potentials & perspectives of repetitive sensory stimulation · role of neurotrophic factors in...

Institut für Neuroinformatik

- Neural Plasticity Lab -Ruhr-Universität Bochum

[email protected]

Hubert Dinse

Potentials & Perspectives

of repetitive sensory stimulation in stroke rehabilitation 0

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rationale for using sensory stimulation

effects in healthy populations

effects in patient populations

future work

restoration of function

through neuroplasticity mechanisms

training & massed practice

restoration of function

through neuroplasticity mechanisms

Alternatives:targeted brain activation

training

how to induce plasticity and learning?

humans

cells/synapses

training


repetitive stimulation(spatio-temporal constraints)

humans

training


repetitive stimulation(spatio-temporal constraints)

cells/synapses repetitive stimulation(spatio-temporal constraints)

humans

humans

Nomenclature

“co-activation”“repetitive sensory stimulation”

“passive stimulation”“exposure-based learning”

“peripheral high-frequency stimulation”“peripheral nerve stimulation”

Conforto AB, Kaelin-Lang A, Cohen LG (2002) Ann Neuro 51: 122Celnik P, Hummel F, Harris-Love M, Wolk R, Cohen LG (2007) Arch Phys Med Rehabil 88: 1369Dinse HR, Kalisch T, Ragert P, Pleger B, Schwenkreis P, Tegenthoff M (2005) Transaction Appl Perc 2: 71Gutnisky DA, Hansen BJ, Iliescu BF, Dragoi V (2009) Curr Biol 19: 555Johansson BB, Haker E, von Arbin M, Britton M, Långström G, Terént A, Ursing D, Asplund K (2001) Stroke 32: 707Kalisch T, Tegenthoff M, Dinse HR (2009) Front Neurosci 3: 96Ng SS, Hui-Chan CW (2007) Stroke 38: 2953 Sawaki L, Wu CW, Kaelin-Lang A, Cohen LG (2006) Stroke 37: 246Wu CW, Seo HJ, Cohen LG (2006) Arch Phys Med Rehabil 87: 351Yavuzer G, Oken O, Atay MB, Stam HJ (2007) Arch Phys Med Rehabil 88: 710

(r=0.724; p=0.018)

3 h coactivationPleger, Foerster, Ragert, Dinse, Schwenkreis, Nikolas,Tegenthoff (2003) Neuron

pre

Relation between reorganization & tactile perceptiontactile co-activation on right index-fingerspatial 2-point discriminationCortical activation: BOLD signals

disc

rimin

atio

nim

prov

emen

t[p

ost -

pre]

normalized SI enlargement [post - pre]

placebo amphetaminememantine

Dinse, Ragert, Pleger, Schwenkreis, Tegenthoff (2003) Science

med

io-la

tera

l shi

ft[m

m p

re-p

ost]

discrimination improvement [post - pre]

-4

0

4

8

12

0 0.1 0.2 0.3 0.4 0.5

memantine

placebo

amphetamine

pre

post

Relation between reorganization & tactile perceptiontactile co-activation on right index-fingerspatial 2-point discriminationCortical activation: SEP recording and electric source localization

Höffken, Veit, Knossalla, Lissek, Bliem, Ragert, Dinse, Tegenthoff (2005) J Physiol

decrease in paired pulse suppression (post-pre)

psyc

hoph

ysic

al im

prov

emen

tth

resh

old

post

-pre

(mm

)

r=0.6; p=0.03

pre

3 h coactivation

Relation between reorganization & tactile perceptiontactile co-activation on right index-fingerspatial 2-point discriminationCortical excitability: SEPs after median nerve paired-pulse stimulation

.

