Plastic Changes After Spinal Cord Injury
Summary and Keywords
Spinal cord injury has instantaneous, destructive effects on bodily functions, as readily demonstrated by muscle paralysis and non-responsiveness to sensory stimulation. This primary response has underlying features at molecular, cellular, tissue and organ levels which will, in a relatively brief time, initiate a secondary cascade of events that exacerbates the extent of the primary focus of damage. Interestingly, the initial extent of motor and sensory loss often is followed by limited, but significant spontaneous functional recovery. Recovery may be due to intrinsic central pattern generators such as for locomotion, the uncovering of dormant anatomical and physiological pathways such as the crossed phrenic for respiration, or to the sprouting of undamaged axons within the spinal cord to establish new connections around or across the injury site. Together the responses to injury and spontaneous efforts for repair represent plastic changes in the central nervous system (CNS) that may result in meaningful functional outcomes, though aberrant sprouting is a possible negative consequence of neuroplasticity that lends caution to the desire for extensive but uncontrolled sprouting.
The immediate consequences of a spinal cord injury (SCI) are loss of purposeful movement and alterations in responses to external stimuli, indicative of disruption of motor and sensory pathways. If this were the extent of the effects of injury, then experimental approaches to foster recovery of function could in some sense be more direct in their design, such as attempting to reconnect axon A to target neuron B for return of a specific function. Unfortunately, SCI triggers a wide range of responses that can be grouped into the primary (acute) phase that is a direct result of the physical trauma incurred by the spinal cord, which then evolves into the secondary phase of dysfunction with persisting (chronic) neurologic instability (Figure 1). It is important to keep in mind that effects of SCI are not confined to the injury site but encompass more distant regions within the central nervous system (CNS) (including the brain) and that most all organ systems of the body may be affected to some extent. To get the full picture of the effects of SCI, molecular and cellular changes, synaptic changes, neuronal responses, glial cell responses, vascular changes, local environmental changes (biochemical and structural), changes in denervated targets, and systemic changes would need to be examined (Figure 1).
Simply defined, a plastic change or plasticity denotes the capacity to be shaped or formed, referring to something that is easily influenced, impressionable, or constructive. Neuroplasticity denotes an ability of neurons and adjacent glial cells to adjust their activity and even their morphology to alterations in their physical or chemical microenvironment or patterns of use. The response to change can be as straightforward as learning and memory in the execution of normal activities or as complex as axon retraction, axon sprouting, or abortive regeneration in response to injury. Axon sprouting is one component of neuroplasticity that can arise from damaged or undamaged axons (Steward, 2014). Collateral sprouting, also called reactive reinnervation, refers to the growth of additional presynaptic processes from the preterminal axon or growth from existing terminals. It is important to distinguish this as growth from an uninjured axon. Compensatory sprouting refers to additional growth and connectivity from an injured axon in the attempt to maintain a certain total axonal arbor. Often this results in the increase in processes proximal to the site of injury. Regenerative sprouting also occurs following axon injury and denotes regrowth of that axon to re-establish connection with the original target or the establishment of alternative pathways to transmit information beyond the lesion site. As a note of caution, not all neuroplasticity results in a positive outcome, as demonstrated by the onset of neuropathic pain or autonomic dysreflexia in a sizable proportion of the SCI community (Brown & Weaver, 2012).
This article presents a brief overview of three aspects of plastic changes after SCI: first is information about spontaneous sprouting of cortical, supraspinal, and propriospinal pathways in the attempt to form new connections around an injury site; second are examples of plasticity that can be functionally appropriate or aberrant; and third is an introduction to the often unrecognized response of distant brain centers to SCI that may present clinically as cognitive or mood disorders. This article focuses on changes in neurons and their axonal processes and attempts to re-establish lost connections and restore function. For clarity and brevity, it does not present information on the myriad of experimental or clinical therapeutic interventions under investigation designed to promote or enhance neuroplasticity or regeneration. The authors certainly recognize that strengthening or reshaping of new connections by physical training or rehabilitation likely will be necessary to ensure the desired or maximal functional outcome (Onifer, Smith, & Fouad, 2011; Fouad & Tetzlaff, 2012).
As an important part of plasticity, there often is a degree of recovery of function that occurs too soon after injury to be due to regeneration and more likely this “spontaneous recovery” can be attributed to return of function from spared neural circuitry (Weidner, Ner, Salimi, & Tuszynski, 2001; Bareyre et al., 2004; Ballermann & Fouad, 2006). An interesting observation in an early study of unilateral cervical contusion injury in rats (Sandrow, Shumsky, Amin, & Houle, 2008) was the significant behavioral improvement between 3 and 7 days after a moderate injury primarily affecting use of the right forelimb. There was an 8-point increase on the forelimb locomotor scale, indicative of improvement from slight movement of one or two joints to frequent plantar stepping. Significant improvement in grid walking and grip strength also occurred. Importantly these improvements were maintained for many weeks and were not diminished by a delayed neural tissue transplantation procedure. Curiously, there appears to be a much greater degree of spontaneous recovery in experimental SCI models compared to the human injury condition, and it is important to further researchers’ understanding about neuroplasticity within animals as a representation of what may effectively be pursued for promoting recovery in humans. Given the large body of work on SCI in rodents, the focus in this article is primarily on studies using this animal model.
