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Prosthetics Applications inPlastic Brain

Smart Prosthetics:

Exploring Assistive Devices for the Body and Mind

The National Academies/ Keck Futures InitiativeIrvine, California

Randolph J. Nudo, Ph.D.Director, Landon Center on Aging

Professor, Department of Molecular andIntegrative Physiology

University of Kansas Medical CenterKansas City, KS

Theo & Alfred M. Landon Center on Aging

What is brain plasticity?

Brain plasticity is the capability of the brain toalter its functional organization as a result ofexperience.

As such, plasticity refers to the phenomenonof change, not to the specific underlyingmechanisms.

Correlates of brain plasticity Cortical maps Synaptic morphology Dendritic morphology Synaptic strength

Receptor binding Axonal trajectory Gene expression Neurogenesis others

Metaplasticity: a change in the ability to inducesynaptic plasticity (plasticity of plasticity)


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Why is plasticity is important for brainprosthetics applications?

Premise: Effectiveness of brain-machineinterface dependent upon activity-drivenremodeling of existing brain circuitry. Surrogate devices must account for changing

neural environment Devices themselves may alter neuronal networks Injured brain is not simply a normal brain with a

missing part

Maturation of brainplasticity principles

Mid-1800s Other brain regions may take over lost functions

Early 1900s First demonstrations that brain functions are malleable Recovery after injury modified by use

Mid-1900s The Hebbian synapse; enriched environments

1980s Principles guiding exp.-dependent recovery emerge Neuroplasticity accepted as principle of brain function

1990s Imaging of human brain plasticity

Flourens - 1840s Sherrington - 1910s

Somatosensory cortex plasticity

Merzenich and colleagues


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Rodent whisker-barrel cortex

Feldman & Brecht, Science, 310:810, 2005

Visual cortex plasticity

Hofer et al., Curr Opin Neurobiol, 16:451, 2006

Plasticity in auditory cortex

Nucleus basalis stimulation + auditory tone

Kilgard & Merzenich, Science, 279:1714, 1998


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Mapping the motor cortex

Intracortical microstimulation

Anatomy of cortical motor outputs

Rathelot & Strick, PNAS, 103:8257, 2006


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Remodeling of motor cortexafter skill training

Nudo et al., J Neurosci, 16:785, 1996

Structural changes associated withmotor skill training

Skill- or learning dependent, not simply use-dependent!

Stroke statistics

3rd leading cause of death Leading cause of long-term

disability Every 45 sec someone in

U.S. has a stroke Over 4 million Americans

living with stroke 700,000 new strokes each

year in US; 15 millionworldwide


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Motor recovery after stroke

Duncan, et al., Neuropharmacology, 39:835-841, 2000; Nudo, 2006

0 1 63Months post-infarct

M a n u a

l P e r f o r m a n c e

100%

ProxMCAO

Total M1 hand

Subtot. M1 hand

Human stroke Monkey experimental infarct

M1+PM hand

Theories of recoveryafter brain injury

Reversal of diaschisis (von Monokow, 1914) Normalization of blood flow, metabolism, etc.

Behavioral compensation Alternative strategies

Adaptive plasticity (vicariation or neural compensation?) Unmasking, LTP, LTD, sprouting, synaptogenesis,

angiogenesis, etc.

Effect of subtotal M1 infarct onadjacent, M1 motor maps

Nudo et al., Science, 1996; CI Therapy photo courtesy E. Taub


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Effects of M1 infarct on PMv maps

Before stroke

5 mos. after stroke-40

-20

0

20

40

60

20 30 40 50 60 70 80 90 100

%M1 LOSS

% P

M V G A I N

Frost et al., J Neurophysiol, 2003; Dancause et al., J Neurophysiol, in press.

Lashleys principles of massaction/equipotentiality: Was he right?

