Spinal cord injury: overview of experimental ...

Rev. Neurosci. 2015; aop

Marc Fakhoury*

Spinal cord injury: overview of experimental approaches used to restore locomotor activity Abstract: Spinal cord injury affects more than 2.5 million people worldwide and can lead to paraplegia and quadriplegia. Anatomical discontinuity in the spinal cord results in disruption of the impulse conduction that causes temporary or permanent changes in the cord’s normal functions. Although axonal regeneration is limited, damage to the spinal cord is often accompanied by spontaneous plasticity and axon regeneration that help improve sensory and motor skills. The recovery process depends mainly on synaptic plasticity in the preexisting circuits and on the formation of new pathways through collateral sprouting into neighboring denervated territories. However, spontaneous recovery after spinal cord injury can go on for several years, and the degree of recovery is very limited. Therefore, the development of new approaches that could accelerate the gain of motor function is of high priority to patients with damaged spinal cord. Although there are no fully restorative treatments for spinal injury, various rehabilitative approaches have been tested in animal models and have reached clinical trials. In this paper, a closer look will be given at the potential therapies that could facilitate axonal regeneration and improve locomotor recovery after injury to the spinal cord. This article highlights the application of several interventions including locomotor training, molecular and cellular treatments, and spinal cord stimulation in the field of rehabilitation research. Studies investigating therapeutic approaches in both animal models and individuals with injured spinal cords will be presented. Keywords: axon regeneration; locomotor training; pharmacological treatment; rehabilitation; spinal cord injury. DOI 10.1515/revneuro-2015-0001 Received January 7 , 2015 ; accepted January 26 , 2015

*Corresponding author: Marc Fakhoury, Faculty of Medicine, Department of Neuroscience, University of Montreal, Montreal H3C 3J7, QC, Canada, Tel: + 1 (514) 710-7060, e-mail: m [email protected]

Introduction Spinal cord injury (SCI) is one of the most devastating and debilitating conditions that an individual can sustain (West et al., 2013). It leads to temporary or permanent changes in the spinal cord’s normal motor, sensory, and autonomic functions (Krassioukov, 2009). Cardiovascular complications can also ensue following the early stages of high SCI, which may cause profound hypotension and cardiac arrest (West et al., 2013). Damage to the spinal cord most often results from a trauma due to a motor vehicular accident or sport injuries (Raineteau and Schwab, 2001) and can originate from diseases such as transverse myelitis (Kim et al., 2012) , fibrocartilaginous embolism (Han et al., 2004 ), and spinal cord vascular malformation (v an den Berg et al., 2010). The symptoms of SCI vary widely depending on where the spinal cord and nerve roots were damaged. High cervical lesions lead to partial or full tetraplegia, characterized by paralysis of the four limbs, whereas lower lesions lead to paraplegia, which is characterized by paralysis of the lower part of the body (Raineteau and Schwab, 2001). It is estimated that over 130,000 individuals are affected by SCI every year, and more than 2 million people worldwide are living with SCI-related disability (Wyndaele and Wyndaele, 2006). In addition to the devastating effects that SCI has on the individual, this condition can be a heavy burden to the society in terms of economic costs.

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M. Fakhoury: Rehabilitation after spinal cord injury

SCI causes the death of cells such as neurons, oligodendrocytes, and astrocytes and leads to extensive loss of sensory and motor skills below the site of injury (Anderson, 2004; Thuret et al., 2006). Following initial damage to the spinal cord, additional changes occur, such as ongoing apoptosis of oligodendrocytes and extensive demyelination of axons (Crowe et al., 1997; Guest et al., 2005). Studies also suggest that SCI is followed by spontaneous repair in motor and sensory functions (Raineteau and Schwab, 2001; Weidner et al., 2001). Within the first days after SCI, the initial recovery of function is mostly due to metabolic changes at the site of damage (Raineteau and Schwab, 2001). Moreover, remyelination of injured axons, which helps enhance the conduction in ascending and descending fibers, can frequently take place after SCI (Gensert and Goldman, 1997). Although there is enough evidence demonstrating the ability of intact corticospinal axons to sprout after SCI, spontaneous plasticity of the corticospinal tract (CST) remains limited (Rosenzweig et al., 2010). Clearly, more research needs to be done to better characterize the mechanisms of axonal regeneration and functional recovery after SCI. A better understanding of these plastic mechanisms might open avenues for the development of new rehabilitative approaches for paralyzed patients. Here, I will discuss the mechanisms underlying spontaneous plasticity following damage to the spinal cord and introduce strategies that could promote axonal regeneration and functional recovery after SCI.

