Electrical Stimulation as a Tool to Promote Plasticity of the Injured Spinal Cord

Abstract

Introduction

Neurons in the central nervous system (CNS) are unable to regenerate their axons following injury. This inability is based on various factors, including the presence of growth inhibitory factors in CNS myelin and at the lesion site, a lack of trophic support, and an age-related reduction in the intrinsic neuronal capacity to grow.^1,2 Considering the debilitating effects of CNS injuries, approaches to enable repair are desperately needed. One method to promote and possibly direct axonal outgrowth, to re-establish lost connections, and to restore function is electrical stimulation (ES), an area of research that began nearly a century ago.^3,4 These early experiments demonstrated the wide range of effects that ES can have on neurons, including promoting neurite outgrowth. The ability of ES to generate an electric field (EF) in the target tissue to influence neuronal outgrowth in vitro was subsequently explored in animal models of spinal cord injury (SCI).^5,6 We are defining EF as the electrical field created across tissue between an anode and a cathode. Although ES will generally generate an EF, the intention of ES frequently goes beyond the creation of an EF and is intended to increase the excitability of the target neurons to increase spiking or to enable enhanced responses to afferent or descending inputs (i.e., to bring them closer to the threshold for firing). Since the publication of these seminal articles,^5,6 the use of ES to restore function after SCI has expanded considerably, and ES is currently used for a variety of purposes. Recently, ES has become more prominent in the field of SCI, as it is clinically used to activate or facilitate the activation of neuronal networks below a lesion rather than to promote axonal outgrowth.

The intent of this review is to provide an overview of the major areas of ES that are used to treat SCI and to clarify their differential purposes and approaches. Considering the vast literature for each of the different areas, our objective is not to provide a comprehensive review for each of them, but rather to provide an overview and clarify their relationship to each other. For this purpose, we consider four major uses for the study of ES based on the proposed or documented underlying mechanism, which are summarized in Figure 1: (1) using ES to introduce an EF at the site of injury to promote axonal outgrowth and plasticity; (2) using spinal cord ES to activate or to increase the excitability of neuronal networks below the injury; (3) using motor cortex (MCX) ES to promote corticospinal tract (CST) axonal outgrowth and plasticity; and (4) leveraging the timing of paired cortical and peripheral stimuli to produce plasticity.

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FIG. 1.

The difference in the approach and location of electrical stimulation following spinal cord injury of the four applications discussed in this review are summarized. (A) Cortical stimulation to activate growth promoting cellular pathways with the intention to promote axonal outgrowth (i.e., collateral sprouting and regeneration). (B) Using electrical fields across the spinal lesion to promote axonal growth (i.e., regeneration) through the lesion. (C) Paired stimulation (here cortex and a peripheral nerve) to strengthen synaptic connections by coactivating pre- and post-synaptic neurons. (D) Electrical stimulation to activate (or facilitate activation) of spinal circuitry below the level of the injury.

This review will focus on ES to enhance spinal circuit functions, the strength and efficacy of spared motor pathways, and the ultimately motor recovery after SCI. For each approach, we address the questions of the mechanisms recruited and the neural target engaged by the stimulation. We describe animal behavioral studies demonstrating efficacy in motor recovery after injury. Further, putative mechanisms for repair of the CST, a key pathway for movement in humans and many animals, and improved recovery of motor function, will be discussed. These mechanisms serve as the basis for translating ES in animals with SCI to humans. Each of the studies discussed in this review is based on similar, but different, ES protocols and stimulation parameters (and therefore potentially different mechanisms). Because of this, direct comparison among the different studies is difficult. Also, the animal and injury models used in experiments from each study vary substantially (a list of which, including ES parameters and major results, can be seen in Appendix Table A1).

Promoting Spinal Neuronal Outgrowth with Weak EFs Applied to the Lesioned Tissue

Spinal cord ES was initially explored to target axons that were damaged after SCI in order to bias the direction and possibly extent of neurite outgrowth. Evidence suggests that spinal cord direct current ES creates a relatively static EF. Importantly, SCI in lamprey was reported to rapidly create an EF at the injury site, likely based on Na⁺ and Ca⁺⁺ influx, possibly important for the regenerative response of the neurons.⁷ This is similar to what is seen in wound healing, where injury-induced EFs have been said to direct cell migration and growth^8,9 and developmental biology, where neural tube formation can greatly be affected by ES.^10,11 Various cellular changes caused by an EF have been discussed, including asymmetrical distribution of charged protein/channels, redistribution of the actin cytoskeleton, changes in the localization and expression of focal adhesion proteins, and nchanges in the Rho pathways,^12,13 and a major factor linking these effects seems to depend on voltage-gated ion channels, and possibly flow of Ca⁺⁺ ions.¹⁴

