Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics

REVIEW

Plasticity After Spinal Cord Injury: Relevance to Recovery
and Approaches to Facilitate It
Stephen M. Onifer,1,2 George M. Smith,1,3 and Karim Fouad4
1

Spinal Cord and Brain Injury Research Center, University of Kentucky, College of Medicine, Lexington( Kentucky 40536-0509;
2
Department of Anatomy and Neurobiology, University of Kentucky, College of Medicine, Lexington( Kentucky 40536-0098;
3
Department of Physiology, University of Kentucky, College of Medicine, Lexington( Kentucky 40536-0298; 4Rehabilitation
Medicine, University of Alberta, Edmonton, Alberta T6G 2G4, Canada

Summary: Motor, sensory, and autonomic functions canspontaneously return or recover to varying extents in bothhumans and animals, regardless of the traumatic spinal cord
injury (SCI) level and whether it was complete or incomplete.
In parallel, adverse and painful functions can appear. The
underlying mechanisms for all of these diverse functionalchanges are summarized under the term plasticity. Our review
will describe what is known regarding this phenomenon after
traumatic SCI and focus on its relevance to motor and sensory
recovery. Although it is still somewhat speculative, plasticity
can be found throughout the neuraxis and includes various
changes ranging from alterations in the properties of sparedneuronal circuitries, intact or lesioned axon collateral sprouting,and synaptic rearrangements. Furthermore, we will discuss aselection of potential approaches for facilitating plasticity as
possible SCI treatments. Because a mechanism underlying

spontaneous plasticity and recovery might be motor activity
and the related neuronal activity, activity-based therapies arebeing used and investigated both clinically and experimentally.
Additional pharmacological and gene-delivery approaches,
based on plasticity being dependent on the delicate balance
between growth inhibition and promotion as well as the basic
intrinsic growth ability of the neurons themselves, have beenfound to be effective alone and in combination with activitybased therapies. The positive results have to be tempered withthe reality that not all plasticity is beneﬁcial. Therefore, atremendous number of questions still need to be addressed.
Ultimately, answers to these questions will enhance plasticity’s
potential for improving the quality of life for persons with SCI.
Key Words: Spinal cord injury, plasticity, rehabilitation,chondroitin sulfate proteoglycans, Nogo-A, Neurotrophins,
gene delivery.

INTRODUCTION

the term plasticity. Our review will describe what is
known about this phenomenon after traumatic injury to
the adult spinal cord and focus on its relevance to motorand sensory recovery. Furthermore, we will discuss aselection of potential approaches for facilitating plasticity
as possible treatments for traumatic SCI.

Devastating long-term dysfunctions occur after traumatic adult spinal cord injury (SCI) and lead to overwhelming physical, psychosocial, and ﬁnancial
hardships. Depending on lesion severity, motor, sensory,
and autonomic functions can spontaneously return or
recover to varying extents in both humans and animals
after SCI. In parallel, adverse and painful functions canbegin to occur. Examples of these are described in thisissue’s article regarding autonomic dysreﬂexia andspasticity [1]. The underlying mechanisms for all ofthese diverse functional changes are summarized underElectronic supplementary material The online version of this article(doi:10.1007/s13311-011-0034-4) contains supplementary material,
which is available to authorized users.
Address correspondence and reprint requests to: Stephen M. Onifer, Ph.D.,
Spinal Cord and Brain Injury Research Center, University of Kentucky,
College of Medicine, B457 Biomedical and Biological Sciences Research
Building, 741 South Limestone St., Lexington, KY 40536-0509. E-mail:smonif2@email.uky.edu.

SPONTANEOUS FUNCTIONAL RETURN
AND RECOVERY AFTER SCI

Regardless of its level, and whether the injury to thespinal cord was complete or incomplete, plasticity can befound throughout the neuraxis. This includes various
changes, ranging from alterations in the properties ofspared neuronal circuitries, intact or lesioned axon
collateral sprouting, and synaptic rearrangements.
Although this plasticity has been associated with spontaneous functional return and recovery [2], the underlying
mechanism is still fairly speculative. Furthermore, theVol. 8, 283Y293, April 2011 * The American Society for Experimental NeuroTherapeutics, Inc.

