EVIDENCE FOR ABERRANT SENSORY AND MOTOR LEARNING IN FOCAL by ulf16328

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									1       EVIDENCE FOR ABERRANT SENSORY AND MOTOR LEARNING
2      IN FOCAL DYSTONIA:     IMPLICATIONS FOR LEARNING BASED
3                SENSORIMOTOR TRAINING TO IMPROVE
4                   MOTOR CONTROL AND COGNITION
5                           BY NANCY BYL
6
7               THE MODERATOR:    I WANT TO THANK YOU VERY MUCH
8    FOR BEARING THE TIME FOR THE FIRST LECTURE.      IT'S MY
9    GREAT PLEASURE TO INTRODUCE THE SECOND SPEAKER TODAY.
10   THIS IS DR. NANCY BYL.      SHE'S A PROFESSOR OF PHYSICAL
11   THERAPY, UNIVERSITY OF CALIFORNIA SAN FRANCISCO, AND
12   SHE WILL TALK TO US TODAY ABOUT EVIDENCE FOR ABERRANT
13   SENSORY AND MOTOR LEARNING IN FOCAL DYSTONIA:
14   IMPLICATIONS FOR LEARNING BASED SENSORIMOTOR TRAINING
15   TO IMPROVE MOTOR CONTROL AND COGNITION.      DR. BYL.
16              DR. BYL:   I WILL DESCRIBE THE APPLICATIONS OF
17   BASIC SCIENCE TO LEARNING BASED TRAINING AND HIGHLIGHT
18   MORE SPECIFICALLY SENSORIMOTOR TRAINING AS IT RELATES
19   TO PATIENTS WHO I BELIEVE EXPRESS WHAT IS CALLED AN
20   ABERRANT LEARNING PHENOMENA LEADING TO ABNORMAL MOTOR
21   CONTROL.   I WILL SHARE THE EVIDENCE BEHIND THIS THEORY.
22   I WILL DISCUSS WHAT TREATMENT POTENTIAL EXISTS WHEN
23   APPLYING THIS THEORY TO PATIENTS, AND I ALSO WILL GIVE
24   EXAMPLES OF TRAINING, AND SUMMARIZE THE APPLICATIONS
25   AND THE EFFECTIVENESS OF THIS PARADIGM TO OTHER



                                    1
1    PATIENTS.
2                IT HAS BEEN WELL ACCEPTED THAT THE CENTRAL
3    NERVOUS SYSTEM MAKES ITS GREATEST CHANGES DURING THE
4    GROWING YEARS AS A PART OF NORMAL DEVELOPMENT AND
5    MATURATION.    BUT TODAY WE ALSO KNOW THAT THE NERVOUS
6    SYSTEM CHANGES THROUGHOUT OUR LIFETIME IN RESPONSE TO
7    AGING, INJURY, AND DISEASE.       WHAT IS MOST IMPORTANT IS
8    THAT WE CAN DRIVE CHANGES IN THE CENTRAL NERVOUS SYSTEM
9    WITH LEARNING-BASED TRAINING.
10               OUR POTENTIAL FOR NEURAL ADAPTATION, HOWEVER,
11   VARIES, AND IT VARIES BY OUR GENETICS, OUR BASIC
12   ANATOMY, OUR PHYSIOLOGY, OUR NEURAL TRANSMITTERS AND
13   HORMONES, AS WELL AS OUR PERSONALITY, OUR COMMITMENT,
14   AND OUR MOTIVATION FOR CHANGE.
15               OUR ABILITY TO CHANGE IS ALSO DEPENDENT ON
16   OUR ABILITY TO FACILITATE BETTER SIGNALS, TO BALANCE
17   EXCITATION AND INHIBITION OF OUR NEURAL NETWORKS, AS
18   WELL AS OUR OPPORTUNITY TO TAKE ADVANTAGE OF AND
19   PARTICIPATE IN LEARNING-BASED ACTIVITIES WITHIN OUR
20   ENVIRONMENT.
21               IN THIS CLASSIC DIAGRAM OF PLASTICITY BY
22   MERZENICH AND JENKINS, YOU CAN SEE THAT WE CAN CHANGE
23   NEURAL STRUCTURE BY ATTENDED REPETITIVE PRACTICE.      IN
24   THIS CASE IN A1 AND 2, YOU CAN SEE THE EXPANSION OF THE
25   CORTICAL REPRESENTATION OF THE DIGITS AFTER FOLLOWING A



                                   2
1    SENSORY ATTENDED RETRAINING PROGRAM.    ON THE RIGHT YOU
2    CAN SEE THAT THE NORMAL RECEPTIVE FIELDS ON THE HAND
3    BECOME SMALLER WITH TRAINING, THEY BECOME MORE DENSE
4    AND MORE NUMEROUS, MAKING THE REPRESENTATION MORE
5    SPECIFIC.
6                LEARNING BEGINS WHEN INFORMATION IS
7    TRANSMITTED FROM THE PERIPHERAL NERVOUS SYSTEM THROUGH
8    THE RECEPTORS AND THE PERIPHERAL NERVES TO THE SPINAL
9    CORD.   ADAPTIVE CHANGES ARE SEEN THROUGHOUT THE NERVOUS
10   SYSTEM, EVEN THOUGH MOST OF OUR BASIC SCIENCE STUDIES
11   ON PLASTICITY HAVE FOCUSED ON THE CORTEX.
12   UNFORTUNATELY EVEN THE HEALTHIEST NERVOUS SYSTEM HAS A
13   FINITE LIMIT FOR CHANGE BASED ON ANATOMICAL AND
14   PHYSIOLOGICAL CONSTRAINTS, INCLUDING TIME CONSTANTS,
15   COMPETITION FOR MYELIN, KEEPING TRACK OF FEEDBACK, AND
16   TEMPORAL INTEGRATION.    WHEN THESE LIMITS ARE REACHED,
17   LEARNING MAY GO ASKEW, WHICH WE REFER TO AS NEGATIVE OR
18   ABERRANT LEARNING.
19               LEARNING CAN BE ABERRANT WHEN AN INDIVIDUAL
20   HAS LOW SELF-ESTEEM, FEELS NEGATIVE, IS UNDER STRESS,
21   RESORTS TO NONLEARN OR HABITUAL BEHAVIORS, HAS AN
22   INJURY OR A DISEASE, OR EXCEEDS THE LIMITS OF THESE
23   NEURAL CONSTRAINTS.
24               SOME OF THE ABERRANT LEARNING CONDITIONS
25   INCLUDE BAD HABITS LIKE SMOKING, DISEASE, LIMITATIONS



                                  3
1    IN STRUCTURE, A COMPENSATORY LIMP, FOR EXAMPLE, FROM
2    PAIN OR EXCESSIVE ADAPTATION OF THE NERVOUS SYSTEM
3    FOLLOWING NEAR SIMULTANEOUS, NEAR STEREOTYPICAL
4    REPETITIONS.
5                IN THIS PARTICULAR DIAGRAM YOU CAN SEE THIS
6    IS AN EXAMPLE OF ABERRANT LEARNING, THE CORTICAL
7    SENSORY CHANGES THAT HAVE OCCURRED IN THE DIGITS
8    FOLLOWING EXCESSIVE REPETITIVE STEREOTYPICAL MOVEMENT.
9    THE CORTICAL REPRESENTATION IN THIS PARTICULAR CASE IS
10   REDUCED, BUT IN THIS PICTURE YOU SEE THAT THE RECEPTIVE
11   FIELDS BECOME VERY LARGE AND NOT ONLY OVERLAP ADJACENT
12   DIGITS, BUT ALSO OVERLAP THE DORSAL AND GLABROUS
13   SURFACE OF THE HAND.    THE BRAIN CAN NO LONGER
14   DIFFERENTIATE INDIVIDUAL DIGITS AND CONTROL THEIR
15   MOVEMENT.
16               FOCAL HAND DYSTONIA MAY BE AN EXAMPLE OF
17   EXCESSIVE STEREOTYPICAL NEAR SIMULTANEOUS REPETITIVE
18   MOVEMENTS OF THE HAND PRACTICED OVER LONG PERIODS OF
19   TIME.   IT IS DEFINED AS A DISABLING MOVEMENT DISORDER
20   OF INVOLUNTARY IN RANGE CO-CONTRACTIONS OF THE FLEXORS
21   AND EXTENSORS WHEN PERFORMING A TARGET TASK.      THERE IS
22   EXCESSIVE EXCITATION AND AN ADEQUATE INHIBITION.       FOCAL
23   HAND DYSTONIA MAY ACTUALLY ALSO REPRESENT A LEARNED
24   CONDITION IN GIFTED PERFECTIONISTS WHO PERFORM HIGHLY
25   REPETITIVE WORK AND HAVE AN UNUSUALLY ADAPTIVE PLASTIC



                                  4
1    NERVOUS SYSTEM THAT ALLOWS THEM TO ACHIEVE SUPERIOR
2    RAPID SKILLED MOVEMENTS, AS YOU SEE IN THIS PIANIST AND
3    ALSO IN THIS CARTOONIST.    ALTHOUGH THE INCIDENCE OF
4    OCCUPATIONAL FOCAL DYSTONIA HAS BEEN CONSIDERED LOW, IN
5    RECENT YEARS INCREASED STRESS IN SOCIETY, INCREASED
6    DEMAND FOR COMPUTER USE, INCREASED COMPETITION FOR
7    MUSICAL PERFORMANCE, AND INCREASED AWARENESS, THERE ARE
8    MORE CASES OF FOCAL DYSTONIA BEING DIAGNOSED.
9                FOR EXAMPLE, 50 TO 60 PERCENT OF MUSICIANS
10   HAVE PROBLEMS WITH REPETITIVE STRAIN INJURY.
11   APPROXIMATELY 10 PERCENT OF THEM MAY DEVELOP FOCAL HAND
12   DYSTONIA.
13               SCIENTISTS HAVE IDENTIFIED MANY DIFFERENT
14   GENES TO EXPLAIN THE ORIGIN OF GENERALIZED DYSTONIA;
15   HOWEVER, THE CONTROVERSY ON THE ETIOLOGY OF FOCAL HAND
16   DYSTONIA CONTINUES TO THIS DAY.    WHILE MOST AGREE THERE
17   IS A LACK OF INHIBITION, THERE IS SOMETHING UNIQUE
18   ABOUT THE FOCAL OCCUPATIONALLY RELATED DYSTONIAS.    IT
19   IS JUST VERY DIFFICULT TO EXPLAIN THE DISORDER IN TERMS
20   OF NEURAL STRUCTURE WHEN THE ABNORMAL MOVEMENTS ONLY
21   OCCUR WHEN PERFORMING A TARGET TASK OR WHEN MOVING A
22   PARTICULAR BODY PART.
23               WHAT IS INTERESTING IS THAT ALL THE
24   INDIVIDUALS WHO HAVE THE GENE FOR DYSTONIA DO NOT
25   NECESSARILY DEVELOP A CLINICAL DYSTONIA.    FOCAL



                                  5
1    DYSTONIA IS UNDOUBTEDLY MULTIFACTORIAL.   THERE IS
2    PROBABLY AN ACCUMULATION AND AN INTERACTION OF MANY
3    RISK FACTORS THAT LEAD TO THE CLINICAL PRESENTATION OF
4    THE PROBLEM, INCLUDING GENETICS, NEUROPHYSIOLOGY,
5    SENSATION POTENTIAL FOR PLASTICITY, ENVIRONMENT,
6    BEHAVIORAL CHARACTERISTICS AND PERSONALITY.
7             CLEARLY THOSE AT RISK ARE INDIVIDUALS WITH A
8    TYPE A PERSONALITY WHO ARE CLEARLY PERFECTIONISTS AND
9    ARE DRIVEN TO WORK LONG HOURS UNDER STRESS OFTEN USING
10   UNSAFE BIOMECHANICS.   THEY MAY HAVE ALSO HAD A PREVIOUS
11   INJURY, MAYBE SOME PHYSICAL RESTRICTIONS, AND MAYBE
12   HAVE EXCESSIVE NEUROPLASTICITY.
13            IN PATIENTS WITH FOCAL DYSTONIA, THERE ARE
14   SEVERAL SENSORY DIFFERENCES THAT CAN BE NOTED.   FIRST
15   OF ALL, THEY ALL HAVE A SENSORY TRICK, A PLACE THAT
16   THEY CAN TOUCH OR PROVIDE A CUTANEOUS INPUT THAT
17   DECREASES THE SEVERITY OF THE DYSTONIC POSTURING.    ALSO
18   WHEN BOTULINUM TOXIN IS INJECTED TO STOP THE MUSCLE
19   CONTRACTIONS, THE FIRING PATTERN CHANGES AS IF THE
20   PROPRIACEPTIVE FEEDBACK ALLOWS OTHER MUSCLES TO COME
21   INTO ACTION.
22            LIDOCAINE CAN DECREASE SENSATION OF
23   PROPRIOCEPTION AND TEMPORARILY REDUCE THE CRAMPING.
24   INTERESTINGLY, MICROCURRENTS, WHICH IS NOT EVEN FELT OR
25   PERCEIVED BY NORMAL HEALTHY INDIVIDUALS, WILL ACTUALLY



