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Published in final edited form as:
J Rehabil Res Dev. 2008 ; 45(2): 229–240. doi:10.1682/JRRD.2007.03.0047.

Activity-dependent plasticity in spinal cord injury
James V. Lynskey, PhD, PT1,2, Adam Belanger, MS1,3, and Ranu Jung, PhD1,3,*
1 Center for Adaptive Neural Systems, Ira A. Fulton School of Engineering, Arizona State University, Tempe,
AZ
2 Department of Physical Therapy, Arizona School of Health Sciences, A.T. Still University, Mesa, AZ
3 Harrington Department of Bioengineering, Ira A. Fulton School of Engineering, Arizona State University,
Tempe, AZ

Abstract
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The adult mammalian central nervous system (CNS) is capable of considerable plasticity, both inhealth and disease. After spinal neurotrauma, the degrees and extent of neuroplasticity and recovery
depend on multiple factors, including the level and extent of injury, postinjury medical and surgicalcare, and rehabilitative interventions. Rehabilitation strategies focus less on repairing lostconnections and more on influencing CNS plasticity for regaining function. Current evidence
indicates that strategies for rehabilitation, including passive exercise, active exercise with somevoluntary control, and use of neuroprostheses, can enhance sensorimotor recovery after spinal cord
injury (SCI) by promoting adaptive structural and functional plasticity while mitigating maladaptivechanges at multiple levels of the neuraxis. In this review, we will discuss CNS plasticity that occurs
both spontaneously after SCI and in response to rehabilitative therapies.

Keywords
central nervous system; electrical stimulation; exercise; neuromuscular; neuroprostheses;
neurotrophic factors; plasticity; recovery; rehabilitation; spinal cord injury; therapy

INTRODUCTION
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Spinal cord injuries (SCIs) disrupt both axonal pathways and segmental spinal cord circuitry,
producing severe impairments of motor, sensory, and autonomic function at and below thelevel of the injury. However, significant recovery can and often does occur in the first year
following SCIs classified as incomplete [1–4]. The amount and extent of recovery depend on
multiple factors, including the level and extent of injury, postinjury medical and surgical care,and rehabilitative interventions. Rehabilitative therapies, such as intense repetitive training(“massed practice”) [5] and locomotor training [6–7], have been shown to promote recovery
after incomplete SCI in humans. Although the mechanisms mediating this recovery are notfully understood, activity-dependent plasticity likely plays a major role.
In this review, we discuss central nervous system (CNS) plasticity after SCI, occurring bothspontaneously after injury and in response to rehabilitative therapies. Plasticity is a term widely*Address all correspondence to Ranu Jung, PhD; Center for Adaptive Neural Systems, Arizona Sate University, PO Box 879709, Tempe,
AZ 85287-9709; 480-965-9052; fax: 480-727-7624. Email: ranu.jung@asu.edu.
J. Lynskey and A. Belanger contributed equally to this effort.
The authors have declared that no competing interests exist.

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used to describe a variety of biological phenomena. Merriam-Webster’s Medical Dictionary
defines plasticity as “the capacity for continuous alteration of the neural pathways and synapsesof the living brain and nervous system in response to experience or
injury” (http://medical.merriam-webster.com/). Furthermore, these plastic changes underlie
learning, memory, and recovery from neural injury [8]. Several published reports support theview that the CNS is capable of significant plasticity after SCI and that rehabilitativeinterventions after neural injury affect this plasticity at several levels [8–10]:• Behavioral (recovery of sensory, motor, or autonomic function).
•

Physiological (normalization of reflexes, strengthening of motor-evoked potentials).

•

Structural/neuroanatomical (axonal sprouting, dendritic sprouting, neurogenesis).

•

Cellular (synaptogenesis, synaptic strengthening).

•

Molecular (up-regulation of neurotransmitters and neurotrophic factors, alterations
in gene expression).