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ONIFER ET AL.

continuous decline of neuronal function has beenreported, and it is unclear whether this should be or isregarded as plasticity (reviewed in Dietz et al. [3]).
The contributions of plasticity to functional return andrecovery are hard to discriminate from other possible
processes including the recovery from spinal shock andthe effect of spontaneous remyelination of spared, but
demyelinated axons (eg, see [4]). As for spinal shock, theneuronal mechanism is only vaguely known and could
involve the breakdown of membrane potentials, excessive
neurotransmitters levels, and the loss of neuromodulators
regulating the excitability in the spinal cord [5]. The
subsequent recovery could be due to plasticity and/or
simple restoration of membrane potentials.
Well-documented examples of plasticity come fromthe recovery of locomotion in humans and animals
following traumatic and experimental SCI. For example,
electromyographic (EMG) activity in human leg muscles
reappeared during assisted locomotion a few months
after complete cervical or thoracic SCI [6]. Importantly
for inter-limb coordination, EMG activity in humanupper extremity muscles began to be evoked by tibial
nerve stimulation months after complete cervical SCI [7].
Comparably, Basso, Beattie, and Bresnahan open ﬁeld
locomotor rating scale scores [8] indicate that slightmovement of a rat hind-limb joint occurred by 1 week
after thoracic spinal cord transection and that slight-toextensive joint movements were seen thereafter [9].
Similarly, in mice with SCI, the Basso Mouse Scaledemonstrates a return of hind-limb movements by 1
week after thoracic spinal cord transection [10]. The
onset for return of spontaneous function in both humans
and animals after complete SCI could be due to therestoration of motoneuron excitability by constitutive
expression of 5-HT2C receptors [11, 12]. Additionally,
adaptations in polysynaptic ﬂexor reﬂexes involved inlocomotor circuits [6, 13] and synaptic rearrangements
may contribute to this ﬁrst phase of recovery as well[14]. The temporal differences in the spontaneous functional return onset may be due to the relatively higher
metabolism of rodents. Also, quadrupedal animals areable to move around their environment soon after injury
by using their forelimbs to drag their paralyzed body incontrast to the wheelchair bound and/or medically unstableperson with complete SCI who frequently suffers frommultiple organ trauma. Because the circuitry connecting
skin and muscle primary afferents with spinal interneurons
and motoneurons is intact and active after complete SCI[15], sensory information involved in orchestrating stepping movements [16] is transmitted to the animal’s spinal
cord when the body and joints are moved.
As for incomplete SCI, there was generally more
spontaneous recovery in rats by 1 to 2 weeks after
transection of their thoracic spinal cords, in which 7
weeks earlier they had undergone contusive injuries,
Neurotherapeutics, Vol. 8, No. 2, 2011

compared with that found in rats with transection alone[9]. Similarly, cats receiving a complete transection
following the recovery of a hemisection underwent
substantial plasticity, and therefore were immediately
capable of supporting their weight on a treadmill [17].
Moreover, plantar stepping that returned to a mouse
hind-limb ipsilateral to a thoracic spinal cord hemisection
was abolished by delayed, contralateral hemisection[18]. These results indicate that the spinal cord is able
to adapt after incomplete injury by mechanisms involving functional redundancy [19], locomotor networks
preserved after a second complete lesion [17], sparedlong-tract axon collateral sprouting [20], sprouting of
spinal interneurons even capable of bridging a staggered
hemisection [18], and/or adaptations of motoneurons[21] in the thoracolumbar spinal cord caudal to the
SCI.
Long-tract axon collateral sprouting is also involved in
the plasticity that follows complete axotomy of speciﬁc
white matter pathways. For example, rat cervical spinal
cord dorsal funiculotomies, that is, axotomy of the upper
body primary afferents in the dorsal columns fasciculus
cuneatus and the lower body primary afferents in the
fasciculus gracilis, as well as the dorsal corticospinal
tracts, signiﬁcantly decreased trained reaching for,grasping of, retrieving, and eating food pellets for 2 and3 weeks, but not at 4 weeks [22]. This spontaneousfunctional recovery occurring at 4 weeks was mediatedby ventral corticospinal tract axon collateral sprouting, as
demonstrated by recovery abolishment for 3 weeks whenthe ventral corticospinal tracts were transected bilaterally
at week 4. Furthermore, spontaneous recovery did notoccur for 4 weeks when bilateral dorsal columns, dorsal
corticospinal tracts, and ventral corticospinal tract transections were combined.
Further evidence of plasticity comes from observations
in both human and animal central nervous system (CNS)
regions away from the SCI site. We and others havereported spontaneous changes in the size of somatotopic
maps of activation occurring in the somatosensory andmotor cortices, as well within the brainstem (reviewed in
Fouad et al. [2], Raineteau and Schwab [23], and Kaas etal. [24]). Here, as well, axon collateral sprouting appears
to be involved. For example, we found that rat hindlimb
corticospinal tract axons axotomized in the thoracic
spinal cord dorsal funiculus sprouted axons into thecervical spinal cord gray matter [25]. Associated withthis was novel forelimb and trunk muscle activity being
evoked by hindlimb motor cortex stimulation. Subsequently, it was seen that these collateral axon sprouts
innervated both short- and long-propriospinal neurons[26]. Interestingly, the connections with long propriospinal neurons that bridged the lesion and innervated lumbar
spinal cord motoneurons persisted and they were foundto be electrophysiologically functional with hindlimb

