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date: 23 April 2019

Mechanisms of Behavioral Changes After Spinal Cord Injury

Summary and Keywords

Spinal cord injury results in a wide range of behavioral changes including impaired motor and sensory function, autonomic dysfunction, spasticity, and depression. Currently, restoring lost motor function is the most actively studied and sought-after goal of spinal cord injury research. This research is rooted in the fact that although self-repair following spinal cord injury in adult mammals is very limited, there can be some recovery of motor function. This recovery is strongly dependent on the lesion size and location as well as on neural activity of denervated networks activated mainly through physical activity (i.e., rehabilitative training). Recovery of motor function is largely due to neuroplasticity, which includes adaptive changes in spared and injured neural circuitry. Neuroplasticity after spinal cord injury is extensive and includes mechanisms such as moderate axonal sprouting, the formation of new synaptic connections, network remapping, and changes to neuron cell properties. Neuroplasticity after spinal cord injury has been described at various physiological and anatomical levels of the central nervous system including the brain, brainstem, and spinal cord, both above and below injury sites. The growing number of mechanisms underlying postinjury plasticity indicate the vast complexity of injury-induced plasticity. This poses important opportunities to further enhance and harness plasticity in order to promote recovery. However, the diversity of neuroplasticity also creates challenges for research, which is frequently based on mechanistically driven approaches. The appreciation of the complexity of neuronal plasticity and the findings that recovery is based on a multitude and interlinked adaptations will be essential in developing meaningful new treatment avenues.

Keywords: spinal cord injury, behavior, plasticity, neural repair, animal models, humans, rehabilitative training, compensation, spinal shock, remyelination

Introduction to Spontaneous Recovery Following Spinal Cord Injury

Spinal cord injury (SCI) damages descending and ascending axons in the white matter, thereby interrupting communication between the brain and spinal regions below the injury. This is accompanied by cell damage including loss of neurons and glial cells near the injury site (Bramlett & Dietrich, 2007; Ek et al., 2010; Norenberg, Smith, & Marcillo, 2004). This cell damage leads to a complex cascade of effects including inflammation (Fenrich, Weber, Rougon, & Debarbieux, 2013; Keane, Davis, & Dietrich, 2006; Prüss et al., 2011; Schwab, Brechtel, Nguyen, & Schluesener, 2000; Schwab, Zhang, Kopp, Brommer, & Popovich, 2014), suppression of the immune system (Brennan & Popovich, 2018; Brommer et al., 2016; Failli et al., 2012; Meisel, Schwab, Prass, Meisel, & Dirnagl, 2005; Prüss et al., 2017; Riegger et al., 2007; Schwab et al., 2014), gut dysbiosis (Kigerl et al., 2016; Kigerl, Mostacada, & Popovich, 2018), progressive axon demyelination and degeneration (Fenrich et al., 2012; Kerschensteiner, Schwab, Lichtman, & Misgeld, 2005; Papastefanaki & Matsas, 2015; Plemel et al., 2014), and changes in blood supply of the cord (Li et al., 2017; Oudega, 2012). In its entirety the effects of a SCI can lead to deficits in motor, sensory, and autonomic function (Ahuja et al., 2017; Weaver, Fleming, Mathias, & Krassioukov, 2012), spasticity (Dietz & Sinkjaer, 2012; Holtz, Lipson, Noonan, Kwon, & Mills, 2017), neuropathic pain (Hatch et al., 2018), autonomic dysreflexia (Blackmer, 2003; Curt, Nitsche, Rodic, Schurch, & Dietz, 1997; Krassioukov, Warburton, Teasell, & Eng, 2009), and a decline in mental health (e.g., anxiety and depression; Craig, Hancock, & Dickson, 1994; Fann et al., 2011; Hancock, Craig, Dickson, Chang, & Martin, 1993; Luedtke et al., 2014; Maldonado-Bouchard et al., 2016). Importantly, it was once believed that most of the effects of a SCI were permanent, since it was commonly assumed that the central nervous system (CNS) is hardwired and lacks repair mechanisms. This view has become obsolete, and this article provides an update on the mechanisms involved in enabling moderate functional recovery following SCI, with a focus on motor function.

Mechanisms Related to Functional Recovery

There are various mechanisms contributing to recovery following SCI, with some of them taking place soon after injury and others weeks thereafter. Such mechanisms include the recovery from spinal shock, remyelination, and plasticity, which are discussed not according to importance, but rather to the time points after injury they potentially contribute to recovery.