Spontaneous plasticity and functional recovery Previous studies have demonstrated that lesions of the spinal cord are followed by extensive compensatory collateral sprouting of axons in the CST (Weidner et al., 2001; Rosenzweig et al., 2010). Cortical plasticity is considered a key event that helps mediate the recovery of locomotor activity after SCI (Weidner et al., 2001; Seo and Jang, 2015). The mechanisms of cortical reorganization are still not very clear, but it is thought that this process might occur through modifications of synaptic strength or through the appearance of new circuits and axonal branches (Raineteau and Schwab, 2001). In paralyzed patients and animal models of SCI, several studies suggest that cortical projections controlling intact body parts invade and project toward cortical regions that have been affected by the injury (Topka et al., 1991; Bruehlmeier et al., 1998; Rosenzweig et al., 2010). For example, Rosenzweig et al. (2010) have shown that corticospinal projections undergo spontaneous plasticity and could reconstitute a large proportion of the prelesion axon density. In their study, C7 spinal cord hemisections were administered to adult rhesus monkeys, which resulted in motor impairments of the ipsilateral limbs (Rosenzweig et al., 2010). However, 4 weeks after the lesion, the animals exhibited spontaneous recovery in motor activity, evidenced by their ability to successfully retrieve an object from a flat surface. Electromyographic activity was also recorded during the task before and after injury and showed increased activity during successful retrievals (Rosenzweig et al., 2010). Cortical plasticity is not the only factor mediating functional recovery after SCI. Several studies have shown that neural plasticity also occurs at the subcortical level (Lawrence and Kuypers, 1968; Bunday et al., 2014). Subcortical regions that undergo spontaneous reorganizations include the pontine nuclei, the nucleus raphe magnus, the reticular formation, and the red nucleus (Antal, 1984; Raineteau and Schwab, 2001). For instance, it was shown that monkeys subjected to specific lesions of the red nucleus exhibit partial or complete inhibition of functional recovery after SCI (Lawrence and Kuypers, 1968). Taken together, there is enough evidence showing that spontaneous plasticity takes place at cortical and subcortical regions after SCI and that this process may help improve recovery of locomotor activity. However, the extent of spontaneous functional recovery varies a lot after SCI and can take month to years to fully develop (Raineteau and Schwab, 2001). Therefore, experimental interventions are needed to further accelerate recovery after damage to the spinal cord.

Effect of treadmill training on functional recovery In attempts to enhance functional recovery after SCI, several studies have investigated the effect of treadmill training on spinal changes and rehabilitation (EngesserCesar et al., 2005; Martinez et al., 2012) . A conventional training program primarily provides compensatory strategies to regain motor activity and recover from damages to the spinal cord. Functional recovery after locomotor training is mostly due to strengthening of the cortical input and adaptation of spinal neuronal networks to physiological proprioceptive inputs (Anwer et al., 2014). It has been shown that treadmill training following SCI leads to cortical reorganization and plastic changes that significantly improve the coordination of movements (Martinez et al., 2012). In a subsequent series of studies, spontaneous functional recovery was facilitated by training spinalized cats to step on a moving