Axonal sprouting in adult cortex

Local sprouting in visual cortex afterexperimental scotoma (Darian-Smith &Gilbert, 1994)

Lesion-induced corticostriatal sprouting(Napierski, et al., 1996)

Intracortical sprouting after peripheral nerveinjury (Florence, et al,. 1998)

Intracortical sprouting after injury

Carmichael, The Neuroscientist, 9:64-75, 2003


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Intracortical connectivity of PMv

Dancause et al., J Comp Neurol 495:374, 2006; Dancause et al., Cereb Cortex 16:1057, 2006

PMv terminals in flattened cortex

Intracortical connectivity of PMv

Dancause et al., J Comp Neurol, 2006

28%2%

22%

6%

8%

3%

2%

7%

8%

1%

1%


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Novel projections of PMv to S1Normal

1/2

5 months post-infarct

Dancause et al., J Neurosci, 25:10167-79, 2005

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PO/IP

PMv PMd 6%PMv SMA 8%PMv S1 1%

Axonal trajectory of novel pathway

Dancause et al., J Neurosci, 25:10167-79, 2005

Novel intracortical pathwaysafter cortical injury


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All the kings horses and all the kings men

Temporal profile of remote events

Carmichael, Exp Neurol 193:291, 2005

Summary

Non-human primate models provide uniqueopportunities to examine plasticity of complex

cortical networks after experimental ischemia. Focal ischemic injury results in substantial alterationin neuroanatomical pathways interconnectingcortical areas.

Additional studies will be needed to determine thefunctional significance of this neuroanatomicalrewiring.


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Therapeutic windowsafter stroke

Acute phase Chronic phase

Pharmacotherapy Physical/occupational therapy

Adjuvant therapies

D-amphetamine

Electrical stimulation

Effects of D-Amphetamine + training onmotor recovery and brain plasticity

Post-infarct day 10: 0.25 mg/kg d-amph orsaline; reach/retrieval training

Post-infarct days 11-23: reach/retrievaltraining

Barbay et al., Neurorehab Neural Repair, in press; Stroemer, et al, Stroke, 29:2381, 1998

Cortical Electrical Stimulation

Adkins-Muir & Jones, Neurol Res, 2003


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Cortical electrical stimulationcombined with physiotherapy


Dendritic structural changesinduced by cortical stimulation


Epidural electrode implanted over hand area inaffected hemisphere as identified by f MRI

The lead is tunneled to the subclavicular IPG

pocket IPG programmed via an external device Stimulation activated during targeted

rehabilitation activities

The Stroke Recovery Treatment System TM*Developed by Northstar Neuroscience, Inc

* Caution: Investigational device. Limited by Federal (or United States) law to investigational use.


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Cortical stimulation parameters

Frequency Intensity Pulse width Mode (mono- bi-polar) Polarity Temporal pattern Location Time after infarct

Teskey

Sheffield, Fowler

KleimJones

Nudo, Plautz

KUMC Cooperative Program inTranslational Research (U54)

2005-2009

Putative mechanisms Physiological

Excitability changes in CS neurons Excitability changes in spinal cord motoneurons Receptor/neurotransmitter regulation (GABA, glutamate) Recruitment of local networks LTP, LTD Suppression of contralesional hemisphere

Anatomical Dendriticgrowth Axonal growth Other neurotrophic influences Angiogenesis Stem cells

Generation of new cortical tissue andfunctional recovery after stroke

Kolb et al., J Cereb Blood Fl Metab, Epub ahead of print, 2006


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Combinatorial approaches tobrain repair: principles and considerations

Brain plasticity occurs throughout life. Brain plasticity is common in widespread regions of

cortical and subcortical structures. Much like developmental sensitive periods, injury-

induced plasticity follows temporally programmedcascades of growth-promotion and inhibition.

The most effective approaches for restoration offunction after CNS injury are likely to combineprosthetic devices with pharmcacological andbehavioral interventions.

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NudoKeck Updated 10-13-06