Neural Plasticity: Foundation For Neuroehabilitation · Foundation For Neuroehabilitation. A Century Of Medical Advances 1900 1922 Insulin 1928 Penicillin 1945 Influenza ... Immunology

Jeffrey A. Kleim, Ph.D.Associate Professor

School of Biological andHealth Systems Engineering

Arizona State University

[email protected]

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

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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

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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

Automotive Engines

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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

[email protected]

Book  Release!