                                 6
1    STIMULATE THE FIRING OF THE MUSCLE AFFERENTS IN
2    PATIENTS WITH DYSTONIA.    IN ADDITION, TRANSMAGNETIC
3    STIMULATION, WHICH IS ALSO INHIBITORY IN NORMAL HEALTHY
4    PATIENTS, WILL, IN FACT, BE EXCITORY IN PATIENTS WITH
5    DYSTONIA.
6                THERE CLEARLY SEEMS TO BE AN IMBALANCE OF
7    INHIBITION AND EXCITATION IN THE PRESYNAPTIC FIRING IN
8    THE SENSORY CORTEX BOTH IN 3 A AND 3 B, AND INCREASED
9    THICKNESS OF THE GRAY MATTER IN 3 B HAS BEEN REPORTED.
10   ALTHOUGH OUR ORIGINAL STUDIES FOCUSED ON SENSORY
11   DEGRADATION, IN ESTABLISHED DYSTONIA, ABNORMAL
12   TOPOGRAPHY OF THE MAPS OF OTHER AREAS OF THE CORTEX
13   HAVE ALSO BEEN REPORTED.    SPECIFICALLY IN THE THALAMUS,
14   THE BASAL GANGLIA, AS WELL AS THE SENSORIMOTOR AND
15   MOTOR CORTICES.
16               CLINICALLY PATIENTS WITH FOCAL HAND DYSTONIA
17   HAVE ABNORMAL RESPONSES TO SENSORY EVOKED STIMULI AND
18   DEMONSTRATE DECREASED ACCURACY IN CUTANEOUS SENSATIONS,
19   HAPTIC EXPLORATION, AND SPATIAL ORIENTATION.
20               SO IT IS OUR HYPOTHESIS THAT EXCESSIVE,
21   REPETITIVE, STEREOTYPICAL, NEAR SIMULTANEOUS
22   STIMULATION TO THE DIGITS CAN DEGRADE THE CORTICAL HAND
23   REPRESENTATION, AND THIS WILL INTERFERE WITH VOLUNTARY
24   MOTOR CONTROL.
25               IN TRYING TO PROVE THIS HYPOTHESIS, SEVERAL



                                  7
1    ANIMAL MODELS HAVE BEEN DESIGNED.       THESE HAVE BEEN
2    DESIGNED BOTH WITH RATS AS WELL AS WITH PRIMATES.
3    THESE TWO MODELS HAVE BEEN USED TO STUDY THE ETIOLOGY
4    OF REPETITIVE STRAIN INJURY AND FOCAL HAND DYSTONIA.
5    I'VE BEEN INVOLVED IN THE PRIMATE MODEL, AND WE ALSO
6    HAVE SOME VERY GOOD MODELS FOR STUDYING NEUROPLASTICITY
7    IN HUMAN SUBJECTS.
8                MARY BARBE AND ANN BARR DEVELOPED A RAT MODEL
9    OF REPETITIVE STRAIN INJURY, TRAINING THEIR RATS 30
10   MINUTES TWICE A DAY FOR OVER SIX WEEKS TO REALLY REPORT
11   THE CONSEQUENCES OF REPETITIVE OVERUSE.       THESE
12   RESEARCHERS REPORT AN INTERESTING SEQUENCE OF EVENTS
13   STARTING WITH LOCAL INFLAMMATION ON THE TRAINED SIDE,
14   WHICH THEN BEGINS TO SPREAD TO THE UNTRAINED SIDE, AND
15   THEN CHANGES ARE MEASURED IN THE SPINAL CORD.
16   ULTIMATELY SOME OF THE RATS LOSE MOTOR CONTROL AND CAN
17   NO LONGER PERFORM THE TASK, AND THEN THESE CHANGES ARE
18   ALSO NOTED IN THE SENSORY AND MOTOR CORTEX WITH
19   ABNORMAL TOPOGRAPHY.
20               WE DEVELOPED TWO PRIMATE MODELS TO STUDY HAND
21   DYSTONIA.    ONE INVOLVED RAPID OPENING AND CLOSING OF
22   THE HAND AND THE SECOND TOUCHING TWO SEPARATE POINTS
23   QUICKLY AND SIMULTANEOUSLY.       AND YOU SEE THOSE ON THE
24   RIGHT AND THE LEFT OF THE SCREEN.       WE DOCUMENT AFTER
25   TRAINING AT LEAST TWO-THIRDS OF THESE PRIMATES WHO



                                   8
1    DEVELOPED PROBLEMS IN MOTOR CONTROL.    WE DOCUMENTED
2    WHAT WE CALLED ABERRANT LEARNING.   THERE WAS A LOSS OF
3    THE PRECISE REPRESENTATIONAL SPECIFICITY OF THE TRAINED
4    SIDE.   THERE WAS A REDUCTION IN THE AREA OF THE
5    CORTICAL REPRESENTATION, THERE WERE LARGE RECEPTIVE
6    FIELDS OVERLAPPING ADJACENT DIGITS AND ACROSS SURFACES.
7    WE ALSO NOTICED A MILD LOSS OF DIFFERENTIATION OF THE
8    DIGITS ON THE UNTRAINED SIDE.   WHAT WAS CONSISTENT ON
9    BOTH WAS THE ENLARGEMENT OF THESE CUTANEOUS RECEPTIVE
10   FIELDS THAT SERIOUSLY OVERLAP THE ADJACENT DIGITS AND
11   THE GLABROUS AND THE DORSAL SURFACES.   ALTHOUGH THESE
12   PRIMATES LOST THE ABILITY TO CONTINUE TO PERFORM THE
13   TARGET TASK, ALL OTHER HAND MOVEMENTS WERE ENTIRELY
14   NORMAL.
15             IN ANIMALS WITH DYSTONIA, THE NEURONAL
16   REPRESENTATION OF A SINGLE DIGIT PERSISTED ACROSS LARGE
17   CORTICAL DISTANCES, UP TO 1600 MICRONS; WHEREAS, IN A
18   NORMAL NONTRAINED PRIMATE, THE NEURONAL REPRESENTATION
19   OF A DIGIT CHANGES APPROXIMATELY EVERY HUNDRED MICRONS.
20   AND YOU CAN SEE THAT IN BOTH OF THESE PLOTS.
21             IN ONE ANIMAL WE WERE ABLE TO IMPLANT AN
22   ELECTRODE OVER THE DIGITS D 1 AND D 2 BEFORE WE BEGAN
23   THE TRAINING.   WE WERE CLEARLY LOCATED OVER THE AREAS
24   OF DIGIT 1 AND DIGIT 2.   WITH THE ONSET OF THE
25   DYSTONIA, WE NOTICED THAT THE SIZE OF RECEPTIVE FIELDS



                                 9
1    INCREASED PROPORTIONAL TO THE TRAINING TIME, WHICH YOU
2    CAN SEE ON THE LEFT.   THE OTHER INTERESTING THING WAS
3    AS THE DYSTONIA PROGRESSED, THE AREA OF THE
4    REPRESENTATION OF THE DIGITS 1 AND 2 WHICH HAD BEEN
5    CAREFULLY PLOTTED WITH THE ELECTRODE WERE ESSENTIALLY
6    REPLACED WITH THE EXPANSION OF THE WHISKER INTO THE
7    AREA OF THE REPRESENTATION OF DIGITS.     SO THE ELECTRODE
8    WAS NO LONGER OVER THE AREA OF D 1 AND D 2 AS THAT AREA
9    WAS BECOMING SMALLER IN SIZE AND THE ADJACENT AREA
10   EXPANDING IN SIZE.
11            IN ONE CLINICAL STUDY WE ALSO REPORTED
12   DECREASED SENSORY DISCRIMINATION IN PATIENTS WITH HAND
13   DYSTONIA AND A SIMILAR LOSS OF DIGITAL DIFFERENTIATION
14   AS MEASURED BY MAGNETIC RESONANCE IMAGING; IN OTHER
15   WORDS, LOOKING AT THE SENSORY AND MOTOR EVOKED
16   RESPONSES.
17            HERE IN THIS SLIDE YOU CAN SEE WHAT A NORMAL
18   EVOKED RESPONSE WOULD BE FOR THE MOTOR CORTEX, THE
19   MOTOR EVOKED FIELD, THE SENSORIMOTOR EVOKED FIELD, AND
20   THE SENSORY EVOKED FIELD.    AND YOU CAN SEE THAT THERE
21   IS A NICE CLEAR ORGANIZATION THAT IS CONSISTENT ACROSS
22   SENSORY AND MOTOR STIMULI.
23            IN THE PATIENTS WITH DYSTONIA, WE FOUND A
24   DISTINCTION BETWEEN THOSE WHO ARE SEVERE DYSTONIA AND
25   THOSE WHO ARE MILD DYSTONIA.      THE AMPLITUDE WAS



                                  10
1    SIGNIFICANTLY HIGHER FOR PATIENTS WITH SEVERE DYSTONIA
2    ON THE AFFECTED AND UNAFFECTED SIDES; BUT FOR THOSE
3    WITH MILD DYSTONIA, THE AMPLITUDE WAS REDUCED COMPARED
4    TO NORMALS.    ON THE SENSORY EVOKED POTENTIALS, THE
5    AMPLITUDE WAS, AGAIN, SIGNIFICANTLY LOWER FOR PATIENTS
6    WITH MILD DYSTONIA COMPARED TO CONTROLS AND
7    SIGNIFICANTLY HIGHER FOR THOSE WITH SEVERE DYSTONIA.
8             AND IN THESE REPRESENTATIONS YOU CAN SEE THAT
9    THERE IS A REDUCTION IN THE AMPLITUDE IN PATIENTS WITH
10   MILD DYSTONIA BOTH FOR THE MOTOR EVOKED FIELDS, THE
11   SENSORIMOTOR EVOKED FIELDS, AND THE SENSORY EVOKED
12   RESPONSES.    YOU ALSO NOTICE IN THE SEVERE PATIENTS WITH
13   SEVERE DYSTONIA, THE AMPLITUDE IS UNUSUALLY LARGE
14   COMPARED TO CONTROLS.
15            IN ADDITION, FOLLOWING THE STIMULATION, THERE
16   WAS A SPREAD OF ACTIVATION OF STIMULI INDUCED ACROSS A
17   LARGER AREA ON BOTH THE AFFECTED AND UNAFFECTED SIDE,
18   AND THE CORTICAL REPRESENTATION OR ACTIVATION WAS ALSO
19   LARGER COMPARED TO CONTROLS.
20            THE ARGUMENT TODAY, HOWEVER, IS IN THE
21   PATIENTS WITH DYSTONIA VERSUS THE ANIMALS WHERE WE
22   INDUCE THE DYSTONIA, ARE THE CHANGES IN THE CORTEX
23   REALLY A CAUSE OR EFFECT OF THE MOTOR MOVEMENT
24   DYSFUNCTION?    IN OUR ANIMAL STUDIES WE FEEL CONFIDENT
25   THAT THE CORTICAL CHANGES ARE A CONSEQUENCE OF



