Review Article

Introduction: The
Address correspondence
to Dr Mary L. Dombovy,
Unity Health System
Dept of Physical Medicine

Evolving Field of and Rehabilitation,

89 Genesee St,
Rochester, NY 14611,

Neurorehabilitation mdombovy@unityhealth.org.
Relationship Disclosure:
Dr Dombovy’s institution
is compensated for her
Mary L. Dombovy, MD, MHSA, FAAN litigation and testimony.
Unlabeled Use of
Products/Investigational
ABSTRACT Use Disclosure:
Dr Dombovy discusses the
Over the past 15 years, our understanding of how the nervous system responds to unlabeled use of
brain injury, spinal cord injury, and stroke has expanded exponentially. Research dem- pharmaceuticals and
information on
onstrates that the CNS, once thought to be unable to regenerate, maintains a degree investigational treatments.
of plasticity that responds to activity and pharmacologic therapy, producing both Copyright * 2011,
neurophysiologic changes and clinical recovery. Removing barriers to optimize axonal American Academy of
regrowth appears to further enhance this plasticity. Functional imaging, magnetic Neurology. All rights
reserved.
stimulation, and quantitative electroencephalography allow investigators to localize
and monitor changes in brain activity during both spontaneous recovery and treatment
paradigms. Neurorehabilitation research is difficult and funding is insufficient. Newer
research approaches and better collaboration between researchers and clinicians are
warranted. Clinical adoption is slow because of cost and time pressures. Demon-
stration that treatments promoting CNS plasticity result in better functional outcomes
and reduced overall costs is needed.

Continuum Lifelong Learning Neurol 2011;17(3):443–448.

CNS PLASTICITY AND REPAIR specific behavioral training.5 With the

FOLLOWING INJURY
Until the late 1960s, researchers gener-
ally believed that once development
was over, any regeneration in the adult
CNS would be very limited and any re-
covery following insult to the brain or
spinal cord was the result of substitu-
tion (training in compensatory tech-
niques). Through the 1970s and 1980s
multiple animal studies demonstrated
CNS structural changes as well as adap-
tive improvements in both normal adult
animals and adult animals given behav-
iorally specific training following inju-
ries.1,2 Moving from the 1990s into the
current decade, research investigated
neural stem cell therapy,3,4 nerve growth
factors, and enzymes that produced
local environments favorable to neuro-
nal and axonal growth. Recently, these
approaches have been combined with
advent of functional imaging and mag-
netic stimulation, the past decade wit-
nessed documentation in adult humans
of neural network reorganization during
recovery and in response to behavioral
therapy and pharmacologic manipula-
tion well past the period of spontaneous
recovery.1,6Y8 What have we learned?
What are the implications for clinical
practice?
CNS plasticity involves neurogenesis,
programmed cell death, dendritic and
axonal sprouting, long-term potentia-
tion and long-term depression of synap-
tic transmission, and recruitment of the
adjacent cortex and the contralateral
hemisphere. As a concept, plasticity re-
fers to changes in neural networks in
response to training, injury, rehabilita-
tion, pharmacotherapy, electrical and
magnetic stimulation, and stem cell

