Special Report

Brain Plasticity and Stroke Rehabilitation

The Willis Lecture
Barbro B. Johansson, MD, PhD

Abstract—Neuronal connections and cortical maps are continuously remodeled by our experience. Knowledge of the
potential capabilityof the brain to compensate for lesions is a prerequisite for optimal stroke rehabilitation strategies.
Experimental focal cortical lesions induce changes in adjacent cortex and in the contralateral hemisphere. Neuroimaging
studies in stroke patients indicate altered poststroke activation patterns, which suggest some functional reorganization.
To what extent functional imaging data correspond to outcome data needs to be evaluated. Reorganization may be the
principle process responsible for recovery of function after stroke, but what are the limits, and to what extent can
postischemic intervention facilitate such changes?
Postoperative housing of animals in an enriched environment can significantly enhance functional outcome and can
also interact with other interventions, including neocortical grafting. What role will neuronal progenitor cells play in
future rehabilitation—stimulated in situ or as neural replacement? And what is the future for blocking neural growth
inhibitory factors? Better knowledge of postischemic molecular and neurophysiological events, and close interaction
between basic and applied research, will hopefully enable us to design rehabilitation strategies based on neurobiological
principles in a not-too-distant future. (Stroke. 2000;31:223-230.)
Key Words: neuronal plasticity n recovery n rehabilitation n stroke

S ince regeneration of transectioned central axons has

never been convincingly demonstrated in higher mam-
mals, it seems in most instances that one must resort to the
cortical representation areas, cortical maps, can be modified
by sensory input, experience, and learning (Figure 1), as well
as in response to brain lesions.17–30 The potential relevance
assumption that intact fibers take over for the damaged for stroke rehabilitation of those data was proposed more than
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ones.”1 a decade ago.19 Transient alterations of cortical representation

The above words were written in 1973 by Alf Brodal, a
Norwegian neuroanatomist, based on his own experience
after a stroke. To what extent has his assumption been shown
to be correct? In this review I will present current concepts on
brain plasticity in intact and lesioned brain, and evidence that
postischemic interventions can alter molecular events and
influence functional recovery after brain lesions.
Current Concepts on Brain Plasticity
That neuronal cortical connections can be remodeled by our
experience was suggested by Hebb half a century ago.2,3
Since then, many studies have demonstrated chemical and
anatomic plasticity in the cerebral cortex of adult animals.4 –16
Animals reared or housed as adults in complex environments
with access to various toys and activities develop more
dendritic branching and more synapses per neuron and have
higher gene expression for trophic factors than animals
housed individually or in small groups in standard cages.4 –12
Similar changes can be induced during learning.13–16
Another aspect of brain plasticity, first and most exten-
sively demonstrated by Merzenich and coworkers, is that
areas may be common in everyday life, as indicated by
transcranial magnetic stimulation studies during learning
tasks in human volunteers.31 If we regularly have to perform
a very skilled motor task, the cortical representation for the
muscles involved will remain enlarged, as seen for the fingers
of the left but not the right hand in string players.32 Similarly,
the sensorimotor cortical representation of the reading finger
is expanded in blind Braille readers33 and, furthermore,
fluctuates with the reading activity pattern.34
Possible Mechanisms Behind Brain Plasticity
Several mechanisms are likely to be involved in brain
plasticity.35 Activity-dependent modification of synaptic con-
nections and reorganization of adult cortical areas are thought
to involve long-term potentiation (LTP) and long-term de-
pression (LTD), mechanisms by which information is stored
in the mammalian central nervous system.36 –37 Synaptic
plasticity in cortical horizontal connections has been pro-
posed to underlie cortical map reorganization.38 – 40 Gluta-
mate, the main excitatory neurotransmitter, plays a crucial

Presented as the Willis Lecture at the 24th American Heart Association International Conference on Stroke and Cerebral Circulation, Nashville, Tenn,
February 4, 1999. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
From the Division for Experimental Neurology, Wallenberg Neuroscience Center, University Hospital, Lund, Sweden.
