A spinal cord injury (SCI) causes immediate and sustained hemodynamic instability that threatens neurological recovery and impacts quality of life. Here we establish the clinical burden of chronic hypotensive complications due to SCI in 1,479 participants and expose the ineffective treatment of these complications with conservative measures. To address this clinical burden, we developed a purpose-built implantable system based on biomimetic epidural electrical stimulation (EES) of the spinal cord that immediately triggered robust pressor responses. The system durably reduced the severity of hypotensive complications in people with SCI, removed the necessity for conservative treatments, improved quality of life and enabled superior engagement in activities of daily living. Central to the development of this therapy was the head-to-head demonstration in the same participants that EES must target the last three thoracic segments, and not the lumbosacral segments, to achieve the safe and effective regulation of blood pressure in people with SCI. These findings in 14 participants establish the path to designing a pivotal device trial that will evaluate the safety and efficacy of EES to treat the underappreciated, treatment-resistant hypotensive complications due to SCI.

The use of kilohertz-frequency (KHF) waveforms has rapidly gained momentum in transcutaneous spinal cord stimulation (tSCS) to restore motor function after paralysis. However, the mechanisms by which these fast-alternating currents depolarize efferent and afferent fibers remain unknown. Our study fills this research gap by providing a hypothesis-and evidence-based investigation using peripheral nerve stimulation, lumbar tSCS, and cervical tSCS in 25 unimpaired participants together with computational modeling. Peripheral nerve stimulation experiments and computational modeling showed that KHF waveforms negatively impact the processes required to elicit action potentials, thereby increasing response thresholds and biasing the recruitment towards efferent fibers. While these results translate to tSCS, we also demonstrate that lumbar tSCS results in the preferential recruitment of afferent fibers, while cervical tSCS favors recruitment of efferent fibers. Given the assumed importance of proprioceptive afferents in motor recovery, our work suggests that the use of KHF waveforms should be reconsidered to maximize neurorehabilitation outcomes, particularly for cervical tSCS. We posit that careful analysis of the mechanisms that mediate responses elicited by novel approaches in tSCS is crucial to understanding their potential to restore motor function after paralysis.

A growing number of complex neurostimulation strategies promise symptom relief and functional recovery for several neurological, psychiatric, and even multi-organ disorders. Although pharmacological interventions are currently the mainstay of treatment, neurostimulation offers a potentially effective and safe alternative, capable of providing rapid adjustment to short-term variation and long-term decline of physiological functions. However, rapid advances made by clinical studies have often preceded the fundamental understanding of mechanisms underlying the interactions between stimulation and the nervous system. In turn, therapy design and verification are largely driven by clinical-empirical evidence. Even with titanic efforts and budgets, it is infeasible to comprehensively explore the multi-dimensional optimization space of neurostimulation through empirical research alone, especially since anatomical structures and thus outcomes vary dramatically between patients. Instead, we believe that the future of neurostimulation strongly depends on personalizable computational tools, i.e. Digital Neuro Twins (DNTs) to efficiently identify effective and safe stimulation parameters. DNTs have the potential to accelerate scientific discovery and hypothesis-driven engineering, and aid as a critical regulatory and clinical decision support tool. We outline here how DNTs will pave the way toward effective, cost-, time-, and risk-limited electronic drugs with a broad application bandwidth.

Kilohertz-frequency (KHF) waveforms are gaining traction in transcutaneous spinal cord stimulation (tSCS) for motor recovery after paralysis. However, the mechanisms by which these fast-alternating currents depolarize proprioceptive afferent and motor efferent fibres remain unknown. To address this gap, we conducted a study in 28 participants showing, through peripheral nerve stimulation experiments and computational modelling, that KHF waveforms negatively impact the processes required to electrically induce action potentials, thereby increasing response thresholds and biasing recruitment towards motor efferent fibres. While these results translate to tSCS, we also demonstrate that lumbar tSCS still results in the preferential recruitment of proprioceptive afferent fibres, whereas cervical tSCS favours recruitment of motor efferent fibres, regardless of the waveform used. Given the assumed importance of proprioceptive afferent stimulation in motor recovery, our work suggests that the use of KHF waveforms warrants careful consideration in the context of neurorehabilitation applications, particularly for cervical tSCS. We posit that a thorough analysis of the mechanisms mediating responses elicited by novel tSCS approaches is crucial for understanding their potential to restore motor function after paralysis.

Transcutaneous spinal cord stimulation (tSCS) applied over the cervical or lumbar spinal cord facilitates motor function after paralysis. However, emerging electrophysiological evidence indicates mechanistic differences between cervical and lumbar tSCS and across different cervical tSCS paradigms. To clarify these discrepancies, we developed and validated a multi-scale, whole-body computational model of tSCS-induced volume conduction, axonal recruitment, and synaptic transmission. Across 24 cervical and four lumbar tSCS paradigms, simulations showed that somatosensory afferents consistently exhibit lower stimulation thresholds than motor efferents. In turn, region-specific synaptic transmission differences may explain electrophysiological discrepancies between cervical and lumbar tSCS. Across cervical tSCS paradigms, substantial volume conduction and axonal recruitment differences were observed that explain electrophysiological discrepancies. Specifically, clinically-prevalent paradigms, including those with anodes placed over the clavicles or iliac crests, engaged peripheral nerves in addition to spinal roots. This effect was amplified by multiphasic waveforms, which introduced recruitment sites near the anodes. By integrating simulations with electrophysiological recordings in 14 able-bodied individuals, we investigated previously unexplored cervical tSCS paradigms on their capacity to recruit somatosensory afferents relative to motor threshold.