At the Villa Beretta Rehabilitation Research Innovation Institute, the clinical application of Transcutaneous Spinal Cord Stimulation (tSCS) is being expanded. This electroceutical technology modulates spinal circuits and offers new perspectives for sensory-motor and autonomic rehabilitation. Early results are satisfactory in terms of patient compliance and the induction of clinically and functionally meaningful responses that merit further investigation. Additional research is necessary to clarify its neurobiological mechanisms and explore potential applications throughout the entire continuum of care
At the Villa Beretta Rehabilitation Research Innovation Institute, the clinical application of Transcutaneous Spinal Cord Stimulation (tSCS) is being expanded using two devices: Aneuvo and Onward. tSCS is one of the latest advancements in electroceuticals, meaning the use of electrical currents to neuromodulate neural circuits. By placing electrodes on the skin along the spinal column, electrical impulses are delivered to reset spinal circuits.
Neurobiological mechanisms
tSCS primarily acts by activating large-diameter afferent fibers (Aβ and proprioceptive Ia fibers) in the dorsal roots of the spinal cord. These afferent signals propagate along two main pathways: ascending through the posterior columns to supraspinal centers—such as the brainstem, thalamus, and sensorimotor cortex—where they modulate corticospinal excitability and lower the activation threshold of descending motor pathways; and intraspinally, engaging specific interneuronal populations, including Ia inhibitory interneurons, Renshaw cells, and propriospinal neurons, which form the integrative architecture of spinal motor control.
Through this dual action, tSCS normalizes interneuronal function by reducing pathological noise, excessive signal amplification, and defective inhibition characteristic of the post-lesional spinal state. At the neurobiological level, repeated tSCS sessions are associated with the upregulation of the KCC2 cotransporter, which restores the physiological hyperpolarizing effect of GABAergic transmission—one of the key mechanisms underlying spasticity reduction and the metaplastic reorganization of spinal circuits.
Electrical current is delivered by modulating specific parameters—pulse duration, frequency, and amplitude—to elicit responses involving motor, sensory, pain-related, and autonomic functions. Through neuromodulation of the autonomic nervous system, benefits are observed in voluntary control of the bladder and bowel, as well as in the reflex activity of their musculature.
What we have observed so far
Early clinical experience is promising: patients show good compliance and exhibit clinically and functionally significant responses that merit further systematic investigation. Patients report improved motor control, with movements becoming smoother and more effortless. The effects of tSCS extend beyond the stimulation session, lasting for several hours afterward, although there is considerable interindividual variability. Repeated sessions tend to prolong and consolidate these effects over time.
Future scenarios
Transcutaneous Spinal Cord Stimulation is an extremely powerful tool that unlocks therapeutic possibilities previously unexplored. Its intrinsic efficacy and broad applicability span the entire spectrum of patient care—from the early sub-acute phase, as soon as one month after spinal cord injury, to the chronic phase, where it serves as a valuable and practical treatment option.
A particularly significant aspect of tSCS lies in its ability to support truly multimodal treatment strategies. When integrated with robotics, task-specific training, and other neuromodulatory approaches, tSCS becomes a powerful tool for inducing lasting neurobiological changes through mechanisms related to nervous system metaplasticity—that is, the ability of the nervous system to modify its own potential for plasticity over time, altering the threshold and direction of synaptic and circuit-level reorganization.
This neuromodulation approach requires further scientific investigation to better understand its effects not only at the neurophysiological level but also at the neurobiological level. Can tSCS induce anti-inflammatory or anti-neuroinflammatory processes? This is one of the key questions that must be addressed. Another crucial aspect concerns its potential to facilitate neurotransmitter release and restore synaptic function, both of which are essential for improving motor function.