SPONTANEOUS PLASTICITY AFTER SCI

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Based mostly on the results of studies using animal models, reorganization of the CNS,
including synaptic plasticity, axonal sprouting, and cellular proliferation, has long been known
to spontaneously occur following spinal cord lesions [11–20]. This reorganization occurs inthe spinal cord circuitry caudal to injury, in the spinal cord around the lesion, in the spinal cordrostral to injury, and in supraspinal structures.

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In 1929, Pike and colleagues observed spontaneous hind limb recovery after spinal cordhemisection in cats and proposed that “the mechanism which takes over control of movementsof the limb lying below the level of the lesion includes motor fibers coming down on the
opposite side of the spinal cord, and commissural neurons lying in the spinal cord below thelevel of the lesion” [21]. A recent study reported that after midthoracic dorsal hemisection, thecorticospinal tract collaterals of the hind limb sprout into the cervical gray matter where they
contact descending propriospinal neurons and a new intraspinal circuit is formed [22].
Additionally, the affected propriospinal neurons arborize on lumbar motoneurons so that the
detoured corticospinal signals reach their original targets [22]. Over time, these newconnections self-prune to include only circuits that bridge the lesion site. At the level of thelesion, descending efferent corticospinal, raphespinal, reticulospinal, and coeruleospinal axons
sprout and/or regenerate into the lesion cavity after incomplete contusive SCIs [18,23].
Additionally, cellular proliferation occurs around the lesion-producing oligodendrocytes andastrocytes, possibly replacing some of the cells lost during injury and remyelinating axons[17,20,24]. Thus the adult CNS can create novel pathways and substrates to reestablish lost
supraspinal control to the spinal cord caudal to injury, possibly mediating some of the
spontaneous recovery observed.
Reorganization of cortical maps has also been reported to occur spontaneously after bothcomplete and incomplete SCIs in humans [25–27] and rodents [22]. The underlying
mechanisms are hypothesized to be similar to those mediating reorganization after corticalinjury, including disinhibition of latent cortical connections and axonal sprouting in multiple
levels of the neuraxis [9,22,28]. Another mechanism may be injury-induced structural plasticity
in the dendritic spines of cortical motoneurons. For example, changes in dendritic spine density
and morphology in neurons of the motor cortex have been observed to occur over 3 days to 2
weeks after a fourth cervical spinal overhemisection in rodents [29]. Thus spontaneous
plasticity after SCI does not appear to be limited to the spinal cord but can occur in supraspinal
structures. However, how these cortical changes affect sensorimotor function, if at all, is not
currently known.

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As would also be expected, SCIs (both complete and incomplete) also produce considerable
changes in the spinal cord circuitry caudal to injury. At the morphological level, SCIs can
produce significant changes in dendritic morphology and marked loss of dendritic branching[30–32]. Structural plasticity at the dendritic level affects the integration of synaptic inputs tothe neurons and can hence profoundly influence the electrophysiological responses of theneurons and therefore the neural circuitry [33–34]. After experimental SCI in rodents, one canobserve increased group Ia afferent excitatory postsynaptic potentials, alterations in H reflexes,
and changes in passive and active motoneuron resting membrane potentials, including
development of persistent ionic current-based plateau-potentials [35–39]. In addition,
spontaneous sprouting of afferent axons, including calcitonin gene-related protein positive C
fibers, has also been well documented around and below the lesion site in rodents, which
contributes to the development of hyperreflexia and autonomic dysreflexia [19,40–41]. These
anatomical and electrophysiological changes indicate that spinal cord circuitry with impaired
or absent descending supraspinal and spinal input is more excitable by peripheral stimulationand may partially explain the exaggerated reflex responsiveness, hypertonicity, and autonomic
disturbances that occur after SCIs.

NIH-PA Author ManuscriptThus, from days to weeks after experimental SCI in animal models, spontaneous cellular,
structural, and electrophysiological changes occur along the entire neuraxis. Evidence supports
similar changes after SCI in humans [42]. Some of these spontaneous changes appear to beadaptive (promoting recovery and providing targets for therapy) and some appear to bemaladaptive (inhibiting recovery and impairing function). Rehabilitative strategies could be
used to enhance adaptive plasticity and/or mitigate maladaptive plasticity to enhance recovery
after SCI.