Sprouting of Descending Spinal Pathways
The corticospinal tract (CST) is comprised of axons projecting from layer V pyramidal neurons in the cerebral cortex through the corona radiata and internal capsule, into the caudal medulla. Along the path through the brainstem as the cortical pyramids, there is extensive collateral sprouting to all motor control regions. In rodents, approximately 85% of CST axons decussate at the medullary pyramids and descend primarily in the contralateral dorsal funiculus to all spinal segments, synapsing with neurons in every lamina throughout the gray matter. Early work by Metz, Dietz, Schwab, and van de Meent (1998) demonstrated that after unilateral pyramidotomy to ablate the CST in adult rats, behavioural deficits in locomotion and balance returned to near baseline levels after 1 month (Metz et al., 1998). These findings highlight the critical contribution of subcortical pathways to motor function and the potential for improvement after SCI. Although the CST is the primary source of fine motor control from the brain, the substantial proportion of redundancy in motor circuitry via subcortical projections offers a potential mechanism for functional reorganization after SCI (Lemon, 2008; Fink, Strittmatter, & Cafferty, 2015).
Central nervous system (CNS) axons exhibit limited intrinsic regenerative capacity compared to peripheral nervous system (PNS) axons (Yiu & He, 2006; Liu, Tedeschi, Park, & He, 2011); however, CNS axons that are spared from injury can form collateral sprouts over short distances to synapse with intact brainstem or propriospinal motor circuits (Raineteau, Fouad, Noth, Thallmair, & Schwab, 2001; Raineteau & Schwab, 2001; Bareyre et al., 2004; Bareyre, Kerschensteiner, Misgeld, & Sanes, 2005; Courtine et al., 2008; Siegel, Fink, Strittmatter, & Cafferty, 2015). A study by Fouad, Pedersen, Schwab, and Brosamle (2001) identified axotomized thoracic CST axons forming functional connections with cervical gray matter, evoking previously unseen forelimb and trunk muscle activity upon cortical stimulation (Fouad et al., 2001). Additionally, Ghosh et al. (2010), using neuronal tracing methods, demonstrated that after lateral hemisection, intact CST axons created new synapses within the spinal cord caudal to the lesion. These collaterals allowed the ipsilateral cortex to exert functional control of the denervated hind paw (Ghosh et al., 2009; Ghosh et al., 2010).
Apart from the predominant dorsal funiculus CST input, some axons from the motor cortex descend ipsilaterally through the ventral, lateral, and dorsolateral tracts of the spinal cord (Vahlsing & Feringa, 1980; Joosten, Schuitman, Vermelis, & Dederen, 1992; Brosamle & Schwab, 1997). Given the segregated nature of these tracts, it is possible that spared CST axons provide a promising resource for plasticity after an incomplete SCI. Weidner et al. (2001) elucidated the distinct role of each CST tract in restoration of skilled forelimb movement after targeted ablation at the cervical level. The greatest deficits in pellet retrieval were seen after bilateral transection of both dorsal and ventral CST tracts, with the deficit persisting up to 4 weeks post-injury. Transection of the medullary pyramids to ablate all major and minor tracts resulted in a persistent deficit in proximal and distal forelimb function during pellet retrieval. Targeted ablation of the major CST tract beneath the dorsal funiculus resulted in significant forelimb motor impairment for the first 3 weeks after injury; yet, pellet retrieval reaching levels were not significantly different from intact rats by the fourth week. Utilizing biotinylated dextran amine (BDA) anterograde tracing of motor cortex neurons, functional improvement in these rats was shown to positively correlate with a significant increase in projections from the ventral CST to medial choline acetyltransferase-positive motor neurons of the ventral horn at C4. This functional plasticity was not seen in injuries that damaged the ventral CST, and functional forelimb recovery after dorsal CST transection was eliminated if a subsequent ventral transection was performed 4 weeks after the initial injury (Weidner et al., 2001). These studies provided novel insight into the importance of the minor CST tracts for functional plasticity despite the small proportion of axons traveling in these pathways.
In addition to CST circuits, subcortical pathway plasticity contributes to the restoration of motor control. The rubrospinal tract (RST) travels near the CST as it descends in the dorsal-lateral funiculus and shares many aspects of CST function. The RST originates in the red nucleus of the brainstem and decussates at the ventral tegmentum to synapse on contralateral intermediate gray matter of the spinal cord. While the RST contributes to upper and lower limb motor control in evolutionarily lesser species, it is mainly responsible for gross motor control of upper limbs in humans. Because of its overlap with the CST, the RST can compensate for fine motor control after injury (Fink & Cafferty, 2016). After specific ablation of the CST at the medullary pyramid, rodent performance in grid-walking analysis, a measure of skilled locomotor function, was significantly impaired (Siegel et al., 2015). At 4 weeks post-injury, skilled locomotor ability demonstrated spontaneous improvement, but a deficit remained when compared to baseline ability. Anterograde tracing in the red nucleus revealed a significant increase in bilateral projections to the basilar pontine nuclei in the brainstem and collaterals to the ventral gray matter in the spinal cord after bilateral pyramidotomy. Plasticity in RST projections to both regions could provide a source for spontaneous locomotor improvement seen after injury, given their role in motor control and coordination (Siegel et al., 2015).
The serotonin system is most closely associated with mood and emotional regulation; however, serotonergic projections from the nucleus raphe magnus (NRM) to the spinal cord gray matter also modulate nociceptive and motor input (Jones & Light, 1990; Mason, 2001; Liang et al., 2015). The importance of serotonin (5-HT) to motor circuitry has been demonstrated in animal models of SCI, where intrathecal administration of 5-HT can initiate rhythmic locomotor responses (Barbeau & Rossignol, 1990, 1991). Descending serotonergic axons are principally located in the lateral funiculus and form networks around neurons of the ventral horn (Saruhashi, Young, & Perkins, 1996). After descending ipsilaterally from the brainstem, some of these axons cross the midline through dorsal or ventral gray commissures, suggesting a source of plasticity after injury to one side of the spinal cord (Steinbusch, 1981; Krukoff, Ciriello, & Calaresu, 1985; Saruhashi et al., 1996). After T8 hemisection injury, it was demonstrated that serotonergic axons rostral to the lesion formed large varicosities in ipsilateral white matter and were drastically reduced in the ventral horn caudal to the lesion (Saruhashi et al., 1996). However, in a more chronic injury state, the number of serotonergic axons in the lumbosacral ventral horn had increased significantly. This increase was positively correlated with locomotor ability in the open field, indicating a role for the serotonergic system in functional recovery after SCI. Although this experimental design could not distinguish between regeneration of severed axons and plasticity of spared fibers, the presence of commissural serotonergic fibers from the contralesional spinal cord indicated a likely source of increased serotonergic density in the ipsilateral cord at 4 weeks post-injury (Saruhashi et al., 1996). Providing additional support for serotonergic plasticity after SCI, Kim, Liu, Park, and Strittmatter (2004) demonstrated a reversal of hindlimb motor recovery following specific serotonergic neuron ablation (Kim et al., 2004). Plasticity in the serotonergic systems after injury also occurs in the form of novel motor circuitry. Siegel et al. (2015) demonstrated the importance of the RST input to the NRM in spontaneous locomotor recovery following CST transection. Locomotor improvement was correlated with a significant increase in RST axon terminals in the NRM. Targeted silencing of NRM with inhibitory designer receptors exclusively activated by designer drugs (DREADDs) reversed locomotor ability to that seen at only 4 days post-injury (Siegel et al., 2015). The ability of spared motor circuitry to compensate for CST loss provides promising targets for future functional therapy after SCI.
The reticular formation is comprised of multiple brainstem nuclei contributing to motor and sensory function. The reticular nuclei of the pons and medulla elicit opposing bilateral actions on flexor and extensor motor neurons and are involved in gait and postural stability, projecting through the reticulospinal tract (ReST) in the ventrolateral funiculus. Dual retrograde tracer injection further elucidated reticulospinal circuitry (Reed, Shum-Siu, & Magnuson, 2008). A portion of medullary reticulospinal neurons have axons that cross the midline rostral to T9 and innervate gray matter in both cervical 5/6 and thoracolumbar levels, indicating potential for bilateral motor control that could circumvent a lesion that interrupts CST input to the hindlimbs. Additionally, these neurons were most prominently located in the gigantocellular group of the reticular formation, providing a target for enhancement of plasticity. ReST innervation spanning multiple segments was less prominent in more caudal cervical and lumbar sections (Reed et al., 2008). ReST axons have also been shown to exhibit plasticity with injury. After lateral hemisection of the cervical spinal cord, tracer injections above and below the lesion demonstrate an increase in contralateral cell labeling in the gigantocellular reticular nucleus and an increase in number of axons crossing the midline into the denervated spinal cord, respectively (Zorner et al., 2014). Further analysis of ReST plasticity revealed an increase in supraspinal projections from the mesencephalic locomotor region to the gigantocellular reticular nucleus contralateral to the side of injury, strengthening the potential of this region to enhance motor control. Ablation of the ipsilateral or contralateral gigantocellular reticular nucleus 16 weeks after cervical hemisection revealed specific patterns of bilateral hindlimb motor deficits that are not seen with ablation in an intact rat (Zorner et al., 2014). These data suggest that the ReST and its supraspinal inputs exhibit plasticity that can contribute to restoration of locomotor function after incomplete spinal cord injury.
Although the ReST is generally not involved directly with precise motor function, the enhanced presence of synapses on spinal motoneurons suggests sprouting that potentially reinnervates specific damaged pathways (Fink & Cafferty, 2016). Using unilateral BDA injection into the medullary reticular formation, Ballermann and Fouad (2006) assessed the ability of spared or severed ReST axons to extend into gray matter below and above the lesion site, respectively. After thoracic hemisection contralateral to the injection site, there was a significant increase in collaterals from spared fibers into the dorsal horn ipsilateral to injection at 42 days post-injury. This increase positively correlated with the ability to ambulate post-injury, as assessed by the Basso, Beattie, Bresnahan (BBB) locomotor rating scale. Conversely, there were no significant differences in density of sprouting from severed axons with hemisection ipsilateral to the injection site. This pattern of plasticity is distinct from the CST, which can circumvent the lesion site by forming compensatory collaterals above the lesion when axons are severed. However, it was determined that many collaterals from spared fibers entered the intermediate lamina, where commissural interneurons of the central pattern generator reside. Functional synapses with these interneurons could allow for innervation of the injured side without the need for sprouting across midline (Ballermann & Fouad, 2006).
Spinal cord interneurons whose axons project to different spinal segments are termed propriospinal neurons (PNs), and they provide an important source of neuroplasticity after SCI. PNs are represented by two basic categories of cells: those with axons that extend for a relatively short distance that are important for maintaining the transmission of intersegmental information down the spinal cord; and those with long projecting axons that are responsible for integrating forelimb and hindlimb movement, with axons either ascending or descending between the cervical and lumbar locomotor centers (Conta & Stelzner, 2004; Conta & Stelzner, 2009). Siebert, Middleton, and Stelzner (2010) measured the intrinsic post-injury response of thoracic PNs above the level of injury and found significant increase in regeneration-associated genes and cell survival and neuroprotective genes at 3 days but not at 7 days post-injury, indicative of an early but transient response to axotomy. Flynn, Graham, Galea, and Callister (2011) emphasized the potential role of PNs in contributing to recovery of motor function based upon their location throughout the spinal cord and their proximity to injury at any spinal level, their dense intersegmental projection pattern, and the substantial number of these cells. The authors’ work (Sachdeva, Theisen, Ninan, Twiss, & Houle, 2016) with a lower thoracic SCI and transplantation of segments of peripheral nerve to support axon growth showed strong regenerative effort by mid-lower thoracic PNs and mid-lower lumbar PNs when provided an appropriate substrate. Thus, PNs appear to have a strong potential for contribution to spinal cord plasticity and local efforts to restore functional continuity. How PN plasticity may influence functional recovery after SCI was demonstrated by Courtine and colleagues (2008). They used an opposite side, time-staggered lateral hemisection approach at T7 and T12 levels to limit the relay of descending motor information to PNs within the spared central gray. Anatomical evidence of near total interruption of long descending supraspinal pathways suggested reorganization and sprouting of descending fibers on PNs with short axons for intersegmental integration, behavioral and physiological evaluation of supraspinal control of stepping showed that “precise restoration of point-to-point connections made by long-tract descending axons from the brain to the lumbosacral locomotor circuits is not required to achieve meaningful functional recovery” (Courtine et al., 2008).
There is additional evidence that PNs provide a potential route for axons transmitting descending motor commands to circumvent the lesioned spinal cord tissue. In this manner, the cervical PN network may be considered an extension of the brainstem reticular system necessary to synchronize motor circuits throughout the spinal cord (Zaporozhets, Cowley, & Schmidt, 2006). By use of anterograde axonal tracing techniques, work by Filli et al. (2014) demonstrated regionally specific increases in the number of reticular formation neurons sending axons to the ipsilateral cervical cord after C4 hemisection. Interestingly, most of these fibers were located rostral to the lesion site, principally found in the intermediate and ventromedial gray matter of C3–C4, and they expressed the excitatory synaptic marker vGLUT2. Utilizing a retrograde tracer injected at the C6–C8 level (caudal to the lesion), the synaptic target of these ReST neurons was found to be mid-cervical propriospinal neurons. Because the tracer was injected ipsilesionally, retrograde labeling of these rostral neurons suggested that their axons crossed into the contralesional white matter to circumvent the lesion, and many of them subsequently crossed midline a second time to innervate the ipsilesional C6–C8 intermediate gray and ventral horn. (Filli et al., 2014).
To further study the ability of injured ReST axons to form functional collaterals, May et al. (2017) utilized similar reticular formation tracing techniques as Ballermann and Fouad (2006), combined with a staggered hemisection model. An over-hemisection to include a complete dorsal funiculus was performed at T7 and an additional hemisection contralateral to the first was performed at T9. These injuries were performed either concomitantly or with a delay of 14 days between surgeries. The alternating hemisection injuries minimized sparing of ReST fibers, but provided a bridge to allow connection with PNs. Retrograde tracing caudal to the lesion, in combination with anterograde tracing from the reticular formation, allowed visualization of any PNs from the tissue bridge projecting to the lumbar region. Despite a lack of significant difference in traced ReST collaterals entering the gray matter from white matter tracts between the concomitant and delayed groups, the collaterals present in the delayed group demonstrated growth over longer distances once in the gray matter. Synaptophysin contacts between PNs and traced ReST axons were significantly higher with temporally separated lesions, which correlated with increased locomotion as assessed by open field scoring (May et al., 2017).
Sprouting CST axons utilize the spared PN circuitry after SCI as well. After thoracic dorsal hemisection, Bareyre et al. (2004) demonstrated that CST axons increase collaterals to cervical long and short PNs with axons ventral to the lesion. There was an expanded PN axonal arborization among lumbar motoneurons, thus forming new, functional intraspinal circuitry capable of relaying information from the brain to spinal targets. However, at 12 weeks post-injury, only the long propriospinal connections remained. Additionally, they determined that long propriospinal neurons in the cervical cord were forming functional synapses with lumbar motor neurons that had been retrogradely labeled with Cholera Toxin B. Interestingly, these synaptic connections could be traced all the way to motor cortex neurons after pseudorabies virus injection into the hindlimb muscle. Additionally, hindlimb EMG measurements were recorded after intracortical stimulation and demonstrated a reoccurrence in most animals 12 weeks after injury, which could be abolished by unilaterally severing the sprouting CST axons at the medullary pyramids (Bareyre et al., 2004). This bridging PN plasticity provides an excellent target for re-establishing lost motor circuitry without pursuing a complete regeneration of severed cortical axons.
Crossed Phrenic Pathway
Injury to the cervical spinal cord above the level of phrenic motor control, localized to the cervical 3–6 segments, can lead to disruption of bulbar respiratory control and paralysis of associated respiratory musculature. Early experiments by W. T. Porter in 1895 first demonstrated that upon additional phrenic challenge, such as transection of the contralesional phrenic nerve, the previously paralyzed ipsilesional diaphragm regains functional motor ability (Porter, 1895). This functional restoration phenomenon, known as the crossed phrenic pathway, is thought to be activated by modulation of neuronal output from bulbar respiratory centers (Lewis & Brookhart, 1951; Goshgarian, 2003) as well as morphological plasticity of “functionally ineffective” synapses (Goshgarian & Guth, 1977). Substantial progress has been made in elucidating the circuitry of the respiratory system that could allow phrenic input to circumvent spinal cord injury. In addition to each brainstem ventral respiratory group sending bilateral inputs to cervical motor neurons, decussating at the medullary pyramids (Ellenberger & Feldman, 1988; Ellenberger, Feldman, & Goshgarian, 1990; Feldman, Loewy, & Speck, 1985), axon collaterals from these inputs branch at the level of the phrenic motor pool to innervate the diaphragm bilaterally (Moreno, Yu, & Goshgarian, 1992; Goshgarian, Ellenberger, & Feldman, 1991). Prakash, Mantilla, Zhan, Smithson, and Sieck (2000) discovered a small group of phrenic motor neurons with dendrites that cross the spinal midline, providing another potential source of bilateral motor control. Retrograde trans-synaptic tracing demonstrated a direct, bilateral connection of the ventral respiratory group to phrenic motor neurons ipsilateral to the hemisection, with no labeling of propriospinal neurons in the cervical cord (Moreno et al., 1992), suggesting that propriospinal plasticity does not play a role in functional hemidiaphragm restoration after cervical hemisection.
Morphological changes in the phrenic motor nucleus of the spinal cord began to appear through electron microscopy at 2 hours post-injury (Goshgarian, Yu, & Rafols, 1989) and continued to develop at 30 days after hemisection (Tai & Goshgarian, 1996). Injury-induced plasticity included a significant increase in axon terminals making synaptic contacts with multiple post-synaptic regions in the same plane (Goshgarian et al., 1989), increased post-synaptic density length in both glutamatergic and GABAergic terminals (Tai & Goshgarian, 1996), and increased length and overall number of dendro-dendritic membrane appositions in motor neurons due to retraction of surrounding astroglial processes (Goshgarian et al., 1989; Sperry & Goshgarian, 1993). These cellular changes could allow synaptic input that is subthreshold for activation in normal or acute SCI animals to initiate motor neuron activity upon respiratory challenge and subsequent increase in bulbar respiratory output, initiating the crossed phrenic phenomenon (Goshgarian, 2003).
Recently, it was discovered that crossed phrenic activation after contralesional phrenicotomy in cervical hemisection models may be partly due to a decrease in inhibitory feedback from contralateral sensory afferents of the diaphragm (Golder et al., 2003; Vinit, Stamegna, Boulenguez, Gauthier, & Kastner, 2007). If these sensory afferents are specifically disrupted with contralateral dorsal rhizotomy at the cervical level after a C2 hemisection, crossed phrenic activation is seen without further respiratory challenge (Goshgarian, 1981; Fuller, Johnson, Johnson, & Mitchell, 2002). Increased dorsal horn sensory neuron activity seen after SCI (Hains, Willis, & Hulsebosch, 2003) could partially explain why increased respiratory center output is required to activate the crossed phrenic pathway after hemisection. Application of a GABA-A antagonist to the cervical cord to prevent this inhibitory sensory drive to phrenic motor neurons resulted in crossed phrenic activation of the ipsilesional phrenic nerve (Zimmer & Goshgarian, 2007). An alteration in GABAergic tone after chronic SCI could partially account for spontaneous development of crossed phrenic activation in some rats.
Plasticity in the phrenic circuit is not limited to crossed phrenic pathways in rats, with spontaneous recovery of hemi-diaphragmatic function appearing inconsistently 6 weeks after C2 hemisection but with more stability at 16 weeks post-injury (Nantwi, El-Bohy, Schrimsher, Reier, & Goshgarian, 1999). Phrenic nerve activity ipsilateral to the hemisection recovered to about 30% of control levels by 16 weeks post-injury, with respiratory bursting patterns in the hemidiaphragm that are comparable to those of intact animals (Nantwi et al., 1999). This spontaneous recovery of function may be partially due to plasticity in ipsilateral phrenic circuits spared after injury. Utilizing a chronic lateral cervical hemisection model that spares the medial spinal cord, Vinit, Gauthier, Stamegna, and Kastner (2006) found a complete reduction in phrenic nerve and hemidiaphragm activity on the side ipsilateral to injury similar to a complete hemisection. The spared medial tissue contains a minor, ipsilateral phrenic pathway that could provide a source of plasticity contributing to functional restoration after injury. After spontaneous hemi-diaphragmatic recovery, a subsequent lesion of the contralateral spinal cord containing the cross-phrenic axons did not greatly diminish recovered ipsilateral phrenic nerve activity (Vinit et al., 2008). This would suggest that disruption of the crossed phrenic inputs after chronic SCI is not sufficient to reverse spontaneous recovery provided by ipsilateral circuit plasticity (Vinit et al., 2008). However, the exact mechanism of this spontaneous recovery in more complete lesion models and how acute respiratory recovery may differ from chronic time points needs further study.