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treadmill. After receiving a spinal hemisection and a spinalization at the thoracic level, cats that were trained quickly recovered their initial symmetric walking pattern through reestablishment of kinematic parameters (Martinez et al., 2012). In contrast, adult cats that were not trained still had the same asymmetrical state of locomotion observed after SCI (Martinez et al., 2012). The beneficial effect of treadmill training on motor recovery has also been demonstrated in rodents (Goldshmit et al., 2008; Sun et al., 2013). One week following a low thoracic hemisection, mice were trained to run daily on a treadmill (Goldshmit et al., 2008). Four weeks after exercise, trained mice were able to use their paretic hindlimb, whereas untrained mice failed to recover their locomotor activity and showed increased muscle atrophy at the level of the lesion. Taken all together, these studies suggest that treadmill training is a powerful tool that can enhance rehabilitation and induce significant improvements on locomotor activity after damage to the spinal cord (Goldshmit et al., 2008). Results from animal models of SCI have also been tested and validated in human clinical trials with the use of specialized training protocols (Field-Fote et al., 2005; Anwer et al., 2014). Several studies have reported that treadmill training induces reorganization of the CST in injured individuals, leading to increased neural regeneration and improved locomotor activity (Knikou, 2012; Anwer et al., 2014). One of the most commonly used rehabilitative programs is the body-weight-supported treadmill training (BWSTT), which enables individuals with motor deficits to support their own body weight through upper body harness (Lo and Triche, 2008; Knikou, 2012). In order to assess the effectiveness of the BWSTT on functional recovery, a study has evaluated the cortical excitability changes in patients with SCI based on alterations of the motor evoked potential (MEP), before and after training (Knikou, 2012). It was shown that the use of BWSTT leads to significant improvements in muscle activation patterns, as measured by changes in MEP of the tibialis anterior (TA) muscle (Figure 1). BWSTT was also able to improve clinical outcome in patients with SCI by altering the efficacy of corticospinal descending motor volleys synapsing with spinal motor neurons (Knikou, 2012). Overall, treadmill training appears to be an effective approach for restoring locomotor activity in the absence of normal supraspinal input. However, the mechanisms by which exercise improves motor functions after SCI are still not very well understood, and more work needs to be devoted to the development of safe and effective rehabilitative strategies (Thuret et al., 2006).

Molecular and cellular approaches for SCI There is a wide range of molecular and cellular compounds that are currently being used for neurological recovery following damage to the spinal cord (Table 1). Cellular therapies include, but are not limited to, the transplantation of Schwann cells, embryonic stem cells, and olfactory nervous system cells (Thuret et al., 2006). By reconstituting damaged circuits and creating a favorable environment for axon regeneration, these cells promote functional recovery after SCI (Thuret et al., 2006). One of the major challenges in cellular therapy is that the survival and integration of endogenous cells cannot be easily controlled. Although some studies have reported improvement in functional recovery after cellular therapy (Ogawa et al., 2002; Takami et al., 2002), the use of this method alone does not always lead to optimal results in patients with SCI (Pearse et al., 2004). A better understanding of the underlying mechanisms of cell-based therapies, along with careful animal testing, is needed to evaluate the efficacy of such approach in the treatment of SCI. On the other hand, molecular therapeutic interventions consist of protecting neurons from secondary cell death, as well as promoting axonal sprouting and regeneration (Thuret et al., 2006). Among these treatment strategies, methylprednisolone (MP) is one of the most frequently used neuroprotective agent in patients with SCI (Bracken et al., 1985; Breslin and Agrawal, 2012). MP is an inhibitor of lipid peroxidation and has been shown to reduce posttraumatic degenerative changes in the injured spinal cord, both in patients and animal models of SCI (Hall, 2001; Sayer et al., 2006; McDonald, 2008). Although MP has received a lot of attention as a neuroprotective agent for SCI, its benefit to motor function and neurological recovery is still in question (Bracken, 2001; Weaver et al., 2005). Several studies have reported conflicting results showing that the immunosuppressive therapy with MP is nonselective and fail to improve neurological outcomes in patients with SCI (Hugenholtz, 2003; Weaver et al., 2005). As a result, MP is often administered in combination with growth factors to further enhance its therapeutic effects and increase its specificity (Ji et al., 2005). Moreover, like most corticosteroids, long-term use of MP can generate severe side effects in patients, such as polytrauma, respiratory dysfunction, and sepsis (Hugenholtz, 2003; Lee et al., 2007). Safer treatments include medications like Tirilazad (Table 1), which is a non-glucorticoid that exerts neuroprotective roles and generates fewer side effects than MP does (Hall, 2001).

