>>WELCOME BACK, EVERYONE
IF YOU WERE WITH US YESTERDAY,
AND THOSE JOINING TODAY TO THE
COMBINED WEBINAR ON THE BRAIN
ACROSS THE LIFESPAN, LOOKING AT
TOOLS AND METHODOLOGIES FOR
MEASURING THE CHANGING BRAIN.
YESTERDAY WE HAD A GREAT SET OF
TALKS FOCUSING ON UNDERSTANDING
NEW WAYS, STATE-OF-THE-ART WAYS
OF MEASURING BRAIN STRUCTURE AND
FUNCTION.
WE'RE GOING TO CONTINUE THAT
TODAY WITH ALSO SCALING BACK A
LITTLE BIT, TRYING TO UNDERSTAND
HOW WE CAN BRING SOME OF THOSE
TECHNOLOGIES TO OTHER GEOGRAPHIC
SETTINGS AND AREAS.
TO KICK OFF DAY 2 IT'S MY
PLEASURE TO INTRODUCE DR. RASA
IZADNEGAHDAR, WHO IS THE
DIRECTOR OF THE MATERNAL NEWBORN
CHILD HEALTH DISCOVERY AND TOOLS
TEAM AT THE BILL AND MELINDA
GATES FOUNDATION, A TEAM THAT
FOCUSES ON IDENTIFYING
DEVELOPING AND VALIDATING TOOLS
AND TECHNOLOGIES AS WELL AS
PRODUCTS THAT IMPROVE CHILD AND
MATERNAL NEWBORN HEALTH, AN
IMPORTANT METRIC AGAINST WHICH
TOOLS AND TECHNOLOGIES ARE BEING
EVALUATE AND MEASURED AGAINST.
I'LL TURN TO RASA TO WELCOME US
TO DAY 2 OF THE WORKSHOP.
>> THANKS.
HELLO, COLLEAGUES.
THANK YOU FOR PUTTING TOGETHER A
PACKED DAY YESTERDAY, THE
CELLULAR LEVEL, UNDERSTANDING
WHAT WE'VE LEARNED.
IT IS TRULY INSPIRING AFTER
SEVERAL YEARS OF BEING IN
LOCKDOWN AND NOT IN REAL LIFE
SETTING BUT AT LEAST IN A
VIRTUAL SETTING GETTING TO HEAR
SO MUCH INTERESTING WORK IN THIS
PLACE AND THINK ABOUT POTENTIAL
WE HAVE IN ORDER TO MOVE THIS
FIELD FORWARD TOGETHER FROM THE
GATES FOUNDATION, NIH, AND OUR
COLLABORATORS THAT ARE SHARED
AND SEPARATE.
I TRULY BELIEVE THE PATH AHEAD
OF US IS A UNIQUE ONE.
ONE WHERE THE FIELD IS AT A
TURNING POINT WHERE THERE'S AN
INFLUX OF NEW TOOLS, AN
OPPORTUNITY TO REALLY UNDERSTAND
AND LINK FUNDAMENTAL BIOLOGY TO
PHENOTYPES THAT WE'RE
UNDERSTANDING, THAT WE'RE
SEEING, AND TO TAKE AN APPROACH
TO SCIENCE THAT PURCHASE --
SURPASSES CHALLENGES OF THE
PAST.
WE HAVE AN OPPORTUNITY TO SHIFT
HOW FUNNEL MENTAL UNDERSTANDING
OF DEVELOPMENT MOVES AWAY FROM
SOME OF THE BASICS OF
ANTHROPOMETRY, FOUNDING
PRINCIPLES OF WHETHER TOOLS ARE
USEFUL OR POPULATIONS ARE
LAGGING TO TRUE UNDERSTANDING OF
WHAT'S DEVELOPMENT POTENTIAL
MEANS, NOT JUST BY GROWTH BUT
UNDERSTANDING THE BRAIN, ITS
NEURAL NETWORKS, ITS STRUCTURE
AND FUNCTION AND HOW IT COMES
TOGETHER FUNDAMENTALLY TO HELP
DEVELOP AT A POPULATION LEVEL A
COHORT THAT IS ABLE TO THRIVE
LIVING A HEALTH AND HAPPY LIFE.
THERE ARE THREE THINGS I'D LIKE
TO PUSH US TO CONSIDER AS WE
THINK WITH TECHNOLOGIES ASSESSED
YESTERDAY, OPPORTUNITIES BEFORE
US TODAY.
THE FIRST ONE IS THE TOOLS
THEMSELVES, THESE CON
CONSTITUENT COMPONENTS TO ASSAY,
TO UNDERSTAND, THAT IS AN
ENTIRELY SHIFTING FIELD, WE'RE
TRYING TO UNDERSTAND
COMMONALITIES ACROSS
POPULATIONS, DIFFERENCES, AND
THIS GIVES UNIQUE INSIGHT INTO
THE HETEROGENEITY THAT'S THERE,
GIVES US AN OPPORTUNITY TO NOT
JUST TAKE NEW TOOLS TO PLACES
THAT HAVEN'T BEEN THERE BEFORE
BUT THINK ABOUT TOOLS TO EXTEND
INTO THE HOME TO CORRELATE WITH
WHAT WOULD OTHERWISE HAVE BEEN
IN A SIGNIFICANTLY LIMITED
ACCESS FACILITY OF THE PAST.
THAT'S A LEVEL OF INNOVATION IN
THIS SPACE AND INSPIRES ME AND
OUR TEAM AND COLLABORATORS WITH
YOU TO THINK MORE BROADLY IN
TERMS OF WHO IS BEING MEASURED
WITH THE TOOLS AND WHAT WE'RE
UNDERSTANDING FROM THE
PERSPECTIVES THAT ARE THERE.
CONTINUING TO PUSH TO TURN SOME
OF THE UNDERSTANDING OF WHAT THE
CHANGES ARE INTO MEASURES THAT
CAN BE SCALED EVEN IN RESEARCH
SETTINGS, BUT REDEFINING
RESEARCH SETTINGS TO BE AS
CLOSER TO THE HOME OR FUNCTIONAL
ENVIRONMENT OF THE DEVELOPING
BRAIN AND THE CHILD IS PART OF
OUR GOALS.
THE SECOND IS THE POPULATIONS,
THE COHORTS WE HAVE, THE WAY
THAT WE GO ABOUT IDENTIFYING WHO
BECOMES PARTICIPANTS THAT ARE
SUBJECT TO THE ASSAYS, AND ARE
WORKING WITH US IN TERMS OF THE
MEASURES AND HOW MUCH IS THAT A
PARTNERSHIP WITH THOSE
POPULATIONS, HOW MUCH ARE WE
TAKING THE APPROACH TO IDENTIFY
POPULATIONS THAT ARE NOT JUST
THE EASIEST ONES TO FIND, THAT
ARE NOT THE ONES THAT REALLY ARE
DEVELOPING ON PACE WITH WHAT WE
WOULD LIKE TO SEE, OR THE ONES
THAT HAVE DEFINITIVE CHALLENGES
THAT HAVE LED THEM TO COME TO
CARE, BUT REALLY LOOKING AT WHO
COMPRISES SOME OF THE RESIDUAL
MORBIDITY AND LAGGING
DEVELOPMENTS IN THE COMMUNITY,
HOW DO WE REACH THOSE
POPULATIONS, HOW DO WE NOT JUST
TAKE THE TOOLS TO WHERE IT'S
EASIEST AT THE PORT OF ENTRY TO
BE ABLE TO UNDERSTAND WHAT THEIR
VALUE IS BUT REALLY PUSH INTO
COMMUNITIES ALONGSIDE THE VOICES
OF FOLKS IN THOSE COMMUNITIES IN
TERMS OF HELPING UNDERSTAND
WHERE AND WHAT NEURODEVELOPMENT
LOOKS LIKE.
AND THAT BRINGS ME TO THE THIRD
ONE, WHICH IS THE APPROACH WE
USE IN BRINGING TOGETHER THESE
COHORTS WITH THE TOOLS.
I FUNDAMENTALLY BELIEVE THAT
SHEDDING LIGHT ON THE TRAJECTORY
OF NEURODEVELOPMENT IS ABOUT AND
CAN BE ABOUT EQUITY.
IT CAN BE ABOUT UNDERSTANDING
HOW UNDERSERVED POPULATIONS,
WHETHER THEY ARE IN THE U.S. OR
WHETHER THEY ARE GLOBALLY, ARE
IMPACTED BY SOME OF THE
STRUCTURAL BIASES THAT ARE
THERE, WHEREVER THEY MAY BE,
SOME ENVIRONMENTAL FACTORS THAT
ARE THERE, AND SOME OF THE
SPECIFIC INHERENT ASPECTS OF THE
ENVIRONMENTS THEY LIVE IN AND
HOW DO WE ADDRESS THOSE.
IF WE TAKE BROAD APPROACH TO
WHAT TOOLS CAN DO, IN TERMS OF
WHERE THEY CAN GO, EXPANSIVE IN
TERMS OF COHORTS WE LOOK AT,
DOWN TO GRANULAR DETAIL, NOT
JUST A CROSS-SECTIONAL
ASSESSMENT FROM WHICH WE
EXTRAPOLATE GENERALIZATIONS
ACROSS POPULATIONS BUT DIG INTO
UNDERSTANDING HETEROGENEITY OF
NEURAL DEVELOPMENT ACROSS
POPULATIONS, ACROSS SETTINGS, I
THINK WE REALLY HAVE THE
OPPORTUNITY TO BRING FORTH AN
UNDERSTANDING THAT GOES BEYOND
SOME OF THE IMBALANCES THAT HAVE
EXISTED IN THIS FIELD, INCLUDING
SPECIFIC FOCUS ON HIGH INCOME
SETTINGS, HIGH-INCOME
POPULATIONS, AND REALLY ALLOWS
US TO DIG DEEPER INTO THE
TRAJECTORY OF NEURODEVELOPMENT
AS IT UNFOLDS FOR ALL BECAUSE
THE POWER IN WHAT WE HAVE IS
TRANSCENDENT OF THOSE DIVISIONS
AND QUALIFICATIONS AND WE HAVE
BEFORE US AS WE SAW YESTERDAY
AND WILL HEAR ABOUT TODAY SOME
OF THE TOOLS TO GET AT.
SO FOR ME IT'S REALLY ABOUT
PARTNERING WITH THE COMMUNITIES
AND POPULATIONS TO BE ABLE TO
ACHIEVE MEANINGFUL SCIENCE,
MEANINGFUL DATA THAT HELPS TO
MOVE THE FIELD FORWARD.
I'M EXCITED HOW THE DAY WILL
UNFOLD AND LOOK FORWARD TO
TAKING THIS ON AND APPRECIATE
EACH OF YOU WHO CONTRIBUTED TO
MAKING THIS POSSIBLE AND MOVING
THE FIELD FORWARD TOGETHER.
THANK YOU.
>> THANK YOU FOR THOSE WELCOMING
REMARKS.
IN A MOMENT WHEN THE SLIDES COME
UP I'D LIKE TO GIVE A SHORT
REMINDER OF TODAY'S EVENTS AND
HOW TO USE VIRTUAL SYSTEMS.
STILL SEEING THE CONTENT SHARING
IS LAUNCHING.
HERE WE ARE.
YOU HAVE CANS TO THE NEXT SLIDE.
SO YOU CAN FIND AGENDA AND BIOS
ON THE MEETING WEBSITE, LINK IN
THE UPPER RIGHT-HAND CORNER OF
THE SLIDE.
SO THE FIRST SESSION TODAY WILL
BUILD OFF THE EXCITING WORK
PRESENTED YESTERDAY, AND FOCUS
ON STATE OF THE ART IN MEASURING
BRAIN ACTIVITY OVER TIME.
AND FOLLOWING THAT SESSION WE'LL
EXPAND ON SOME OF THE IDEAS
MENTIONED IN YESTERDAY'S PANEL,
IN A PANEL FOCUSED ON SCALING
TECHNOLOGIES FROM THE INDIVIDUAL
TO POPULATION LEVELS
PARTICULARLY IN LOW AND MIDDLE
INCOME SETTINGS.
FINALLY, WE HAVE THE REAL
PRIVILEGE OF HEARING CLOSING
THOUGHTS FROM DR. JOHN NGAI,
DIRECTOR OF THE NIH BRAIN
INITIATIVE.
THIS LAST HALF HOUR WILL BE AN
OPEN FORUM MODERATED BY DR. NGAI
FOR FUTURE DIRECTIONS GLEANED
FROM THE PAST TWO DAYS OF TALKS
AND DISCUSSIONS.
I HOPE YOU CAN STAY TUNED TO BE
PART OF THAT OPPORTUNITY.
NEXT SLIDE PLEASE.
AS A REMINDER TO AUDIENCE
PARTICIPATING THROUGH THE
VIDEOCAST WE'LL SAVE ALL
QUESTIONS FOR AFTER THE
PRESENTATIONS BUT YOU CAN BE
SUBMITTING YOUR QUESTIONS AND
COMMENTS THROUGH THE LIVE
FEEDBACK SYSTEM THROUGHOUT THE
MEETING.
THIS IS ACCESSED THROUGH THE
SEND LIVE FEEDBACK BUTTON BELOW
THE LIVE FEED ON THE VIDEOCAST
PAGE.
YOUR CONTRIBUTION MATTERS SO
FEEL FREE TO SUBMIT YOUR
THOUGHTS.
NEXT SLIDE.
I WANT TO THANK AGAIN EVERYONE
THAT'S CONTRIBUTED, AND
SPECIFICALLY THANK DR. SEAN
DONEY, ON THE BILL AND MELINDA
GATES FOUNDATION, AND SPEAKERS
AND PANELISTS FROM YESTERDAY FOR
DELIVERING GREAT TALKS AND
DISCUSSION, I LOOK FORWARD TO
HEARING WHAT'S IN STORE FROM THE
SPEAKERS TODAY.
NOW I'M GOING TO TURN THE
PROGRAM OVER TO HELENA.
>> HELLO, I'M A PROGRAM OFFICER
AT NICHD, I WILL INTRODUCE DR.
TERRY JERNIGAN, OUR MODERATOR, A
DISTINGUISHED PROFESSOR,
DIRECTOR OF THE CENTER FOR HUMAN
DEVELOPMENT AT THE UNIVERSITY OF
CALIFORNIA, SAN DIEGO.
SHE HAS STUDIED HUMAN BRAIN,
FOCUSING ON AGING,
NEURODEVELOPMENT,
NEUROPSYCHIATRIC AND SUBSTANCE
USE DISORDERS AND
NEURODEGENERATIVE DISORDERS.
FOR THE LAST DECADE, RESEARCH
INTERESTS HAVE BEEN DEVELOPING
MIND AND BRAIN, WITH FOCUS ON
DYNAMIC NEURODEVELOPMENT OF
PROCESSES THAT GIVE RISE TO
HUMAN INDIVIDUALITY AND THOSE
THESE ARE AFFECTED BY
EXPERIENCE, SUBSTANCE EXPOSURE,
AND GENETIC VARIATION AND OTHER
VECTORS.
CO-DIRECTOR OF COORDINATING
CENTER FOR ABCD STUDY, HAS
SERVED ON THE NATIONAL ADVISORY
COUNCIL ON DRUG ABUSE AND
COUNCIL OF COUNCILS OF THE
NATIONAL INSTITUTES OF HEALTH,
CURRENTLY SERVES ON THE NIH
HELPING END ADDICTION LONG-TERM,
"HEAL," MULTI-DISCIPLINARY WORK
GROUP, SCIENTIFIC ADVISORY GROUP
OF SEVERAL ORGANIZATIONS IN THE
UNITED STATES AND EUROPE.
PLEASE WELCOME DR. TERRY
JERNIGAN.
TAKE IT AWAY.
>> THANK YOU FOR THAT.
THANKS TO THE ORGANIZERS FOR
INVITING ME TO JOIN YOU TODAY.
I MUST SAY I REALLY APPRECIATE
THE REMARKS OF DR. IZADNEGAHDAR
WHO SET THE STAGE FOR THIS
SESSION, AND I HOPE THAT YOU'LL
SEE SOME RESONANCE BETWEEN MY
REMARKS AND YOURS.
LET ME START US OFF TODAY BY
BRINGING ATTENTION TO THIS
REMARKABLE REPORT, NEXT SLIDE
PLEASE, THAT APPEARED A FEW DAYS
AGO NOW IN "NATURE" AUTHORED BY
HUNDREDS BUT FOR WHICH THE LEAD
JUNIOR AND SENIOR AUTHORS ARE
LISTED HERE.
THEY COMBINE BRAIN IMAGING DATA
FROM OVER 100,000 INDIVIDUAL
PARTICIPANTS, RANGING IN AGE
FROM 16 POST-CONCEPTION WEEKS TO
100 YEARS OF AGE.
NOW, THIS SESSION IS TITLED,
MEASURING BRAIN ACTIVITY, AND SO
LET ME CLARIFY.
ALTHOUGH WE WILL HEAR VERY
INTERESTING THINGS ABOUT THE USE
OF MRI TO MEASURE BRAIN
ACTIVITY, THIS PAPER REPORTS
ONLY ON VERY COMMON BRAIN
IMAGING PHENOTYPES PRODUCED WITH
WELL-STANDARDIZED THOUGHTS, FROM
WHAT WE REFER TO AS STRUCTURAL
NEUROIMAGE, WHAT I REFER TO AS
BIOLOGY NEUROIMAGING, VOLUMES OF
THE CEREBRAL HEMISPHERE,
SEPARATE VOLUMES OF THEIR GRAY
AND WHITE MATTER, AND SEPARATE
VOLUMES OF THE SUBCORTICAL AND
CORTICAL STRUCTURES, AVERAGE
THICKNESS OF THE CORTEX AND THE
SURFACE AREA OF THE CORTEX.
AND THIS FIGURE'S MEANT TO
HIGHLIGHT FOR THESE GLOBAL BRAIN
PHENOTYPES THAT THE LIFESPAN
TRAJECTORIES THEY EXHIBIT ARE
DISTINCT, ALMOST ALL
NON-MONOTONIC, DIFFERING WITH
RESPECT TO PEAKS, INFLECTION
POINTS IN THE LIFE PAN, IN
PERIODS OF MAXIMAL AGE-RELATED
CHANGE.
SO THOUGH WE THINK OF THESE AS
ANATOMICAL MEASURES, THEY ARE
DERIVED FROM DISTRIBUTIONS OF
SIGNAL VALUES DIRECTLY RELATED
TO THE UNDERLYING BIOLOGY OF THE
TISSUE WITHIN THE SAMPLE SPACE.
SO, THESE CHANGES MUST REFLECT
ONGOING CELLULAR ALTERATIONS
WHICH ALMOST CERTAINLY INCLUDE,
DEPENDING ON AGE RANGE, CELL
PROLIFERATION, DIFFERENTIATION,
BUT ALSO ELIMINATION OF
OVER-PRODUCED CELLS, CELL
PROCESSES, CHANGING PATTERNS OF
STRUCTURAL CONNECTIVITY,
CHANGING CELL PHENOTYPES, ET
CETERA.
AND THOUGH THIS SLIDE SHOWS ONLY
THE TRAJECTORIES FOR THESE
GLOBAL PHENOTYPES, ELSEWHERE IN
THE PAPER RESULTS ARE PRESENTED
TO ILLUSTRATE SUBSTANTIAL
ANATOMICAL HETEROCHRONICITY IN
THE TRAJECTORIES ACROSS
DIFFERENT REGIONS WITHIN THE
CEREBRAL CORTEX, FOR EXAMPLE, SO
EVEN A MUCH MORE COMPLEX AND
HETEROCHRONOUS PATTERN.
EVEN THIS VERY GLOBAL ANATOMICAL
VIEW OF THE LIFESPAN OF THE
HUMAN BRAIN, IT IS OBVIOUS ITS
BIOLOGICAL STATE IS NEVER
STABLE.
IT'S SUBSTANTIALLY AGE
DEPENDENT, AND IS CHANGING AT
LEAST SUBTLY THROUGHOUT THE
ENTIRE LIFESPAN.
AS WE LISTEN TO THE FASCINATING
PRESENTATIONS IN THIS SESSION,
OF THE MANY WAYS WE CAN OBSERVE
BRAIN ACTIVITY, WE SHOULD KEEP
IN MIND ALMOST ALL DIFFERENCES
IN BRAIN FUNCTION AMONG
INDIVIDUALS IN THE POPULATION
INCLUDING THOSE THAT MARK BRAIN
DYSFUNCTION, OF PARTICULAR
INTEREST TO US HERE, EMERGE
GRADUALLY.
TRUE INTERACTIONS BETWEEN THESE
AGE-DEPENDENT BIOLOGICAL
PROCESSES, AND A WIDE ARRAY OF
RELEVANT EXPERIENCES AND
ENVIRONMENTAL EXPOSURES, THAT
ACT TO SHAPE THE BRAIN'S
FUNCTIONAL RESPONSES.
IT FOLLOWS THEN THAT
UNDERSTANDING THE ORIGINS OF
ADVERSE OUTCOMES, MECHANISMS
THAT CONTRIBUTE TO THEIR
PROGRESSION, AND THOSE THAT
COULD PREVENT OR MITIGATE THEM,
WILL REQUIRE A DELIBERATE PLAN
TO CONNECT THE DOTS ACROSS
LEVELS, SCALES, PARADIGMS, AT A
GIVEN AGE, AND THEN ACROSS THESE
SETS OF OBSERVATIONS AT
DIFFERENT AGES OF PEOPLE AND
SOMETIMES EXPERIMENTAL ANIMALS.
NEXT SLIDE.
AS WE ALL KNOW HERE, AT SOME
LEVEL AT LEAST, THE JOB OF THE
BIOLOGICAL HUMAN BRAIN IS TO
EXTRACT SIGNIFICANT AND
MEANINGFUL INFORMATION FROM THE
ENVIRONMENT, TO ENCODE IT IN A
BIOLOGICALLY INSTANTIATED MODEL
OF THE WORLD, AND THEN
ADAPTIVELY TO MODIFY THAT MODEL
IN RESPONSE TO MISMATCHES
BETWEEN THE MODEL AND THE WORLD.
AND AS EVERY OBSERVATION OF
BRAIN ACTIVITY WE MAKE REFLECTS
A COMBINATION OF THE BIOLOGICAL
STATE OF THE BRAIN AND STATE OF
THE WORLD DURING THE EPIC OF
DATA COLLECTION, BUT AT LEAST
EQUALLY THE ENTIRE HISTORY OF
BRAIN EXPERIENCE INTERACTIONS,
BOTH PROXIMAL TO THE
OBSERVATIONAL PERIOD AND REMOTE
IN TIME.
SO, ONE OF THE CHALLENGES WE
HAVE IS TO DETERMINE HOW WE CAN
MODEL THESE DISTINCT INFLUENCES,
ON THE BRAIN ACTIVITY THAT WE
OBSERVE, AS WE MOVE TOWARDS
PERSONALIZED NEUROSCIENTIFIC
SOLUTIONS TO MINIMIZE BRAIN
DYSFUNCTION.
NOW, THIS IS A VERY BIG
CHALLENGE, AND I'M NOT SURE HOW
WE ADDRESS IT, BUT I WOULD
SUGGEST THAT WE CONTINUE THE
TREND WHICH IS WELL ILLUSTRATED
IN THE WORK WE'LL HEAR ABOUT
NEXT, TO WORK IN LARGER, EVER
LARGER, COLLABORATIVE TEAMS TO
EXPAND THE RANGE OF TECHNIQUES
TO INVESTIGATE NEURAL CORRELATES
OF THESE THINGS OBSERVABLE IN
VIVO.
IMPORTANTLY, TO FIND WAYS TO
SITUATE OUR FINDINGS WITHIN A
LIFESPAN PERSPECTIVE BY
INCLUDING AGE AS EXPERIMENTAL
VARIABLE IN OUR RESEARCH AND
WHENEVER POSSIBLE BY OBSERVING
CHANGES IN BRAIN ACTIVITY OVER
TIME AND IN CONTEXT IN
LONGITUDINAL RESEARCH DESIGNS
AND STUDIES.
OKAY.
SO MORE THAN ENOUGH FROM ME.
LET'S MOVE TO OUR FIRST SPEAKER,
ELLEN GRANT.
DR. GRANT IS PROFESSOR OF
PEDIATRICS AND RADIOLOGY AT THE
HARVARD MEDICAL SCHOOL, AND
FOUNDING DIRECTOR OF THE FETAL
NEONATAL NEUROIMAGING AND
DEVELOPMENTAL SCIENCE CENTER,
HOLDS BOSTON CHILDRENS CHAIR IN
NEONATOLOGY, CLINICAL
RADIOLOGIST AT THAT HOSPITAL AS
WELL.
HER GROUP DEVELOPS AND OPTIMIZES
TOOLS AND ANALYSIS STREAMS TO
DETECT AND UNDERSTAND NORMAL AND
ABNORMAL BRAIN PHYSIOLOGY AND
DEVELOPMENT.
SHE DOES THIS WORK IN CHILDREN
WITH FOCUS ON YOUNGEST, FETUS
AND INFANTS, SHE'S WORKED WITH
MRI, MEG, AND NEAR-INFRARED
SPECTROSCOPY, NOVEL MRI ANALYSIS
AT THE FOREFRONT OF FETAL AND
PLACENTAL MRI, HAS BUILT A NOVEL
PEDIATRIC MEG SYSTEM, PIONEERED
NIRS.
HER TEAM DEVELOPING A
COMPUTATIONAL INFRASTRUCTURE TO
FACILITATE AND SUPPORT DEEP
LEARNING APPROACHES ON LARGE
DATASETS AS WELL AS REALTIME
DATA ANALYSIS.
DR. GRANT IS SENIOR FELLOW OF
INTERNATIONAL SOCIETY OF
MAGNETICS RESONANCE IN MEDICINE,
ON THE BOARD OF SCIENTIFIC
COUNSELORS AT NICHD, 2021
RECEIVED OUTSTANDING
CONTRIBUTION IN RESEARCH AWARD
AMERICAN RESEARCH OF NEUROLOGY
AND IN 2022 GOLD MEDAL AWARD.
FIRST DISTINGUISHED FIRST
SPEAKER, DR. GRANT, PLEASE.
>> THANK YOU VERY MUCH FOR THE
WONDERFUL INTRODUCTION, TERRY.
IT'S AN HONOR TO BE INCLUDED AS
A SPEAKER TODAY.
YOUR COMMENTS FIT INTO THE TALK
I PUT TOGETHER, TALKING ABOUT
ACTIVITY OR FUNCTION IN THE
DEVELOPING BRAIN.
I HAVE DISCLOSURES NOT RELEVANT
TO CONTENT OF THIS TALK.
WHAT I'M GOING TO TALK ABOUT IS
IMAGING FUNCTION IN THE
DEVELOPING BRAIN AND WHEN I TALK
ABOUT THE DEVELOPING BRAIN I
MEAN THE FIRST THOUSAND DAYS
FROM CONCEPT TO TWO POST-NATAL
YEARS.
WE HAVE TO UNDERSTAND DEVELOPING
NEURONAL ACTIVITY, DEVELOPING
COUPLING, DEVELOPING
NEUROMETABOLISM AND MODALITIES
TO CAPTURE EACH, AND IN THE END
HOW MOTION AS MEANS TO INCUR
DEVELOPMENT IN THE DEVELOPING
FUNCTION IN THE FETAL BRAIN.
SO OVERVIEW ABOUT THE DEVELOPING
BRAIN, FETAL MRI IN THE LATE
FIRST TRIMESTER YOU CAN START TO
SEE THE LAYERS, THE INITIAL PART
WHERE THE NEURONS AND GLIA ARE
BORN.
THESE WILL BE THE FUTURE WHITE
MATTER.
THE ZONE IS TRANSIENT WHERE
THERE'S NEURONS THAT TRANSLATE
BEFORE THEY EXTEND INTO THE
CORTICAL PLATE, AND THE CORTICAL
PLATE IS DENSELY PACKED WITH
NEURONS, WILL BECOME THE FUTURE
CEREBRAL CORTEX.
BEGINNING AROUND 12 GESTATIONAL
WEEKS THE SPONTANEOUS ACTIVITY
SUGGESTS THIS IS PREDOMINANTLY
IN THE SUBPLATE ZONE, CONTINUES
UNTIL 26 WEEKS GESTATIONAL AGE,
MOST ACTIVITY IN SYNAPTIC
DEVELOPMENT IS IN THIS REGION.
ENDOGENOUS AND RESPONSIBLE
SPONTANEOUS DRIVEN BY GENETIC
PHENOMENA.
THE FINAL NEURONS ESTABLISH
CONNECTION TO THE CORTICAL
PLACE, BEGINNING OF NEURAL
ACTIVITY.
32 WEEKS GESTATIONAL AGE CORPUS
CALLOSUM CONNECTIONS THAT
DEVELOP INTO THE CORTEX, LONG
RANGE CORTICAL CONNECTIONS
DEVELOP IN THE CEREBRAL CORTEX.
SYNCHRONIZED SENSORY-DRIVEN
NEURAL ACTIVITY.
CIRCUITS WITH ENDOGENOUS
ACTIVITY START FIRST, PRIMARILY
GENETICALLY DRIVEN, GRADUALLY
REPLACED BY ADULT CIRCUITS
INFLUENCED BY THE ENVIRONMENT.
SO AS WE SAID, FIRST TRIMESTER
AND EARLY SECOND,
SYNAPTOGENESIS, SYNAPTIC
DEVELOPMENT GENETICALLY DRIVEN.
LATE SECOND TRIMESTER AND
ONWARD, ENVIRONMENTAL INFLUENCES
ON SYNAPTIC DEVELOPMENT, AT THIS
POINT IN TIME WE DO HAVE EXOMAL
AND SYNAPTIC DEVELOPMENT WITH
INFLUENCES BY THE ENVIRONMENT.
IF WE WANT TO MONITOR NEURAL
ACTIVITY SPECIFICALLY WE NEED TO
PICK UP ELECTROMAGNETTICS
FIELDS.
BECAUSE OF AMNIOTIC FLUID,
PEOPLE HAVE BEEN PICKING UP
MAGNETIC FIELD CHANGE DUE TO
NEURAL ACTIVITY.
AN EXAMPLE OF A SPONTANEOUS
ACTIVITY AFTER REMOVAL OF
MATERNAL AND FETAL HEARTBEAT,
AND RESPONSE TO AUDITORY
STIMULUS WITH FETAL HEAD IS
HERE.
THESE TOOLS ARE CHALLENGING AND
SIGNAL ANALYSIS IS DIFFICULT TO
PERFORM MOTION OF THE FETUS AND
MOTHER, NOISE AND CONTAMINATION
FROM THE ENVIRONMENT.
THESE ARE STILL IN EARLY
DEVELOPMENT, I HAVE FAITH AS WE
MOVE FORWARD THERE WILL BE
IMPROVEMENT IN ANALYSIS
TECHNIQUES AND THESE SYSTEMS TO
BE ABLE TO REALLY PICK UP THE
DEVELOPING FETAL NEURAL
ACTIVITY.
IN TERMS OF LOCAL ACTIVITY AND
HOW IT'S IMPORTANT TO GET THE
NEURAL ACTIVITY ITSELF AS A
COMPLEMENT TO UNDERSTAND RESTING
STATE, I'M SHOWING TYPICALLY
DEVELOPING PERSON ON THE TOP
ROW, CHILD OF CEREBRAL PALSY,
AND THEY WERE WITH DCP, ONE
THROUGH FIVE ORGANIZED IN THE
HOMOUNCULUS.
TO PINPOINT WHERE THE NEURAL
ACTIVITY IS OCCURRING DRIVING
THIS DIGITAL FUNCTION WE NEED TO
GO AFTER THAT NEURAL ACTIVITY.
DTI SHOWS DIFFERENCES, RSFMRI,
ONE IMPORTANT POINT IN
UNDERSTANDING HOW NEURAL
ACTIVITY DRIVES DEVELOPING
CONNECTIVITY AND ALTERED AXONAL
PRUNING AND SYNAPTIC
REORGANIZATION.
THERE ARE DEVICES OPTICALLY
PUMPED MAGNETOMETERS, THE REASON
THEY ARE ADVANTAGEOUS THEY ARE
LESS EXPENSIVE, PROTOTYPE FIELD
MONITOR, THIS IS THE SHIELDED
USED TO PICK UP ACTIVITY, SO
ONGOING WORK IS HAPPENING IN
DEVELOPING THESE OPTICALLY
PUMPED MAGNETOMETERS FOR FETAL
MONITORING AND FETAL ACTIVITY.
THIS IS USED FOR THE DEVELOPING
BRAIN, CENTERS CLOSE TO THE
BRAIN.
WORKING WITH COLLABORATORS HERE
IN COLORADO TO DEVELOP A SYSTEM,
OPTICALLY PUMPED MAGNETOMETERS
GET CLOSER TO THE BRAIN, STILL A
LOT OF WORK TO DEVELOP THIS BUT
THEN WE CAN DO THE MONITORING
WITHOUT LIQUID HELIUM AND
DEVICES ASSOCIATED WITH IT.
IN ENGLAND THEY ARE ALSO
WORKING ON THIS, ALLOWING TO
BETTER LOCALIZE NEURAL ACTIVITY,
STILL MUCH TO BE DONE IN FITTING
TO THE HEAD SO THE HEAD CAN
MOVE.
THE COUPLING IS POORLY
UNDERSTAND DURING DEVELOPMENT.
WE HAVE NEUROVASCULAR RESPONSES
IN THE CONTEXT OF
VASCULOGENESIS, HIGH NEURONAL
AND SYNAPTIC DENSITY, THEY
MIGRATE, EVENTUALLY WITH THE
RESPONSES, THOUGHT TO BE
CRITICAL IN COULD HAVE -- IN
GOVERNING.
WE DO NOT KNOW WHEN THESE
MECHANISMS FULLY DEVELOP AND
DON'T KNOW WHEN THEY BEGIN TO
WORK AS DESCRIBED IN THE ADULTS.
WE HAVE TO BE CAUTIOUS IN
INTERPRETING FUNCTIONAL
NEUROVASCULAR COUPLING STUDIES
IN TERMS OF WHAT THEY MEAN WITH
NEURAL ACTIVITY DURING
DEVELOPMENT.
WE DO KNOW WITH fMRI THERE'S A
DIFFERENT HEMODYNAMIC RESPONSE
THAT CHANGES WITH TIME.
WE SEE PRE-TERM IN GREEN,
NEONATE IN RED, TYPICAL ADULT
RESPONSE IN BLUE.
IT'S IMPORTANT TO UNDERSTAND
THERE ARE THESE CHANGES,
ESPECIALLY IF WE'RE DOING
FUNCTIONAL EXPERIMENTS DURING
THIS RAPID DEVELOPMENTAL PHASE
NEED TO USE INDIVIDUAL
HEMODYNAMIC CURVE TO UNDERSTAND
WHERE THE NEURAL ACTIVITY IS
ORIGINATING.
THE DEOXY HEMOGLOBIN RESPONSE IS
LARGER, SIGNAL INTENSITY GOES
DOWN.
TYPICAL POSITIVE BLOOD VOLUME,
INCREASES, OXYGEN IS HIGHER.
WE SEE DIFFERENT RESPONSES,
NEGATIVE FROM TWO CAUSES,
INSUFFICIENT HYPEREMIA OR
VASOCONSTRICTION, OXYHEMOGLOBIN
INCREASES.
WE'VE EXPLORED THIS IN PRE-TERM
WHERE IS WE SAW NORMAL RESPONSES
AND INVERTED RESPONSES, AND
FOUND THAT AT 4 TO 6 WEEKS IS
THE MOST COMMON TIMES FOR
INVERTED RESPONSE, WITH NORMAL
NADIR, FETAL HEMOGLOBIN
TRANSITIONS TO ADULT HEMOGLOBIN,
HIGH BLOOD FLOW BECAUSE OF LOW
HEMOGLOBIN LEVELS, THEREFORE
VERY LITTLE FUNCTIONAL RESERVE
IN TERMS OF CEREBRAL BLOOD FLOW
DID GIVE RISE TO POSITIVE
RESPONSE.
ANIMAL STUDIES SHOWS BLOOD
PRESSURE CHANGES AS WELL.
WE HAVE TO BE CAUTIOUS.
THERE ARE GAPS IN KNOWLEDGE
ABOUT NEUROVASCULAR COUPLING
ESPECIALLY IN DEVELOPING HUMAN
BRAIN, LOCAL AND SYSTEMIC
FACTORS MAY AFFECT DURING THIS
RAPIDLY DEVELOPING TIME PERIOD.
