Mechanisms for recovery of motor function following
cortical damage
Randolph J Nudo
Recent studies of focal injury to the cerebral cortex have
demonstrated that the remaining, intact tissue undergoes
structural and functional changes that could play a substantial
role in neurological recovery. New information regarding the
molecular and cellular environment in the adjacent, intact tissue
has suggested that waves of growth promotion and inhibition
modulate the self-repair processes of the brain. Furthermore,
recent studies have documented widespread
neurophysiological and neuroanatomical changes in regions
remote from a focal cortical injury, suggesting that entire
cortical networks participate in the recovery process.
Addresses
University of Kansas Medical Center, Landon Center on Aging,
MS 1005 3901 Rainbow Boulevard, Kansas City, KS 66160 USA
Corresponding author: Nudo, Randolph J (rnudo@kumc.edu)
Current Opinion in Neurobiology 2006, 16:638–644
This review comes from a themed issue on
Motor systems
Edited by Eve Marder and Peter L Strick
Available online 3rd November 2006
0959-4388/$ – see front matter
Published by Elsevier Ltd.
DOI 10.1016/j.conb.2006.10.004
Introduction
The cerebral cortex adapts to changing environmental
demands throughout an individual’s life. Dendrites and
spines branch and proliferate, synapses form and degen-
erate, and the efficacy of synaptic contacts is modulated
within a complex intracortical network. Thus, it is not
surprising that after an injury to the cerebral cortex, the
structure and function of sensory and motor regions is
drastically altered. Limited motor recovery can occur
spontaneously after injury to the motor cortex; therefore,
it will be interesting to determine which neural mechan-
isms underlie such recovery. Post-injury plasticity has
been documented not only at the molecular, synaptic,
cellular, network and systems levels in experimental
animals but also many of these plasticity events have
been correlated with alterations in cortical function using
neuroimaging and stimulation techniques in humans.
Basic phenomenology is now giving way to specific
hypotheses regarding the mechanisms by which motor
function is re-acquired after injury. In this review, we
summarize some of the important new findings in this
evolving field.
Current Opinion in Neurobiology 2006, 16:638–644
Early demonstrations of post-injury plasticity
Direct evidence that adjacent regions of the cortex are
functionally altered after cortical injury can be traced to
surface stimulation studies by Glees and Cole [1] in the
early 1950s. After a focal injury to the primary motor
cortex (M1) thumb representation, the damaged repre-
sentation reappeared in the adjacent cortical territory.
Studies in the somatosensory cortex by Jenkins et al.
[2] seemed to parallel these results. However, using
intracortical microstimulation (ICMS) techniques, some-
what different findings were observed in motor cortex by
Nudo et al. in the 1990s [3,4]. Small, subtotal lesions were
made in a portion of the M1 distal forelimb representation
(DFL) in squirrel monkeys, and the animals were allowed
to recover spontaneously (i.e. without the benefit of
rehabilitative training) for several weeks. In contrast to
earlier findings, the remaining DFL was reduced in size,
giving way to expanded proximal representations [3].
Importantly, in animals that underwent rehabilitative
training with the impaired limb, the DFL was preserved
[4]. These results, in addition to others since then, have
led to the conclusion that behavioral experience is a
potent modulator of post-injury cortical plasticity.
New insights into the cellular and molecular
mechanisms underlying local reorganization
Although studies of representational maps in motor cortex
are largely phenomenological, it is now clear that focal
cortical injury results in specific neurophysiological and
neuroanatomical changes in both adjacent and remote
cortical tissue. Structural alterations occur in adult mam-
malian cortex as a consequence of experience [5]. Not
surprisingly, focal cortical injury results in local neuroa-
natomical changes. Between three and 14 days after
cortical infarction, rats demonstrate increased growth-
associated protein 43 (GAP-43) immunoreactivity, sug-
gesting neurite outgrowth in the peri-infarct region [6,7].
