Jeffrey A. Kleim, Ph.D.Associate Professor
School of Biological andHealth Systems Engineering
Arizona State University
Neural Plasticity:Foundation For Neuroehabilitation
A Century Of Medical Advances19
00
1922
Insulin
1928
Penicillin
1945
Influenza
Vaccine
1955
Polio Vaccine
1968
Heart
Transplant
1981
AIDS Virus
Identified
2000
Neurorehabilitation?
“….the phenomena of habit in living beings are due to the plasticity of the organic materials of which their bodies are composed ….nervous tissue seems endowed with a very extraordinary degree of plasticity.” (William James, 1887).
Neural Plasticity
2,100
1,800
1,500
1,200
900
600
300
1965
# Pa
pers
Year
2,400
1970 1975 1980 1985 1990 1995 2000 2005
2,700
3,000
2010
The Paradigm Shift In Neurorehabilitation
NeurorehabilitationNeural Plasticity
Learning Relearning
Rehabilitation Is A Relearning Process
Neurorehabilitation
Neurorehabilitation
Neural Signals
Behavioral Signals
Neural Plasticity
Functional Improvement(Kleim, 2012)
Neurorehabilitation: Exploiting Neural Plasticity
Why Do Animal Studies Always Work?
Salience
Repetition
Intensity
Difficulty Timing
Specificity
Repetition
Intensity
Salience
Timing
Specificity
Difficulty
Behavioral Signals
Plasticity
Kleim et al., 2012
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The Inadequacy Of Existing Programs
-less than 10% of all stroke patients have access to rehabilitation programs that can induce meaningful improvements.
-of those that do receive therapy, most receive 1/6th of the therapy required to induce meaningful improvements.
Why Can’t We Achieve This In Human Patients?
Neurorehabilitation
Behavioral Signals
Functional Improvement
Neural Signals
Neural Plasticity
AttentionFatigue Spasticity Limited TimeDepression
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Can We Achieve This In Human Patients?
10
20
30
40
B1 B2 B3 1 2 3 4 5 P1 P2
ARAT
Time
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The More Repetition The Better The Improvement
Intensity: 6 hours/day.
Constrain Induced Movement Therapy
Repetition: 10-15 days.
Difficulty: shaping on progressively harder tasks
Salience: ADL tasks.
CI Therapy Comparison
Gray Matter Changes With Rehabilitation
Pre50
55
60
65
70
Ap
ha
sia
Qu
oti
en
t
Post 3 Months
Western Aphasia Battery
Constraint Induced Language Therapy (CILT)
Repetition Action Naming
Pre50
60
70
80
90
Ap
ha
sia
Qu
oti
en
t
Post 3 Months Pre30
40
50
60
70
%C
orr
ec
t
Post 3 Months
Pre50
55
60
65
70
Ap
ha
sia
Qu
oti
en
t
Post 3 Months
Western Aphasia Battery
Constraint Induced Language Therapy (CILT)
Repetition Action Naming
Pre50
60
70
80
90
Ap
ha
sia
Qu
oti
en
t
Post 3 Months Pre30
40
50
60
70
%C
orr
ec
t
Post 3 Months
R L R L
Pre-CILT
CILT Enhances Arcuate Fasciculus Integrity
Post-CILT
R L R L
Pre-CILT
CILT Enhances Arcuate Fasciculus Integrity
Post-CILT
Takahashi et al., 2009
15 Sessions (Repetition)90 Repetitions/Session (Intensity)Progressively increased range of motion (Difficulty)Pronation/grasp movements (Timing/Specificity)Visually Guided (Salience)
Hand Wrist Assistive Rehabilitation Device (HWARD)
Hand Wrist Assistive Rehabilitation Device (HWARD)
10
20
30
40
50
60
% Im
pro
vem
ent
0
ARATBox
/Blo
cks
Fugl
-Mey
erAsh
worth
ROM
Peg B
oard
SIS
Grasp
Pinch
HWRDControl
*
*
*
*
*
*
**
Takahashi et al., 2009
Intensity
SMART- Arm
Repetition
Difficulty
Salience
Specificity
Timing
Drives recovery
1.0
0
Baseline
Motor Assessment Scale Distance Reached
Post 2 Months
2.0
3.0
MA
S (
sc
ore
)
Dis
tan
ce
(c
m)
20
Baseline Post 2 Months
30
40
SMART
Control
Neurorehabilitation
Neurorehabilitation
Neural Signals
Behavioral Signals
Neural Plasticity
Functional Improvement
Neurorehabilitation: Exploiting Neural Plasticity
Clinically Exploiting Neural Signals
Neurophysiological:-rTMS -TDCS
Neuropharmacological:-L-DOPA -Fluoxetine
Cortical Stimulation
Transcranial Direct Cortical Stimulation (TDCS)
28
Study Measure ResultHummel (2005) Jebsen
Hesse (2007) Fugl-Meyer
Boggio (2007) Jebsen
KIm (2010) Fugl-Meyer
Lindenberg (2010) Fugl-Meyer
Geroin (2011) 6 Min walk
Madhavan (2011) Tracking accuracy
Tanaka (2011) Knee extension
Bolognini (2011) MAL/Fugl-Meyer
Nair (2011) Fugl-Meyer
Rossi (2012) Fugl-Meyer
Zimerman (2012) Digit sequence
Transcranial Direct Current Stimulation
0 30 9060
10
20
30
40
50
60
Days Post-Stroke
Fugl
-Mey
er S
core
Fluoxetine
Placebo
Fluoxetine
(Chollet et al., 2011)
Drug Transmitter Measure Citation
Fluoxetine
Fluoxetine
Fluoxetine
Serotonin
Serotonin
Serotonin
HSS, Barthel Index Dam et al., 1996
Peg board, tapping Pariente, et al (2001)
Fugl-Meyer Chollet et al., (2011)
Escitolapram Serotonin RBANS, WISC-R Jorge et al., (2010)
Donepezil Acetlycholine Fugl-Meyer, WMFT Nadeau et al., (2010)
Donepezil Acetlycholine Fugl-Meyer Berthier et al., (2003)
L-DOPA Dopamine Fugl-Meyer, Barthel Sonde et al., (2007)
Ropinirole Dopamine Gait velocity Cramer et al., (2009)
Amphetamine DA/NE Fugl-Meyer Cirosotomo et al., (2009)
Amphetamine DA/NE Fugl-Meyer
Amphetamine DA/NE Fugl-Meyer
Amphetamine DA/NE Fugl-Meyer
Gladstone et al., (2006)
Reding et al., (1995)
Walker-Bateson (1995)
Drug Studies In Stroke
Neurorehabilitation
Neurorehabilitation
Neural Signals
Behavioral Signals
Neural Plasticity
Functional Improvement
Can Genotype Influence Treatment Efficacy?