                                 11
1    TRAINING, AND THAT THEY ACTUALLY CHANGE AND SPREAD WITH
2    INCREASED SEVERITY AND DURATION OF DYSFUNCTION.    ON THE
3    OTHER HAND, WE DON'T MAP AND WE DON'T TEST PATIENTS WHO
4    DON'T HAVE DYSTONIA PRIOR TO THE DEVELOPMENT OF THESE
5    ABNORMAL SOMATOSENSORY CHANGES, AND WE BELIEVE THE
6    BILATERAL REPRESENTATION AND CHANGES PROBABLY REPRESENT
7    AN INTERACTION OF GENETICS OR RISKS FOR DYSTONIA AS
8    WELL AS REPETITIVE PRACTICE.
9                WHAT IS FASCINATING ABOUT THIS DISORDER OF
10   FOCAL HAND DYSTONIA IS THAT THERE IS NO SPONTANEOUS
11   RECOVERY.    IF A PATIENT WITH FOCAL DYSTONIA SIMPLY
12   STOPS PERFORMING THE TARGET TASK, THE DYSTONIA DOES NOT
13   DISAPPEAR.    I'VE SEEN A PATIENT WHO IS A PIANIST WHO 20
14   YEARS LATER SAT DOWN AT THE PIANO, HAD NOT PLAYED THE
15   PIANO FOR 20 YEARS, THE DYSTONIA WAS STILL PRESENT.
16   THE TASK-SPECIFIC DYSTONIA HAS ONLY ONE OPTION, AND
17   THAT IS TO RETRAIN THE BRAIN.
18               PATIENTS WITH GENERALIZED DYSTONIA ARE VERY
19   DIFFICULT TO TREAT, AND TODAY THEY ACTUALLY IMPLANT
20   STIMULATORS IN THE GLOBUS PALLIDUS, AND COMBINING THE
21   STIMULATION WITH TRAINING, PARTICULARLY LEARNING-BASED
22   TRAINING, THESE PATIENTS CAN LIVE A FUNCTIONAL LIFE.
23               NEUROLOGISTS TELL THE PATIENTS THAT THERE
24   REALLY IS NO CURE FOR FOCAL HAND DYSTONIA, BUT WITH
25   APPROPRIATE INJECTIONS OF BOTULINUM TOXIN TO INTERFERE



                                 12
1    WITH THE TRANSMISSION OF THE IMPULSE TO THE MUSCLE, AND
2    WITH TRAINING, PARTICULARLY LEARNING-BASED TRAINING,
3    THE SIGNS AND SYMPTOMS OF DYSTONIA CAN BE MANAGED.
4             FOCAL DYSTONIA IS AN INVOLUNTARY -- IF FOCAL
5    HAND DYSTONIA IS AN INVOLUNTARY DISORDER OF MOVEMENT
6    CONSEQUENT TO ABERRANT LEARNING, THEN MOTIVATED
7    INDIVIDUALS SHOULD BE ABLE TO RESTORE NORMAL MOTOR
8    SKILLS BY RETRAINING THE BRAIN, PARTICULARLY FOLLOWING
9    THE PRINCIPLES OF NEUROPLASTICITY AND INTEGRATING
10   SENSORY, SENSORIMOTOR, AND MOTOR PARADIGMS.
11            WHAT IS IMPORTANT ABOUT LEARNING-BASED
12   TRAINING IS THAT YOU HAVE TO SET A STRONG FOUNDATION
13   FOR LEARNING TO TAKE PLACE.    THAT MEANS THAT THE
14   FOUNDATION OF LEARNING MUST BE BASED ON FITNESS AND
15   WELLNESS, INCLUDING ATTENTION TO PHYSICAL CONDITIONING,
16   FLEXIBILITY, STRENGTHEN ENDURANCE, AS WELL AS GOOD
17   BIOMECHANICS, APPROPRIATE ADJUSTMENTS AND MANAGEMENT OF
18   SOCIAL CHALLENGES, PSYCHOLOGICAL DIFFERENCES,
19   NUTRITIONAL STATUS, AND PARTICULARLY STRESS MANAGEMENT.
20            IT IS ALSO IMPORTANT FOR PATIENTS TO BECOME
21   AWARE OF HOW TO USE THEIR LIMBS IN A STRESS FREE WAY
22   THAT USES NORMAL MOVEMENTS, GOOD BIOMECHANICS, AND GOOD
23   POSTURE, EMPHASIZING THE USE OF THE INTRINSIC MUSCLES
24   OF THE HANDS WITH PROXIMAL CONTROL FROM THE SHOULDER
25   AND STRONG ATTENTION TO SENSORY INFORMATION TO GUIDE



                               13
1    THE MOVEMENT RATHER THAN OVERPOWER THE MOVEMENT WITH
2    HIGH LEVELS OF REPETITION AND UNNECESSARY ALTERNATING
3    MOVEMENTS.
4             APPLYING THE PRINCIPLES OF BASIC SCIENCE TO
5    CLINICAL LEARNING-BASED TRAINING, IT APPEARS THAT THE
6    BEHAVIORS THAT ARE TRAINED MUST REQUIRE ATTENTION,
7    REPETITION, POSITIVE FEEDBACK, NONSTEREOTYPICAL
8    MOVEMENTS, STIMULI DELIVERED SEPARATELY IN TIME,
9    PROGRESSION OF DIFFICULTY OF TASK PERFORMANCE, AND
10   PRACTICE SPACED OVER TIME.
11            THE RESEARCH IN NEUROSCIENCE ALSO SUPPORTS
12   THAT OTHER THINGS CAN REINFORCE LEARNING.      FIRST OF
13   ALL, LEARNING SHOULD BE FUN.      AND WHEN IT ISN'T FUN,
14   PEOPLE WON'T DO IT.   BEFORE YOU BEGIN LEARNING-BASED
15   TRAINING, YOU MUST GET CONSENSUS OF THE PATIENT, THE
16   FAMILY, AND THE PHYSICIAN ABOUT THE GOALS OF TREATMENT.
17   IT IS ALSO ESSENTIAL TO EDUCATE THE PATIENT AND THE
18   FAMILY ABOUT WHAT WE KNOW TODAY ABOUT NEUROPLASTICITY.
19   IT IS ABSOLUTELY ESSENTIAL TO STOP THE ABNORMAL
20   MOVEMENTS BECAUSE IF THEY CONTINUE TO BE REPEATED, THEN
21   THE ABERRANT LEARNING CONTINUES.      WE MUST REINFORCE
22   QUALITY NORMAL MOVEMENTS, IMAGE SUCCESS, BEING
23   CONFIDENT, HAVING HIGH SELF-ESTEEM, AND BEING ABLE TO
24   IMAGE THE POSSIBILITY OF RESTORING NORMAL MOVEMENT IS
25   CRITICAL TO SUCCESSFUL LEARNING.      COMPLYING WITH THE



                                  14
1    PRACTICE NECESSARY, THE SCHEDULE, AND PERSEVERING WITH
2    TRAINING OVER TIME IS ESSENTIAL.
3               WE ALSO KNOW WE CAN REINFORCE LEARNING BASED
4    ON RESEARCH, THAT IF WE TRAIN BOTH HEMISPHERES, WE KNOW
5    THAT THE CONTRALATERAL HEMISPHERE IS EXCITORY TO THE
6    INVOLVED LIMB WHERE THE PATHWAYS ON THE IPSILATERAL
7    SIDE TEND TO BE INHIBITORY.      LEARNING CAN ALSO BE
8    ENHANCED BY ADDING AN ELEMENT OF SURPRISE OR EVEN A
9    PRELIMINARY PRETRAINING EXPOSURE TO WHAT IS EXPECTED AS
10   IN A SUBLIMINAL STIMULUS.   WE ALSO KNOW THAT TRAINING
11   MUST BE PROGRESSED IN DIFFICULTY, BUT THE AMOUNT OF
12   PROGRESSION MUST BE CAREFULLY STAGED SO NOT TO EXCEED
13   THE CAPACITY OF THE NERVOUS SYSTEM FOR CHANGE.     IT'S
14   ALSO IMPORTANT TO INCREASE THE FUNCTIONAL TOPOGRAPHY OF
15   THE HAND AND NOT JUST THE ANATOMICAL SENSORY AND MOTOR
16   REPRESENTATION.   AND IT HAS BEEN SHOWN THAT YOU CAN
17   MAGNIFY THE FUNCTIONAL TOPOGRAPHY BY PERFORMING THE
18   SAME TASK WITH AN ALTERNATIVE LIMB, SUCH AS LEARNING TO
19   WRITE WITH YOUR FOOT IF YOU HAVE A DYSTONIA FOR
20   WRITING.
21              HERE IS AN EXAMPLE OF USING DIFFERENT
22   POSITIONS TO PLACE PEOPLE IN TO PERFORM A TARGET TASK.
23   IN ORDER TO REALLY INHIBIT THE DYSTONIA, YOU WANT TO
24   PUT PEOPLE IN A POSITION WHERE THEY CAN FUNCTION
25   WITHOUT THE DYSTONIC MOVEMENTS.     THIS HAPPENS TO BE A



                                 15
1    MOVIE, AND I HAVE NO WAY OF ACTIVATING IT FROM THE
2    PLATFORM HERE.
3                OKAY.   THE PRINCIPLES OF LEARNING-BASED
4    TRAINING ARE IMPORTANT IF I APPLY THEM SPECIFICALLY TO
5    SENSORIMOTOR TRAINING.     SO, IN GENERAL, YOU FOLLOW ALL
6    THE GUIDELINES I'VE ALREADY MENTIONED; BUT WHEN YOU
7    MOVE TOWARD SENSORIMOTOR RETRAINING, THIS REQUIRES ONE
8    TO THINK ABOUT SENSORY, THE INPUTS AND THE FEEDBACK,
9    RATHER THAN THINKING ABOUT MOTOR.     THE LEARNING WOULD
10   TAKE CARE IN PARADIGMS WHICH WERE TAKING A LOT OF
11   INFORMATION FROM CUTANEOUS AND JOINT PROPRIACEPTIVE
12   FEEDBACK, MINIMIZING VISUAL CUES.     USING A VARIETY OF
13   SENSORY MODALITIES TENDS TO HELP GENERALIZE LEARNING,
14   INCLUDING ACTIVE AND PASSIVE STIMULI SEEMS TO BE
15   CRITICAL.    INDIVIDUALS MUST BE FORCED TO MAKE A
16   DECISION ABOUT A PARTICULAR SENSORY OR SENSORIMOTOR
17   EXPERIENCE, AND IT MUST BE IMPORTANT TO EMPHASIZE
18   INTEGRATING SENSORY PROCESSING INTO ALL FUNCTIONAL
19   ACTIVITIES.
20               I BELIEVE THERE ARE FIVE PHASES AND PROBABLY
21   MORE TO BEGIN A PROGRESSIVE LEARNING-BASED TRAINING
22   PROGRAM IN SENSORIMOTOR LEARNING.     THE FIRST PHASE IS
23   JUST TO BE ABLE TO IMAGINE THAT YOUR HAND IS NORMAL.
24   THE SECOND PHASE IS TO IMPROVE SENSORY DISCRIMINATION.
25   THE THIRD PHASE IS TO PERFORM AND CONCENTRATE ON



                                  16
1    DEVELOPING GRADED CONTROLLED MOVEMENTS.    THE FOURTH
2    PHASE IS TO WORK ON SENSORY MOTOR SKILLS, AND THE LAST
3    PHASE IS TO RESTORE FINE MOTOR CONTROL WITHOUT TREMORS
4    OR ABNORMAL MOVEMENT FIRST AT THE NONTARGET AND THEN
5    FINALLY AT THE TARGET TASK.
6                THE GOAL OF BEING ABLE TO IMAGINE USING YOUR
7    HANDS NORMALLY IS THE FIRST PLACE TO START.    THERE ARE
8    A SERIES OF PICTURES THAT YOU COULD LOOK AT OF THE
9    HANDS AND THE GOALS TO LOOK AT THOSE PICTURES WITHOUT
10   FEELING THE ABNORMAL MOVEMENT OR IN SOME CASES FEELING
11   ANY PAIN.    YOU SHOULD BE ABLE TO LOOK AT THOSE PICTURES
12   AND DECIDE IF IT'S A RIGHT OR LEFT HAND, AGAIN, WITHOUT
13   ANY ABNORMAL MOVEMENT.    YOU SHOULD BE ABLE TO VISUALIZE
14   THE POSITION OF THE HAND.    THEN USING A MIRROR, YOU
15   WOULD BEGIN TO IMITATE THOSE POSITIONS, AND, FINALLY,
16   YOU WOULD COPY THOSE POSITIONS.    YOU COULD ALSO WATCH A
17   VIDEO OF SOMEONE ELSE PERFORMING THE TASK AND IMAGINE
18   IT'S YOUR HAND.
19               WE HAVE A SERIES OF NEAR 360 DIFFERENT
20   PICTURES FOR PATIENTS TO LOOK AT AND MAKE THE JUDGMENT
21   OF RIGHT OR LEFT AND BEGIN TO IMAGINE GETTING INTO
22   THESE POSITIONS, AND THIS IS JUST AN EXAMPLE.
23               THE GOAL OF THE SECOND PHASE OF TRAINING IN
24   SENSORY DISCRIMINATION IS TO REDIFFERENTIATE THE TOP
25   GRAPHICAL REPRESENTATION BY IMPROVING THE PRECISION AND