Although ES and the generation of EFs for promoting outgrowth dates back nearly a century,^3,4 its application to SCI in animals has been much more recent.^5,15–24 With a few exceptions,^22–24 the majority of early studies examining the rationale behind the use of ES post-SCI in animal models have emanated from the laboratory of Borgens and colleagues.^5,7,15–21 It should be noted that in these early studies, Borgens and colleagues used both static direct current (DC) and alternating or repetitive ES. Because of the potential damaging effects of applied DC, studies generally used very low currents (on the order of 10s of microamperes in guinea pigs, and 600 μA in dogs) that generally do not activate spinal circuits or muscle.^25–27 Only recently have experimental and computational studies begun to calibrate the EF values necessary for producing biological/biophysical effects. The extent to which microampere-level body surface currents will generate sufficient fields in the spinal cord needs to be validated by direct measurements or informed by predictive modeling. In this way, we will be able to evaluate if this form of stimulation weakly modulates neuronal membrane potential to bias network function, as proposed for transcranial DC stimulation.²⁸

Much of the work from Borgens' in-vivo studies in injured spinal cords has been based on the findings that neurons respond to EFs in vitro. EFs alter local ion gradients, which is thought to encourage growth of lesioned axons. The idea that axons demonstrate outgrowth toward a cathode and regress from an anode in vitro has been around for quite some time.^29,30 In an in-vitro experiment in which EF polarity was reversed, McCaig found that there was an asymmetrical response in neurite outgrowth with the cathode-facing outgrowth being faster than anode-facing regression).³¹ This suggested that neurite outgrowth could be achieved in opposite directions by reversing the EF polarity. The Borgens group applied these ideas to several of their own models of SCI. Here, we will discuss their use of epidural ES to produce an EF at the site of SCI in order to promote axonal outgrowth into the lesion. However, this is not to be mistaken for epidural ES or intraspinal micro-stimulation below the SCI, approaches used to excite local circuitry and/or central pattern generators to evoke or facilitate functional movement patterns. This approach has been studied in humans and animals, respectively, and will be discussed later in this article in the context of the clinical applicability of ES and EFs.

One of the first studies to examine the effects of an imposed EF on spinal cord axon regeneration was performed in a complete spinal cord transection lamprey model.⁵ In this experiment, larval lamprey underwent ES in the form of 10 μA DC applied across the spinal cord lesion for 5 or 6 days. A strength of this model for elucidating the mechanisms by which applied fields can promote axon outgrowth is that stimulation was delivered directly to the spinal cord using indwelling Ringer-based electrodes. This ensured delivery of current to the injury site and a reasonable estimate of current value. Following the stimulation-induced enhancement of their constitutive capacity for axonal outgrowth, Mauthner cell axons were dye filled to reveal a significantly higher number of axonal processes growing into and across the lesion in stimulated versus sham animals. Intracellular recordings demonstrated action potentials crossing the lesion.⁵ Subsequent studies investigated ES after complete and partial transection in a guinea pig model. These studies showed increased axonal growth in the experimental groups into, but not across the lesion site.^17,18 Although these studies did not include behavioral data, a follow-up study demonstrated functional recovery in a group of electrically stimulated guinea pigs when the EF was applied rostral to the site of the lesion.¹⁶ Moreover, further experimentation with DC ES to produce a static field in awake dogs with complete paraplegia and implantation of an ES pack promoted moderate functional recovery.²¹

In the dog model, an oscillating field stimulator (OFS) was used based on the idea that alternating the polarity of an EF can result in neuronal outgrowth in opposite directions. It was reasoned that alternating the polarity might promote outgrowth of ascending sensory fibers in one direction of current flow, and outgrowth of descending motor fibers in the other. Whereas polarity-dependent effects with DC ES have been reported,^6,29–31 oscillating ES may directly activate axons that can trigger upregulation of growth-promoting signaling pathways in neurons.