Central Pattern Generator and Locomotor Recovery
There has been considerable work directed toward understanding the intricacies of the spinal central pattern generator (CPG) and the influence of supraspinal and sensory afferent input under normal and post-injury conditions. Spontaneous locomotor recovery after a partial spinal cord injury likely involves plasticity of the individual components, such as spared motoneurons, remaining motor and sensory pathways and segmental spinal reflexes, in addition to intrinsic changes to the CPG. This point was described in several reviews by Rossignol and colleagues (Rossignol & Frigon, 2011; Rossignol et al., 2011; Martinez & Rossignal, 2013). To address the impact of SCI on underlying mechanisms of locomotor activity would require much more depth than is possible in this format. Fortunately, an extensive discussion of this area by Serge Rossignol appears in the Oxford Research Encyclopedia of Neuroscience (Rossignol, 2017).
Aberrant Afferent Plasticity—Neuropathic Pain
Sensory modalities like proprioception, touch, and pain are relayed from the periphery (skin, muscle, etc.) to the spinal cord by primary sensory neurons located within the dorsal root ganglia (DRG) found at each level of the spinal cord. There are many subtypes of primary sensory neurons whose afferents synapse in the superficial dorsal horn and intermediate zone of the spinal cord. These subtypes are distinct in size, molecular phenotype, and degree of myelination. Large, myelinated neurons that provide proprioceptive information innervate muscle spindles and Golgi tendon organs (GTOs). Another subclass of large myelinated neurons (Aβ) innervate the skin and serve as low-threshold mechanoreceptors of touch, pressure, and vibration. Aδ neurons are lightly myelinated medium-sized neurons that are polymodal, transmitting pressure, cold, and some pain information. The perceptions of pain, temperature, itch, and social touch are mediated by small, unmyelinated c neurons. While the DRG does not demonstrate any somatotopy, the distribution of the central terminals of the different primary neuron subtypes is anatomically distinct (Grant, 1995, Figure 2). The central peptidergic c fibers terminate in lamina I and the outer layer of lamina II, and non-peptidergic c fibers terminate in the inner layer of lamina II. Lightly myelinated Aδ fibers, which transmit both noxious and innocuous information and terminate in laminae I and V; Aβ fibers (also called type II fibers), which transmit innocuous sensory information terminating in laminae III and IV; and the central axons of Ia and Ib neurons terminate in deep gray matter lamina of the intermediate zone (Brown, 1981).
The central axon of the Aα subgroup, also known as group Ia, Ib, and group II afferents, innervates muscle spindles and GTOs in the periphery terminate in laminas VII and IX in the ventral horn. The central projection of the Aβ subgroup transmits low-threshold mechanosensory information and terminates in deep dorsal horn laminae (IV and V). The Aδ subtype of primary sensory neurons is polymodal, transmitting both innocuous mechanosensory information as well as nociceptive information from the periphery to superficial lamina I and deep dorsal horn lamina V. Two main subclasses of c fibers, the peptidergic (pep) and non-peptidergic (non-pep), terminate in lamina I and lamina II, respectively. These small diameter neurons transmit thermoception, nociception, and pruritoception.
Plasticity in the nociceptive system likely evolved as a defense mechanism by transiently increasing the sensitivity of neurons in the pain pathway, providing protection of a wound until it healed (Price & Dussor, 2014). However, after injury to the nervous system, this protective mechanism does not resolve and chronic neuropathic pain develops (Costigan, Scholz, & Woolf, 2009). Clinical hallmarks of SCI-induced neuropathic pain include allodynia—when innocuous stimuli elicit a painful response and hyperalgesia—when noxious stimuli elicit an exaggerated painful response. While direct damage to ascending and descending systems is certainly a contributor to aberrant nociceptive processing after SCI (Hains et al., 2003; Hains, Saab, & Waxman, 2005; Gwak, Crown, Unabia, & Hulsebosch, 2008; Masri et al., 2009; Davoody et al., 2011), plasticity occurring in the primary sensory neurons may be sufficient to induce pain. This maladaptive, dysfunctional plasticity is supported by both anatomical and electrophysiological evidence.
Dramatic arborization of sensory afferent fibers occurs in the deep dorsal horn (laminas III–V) above, at, and below the lesion epicenter in clinical (Kakulas, 2004) as well as experimental SCI (Krenz & Weaver, 1998; Ondarza, Ye, & Hulsebosch, 2003; Weaver et al., 2001). The authors recently showed a similar increase in the density and distribution of non-peptidergic c afferents within the dorsal horn in rats with SCI-induced neuropathic pain (Detloff, Smith, Quiros-Molina, Ganzer, & Houlé, 2014; Detloff et al., 2016). They showed that SCI-induced pain correlates with an increase in the density and expansion of the topographical distribution of both peptidergic and non-peptidergic nociceptive afferents in the dorsal horn (Figure 3). An overlapping distribution of peptidergic non-peptidergic primary afferent fibers in the dorsal horn that correlates with allodynic behavior could implicate one of two possibilities. The first is that nociceptive primary sensory neurons may be expanding their terminal fields into regions of the dorsal horn that is normally innervated by large, cutaneous Aβ primary sensory neurons, or vice versa. It can be inferred from either of these scenarios that these additional aberrant afferent inputs creates a disruption of the balance between primary afferent, descending modulatory, and spinal interneuronal inputs on dorsal horn neurons in deeper dorsal horn laminae (Woolf, 1983; Woolf & Walters, 1991; Woolf, Shortland, & Coggeshall, 1992; Shortland, Woolf, & Fitzgerald, 1989; Shortland & Woolf, 1993). The second possibility is that the aberrant distribution of afferents is not sprouting, but rather represents a change in the phenotypic or molecular identity of other types of primary sensory neurons (i.e., non-nociceptive neurons become nociceptive) (Nitzan-Luques, Devo, & Tal, 2011; Nitzan-Luques, Minert, Devor, & Tal, 2013; Bester, Beggs, & Woolf, 2000; Molander, Hongpaisan, & Persson, 1994). Injuries to the spinal cord or peripheral nervous system activate genomic programs in all primary sensory neurons (not just nociceptive c neurons). One consequence of transcriptional changes is that some low-threshold Aβ neurons acquire the molecular phenotype of c neurons (Woolf & Costigan, 1999; Nitzan-Luques et al., 2013). This allows these neurons to respond to stimuli in a nociceptive rather than cutaneous manner (i.e., central sensitization). De novo expression of calcitonin gene-related peptide (CGRP) in Aβ afferents has been shown in rats with SCI-induced autonomic dysreflexia, and this change in expression could render these afferents capable of enhancing pain (Hou, Duale, & Rabchevsky, 2009). SCI induces alterations in the electrophysiological properties of neurons as well. Bedi et al. (2010) showed that SCI increased the incidence of spontaneous activity and robust hyperexcitability of primary sensory neurons that transmit pain information. Reduction of this heightened activity and excitability is sufficient to reduce pain behavior after experimental SCI. Taken together, these data suggest that an aberrant anatomical and functional plasticity of primary sensory neurons is strongly correlated with the dysfunction of the sensory system, namely pain development after SCI.