ENHANCING CNS PLASTICITY AND RECOVERY USING REHABILITATIONSTRATEGIES AFTER SCI

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The idea that neural activation may lead to anatomical and chemical changes in the CNS was
first postulated in the 19th and early 20th centuries by influential figures such as Darwin,
Ramón y Cajal, and Hebb. Further corroboration of this idea has occurred through numerous
studies conducted over the last 50 or more years [8,43] and has led to strategies to elicit activitydependent plasticity to promote recovery after spinal neurotrauma [1]. As summarized in the
Figure, rehabilitative therapies can promote plasticity both rostral and caudal to injury in the
spinal cord by activating the nervous system and influencing multiple substrates. One approachto activating the nervous system, particularly in the context of the sensorimotor system, is to
use rehabilitative strategies that include stimulating somatic sensory afferents and activating
functional movements. In this section, we review three such strategies for providing therapy
to promote plasticity and recovery: (1) use of passive exercise, (2) use of active modes of
exercise, and (3) use of neuroprostheses for electrical activation of motoneurons and sensory
afferents.
Passive Exercise
Passive exercise can be used for inducing functional ranges of joint motion and sensory
feedback to maintain or improve neuromuscular function after complete or incomplete SCIs,
respectively. Motorized cycling is one such approach that both research laboratories andclinical settings now use to provide passive exercise. An advantage of this approach is that
performing the exercise does not require any volitional control and can be initiated at earlytime points after injury.
Neural circuits within the spinal cord form reflex pathways that work together to help control
the coordination of complex movements. These reflex pathways are not only triggered by

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sensory afferents but are also modulated by supraspinal inputs. After SCI, supraspinal control
is impaired because of the tissue damage described earlier, thereby leaving the spinal neuralcircuitry to be driven primarily by the peripheral sensory input [44–45]. This shift toward
peripheral control may contribute to the development of spasticity and abnormal muscle tone.
An important sensory input to the spinal cord neural circuitry is from the group Ia muscle
spindle afferents. Stretching of a limb muscle caused by joint movement activates the H reflex
via the group Ia afferents. The reflex activation recruits synergistic muscles and inhibits
antagonists [46]. Passive exercise activates the H reflex and, through repetition training,appears to be able to “condition” the caudal spinal circuitry to “normalize” specific spinal
reflexes in the absence of supraspinal control [47]. Passive exercise has been provided withuse of bicycles and robotic assistance [48]. Use of a motorized bicycle in rats [37,47,49] andin humans [50–51] causes some normalization of motoneuron electrophysiology, causes
habituation of the H reflex and decreased spasticity, and can influence dendritic morphology[32]. However, at least for humans, continued cycling is required to maintain the effects. Most
likely, exercise paradigms that promote activation of load receptors that trigger some of thereflex pathways will be beneficial [4,45,52–53], as will approaches that include plantar
cutaneous stimulation [4,54]. Thus continued research to increase our understanding of CNS
plasticity mediated by passive exercise after SCI could help determine if passive exercise alone
can lead to improved sensorimotor function.

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Active Exercise
Another rehabilitation strategy following SCI is active exercise. This exercise approachrequires subjects to perform assisted or unassisted active movements using varying degrees ofsupraspinal and/or segmental spinal control. Multiple approaches have been used to provide
active exercise in people with incomplete SCIs. These approaches include locomotor training(manual-assisted and robot-assisted partial weight-supported treadmill training, as well as
overground locomotion), repetitive upper-limb training, and general exercise/environmental
enrichment. Using active voluntary exercise as a rehabilitation technique targets harnessing
the neuroplasticity seen with passive exercise but with added benefits. Voluntary exercise
elicits not only functional ranges of joint motion but also functional activation of muscles andmultiple modes of afferent stimulation.
Increasing postinjury activity via locomotor training has been shown to improve motor
recovery, although some questions remain about the role and degree of specificity of locomotor
training needed to achieve significant recovery [55]. In rodents, exercise and treadmill training
can support partial recovery of hind locomotion [10,56–59] and sensation [57] after incomplete
SCIs. Studies conducted on spinal cord-transected cats suggest that recovery after locomotor
training is task-specific and relies on sensory feedback mechanisms [60–61].