Spinal Shock

In addition to the long-term deficits caused by the disruption of axons and the loss of cells, immediately after SCI there is a transient loss or diminishment of function and reflexes caudal to the injury site, which is called spinal shock. Although spinal shock was already described hundreds of years ago (see Ditunno, Little, Tessler, & Burns, 2004) and represents a major behavioral change with symptoms that can be measured clinically, the mechanisms underlying spinal shock are complex and not well understood (Ditunno et al., 2004; Hiersemenzel, Curt, & Dietz, 2000; Ko, Ditunno, Graziani, & Little, 1999; Popa et al., 2010). In brief, some of the pathophysiological events that likely contribute to spinal shock include a local (at the lesion site) breakdown in membrane metabolism and cellular ion balance, edema, loss and contractions of blood vessels (thus preventing essential metabolites to reach the cells), massive influx of immune and blood cells, and excitotoxicity. In addition to the primary injury, these pathologies likely contribute to a concomitant decrease in neuronal excitability caudal of the injury due to a loss of descending neuromodulatory input (e.g., serotonin, norepinephrine; D’Amico, Condliffe, Martins, Bennett, & Gorassini, 2014; Ditunno et al., 2004; Li et al., 2014; Popa et al., 2010). As a result, spared spinal circuitry is rendered nonfunctional and axons are unable to conduct signals. Obviously, this “shutdown” of neurotransmission masks the actual injury severity and makes it very difficult to predict functional outcomes.

Depending on lesion severity, symptoms of spinal shock can persist for many weeks after injury, yet many of the factors that contribute to spinal shock are resolved within the first few days, leading to partial recovery of reflexes and function (Ditunno et al., 2004). For example, over the first 10 days after injury motoneurons caudal of the injury begin to develop neuronal independence from descending neuromodulators leading to increased neural activity (Murray et al., 2010), which can be responsible for a significant amount of functional recovery (Fouad et al., 2010). Understanding the mechanisms involved in recovery from SCI are further complicated because plasticity (see the “Plasticity” section) can occur before spinal shock subsides and actually contributes to its decline (e.g., serotonin independence; Murray et al., 2010). These overlapping timelines and mechanisms make it difficult to impossible to tease out what parts of recovery are due to adaptive plasticity or decline of spinal shock.


Myelination, even in the uninjured nervous system, is a dynamic process that has been shown to be involved in motor learning (McKenzie et al., 2014). Furthermore, following SCI spared axons can be rendered nonfunctional due to the loss of myelin (e.g., Blight, 1983; Bresnahan, King, Martin, & Yashon, 1976; Waxman, 1989). This raises questions about whether demyelination exacerbates functional deficits after SCI, whether there is spontaneous remyelination, whether injury-induced loss of myelin interferes with motor learning, and importantly whether remyelination is a useful target to promote repair, motor learning, and thus recovery (Plemel et al., 2014). The answers to these questions are, however, not straightforward and are much debated. Spontaneous remyelination has been reported (Gensert & Goldman, 1997; Hesp et al., 2015), and it has been shown that promoting remyelination, for example with cell grafts, improves functional recovery in animal models of SCI (Cao et al., 2005; Cummings et al., 2005; Hofstetter et al., 2005; Karimi-Abdolrezaee, Eftekharpour, Wang, Morshead, & Fehlings, 2006; Lee, Yoon, Park, & Lee, 2005; Mitsui, Shumsky, Lepore, Murray, & Fischer, 2005). However, other studies report the absence of unmyelinated axons after SCI in rodents (Lasiene, Shupe, Perlmutter, & Horner, 2008; Powers et al., 2012). Some reports demonstrate sufficient survival and differentiation of oligodendrocyte precursor cells (Hesp et al., 2015; Tripathi & McTigue, 2007); others again report that recovery remains unchanged when myelination is prevented (Duncan et al.,2018). In other words, at the moment there seems to be a lack of knowledge whether spontaneous remyelination is necessary and/or actually contributes to the spontaneous recovery seen after SCI.


