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. Author manuscript; available in PMC: 2026 May 6.
Published in final edited form as: Curr Opin Neurol. 2025 Oct 3;38(6):654–659. doi: 10.1097/WCO.0000000000001431

Electrical and optogenetic spinal cord stimulation for movement recovery after spinal cord injury

Richard P Henderson 1,2, Sarah E Mondello 1,3, Chet T Moritz 1,2,3,4
PMCID: PMC13142174  NIHMSID: NIHMS2165230  PMID: 41069191

Abstract

Purpose of review

In this review, we discuss electrical and optogenetic technologies for stimulating the spinal cord to improve movement after spinal cord injury (SCI).

Recent findings

Paralysis or paresis following spinal cord injury severely impairs control and movement of the extremities. Restoring movement in the upper and lower extremities is a top priority for this population. Invasive and non-invasive electrical stimulation of the spinal cord can modulate the activity of spinal circuits, resulting in improvements in motor and sensory function. More recently, optogenetic stimulation has emerged as another technique capable of modulating spinal circuity to facilitate movement recovery in animal models. Recent studies are offering new insights into the effects of parameter selection, multisite stimulation, and the combined effects of stimulation and wearable robotic exoskeletons, all with the goal of restoring movement after SCI.

Summary

Modulating the activity of the spinal cord via electrical and optogenetic stimulation is a promising intervention for improving movement after spinal cord injury. Future studies should determine optimal stimulation parameters, synergistic effects when combined with wearable robotics, and the safety of optogenetics in the human spinal cord. Such work will best position these emerging technologies for clinical translation.

Keywords: electrical stimulation, optogenetic stimulation, paralysis, motor function, spinal cord injury

INTRODUCTION

Paralysis after spinal cord injury (SCI) is defined as the complete absence of muscle activity. More common after SCI is paresis, or incomplete paralysis, which is characterized by severe muscle weakness and significant loss of volitional movement. After SCI, the majority of individuals retain some muscle activity below their injury [1] indicating the partial sparing of motor pathways. These spared pathways may be subsequently targeted using neural stimulation to improve movement.

Guided by the principles of experience-dependent neuroplasticity [2], rehabilitation for motor recovery after SCI has focused on task-specific, activity-based therapies such as locomotor training [3]. This focus on intensive and task-specific activities has facilitated motor recovery in areas such as walking for people with incomplete SCI [4]. Reports from the SCI community, however, indicate that exercise-based interventions alone are not achieving levels of motor recovery that significantly improve quality of life [5]. In response, neuromodulatory technologies, such as electrical stimulation, are used to enhance the effectiveness of exercise-based interventions.

Electrical spinal cord stimulation, delivered invasively or non-invasively, modulates the activity of spinal circuits primarily through the depolarization of sensory axons in posterior spinal roots (Fig. 1) [6, 7**]. Invasive stimulation through a surgically placed epidural paddle electrode, referred to as epidural spinal cord stimulation, is commonly used to treat chronic pain [8]. Early animal experiments demonstrated that epidural stimulation facilitates rhythmic stepping even in the absence of supraspinal input [9].

FIGURE 1.

FIGURE 1.

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Electrical and optogenetic spinal cord stimulation for improving movement after spinal cord injury. Optogenetic and epidural spinal cord stimulation are delivered through implants surgically positioned dorsal or posterior to the spinal cord, and outside the protective dura mater. Transcutaneous spinal cord stimulation is delivered through electrodes placed on the skin surface over the posterior spinal cord.

Epidural spinal cord stimulation has advanced to improving movement after SCI in studies of both animals [10] and humans [11, 12]. Non-invasive stimulation, referred to as transcutaneous spinal cord stimulation, delivers electrical stimulation through electrodes on the skin, and has improved movement in humans after SCI in both the upper [13,14*,15] and lower extremities [16].

While electrical spinal cord stimulation has shown early successes, optogenetic stimulation is emerging as another promising strategy for movement restoration after SCI (Fig. 1). Optogenetic stimulation is a research tool and potential therapeutic approach that involves genetically altering cells to express light-sensitive ion channels, which can then be activated by light [17]. Similar to electrical spinal cord stimulation, optogenetic stimulation can modulate the activity of spinal circuits [18, 19]. Unlike electrical stimulation, however, optogenetic stimulation can alter the activity of specific cell-types [17, 20]. Early preclinical SCI studies report encouraging outcomes using optogenetic spinal cord stimulation for movement recovery [21].

Recent reviews summarize the use of spinal cord stimulation in SCI to improve motor function [22, 23] and modulate neurophysiology [7**, 24**, 25]. In this review, we will discuss parameter selection and optimization for epidural and transcutaneous spinal cord stimulation. In addition, we review the potential benefits of multisite stimulation and electrical stimulation combined with wearable robotic exoskeletons. Lastly, we summarize the state-of-the-art for optogenetic spinal cord stimulation for improving motor recovery after SCI, as well as next steps and future challenges to implementing this technology in humans.

PARAMETER SELECTION FOR ELECTRICAL STIMULATION

An important area of epidural and transcutaneous spinal cord stimulation research is the identification of optimal parameters for the treatment of motor impairments after SCI. Although a broad range of values are reported in the literature [26, 27], the specific parameters used to achieved favorable motor outcomes provide insight into potentially effective stimulation settings. For example, pulse frequencies between 20 – 50 Hz are commonly used in both epidural and transcutaneous spinal cord stimulation to improve walking [12, 16, 28], and upper limb function [11, 13,14*,15, 29]. While the frequencies are similar, a key difference between epidural and transcutaneous stimulation is the current intensity or stimulation amplitude. Transcutaneous stimulation requires higher stimulation current intensities to penetrate the skin and subcutaneous tissues and activate the spinal cord posterior roots [6]. In both stimulation approaches, however, the current used in facilitating motor recovery is commonly set between the sensory and motor thresholds, so as to not interfere with movement performance [13, 14*, 16, 29, 30*]. Importantly, both epidural and transcutaneous stimulation can lead to long-term improvement in movement recovery that persisted beyond stimulation [13, 16, 31].

Given the variability in motor impairments after SCI across individuals, it is unlikely that a single set of stimulation parameters will be optimal for all individuals. Instead, the detailed reporting of parameters used to target specific impairments for different SCI populations will improve the effectiveness of spinal cord stimulation. Initial guidelines attempt to standardize the reporting of the hardware, electrode configuration, parameters, and dosage used during spinal cord stimulation [32*]. As an example, a detailed description of the electrode configurations and stimulation parameters was published following the completion of a multisite clinical trial using transcutaneous spinal cord stimulation to improve arm and hand function in chronic SCI [30*]. Efforts such as these can facilitate our understanding of the effects associated with specific stimulation parameters and inform clinical use of spinal stimulation.

Parallel to increased transparency when reporting stimulation parameters, efforts are also underway to identify therapeutic stimulation parameters specific to the targeted motor impairment or rehabilitation activity. For example, stimulation frequencies around 30 Hz are reported to facilitate rhythmic stepping movements after SCI [33]. Using spinal stimulation amplitudes near the motor threshold with pulse frequencies between 25 – 60 Hz has been reported as effective for facilitating standing in the SCI population [34]. Alternatively, spinal cord stimulation can also reduce unwanted muscle activity such as spasticity, spasms, or hypertonia. In this case, higher stimulation frequencies are used, such as 50 Hz for transcutaneous spinal cord stimulation [35], and 1.2 kHz for epidural spinal cord stimulation [36**].

An important parameter when using transcutaneous spinal cord stimulation is the carrier frequency. Typically in the range of 5 – 10 kHz, this high-frequency waveform is thought to increase the pain threshold and therefore lower pain perception while receiving electrical stimulation [37]. In agreement with this hypothesis, transcutaneous spinal cord stimulation with a carrier frequency has permitted the use of high stimulation intensities with low levels of discomfort [13, 14*, 16, 38]. However, threshold testing with single pulses has shown that modulating pulses with a carrier frequency requires increased stimulation amplitudes to evoke a sensory or motor response, potentially offsetting the increase in user comfort [39, 40]. Comparing continuous stimulation with and without a carrier frequency led to contradictory results: one study reported a decrease in corticospinal excitability [41], while a second study found heighten excitability [42]. Importantly, use of a 5 kHz carrier frequency led to greater short-term improvements in arm and hand function in people with SCI compared to stimulation without a carrier frequency [41]. Similarly, a 10 kHz carrier frequency was used in the multi-site clinical trial that demonstrated safety and efficacy in improving hand strength and sensation [14*].