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In rodent and feline models of thoracic SCI, the effects of locomotor training on neuroplasticity
have been observed at the cellular level. The training decreases expression of inhibitory
molecules [62], increases expression of neurotrophic factors [57], and alterselectrophysiological properties in the lumbar enlargement [10,37]. These changes might
mitigate some of the spontaneously occurring maladaptive plasticity that can cause spasticity
and enable the isolated (partial or complete) spinal cord to produce locomotion with little orno descending control.
Locomotor training, both overground and on a treadmill using partial body weight support, hasalso been shown to promote recovery in humans with incomplete SCIs [4,6–7,9,44,63–69].
Evidently, the active exercise paradigm mediates plasticity at multiple levels of the neuraxis
including the cortex, descending supraspinal motor pathways, and spinal cord circuitry caudal
to injury.

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In humans, intense repetitive training (massed practice) after a cervical spinal injury and robotic
locomotor training after a thoracic spinal injury appear to promote cortical plasticity as cortical
map reorganization [5,70–71]. As with spontaneously occurring cortical plasticity, thesubstrates and implications of this activity-dependent cortical reorganization after SCI areunclear. However, recent data from neurologically intact nonhuman primates indicate that
activity can reorganize the motor cortex, such that cortical motoneurons “learn” to control
additional muscles and produce novel movements when stimulated [72]. Rehabilitative
therapies may possibly promote a “rewiring” of the cortex to bypass pathways interrupted byan incomplete SCI, thereby reestablishing supraspinal control of caudal circuitry using novel
supraspinal-spinal circuits. In fact, locomotor training on a treadmill after incomplete SCI in
humans promotes improved corticospinal drive to muscles of the lower limb that correlateswith improved locomotor function [73–74]. This increased corticospinal drive could comefrom plasticity occurring in the cortex (see aforementioned data) or in the descending pathways
themselves. In rodents after incomplete SCI, increased activity via enriched environment
promotes plasticity in spared corticospinal but not raphespinal or rubrospinal axons [75].*

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Based on studies in animal models, a possible molecular mechanism has been proposed for theneuroplasticity events known to occur because of voluntary exercise after SCI. Brain-derived
neurotrophic factor (BDNF) and its associated receptor, tyrosine kinase B (TrkB), may be theprimary modulators of a biochemical cascade resulting in neuroplasticity. BDNF is known tosynthesize and phosphorylate synapsin 1 [16,76], a phosphoprotein responsible forneurotransmitter release and axonal growth [77–78]. In rodent models of SCI, increased
expression of BDNF, TrkB, and synapsin 1 occurred in the spinal cord starting in the secondary
phase and persisting in the chronic phase following injury after voluntary exercise [79].
In rats with SCI following voluntary exercise, further elevation of BDNF levels was found inskeletal muscles and in the innervating level of the spinal cord [80]. Other research has also
found that BDNF can be retrogradely transported through motoneurons from the skeletal
muscles to the spinal cord [81–82]. These data suggest that up-regulation of BDNF expression
may have a causal relationship with neuroplasticity, neuronal growth, and functional recovery
and that increased recovery results from voluntary exercise. BDNF and other neurotrophic
factors have been hypothesized to facilitate neuronal plasticity in an autocrine or paracrine
fashion [83]. This neurotrophic up-regulation is not only activity-dependent but also activityspecific, which reinforces the notion that differential recovery results from differential
voluntary exercise regimes [57]. All the nuances of BDNF up-regulation appear to coincidewith the recovery observed following rehabilitation after incomplete SCI. This finding suggeststhat neuroplasticity can occur through a BDNF-mediated pathway [80,84–88].

