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(38) Neural Mechanisms Underlying Voluntary Control of Motoneurons after paralysis with Spinal Cord Stimulation

Friday, June 13, 2025
5:50 PM - 6:30 PM ET
Location: Sky View
Introduction: In the last two decades, a series of animal and clinical studies showed that epidural electrical spinal cord stimulation (SCS) can restore some degree of motor control of lower and upper limbs in people with spinal cord injury and stroke1–8. The most striking observation that emerged from clinical trials is the evidence that, during SCS, humans with motor paralysis appear able to voluntarily control their previously paralyzed limbs2,9. The main hypothesis in the field is that SCS increases spinal excitability (i.e. bring motoneuron closer to the firing threshold). While intuitively plausible, no proposed mechanism has ever been tested. Deciphering the mechanisms underlying the recovery of voluntary motor control is critical to explain a large part of the clinical outcomes and further optimizing SCS therapy.

Methods: We built on established biophysics of membrane dynamics10–13 to develop a model of motoneuron membrane and calculate the membrane potential while receiving excitatory inputs from both sensory afferents recruited by SCS and residual supraspinal fibers (Figure 1a). We then tested model predictions on the patterns of single motoneuron firing rates with motor units recordings in monkeys and humans with spinal cord injury and stroke.

Results: Our combined simulated and experimental data shows that residual supraspinal inputs can bring subthreshold SCS-mediated excitatory postsynaptic potentials (EPSPs) into suprathreshold action potentials (Figure 1b,c). In other words, in the presence of residual supraspinal inputs, action potentials are triggered by otherwise subthreshold SCS pulses, becoming effectively entrained to stimulation interpulse interval and its integer multiples14–16. However, residual supraspinal inputs can control the overall motoneuron pool firing rate by modulating the number of SCS pulses that are transformed into action potentials (Figure 2). Finally, we show that only a subset of SCS parameters enables this volitional modulation and, unfortunately, the functional parameter space shrinks with lesion severity.

Conclusion: We uncovered the neural mechanisms underlying the recovery of voluntary motor control following paralysis with SCS. Our findings suggest that the efficacy of continuous SCS may be limited in cases of severe lesions, where alternative spatiotemporal stimulation strategies could be necessary. Notably, we observed that action potentials, even when highly entrained to pulsatile artificial stimulation, remain modifiable by natural neural activity—a mechanism that likely extends to other pulsatile neurostimulation technologies16,17