Between 14 and 60 days post-infarct, synaptophysin
staining is significantly elevated, signifying increased
synaptogenesis [6]. Although these studies used some-
what indirect measures, axonal sprouting has been
demonstrated definitively in peri-infarct tissue in the
rat barrel cortex using tract-tracing methods [8]. Local,
surviving neurons become hyperexcitable, with asso-
ciated upregulation of N-methyl D-aspartate (NMDA)
receptors and downregulation of g-aminobutyric acid
subtype A (GABAa) receptors [9].
Recent data in rodent models have now demonstrated
that perilesional neurons (neurons in the intact cortical
tissue adjacent to a focal injury) respond to injury with the
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 Mechanisms for recovery of motor function following cortical damage Nudo 639
expression of a specific and highly coordinated set of
genes [10]. In a landmark study, Carmichael and co-
workers [11] defined spatial and temporal patterns of
expression profiles of growth-associated genes in the rat
barrel field infarct model. They found that a focal infarct
induces sequential waves of expression of growth-pro-
moting genes throughout the period of axonal sprouting.
Spatially, a growth-promoting region was distinguished in
which growth-promoting proteins are increased, and
growth-inhibitory proteins are decreased. This region
corresponds to the zone of axonal sprouting found pre-
viously, and is distinct from the glial scar immediately
adjacent to the infarct. It now appears that such neuronal
growth programs are turned on early after focal infarct and
might underlie the brain’s self-repair processes. A
more recent study suggests that such growth programs
are turned on even in aged brains, but demonstrate a
unique temporal profile [12]. Exploiting this new under-
standing of cellular and molecular events following injury
might provide new treatment approaches for recovery
after CNS injury [13].
Recent studies in human stroke survivors suggest that the
intact, peri-infarct cortex plays a role in neurological
recovery [14–16]. In an functional magnetic resonance
imaging (fMRI) study, Cramer et al. [17] demonstrated
that stroke survivors with good recovery show activity in
the peri-infarct rim, although this activity is diminished
compared with that in controls. In addition, after larger
infarcts and in patients with poor behavioral outcome
there appears to be a shift in activity towards the non-
stroke hemisphere [18]. Furthermore, after several
weeks of rehabilitation, motor representations in the
injured hemisphere are enlarged relative to the initial
post-injury map [19,20]. Also, constraint-induced move-
ment therapy, in which goal-directed movement with the
impaired hand is encouraged, produces a significant enlar-
gement of the representation of the paretic limb in the
injured hemisphere [21], closely paralleling results in
non-human primates. Thus, a more normal fMRI pattern,
in which the majority of neuronal activation is located in
the hemisphere contralateral to the impaired hand (i.e.,
the injured hemisphere), seems to be associated with
better recovery [22].
Plastic events remote from the cortical injury
Mammalian brains are endowed with a rich intracortical
network that enables reciprocal communication among
the various sensory and motor areas. Injury to motor
cortex causes potent disruption of integrated sensorimo-
tor networks, resulting in loss of fine motor control [23].
For example, M1 normally receives substantial input
from somatosensory cortex, conveying proprioceptive
and cutaneous information that is presumably integrated
with motor output commands in M1. These somatosen-
sory inputs terminate in M1 in a segregated fashion, with
proprioceptive inputs primarily in the rostral portion of
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the M1 DFL and cutaneous inputs in the caudal portion
[24]. Subtotal lesions of the rostral versus caudal sectors of
the M1 DFL result in dissociable deficits related to the
nature of the somatosensory inputs [25]. Thus, lesions in
M1 do more than disrupt motor output pathways through
corticofugal tracts. Such lesions effectively disconnect
motor cortex from the somatosensory system.
Even when the motor cortex is left intact after middle
cerebral artery occlusion (MCAo), motor maps as defined
by ICMS are disrupted, as recently demonstrated in rats
by Gharbawie et al. [26]. The excitability of areas remote
from the site of infarct is altered for significant periods of
time after injury. Upregulation of NMDA receptors and
downregulation of GABAa receptors has been observed in
both the ipsilesional and the contralesional hemisphere
[27]. Reorganization of motor maps also occurs in remote
motor areas interconnected with the injured territory. For
example, examination several months after a near-total
lesion in the M1 DFL in squirrel monkeys shows that the
ventral premotor cortex (PMv) DFL has expanded [28].