PLASTICITY AFTER SPINAL CORD INJURY

motor cortex stimulation and hindlimb muscle EMG
activity recording. Moreover, recovery of hindlimb
placing was associated with axon sprouting. Additionally, Jain et al. [27] observed that complete lesions of the
primate cervical spinal cord dorsal columns deactivated
the forelimb, trunk, and hind limb representations in thesomatosensory cortex. Afferents from the face reactivated these deactivated representations. Associated withthis was sprouting of trigeminal primary afferents into
the brainstem cuneate nuclei, the target of forelimb andother upper extremity primary afferents [28]. Incomplete
lesions of the dorsal columns led to sprouting of spared
forelimb primary afferents in the cuneate nuclei andreactivation of forelimb representations [24, 27]. In
contrast, reactivation of hind limb representations in the
rat somatosensory cortex did not occur following incomplete lesions of the thoracic spinal cord dorsal columns[29]. This suggests species and/or mechanistic differences.

FACILITATING PLASTICITY TO IMPROVEFUNCTIONAL RETURN AND RECOVERY
AFTER SCI

It is now possible to conclude from clinical andexperimental evidence that both the adult central andperipheral nervous systems respond to traumatic SCI
with plasticity. As for complete SCI, plasticity seems to
be maintaining the disconnected spinal cord and possibly
preparing it to be re-innervated. In the case ofincomplete SCI, plasticity results in recovery to varying
extents of functions involving both motor and sensory
systems. When plasticity needs to be enhanced to further
improve these functions in persons with SCI, additional
facilitatory approaches may be extremely useful. Here,we will discuss some activity-based, pharmacological,
and gene-delivery approaches that have been found toenhance plasticity. Long-distance, lesioned CNS axon
regeneration is not involved due to the time after SCI thatit takes [30]. Therefore, approaches that promote longdistance axon regeneration will not be discussed here.
However, one is portrayed regarding peripheral nerve
grafting in another article in this issue [31].
Activity-based approaches
As previously discussed, a mechanism underlying
spontaneous recovery and plasticity might be motor
activity and the related neuronal activity. Triggered byeither training or electrical stimulation, neuronal activity
results in the up-regulation of brain-derived neurotrophic
factor (BDNF) and 3'-5'-cyclic adenosine monophosphate(cAMP) levels, both of which have been implied inplasticity [32–35]. Thus, a logical step to encourage
spontaneous recovery is rehabilitative training, which
indeed is currently the most successful treatment for SCI.

285

The breakthrough of rehabilitative training following SCI isbased on studies in cats, showing that following complete
transection a locomotor pattern could be initiated in theparalyzed hindlimbs [36, 37]. Although no connection to
the brain existed, this locomotor "recovery" could be
ampliﬁed with treadmill training, ultimately resulting inweight-supported stepping on a treadmill [38, 39]. The
promising results of treadmill training in cats were soontranslated to clinical applications [40], where it is now
viewed as a potent therapy (reviewed in van Hedel andDietz [41]). Although it has been argued as to whether
weight-supported treadmill training is superior to weightsupported over ground locomotor training [42], it isaccepted that it signiﬁcantly aids rehabilitation training.
The effect of locomotor training on recovery following
SCI triggered investigations into the underlying mechanisms, and it is now generally accepted that plasticity in
the CNS is a major contributor. More recent studies using
cervical lesion models, with the functional emphasis on
ﬁne motor control of hand/paw function, conﬁrmed theseideas and related plasticity at various levels of the CNS
to the recovery of motor function. Not surprisingly, themechanisms read like a list found under spontaneous
plasticity including the up-regulation of growth/plasticity
associated factors ([43]; reviewed in Krajacic et al. [35]and Vaynman et al. [44]) and sprouting of lesioned ﬁbers[45], as well as changes in spinal circuitries [17, 38, 39,
46–48], cortical maps [35, 45], and in neuronal properties [49, 50].
Although rehabilitative training following SCI isnormally associated with beneﬁcial effects on recovery,
possible negative consequences also have to be kept inmind. One critical issue that has been identiﬁed in stroke
research is the negative effect of training very early after
injury on functional outcome and lesion/injury size.
Although it is generally presumed that an early training
onset is most beneﬁcial, there are only few yet
controversial reports in animal models of SCI. For
example, swim training initiated acutely following
thoracic SCI was less efﬁcient compared to a 2-weekonset, and it was paralleled by a signiﬁcantly increased
extravasation in and around the injury site [51]. This result
has not been found in rats with cervical SCI and different
training (reaching) onsets [43]. In a similar scenario, we
have only observed negative effects on an untrained taskwith early onset of training [45], an effect perhaps masked
in the functional outcome of the trained task. Anothercritical complication following SCI is autonomic dysreﬂexia, which has been proposed to be exaggerated bytreadmill training [52], but this is not commonly reported
after treadmill training in individuals with SCI.
Another somewhat negative effect of training is theinteraction between recovery in a trained task and that ofan untrained task. Not surprisingly, training in one task
does not necessarily translate into improvements in
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ONIFER ET AL.