The success of early studies of ES of the spinal cord led to the first clinical trial in humans in 2005.³² This was a phase 1a study and consisted of an OFS device implanted in 10 complete SCI patients (level C5-T10). The device was placed within 18 days of injury with the electrodes spanning one segment on either side of the level of injury in an extra-spinal location (no contact with any neural elements). The device was left implanted for 15 weeks, after which time it was removed and its function tested. Outcome measures from this study included ongoing neurological examination by an unblinded study neurologist, surgeon, and research nurse using the American Spinal Injury Association (ASIA) Impairment Scale (AIS), somatosensory evoked potentials (SSEPs), and the Visual Analog Scale (VAS) for pain at baseline, 6 weeks, 6 months, and 1 year post-implantation. The trial concluded that the surgical procedure and OFS implant were well tolerated and safe, and resulted in improvement in all parameters assessed. This resulted in approval of further patient recruitment, in which an additional four patients were included and compared with 14 historical control patients. Results from this expanded study were subsequently filed in a report to the Securities and Exchange Commission by the owner of the technology.³³ Patients treated with OFS showed marked improvement in all domains assessed, with the exception of motor recovery, a significant limitation to the trial. However, as pointed out by Tator, much of the enthusiasm from this preliminary and seminal clinical work is tempered by the unblinded nature of the assessments, the small number of patients included, minor to moderate neurological recovery, lack of a control group, and lack of a peer-reviewed publication.^34,35

ES to Increase Excitability or Directly Activate Spinal Neuronal Networks below the Level of Injury

The second distinct mechanism of action for ES following SCI is to increase the excitability of neuronal networks in the spinal cord or directly activate distinct neuronal motor pools. In contrast to experiments in which the creation of an electric field was the intent, the applied currents are higher and are not applied at the lesion site, but rather below the level of the injury (Figure 1). This field of research is now commonly referred to as “neuromodulation”; however, historically, neuromodulation in the field of motor control was not limited to ES. Research on neuromodulation was pioneered in various in-vivo animal models and in in-vitro preparations. The first form of neuromodulation described is likely based on research in decerebrate cats in which stimulation of the mesencephalic locomotor region (MLR), a small region in the brainstem, could initiate and modulate stepping. Interestingly, the higher the intensity of this stimulation, the faster that animals would walk, even changing their gate from walking to trotting and ultimately to galloping.³⁶ In order to explore spinal pattern generating networks for locomotion in isolation and to learn how to imitate their activity, isolated spinal cords (in vitro) were utilized as well as adult cats^37–39 and rats^40,41 with a complete thoracic spinal cord transection. Various groundbreaking in-vitro experiments with spinal cords from neonatal rats not only showed that pattern-generating networks can produce rhythmic output without descending motor and sensory input, but also demonstrated the powerful effects of peptides, such as dopamine or serotonin, in triggering and modulating network activity.^42,43

The seminal work of Barbeau and Rossignol^44,45 explored the role of monoamines and noradrenergic and dopaminergic drugs in cats with spinal transections. These animals were trained to step on a treadmill, and represented an optimal model to study the spinal networks in vivo. They found that neither serotonergic nor dopaminergic agonists successfully induced locomotion, which was, however, achieved with noradrenergic precursors and the agonist clonidine. Further, Barbeau and Rossignol reported that serotonergic agonists and precursors modulated the stepping pattern, suggesting that these drugs increased excitability of the spinal networks.^44,45 These studies pioneered the field of chemical neuromodulation after SCI, and laid out the path for various possible treatment approaches. One of these approaches was to implant serotonin-producing cells into the spinal cord of rats with complete spinal transections to compensate for the lack of descending serotonergic innervation, and thus to enhance the excitability of spinal networks.^46,47 In both cases, this approach was reported to restore coordinated hindlimb movements in the animals.

Resulting from years of studies in cat locomotion, another powerful neuromodulatory factor that has been frequently employed, but rarely reported, is cutaneous stimulation or exteroceptive stimuli. This approach of gentle mechanical stimulation of the perineal area in cats was regularly employed to initiate walking. However, this has rarely been considered for clinical translatability.^48–50

Currently, the term “neuromodulation” has been somewhat misused, as it is generally referred to as ES-induced modulation. Considering the current excitement regarding ES-induced neuromodulation, it is surprising to learn that this approach has been around for many years, and originated in the field of pain control.⁵¹ Another fact is that ES of spinal networks to enhance motor function was performed in humans long before it was considered in animal models of SCI. In 1980, Sherwood and colleagues explored epidural stimulation to enhance motor function in individuals with upper motoneuron disorders,⁵² and in 1998 it was shown for the first time that lumbosacral epidural stimulation can facilitate rhythmic motor activity in functionally complete SCI.⁵³ The human trials and possible mechanism of where stimulation exerts its modulatory effects will be discussed in more details in subsequent sections of the review.