WE SEE DEVELOPING FUNCTION OF
CONNECTIVITY, IN VIENNA THEY
HAVE SHOWN ASSOCIATION BETWEEN
CORTICAL FUNCTION ACTIVITY
INCREASING WITH GESTATIONAL AGE,
OCCURRING WHEN YOU EXPECT THE
CHILD CORTICAL NEURONS TO ENTER
THE CORTICAL PLATE.
ROIs INCLUDED SUBPLATE.
WE HAVE TO BE CAREFUL IN OUR
INTERPRETATION, WE DON'T KNOW
WHETHER THESE ARE DRIVEN BY
NEURAL ACTIVITY OR BY DEVELOPING
NEUROVASCULAR VOLUME ASSOCIATED
WITH THE CORTICAL -- INSERTION
INTO THE CORTICAL PLATE.
IT'S IMPORTANT TO THINK ABOUT
BALANCING STRUCTURAL FUNCTION
AND CONNECTIVITY AND LEVERAGE TO
UNDERSTAND MORE ABOUT THE
DEVELOPING BRAIN.
THESE ARE A GROUP OF NEONATES WE
STUDIED AND FOUND STRUCTURAL
SUBSTRATE CONNECTIVITY, THEY ARE
LOOKING LIKE THE TYPICAL
CONNECTIVITY PATTERNS, BUT AT
BIRTH DRIVEN BY SOMATOSENSORY
AND SALIENT PROCESSING, MULTIPLE
REGIONS AS WE SEE HERE IN THE
ADULT BRAIN.
THIS IS THE IMPORTANT DYNAMIC
RELATION BETWEEN STRUCTURE AND
FUNCTION AT EARLY AGES, WHERE
EARLY ON IN DEVELOPMENT NEURONS
LATER WILL BE REPURPOSED FOR
OTHER TASKS ARE INVOLVED IN
EARLY DEVELOPING FUNCTION.
AND UNDERSTANDING THIS IS
SOMETHING WE NEED TO PUSH ON TOO
BECAUSE IDEALLY WE WANT TO KNOW
HOW TO LEVERAGE THESE
DIFFERENCES BETWEEN STRUCTURAL
AND FUNCTIONAL CONNECTIVITY TO
OPTIMIZE LATER FUNCTIONAL
PROCESSING.
THOROUGH FIELD OF EXPERIMENTING,
RESTING STATE NETWORKS, USING
PROPAGATION TECHNIQUES TO ALLOW
CONNECTIVENESS INFORMATION TO
PROPAGATE OVER TIME, YOU COULD
PROBE CONNECTIVITY AREAS AND
HAVE LOW CONNECTION STRENGTH,
THEREFORE PLAYING A ROLE IN
OVERALL ANALYSIS WHEN USING ONE
POINT IN TIME.
WE FOUND NO DIFFERENCE IN
STANDARD ACTIVITY BUT PERIPHERAL
CONNECTIONS CAN BE PROBABLY
LONGER TIME, PROPAGATION THROUGH
THESE CONNECTIONS, SIGNIFICANTLY
DIFFERENT IN AUTISM VERSUS
CONTROL, PROBING THESE FEEDER
NETWORKS IS IMPORTANT IN
UNDERSTANDING LATER ADAPTIVITY,
GENETICALLY FORMED NETWORKS,
WHERE PERIPHERAL CONNECTIONS ARE
ADAPTIVE, BEING ABLE TO MONITOR
AND SHAPE THEM IS SOMETHING
REALLY IMPORTANT MOVING FORWARD.
NEURONAL METABOLISM, WE'VE
DEVELOPED THESE DEVICES
QUANTITATIVE DEVICES THAT GO TO
THE BEDSIDE USING OXYGEN
SATURATION AND QUANTITATIVE
MEASURES OF CEREBRAL BLOOD FLOW,
OXYGEN CONSUMPTION OF THE
BEDSIDE, GETTING A GOOD IDEA OF
SYNAPTIC DENSITY, FUNCTIONAL OF
THE CORTEX USING THIS.
AND WHEN WE LOOK AT CHANGES OVER
DEVELOPMENT DURING THE FIRST
YEAR DON'T SEE CHANGES IN OXYGEN
SATURATION BUT MEASURING
CONSUMPTION WE SEE INCREASES
OVER THE FIRST YEAR PARALLELLING
WHAT WAS PICKED UP WITH PRIOR
STUDIES WITH PET AND NEARING
WHAT WE EXPECT TO SEE WITH
SOMATO SYNAPTIC DEVELOPMENT WITH
INCREASING OPTIC CONSUMPTION AS
NUMBER OF SYNAPSES INCREASE.
IN FACT MORE RECENTLY WE'VE
LOOKED AT NEONATES WITH
ENCEPHALOPATHY, TREATED WITH
THERAPEUTIC HYPOTHERMIA, HIGHER
CONSUMPTION CORRELATED AT 2
YEARS OF AGE, POST TREATMENT
CMRO2, MEASURING THE SYNAPSES
THAT SURVIVAL AND ARE FUNCTIONAL
AFTER TREMENDOUS, CORRELATED
WITH COGNITIVE OUTCOMES,
OUTPERFORMED MRI BECAUSE 50% OF
MRIs ARE NORMAL FINDINGS, YOU
SEE COGNITIVE SCORE IN THE MILD
RANGE.
THESE MEASURES ARE REALLY THINK
POTENTIAL MEASURE OF PREDICTING
LATER COGNITIVE FUNCTION.
WE'RE MOVING TO HIGH TEMPORAL
RESOLUTION MONITORING, YOU CAN
SEE CONSUMPTION, EXTRACTION
DIFFRACTION, TO BETTER EXPLORE
COUPLING.
YOU SEE TRANSITION FROM AWAKE TO
SLEEP, DECREASE IN CMRO2 WITH
THAT TRANSITION.
WE ALSO HAVE TO THINK ABOUT
USING SPECTROSCOPY TO UNDERSTAND
UNDERLYING METABOLIC
DEVELOPMENT.
IT'S IMPORTANT TO UNDERSTAND
BALANCE BETWEEN EXCITATORY AND
INHIBITORY NEUROTRANSMITTERS.
THOSE PLAY A CRITICAL ROLE
UNDERSTANDING EARLY BRAIN
FUNCTIONAL DEVELOPMENT,
IMPORTANT ROLE IN RESTING NATURE
NEURAL ACTIVITY, GLUTATHIONE
PROVIDES INFORMATION ON
OXIDATIVE STRESS HELPFUL TO
UNDERSTAND HOW NETWORKS ARE
PRUNED AND WHETHER OXIDATIVE
STRESS MAY PLAY A ROLE ON
PRUNING.
MRI PROVIDES INSIGHT, IN TERMS
OF WHAT INTERVENTIONS OR
STRATEGIES WE MIGHT USE TO
OPTIMIZE OUTCOMES.
THESE MOLECULES TARGET IN THE
FUTURE STUDIES.
FETAL MOTION TO INFER FUNCTION,
WE'VE BEEN DOING FETAL IMAGING,
EVERY THREE SECONDS WE CAN SEE
THE FETUS MOVING.
WE STARTING USING MACHINE
LEARNING STRATEGY TO TRACK
JOINTS AND FETAL MOTION TO
QUANTIFY FETAL MOTION OVER TIME.
AND USING THIS QUANTIFICATION OF
FETAL MOTION WE'VE-STARTING TO
EXPLORE HOW IT CHANGES WITH
DEVELOPMENT.
WHAT WE SEE IN FETUSES LESS THAN
30 GESTATIONAL WEEKS MOTION OF
UPPER EXTREMITY MORE THAN MOTION
OF THE SIGNIFICANTLY MORE THAN
MOTION OF THE LOWER EXTREMITIES.
THAT MIGHT BE REFRACTION OF
DEVELOPING NEURAL ACTIVITY.
MOVEMENT OF UPPER LIMBS ARE ALSO
ENVIRONMENTALLY DRIVEN.
CORTICOSPINAL TRACK DOESN'T
REACH THE AREA UNTIL 29 OR 30
WEEKS, WE THINK LEG MOVEMENT IS
LOWER BECAUSE OF LACK OF
CORTICOSPINAL TRACK INNERVATION,
WAYS WE CAN UNDERSTAND FETAL
BEHAVIOR IN UTERO AND FUNCTION
BY LOOKING AT PHYSICAL MOTION OF
THE FETUS DURING DEVELOPMENT.
THERE ARE MANY EMERGING TOOLS TO
HELP CHARACTERIZE DEVELOPING
BRAIN FUNCTION.
WE NEED TO INTERPRET IN THE
CONTEXT OF KNOWN DEVELOPMENTAL
STAGE.
RESPONSE IN ADULT IS NOT THE
SAME AS RESPONSE IN NEONATE.
AGAIN, FETUS BELOW 25 WEEKS
GESTATIONAL AGE IS ENDOGENOUS
ACTIVITY SO WE NEED TO
UNDERSTAND THAT AND BETTER
UNDERSTAND UNDERLYING MECHANISMS
THAT DRIVE DEVELOPMENT OF
NEURONAL ACTIVITY, NEUROVASCULAR
COUPLING AND METABOLISM.
THERE'S STILL MUCH UNKNOWN.
THERE'S MUCH TO LEARN BY USING
IMAGING TO GUIDE INTERVENTION
THAT CAN IMPROVE LONG-TERM
OUTCOMES.
I THANK MY TEAM AND
COLLABORATORS AT M.I.T. AND
POSTDOCS AND STUDENTS THAT
HELPED WITH THIS WORK.
THANK YOU.
>> THANK YOU, DR. GRANT.
WE'RE BEHIND SO WE'RE GOING TO
GO RIGHT INTO THE NEXT
PRESENTATION, THE SECOND SPEAKER
DR. NOA OFEN, DIRECTOR OF THE
COGNITIVE AND BRAIN DEVELOPMENT
LABORATORY AT WAYNE STATE
UNIVERSITY, INVESTIGATES
STRUCTURAL AND FUNCTIONAL BRAIN
DEVELOPMENT ACROSS A WIDE AGE
RANGE OF TYPICALLY DEVELOPING
CHILDREN AND ADULTS, USING TESTS
OF COGNITIVE ABILITIES COMBINED
WITH NEUROIMAGING TECHNIQUES,
RESEARCH PROGRAM AIMS TO
ELUCIDATE MECHANISMS
CONTRIBUTING TO HUMAN MEMORY
DEVELOPMENT CHARACTERIZED HOW
CHANGES IN THE FUNCTIONAL AND
STRUCTURAL ORGANIZATION OF THE
BRAIN SUPPORTS GROWTH TO ENCODE,
MAINTAIN, RETRIEVE INFORMATION.
SHE ALSO INVESTIGATES
ENVIRONMENTAL AND GENETIC
FACTORS THAT ACT AS MODIFIERS OF
TYPICAL DEVELOPMENT AND PURSUES
RAMIFICATIONS FOR CLINICAL
POPULATIONS SUCH AS CHILDREN
WITH EPILEPSY.
CONDUCTED RESEARCH AND STANFORD
AND M.I.T. BEFORE JOINING WAYNE
STATE IN 2011.
>> THANK YOU VERY MUCH.
SO, IN MY TALK I'M GOING TO --
FIRST, THANK YOU FOR THE
INVITATION TO SPEAK IN THIS
EXCITING WORKSHOP.
AND I WANT TO TAKE IT TO OLDER
AGE, THE FOCUS I'M GOING TO BE
TAKING ON THE CHALLENGE OF
LINKING WITHIN COGNITION AND
BRAIN DEVELOPMENT.
THE CHILD COMES INTO THE WORLD
WITH VERY LIMITED ABILITY TO
INTERACT, OVER UNFOLDING OF MANY
PROCESSES LEARN TO WALK, TALK,
CRIME, FORMAL EDUCATION, READ,
WRITE, MATH, CHESS, MUSIC, MAYBE
GET TO NEUROSCIENCE, UNDERLYING
ABILITIES IS UNFOLDING OF MANY
DEVELOPMENTAL PROCESSES
SUPPORTED BY DEVELOPMENT OF THE
BRAIN.
THE BIG QUESTION I POSE IN MY
RESEARCH, TRYING TO MAP THOSE
COGNITIVE DEVELOPMENTAL CHANGES
TO THE DEVELOPMENT OF THE BRAIN.
IN A WAY YESTERDAY WE TALKED
ABOUT THE BIG QUESTION, MODEL
SYSTEMS, SO IN A WAY WHAT I'M
DOING IS LIMITING THIS BIG SPACE
OF COGNITION INTO JUST BEING
INTERESTED IN MEMORY AND
DEVELOPMENT OF MEMORY.
TO DO THIS WE NEED TO BE VERY
CAREFUL IN CHARACTERIZING
MEMORY, CHARACTERIZING COGNITIVE
SPACE WE'RE TRYING TO MAP, HOW
DOES BRAIN FUNCTION GIVE RISE
TO, AND IN THIS TALK THE FOCUS
IS GOING TO BE ON BRAIN
FUNCTION, USING FUNCTIONAL BRAIN
METHODS SUCH AS FUNCTIONAL MRI,
INTRACRANIAL AS I'LL SHOW LATER,
THINKING ABOUT BRAIN FUNCTION
USING TO LOOK AT NEURAL
CORRELATES UNDERLYING COGNITIVE
PROCESSES.
WE'VE HAD TALKED ABOUT YESTERDAY
THAT REALLY WE CAN ALSO QUANTIFY
SIGNAL WORK LOOKING AT THE BRAIN
STRUCTURE OF CHANGES SUCH AS ONE
PRESENTED EARLIER IN THE
INTRODUCTORY REMARKS TO THIS
SESSION BY DR. JERNIGAN, AND
PRESIDENT -- THE WAY I THINK,
THEY PROVIDE CONSTRAINTS TO THE
BUILDUP OF CAPACITY, COGNITIVE
CAPACITY ACROSS THE LIFESPAN.
SO, WE FOCUS ON BRAIN FUNCTION,
I'M GOING TO SHOW THE ONE
EXAMPLE, FIRST WHAT'S VERY
EXCITING ABOUT BRAIN FUNCTION WE
CAN TAKE SNAPSHOTS OF THE BRAIN
AND FUNCTION, FOR EXAMPLE IN
MEMORY ACROSS DIFFERENT STAGES
OF THE MEMORY FROM ENCODING TO
THE STORAGE AND MEMORY RETRIEVAL
WITH NO FUNCTIONAL NEUROIMAGING,
PROVIDING MORE THAN PERFORMANCE
ALONE.
AN EXAMPLE, SHOWING PICTURES,
ASKING PARTS TO LABEL, SO WE
KNOW THEY ARE PAYING ATTENTION,
ALSO ASK OUTSIDE THE SCANNER
WHETHER THEY REMEMBER, SOME DO,
SOME FORGET, WHICH ALLOWS US TO
SORT BRAIN SIGNALS RECORDED WHEN
THEY STUDIED THE PICTURES BASED
ON SUBSEQUENT MEMORY OF THE
PICTURES, GIVING US A CONTRAST
TO SEE WHAT THE BRAIN WAS DOING
WHEN THEY LATER REMEMBERED
COMPARED TO WHEN THEY LATER
FORGOT.
BEFORE WE GO AND LOOK AT WHAT
THE BRAIN WAS DOING, IT'S
IMPORTANT THAT WE TAKE A LOOK AT
THE AGE DIFFERENCES BECAUSE WE
WANT TO UNDERSTAND, GET THE
CORRELATES OF WHAT COULD
COGNITIVELY BECOME MORE ABLE TO
DO, AS YOU CAN SEE HERE IN THE
AGE RANGES I FOCUS ON, ABOUT 5,
ALL THE WAY IN A CROSS-SECTIONAL
CONTINUOUS VARIABLE, WE SEE THAT
THERE IS INDEED AN INCREASE IN
THE ACCURACY, INCREASE IN MEMORY
PERFORMANCES.
NOW WE HAVE BRAIN MEASURES TO
LOOK AT WHAT EXPANSES, THE FIRST
QUESTION WE WERE ASKING IS
WHEREAS IN WHERE IN THE BRAIN
DOES MEMORY ACTIVATION DIFFER BY
AGE.
BUT WHAT WE WANT TO UNDERSTAND
IS HOW.
HOW DOES THE BRAIN SUPPORT
MEMORY AND I'LL GET TO THE HOW
LATER.
THIS IS THE FIRST STUDY ON TRIAL
BY TRIAL LEVEL LOOKING AT WHAT
WAS REMEMBERED VERSUS FORGOTTEN
ACROSS ALL INDIVIDUALS WHO FOUND
ACTIVATIONS WE EXPECT IN THE
MEDIAL TEMPORAL LOBE, CRUCIAL
FOR MEMORY, HIPPOCAMPUS IN
AMNESIA, PRE-FRONTAL CORTEX,
ALSO IMPORTANT FOR MEMORY,
SPECIFIC SUBTLE EFFECTS ON
MEMORY THAT HAPPEN TO BE THOSE
MORE PROTRACTED ACROSS
DEVELOPMENT.
WHEN WE LOOK ACROSS AGE WE FIND
ACTIVATIONS IN THE MEDIAL
TEMPORAL LOBE WAS STABLE ACROSS
AGE BUT DID FIND INCREASE IN
REGIONS IN THE PREFRONTAL CORTEX
IN THE WAY THEY SUPPORT
SUBSEQUENT MEMORY.
LEADING US TO THINK THE
FUNCTIONAL MATURATION OF THE
PREFRONTAL CORTEX IS RELATED TO
MEMORY DEVELOPMENT, MIRRORING
STRUCTURAL DEVELOPMENT WHICH WE
KNOW IS MORE PROTRACTED FOR
THESE REGIONS, SPECIFICALLY
PRE-FRONT CORTEX.
SO WE KNOW, WE WANT TO MOVE
BEYOND THAT INCREASING OUR LENS,
FOCUSING ON PREFRONTAL CORTEX
INCREASING MEASURES WE'RE
LOOKING INTO BASED ON WHAT
ADVANCES IN RESEARCH.
YOU SEE ACTIVATION ACROSS A
LARGER SAMPLE IN PREFRONTAL
CORTEX, POSITIVE REGIONS IN
WHICH WE HAVE MORE ACTIVATION TO
REMEMBER COMPARED TO LATER
FORGOT, ALSO SEE ROBUST
BLUE-COLORED REGION HERE,
REGIONS WITH INCREASED
DEACTIVATION FOR HITS COMPARED
TO MISSES.
TURNS OUT TO BE BOTH IMPORTANT
FOR THE AGE DIFFERENCES,
SUPPORTING AGE DIFFERENCES IN
ACCURACY.
SO IN THIS CASE WE CAN SEE THAT
WITH AGES INCREASE IN ACTIVATION
FOR HIT BUT ALSO ROBUST INCREASE
IN DEACTIVATIONS FOR HITS, AMONG
SUPERIOR FRONTAL REGIONS, IT WAS
SPECIFICALLY THESE REGIONS THAT
EXPAND AGE-RELATED IMPROVEMENT
OR DEVELOPMENT OR GAINS IN
PERFORMANCE, TAKES US TO WHERE,
HOW COULD THAT BE, AND MAYBE
LINK TO REGIONS DOING MORE
THOUGHT SUPPRESSION AND THINKING
IT'S NOT JUST YOU NEED TO PAY
MORE ATTENTION BUT MAYBE REDUCE
OR BE ABLE TO EFFECTIVELY ENGAGE
INTRUSIVE THOUGHTS TO PERFORM
OVERALL.
MORE INTO MOVING FORWARD FROM
THE WHERE IS LOOKING AT ANALYSIS
LOOKING AT BRAIN CONNECTIVITY,
FUNCTIONAL BRAIN CONNECTIVITY,
THE FUNCTION, THERE'S MORE FOR
SUBSEQUENTLY REMEMBERED COMPARED
TO SUBSEQUENTLY FORGOTTEN ITEMS.
AND WHAT WE FIND THOSE THAT AGE
DIFFERENCES IN THE CONNECTIVITY
PATTERNS OF BOTH POSITIVE AND
NEGATIVE SUBSEQUENT MEMORY, IN
BOTH CASES WITH AGE THOSE WERE
MORE CONNECTED, RESPECTIVELY,
WITH MEDIAL TEMPORAL LOBE.
NOW WE TAKE IT INTO A MORE
NETWORK PHENOMENA THAT EXPLAINS
AGE-RELATED INCREASES IN
COGNITION IN THIS CASE MEMORY.
WE WANTED TO KNOW HOW BRAIN
ACTIVITY SUPPORTS MEMORY
DEVELOPMENT, WOULDN'T IT BE
GREAT IF WE WERE ABLE TO
DIRECTLY RECORD ACTIVITY, BRAIN
ACTIVITY, FROM THE DEVELOPING
BRAIN AS THEY ENGAGE IN
COGNITIVE TASKS, AN OPPORTUNITY
THAT WE JUMPED ON ABOUT FIVE OR
SIX YEARS AGO IN COLLABORATION
WITH THE UNIVERSITY OF MICHIGAN
AND DR. NGAI AND DR. JOHNSON AT
NORTHWEST AND BERKELEY,
RECORDING DATA FROM THE BRAIN OF
INDIVIDUALS UNDERGOING BRAIN
MAPPING AS PART OF EPILEPSY
CLINICAL TREATMENT, AND WHAT
THAT GIVES US NOW SPATIALLY
LOCALIZED TEMPORAL RECORDINGS OF
BRAIN ACTIVITY.
THESE PATIENTS WOULD UNDERGO
EXACT SAME OR SIMILAR TASKS THAT
I'VE JUST SPENT TIME DESCRIBING
TO YOU, AND WE CAN ASK, OKAY,
HOW IS BRAIN ACTIVITY SUPPORTING
SUBSEQUENT MEMORY.
STARTED BY FOCUSING ON PRE-FRONT
CORTEX AND AS YOU CAN IMAGINE WE
HAVE QUITE A SPARSE COVERAGE OF
ELECTRODES ACROSS INDIVIDUALS,
BRINGING THEM TOGETHER, YOU CAN
SEE WITHIN THIS FIRST STUDY WE
PUBLISHED WITH 17 CHILDREN AND
ADOLESCENTS, NICE COVERAGE
ACROSS PRE-FRONT CORTEX, ABLE TO
LOOK NOW FOR THE FIRST TIME,
PRECISE TIMING, WHAT YOU SEE
HERE IS HIGH FREQUENCY ACTIVITY,
RESPONSE TO ENCODING TASK, THIS
IS THE WHITE LINE, YOU CAN SEE
THIS ACTIVITY IN THE FRONTAL
CORTEX, WHILE TRACKING, WAS
PRECEDING THE RESPONSE AND WHAT
WAS EXCITING TO US IS TO THOUGH
THAT THOSE LATENCY, TIMING IN
THE GYRUS, RELATED TO
DEVELOPMENTAL GAINS IN MEMORY,
THOSE THAT HAD EARLIER ACTIVITY,
THOSE PERFORMED BETTER AND
SPECIFICALLY THOSE THAT WERE
OLDER AND HAD ACTIVITY EARLIER,
PARTICULARLY WERE PERFORMING
BETTER, COMPARED TO PARTICIPANTS
NOT AS FAST IN THE YOUNGER
CHILDREN, PRECISE TIMING OF
BRAIN ACTIVITY RELATING TO
MEMORY DEVELOPMENT.
WE ALSO LOOKED AT SPECTRAL
COMPOSITION LOOKING FOR HITS AND
MISSES, EXAMPLES TO OTHER
REGIONS, WE DID NOT FIND ROBUST
EFFECT ACROSS INDIVIDUALS BUT
DID FIND A LOT OF DIVERSITY,
DIVERSITY WAS AMONG, YOU CAN SEE
HERE IN TWO EXAMPLES FROM
6-YEAR-OLD AND 19-YEAR-OLD,
DIVERSITY WAS ROBUST BETWEEN THE
TWO ELECTRODES, BETWEEN TIME
POINTS, BETWEEN FREQUENCY
RANGES, BUT AMOUNT OF DIVERSITY
WAS QUITE SIMILAR ACROSS
INDIVIDUALS.
LEAVING US WITH MORE WORK TO DO
TO QUANTIFY EFFECTS THAT ARE
MORE ROBUST IN SUBSEQUENT
MEMORY.
WE WERE INTERESTED IN
IDENTIFYING EFFECTS RELATED TO
MEMORY ACTIVITY FROM MEDIAL
TEMPORAL LOBE ACTIVATION, HERE
LOOKING AT THE SPECTRAL
DECOMPOSITION FOR HITS AND MISS,
DOING THE DIRECT CONTRAST WE DID
FIND TWO FREQUENCIES, LOW
FREQUENCY RANGES, THAT SHOWED
MEMORY EFFECT ACROSS ALL
INDIVIDUALS.
HERE YOU CAN SEE RESPONSES, RAW
DATA FROM A 6-YEAR-OLD, AND
19-YEAR-OLD, FILTERED FOR TWO
SEPARATE, FOR HIGH AND LOW
FREQUENCY, AND OVER HERE SHOWING
SLOW AND FAST IN THE TWO ENDS OF
THE FREQUENCIES ACROSS ALL
INDIVIDUALS, AND MANY ELECTRODES
IN WHICH WE IDENTIFIED,
STRIKINGLY THOSE, WE FOUND
SELECTIONS VARIED AS FUNCTION OF
AGE IN BOTH MEDIAL TEMPORAL
L OBE, SUGGESTING BRAIN
DEVELOPMENT IS ASSOCIATE WITH
DIFFERENTIATION OF THE
SELECTIONS, THIS IS REALLY
INTERESTING AND IMPORTANT
BECAUSE WE FOUND THAT BOTH OF
THESE FREQUENCIES WAS IMPORTANT
IN THE COMMUNICATION BETWEEN
MEDIAL TEMPORAL LOBE AND
PREFRONTAL CORTEX.
FOR TWO OF THESE WE HAVE PRECISE
TIMING FOR THESE EFFECTS, IN
SLOW AND FAST DATA, SPECIFICALLY
AGAIN RELATED OR EXPLAINING
DEVELOPMENTAL GAINS IN MEMORY
PERFORMANCE SUCH AS THOSE
EFFECTS WERE STRONGER AMONG
OLDER PARTICIPANTS BETTER
PERFORMING THE TASK.
ALSO WITH OVERALL SUGGESTING
MEDIAL TEMPORAL PREFRONTAL
CORTEX INTERACT.
ALSO INTERESTED, WE HAVE
OPPORTUNITIES TO LOOK AT EFFECTS
HAPPENING AT THE VERY ENTRY.
EXCUSE ME, SOMETHING SHARED THE
SCREEN, AM I CORRECT?
I HAVE LOST MY SCREEN?
>> SOMEBODY ELSE STARTED
SHARING.
DO YOU MIND PULLING YOUR SLIDES
BACK UP?
>> ARE THEY GOOD NOW?
>> YES, WE'RE GOOD.
>> THANK YOU SO MUCH.
WE ALSO HAVE COVERAGE IN THE
OCCIPITAL CORTEX AND CAN ASK
FURTHER QUESTIONS.
FOR EXAMPLE, WE CAN SEPARATE BY
THE MORE VISUAL/VISUAL AND
CONCEPTUAL FEATURES, INTERESTING
BECAUSE AS IT COMES TO
QUANTIFYING COGNITION WE FOUND
THAT IT'S JUST FOR THE HIGH
COMPLEXITY SCENES, BY THE NUMBER
OF UNIQUE CATEGORIES, WHERE WE
SEE IN PERFORMANCE AGE GAINS.
LOW COMPLEXITY SEEM TO BE ABLE.
LOOKING IN LOW FREQUENCY,
SPANNING SPECIFICALLY THE ALPHA
FREQUENCY WHICH IS IMPORTANT IN
OCCIPITAL ACTIVITY, WE INDEED
FOUND IT WAS AN INTERACTION OF
THE DIFFERENCE BETWEEN THE HIGH
COMPLEXITY AND LOW COMPLEXITY
WITH AGE SUCH AS DECREASE IN
POWER FOR THE ALPHA RANGE OR
DESYNCHRONIZATION IN HIGH
FREQUENCY RANGE INCREASED WITH
AGE SO WE HAVE INCREASE IN
REDUCED POWER AND AGAIN THIS IS
SPECIFICALLY JUST FOR THE HIGH
COMPLEXITY, NOT FOR LOW
COMPLEXITY.
EXPLAINED DEVELOPMENTAL GAINS IN
MEMORY.
THAT IS THE OLDER PARTICIPANTS
WHO PERFORMED BETTER SHOWED MORE
OF THIS EFFECT.
SO NOW WE HAVE fMRI A
FANTASTIC PLACE TO GAIN INSIGHT
ABOUT WHAT ARE CORRELATES OF
DEVELOPMENT IN COGNITION, WE
HAVE INTRACRANIAL RECORDINGS
THAT GAVE US LOCALIZATION AND
PRECISE TIMING ACROSS
DEVELOPMENT TO IDENTIFY
NEUROPHYSIOLOGICAL MECHANISMS AS
I'VE SHOWN INITIAL SUCCESSES TO
THIS END THAT ARE LINKED TO
MEMORY DEVELOPMENT AND I THINK
ONE OF THE EXCITING
OPPORTUNITIES STILL LYING AHEAD,
HAVING THIS PRECISE LOCALIZATION
AND TIMING WE MIGHT BE ABLE TO
RETHINK ASPECT OF COGNITION.
I LIKED YESTERDAY'S PEOPLE
ENDING WITH LIKE WHAT ARE
ASCENDING CHALLENGES, WHERE DO
WE LIVE AND IT WAS WONDERFUL
POINTERS, IN THE INTRODUCTORY
COMMENTS, IN EACH OF THE -- IN
DR. GRANT'S TALK EARLIER, I'LL
ADD IT'S REALLY IMPORTANT TO BE
ABLE TO LOOK AT LONGITUDINAL
DATA.
WE CAN'T REALLY TALK ABOUT
CHANGE WITHOUT BEING ABLE TO
TAKE THE SAME INDIVIDUALS,
LONGITUDINAL DATA, CHALLENGES,
IN TERMS OF PROPER ANALYSIS AND
INTERPRETATION, IT'S ALWAYS
POSSIBLE IN INTRACRANIAL DATA,
LONGITUDINAL, SO SHOULD BE
PAIRED WITH FUNCTIONAL MRI
STUDIES, WE NEED TO BE MINDFUL
OF ISSUES.
AS COMES TO THE BRAIN SIMILAR
CONCEPTS APPLY BUT IT'S REALLY
ONE OF THE BIGGEST CHALLENGES
CLOSING THE GAP ACROSS SCALES,
LEVELS OF ORGANIZATION,
REMINDING OURSELVES LIMITATIONS
FOR EACH OF THE MEASUREMENTS WE
BRING INTO THE TABLE, AND ALSO
MINDFUL ON RELIABILITY ISSUES,
COGNITION, BECAUSE PEOPLE DRINK
COFFEE OR NOT, IN TERMS OF
CHILD, BAD DAY OR GOOD DAY,
THOSE HAVE TO BE ASPECTS THAT WE
ARE MINDFUL THAT WE CANNOT
ALWAYS UNDERSTAND THE SOURCES OF
VIABILITY, LARGE DATASETS ARE OF
COURSE ONE WAY TO GET BY, SAME
FOR THE BRAIN, AND ONCE WE HAVE
THESE IN PLACE WOULD BE ABLE
TO -- AS WE STRIVE WE'LL BE
BETTER ABLE TO UNDERSTAND
MODIFIERS OF DEVELOPMENT ACROSS
TIME SCALES AND ORGANIZATION.
I'M GOING TO END BY THANKING MY
LARGE TEAM IN THE LAB AND
COLLABORATORS AND FUNDING
MECHANISMS THAT SUPPORTED THIS
WORK.
THANK YOU.
>> THANK YOU.
ANOTHER WONDERFUL TALK.
WE'RE RUNNING BEHIND SO I'M
GOING TO MOVE THIS FORWARD.
NEXT SPEAKER IS DR. GEORGE
DRAGOI, ASSOCIATE PROFESSOR OF
PSYCHIATRY AND NEUROSCIENCE,
DEPARTMENT OF PSYCHIATRY AND
MEMBER OF THE WUSI INSTITUTE AT
YALE UNIVERSITY, M.D. FROM
UNIVERSITY OF MEDICINE AND
PHARMACY IN ROMANIA AND Ph.D.
IN BEHAVIORAL NEUROSCIENCE FROM
RUTGERS UNIVERSITY WHERE HE
WORKED IN THE LABORATORY OF DR.
PAZAKI, COMPLETED POSTDOCTORAL
STUDIES IN M.I.T., REVEALED
EXISTENCE OF PRE-CONFIGURED
CELLULAR ASSEMBLIES, SPATIAL
SEQUENCES IN FUTURE EXPERIENCE
IN NAIVE ANIMALS.
LET'S GET RIGHT TO IT.
>> THANK YOU FOR THE
INTRODUCTION.
THANK YOU FOR INVITING ME TO THE
WORKSHOP.
MY LAB IS INTERESTED IN
UNDERSTANDING THE NEURAL
MECHANISMS OF LEARNING AND
MEMORY.
PARTICULARLY WITH RATS, TO STUDY
THAT.
I'VE BEEN DOING THIS FOR 25
YEARS, AND MOSTLY USING ADULT
ANIMALS BUT SINCE TEN YEARS AGO
STARTED DEVELOPMENTAL APPROACH
I'M GOING TO BE TALKING ABOUT
TODAY.
SO, MEMORY IS FORMED INTO
STAGES, ENCODED.
IT IS BELIEVED AND THIS
SIGNIFICANT AMOUNT OF
INFORMATION ABOUT THIS
(INDISCERNIBLE)
HERE'S A RODENT MODEL OF
ENCODING AND CONSOLIDATION AS
ANIMALS EXPLORE LINEAR TRACK.
THESE ARE NEURONS.
THIS IS UNFOLDING
[ GARBLED AUDIO ]
AS THE ANIMAL GOES TO SLEEP OR
RESTING, THE PROCESS OF MEMORY
CONSOLIDATION IS BEING
INITIATED.
THE SAME NATIONAL HURRICANE
CENTER CAN FIRE IN THE SAME
ORDER IN A MUCH FASTER TIME
SCALE AS YOU CAN SEE, THE EXACT
SAME NEURONS ARE 20 TIMES
FASTER, BEING REPLAYED, DURING
SLEEP, IT IS BELIEVED THIS TYPE
OF INFORMATION IS REQUIRED AND
IT'S ENFORCING THROUGH WAY OF
AUTONOMOUS INFORMATION, THIS
TIME COMPRESSION WAS SOMETHING
SPECIFIC THAT CAN ONLY BE
OCCURRING IN THIS SLEEP
SESSIONS.
HOWEVER, SEVERAL YEARS LATER
WE'VE SHOWN DURING DATA
OSCILLATION
[ GARBLED AUDIO ]
THIS TYPE OF COMPRESSION HAS
OCCURRED DURING PROCESS OF
ENCODING, HERE IS CARTOON
DESCRIPTION OF OSCILLATION, YOU
CAN SEE THE SAME NEURONS FIRE
NOW WITHIN DATA CYCLE.
SO THIS IS ABOUT SIMILAR TYPE OF
TEMPORAL COMPRESSION, I WOULD
SAY ABOUT 15 TIMES COMPRESSED.
YOU CAN SEE HERE WHAT WE CALL
DATA SEQUENCES, THESE SEQUENCES
THAT OCCUR DURING THETA, MAP
DISTANCES BETWEEN INDIVIDUAL
LOCATIONS ALONG THE TRAJECTORY
OF THE ANIMAL, ABOUT ONE ORDER
OF MAGNITUDE FASTER TIME SCALE
COMPARED TO WHAT HAPPENED IN
SPACE.
THERE'S A SPECIAL TO TEMPORAL
COMPRESSION OF INFORMATION
COMPRESSED DURING THE ENCODING
AND DURING THE CONSOLIDATION.
EVEN MORE INTERESTINGLY, WE'VE
SHOWN THAT IN FACT THE SAME
SEQUENCES, THE SAME NEURONS CAN
FIRE IN SIMILAR SEQUENCES IN
SLEEP PRECEDING FIRST-TIME
EXPRESSION OF SEQUENCES ON DE
NOVO RUN, ANIMALS KEPT NAIVE
THROUGHOUT THE LIFETIME, THESE
ARE ADULTS, THE VERY FIRST TIME
ON THE LINEAR TRACK THE NETWORK
EXPRESSES SEQUENCE OF NEURONAL
FIRING, COULD HAVE BEEN OBSERVED
EVEN BEFORE.