Pharmacogenomics
Oncology PsychiatryVirologyNeurology CardiologyDermatology
Hematology
-the action of 110 FDA approved drugs are influenced by single nucleotide polymorphisms (SNPs).
1,5000 SNPs.
Immunology
All drugs previously tested in stroke trials are affected by SNPs.
Polymorphisms In “Plasticity Genes”
Human BDNF Val/Met66 Polymorphism:
-20% population is val/met (heterozygous)
-4% population is met/met (homozygous)
-results in aberrant BDNF transport/release
Genetic Influences On The Capacity For Plasticity
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(CNN) -- The next time you see a motorist
obliviously straddling two lanes, don't fault
bad driving, but genetics.
In a study published recently in the journal
Cerebral Cortex, researcher Steven Cramer
found that people with a certain gene variant
performed more than 30 percent worse on a
driving test than people without it.
The study by Cramer, a neurology professor
at the University of California Irvine, might
also help explain why there are so many bad drivers on U.S.
highways: About 30 percent of Americans have the variant.
Ordinarily, when a person performs a task, a protein called brain-
derived neurotrophic factor (BDNF) is secreted to the area of the
brain that is associated with that activity.
The protein helps facilitate communication among brain cells and
helps retain memory.
However in people who have the gene variation that Cramer
studied, BDNF secretion is limited.
"These people make more errors from the get-go, and they forget
more of what they learned after time away," Cramer said in a
statement.
Cramer and his team of researchers set out to find how the variant
affected driving.
They recruited 29 people to drive 15 laps on a simulated course
with difficult curves and turns. Twenty-two of the participants did not
have the gene variant; seven did.
The researchers wanted to see how effectively the participants
learned to navigate the twists and turns in each subsequent lap.
Four days later, they repeated the test. The participants with the
variant did worse both times. They also retained less the second
go-round.
"I'd be curious to know the genetics of people who get into car
crashes," Cramer said. "I wonder if the accident rate is higher for
drivers with the variant."
Unfortunately, a test to determine whether someone has the gene
variant is not commercially available.
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Blame genetics for bad driving, studyfindsOctober 29, 2009 7:41 a.m. EDT
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A study found that a gene variant found in about 30 percentof Americans may provoke bad driving.
STORY HIGHLIGHTS
Study finds bad driving mayhave genetic basis
People with certain genevariant performed worse ondriving test that those without it
Nearly 30 percent of Americanshave variant, according to study
RELATED TOPICS
Genetics
Science and Technology
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1.5
2.0
2.5
3.0
3.5
4.0
Admission 1 Month 3 Months
BDNF-SNPControl
BDNF Polymorphism and Stroke RecoveryM
od R
anki
n Sc
ale
*
(Kim et al., 2013)
0
5% A
chie
ving
Min
imal
Dis
abilit
y
10
15
20
25
30
35
40
APOE-4-SNPControl
APOE Polymorphism and Stroke Recovery
(Cramer et al., 2013)
Gene Measure
COMT Working memory, impulsivity
BDNF Executive function, motor performance
DRD2 Working memory, impulsivity
ANKKI Working memory, executive function
PPPIRIB Working memory, executive function
MAO-A Working memory, inhibition
5HTTLPR Decision making, inhibition, impulsivity
5HT6 Executive function
5HT1A Inhibition, impulsivity
5HTR2B Inhibition, impulsivity
5HTR2A Inhibition, impulsivity
TPH Aggression
TPH Aggression
(Weaver et al., 2012)
Polymorphisms and Traumatic Brain Injury
25
50
75
100
Dose
Res
pon
se
Genotype 1
Genotype 2
Genotype 3
Pharmacogenomics
25
50
75
100
Treatment
Res
pon
se
Genotype 1
Genotype 2
Genotype 3
“Therapogenomics?”
TANAS Publishing
www.tanaspub.com
An interactive E-Book written for therapists, physicans and patients.
Clearly explains key concepts related to treating brain injury.
Over 150 custom animations and illustrations.
Educational package with 200 Powerpoint slides for teaching.
IPad and laptop formats available.
Jeffrey A. Kleim, Ph.D.
NEURAL PLASTICITYFoundation For Neurorehabilitation
Book Release!