Correspondence to Barbro B. Johansson, MD, PhD, Division for Experimental Neurology, Wallenberg Neuroscience Center, University Hospital,
S-221 85 Lund, Sweden. E-mail Barbro.Johansson@neurol.lu.se
© 2000 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org

223
 224 Stroke January 2000
Figure 1. The area or somatosensory cortex (black) in a mon-
key before (A) and after (B) controlled tactile stimulation.
Reprinted with permission.21
role. Cortical map reorganization in the primary somatosen-
sory cortex can be prevented by blockade of N-methyl-D-
aspartate (NMDA) receptors.41– 43 g-Aminobutyric acid
(GABA)-A receptor antagonists can facilitate LTP induction
in neocortical synaptic systems, and the induction can be
blocked by GABA-A receptor agonists.40 Transmitters re-
leased by the diffuse neuromodulatory systems originating in
locus coeruleus (noradrenalin), nucleus basalis (acetylcho-
line), lateral tegmentum (dopamine), and raphe nuclei (sero-
tonin) may modify the process.44,45 Nitric oxide is another
candidate for dynamic modulation of cerebral cortex synaptic
function.46 There is evidence that mechanisms involved in
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synaptic plasticity varies between cortical regions.35,47 Local
neurotrophin actions, transmitter release, and synaptic protein
synthesis are thought to promote synaptic remodeling and
changes in receptor expression or activation.12 As illustrated
in Figure 2, dendritic spines, which receive the vast majority
of excitatory synaptic contacts in the mammalian brain, are
continuously being formed and modified.48
There is increasing evidence that astrocytes take an active
part in synaptic plasticity.49,50 Rapid astrocytic changes in
cortex and ultrastructural evidence for increased contact
between astrocytes and synapses in rats reared in a complex
environment suggest a close relationship between astrocytic
plasticity and experience-induced synaptic plasticity.51,52
Nonsynaptic transmission may also play a role in plasticity
processes.53 Plastic changes occur not only in the cortex but
have also been demonstrated in subcortical regions, including
thalamus and brain stem.54,55
Spontaneous Events and Training Effects
After a brain lesion, changes in other brain regions have been
documented at different postlesion times, from minutes to
months.54,55 Postlesion events may be due to deafferentation,
removal of inhibition, activity-dependent synaptic changes,
changes in membrane excitability, growth of new connec-
tions, or unmasking of preexisting connections.27 Unmasking
has generally been proposed to be responsible for rapid
changes in cortical maps,56 and there is evidence that synaptic
plasticity can be very rapid.48
Cortical mapping by intracellular recordings in primates
has demonstrated that the tissue surrounding a small lesion in
the hand-representation area of primary motor cortex in adult
monkeys undergoes a further territorial loss in the functional
representation of the affected body part, perhaps through
nonuse or disruption of local intrinsic cortical circuitry.28 This
further tissue loss could be prevented and functional reorga-
nization in the undamaged surrounding motor cortex stimu-
lated by retraining of hand use, starting 5 days after induction
of the lesion.29 Similarly, reorganization of primary somato-
sensory cortex occurs in parallel with sensorimotor skill
recovery in monkeys after restricted lesions. No significant
changes were recorded in the hand representation area in
somatosensory cortex in the opposite intact (untrained)
hemisphere.30
Figure 2. Confocal images of dendritic
spines of pyramidal neurons from
somatosensory cortex in an adult rat
housed together with 3 other rats in a
standard cage (left) or during 3 weeks
housed in an enriched environment
(right). Lucifer yellow, a fluorescent dye,
has been microinjected into the individ-
ual neurons (P. Belichenko, MD, PhD,
and B.B. Johansson, MD, PhD, unpub-
lished data, 1998).

Morphologic studies in the rat indicate that cortical lesions
can induce an increase of dendritic branching in the contralat-
eral hemisphere, with a maximum 2 to 3 weeks after the
lesion.57 If the rats were prevented from using the intact
forelimb, both the morphologic changes and functional re-
covery were inhibited.58 Although some studies with other
techniques could not verify those findings,59,60 a detailed
electromicroscopic longitudinal study61 has confirmed the
development of time-dependent morphologic changes with a
significant increase in dendritic volume in cortical layer of
the contralateral motor cortex 18 days after the lesion, and in
the number of synapses per neuron 30 days after the lesion.