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Another compound used in treating SCI is baclofen, a Gamma-aminobutyric acid type B (GABAb) receptor agonist that is able to relieve spasticity related to motor disorders (Chiodo and Saval, 2012; Barry et al., 2013). The beneficial effects of baclofen on motor recovery result from regulation of the synaptic transmission at spinal and supraspinal sites (Curtis et al., 1997). Baclofen administration, which can be done either orally or intrathecally, alleviates the symptoms of spasticity by increasing GABAergic inhibition in cortical and subcortical areas (Kumru and Kofler, 2012; Barry et al., 2013). In a study investigating the therapeutic effects of this drug, the MEP was measured in healthy individuals, in patients who took baclofen as part of their daily therapy, and in patients who took no drug since their diagnosis (Bunday et al., 2014). Compared to nontreated patients, treated patients and healthy individuals showed reduced MEP size in the dorsal interosseous muscle during precision grip, suggesting that baclofen helps restore the premotoneuronal subcortical pathways that are lacking after injury to the spinal cord (Bunday et al., 2014). Although evidence suggests that baclofen efficiently promotes functional recovery after SCI, a disadvantage of using this drug is that it is not very well tolerated by most patients, and its discontinuation may lead to complications such as seizures and psychic symptoms (Dario and Tomei, 2004). Tizanidine, which is also used to treat SCIrelated spasticity (Table 1), has been proposed as an alternative approach for patients who are not tolerant to baclofen (Nance et al., 1994; Dario and Tomei, 2004). Overall, the delivery of molecular and cellular compounds to the lesioned spinal cord has proven efficient in promoting axon regeneration and controlling secondary injury processes after SCI (Hall, 2001; Bunday et al., 2014). Depending on the severity and nature of the SCI, they are frequently being used in combination to further promote functional recovery of locomotor activity in affected individuals (Middleton et al., 1996; Pearse et al., 2004).

Neuroprostheses for spinal cord stimulation and rehabilitation

Neuroprostheses are assistive devices that can restore the loss of motor functions following damage to the brain or spinal cord (Prochazka et al., 2001; Guggenmos et al., 2013). By bridging the gap between the motor intention encoded in cortical signals and the sublesion locomotor infrastructure, a neuroprosthetic device could theoretically reestablish the communication between supraspinal and spinal circuits (Jackson and Zimmermann, 2012) (Figure 2). Several types of electronic devices that interface with the spinal cord are currently being developed in the hope of facilitating the rehabilitation of patients with SCI (Jackson and Zimmermann, 2012; Collinger et al., 2013). Neuroprostheses can either be external or implanted devices (Prochazka et al., 2001; Popovic et al., 2002) and are used to stimulate the spinal cord and muscles following SCI (Jackson and Zimmermann, 2012). Spinal cord stimulation is already in widespread clinical use and has been shown to restore the motor circuits, leading to enhanced limb movement in patients with SCI (Harkema et al., 2011; Jackson and Zimmermann, 2012). Such stimulation can be done through epidural excitation, where an array of electrodes is implanted over the dorsal surface of the spinal cord (Mondello et al., 2014; Sayenko et al., 2014). At high intensities, epidural stimulation has shown to generate rhythmic stepping patterns and voluntary limb movements in patients with SCI (Edgerton and Harkema, 2011; Sayenko et al., 2014). Although implantation of microwires into the central neural tissue may cause ongoing inflammatory responses (Biran et al., 2005 ), chronic administration of epidural stimulation is usually well tolerated in animal models of SCI, as long as the microwires are small and biocompatible (Jackson and Zimmermann, 2012). The safety and efficiency of epidural stimulation of the spinal cord have also been tested and validated in humans (Hunter and Ashby, 1994; Harkema et al., 2011). A study involving a paraplegic patient reported full weight-bearing standing within 7 months after implantation of a multielectrode array on the spinal cord (H arkema et al., 2011). Epidural stimulation is thus an efficient tool to replace the missing source of excitation after the interruption of descending pathways in SCI and could lead to improved coordination and functional recovery in paralyzed patients. Other methods, such as intraspinal and subdural stimulations, are also commonly used for stimulating the spinal cord (Sharpe and Jackson, 2014). Intraspinal stimulation preferentially recruits small motor units and produces prolonged weight-bearing standing and stepping in animal models of SCI (Saigal et al., 2004; Bamford et al., 2010). In contrast, subdural stimulation generates more selective responses compared to epidural and intraspinal stimulation but can lead to several complications such as epileptic seizures and wound infections in individuals (Tronnier and Rasche, 2013). Stimulation of the spinal cord is thus a powerful tool for locomotor recovery, and assistive neuroprosthetic devices will continue to play an important role in axonal regeneration and locomotor recovery. Nonetheless, more research is needed to


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promote the development of next-generation devices that could enhance rehabilitation and be of practical use in the day-to-day lives of patients with SCI.