SO WE THESE EVENTS REPLAY,
DISTINGUISHED FROM PREVIOUS, WE
THINK THIS IS PROOF THAT
PRE-CONFIGURED EVEN IN ADULT
NAIVE ANIMALS, INTO TEMPORAL
SEQUENCE MOTIFS, SOME WILL BE
RECRUITED AND ASSOCIATED WITH
INDIVIDUAL LOCATIONS OR EVENTS
THAT HAPPENED ALONG THIS
EXPERIENCE AND THEN THEY BECOME
MORE OF AN INDEX, CAN LATER BE
USED TO RETRIEVE THAT
INFORMATION.
AT THE SAME TIME THIS IS
TEMPORAL SEQUENCES, AT THE SAME
TIME ANIMAL TRAJECTORY, POSITIVE
PLOTTED AGAINST TIME, THE ANIMAL
IS RESTING, THE ONE IS MOVING,
AND HERE WE SHOW IN YELLOW THE
TRAJECTORY, REACHES THE OTHER
END, RESTING THERE AGAIN, AND
THE HEAT MAP SHOWS ENCODED
POSITION OF ANIMAL FROM NEURAL
ACTIVITY, YOU CAN APPRECIATE A
VERY GOOD DESCRIPTION OF THE
ANIMAL TRAJECTORY JUST SIMPLY
BASED ON THE ENSEMBLE ACTIVITY
OF CELLS.
IN THE SLEEP PRECEDING THIS DE
NOVO ROUND THE SAME NEURONS
EXPRESS WHAT LOOKS LIKE VIRTUAL
TRAJECTORIES FROM WHAT WILL
BECOME LATER TRAJECTORIES,
PRE-CONFIGURED SEQUENCES IN
NEURONAL SAMPLES SELECTED AND
RECRUITED AND PLAYED, ASSOCIATED
WITH NOVEL INFORMATION TO ENCODE
NEW EPISODE RATHER THAN BEING
CREATED DE NOVO DURING THE
EXPERIENCE.
THIS IS OUR WORKING MODEL.
PROCESS OF ENCODING IS USING
PRE-CONFIGURED SEQUENCES OF
FIRING THAT ARE SELECTED DURING
NOVEL EXPERIENCES AND THEN THE
ASSOCIATIONS WITH NOVEL STIMULI
CONSOLIDATION IS INITIATED VIA
PLASTICITY --
[ GARBLED AUDIO CLOSE
PARENTHESES ].
TO DESCRIBE THIS AGAIN, WE HAVE
SEQUENCES SHOWN AND WE HAVE
CODING OF TRAJECTORY DURING
ACTIVITY --
[ GARBLED AUDIO ]
FINALLY, AFTER THE EXPERIENCE
ENDED, THE SAME NEURONS ARE
FIRING IN THE SAME ORDER
MULTIPLE TIMES THROUGHOUT SLEEP.
HOWEVER--
[ GARBLED AUDIO ]
TYPICALLY REFLECTS BETTER THE
DETAILS AND PRECISION OF THE
EXPERIENCE COMPARED TO THE
PREEXISTING TASK.
SO WE THINK THE PHENOMENA OF
REPLAY PARTICIPATES IN CODING --
[ GARBLED AUDIO ]
THE QUESTION TODAY WHAT IS THE
DEVELOPMENTAL TIMELINE
CONSIDERING ANIMALS DURING
DEVELOPMENT PROCURE
(INDISCERNIBLE) FOR OUR ATTEMPTS
TO UNDERSTAND WHAT IS UNDERLYING
NEURAL INFORMATION.
SO AT THE TIME WE STARTED THIS
EXPERIMENT, THIS IS WHAT WAS
KNOWN, POSTNATAL DAY 14, A DAY
OR TWO LATER PLACE CELLS CAN BE
FOUND (INDISCERNIBLE) THE
RELATIONSHIP IN THE CORTEX,
BRAIN CELLS ACTUALLY MATURE LIKE
ACTIVITY MUCH LATER, ABOUT A
WEEK LATER.
FINALLY ANOTHER TIME POINT IS
THE END OF INFANTILE AMNESIA
PERIOD, ENDS AT 2 TO 4 YEARS
OLD, MAPPED TO BE HAPPENING AT
AROUND POSTNATAL DAY 23, 24 IN
THE RATS.
THAT'S WHAT WAS KNOWN.
NOTHING REALLY ABOUT NEURONAL
ENSEMBLES, NOTHING ABOUT REPLAY
AND PRE-PLAY AND CONSEQUENCES IN
THE HIPPOCAMPUS.
WE DECIDED TO TACKLE QUESTIONS
OF EMERGENCE OF ENSEMBLE
NEURONS.
WE IMPLANTED YOUNG RATS WITH
SILICON PROBES, TOTAL OF 64,
THESE ARE THE SHANKS
(INDISCERNIBLE).
THIS IS AN EXAMPLE IN WHICH ALL
EIGHT SHANKS WERE SUCCESSFUL,
NEURONS RECORDED, 67 NEURONS IN
THIS CASE.
BECAUSE WE'RE INTERESTED IN
REPLAY, PURPLE IS ESSENTIALLY
BORROWED (INDISCERNIBLE).
THIS IS AN EXAMPLE ACROSS
DEVELOPMENT, ADULT ON RIGHT
SIDE, YOU SEE THIS IS THE
LOCATION.
THIS IS THE TRACK.
YOU CAN SEE PLACES ARE WELL
TUNED FOR INDIVIDUAL LOCATIONS
ACROSS TRAJECTORY OF THE ANIMAL,
DAY 15, THE ANIMALS RUN WELL,
THESE ARE THE SEQUENCES.
YOU CAN SEE THEY GRADUALLY TUNE
TO INDIVIDUAL PLACES ACROSS
AGES.
THIS DECODING OF ANIMAL POSITION
BASED ON NEURONAL ACTIVITY
RECORDED SIMULTANEOUSLY IN
YELLOW, THIS IS ACROSS AGES, IN
YELLOW SHOWING THE ACTUAL
TRAJECTORY THE ANIMAL FROM THE
BEGINNING ACROSS TIME.
HEAT MAP SHOWS DECODED POSITION
OF THE ANIMAL BASED ON NEURAL
ACTIVITY ALONE.
YOU CAN SEE AS EARLY AS
POSTNATAL DAY 15, DEPICTING
QUITE WELL THE CURRENT LOCATION,
INDIVIDUAL LABS, AND IT GETS
ONLY BETTER INTO ADULTHOOD.
HERE IS A MEASUREMENT OF THE
ERROR OF THE DECODER.
YOU CAN SEE WHILE THERE IS
IMPROVEMENT ACROSS AGES FROM DAY
15, 16, ERROR IS 11 CENTIMETERS
FOR 1-METER TRACK, 10%, GETS
DOWN TO ABOUT 4% OR SO IN ADULT.
HOWEVER, ALL THESE NUMBERS, ALL
THESE ERRORS, ARE WAY, WAY
SMALLER WHEN COMPARED WITH
SHUFFLE.
WE'RE GETTING MUCH HIGHER ERROR
SO WE BELIEVE AS EARLY AS
POSTNATAL DAY 15 THE NETWORK IS
TUNED TO ENCODE ANIMAL LOCATION.
WE STUDY DATA SEQUENCES.
AS I MENTIONED, SHORT MOTIFS
THAT BIND, PAST, CURRENT AND
FUTURE LOCATION IN THE THETA
CYCLE, WHERE THE PLASTICITY
INFORMATION CAN BE COMBINED
PREEXISTING WITH EXTERNAL
STIMULI, COMBINED IN THE DATA
EPISODE.
SO THIS IS OUR DATA SEQUENCES IN
ADULT.
YOU SEE BINDING IN THE THETA
EPISODE OF PAST, CURRENT, AND
FUTURE LOCATIONS.
HOWEVER, WHEN WE LOOK DURING
DEVELOPMENT, WE ESSENTIALLY
COULD NOT SEE EMERGENCE UNTIL
POSTNATAL DAY 23 AND 24, ALSO
THE AGE AT WHICH INFANTILE
AMNESIA IS BELIEVED TO BE
ENDING.
THIS IS AN INTERESTING
CORRELATION BETWEEN EMERGENCE OF
SEQUENCES WHICH ESSENTIALLY
BRING IN SPECIFIC INFORMATION
ABOUT THAT EXPERIENCE, AND WE
BELIEVE THAT THAT IS CRITICAL
FOR INITIATION OF ENCODING.
THIS IS QUANTIFICATION OF SINGLE
EXAMPLE, QUANTIFICATION OF THIS
PHENOMENON AS WE COMPUTE RATIO,
ESSENTIALLY COMPARING THIS
QUADRANT, SOME OF THE FIRST AND
THIRD QUADRANT, WITH SECOND AND
FOURTH QUADRANT, A COMPUTATION
IN ADULTS HIGHER THAN THE
SHUFFLES, SO IT IS 23 AND 24 AS
SHOWN HERE BUT NOT ANY OTHER
AGES, ALTHOUGH YOU CAN SEE ONE
ANIMAL THAT SHOWS THAT.
INTERESTINGLY, WHEN WE COMPARE
PLASTICITY OR EMERGENCE OF DATA
SEQUENCES DURING THE FIRST TIME,
VERSUS SECOND, ON THE SAME DAY,
SAME AGE, WE COULD NOT SEE ANY
SIGNIFICANT DIFFERENCE.
HOWEVER, WHEN WE COMPARED FIRST
TIME AROUND, VERSUS FIRST TIME
AROUND P 23, 24, NEXT STAGE
GROUP, COULD SEE SIGNIFICANT
DIFFERENCE BETWEEN THE GROUPS,
STRONGER SIGNIFICANCE WITH 23,
24.
FINALLY THE LAST DATA SLIDE OF
MY PRESENTATION, WE WERE
INTERESTED IN EMERGENCE OF
SEQUENCES THAT ARE EXPRESSED
PRIMARILY DURING SLEEP.
AS I MENTIONED, IN OUR CASE WE
TESTED AND REPLAYED, THIS IS HOW
THEY LOOK IN ADULTS.
THIS IS DEPICTION OF FUTURE
ANIMAL TRAJECTORY, AND HERE IS
THE DEPICTION OF THE SAME
TRAJECTORY.
AND PLASTICITY REPLAY STRONGER.
VERY INTERESTINGLY POSTNATAL DAY
15, 16, COULD ONLY SAY WHAT WE
CALL STATIONIER -- STATIONARY
SEQUENCES.
INDIVIDUAL LOCATIONS MAPPED BY
NEURONS, AT LEAST FIVE FIRING
TOGETHER, NO SEQUENTIAL
ACTIVATION, THE NETWORK IN AAA
MODE INSTEAD OF ABCD LATER IN
ADULTS.
LATER ON POSTNATAL DAY 17 AND 18
TOWARDS P21, 22 WE CAN SEE
PRE-PLAY AND REPLAY, FUTURE AND
PAST TRAJECTORY, INITIALLY OF
SHORT LENGTH, SO THIS IS PORTION
OF LINEAR TRACK THAT GROW LONGER
TOWARDS P21, 22, WITH GROUPS OF
THESE EVENTS OR AGES IN STAGES,
THE LACK OF PLASTICITY, SO
REPLAY IS NOT STRONGER THAN
PRE-PLAY IN THESE AGES.
FINALLY IN STAGE 3, P 23, 24,
THIS IS THE TIME SEQUENCES
EMERGE, WE SEE PRE-PLAY AND
REPLAY AT THE NEURON ENSEMBLE
LEVEL, REPLAY EXCEEDS PRE-PLAY
IN DESCRIBING OR DEPICTING THE
RECENT EXPERIENCE OF THE ANIMAL.
THIS IS DATA, GROUP DATA SHOWING
THE SAME, WE'RE LOOKING
SPECIFICALLY FOR SEQUENCES, NOT
STATIONARY EVENTS.
THOSE ARE STAGE 1.
THEY SHOW PLASTICITY IN REPLAY
SIMILAR TO ADULTS.
IN SUMMARY WE'RE POPULATING THIS
TIME AXIS DURING THE DEVELOPMENT
WITH THREE STAGES.
STAGE 1 REPRESENTATION OF
INDIVIDUAL LOCATION, STATIONARY
FRAMES.
STAGE 2 P 17 TO P2 2
REPRESENTATION OF INCREASELY
LONGER TRAJECTORIES, NETWORK
CONFIGURATION, LACK OF DATA
SEQUENCE, NO PLASTICITY.
STAGE 3 SHOWING SIGNS, WE THINK
EMERGENCE OF LONG-TERM MEMORY WE
DESCRIBED EMERGENCE OF DATA
SEQUENCES IN CONCERT WITH
PLASTICITY AND REPLAY.
SO, THIS IS WHAT WE KNOW, WHAT
WE DON'T KNOW IS WHAT LEADS TO
THIS DEVELOPMENT OF THESE STAGES
IN ESSENCE WHAT IS THE ROLE OF
INNATE VERSUS EXTERNAL
ENVIRONMENT, EXPERIENCE AND
EXTERNAL ENVIRONMENT, IN LEADING
TOWARDS THE STAGES OF THIS
EXPERIMENTS CURRENTLY ONGOING IN
THE LAB, AS WELL AS OTHER
EXPERIMENTS THAT WE'RE TRYING TO
UNDERSTAND WHAT DRIVES THE SHIFT
FROM STAGE 1 TO STAGE 2 AND
STAGE 2 TO STAGE 3 IN THESE
DEVELOPING ANIMALS.
AND SINCE THIS WORKSHOP IS ABOUT
MEMORY FUNCTION ACROSS THE
LIFETIME, THIS IS EXACTLY WHAT
I'VE SHOWN YOU SO FAR IN THE
DEVELOPMENT, WE HAVE EXTENSIVELY
DURING ADULTHOOD, I ACKNOWLEDGE
WHAT IS THE NEXT INTERESTING
POINT TO BE ADDED IS AGING, AND
ESSENTIALLY WHAT DRIVES SHIFT IN
NEURONAL ACTIVITY FROM ADULTHOOD
TO AGING THAT LEADS, AGAIN, TO
AMNESIA AND WHETHER THAT IS
ANYWHERE SIMILAR TO INFANTILE
AMNESIA THAT WE'VE BEEN
DESCRIBING.
WE AND OTHERS HAVE BEEN
DESCRIBING.
THIS WORK IS FUNDED BY MOST
NOTABLY NIH.
THESE ARE THE CURRENT PEOPLE IN
THE LAB LISTED HERE, OLD LAB
FOLKS, AND YALE IS PART OF THIS.
THANK YOU AGAIN.
>> THANK YOU, GEORGE.
I'M LOOKING FORWARD TO THE
QUESTION-AND-ANSWER PERIOD BUT
NOW WE NEED TO MOVE QUICKLY ON
AND INTRODUCE NEXT SPEAKER,
VALENTINA EMILIANI, RECEIVED
Ph.D. FROM UNIVERSITY IN IT
ITALY, FELLOWSHIP IN GERMANY,
JOINED INSTITUTE IN FRANCE,
REWARDED BY A EUROPEAN YOUNG
INVESTIGATOR GRANT IN 2005 AND
FORMED A GROUP AT PARIS
DESCARTES UNIVERSITY, RESEARCH
DIRECTOR.
2014 CREATED A RESEARCH UNIT AT
PARIS DESCARTES, IN 2019 MOVED
TO DIVISION INSTITUTE DIRECTING
DEPARTMENT OF PHOTONICS, GROUP
PIONEERED USE OF ENGINEERING FOR
NEUROSCIENCE, PROPOSED SEVERAL
APPROACHES TO SCULPT EXCITATION
VOLUME TODAYORDER TO TARGET.
WE'LL HEAR MORE ABOUT THE
RESEARCH, RECIPIENT OF A PRIZE
FROM BETANCOURT-SHULER
FOUNDATION, SILVER MEDAL FROM
CNRS, DEHAN PRIZE AT THE
INTERFACE OF PHYSICS, BIOLOGY
AND MEDICINE AND BIOPHOTONICS
AWARD.
IN 2019 PRESIDENTIAL ADDRESS IN
CHICAGO TO NEUROSCIENCE.
>> THANK YOU.
IS IT OKAY?
>> EXCELLENT.
>> THANK YOU FOR THE
INTRODUCTION AND MANY THANKS FOR
INVITATION TO TALK TODAY.
WE HAVE HEARD ABOUT IN THE LAST
TALK ABOUT IMAGING, NOW TO
RECORD NEURAL ACTIVITY.
WE'LL SEE IN THE NEXT TALK FROM
HOD THIS CAN BE DONE, MY LECTURE
IS MORE TO GIVE A VIEW OF WHAT
MY LAB AND OTHERS HAVE DONE IN
THE PAST YEAR TO MANIPULATE
USING LIGHT IN THE SAME
SINGLE-CELL RESOLUTION.
IN ORDER TO USE LIGHT TO
MANIPULATE, FIRST CHALLENGED TO
MAKE SENSITIVE TO LIGHT.
TODAY IT'S POSSIBLE TO EXPRESS
SPECIFIC LIGATED CHANNEL,
POSSIBLE TO CONTROL INHIBITION
USING LIGHT.
SO TAKING ADVANTAGE OF
OPTOGENETICS BY COMBINING THIS
APPROACH THAT SHINE LIGHT ON
LARGE REGION.
BECAUSE OF PRECISION IN
TARGETING IT WAS POSSIBLE TO
CORRELATE THE EVOKED ACTIVITY
WITH SPECIFIC TYPE ILLUMINATED
IN LIGHT MANIPULATION.
THIS APPROACH ENABLED TO HAVE
TECHNOLOGY TO PROBE BRAIN
FUNCTION WITH CELL TYPE
SPECIFICITY IN NON-INVASIVE WAY.
DESPITE THE IMPACT THIS
APPROACH, INTRINSIC RELATED TO
THE FACT BY SHINING LOT WE
CANNOT ONLY SYNCHRONOUSLY
ACTIVATE SPECIFIC.
NOW IF YOU LOOK AT THE ACTIVITY
AND YOU WILL SEE OTHER EXAMPLES
IN THE NEXT TALK, WE SEE IN MOST
OF THE CASE EVEN GENETICALLY
IDENTICAL SETS, THERE ARE MANY
OTHER SIMILAR ACTIVITY, EVEN
GENETICALLY IDENTICAL, WE NEED
EACH ELEMENT CAN CONTRIBUTE INTO
THE ACTIVITY WITH SPECIFIC
SPATIAL TEMPORAL.
THE NEXT QUESTION WE MIGHT ASK
TODAY TO TRY TO UNDERSTAND HOW
THIS SPECIFIC PATTERNS ARE
LINKED, FUNCTIONALLY CONNECTED,
CRITICAL NUMBER OF SETS COULD BE
CONTROLLED TO EVOKE A CERTAIN
RESPONSE.
WE NEED TOE TRANSITION INTO A
MORE SOPHISTICATED APPROACH,
CIRCUIT OPTOGENETICS,
MANIPULATING SINGLE OR MULTIPLE
TARGETS INDEPENDENTLY IN SPACE
AND TIME.
WHAT DO WE NEED FOR CIRCUITS
OPTOGENETICS?
CAPABILITY TO TARGET SINGLE OR
SPECIFIC GROUP OF CELLS WITH
SINGLE-CELL RESOLUTION, ALSO
CAPABILITY TO DELIVER LIGHT IN
MULTIPLE PLANES AND OBVIOUSLY
CONTROL ACTIVATION OR
INHIBITION OF NEURONS IN
TEMPORAL SCALE.
THIS IS CURRENTLY USING IMAGING.
YOU WILL SEE THIS IN THE NEXT
TALK.
CAN WE USE THE SAME APPROACH IN
OPTOGENETICS?
IT'S A CHALLENGE, IF WE USE
CONVENTIONAL MICROSCOPE IN MOST
OF THE CASE THE USE IS VOLUME
SHOWN IN ANIMAL SETS IS NOT
ENOUGH TO OPEN ENOUGH CHANNEL TO
BRING THE NEURONS, TO CONTROL
ACTION POTENTIAL, TO INHIBIT THE
ACTIVITY OF SPECIFIC CELLS.
ALSO, CONVENTIONAL TWO-PHOTO
ONMICROSCOPY, IF WE WANT TO
CONTROL ACTIVITY OF MULTIPLE
CELLS WE CAN ONLY DO THIS IN A
SEQUENTIAL WAY AND WHEN THIS
NUMBER IS HIGH WE WON'T HAVE
TEMPORAL RESOLUTION TO REACH
MULTIPLE TARGETS.
SO REQUIRES FROM ONE SIZE TO
FIND SOLUTION TO INCREASE SIZE
AND FIND SOLUTION TO EACH
SIMULTANEOUSLY MULTIPLE TARGETS.
AND SO FOR THE FIRST PART
INCREASE SIZE OF ILLUMINATED
CELL MEMBER, TWO POSSIBLE
SOLUTIONS THAT CAN BE DONE.
TO SCAN TO OPEN ALL THE CHANNELS
EXPRESSING ON MEMBRANE OR
PRODUCE LARGE STOP SO ALL
CHANNEL ARE OPEN SIMULTANEOUSLY.
SO THE MAIN DIFFERENCE BETWEEN
THE TWO APPROACH FOR SINGLE-CELL
RESOLUTION IS TO -- FIRST ONE IS
MORE TREATABLE WHEN COMBINED
WITH LOW OPENING AND CLOSING
TIME, HAVING THE ADVANTAGE ALSO
USED TO MIMIC ACTIVITY OF FASTER
SPIKE IN CELLS.
HOW CAN WE MAKE THIS LARGER?
TO ILLUMINATE THE ENTIRE NEURON?
WE HAVE PROPOSED YEARS AGO TO DO
THIS BY USING APPROACH OF
COMPUTER GENERATED HOLOGRAPHY,
THE KEY DEVICE IS LIQUID CRYSTAL
SCREEN, SO THAT EVENTUALLY WE
CAN PRECISELY PRODUCE ANY
ARBITRARY SHAPE WE CHOOSE BY
COMPUTER AND THIS IS DONE BY
PROJECTING ON THE LIQUID
CRITICAL CORRESPONDING HOLOGRAM.
EVENTUALLY COVER ALL THE MEMBER
OF THE TARGET THAT WE HAVE
CHOSEN.
HOW CAN WE DO THIS
SIMULTANEOUSLY?
IT ENABLES TO DELIVER
(INDISCERNIBLE) THIS APPROACH
CANNING ALSO USED TO PRODUCE,
FOR EXAMPLE, DISTRIBUTION OF
MULTIPLE POINTS THAT CAN HAVE
THREE DIMENSIONAL GEOMETRY.
WE CAN PRODUCE A SORT OF 2D OR
3D, MULTIPLE NEURONS CAN BE
SIMULTANEOUSLY ACTIVATED.
IN THIS CASE THE APPROACH CAN
GENERATE PATTERNS ON MULTIPLE
FOCUS SO WE CAN HAVE FULL
THREE-DIMENSIONAL SCANLESS
APPROACH.
IN THE SECOND CASE WHEN WE WANT
TO REACH MULTIPLE TARGETS AND WE
WANT TO KEEP SINGLE CELL
SOLUTION, SYSTEM REQUIRES ALSO
TO INCLUDE APPROACH OF TEMPORAL
FOCUSING ENABLES TO NICELY
CONFINE THE LIGHT ALONG THE
CONFINEMENT SO TODAY THE MOST
USED APPROACH FOR THREE
DIMENSIONAL HOLOGRAPHIC PATTERN
USES FIRST SPECIAL LENS CREATING
A SECOND SHAPE, TYPICALLY A DISC
WE COVER THE MEMBRANE.
DISC IS FOCALIZED, THAT ENABLES
TO CONTROL AXIAL EXTENSION OF
DISK.
WE PRODUCE MULTIPLE POINTS.
TWO DEVICES WORKING TOGETHER.
SO WE CAN REACH LIKE WHAT IS
SHOWN HERE, NOW YOU CAN IMAGINE
THE TALK IS GOING TO DIFFERENT
NEURON SETS SO CAN YOU CONTROL.
THERE ARE MUST BE VARIANTS,
DEPENDING HOW THE FIRST SHAPE IS
DONE.
IN DIFFERENT APPROACH MORE OR
LESS THEY ALL CAN REACH THE
DISTRIBUTION OF LIGHT ON
HUNDREDS OF TARGETS IN CUBIC
VOLUME, JUST TO GIVE A FEW
ORDERS OF MAGNITUDE.
ARE WE ON THE WAY TO USE THIS
APPROACH FOR SINGLE CELL
OPTOGENETICS?
IT REQUIRES TO WORK, WE
INTEGRATE WHAT MANY OTHER LABS
HAS DONE IN THE PAST YEAR TO
DEVELOP STRATEGIES THAT COULD
CONFINE, TODAY THIS IS OF KEY
IMPORTANCE, EVEN IF WE CAN SHAPE
THE LIGHT IN A PRECISE WAY TO
REACH JUST A SINGLE TARGET IT'S
VERY COMMON IF WE HAVE MULTIPLE
SETS AROUND THE PROCESS IS
CROSSING ILLUMINATION VOLUME AND
SO WE WOULD LOSE THE SINGLE CELL
SOLUTION.
BUT TODAY IF YOU COMBINE LIGHT
SHAPING, IT'S POSSIBLE TO BE
PRECISE AND I'LL SHOW AN EXAMPLE
HERE.
DATA FROM MY LAB IN VIVO,
CORTEX.
YOU SEE, FOR EXAMPLE, WE'RE
SENDING THREE HOLOGRAPHIC ON
THREE NEURONS, THREE RESPONDING
SHOWN BY THE RESPONSE AND WE
CHOOSE TO ACTIVATE ONE OF THE
THREE, ONLY ONE IS RESPONDING,
WE'RE ON OUR WAY TO HAVE PRECISE
CONTROL OF NANOACTIVITY WITH
CELLULAR RESOLUTION.
ALL THESE APPROACHES RELATIVELY
RECENT SO BECAUSE FROM ONE SIDE
WE HAVE TO IMPROVE THE MORE AND
MORE THE FOCUS SIMULATION
APPROACH BUT THEN BECAUSE WE
WANT TO REACH MORE TARGET,
HAVING NEW LASER TO DEVELOP
MULTIPLE POWER AND HAVING THIS
SO THE COMBINATION OF THESE
APPROACHES RELATIVELY RECENT BUT
WE START NOW TO SEE MORE AND
MORE COMBINATION OF APPROACH
USED IN SOLVE KEY BIOLOGICS
PERFORMING HIGH-THROUGHPUT, TO
USE OPTOGENETICS AND SINGLE CELL
TO FORM ACTIVATION TO ILLUMINATE
MULTIPLE PRESYNAPTIC CELLS WHILE
RECORDING USING ELECTRIC OR
LIGHT, EVOKED RESPONSE IN
SPECIFIC SET, THIS IS A CLASS
CLASSICAL NUMBER OF EXPERIMENTS,
THERE ARE ANOTHER CLASS OF
EXPERIMENTS PUBLISHED IN THE
PAST YEAR WHERE THIS KIND OF
APPROACH WAS USED TO PROBE
THRESHOLD OF PERCEPTION, TO BE
ACTIVATED TO RECREATE
PERCEPTION.
ENOUGH TO EXCITE FROM ONE TO TEN
CELLS, IN THIS CLASS OF
EXPERIMENT THE NUMBER OF CELLS
THAT HAS TO BE EXCITED IN SOME
CASES WAS HIGHER FROM TEN TO A
HUNDRED CELLS.
NOW IN THE REMAINING PART OF THE
TALK I WOULD LIKE TO THINK OF IS
IT POSSIBLE TO THINK OF
CONTROLLING EVEN LARGER
CIRCUITS, STIMULATING LARGE
NUMBER OF CELLS, UP TO THIS
POINT FROM THIS POINT OF VIEW
WHICH IS THE LIMIT THAT, WHAT
ARE THE REASONS THAT COULD LIMIT
MAXIMUM NUMBER WE CAN REACH.
SO AN IMPORTANT ADVANCE IN
OPTOGENETICS DONE THANKS TO
DEVELOPMENT OF LOW REPETITION
LASERS THAT ENABLE TO INCREASE
EXCITATION PEAK POWER, POSSIBLE
TO REACH A HIGH NUMBER OF CELLS,
PLUS LATER CAN DELIVER MORE
WATT, TODAY TO ACTIVATE SINGLE
CELL WE NEED ABOUT 10 TO 20
NANOJOWL, ACTIVATING THOUSANDS
OF CELLS, THEORETICALLY.
WE HAVE TO CONSIDER THOSE NUMBER
VALID FOR SUPERFICIAL CELLS SO
IF YOU'RE DISCUSSING THE POWER
IT IS MUCH HIGHER, THOUSANDS OF
CELLS CAN BE REDUCED, AND ALSO
EVEN IF WE CAN ACTIVATE
THOUSANDS OF CELLS WE HAVE TO
TAKE INTO ACCOUNT CERTAIN POINT
DAMAGE, WE SEND TOO MANY WE CAN
EXCEED THE SINGLE FOR IMPORTANT
DAMAGE EFFECT.
WE DEVELOPED RECENTLY TO TRY TO
SOLVE THOSE PROBLEMS, TO
INCREASE NUMBER OF TARGETS AND
MINIMIZE COLLATERAL THERMAL
DAMAGE EFFECT.
THIS IS SIMILAR TO WHAT I SHOWED
BEFORE.
THERE ARE TWO VARIANTS WITH
RESPECT TO WHAT I'VE SHOWN YOU
BEFORE, THE FIRST ONE IS NOT
ADDRESSED BY USING SINGLE
HOLOGRAM BUT NOW ADDRESSED WITH
MULTIPLE HOLOGRAMS VERTICALLY
ALIGNED, NOW WE HAVE INSERTED,
MOVING LIGHT THROUGH THE
DIFFERENT HOLOGRAMS, AND THIS
CAN BE DONE AT THE SPEED ONLY
LIMITED BY SPEED (INDISCERNIBLE)
SO WE CAN GENERATE MULTIPLE
DISTRIBUTION TO QUICKLY REFRESH
FROM ONE TO ANOTHER.
WHY THIS COULD HELP IN
INCREASING NUMBER OF SPOTS AND
WHY THIS COULD HELP IN REDUCING
THE TEMPERATURE, THE TEMPERATURE
RISE, WE HAD TO -- FOR THAT TO
INTRODUCE THE IDEA OF CYCLIC
ILLUMINATION, IT IS POSSIBLE TO
PROVE EXPERIMENTAL THAT THERE
ARE TWO WAYS TO CONTROL THE
ACTIVATION OF A CELL SO WE CAN
EITHER USE -- BETWEEN 5 TO 20
MILLISECONDS, TO EVOKE ACTION
POTENTIAL OR CERTAIN RESPONSE
BUT THE SAME ACTIVITY CAN ALSO
BE PRODUCED, INSTEAD OF USING
LONG PATHS WE USE SHORTER PATHS
OF SLIGHTLY HIGHER INTENSITY AND
THIS WILL BE ABLE TO PRODUCE THE
SAME CURRENT.
SO WHY THIS IS AN ADVANTAGE
BECAUSE NOW YOU CAN USE THE TIME
INTERVAL BETWEEN ONE AND THE
OTHER TO MOVE YOUR ILLUMINATION
LIGHT ACROSS THE DIFFERENT
HOLOGRAMS, SO IN CONVENTIONAL
HOLOGRAPHY YOU COULD ACTIVATE A
SINGLE CELL OR SINGLE GROUP OF
CELLS, NOW WE CAN ACTIVATE ALL
THE CELLS, ALL THE GROUP OF
CELLS, ENCODED IN THIS MULTIPLE
HOLOGRAMS, WE'RE ABLE TO CONTROL
UP TO OL UP TO 25 INDEPENDENT
HOLOGRAMS.
WE CAN ACTIVATE MORE GROUP OF
CELLS BUT EACH OF THEM WOULD
REQUIRE SQUARE ROOT OF H HIGHER
POWER THAN CONVENTIONAL, OVERALL
A GAIN OF SQUARE ROOT OF H, SO
BECAUSE THIS NUMBER IS TODAY
ABOUT 25 WE CAN INCREASE UP TO A
FACTOR OF FIVE THE NUMBER OF
CELLS THAT WE CAN ACHIEVE USING
CONVENTIONAL CONFIGURATION, AND
THE SAME EFFECT IS THAT WE CAN
MINIMIZE THE THERMAL DAMAGE.
THIS IS SOMETHING WE CAN SEE
HERE, SO A FEW YEARS AGO
DEVELOPED A SYSTEM TO EVALUATE,
TEMPERATURE RISE THAT WE CAN
EVOKE AND NOW THIS MODEL CAN
EVALUATE AND WE CAN EXPERIMENT
AND PROVE AS LONG AS WE
STIMULATE A SINGLE CELL THE
LOCAL TEMPERATURE RISE IS WELL
BELOW, NOW WHEN WE START TO
ILLUMINATE MULTIPLE TARGETS,
THIS IS THE CASE WHERE NOW WE'RE
USING THE SAME STIMULATION
PARAMETER NOW TO ACTIVATE 100
CELLS.
YOU SEE THE TEMPERATURE RISE CAN
BE HIGH AND LAST RELATIVELY LONG
TIME.
SO THE ADVANTAGE IS THAT BECAUSE
WE CAN USE LOWER POWER AND ALSO
BECAUSE WE HAVE MULTIPLE PATHS
THAT ENABLES MORE THERMAL
DISSIPATION, IF WE USE HERE 25
HOLOGRAMS, THE TEMPERATURE 20
HOLOGRAMS, TEMPERATURE RISE IS
MUCH BELOW WHAT WE WOULD ACHIEVE
IF WE SEND 100 SPOT IN
CONVENTIONAL WAY.
COMBINED ALLOWS INCREASE NUMBER
OF CELLS AND MINIMIZE THERMAL
PHOTODAMAGE EFFECT.
THE GENERAL CONCLUSION TODAY ON
MANIPULATION SIDE THE
COMBINATION OF MULTIPLE ADVANCE
IN COMPLEMENTARY DISCIPLINES,
WE'RE ON THE WAY TO CONTROL
LARGE POPULATION OF CELLS IN
SAFE CONDITION AND TEMPORARY
SOLUTION, FURTHER DIRECTION IS
NOW TO BE ABLE TO INCREASE EVEN
FURTHER, EVENTUALLY REACH DEEPER
BRAIN AREA BY DEVELOPING
HOLOGRAPHIC ENDOSCOPY SO WE CAN
ACTIVATE THE SAME POPULATION OF
CELLS AND THEN WE CAN GO VERY
FAST NOW IN CONTROLLING CELLS,
GREAT ADVANTAGE COMBINED WITH
MASTER MULTI-TARGET IMAGING.
I'M OUT OF TIME.
I WILL GIVE YOU THE SLIDE TO
THANK THE PEOPLE OF MY LAB,
COLLABORATORS AND FUNDING
SOURCES.
>> AN INCREDIBLE TALK.
MOVING ON, NEXT IS HOD DANA,
ASSISTANT PROFESSOR AT CASE
WESTERN RESEARCH UNIVERSITY,
RECEIVED HIS BACHELOR'S AND
Ph.D. IN BIOMEDICAL
ENGINEERING IN ISRAELI INSTITUTE
OF TECHNOLOGY, HE DID HIS
POSTDOCTORAL TRAINING AT THE
HOWARD HUGHES MEDICAL INSTITUTE
AT JANELIA CAMPUS, AND ALSO WAS
INVOLVED IN DEVELOPMENT AND
TESTING OF NEW CALCIUM SENSORS
FOR RECORDING NEURONAL ACTIVITY.
HE JOINED THE DEPARTMENT OF
NEUROSCIENCES AT THE LERNER
INSTITUTE OF CLEVELAND CLINIC, A
PROFESSOR OF MEDICINE, LAB
DEVELOPED NON-LINEAR OPTICAL
METHODS TO STUDYING HOW BRAIN
ACTIVITY IS AFFECTED BY
NEURODEGENERATIVE CONDITIONS,
RECENTLY HE AND COLLEAGUES WERE
AWARDED A GRANT TO DEVELOP NEXT
GENERATION OF CAMPARI SENSOR.
HE'S GOING TO TALK ABOUT IT NOW.
>> DO YOU SEE MY SLIDES
PROPERLY?
>> YES.