                                 17
1    THE ACCURACY OF SENSORY DISCRIMINATION, PARTICULARLY
2    USING CUTANEOUS AND HAPTIC TASKS TO TARGET THE
3    REDIFFERENTIATION.
4             THIS IS AN EXAMPLE OF A SENSORY TASK THAT IS
5    CONCENTRATING ON CUTANEOUS RECEPTORS WHERE SOMEONE IS
6    DRAWING DIFFERENT TYPES OF DESIGNS AND FIGURES IN WHICH
7    THE PATIENT HAS TO REPRODUCE EITHER BY DRAWING THEM ON
8    THEIR OWN HAND IN THE SAME PLACE IN THE SAME SIZE OR
9    REPRODUCING THEM ON A PIECE OF PAPER.   THE DESIGNS GET
10   HARDER, AND THE SIZE OF THE STIMULUS GETS SMALLER.
11            HERE IS AN EXAMPLE OF HAPTIC TRAINING OR
12   STEREOGNOSIS.   THAT IS FEELING AND MATCHING OBJECTS,
13   LEARNING TO READ BRAILLE, MATCHING BUTTONS THAT ARE THE
14   SAME, AND BEGINNING TO SORT BY SIZE AND BY SURFACE
15   COARSENESS ON DIFFERENT OBJECTS.
16            IT'S ALSO NECESSARY TO MOVE TO THIS PHASE III
17   AS SOON AS POSSIBLE IN ORDER TO LEARN TO LIGHTLY HANDLE
18   AND MOVE OBJECTS WHILE KEEPING THE HAND IN A NORMAL
19   FUNCTIONAL POSITION.   AND HERE YOU CAN SEE SOMEONE HAS
20   THE TREADMILL BELT WORKING UNDERNEATH THEIR HAND WHILE
21   THEY'RE TRYING TO DO THE TARGET TASK.   SOMEONE TAKING A
22   PLASTIC FAN AND TOUCHING THE PLASTIC BLADES WITHOUT
23   STOPPING THE FAN OR PLACING YOUR HAND ON A SCALE AND
24   MAINTAINING THAT WEIGHT FOR CERTAIN PERIOD OF TIME IN
25   ORDER TO CONTROL AND NOT BE TOO HARD OR TOO SOFT ON THE



                                18
1    SCALE.
2             PHASE IV IS THE SENSORIMOTOR SKILL
3    RETRAINING, AND THE GOAL IS TO IMPROVE THE REGULATION,
4    THE QUANTITY, THE QUALITY, AND THE ACCURACY OF
5    SENSORIMOTOR SKILLS TO REPRODUCE THE NORMAL MOVEMENTS.
6    THE GOAL IS TO LET THE SENSATION OF THE OBJECT CONTROL
7    AND GUIDE THE HAND.   ONE OF THE GREATEST THINGS TO DO
8    IN SENSORIMOTOR TRAINING IS TO PLAY GAMES THAT ARE
9    BASED ALL ON SENSORY INPUTS AND SENSORY FEEDBACK.    THIS
10   WOULD INCLUDE PLAYING GAMES WITH YOUR EYES CLOSED WITH
11   OTHER PEOPLE SO YOU STIMULATE AN ELEMENT OF
12   COMPETITION.   YOU CAN PLAY BLACKJACK AND YOU CAN ALSO
13   PLAY YATZE AND SCRABBLE WITH BRAILLE CARDS, AND THAT IS
14   EVEN MORE CHALLENGING.
15            AS WE PROGRESS IN SOME OF THE SENSORIMOTOR
16   TASKS, THIS IS USING THE BRAILLE CARDS, YOU CAN USE
17   MIRRORS TO GIVE POSITIVE FEEDBACK BY PUTTING THE
18   UNAFFECTED SIDE IN FRONT OF THE MIRROR AND THE AFFECTED
19   SIDE BEHIND THE MIRROR.   THEN YOUR AFFECTED SIDE
20   ACTUALLY LOOKS LIKE THE MIRROR IMAGE, AND NOW YOU GET
21   POSITIVE FEEDBACK THAT YOUR HAND IS MOVING NORMALLY.
22   WITH THIS MIRROR IMAGE YOU CAN PRACTICE BOTH SENSORY
23   TASKS AS WELL AS MOTOR TASKS.
24            HERE IS ANOTHER EXAMPLE OF SENSORIMOTOR SKILL
25   TRAINING WHERE THERE ARE BEANS AND THERE ARE QUARTERS



                                19
1    AND NICKELS AND DIMES IN THE BUCKET, AND THE PATIENT
2    HAS TO GO IN AND FIND SAY TEN QUARTERS AND NOTE THE
3    SPEED OF WHICH IT TAKES THEM TO FIND THE QUARTERS AND
4    TRY TO CONTINUE TO IMPROVE THAT SPEED.   YOU CAN ALSO
5    FEEL LETTERS AND SPELL WORDS.   YOU CAN ASSEMBLE PUZZLES
6    WITH YOUR EYES CLOSED AND MATCH THE PUZZLE WITH THE
7    PIECES OF PUZZLE BEHIND A BARRIER SO YOU DON'T SEE THE
8    PIECES, BUT YOU FEEL THE PIECES.
9             IN THE LAST PHASE THE FINE MOTOR CONTROL
10   PHASE, THE GOAL IS TO IMPROVE FINE MOTOR CONTROL ON THE
11   TARGET TASK.   HOWEVER, FOR THE MOST PART YOU MUST START
12   ON A NONTARGET TASK, PARTICULARLY IN DIFFERENT BODY
13   POSITIONS, IN DIFFERENT CHALLENGING ENVIRONMENTS WITH
14   DIFFERENT SENSORY INTERFACES.   THE GOAL IS NOT TO
15   INDUCE THE ABNORMAL MOVEMENT.   AND HERE I SHOW A
16   PICTURE OF A TREADMILL WHERE WE ACTUALLY OFTEN BEGIN TO
17   HAVE PEOPLE WORK ON WRITING RETRAINING WHILE THEY'RE
18   WALKING ON THE TREADMILL WITH THEIR EYES CLOSED.
19            WHEN YOU TRAIN ON THE TARGET TASK, IT'S
20   IMPORTANT TO USE A LOT OF SENSORY FEEDBACK OR GET THEM
21   IN THESE UNUSUAL POSTURES, MAYBE EVEN PROVIDE TEMPORARY
22   STABILIZATION WITH A SPLINT AS NEEDED TO PREVENT
23   ABNORMAL MOVEMENTS.   THE CHANGE IN PARADIGM OF MOVING
24   FROM PROXIMAL CONTROL VERSUS DISTAL MOVEMENTS IS A HARD
25   TASK TO CHANGE, BUT YOU CAN DO THIS WHEN THE BACKGROUND



                                20
1    IS ALTERED.
2                HERE IS A CASE OF A PATIENT WITH A FOCAL HAND
3    DYSTONIA ON A KEYBOARD.    HE HAS A KEYBOARDER'S
4    DYSTONIA.    AND NOW HE'S WORKING ON WHAT HE WOULD
5    CONSIDER A NONTARGET TASK, AND THAT IS SIMULATING A
6    STEERING WHEEL IN A CAR.    AND HE IS AT THIS POINT
7    WALKING ON A TREADMILL WITH HIS EYES CLOSED TRYING TO
8    TURN THIS SIMULATED STEERING WHEEL WITH KEEPING HIS
9    HAND IN ABSOLUTELY NORMAL POSITION.
10               HERE'S ANOTHER EXAMPLE OF WORKING ON FINE
11   MOTOR CONTROL IN AN UNUSUAL ENVIRONMENT.    AND IN THIS
12   CASE IT IS USING SHAVING CREAM SO THAT THEY ARE
13   LEARNING TO WRITE.    THEY WRITE MESSAGES THAT I HAVE
14   WRITTEN ON THE PAPER IN FRONT OF THEM.    THEY THEN GET
15   THEIR WRITING SMALLER AND SMALLER, BUT THEY'RE GETTING
16   A LOT OF SENSORY FEEDBACK BECAUSE OF THE SHAVING CREAM.
17               HERE'S AN EXAMPLE OF FINE MOTOR PRACTICE
18   TRYING TO RESHAPE THE USE OF THE HAND.    IN THIS
19   PARTICULAR CASE WE'RE TRYING TO MAKE BOTH THE DYSTONIC
20   HAND AND THE UNAFFECTED HAND LOOK ALIKE, BOTH LOOK
21   ALIKE IN A FUNCTIONAL TASK AS WELL AS LOOK ALIKE WHEN
22   THE HAND IS SIMPLY OPEN AND THE PALM IS UP.    AND YOU
23   WILL NOTICE HE HAS A SMALL SPLINT ON THE METACARPAL
24   PHALANGEAL JOINT OF THE FIFTH DIGIT, TRYING TO PREVENT
25   THE EXPRESSION OF ANY ABNORMAL DYSTONIC MOVEMENTS.



                                 21
1             HERE IS A CASE OF USING BIOFEEDBACK TO TRY TO
2    IMPROVE KEYBOARDING CONTROL AND STOP ALL OF THE
3    ABNORMAL MOVEMENT ON THE KEYBOARD.    AND THE FEEDBACK IS
4    ACTUALLY AN AUDITORY FEEDBACK, AND THE ELECTRODE IS
5    PLACED EITHER ON THE MUSCLES THAT YOU WANT TO EXCITE OR
6    THE MUSCLES THAT YOU WANT TO QUIET.    THE BALL IN THE
7    HAND, THE HALF-SHAPE BALL, IS TO KEEP THE HAND SHAPED
8    IN A FUNCTIONAL POSITION.   THE LUMBAR ROLL IS TO
9    IMPROVE THE POSTURE.   AND THESE TRAINING DEVICES ARE
10   ONLY A WAY TO MOVE PEOPLE FORWARD ON THE TARGET TASK.
11   IT'S ALSO IMPORTANT TO WORK ON FINE MOTOR SKILL
12   DEVELOPMENT AT TARGET TASKS WITH THE ALTERNATIVE TYPES
13   OF DEVICES.
14            SO HERE IS A KEYBOARD, THE DEVORE KEYBOARD,
15   WHERE YOU CAN'T ACTUALLY USE TOUCH TYPING.    AND THEN
16   YOU SEE A PATIENT PRACTICING WRITING, PICKING UP A PEN
17   AND PUTTING IT DOWN, USING THE MIRROR, AND THEN
18   BEGINNING TO WRITE USING THE MIRROR AND USING THE IMAGE
19   OF THE UNAFFECTED SIDE TO GUIDE THE DYSTONIC HAND.
20            HERE IS AN EXAMPLE OF USING A SIMULATED
21   INSTRUMENT TO TRY TO GET BACK TO PLAYING THE TARGET
22   INSTRUMENT.   USING A DOWEL INSTEAD OF A FLUTE, USING A
23   DRUM PAD INSTEAD OF A DRUM, AND YOU CAN SEE IN THE
24   DRUMMER THERE IS BIOFEEDBACK THAT'S PLACED ON THE ARM
25   TO TRY TO GIVE HIM FEEDBACK ABOUT WHETHER HE'S DOING