In summary, optimizing spinal cord stimulation parameters remains challenging given the large parameter space and heterogeneity of individuals and motor impairments. Recently, however, the use of effective stimulation parameters led to the FDA approval of transcutaneous spinal cord stimulation for hand impairments following SCI [14*]. Ongoing efforts are comparing the effects of different stimulation parameters on specific motor impairments to expand the indications for use.

MULTISITE ELECTRICAL SPINAL CORD STIMULATION

Multisite electrical spinal cord stimulation involves simultaneously stimulating two or more locations of the spinal cord. The implants used for epidural spinal cord stimulation contain tens of electrode contacts and permit stimulation of distinct spinal segments. Different electrode combinations can further be combined sequentially to produce individual limb movements. For example, patterned stimulation of the lumbosacral spinal cord via epidural spinal cord stimulation can improve walking by generating muscle activity and lower limb movement in a spatiotemporal sequence specific to each gait phase [12, 33].

While epidural spinal cord stimulation can target different spinal segments within the same region, epidural combined with transcutaneous spinal cord stimulation can simultaneously stimulate distant spinal regions. For example, combining cervical transcutaneous stimulation with lumbosacral epidural stimulation led to improved lower limb and muscle coordination during walking in motor complete SCI, compared to epidural stimulation alone [28]. After SCI, increases in volitional muscle activity have been observed in both the upper [43] and lower extremities [44] using multisite transcutaneous spinal cord stimulation. Additionally, some changes in motor function can persist after long-term intervention with multisite transcutaneous spinal cord stimulation, such as increases in walking distance [16], as well as improved arm and hand function [38]. Neither treatment study, however, directly compared multisite to single-site spinal cord stimulation.

In summary, multisite electrical spinal cord stimulation may modulate spinal networks critical for movement in a more robust and coordinated manner than single-site stimulation. Future studies should directly compare stimulation at a single site versus multiple sites, and capture the long-term effects on movement recovery after SCI.

COMBINING ELECTRICAL SPINAL CORD STIMULATION WITH WEARABLE ROBOTIC EXOSKELETONS

Wearable robotic exoskeletons have potential for improving activity-based rehabilitation after SCI. The external support provided by an exoskeleton is adaptable, can provide real-time feedback regarding kinematics and assistance levels, and allows the user to achieve a high number of repetitions with less physical strain on the clinicians. Despite this potential, the evidence remains unclear for the benefit of wearable robotic exoskeletons compared to conventional activity-based therapies for motor recovery after SCI [45, 46]. Lack of exercise intensity, active engagement of the user, and availability of a companion may be factors limiting the effectiveness of robotic exoskeletons [4, 47].

To address some of the limitations of wearable robotic exoskeletons, epidural and transcutaneous spinal cord stimulation may be used to increase volitional muscle activity during exoskeleton training. Electrical spinal cord stimulation is hypothesized to transform spinal circuits into a state of heightened responsiveness, enabling weak supraspinal inputs to produce more robust and coordinated motor output [15]. Indeed, studies show that electrical spinal cord stimulation can reduce external exoskeleton assistance [48] and lead to greater improvements in walking distance and lower extremity strength compared to training with robotic exoskeletons alone [49]. In the upper extremities, combining transcutaneous spinal cord stimulation with robotic exoskeletons led to increased strength and prehension compared to training alone [50]. Additionally, feedback from robotic sensors has been used to measure changes in joint torque in response to amplitude increases during cervical transcutaneous spinal cord stimulation, highlighting an additional benefit when combining these two technologies [51*].