After a focal brain infarct, an increased density and
distribution of GAP 43 immunoreactivity has been observed
in the ipsilateral cortex 3 to 14 days after the vascular
occlusion and of synaptophysin immunoreactivity in the same
areas at postoperative days 14 to 60. A larger distribution of
synaptophysin immunoreactivity was also noted in the con-
tralateral hemisphere.62 An increased neuronal labeling of
MAP-2, GAP-43, and cyclin D1 immunoreactivity from day
2 and up to 28 days has been found in the penumbra zone.63
Enriched Environment and Neurotrophic Factors
There is substantial evidence that the postoperative environ-
ment can influence the outcome after experimental brain
damage, such as traumatic brain lesions, hippocampal sec-
tioning, and cortical ablation.64,65 After an experimental brain
infarction, rats housed in an enriched environment with the
opportunity for various activities and interaction with other
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rats perform significantly better than rats housed in standard
laboratory environment,66 even when the transfer to an
enriched environment was delayed for 15 days.67 A compar-
ison between enriched environment, social interaction, and
physical activity in the form of wheel-running indicated that
social interaction was superior to wheel-running and that an
enriched environment which allowed free physical activity
combined with social interaction resulted in the best
performance.68
We hypothesized that the beneficial effect of enriched
environment might be caused by increased synthesis of
neurotrophic factors. Neurotrophic factors are polypeptides
capable of promoting neuronal survival. Local neurotrophin
action may promote synaptic remodeling and changes in
receptor expression.12 Ischemia is a strong inducer of gene
expression in the brain.69 –71 More than 90 different genes
have been shown to be acutely induced, generally with an
early peak within minutes or hours of onset of ischemia and
a rapid return to normal or subnormal levels. Whether the
early transient increase in gene expression during the initial
postischemic hours is related to outcome is not known. There
is some evidence that trophic factors can rescue neurons in
the acute stage. In addition to reducing infarct size even when
given hours after the ischemic insult, basic fibroblast growth
factor (bFGF) may attenuate the thalamic degeneration fol-
lowing cortical infarction.72–74 Nerve growth factor (NGF)
has been reported to improve memory and motor functions
and reduce dendritic atrophy in the remaining pyramidal
neurons.75 As reviewed elsewhere,76 several other growth
factors, including brain-derived growth factor (BDNF), insu-
Johansson Stroke and Brain Plasticity 225
lin growth factor-1, transforming growth factor b1, and glial
cell line– derived neurotrophic factor, have been reported to
be beneficial in the early ischemic period. Whether some of
these trophic factors can be beneficial in the rehabilitation
phase has not yet been evaluated. Because of the poor
penetration of many growth factors into the brain, an inter-
esting approach is to use substances that induce endogenous
growth factor synthesis in the brain after peripheral adminis-
tration. A b2-adrenoceptor agonist as been shown to reduce
infarct volume and induce an earlier and more pronounced
increase in mRNA of nerve growth factor (NGF), bFGF, and
transforming growth factor-b1 (TGF-b1) than was seen in
untreated rats after permanent focal ischemia. 77
Cholecystokinin-8 increases both NGF protein and NGF
mRNA in mouse cortex and hippocampus when injected
intraperitoneally at physiological doses and may thus repre-
sent a potential experimental model for investigating the
effects of endogenous NGF upregulation after brain lesions.78
Based on data on the role of BDNF for plasticity in the
intact brain,79,80 we have studied the late postischemic gene
expression for this protein in rats killed 2 to 30 days after the
ischemic event. Moreover, intraventricular BDNF has been
shown to rescue neurons in acute ischemia.81 Unexpectedly, a
secondary increase in BDNF gene expression observed in
control rats did not occur in rats housed in an enriched
environment, who had significantly lower BDNF expression
in ipsilateral and contralateral cortex than rats in a standard
environment 2 to 12 days after the insult.82 Similar results
were obtained for expression of NGFI-A mRNA,83 a gene
that earlier had been shown to be activated in an enriched
environment in intact rats.10 However, a late increase of
NGFI-A mRNA expression was observed at 30 days after the
lesion, which suggested that it might be important for later
postischemic events.83
The reason for the early dampening of the postischemic
increase seen in control animals for BDNF is not clear. BDNF
