINION, WHAT ARE THE
BEST STRATEGIES OR METHODS TO
MITIGATE THIS ISSUE THAT CAN YOU
USED IN CLINICAL INVESTIGATIONS?
>> THAT'S A GREAT QUESTION, AND
THE D.T.I. TRACTOGRAPHY DOES
SUFFER FROM THE PROBLEM OF
CROSSING FIBERS, AND IT'S NOT
THAT WE DIDN'T KNOW ABOUT IT.
ACTUALLY IN THAT ABSTRACT THAT I
SHOWED YOU FROM 1998, I
MENTIONED KISSING AND CROSSING
AND MERGING AND AS ARTIFACT THAT
COULD POTENTIALLY AFFECT YOUR
ABILITY TO FOLLOW TRACTS.
SO THERE ARE MORE SOPHISTICATED
DIFFUSION METHODS YOU CAN USE
BESIDES D.T.I. THAT ARE MORE
ORIENTATIONAL LISTENSTIVE.
THEY DON'T MAKE AN ELLIPSOID,
THEY ACTUALLY MEASURE DIRECTLY
THAT DISPLACEMENT DISTRIBUTION.
IN FACT, THE MAP MRI THAT I
SHOWED YOU, ONE OF MY LAST
SLIDES, IS ONE SUCH METHOD.
AND YOU CAN FOLLOW THE
PROBABILITIES MUCH MORE CLEANLY
WHEN YOU'RE NOT ASSUMING THEY
FOLLOW AN ELLIPSOIDAL SHAPE BUT
THEY'RE MULTILOBULAR AND YOU CAN
FOLLOW PATHWAYS FROM LOBE TO
LOBE IN THOSE PROBABILITY
DISTRIBUTIONS.
I THINK A SMART THING TO BE ABLE
TO DO, AND IT'S REALLY NOT DONE
YET BUT -- IS TO USE
COMPLEMENTARY INFORMATION THAT
WE CAN OBTAIN ABOUT TRACTS AND
FIBERS IN THE NEARBY REGIONS AND
CONSTRAIN THE TRACT FOLLOWING SO
THAT IT KIND OF ANATOMICALLY
KOSHER TO DO IT, SO YOU DON'T
END UP GOING KISSING VERSUS
CROSSING OR JUMPING OFF ON TO
THE WRONG PATHWAY.
SO I WOULD SAY THOSE ARE
APPROACHES.
IT NOT FULL -- TRACTOGRAPHY IS
REALLY A MODEL.
YOU'RE BASICALLY FOLLOWING
DIFFUSION AND THE FASTEST
DIRECTION AND YOU CAN BE LED
ASTRAY.
THERE'S NO QUESTION ABOUT IT.
IT NOT FOOLPROOF.
>> SO QUESTION FROM ROB TYCO.
YOU MENTIONED HIGHER RESOLUTION
IMAGES TOWARDS THE END OF THIS
BEAUTIFUL LECTURE.
ARE THERE SPECIFIC TECHNOLOGICAL
ADVANCES THAT ARE CONTRIBUTING
TO PROGRESS IN THIS DIRECTION?
IS THERE A NEED FOR BETTER
HARDWARE, HIGHER FIELD MAGNET OR
SUCH THINGS?
OR NEW DATA ANALYSIS ALGORITHM
OR JUST NEW IDEAS?
>> ROB, THAT'S A GREAT QUESTION
AND HIGHER RESOLUTION IS
SOMETHING WE REALLY ARE LOOKING
TOWARD.
I THINK IT A COMBINATION OF
IMPROVED HARDWARE, MAYBE HAVING
BETTER RADIO FREQUENCY PICKUP
COILS THAT HAVE LESS NOISE.
STRONGER MAGNETIC FIELDS, IT'S A
DOUBLE EDGED SWORD.
YOU CAN GET HIGHER SIGNAL TO
NOISE THAT WAY, BUT THEN IT
MAKES A LOT OF THE OTHER
ELECTRONICS MORE PROBLEMATIC.
I THINK IT'S A COMBINATION OF
ALL THE THINGS YOU MENTIONED:
BETTER MODELING, BETTER
HARDWARE, BETTER ELECTRICAL
ENGINEERING CONCEPTS, BETTER
GRADIENT DESIGN.
I THINK -- I'D LOVE TO TALK TO
YOU MORE ABOUT IF YOU HAVE SOME
IDEAS, BECAUSE IT'S REALLY
SOMETHING THAT IS PROVIDING
TECHNOLOGICAL LIMITS NOW TO WHAT
WE CAN SEE.
>> SO WE HAVE ONE FINAL QUESTION
FROM YOUR COLLEAGUE, CARLO.