Neuroplasticity (or simply plasticity) is a term used to describe adaptive changes in neural circuitry (injured or not). Thus processes such as learning (including motor learning) and its associated mechanisms (including long-term potentiation and sensitization, changes in dendritic spines, and sprouting of neurons) are all considered within the envelope of the term “plasticity.” Although axons in the adult mammalian spinal cord generally do not regenerate over a significant distance after SCI (for exceptions see Fenrich et al., 2007; Fenrich & Rose, 2009), plasticity does occur in response to injury and can be considered a repair mechanism. Such plasticity is enabled by the upregulation of genes and activation of signaling pathways required for neurite outgrowth (Batty, Fenrich, & Fouad, 2017; Fagoe, van Heest, & Verhaagen, 2014; Finelli, Wong, & Zou, 2013; Kadoya et al., 2009) and a concomitant downregulation of growth inhibitory molecules like chondroitin sulphate proteoglycans for example in the cortical gray matter (Orlando & Raineteau, 2015). This triggers postinjury rewiring, one of many types of postinjury plasticity. However, it is important to note that plasticity in the injured nervous system is not exclusively beneficial, because it contributes to maladaptive changes such as neuropathic pain, autonomic dysreflexia, and a decline in mental health including depression and anxiety (Cameron, Smith, Randall, Brown, & Rabchevsky, 2006; Gwak, Hulsebosch, & Leem, 2017; Hou, Duale, & Rabchevsky, 2008; Hou et al., 2009; Krenz, Meakin, Krassioukov, & Weaver, 1999; Maldonado-Bouchard et al., 2016; Walters, 2018). Sometimes plasticity can include elements that are both beneficial and detrimental. For example, mechanisms contributing to spasticity are also involved in the restoration of muscle tone, which is required for successful motor function.

Underlying mechanisms for post-SCI plasticity are very broad and include changes in cellular properties (e.g., neuronal excitability), existing synaptic connections (rostral and caudal to an injury), the formation of new synapses from injured or spared nerve cells, and growth of new axon collaterals. A detailed discussion of all forms of plasticity is thus beyond the scope of this article, and the reader is referred to more specific reviews (e.g., Carmichael, 2016; Hedrick & Yasuda, 2017; Lisman, Cooper, Sehgal, & Silva, 2018). This article focuses on the neuroanatomical and connectivity changes that occur to injured and spared neurons above and below injury sites, as well as in specific brain and brainstem regions that are important for motor control.

The idea that the injured spinal cord could undergo adaptive changes has been studied for an extended period of time (Bregman & Goldberger, 1982; Eccles, 1976; Jane, Evans, & Fisher, 1964; Wall, 1975). However, with the discoveries that neurons were capable of growing into peripheral nerve grafts (David & Aguayo, 1981), and subsequent discoveries of several axon growth inhibitory molecules (Chen et al., 2000; Davies et al., 1997; Grandpre, Nakamura, Vartanian, & Strittmatter, 2000; McKerracher et al., 1994; Mukhopadhyay, Doherty, Walsh, Crocker, & Filbin, 1994; Prinjha et al., 2000) that can be blocked pharmacologically (Bradbury et al., 2002; Caroni & Schwab, 1988; Paveliev et al., 2016; Yick, Wu, Kwok-Fai So, Yip, & Kwok-Yan Shum, 2000), much of the research community has focused on long-distance regeneration as a cure for SCI. Fortunately, there was a resurgence in the study of plasticity after SCI where it was found that the CNS is capable of rewiring spared circuitry in a functional meaningful way. Thus significant functional benefits can be achieved by relatively subtle changes in synaptic connectivity, neuromodulation, or short-distance collateral sprouting (Ballermann & Fouad, 2006; Bareyre et al., 2004; Courtine et al., 2009; Krajacic, Weishaupt, Girgis, Tetzlaff, & Fouad, 2010; Lavrov et al., 2006; Murray et al., 2010; May et al., 2017; Petruska et al., 2007; Tillakaratne et al., 2002). Such plasticity has been reported for numerous locations of the CNS.

Spinal Plasticity Caudal to a SCI

SCI in humans are often anatomically incomplete with the consequence that spared axons bypass the injury site. In animal models it has been shown that such spared descending fibers can grow new collaterals and innervate targets that lost their input due to injury. For instance, spared axons from the corticospinal tract (CST; Liu et al., 2015; Liu, Yip, Priestley, & Michael-Titus, 2017; Weidner, Ner, Salimi, & Tuszynski, 2001) and reticulospinal tract (Asboth et al., 2018; Ballermann & Fouad, 2006; Filli et al., 2014; Hao, Wang, Dan, Poo, & Zhang, 2009; May et al., 2017) have been shown to compensate for injured fibers, which was related to motor recovery.

Sensory fibers and intraspinal circuitry below the injury can also undergo considerable remodeling. For example, afferents sprout to form new connections and project to regions containing spinal interneurons below injury sites (Krenz & Weaver, 1998). Sensory afferent sprouting likely contributes to changes in spinal interneuron networks and can lead to spasms (Jiang, Zaaimi, & Martin, 2016; Kapitza et al., 2012), autonomic dysreflexia (Cameron et al., 2006; Hou et al., 2008, 2009; Krenz et al., 1999), pain (Gwak et al., 2017; Walters, 2018), and other neurological dysfunctions (Beauparlant et al., 2013). These examples of sensory afferent and spinal interneuron plasticity highlight the fact that not all plasticity after injury is beneficial.