>> SO, I WANT TO THANK THE
ORGANIZERS FOR THIS WORKSHOP,
TODAY I WILL TALK ABOUT LARGE
SCALE CELLULAR RESOLUTION
RECORDING OF NEURONAL ACTIVITY
IN FREELY MOVING MICE.
WE FIRST START WITH INTRODUCING
WHY WE WANT TO RECORD BRAIN
ACTIVITY WITH CALCIUM SENSORS,
FROM BEHAVING RODENTS AND
CHALLENGES WE FAILS.
I WILL INTRODUCE CAMPARI, A NEW
SENSOR, HOW WE USE IT TO RECORD
LARGE SCALE ACTIVITY IN FREELY
MOVING MICE, DATA SHOWS ACTIVITY
ACROSS THE LIFESPAN OF MICE.
SIMILAR SLIDE WAS PRESENTED
YESTERDAY, MY MESSAGE HERE I
WANT TO CONVINCE CALCIUM IMAGING
IS INTERESTING AND USEFUL.
THE BRAIN PERFORMS ACTIVITY OVER
MULTIPLE SPATIAL AND TEMPORAL
SCALES.
HERE I'M TRYING TO SUMMARIZE
REPRESENTATION OF TIME ON
X-AXIS, AND PRESENTATION OF
SPACE IN Y-AXIS.
OVER THE TIME AXIS, FROM
MILLISECOND RANGE, FIRING OF
SINGLE ACTION POTENTIALS, TO
PROCESSES THAT TAKE MORE TIME,
LEARNING, AGING, DISEASE
PROGRESSION THAT CAN LAST FOR
YEARS.
ONE MICRON IN SIZE, AND SIZE OF
CELLS IS TEN MICRONS, BRAIN OF
THE HUMAN SPANS TENS OF
CENTIMETERS.
IN ORDER TO RECORD FROM THE
BRAIN THERE ARE MULTIPLE METHODS
THAT CAN BE USED, EACH METHOD
USES DIFFERENT PHYSICAL PROCESS,
AND THEREFORE HAS DIFFERENT
RANGE.
FOR EXAMPLE FUNCTIONAL MRI WE
TALKED ABOUT EARLIER TODAY AND
YESTERDAY, CAN SCAN THE WHOLE
BRAIN, NON-INVASIVE, DOESN'T DO
DAMAGE USED OVER LONGER TIME
PERIOD WITHOUT ANY DAMAGE.
THE TEMPORAL RESOLUTION OF
fMRI IS 1 MILLISECOND, SPATIAL
RESOLUTION IS 1 MILIMETER.
THIS IS BASICALLY USEFUL,
DYNAMIC RANGE OF fMRI.
ANOTHER METHOD IS INTRACELLULAR
RECORDINGS WHERE ELECTRODES ARE
INSERTED INTO THE MOUSE OR HUMAN
BRAIN TO REPORT ACTIVITY OF
SINGLE CELLS, YOU CAN GET
SUBMILLISECOND RESOLUTION,
RESOLUTION OF MICRONS, BUT
RECORDING USUALLY LASTS FOR UP
TO SEVERAL MINUTES, MAYBE
LONGER, AND YOU CAN RECORD ONLY
FROM SMALL AMOUNT OF CELLS
SPANNING SMALL FRACTION OF THE
BRAIN.
THERE ARE OTHER THOUGHTS, I'M
NOT GOING TO GET INTO DETAILS
BUT ACCORDING TO METRICS I JUST
PRESENTED, CALCIUM IMAGING IS
THE MOST VERSATILE METHOD
BECAUSE WE CAN DETECT THE FIRING
OF SIX ACTION POTENTIALS, ALSO
TO RECORD FROM THE SAME ANIMAL
OVER AND OVER AGAIN, OVER MANY
MONTHS.
THE RECORDING METHODS WE USE
ALLOW US TO SEE SUBMICRON
RESOLUTION BUT ALSO TO RECORD
MILLIMETERS OF TISSUE,
CONTAINING MANY THOUSANDS OF
CELLS, TODAY I WILL PRESENT NEW
METHOD THAT ACTUALLY TRIED TO
EXPAND THAT EVEN FURTHER.
TO RECORD CALCIUM IMAGING, THE
MOST COMMONLY USED TOOL IS
GENETIC ENCODEED INDICATORS,
GECIs, BY INJECTION OR
GENERATED ANIMALS.
HERE IS THE STRUCTURE OF THE
MOST COMMONLY USED, GCaMP,
GREEN FLUORESCENT PROTEIN BINDS
TO CALCIUM DOMAIN.
WITH NO CALCIUM AROUND THE
PROTEIN IS ENGINEERED TO BE VERY
DIM, FIRST IS INEFFICIENT, BUT
ON THE RIGHT-HAND SIDE THERE IS
A CHANGE IN THE GFP RETAINS
BRIGHTNESS.
WITH CALCIUM THIS PROTEIN IS
VERY BRIGHT, WITHOUT CALCIUM
IT'S VERY DIM.
USING THE SENSORS WE CAN DO THE
LONG-TERM EXPERIMENTS, GENETIC
TOOLS TARGET TO SPECIFIC CELL
TYPES, EXPRESSION CAN BE TURNED
ON AND OFF, AND WE CAN GENERATE
TRANSGENIC LINES.
SO BASICALLY EXPRESS PROTEIN AS
PART OF THE GENOME.
TO RECORD THE SIGNAL FROM THE
MOUSE OR RODENT BRAIN OR OTHER
ANIMALS, DR. EMILIANI PRESENTED
EXCITING DATA, TWO PHOTON
MICROSCOPY FIRST DEMONSTRATED 30
YEARS AGO, ALLOWS SUBMICRO
RESOLUTION IN THE HUMAN BRAIN,
THE IMAGE IS A DEMONSTRATION OF
SINGLE PHOTON FLUORESCENCE WHICH
GENERATES SIGNAL FROM ALL OVER
THE PLACE, WHEREVER THERE IS
LIGHT AND FLUORESCENT MEDIUM BUT
TWO-PHOTON IN A TINY SPOT, A
WELL-KNOWN TECHNIQUE ANDLY SKIP
THE DETAILS FOR NOW BUT SHOW AN
IMAGE WHERE WE CAN SEE SINGLE
CELLS INSIDE THE MOUSE BRAIN,
EACH RING SHAPE YOU SEE HERE IS
A SINGLE CELL, YOU CAN SEE CELLS
AND SUBCELLULAR PROCESSES.
IF THE THOUGHT IS BEING --
RECORDING IS FAST ENOUGH, YOU
CAN ALSO RECORD MOVIES LIKE DR.
EMILIANI SHOWED WHEN CELLS ARE
FLASHING, EVERY TIME YOU SEE A
CELL FLASHES THIS IS THE FIRING
OF ACTION POTENTIALS.
THIS IS A VERY EFFICIENT AND
USEFUL TECHNIQUE.
NOW, WE HAVE PREVIOUS TALKS
TODAY AND YESTERDAY ABOUT
RECORDING FROM HUMAN AND
EXCELLENT BEAUTIFUL DATA AND THE
QUESTION IS WHY DO WANT TO
RECORD FROM ANIMALS,
SPECIFICALLY FROM BEHAVING
RODENTS.
THE ANSWER WITH ANIMALS WE CAN
DO EXPERIMENTS AND INTERVENTIONS
NOT FEASIBLE WITH HUMAN.
FOR EXAMPLE, WE CAN DO GENETIC
MANIPULATIONS, OR WE CAN DO
INVASIVE INTERVENTIONS.
THESE TOOLS CAN BE USED FOR
LONGITUDINAL RECORDINGS TO PROBE
PROCESS AND LEARNING, MEMORY
FORMATION LIKE SHOWN BEFORE,
AGING AND DISEASE PROGRESSION.
AND WHEN ANIMALS WE STUDY ROLE
OF SPECIFIC CELL TYPES, IN THIS
PHENOMENA.
SO TO RECORD FROM BEHAVING
RODENTS, THERE ARE TWO MAIN
APPROACHES TODAY.
FIRST ONE IS TO FIX THE RODENT
HEAD UNDER MICROSCOPE OR
MESOSCOPE WHICH HAS ACCESS TO
LARGER REGION, SECOND TO FIX
MINIATURIZED DEVICE.
THE MOUSE CAN STILL PERFORM SOME
BEHAVIORAL TASKS LIKE RUNNING ON
THIS WHEEL OR TREADMILL OR TO BE
TRAINED TO SOME TASK.
AND THEN USING A MICROSCOPE WE
CAN RECORD FROM THE MOUSE BRAIN.
I LIKE THIS MOVIE, FIRST IT
SHOWED THE LARGE AREA THAT CAN
BE RECORDED.
ACTUALLY TO RECORD FAST ENOUGH,
IT CAN BE DONE FROM RELATIVELY
SMALL NUMBER OF PLANES YOU CAN
SEE HERE.
INSIDE THE PLANES WE CAN GET
ACTIVITY TRACES OF ALL CELLS AND
HERE IS, AGAIN, A GREAT EXAMPLE.
NOW, THE SECOND APPROACH, WE
DON'T FIX IN THIS CASE THE MOUSE
HEAD BUT WE FIX DEVICE TO THE
HEAD, LOOKING LIKE THIS.
THE MOUSE CAN MOVE AROUND WITH
THIS DEVICE ON ITS HEAD.
DURING THIS MOVEMENT THE
RECORDING HAPPENS.
THE RECORDED DATA LOOKS
SOMETHING LIKE THAT.
THIS MOVIE SHOWS FIRST THE
BEAUTIFUL PERFORMANCE
CAPABILITY, WE CAN GET NICE
RESOLUTION RECORDING WHILE THE
MOUSE IS MOVING AROUND AND DOING
SOMETHING.
ALSO WE SEE SOME OF THE
CHALLENGES, FIELD OF VIEW IS
SMALL, OPTICAL QUALITY IS
COMPROMISED COMPARED TO THE
MICROSCOPES.
BOTH APPROACHES HAVE SOME
CHALLENGES.
FOR EXAMPLE, WHEN WE DO HEAD
FIXATION OR MOUSE OR RAT WE
FORCE THEM INTO UNNATURAL
POSITION.
THIS BY ITSELF MIGHT AFFECT HOW
THE BRAIN WORKS, HOW IT
PROCESSES INFORMATION OR WHAT
CIRCUITS ARE ACTIVATED.
FOR THE SECOND APPROACH WHEN
DEVICE IS ATTACHED TO LET'S SAY
A MOUSE HEAD, THIS DEVICE WEIGHT
IS ACTUALLY FITS ON THE MOUSE
HEAD, FOR MICE IT CAN BE 10 TO
20% OF THEIR BODY WEIGHT FORCING
THEM TO HAVE LESS RESTRICTED
MOVEMENT, SOME RESTRICTION THAT
CAN ALSO AFFECT THE WAY THEIR
BRAIN PROCESSES INFORMATION AND
CIRCUITS THAT ARE ACTIVATED.
IN ADDITION THE TWO APPROACHES
ARE SUITED TO LARGE PLANE OR
SMALLER NUMBER OF PLANES
ACTUALLY SHIFTED BUT NOT REALLY
FOR THREE DIMENSIONAL RECORDING,
AND THE BRAIN IS A THREE
DIMENSIONAL OBJECT.
THEY MIGHT NEED IMPORTANT
INFORMATION.
WE WORKED IN MY LAB TO DEVELOP A
THIRD APPROACH FOR RECORDING
FROM BEHAVING MICE.
THE GOALS IS TO ALLOW FREE
MOVEMENT WITH NO MECHANICAL
RESTRICTION, ALLOW SIMULTANEOUS
THREE DIMENSIONAL RECORDING FROM
LARGE BRAIN REGION.
THIS IS HOPEFULLY ALLOWING US TO
GET NATURALISTIC BRAIN
ACTIVATION PATTERNS.
WE WANT TO MAINTAIN SINGLE-CELL
RESOLUTION AND WANT THIS METHOD
TO BE SIMPLE TO BE ADOPTED BY
MANY LABORATORIES.
WE USE A NEW CALCIUM SENSOR
CAMPARI, UNLIKE THE PREVIOUS ONE
I SHOWED YOU DOESN'T CAPTURE
ACTIVITY BY CHANGE OF
FLUORESCENCE ACTIVITY BUT CHANGE
OF COLOR.
IT'S A GREEN FLUORESCENT
PROTEIN, HIGH CALCIUM LEVELS,
ANY ILLUMINATION WITH A
400-NANOMETER PURPLE LIGHT, WILL
CHANGE COLOR TO RED.
YOU CAN THINK ABOUT AN END GATE,
TO GET THINGS TOGETHER, SIMILAR
ACTIVITY, AND LIGHT AND
TRANSFORMS INTO PERMANENT CHANGE
IN SIGNAL.
EXPERIMENTALLY, IT WILL LOOK
LIKE THAT.
YOU START EXPERIMENT WITH
NEURONS LABELED GREEN,
EXPERIMENT STARTS WHEN YOU TURN
ON THE LIGHT.
ACTIVITY OF NEURONS WILL CAUSE
THEM TO CHANGE COLOR FROM GREEN
TO RED, WHEN YOU TURN OFF THE
LIGHT EXPERIMENT IS OVER.
NOW YOU HAVE ACTIVITY, THAT IS
IMPRINTED, YOU CAN READ IN
POST-PROCESSING MODE OR THINK
ABOUT A CAMERA THAT ALLOWS YOU
TO CAPTURE SNAPSHOTS OF THE
NEURAL NETWORK.
SO TO DEMONSTRATE THE NEW METHOD
WE FOLLOWED THREE SIMPLE STEPS,
FIRST WE EXPRESSED CAMPARI IN
FIVE BRAIN REGIONS OF THE MOUSE
CORTEX, THREE MOTOR REGIONS THAT
CORRESPOND TO OTHER AREAS, AND
TWO SOMATOSENSORY REGIONS.
WE TRAINED THEM TO REPORT
BEHAVIORAL TASKS.
TO RECORD ACTIVITY WE TURN ON
SPECIFIC LAMP THAT ILLUMINATES
AND RECORD CAMPARI SIGNAL.
REANESTHETIZE AND RECORD FROM
SINGLE CELLS USING TWO PHOTO
MICROSCOPY LED BY DR. DAS FROM
MY LAB WITH DR. RABER'S LAB AND
HERE ARE MOVIES FROM THE
EXPERIMENTS THEMSELVES.
THIS IS A NOVEL OBJECT
RECOGNITION TASK, LIGHT SOURCE
AT THE TOP, MICE IS FREE TO MOVE
AND EXPLORE.
THERE IS ENCLOSED ARENA BUT
WITHIN THIS ARENA THE MOUSE CAN
PERFORM IN A FREELY MOVING
NATURE.
SECOND TASK STUDIED, WHEN THE
MOST IS ON A ROTATING ROAD,
NEEDS TO MAINTAIN BALANCE, THE
LIGHT SOURCE AT THE TOP OF THE
MOVIE.
THIRD TASK IS CONDITIONING, THE
MOUSE LEARNS TO ASSOCIATE FOOD
SHOCK WITH AUDITORY CUE AND
BASICALLY THE MOUSE RECEIVES
AUDITORY CUE WITHOUT ANY SHOCK
AND AGAIN WE RECORD CORTICAL
ACTIVITY.
AFTER THE EXPERIMENT, WE
ANESTHETIZE AND READ THE SIGNAL,
HOW ACTIVITY IS IMPRINTED.
RED CELLS ARE MORE ACTIVE.
HERE WE RECORD FROM THE BRAIN
SURFACE, DOWN TO 330 MICRONS
DEEP.
YOU CAN SEE INDIVIDUAL CELLS,
SOME OF THEM ARE GREEN, SOME ARE
MORE RED, SOME ARE YELLOW,
DIFFERENT LEVELS OF ACTIVITY.
AGAIN, THIS RECORDING IS DONE
AFTER THE EXPERIMENT IS
COMPLETED.
THIS EXAMPLE DATA SHOWS THE SAME
FIELD OF VIEW FROM THE SAME
MOUSE FOR THE THREE DIFFERENT
TASKS, 14 DAYS APART.
YOU CAN SEE WE GET DIFFERENT
ACTIVATION PATTERNS OF THE
CELLS.
WHEN WE QUANTIFY ACROSS SIX
MICE, WE SEE THAT FOR THE NOVEL
OBJECT RECOGNITION TASK THERE IS
2 1/2-FOLD HIGHER LEVEL THAN THE
CONDITIONING TASK.
IF WE BREAK DOWN ACTIVITY
PATTERNS INTO MOTOR VERSUS
SOMATOSENSORY YOU CAN SEE ON THE
INSET SOMATOSENSORY REGIONS WERE
MORE ACTIVE THAN MOTOR REGIONS,
WHEN WE BREAK INTO SPECIFIC
TASKS THIS INCREASE WAS TASK
SPECIFIC.
FURTHER INTO THE MOTOR AREAS WE
RECORDED, WE SEE THIS AREA MORE
ACTIVE, THEY BOTH PROJECT TO THE
SAME LIMB.
AND THIS ACTIVITY IN BETWEEN THE
TWO REGIONS.
THIS IS PRELIMINARY DATA FROM
OUR LAB WHEN WE WANT TO RECORD
ACROSS THE MOUSE LIFESPAN.
I SHOWED BEFORE ACTIVITY LEVEL
ACROSS THE THREE TASKS WAS FROM
YOUNG HEALTHY MICE.
WHEN WE RECORDED FROM OLDER
MICE, 1 YEAR OLD, THE SAME TASK,
PRELIMINARY DATA, SO STILL NOT
FINAL, BUT WE SEE FIRST HIGHER
ACTIVITY LEVELS FOR ALL TASKS.
WE GET MORE RED SIGNAL FROM
CAMPARI, RED TO GREEN RATIO
INCREASES.
WHEN WE TEST IN OLD MICE THAT
ALSO EXPRESS HUMAN TAU GENE SO
THEY ARE SUFFERING FROM SOME TAU
PATHOLOGIES, SIMILAR TO
ALZHEIMER'S DISEASE PATHOLOGIES,
WE SEE THAT IN ADDITION TO
HIGHER ACTIVITY LEVELS, THE FEAR
CONDITIONING TASK ALSO SHOWS
HIGHER ACTIVITY LEVEL THAN THE
OTHER GROUPS, AND NOW IT'S
SIMILAR TO THE NOVEL OBJECT
RECOGNITION.
WE NEED TO DIG FURTHER AND WE
HAVE MORE DATA TO RECORD THAN TO
ALIGN WITH BEHAVIORAL DATA, BUT
THAT'S VERY INTERESTING IF YOU
CONSIDER THAT SOME OF THE
PATHOLOGIES MIGHT BE MEMORY
DEFICITS.
THEY MIGHT FORGET FASTER THE
FEAR CONDITIONING PART AND MOVE
TO NOVEL OBJECT.
I HOPE THAT TO TALK MORE IN
FUTURE TALKS.
STILL PLANNING TO RECORD FROM
OLDER AND MIDDLE AGE MICE AND
CHANGE IN LIFESTYLE AFFECTING
BRAIN ACTIVITY LIKE DIFFERENT
DIET OR PHYSICAL ACTIVITY.
OF COURSE WE ALL WANT TO TEST
HOW TREATMENT WORKS.
IF THERE ARE EFFICIENT
TREATMENTS WE WANT TO SEE IF
THEY CAN PERFECT THE NEURON
CIRCUITRY.
WITH THAT I CONCLUDE.
I THANK DR. DAS AND MY LAB
MEMBERS, DR. RABER AND HOLDEN
AND SCHREITER AND FUNDING
SOURCES.
>> THANK YOU, DR. DANA.
OUR LAST SPEAKER TODAY IS
VIVIANA GRADINARU, 2021 AAAS
FELLOW, PH.D. FROM STANFORD
UNIVERSITY, BACHELOR'S FROM CAL
TECH, PROFESSOR OF NEUROSCIENCE
IN BIOLOGICAL ENGINEERING,
DIRECTOR OF CENTER FOR MOLECULAR
NEUROSCIENCE AT CHEN INSTITUTE
AT CAL TECH.
SHE IS A CO-FOUNDER AND BOARD
MEMBER OF CAPSIDDA
BIOTHERAPEUTICS, A GENE THERAPY
COMPANY, RECEIVED AMONGST MANY
HONORS THE NIH DIRECTOR'S
INNOVATOR AND PIONEER AWARDS,
PRESIDENTIAL EARLY CAREER AWARD
FOR SCIENTISTS AND ENGINEERS,
OUTSTANDING YOUNG INVESTIGATOR
AWARDS FROM BOTH AMERICAN
SOCIETY OF GENE AND CELL THERAPY
AND SOCIETY FOR NEUROSCIENCE.
SHE'S BEEN HONORED AT A WORLD
ECONOMIC FORUM YOUNG SCIENTIST.
>> THANK YOU VERY MUCH.
I'M ON NEUROTECHNOLOGYIST, TODAY
I'M EXCITED TO PUT THE TOOLS
WE'VE BEEN DEVELOPING WITH MY
GROUP OF CAL TECH AND
COLLABORATORS, IN THE SERVICE OF
INVESTIGATING THE BRAIN ACROSS
OF LIFESPAN.
IT WAS MENTIONED ALREADY THIS IS
MY SLIDE, THE BIG CHALLENGE
WE'RE DISCUSSING IS HOW TO
ACCESS THE BRAIN ACROSS THE
LIFESPAN AND CHALLENGE I FOCUS
ON PARTICULARLY IS HOW CAN WE
TAKE MANY OF THE GENETIC TOOLS
YOU HEARD ABOUT, AND WONDERFUL
TO HEAR PROGRESS ON CAMPARI, WE
WERE EARLY ADOPTERS WHEN IT IT
CAME OUT AN POTENTIAL IS
AMAZING.
HOW CAN WE USE TOOLS IN ADULT
AND AGING BRAIN, EVEN MORE SO IN
THE DEVELOPING BRAIN,
SIGNIFICANT ANATOMICAL
CHALLENGES WITH THEM.
THE ADULT AND AGING BRITAIN
BRAIN HAVE THE CHALLENGE OF
GETTING ACROSS THE BLOOD-BRAIN
BARRIER AND PLACENTA, AND HAVE
DIFFERENT STATES FOR THESE
BARRIERS, SO IT'S VERY IMPORTANT
TO MEASURE NOT ONLY ACROSS
LIFESPAN BUT ALSO ACROSS DISEASE
STATES.
HOW DO WE GET ACCESS TO ONLY THE
ONES WE WANT AND ONLY IN THE
BRAIN REGIONS THAT NEED TO BE
MODULATED OR MEASURED.
AND HOW CAN WE DO THIS IN
NON-TRANSGENIC FASHION TO ENABLE
BEYOND TRANSGENIC MODELS, ACROSS
LIFESPAN.
AND THE MOTIVATION IS HIGH TO
SOLVE THE CHALLENGE BECAUSE THE
COMMUNITY OVER DECADES HAS
CREATED MANY WONDERFUL TOOLS YOU
ALREADY HEARD ABOUT.
ALSO TOOLS THAT CAN ALLOW ONE TO
GENETICALLY PROBE TO MEASURE AND
RIGHT INACTIVITY.
HOW DO WE TAKE THE WONDERFUL
TOOLS AND MAKE GOOD USE OF THEM
FROM THE SMALL AND
TRANSGENICALLY AMENABLE MOUSE
BRAIN TO THE LARGER
NON-TRANSGENIC BIG BRAINS, IN
ORDER TO HAVE A CHANCE AT
UNDERSTANDING COMPLEX BEHAVIORS.
WE'RE ENCOUNTERING CHALLENGES
AROUND DELIVERY OF GENES AND
PHOTONS, THE MORE CHALLENGES YOU
HAVE AS YOU HEARD IN THIS
SECTION ALREADY.
AND FOR THIS WE HAVE TO
REENGINEER SOME OF THE
OPTOGENETIC TOOLS AND ALSO
ENGINEER SOME GENE DELIVERY
TOOLS IN ORDER TO PAIR THEM AND,
FOR EXAMPLE, TO BE ABLE TO
ACHIEVE DELIVERY OF HIGH
CONDUCTIVITY AC SENSE THAT
METHODS THAT CAN HAVE BROAD
REACHING COVERAGE AND LOOK
ACROSS LIFESPAN.
MOST SPECIFICALLY, IN TERMS OF
GENE DELIVERY, THERE ARE A FEW
WISHES.
THAT DEPENDS ON APPLICATION AND
DEPENDS ON THE RESEARCH QUESTION
AT HAND.
WHILE HAVING ABILITY TO BE
HIGHLY CELL TYPE-SPECIFIC FOR
DIFFERENT SUBNEURONAL TYPES AND
ALSO NON-NEURONAL CELL TYPES,
ABUNDANT AND VERY IMPORTANT IN
BRAIN PROCESSING, ALSO EQUALLY
IMPORTANT IS CIRCUIT BASED
PROJECTION OR TARGETING, GENETIC
TARGETING BASED ON CIRCUITRY,
RETROGRADE TRANSPORT, WE ARE
ABLE TO DO THIS IN OUR FIELD
WITH DIFFERENT ROUTES OF
ADMINISTRATION, WHETHER IT'S
THROUGH VENTRICLES OR INJECTION,
OR DELIVER THINGS DIRECTLY TO
THE TISSUE THROUGHOUT THE
MAMMALIAN BODY WITH INCREASING
LEVELS FROM RODENTS TO NON-HUMAN
PRIMATE.
ONE VECTOR OF CHOICE FOR GENE
DELIVERY HAS BEEN THE VECTOR
THAT WE KNOW A LOT ABOUT ITS
BIOLOGY AND FUNCTION, BENEFITING
FROM FIVE DECADES OF RESEARCH,
BASIC DISCOVERY TO TODAY WHERE
FORTUNATELY NOT ONLY IS THE AAV
APPROVED AS VECTOR TO IMPROVE
DISEASE OUTCOME AND IF I MAY SAY
EVEN CURE MONOGENIC DISORDERS,
HAS GREAT POTENTIAL IF WE'RE
FOCUSED ON CRITICAL MISSING
POINTS AROUND GENE DELIVERY TO
THE BRAIN ARE STILL AFFECTING
US, AND ONE BIG DIFFICULTY IS
HAVING EXPRESSION THROUGHOUT
NON-TRANSGENIC BRAIN, AS A
REMINDER AND SPEAKERS HAVE
MENTIONED THIS MODALITY
THROUGHOUT THE WORKSHOP WE CAN
DO THE DIRECTION DELIVERY AND
THIS CAN HAVE -- FOR SOME
APPLICATIONS IT'S ADEQUATE.
IF ONE DESIRES BROAD HOMOGENOUS
COVERAGE WITH CELL TYPE
SPECIFICITY IT'S DIFFICULT TO
TAKE FROM THE MOUSE BRAIN, HERE
IS DIFFUSION YOU OBTAIN IN A
MOUSE BRAIN, SCALE UP TO
INCREASINGLY LARGER BRAINS.
ONE WAY TO BYPASS THIS CHALLENGE
IS INSTEAD OF DIRECT
INTRACRANIAL DELIVERY TO ACCESS
VASCULATURE TO DELIVER SUCH
CAPSIDS THAT PACKAGE WITH THE
GENE OF INTEREST AND GENE
REGULATORY AMOUNTS FOR
SPECIFICITY TO DELIVER THROUGH
BLOODSTREAM AND ACCESS VIA THIS
ROUTE WITH BROAD COVERAGE ORGANS
OF INTEREST INCLUDING THE BRAIN.
THE CHALLENGE UNLIKE HEART OR
MUSCLE, THE BRAIN IS PROTECTED
BY THE BLOOD-BRAIN BARRIER,
DIFFICULT TO GET RESEARCH TOOLS
OR THERAPIES.
ONE APPROACH INSPIRED FROM WORK
FROM DR. ARNOLD THAT PIONEERED
DIRECT EVOLUTION WAS TO USE
DIRECTED EVOLUTION ON THE AAV
CAPSID AND DIVERSIFY THE AAV
CAPSID SURFACE IN ORDER TO
RENDER PROPERTIES OR CREATE NEW
INTERACTIONS THAT MIGHT MEDIATE
CROSSING THE BLOOD-BRAIN BARRIER
IN MAMMALS.
THIS APPROACH IS QUITE
ENGINEERING FOCUSED BECAUSE WE
DEAL WITH VERY LARGE NUMBER OF
VARIANTS AND I GUESS INCOMPLETE
BIOLOGICAL PERFORMANCE, AND LOW
COVERAGE, YOU HAVE TO COMBINE
THE HIGH-THROUGHPUT OF DIRECT
EVOLUTION WITH INTENSE DATA
SCIENCE, AND NARROW DOWN
THEORETICAL LIBRARY PUT INTO THE
SYSTEM IN A WAY THAT ALLOWS ONE
TO SELECT A FEW CAPSIDS WITH
DESIRED PROPERTIES THAT CAN
PERFORM DESIRED TASKS SUCH AS
CROSSING BLOOD-BRAIN BARRIER.
AAV 9 HAS A WEAK PERFORMANCE
CROSSING THE BLOOD-BRAIN BARRIER
IN ADULT BRAIN, IMPORTANT IN
CONTEXT OF THE WORKSHOP, I HAVE
TO MENTION AND GIVE CREDIT TOE
AAV9, AN APPROVED GENE THERAPY
DELIVERED IN CHILDREN TO DELIVER
THE SMN GENE TO IMPROVE OUTCOME
FOR SPINAL MUSCULAR ATROPHY.
IT CROSSES THE BLOOD-BRAIN
BARRIER IN NEONATES WITH GOOD
COVERAGE.
AS THE ORGANISM MATURES, IT DID
NOT CROSS AS EFFICIENTLY.
THE PERFORMANCE OF GENE DELIVERY
VECTORS ACROSS LIFESPAN IS A
VERY IMPORTANT VARIABLE.
IN THIS CASE IN ADULT BRAIN UPON
ENGINEERING THROUGH DIRECT
EVOLUTION YOU CAN OBTAIN
INCREASINGLY BETTER VECTORS THAT
CAN DELIVER GENES WITH SIMPLE
BLOODSTREAM INJECTION.
ONLY THE CAPSID IS MODIFIED, YOU
CAN BE CREATIVE WITH CARGO AND
CAN PACKAGE SENSORS OR
MORPHOLOGY LABELS WITH GENE
REGULATORY ELEMENTS TO GET
ACCESS TO DIFFERENT CELL TYPES
AND SUBTYPES TO MAMMALIAN BRAIN,
HERE I'M SHOW THE MOUSE BRAIN.
FURTHERMORE YOU CAN USE
COMBINED, FOR EXAMPLE, TWO VIRAL
VECTOR APPROACHES TO MIMIC THE
GOLGI-TYPE LABELING, IMPORTANTLY
IN THIS CASE SURRENDERING
GENETIC INFORMATION.
DELIVERINGFLUORESCENT PROTEINS
IN A SYSTEM TO ALLOW ONE TO
COMBINE TISSUE CLEARING OF THE
MOUSE BRAIN, CAN NOW ALLOW ONE
TO TRACE THE MORPHOLOGIES OF
CELLS THROUGHOUT THE BRAIN AND
IN A WAY ONE CAN CONTROL DENSITY
OF LABELS BECAUSE IT BECOMES
VIRTUALLY IMPOSSIBLE TO
RECONSTITUTE MORPHOLOGIES OF
SCALE AND ONE MIGHT WANT TO
DELIVER ACTUATORS TO AFFECT
NEURAL ACTIVITY AND ULTIMATELY
BEHAVIOR.
WITH SYSTEMIC DELIVERY IT'S
WORTH NOTING THERE'S FEWER COPY
NUMBERS.
CAN YOU DELIVER ENOUGH CHEMO
GENETIC OR OPT GENETIC TOOLS TO
HAVE A PHYSIOLOGIC EFFECT?
IN AN ANIMAL WHERE WE HAVE THE
BENEFITS, IN MOUSE MODEL IN A
HAS BENEFITS OF TARGETING
DOPAMINERGIC CELLS, YOU CAN SEE
IN THE VIDEO WITH CHEMICAL
LIGAND HYPERLOCOMOTORRING
ANIMAL, WITH THE CONTROL
LOCOMOTION IS BASELINE.
YOU CAN USE NON-INVASIVE WAY TO
MODULATE BEHAVIOR IN GENETICALLY
SPECIFIC FASHION.
THIS TASK WAS HARDER
FOREOPTOGENETICS, WE WERE
MOTIVATED TO MAKE SYSTEMIC
DELIVERY WORK FOR THE BENEFITS I
DESCRIBED BEFORE.
HOWEVER, CONDUCTIVITY OF EARLIER
OPSINS WAS NOT HIGH ENOUGH TO
MATCH THE LOWER MULTIPLICITY
WITH SYSTEMIC DELIVERY.
WHAT WE DID IN ORDER TO ADVANCE
USE OF OPTOGENETIC SENSORS WAS
ENGINEER TO INCREASE
CONDUCTIVITY, USING A SIMILAR
APPROACH FOR AAV, DIRECT
EVOLUTION, BUT HAD TO COUPLE
WITH MACHINE LEARNING, PATCH
CLAMP OR MEASURE CURRENTS VERY
LOW THROUGHPUT WHILE DIRECT
EVOLUTION IS HIGH-THROUGHPUT SO
WE NEEDED DATA APPROACH TO
BRIDGE MODALITIES WHERE WE WOULD
GENERATE COMPLEXITY FROM PARENT
OPSINS AND MEASURE ONLY A SUBSET
OF RESULTING VARIANTS LOCALIZING
THROUGH PLASMA MEMBRANE AND
LEARN FROM DATA AND PREDICT ON
THE SPACE THAT'S BEYOND SINGLE
CELL PATCHING PROBABILITIES, AND
THROUGH THIS PROCESS A FORMER
GRADUATE STUDENT FOUND OPSINS
WITH HIGHER CONDUCTIVITY.
YOU CAN SEE WITH DIRECTION
INJECTION PERFORMANCE OF
CHANNELRHODOPSIN AND PERFORMANCE
OF OPSINS THAT CLAIRE GENERATED
WITH DIRECT EVOLUTION AND
MACHINE LEARNING.
CONDUCTIVITY OF THESE ADVANCED
OPSINS SHE CALLED THEM CHARGERS
IS HIGH ENOUGH SO THEY HAVE VERY
GOOD PERFORMANCE WITH DELIVERY,
TESTED IN A BEHAVIORAL CONTEXT
BY PACKAGING IMPROVED HIGHER
CONDUCTIVITY OPSIN CHARGER TOOL
IN A CAPSID THAT I PRESENTED
BEFORE THAT'S DELIVERED TO THE
BLOODSTREAM OF A WILDTYPE MOUSE.
THEN YOU CAN HAVE THE OPSIN
DISTRIBUTION NON-INVASIVE
THROUGHOUT THE BRAIN AND IN
ORDER TO ACTIVATE CELLS CLAIRE
AND ELLIOTT, DR. ROBINSON HAS
HIS OWN HOW, THEY THINNED THE
SKULL, APPLIED THE LIGHT, WERE
ABLE TO AFFECT LOCOMOTION IN THE
WILDTYPE MOUSE WITHOUT ANY
BREAKING OF THE SKILL OR ANY --
THROUGH THE BRAIN PARENCHYMA.
WHEN ONE CONTROLS BEE --
BEHAVIOR, IF THE INTENTION IS
THE BRAIN AND DELIVERY SYSTEMIC,
THERE STILL BE CO-FOUND FROM
OTHER ORGANS, IMPORTANT TO
HIGHLIGHT BECAUSE WE WORKED WITH
STANFORD TO LABEL ENGINEERED
CAPSIDS WITH PET REPORTERS THAT
ALLOWED US TO SEE
BIODISTRIBUTION OF PARENT
CAPSIDS AND ENGINEERED CAPSIDS,
WHILE AAV9 SHOWS VERY LITTLE
PRESENCE IN RODENT BRAIN, EVEN A
DAY AFTER DELIVERY, PHP.EB WAS
STRONG IN THE BRAIN, STRONG
EXPRESSION IN HEART, LIVER,
OTHER ORGANS, IMPORTANT TOOL TO
CONTINUALLY WORK ON REFINING
SELECTIVITY AND SPECIFICITY OF
SUCH GENE DELIVERY METHODS.