                                 22
1    THE TASK PROPERLY.
2             IT IS ALSO POSSIBLE TO USE MIRROR FEEDBACK TO
3    RETRAIN FACIAL DYSTONIA.   BY PUTTING THE TWO MIRRORS AT
4    A 90-DEGREE ANGLE, YOU TAKE THE SIDE OF THE FACE THAT
5    IS DYSFUNCTIONAL AND THEY GET THE IMAGE OF THE
6    FUNCTIONAL SIDES OF THE FACE, AND NOW THEY CAN PRACTICE
7    NORMAL MOVEMENTS OF THE MUSCLES OF THE FACE AND GET THE
8    FEEDBACK THAT THEIR FACE LOOKS NORMAL.
9             AT THIS TIME WE HAVE DONE SEVERAL CASE
10   STUDIES AND SEVERAL EXPERIMENTAL STUDIES DEMONSTRATING
11   THAT LEARNING-BASED SENSORIMOTOR TRAINING CAN BE
12   EFFECTIVE WITH APPROXIMATELY 95 PERCENT OF THOSE WHO
13   ACTUALLY COMPLY WITH THE PROGRAM.   THOSE WHO COMPLY
14   WILL MAKE SOMEWHERE BETWEEN 75 TO 90 PERCENT
15   IMPROVEMENT AS MEASURED BY CLINICAL PERFORMANCE
16   VARIABLES AND MAGNETIC SOURCE IMAGING.   WHILE 8 PERCENT
17   DO RETURN TO WORK, ONLY 50 PERCENT OF THE MUSICIANS
18   HAVE BEEN ABLE TO RETURN TO FUNCTIONAL AND PROFESSIONAL
19   PERFORMANCE.
20            WHAT IS CRITICAL ABOUT THOSE WHO GET BETTER
21   IS THE FACT THAT THEY'VE HAD POSITIVE EXPECTATIONS TO
22   IMPROVE, THEY HAVE BEEN WILLING TO PRACTICE, MENTAL
23   PRACTICE AND NOT ALL PHYSICAL PRACTICE, THEY COMPLY
24   WITH THE REPETITIVE TRAINING STRATEGY, THEY CAN CHANGE
25   THEIR TECHNIQUES, AND THEY CAN ACTUALLY STOP THE



                                23
1    ABERRANT NORMAL MOVEMENTS.    ALTHOUGH INTERVENTION WAS
2    TARGETED TO IMPROVE THE UPPER LIMB IN PATIENTS WITH
3    FOCAL HAND DYSTONIA, SIMILAR STRATEGIES HAVE BEEN
4    APPLIED WITH PATIENTS WITH CERVICAL DYSTONIA ALSO WHO
5    REPORT, NOT ONLY IMPROVEMENT IN THE CERVICAL DYSTONIA,
6    BUT IMPROVEMENT IN THEIR SPEECH AND THEIR ARTICULATION
7    AND THEIR LANGUAGE.
8             WE ARE CURRENTLY INVOLVED IN A RANDOMIZED
9    CLINICAL TRIAL WITH A SMALL NUMBER OF PATIENTS WITH
10   FOCAL HAND DYSTONIA, AND THEY'RE DOING TWO TYPES OF
11   LEARNING-BASED TRAINING.    ONE IS GENERAL MEMORY-BASED
12   TRAINING, WHICH IS BASED ON A BRAIN FITNESS PARADIGM,
13   AND THE OTHER IS LEARNING-BASED SENSORIMOTOR TRAINING.
14            THESE PATIENTS WILL BE RANDOMLY ASSIGNED TO
15   ONE OF TWO GROUPS.    THEY BOTH DO BRAIN FITNESS AND
16   SENSORIMOTOR TRAINING.    ONE CAME IN FOR AN INTENSIVE
17   TWO WEEKS OF LEARNING-BASED SENSORIMOTOR TRAINING, AND
18   THE OTHER DID ALL THE LEARNING-BASED SENSORIMOTOR
19   TRAINING AT HOME.    ALL HAD VIDEOTAPES TO REALLY REMIND
20   THEM HOW TO DO THE TRAINING, ALL HAD HANDBOOKS,
21   EVERYTHING WAS IN WRITING, AND ALL WERE TO REPORT THE
22   AMOUNT OF TIME THEY WERE COMPLYING WITH THE PROGRAM.
23            THE PRELIMINARY ANALYSIS OF THOSE COMPLETING
24   THE PROGRAM DEMONSTRATES THE CHALLENGE OF COMPLIANCE.
25   AND WHILE I RECOGNIZE THE NEUROPHYSIOLOGY OF LEARNING,



                                  24
1    I THINK WE UNDERSTAND THE DECODING PROCESS.    IF
2    PATIENTS DON'T COMPLY WITH THE REPETITIONS AND THE
3    CODING AND THE DECODING, I CAN TELL YOU THERE IS NO
4    LEARNING.
5                THOSE WHO ARE COMPLYING WITH BOTH THE
6    PRACTICE PROGRAM FOR THE BRAIN FITNESS PROGRAM, WHICH
7    IS BASED ON MEMORY, AND THOSE CONCENTRATING AND
8    COMPLETING THE PROGRAM ON LEARNING-BASED SENSORIMOTOR
9    TRAINING APPEAR TO BE MAKING THE GREATEST GAINS.
10               AND YOU CAN SEE ON JUST THIS BRIEF SUBJECTIVE
11   OUTLINE HERE THAT THOSE WHO ARE DOING THE BRAIN FITNESS
12   TRAINING AT THE SAME TIME THEY'RE DOING THE
13   LEARNING-BASED TRAINING AND THEY'RE COMPLYING WITH THE
14   PROGRAMS LOOK LIKE THEY'RE HAVING THE BEST OUTCOME.
15               SO IS LEARNING-BASED SENSORIMOTOR TRAINING
16   EFFECTIVE?    WE HAVE ALSO REPORTED A SIMILAR STRATEGY
17   USED WITH PATIENTS STABLE POST STROKE.    WE HAVE
18   DEMONSTRATED THAT THESE PATIENTS CAN IMPROVE
19   SENSORIMOTOR FUNCTION EVEN THOUGH THEY MIGHT BE ONE TO
20   FIVE YEARS POST STROKE.    FURTHERMORE, THE MORE
21   INTENSIVE TRAINING IS ASSOCIATED WITH THE GREATEST
22   IMPROVEMENT.    WE FOUND PATIENTS TRAINING DAILY FOR SIX
23   WEEKS WERE ABLE TO MAKE 50 PERCENT GAINS IN FUNCTIONAL
24   ABILITIES COMPARED TO THOSE TRAINING ONCE A WEEK FOR
25   SIX WEEKS.



                                 25
1                SO, IN CONCLUSION, IT'S CLEAR FROM OUR
2    RESEARCH THAT IT IS POSSIBLE TO APPLY THE PRINCIPLES OF
3    BASIC NEUROSCIENCE AND PLASTICITY TO CLINICAL PRACTICE,
4    BUT COMPLIANCE, PATIENT COMPLIANCE, FAMILY SUPPORT IS
5    CRITICAL.    IT IS PARTICULARLY CRITICAL IF YOU ARE GOING
6    TO ACHIEVE ADEQUATE REPETITIONS TO GET THE CHANGE
7    REQUIRED IN THE BRAIN.    WITHOUT THESE REPETITIONS OF
8    NORMAL REPETITIONS AND AVOIDING ABNORMAL MOVEMENTS, WE
9    HAVE A SERIOUS PROBLEM IN LEARNING.    WE DEFINITELY NEED
10   TO DO MORE RESEARCH TO CLARIFY BOTH THE TYPE, THE
11   TIMING, AND THE INTENSITY OF BEHAVIORAL TRAINING NEEDED
12   TO MODIFY STRUCTURE.    FOR EXAMPLE, WE KNOW OUR ANIMALS
13   REQUIRED 2,000 REPETITIONS A DAY AT A MINIMUM FIVE DAYS
14   A WEEK FOR AN AVERAGE OF 12 WEEKS TO DEVELOP THE
15   DYSTONIA.
16               IT IS ALSO CLEAR FROM OUR RESEARCH THAT
17   CLINICAL-BASED TRAINING SHOULD BE COUPLED WITH
18   TECHNOLOGY, ROBOTICS, AND COMPUTERIZED TRAINING
19   PROGRAMS TO ASSURE COMPLIANCE, FUN, REWARD, AND
20   APPROPRIATE PROGRESSION OF TASK DIFFICULTY.    IN
21   ADDITION, IT IS MY VIEW THAT THESE LEARNING-BASED
22   PROGRAMS SHOULD BE AVAILABLE IN COMMUNITY-BASED
23   SETTINGS AND NOT IN A HOSPITAL-BASED SETTING.    EVEN
24   THOUGH THERE MAY NEED TO BE SOME SUPERVISION BY A
25   SKILLED REHABILITATION SPECIALIST, THE PATIENT NEEDS TO



                                 26
1    BE PRIMARILY IN CHARGE OF THE REHAB.
2             THUS, IT IS CRITICAL TO CREATE PARTNERSHIPS
3    BETWEEN CLINICIANS, BASIC SCIENTISTS, ENGINEERS, AND
4    PROGRAMMERS TO INNOVATE PARADIGMS OF TRAINING THAT ARE
5    BUILT ON THE PRINCIPLES OF NEUROPLASTICITY.      WHILE
6    THERE ARE SOME LEARNING PROGRAMS THAT CLEARLY EXIST AND
7    ARE AVAILABLE TODAY, THERE ARE SOME ROBOTIC DEVICES
8    THAT ARE AVAILABLE FOR US TO USE IN THE CLINIC, AND
9    THERE ARE ALSO MACHINES THAT WILL HELP STEP THE LEG OF
10   A PATIENT WHO HAS A PARALYSIS OF THE LEG, BUT MANY OF
11   THESE DEVICES ARE NOT SMART; THAT IS, THEY ARE NOT TIED
12   TO LEARNING-BASED TRAINING.       THEY'RE SIMPLY DEVICES
13   THAT ARE ORIENTED TOWARDS REPETITION, BUT NOT
14   LEARNING-BASED APPROACHES.
15            SO I GATHER FROM MY INABILITY TO USE MY
16   MOVIES THAT I CAN'T ACTUALLY SHOW YOU THE EXAMPLE OF
17   CASES AND HOW THEY'VE IMPROVED.      SO I WILL OPEN IT UP
18   FOR QUESTIONS.
19            THE MODERATOR:   THANK YOU VERY MUCH, DR. BYL,
20   FOR A FANTASTIC AND VERY STIMULATING PRESENTATION.         I
21   HAVE SOME QUESTIONS FOR YOU.
22            WHAT DO YOU THINK IS THE MAJOR LIMITATION IN
23   MAXIMIZING THE PLASTICITY OF THE BRAIN?
24            DR. BYL:   I OBVIOUSLY BELIEVE THAT MY
25   EXPERIENCE WORKING IN ANIMAL-BASED RESEARCH AND THEN



                                  27
1    TRYING TO APPLY MY FINDINGS IN A MORE BASIC SCIENCE
2    LABORATORY TO THE CLINIC, MY FRUSTRATION IS PATIENT
3    COMPLIANCE.   CLEARLY WHEN WE TRAIN ANIMALS, WE HAVE
4    METHODS TO CONTROL THEIR BEHAVIORS AND WE CAN CONTROL
5    THE AMOUNT OF TIME THEY DO THE REPETITIVE BEHAVIORS,
6    BUT IN THE REAL WORLD WITH REAL PATIENTS WHO ARE LIVING
7    IN REAL LIFE, IT IS VERY, VERY DIFFICULT TO GET THEM TO
8    COMMIT TO THESE LEARNING-BASED RETRAINING PARADIGMS
9    EVEN WHEN THEY PERFORM AND DO JOBS THAT DEMAND HIGH
10   LEVELS OF REPETITION THAT TOOK THEM TO THE POINT OF
11   SUCCESS TO BEGIN WITH.    IT'S AMAZING TO ME HOW
12   DIFFICULT IT IS TO HAVE SOMEONE SPEND THE SAME AMOUNT
13   OF TIME RETRAINING THE BRAIN TO GET RID OF AN ABERRANT
14   MOVEMENT AS OPPOSED TO TRAINING TO BECOME A BETTER
15   PERFORMING ARTIST.
16            THE MODERATOR:    SO MAYBE WE NEED ANOTHER
17   PROSTHETIC DEVICE TO ENHANCE LEARNING.
18            DR. BYL:    WHAT'S INTERESTING IS THAT THE
19   DEVICES I SAW THIS LAST WEEKEND AT A CONFERENCE I WAS
20   ATTENDING ALL HAVE THE POTENTIAL TO TAKE A PATIENT WITH
21   A STROKE WHO HAS NO MOVEMENT AND BEGIN TO PROVIDE SOME
22   PASSIVE AND THEN INTERACTIVE MOVEMENT; BUT, AGAIN, THEY
23   ARE NOT TIED TO LEARNING-BASED TRAINING PROGRAMS.     SO
24   PATIENTS WOULD EASILY LOSE THEIR INTEREST IN JUST
25   HAVING THAT ACTIVITY.