Changes in neuronal properties also occur below injury sites and are commonly studied in spinal motoneurons. Motoneuron excitability is normally regulated by descending monoamines. When SCI severs descending serotonin (5-HT) axons, neurons below the lesion lose excitatory drive, leaving networks unresponsive in the days following injury (see “Spinal Shock” section). However, over time neuronal excitability is restored by different mechanisms, including the expression of constitutively active excitatory 5-HT2C receptors (Murray et al., 2010) and changes in the potassium-chloride co-transporter KCC2 (Boulenguez et al., 2010).

Last, all of the forms of plasticity discussed in this section contribute to changes in the pattern-generating networks of the spinal cord. Importantly, these networks have been shown to adapt, rearrange, and even learn following injury in an activity-dependent manner in rodents (Caudle et al., 2011), cats (Barbeau & Rossignol, 1987; Lovely, Gregor, Roy, & Edgerton, 1986), and humans (Dietz, Colombo, & Jensen, 1994; Wernig & Müller, 1992).

Spinal Plasticity Rostral to a SCI

Various studies on spinal plasticity have focused on sprouting of injured CST axons rostral to the injury site. It was found that these CST axons can sprout new collaterals and innervate alternative targets, including interneurons located close to the central canal (Bareyre et al., 2004; Fouad, Pedersen, Schwab, Brösamle, & Brosamle, 2001; Vavrek, Girgis, Tetzlaff, Hiebert, & Fouad, 2006). Many of these interneurons are commissural and thus cross the midline with projections rostral and/or caudal in the contralateral white matter. Therefore, these interneurons offer a viable detour for descending signals to bypass unilateral injuries (Courtine et al., 2008, 2009). Other tracts also have the ability to rearrange following injury, which does not necessarily mean increased sprouting. For example, in some injury models reticulospinal axons reduce their projections rostral to an injury (Weishaupt, Hurd, Wei, & Fouad, 2013). Other descending systems that have been reported to respond with adaptions rostral to the injury include the rubrospinal tract and serotonergic axons (Hawthorne et al., 2011; Lawrence & Kuypers, 1968; Tsukahara, Fujito, Oda, & Maeda, 1982; Z’Graggen et al., 2000).

Plasticity in the Brainstem

Brainstem nuclei receive inputs from higher cortical regions and other brainstem regions and project to the spinal cord, thus playing key roles in motor function before and after SCI. Plasticity of brainstem projections to the spinal cord are well characterized and important for recovery after SCI (e.g., rubrospinal tract (RST), reticulospinal tract (RtST), Raphe), thus it seems likely that connectivity within the brainstem also changes. This has recently been shown by Zorner et al. (2014), who found that following a unilateral spinal cord hemisection, gigantocellular reticular nuclei contralateral to the SCI receive new inputs from the mesencephalic locomotor region ipsilateral to the SCI, resulting in new connections that bypass the injury. In 2018, a study by Asboth and colleagues characterized a cortico-reticulo-spinal circuit that emerges after SCI, highlighting the importance of new brainstem connections in mediating recovery. Cortico-red nucleus changes have also been shown in several studies (Lawrence & Kuypers, 1968; Tsukahara et al., 1982; Z’Graggen et al., 2000).

Cortical Plasticity

Following SCI, neurons in the brain lose connections to their targets in the spinal cord. In the most dramatic scenario, some cortical neurons could be cut off from all their targets, rendering them obsolete. To become part of a neural network, these neurons must form new connections, which can be accomplished by forming new synapses to alternate targets within the cortex. This is well reflected in findings of changes in cortical maps following SCI in rodents (Girgis et al., 2007; Krajacic et al., 2010; Martinez et al., 2010), primates (Jain, Catania, & Kaas, 1997; Nishimura & Isa, 2012; Wall, Xu, & Wang, 2002), and humans (Bruehlmeier et al., 1998; Kaas et al., 2008; Moore et al., 2000; Wall et al., 2002). These changes in cortical networks are largely due to neurons that formerly innervated one part of the body (e.g., hind limbs) making new connections with areas that control other parts of the body (e.g., forelimb, back, or whiskers; Fouad et al., 2001; Girgis et al., 2007). Cortical remapping after SCI has even been linked to changes in the expression of plasticity-associated genes in rodents (Fouad et al., 2001; Girgis et al., 2007; Martinez et al., 2010), primates (Higo et al., 2009, 2018), and humans (Freund, Rothwell, Craggs, Thompson, & Bestmann, 2011; Freund, Weiskopf, et al., 2011; Green, Sora, Bialy, Ricamato, & Thatcher, 1998).