Although local axonal sprouting and synaptogenesis have
been found in the peri-infarct cortex, until recently
relatively little was known regarding changes in long-
range intracortical networks after focal injury. We
recently examined the intracortical connections of the
reorganized PMv DFL after an MI DFL injury [29].
Quantitative examinations of the terminal fields of PMv
intracortical fibers demonstrated little change, with the
exception of one cortical area. Each animal that had
sustained an injury to the M1 DFL displayed a remark-
ably consistent, dense cluster of PMv terminal boutons
within the primary somatosensory cortex (S1) hand repre-
sentation. This projection from PMv to S1 was sparse to
non-existent prior to the lesion, and thus represents a
novel intracortical connection between frontal and par-
ietal cortex that was induced by the lesion. It has been
known for some time that after cortical lesions in rats,
corticostriatal fibers, which primarily connect various
motor areas with the ipsilateral striatum, sprout from
the intact (contralesional) cortex and terminate in the
contralateral striatum, that is, on the side of the lesion
[30]. Under certain conditions, the intact cortex can send
novel projections to denervated portions of the red
nucleus and spinal cord as well [31]. This recent study
in nonhuman primates represents the first evidence of a
major alteration of intracortical wiring patterns among
different cortical fields (see Figure 1).
Sprouting of axons after cortical injury appears to be
activity-dependent. After a focal ischemic infarct in rats,
synchronous neuronal activity is a signal for post-infarct
axonal sprouting to be initiated from the intact cortical
hemisphere to peri-infarct cortex and the contralateral
dorsal striatum [32]. It follows that differences in post-
infarct behavioral experience will influence which areas
Current Opinion in Neurobiology 2006, 16:638–644
640 Motor Systems

Figure 1

Schematic illustration of the effects of a unilateral cortical lesion (red circle) on spared cortical tissue as depicted in a nonhuman primate brain.
Time-dependent neurophysiological and neuroanatomical alterations occur in the peri-infarct region (pink region surrounding lesion) and remote
cortical areas. These include alteration in neurophysiological maps of motor representations, neurotransmitter receptor regulation, dendritic
sprouting (not shown), local and remote axonal sprouting (short and long green arrows, respectively) and synaptogenesis (small black dots).
These changes are accompanied by waves of growth-promoting and growth-inhibiting proteins (large white and black circles, respectively) that
might trigger axonal sprouting and provide guidance to regenerating axons. Similar changes have been documented in the contralesional
(undamaged) cortex, and are thought to be related to behavioral compensation in the ipsilesional forelimb, and possibly recovery of function
by the contralesional forelimb. Recent studies suggest that lesion size is an important factor in determining the role of remote cortical plasticity.
Concentric circles in PM denote expanded motor representations. Abbreviations: M1, primary motor cortex; PM, premotor cortex; S1, primary
somatosensory cortex.

of cortex become targets for sprouting axons by differ-
entially activating task-specific cortical areas.
Unilateral damage to motor cortex in rats results in time-
dependent changes in the contralateral motor cortex [33].
Dendritic arborization occurs within about two weeks
post-lesion, followed by an increase in synaptogenesis
in layer V by about one month post-lesion. These changes
are thought to be associated with behavioral compensa-
tion of the ipsilesional (less-affected) limb (Figure 1).
Luke et al. [34] have demonstrated that after a unilateral
lesion in the sensorimotor cortex, rats actually performed
better with the ipsilesional limb than sham-operated
controls, demonstrating this hyper-reliance, or extreme
tendency to use the ipsilesional limb for balance, support,
grasping and grooming. These rats also demonstrated
increased synapses per neuron in layer V of motor cortex,
and alterations in the morphology of synaptic boutons.
Bury and Jones [35] provided evidence that compensatory
hyper-reliance is related to denervation-induced changes
rather than to increased forelimb use.
