Neural mechanisms underlying the recovery of voluntary control of motoneurons after paralysis with spinal cord stimulation

Josep-Maria Balaguer¹, Genis Prat-Ortega², Julia Ostrowski³, Luigi Borda⁴, Nikhil Verma⁴, Prakarsh Yadav⁴, Erynn Sorensen¹, Roberto de Freitas², Scott Ensel¹, Serena Donadio⁵, Lucy Liang¹, Jonathan Ho⁶, Arianna Damiani⁷, Erinn M Grigsby⁸, Daryl P Fields², Jorge A Gonzalez-Martinez⁹, Peter C Gerszten⁹, Lee E Fisher¹⁰, Douglas J Weber¹¹, Elvira Pirondini¹², Marco Capogrosso¹³

Affiliations

¹ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA; Center for Neural Basis of Cognition, Pittsburgh, PA, USA.
² Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
³ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Center for Neural Basis of Cognition, