Spinal Cord Transcutaneous Stimulation in Cervical Spinal Cord Injury: A Review Examining Upper Extremity Neuromotor Control,Recovery Mechanisms,and Future Directions

Search strategy

For this review, a comprehensive search was conducted in the PubMed database to identify relevant articles. The eligibility criteria for inclusion in this review were as follows: (1) studies involving adults with cervical SCI and (2) studies examining the application of scTS to the cervical region and task-specific training to improve UE deficits or facilitate recovery. The search was focused on the following keywords: transcutaneous spinal cord stimulation, non-invasive spinal cord stimulation, neuromodulation, cervical SCI, UE deficits, and task-specific training. The search encompassed articles from the inception up until July 30, 2023. After evaluating the abstracts, the articles that met the required inclusion criteria were retrieved in their full-text version. The identified articles underwent a thorough data extraction process. To ensure accurate citation and eliminate duplicates, the search results were imported into EndNote, a reference management software.

Improved hand function on GRASSP, grip-strength, and CUE-T functional outcomes

Seven studies utilized the Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP) as the primary functional outcome measure to evaluate the effectiveness of scTS combined with task-specific training on UE motor recovery. ^{28,30 –32,58,60,61} All seven GRASSP-based studies reported a significant increase in scores following the intervention, indicating improved functional performance. Three out of these seven studies and two additional studies employed grip strength, as an additional functional outcome measure. ^{27 –29,32,58} Moreover, the two studies measuring grip strength demonstrated post-intervention improvements when scTS was combined with task-specific training. Notably, one study exclusively assessed and reported positive enhancements in the Capabilities of Upper Extremity Test (CUE-T). ⁵⁹ Further, four studies evaluated lateral pinch strength ^{30 –32,58} and consistently demonstrated significant improvements in both left and right lateral pinch force following training with scTS. In addition, one of these studies reported notable enhancements in tip-to-tip, lateral key, and total prehension ability bilaterally, further highlighting the positive impact of scTS on fine motor control and overall prehensile capabilities following cervical SCI. ⁵⁸

Improvements in other functional outcomes

In addition to GRASSP, Freyvert et al. reported significant improvement in hand function, as evaluated by the Action Research Arm Test, post-intervention. ²⁹ Tefertiller et al. utilized the Nine-Hole Peg Test to quantify finger dexterity and reported improvements in scores for every participant who completed the test. ⁵⁹ Further, García-Alén et al. reported a significant enhancement in the Box and Block Test scores for both the control (scTS) and experimental (robotic + scTS) groups. ⁵⁸

Reduction in spasticity

Two studies investigated the effects of training with scTS on spasticity using the Modified Ashworth Scale (MAS). Inanici et al. reported a notable average decrease in MAS scores of 3.5 for the group, indicating reduced spasticity levels. ³⁰ Similarly, Huang et al. found that the combination of stimulation and buspirone tended to decrease the overall spasticity as measured by the MAS and the visual analog scale, and also reduced the occurrence of spasms, which was assessed by the Penn Spasm Severity/Frequency Scale. ²⁸

Improved motor and sensory function on ASIA assessment

The severity of SCI was evaluated and quantified using the American Spinal Injury Association (ASIA) assessment in all ten conducted studies. Three studies utilized the UE motor score (UEMS). ^27,29,59 Freyvert et al. reported a substantial 7-point improvement (group) in UEMS post-intervention for the group assessed. ²⁹ Gad et al. found that four out of six participants displayed UEMS improvements of 1 or 2 points (either right or left), with only one participant experiencing a notable 4-point increase bilaterally. ²⁷ In the study by Tefertiller et al., four out of seven participants demonstrated significant UEMS enhancements of 5, 7, and 11 points. Interestingly, the remaining three participants, two experienced a decrease in motor score, one reported no change, and two reported a decrease in sensory score after the intervention. ⁵⁹ Four studies utilized the ASIA Impairment Scale to assess both motor and sensory functions. ^28,30,31,59 Inanici et al. reported an improved neurological level of injury from C3 to C4 in one patient following the application of scTS combined with training. ³¹ Further, in their subsequent study, all six participants demonstrated improvements in their overall neurological level of injury and sensation bilaterally after undergoing 4 weeks of UE training with stimulation. ³⁰ Huang et al. found that individuals with limited residual hand motor function who received a combination of buspirone and scTS experienced improved sensory scores for light touch and pinprick, although motor scores did not exhibit significant changes. ²⁸ In a separate study, four out of seven participants who received functional task-specific training for UE in combination with scTS reported improved motor scores. ⁵⁹ These findings highlight the potential for improved motor and sensory outcomes on ISNCSCI-recommended ASIA evaluation when training is combined with spinal cord stimulation. It could be suggested that training alone may be responsible for improvements in motor and sensory outcomes. However, previous studies have not reported significant improvements in hand motor function without stimulation. In addition, patients with chronic SCI typically show minimal to no recovery of motor function. ^64,65 Interestingly, Inanici et al. found that training alone did not improve hand motor function, but after four subsequent weeks of training with stimulation, participants showed improved hand motor function and performance. ^30,31 Similarly, Freyvert et al. demonstrated that a combined approach facilitated the recovery of hand function in patients with chronic SCI, as training alone did not lead to significant improvement in function. ²⁹ Therefore, a combinatorial approach of stimulation with task-specific training can promote substantial recovery of hand function in patients with chronic SCI.

Altered spinal cord network excitability evident from spinal cord-evoked potentials

Four studies examined changes in spinal cord-evoked potentials following training. ^27,31,32,60 Inanici et al. observed a progressive increase in the amplitude of short latency and reemergence of long latency responses, specifically in the right opponens pollicis muscle after the training compared with the baseline. ³¹ Gad et al. reported an increase in spinal-evoked responses in distal arm muscles, while demonstrating a decrease in evoked response amplitude in proximal muscles, such as the biceps brachii, after the intervention. ²⁷ Another case study demonstrated increased spinal-evoked potentials in both proximal and distal muscles, particularly in early and late latency responses following intervention. ³² These neurophysiological findings suggest that scTS combined with training modulates spinal network excitability and allows remodeling of the intersegmental neural pathways responsible for the reemergence of the polysynaptic late responses, potentially leading to functional improvements post-SCI. ^37,66

Improved quality-of-life measures

Regarding the assessment of quality of life, four studies employed the Spinal Cord Independence Measure III questionnaire. These studies reported increases in self-care score by 1 point, ³¹ 4 points for the group, ³⁰ and an overall score improvement of 20 points for the group, ²⁸ and a 3-point increase for the group. ⁵⁸ Further, three studies utilized the World Health Organization-Quality of Life-Brief questionnaire, ^30,31,58 with findings indicating a 1-point increase in social relationships, ⁵⁸ a significant improvement of 19 points in psychological well-being and physical health domain for the group, ³⁰ and a 3-point enhancement in the physical health domain. ⁵⁸ In addition to the aforementioned findings, Inanici et al. also observed improvements in bladder function, assessed as part of the quality-of-life measurement using SF-Quavean. ³¹ Huang et al. also reported enhancements in the Capabilities of Upper Extremity Questionnaire score, providing insights into participants’ functional levels post-intervention. ²⁸ These results underscore the positive impact of the intervention on various aspects of quality of life, including self-care, social relationships, psychological well-being, and bladder function.

Durability of motor outcomes

Four studies assessed the durability of improved motor outcomes after the cessation of intervention to explore the long-term carryover effects of scTS on UE functional recovery. ^28,29,31,32 Among these studies, two included a 3-month post-follow-up period. Inanici et al. reported that the improvements in GRASSP scores and lateral pinch strength were maintained during the follow-up period. ³¹ Freyvert et al. observed sustained improvement in hand grip force for three participants. These improvements in grip strength were accompanied by a significant increase in EMG amplitude in the biceps brachii, wrist flexors, and extensor muscles. ²⁹ Zhang et al. conducted follow-up assessments at three time-points (1, 2, and 3 months post-intervention) for one participant. ³² The functional gains in strength and prehension ability on the right side were maintained compared with the left side. In addition, the gains in hand grip strength were sustained for both the left (11–73% above baseline) and the right hand (233–250% above baseline). The functional task improvements measured using the Neuromuscular Recovery Scale were maintained throughout the 3-month follow-up period. Huang et al. reported that three out of five participants with residual hand force at baseline, maintained improvements in hand function for up to 5 months post-intervention. ²⁸ However, the remaining seven participants did not demonstrate changes in the hand grip force during the follow-up period. These findings highlight the potential for sustained improvements in motor function following scTS combined with task-specific training, but also suggest individual variability in long-term outcomes.