The translational potential of tSCS extends beyond spinal cord injuries, with possible applications in neurodegenerative diseases, neuroinflammatory conditions, and brain injuries. A significant scientific reference in this context is the work of Marco Capogrosso, Director of the Spinal Cord Stimulation Laboratory at the University of Pittsburgh, who employed cervical epidural stimulation via implanted electrodes—a more invasive approach distinct from tSCS—to support upper limb recovery in patients after stroke. In this setting, spinal stimulation contributed to remodulating cortical areas no longer under effective corticospinal control, fostering a more favorable interaction between supraspinal and spinal systems and facilitating motor recovery. Although epidural and transcutaneous spinal stimulation differ substantially in spatial selectivity, current delivery, and clinical accessibility, Capogrosso’s findings provide an important neurophysiological framework: they demonstrate that modulating spinal circuits can amplify residual descending drive and promote motor reorganization after brain injury—a principle that tSCS, through its non-invasive mechanism, aims to translate into broader and more accessible clinical practice.
tSCS opens further scenarios for combined use with robotics, targeting both upper limb recovery and gait improvement. In this context, it is crucial to identify specific stimulation targets within the spinal cord at both cervical and lumbar levels, tailored to the patient’s clinical condition.
It is important to recognize that each certified device available on the market requires precise identification of its electroceutical potential. Variations in electrode types, current modalities, and current regulation make each device a unique electroceutical tool that is not interchangeable with others.
As part of electroceutical neuromodulation, tSCS must be integrated into the broader rehabilitation pathway, aligned with the patient’s clinical condition and the temporal progression of their recovery. The potential to extend treatment to the home setting supports the development of a true continuum of care but requires careful planning and genuine multimodal integration of therapies—with the shared goal of inducing durable biological modifications through metaplastic mechanisms of the nervous system.
Collaboration within the rehabilitation team is essential. In this context, the bioengineer plays a key role by contributing a precise and scientifically grounded approach to rehabilitation treatment.
References and Scientific Background
Harkema S et al.
Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study.
Lancet, 2011; 377:1938–1947
This landmark case study established that epidural electrical stimulation of the lumbosacral spinal cord can restore voluntary movement, standing, and stepping in a patient with clinically complete motor paraplegia. By demonstrating that spinal circuits below the lesion retain residual functional capacity when appropriately activated, the study provided the foundational neurophysiological framework upon which all subsequent spinal cord stimulation approaches — including tSCS — are built. The concept of resetting interneuronal networks and engaging central pattern generators through electrical input is directly derived from the principles validated in this work.
Powell MP et al. (Capogrosso M, co-senior author)
Epidural stimulation of the cervical spinal cord for post-stroke upper-limb paresis.
Nature Medicine, 2023; 29(3):689–699
This first-in-human study demonstrated that targeted cervical epidural stimulation via implanted leads can immediately improve arm and hand strength, kinematics, and functional performance in two patients with chronic post-stroke hemiparesis. Crucially, some improvements persisted after stimulation was switched off, suggesting restorative as well as assistive mechanisms. Although the approach is invasive and methodologically distinct from tSCS, the neurophysiological principle is directly relevant: modulating intact spinal circuits below a supraspinal lesion can amplify residual corticospinal drive and promote motor reorganization. This work provides a high-impact scientific rationale for applying the same principle non-invasively through tSCS in brain injury rehabilitation.
Moritz C, Field-Fote EC, Tefertiller C et al.
Non-invasive spinal cord electrical stimulation for arm and hand function in chronic tetraplegia: a safety and efficacy trial (Up-LIFT).
Nature Medicine, 2024; 30(5):1276–1283
This prospective multicenter pivotal trial — involving 65 participants with chronic cervical spinal cord injury — evaluated the safety and efficacy of non-invasive transcutaneous cervical spinal cord stimulation (ARC-EX Therapy, ONWARD Medical) combined with structured rehabilitation. Seventy-two percent of participants met the primary effectiveness endpoint, showing meaningful improvements in both upper limb strength and functional performance compared to rehabilitation alone. The trial led directly to the first FDA authorization of a non-invasive tSCS system for spinal cord injury.
Boulenguez P et al.
Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury.
Nature Medicine, 2010; 16:302–307
This study identified a critical neurobiological mechanism underlying post-lesional spasticity: spinal cord injury causes downregulation of the KCC2 cotransporter in motoneurons caudal to the lesion, shifting GABAergic transmission from its normal hyperpolarizing (inhibitory) effect to a depolarizing (excitatory) one. This disruption of the excitatory/inhibitory balance contributes directly to hyperreflexia and spasticity. The paper provides the molecular foundation for the KCC2-related mechanism described in the text, and supports the hypothesis that tSCS — through repeated afferent activation — may partially restore KCC2 expression and thereby re-establish physiological inhibitory tone in spinal circuits, contributing to spasticity reduction and metaplastic reorganization.