THIS IS SORT OF AN OPEN-ENDED
QUESTION BUT I THINK IT'S
SPECIFICALLY IN YOUR EXPERIENCE,
COULD YOU COMMENT ON THE PROCESS
FOR GETTING INTELLECTUAL
PROPERTY PROTECTED BY NIH?
OBVIOUSLY THE ANSWER TO THAT --
MAYBE WE SHOULD ASK PHIL.
IT'S A LONG ANSWER.
BUT DO YOU WANT TO SAY IN TERMS
OF YOUR CONTRIBUTIONS WHAT
ISSUES YOU FACED?
>> WELL, I MEAN, I COULD HAVE
GIVEN A WHOLE HOUR-LONG SAGA
ABOUT INTELLECTUAL PROPERTY
ISSUES.
BUT I DIDN'T THINK THAT WAS
GOING TO BE AS INTERESTING, EVEN
THOUGH, YOU KNOW, MAYBE THERE
ARE SOME PEOPLE IN THE AUDIENCE
WHO WOULD HAVE LIKED TO HAVE
HEARD THAT.
BUT GENERALLY IF YOU HAVE AN
IDEA, YOU GO TO YOUR TECHNOLOGY
TRANSFER COORDINATOR IN YOUR
INSTITUTE AND YOU FILL OUT AN
EMPLOYEE INVENTION REPORT, AND
THAT GETS CONSIDERED AND IT MAY
GET FILED BY A LAW FIRM OR BY
THE OFFICE OF TECHNOLOGY
TRANSFER.
AND THAT REALLY IS THE BEST WAY
TO PROTECT GOVERNMENT OWNED
INTELLECTUAL PROPERTY.
IT IMPORTANT THAT EVERYBODY
KNOWS IF THEY INVENT STUFF AT
THE NIH, THAT THEY'RE NOT REALLY
THE OWNER, THEY END UP ASSIGNING
TO THE GOVERNMENT, AND THE
GOVERNMENT DOES WITH IT WHAT
THEY WANT.
BUT WE HAVE A VERY WELL
ESTABLISHED PROGRAM FOR
INVENTING THINGS AND
DISSEMINATING THEM.
ONCE THE PATENTS ARE ISSUED,
THEY CAN BE LICENSED TO
COMPANIES AND THEY VERY OFTEN
WILL TAKE THINGS TO THE FDA TO
GET APPROVAL AND THEN THEY MAY
EVEN FIND THEIR WAY INTO THE
MARKETPLACE.
SO THAT'S SORT OF THE OVERALL
OUTLINE, BUT THERE IS
BASICALLY -- IT WAS PHIL CHEN'S
WORK THAT ALLOWED THIS MECHANISM
TO GO FORWARD IN A SEAMLESS WAY
SO THAT NIH INVENTORS CAN SEE
THINGS THAT THEY DO EEBTL EVENTUALLY
FIND THEIR WAY TO BEING SOLD AS
INSTRUMENTS OR METHODS OR DRUGS
OR WHATEVER.
>> PETER, THANK YOU.
THAT'S THE LAST QUESTION THAT I
HAVE, AND WE'RE A LITTLE BIT
OVER TIME, BUT LET ME THANK YOU
FOR A REALLY FASCINATING,
TERRIFIC LECTURE, AND THANK PHIL
AGAIN FOR MAKING ALL OF THIS
POSSIBLE.
WE REALLY APPRECIATE IT.
ANY FINAL WORDS, PHIL?
>> WOW, THIS HAS BEEN
HEARTWARMING TO HEAR THE
ADVANCES, YOU KNOW, NMR AND MRI
ALL CAME ALONG THROUGH THE
YEARS, AND NIH WAS AT THE
FOREFRONT OF MUCH OF THIS.
I REMEMBER WHEN TED BECKER WAS
DOING THINGS IN THE LAB AND THE
RADIOLOGY DEPARTMENT STARTED
GETTING EQUIPMENT AND SO ON.
FINALLY NOW WE'VE GOT THIS
WONDERFUL NEW TECHNIQUE WHICH
WAS UNHEARD OF BACK THEN.
I HAD NO IDEA THAT SOMETHING
LIKE THIS COULD HAPPEN.
>> WELL, PHIL, TED WAS REALLY A
VISIONARY.
TED WAS A VISIONARY, AND HE
REALLY CREATED AN -- I DON'T
KNOW IF CAN YOU HEAR ME.
HE CREATED AN INFRASTRUCTURE FOR
MRI RESEARCH, WHICH WAS AN
INCREDIBLE STIMULUS FOR MANY,
MANY GREAT INVESTIGATORS ON THE
CAMPUS.
AND WE'RE VERY GRATEFUL TO HIM
AS WELL FOR HIS -- HE WAS THE
PHIL CHEN OF MRI, AND WE'RE VERY
GRATEFUL TO ED BECKER AS WELL
FOR HIS EFFORTS.