Under normal conditions, peptidergic and non-peptidergic primary afferent fibers terminate in distinct dorsal horn laminae. Peptidergic fibers terminate in lamina I and the outer layer of lamina II (also called IIo), while non-peptidergic afferent fibers terminate in the inner layer of lamina II (denoted as Iii). After unilateral cervical SCI, both subtypes of nociceptive primary afferent fibers increase their topographic distribution in the dorsal horn of the spinal cord which corresponds to the development of chronic neuropathic pain. Animals demonstrating pain-like behaviors have significantly greater distribution and density of both peptidergic and non-peptidergic primary afferent fibers within the superficial dorsal horn laminae.
Changes in Brain Function
Sensorimotor Cortex Plasticity
Cortical reorganization of motor and sensory areas has been demonstrated after SCI in human subjects as well as in rodent models (Raineteau & Schwab, 2001; Moxon, Oliviero, Aguilar, & Foffani, 2014). Within minutes of a thoracic transection lesion there is evidence of functional reorganization in the primary somatosensory cortex (i.e., an increase in cortical responses evoked by forepaw stimuli and a switch to a network state of slow-wave activity) (Aguilar et al., 2010). Based upon the observation of post-SCI expansion of forelimb cortical representation to include the denervated hindlimb cortex (Endo, Spenger, Tominaga, Brene, & Olson, 2007), Ghosh and colleagues (2009) examined the sensory representation and corticospinal projections of the cortex ipsilateral to a C3–4 lateral hemisection lesion. At 12 weeks, they detected enhanced representation of the unimpaired forepaw; stimulation of the ipsilesional hind paw showed distinct activation of hindlimb areas in the intact, ipsilateral cortex; and anterograde tracing showed sprouting of corticospinal tract axons to recross the midline at cervical and lumbar spinal cord levels. The authors noted the potential of this sprouting to functionally compensate for disconnected contralateral neurons.
Imaging studies in humans with SCI often demonstrate an increase in cortical activity and metabolism corresponding to spared regions, such as the upper limbs (Roelcke et al., 1997; Bruehlmeier et al., 1998; Curt et al., 2002a; Curt, Bruehlmeier, Leenders, Roelcke, &, Dietz, 2002b). There are robust differences in the degree of cortical plasticity and functional recovery based on the developmental stage of the nervous system at the time of SCI. Rodent models appear less consistent and generally are characterized by the age of the animal at the time of injury and the injury severity. Interestingly, rats receiving spinal cord transection in adulthood have shown an increase in blood flow to somatosensory regions of the cortex (Endo et al., 2007) that do not correlate with an increase in neuronal activity in the same region, as measured by electrophysiological techniques (Graziano, Foffani, Knudsen, Shumsky, & Moxon, 2013). Many labs have demonstrated the enhanced ability of the cortex to reorganize after a neonatal SCI, with earlier injury time points resulting in greater cortical plasticity into adulthood. Giszter, Kargo, Davies, and Shibayama (1998) and Giszter, Davies, and Graziani (2007) determined that after a neonatal T8–T9 transection, adult rats that regained weight-supported stepping had an expanded motorcortex representation of axial trunk muscles, likely working in synergy with novel forelimb sensory representation to maintain balance and reduce force transmission to hindlimbs. In adult rats, a study of exercise therapy and serotonin agonist administration after SCI demonstrated a response like that observed in the neonatal preparation (i.e., reorganization of the motor cortex to enhance trunk muscle recruitment) (Manohar, Foffani, Ganzer, Bethea, & Moxon, 2017). The increase in trunk representation corresponded with functional increases in weight-supported stepping that were reduced upon lesion of the corresponding remodeled cortex. Additionally, the presence of a remodeled trunk motor cortex correlated with an increase in axonal sprouting to the spinal cord rostral to the lesion site. Somatosensory cortex representing forelimbs was also expanded after treatment, again suggesting a synergistic role between the two modalities in achieving functional improvements (Manohar et al., 2017).