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Voluntary exercise, as just described, shows promise as an effective promoter of recovery andactivity-dependent plasticity throughout the neuraxis after incomplete SCI. In future
multifaceted treatment, strategies could be used to maximize the effectiveness of rehabilitative
therapies. Passive exercise, such as motorized cycling, could be administered early postinjury(to promote plasticity caudal to injury and possibly mitigate spasticity) followed by more active
exercise (to promote plasticity both rostral and caudal to injury). However, voluntary exercise
can only be performed by individuals who have some preexisting level of motor function,
which limits rehabilitative interventions to those with incomplete SCIs.

*Lynskey JV, McAtee M, Dai HN, Iarikova E, Hamers FP, Bregman BS. Environmental enrichment promotes recovery of forelimb
movements and supraspinal pathway plasticity after cervical spinal cord injury in adult rats [abstract]. In: 2005 Proceedings of the 11th
International Symposium on Neural Regeneration; 2005 Dec 14–18; Pacific Grove, California.
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Neuroprostheses for Rehabilitation

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Use of neuroprostheses is another rehabilitative strategy that combats the limitations of bothpassive and active voluntary exercise. Neuroprostheses use electrical stimulation to activate
neural structures [89]. In applications in people with SCI, functional electrical stimulation(FES) is one neuroprosthetic approach to improve locomotor function that stimulates theperoneal nerves to elicit a flexion withdrawal reflex and thereby cause limb movement [90].
A second approach is functional neuromuscular stimulation (FNS). It stimulates multiple leg
muscles at their motor points in an appropriate sequence to produce coordinated functional
movements, such as grasping, standing, or rhythmic leg movement [91–95]. A third approachcalled epidural spinal cord stimulation (ESCS) stimulates the dorsal aspect of the spinal cord
at a particular spinal level using implanted electrodes [96–98].
When used in a paradigm for motor therapy, neuroprostheses seek to enhance standard
therapist-provided rehabilitation by generating active muscle contractions, generating
improved movement patterns, and reducing the physical demands on the therapists. FES
therapy, which elicits the flexion withdrawal reflex to assist persons with an incomplete SCI
bring their leg into the swing phase of gait, has resulted in a carryover of increased functional
mobility and speed, decreased effort, and improved intralimb coordination during unstimulated
overground locomotion [90,99–104]. Electrical stimulation of sensory afferents alone may also
contribute to recovery after incomplete SCI [105].

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Since the flexion withdrawal reflex habituates, its use in a repetitive therapy paradigm hassome inherent limitations. Use of FNS to stimulate the muscles via the motor points attempts
to overcome this limitation. As therapy, FNS can decrease the fatigability of muscles after SCI[106–107], reverse muscle atrophy, and increase bone density [108]. FNS, along with cycling
exercise, may also promote recovery in individuals with chronic incomplete SCIs [109–110].
Since muscles fatigue with ongoing stimulation and have nonlinear properties, using an
adaptive control approach would help tailor the stimulation to the individual muscle properties
and automatically adjust stimulus strength for repeatable movements [111–113].
ESCS, which has traditionally been used as a modality for pain control [114], has been shown
to reduce spasticity after SCI [97–98,115]. Appropriate levels of ESCS can promote stepping
movements and even locomotion in humans [96,116–118] and animals (rodents and cats)[119–120] with SCIs.

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How electrical stimulation likely promotes recovery remains unclear, but the mechanisms may
include plastic changes at the cellular/molecular and circuitry levels. The sensory afferent input
provided by peripheral electrical stimulation likely provides drive to the spared CNS. In
decerebrate cats, electrical stimulation of hind limb muscles can cause reflex withdrawal of
the contralateral hind limbs [121] and direct electrical stimulation of sensory afferents in thedorsal root entry zone can activate the lumbar spinal pattern generator [122]. ESCS appears to
produce significant plastic changes. These changes include altering the electrophysiologicalproperties of spinal motor pattern-generating circuitry [115,123–124], altering amino acidneurotransmitter levels in the spinal cord (glycine and taurine) [125], and altering blood flow
(both centrally and peripherally) [126–128].
Electrical stimulation may also trigger the BDNF-mediated mechanism of recovery describedearlier. Direct electrical stimulation to both motor [129–131] and sensory [132] peripheral
neuron cell bodies increases BDNF and TrkB expression in those cells and leads to axonal
regeneration. Additionally, electrical stimulation can partially restore segmental spinal reflex
responses in the lumbar spinal cord, in particular the H reflex [133], that are altered by thoracic
SCI [134]. For continued examination of the circuit level and cellular mechanisms, a rodentmodel for FNS therapy has recently been developed [135–136]. Short-term FNS therapy in a