Continuum Lifelong Learning Neurol 2011;17(3):443–448 www.aan.com/continuum 443

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 Introduction

KEY POINTS
h CNS neural networks
have a greater capacity
to reorganize than
previously thought.
h Plasticity refers to
changes in neural
networks in response
to injury, training,
pharmacotherapy,
stimulation techniques,
and cellular therapies.
h Transplanted cells
produce their effects
by enhancing the local
environment rather
than by multiplication
or tissue integration.
h Specific activity is
required to promote
adaptive plasticity.
h Widespread cortical
activation is associated
with incomplete
recovery; focal
activation near the
involved area is
associated with
good recovery.
h Activation of the
uninvolved hemisphere
may interfere
with recovery.
and gene therapy.5,6,9 Although activity-
directed plasticity can be beneficial, left
undirected it may be abortive and de-
trimental, resulting in spasticity, aber-
rant movement, and neuropathic pain.1
Even with appropriate activity, regen-
eration in the CNS is limited because of
local structural (glial scar), chemical,
and hormonal microenvironments that
restrict growth.5,7 Interestingly, follow-
ing stem cell or progenitor cell injec-
tions, very few of the cells survive. An
increasing number of studies suggest
that exogenous cells serve as a source
of trophic support, enhancing regener-
ation of existing neurons in both the
brain and spinal cord.10Y12 Bersano and
colleagues13 conclude: ‘‘It is emerging
that cell therapy works mostly by pro-
viding trophic support to the injured
tissue and brain, fostering both neuro-
genesis and angiogenesis.’’ Evidence is
also mounting from animal models in
studies using stem and progenitor cells
and neuronal growth factors that spe-
cific activity involving the impaired
parts is necessary to promote func-
tional recovery after brain and spinal
cord injury.14,15
Theories of recovery following brain
injury and stroke have evolved: Exten-
sive use of widespread uninjured areas
of the brain during activity of the in-
volved part is not associated with the
best recovery, but rather with incom-
plete recovery. Better recovery, whether
motor or language, is associated with
smaller areas of activation. fMRI, trans-
cranial magnetic stimulation (TMS), and
transcranial direct current stimulation
(tDCS) allow monitoring of brain activity
during recovery. TMS and tDCS can also
be used to manipulate brain activity at
rest and during rehabilitation while ob-
serving clinical effects. Soon after a
stroke, brain activation during sensori-
motor tasks involving the affected upper
extremity occurs in multiple cortical
areas, including the primary, premotor,
and supplementary motor areas of both
hemispheres. In those experiencing a
good recovery, over time this area con-
tracts, involving only the peri-infarct and
connected cortical areas of the involved
hemisphere.16Y18 Patients with poor re-
covery continue to show a more diffuse,
and at times contralesional, activation
during sensorimotor tasks.16
Another study19 confirms a similar
pattern of cortical reorganization during
recovery of motor function in the lower
extremity. Using PET combined with
TMS, Winhuisen and colleagues20 dem-
onstrated activation of the right inferior
frontal gyrus in those with poor recov-
ery from aphasia during performance
on a semantic task. Those with good
recovery demonstrated a more ‘‘normal-
ized’’ activation of the left hemisphere.
Using serial fMRI and a comprehension
task in poststroke patients with aphasia,
Saur and colleagues21 demonstrated
early widespread activation in both hemi-
spheres that consolidated as recovery
progressed, with near-normal activation
of the left hemisphere language area in
those with excellent recovery.
Over the past several years, numerous
studies have demonstrated that rehabil-
itation programs based on repetitive
practice involving the affected extremity
and reduction of sensory input to the
unaffected extremity produce both cor-
tical reorganization and clinical improve-
ment.22,23 Suppression of the intact
contralateral hemisphere via TMS and
tDCS both induces cortical changes and
produces clinical improvement follow-
ing stroke.24 Although the effects were
moderate and short-lived in most sub-
jects, the treatments produced no ad-
verse effects, and pairing TMS or tDCS
with therapy over a longer time period is
under investigation.25 A further discus-
sion of emerging approaches to therapy
occurs in a subsequent article.
Most studies of recovery and the ef-
fects of therapy following brain injury