Factors Influencing Plasticity and Recovery

Lesion Severity and the Limitations of Plasticity

Following SCI, the occurrence of plasticity depends on the size and location of the lesion. For example, small injuries will often result in minor deficits that can be resolved with time as sufficient amounts of spared neuronal “hardware” is available to rewire the nervous system (Fouad, Forero, & Hurd, 2015). In contrast, severe injuries are more likely to result in damage to key pathways that could otherwise substantially add to recovery. This clearly delineates the limitation of plasticity, as it is not a repair process of boundless ability. Plasticity requires substrate to work with and, for example, cannot restore the complete loss of a spinal tract (see Fouad et al., 2015). In other words, injury-induced plasticity should not be viewed as a potential cure for SCI but as a treatment to optimize spared circuitry resulting in a limited degree of adaptation. In addition, the location of the lesion is another important factor for two reasons. First, descending tracts, such as the CST, project down the spinal cord in bundles located in discrete parts of the white matter. Thus severe injuries to tracts that are essential for certain functions will likely result in more permanent impairment since other spared spinal tracts (that play a different role in motor control) will be less effective in replacing the lost axons and the information they carried. This is nicely highlighted in rat models of cervical SCI, in which injuries that spare a small proportion of either the CST and/or the rubrospinal tract allow for considerable recovery in a reaching and grasping task (Hurd, Weishaupt, & Fouad., 2013). Conversely, if injuries are of similar size to those that allow for considerable recovery but the injury results in a complete loss of the CST and RST, recovery is effectively eliminated (Hurd et al., 2013). It is thus generally assumed that incomplete injuries that spare most tracts to some extent offer the best opportunity for plasticity and recovery of function compared to more discrete injuries that completely sever key tracts. A second reason why location is an important determinant of recovery is that the spinal cord contains premotor interneurons and motoneurons that are essential for motor function (especially in the cervical and lumbar enlargements). If a large population of these neurons die or are severely damaged, they cannot be replaced, and function can likely not be recovered by plasticity. It is thus important to keep in mind that SCI-induced functional deficits are not only based on disconnecting the brain from the periphery but also on direct damage to spinal circuitry.


The role of activity in rewiring brain circuitry has been best explored in the developing nervous system, where neuronal circuitry is wired according to its use in a coordinated and competitive manner (Hormigo et al., 2017; Wiesel & Hubel, 1965; Zhang & Poo, 2001). Similarly, in motor learning paradigms or following brain injuries, cortical connectivity is governed in a use-dependent manner. These findings have given rise to terms like fire together wire together (Hebb, 1949) and experience-dependent plasticity (Greenough, Black, & Wallace, 1987). One of the best-known examples comes from the visual system, where disuse during development of the visual cortex results in a lack of innervation and cortical blindness (Wiesel & Hubel, 1965). These principles of use-dependent plasticity also appear to be true after SCI. For example, promoting plasticity in the absence of training can result in neuroanatomical plasticity without functional recovery (Jack et al., 2017; Tom, Kadakia, Santi, & Houlé, 2009). Other examples come from studies in animal models (mainly cats) with complete SCI, where spinal neural networks below the level of a lesion can be adapted and conditioned with training (Barbeau & Rossignol, 1987; Frigon & Rossignol, 2006; Lovely et al., 1986; Rossignol, Bouyer, Barthelemy, Langlet, & Leblond, 2002). If untrained, these animals will remain unable to support their weight with their hindlimbs or to step on a treadmill. With training, however, this ability gradually reappears. In other words, spinal circuitry can learn, and sensory inputs are the primary teachers of the spinal circuitry (Bigbee et al., 2007; Wolpaw & Tennissen, 2001). Importantly, the spinal cord can also retain learned information, as training effects following an incomplete lesion are retained even after a second complete spinal transection (Martinez, Delivet-Mongrain, Leblond, & Rossignol, 2012). Besides the important role of activity on shaping and maintaining circuitry, all of these studies undisputedly show that functional recovery, at least to a certain degree, does not require restoration of the connectivity between the brain and the spinal cord but can depend entirely on the plasticity of spinal circuitry.