is related to synaptic activity. Cortical networks adjacent to a
focal brain ischemia are hyperexcitable because of an imbal-
ance between excitatory and inhibitory synaptic func-
tion.84 – 86 Hyperexcitability has been recorded not only
around the infarct but also in the contralateral hemisphere
measured 1 week after the ischemic event.87– 89 Both a
detrimental role (impaired processing of incoming informa-
tion) and a beneficial role (adaptation and favorable recovery)
of this hyperexcitability have been proposed.87 Could it be
that rats in an enriched environment have a better balance
between inhibitory and excitatory transmission and that
depression of hyperexcitability might be beneficial in the
early stage? Clearly, more studies are needed before any
conclusions can be drawn. The relationship between growth
inhibitory and growth promotor factors are likely to be
important, and it should be noted also that growth inhibitory
factor mRNA is increased during the postischemic period
after focal ischemia in the rat.90 The recent reports on
increased corticofugal plasticity after neutralization of a
myelin-associated neurite growth inhibitor is a reminder that
inhibitors of brain plasticity may be just as important as
stimulating factors for postischemic functional outcome.91,92
 226 Stroke January 2000
Pharmacological Interventions
The possible role of pharmacological interventions in the
postischemic rehabilitation phase has been extensively re-
viewed by other authors.93–98 I will here restrict myself to a
few comments. Considering the many complex events that
occur in postschemic brain, it is likely that the efficacy of a
drug can vary with the postischemic time, size and type of
lesion, and interactions with other therapeutic interventions.
In a recent review, Schallert and Hernandez97 write: “depend-
ing on the site, extent and nature of the injury and secondary
degenerative events, and the timing of drug administration,
GABA agonists may have either negative or positive effects.
In many research reports, rather bold suggestions have been
offered about the potential clinical efficacy of GABAergic
drugs without regards to these important variables”. Interac-
tions between drugs and environmental factors is another
aspect. If combined with test-specific training, norepineph-
rine, amphetamine, and other a-adrenergic stimulating drugs
can enhance motor performance after unilateral ablation of
sensorimotor cortex95,99 and have also been shown to enhance
the immunoreactivity to synaptic proteins after focal brain
ischemia.100 However, amphetamine had no additional effect
on outcome in rats housed in an enriched environment after
focal brain ischemia,101 perhaps due to enhanced noradrener-
gic release under such housing conditions.
What Is the Possible Role of Neurogenesis?
Neural stem cells, multipotential cells that are precursors to
neurons and glia, have been identified in the adult vertebrate
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central nervous system. Although first reported to be present
in brains from rodents in the sixties,102,103 it is only during the
last years that they have been extensively studied.104,105 They
are predominantly found in the periventricular ependymal or
subependymal zone and in the dentate gyrus but may also be
present in small numbers in other regions.106 Stem cells from
the adult brain proliferate and differentiate into neurons and
glia in tissue culture with the same efficiency for neuronal
differentiation as found in fetal stem cells. That stem cells are
present also in human brains was first shown in tissue culture
from the subependymal zone and periventricular white mat-
ter.107 Recent studies have shown that they can differentiate
to neurons in the adult human dentate gyrus in vivo.108 With
the observation that such cells in experimental studies can be
manipulated in vivo by growth factors and by environmental
enrichment,109 –111 the clinical potential of in vivo manipula-
tion of stem cells in humans is currently subject to much
speculation.104 –106
The aspects of neurogenesis that are relevant for this
review are the following: (1) Does neurogenesis increase in
response to brain lesions? (2) If so, is neurogenesis related to
outcome? (3) Can those events be influenced by postlesion
interventions? and (4) Can stem cells or progenitor cells be
used for transplantation after stroke? The first question can be
answered affirmatively. It has been shown to occur in
excitotoxic and mechanical lesions in the dentate gyrus
(hippocampus) in the adult rat112 and after transient global
ischemia in gerbils.113 The second and third questions remain
to be answered, and the fourth question will be discussed in
the transplantation section below.