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rodent model of contusion injury also results in a carryover into improved symmetry oftreadmill walking [137].

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Thus electrical stimulation, used alone or combined with active exercise, promotes recovery
and plasticity after neural injury. Multiple characteristics of therapeutic electrical stimulation(including being noninvasive, not requiring volitional muscle control, producing gradedmuscle contractions, and producing functional ranges of motion) allow for its use as both an
early intervention (possibly along with passive exercise) and a chronic intervention (along withlocomotor training).

ENHANCING CNS PLASTICITY AND RECOVERY USING MULTIFACETED
TREATMENT APPROACHES AFTER SCI

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Scientists and clinicians have widely theorized that given the myriad of issues preventing
recovery of function after SCI, multifaceted treatment approaches will be most successful[1]. In fact, the goals of most rehabilitative strategies are to complement and optimize the moreinvasive transplantation and pharmacological treatment strategies required to “cure” SCI.
These goals are reasonable considering that the data from initial treatment approaches ofcombined locomotor training and pharmacological interventions after complete SCI in catsproduced favorable results [44]. However, recent studies using similar approaches after
incomplete SCIs in rodents have not produced the anticipated additive results. In rodents,
combined treatment involving passive motorized cycling and stromal cell transplants did not
improve plasticity or sensorimotor behavioral recovery after incomplete contusive injury[138]. In addition, electrical stimulation combined with peripheral nerve grafts does not
improve rubrospinal tract regeneration after partial transection [139]. Furthermore, treatment
combining robotic-assisted locomotor training on a treadmill and quipazine administration
does not enhance recovery of locomotion [140]. Thus despite multiple studies in animal modelsof SCI and tremendous advances in our understanding of the postinjury response process,significant gaps remain in the mechanisms and substrates underlying treatment-mediatedrecovery (rehabilitation, transplantation, and pharmacology). Development of successful
multifaceted treatment paradigms applicable to people with SCI will require enhancing ourknowledge of the mechanisms targeted by both the individual and combined therapeutic
regimens. The windows of opportunity for application of one or more of these interventional
strategies will also need to be assessed.

CONCLUSIONS
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The adult mammalian CNS is capable of considerable spontaneous structural and functional
plasticity, both in health and disease. Significant evidence from both human and animal studies
indicates that rehabilitation strategies exploit this plasticity to promote recovery. Furthermore,
rehabilitative strategies are not limited to targeting activity-dependent plasticity of the spinal
cord below an injury but appear to promote plasticity in both cortical and descending pathways.
While our understanding of rehabilitation-mediated activity-dependent plasticity after SCI has
greatly increased, significant gaps remain and continued diligent research is required to
optimize the effectiveness of rehabilitative interventions, given alone and as part of amultifaceted treatment approach.

Acknowledgements
This material was based on work supported in part by the National Institutes of Health, National Center for Medical
Rehabilitation Research, grant R01HD40335 to Ranu Jung.

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Page 8Abbreviations
BDNF

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brain-derived neurotrophic factor
CNS
central nervous system
ESCS
epidural spinal cord stimulation
FES
functional electrical stimulationFNSfunctional neuromuscular stimulation
SCI
spinal cord injury
TrkB
tyrosine kinase B

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Figure.

Activity-dependent plasticity after spinal cord injury (SCI). Following SCI, rehabilitative
therapies can promote significant structural and functional plasticity within central nervous
system both rostral and caudal to injury.

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