another task [53–56]. Even more surprising are ﬁndingsthat training in one task can even have detrimental effects
on another task. For example, cats with complete SCI
transections trained to walk on a treadmill had difﬁculties
in standing in contrast to cats trained to stand, which
performed worse in walking than untrained cats [53, 56].
Likewise, rats with cervical SCI trained in a reachingtask showed deﬁcits in crossing a horizontal ladder [45]or increased activity induced by environmental
enrichment promoted recovery in untrained tasks, butinterfered with the training in reaching tasks [57]. Theseobservations suggest that the injured CNS will be rewired
task speciﬁcally, probably at the cost of other tasks.
Pharmacological and gene-delivery approaches
Plasticity within the adult CNS is dependent on thedelicate balance between growth inhibition and promotion, as well as the basic intrinsic growth ability of theneurons themselves. A number of pharmacologicalapproaches addressing these issues also are being
investigated for promoting plasticity after experimental
SCI (reviewed in Kwon et al. [58]). In the next
paragraphs, we will focus on selected pharmacologicalapproaches that ultimately may be used to treat SCI inpatients (Table 1).
Chondroitinase ABC.
Chondroitin sulfate
proteoglycans (CSPGs), a class of developmentally
regulated macromolecules [59], are major componentsof the CNS extracellular matrix. Furthermore, CSPGs
produced by neurons and astrocytes form lattice-like
perineuronal nets that shroud adult neuronal cell bodies
and proximal dendrites [60, 61]. Concentrations of some
CSPGs increase in humans and animals not only at the SCI
site [62–71] but also rostral [70] and caudal [72] to it.
There have been numerous reports regarding thetherapeutic effects on anatomy, electrophysiology, andbehavior of altering constitutive and newly synthesized
CSPGs in animals after SCI. Bradbury and colleagues
were the ﬁrst to demonstrate that CSPGs inhibitedfunctional recovery after SCI [73]. They intrathecallyinfused the bacterial enzyme chondroitinase ABC(chABC) at rat cervical spinal cord dorsal funicultomies
to digest chondroitin sulfate glycosaminoglycan chainscovalently attached to the CSPG core proteins. This
prevented corticospinal tract axon retraction, promoted
regeneration of corticospinal tract axons and primaryafferents for a short distance beyond the SCI, restoredcorticospinal tract neurotransmission, and improved bothskilled locomotion and walking. These and subsequent
results [74–76] further demonstrated that corticospinal
tract axons injured in the spinal cord were capable ofundergoing regenerative sprouting for short distances, aswell as that forelimb functions were improved andhindlimb movements returned following chABC adminNeurotherapeutics, Vol. 8, No. 2, 2011

