Prosthetics Applications in

Plastic Brain
Smart Prosthetics:
Exploring Assistive Devices for the Body and Mind

The National Academies/ Keck Futures Initiative

Irvine, California

Randolph J. Nudo, Ph.D.

Director, Landon Center on Aging
Professor, Department of Molecular and
Integrative Physiology
University of Kansas Medical Center
Kansas City, KS
Theo & Alfred M. Landon Center on Aging

What is brain plasticity?

• Brain plasticity is the capability of the brain to
alter its functional organization as a result of
experience.
• As such, plasticity refers to the phenomenon
of change, not to the specific underlying
mechanisms.

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 induce

synaptic plasticity (plasticity of plasticity)

1
 Why is plasticity is important for brain
prosthetics applications?
• Premise: Effectiveness of brain-machine
interface dependent upon activity-driven
remodeling 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 brain
plasticity principles
Flourens - 1840s Sherrington - 1910s

• 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

Somatosensory cortex plasticity

Merzenich and colleagues

2
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

3
 Mapping the motor cortex

Intracortical microstimulation

Anatomy of cortical motor outputs

Rathelot & Strick, PNAS, 103:8257, 2006

4
 Remodeling of motor cortex
after skill training

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

Structural changes associated with

motor 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 million
worldwide

5
 Motor recovery after stroke
Human stroke Monkey experimental infarct
100%

Manual Performance
Subtot. M1 hand

Total M1 hand

M1+PM hand

Prox MCAO

0 1 3 6
Months post-infarct

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

Theories of recovery
after 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 on

adjacent, M1 motor maps

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

6
Effects of M1 infarct on PMv maps
Before stroke
60

40
% PMV GAIN
20

0
20 30 40 50 60 70 80 90 100
-20
5 mos. after stroke
-40
% M1 LOSS

Lashley’s principles of mass

action/equipotentiality: Was he right?

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

Axonal sprouting in adult cortex

• Local sprouting in visual cortex after
experimental scotoma (Darian-Smith &
Gilbert, 1994)
• Lesion-induced corticostriatal sprouting
(Napierski, et al., 1996)
• Intracortical sprouting after peripheral nerve
injury (Florence, et al,. 1998)

Intracortical sprouting after injury

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

7
 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

3%

8%

2%
1% 28% 6% 2%
1%

22%

8%

7%

Dancause et al., J Comp Neurol, 2006

8
 Novel projections of PMv to S1
Normal 5 months post-infarct

1/2
1/2

PO/IP

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

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

Axonal trajectory of novel pathway

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

Novel intracortical pathways

after cortical injury

9
 “All the king’s horses and all
the king’s men…”

Temporal profile of remote events

Carmichael, Exp Neurol 193:291, 2005

Summary
• Non-human primate models provide unique
opportunities to examine plasticity of complex
cortical networks after experimental ischemia.
• Focal ischemic injury results in substantial alteration
in neuroanatomical pathways interconnecting
cortical areas.
• Additional studies will be needed to determine the
functional significance of this neuroanatomical
rewiring.

10
 Therapeutic windows
after stroke

Pharmacotherapy Physical/occupational therapy

Acute phase Chronic phase

Adjuvant therapies

D-amphetamine
Electrical stimulation

Effects of D-Amphetamine + training on

motor recovery and brain plasticity

• Post-infarct day 10: 0.25 mg/kg d-amph or

saline; reach/retrieval training
• Post-infarct days 11-23: reach/retrieval
training

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

Cortical Electrical Stimulation

Adkins-Muir & Jones, Neurol Res, 2003

11
 Cortical electrical stimulation
combined with physiotherapy

Adkins-Muir & Jones, Neurol Res, 2003

Dendritic structural changes

induced by cortical stimulation

Adkins-Muir & Jones, Neurol Res, 2003

The Stroke Recovery Treatment SystemTM*

Developed by Northstar Neuroscience, Inc

• Epidural electrode implanted over hand area in

affected hemisphere as identified by fMRI
• The lead is tunneled to the subclavicular IPG
pocket
• IPG programmed via an external device
• Stimulation activated during targeted
rehabilitation activities

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

12
 Cortical stimulation parameters

• Frequency
• Intensity
Teskey
• Pulse width
• Mode (mono- bi-polar) Sheffield, Fowler
Nudo, Plautz
• Polarity
• Temporal pattern Jones Kleim

• Location KUMC Cooperative Program in

• Time after infarct Translational 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
– Dendritic growth
– Axonal growth
– Other neurotrophic influences
– Angiogenesis
– Stem cells

Generation of new cortical tissue and

functional recovery after stroke

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

13
 Combinatorial approaches to
brain 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 programmed
cascades of growth-promotion and inhibition.
• The most effective approaches for restoration of
function after CNS injury are likely to combine
prosthetic devices with pharmcacological and
behavioral interventions.

14