                                 28
1              THE MODERATOR:    ANOTHER QUESTION.     WHAT IF
2    THERE IS A GENETIC ETIOLOGY THAT IS ULTIMATELY
3    IDENTIFIED FOR LOCAL HAND DYSTONIA?    COULD
4    LEARNING-BASED TRAINING STILL BE EFFECTIVE?
5              DR. BYL:    THANKS FOR ASKING THAT QUESTION.      I
6    HAD A MOVIE TO SHOW YOU OF A PATIENT WHO WAS EXACTLY
7    THAT.   A PATIENT WITH A GENERALIZED DYSTONIA, PROBABLY
8    HAS A SERIOUS GENETIC CONTRIBUTION TO THAT DYSTONIA,
9    AND ESSENTIALLY THE LEARNING-BASED TRAINING PROGRAM WAS
10   RELATIVELY EFFECTIVE.    BUT GIVEN THE DEMANDS OF TAKING
11   CARE OF A YOUNG FOUR-YEAR-OLD, GIVEN THE DEMANDS OF
12   KEEPING THE HOUSE, GIVEN THE DEMANDS OF COMMUTING TO
13   COME AND SEE ME FOR LEARNING-BASED SENSORY TRAINING,
14   SHE MADE IMPROVEMENT, BUT NOT TO THE SAME DEGREE THAT
15   SHE WOULD HAVE MADE IMPROVEMENT WITH DEEP BRAIN
16   STIMULATORS IMPLANTED.
17             SO SHE HAD DEEP BRAIN STIMULATORS IMPLANTED,
18   AND THOSE ALONE WERE NOT ENOUGH TO CHANGE THE PARADIGM
19   OF HER DYSTONIA.     SO, IN FACT, WHEN WE ADDED
20   LEARNING-BASED TRAINING TO THE IMPLANTED ELECTRODES, IT
21   WAS ACTUALLY IMPORTANT TO SEE HOW MUCH IMPROVEMENT SHE
22   HAD IN MOTOR CONTROL.
23             THE MODERATOR:    SO IS ANYONE CURRENTLY
24   WORKING ON COMPUTERIZED TECHNOLOGY TO FACILITATE THIS
25   TYPE OF LEARNING?



                                  29
1             DR. BYL:    I'VE BEEN WORKING WITH POSIT
2    SCIENCE IN SAN FRANCISCO, AND THEY HAVE THIS
3    LEARNING-BASED MEMORY PROGRAM FOR PATIENTS WITH
4    ALZHEIMER'S DISEASE.    AND IT'S BEEN APPLIED IN THE PAST
5    FOR PATIENTS WITH LEARNING DISABILITIES.      AND, IN FACT,
6    THEY ARE WORKING ON A SMALL BUSINESS GRANT TO DEVELOP
7    SOME SENSORY INTERFACES THAT WE COULD USE FOR TRAINING
8    ABOUT PATIENTS WITH HAND DYSTONIA.      SO IT IS MY VIEW
9    THAT THAT'S PART OF THE PROCESS.    IT DOESN'T REALLY
10   ADDRESS THE PATIENTS WHO HAVE BALANCE DISORDERS AND
11   OTHER KINDS OF CONDITIONS THAT LEAD TO FALLING, BUT
12   CERTAINLY HAS THE POTENTIAL, I BELIEVE, TO BE
13   INTEGRATED INTO COMMUNITY-BASED FITNESS CENTERS.      AND
14   INSTEAD OF JUST GETTING ON THE BIKE AND RIDING YOUR
15   BIKE, YOU OUGHT TO BE DOING A LEARNING-BASED TRAINING
16   PROGRAM, EITHER SOMETHING THAT'S SENSORIMOTOR IN NATURE
17   OR SOMETHING THAT'S LEARNING BASED IN TERMS OF MEMORY.
18            YOU CAN GO AHEAD AND PLAY THAT WHILE I ANSWER
19   QUESTIONS.
20            THE MODERATOR:    THANK YOU.    OKAY.   SO WE'RE
21   READY TO PLAY SOME VIDEOS, THE MOVIES.
22            DR. BYL:    HERE'S A PATIENT WHO ACTUALLY HAS A
23   PRETTY SEVERE HAND DYSTONIA, FOR THOSE OF YOU WHO
24   HAVEN'T SEEN IT.    AND WHAT I'M TRYING TO DEMONSTRATE IS
25   THAT THE DYSTONIA IS WORSE WHEN SHE'S SITTING IN THE



                                 30
1    TARGET POSITION OF WHICH SHE USES THE COMPUTER.        WHEN
2    SHE CHANGES HER POSITION AND NOW JUST DROPS HER HAND ON
3    THE KEYBOARD WHEN SHE IS SUPINE, THAT ACTUALLY THE
4    AMOUNT OF DYSTONIC MOVEMENTS IS REDUCED.
5                LET'S GO TO THE NEXT ONE AND CLICK ON THE ONE
6    ON THE BOTTOM TO THE LEFT, ON THE LEFT.        AND NOW YOU
7    CAN SEE THAT AFTER SHE WE WENT THROUGH SOME RETRAINING,
8    THAT SHE NOW IS ABLE TO USE HER HANDS ON THE COMPUTER
9    WITHOUT THE -- SHE'S IN A SITTING POSITION, BY THE WAY.
10   AND SHE IS NOW ABLE TO USE HER HANDS ON THE COMPUTER,
11   ALBEIT SLOWER, BUT MOVING FROM A PROXIMAL STRATEGY
12   RATHER THAN USING THE FLEXORS AND THE EXTENSORS OF THE
13   DIGITS.
14               GO BACK ONE.    AND LET'S SHOW YOU THIS ONE SO
15   YOU CAN SEE THE SEVERITY OF THE DYSTONIA THAT CAN
16   OCCUR.    HERE'S A PATIENT WITH A CERVICAL DYSTONIA THAT
17   I WAS TALKING ABOUT.       SHE'S YOUNG, SHE IS BRIGHT, SHE'S
18   HEALTHY, SHE HAS A VERY NICE FAMILY, AND SHE NOW IS
19   STRUGGLING TO OVERCOME THE SEVERE CERVICAL DYSTONIA
20   THAT SHE HAS HERE.
21               WE DON'T HAVE TIME TO PLAY ALL THE MOVIES,
22   BUT I'D LIKE TO SHOW YOU WHAT HAPPENED WITH HER AFTER
23   SHE HAD THE DEEP BRAIN STIMULATORS AND WENT THROUGH
24   SENSORIMOTOR RETRAINING.       LET'S GO ON.   GO ON TO THE
25   NEXT ONE.    GO TO THE TOP LEFT.



                                    31
1             SO HERE'S THE SAME PATIENT APPROXIMATELY
2    EIGHT WEEKS -- YOU WANT TO PRESS THE MUTE BUTTON.   SO
3    HERE SHE IS ABOUT EIGHT WEEKS AFTER THE DORSAL
4    STIMULATORS HAVE BEEN PLACED IN THE GLOBUS PALLIDUS.
5    WE'VE NOW BEEN WORKING ON THE SENSORIMOTOR TRAINING,
6    AND YOU CAN SEE THAT SHE IS ABLE TO BETTER CONTROL HER
7    HEAD POSITION EVEN WHEN SHE'S WALKING, WHICH YOU SAW
8    BEFORE WAS THE WORST THAT SHE DID WAS WALKING, AND THEN
9    CREATING THE CERVICAL TORTICOLLIS.
10            IF WE GO TO THE NEXT PICTURE ON THE RIGHT,
11   YOU CAN SEE THAT SHE'S -- STOP THE ONE ON THE LEFT, AND
12   THEN GO TO THE ONE ON THE RIGHT.   YOU CAN SEE THAT AT
13   EIGHT WEEKS SHE'S STILL HAVING TROUBLE ORIENTING
14   HERSELF TO GRAVITY.
15            WHY DON'T WE GO TO THE NEXT ONE.     MAYBE THAT
16   ONE DOESN'T WORK.   GO AHEAD.
17            SO NOTICE THAT WHEN SHE CHANGES THE POSITION
18   OF HER ARMS, IT ALSO TENDS TO HEIGHTEN HER AWARENESS OF
19   WHERE HER HEAD IS IN SPACE, HELPS HER ORIENT HER HEAD,
20   AND THE IDEA OF FINDING THE KINDS OF THINGS THAT SHE
21   NEEDS TO DO AT HOME TO CONTINUE TO MOVE HER FORWARD IN
22   ORIENTING TO GRAVITY AND OTHER SENSORIMOTOR
23   ADJUSTMENTS.   AND YOU WILL SEE IN THIS PICTURE ON THE
24   RIGHT THAT I HAVE HER DOING EVERYTHING SHE CAN THINK OF
25   TO DO THAT BRINGS HER HEAD INTO NEUTRAL.    SO HERE SHE



                                32
1    IS JUST TRYING TO MOVE HER HEAD BACK AND FORTH WITH
2    GRAVITY ELIMINATED BECAUSE WHEN GRAVITY IS ELIMINATED,
3    SHE ACTUALLY HAS MORE CONTROL OF HER HEAD.
4             AND IF WE GO TO THE NEXT PICTURE AND STOP
5    THAT ONE, YOU WOULD SEE THAT I GET HER ON HER ALL FOURS
6    AGAIN, AND YOU WILL SEE HER RIGHT HER HEAD, AND YOU CAN
7    SEE IT'S EASIER FOR HER, AGAIN, TO BRING HER HEAD INTO
8    NEUTRAL WHEN SHE'S ON ALL FOURS AS OPPOSED TO WHEN SHE
9    IS UPRIGHT.   AND IN THE PICTURE ON THE RIGHT, YOU WILL
10   SEE THAT SHE CAN GET INTO A SIDE LYING POSITION AND HER
11   HEAD LOOKS GREAT.    THESE ARE ALL THE THINGS THAT SHE
12   NEEDS TO DO WHEN SHE IS HOME PLAYING WITH HER SON AND
13   TRYING TO DO WHAT IS THE NORMAL MOVEMENT TO REINFORCE
14   THE BENEFIT OF THESE STIMULATORS AS OPPOSED TO THE
15   ABNORMAL MOVEMENT.
16            OKAY.    SO MAYBE WE SHOULD GO AHEAD WITH THE
17   QUESTIONS.
18            THE MODERATOR:    WE HAVE MORE QUESTIONS.
19   THANK YOU.    SO WHAT IS THE CASE?   ARE MOST PHYSICAL
20   THERAPISTS ENGAGED IN THIS TYPE OF LEARNING-BASED
21   TRAINING THESE DAYS?
22            DR. BYL:    TRADITIONALLY THE REPETITION, THE
23   ATTENTION, THE PROGRESSION OF DIFFICULTY, AND THE KIND
24   OF STAGED PROGRESSION OVER TIME IS VERY HARD TO DO IN
25   THE CURRENT SORT OF THERAPY SETTING.    AND I ALSO DON'T