istration. Additionally, collateral sprouting of intact
axons has been observed. We found that chABC
injections at the brainstem after cervical spinal corddorsal quadrant lesions promoted collateral sprouting offorepaw primary afferents remaining in the target cuneate
nuclei [77]. Moreover, receptive ﬁeld mapping showedthat this sprouting led to more cuneate nuclei neurons
responding physiologically to forepaw digits tactile
stimulation. Infusing chABC at cervical spinal corddorsal funicultomies, Barritt et al. [78] conﬁrmed injured
corticospinal tract regenerative sprouting within thedorsal funiculi, as well as into gray matter at the SCI
and both rostral and caudal to it. They also uncovered
intact serotonergic axon collateral sprouting within whitematter at the SCI, which was aberrant, and gray matter
caudal to it. Aberrant calcitonin gene-related peptide(CGRP)-immunoreactive, primary afferent collateralsprouting within white matter caudal to the SCI was also
seen. A further investigation revealed that chABCmediated, aberrant CGRP-containing primary afferent
sprouting caudal to a SCI did not lead to increased
innervation of dorsal horn nociceptive neurons or thedevelopment of thermal hyperalgesia and mechanicalallodynia. Tom et al. [79] demonstrated serotonergic
axon collateral sprouting throughout gray matter rostralto cervical spinal cord hemisection following a rostral
intraspinal ChABC injection. A caudal intraspinal
chABC injection did not promote sprouting caudal tothe hemisection, but it did caudal to a cervical spinal cordhemi-contusion, a clinically relevant SCI model. The
synaptic component synapsin did not change, andforelimb function during open ﬁeld and skilled locomotion did not improve, even though chABC-mediatedserotonergic axon, and possibly other axon, sprouting
occurred.
When combined with other approaches, chABC also has
been effective. It has enhanced a variety of cellulartreatments in experimental SCI (reviewed in Smith andOnifer [80]). Moreover, chABC administered in Gelfoam at
cervical spinal cord hemisection sites combined withintraperitoneal lithium injections led to more ipsilesional
forelimb usage [81]. Hindlimb movements returned andlocomotion recovery improved after thoracic spinal cord
transection and contusion when systemic chABC delivery
was combined with intraperitoneal insulin and glucose
injections [82] and chABC delivery in Gelfoam at the SCI
site was combined with clenbuterol in drinking water [83].
Improved locomotion recovery occurred when an agarose
gel scaffold embedded with microtubules was loaded with
chABC and neurotrophin-3 (NT-3) and administered atthoracic spinal cord dorsal over-hemisections [84].
Collectively, these anatomical, electrophysiological,
and behavior results indicate that reducing inhibitory
CSPGs after SCI has the potential of promoting both
intact and lesioned axon sprouting, without side effects,

PLASTICITY AFTER SPINAL CORD INJURY

287

Table 1. Pharmacological and Gene Delivery Approaches
Agent

Axon Sprouting

Improved Function

chABC
chABC
ex vivo genedelivery

CollateralRegenerative

Nogo-A
IN-1 antibody
Nogo-A antibody
Neurotrophins
NGF
BDNF
Pegylated BDNF
29D7
NT-3
Adenovirus
Adeno-associatedvirus
Lentivirus

Reported Side
Effects

Effective
Combinatorial
Use

Forelimb
Hindlimb

None

Activity
Cell and tissuetransplants
Lithium
Insulin andglucoseClenbuterol
NT-3

CollateralRegenerative

Forelimb
Hindlimb

None

Collateral:enhanced
and reduced

Forelimb
Hindlimb

Pain
Weight loss
Autonomic
dysreﬂexia

GDNF
Semaphorin 3A
Cell and tissuetransplants

BDNF brain-derived neurotrophic factor, chABC chondroitinase ABC, NGF nerve growth factor, NT-3 neurotrophin-3.

and leading to improved functional recovery whenneurons are innervated. Therefore, optimization of thisapproach is needed. This requires understanding its
mechanism of action. Thus far, it is known that injured
axons sprout after chABC administration. Importantly,
intact axons only sprout where CSPG digestion, degeneration, and denervation occur [57, 78]. This suggeststhat chABC may modulate immune/inﬂammatory
responses, liberate extracellular matrix-bound facilitatory
factors, and overcome interactions between inhibitory
CSPGs and extracellular matrix molecules in the injured
CNS (reviewed in Crespo et al. [85], Bradbury andCarter [86]). Attenuating the decline in axonal conduction through the SCI site could be involved [87].
Additionally, chABC may reduce growth inhibitory
responses in neurons and provide neuroprotection bydigesting chondroitin sulfate glycosaminoglycan chainsthat mediate the interaction between CSPGs and theneuron transmembrane receptor protein tyrosine phosphatase sigma [88, 89].
For translation of this potentially therapeutic approachto the clinic, chABC has been shown to be effective in
adults of other species. Faster recovery onset and better
performance of skilled locomotor tasks, as well as hindlimb movements occurred in cats when chABC was
intrathecally infused after thoracic spinal cord hemisection [90]. Furthermore, alternate chABC delivery
strategies are being investigated. Compared with a single,
intraspinal chABC injection, bioactive chABC was
detected longer and CSPG digestion was more extensive