Safety and adverse effects

Studies investigating the neuro-rehabilitative effects of spinal cord stimulation strategies have recognized the significance of documenting and reporting on safety measures. In the studies highlighted in this review, researchers monitored and documented adverse events linked to scTS to the cervical region. Among the nine studies examined, six studies explicitly documented and reported on the safety and adverse effects associated with stimulation. ^{30 –32,58 –60} Notably, in the studies conducted by Inanici et al. in 2018 and 2021, participants tolerated the stimulation well, with anticipated hyperemia occurring under the stimulation site of the neck, which resolved within 5–10 min. Hyperemia or skin redness was the most reported adverse event and was anticipated due to scTS-induced local chemical changes at the skin level during stimulation. No other significant adverse effects related to scTS were observed throughout the training and experiment sessions. ^30,31 Similarly, Zhang et al. and Tefertiller et al. reported no serious unexpected adverse events that impeded participants from continuing with their training. ^32,59 In the study conducted by Garcia-Alen et al., two out of 15 participants reported a worsening of UE spasticity. In addition, one participant experienced a feeling of nausea, while two others reported coughing during stimulation. Notably, two participants also experienced episodes of autonomic dysreflexia during stimulation. To address and mitigate these adverse events, the stimulation intensity was promptly reduced, and continuous follow-up was conducted to monitor emerging symptoms. ⁵⁸ Although the available data on participants who experienced autonomic dysreflexia with stimulation are not comprehensive, it is clear that further details are needed to draw firm conclusions on the association between stimulation and incidences of autonomic dysreflexia. It is also important to identify any history of autonomic dysreflexia, typical signs and symptoms, medication, and how to monitor these symptoms from patients’ medical records to ensure proper care. Therefore, it is important to take appropriate measures when optimizing or intervening by increasing the stimulation intensity. Specifically, caution is warranted while utilizing scTS to ensure that the benefits of the intervention are not outweighed by any potential risks.

scTS alters spinal cord network excitability

Experimental ^18,20 studies and computational models ^68,69 suggest that unmodulated low-frequency (0.2–2 Hz) scTS putatively exerts its effect mostly via activation of posterior root structures. More recent findings, such as (1) reduction in spinal cord-evoked responses during paired-pulse stimulation indicating toward post-activation depression (PAD) (classical hallmark for sensory fiber activation) ⁷⁰ and (2) similar latency and morphology of the spinal cord-evoked responses with unmodulated and modulated scTS indicate that both forms of scTS potentially interact with large-to-medium-diameter sensory fibers located in the dorsal root afferent scTS. ⁷¹ Through sensory afferent connections with segmental motor neurons and interneurons via mono (type Ia), di (type Ib) polysynaptic (type II) pathways, sensory afferent’s repeated stimulation potentially modulates the membrane excitability of these structures. ⁷² Consequently, this altered membrane excitability results in excitation or inhibition of these neural structures. The increased neuronal excitability elevates the spinal cord into an optimal state, allowing weak or residual descending inputs to exert greater and more effective supraspinal control over the sensorimotor spinal network. ^27,31,73,74 Recent findings, such as greater amplitudes of UE spinal-evoked responses and reemergence of long latency polysynaptic responses, support increase in the excitability of the spinal cord network following scTS combined with task-specific training. ^27,31,75

In addition to the facilitatory effects, the inhibitory effect of repeated scTS on the membrane potential, particularly the PAD caused by a transient decrease in neurotransmitter release from Ia sensory terminals, ^18,20 needs further exploration. Decreased neuronal excitability potentially results in improved motor activation by attenuating the deleterious effects of reflex hyperexcitability seen in individuals with SCI. ⁷⁶ It is likely that scTS exerts both excitatory and inhibitory effects in a synchronized manner to allow motor function execution. However, the specific contributions and interactions of these mechanisms in augmenting functional recovery post-SCI remain largely unknown and require further investigation.

scTS alters pre-synaptic inhibition

Motor task execution also relies on the local inhibitory interneurons that shape the response to the diverse excitatory inputs from the supraspinal structures. ⁷⁷ These interneurons have been found to form axo-axonic connections with the sensory afferents, and can regulate the sensory-motor drive via pre-synaptic inhibition through GABAergic action. ⁷⁸ In addition to the sensory afferents, these interneurons are also known to share connections and regulate other neural entities, such as primary major descending pathways and local spinal neural circuitry, likely interacting with the scTS. More importantly, these interneurons hold prime importance in regulating the coordination between the agonist and antagonist muscles. Therefore, reemergence of the coordinated contraction of agonist–antagonist muscles can potentially be due to the altered pre-synaptic inhibition during natural or augmented motor recovery post-SCI. ⁷⁹ Pre-synaptic inhibition of the monosynaptic responses is heavily dysregulated in individuals with SCI due to decreased supraspinal control. ⁸⁰ Therefore, improved activation of inhibitory intraneuronal circuitry potentially plays a crucial role in reducing spinal hyper-reflexibility and improved motor function execution. ⁷⁶ Moreover, improved pre-synaptic inhibition likely restricts the primary afferent transmission to spinal motor neurons and reduces motor neuron inadvertent activation. ⁸¹

scTS alters supraspinal structure excitability

Recent studies involving functional magnetic resonance imaging and electroencephalography recording from the cortical and subcortical regions of neurologically intact individuals during motor performance in the presence of scTS suggest immediate changes in the cortical sensorimotor areas involved in UE motor control. These changes suggest that scTS can likely neuromodulate supraspinal sensorimotor networks and facilitate effective integration of the ascending sensorimotor information at the cortical level. ^82,83 Similarly, following scTS to the cervical region, increased amplitudes of motor-evoked potentials (MEPs) recorded from UE muscles have been reported, indicating improved activation of CST pathways innervating UE. ^84,85 Apart from increasing the cortical activation, scTS is also known to improve the intracortical inhibition required to perform a coordinated motor task. ⁸⁵ The biaxial neuromodulatory changes occurring at the supraspinal and spinal levels allow effective integration of ascending and descending neural information necessary for successful motor task execution. In addition, sensory improvements following scTS application likely indicate that the sensory pathways can be modulated with scTS leading to improved ascending sensory and proprioceptive inputs to the spinal cord, resulting in improved motor task execution. ^28,30,31,86

Remodeling of the spared neural circuitry at the spinal cord level

Remodeling or establishing new neural detours between the supraspinal pathways and the spared neural circuitry below the injury level plays a crucial role in neural recovery following SCI. ^87,88 Such anatomical adaptations enable uninterrupted flow of neural information between the cortex and distal end-organs. ^44,89 In rats and non-human primates with complete or incomplete mid-thoracic SCI, CST axons sprout onto the long PSN, which in turn arborizes over the lumbosacral motor neurons resulting in improved locomotion and CST conduction across the injury site. ^87,90 In addition, recent findings suggest the facilitatory effects of scTS to the cervical region combined with lumbosacral scES on voluntary control of stepping movements in individuals with SCI. ⁹¹ These findings highlight the pivotal role of spared neural structures, especially the PSN, in facilitating the effective reorganization of neural circuitry to bypass the injury site following an SCI. Recent findings from neurologically intact individuals suggest that a long PSN can be a potential target to accelerate the establishment of viable neural pathways to bypass the injury site and can facilitate the neural transmission from the supralesional to sublesional neural circuitry. ^84,92 Moreover, as most cervical SCIs occur around C5 spinal level, the short PSN can be potentially neuromodulated to establish detours between the upper (C3-C4) and lower cervical (C7-T1) spinal cord to bypass the injury site and enable uninterrupted flow of neural information between the cortex and UE muscles.

Increased benefits combining scTS with task-specific training

Pre-clinical and clinical studies suggest that the combination of spinal cord stimulation and task-specific training results in greater activity-dependent neuroplastic changes for motor recovery post-SCI. ⁹³ Indeed, in individuals with cervical SCI, greater changes in the UE motor function are observed when scTS is added to the task-specific training plan. ^{29 –31} Most likely, scTS combined with task-specific training potentially strengthens or accelerates the rate of establishment of the abovementioned neurophysiological or neuromodulatory changes resulting in UE functional recovery post-cervical SCI. ^94,95

Stimulation site selection, optimization, and progression with training

Identifying the optimal number of stimulation sites and their locations is crucial in achieving effective targeting of the sensorimotor neuronal pool and resulting motor outcomes. ^21,96,97 Future studies should provide a comprehensive rationale for the selection of stimulation site(s). The selection of the number of stimulation sites should consider factors such as target neural pathways, desired motor response, and individual patient characteristics. A thorough understanding of the underlying neural circuitry and its functional relevance to the motor outcome is crucial in guiding the decision-making process. In addition, future studies should employ rigorous methodologies and comparative analyses to evaluate the effectiveness of different stimulation site configurations, including frequency and pulse-width. By addressing these criteria and providing a rationale for selecting the appropriate number of stimulation sites, future research can further enhance our understanding of the optimal strategies for achieving positive motor outcomes. The studies highlighted in this review elucidate the application of rectangular currents, either in biphasic or monophasic configurations. The preference for these distinct waveforms stems from the understanding that biphasic waveform exhibits heightened tolerance to stimulation intensity due to its limited electrochemical polarization effect. Consequently, this characteristic permits the administration of higher current intensities with reduced discomfort, a benefit over monophasic waveform. ⁹⁸ Nonetheless, there are limited studies investigating and comparing the effects of various waveforms on motor responses, and long-term safety and efficacy profiles are needed. Future studies should explore these parameters to improve waveform selection criteria for interventions targeted to improve UE motor function. Moreover, Sharma et al. demonstrated greater activation of UE muscles with anode over the clavicles compared with the iliac crest. ⁶⁶ Future studies targeting UE motor recovery can potentially utilize similar cathode–anode electrode configurations.

The majority of studies highlighted in this review utilized subjective criteria to identify the optimal stimulation intensity during training. Researchers reported adjusting stimulation intensities based on subjective feedback from participants while performing selected motor tasks. Although easy to implement and user-friendly in nature, the absence of objective criteria for intensity selection poses a challenge for replicating the study in other research setup and clinical facilities, hence affecting clinical translation. Objective criteria are necessary to ensure standardization and could include factors such as muscle activation thresholds, sensory perception, tolerance, and/or motor performance measures. By incorporating objective measures, researchers and clinicians can establish clear guidelines for adjusting stimulation intensity based on the specific training tasks and observed motor improvements. As participants make progress in their training, it is essential to regularly re-assess and fine-tune the stimulation intensity and dosage. This adjustment should be based on both the training task requirements and the individual’s demonstrated motor improvements. This dynamic approach to intensity modulation allows for ongoing optimization and personalized treatment plans. To bridge this gap, future studies should focus on addressing these concerns by highlighting and providing objective criteria for the optimization and progression of stimulation intensity during training. Addressing these important factors will contribute to the refinement of neurotherapeutic interventions and ultimately improve the efficacy and precision of motor rehabilitation approaches.

Modulated versus unmodulated scTS

Unlike epidural stimulation, which is positioned closer to the target neural structure and involves lower stimulation intensities (2.5–20 mA), ^8,13 scTS involves the delivery of relatively high-intensity stimulation (30–200 mA) via self-adhesive electrodes placed directly over the skin. ⁹⁹ scTS readily activates cutaneous sensory fibers due to their lower activation thresholds and can result in unwanted sensations, such as tingling, burning, pain, and intense discomfort. More importantly, given that the average duration of scTS session can range between 30 and 120 min, ^31,32 such discomfort can adversely affect the motor training execution and progression. To suppress sensory hyperactivation and to achieve greater stimulation intensities, modulated scTS is often utilized, involving stimulation pulses wrapped within 5–10 kHz carrier frequency, also known as Russian currents. ¹⁰⁰ In neurologically intact individuals, modulated scTS at 5 kHz modulation allows stimulation delivery at 103 mA with no pain, while unmodulated scTS has a maximal tolerable amplitude of 39 mA. ⁷¹ Recent evidence suggests that at motor threshold levels, 10 kHz-modulated monophasic scTS requires more charge to evoke similar amplitude spinal cord responses compared with an unmodulated monophasic pulse. ⁷⁰ The available scientific evidence is drawn from studies involving neurologically intact individuals. As pain and altered sensations are commonly reported by individuals with SCI, ¹⁰¹ the findings may not be directly generalized to this population.