• tactile acuity (2-point discrimination)• frequency (flutter) discrimination• reaction times• Braille sign recognition• fine motor movements (finger–hand)• haptic object recognition• every day life performance

improvement of tactile & sensorimotor performance

Effects of repetitive sensory stimulation

Spinal cord

Brain stem

Thalamus

repetitive sensory

stimulation

brain activation&

induction of plastic reorganization


Spinal cord

Brain stem

Thalamus

repetitive sensory

stimulation

LTP-like processes

Δ synaptic efficacy

Δ sensorimotor processing

Δ sensorimotor behavior

brain activation&

induction of plastic reorganization


Co-activation in healthy elderly subjects

Kalisch, Tegenthoff, Dinse (under revision)

Peg board - pin plugging65 to 89 yrs

0

5

10

15

20

25

30

post post 2weeks

post 3weeks

post 4weeks

rec 1week

rec 2weeks

Tim

e –

gain

rela

tive

to p

re[%

]

right hand co-activated 2 days / week for 4 weeks

Application of repetitive sensory stimulationin the treatment of impaired subpopulations

.

improvement of sensorimotor performancein patients suffering from stroke

targeting: - touch- proprioception- haptics- motor performance


improvement of sensorimotor performancein patients suffering from stroke

advantages: - easy to apply- easy to use at homes- high compliance- inexpensive

9-holepegboard

Hand tapping

Touch threshold

Haptic object/form recognition

Practical tasks (Wolf-Motor/JTHF)

Tactile acuity

Moberg

Stimulation statistics: intermittent high-frequency

- electrical stimulation of the fingers

- trains of pulses with an inter-train interval of 5 s

- train duration 1 sec with 20 single pulses @ 20 Hz

- single pulse duration 200 microsec

- pulse trains stored digitally and played back via MP3 player allowing unrestricted mobility of the subjects during stimulation

stimulation session of 1 hour 12000 stimuli

.

Ragert, Kalisch, Bliem, Franzkowiak, Dinse (2008) BMC Neuroscience

Subacute patientsage 55 to 76 years post-stroke: 4.2 ± 1.3 weeksmedia infarct, thalamic infarct

stimulation: 45 minutes 5 days / week, for 2 weekstotal: 7.5 h, ~90.000 stimulifollow-up after 3 months

complementary treatment:standard physiotherapy

Grating orientation taskTactile acuity

disc

rimin

atio

n th

resh

old

(mm

)

01

23

45

67

8

Baseline End-treatment

Follow-upmidtreatment

no discrimination ability

Grating orientation taskTactile acuity

disc

rimin

atio

n th

resh

old

(mm

)

01

23

45

67

8


Follow-upmidtreatment

-40

-30

-20

-10

0

End-treatment Follow-upmid

treatment

no discrimination ability

Time to pick up and to correctly identify item

Moberg

0

20

40

60

80

Tim

e (s

ec)


Follow-up

Time to pick up and to correctly identify item

Moberg

0

20

40

60

80

Tim

e (s

ec)


Follow-up

-60

-50

-40

-30

-20

-10

0

End-treatment Follow-up

chan

ge in

per

form

ance

(%

to b

asel

ine)

0

10

20

30

40

Tactileacuity

Formrecognition

Mobergpick up

9-holepegboard

impr

ovem

ent (

%)

End-treatment

Follow-up

Comparison of restoration effects - subacute

Dinse, Bohland, Kalisch, Kraemer, Freund, Beeser, Hömberg, Stephan (2008) Europ J Neurol

R2 = 0.2938-40

-30

-20

-10

00 10 20 30 40 50

R2 = 0.4402-80

-60

-40

-20

00 20 40 60 80

at end-treatment

performance at baseline (sec)

perc

ent c

hang

e (%

)

Moberg9-holepegboard

perc

ent c

hang

e (%

)baseline dependence

R2 = 0.7106-40

-30

-20

-10

00 10 20 30 40 50

R2 = 0,576-80

-60

-40

-20

00 20 40 60 80

at follow-up

performance at baseline (sec)

perc

ent c

hang

e (%

)

perc

ent c

hang

e (%

)baseline dependence

Moberg9-holepegboard

Chronic patientsage 57 to 67 years post-stroke: 30 ± 1.3 monthsmedia infarct

stimulation: 90 minutes 4 days / week, for 6 weekstotal: 36 h, ~400.000 stimulifollow-up after 4 weeks

complementary treatment:n.a.