In summary, combining electrical spinal cord stimulation with wearable robotic exoskeletons is a hybrid approach that may facilitate volitional engagement while permitting adjustable assistance and a high volume of task-specific repetitions. Future studies should seek to maximize the synergistic effects of this combined approach and better understand the long-term changes in motor function that persist after treatment with the combination of each technology.

OPTOGENETIC SPINAL CORD STIMULATION

Optogenetic stimulation is in the early stages of its investigation as a possible SCI therapeutic. This mode of neuromodulation uniquely provides a targeted approach to selectively excite or inhibit specific neuronal or glial subtypes to understand their role in different processes and behaviors. One of the first studies investigating its therapeutic potential determined that optogenetic stimulation of the cervical spinal cord led to the restoration of respiration following an acute high cervical (C2) SCI in rodents [52].

Subsequent studies in rodents found that neuron-specific optogenetic stimulation could also evoke forelimb movements [18] and facilitate robust recovery of forelimb function after incomplete cervical SCI [21].

Optogenetic spinal cord stimulation of neuron-specific populations may promote even more robust movement recovery after SCI, although which cell types to target remains unknown. Understanding the functional outcomes of optogenetic stimulation targeting glutamatergic, glycinergic, or gabaergic neurons will be valuable for determining the roles of excitatory and inhibitory transmission in SCI. Previously, the v2a interneurons were identified as uniquely supportive of motor recovery after SCI and could be a potential target for stimulation [53]. The unique characteristics of optogenetic stimulation make it a potentially transformative neuromodulatory technique that could both robustly improve motor function in individuals with SCI and answer foundational questions regarding the roles of specific cell populations in supporting movement recovery.

Translating optogenetic spinal cord stimulation from animal models to the clinic will require safety and efficacy studies of intraspinally delivered adeno-associated viral (AAV) vectors and light-producing implants. There are clinical trials underway, however, using optogenetic stimulation to treat blindness due to retinitis pigmentosa. These trials incorporate AAV injections into the eye and optogenetically stimulate the eyes with either specialized glasses or ambient light [54]. Recently, it was reported that a patient receiving optogenetic stimulation had recovered some vision capabilities with minimal side-effects [55], validating both the clinical safety and efficacy of optogenetic stimulation. Further, delivery of the AAV viral vector is now used in numerous clinical studies to treat a variety of genetic and cardiovascular conditions with minimal side-effects. Such findings highlight the probable safety of optogenetic viral vector administration and the promise of moving optogenetic spinal cord stimulation toward clinical translation for SCI.

CONCLUSION

While there is currently no cure for paralysis after spinal cord injury, emerging therapeutics are beginning to demonstrate success in partially restoring movement. To date, the combination of task-specific rehabilitation with electrical or optogenetic stimulation of the spinal circuits appears particularly promising for facilitating movement recovery. To further facilitate recovery, approaches are needed to tailor spinal cord stimulation delivery to each individual. An optimal set of stimulation parameters and locations should be identified for each group of motor impairments and injury severity to enhance the task-specific effects of rehabilitation training. Additionally, combining spinal cord stimulation with wearable robotic exoskeletons is a promising approach that could lead to greater movement recovery compared to either intervention alone. Recent progress gives reason to be optimistic about electrical and optogenetic stimulation improving volitional control of movement after spinal cord injury.

KEY POINTS.

  • Electrical and optogenetic spinal cord stimulation are two neuromodulatory technologies that show promise for facilitating movement recovery after spinal cord injury.

  • Optimizing stimulation sites and parameters, as well as exploring the benefits of combining stimulation with wearable robotics, are important research efforts for enhancing the therapeutic potential of epidural and transcutaneous spinal cord stimulation.

  • Scaling up optogenetic spinal cord stimulation and continuing to investigate its efficacy and safety profile are critical steps before translating this technology to humans with spinal cord injury.

Acknowledgments

We thank Dr. Soshi Samejima for his support during the writing of this review.

Financial support and sponsorship

This work was supported by NIH/NINDS (R01NS115025), NIH/NINDS (R01NS134713), Craig H. Neilsen Foundation (732676), Mission Yogurt and the Wings for Life Foundation.

Footnotes

Conflicts of interests

CTM serves on the SpineX advisory board and is a paid consultant for Onward Medical.

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