444 www.aan.com/continuum June 2011

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have focused on motor function follow-
ing stroke, and other deficits such as
neglect, cognitive function, memory, and
aphasia have received less attention. A
recent investigation showed promising
effects of inhibitory TMS in suppressing
the right hemisphere Broca analogue to
improve naming in patients who were
more than 5 years poststroke.26 Another
report revealed that a breakdown in
ventral frontoparietal networks under-
lies behavior deficits in spatial neglect
and that nonspatial attention training
both improved neglect and showed
changes in cortical activation in these
networks.27
Although to date traumatic brain in-
jury (TBI) has received less attention, lit-
erature is emerging to describe patterns
of cortical reorganization during sponta-
neous recovery and in response to reha-
bilitation strategies. Kim and colleagues28
used fMRI to describe changes in the at-
tentional network after TBI that shifted
activation from the anterior cingulate gy-
rus to the frontal and temporal parietal
areas. Following a cognitive/attentional
retraining task, activation shifted more to-
ward the cingulate gyrus, thus approach-
ing a more normal pattern. Dobkin29
suggests that investigators consider
working across disease platforms,
focusing on specific impairments and
disabilities rather than separating re-
search by diagnostic or disease cate-
gory. Stroke and spinal cord injury (SCI)
remain easier to study because of the
focal nature of the injury, as compared
to TBI where the injury is complex,
superimposing areas of focal damage
upon diffuse injury.
Cellular transplantation and use of
trophic factors and other pharmacologic
therapies after SCI have shown some
success in both human and animal
models.10,30 Olfactory axons possess a
unique ability to penetrate the glial scar
that forms at the site of injury. A recent
study demonstrated the ability of im-
Continuum Lifelong Learning Neurol 2011;17(3):443–448
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
planted olfactory glia to produce axons
that bridged the gap between avulsed
dorsal roots and the dorsal root entry
zone of the spinal cord when driven
by a training program.31 This anatomic
connection correlated with recovery of
skilled paw function. The importance of
functionally specific training is demon-
strated by other studies that show that
a rehabilitation task not identical to the
desired behavior/pattern of use may
produce undesirable results.32Y34 Con-
cern exists that aberrant regeneration
in the spinal cord may lead to the in-
creased spasticity and neuropathic pain
often seen in people with partial SCI.
In humans, rehabilitation approaches
using body weightYsupported tread-
mill training in incomplete SCI show
promise for improving overground
ambulation.35
Major unsolved questions remain:
Which cellular implants and trophic
factors produce the best results? Given
that training is an important adjunct to
cellular therapies after SCI, TBI and
stroke,15,36,37 what is the optimal tim-
ing, duration, and intensity of therapy?
Because improvement after rehabilita-
tion interventions appears to be limited
in those with severe impairments and
limited corticospinal tract integrity after
SCI and stroke, who should be the re-
search subjects? Chronicity and stability
of baseline function may be important
for determining effects of treatment,
but the early phase postinjury may re-
present the best time to enhance recov-
ery. Evidence also suggests that both
presurgical and postsurgical rehabili-
tation programs may be important in
those undergoing cellular implantation
procedures.15
As our understanding of the tremen-
dous potential for recovery after neuro-
logic injury evolves, translation of this
knowledge into clinically meaningful
results and useful treatments has been
slow. Nervous system reorganization
www.aan.com/continuum 445
 Introduction
KEY POINTS
h Basic research is
disconnected from
clinically meaningful
intervention.
h Collaborative models
and new research
designs are needed.
446 www.aan.com/continuum
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
is complex, involving multiple levels,
systems, and connections. The process
involves molecular, anatomical, and
neurochemical changes. Neural net-
works are dynamic, with constant mod-
ification occurring as a result of activity,
environment, injury, and recovery.
When a focal injury to the nervous sys-
tem occurs, the deficits and the recov-
ery are the result of this experience-
driven reorganization rather than the
result of the loss of a particular focal
area of tissue.
Current models for translating basic
science discoveries into clinically mean-
ingful rehabilitation approaches have
failed. The Cumberland Consensus
Working Group38 enumerates the fol-
lowing problems: (1) most clinical trials
are small in scale; (2) patient recruit-
ment for larger trials is difficult; (3)
outcomes, especially those that are
meaningful to patients, remain ill de-
fined; (4) basic research in academia is
poorly integrated with practical issues in
clinical settings; and (5) partnerships
among industry, patients, and clinicians
are poorly developed. In addition, fund-
ing for clinical research remains limited.
Researchers and clinicians pursue indi-
vidual approaches to improving neural
restoration, facilitated by a system of
funding that does little to encourage
collaboration across disciplines. For ex-
ample, a basic scientist may spend a
lifetime developing molecules to facili-
tate neurogenesis in a rat to cause a
small but measurable impact on grasp-
ing, while a clinician is looking for ways
to get a patient to a functional level that
enables return home. The randomized
controlled trial, the standard of research
design, makes the identification of pos-
sible treatment effects against the back-
ground of clinical recovery a major
challenge.
Because of time constraints on ther-
apy, lack of support and funding, a scien-
tific community driven by the number of
publications, and declining clinician
reimbursement and pressure to reduce
length of stay, the molecule may never
see meaningful utility. The translational
research pipeline from discovery to
clinical implementation for neurorehabi-
litation and restorative neurology is
stagnated. Cheeran and colleagues38
encourage a change in funding mecha-
nisms to target consortiums that include
basic and clinical scientists, clinicians,
and patient representatives to facilitate
research that results in clinical imple-
mentation. Forsyth and colleagues39
offer disease process modeling, using
endpoints derived from models of re-
covery trajectories, as an alternative to
the randomized controlled trial. Com-
parative effectiveness research, in which
a specific treatment approach is com-
pared to another treatment approach,
may also help compare the benefits of
one rehabilitation treatment to another
without assigning patients to a control
group.
Creative methods of care delivery and
reimbursement are needed to facilitate
implementation of those approaches that
have already been shown to be beneficial.
This requires physician leadership in
both policy development and in the
day-to-day direction of the rehabilitation
team. Neurorehabilitation physicians
must insist on implementation of new
approaches that produce superior out-
comes and remain actively involved in
advocating for their patients and pushing
for the funding of ongoing research.
ACKNOWLEDGMENT
I would like to thank Nancy Stuhlmiller
for her countless hours of work and
support for this project and all of
the members of Unity Health System’s
Department of Rehabilitation and
Neurology who wrote articles and
participated in the production of the
issue.
June 2011
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