Task-specific training following SCI is administered in the clinic as rehabilitative motor training (referred to as “training”) and is considered one of the most effective treatments for promoting plasticity and recovery after SCI (Harkema, Hillyer, et al., 2012; Musselman, Fouad, Misiaszek, & Yang, 2009; Yang & Musselman, 2012; Yang et al., 2014). This training comprises activity in specific neuronal circuitry and the associated movement patterns, explaining why task-specific training often has task-specific effects (de Leon, Hodgson, Roy, & Edgerton, 1998a, 1998b; de Leon, Tamaki, Hodgson, Roy, & Edgerton, 1999; Girgis et al., 2007; May, Fouad, Shum-Siu, & Magnuson, 2015). Conversely, restricting activity can have the opposite effect and can inhibit recovery. A dramatic demonstration of the role of activity in recovery was shown by Caudle et al. (2011). In this study, the researchers explored the role of activity by reducing hindlimb function after partial thoracic SCI in rats, a SCI model that normally allows considerable locomotor recovery. Their hypothesis was that this “spontaneous” recovery is because the animals navigate their home cages and are actually doing low-intensity “self-training” as proposed in Fouad, Metz, Merkler, Dietz, and Schwab (2000). To test this idea, Caudle et al. mounted the hindquarters of rats with thoracic SCI in a “wheelchair” to restrict hindlimb movements and sensory feedback (due to dragging the hindlimbs on the cage floor), which greatly reduced locomotor recovery. Further supporting the idea of activity-dependent plasticity after injury, Raineteau, Fouad, Noth, Thallmair, and Schwab (2001) demonstrated that testing specific motor tasks is a form of training, whereby animals that undergo more frequent and/or more rigorous testing show improved motor function compared to animals with less testing. In other words, the mechanisms underlying recovery observed with self-training, regular testing, and rehabilitative training are likely overlapping and similar. In animal models it is challenging to decide where testing ends and training begins, but for both animal models and humans alike, it is commonly agreed upon that intensity of the activity matters significantly (Cha et al., 2007; de Leon, See, & Chow, 2011; Leech, Kinnaird, Holleran, Kahn, & Hornby, 2016; Starkey et al., 2014; Torres-Espín, Forero, Fenrich, et al., 2018; Torres-Espín, Forero, Schmidt, Fouad, & Fenrich, 2018; Wessels, Lucas, Eriks, & de Groot, 2010).

Linking Activity to Molecular Pathways

Numerous studies have shown that training at sufficient intensity has pharmacological effects on spinal networks, which can augment plasticity and thus recovery. For example, treadmill training and training in a reaching task is associated with increased levels of brain-derived neurotropic factor (BDNF; Ang & Gomez-Pinilla, 2007; Boyce, Park, Gage, & Mendell, 2012; Côté, Azzam, Lemay, Zhukareva, & Houlé, 2011; de Leon et al., 2011; Girgis et al., 2007; Joseph, Tillakaratne, & de Leon, 2012; Macias et al., 2009; Vaynman, Ying, & Gómez-Pinilla, 2004; Weishaupt, Li, Di Pardo, Sipione, & Fouad, 2013; Wu et al., 2016). This is signifcant as BDNF has various effects including promoting neurite outgrowth and enhancing neuro-excitation (Boyce et al., 2012; Boyce & Mendell, 2014; Zhou & Shine, 2003).

Cyclic adenosine monophosphate (cAMP) is an important second messenger system that is involved in regulating plasticity and is influenced by activity. Its levels are critical for allowing neurite outgrowth, especially in the growth-inhibitory environment of the adult mammalian CNS (Cai et al., 2001). Inactivity and disuse of affected motor systems decreases cAMP levels in the brain and spinal cord (Krajacic, Ghosh, Puentes, Pearse, & Fouad, 2009). This can partly explain the success of certain cAMP-elevating drugs and electrical stimulation (which also increases cAMP and calcium) in promoting neurite growth and functional recovery (Carmel, Berrol, Brus-Ramer, & Martin, 2010; Carmel, Kimura, Berrol, & Martin, 2013; Carmel, Kimura, & Martin, 2014; Pearse et al., 2004; Udina et al., 2008). It is noteworthy that elevating cAMP levels in parallel to training was reported to increase training efficacy after stroke (MacDonald et al., 2007). This effect might be mediated by exchange protein directly activated by cAMP 2, a downstream target of cAMP that showed powerful effects on neurite outgrowth and recovery after SCI (Batty et al., 2017; Murray, Tucker, & Shewan, 2009; Wei et al., 2016). It is important, however, to keep in mind that simply enhancing plasticity using pharmacological approaches might not have beneficial effects, but rather enhanced plasticity needs to be combined with some kind of motor training to translate the plasticity into functional recovery (García-Alías, Barkhuysen, Buckle, & Fawcett, 2009; Torres-Espín, Forero, Fenrich, et al., 2018; Weishaupt, Li, et al., 2013). Therefore, activity of neuronal networks is not only essential for promoting plasticity and for normal CNS development but also to promote meaningful plasticity following injuries of the brain and the spinal cord.