In contrast to hyper-reliance and improved behavioral
capacity with the ipsilesional limb demonstrated in rats, a
growing number of studies in human stroke survivors with
unilateral lesions has demonstrated impaired motor con-
trol of the ipsilesional distal forelimb [36–38]. Whether
ipsilesional impairments result from disruption of callosal
connections, ipsilateral corticospinal pathways, or path-
ways at some other level of the neuraxis is as yet unclear.
Finally, although it is widely known that CNS injury
increases neurogenesis, the role of neural stem cells and
progenitor cells in recovery after injury has been unclear
[39]. However, Zhang et al. [40] have demonstrated that
after stroke in adult rats, immature neurons in the subven-
tricular zone (SVZ) migrate in a chain-like structure towards
the ischemic border in the striatum. Similar results were
found by Komitova et al. [41]. Importantly, the results of
Komitova et al. demonstrate that post-infarct environmen-
tal enrichment results in increased numbers of neural stem
and/or progenitor cells and neurogenesis in the SVZ.
Finally, using laser-capture microdissection, Liu et al.

Current Opinion in Neurobiology 2006, 16:638–644 www.sciencedirect.com

 Mechanisms for recovery of motor function following cortical damage Nudo 641
[42] analyzed gene expression profiles of endogenous
SVZ progenitor cells in adult mice after MCAo. They found
that SVZ cells after stroke expressed many genes involved
in neurogenesis during embryonic development that are
not present in normal SVZ cells. Thus, the notion that the
ontogenetic environment is recapitulated after CNS injury
is gaining support. Whether neural stem cells or progenitor
cells become incorporated into cortical networks, or func-
tion as reservoirs for growth-promoting and growth-inhibit-
ing proteins after stroke, is an important question for future
research. Nonetheless, evidence for endogenous neuro-
genesis in the adult brain after injury, and the role of
post-injury behavioral experience on this process, has
prompted guarded optimism for proceeding with cellular
therapies for neurological disorders, such as stroke [43].
Re-emergence of the mass action principle
More than 75 years ago, Lashley [44,45] postulated his
classic theories regarding the relationship between cere-
bral mass and behavioral change. According to his hypoth-
esis, lesion volume is generally assumed to be associated
with the severity of deficits, whereas lesion location is
related to the specificity of deficits. Frost et al. [28]
recently demonstrated that the PMv DFL expands lin-
early with respect to the size of the M1 injury. An
interpretation formed on the basis of Lashley’s principles
would suggest that after small M1 lesions, the surviving
M1 tissue could potentially subserve the recovery of
function. For example, after a small, subtotal lesion in
the M1 DFL, the adjacent, intact DFL might be able to
accommodate some degree of functional recovery, and
thus, this local region might be the focus of reorganization
of motor maps. After larger lesions, reorganization of the
adjacent tissue might not suffice. As more and more of the
M1 DFL is destroyed, there might no longer be sufficient
distal representations (and associated descending fibers)
to enable recovery to occur by this process. More distant
forelimb motor representations, perhaps those in premo-
tor cortical areas, or even the contralateral hemisphere,
might then be engaged.
Biernaskie et al. [46] have recently examined the effects
of lesion size after MCAo on responses in the contralesional
hemisphere. Following recovery, the role of the contrale-
sional (undamaged) cortex in recovery was examined by
microinjecting lidocaine to deactivate it. If the original
deficits were reinstated, it would infer that the contralateral
cortex participated in recovery. Reinstatement of beha-
vioral deficits in the lesion-affected limb was only seen in
animals with large infarcts. Smaller infarcts followed by
lidocaine disruption didn’t seem to cause any effects, and
the subjects behaved no differently than controls. Similar
findings were found by Shanina et al. [47] using small
photothrombotic lesions followed by a second lesion on the
contralateral side. Finally, Hsu and Jones [48] recently
demonstrated that the paradoxical hyperfunctionality of
the ipsilesional forelimb after unilateral sensorimotor cor-
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tex lesion in rats was lessened by larger infarcts. One
possible interpretation of these data is that if lesions are
small, recovery of function can be accomplished largely by
ipsilesional plasticity mechanisms. In that case, contrale-
sional plasticity is more involved with increasing compen-
satory behaviors of the ipsilesional limb. By contrast, when
lesions are large, ipsilesional plasticity mechanisms are
limited, and contralesional plasticity is more involved with
recovery of function of the contralesional limb. The current
data are thus in accordance with previous studies suggest-
ing that lesion size is a major factor involved in the initia-
tion of the vicarious processes that purportedly plays a role
in recovery from CNS lesions.