Conclusion and future directions The past decades have seen impressive advances in understanding axonal sprouting and neural plasticity following damage to the spinal cord. SCI leads to the disruption of nerve fiber bundles that convey ascending sensory and descending motor information and results in severe dysfunctions for all body parts below the area of the lesion (Raineteau and Schwab, 2001). A growing number of investigators are pushing their way through discovering and developing new strategic plans for treating such damage. Locomotor training, such as BWSTT, has emerged as a promising tool for improving functional ambulation after SCI (Hicks and Ginis, 2008; Knikou, 2012). Although BWSTT has proven to be very useful in rehabilitation and locomotor recovery, there is insufficient evidence to conclude that this approach is the most effective for the recovery of normal walking pattern in patients with SCI (Brick, 2014). Rehabilitation in the SCI population would seem to greatly benefit from research conducted in the form of randomized controlled trials to determine the type of training that could lead to the highest degree of recovery after damage to the spinal cord (Mehrholz et al., 2012). The clinician must also consider the nature and etiology of the injury, and continued monitoring of the patient is required in order to implement the best strategy for rehabilitation (Harkema et al., 2012). Treatment of SCI also relies on the use of molecular and cellular approaches, which involve mainly delivering therapeutic agents that could combat secondary injuries following acute trauma. Loss of sensory and functional inputs below the level of injury as well as muscle spasticity are two of the most prevalent secondary complications after SCI (Rabchevsky and Kitzman, 2011 ). In order to restore the conduction in ascending and descending fibers at the level of the injury, several studies examined experimental interventions that could promote axonal regrowth and sprouting (Rabchevsky et al., 2000; Chen et al., 2013). Exogenous administration of cells and growth factors has been proposed as a potential therapeutic treatment for SCI because of their ability to regulate synaptic plasticity and axon proliferation (Thuret et al., 2006). The use of corticosteroid drugs, such as MP, also results in significant recovery of locomotive function in patients with SCI (Bracken, 2001). On the other hand, drugs used to treat spasticity in patients with SCI include baclofen, a GABAb receptor agonist. Other strategies would be to use a combination therapy consisting of two or more drugs in order to ameliorate the therapeutic effects of baclofen and reduce its adverse effects (Middleton et al., 1996). Taken all together, molecular and cellular therapy has proven efficient in promoting axon regeneration and reducing spasticity in patients with SCI. However, to date, few interventions have achieved the magnitude of axon regrowth and synapse regeneration that would be needed to provide patients with SCI the ability to stand and walk (McDonald, 2008). Because of the complexities involved in SCI, results from animal models often fail to prove useful in human clinical trials (McDonald, 2008). The development of animal models that closely mimic what is observed in patients with SCI is therefore needed and will be crucial to the development of novel targeted therapies. Another aspect of SCI treatment involves the stimulation of the spinal cord through an implanted neuroprosthetic device. By enhancing axon sprouting and regeneration, electrical stimulation of the spinal cord helps reconnect the intrinsic circuits below the level of the injury. This technique helps restore, at least partially, the functional motor and sensory loss seen in patients with SCI (H amid and Hayek, 2008). Although numerous studies have demonstrated the beneficial effects of electrical stimulation on locomotor activity after damage to the spinal cord, there are several limitations with the use of neural interfaces in patients with SCI (Bamford et al., 2010). The implantation of microwires into the central neural tissue is often associated with traumatic injury and ongoing inflammatory responses (Janatova, 2000; Biran et al., 2005). Also, because cytotoxic effects frequently occur at the electrode-tissue interface, long term-use of neuroprosthetic devices is not recommended. Therefore, in attempts to reduce the damage during implantation, cautious care must be taken during the design of the microwires and their implantation into the spinal cord (Bamford et al., 2010). Moreover, the materials being used must be biocompatible and should last for at least 5 to 10 years without the need for replacement (Bamford et al., 2010). The fact that several technologies are now moving from laboratory experimentation in animal models of SCI to preliminary clinical trials is very promising. In this review, I talked about the spontaneous plasticity that takes place after damage to the spinal cord and discussed a variety of therapeutic approaches used to promote rehabilitation after SCI. However, it is important to point out that individual approaches are unlikely to emerge as a potential cure for SCI, but it is rather the tailored combination of different strategies that will lead to significant improvements in outcome. Insights arising from the results of future