In animals, epidural stimulation was frequently used as a tool to explore pattern- generating networks in the spinal cord. These studies showed that placing electrodes above the cervical or thoracic spinal cord could trigger quadrupedal or bipedal locomotion, respectively, in cats.⁵⁴ Various later studies in cats³⁹ and rats⁴¹ have bolstered knowledge about the use of epidural stimulation in animal models and evolved as treatments for SCI.^55,56 More recently, studies have focused on combining epidural stimulation of spinal circuitry with other treatment approaches, including training and pharmacological neuromodulation.^41,56–60 These studies have been summarized in detail in excellent reviews, and the reader is referred to these articles for specific details on the stimulation parameters.^61–64

Considering that the specificity of neuromodulatory epidural stimulation is limited, and the result is typically a subthreshold stimulation increasing neuronal excitability, approaches to stimulate spinal networks directly and in a more targeted fashion have also been explored. For example, a somewhat different approach is to use epidural stimulation to produce a spatiotemporal activation configuration that produces a locomotor pattern. This approach to epidural stimulation has been pioneered by Courtine and collaborators, by whom a stimulation paradigm was developed to activate muscle synergies to improve locomotion.⁶⁵ This approach has then been combined with a closed-loop brain–spine interface, in which it was reported to restore weight-bearing locomotion in non-human primates^66,67 and rats.⁶⁸

Another approach for a more targeted stimulation of specific neuronal populations is intraspinal micro-stimulation, which requires the direct implantation of electrodes into the spinal cord (enabling more precise targeting of interneuron and motoneuron pools). The cost of increased invasiveness from this approach comes with the benefit that targeted stimulation can evoke specific and sequential movements such as leg extension or flexion,^69,70 preferentially by recruiting fatigue-resistant muscle fibers.⁷¹ With a large number of electrodes and appropriate orchestration of the stimulation at different spinal locations, overground stepping with propulsive and supportive forces could be elicited in anesthetized cats, often for very extended periods of time.⁷²

An interesting vision for the future is to control such intraspinal stimulation with cortical activity, to control movements while bypassing the injured spinal cord.^73–75 The value of intraspinal stimulation has also been explored at the cervical (C4-C5) level to evoke forelimb function in rats following a severe, lateralized contusion injury⁷⁶ and in spinally intact primates,⁷⁷ from which a variety of hand and arm movements were elicited. However, the question remains whether the highly complex stimulation patterns required to control arm and hand function can be achieved using this approach. Similarly, intraspinal stimulation was recently reported to promote diaphragm activity.⁷⁸ In these elegant studies, medullary respiratory input in rats with cervical hemisection was utilized to trigger cervical intraspinal stimulation to activate the diaphragm.

Less invasive than either intraspinal or epidural stimulation is transcutaneous stimulation, in which electrodes can be easily applied and removed (reviewed in Mayr and coworkers⁷⁹). Similar to epidural stimulation, this field was also pioneered in studies on pain, in which transcutaneous nerve and dorsal column stimulation were reported as effective modalities for pain treatment.^80,81 The ability of transcutaneous stimulation to evoke and modulate spinal reflex function reliably was demonstrated in various studies, and made it an attractive approach to treat and assess SCI.^82,83 It was suggested that transcutaneous stimulation was able to activate large diameter afferents in both dorsal^84,85 and, depending on location, ventral roots.^86–88 Consequently, transcutaneous stimulation has been used as a tool to assess supraspinal and spinal connectivity,⁸⁹ and has already produced promising and persistent results in treating individuals with cervical SCI when combined with training.⁹⁰ Recently it was reported that even a single session of transcutaneous stimulation in individuals with incomplete SCI had excitatory effects on spinal and inhibitory effects on cortical circuitry, possibly contributing to recovery.⁹¹

Phasic Electrical Stimulation to Increase Neuronal Axon Growth Promoters and Intracellular Signaling

The third mechanism for ES after SCI is to increase intracellular signaling in stimulated neurons to upregulate axon growth-promoting factors and regeneration-associated genes in injured and spared neurons. Different from the approaches discussed previously regarding the stimulation, ES after SCI is generally applied to the cell body of the long-axon projection neurons. As such, in this case, the intention is to repair injured corticospinal axons by targeting their cell bodies in the cortex by ES (see Figure 1).