Is there a sensitive period for post-injury
plasticity and recovery potential?
One of the most crucial questions that must be addressed
by basic research is whether there is a period of time after
cortical injury in which the remaining, intact system is
more amenable to rehabilitative interventions, through
drugs [49–51], electrical stimulation [52–54], behavior
(physiotherapy) or some combination of treatments.
The time-dependent cascade of events in peri-infarct
and remote areas would suggest that neuroplasticity
mechanisms have a long time course, although effects
might diminish with time. Recent studies on animal
models have begun to confirm that behavioral training
after focal injury is most effective for restoring baseline
behavioral performance, peri-infarct neurophysiological
maps and enhanced neuroanatomical changes in
the contralesional hemisphere when introduced within
the first week after injury. In a rat MCAo model, Bier-
naskie [55] found that functional outcome and dendritic
branching patterns in the contralesional hemisphere were
attenuated when rehabilitation was initiated at 14 or 30
days post-infarct. After a focal cortical infarct in rats, Hsu
and Jones [56] showed that delaying reach training for 25
days resulted in poorer behavioral recovery compared
with that after training initiated at 4 days post-injury,
but no differences in synaptic morphology in the con-
tralesional hemisphere. In a nonhuman primate model of
focal ischemia in the M1 DFL, Barbay et al. [57] showed
that delayed training resulted in attenuated maintenance
of the spared M1 DFL. However, previous studies
demonstrated an exaggerated lesion after early excessive
use of the impaired forelimb (by casting the unimpaired
limb) in rats [58]. It is thought that such excessive use can
exacerbate NMDA-mediated excitotoxicity, because the
peri-infarct region is hyperexcitable after injury [59,60].
However, as these recent studies demonstrate, at least in
conditions of moderate post-injury use, the early exag-
geration of the lesion is not observed.
Conclusions
Injury to the motor cortex results in a potent disruption of
coordinated networks and their underlying emergent
properties, resulting in loss of fine motor control, and
Current Opinion in Neurobiology 2006, 16:638–644
642 Motor Systems
the employment of compensatory movement strategies.
It now appears that such a disruption to the cortical motor
network triggers a major reassembly of inter- and intra-
areal cortical networks. Post-injury behavioral experience
appears to be crucial to the reassembly of adaptive
modules. Recent data suggest that the basic intracortical
wiring plan is substantially altered. Waves of growth-
promoting and growth-inhibiting proteins are expressed
in the peri-infarct tissue and might initiate and guide
novel axonal connections. This new information provides
both a challenge and an opportunity to understand the
inherent restorative mechanisms of the brain after stroke.
If the brain possesses mechanisms for vicarious of func-
tion, we might be able to exploit such mechanisms to
maximize recovery.
Update
Although several recent studies have demonstrated that
SVZ progenitor cells migrate to the site of injury, sub-
stantial growth of new neural tissue has not been
observed. However, in a new study in rats, Kolb et al.
[61] found that following cortical injury and subsequent
therapeutic treatment, the injury cavity became filled
with cells that stain positively for neuronal antigens.
These events were correlated with significantly improved
behavioral recovery. This study is remarkable as it vali-
dates the therapeutic potential for treatments that induce
regeneration of new tissue after injury.
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remarkable results show that the cavity that normally appears after such a
lesion became filled with cells that stain positively for neuronal antigens.
The EGF and EPO treated animals improved significantly compared with
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