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experimental studies will hopefully lead to the development and identification of better therapeutic interventions that could restore locomotor activity and enhance the quality of life in patients with SCI. Acknowledgment: The author is a recipient of an award from the Natural Sciences and Engineering Research Council of Canada. Financial disclosure: The author declares no potential conflict of interest.


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350 300 250 200 150 100 50 0 1245678910111213141516 3 Heel strike

Stance

Swing Swing initiation

Swing-tostance

Step cycle divided into 16 equal time windows (or bins) Before BWSTT After BWSTT

Figure 1: Effect of BWSTT on MEP modulation. The amplitude of TA MEP is illustrated before (dashed line) and after (solid line) BWSTT sessions. The step cycle is divided into 16 equal time windows or bins. The gray region denotes stance phase. Bins 1, 8, 9, and 16 correspond approximately to heel strike, stance-to-swing transition, swing phase initiation, and swing-to-stance transition, respectively. (Reproduced with permission from Knikou, 2012 ).

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Table 1 : Molecular and cellular therapies used for SCI. Treatment

Properties and mode of action

Drugs Baclofen

Muscle relaxer that treats spastic movement disorders

Diazepam

Benzodiazepine that causes muscle relaxation

Broderick et al., 1997

Erlotinib

Inhibits tyrosine kinase and reduces inflammation

Kjell et al., 2014

Pregabalin

Treats SCI-related neuropathic pain

Cardenas et al., 2013

Methylprednisolone

References

Barry et al., 2013

Inhibits lipid peroxidation and inflammation

Sayer et al., 2006

Tizanidine

Adrenergic agonist that has antisplasticity effects

Nance et al., 1994

Tirilazad

Reduces inflammation and protects neuronal tissues

Hall, 2001

Neurotoxin that reduces SCI-related spasticity

Marciniak et al., 2008

Enzymes and toxins BTX Chondroitinase ABC

Regenerates CST axons and reduces inflammation

Alluin et al., 2014

Sialidase

Enzyme that promotes axon regeneration

Mountney et al., 2010

Growth factors bFGF

Rabchevsky et al., 2000

Enhances axon remyelination and cell survival

EGF

Increases ependymal cell proliferation and white matter density

Jimenez Hamann et al., 2005

NGF

Causes neuronal regeneration and axonal remodeling

Chen et al., 2013

PDGF

Regulates axon preservation and sprouting

Neurotrophic factors BDNF

Lutton et al., 2012

Song et al., 2008

Regenerates ascending sensory neurons

CNTF

Promotes the survival and differentiation of olygodendrocytes precursor cells

GDNF

Increases axonal regeneration and remyelination

Zhang et al., 2009

Neurotrophins

Increases axon proliferation and remyelination

McTigue et al., 1998

Cellular therapy Schwann cell

Talbott et al., 2007

Glial cell that myelinates sensory and spinal axons

Oudega and Xu, 2006

Embryonic stem cell

Increases neural plasticity and axonal regeneration

Mitsui et al., 2005

Olfactory nerve cell

Promotes axon regeneration and prevents tissue loss

Sasaki et al., 2006

BTX, botulinum toxin; bFGF, basic fibroblast growth factor; EGF, epidermal growth factor; NGF, nerve growth factor; PDGF, platelet-derived growth factor; BDNF, brain-derived neurotrophic factor; CNTF, ciliary-derived neurotrophic factor; GDNF, glial cell-derived neurotrophic factor


Figure 2: Therapeutic effects of closed-loop neuroprostheses.

After SCI, the normal sensorimotor loop is disrupted. A neural prosthetic device could replace injured descending connections by recording brain activity and stimulating spinal circuits below the level of the injury. Moreover, volitional drive to the motor cortex may be enhanced through neurofeedback mechanisms such as proprioception and vision.

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