We distinguish two forms of axonal outgrowth: regeneration and sprouting. Axonal regeneration is defined as outgrowth of an axotomized neuron from its terminal, lesioned end at the site of injury, whereas axon sprouting is defined as outgrowth from spared axons or axotomized neurons proximal to the site of injury.¹⁰⁹ Mature neurons have a reduced intrinsic capacity for axonal outgrowth that severely hampers both axonal regeneration and sprouting.¹¹⁰ The principal goal of phasic ES is to enhance this axon growth capacity and, in turn, produce structural, and possibly genetic, changes that are durable and can persist after the stimulator is turned off. Phasic ES can be distinguished from subjecting injured neurons to very weak currents and EFs, in that the former are expected to activate the neuron to produce action potentials or to raise excitability close to threshold. The latter on the other hand may bias transmembrane functions and Ca⁺⁺ influx in more subtle ways.

The use of phasic ES triggers action potentials (as evidenced by c-Fos expression and downstream EMG responses) at and rostral from the site of SCI (such as in upper motor neurons upstream of the injury or downstream sensory neurons).^111,112 Here, the objective of ES is to engage mechanisms, including elevating cyclical adenosine monophosphate (cAMP), the growth factor brain derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR), and Janus kinases/Signal transducer and activator of transcription proteins (Jak/Stat) associated signaling, to promote axonal outgrowth. These ideas and their link to ES of the CNS and its descending pathways have been gathered initially from the peripheral nervous system and the growth-promoting effects of a peripheral nerve conditioning lesion. Further, studies have identified that the reduced axon regenerative capacity of mature neurons can be enhanced, like that of immature neurons, by manipulating neuronal activity and signaling.

Pairing Stimulation To Promote Transmission In Specific Pathways

The fourth mechanism for ES after SCI is to leverage the timing of paired stimulation to produce plasticity. The idea is based on work from Hebb proposing that synaptic plasticity occurs when pre- and post-synaptic neurons are active together within a narrow time window.¹⁴⁷ This process is frequently referred to as “fire together, wire together.” This wiring (or synaptic adaptation) can naturally occur when multiple neurons that are active simultaneously connect to a common target and can thus activate it. In vitro, this can be recapitulated where it has been demonstrated that synaptic strength can be amplified by precisely timing pre-synaptic activity and depolarization of the post- synaptic cell.¹⁴⁸

Paired associative stimulation (peripheral and MCX stimulation) has been used for some time.^149–155 The approach of paired associative stimulation or paired pulse stimulation can be used to potentiate either voluntary movements or the motor response to another stimulus. The idea is that if the timing is correct, the neural consequences of the two stimuli will interact in adaptive ways and, one hopes, lead to persistent forms of plasticity. Such stimulation can use a single site (e.g., MCX ES) or two different sites (e.g., MCX and a peripheral nerve or muscle). The interstimulus interval (ISI) is typically adjusted so that a peripheral stimulus activates the cortex at the time that the MCX stimulus is triggered, implying a cortical locus for plasticity. Of particular interest is when the ISI enables facilitation at the spinal cord level, implying plasticity at the spinal level.^150,151 This convergence of descending and afferent signaling may be on common post-synaptic interneurons or common neural populations.¹⁵¹ Unlike in rodents where the CST does not make corticomotoneuronal connections, in the human, convergence for the CST would additionally be expected to be on motoneurons, which may make this modality more impactful than signal convergence occurring solely on interneurons.

In an example of dual stimulation at a single cortical site, Perez and colleagues used a TMS pulse interval based on the timing of the normal pattern of MCX-evoked activation of the CST, which recruited strong temporal summation in cervical SCI subjects.¹⁵⁶ This resulted in stronger MEPs and, remarkably, the participants were able to perform basic motor tasks (involving hand dexterity) better after the therapy. The time intervals are tailored to the timing of synaptic events evoked by an MCX stimulus. If the stimulus mimics a phasic movement control signal, then the synaptic events associated with that signal are partially replicated with the paired stimulation protocol. Importantly, if alternate timing is used, there is no MEP plasticity or improvement in motor function. This is an example of a stimulation protocol that can be coupled with motor training to enhance the efficacy of rehabilitation. For two stimulation sites, such as motor cortex and the periphery (see Figure 1), the interstimulus interval can be adjusted so that the evoked responses from stimulation of both sites converge at the spinal level.