                                 33
1    THINK THAT PEOPLE ARE READING THE LITERATURE IN
2    NEUROSCIENCE TO KNOW HOW TO APPLY THE BASIC SCIENCE
3    PRINCIPLES TO PRACTICE.       AND AS YOU KNOW, THE NEW
4    THRUST OF NIH IS TO WORK TOWARDS TRANSLATIONAL AND
5    CLINICAL RESEARCH.       AND THIS IS EXACTLY WHAT WE'RE
6    TRYING TO DO ABOUT LEARNING-BASED TRAINING.
7                SO MY GOAL IS THAT WE NEED TO SHARE THIS
8    INFORMATION AS WIDELY AS WE CAN, AND THEN WE NEED TO
9    INTEGRATE WITH ENGINEERS TO REALLY GET THE NEW
10   TECHNOLOGY TO MAKE THIS MORE FUN, TO PROGRESS IT IN
11   SMALLER INSTRUMENTS, AND MAKE IT POSSIBLE FOR PEOPLE TO
12   DO THIS AT HOME.       I DON'T BELIEVE THAT PEOPLE CAN COME
13   IN AND RECEIVE REIMBURSEMENT AND THERAPY BY COMING IN
14   TO SEE THE THERAPIST FOR ALL THE REPETITIONS THAT ARE
15   NECESSARY TO CHANGE THE BRAIN.
16               THE MODERATOR:     AND ACTUALLY WILL INSURANCE
17   PAY FOR THIS TYPE OF TRAINING?       IS THAT THE COMMON
18   PRACTICE?
19               DR. BYL:    WELL, IN CALIFORNIA, AND MANY OF
20   YOU ARE NOT FROM CALIFORNIA, WE CERTAINLY ARE SORT OF
21   STRUGGLING WITH THE SORT OF CAPITATED PACKAGES OF
22   HEALTHCARE.    AND THROUGH WORKERS COMPENSATION AND
23   CAREFUL REVIEW OF THE STUDIES AND SHARING THE
24   LITERATURE ON TREATING FOCAL DYSTONIA AND APPLYING
25   BEHAVIORAL NEUROSCIENCE TO PRACTICE, I HAVE BEEN ABLE



                                    34
1    TO GET APPROVAL FOR PATIENTS TO GET A SERIES OF
2    TRAINING SESSIONS WITH ME.     BUT THE GOAL IS TO GIVE
3    THEM VIDEOTAPES AND HANDBOOKS AND ACTIVITIES THAT THEY
4    CAN COME AND CONTINUE TO DO AT HOME EVERY DAY EVEN
5    THOUGH THEY MAY ONLY SEE ME ONCE A WEEK OR ONCE A
6    MONTH.   SO MY GOAL IS TO MAKE EVERY PATIENT THEIR BEST
7    THERAPIST, THAT THEY NEED TO UNDERSTAND THE PRINCIPLES,
8    THEY NEED TO KNOW HOW TO APPLY THEM, AND THAT, IN FACT,
9    SOME WILL BE REIMBURSED FOR THEIR THERAPY, BUT THE BULK
10   OF THE TRAINING MUST GO ON WITH THE PATIENT AND THEIR
11   OWN SELF-MOTIVATION TO IMPROVE.
12               THE MODERATOR:   THANK YOU.   ANOTHER QUESTION.
13   IF A PERSON HAD AN INTERRUPTION OF THEIR INPUT TO THE
14   SENSORY AREAS OF THE CORTEX, THEN PRESUMABLY THERE IS
15   SOME ALTERATION OF THE CORTICAL MASS.      IF ONE WERE NOW
16   TO WANT TO CREATE A SMART PROSTHESIS ACTIVATING THESE
17   AREAS, SAY, FOR SENSORY SUBSTITUTION, THEN THE CORTEX
18   MAP MIGHT NOT BE USEFUL.     CAN YOU CONCEPTUALIZE HOW
19   WITH PLASTICITY THAT LEADS TO REMAPPING, AND INPUT
20   COULD BE PROVIDED THAT MIGHT RELATE TO THE DESIRED
21   SENSORY SUBSTITUTION?
22               DR. BYL:   WELL, I'M NOT SURE THAT SENSORY
23   SUBSTITUTION IS WHAT I WOULD CONSIDER POSITIVE
24   LEARNING.    IN THE CASE OF A PATIENT POST STROKE, THEN
25   YOU ARE GOING TO TRY TO RECRUIT DIFFERENT AREAS OF THE



                                  35
1    BRAIN TO BE USED FOR AREAS THAT HAVE BEEN DAMAGED.      BUT
2    IN PATIENTS WITH FOCAL HAND DYSTONIA, THEY DON'T HAVE
3    AN AREA THAT IS, QUOTE, DAMAGED.    THEY HAVE AN AREA
4    THAT HAS BEEN SORT OF REORGANIZED IN AN ABERRANT WAY,
5    AND THE GOAL IS TO CHANGE THAT MAP SO THAT IT IS
6    PROCESSING INFORMATION IN A NORMAL WAY TO PRODUCE THE
7    NORMAL OUTPUTS.    SO I DON'T THINK SUBSTITUTION IS THE
8    RIGHT APPROACH FOR A PATIENT WITH DYSTONIA.     BUT
9    SUBSTITUTION MAY BE THE RIGHT STRATEGY FOR A PATIENT
10   WITH A STROKE.
11            SO WHAT YOU DO IS YOU TRY TO FIND THE THINGS
12   THEY CAN DO AND THE POSITIONS THAT THEY CAN DO THOSE IN
13   WHERE THEY HAVE THE MAXIMUM.     YOU WANT TO USE THE
14   NEURONS THAT ARE AVAILABLE TO THEM, BOTH SENSORY AS
15   WELL AS MOTOR.    AND I THINK UNFORTUNATELY WE SPEND MUCH
16   MORE TIME IN PHYSICAL THERAPY DEALING WITH THE MOTOR,
17   LOOKING AT THE MOTOR OUTPUTS, AND VERY LITTLE TIME
18   LOOKING AT THE SORT OF SENSORY GUIDED MOVEMENTS WHICH
19   ARE ABSOLUTELY ESSENTIAL FOR HAVING NORMAL MOVEMENTS
20   EITHER POST STROKE, POST HEAD INJURY, POST TUMOR, OR IN
21   THE CASE OF DYSTONIA.
22            THE MODERATOR:     THANK YOU.   ANOTHER QUESTION.
23   YOUR STUDIES SHOW THAT REPEATED HAND USE CAUSE CORTICAL
24   CHANGES, AND SOME OF THESE CHANGES COULD BE ABERRANT.
25   REPETITIVE USE REHABILITATION THERAPY HAS BEEN



                                 36
1    SUGGESTED AS AN APPROACH FOR IMPROVED RECOVERY AFTER
2    NEUROTRAUMA AND STROKE.   NEUROPROSTHESIS COULD BE
3    UTILIZED TO PROVIDE SUCH A THERAPY.   WHAT CAUTIONARY
4    APPROACHES DO YOU SUGGEST SHOULD BE CONSIDERED IN USE
5    OF NEUROPROSTHESIS FOR REHABILITATIVE THERAPY?
6             DR. BYL:   I THINK THE SAME AS I MENTIONED
7    FROM THE APPLICATION OF NEUROSCIENCE TO PRACTICE, THAT
8    THE TYPES OF ACTIVITIES THE NEUROPROSTHESIS IS
9    ENCOURAGING MUST BE ATTENDED, THEY MUST BE PRACTICED,
10   THEY MUST HAVE VARIABILITY, THEY MUST BE PROGRESSED IN
11   DIFFICULTY, THEY MUST BE SPACED OVER TIME, AND THEY
12   MUST GIVE REWARD AND FEEDBACK, AND GIVE SOME
13   INFORMATION ABOUT ERROR AND CORRECTION, AND SOME
14   FEEDBACK ABOUT THE QUALITY OF PERFORMANCE.
15            YOU CAN'T ALLOW A PERSON TO MOVE FORWARD AND
16   HAVE A HABITUAL JUST RAPID ALTERNATING RESPONSE
17   CREATING WHAT IS -- WHAT I WOULD CALL NEAR
18   STEREOTYPICAL MOVEMENTS THAT OCCUR SO RAPIDLY IN TIME
19   THAT THEY CAN'T BE INTEGRATED OVER TIME, THIS SORT OF
20   TEMPORAL CONSTANTS IF YOU WILL.   SO I THINK THAT
21   PROSTHETIC DEVICES HAVE A MUCH GREATER ABILITY TO DO
22   THAT AND TO MEASURE HOPEFULLY SOME INTERACTIVE FORCE OR
23   SENSORY FEEDBACK FROM THE DEVICE ITSELF TO PROGRESS TO
24   THE NEXT STEP, JUST MINIMAL DETECTABLE DIFFERENCE, IF
25   YOU WILL, TO PROGRESS LEARNING THAT DOESN'T EXCEED YOUR



                                37
1    ABILITY TO CODE FOR THAT CHANGE.
2             THE MODERATOR:   ANOTHER QUESTION.   ASSUMING
3    THAT SENSORY INFORMATION RELATED TO THE PROSTHETIC HAND
4    FUNCTION CAN BE DELIVERED TO THE BRAIN VIA SOME TYPE OF
5    NEURAL INTERFACE, WHAT SENSORY MODALITIES ARE MOST
6    LIKELY TO BE CRITICAL FOR ALLOWING RUDIMENTARY
7    MANIPULATION OF AN OBJECT WITH A PROSTHETIC HAND
8    WITHOUT VISION?
9             DR. BYL:    WELL, EVEN THOUGH OUR PRIMARY
10   RESEARCH FOCUSED ON THE SOMATOSENSORY CORTEX, AREA 3 B,
11   WE'RE NOW VERY CLEAR THAT THERE ARE PROBABLY JUST AS
12   MANY OPPORTUNITIES TO ENCODE INFORMATION FROM AREAS 3
13   A, FROM THE MOTOR CORTEX, AND THE SENSORY NEURONS THAT
14   ARE IN THE MOTOR CORTEX, AND I THINK IT'S CRITICAL THAT
15   YOU FOCUS ON THE CUTANEOUS, YOU FOCUS ON THE MUSCLE
16   AFFERENTS, YOU FOCUS ON THE JOINT RECEPTORS, AND YOU
17   FOCUS ON VIBRATION AS A SORT OF A MULTI SORT OF
18   STIMULUS MODALITY.   AND I ALSO ENCODE AND WORK ON
19   AUDITORY TRAINING IN ADDITION TO WHAT I WAS GOING TO
20   SHOW YOU WITH THAT PATIENT, THE AMOUNT OF SPEECH
21   TRAINING THAT WE WERE ABLE TO DO WITH HER USING THE
22   SAME KIND OF APPROACH.
23            SO I THINK ALL THE SENSORY INPUT SYSTEMS ARE
24   IMPORTANT IN GENERALIZING LEARNING, AND WE HAVE
25   CERTAINLY SHOWN THAT WE CAN TRAIN THE SOMATOSENSORY



                                38
1    CORTEX AND SEE IMPROVEMENTS IN AUDITORY DISCRIMINATION
2    AND ALSO VICE VERSA.     SO IT'S IMPORTANT TO INCORPORATE
3    ALL SENSORY MODALITIES TO MAKE THE MAXIMUM OPPORTUNITY
4    FOR LEARNING.
5                THE MODERATOR:   THANK YOU.   WHERE DO THESE
6    RULES FOR SENSORIMOTOR RETRAINING COME FROM, EMPIRICAL
7    DATA, THEORY, OR COMMON SENSE?
8                DR. BYL:   WELL, I THINK COMMON SENSE
9    CERTAINLY HEIGHTENS THE VALIDATION THAT THIS APPROACH
10   IS CORRECT.    HOWEVER, ALL OF THE WORK THAT'S BEEN DONE
11   IN THE KECK CENTER AT UCSF AND PARTICULARLY BY MIKE
12   MERZENICH AND ALL THE FOLKS WHO HAVE STUDIED IN THAT
13   LABORATORY, THAT EVERYONE KNOWS THAT YOU MUST INDEED
14   HAVE SOME WAY TO GET AN ANIMAL TO ATTEND TO THE TASK IN
15   ORDER TO SEE REALLY CHANGES IN LEARNING-BASED
16   STRUCTURE.    SO IF YOU'RE NOT GOING TO PAY ATTENTION,
17   THEN IT BECOMES HABITUATED, AND YOU NO LONGER RESPOND
18   TO THE STIMULUS.
19               SO IT IS WELL-FOUNDED IN THE BASIC SCIENCE
20   RESEARCH.    I THINK IT'S ALSO BEEN REINFORCED IN
21   EDUCATION THEORY, PARTICULARLY IN SPECIAL EDUCATION,
22   BUT THE STRONGEST SUPPORT FOR THESE PRINCIPLES REALLY
23   IS ABSTRACTED FROM THE BASIC SCIENCE WORK IN
24   NEUROSCIENCE.
25               THE MODERATOR:   THANK YOU.   ASSUME FOR A