IN ORDER TO ACHIEVE THIS WE
PERFORMED THE SELECTIONS IN
PARALLEL IN PRE-TRANSGENIC MICE,
APPLIED DEPENDING ON THE CRE
RECOMBINATION WAS EXPRESSED,
APPLY PRESSURE FOR POSITIVE
SELECTION, FOR EXAMPLE, TO
TARGET DIFFERENT CELL TYPES
WITHIN THE BRAIN OR NEGATIVE
SELECTION, TO STAY AWAY FROM THE
LIVER OR HEART, AND BY LOOKING
AT THE MOTIFS OF THE CAPSIDS,
PEPTIDE CHANGES, WE WOULD LOOK
AT CHANGES IN MOTIF FOR POSITIVE
AND NEGATIVE SELECTION, THIS
RESULTS IN QUITE LARGE DATASET
BUT THEY BECOME DOWNSTREAM ONCE
YOU BREAK DOWN INTO PATTERNS AND
CLASH ON MOTIFS IN DIFFERENT
SPECIES, AND THIS PROCESS
ALLOWED US TO SYSTEMATICALLY
EXTRACT CAPSIDS PSYCHOTROPIC OR
BIASED, SOME NOT SPECIFIC, SUCH
AS PHP.N, WORTH NOTING PATTERNS
ARE OBTAINED WITH UBIQUITINNOUS
PROMOTERS, IN TERMS OF
MORPHOLOGY OF CELL TIMES IS DUE
TO CAPSID AND NOT GENE
REGULATORY ELEMENTS.
WITH SINGLE CELL SEQUENCING,
THERE'S METHODS FOR BOTH NOW, WE
CAN COLLECT INFORMATION ABOUT
SPECIFICITY ABOUT VECTORS, THE
COMBINATION OF HIGH-THROUGHPUT
DIRECTED EVOLUTION, INCREASINGLY
HIGH-THROUGHPUT ABILITY TO
ANALYZE AND PROFILE ACT TO EXACT
CAPSIDS WITH INCREASINGLY
DESIRED PROTEINS SUCH AS
TARGETING MOUSE BRAIN FOR
SYSTEMIC DELIVERY YOU ABOUT
AVOID THE LIVER.
YOU CAN SEE THE PARENT, AAV 9,
PERFORMANCE IN THE BRAIN, WEAK,
INTERMEDIATE PHP.B CROSSING THE
BLOOD-BRAIN BARRIER, A LOAD
COULD CAUSE UNWANTED SIDE
EFFECTS, REQUIRING HIGHER DOSAGE
FOR ANIMAL, TO A VARIANT THAT
CAN CROSS THE BLOOD-BRAIN
BARRIER, IMPORTANTLY AVOIDING
PERIPHERAL TISSUES INCLUDING THE
LIVER HERE.
IT'S WORTH NOTING IN THE CONTEXT
OF THE WORKSHOP BIOLOGICAL
VARIABLES ARE EXTREMELY
IMPORTANT.
AND IN THIS CASE I'M
ILLUSTRATING CAN MOUSE BRAIN
DIFFERENCE.
YOU CAN SEE PERFORMANCE OF AAV 9
AND ENGINEERING PHP.B, DIFFERENT
STRAINS, CONTROLLED MOUSE
STRAINS, STRIKING DIFFERENCES
BETWEEN, FOR EXAMPLE, 57 BLACK 6
AND BALB/C.
A FEW LESSONS TO LEARN, ONE, THE
BLOOD-BRAIN BARRIER IS
HETEROGENEOUS, EVEN ACROSS
DIFFERENT MOUSE STRAINS, SO IT
IS EXTREMELY IMPORTANT TO
CONSIDER BIOLOGICAL VARIABLES
SUCH AS SEX, AGE, IN THIS CASE
GENETIC BACKGROUND OR IF I CAN
EXTEND IT, IN THE CONTEXT OF
HUMAN GENE THERAPY ANCESTRY.
THIS IS A VERY IMPORTANT POINT
BUT ALSO BECAUSE YOU SEE THERE'S
VERY CRISP PATTERNS GIVES US
MECHANISTIC INSIGHT, AND THIS
CAN ALLOW US TO BYPASS THIS
PROBLEM SYSTEMATICALLY AND
INDEED BY TAKING INTO ACCOUNT
BIOLOGICAL VARIABLES, BEING
AWARE, ONE CAN BYPASS
LIMITATIONS AND HAVE -- NOW,
I'LL CLOSE SOON, WE HAVE CAPSIDS
TO COVER MOUSE STRAINS, AND EVEN
NON-HUMAN PRIMATE, THIS IS AN
EXAMPLE IN THE MARMOSET BRAIN
WHERE ENGINEERED AAVs TO
BLOODSTREAM DELIVERY CAN
EFFICIENTLY COVER THE MARMOSET
BRAIN.
IN MOST RECENT WORK WITH
WONDERFUL COLLABORATORS FROM
DAVIS LED BY DR. DREW FOX, WE
WERE ABLE TO DELIVER GENES
ACROSS THE BLOOD-BRAIN BARRIER
TO MACAQUE BRAIN, NEONATE AND
INFANT MACAQUE BRAIN.
NON-TRANSGENIC PATTERN WE CAN
DELIVER MULTIPLE GENES ACROSS
MONTH OLD RHESUS MACAQUE, CAN
GOOD DISTRIBUTION BRAIN-WIDE,
SHOWING EXAMPLES FROM CORTEX,
CEREBELLUM, PALAMOSE.
THIS IS COLLECTION IS
INCREASING, AND THERE'S MORE
DETAILS ON THE WEBSITE, MANY
TOOLS ALREADY OR SOON AVAILABLE
ON OUR GENE, COVERED IN THIS
REVIEW THAT SHOULD SOON BE OUT,
OPEN ACCESS FOR EVERYBODY TO
READ.
IN CLOSING I WILL PUT THE KEY
CHALLENGES THAT WE NEED
EFFICIENT SPECIFIC AND
NON-SPECIFIC DELIVERY TO ALL
BRAINS TO MAXIMIZE ABILITY TO
DELIVER DIVERSIFIED GENETIC
CARGO ACROSS THE LIFESPAN, AND
THERE ARE OF COURSE WISHES FOR
EFFICIENCY AND SAFETY IN
WIDESPREAD DELIVERY ACHIEVED
WITH SYSTEMIC METHODS, BUT WE
NEED TO TAKE INTO ACCOUNT OFF
TARGET EFFECT AND COMPATIBILITY
WITH CARGO, EXTREMELY IMPORTANT
TO WORK ON TROPIC CAPSIDS TO
MINIMIZE GENE REGULATORY
ELEMENTS, MAYBE TOWARDS CAPSID
SIZE INCREASE BUT THAT'S A
DIFFICULT TASK.
I WILL THANK MY TEAM AND VERY
GRATEFUL TO THE BRAIN INITIATIVE
THAT FUNDED THIS AAV WORK AND
ESPECIALLY WAYS TO AMPLIFY AND
DISTRIBUTE AND COLLABORATE WITH
THE TOOLS.
THERE'S A FEW RESOURCES HERE IF
YOU'RE INTERESTED TO USE TOOLS
AND I'LL PAUSE HERE.
>> THANK YOU VERY MUCH.
THIS HAS BEEN AN AMAZING SET OF
TALKS.
I COULD WAX LYRICAL AND OF BUT
I'M NOT GOING TO DO THAT.
I WANT TO MOVE IMMEDIATELY TO
THE QUESTIONS AND OUR
DISCUSSION.
BECAUSE THERE ARE A NUMBER OF
QUESTIONS AND I THINK WE MIGHT
WANT TO START WITH THE CHAT,
WHICH ARE FOR ELLEN GRANT.
WE HAVE -- LET'S SEE FOR DR.
GRANT.
I WANT TO GO BACK TO THE ONE IN
THE CHAT.
THE QUESTION TO DR. GRANT,
THANKS FOR A WONDERFUL
PRESENTATION.
HOW DO SPONTANEOUS ACTIVITY
TRANSIENT OR SAT WAVES SIGNAL
DEVELOPMENT OF MATURE CIRCUITS?
WHAT DO YOU THINK IS THE ROLE OF
THE SPONTANEOUS ACTIVITY IN THE
ADULT OR AGING BRAIN?
>> WELL, FIRST, SPONTANEOUS
ACTIVITY TRANSITS ARE ONLY IN
THE MATURE BRAIN, MOVING TO
MATURE PATTERN WITH
CORTICAL-CORTICAL INSTEAD OF
SUBPLATE NEURONS, I DON'T KNOW
THAT THERE IS A ROLE IN ADULT
MAJORING BRAIN.
SUBPLATE NEURONS DISAPPEAR LATER
IN GESTATION, NOT PRESENT IN
AGING BRAIN.
>> THANK YOU FOR THAT.
NEXT A QUESTION FOR GEORGE
DRAGOI FROM HOLLIS CLINE.
THANK YOU FOR YOUR INTERESTING
TALK.
REGARDING DEVELOPMENT OF CIRCUIT
FOR REPLAY, PRE-PLAY, PRE-PLAY,
HAVE YOU TESTED, IF YOU BLOCK
SPONTANEOUS PRENATAL WAVES IN
THE RETINA WHICH MIMIC NATURAL
OBJECT FLOW OR -- ARE PLACED
CELLS DISRUPTED?
>> THANK YOU FOR THE QUESTION.
SO WE'RE INVESTIGATING THE ROLE
OF PRE-PLAY, NOT THROUGH
BLOCKING SPONTANEOUS PRENATAL
RETINAL WAVES.
WE DID NOT SEE SIGNIFICANT
PRE-PLAY AT 15, 16, ONLY
POSTNATALLY.
SO, YEAH, I THINK THAT'S
SOMETHING TO THINK ABOUT MORE
FOR THE FUTURE.
>> OKAY.
WE HAVE A COUPLE QUESTIONS FOR
DR. EMILIANI.
I THINK THE FIRST ONE, LET'S SEE
IF I CAN MAKE SURE I GO TO THE
FIRST ONE FIRST.
THANK YOU FOR YOUR WONDERFUL
TALK.
HOW EASILY CAN HOLOGRAPHIC TOOLS
BE EXTENDED TO STRUCTURES DEEPER
IN THE BRAIN?
>> YES, SO THANKS FOR THE
QUESTION.
THERE IS SOME WAY, TO COUPLE
THIS APPROACH TO IMPLANTABLE
GREEN LENS, WE'VE SHOWN THE
PROPAGATION OF TEMPORALLY
FOCUSED HOLOGRAPHIC, GOING
THROUGH THE GREEN LENS, SO THIS
IS USUALLY THE FIELD OF VIEW IS
SMALLER THAN WHAT WOULD BE
ACHIEVABLE WITH CONVENTIONAL
OBJECTIVE BUT NORMALLY DEEPER
REGION ALSO CONTROL WITH REDUCED
NUMBER OF CELLS SO I THINK THIS
IS DOABLE.
AND STILL IF WE JUST WANT TO
COUPLE NORMAL MICROSCOPE WITH
GREEN LENS, THIS WILL STILL
REQUIRE SAME ANIMAL, MORE
RECENTLY WORKING ON DEVELOPING
HOLOGRAPHIC SYSTEM WHERE WE CAN
DO FREELY MOVING ANIMALS, IN
THIS CASE HOLOGRAPHIC AND TERM
FOLLOW FOCUS WITH FIBER BUNDLE
AND GREEN LENS ENABLE TO
MANIPULATE IN FREE MOVING
ANIMALS.
WE HAVE TO USE IMPLANTABLE GREEN
LENS, 150 MICROMETERS IN
DIAMETER, CONTROL FOR 30, 40
CELLS IN A PLANE, SO DEPENDS NOW
WHICH IS THE BRAIN REGION THAT
IS INTERESTED IN, BUT IS DOABLE.
BECAUSE OF SMALLER FIELD OF
VIEW.
>> SO DR. DANA HAD ANOTHER
QUESTION HERE.
ONE OF THE ROOTS THAT DEPTH
IMAGING WAS IMPROVED FOR TWO
PHOTON MICROSCOPY WAS THE SWITCH
TO LONGER, 1300 TO
1700-NANOMETER WAVELENGTHS, CAN
SIMILAR BE USED TO INCREASE
HOLOGRAPHY?
>> ANOTHER WAY TO GO DEEPER IF
WE DON'T WANT TO USE THE GREEN
LENS TO GO TO THIS REQUIRE
PROBABLY WE'RE INTO THE
THREE-FOLD GENE SO THERE HAVE
BEEN VERY FEW YEARS AGO
PUBLICATION SHOWING FOCAL
OPTOGENETICS, PRELIMINARY DATA
IN CULTURED CELLS.
I THINK THERE'S A POSSIBILITY,
THEY WILL ENABLE TO BEGIN WITH
RESPECT TO PHOTOMICROSCOPY GO
DOWN TO 700, 800 MICROMETERS, WE
WANT TO GO EVEN DEEPER, SOLUTION
TO USE THE GREEN LENS.
>> NOW A QUESTION FOR DR. DANA
FROM DANIEL GLEN.
HAS CAMPARI BEEN COMPARED TO
(INDISCERNIBLE).
>> I WOULD SAY NO, NOT COMPARED.
>> SECOND QUESTION FOR YOU, IS
CAMPARI REVERSIBLE?
AFTER A CELL IS ACTIVE, DOES IT
GO BACK TO BASELINE AFTER ANIMAL
LEARNS A NEW BASELINE, IS IT
POSSIBLE TO PREDICT WHEN A
NEURON BECOMES ACTIVE AFTER
IMAGING THEM 2P MICROSCOPE?
>> CAMPARI, THE CHANGE TO
INFRARED IS IRREVERSIBLE ON
PROTEIN LEVELS, BUT PROTEINS DO
NOT LIVE FOREVER IN THE HUMAN,
NOT THE HUMAN, IN THE MOUSE
BODY.
THERE IS DEGENERATION OR DECLINE
OF SIGNAL MANUFACTURING NEW
GREEN PROTEIN SO WE TESTED THAT,
RUFFLY AFTER SEVEN DAYS 95% IS
GONE, YOU CAN REUSE CAMPARI.
FROM OTHER WORK, YOU CAN ERASE
AND RESTART BUT WE HAVEN'T
TESTED YET.
REGARDING THE SECOND QUESTION,
ONE OF THE CHALLENGES OF USING
CAMPARI, YOU GET A SNAPSHOT OF
ACTIVITY.
IT'S INTEGRATION OVER THE ENTIRE
ACTIVITY DURING THE TIME YOU
RECORDED.
SO WE CANNOT SAY EXACTLY WHAT
WAS THE TIMING OF THE ACTIVITY
BUT ONLY INTEGRATION OVER THE
ACTIVITY DURING THAT TIME.
>> OKAY.
ANOTHER QUESTION FOR DR.
GRADINARU, IS IT POSSIBLE FOR
SPECIFIC CELL TIMES WITH
SYSTEMIC INJECTION OF THESE
OPSINS?
>> THANK YOU FOR THE QUESTION.
SO IN MICE, A LOT IS POSSIBLE.
HOWEVER, DEPENDING ON THE
APPLICATION MIGHT NOT BE
DESIRABLE.
AS PROFESSOR EMILIANI MENTIONED,
IF YOU'RE GOING FOR DEBRAIN
AREAS YOU NEED TO IMPLANT
OPTICAL ELEMENTS CLOSE TO THE
CELLS.
BECAUSE DIFFUSION WAS PART
INJECTION IN THE MOUSE MIGHT
COVER RELEVANT AREAS MIGHT NOT
NECESSARILY BE DESIRABLE.
I'LL MENTION SITUATIONS IT WOULD
BE DESIRABLE.
FOR EXAMPLE IF YOU'RE DOING
LARGE AREA CORTICAL
STIMULATIONARY RECORDING WITH
CRANIAL WINDOW, WITH SYSTEMIC
DELIVERY, WITH PROMOTERS, YOU
COULD GET GOOD COVERAGE OF CORE
NEXT AND UNIFORM COVERAGE
WITHOUT DAMAGING PRECISELY THE
CELLS YOU WANT TO RECORD FROM
BECAUSE IF YOU DO SPOT INJECTION
YOU WILL DAMAGE OR CREATE
INFLAMMATION AT THE SPOT AREA.
AND THERE WILL BE HETEROGENEITY
IN EXPRESSION.
FOR LARGE CORTICAL AREAS IT'S
DESIRABLE.
AS YOU GO TO LARGER BRAINS IT
STARTS BEING NECESSARY TO
BROADEN THE COVERAGE AREA, WITH
SPOT INJECTION IN A MOUSE, AND
IN A MACAQUE BRAIN, YOU'LL GET
THE SAME VOLUME.
THAT MIGHT BE ENOUGH
PHYSIOLOGICALLY IN A MOUSE BUT
NOT IN A NON-HUMAN PRIMATE.
SO THEN HAVING THE OPTION OF
SYSTEMIC DELIVERY BECOMES MORE
IMPORTANT AS YOU'RE TRYING TO
COVER LARGER AND LARGER BRAIN
AREAS.
>> THANK YOU.
ANOTHER QUESTION FOR YOU FROM
DAVID ASH BROOK.
ANY HYPOTHESES ON DIFFERENT
MOUSE BRAINS, HAS THIS BEEN DONE
ON DBA/2J?
INTERESTING TO SEE IF POSSIBLE
TO MAP A RESPONSIBLE LOCI.
>> ABSOLUTELY.
REALLY INTERESTING AS WELL,
SINCE THEN THIS CAPSID EMERGED
TO SOMEWHAT BLIND DIRECTED
EVOLUTION PROCESS, WITHOUT
MECHANISTIC UNDERSTANDING.
YOU HAVE THE PEPTIDE PROPERTIES
AND YOU ALSO HAVE PERFORMANCE IN
DIFFERENT MOUSE STRAINS, THIS
WAS ACTUALLY VERY SUCCESSFULLY
USED BY INDEPENDENT GROUPS,
THREE PAPERS REPORTED IT WORKS,
PRESENT IN 57 BUT NOT OTHER
MOUSE STRAINS, ALSO NOT PRESENT
IN NON-HUMAN PRIMATE, FOR
EXAMPLE.
FOR DPA, ONE OF THE PAPERS I
MENTIONED, NATURE PROTOCOLS,
NATURE METHODS, WE HAVE VECTORS
THAT WORK IN DBA STRAIN AS WELL
BUT IT'S VERY IMPORTANT THAT
CROSSING AND EXPERIMENTAL MICE
IS TAKEN INTO ACCOUNT.
NOW FOR RODENTS WE HAVE
COMBINATIONS COVERED, COLLECTING
INFORMATION SO RESEARCHERS KNOW
IF THEY WANT TO USE THIS IN A
PARTICULAR MOUSE STRAIN THEY CAN
SEE WAS IT DONE BEFORE, WOULD IT
WORK, WOULD IT NOT.
>> THANK YOU.
NOW DR. EMILIANI HAS A QUESTION.
IS CAMPARI SENSITIVE TO A SINGLE
SPIKE? IF NOT HOW MANY NEED TO
BE PRODUCED TO BE DETECTED?
>> THE ANSWER IS CAMPARI AS
DEVELOPED IS NOT SENSITIVE TO
SINGLE SPIKES.
ACTUALLY WE HAVE A PROJECT NOW
TO DEVELOP NEXT GENERATION WITH
IMPROVED SENSITIVITY.
AND THEN HOPEFULLY WE'LL HAVE
PRECISE NUMBERS.
NOW, REGARDING HOW MANY SPIKES
ARE NEEDED, IT REALLY DEPENDS ON
THE TISSUE QUALITY.
I WOULD ASSUME IN A GOOD
EXPERIMENT WE CAN PROBABLY
DETECT AROUND OVERALL ACTIVITY
OF TEN ACTION POTENTIALS IN THE
RECORDING BUT THIS IS A ROUGH
ESTIMATION.
>> OKAY.
I THINK WE HAVE COVERED THE
QUESTIONS CURRENTLY IN THE CHAT.
WE HAVE A LITTLE MORE TIME.
WE'VE BEEN GIVEN A FIVE-MINUTE
EXTENSION, BUT WE HAVE TO END AT
2:55, YOUR TIME.
WE DO HAVE A FEW MINUTES TO GO
NOW.
PERHAPS I SHOULD FIRST ASK IF
THERE'S ANYONE WHO WOULD LIKE TO
ASK A QUESTION NOW IN THIS
DISCUSSION WHO IS HERE IN THE
GROUP AT THIS POINT WHO HASN'T
PUT ANYTHING IN THE CHAT?
>> I HAVE A QUESTION.
YOU MENTIONED IN YOUR TALK AT
THE BEGINNING THAT THE
THERAPEUTIC RISE FOR TECHNOLOGY,
WHAT ARE THE CONCERNS, WHAT IS
THE LIMITATION FROM MARMOSETS TO
HUMAN?
>> MAYBE THE BIGGEST LIMITATION
IS SIXTY, AND I HAVE TO MENTION
HIGH DOSE SYSTEMIC DELIVERY
CAUSED SEVERELY UNWANTED SIDE
EFFECTS INCLUDING DEATH IN THE
RECENT YEARS.
AND THIS POINTS TO THE FACT THAT
THE TARGETING IS EQUALLY
IMPORTANT AND WORTHWHILE GOAL
TARGETING THE ORGAN OF INTEREST.
SO MANY COMPLICATIONS FROM
SYSTEMIC DELIVERY OF CHEMICALS
OR BIOLOGICALS COMPOUND LIVER
EFFECTS, SO DETARGETTING FROM
THE LIVER IS A VERY IMPORTANT
STEP TOWARDS SAFETY.
NOW, IF WE THINK ABOUT EFFICACY,
WE THINK ABOUT BRAIN AREAS,
HETEROGENEITY OF CELL TYPES IN
THE BRAIN PHENOMENON IS
INTERESTING FOR SCIENTISTS BUT
ALSO VERY CHALLENGING IF YOU PUT
IN DISEASE CONTEXT, SO BEING
VERY SPECIFIC ON NEURONAL
SUBTYPES, THINKING ABOUT
EPILEPSY MAKES A DIFFERENCE WITH
NEURONS ARE EXCITATORY OR
INHIBITORS CLASSES.
SPECIFICITY IS A VERY IMPORTANT
CONSIDERATION.
AND SAFETY HAND IN HAND.
NOW, WE SEE BECAUSE VECTORS ARE
USED, I DON'T WANT TO DISTRACT
FROM THE FACT THAT AAVs ARE A
THERAPY BUT ARE IMPROVING LIVES,
EXTENDING LIFESPANS OF PATIENTS
THAT HAVE VARIOUS DISORDERS, AND
IT'S AN EXTREMELY POTENT
CAPABILITY THAT WE CANNOT NOT
MEET THE CHALLENGE OF THE DAY.
AND THEY ARE BEING USED AND I
THINK BY FURTHER DEVELOPING AND
REFINING THEM WE COULD START TO
ADDRESS SYSTEMATICALLY FIRST
MONO GENETIC DIS ORDERS, LATER
ON COMPLEX DISORDERS AS WELL.
>> ANY OTHER QUESTIONS OR
COMMENTS?
>> WITH VIRAL VECTORS YOU KNOW
WHERE IT'S SUPPOSED TO GO AND
CAN TELL IT TO GET THERE BUT HOW
DO YOU KNOW IF IT'S HAVING THE
FUNCTION YOU ANTICIPATE WHENS
YOU TRANSLATE TO HUMAN SUBJECTS,
WHAT TYPES OF MONITORING ARE
PEOPLE SPEAKING OF TO SEE IF
ACTION IS EXPECTED?
>> IN THE MOUSE WE HAVE BENEFIT
OF LOOKING AT THE TISSUE, RIGHT?
AND WE WILL NOT HAVE THAT IN THE
HUMANS.
THE ENTIRE FIELD OF BIOMARKERS
BECOMES EXTREMELY IMPORTANT AND
I SHOWED QUICKLY ONE SLIDE ON
PET MARKERS, YOU CAN HAVE PET
REPORTERS FOR THE CAPSID, ALSO
FOR CARGO, AND HAVE BEEN WORKING
OVER YEARS TO LABEL CERTAIN
VECTORS OR CARGO ELEMENTS FOR
NON-INVASIVE IMAGING.
NOW RESOLUTION IS NOT AS HIGH,
OF COURSE, AS WE WOULD HAVE WITH
HISTOLOGY.
BUT IT BECOMES VERY IMPORTANT
FOR US.
PET IMAGING WITH INCREASINGLY
SPECIFIC LABELS AND MAYBE EVEN
MULTIPLEX LABELS, DIFFERENT
MARKERS CAN BE IMAGED AT THE
SAME TIME IN THE SAME ANIMAL.
AND THEN IT'S WORTH NOTING AT
LEAST FOR MANY OF THE STARTING
DISORDERS, MANY OF THEM FALL IN
THE CLASS OF LYSOSOMAL STORAGE
DISORDERS
SO IF YOU INTRODUCE A CARGO THAT
SECRETES ELEMENT MEASURED IN
THE BLOODSTREAM OR CSF MAYBE YOU
CAN GET REALTIME INDICATION HOW
THE THERAPY IS DOING.
THIS BEING SAID IT'S REALLY
IMPORTANT VECTORS HAVE A STOP
LINE, IF THINGS GO OVERBOARD AND
WRONG THERE'S A POINT, WE
SHOULDN'T TAKE LIGHTLY THIS IS
NOT A SMALL MOLECULE THAT WILL
GET CLEARED.
IT'S SOMETHING THAT STAYS.
THAT'S ITS POWER AND ITS DANGER
AS WELL.
>> THANK YOU.
>> THANK YOU FOR THE QUESTION.
>> WE HAVE ANOTHER QUESTION
COMING FROM AMANDA I THINK.
IT'S FOR THE WHOLE GROUP.
ARE THERE STRATEGIES YOU WOULD
RECOMMEND FOR INTEGRATING DATA
COLLECTED FROM DIFFERENT LIFE
STAGES?
FOR EXAMPLE PERINATAL VERSUS
AGED TIME POINTS?
GIVEN METHODOLOGIES ARE OFTEN
DIFFERENT.
I THINK THIS IS A GENERAL
QUESTION, IT WOULD BE NICE TO
HEAR PEOPLE TALK ABOUT WHICH I
WOULD STATE, TO EXTEND SCOPE OF
THIS A LITTLE BIT, CONNECTING
THE DOTS ACROSS THE PARADIGMS AT
A GIVEN TIME IN THE AGE LIFESPAN
BUT ALSO TAKING THOSE SETS OF
CONNECTED DOTS AT A PARTICULAR
POINT IN THE LIFESPAN AND
EXTENDING THROUGHOUT THE
LIFESPAN, WHAT STRATEGIES COULD
BE INTEGRATED YOU COULD IMAGINE
ACHIEVING AS A SCIENTIFIC
COMMUNITY, IN PARTICULARLY HOW
YOUR LAB COULD CONTRIBUTE.
>> I'LL JUMP START THAT
DISCUSSION.
I APPRECIATE THIS QUESTION.
I THINK PART OF WHAT TERRY WAS
TALKING ABOUT IS ACROSS
DIFFERENT SCALES, SO DIFFERENT
LEVELS OF ORGANIZATION.
I THINK IT'S REALLY CHALLENGING
TASK.
AND THE KEY IS REALLY FINDING
THE RELEVANT QUESTIONS THAT HAVE
CONTINUUM WITHIN THIS.
AND RELEVANT VARIABLES THAT CAN
BE STRETCHED ACROSS.
YESTERDAY WE TALKED ABOUT SEX,
SOMETHING WE CAN STRETCH ACROSS
AND SEE HOW THAT MODERATES
ACROSS LEVELS, A FIXED VARIABLE.
IN THE WORK THAT I'VE BEEN
DOING, I LIMITED THE DATA I
COLLECTED, COLLECTED WITH AGES
CONTINUOUS VARIABLE, PRECISELY
SO I WILL BE ABLE TO KIND OF DO
MORE OF AN INTEGRATION ACROSS
LIFESPAN, AND HARMONIZING WITH
OTHER PEOPLE, COLLEAGUES I WORK
WITH WITH SIMILAR THINGS ALONG
THE AGING, ALONG THE ADULT
LIFESPAN, SO WE CAN HAVE PEOPLE
LOOKING AT VOLUME, FROM AGE 8 TO
82, FOR EXAMPLE, WITH USING
SIMILAR METHODS SO WE ALLOW TO
STITCH TOGETHER THOSE DATA, EVEN
THOUGH THEY ARE NOT DONE WITHIN
THE SAME LAB.
I THINK THIS IS POSSIBLE BECAUSE
WE HAVE THE SAME QUESTION,
WANTED TO KNOW ABOUT HIPPOCAMPAL
VOLUME ACROSS THE LIFESPAN, THAT
MEASURE ALLOWED US TO STITCH
TOGETHER DATA COLLECTED ACROSS
DIFFERENT LABS.
IF WE HAVE QUESTIONS RELEVANT
ACROSS THIS LIFESPAN WE CAN DO
THAT.
THE QUESTION ABOUT COGNITION, WE
HAVE MAYBE THOSE, WE CAN STITCH
THOSE TOGETHER BY LOOKING AT
WHAT MIGHT BE THE PRECURSORS OF
LATE COGNITIVE ABILITIES ONCE WE
GET TO CERTAIN LEVEL OF
COGNITIVE ABILITIES CAN BUILD A
TASK THAT WORKS ACROSS THE
LIFESPAN.
YOU DON'T NEED TOO MUCH COMPLEX
KNOWLEDGE TO SEE AND TRY TO
REMEMBER THE SCENE, SOME
THOUGHTS I HAVE.
>> I'LL ADD IT'S IMPORTANT TO
HAVE MULTIPLE MODALITIES WITH
WHICH TO GATHER INFORMATION, AND
TO CREATE THEORETICAL
CONSTRUCTS, MAYBE NOT COMPARING
THE SAME ENERGY AT EACH AGE
GROUP, DIFFERENT MODALITY OR
STRATEGY, BUT THEY ARE
CONTRIBUTING TO A THEORY THAT
CONNECTS ALL AGES.
WHAT I USED IN, SAY, NEURAL
ACTIVITY IN A FETUS MAY BE
DIFFERENT THAN WHAT WE USED WITH
NEURAL ACTIVITY IN AN
80-YEAR-OLD BUT THE THEORIES OF
SYNAPTIC DEVELOPMENT OR
DEGENERATION GO TO THE FIELDS
AND COME AT IT FROM DIFFERENT
DIRECTION, DEPENDING WHETHER
IT'S HUMAN OR ANIMAL.
>> ANY OTHER SPEAKERS WANT TO
TALK ABOUT HOW THEY SEE US
CONNECTING THE DOTS?
EITHER AT A GIVEN TIME POINT
AMONG DIFFERENT LEVELS OF
ANALYSIS OR ACROSS THE LIFESPAN?
I KNOW YOU'RE ALL CONTRIBUTING
TO THAT SO I DON'T WANT TO -- I
GET IT FROM ALL YOUR
PRESENTATIONS EVERYONE IS
CONTRIBUTING BUT IF YOU CAN
THINK OF WAYS YOU COULD
CONTRIBUTE MORE, MOVE FARTHER IN
DEVELOPING THE EXTREMELY LARGE
SPACE OF OBSERVATIONS ACROSS THE
LIFESPAN, GOING DEEPLY INTO
MECHANISMS AT EACH POINT ACROSS
THE LIFESPAN THAT CAN ONLY BE
DONE COLLABORATIVELY BY THE
SCIENTIFIC COMMUNITY.
HOW YOU THINK YOU COULD -- WE
COULD MOVE FORWARD IN CREATING
THAT SHARED VERY IMPORTANT
DATASET, YOU KNOW, TO EXPLORE
MORE DEEPLY WHAT'S GOING ON
HERE.
>> I WANT TO SECOND WHAT ELLEN
HAS SAID.
CONCEPTUALLY WE COULD CONNECT
ACROSS DIFFERENT METHODOLOGIES
AND AGES AND SPECIES BUT IT
WOULD BE RELATIVELY HARD TO
CONNECT ACROSS DIFFERENT
METHODOLOGIES LIKE fMRI TO
PHYSIOLOGY, DIFFERENT
RESOLUTIONS AT DIFFERENT TIME
AND SPACE BUT CONCEPTUAL ONE
METHOD MAYBE CAN BE EXPLORED
WITH THE OTHER METHOD IF IT'S
FOUND IN ONE -- IN RODENTS, CAN
BE EXPLORED IN THE HUMAN.
THOSE KIND OF CONCEPTS I THINK.
SOME MAY WORK, SOME MAY NOT BE
AS GENERAL.
BUT IT'S NOT A DIRECT LINK
BETWEEN DIFFERENT, YEAH,
DESIGNS.
>> SINCE YOU RESPONDED, LET ME
ASK YOU A QUESTION.
FASCINATED BY THIS P 23
PHENOMENON THAT YOU SHOWED,
WHERE YOU SEE FIRST TIME RUN,
PLASTICITY APPEARS, IF I GET
THAT RIGHT.
I'M WONDERING WHAT ARE YOUR
FAVORITE EXPLANATIONS, CELLULAR
OR SIGNALING LEVEL, THAT MAY
UNDERLIE THIS VERY INTERESTING
TRANSITION, YOU KNOW, WHAT ARE
THE NEURAL OR SORT OF SIGNALING
MECHANISMS THAT YOU THINK MIGHT
BE INTERESTING, ARE SOME
TECHNIQUES WE HEARD AFTER YOURS
THAT COULD BE USED TO BETTER
INTERROGATE THAT QUESTION.
YOU MAY ALREADY KNOW THE ANSWER
BUT I'M JUST INTRIGUED BY WHAT
IS TRIGGERING THAT SHIFT.
>> SO, THE NUMBER OF RECEPTORS
AND MOLECULES SOMEHOW
ACTIVITYING FROM IMMATURE FORM
TO ADULT -- SHIFTING FROM
IMMATURE TO ADULT FORM, THERE'S
UPREGULATION, DOWNREGULATION.
SO WE'RE FOLLOWING ON THAT TRACK
A LITTLE BIT TO SEE IF WE ADD
SOME THAT CAN ACCELERATE
TRANSITION FROM ONE RECEPTOR
TYPE TO ANOTHER COULD IN
PARALLEL SEE ACCELERATION OF
THIS ACROSS STAGES.
AGAIN, THAT WOULD BE ANOTHER
TYPE OF CONNECTIVITY ACROSS LABS
WHERE MOLECULAR BIOLOGY NEEDS TO
BE COMBINED WITH COMPLEMENT
PHYSIOLOGY ONES.
BUT USING THE SAME SPECIES, SAME
BASIS.
>> FOCUSING ON ONE DEVELOPMENTAL
PHENOMENON IN THIS CASE, COULD
BE A UNIFYING THEME TO THAT.
ALL RIGHT.
OKAY.
I THINK --
>> TO FOLLOW -- WE'RE OUT OF
TIME?
IN THE MEASURES YOU HAVE, WHICH
SEEMS LIKE ALSO MAY HAVE GOT
CLOSER TOGETHER, SO THAT MIGHT
BE A PLACE WHERE WE CAN KIND OF
LINK, YOU AND I CAN START
THINKING WHAT MIGHT IT MEAN THAT
WE GET LIKE SLOW, FASTER, IN THE
MEASURES WE HAVE ACROSS AN OLDER
ADULT BRAIN.
SO THIS IS AGAIN -- .
>> DATA FREQUENCY GOT FASTER BUT
NOT BY A LOT.
>> OKAY.
I THINK OUR TIME HAS ELAPSED, IF
WE'RE GOING TO GIVE THE GROUP A
BREAK.
>> WELCOME BACK.
I'M A PROGRAM OFFICER AT THE
BILL AND MELINDA GATES
FOUNDATION.
THIS IS OUR LAST SESSION.
SINCE YESTERDAY, MID-AFTERNOON,
WE'VE BEEN ON THIS PATH OF
RELENTLESS PATH OF ACHIEVING
HIGHER LEVELS OF SCALE.
FROM CIRCUITS, TO CELLULAR
REPORTING.
LAST SESSION, A DIFFERENT FORM
OF SCALE.
AT THE GATES FOUNDATION WE'RE
INTERESTED IN POPULATION LEVEL
SCALES, THINKING ABOUT HOW WE
CAN HAVE IMPACT LEVEL IMPACTS,
THROUGHOUT THE POPULATION LEVEL.
AND WE STARTED THE MEETING
TODAY, TALKING ABOUT HOW MOST
INTERVENTIONS UP UNTIL NOW HAVE
BEEN FOCUSED ON MORBIDITY OR
MORTALITY, ON PHYSICAL GROWTH,
DONE AT SCALE, HEAD
CIRCUMFERENCE, HEIGHT, WAIT.