Following their work in rodents and primates, Courtine and colleagues⁵⁷ applied epidural stimulation to activate motoneurons via proprioceptive circuits in the dorsal roots in individuals with chronic severe SCI. This technology was applied to selected roots in a timed manner triggered by residual movements while the participants were walking in a gravity assist device.¹⁵⁷ This approach resulted in immediate recovery of locomotor function, and over a few months, enabled recovery of voluntary control of originally paralyzed muscles even without stimulation. Underlying mechanisms in this scenario was an increase in motoneuron excitability.

An important new development is to substitute one “stimulus” in a paired-stimulation protocol for a naturally occurring neural event, such as a recorded action potential, local field potential, or EMG response. In primate studies, spontaneous EMG responses or cortical activity have been used to trigger spinal cord microstimulation to strengthen the ventral spinal cord connections mediating the EMG response.^158,159 After cervical injury, this approach can lead to improvement of motor function for 3 additional weeks without stimulation.¹⁶⁰ Further, the detailed research on electrical activation of spinal circuitry has been rapidly expanding to include closed-loop brain–spinal cord interfaces that were reported to be able to restore weight-bearing locomotion in non-human primates^66,67 and rats.⁶⁸

Approaches that optimize the timing of ES events may lead to greater strengthening of the targeted connections than other approaches. However, as timing is critical to strengthening plasticity, the wrong timing can lead to much weaker connections. For example, in models of spike-timing dependent plasticity (STDP), the stimulus that is being used to strengthen the motor response must precede the response over a critical time window for strengthening to occur. If it follows the response, again within a critical time window, the response is weakened. This is an important concern for translation of approaches that make use of STDP. Similarly, the selective reinforcement via STDP of spared motor pathways and their functional response after injury during the rehabilitative process assumes that the response is adaptive. If indeed adaptive, the use of STDP technology and mechanisms would support improved motor control if strengthened.

Synthesis and Future Directions

ES offers itself as a straightforward treatment approach and is currently explored primarily for neuromodulation to excite neuronal networks directly. It is important to recognize that as rehabilitative training may not be feasible in the setting of acute trauma, ES may be an alternative if both it and rehabilitative training work via complementary mechanisms. ES can be applied during the acute injury period when rehabilitation is not possible, in order to begin to repair damaged neural networks.

As discussed, ES to promote recovery after SCI is more than simply increasing the excitability of the spinal cord neural networks caudal to the injury. An entire body of literature exists supporting the notion that different modalities of ES can help promote and direct axonal outgrowth. We are now beginning to understand some of the cellular mechanisms that underlie the capacity of ES to promote axonal outgrowth. Animal studies show that more active inputs to neurons in spinal motor circuits, and the spinal neurons themselves, are able to secure more and stronger connections than their less active counterparts reflecting activity-dependent synaptic competition.^26,124 If this is similar to the normal establishment of synaptic connections, where use-dependent processes and training strengthen connections that support function and (in the case of development) eliminate unnecessary connections, it helps to explain how ES-assisted rehabilitation could lead to stronger and more effective connections. Choice of which pathway to stimulate is particularly critical with ES because of the novel activity-dependent competitive interactions that ES may produce; stimulation of the wrong pathway could be detrimental to recovery, akin to what is seen in task-specific training. Given our limited understanding of the role of different motor pathways in everyday movements (apart from the CST) and the importance of afferent input in facilitating movement, we have even less of an understanding of which pathways are best promoted after injury.

It is important to understand how ES can be applied to the chronically injured person. Whereas it is generally hypothesized that there is an early time window for axon growth into and through a lesion site, activity-dependent CST axon sprouting may occur weeks after injury. With scar formation after SCI, there likely will be a time window in which electrical stimulation needs to be implemented to promote axonal growth at and through the injury site, and behavioral recovery. Nevertheless, spinal ES in chronically injured people may lead to outgrowth of spared axons below the lesion. Intriguingly, the limited reports of some improvement being observed after persistent stimulation in chronic SCI individuals, as well as after the stimulator is turned off, may be the result of the durable structural plasticity induced by ES.

There are many challenges to translate ES-based approaches to clinical practice. Among these is better target engagement by the stimulation. This assumes that we know what the target is, so that we can optimize electrode placement. Imaging-based finite element method (FEM) modeling is a way to standardize electrode placement and reduce between-study/subject variability, leading to an individualized, patient-specific approach to ES. Dosing, such as for pharmaceutical interventions, will also have to be carefully worked out. Nevertheless, these challenges can be addressed with further animal research in which biological parameters can be rigorously examined in order to translate these minimally invasive approaches to people with SCI, both acutely and chronically.

Acknowledgment

References