Mood Disorder—Post-SCI Depression
Incidence of depression is three times higher in patients with SCI, with very few guidelines for targeted treatment (Fann et al., 2011). Comorbidity of depression and SCI has a profound impact on quality of life, correlating with less functional improvement during rehabilitation as well as an increase in overall morbidity (Fann et al., 2011). The estimated lifetime cost per person of SCI treatment is $5 million, with annual costs for acute treatment often exceeding 50% of patient income (World Health Organization, 2013). This cost is also higher in patients with depression, compounded by a decrease in independent functioning, longer periods of bed rest, and a greater need for paid personal care (Fann et al., 2011).
Tissue damage after SCI stimulates the production of cytokines that can cross the blood–brain barrier to enter the CNS, causing secondary damage well beyond the site of the initial lesion (Popovich et al., 1999; Schwab, Zhang, Kopp, Brommer, & Popovich, 2014). Interactions of the immune system and serotonin metabolism provide a potential link for a specific etiology of depression and SCI. The raphe nuclei, the main source of serotonin to the brain, can specifically be affected through damage to descending projections to the spinal cord that modulate motor circuits (Schmidt & Jordon, 2000). Axonal injury and subsequent degeneration of injured descending serotonergic projections from the raphe nuclei to each level of the spinal cord could potentially cause an inflammatory reaction within the dorsal raphe nucleus, a region with diffuse serotonergic projections to limbic regions (Beattie, Farooqui, & Bresnahan, 2000; Schmidt & Jordon, 2000). Dyfunction in limbic circuitry, parts of which are represented in Figure 4, has been implicated in the development of psychiatric diseases such as schizophrenia, obsessive-compulsive disorder, anxiety, and drug abuse (Hensler, 2006).
Utilizing a moderate T9 midline contusion injury model, Luedtke et al. (2014) established a battery of behavioral tests, including Sucrose Preference, Forced Swim Test, Social Interaction, and Burrowing to accurately identify a depressive phenotype in male rodents after SCI. A subsequent study from Maldonado-Bouchard et al. (2016) confirmed that tumor necrosis factor α (TNFα) was increased in serum and hippocampal lysate from male rats with a depressive-anxious phenotype after chronic SCI. Using a similar injury and depressive battery in adult female rats, the authors have preliminary data (Farrell, Detloff, & Houle, 2017) that shows a significant increase in the level of TNFα in the dorsal raphe in rats that display a depressive phenotype. Inflammatory cytokines such as TNFα can have many modulatory effects on neuronal circuitry, from altering GABA and AMPA membrane trafficking to increasing metabolism of serotonin and its precursors (Clement et al., 1997; Ferguson et al., 2008; Beattie, Ferguson, & Bresnahan, 2010; Stuck et al., 2012; Pribiag & Stellwagen, 2013). Disrupting the excitatory–inhibitory balance of serotonergic activity could contribute to a depressive phenotype after SCI. This balance also could be disrupted through dysregulation of glutamate homeostasis, normally tightly controlled by locally residing astrocytes. Astrocytes are heavily responsible for reuptake of extracellular glutamate through expression of glutamate transporter 1 (GLT1) (Maragakis & Rothstein, 2004). In vitro cell culture and tissue slice studies have demonstrated the ability of TNFα to decrease expression of GLT1 on astrocytes (Fine et al., 1996; Pitt, Nagelmeier, Wilson, & Raine, 2003; Zou & Crews, 2005). Using the authors’ T9 contusion model of depression, they confirmed a significant decrease in the level of GLT1 in the dorsal raphe of rats with depressive phenotype, suggesting that regulation of serotonergic neuron activity has a role in onset or maintainance of post-SCI depression.
Along with inflammatory changes in the CNS, SCI leads to plasticity in mRNA and protein expression in a variety of brain regions involved in depressive pathology. Wu et al. (2014) performed depression and cognitive behavioral assessments in mice 56 days after moderate T9 contusion injury to assess changes in inflammatory state and cellular function with this pathology. Depressive phenotype in these mice was associated acutely with a significant increase in hippocampal mRNA for cyclin D1, A1, A2, and PCNA, with the last three remaining elevated through 3 months post-injury (Wu et al., 2014). These proteins are involved with activation and maintenance of the cell cycle, even in post-mitotic cells, which has been shown to cause neuronal apoptosis in vitro and in vivo (Padmanabhan, Park, Greene, & Shelanski, 1999, Wu et al., 2011). This effect was confirmed by a significant reduction in hippocampal cell number in SCI mice at the chronic time point (Wu, Stoica, & Faden, 2014). Subsequent work from Wu et al. (2016) established additional cellular plasticity in the form of endoplasmic reticulum stress protein upregulation in the cortex, hippocampus, and thalamus, suggesting an alteration in neuronal function associated with post-SCI depression. These regions are heavily involved in emotional processing and receive direct input from the dorsal raphe (Matsuzaki, Takada, Li, Tokuno, & Mizuno, 1993). These findings suggest that changes in supraspinal circuitry and neuronal function after SCI could lead to the development of effective disorders such as major depressive disorder.
“Plasticity” can mean something very different to each investigator, which is not surprising given the wide range of changes in molecular, cellular, and functional activity observed throughout the CNS after a spinal cord injury. In most cases, researchers eagerly anticipate some beneficial effects of plasticity, yet remain cognizant of the potential for worsening conditions due to aberrant plasticity. While it is not possible to prevent the initial trauma to the spinal cord suffered during a motor vehicle accident or fall, it is encouraging that some semblance of spontaneous recovery attributable to CNS plasticity often is observed and that labs around the world are focused on therapeutic interventions to further advance the return of function after SCI.
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