Improvement in chronic stroke patients

Smith, Dinse, Kalisch, Johnson, Walker-Batson (in press) Arch Phys Med Rehabil

left hemispheric stroke

S 1 6 monthsS 2 18 months

0.0

0.2

0.4

0.6

0.8

1.0

baseline mid end follow-up

Rat

io:

affe

cted

/ hea

lthy

side

S 3 60 monthsS 4 36 months

0.0

0.2

0.4

0.6

0.8

1.0


Rat

io:

affe

cted

/ hea

lthy

side right hemispheric stroke

Improvement in chronic stroke patients

tapping

0.0

0.2

0.4

0.6

0.8

1.0


Rat

io a

ffec

ted

/ hea

lthy

side

Haptic object

0.0

0.2

0.4

0.6

0.8

1.0


Rat

io a

ffec

ted

/ hea

lthy

side

Smith, Dinse, Kalisch, Johnson, Walker-Batson (in press) Arch Phys Med Rehabil

Chronic patientsage 38 to 61 years post-stroke 4.8 ± 2.5 yearsmedia infarct, thalamic infarct

stimulation: 45 to 60 minutes 5 days / week, for 6 to14 monthstotal: > 1 million stimulifollow-up every 2 to 4 months

complementary treatment:n.a. / general physiotherapy

• touch threshold (Frey Hairs)

• tactile acuity (GOT, 2PD)

• haptic object recognition

• hand/arm motor performance (MLS)

• multiple choice reaction times (visuo-tactile task)

• Actigraphy

• hand functions in daily activities (Jebsen Taylor, video-based)

• SEPs (high density EEG)

Effect of repetitive sensory stimulation (chronic patient, right-handed, 48 years, left thalamus infarct 1997 )

digit 2 right

digit 4 right

baseline 7 weeks 22 weeks 36 weeks

0

50

100

150

200

250

300

350

after 36 weeks: ~2 million stimuli

Touch thresholdth

resh

old

(mN

)

no sensation

healthyleft fingers

Effect of repetitive sensory stimulation(chronic patient, right-handed, 48 years, left thalamus infarct 1997 )

Multiple choice reaction times

baseline

left right

7 weeks 22 weeks 36 weeks

RT

(ms)

1600

1200

800

400

0


0

10

20

30

40

50

60

70

80

90

100

baseline 7 weeks 36 weeks

Hand dominance test (HDT)


HD

T sc

ores

extreme left handedness

extreme right handedness

right handedness

left handednessambidexterity

SEPs (high density EEG) air-puff stimulation, right digit 2

baseline

baseline

after 36 weeks

SEPs (high density EEG) air-puff stimulation, right digit 2

Future work

Optimization & development of RSS protocols

Optimization & development of RSS devices

Role of neurotrophic factors in RSS

Individual strategies for combining RSS with training

Evolution of stimulation devices…

Role of neurotrophines in RSS

family of growth factors– produced in blood and brain

NGF – nerve growth factor

BDNF – brain-derived neurotrophic factor

Production & maintenance of connections between nerve cells

Synaptic plasticity

Neurogenesis

Mattson (2008) Ageing Res Rev

Sensory stimulation

Growth factorsStress resistance genesEnergy metabolismAntioxidant enzymesHeat shock proteins

Mild / transientCellular stress

Future work

Optimization & development of RSS protocols

Optimization & development of RSS devices

Role of neurotrophic factors in RSS

Individual strategies for combining RSS with training

Summary & Conclusion

Repetitive sensory stimulation (RSS) was used as stand-alone or complementary rehabilitation therapy in subacute and in chronic stroke patients

RSS consisted of intermittent high-frequency electrical stimulation of the fingers of the affected hand

RSS improved hand-arm functions of the affected side for touch, tactile and haptic performance, proprioception and motor performance

Improvement was preserved or further enhanced several weeks follow-up

Two advantages: RSS is inexpensive and passive, i.e. it does not require the active cooperation of the patient

These properties together with the effectiveness make RSS-based principles prime candidates for therapeutic intervention, particularly for out-patients

Tobias Kalisch, Jan Kattenstroth

Martin Tegenthoff, Oliver Höffken

Volker Hömberg, Klaus Martin Stephan, Matthias Kraemer

Wolfgang Greulich, Petra Gerhardt

Delaina Walker Batson, Patricia S. SmithMark Johnson

Thank you for your attention

RuhrUniversityBochum

potentials & perspectives of repetitive sensory stimulation · role of neurotrophic factors in...

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