WEIGHT.
WE NEED TO TAKING METHODS WE
HAVE, WHAT WE LEARNED OVER THE
PAST TWO DAYS AND SCALE THEM UP,
NO SMALL FEAT WHEN YOU THINK
THAT, FOR EXAMPLE, SMALL
COMMUNITY HOSPITAL IN RHODE
ISLAND HAS THE SAME NUMBER OF
MRI MACHINES AS THE ENTIRE
COUNTRY OF MALAWI, HOW CAN WE
SCALE TECHNIQUES UP.
THAT'S THE CHARGE FOR THE LAST
PANEL.
I HAND IT OVER TO THE CHAIR, DR.
OGBOLE, A NEURORADIOLOGIST FROM
NIGERIA, SPANS THE SPECTRUM OF
THE LIFESPAN.
HIS INTEREST SPAN FROM PEDIATRIC
EPILEPSY TO DEMENTIA AND STROKE.
HE'S DONE AN AMAZING JOB
ADVANCING NEURORADIOLOGY
THROUGHOUT AFRICA AND CURRENTLY
IS RESEARCH SCHOLAR AT
UNIVERSITY OF OXFORD.
>> THANK YOU VERY MUCH, SEAN.
CAN YOU HEAR ME?
CAN YOU SEE MY SLIDES IN.
>> YOU'RE GOOD.
>> SLIDES ARE GOOD?
THANK YOU VERY MUCH.
WE'RE LOOKING AT BOTH
MEASUREMENTS BETWEEN POPULATION
AND INDIVIDUAL LEVELS.
BEATING TO BENTLEY.
I LOVE CARS.
THE BEETLE IS SIMPLE, TECHNOLOGY
BROUGHT INNOVATION, IT'S
POSSIBLE TO PUT TECHNOLOGY
INSIDE AN ELECTRIC CAR, THINGS I
WILL BE TALKING ABOUT.
WE HAVE GOOD SPEAKERS LINED UP.
WHAT ARE WE LOOKING AT MOSTLY?
GENERALLY YOU FIND MRI, IN THE
LAST 40 YEARS, FOCUSED ON
RESEARCH (INDISCERNIBLE)
ADVANCED CENTERS NOW USE JUST
LIKE MRIs, PROPOSED 7 TESLA
MAY REPLACE 3 TESLA ACROSS THE
WORLD IN THE NEXT FEW YEARS.
WE'RE SEEING ADVANCES IN MR
TECHNOLOGY BECAUSE OF DATA
ACQUISITION, IMAGE
RECONSTRUCTION, COMPRESSED
SENSING, FINGERPRINTING, A.I.
TECHNOLOGY BRINGING TECHNOLOGY
TO BEAR.
(INDISCERNIBLE)
AND MORE CLINICALLY RELEVANT,
WITH THE SHIFT IN PARADIGM.
GLOBAL ACCESS, THERE ARE SEVERAL
CONFLICTS.
MOST FACILITIES, NOT
TRANSLATABLE TO THE CLINIC, LOW-
AND MIDDLE-INCOME COUNTRIES, THE
ISSUE OF EQUALITY, MOST SYSTEMS
ARE NOT WELL DISTRIBUTED AMONG
COUNTRIES, THERE'S A NEED TO
MAKE SURE THESE SYSTEMS ARE
ACTIVELY DISTRIBUTED, WE FIND
RICH INDIVIDUALS HAVE ACCESS
EVEN WITHIN POOR COUNTRIES, 1%
OF POPULATION, THE REST OF THE
POPULATIONS SUFFER, THE
DISTRIBUTION AMONG LOWER INCOME
COUNTRIES, MOST SYSTEMS IS
MOSTLY CONDUCTED IN URBAN AREAS.
A LOT OF QUESTIONS WE'RE TRYING
ANSWER TODAY, IN TERMS OF
POPULATION AND POPULATION
ACCESS.
HOW CAN POPULATION AFFORD THESE
SYSTEMS EVEN IF THEY BECOME
AVAILABLE AND CLINICAL IMPACT
THESE SYSTEMS ARE ABLE TO
PRODUCE.
MRI HAS POTENTIAL, THE CLINICAL
IMPACT OF THE POPULATION IS NOT
COMMENSURATE WITH ABILITY, AND
POSSIBLE TO GET AT ANSWER, YOU
KNOW, QUESTIONS.
WE NEED MULTIPLE SYSTEMS.
AFRICA HAS LEAST ACCESS TO MRI
TECHNOLOGY.
THE ENTIRE POPULATION OF THE
U.S., 37 TIMES MORE THAN THE
ENTIRE REGION.
WHEN YOU COMPARE TO OTHER
REGIONS OF THE WORLD, BETWEEN
MRI AND ABILITY AS WELL AS LIFE
EXPECTANCY (INDISCERNIBLE) LIFE
EXPECTANCY.
SO IF IT'S POSSIBLE, IF WE MAKE
TECHNOLOGY, IT'S POSSIBLE TO
IMPROVE HEALTH OUTCOMES OF THESE
POPULATIONS.
THERE ARE CHALLENGES.
THIS IS A GRAPH OR PICTURE THAT
REPRESENTS THE GLOBAL ACCESS TO
MRI, ELECTRICITY, YOU CAN SEE
HOW DARK AFRICA IS.
YOU CAN SEE THE COUNTRIES WHERE
NEUROSCIENCE (INDISCERNIBLE)
THAT HAVE ACCESS TO ELECTRICITY.
SO IF WE HANDLE PROGRESS,
INFRASTRUCTURE, CAN HANDLE
ELECTRICITY CHALLENGES.
LACK OF STORAGE, MAINTENANCE, WE
MUST PROPOSE HOW TO BUILD
CAPACITY IN THIS REGION AND ALSO
REDUCE BRAIN DRAIN.
[ GARBLED AUDIO ]
WE NEED TO MARRY STRUCTURE AND
FUNCTION, TO HARMONIZE, THE
BRAIN LIMITED FUNCTION, PEOPLE
WHO -- (INDISCERNIBLE).
[ GARBLED AUDIO ]
THERE'S THE ISSUE OF NEED OR
OBJECTIVITY.
PROVIDING IMAGING DATA WILL
ANSWER QUESTIONS FOR CLINICAL
NEEDS OF PEOPLE IN LOWER AND
MIDDLE INCOME COUNTRIES.
VENDORS OF COURSE (
INDISCERNIBLE) ASSISTANCE WITH
TECHNOLOGY.
LOOK AT THIS IMAGE.
SO THERE'S A NEED TO LOOK AT
CHANGE IN THE ENVIRONMENT,
DISTRIBUTING ACROSS AFRICA, HAS
POTENTIAL TO CHANGE.
FIVE TESLA SYSTEMS, EQUIVALENT
TO 1.5 SYSTEMS, WE CAN ACHIEVE
MORE WITH LESS.
SUSTAINABLE.
WANTS TO DEVELOP MRI MACHINE
(INDISCERNIBLE).
[ GARBLED AUDIO ].
WE NEED TO UNLOCK THE DOOR,
DEMOCRATIZE NEUROIMAGING
GLOBALLY.
PROVIDE NEUROIMAGING GLOBALLY,
WIRELESS DEVICES, EEG, EMG, CAN
ALSO HELP PROVIDE DATA FOR
GLOBAL POPULATION.
SCALABLE NEUROIMAGING TOOLS, TO
PROVIDE CLINICAL AND USEFUL
RESEARCH.
FOR LOW- AND MIDDLE-INCOME
COUNTRIES THE CHALLENGE WE MUST
EMBRACE THROUGH TECHNOLOGY,
CHALLENGES AROUND IT, ENHANCE
LACK OF PAUCITY, USE TO USE
SYSTEMS THAT ARE SUSTAINABLE.
WE NEED TO MAKE DATA MORE
GENERALIZABLE.
I WANT TO WELCOME THE SPEAKERS
AND DISCUSSION.
THANK YOU VERY MUCH.
I WOULD LIKE TO SHARE THE
SCREEN, LAUREL GABARD,
NORTHEASTERN UNIVERSITY.
I'LL STOP SHARING SO YOU CAN
SHARE YOUR SCREEN.
>> THANKS.
THANKS FOR HAVING ME AS PART OF
THIS WORKSHOP.
IT'S BEEN GREAT.
>> LET ME INTRODUCE YOU.
>> YES, OF COURSE.
>> LET'S START WITH YOUR
INTRODUCTION, WE'LL HAVE A TALK
BY LAUREL GABARD DURNAM,
ASSISTANT PROFESSOR OF
PSYCHOLOGY NORTHEASTERN
UNIVERSITY, B.A. DEGREE FROM
HARVARD, Ph.D. IN PSYCHOLOGY
FROM COLUMBIA UNIVERSITY,
POSTDOCTORAL FELLOWSHIP AT
BOSTON CHILDREN'S HOSPITAL, A
DEVELOPMENTAL, COGNITIVE
NEUROSCIENCE RESEARCH EXPLORING
DIFFERENT ENVIRONMENT AND
NEUROPLASTICITY CAN SHIFT AND
HINDER DEVELOPMENT.
THANK YOU FOR JOINING US.
>> THANKS FOR THE LOVELY
INTRODUCTION, GODWIN.
I'M GOING TO SHARE WHAT IS
HOPEFULLY A HOPEFULLY TALK ABOUT
SCALING DEVELOPMENTAL EEG ACROSS
CONTINENTS.
NEXT SLIDE PLEASE.
THE FRAMEWORK BOTH YESTERDAY AND
TODAY IN TERMS OF THINKING ABOUT
THESE BRAIN OR PLASTICITY,
EXPERIENCE BY TIME AND
INTERACTION, MOVES SO SMOOTHLY
BETWEEN THE NEED FOR DEEP
PHENOTYPING AND SCALABLE
PHENOTYPING.
ON ONE HAND WE NEED TO THINK
ABOUT UNDERSTANDING MECHANISMS
AND TRANSLATING BETWEEN
COMPUTATIONAL AND ANIMAL MODELS
AND HUMAN MEASURES OF EARLY
BRAIN DEVELOPMENT, IN MY CASE
THINKING ABOUT MECHANISMS AND
TIMING FOR SENSITIVE PERIODS
WHEN THE BRAIN IS ESPECIALLY
PLASTIC AND RECEPTIVE TO
EXPERIENCES, BUT THIS IS ALSO
POWERFUL BECAUSE IT TELLS US
WHAT AND HOW AND WHEN TO DO
INTERVENTIONS OR TO EFFECT BRAIN
CHANGE TO PROMOTE INFANT BRAIN
HEALTH.
AND SO IN THIS SPACE WE ALSO
NEED TO MEASURE THE RIGHT
MEASURES, AT THE RIGHT
DEVELOPMENTAL MOMENTS TO MAKE
SURE WE CAN REALLY GET UTILITY
OUT OF THESE TOOLS.
SO TODAY I'M GOING TO FOCUS ON
GOING FROM DEEP TO SCALABLE,
CLINICAL SETTINGS, OFFICES AND
NICUs, MOVING ACROSS COUNTRY
AND RESOURCE SETTINGS.
NEXT SLIDE PLEASE.
THERE'S NOT ENOUGH TIME TO GO
THREE -- THROUGH ALL BUT
WHETHER THEY ARE GOING TO BE
FEASIBLE AND INCLUSIVE,
ACCESSIBLE AND CAPACITY BUILDING
FOR THOSE IMPLEMENTING
TECHNOLOGY, AND WHETHER THEY ARE
EFFECTIVE WITHIN THE CONTEXT
TELLING US SOMETHING USEFUL AND
NEW ABOUT CHILD DEVELOPMENT.
NEXT SLIDE PLEASE.
WHEN WE THINK ABOUT FEASIBILITY,
EEG FEASIBILITY, ONE OF THE
IMPLICIT CONSTRUCTS WE NEED
CONSISTENT AND RELIABLE
MEASURES, TO HAVE CONFIDENCE
WHEN WE TAKE THE READOUTS THEY
ARE TELLING US SOMETHING ABOUT
THAT CHILD RATHER THAN NOISE OR
ARTIFACT.
WE HAVEN'T BEEN QUITE AS
CAREFUL, WE'VE BEEN SPENDING
TIME IN THE SPACE, THE GOOD NEWS
IS WHETHER YOU LOOK ACROSS
RESOURCE SETTINGS, CLINICAL OR
NEUROTYPICAL POPULATIONS IN
EARLY LIFE YOU NEED ONE MINUTE
OF GOOD DATA TO DERIVE A NUMBER
OF FEATURES WITH INCREDIBLY GOOD
INTERNAL CONSISTENCY.
SO THIS IS REALLY EXCITING FOR
ME BECAUSE A MINUTE OF DATA IS
FEASIBLE FOR INFANTS AND
CHILDREN TO GIVE US.
NEXT SLIDE PLEASE.
ANOTHER RELATED CHALLENGE WE
NEED TO EXTRACT THESE FEATURES
WITH THE SAME DEGREE OF
RELIABILITY ACROSS SETTINGS AND
ACROSS EEG DENSITIES.
SO WHEN WE THINK ABOUT SCALING
UP WE'RE MOVING FROM DENSE
ELECTRODE ARRAYS THAT WE USE IN
RESEARCH HERE, FOR EXAMPLE, TO
MUCH MORE MOBILE LOW DENSITY
SOLUTIONS THAT WE CAN HOPEFULLY
DEPLOY IN RESOURCE SETTINGS THAT
ARE LOWER THAN OURS HERE IN THE
STATES.
AND SO WE'VE BEEN SITTING IN THE
SPACE BY DEVELOPING SOFTWARE
HAPPE SOFTWARE WE CALL IT, EEG
DENSITY INDEPENDENT, DEPLOYED IN
THESE SETTINGS AND WORKS JUST AS
WELL GIVING US GOOD RELIABLE
DATA FROM TWO ELECTRODES OR 128,
THINKING ACROSS THE LIFESPAN.
I'M A DEVELOPMENTALLIST BUT THE
GOAL IS TO BE USEFUL ACROSS AGES
AS WELL.
WHEN WE THINK ABOUT INCLUSIVITY
FOR THESE EEG METHODS WE'RE
WORKING TO FORMALIZE SOLUTIONS
TO MAKE SURE EVERY INFANT CAN
CONTRIBUTE TO THIS WORK BUT
HARDWARE PARTNERS MENTIONED HERE
ARE REALLY PRO-ACTIVE IN
GENERATING NEW SOLUTIONS TO
REMAIN INCLUSIVE AS WE CONTINUE
TO INNOVATE, A REALLY IMPORTANT
AND ENJOYABLE SPACE THAT I'M
SURE WE'LL CONTINUE TO SIT WITH
AND NEED TO HIT WITH. -- SIT
WITH.
NEXT SLIDE PLEASE.
LET'S THINK ABOUT WHETHER TOOLS
ARE ACCESSIBLE FOR THOSE ROLLING
THEM OUT IN DIFFERENT CONTEXTS.
NEXT SLIDE PLEASE.
AGAIN, ON THE HARDWARE FRONT EEG
IS BECOMING COST EFFECTIVE AND
AFFORDABLE, TO THE HUNDREDS OF
DOLLARS.
WE'VE BEEN FOCUSING ON THE
SOFTWARE SIDE AGAIN.
WE PURPOSELY BUILT HAPPE TO
SERVE A BROAD USER BASE WITH
VARIED SKILL SET, PART IS
AUTOMATED PROCESSING WE CAN ROLL
OUT ONCE WE VERIFY THE SOFTWARE
IS WORKING FOR SPECIFIC
CONTEXTS, SPECIFIC SITE.
BECAUSE A TOOL ISN'T SCALABLE IF
IT NEEDS ONGOING EXPERT REVIEW
OR SOMEONE TO HAVE TRAINED IN MY
LAB FOR SEVERAL YEARS BEFORE
THEY RUN THIS.
NOT TO SAY WE DON'T BELIEVE IN
MONITORING THE DATA AND CHECKING
IN BUT WE USE EMPIRICAL
BENCHMARKS AND DATA-DRIVEN
APPROACHES RATHER THAN
SUBJECTIVE EXPERT REVIEW.
WE PROVIDE BENCHMARKS TO HELP
MONITOR EQUIPMENT, PROTOCOL,
ADHERENCE, AND DATA QUALITY TO
DO THIS CAPACITY BUILDING.
SO SITES CAN TAKE TOOLS AND RUN
THEMSELVES.
HERE ARE TWO EXAMPLES, ONE
MEASURE FOR LINE NOISE AND DATA
RETENTION IN STAFF TRANSITION,
WE MEASURED CHANGES IN ELEMENTS
OF STUDY DESIGN BUT WE'RE
WORKING TO OFFER MORE, SO WE CAN
STEP BACK FURTHER AND FURTHER
FROM THE PROCESS.
AND WHETHER THE TOOLS ARE
EFFECTIVE.
NEXT SLIDE.
AND HERE I'LL LEAVE YOU WITH TWO
SNIPPETS THAT SUGGEST THIS IS
THE CASE FOR EEG, ESPECIALLY
EARLY IN LIFE WHEN WE CONSIDER
DEVELOPMENTAL CHANGE.
WE'VE GOT PREDICTIVE CAPABILITY
OF EEG IN FIRST YEAR FOR
DIFFERENT CLINICAL POPULATIONS,
IN PARTICULAR THINKING ABOUT WHO
IS GOING TO RECEIVE AN AUTISM
DIAGNOSIS IN EARLY LIFE, AS WELL
AS ACROSS RESOURCE SETTINGS FOR
PREDICTING LANGUAGE SETTINGS IN
THE SECOND YEAR AS THEY BEGIN TO
EMERGE.
SO WE THINK THIS WORK IS
DEMONSTRATING ACROSS HUNDREDS OF
PARTICIPANTS UTILITY OF THINKING
ABOUT THE INDIVIDUAL AT SCALE,
SOME OUTCOMES WE CARE DEEPLY
ABOUT.
FINAL SLIDE PLEASE.
WE'VE ONLY HAD TIME TO TOUCH
QUICKLY ON EACH OF THESE THEMES
BUT A STRONG START IN SORT OF
MOVING BACK AND FORTH BETWEEN
THE SPACES, MAKING SURE WE
CONTINUE TO PRIORITIZE
INCLUSIVITY IN THIS WORK AND
CONTINUE TO DEVELOP TOOLS THAT
WILL MAKE THIS ACCESSIBLE AND
ABLE TO BE USED TO ACTUALLY
SUPPORT BRAIN HEALTH FOR BABIES
REGARDLESS OF WHERE THEY ARE
BORN AND RAISED.
NEXT SLIDE.
I'LL THANK INDIVIDUALS IN MY LAB
TWO CONTRIBUTED TO THE WORK I'VE
SHOWN YOU TODAY AND TO SOME
COLLABORATORS, ESPECIALLY
SANTIAGO MORALES AND CHUCK
NELSON WHO CONTRIBUTED TO THE
SLIDES.
>> THANK YOU FOR THE STRONG
INSIGHTS INTO EEG AND CAPABILITY
IN EARLY LIFE.
WE'RE GOING TO HAVE QUESTIONS
LATER.
LET'S HAVE THE NEXT SPEAKER,
JOSEF PARVIZI.
WILL YOU SHARE YOUR SCREEN?
OKAY.
>> GOOD AFTERNOON, EVERYBODY.
>> A BRIEF INTRODUCTION, MEDICAL
INTERNSHIP AT MAYO CLINIC,
NEUROLOGY RESIDENCY AT HARVARD
MEDICAL SCHOOL BEFORE JOINING
THE FELLOWSHIP TRAINING IN
CLINICAL NEUROPHYSIOLOGY, WORKED
AT STANFORD UNIVERSITY MEDICAL
CENTER SINCE 2007, SPECIALIZES
IN TREATING PATIENTS WITH
UNCONTROLLABLE SEIZURES,
PRINCIPAL INVESTIGATOR IN THE
LABORATORY OF BEHAVIORAL AND
COGNITIVE NEUROSCIENCE, WHOSE
RESEARCH ACTIVITIES HAVE BEEN
SUPPORTED BY NIH, NATIONAL
SCIENCE FOUNDATION, SEVERAL
OTHER PRIVATE FOUNDATIONS.
>> THANK YOU SO MUCH, DR.
OGBOLE.
DO YOU SEE MY SCREEN?
>> YES.
>> WE SEE YOUR SCREEN.
>> WONDERFUL.
>> AS YOU ALL KNOW, IN ORDER TO
GET AN EEG FROM THE HEAD OF AN
INDIVIDUAL, YOU HAVE TO HAVE
SPECIALIZED TECHNICIANS,
ESPECIALLY IN PATIENT SETTINGS,
E.R. SETTINGS, ALSO IN LAB
SETTING YOU NEED RESEARCH
ASSISTANT TRAINED TO OPERATE THE
MACHINERY, DEALING WITH VERY
LARGE AND EXPENSIVE EQUIPMENT.
AND SPECIALIZED PEOPLE IN THE
CLINICAL SETTINGS, NEUROLOGISTS
WITH TRAINING IN CLINICAL
NEUROPHYSIOLOGY TO BE ABLE TO
READ EEGs.
UNFORTUNATELY, THIS CREATES A
BIG LOCAL EVENT TIMELY AND
EXTREMELY COSTLY, AND AS A
RESULT MANY ACTUALLY LARGE
MAJORITY OF HOSPITALS IN THE
UNITED STATES CANNOT EVEN AFFORD
OFFERING THIS TYPE OF EEG
SERVICES FOR CLINICAL USE DURING
AFTER-HOURS.
IT'S VERY COSTLY AND IT IS TIME
CONSUMING.
I FOUNDED THIS COMPANY, AND I
SPEAK ON BEHALF OF LARGE TEAM OF
DEVELOPERS IN OUR COMPANY, IN
SILICON VALLEY, ALTERNATIVE THAT
MAKES ACQUISITION OF EEG
EXTREMELY EASY AND COST
BENEFICIAL.
IT INCLUDES ONE PORTABLE
PACKET-SIZED BATTERY OPERATED,
YOU DON'T NEED ELECTRICITY FOR
THIS EEG RECORDER, ALSO
DISPOSABLE HEADBAND.
YOU CAN USE IN FDA ON ONE
PATIENT, 20 OR 30 TIMES ON THE
SAME PATIENT.
AND RISK OF INFECTION IS NOT A
PROBLEM, YOU CAN USE IT ON AS
MANY PATIENTS AS YOU WANT.
IT GOES AROUND THE CIRCUMFERENCE
OF HEAD AS I WILL SHOW IN THE
NEXT SLIDE.
IT TAKES ABOUT TWO MINUTES TO
APPLY.
FORTUNATELY, IT HAS BEEN
DESIGNED THAT IT DOESN'T NEED
MUCH PRIOR TRAINING.
LESS WITH DESIGN AWARDS AND MADE
SURE THIS IS GOING TO BE
EXTREMELY EASY AND INTUITIVE TO
APPLY.
WHAT HAPPENS HERE IS THAT YOU
ACTUALLY PUT THE HEADBAND AROUND
THE HEAD, AND IT'S CONNECTED TO
THE BATTERY-OPERATED DEVICE WITH
A WIRE.
WE DIDN'T WANT TO DO BLUETOOTH
BECAUSE OF LACK OF FIDELITY OF
THESE TYPE OF HIGH TECH TYPE OF
CONNECTIONS.
WE WANTED TO BE VERY SOLID.
SO, IT PROVIDES YOU INFORMATION
WITHIN FIVE MINUTES OR SHORTER
IN FOUR DIFFERENT MANNERS.
ONE IS YOU CAN SEE IT AT THE
BEDSIDE, ON THE SCREEN, HOW THE
EEG LOOKS LIKE, IN CLINICAL
SETTINGS ESPECIALLY IN YOU ARE A
PEDIATRIC NEUROLOGIST ASSESSING
A KID WHO IS ALTERED OR AGITATED
OR LETHARGIC, YOU BASICALLY CAN
DIAGNOSE STATUS IN MINUTES BY
REVIEWING EEG AT THE BEDSIDE.
IF YOU DON'T KNOW HOW TO READ IT
THERE'S AN ALGORITHM THAT
CONVERTS EEG INTO A SONIFIED
SPACE TO APPRECIATE THE SOUND OF
THE BRAIN.
MORE IMPORTANTLY, IF YOU HAVE A
PHONE THAT CONNECTS WITH THE
RECORDER OR IF YOU HAVE THE
RECORDER IN A WI-FI-FRIENDLY
ENVIRONMENT IT SENDS THE SIGNAL
TO WI-FI.
IN THE CLOUD WE HAVE THE
COMPUTATIONAL ALGORITHMS PLACED.
YOU CAN USE THE CLOUD TO REVIEW
THE EEG BACK AND FORTH LIKE ANY
NEUROLOGIST DOES.
THIS IS WHERE YOU CAN ACTUALLY
SEE THE TRACING.
YOU CAN DOWNLOAD THE TRACING,
AND DO YOUR RESEARCH ANALYSES.
YOU CAN ALSO RELY ON ARTIFICIAL
INTELLIGENCE ALGORITHMS THAT WE
HAVE PLACED.
THE VERY FIRST FDA-APPROVED A.I.
ALGORITHM IS A SEIZURE LOAD
ESTIMATE ALGORITHM THAT I WILL
TELL YOU BRIEFLY.
HERE IS TWO MINUTES ON HOW THE
EEG IS SO EASILY SET UP.
>> IT'S COMPOSED OF A RECORDER
AND HEADBAND, DESIGNED TO
STRETCH TO FIT MOST ADULT HEAD
SIZES, CAN ACCOMMODATE THICK
LONG HAIR.
PLACE THE HEADBAND, ATTACH AND
SECURE ON THE FOREHEAD.
THERE ARE 2004 CLASPS TO
ACCOMMODATE HEAD SIZES.
MAKE SURE THE CLASP CLOSURE IS
CENTERED ON THE PATIENT'S
FOREHEAD.
THE HEADBAND'S POSITION IS ABOVE
THE PATIENT'S BROW LINE.
PLUG THE HEADBAND INTO THE
DEVICE.
STARTING FROM THE HOME SCREEN,
PRESS THE RECORD BUTTON.
SOFTWARE WILL ASK YOU TO ENTER
THE PATIENT ID OR MEDICAL RECORD
NUMBER.
ONCE ALL THE PATIENT INFORMATION
HAS BEEN ENTERED YOU'LL BE ASKED
TO CONFIRM PATIENT INFORMATION.
THIS WILL TAKE YOU TO THE CHECK
ELECTRODE PAGE.
ROTATE ELECTRODES BACK AND FORTH
FOR SEVEN FULL ROTATIONS,
PARTING THE HAIR, BE SURE TO
DIRECT GENTLE PRESSURE TOWARDS
THE PATIENT'S HEAD WITH THE
ELECTRODES.
AFTER SEVEN ROTATIONS RETURN AND
SQUEEZE INTO THE KNOB.
>> THAT'S HOW YOU GET THE EEG
WITHIN TWO MINUTES ON THE
SCREEN.
YOU CAN REVIEW IT.
ALSO WITH THE SOUND YOU'LL BE
ABLE TO ACTUALLY HEAR, FOR
EXAMPLE, IF THERE'S SEIZURE
YOU'LL HEAR IT LIKE THIS.
SO, MOST IMPORTANT PART IS THE
SEIZURE ALGORITHM WHICH I WON'T
GO INTO DETAIL.
BASICALLY GIVES YOU A TREND
LINE, ESTIMATE OF HOW MUCH
PATHOLOGICAL ACTIVITY IS
PRESENT, VERY IMPORTANT IN A
VERY ELDERLY INDIVIDUAL AT HOME
WITH ALZHEIMER'S DISEASE AND YOU
WANT TO ACTUALLY KNOW IF THE
PATIENT JUST HAD A SEIZURE OR IS
HAVING A SEIZURE, WITHIN TWO
MINUTES, OR A CHILD NOT VERY
COOPERATIVE WITH THE TECHNICIAN
TO PUT THE ELECTRODES ON THE
HEAD.
TO SHOW EXAMPLES OF HOW IT LOOKS
IN CLINICAL CONDITIONS SO YOU
CAN GET YOUR IMPRESSION.
HAPPY TO ANSWER ANY QUESTIONS
LATER ON BUT IF YOU'RE
INTERESTED IN THIS TECHNOLOGY,
PLEASE FEEL FREE TO REACH OUT TO
ME DIRECTLY.
YOU HAVE MY E-MAIL ADDRESS.
>> THANK YOU VERY MUCH.
>> THANK YOU SO MUCH.
>> THANK YOU VERY MUCH, JOSEF.
WONDERFUL TALK.
MOVING QUICKLY, WE'RE RUNNING
BEHIND THEM.
SARAH FOX, LEAD INVESTIGATOR OF
THE INTERDISCIPLINARY STUDY.
>> THANK YOU.
I THINK I'LL TALK ABOUT SOME
WORK I'VE BEEN DOING USING THE
TECHNOLOGY I'VE BEEN DEVELOPING
ON SPECTROSCOPY IN GLOBAL HEALTH
SETTINGS AND TO UNDERSTAND
IMPACTS OF MULTI-DIMENSIONAL
CONSTRUCT OF POVERTY RATHER THAN
JUST MEASURING INCOME AND
EDUCATION OF PARENTS, TRYING TO
THINK ABOUT ALL THE CONSEQUENCES
OF POVERTY AND IN DIFFERENT
CONTEXT.
SOMETHING SAID IN PREVIOUS
SESSIONS, THE VAST MAJORITY OF
RESEARCH THAT GOES ON IN INFANT
NEUROIMAGING STUDIES IS CARRIED
OUT IN THE GLOBAL NORTH.
ANOTHER POINT TO EMPHASIZE
LONGITUDINAL STUDY DESIGNS ARE
STILL VERY MUCH THE EXCEPTION TO
THE NORM.
I WANT TO JUST VERY QUICKLY SHOW
HOW WE ARE USING THESE
NEUROIMAGING TECHNOLOGIES TO
INTEGRATE INTO GLOBAL HEALTH
SETTINGS.
AND I HOPE TO KIND OF EMPHASIZE
THE POWER OF STUDY DESIGN,
DURING EARLY LIFE.
TO DO THAT I WILL FIRST TALK
ABOUT THE BRAIN IMAGING FOR
GLOBAL HEALTHY I'M A LEAD
INVESTIGATOR ON, IN GAMBIA, AND
THIS STUDY AS WAS DISCUSSED
EARLIER AS WELL IS SOMETHING
THAT IS A LARGE COLLABORATIVE
TEAM THAT USES MANY DIFFERENT
BACKGROUNDS OF RESEARCH,
NUTRITION, MATERNAL HEALTH,
DEVELOPING TECHNOLOGY,
NEUROSCIENCE, PSYCHOLOGY,
BRINGING IN LOTS OF THESE AREAS
IS ONE OF THE STRENGTHS OF THE
PROJECT AS WELL.
THE BACKBONE OF THE WORK WE'RE
DOING IN INTEGRATING
NEUROIMAGING WITH EEG, IT'S IN
THE CONTEXT OF UNDER NUTRITION
RESEARCH THAT HAS LARGELY
FOCUSED ON IMPACT.
HAVEN'T REALLY LOOKED TO OTHER
CONSEQUENCES, THIS IS HOW WE
INTEGRATED THIS INTO THE HUGE
STUDY THAT THINKS ABOUT LOTS OF
FACTORS AND ENVIRONMENT.
TO GET HIGHLIGHTS OF THINGS
WE'RE LOOKING AT HERE, WHAT WE
ARE ABLE TO SEE IN THE RESEARCH
COMING OUT RIGHT NOW IS THAT WE
CAN SEE THAT EARLY GROWTH TO
FIVE MONTHS, CHANGES BETWEEN
BIRTH AND FIVE MONTHS OF AGE,
RELATE TO NEUROCOGNITIVE AND
NEURAL COG ANY ACTIVITY AT TWO
YEARS, WE HAVE EVIDENCE EARLY
NEUROMARKERS AT FIVE MONTHS ARE
RELATING TO LATER MARKERS OF
EXECUTIVE FUNCTION, THREE TO
FIVE YEARS.
AND IMPORTANTLY, IT'S REALLY
WE'VE GOT MULTIPLE LONGITUDINAL
TIME POINTS BECAUSE NOT ONLY CAN
WE SORT OF HAVE THIS AND THESE
TWO BEGINNING AND ENDPOINTS, BUT
WE CAN ALSO UNCOVER NON-LINEAR
PATTERNS TO TRY TO UNDERSTAND
HOW THERE MIGHT BE DIFFERENT
POINTS, IMPORTANT TO US IN KEY
FINDINGS.
I THINK ANOTHER IMPORTANT AREA,
THINKING ABOUT HOW WE MIGHT BE
ABLE TO SCALE UP THIS
NEUROIMAGING INTO CONTEXT IS
EXPLOSION IN THE LAST FEW YEARS
HOW MANY SITES HAVE STARTED
DOING THIS AND THE FACT THAT WE
HAVE MULTI-DISCIPLINARY NETWORKS
WORKING TOGETHER IN
UNDERSTANDING THE FINDINGS WE
HAVE, SO WE MIGHT USE THE SAME
PARADIGMS, SIMILAR TECHNOLOGY.
ONE EXAMPLE OF SEARCH ON
GLOBEFNIRS AS IT'S CALLED.
THIS IS SOMETHING THAT LAUREL
TALKED ABOUT IN HER TALK ABOUT
EEG.
ONE OF THE KEY CHALLENGES THAT
WE HAVE MET WITH THIS RESEARCH
THAT WE'RE PROUD OF, IN A SENSE,
WE HAVE LOCAL EXPERTISE IN THE
DATA SECTION IN GAMBIA, HAVE A
LARGE TEAM OF RESEARCHERS IN THE
GAMBIA, ALL BUT ONE ARE FROM THE
GAMBIA, WEST AFRICA.
SO THEY BEEN TRAINED IN THIS
KIND OF TECHNOLOGY.
THEY KNOW HOW TO RUN THIS STUDY.
SO THEY LEAD THE DATA
COLLECTION.
THERE ARE CHALLENGES TO BE
ADDRESSED IN HOW WE SCALE THIS
UP, THIS IS ONE EXAMPLE, I COULD
GIVE TEN SLIDES OF THESE, THINGS
WE NEED TOE THINK ABOUT.
WITH YOU THING, THERE ARE
PRACTICAL ISSUES THAT GODWIN
NICELY ILLUSTRATED WITH THE
ELECTRICITY EXAMPLE, AND
CAPACITY BUILDING ISSUES WHICH
HE ALSO TALKED ABOUT IN TERMS OF
THIS BRAIN DRAIN.
WE DON'T HAVE ANYONE THAT CAN
ANALYZE DATA ON SIZE, PSYCHOLOGY
HAS JUST.
>> ONE MINUTE WARNING.
>> FOR THE FIRST TIME THIS YEAR
IN THE GAMBIA, WE MAY SEE A NEW
GENERATION OF RESEARCHERS THAT
WILL BE OUT TO DO THIS BUT WE
NEED TO THINK ABOUT HOW WE CAN
BUILD THIS CAPACITY.
WE'VE GOT RESEARCHERS
SPECIALIZED, TRAINING HUB IN
WEST AFRICA, FOR EXAMPLE, WE
NEED TO ACCELERATE THIS.
TO GIVE AN EXAMPLE OF HOW I
THINK THE TECHNOLOGY IS RAPIDLY
IMPROVING, WE'RE NOW USING
WEARABLE FNIRs IN THE HOME,
IT'S CALLED LUMO, LONDON-BASED
COMPANY.
WE CAN TAKE THIS KIT INTO THE
HOMES, HAVE FAMILY MEMBERS
WATCHING IT.
THIS IS REALLY IMPORTANT FOR
ADDRESSING THESE ISSUES WHICH
EXIST IN HIGH-INCOME COUNTRIES
AS WELL BUT WE BASICALLY DO
RESEARCH IN URBAN POPULATIONS
WITH NEUROIMAGING, DON'T TAKE
TECHNOLOGY TO THE PEOPLE.
THIS IS WHAT THIS CAN DO.
ONE OF THE STUDIES I'M LEADING
TO UNDERSTAND IMPACT OF POVERTY
ON BRAIN DEVELOPMENT IN RURAL
CONTEXT, IN AREAS WHERE YOU
DON'T GET PEOPLE TO COME INTO
YOUR RESEARCH, ALSO IN THE
HOSPITALS, AND A FINAL EXAMPLE,
THIS WEARABLE FNIRs AND THE
WORK BEFORE US IS NOW ENABLING
US TO INTO INTERVENTIONS, THIS
IS NOT ME, LED BY A COLLEAGUE IN
THE GAMBIA, NOW USING THIS TO
ASSESS OUTCOME, MEASURING THE
BRAIN WILL HELP US REVEAL
PROCESSES UNDERLYING POVERTY WE
MAY NOT HAVE AN ABLE TO SEE
UNTIL LATER IN LIFE WITH
BEHAVIORAL MEASURES.