Taken together the powerful effects of activity on neuroplasticity, it is not surprising that motor training is currently one of the most effective treatments to restore motor function in individuals with SCI and in animal models alike (Battistuzzo, Callister, Callister, & Galea, 2012; Fouad, Hurd, & Magnuson, 2013; García-Alías et al., 2009; Girgis et al., 2007; Harkema, Behrman, & Barbeau, 2012; Ishikawa, Imagama, Ohgomori, Ishiguro, & Kadomatsu, 2015; Musselman et al., 2009; Yang & Musselman, 2012; Yang et al., 2014).


When examining behavioral changes after SCI, it quickly becomes obvious that both animals and individuals with SCI face the challenges of daily living using alternative approaches—that is, they use compensatory methods to complete motor tasks. Compensatory approaches can be common and obvious, (e.g., using a wheelchair to get from point A to point B) or hardly visible (e.g., co-contractions of antagonistic muscles to stabilize a leg when walking or standing). In animal models, strategies that are quite similar to those found in humans have been analyzed and include a more erect (pillar) position of the legs (to overcome problems in weight support), a wider stance and foot rotation (to counteract deficits in balance control), and different muscle activation patterns (Ballermann & Fouad, 2006; Basso, Beattie, & Bresnahan, 1995; Helgren & Goldberger, 1993). A frequently observed compensatory strategy in both humans (Baker & Perez, 2017) and animals (Fouad et al., 2013; Hurd et al., 2013; Torres-Espín, Forero, Fenrich, et al., 2018) with cervical SCI is to abandon a precision grip in favor of a power-grip or scooping strategy. Indeed, compensatory scooping strategies in skilled forelimb motor tasks are so prevalent in several rat models of cervical SCI that we have modified a common skilled forelimb reaching and grasping task (Whishaw & Pellis, 1990) to reduce the incidence of scooping (Fenrich et al., 2015, 2016; Torres-Espín, Forero, Schmidt, et al., 2018).

All compensatory strategies share the same objective: to increase success in the respective task. However, whether compensatory strategies contribute to recovery is less clear. For example, unilateral injuries affect motor function mostly on one side of the body. A common compensatory strategy, therefore, would be to use the unaffected limbs to perform tasks (e.g., if the right hand is injured, use the left hand to open doors). Although such strategies result in successful task completion, the long-term effect is a disuse of the injured limb (Taub, Uswatte, & Pidikiti, 1999). As discussed earlier, recovery of function is highly dependent on usage, suggesting that although highly useful for daily living, some compensatory strategies may ultimately be maladaptive and limit long-term recovery.

Linking Plasticity to Recovery

A frequently used line of thought is to explore post-SCI plasticity at a variety of locations (i.e., caudal of injury, rostral of injury, etc.) in order to harness and amplify its beneficial effects. A prominent and powerful approach to study plasticity is the staggered lesion model (Beauparlant et al., 2013; Courtine et al., 2008; Cowley, MacNeil, Chopek, Sutherland, & Schmidt, 2015; Fouad et al., 2010; Li et al., 2017; May et al., 2017; van den Brand et al., 2012). Animal studies have demonstrated that when the spinal cord is hemisected twice, once on one side and again on the other side several segments away, a surprising amount of locomotor recovery is observed. Although every direct connection from the brain and brainstem is severed, animals recover weight-bearing stepping and left-right coordination of their hindlimbs. This recovery is therefore due to existing commissural connections bridging the lesion (Cowley et al., 2015) and new connections from descending axons to spinal interneurons that bypass the lesion and plasticity caudal of the lesions.