                                  39
1    MOMENT THAT IT IS IMPOSSIBLE TO USE THE STRATEGIES THAT
2    YOU HAVE DESCRIBED IN YOUR PRESENTATION.    CAN YOU
3    CONCEPTUALIZE HOW MIGHT YOU USE A PROSTHETIC DEVICE
4    SUCH AS ONE THAT ENABLES CHRONIC SUBSTITUTIONAL INPUTS
5    TO RESTORE SOME USEFUL FUNCTION IN COGNITIVE DISORDERS?
6               DR. BYL:   WELL, THAT'S AN INTERESTING
7    COMMENT.   I DID TALK ABOUT SUBLIMINAL KIND OF STIMULI
8    BEING DELIVERED PRIOR TO EXPECTING SOME KIND OF OUTPUT,
9    AND CERTAINLY THERE IS MORE AND MORE EVIDENCE THAT IF
10   YOU HAD A NEUROPROSTHETIC DEVICE THAT WAS PROVIDING
11   STIMULATION, EVEN TO SOMEONE WHO COULD NOT MOVE
12   ANYTHING OR WAS IN COMA POST HEAD INJURY, THAT IT'S
13   QUITE POSSIBLE THAT SOME OF THE INFORMATION THAT'S
14   BEING PROVIDED BY THE NEUROPROSTHESIS IS ACTUALLY BEING
15   PROCESSED BY THE NERVOUS SYSTEM, BUT NOT IN A PLACE
16   WHERE THE OUTPUT COULD BE MEASURED.    AND SOME OF THE
17   MENTAL IMAGERY STUDIES THAT HAVE BEEN DONE JUST LOOKING
18   AT ANESTHESIA AND TRYING TO REDUCE THE AMOUNT OF DRUGS
19   NECESSARY TO PUT PEOPLE IN AN ANESTHETIC STATE FOR
20   SURGERY SHOW THAT IF PEOPLE PRACTICE MENTAL IMAGERY
21   PRIOR TO THE SURGERY AND THEY DO SOME IMAGINING AND
22   THEY EVEN BRING MUSIC THAT THEY'D LIKE TO HEAR WHILE IN
23   THE OPERATING ROOM OR STORIES THAT THEY WOULD LIKE TO
24   HEAR, THAT THESE PATIENTS ARE MUCH MORE LIKELY TO TAKE
25   LESS MEDICINES AND TO RECOVER SOONER TO BEGIN TO



                                 40
1    RESTORE THEIR RECOVERY FROM THE SURGERY ITSELF.
2                SO I THINK NEUROPROSTHETIC DEVICES HAVE JUST
3    A WONDERFUL OPPORTUNITY TO DELIVER BOTH THE AUDITORY AS
4    WELL AS SENSORY STIMULI EVEN THOUGH SOMEONE MAY NOT BE
5    ABLE TO ACTIVELY RESPOND TO IT.      BUT ELEMENTS OF
6    SURPRISE, YOU KNOW, THINGS THAT YOU DON'T EXPECT,
7    ELEMENTS OF FUN, NEED TO BE INCORPORATED IN SOME WAY
8    PRIOR TO THE PERSON REALLY BEING ABLE TO ENGAGE FULLY
9    IN THAT LEARNING ACTIVITY.
10               THE MODERATOR:   THANK YOU.   ANOTHER QUESTION.
11   REGARDING THE MIRROR OR ABNORMAL POSITIONS, YOU HAVE
12   THE PATIENT MOVE BOTH HANDS WHILE WATCHING THE
13   REFLECTION OF THE GOOD HAND TO REINFORCE PROPER
14   POSITIONS.    YOU HAVE MENTIONED SOME SUCCESS FOR SUCH
15   PATIENTS.    IS THE MIRROR USEFUL FOR PATIENTS WITH PAIN
16   FROM REPETITIVE BUT PHYSIOLOGICAL MOVEMENTS?
17               DR. BYL:   ABSOLUTELY.   DR. MOSELEY IS SOMEONE
18   WHO'S DONE A LOT OF WORK WITH THE USE OF MIRRORS SINCE
19   WE BEGAN TO DESCRIBE THE USE OF THE MIRROR IMAGES.     AND
20   HIS PRIMARY CONCENTRATIONS ARE ON PATIENTS WITH PAIN.
21   AND HE HAS SHOWN THAT IF YOU FOLLOW THAT SERIES OF
22   HANDS, LATERALITY AND POSITIONING AND THE USE OF
23   MIRRORS, THAT HE CAN WITH A TRIAL OF APPROXIMATELY SIX
24   WEEKS REDUCE THE PAIN IN PATIENTS WHO HAVE COMPLEX
25   REGIONAL PAIN BY ABOUT 50 PERCENT.



                                  41
1             IF THE PATIENT REALLY DOESN'T HAVE THE
2    MOVEMENT ON THE AFFECTED SIDE AND THE IDEA OF IMAGINING
3    THE MOVEMENT IS ALMOST IMPOSSIBLE, THEN SOMEONE EITHER
4    AT HOME OR IN THE CLINIC CAN GET ON THE OTHER SIDE OF
5    THE TABLE AND THEN HELP WITH BOTH HANDS.   SO THE MIRROR
6    IMAGE REPRESENTS THE ASSISTANCE THAT'S BEING PROVIDED
7    IN THE UNAFFECTED ARM AND THE UNAFFECTED HAND AS WELL
8    AS THE AFFECTED HAND.   SO WHATEVER YOU DO IN THAT
9    MIRROR IMAGE YOU MUST DO ON BOTH HANDS BECAUSE IT'S A
10   COMPELLING IMAGE, AND IT CAN BE VERY EFFECTIVE BOTH FOR
11   MOTOR CONTROL AS WELL AS FOR PAIN MANAGEMENT.
12            THE MODERATOR:   THANK YOU.   ANOTHER QUESTION.
13   IN THE CONTEXT OF TRAUMATIC INJURIES SUCH (INAUDIBLE)
14   AMPUTATION, IS IT POSSIBLE (INAUDIBLE) THE MOVEMENT
15   PROBLEMS AND PAIN DUE TO LOCAL PATHOLOGIES AROUND THE
16   TRAUMA SUCH AS SPASTICITY FROM THE POTENTIAL OCCURRENCE
17   OF FOCAL DYSTONIAS AND ABERRANT REMAPPING PROBLEMS
18   AROUND THE INJURED AREAS TO CHOOSE APPROPRIATE THERAPY
19   AND STRATEGY?
20            DR. BYL:   THAT IS A VERY COMPLEX QUESTION.
21   DR. RAMACHANDRAN AT UC SAN DIEGO WAS ONE OF THE FIRST
22   PEOPLE TO INTRODUCE THE USE OF MIRRORS AND MIRROR
23   IMAGING TO RESTORE WHAT IS ESSENTIALLY THE PHANTOM LIMB
24   PAIN THAT OCCURS POST AMPUTATION.   AND HE HAS PUBLISHED
25   SEVERAL ARTICLES SUGGESTING THAT ONCE THE PATIENT CAN,



                                42
1    IN FACT, RESTORE THAT IMAGE OF THAT LIMB BACK TO ITS
2    NORMAL HEALTHY STATE, THEN THEY CAN, IN FACT, GET RID
3    OF PHANTOM LIMB PAIN THROUGH THIS PROCESS.
4                I HAVE FOUND THIS STRATEGY OF USING THE
5    MIRRORS EQUALLY AS EFFECTIVE WORKING WITH A PATIENT
6    POST STROKE OR HEAD INJURY AS I HAVE WORKING WITH A
7    PATIENT WITH DYSTONIA.       SO I DON'T THINK IT'S LIMITED.
8    IT MAY BE LIMITED TO PATIENTS WHO DON'T HAVE SUFFICIENT
9    COGNITIVE ABILITY TO REALLY UNDERSTAND AND TO VISUALIZE
10   THAT IMAGE AS REALLY BEING THEIR AFFECTED HAND OR IN
11   PATIENTS WHO HAVE BILATERAL PROBLEMS AND THEY DON'T
12   HAVE A NORMAL MOVEMENT PATTERN TO FOLLOW ON EITHER
13   LIMB.   IN THOSE CASES I USE MY LIMB AS THE IMAGE IN THE
14   MIRROR AND THEN WORK WITH THEM ONE LIMB AT A TIME,
15   PUTTING THEIR AFFECTED LIMB BEHIND THE MIRROR.        SO IT
16   IS POSSIBLE TO PARTNER THEM WITH OTHER PATIENTS AND
17   PARTNER THEM WITH FAMILY MEMBERS OR PARTNER THEM WITH
18   THERAPISTS TO, AGAIN, TAKE ADVANTAGE OF THE POSITIVE
19   FEEDBACK THAT YOU GET FROM HAVING THAT IMAGE LOOK MUCH
20   HEALTHIER THAN IT IS WHEN YOU LOOK AT THE MOVEMENT
21   YOURSELF.
22               THE MODERATOR:    THANK YOU.   ONE LAST
23   QUESTION, DR. BYL.    WHAT AREAS IN THE BRAIN SHOULD BE
24   TARGETED BY NEURAL INTERFACES TO DELIVER INFORMATION
25   THAT RESTORES SENSORY PERCEPTION OF HAND AND ARM



                                    43
1    FUNCTION?
2                DR. BYL:   WELL, THAT'S AN INTERESTING
3    QUESTION, AND I THINK IT'S STILL A DEBATE.     THERE ARE
4    MANY NEUROSCIENTISTS WHO FEEL THAT IF YOU DRIVE CHANGE
5    HARD ENOUGH IN THE CORTEX, THAT IT WILL DRIVE CHANGES
6    IN THE THALAMUS AND THE BASAL GANGLION AND THE
7    CEREBELLUM.    IN OUR ANIMAL MODEL OF TRAINING, WE FOUND
8    THE DEGRADATION OF THE CHANGES IN THE THALAMUS AS WELL
9    AS IN THE SENSORY AND MOTOR CORTEX.     SO THE QUESTION, I
10   GUESS, THAT NEEDS TO BE RESOLVED IS WHAT DO YOU HAVE
11   THE GREATEST ACCESS TO, AND IT MAY WELL BE THE CORTEX
12   BECAUSE IT'S MORE SUPERFICIAL AND THE BRAIN STEM IS
13   MUCH DEEPER, AND IT'S VERY HARD TO GET TO THE THALAMUS
14   DIRECTLY WITHOUT SOME INTRUSIVE DEVICES.
15               BUT I THINK THAT THE NEUROPROSTHETICS MIGHT
16   HAVE TO CONSIDER MORE THAN JUST BRAIN STIMULATION,
17   WHICH WE'RE NOW DOING ON THE CORTEX AND WE ARE DOING IN
18   THE GLOBUS PALLIDUS, BUT IT'S NOT CLEAR.     EARLY
19   LEARNING IS PROBABLY CEREBELLAR.     LATE LEARNING AND
20   ADJUSTMENTS TO THE SENSORY AND MOTOR OUTPUTS IS REALLY
21   BASAL GANGLIA, AND THEN THE THALAMUS IS OBVIOUSLY A
22   STATION THAT TRANSMITS THAT INFORMATION TO THE CORTEX,
23   AND PARTICULARLY THE PREFRONTAL CORTEX IS INVOLVED IN
24   PLANNING AND INITIATION AND EXECUTIVE MOVEMENTS.
25               SO IT'S A COMPLEX QUESTION, AND I THINK WITH



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1    AN INTERDISCIPLINARY TEAM OF INVESTIGATORS, WE MIGHT BE
2    ABLE TO PROVIDE A BETTER ANSWER FOR WHERE IS THE TARGET
3    GOING TO BE BEST AND MOST EFFECTIVE.   THANK YOU.
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