SO REALLY THERE'S A LOT OF
AVENUES FOR THIS TECHNOLOGY TO
START TO BE USED.
IT'S ACCELERATING RAPIDLY.
THANK YOU SO MUCH, GODWIN.
>> THANK YOU, SARAH, FOR THE
LOVELY TALK.
WE'LL MOVE QUICKLY TO THE NEXT
SPEAKER, JOSEPH CULVER, Ph.D.,
PROFESSOR AT WASHINGTON
UNIVERSITY IN ST. LOUIS, USA, HE
HAS THIS GROUP WHERE HE HAS
DEVELOPED IMPROVEMENTS TO HIGH
DENSITY DIFFUSE OPTICAL
TOMOGRAPHY.
JOSEPH, GO AHEAD.
>> THANK YOU FOR THE PROMISE TO
SPEAK AND INTRODUCING fNIRS.
CAN IT ACT AS A PROXY FOR
fMRI?
IN ANSWER I MAKE THE CASE FOR A
QUALIFIED YES, DEPENDS ON WHICH
TASK AND WHICH FNIRs SYSTEM.
IMAGINE WE WANTED TO IMAGE THE
AUDITORY RESPONSE VERSUS
LANGUAGE RESPONSE ON THE LEFT.
REGIONS ARE SEPARATED BY 15
MILLIMETERS OR MAYBE WE WANT TO
SEPARATE THE FRONTAL PARIETAL
NETWORKS FROM DORSAL ATTENTION,
FROM THE RIGHT.
THESE LOCATIONS ARE SEPARATED BY
15 MILLIMETERS.
IT'S OBVIOUS THE QUALITY OF THE
COGNITIVE ASSESSMENT BY fNIRS
WILL DEPEND ON RESOLUTION AND
FIELD OF VIEW OF SYSTEM.
YOU'LL NEED 15-MILLIMETER
RESOLUTION.
WITH MODERN HIGH DENSITY
fNIRS, DIFFUSE OPTICAL
TOMOGRAPHY, CAN PROVIDE FOR
DETAILED TASKS LIKE RETINA
MAPPING.
ON THE RIGHT SWEEPING FIELD OF
VIEW, THE HD-DO THE MAPS CAN
TRACK CORTICAL RESPONSE.
HIGH DENSITY IMAGING SYSTEMS USE
DENSE OVERLAPPING PATTERNS THAT
YOU SEE ON THE LEFT.
IF YOU DON'T USE HIGH DENSITY
THINGS DON'T WORK AS WELL.
IN PANEL B YOU SEE A MAP OF
AUDITORY CORTEX BUT IN PANEL C,
D, E, WITH SPARSE ARRAYS WE CAN
EXTRACT FROM THE FULL DENSITY
ARRAY MEASUREMENTS, WE END UP
WITH MORE ARTIFACTS, THEY CHANGE
LOCATION AND STRENGTH BASED ON
WHICH SPARSE ARRAY IS USED.
SO HIGH DENSITY RAYS CAN MAP NOT
ONLY TASKS AND NETWORKS LIKE
THESE THREE, AND AGAIN WE CAN
ANALYZE SENSITIVITY OF THESE
NETWORK MAPS TO SEE LOCATION AND
THEY FLIP FROM ONE NETWORK TO
ANOTHER NETWORK IF WE MOVE TO
SEED LOCATION BY 15 MILLIMETERS.
NOW, THERE'S A HUGE DRAWBACK TO
HIGH DENSITY IMAGING ARRAYS,
THESE TRADITIONAL FIBEROPTIC
SYSTEMS ARE BIG.
THIS NULLIFIES MAIN REASONS TO
USE fNIRS OVER fMRI.
THERE'S BEEN A DRAMATIC
IMPROVEMENT IN WEAR ANALYSIS
ITEMS, THESE SYSTEMS ARE PUTTING
ELECTRONICS ON THE HEAD,
COMPUTATIONS OF ENCODING AND
DECODING OF SOURCES FROM THE
DETECTOR SIGNALS.
THESE DECREASED BY A
HUNDRED-FOLD.
THE FIRST COMMERCIAL SYSTEM IS
ONE OF THE FIRST COMMERCIAL
SYSTEMS, THE GOWERLABS THAT
SARAH MENTIONED, AND OUR WASHU
SPIN.
THESE ARE OVERCOME THE PREVIOUS
CONFLICT BETWEEN IMAGE QUALITY
AND WEARABILITY.
THERE'S PLENTY OF ENGINEERING
LEFT, LARGELY A MATTER OF TIME
UNTIL THEY MEET ALL THE SAME
IMAGE QUALITY METRICS AS
FIBER-BASED SYSTEMS.
SO FLOWS BY BRINGING -- I'LL
CLOSE, I BELIEVE WE'LL NEED
WHOLE FIELDS OF VIEW FOR LARGE
POPULATION STUDIES.
WHOLE HEAD SYSTEMS WILL BE
SCALABLE, PROBABLY MORE SCALABLE
THAN ISOLATED PATCHES TO LARGE
POPULATION STUDIES.
WE'LL NEED ACCURATE
CO-REGISTRATION, WE'RE GOING TO
NEED VALIDATED PACKAGES THAT
COMBINE SYSTEM, PARADIGM,
ANALYSIS.
AND THEN WE'RE ALSO GOING TO
NEED TO BUILD INFRASTRUCTURE.
SARAH WAS POINTING TO SOME OF
THOSE TYPES OF STUDIES BEGINNING
TO HAPPEN, IT'S IRONIC THE
GLOBAL HEALTH PROJECTS THAT ARE
PIONEERING THAT IN OUR FIELD.
SO, BASICALLY TO ADDRESS THESE
OPPORTUNITIES THERE'S STILL MANY
SYSTEMS NEEDS, I DON'T HAVE TIME
TO GO OVER DESIGN DETAILS BUT WE
NEED TO SIMULTANEOUSLY OPTIMIZE
THE MEASUREMENT DENSITY, WEIGHT.
>> ONE MINUTE LEFT.
>> ERGONOMICS, COST, POWER,
HEAT, DATA.
THIS IS STARTING TO LOOK LIKE
ANOTHER REALLY LARGE TASK, BUT
THE DEVICES, FOLLOWING ON
COMMENT FROM YESTERDAY, DEVICES
LIKE SMARTPHONES DRIVE ADVANCES
IN MINIATURIZED ELECTRONICS, YOU
CAN TAKE THE FACT THAT fNIRS
DROPS WEIGHT BY TWO ORDERS OF
MAGNITUDE IN SIX YEARS,
REASONABLE TO BELIEVE THESE
BROAD TECHNOLOGY ADVANCES CAN BE
LEVERAGED TO ADDRESS THESE
OPPORTUNITIES.
I'LL CLOSE BY MAKING
ACKNOWLEDGMENTS AND THANKS TO
FUNDING SOURCES.
>> THANK YOU, JOSEPH, FOR A
BEAUTIFUL TALK.
WE MOVE TO THE NEXT SPEAKER,
ANDREW WEBB, POSTDOC IN
DEPARTMENT OF RADIOLOGY.
DR. WEBB, PROFESSOR WEBB, I
WELCOME YOU TO GIVE YOUR TALK.
THANK YOU.
>> THANKS VERY MUCH, GODWIN.
I WANT TO START BY CONTINUING
ESSENTIALLY WHAT YOU SAID IN
YOUR INTRODUCTION ABOUT LOW
FIELD MRI.
I LIKED THE ANALOGY WITH THE
BEETLE, MY FIRST CAR.
IT GOES FROM POINT A TO POINT B,
IT'S GOT THREE MOVING PARTS,
BRAKES, EASIER TO FIX, SAME
THING IN TERMS OF DESIGNING AN
MRI SYSTEM.
THERE'S THIS MASSIVE DISCREPANCY
IF YOU LOOK AT NUMBER OF MRI
UNITS AVAILABLE.
EVERYONE THINKS OF COST, IT'S AN
IMPORTANT ISSUE BUT THERE ARE
MANY OTHER ISSUES TO ADDRESS IF
WE MAKE SOMETHING ACCESSIBLE.
ONE IS THE FACT THAT IT COSTS A
LOT TO MAINTAIN.
IF YOU TAKE ONE OF THESE
SYSTEMS, YOU REALLY NEED A
HIGHLY CONTROLLED ENVIRONMENT TO
PUT IT IN, YOU NEED SUPPLIES
THAT OTHER PEOPLE MENTIONED,
HAVE TO BE RELIABLE, LOTS OF
THINGS.
YOU ALSO NEED VERY EXTENSIVE
TRAINING FOR YOUR PERSONNEL.
WE HAVE TO ADDRESS ALL OF THESE
ISSUES IF WE'RE GOING TO
INCREASE ACCESSIBILITY.
IN TERMS OF PEDIATRICS, MRIs
ARE HORRIBLE, THEY ARE LOAD.
LOW FIELD SYSTEM CAN BE SILENT.
IF WE'RE TRYING TO INCREASE
NUMBER OF PEOPLE WHO CAN HAVE
SCANS CONTRAINDICATIONS SUCH AS
MEDICAL IMPLANTS, ALMOST ALL ARE
SAFE AS LOW FIELD.
HERE IS A SPINAL SCREW HERE, IT
DOESN'T CAUSE ARTIFACTS.
SO OVERALL WHAT THIS MEANS IS
WE'VE GOT MUCH HIGHER
ACCESSIBILITY.
SO THIS IS A SYSTEM THAT WE HAVE
DESIGNED, FOR PEDIATRIC
HYDROCEPHALUS, WORKING WITH
COLLEAGUES IN UGANDA TO BUILD
ONE THIS COMING SUMMER, I'M
SHOWING THIS WITH A LAB
VOLUNTEER, IT FITS ON A CART,
MOVES AROUND AS SARAH SAID, IT'S
A WAY OF BRINGING THE IMAGING
APPARATUS TO THE POPULATION
RATHER THAN THE OTHER WAY
AROUND.
ONE KEY THING TO MAKE IT
SUSTAINABLE AND MODULAR, THIS IS
NOT EXPENSIVE TOOLS, READILY
AVAILABLE MATERIALS.
A LOT OF 3D PRINTING.
AND BASIC ELECTRONICS,
EVERYTHING IS OPEN SOURCE.
ANYBODY CAN GO IN HERE, TAKE A
LOOK, THEY HAVE THE SCHEMATICS
TRYING TO FIX EVERYTHING.
IT'S IMPORTANT TO THINK OFTEN
YOU HAVE COMPANIES AND MAKING
THIS EQUIPMENT, IF YOU UPGRADE,
IT DOESN'T WORK, YOU HAVE TO
CALL THEM IN FOR SERVICING.
EVERYTHING IS OPEN SOURCE, DONE
IN PYTHON.
ENGINEERING DEPARTMENT CAN GET
INVOLVED.
IT'S IMPORTANT TO HAVE REALISTIC
PHANTOMS FOR TRAINING.
WE HAVE ALL KINDS OF SEQUENCES,
PLAYING WITH PARAMETERS, NOT
JUST SCANNING BUT TO UNDERSTAND
THE ENTIRE PROCESS.
USING THESE SYSTEMS, MAYBE 1%,
YOU'RE NOT EXPECTS SAME IMAGE
QUALITY BUT EACH SCAN IS FIVE
MINUTES, GIVING ENOUGH
INFORMATION TO DO, FOR EXAMPLE,
WHITE MATTER, GRAY MATTER, CSF,
SEGMENTATION, IN DEVELOPMENTAL
STUDIES, BUT ALSO CLINICAL
APPLICATIONS LIKE HYDROCEPHALUS
WHERE THE CSF IS IMPORTANT.
HOW GOOD IS GOOD ENOUGH?
WITH 1% TO GET THE SAME IMAGE
QUALITY FROM 3D, FILTERED WITH
DISORGANIZATION DIRECTION, TAKEN
IN ONE MINUTE ON A LOW FIELD
SCANNER.
IF YOU LOOK AT THE INFORMATION,
THIS IS IN COLLABORATORS WORKING
IN THE STATES HERE, QUALITY MAY
BE WORSE, OFTEN YOU CAN GET THE
SAME AMOUNT OF INFORMATION THAT
YOU NEED FROM A CLINICAL POINT
OF VIEW.
AN IMPORTANT THING AS WE MOVE
FORWARD IS WHAT IS ACTUALLY GOOD
ENOUGH FOR THE TASK YOU'RE
INTERESTED IN THANK YOU.
>> THANK YOU, ANDREW.
WE'LL MOVE TO THE NEXT SPEAKER,
ROSALYN MORAN, COMPUTATIONAL
NEUROSCIENCE, UNDERSTANDING
PRINCIPLES OF BRAIN FUNCTION, IN
PARTICULAR TECHNIQUES TO
UNDERSTAND AND TREAT PSYCHIATRIC
DISORDERS.
I WANT TO WELCOME ROSALYN.
>> THANK YOU.
I'LL CONTINUE THE BEETLE AND
BENTLEY DISCUSSION, LOW FIELD
MRI, ANALYTICAL METHODS AND
MODELING IF DEPLOYED WITH THIS
TECHNOLOGY MIGHT IMPROVE HOW
THIS ACCESSIBLE AND RELATIVELY
INEXPENSIVE CAN ADDRESS GAPS IN
PHENOTYPING AND DIAGNOSTICS AND
PROGNOSTICS.
THE PARTICULAR MACHINE WE'RE
TALKING ABOUT HERE IS THE HYPER
FINE, KINGS COLLEGE, GATES
FOUNDATION, WE WANT TO ASK AS
MODELERS WHETHER WE CAN DEVELOP
RELIABLE METRICS AT LOW COST AND
TRANSFORM LOW COST IMAGING INTO
RELIABLE PROGNOSTIC MARKERS OR
MARKERS OF DEVELOPMENT.
TOP LEFT IS THE DISTINCT
DIMENSIONS MODELING CAN OFFER TO
TRANSFORMING THESE LOW FIELD
IMAGES.
SO, THE ONE YOU'VE HEARD OF IS
ON THE Y-AXIS, WHICH IS KNOWN AS
INFORMATION QUALITY TRANSFER,
IMAGE QUALITY TRANSFER, IQT,
IMPROVES RESOLUTION OF IMAGES,
ALSO WE HAVE OTHER TOOLS IN OUR
ARMAMENTARIUM FROM COMPUTATIONAL
NEUROSCIENCE THAT MAY DERIVE
METRICS THAT MAY OR MAY NOT BE
RELIABLE BIOMARKERS AND USEFUL
FOR CLINICAL QUESTION.
AND MULTI-MODALITIES, WE SHOULD
HAVE fNIRS, MODELING MIGHT BE
THE GLUE THAT HOLDS THEM
TOGETHER.
IQT IS FAIRLY NASCENT, TO GO
FROM CT AND CLINICAL GRADE SCANS
TO HIGHER LEVEL RESEARCH SCANS,
DEVELOPED FOR IMAGES, IF WE CAN
INCREASE RESOLUTION OF THE SCAN
WE CAN ALSO HARNESS THE OMICS
DEVELOPMENT IN MODELING, FROM
REGIONAL TISSUE PROPERTIES TO
CONNECTIVITY, POTENTIALLY TO
PSEUDOFUNCTIONAL MEASURES
THROUGH COMPUTATIONAL MODELS.
AND IT MIGHT BE TEMPTING TO
THINK THE FURTHER UP INTO THE
RIGHT WE GO THE MORE RELIABLE
AND USEFUL THESE PREDICTORS ARE
IN TERMS OF AUC.
HOWEVER, I THINK DEVELOPING THE
RELIABILITY AND ESTABLISHING
VALIDITY OF THESE PIPELINES IS
GOING TO TAKE THE COMMUNITY
TIME.
WE MAY WANT TO ATTACK DIFFERENT
PARTS DEPENDING ON OUR QUESTION.
WHAT WE MIGHT CONSIDER IS ERATTA
AND FOCUS ON QUESTION-DRIVEN
MODELING.
FOR EXAMPLE, BRAIN INJURY WITH
FRANK PATHOLOGY WE MAY BE
INTERESTED IN MACROSCOPIC TISSUE
PROPERTIES, AND POTENTIALLY
USING IQT TO IMPROVE RESOLUTION.
WE'VE USED A PREVIOUSLY
PUBLISHED SUPER RESOLUTION
MODEL, AND COMPARED HYPER FINE
SCANS OF SMALLER SAMPLES TO
EQUIVALENT MATCH DATA FROM
SIEMENS AND G.E. SCANNERS, IN
SOME CASES YOU GET ALMOST
PERFECT PREDICTIONS OF GRAY
MATTER VOLUME USING IQT THAT
MATCHED IDENTITY TO THE HIGH
FIELD SCANS.
HOWEVER YOU CAN SEE IN SOME
SCANS, THIS ISN'T THE CASE AND
PREDICTIONS ARE LESS ACCURATE.
WE'VE ALSO LOOKED AT THICK SLICE
CLINICAL SCANS WHERE PATIENTS
HAD STROKE AND PASSED THROUGH
AND SHOWN IN 66% OF 30 OR SO
SCANS WE SEE TISSUE INFILL,
GETTING BASICALLY HALLUCINATING
GRAY MATTER WHERE WE SHOULD BE
IN STROKE PENUMBRA.
INTERIM CONCLUSION MAY WANT TO
USE SOME OF THE BAYESIAN
TECHNIQUES USED SUCCESSFULLY
ALONG THIS AXIS TO IMPROVE THIS
ACCESS, AND GIVE RELIABILITY
MEASURES SO THINGS LIKE MODEL
SELECTION AND MODEL COMPARISON
AT THE OUTPUT SIDE OF THE MODEL
BUT ALSO QUALITY CONTROL
MEASURES AT THE INPUT SIDE TO
SEE WHETHER THESE SUPER
RESOLUTION TECHNIQUES ARE
RELIABLE.
IF WE'RE INTERESTED MORE AS A
COHORT LEVEL, WE WANT TO LOOK AT
STATISTICAL TRENDS IN WHITE
MATTER OR GRAY MATTER TISSUE
VOLUME OVER DEVELOPMENT, THEN
SEAN HAS ALREADY SHOWN THAT THE
HYPER FINE SCANNER REPRODUCES
WITHOUT IQT BUT JUST USING
CAREFUL SEGMENTATION ALGORITHMS
YOU HAVE DEFINE TRAJECTORIES.
THERE HAVEN'T BEEN IMPOSED LEARN
STRUCTURES ON THESE DATA, AND SO
WHAT WE NEED TO ASK IF WE'RE
THINKING ABOUT REGIONAL
PROPERTIES IS WHETHER IQT
MEASURES WILL DO BETTER, AS
RELIABLE.
>> ONE MINUTE LEFT.
>> THANK YOU.
WHAT WE'VE LOOKED AT IS WHETHER
DIFFERENT ANATOMICAL FEATURES
ARE MORE PREDICTIVE AT
INDIVIDUAL LEVEL, LIKE CURVATURE
TEAM TO APPEAR COMPARABLE
COMPARED TO SIEMENS AND G.E.
PREDICTIONS, SO WHAT WE THINK IS
WE MIGHT WANT TO IDENTIFY
SPECIFIC ANATOMICAL FEATURES
RETAINED THROUGH IQT.
IF WE MOVE TO PSYCHIATRIC
DISEASE OR COGNITIVE FUNCTION
WE'RE IN THE REALM OF
MULTI-REGIONAL INTERACTION OR
CONNECTIVITY ANALYSIS.
AND SO WE'VE ALSO LOOKED AT
WHETHER THE HYPER FINE IQT
PIPELINE PRESERVED SIGNAL, EDGES
BASED ON PAIRS OF PARCELLATION
IN THE BRAIN, CORRELATING REGION
TO REGION, COMPARED TO SCANNERS
LOOKING AT COMPARISON TO
THEMSELVES.
AGAIN WE SEE THERE IS STRUCTURAL
CO-VARIATION AT A GROUP LEVEL.
SO WHAT WE'RE DOING IS TRYING TO
CATCH UP WITH THE METRIC OF
SPACES OF IQT AND COMPUTATIONAL
MODELING IN CONTEXT OF
DEVELOPING BRAIN, NEWBORNS,
HUMAN CONNECTOME, SIMULATING LOW
FIELD SIGNALS REQUIRED IF WE'RE
DEVELOPING BASKET OF MODELS FOR
DIFFERENT SORTS OF APPLICATIONS
AND PATHOLOGIES, WE'RE GETTING
THERE, WE NEED BETTER
IDENTIFICATION OF THE TRUE
FEATURES OF HYPERFINE SCAN TO
DEGRADE ACCURATELY LARGE
DATASETS WHICH HAVE BEEN
VALUABLE.
AND THEN FINALLY I'LL MENTION
COMING BACK TO THIS IDEA OF
MULTI-MODALITY, THAT THE
DEVELOPING HUMAN CONNECTOME
COULD POTENTIALLY BE
PSEUDOSIMULATED THROUGH
COVARIATES NETWORK, WE MAY BE
ABLE TO LOOK THROUGH EEG AND
MAYBE SYSTEMS WE'VE HEARD
ALREADY TO LOOK AT LEARNING OVER
THE LIFESPAN AND PINPOINT TO
PARTICULAR CELL TYPES USING DTM.
THIS IS A NICE WAY TO END, A
VERY LARGE AND MATURE LITERATURE
FROM ASD, SAW THAT FUNCTION AS
WELL AS ANATOMY, MRI DATA,
IMPROVED PREDICTIVE CAPACITY OF
MODELS OF AUTISM SPECTRUM
DISORDER, THE PICTURE TO PRODUCE
WHEN WE THINK ABOUT HOW
HYPERFINE AND I.Q.T PIPELINES
FIT THE BILL, OVER THE MONTHS
AND PROBABLY YEARS.
>> THANK YOU, ROSALYN.
>> I THINK WE LOST GODWIN FOR A
MOMENT.
A NICE EXAMPLE OF HOW INTERNET
CONNECTIVITY IS A CHALLENGE IN
AREAS WE WORK IN.
THANKS FOR THE GREAT TALK.
AND NOW WE'LL MOVE TO THE NEXT
TALK, SAVING ALL THE QUESTIONS
UNTIL LATER.
NEXT SPEAKER, YOU WON'T GET THE
SAME INTRODUCTION BUT HOPEFULLY
WE'LL GET GODWIN BACK.
TAKE IT AWAY.
>> THANK YOU, SEAN.
GODWIN, CAN YOU HEAR US?
WE LOST YOU FOR A MINUTE.
>> (INAUDIBLE).
>> THANKS, GODWIN.
I TOO ENJOYED ANALYSIS OF BEETLE
TO BENTLEY AND BACK,
PARTICULARLY BACK TO THE BEETLE.
THE ANALOGY WAS GREAT.
I WILL BRIEFLY IN FOUR MINUTES
TALK ABOUT HOW WE CAN IDENTIFY
FINDINGS IN A POPULATION,
TRANSLATE TO UNDERSTANDING
INDIVIDUALIZED FACTORS, AND
TRANSLATE BACK TO THE
POPULATION.
SO, THE BRAIN IS MALLEABLE
ORGAN, TO UNDERSTAND HOW AN
INDIVIDUAL IS DIFFERENT OR
SIMILAR TO EVERYBODY ELSE, ON A
PERSONALIZED LEVEL IS IMPORTANT
TO GATHER DATA FROM LARGE SCALE
MEMBERS OF INDIVIDUALS FROM
POPULATION, HENCE IDENTIFY
UNIQUE AND SHARED FEATURES, AS
WE STRIVE TO MAKE DECISIONS IN
TERMS OF TREATMENT OR DIAGNOSIS
THAT CAN BE APPLICABLE TO THE
POPULATION WE HAVE TO AMALGAMATE
FINDINGS OR VARIABLES
INDIVIDUALIZED.
A COUPLE EXAMPLES IN THE
CONTEXT.
FIRST I WILL TALK ABOUT HOW THIS
APPLIES TO STROKES AND LANGUAGE
AS A CONSEQUENCE OF STROKES,
MORE SPECIFICALLY APHAGIA, IF
YOU THINK ABOUT THE LIFESPAN, A
CONDITION THAT TYPICALLY AFFECTS
INDIVIDUALS TOWARDS THE OLDER
AGES.
AND AS YOU CAN SEE ON THE
LEFT-HAND SIDE THIS IS A
T1-WEIGHTED IMAGE, DARK IS A
REGION THAT HAS SUFFERED
NECROSIS IN THE PAST, AND THIS
IS SEQUELAE OF THE STROKE, WHEN
IT AFFECTS LANGUAGE-RELATED AREA
THERE'S ISSUES WITH SPEECH,
APHAGIA.
FOR INDIVIDUALS WITH APHASIA, IF
THEY HAVE THE SAME LESION THEY
TYPICALLY DO NOT SHARE THE SAME
DEGREE OF IMPAIRMENT AND
IMPORTANTLY THE SAME TRAJECTORY
AS IT RELATES TO RECOVERY.
STANDS TO REASON THIS IS DUE TO
INTACTNESS OR LACK THEREOF IN
THE REST OF THE BRAIN.
THIS CAN BE MEASURED BY MRI.
THIS COLOR CODED IMAGE WITH RED,
YOU CAN SEE INTEGRITY OF THE
TISSUE ACROSS MULTIPLE SCALES
INCLUDING SPECIFICALLY WHITE
MATTER.
AS YOU KNOW, MEASURING THE
REMAINING NETWORKS, SO SQUARE
IMAGE IS THE INDIVIDUAL'S
CONNECTOME.
BY COMPARING WITH NORMATIVE
DATABASE FROM HUMAN CONNECTOME
PROJECT, IT IS THEREFORE
POSSIBLE TO IDENTIFY IN THE
RESIDUAL BRAIN WHAT IS DIFFERENT
AND SIMILAR BETWEEN AGAIN ONE
PERSON AND THE POPULATION, FROM
THERE WE CAN MAKE MUCH BETTER
INFERENCES WITH REGARDS TO
BEHAVIOR, SPECIFICALLY WITH
REGARDS TO LANGUAGE IMPAIRMENT.
THIS ALLOWS US TO UNDERSTAND
BETTER WHAT ARE THE UNIQUE
FEATURES THAT ARE ASSOCIATED
WITH IMPAIRMENT AND WITH
RECOVERY.
ONE EXAMPLE, THE DIAGRAM ON THE
BOTTOM LEFT-HAND SIDE WITH
ARROWS POINTING TO BRAIN REGIONS
IS A NETWORK ASSOCIATED WITH
COMPREHENSION, IDENTIFIED WITH
COMPARISON BETWEEN INDIVIDUAL
AND POPULATION.
MOVING TO THE NEXT SLIDE, PLY
-- MY LAST SLIDE, EPILEPSY,
TENDS TO EFFECT INDIVIDUALS
ACROSS MULTIPLE SCALES AND IT'S
NOT UNCOMMON TO AFFECT CHILDREN
AND YOUNG ADULTS, YOU SEE A
COMMON FORUM, ASSOCIATED WITH
DAMAGE IN THE HIPPOCAMPUS.
ON THE LEFT-HAND SIDE ON A-1 AND
B-1, CORONAL SLICES FROM
DIAGNOSTIC MRI, ATROPHY OF THE
HIPPOCAMPUS, AND THIS IS FROM
THE PUBLICATION PMID SHOWN
BELOW.
SOMETIMES THIS IS CLEAR CUT IN
DIAGNOSTIC SCANS BUT OFTENTIMES
IT'S NOT.
I'M SHOWING TWO EXAMPLES HERE,
ATROPHY IS NOT CLEAR CUT,
INDIVIDUALS WITH TEMPORAL LOBE
ATROPHY.
IT'S COMMONLY ASSOCIATED WITH
BEYOND WHAT WE CAN SEE WITH THE
HUMAN EYE, SO THAT POPULATION
MOSAIC I'M SHOWING DEMONSTRATES
REGIONS WHERE THERE IS A HIGH
PREVALENCE OF FAINT ATROPHY IN
INDIVIDUALS WITH TEMPORAL LOBE
COMPARED WITH CONTROLS,
SPECIFICALLY THE VOXELIZED AREA
UNDER THE CURVE.
YOU CAN SEE IN RED AREAS WITH A
PATTERN WE CAN IDENTIFY FROM A
POPULATION LEVEL.
THAT ENABLES US TO HAVE A MODEL
WHAT I'M SHOWING ON THE BOTTOM,
WITH THE TRANSPARENT BRAIN THAT
DEMONSTRATES, OR INDICATES,
WHERE WE WOULD EXPECT PATTERNS
OF ATROPHY OR LOCATION, THERE
WOULD BE IN AN INDIVIDUAL
TEMPORAL LOBE.
IF WE USE THIS TO GUIDE
ARTIFICIAL INTELLIGENCE
DIAGNOSTIC MODEL IS WHAT I'M
SHOWING BELOW, A NETWORK THAT IS
POWERED BY THE MODEL THAT WE
HAVE, LIKE THE BEETLE AND
BENTLEY AGAIN THAT INDICATES OR
GUIDES ASSESSMENT OF AREAS WHERE
YOU HAVE ATROPHY, THIS CAN
INCREASE DIAGNOSTIC ACCURACY
SIGNIFICANTLY.
SO, AGAIN, MOVING FROM
POPULATION FINDINGS TO
PERSONALIZED FINDINGS AND BACK
TO THE POPULATION LEVEL, SO I
WANT TO THANK THE INSTITUTIONS
WHERE THE WORK HAS BEEN DONE, MY
COLLABORATORS THAT ARE INDICATED
HERE ON THE RIGHT-HAND SIDE.
THANK YOU VERY MUCH.
>> THANK YOU, DR. BONILHA CAN
YOU HEAR ME?
>> YES, WE CAN.
>> FRANCIS SHEN, YOU'RE NEXT.
(INDISCERNIBLE) IN 2021 AWARDED
CAREER SCHOLARS MEDICAL, ONE OF
TWO AWARDED EVERY YEAR, AMERICAN
LAW INSTITUTE, A PIONEER IN
ESTABLISHING INTERDISCIPLINARY
FIELD (INDISCERNIBLE).
Ph.D. FROM HARVARD.
THANK YOU FOR JOINING US.
>> IT'S A PLEASURE TO BE HERE.
THANKS TO THE ORGANIZERS, AND
THE GATES FOUNDATION, NIH.
I'LL JUMP IN.
IT'S A PLEASURE.
I THANK THE ORGANIZERS FOR
WORKING IN SOME CONVERSATION AND
PERSPECTIVE OF IMPLICATIONS ON
THE DEVELOPMENTS.
WE'RE THINKING ABOUT BEETLES AND
BENTLEYS, IT'S COOL TO HAVE
BEETLED BUT WE ARE REGULATIONS
THERE'S QUALITY CONTROL.
ONE OTHER CONCERN WE MIGHT HAVE,
EQUITY-WISE, IF YOU SAY, MOM,
WHY DOES EVERYONE IN THAT
COMMUNITY HAVE A BEETLE,
EVERYONE IN THAT COMMUNITY HAS A
BENTLEY?
EQUITY CONCERNS.
THE ADVANCES IN TECHNOLOGIES ARE
AWESOME BUT ALONG WITH THAT
COMES CONCERNS THAT WE CAN THINK
ABOUT AND ADDRESS BEFORE THEY
GET OUT OF HAND.
I WANT TO THANK NIH, NIH
"BRAIN," AND ACKNOWLEDGE MY
CO-P.I.s ON A BIG GRANT, AND
OTHER COLLABORATORS, ANYTHING I
SAY ARE MY OWN THOUGHTS AND
WORDS BUT ANYTHING USEFUL HAS
PROBABLY COME FROM MY
COLLABORATORS.
WE'RE PART OF A WORKING GROUP
FUNDED BY NIH "BRAIN" TO THINK
ABOUT THE FUTURE OF FIELD-BASED
WORK, AVALANCHE ACCOUNTABLE TO
fNIRS, YOU NAME IT.
AS NEUROIMAGING GOES INTO THE
FIELD IT'S GOING TO RAISE A
NOVEL SET OF ETHICAL, LEGAL,
SOCIAL ISSUES, WE'RE TRYING TO
ADDRESS THOSE.
IF YOU GET INTERESTED, CHECK OUT
OUR FREE FOR EVERYONE WEBSITE,
NEUROIMAGINGETHICS.ORG, COVERING
DEVELOPMENTS YOU HEARD WITH A
FOCUS ON THE ETHICS AND LEGAL
IMPLICATIONS.
WE START OUR WORK WITH
EXCITEMENT YOU'VE HEARD IN THESE
PRESENTATIONS, WHAT DOES THE
FUTURE LOOK LIKE?
YOU CAN STAND ANYWHERE, WHICH
MIGHT ALLOW YOU TO GET MORE
DIVERSE AND INCLUSIVE RESEARCH
AND GREATER ACCESS, SCANNING
WILL BE FASTER AND CHEAPER,
USING NEW PARADIGMS, ANYONE CAN
SCAN, EVEN IF YOU DON'T
UNDERSTAND EEG OR MRI, THAT'S
OKAY, THE SYSTEM WILL ALLOW YOU
TO INTERPRET YOUR RESULTS,
DEMOCRATIZING ACCESS.
WE HEARD THIS EARLIER TODAY,
NEUROIMAGING AT SCALE.
POPULATION NEUROSCIENCE.
BRAIN HEALTH SCREENING.
THERE ARE REASONS TO BE EXCITE
AND CONCERNED, TO ADDRESS THESE
CONCERNS.
THESE ARE JUST A COUPLE OF
ILLUSTRATIVE CONCERNS, IF YOU
CAN SCAN ANYWHERE, THAT'S GREAT
BUT IT RAISES IMPORTANT
QUESTIONS AND WE'VE HEARD THIS
ALREADY ABOUT LOCAL CAPACITY,
COMMUNICATING, ENGAGING WITH
REMOTE PARTICIPANTS, ISSUES
AROUND RECRUITMENT AND
INCLUSION, IS THERE THE RESEARCH
CAPACITY, INSTITUTIONAL CAPACITY
TO LIVE UP TO THE PROMISE?
THINKING ABOUT FASTER AND
CHEAPER SCANNING, IT'S A
QUESTION OF WHEN CERTAIN
TECHNOLOGY IS APPROACH IT.
THERE'S POTENTIAL OVERUSE, JUST
BECAUSE YOU CAN USE A TECHNOLOGY
DOESN'T MEAN YOU NECESSARILY
SHOULD.
WHAT ARE THE JUSTIFICATIONS?
THERE ARE ISSUES RELATED TO
DEMOCRATIZATION, AN EXCITING
THING TO PUT MR, EEG, fNIRS IN
ANYONE'S HANDS BUT IT COULD END
UP IN THE WRONG HANDS OR LACK OF
TRAINING, IS THERE SUFFICIENT
CAPACITY TO, AGAIN, ALLOW
SOMEONE TO PROPERLY INTERPRET
AND UNDERSTAND IMAGES AND
INFORMATION.
IT OPENS POPULATION
NEUROSCIENCE, AND RAISES
POSSIBILITY THAT TEAMS WILL NEED
TO BE NEWLY TRAINED AND
COORDINATED AND NEWLY
REDEVELOPED TO ENGAGE
POPULATIONS AND THIS RAISES
POSSIBILITY OF DIRECT TO
CONSUMER IMAGING, WE'VE BEEN
THINKING ABOUT THESE AND MANY
ISSUES, ONE IN NEURON, WE
THOUGHT ABOUT INFORMED CONSENT,
A.I., POTENTIAL BIAS.
I WANT TO FLAG ONE, A PIECE IN
NEUROIMAGE LAST YEAR ON EMERGING
ETHICAL ISSUES RAISED BY --
DOESN'T HAVE TO BE HIGHLY
AFFORDABLE MRI BUT NEUROIMAGE
AING IN RESOURCE LIMITED
SETTINGS.
ONE OF THE AWESOME AMAZING
BENEFITS OF DOING RESEARCH WITH
HUMAN PARTICIPANTS, YOU CAN'T DO
THIS WITH ANY NON-HUMAN ANIMALS,
THEY CAN CONTRIBUTE AS
CO-CREATORS OF KNOWLEDGE.