Another approach to investigate the impact of plasticity is to dissect out specific neural-network pathways that are considered to be involved in recovery. This can be achieved with so called re-lesion experiments (Barriere, Leblond, Provencher, & Rossignol, 2008; Courtine et al., 2008; Krajacic et al., 2010; van den Brand et al., 2012; Weidner et al., 2001), by killing specific neuronal populations (Courtine et al., 2008), or by inactivating or stimulating specific neuronal populations using genetic approaches such as optogenetics (Dias et al., 2018; Hilton et al., 2016; Jayaprakash et al., 2016; Jin et al., 2015), using the gamma-aminobutyric acid agonist muscimol (Raineteau et al., 2001) or designer receptors exclusively activated by designer drugs (DREADDs; Hilton et al., 2016; Siegel, Fink, Strittmatter, & Cafferty, 2015). These experiments, however, do not enable definite conclusions on the role and importance of plasticity at specific locations (e.g., brainstem vs. caudal of SCI). For example, in a study examining the contribution of collateral sprouting of injured CST axons following rehabilitative training in a rat model of cervical SCI (Krajacic et al., 2010), it was shown that a second lesion at the level of the pyramidal tract clearly reduced the recovery of rats. Although the role of spared and lesioned CST axons cannot be distinguished, these results clearly show that CST plasticity contributes to recovery. These results also point out the complexity of the system since trained rats with pyramidotomy performed better than untrained rats without, indicating that plasticity in other locations added to the enhanced recovery. This includes adaptations in other tracts or local changes in spinal networks. Over the past few years our knowledge of such mechanisms has substantially increased; however, this has decreased our ability to grasp the complexity of adaptive motor control. In summary, with increasing understanding of the impact of plasticity in different parts of the CNS, and the realization of its complexity, the view on plasticity has reached a certain soberness. It had become clear that the nervous system adapts at various anatomical and physiological levels to an injury. This complexity and findings that various systems can compensate for each other make it difficult to comprehend the full scope of plasticity. This becomes a challenge as our scientific culture frequently focuses on understanding cellular and molecular mechanisms as the ultimate goal. This approach is, however, difficult and possibly misguided considering that our knowledge of the uninjured CNS is still very limited. It appears thus somewhat ambitious to assume that one will be able to interpret the multitude of changes that occur after a SCI, with or without additional treatments. In other words, the appreciation of the entirety of adaptive changes will be important for the development of future treatments.

Besides the challenge to comprehend the adaptive changes that are involved in motor recovery, one could argue that there is a limitation in the capacity to integrate findings from different research areas into the bigger picture of behavior. For example, the contribution of neuropathic pain on behavior, or the post-SCI decline in mental health in animal models, are evaluated separately or rarely considered. Changes in muscle properties or biomechanical compensations are not integrated into a combined picture of recovery and behavior. All of these changes are somehow interconnected. For example, plasticity, neuropathic pain, and mental health can be influenced by inflammation (Freria et al., 2017; Lerch, Puga, Bloom, & Popovich, 2014; Maldonado-Bouchard et al., 2016; Marchand et al., 2009; Torres-Espín, Forero, Fenrich, et al., 2018; Zhou et al., 2018), which undergoes dramatic and long-term changes following SCI (Schwab et al., 2014). Similarly, a decline in tissue oxygenation may further promote inflammation, ongoing degenerative processes, and even decreasing neuro excitability. Furthermore, reports on changes in the gut microbiome (Kigerl et al., 2016, 2018) that link injury, inflammation, and possibly mental health challenges need to be considered when exploring mechanisms of behavioral changes. This is a daunting task.


The majority of SCI research aims to develop treatments for SCI. Animal models enable a controlled approach to study the pathology of SCI and to test therapeutic interventions, which is not possible in the clinical setting. However, over the past decade this same animal research has clearly shown that the field of SCI research has underestimated the complexity of plasticity and how it contributes to behavioral changes and recovery. Without a comprehensive study design and considering a broader range of behavioral changes following SCI, ranging from body to the mind, one may risk failing in these endeavors. We therefore propose a shift in focus in how studies are designed to more effectively evaluate the impact of potential SCI treatments. Specifically, studies should focus primarily on the most clinically relevant behavioral effects of any novel therapy, including changes in motor function in both fine and locomotor tasks, perception of pain, mental health, social interactions, as well as autonomic function. Observing positive outcomes in these behavioral tests will justify and help bring about a more comprehensive examination of the neuroanatomical, cellular, and molecular mechanisms underlying these behaviors. Importantly, maladaptive outcomes in any of these measures must be reported and accepted by the research community. Maladaptive outcomes are vital in understanding the mechanisms underlying these negative effects and will help develop more effective treatments in the future. Last, to increase the translational success from animal studies, preclinical study design should consider the reality of the clinical setting (e.g., lesion variability, gender, rehabilitative training). Although this appears to be a rocky road, it will ensure that the exciting results on neuroplasticity of the past few years will be successfully utilized in treating people with spinal cord injuries.


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