Transplantation
As reviewed elsewhere, implantation of fetal neocortical cells
after cortical lesions has been performed successfully in
several laboratories.76 Transplanted cells can interact with the
host tissue by forming connections but also by being a source
of trophic factors that can influence the surrounding tissue.
Although both anatomic and functional integration with the
host brain have been observed,114 improvement in behavioral
tests have been noticed only when transplantation is com-
bined with posttransplantation housing in an enriched envi-
ronment.115,116 If performed 1 week after ligation of the
middle cerebral artery, but not if delayed for 3 weeks, the
combined procedure can improve functional outcome more
than an enriched environment alone, and it can also reduce
the secondary thalamic atrophy that occurs after cortical
lesions. Although grafting can successfully be performed at
later postischemic times, there is so far no evidence for
functional improvement at later times.
Immortalized embryonic neuronal cells lines or cultured
neural multipotent progenitor cells (the transition from stem
cell to progenitor cell is not sharp) implanted into a lesioned
brain have shown promising results in other experimental
models. When implanted into the neocortex of adult mice
undergoing targeted apoptosis of neocortical pyramidal neu-
rons, they migrate long distances into the regions of cell
death, where they differentiate and make appropriate long-
distance projections.117–119 The results indicate the presence
of environmental signals that promote differentiation of the
implanted cells. Furthermore, adult mature astrocytes in the
host brain have been shown to retain the capacity to transform
into developmental radial glia that may help the active
migration of transplanted neural precursors.120 Whether trans-
plantation of neuronal precursor cells to neocortical infarct
cavities would be a good substitute for the currently used fetal
neocortical tissue block techniques remains to be
demonstrated.
Clinical Evidence for Reorganization of
Cortical Networks
Studies using PET, functional MRI (fMRI), transcranial
stimulation, and magnetoencephalography (MEG) support
the concept of functional reorganization after stroke.121–130
PET studies on blood flow distribution during finger move-
ments in a previously paretic hand have demonstrated com-
plex patterns of activation, with increased activity with large
individual variations.121,122 Until now, studies comparing the
degree and pattern of activation in patients with good and
less-than-good recovery and with specific therapeutic inter-
ventions are few, and the published data are sometimes
contradictory. Because of large individual variations, careful
longitudinal studies of individual patients with specific defi-
cits and well-defined lesions are needed. Individuals may use
different compensation strategies before and after training,128
and the activation pattern can change with time. It has been
reported that changes in activation pattern can be induced by
forced training of the paretic hand even 4 to 15 years after
stroke onset.131 The knowledge that the degree of cortical
lateralization and interhemispheric interaction varies for spe-
cific language components in the normal human brain may be

relevant for the interpretation of data on aphasic
individuals.132
Stroke Units and Early Training
It is well established that early mobilization can reduce
secondary thromboembolic events, pneumonia, and mortality
in acute stroke.133–135 It is now recommended that stroke
patients be admitted to specialized stroke units with specially
trained medical and nursing staff, coordinated multidisci-
plinary rehabilitation, and education programs for patients
and their families. Stroke unit care has been shown to be
associated with a long-term reduction of death and of the
combined poor outcomes of death and dependency, effects
that were independent of patient age, sex, or variations in
stroke unit organization. No study has shown to what extent
the beneficial effect is due to specific rehabilitation strategies,
to the daily time spent in physiotherapy and occupational
therapy, or is a nonspecific effect of a more stimulating
environment with competent staff that can encourage and
support the patients and family members. Scientific evidence
demonstrating the values of specific rehabilitation interven-
tions after stroke is limited. Comparisons between different
methods in current use have so far failed to show that any
particular physiotherapy or stroke rehabilitation strategy is
superior to another. There is some evidence that forced use of
a paretic arm may improve function in the chronic
stage.121,136 –138
Clinical data are thus strongly in favor of early mobiliza-
tion and training. On the other hand, there are some disturb-
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ing animal data indicating that overtraining of the lesioned
forelimb induced by immobilization of the intact forelimb can
expand cortical lesions.139,140 Referring to those studies,
Nudo et al29 started training monkeys 5 days after the lesion.