YOU CAN ENGAGE WITH PARTICIPANTS
BEFORE YOU FULLY FORMULATED
HYPOTHESES, INDEED UNLIKE EVERY
NON-HUMAN ANIMAL THEY MIGHT
INVITE YOU TO ENGAGE IN
RESEARCH, OR MIGHT NOT, THAT
MIGHT BE IMPORTANT TO THINK
ABOUT THAT COMMUNITY ENGAGEMENT
ASPECT, WE EMPHASIZE IN THIS
ARTICLE BIDIRECTIONAL LEARNING,
ENGAGING WITH COMMUNITIES AND
PARTICIPANTS WHERE THESE NEW
DEVICES WILL GO.
LOCAL PARTNERSHIP, SUSTAINED
LOCAL ENGAGEMENT, CREATING
SUSTAINABLE SOCIAL VALUE, IT
REALLY FEEDS INTO A LOT OF THE
ETHICAL CONCERNS THAT CAN BE
ADDRESSED.
THAT OUGHT TO BE ADDRESSED IN
ADVANCE.
I'LL JUST MENTION ONE, THIS IDEA
OF CREATING SUSTAINABLE SOCIAL
VALUE.
THE RESEARCH TEAMS YOU HEARD
FROM ARE EMBRACING THIS.
FOR SOME RESEARCHERS THERE'S THE
LINE WHERE YOU WRITE TO YOUR IRB
AND SAY NO DIRECT BENEFIT FOR
PARTICIPANTS, FULL STOP.
THAT MIGHT NOT BE APPROPRIATE
FOR ETHICAL WHEN DOING CERTAIN
TYPES OF RESEARCH WITH CERTAIN
COMMUNITIES, THINKING ABOUT HOW
LOCAL VALUE WILL BE CREATED.
THERE'S MORE, I DON'T HAVE TIME
TO MENTION IT ALL BUT WILL
SIMPLY SAY THAT WE SHOULD
PREPARE FOR A FUTURE IN WHICH A
LOT OF THESE ISSUES WILL EMERGE,
WE NEED MORE STANDARDIZATION,
CONCERNS ABOUT SAFETY AND
SECURITY, ISSUES AROUND EQUITY
AND PRIVACY, AND DATA FLOW,
AGAIN, HEAVY RELIANCE ON A.I.
AND MACHINE LEARNING.
ALL GREAT THINGS THAT ARE COMING
DOWN THE SPIKE, I'M EXCITED, BUT
WITH THAT EXCITEMENT COMES A SET
OF CONCERNS AND COLLECTIVELY
ETHICAL RESEARCH, WE CAN ADDRESS
AND ANTICIPATE.
THANK YOU AND LOOK FORWARD TO
DISCUSSION.
>> THANK YOU SO MUCH.
THANK YOU SO MUCH.
I THINK WE MOVE TO A DISCUSSION
RIGHT AWAY.
RAISE YOUR HAND AND WE CAN GET
OUR QUESTIONS.
A QUICK ONE SINCE YOU JUST
FINISHED, GOING BACK TO THE
BEETLE AND BENTLEY AGAIN, IF YOU
HAVE COMMUNITIES (INDISCERNIBLE)
IF WE HAVE BEETLES AND MORE
BEETLES, SOME PEOPLE SAY HALF IS
BETTER THAN NONE, WHAT YOU CAN
AFFORD (INDISCERNIBLE).
FRANCIS, PLEASE.
>> WELL, I THINK TWO-TIER SYSTEM
SHOULD BE ANTICIPATED, NOT JUST
WITH THE TECHNOLOGY BUT ALSO
WITH THE SERVICE PLAN THAT COMES
WITH IT SO IT'S NOT HARD TO
IMAGINE THAT YOU GET THE DEVICE
BUT THEN YOU HAVE TO CHOOSE.
DO YOU WANT BRONZE, SILVER, GOLD
SERVICE PLAN?
YOU GET THE BETTER IMAGING, MORE
RESPONSIVE SERVICE.
THERE IS A REAL EQUITY CONCERN,
SOMETHING IS BETTER THAN
NOTHING.
MAYBE THAT'S APPROPRIATE IN SOME
PLACES.
BUT I THINK THERE IS A CONCERN.
AGAIN, IT DEPENDS WHAT THE
QUESTION BEING ASKED IS, WHAT
THE PURPOSE IS, AND IF IT'S THE
CASE THAT ONE IS SUFFICIENT,
LOWER FIELD OR DIFFERENT SYSTEM,
GREAT, IF IT'S THE CASE THAT YOU
MIGHT ALSO WANT CLINICIAN MIGHT
SAY THIS IS USEFUL FOR SCREENING
BUT FOR CLINICAL PURPOSES I ALSO
WANT TO SEE SOMETHING ELSE, ONE
OF THE WAYS THAT MATTERS FOR
INCIDENTAL FINDINGS, DOES THE
RESEARCH TEAM HAVE A PLAN IN
PLACE TO HANDLE INCIDENTAL
FINDINGS THAT MIGHT EMERGE AND
NEED FOR ACCESS TO A NETWORK TO
IDENTIFY AND ADDRESS INCIDENTAL
FINDINGS.
>> THANK YOU.
WE HAVE ANOTHER QUESTION.
I HAVE BEEN ADVOCATE FOR SAFETY
FOR SPECIFIC MRI FOR DECADES,
THE MAGNET MANUFACTURERS IN U.S.
AND EUROPE HAVE NOT SEEN A
MARKET FOR THIS APPROACH.
DO WE HAVE ANY HOPE AFRICAN
COUNTRIES WOULD SHOW THAT
QUANTITATIVE APPROACH AND NOT
THAT EXPENSIVE AND CAN BE
REWARDED.
I'LL START WITH ANDREW WEBB, DO
YOU WANT TO ADDRESS THAT
QUESTION?
>> A POSSIBILITY, MORE SO IN
POPULATION GROWTH.
HOW THE GRAIN HAS GROWN,
DEVELOPING THROUGHOUT THE
LIFESPAN, THE BRAIN HAS GROWN,
NOT SOMETHING WE'VE TYPICALLY
DONE IN THE DEVELOPED WORLD OVER
THE YEARS.
FROM THAT POINT OF VIEW, THERE
IS.
AND ONE OF THE THINGS LOW FIELD,
AS LONG AS WE'RE NOT TRYING TO
GET HIGH RESOLUTION, THINGS
COULD BE DONE ON A REASONABLE
TIME FRAME, CLINICALLY KNOWING
WHAT THE T1 OF A TUMOR IS IS NOT
VERY USEFUL.
IF YOU CAN SEE WHERE THE TUMOR
IS, THAT'S THE IMPORTANT THING.
SO, IF WE'RE GOING TO LOOK FROM
THE ENTIRE CONFERENCE, LOOKING
OVER THE LIFESPAN OF THE BRAIN,
YEAH, I THINK IT MIGHT HAVE A
ROLE, CERTAINLY.
BUT THERE MAY BE OTHERS ACTUALLY
MORE QUALIFIED.
WORKING WITH THE HYPERFINE
SYSTEM IN TERMS OF
QUANTIFICATION.
>> THAT'S OUR PRIMARY FOCUS,
DRIVEN BY ONE, AS A NEW SYSTEM
THAT'S COMING UP, THAT'S BEING
USED IN A WIDER SCALE, THAT
HASN'T BEEN OPTIMIZED FOR
PEDIATRICS, STARTING FROM BASICS
UNDERSTANDING WHAT THE TISSUE
CONTRAST LOOKS LIKE, T1s, TO
OPTIMIZE OTHER SEQUENCES.
THE HOPE IS THAT IT MAY ALSO
GIVE IMPROVED SENSITIVITY TO
SOME INTERVENTIONS THAT THE
FOUNDATION IS CHAMPIONING.
THINGS LIKE AROUND MATERNAL
ANEMIA, MATERNAL AND INFANT
NUTRITION, THESE SORTS OF THINGS
MAY HAVE A GREATER IMPACT OR
MAYBE QUANTITATIVE IMAGING
INTENSIVE TO THOSE INTERVENTIONS
THAN TRADITIONAL QUALITATIVE
IMAGING.
I THINK IN THAT CASE IT'S A
DIFFERENT BEACH HEAD.
WE CAN ACTUALLY HAVE A DIFFERENT
APPROACH, MAYBE TAKE THE
QUANTITATIVE APPROACH.
WE'VE BEEN WORKING AND
SUPPORTING A NUMBER OF OUR
GRANTEES TO FOCUS ON THAT
SPECIFICALLY.
I DO SEE ELLEN HAS A HAND UP.
>> ELLEN, PLEASE GO AHEAD.
>> MAKING A COMMENT, ONE THING
IF RESEARCH IS PERFORMED IN ONE
SPACE ON ONE SCANNER, EVERYWHERE
ELSE MORE DEVELOPED WORLD,
DIFFERENT SCANNER, IT'S HARD TO
COMPARE DIFFERENCES BECAUSE
DIFFERENCES COULD BE DRIVEN BY
SYSTEM YOU'RE USING, SO I THINK
IT'S IMPORTANT THAT THE LOW
FIELD SYSTEMS ARE USED MORE
OFTEN IN HIGH RESOURCE AREAS TO
UNDERSTAND HOW WE CAN COMPARE TO
DATA BEING GATHERED IN
UNDERRESOURCED AREAS.
THE OTHER BIG CHALLENGE IS I CAN
SEE AS A NEURORADIOLOGIST WE
NEED TO TRAIN CLINICIANS HOW TO
READ SUCH SCANS, BECAUSE WE'RE
USED TO 3T SCANS, WE CORROBORATE
WITH UGANDA, VERY LOW RADIOLOGY
SKILLS, TEACHING THEM HOW TO
INTERPRET CTs, IF THEY GET
HYPERFINE DATA I NEED TO LEARN
HOW TO READ AND GET FEEDBACK, WE
NEED TO HAVE THE EDUCATION
PROCESS TIED TO CLINICAL
EXPERTS, SUPPORTING THE
DEVELOPMENT AS IT MOVES INTO THE
FIELD AND WE KNOW IT WON'T BE
JUST NORMAL BRAINS, WE'LL BE
SEEING LOTS OF UNUSUAL THINGS
GIVEN THE HEALTH SITUATIONS IN
THESE UNDERRESOURCED AREAS,
PARTNERSHIP WITH PHYSICIANS IS
IMPORTANT AS YOU PUSH US
FORWARD.
>> DEFINITELY THAT'S A GREAT
POINT.
AGAIN THE INTERESTING THING FROM
EQUITY STANDPOINT WE'RE ALL
STARTING FROM ZERO, ALL
LEARNING.
THIS COUNTRY DIVIDE IS
NON-EXISTENT IN THIS CASE, AN
INTERESTING ASPECT.
THINKING OF HOW WE CAN BRING
EVERYONE TOGETHER AND TRAIN,
HAVE THAT COOPERATIVE TRAINING
AND CAPACITY BUILDING ACROSS THE
BOUNDARIES IS SUPER IMPORTANT,
SOMETHING THAT THE FOUNDATION IS
SUPPORTING.
>> I WANT TO AGREE, GETTING
PEOPLE TO UNDERSTAND HOW TO USE
THIS EFFICIENTLY TO SOME
PROBLEMS IS KEY.
IT WILL ONLY SEE ARTIFACTS,
FIRST TIME I GOT INVOLVED
LOOKING AT HIGH-THROUGHPUT
SYSTEM, IT WAS AMAZING BECAUSE
VESSELS LOOKED LIKE ARTIFACTS,
SMALL VESSELS.
THERE'S A NEED TO BRIDGE THAT
GAP, FOCUS ON BUILDING CAPACITY
ACROSS BOTH SPECTRUMS.
I WANT TO ASK ABOUT IMMIGRATION.
CAN WE HAVE ONE SYSTEM THAT CAN
INTEGRATE ALL OF THIS
INFORMATION, EEG RESULTS, MRI,
IS IT POSSIBLE TO DO THAT ON A
LOW SCALE?
>> YES, I THINK SO.
LAUREL AND I WERE CHATTING ABOUT
PUTTING EEG IN THERE AND WE
TALKED A LITTLE BIT, LOOKING AT
THE SYSTEM THAT SARAH AND JOSEF
WERE SHOWING.
ONE OF THE BIG ADVANTAGES OF THE
LOW FIELD MR, THE BIG MAGNETS
AND GRADIENTS, THE REAL PROBLEM
IS NOT THERE.
IT'S A GREAT IDEA IF THERE'S
REALLY SOME GOOD REASONS TO DO
IT, FROM A CLINICAL POINT OF
VIEW, ENGINEERINGWISE SHOULD BE
POSSIBLE.
>> I AGREE.
HIGH AND LOW DENSITY EEG ON
MYSELF, HYPERFINE SCANNER, WE'RE
TESTING ON OURSELVES RIGHT NOW
BUT I SEE A PATH FORWARD, THAT
WOULD BE INCREDIBLY EXCITING.
>> FROM fNIRS SIDE, THERE ARE
GROUP THAT INTEGRATED fNIRS
WITH EEG, WHERE YOU SPEND YOUR
DEVELOPMENT MONEY BUT THE OTHER
NON-OBVIOUS ADVANTAGE EVER
INTEGRATING IS WE KEEP RUNNING
INTO CO-REGISTRATION ERRORS, AS
WE IMPROVE RESOLUTION YOU
SUDDENLY FEEL THE PAIN OF NOT
KNOWING WHERE YOU ARE ON
SOMEBODY'S HEAD.
GETTING A SCAN WITH A CAP ON,
GETTING THAT TO BE ROUTINE COULD
REALLY CHANGE THE DATA QUALITY.
ON LONGITUDINAL SCANS IF YOU'RE
SCANNING THE THE SAME PERSON
OVER TIME.
>> ANOTHER BROAD QUESTION FOR
EVERYONE.
SHOULD WE BE EMPHASIZING
STUDIES, STUDYING THE
DIFFERENCES?
>> IF YOU LOOK AT THINGS
SUCCESSFUL WITH fMRI, IT'S
BOTH.
THEY HAVE REALLY LARGE SCALE
POPULATION STUDIES AND THEY ALSO
ARE GOING TO REALLY MANY, MANY
HOURS OF IMAGING WITHIN SINGLE
SUBJECTS.
I DON'T KNOW THAT YOU'VE PICKED
ONE OR THE OTHER.
I THINK YOU WANT TO BUILD TOOLS
FOR BOTH.
>> I WOULD JUST SAY THE POINT AS
WELL, I THINK YOU NEED TO LINK
THAT TO THE TOOL THAT FRANCIS
GAVE ABOUT THE ETHICAL
CONSIDERATIONS OF THE
INTERPRETATIONS YOU'RE MAKING
ABOUT THE DATA, SO IF YOU DON'T
HAVE LONGITUDINAL DATA YOU MIGHT
BE MAKING JUDGMENTS ABOUT
DEVELOPMENT COMPLETELY WRONG
BECAUSE YOU MISSED ANY IMPORTANT
AREAS AND I THINK THAT'S SUCH
PAUSE OF A PAUCITY OF
LONGITUDINAL DATA, YOU CAN'T
ANSWER UNTIL YOU GET MORE DATA
BECAUSE THERE'S NOT ENOUGH.
FIRST I DID A LONGITUDINAL STUDY
IN THE GAMBIA, I WANT TO ADD TO
THE PREVIOUS COMMENT AS WELL AND
KIND OF LINKING TO WHAT FRANCIS
IS SAYING ABOUT THE ETHICAL
CONSIDERATIONS, WE SHOULD
REMEMBER AS WELL WE'RE LEARNING
A LOT ABOUT THE DATA THAT WE'VE
PREVIOUSLY INTERPRETED IN
HIGH-INCOME COUNTRIES FOR WORK
IN LOW-INCOME COUNTRIES, DATA
QUALITY IS BETTER IN THE GAMBIA
THAN THE U.K. PARTLY BECAUSE OF
THE WAY IN WHICH WE'RE ENGAGING
WITH THE FAMILIES AND THE WAY IN
WHICH THE INFANTS FIT MORE STILL
BECAUSE THAT'S THE WAY THEY ARE
CULTURE HAS TAUGHT THEM TO SIT
WHEN THEY ARE WITH THEIR
PARENTS, THE DATA IS USEFUL, SIT
MORE STILL.
THEY CAN AGAIN HAVE STRONGER
DATASETS THAT MIGHT TELL US MORE
ABOUT THE DATA WE'VE LOOKED AT
PREVIOUSLY IN THE U.K.
SO WE'VE GOT TO REMEMBER THAT
DIRECTION AS WELL I THINK.
>> I AGREE WITH YOU.
ONE OR TWO MORE QUESTIONS.
DANIEL, WITH MACHINE LEARNING,
USED IN THE VAST -- LIKE THE
HYPERFINE AND LOW FIELD MRI
SCANNERS, DO PANELISTS EXPECT
DATA, TYPICAL SUBJECT DATA,
SEEKS TO LIMIT CLINICAL
APPLICATIONS FOR SMALLER FOCAL
ISSUES, I DON'T KNOW, ANYONE CAN
JUMP IN ON THIS.
>> I THINK IT MAY WELL BE, SO
SOME OF THE MODELS WE'VE USED
THAT WERE DEVELOPED ON NORMATIVE
DATASETS DON'T HAVE PATHOLOGY,
TRAINING SETS WILL FILL IN,
WHICH IS OBVIOUSLY EGREGIOUS IN
THE CLINICAL SETTING, SO THAT'S
I THINK WHERE WE NEED TO BE
REALLY CAREFUL, USING DEEP
LEARNING METHODS AND I THINK THE
PEOPLE WHO HAVE SEEN THIS THE
MOST HAPPILY ARE
NEURORADIOLOGISTS WHO HAVE
ALREADY SEEN WAVE OF LITERATURE
OVER THE PAST TEN YEARS AND SO
THIS CAN BE, BACK TO SEAN, NO
DISPARITY, EVERYTHING WORKING IN
LOW FIELD SCANNERS, ARE GOING TO
HAVE TO DO THE SAME CHALLENGES
SO I THINK THAT'S A CONCERN THAT
NEEDS TO BE AT THE FRONT OF
ANYONE'S MIND WHEN DEVELOPING
THESE MODELS.
>> ANOTHER ONE, TO FOLLOW UP,
TOO MUCH ABOUT CT, FOCUSED
ULTRASOUND, CT IS MORE OFTEN
USED THAN IN THE U.S., ANY
COMMENTS FROM THE PRESENTERS
ABOUT WHERE THIS MAY BE USED
MORE IN AFRICA AND SOUTH
AMERICA?
AND THEN I THINK THE FOCUSED ON
ULTRASOUND AND CT.
IS THERE A PLACE IN TERMS OF
SCALING IN THIS COUNTRY?
SOUTH AMERICA AND AFRICA?
ROSALYN, DO YOU WANT TO JUMP IN?
>> I'M LOOKING TO CLINICAL
COLLEAGUES.
>> HELEN?
>> THE STILL REQUIRES A STABLE
POWER SOURCE, YOU'VE GOT
RADIATION, ESPECIALLY WITH THE
CT, HIGHER RADIATION DOSES, THEY
DON'T HAVE NEAR THE CONTRAST
POTENTIAL MRI HAS.
ON OUR SITE, AT LEAST PORTABLE
CT CAN BE REPLACED, WITH MR
BEAUTIFUL POTENTIAL OF ALL SORTS
OF IMAGE CONTRASTS THAT YOU
NEVER GET WITH CT SCAN.
SO I THINK THAT CT IS --
SENSITIVE, HARD TO MAINTAIN, QA,
ALSO A CHALLENGE IN UNDERSERVED
AREAS.
>> THANK YOU VERY MUCH.
WE'VE HAD AN EXTENSIVE AND VERY
THOUGHTFUL DISCUSSION.
I WOULD LIKE TO ASK ALL THE
PANELISTS TO TAKE A SECOND TO
SAY FINAL WORDS BEFORE WE CLOSE.
ANY THOUGHTS?
FINAL WORD FOR OUR SPEAKERS, YOU
HAVE 30 SECONDS.
>> THAT MEANS WE EACH GET FIVE
SECONDS, RIGHT?
I DON'T KNOW.
YOU SHOULD CLOSE US WITH IN OUR
RENDITION OF THE BENTLEY TO
BEETLE ANALOGY.
THAT SEEMED TO WORK FOR ALMOST
EVERYBODY.
>> I CAN OFFER I'M ALWAYS
LOOKING FOR RENEWED PARTNERS IN
CRIME AND SCIENCE, SO IF ANYONE
IS LOOKING TO GET ENGAGED WITH
THIS RESEARCH OR HAS PARTNERS IN
DIFFERENT SETTINGS THEY WANT TO
TRY OUT FEEL FREE TO REACH OUT.
WE WOULD LOVE TO MAKE THIS TO
SCALE.
>> I MIGHT OFFER ON THE SAME
THEME THAT MANY OF YOU WILL BE
HEARING FROM US, ONE OF OUR
PROJECT GOALS IS TO ENGAGE A LOT
OF YOU STAKEHOLDERS, SO PLEASE
ANSWER WHEN WE KNOCK ON YOUR
E-MAIL ADDRESS AND TELL US WHAT
ETHICAL ISSUES YOU'RE FINDING
AND WHAT SOLUTIONS YOU'RE
ALREADY DEVELOPING AND WE HOPE
TO SHARE THOSE AS WELL.
THANKS AGAIN TO NIH AND GODWIN
FOR A WONDERFUL PANEL.
THANKS.
>> I WANT TO THANK EVERYONE FOR
PARTICIPATING.
WE HAD A WONDERFUL DISCUSSION
AND WE CAN OFFLINE REACH OUT TO
EACH OTHER TO SCALE UP TO REACH
OUT AND INCREASE GLOBAL ACCESS
TO MAKE A DIFFERENCE.
CLINICAL IMPACT, NOT JUST
RESEARCH, TRANSLATE WHAT WE FIND
IN THE RESEARCH LABS TO CLINICS
AND TRANSFORM THE WORLD.
THANK YOU VERY MUCH FOR BEING A
WONDERFUL SESSION.
I'LL LEAVE AMANDA TO CLOSE.
THANK YOU VERY MUCH.
>> AMANDA, I THINK YOU'RE MUTED.
A RARE MISSTEP FOR YOU.
I CAN'T HEAR YOU.
SHOULD I JUST JUMP IN?
BLINK ONCE.
>> WE'LL HAND OVER TO YOU, DR.
NGAI.
>> THANKS.
THIS IS JUST A TERRIFIC TWO DAYS
OF SCIENCE.
EVERYBODY HERE, LIKE ME, LEARNED
A LOT.
I'D LIKE TO THANK THE ORGANIZERS
AND PARTICIPANTS FOR EVERYTHING
HERE.
SINCE WE'RE IN THE VIRTUAL
ENVIRONMENT WE DID NOT HAVE THE
BENEFIT OF YOU FOLKS BEING ABLE
TO TALK AMONGST EACH OTHER
DURING THE BREAKS OR DINNER,
LUNCH, EVEN AT THE BAR.
BUT ACTUALLY I WOULD LIKE TO
ENCOURAGE YOU THAT BASED ON WHAT
YOU'VE SEEN, CONVERSATIONS WE'VE
HAD DURING THE DISCUSSION,
THERE'S A LOT OF OPPORTUNITIES
FOR SOME REALLY GREAT
COLLABORATIONS, SHARING OF IDEAS
AND MAYBE NEW OPPORTUNITIES FOR
MOVING FORWARD.
IN THE LAST FEW MINUTES,
EVERYBODY HAD A LOT TO DIGEST
HERE.
I JUST WOULD LIKE YOU TO THINK
ABOUT WHAT ARE THE MAJOR GAPS,
OPPORTUNITIES AND CHALLENGES
CONSIDERING ALL THAT WE'VE
LEARNED OVER THE LAST TWO DAYS
OR SO.
I JOTTED DOWN A FEW EMERGING AND
COMMON THEMES THAT I SAW WHEN I
DOVE INTO THIS, INTO MY NOTES.
SO IF YOU'LL ALLOW ME, I THINK
THIS IS STATED ON THE FIRST DAY,
I'LL PARAPHRASE, LYMS IN
PROGRESS ARE ENABLED BY
TECHNOLOGY DISRUPTION.
TECHNOLOGY IS THE LIMITING
FACTOR, WE ARE SEE VIRTUOUS
CYCLE BETWEEN GREAT INFORMATION,
HITTING SOME TECHNOLOGY ROAD
BLOCK, INVENTING TECHNOLOGY THAT
ALLOWS YOU TOES ASK BETTER
QUESTIONS AND SO ON AND SO
FORTH, AN IMPORTANT THING.
THIS PLAYED OUT WELL IN THIS
SPACE.
THERE'S A REALLY KEY IMPORTANCE
OF APPROACHES WE HEARD ABOUT
OVER THE LAST TWO DAYS.
THIS WILL HELP US IDENTIFY BOTH
CONSERVED AND DIVERGENT
SOLUTIONS SELECTED OVER
EVOLUTIONARY TIME.
THIS WILL HELP US INFORM THERE
AND HOW TO LOOK IN TERMS OF
ESTABLISHING MODELS OF HUMAN
PROCESSES AND VERY IMPORTANTLY
MECHANISMS OF HUMAN DISEASE.
ESPECIALLY WHERE THERE ARE
CONSTRAINTS WE CANNOT STUDY
HUMANS THEMSELVES.
WE'RE ALWAYS GOING TO NEED GOOD
NON-HUMAN MODELS FOR BETTER
UNDERSTAND HUMAN DISEASES BEFORE
WE CAN GET TO FINDING TREATMENTS
AND CURES.
THERE'S A GREAT POTENTIAL
LEVERAGING SUITES OF TOOLS FROM
MULTIPLE DISCIPLINES TO BRIDGE
NEEDS, INCLUDING SPATIAL AND
TEMPORAL SCALES.
WE SAW INNOVATIONS, NOT JUST
COMBINING GENOMICS BUT ACTUALLY
COMBINING AND INTEGRATING
MOLECULAR BIOLOGY, PROTEIN
ENGINEERING, BEHAVIOR, DATA
SCIENCE, YOU NAME IT.
WE SAW ESPECIALLY EARLIER TODAY
THAT IT'S NOT JUST ENOUGH TO
INVENT A NEW KIND OF MICROSCOPE.
YOU NEED TO MARRY THAT WITH
SENSORS AND ACTUATORS THAT ALLOW
YOU TO MEASURE AND MANIPULATE
NEURAL AND BEHAVIOR FUNCTION AS
WELL.
ALL THAT WE'RE DOING THESE DAYS
IN NEUROSCIENCE AND BIOLOGY IN
GENERAL IS GENERATING GOBS OF
DATA AND THIS IS GOING TO INFORM
TO MAXIMIZE RESOURCES THAT WE
ORGANIZE, INTEGRATE, DISSEMINATE
THIS BODY OF DATA, IT'S GOING TO
BE THE REASON WE SUCCEED WILDLY
OR REALLY FAIL TO MEET THE
POTENTIAL OF ALL THESE
INCREDIBLY POWERFUL NEW
ANALYTICAL TECHNIQUES.
THIS IS CERTAINLY AN IMPERATIVE
ACROSS THE NIH IN THE BRAIN
INITIATIVE IN PARTICULAR.
WE'VE SEEN HOW MACHINE LEARNING
AND OTHER COMPUTATIONAL
APPROACHES ARE VERY POWERFUL BUT
REQUIRE GROUND TRUTH DATA TO
REALLY BE BROUGHT DOWN TO
REALITY.
WE WANT TO MAKE SURE WHAT WE'RE
MODELING ACTUALLY IS TELLING US
SOMETHING REAL, NOT JUST
SOMETHING THAT WINDS UP BEING
SOME GREAT FANTASTIC FIGMENT OF
OUR IMAGINATIONS.
THERE'S A HUGE CHALLENGE ACROSS
LIFE STAGES WITH METHODOLOGIES.
THE BRAIN, WHETHER HUMAN OR
OTHERWISE, IS A CHANGING ORGAN
OVER TIME.
TARGETS WE'RE TRYING TO
INVESTIGATE AND INTERROGATE ARE
CHANGING AS WELL.
IT'S A MOVING TARGET.
METHODOLOGIES WE NEED TO USE TO
STUDY THE MOVING TARGET WILL
HAVE TO BE CHANGED, HOW YOU
INTEGRATE ACROSS MODALITIES IS
GOING TO BE VERY IMPORTANT.
SO WE NEED TO BE MINDFUL OF
SELECTING THE RIGHT TOOLS FOR
THE RIGHT JOB AND MAKE SURE THEY
MATCH THE SUBSTRATE WE'RE TRYING
TO MEASURE AND ULTIMATELY IN
MANY CASES TRYING TO MANIPULATE.
IT'S VERY IMPORTANT TO GRAB ALL
THE APPROACHES IN A STRONG
FRAMEWORK, MENTIONED IN
DISCUSSION TODAY HOW THAT COMMON
FRAMEWORK WOULD HELP US DEAL
WITH THESE CHALLENGES ACROSS
LIFE STANDINGS THAT DEMAND USE
OF DIFFERENT EXPERIMENTAL
TECHNOLOGIES.
ULTIMATELY WE DO NEED TO
DEMONSTRATE CAUSALITY, ONE WAY
IS THROUGH PERTURBATIVE STUDIES,
GLOBAL PANDEMICS OR MAJOR
DISRUPTIONS ACROSS THE PLANET
ARE ACTUALLY THE ULTIMATE, WHICH
WILL ALLOW US TO UNDERSTAND HOW
SUBPOPULATIONS AMONG HUMANKIND
ARE AFFECTED BY PERTURBATIONS.
THERE'S A REALLY CRITICAL
IMPORTANCE OF DIVERSITY IN
COHORTS, CREATING TOOLS THAT
ENABLE STUDY OF DIVERSE STUDY
COHORTS, I THINK IT'S IMPORTANT
TO REMIND YOURSELVES MANY
LESSONS TO BE LEARNED, THERE ARE
MANY LESSONS TO BE LEARNED FROM
VARIABILITY INHERENT IN HUMAN
POPULATION, VARIABILITY DRIVEN
BY DIFFERENCES IN ANCESTRY, LIFE
EXPERIENCE, INCLUDING
SOCIOECONOMIC STATUS, AGE,
DISEASE, AMONG OTHER VERY
IMPORTANT FACTORS.
AND THERE'S A NEED TO
DEMOCRATIZE TECHNOLOGY, THIS
CAME UP OVER THE LAST TWO DAYS,
AS WE HEARD A LOT ABOUT HERE
TODAY TO EXTEND REACH INTO WHOLE
ENVIRONMENTS, MANY OF THESE
ISSUES REPRESENT CONFLICTING AND
SOMETIMES DOUBLE-EDGED SWORDS.
AS FRANCIS SHEN WAS VERY KEEN TO
POINT OUT WE NEED TO BE MINDFUL
UP FRONT ABOUT THE ETHICAL,
LEGAL, SOCIETAL IMPLICATIONS OF
ALL THAT WE DO HERE.
THERE'S HUGE OPPORTUNITIES FOR
THE FIELD IN THE FUTURE, HUGE
OPPORTUNITIES IN TERMS OF
DEVELOPING TECHNOLOGIES THAT
ALLOW US TO UNDERSTAND BETTER
HOW THE HUMAN BRAIN DEVELOPS
OVER TIME, AND AGES OVER TIME,
AND WITH ALL THESE POINTS IN
MIND, I THINK WITH ALL WE
LEARNED THE LAST TWO DAYS HOPING
YOU FOLKS WILL FIND WAYS TO
DEVELOP NEW COLLABORATIONS THAT
MIGHT ALLOW US TO ENABLE SOME
TECHNOLOGY DISRUPTIONS THAT WILL
LEAD US TO ASK BETTER QUESTIONS
THAT WILL GET US FURTHER TO
UNDERSTANDING HOW THE BRAIN
CHANGES OVER TIME AND HOW WE CAN
INTERVENE IN CASES OF DISEASE.
I WILL END THERE.
AND MY ZOOM IS WONKY SO SOMEONE
WILL HAVE TO KICK ME OUT OF
SCREEN SHARE, IF YOU WOULD.
>> THANKS.
>> I DON'T KNOW IF THERE'S ANY
QUESTIONS OR COMMENTS IN THE
LAST FEW MINUTES WE HAVE OR WE
CAN GET OUT OF CLASS A LITTLE
BIT EARLY, IF NOT.
>> THANK YOU FOR THE COMMENTS.
I MEANT TO SAY BEFORE THAT JOHN
NGAI IS DIRECTOR OF THE BRAIN
INITIATIVE, AND THIS WILL BE AN
OPPORTUNITY TO HAVE SOME CLOSING
DISCUSSION, IF WE WANT TO BE
ABLE TO ALL COME TOGETHER AND
DISCUSS ANY LAST PARTING
THOUGHTS BEFORE THE MEETING
CLOSES.
>> AMANDA, THANK YOU FOR HOSTING
THIS WONDERFUL MEETING.
I THINK IT'S VERY EXCITING, AT
LEAST FOR THIS SESSION, THE
OTHER SESSIONS WERE HIGHLY
TECHNICAL, BUT THIS WAS MORE
ACROSS THE LINE.
I WANT TO ASK IF WE COULD
SUMMARIZE THOUGHTS AND
PRESENTATIONS INTO LIKE, I DON'T
KNOW, A COMMENTARY OR SOMETHING
TO BE ABLE TO CONDENSE TALKS AND
PRESENTATIONS IN A WAY WE CAN
PRESENT IT TO THE WORLD TO THINK
ABOUT AND COLLABORATE WITH THE
SPEAKERS.
>> THERE WILL BE A MEETING
REPORT PRODUCED FROM THE
WORKSHOP WITH AN EXECUTIVE
SUMMARY WITH SOME OF THE MAJOR
THEMES HIGHLIGHTED.
YOU CAN LOOK FORWARD TO SEEING
THAT IN THE FUTURE.
WE DO HAVE SOME QUESTIONS IN THE
CHAT.
JOHN, YOU'RE MUTED.
>> YEAH, LET'S SEE.
WHERE SHOULD WE START?
LET'S SEE.
IS THERE A PRIOR TO MAKE MRIs
ARCHIVED FOR ACCESS TO BIOTECH
COMPANIES?
I'M NOT SURE I UNDERSTAND THAT
QUESTION.
ULTIMATELY TECHNOLOGIES WE'RE
DEVELOPING, THE GOAL HERE IS TO
EVENTUALLY HAVE THESE
TECHNOLOGIES ACCESSIBLE, SO SOME
OF THESE WILL HOPEFULLY LEAD TO
COMMERCIALIZATION AND PART OF
THE STRATEGY IS NOT JUST TO GET
THE HIGHEST FIELD, HIGHEST
RESOLUTION MACHINES OUT THERE,
TO ALSO GET MACHINES OUT THERE
THAT MEET THAT NEED, THINK THAT
ANSWERS THE QUESTION.
NOT SURE.
>> SEEMS LIKE IN THE CHAT
THERE'S A LOT OF ENTHUSIASM
AROUND PUTTING OUT A WHITE
PAPER, SO YOU MAY BE CONTACTED
ABOUT THAT IN THE FUTURE.
>> THAT'S I THINK -- AS AMANDA
SAID, THE MEETING CONTRACTOR
WILL PROVIDE A SUMMARY, A
NON-EDITORIALIZED SUMMARY OF THE
CONTENTS AND DISCUSSION OF THE
MEETING, AND I THINK IF THE
FOLKS HERE WANT TO PUT TOGETHER
A WHITE PAPER, THAT'S GREAT, BUT
THAT'S A WRITING ASSIGNMENT, AN
ORGANIZATIONAL WRITING
ASSIGNMENT FOR YOU FOLKS, BUT
COULD LEAD TO COLLABORATIONS,
NEW COLLABORATIONS AMONG
SOMEBODY WHO ALREADY ARE OR, OR
THOSE NOT COLLABORATING, SO WE
CERTAINLY ENCOURAGE THAT.
OKAY.
I THINK THAT'S PRETTY MUCH WHAT
I'M SEEING IN TERMS OF
QUESTIONS, AMANDA.
>> IN THAT CASE, I GUESS WE CAN
CLOSE THE MEETING.
I JUST WANT TO THANK ALL OF YOU
FOR YOUR PARTICIPATION AND BEING
SO ENGAGED.
FOR ALL OF YOUR PRESENTATIONS
THROUGHOUT THE PAST TWO DAYS.
AND YEAH, I THINK THAT'S IT.
WE CAN ADJOURN THE MEETING.