Chen B et al.
Reactivation of dormant relay pathways in injured spinal cord by KCC2 manipulations.
Cell, 2018; 174(6):521–535
Using a mouse model of staggered spinal cord hemisections — which completely interrupts direct brain-to-spinal cord connections while leaving dormant relay circuits intact — this study demonstrated that pharmacological activation of KCC2 in inhibitory interneurons reactivates these silent relay pathways and restores stepping ability. The mechanism involves restoring the hyperpolarizing function of GABAergic interneurons, which had been converted to an excitatory state by post-injury KCC2 downregulation. This work provides compelling evidence that KCC2-mediated modulation of inhibitory interneurons is a key gateway to functional recovery after spinal injury, directly supporting the neurobiological rationale for tSCS-induced metaplasticity described in the text.
Courtine G & Sofroniew MV
Spinal cord repair: advances in biology and technology.
Nature Reviews Neuroscience, 2019; 20(10):614–626
This authoritative review by two leading figures in spinal cord neuroscience provides a comprehensive synthesis of biological and technological strategies for spinal cord repair, including neuromodulation, activity-based rehabilitation, neuroprosthetics, and combinatorial approaches. The authors emphasize the importance of targeting residual spinal circuit plasticity and propose that integrating multiple therapeutic modalities — a principle central to the Villa Beretta approach — is essential for meaningful functional recovery. The review also discusses the translational potential of spinal neuromodulation beyond traumatic injury, encompassing neurodegenerative and neuroinflammatory conditions, directly supporting the broader clinical scenarios outlined in the text.
Godin AG et al.
Differential chloride homeostasis in the spinal dorsal horn locally shapes synaptic metaplasticity and modality-specific sensitization.
Nature Communications, 2020; 11:4490
This study reveals that KCC2 expression is not uniform across the spinal dorsal horn: a gradient in chloride extrusion capacity exists between laminae I and II, with important consequences for inhibitory function and synaptic plasticity. Under high synaptic drive, this gradient produces lamina-specific collapse of inhibition, generating a form of activity-dependent synaptic metaplasticity — that is, plasticity of the plastic capacity itself. This work provides direct mechanistic evidence for the concept of spinal metaplasticity invoked in the text, demonstrating how KCC2-mediated chloride homeostasis shapes the threshold and direction of spinal circuit reorganization, and how repeated afferent stimulation (as in tSCS) may influence this process.
Benavides FD et al.
Cortical and subcortical effects of transcutaneous spinal cord stimulation in humans with tetraplegia.
Journal of Neuroscience, 2020; 40(13):2633–2643
This neurophysiological study directly mapped the supraspinal effects of tSCS in humans with tetraplegia using transcranial magnetic stimulation and somatosensory evoked potentials. The findings demonstrated that tSCS modulates cortical and subcortical excitability — including sensorimotor cortex and brainstem circuits — in addition to its local spinal effects. This is the key empirical support for the dual ascending-descending mechanism described in the text: tSCS-generated afferent signals travel through the posterior columns to modify corticospinal excitability and lower the activation threshold of descending motor pathways, creating the neurophysiological conditions for enhanced voluntary motor output.
Megía García A et al.
Transcutaneous spinal stimulation and motor rehabilitation in spinal cord injury: a systematic review.
Neurorehabilitation and Neural Repair, 2020; 34(1):3–16
This systematic review analyzed the available evidence on tSCS for motor function improvement in spinal cord injury, evaluating methodological quality across published studies and characterizing the feasibility and efficacy of non-invasive spinal stimulation to activate lower and upper limb motor pools. The review confirmed that tSCS can elicit Hoffmann-like reflex activity by activating proprioceptive afferents within the dorsal roots, and that it may engage both spinal and residual supraspinal motor pathways. While calling for more controlled research, it establishes the scientific foundation for the clinical use of tSCS described in the text, including its potential for activation of interneuronal networks and motor pool facilitation across injury levels.
Comino-Suárez N et al.