Housing animals in an enriched environment with the oppor-
tunity to perform various activities but no specific training
significantly improves functional outcome without increasing
tissue loss. However, if combined with more specific training
from 24 hours after the insult, an increased tissue loss was
observed.141 Despite the larger tissue loss in the early training
group, the rats improved more than standard rats, confirming
earlier data of poor correlation between infarct volume and
functional outcome in rats housed in an enriched environ-
ment. The better outcome in the early training group than in
standard rats may be related to compensatory adaptation in
the contralateral hemisphere, subcortical region, or
cerebellum.
Even if the increased tissue loss did not correspond to
unfavorable outcome, it is clearly an unwanted effect, one
which might make the brain more vulnerable to additional
insults or aging. What could be the course of this vulnerable
early postischemic period? Motor activity stimulates the
release of glutamate and catecholamines.142 One possible
explanation for the increased tissue loss might be that
hyperexcitability of the surrounding tissue in the early post-
ischemic period makes the surrounding neurons vulnerable to
excitation. As discussed above in the section on enriched
environment and neurotrophic factors, cortical networks ad-
jacent to a focal brain ischemia are hyperexcitable because of
an imbalance between excitatory and inhibitory synaptic
Johansson Stroke and Brain Plasticity 227
function with increased NMDA receptor-mediated excitation
and decreased efficacy of GABAergic inhibition.84 – 86 In the
presence of excitatory and toxic substances from the ischemic
tissue, an additional release of excitatory substances induced
by motor activity may be harmful in the early postischemic
stage. Consistent with this hypothesis is the observation that
the NMDA receptor antagonist MK-801can prevent second-
ary cortical damage in rats forced to use their impaired limb
after a lesion in the sensorimotor cortex.143
It is important to define the window for a possible
increased vulnerability and additional peri-infarct neuronal
loss. However, I do not think these animal data should make
us change the policy of early mobilization of stroke patients.
Housing animals in an enriched environment, which may
correspond to early mobilization, has no aggravating effects.
The most important tasks in the early stage are to prevent
complications and train the patient to regain balance and body
symmetry. In addition, cortical and lacunar infarcts may
differ.
Age and Plasticity
Age influences the impact of vascular occlusion in ro-
dents,144 –146 but does it also influence functional recovery? In
a comparison between 3- and 20-month-old rats, upregulation
of MAP1B and MAP2 was diminished but not abolished in
the aged compared with the young animals.147 It might not be
fair to compare humans with rats living their entire lives in a
laboratory with little stimulation. The decrease in synaptic
density in aged laboratory rats can be prevented by rearing in
an enriched environment.148 The loss of neurons in aging
humans is to some extent compensated for by selective
dendritic growth. A postmortem comparison of dendrites of
layer II pyramidal neurons in the parahippocampal gyrus of
adult (aged 51 years) and neurologically healthy aged (80
years) individuals showed that the dendritic trees were longer
and more branched in the healthy 80-year-olds.149 In a
population of persons aged 65 years and older, the level of
cognitive function is positively related to the frequency and
intensity of cognitive activity.150 However, it has been shown
that a head injury in young adulthood, although well com-
pensated for at the time, exacerbates cognitive decline in later
years.151 This might be relevant for individuals with repeated
stroke.
Concluding Remarks
The current trend to equate tissue loss with outcome is not
relevant when it comes to postischemic interventions, which
can improve outcome without a change in infarct volume.
That environmental stimulation improves recovery is not a
new observation,152 but it is worthwhile to point out that it can
enhance the effect of other therapies, as shown with neocor-
tical grafting.66 – 68,115 It is not only the number of neurons left,
but how they function and what connections they can make
that will decide functional outcome.
Acknowledgments
Studies from the author’s laboratory were supported by grants from
the Swedish Medical Research Council (Project 14X-4968), the
Bank of Sweden Tercentenary Foundation, the Swedish Heart and
 228 Stroke January 2000
Lung Foundation, the Swedish Association of Neurologically Dis-
abled, and the Swedish Stroke Foundation.
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