when a ﬁbrin gel containing chABC was topically placedat rat cervical spinal cord dorsal funiculotomies [91].
Chondroitinase ABC loses most of its activity within a
few days at 37°C [92]. Thermostabilizing chABC anddelivering it in an agarose gel scaffold embedded withmicrotubules at thoracic spinal cord dorsal over-hemisections improved CSPG digestion compared with asingle, intraspinal injection [84]. However, locomotion
and thermal sensitivity, as well as primary afferent andserotonergic axon growth, were not improved. Additionally, strategies for chABC administration by mammaliancells instead of in vivo delivery of the bacterial enzyme
are also being investigated. We transduced U373 humanastocytoma cells with a Tet-On adenoviral vector encoding chAC to secrete enzymatically active chondroitinasethat increased neurite outgrowth on CSPGs [93]. Directed mutagenesis of N-glycosylation sites on bacterial
chABC facilitated secretion of enzymatically activechondroitinase from transfected COS7 cells, Neu7 cells
derived from astrocytes, and neonatal rat cortical astrocytes [94]. These results raise the possibility of ex vivo
gene delivery of chABC for experimental, and ultimately
clinical, SCI.
Nogo-A. Axon outgrowth inhibition by the CNS
myelin-associated proteins Nogo, myelin-associatedglycoprotein, and oligodendrocyte myelin glycoprotein
is another important target of pharmacologicalapproaches. Like chABC above and neurotrophins
below, Nogo-A neutralization has been found to
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enhance both axon collateral and regenerative sprouting(reviewed in Zörner and Schwab [95]). For example,
regenerative sprouting of rat corticospinal tract axons
into the cervical spinal cord occurred following theirlesion in the pyramids of the medulla andintracerebroventricular treatment with the monoclonal
antibody IN-1 raised against rat NI-250 myelin protein or
Nogo-A [96]. Using the same lesion and treatment, intact
corticospinal tract axon collateral sprouting throughout
cervical spinal cord gray matter was subsequently
observed [97]. Additionally, corticorubral andcorticopontine axon collateral sprouting and also
cortifugal axon regenerative sprouting occurred. Lesion
rats that were treated showed better forelimb reach andpellet retrieval, forelimb use during rope climbing,forelimb rotation during locomotion, and time it took to
remove an adhesive sticker from the forepaw.
Furthermore, we saw intact rubrospinal tract axon
collateral sprouting in the cervical spinal cord when theadult rats were treated intracerebroventricularly with themonoclonal antibody IN-1 following bilateral lesions ofcorticospinal tract axons in the pyramids [98, 99]. Someof the sprouted rubrospinal tract axons appeared tobe making aberrant connections on to motoneurons.
Associated with the anatomical changes was the ability
to evoke EMG activity of forelimb muscles with lower
electrical stimulation intensities applied to the red
nucleus, where the somata of the rubrospinal tract
axons are located, and improved forelimb reach andpellet retrieval recovery. Electrical stimulation of theforelimb motor cortices also evoked forelimb EMG
activity. Because this could be abolished by injecting
muscimol into the red nuclei, it was suggested that thecorticorubral pathway was involved. Both corticospinal
tract axon collateral and regenerative sprouting as well as
improved forelimb reach, grasp, and manual dexterity
recovery, were also seen in primates following cervicaland thoracic SCIs and Nogo-A antibody treatment [100–103], Importantly, adverse effects and pain were notobserved in these and many other experiments.
Collectively, these results have led to a phase I
multicenter clinical trial using intrathecal infusion ofhuman anti-human Nogo-A antibody for treating persons
with complete and incomplete cervical and thoracic SCIs
(reviewed in Zörner and Schwab [95]). Here again, no
adverse effects have been reported.
Neurotrophins. As previously discussed, endogenous
neurotrophin concentrations increase in the spinal
cord as a result of rehabilitative training after injury.
Neurotrophins also have been repeatedly used as
extrinsic factors to induce plasticity of either injured or
noninjured axons. In most experiments, neurotrophinsneed to be administered using a mini-pump to supply
them for extended periods of time. Gene therapy not only
Neurotherapeutics, Vol. 8, No. 2, 2011