Cervical–lumbar coupled stimulation for UE recovery

Delivering scTS to the lumbar spinal cord is likely to neuromodulate the cervical spinal cord due to long PSNs between the cervical and lumbar spinal cord, and likely holds potential in facilitating UE recovery post-cervical SCI. ^45,75,96 Moreover, the neuromodulatory effects on the cervical cord might be more pronounced when scTS is delivered to the cervical and lumbar spinal cord simultaneously. Indeed, in healthy adults, simultaneous application of scTS to the cervical and lumbar region is known to facilitate the amplitude of the H-reflex in flexor carpi radials by 19.6% compared with scTS to the lumbar region alone that results in an 11.1% increase. In addition, simultaneous delivery of scTS to the cervical and lumbar region facilitates the amplitude of flexor carpi radials MEP compared with cervical or lumbar stimulation alone resulting in no change. ^73,84 More importantly, the neuro-rehabilitative effects of this reciprocal organization between the cervical and lumbar spinal cord might be more pronounced post-SCI as pre-clinical studies suggest that PSN are known to establish more viable and effective connections resulting in motor recovery following an SCI. ^45,87 Along the line, recent findings from our group demonstrated immediate improvements in the hand grip and wrist extension strength in the presence of scTS to the thoracolumbar and cervical region in the pediatric population with SCI. ¹⁰² Similar immediate improvements in the activation of the extensor carpi radialis muscle during wrist extension while delivering scTS to the lumbar spinal cord have been demonstrated in adults with complete cervical SCI. ⁶⁰

In addition to the neurofacilitatory effects of scTS to the lumbar region on the cervical spinal cord, the neuromotor control exerted by scTS to the lumbar region on the trunk stability and upright sitting cannot be underweighted as optimal trunk control and upright posture are an essential substrate for the successful execution of the UE motor tasks. ^{103 –105} Recent findings suggest that scTS targeting the lumbar spinal cord along with repeated motor training is effective in enabling trunk stability by improving trunk muscle activation and limits of stability. ^25,26,106 Therefore, therapeutic interventions incorporating cervical and lumbar cord-coupled stimulation could further potentiate the neurofacilitatory effects of scTS targeting cervical cord alone. Moreover, additional multi-modal or paired stimulation strategies, such as lateral electrode placement compared with the midline placement for greater UE muscle activation, ¹⁸ using closed-loop stimulation, ^107,108 paired cortex and spinal cord stimulation, ^109,110 and employing robot-guided motor rehabilitation strategies along with scTS to the cervical region, ⁵⁸ are other emerging avenues that can be further explored to expand the therapeutic effectiveness of scTS in facilitating UE recovery post-cervical SCI.

Selection of intervention

Studies investigating motor function recovery in individuals with SCI have emphasized the importance of high-intensity rehabilitation protocols. ^13,55 ABRT, particularly locomotor training, in combination with stimulation, has demonstrated its effectiveness in improving and restoring ambulation in individuals with SCI. ¹¹¹ As the majority of research focused on recovering locomotion following an SCI, principles governing activity-based locomotor training have been well developed. In contrast, similar training principles for UE recovery have attracted limited attention. Moreover, the complexity of UE neural control, multiple joints with varying degrees of freedom, a wide range of motor tasks performed by UE, and the need to address the diverse motor skills learned before the injury, makes it even more challenging. Studies examined in this review employed diverse training protocols, including stretching, assisted range of motion exercises, overhead press, hand grip strength tasks, fine motor skills practice, and bimanual task performance. ^{27 –32,58,59} However, unlike lower limb training protocols, these interventions lack standardized principles based on neuroplasticity and recovery. ¹¹² Therefore, future studies should prioritize the standardization of training protocols, incorporating the use of standardized objects to facilitate grip and fine motor task training. These standardized protocols will serve as valuable guidance for research trials investigating the efficacy of activity-based training, with or without stimulation, in individuals with SCI.

Patient selection and role of lower motor neuron injury in UE motor recovery

In addition to the major descending tract damage, such as the CST, commonly referred as upper motor neurons, SCI may also damage the lower motor neuron structures, such as motor neurons and spinal nerve. ¹⁰¹ A few longitudinal studies also demonstrate progressive death or degeneration of motor neurons around the lesion epicenter in chronic SCI. ^113,114 In addition, cross-sectional studies have reported signs and symptoms related to lower motor neuron (LMN) dysfunction, such as muscle weakness and atrophy, in humans with SCI at and below the injury site. ^115,116 Theoretically, without structurally intact LMNs at or below the injury site, spared long-axons motor tracts face significant challenges in establishing a functional neural pathway or detour to exert volitional motor control. ^44,89,117 Indeed, newer evidence suggests limited motor recovery in individuals with associated LMN lesions following an SCI. ¹¹⁸ Provided that the scTS exerts its therapeutic effectiveness by increasing spinal network excitability via medium- to large-diameter sensory afferents, ¹⁹ damage of the spinal nerves and motor neurons might pose a greater challenge in facilitating motor and sensory recovery post-SCI. Overall, it becomes crucially important to investigate the intrinsic factors, such as LMN injury or extensiveness of the injury, and their potential role in dictating functional recovery to comprehensively understand the neurofacilitatory capacity of scTS to the cervical region in facilitating UE recovery post-cervical SCI.