supports long-term expression of neurotrophins, but also
this expression can be directed to speciﬁc cells, regions,or within simple or complex gradients [104]. Anotheradvantage is many viruses can be retrogradely transported,
providing a mechanism for genetic transfer into the spinal
cord with minimum trauma. For example, adenovirus
induces high levels of neurotrophin expression in manysystems, but unfortunately induces a fairly robust immune
response if not administered carefully [105]. Injection of
adenovirus into lesioned sciatic nerve supports retrograde
transport to the spinal cord and subsequent transgene
expression in motoneurons without induction of an
immune response [106]. This technique has been used torescue degenerating motoneurons, as well as supporting
sprouting of corticospinal tract axons. Thus, this technique
not only allows noninvasive production of neurotrophinswithin the spinal cord, but it also might increase plasticity or
synpatogenesis onto this major functional output neuron.
Early studies showed that NT-3 acts to enhance rostral
sprouting, but not regeneration, of rat corticospinal tract
axons when injected rostrally into thoracic spinal corddorsal funiculotomies [107]. This study examined only
rostral sprouting of injured axons. In a subsequent study,
infusion of NT-3 into the cervical or thoracic spinal cords
after incomplete lesions of corticospinal tract axons
bilaterally in the pyramids reduced collateral sprouting[108]. Zhou et al. [109] lesioned corticospinal tract axons
unilaterally in the pyramids and induced retrograde
expression of NT-3 within lumbar motor neurons on the
denervated side. The expression of NT-3 induced
collateral sprouting from the uninjured corticospinal tract
axons into the denervated contralateral spinal cord.
Contralateral sprouting was only observed after acuteinjury [109, 110] and could be enhanced with secondary
application of BDNF or glial cell line-derived neurotrophic factor adenovirus within the motor cortex of thelesioned pathway [111]. Adeno-associated virus also canbe retrogradely transported into the spinal cord. It has theadded advantage of being endocytosed at nerve terminals, so it is less invasive than adenovirus for inducing
transgene expression in spinal cord motoneurons [112,113]. Using this method, NT-3 motoneuron expression
induced sprouting of corticospinal tract axons after
cervical dorsal column lesions and limited functional
recovery of foot placement [114].
BDNF administration also facilitates plasticity after SCI.
BDNF infused into the rat motor cortex enhanced rostral
sprouting, but not regeneration, of corticospinal tract axons
injured by thoracic spinal cord dorsal funiculotomies [115].
When we applied this approach after thoracic spinal corddorsal over-hemisection, the collateral sprouting of corticospinal tract axons and innervation of cervical spinal cord
propriospinal interneurons we previously observed [25]was enhanced [116]. Intrathecal infusion of BDNF or
pegylated BDNF caudal to thoracic spinal cord transection

PLASTICITY AFTER SPINAL CORD INJURY

or contusive injury similarly promoted cholinergic axon
sprouting, stimulated hindlimb air-stepping, and improved
both hindlimb joint movements and Basso, Beattie, andBresnahan open ﬁeld locomotor rating scale scores [117,118]. To overcome limitations that would obviate using
BDNF clinically, such as weight loss (reviewed in Lebrun
et al. [119]) and involvement in pain [120], we recently
evaluated a monoclonal antibody (29D7) that has highafﬁnity for TrkB, the receptor for BDNF [121]. Intrathecal
29D7 infusion caudal to cervical spinal cord dorsal
quadrant lesions induced corticospinal tract axon sprouting
rostral to the SCI and improved contralesional forelimbpellet retrieval recovery. No side effects in a sensory test
(plantar heater) were found; however, the drug application
was paralleled by an initial weight loss, and when it was
discontinued, by a signiﬁcant weight gain.
Neurotrophin-induced plasticity does not always result
in beneﬁcial outcomes and the expression of neurotrophins can induce sprouting of other noninjured pathways. Expression of nerve growth factor (NGF) within
the spinal cord induces robust sprouting of endogenous
nociceptive pathways leading to persistent intractable
pain [122]. When NGF expression within the lumbar
spinal cord region was coupled with a complete midthoracic spinal cord transection, the animals developed
severe autonomic dysreﬂexia. This disorder is commonly
observed in individuals with spinal cord injuries andinvolves the conversion of nociceptive input into a
sympathetic over-activation [123], and requires sprouting
not only of nociceptive afferents but also ascending
propriospinal pathways [124]. The sprouting of nociceptive
axons can be inhibited by expression of the chemorepulsive
molecule semaphorin 3A. Co-expression of semaphorin 3A
has been shown to reduce NGF-mediated sprouting,autonomic dysreﬂexia [123], and allodynia [125].
Combining pharmacological and activity-based
approaches
Chondroitinase ABC. Recently, the effects ofcombining chABC and activity on forelimb function
and locomotion recovery have been examined. GarcíaAlías et al. [57] injected and intrathecally infused chABC
at the site of cervical spinal cord dorsal funiculotomies
that extended into the gray matter. This improved
forelimb pellet retrieval by using the Whishaw
apparatus, but not the Staircase apparatus and forelimb
placing. Combining the chABC treatments with 1-h dailypellets and seeds retrieval rehabilitation that began
1-week post-SCI improved pellet retrieval in both
apparatuses. In contrast to the therapeutic effect of taskspeciﬁc rehabilitation, combining the chABC treatmentswith 1-h daily housing in an enriched environment
worsened pellet retrieval on both apparatuses.
Combining this general rehabilitation with chABC,