Long-term safety implications

Adequate documentation and reporting the presence or absence of adverse effects are crucial in establishing the clinical safety and feasibility of the neurotherapeutic approach. In the case of scTS, it is imperative for future studies to address the long-term safety of applying scTS over skin and other physiological systems. Several studies have reported adverse effects such as skin irritation, hyperemia, increased spasticity, and in rare instances, autonomic dysreflexia. ^30,31,58 To ensure the widespread therapeutic potential of scTS, it is essential that studies involving long-term stimulation at the same location thoroughly address and report the long-term safety implications of this technology. This includes assessing any potential risk or complication that may arise from prolonged exposure to stimulation at specific sites. Long-term safety assessments should encompass extended follow-up periods and rigorous monitoring of participants to identify any delayed or cumulative effects that may emerge over time. In addition, future studies should explore strategies to mitigate adverse events and optimize the safety profile of scTS. By addressing the long-term safety considerations associated with scTS, future studies can provide a comprehensive understanding of the technology’s safety profile and facilitate its effective and responsible implementation in clinical settings. This will enhance patient care and contribute to the advancements of scTS as an accessible and accepted neuro-rehabilitative intervention.

Extending therapeutic effectiveness beyond research

Most individuals following cervical SCI first resort to conventional motor rehabilitation strategies that include physical and occupational therapy targeting recovery of lost UE function. Conventional motor rehabilitation aims to facilitate the appropriate afferent inputs to the intact spinal cord to promote activity-dependent plasticity and facilitate motor recovery. ^94,119 Although effective in enhancing hand function in people with tetraplegia, ^120,121 the therapeutic effects are slow and functional regains remain limited. ^30,53 Although limited in number, the discussed published work provides initial indications of scTS to the cervical region as a viable neuromodulatory tool that can be utilized by physicians, physical therapists, and occupational therapists targeting arm and hand function recovery post-cervical SCI. However, several aspects, such as optimal scTS parameters, motor rehabilitation strategies, outcome measures, and therapeutic potential, need to be explored in detail for effective clinical translation. Moreover, given the complexity of cervical SCIs, heterogeneity in the patient population, and recruitment challenges associated with SCI, a well-designed multi-central clinical trial is a demand of the time to gather scientifically grounded evidence to allow successful translation of this promising therapeutic tool from research setup to clinical settings. In addition, the non-invasive nature of scTS and easy-to-use feature make it a suitable neuromodulation device that can accelerate its translation to clinical practice for recovering UE function post-SCI.

Extending therapeutic benefits beyond SCI

Similar to SCI, other neurological diseases, such as stroke, cerebral palsy, multiple sclerosis, peripheral nerve injury, and spinal muscle atrophy, disrupt the normal functioning of major descending tracts (CST, Reticulospinal tract, RuST), and other neural structures along the brain–spinal cord axis. ³⁵ This in turn severely affects the optimal integration of the ascending and descending information required for successful execution of motor functions. Given that sensory afferents in the posterior root structures activated via scTS establish direct or indirect connections with different neural entities along the brain–spinal cord axis, scTS can be used to induce optimal neuromodulatory changes to facilitate motor recovery following the abovementioned neurological diseases. Most likely, scTS improves the activation threshold of the neural structures interacting with scTS, such as motor neurons, interneurons, and motor axons, to a level that allows weak or residual descending pathways projecting to the spinal cord to activate them. ^27,73 Indeed, newer studies provide compelling evidence of scTS therapeutic effectiveness in cerebral palsy, ^122,123 spinal muscle atrophy, ¹²⁴ stroke, ¹²⁵ multiple sclerosis, ^126,127 and peripheral nerve injury. ¹²⁸ The more the populations in which scTS is demonstrated to be therapeutically effective, the more attention and funding it will draw resulting in evidence-based outcomes, ultimately leading to a better and wider acceptance of scTS in clinical settings.