289

however, improved forelimb grip strength comparedwith chABC with task-speciﬁc rehabilitation or chABC
treatments alone, which had no effect. Similarly, thecombination of chABC and general rehabilitation
improved skilled locomotion on a ladder-walking test.
Corticospinal tract and serotonergic axon sprouting
occurred in rats treated with chABC, however, this was
not improved by task-speciﬁc or general rehabilitation.
Jakeman et al. [126] performed thoracic spinal cord
contusions in mice. They injected chABC once into thelumbar enlargement gray matter. CSPGs here have beenshown to increase here in the rat after thoracic SCI [72].
The locomotion and sensory recovery of injured micehoused afterwards with running wheels was similar to
those treated with chABC, without wheels and injured
mice housed with or without wheels. These studies pointout that CSPGs in the injured cervical spinal cord limit
the effects of task-speciﬁc and general rehabilitation onsome forelimb functions recovery [57, 126]. Moreover,
CSPGs here may be important for the effect of generalrehabilitation of some forelimb functional recovery. It is
possible that the ineffectiveness of chABC in the study ofJakeman et al. [126] may have been due to the week
delay between the SCI and treatment, the use of a single
injection, and also that the axon growth may not haveoccurred. Acute then repeated chABC treatments that led
to axon sprouting had positive effects on some forelimb
functions recovery, but not others [57]. Additionally, thechABC injection site may have played a role. Rat
locomotion recovers to lesser extents following
excitotoxic and contusion SCI at the rostral lumbar
spinal cord [127–129]. Wheel running alone also did
not improve locomotion recovery; however, task-speciﬁc
and general rehabilitation alone each had positive,
negative, or no effects on forelimb functional recovery[57]. Therefore, these studies also point out a number ofcritical questions that need to be answered about thispotentially therapeutic combinatorial approach. Amongthem are treatment timing and delivery strategy,
rehabilitation type and timing, and outcome measures.
Nogo-A. The combination of Nogo-A antibody andtraining also has been investigated. Although corticospinal
tract axon and serotoninergic axon sprouting occurred inrats with thoracic spinal cord “T” lesions following
intrathecal Nogo-A antibody administration, bipedal andquadrupedal body-weight supported treadmill training did
not have a synergistic effect on the treadmill kinematics or
inclined climbing [130]. However, it has been reported
that the combination of intrathecal Nogo-A antibody
administration and locomotor training reduced muscle
spasms of rats with incomplete SCI and thermal sensitivity[131]. Therefore, these studies suggest that each treatment
may be acting through different mechanisms that do notinteract. Since Nogo-A antibody treatment is undergoing a
Neurotherapeutics, Vol. 8, No. 2, 2011

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ONIFER ET AL.

phase I clinical trial and rehabilitation training is being
used clinically, it is important that investigations of themechanism behind the lack of synergism be performed.

CONCLUDING REMARKS

Clinical and experimental evidence have convincingly
demonstrated that spontaneous plasticity occurs within
the adult CNS through a variety of events after traumatic
SCI. Additionally, activity-based, pharmacological, andgene-delivery approaches are being found effective,
alone and in combination to facilitate plasticity. The
positive results have to be tempered with the reality that
there are a number of known hurdles. Clearly, not allplasticity is beneﬁcial. Therefore, a tremendous numberof questions still need to be addressed in order to harness
plasticity. These include the following: whether harmfulplasticity can be prevented at the same time when
beneﬁcial changes are encouraged, which type of
postinjury training is most beneﬁcial and when, why
training hinders untrained functions, what doses ofpharmacological and gene-delivery approaches should
be applied and when, and which combinations will act
synergistically. Moreover, promising experimental ﬁndings will need to be reproduced before clinical trials are
performed. Thus far, it has been difﬁcult for investigators
participating in the National Institutes of Health/National
Institute of Neurological Disorders and Stroke “Facilities
of Research Excellence-Spinal Cord Injury-Replication”
program to independently replicate the effects of reported
treatments. Finally, the process of translating experimentalﬁndings to patients is complicated. Overcoming thesehurdles ultimately will allow for using the potential ofplasticity to improve the quality of life for persons with
SCI.
Acknowledgments: Support for the preparation of the manuscript was provided by the Kentucky Spinal Cord and Head Injury
Research Trust (S.M.O.), National Institutes of Health/National
Institute of Neurological Disorders and Stroke grant no. R01
NS060784 (G.M.S.), and the Alberta Heritage Foundation for
Medical Research (K.F.). Full conﬂict of interest disclosure isavailable in the electronic supplemental materials for this article.

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Neurotherapeutics, Vol. 8, No. 2, 2011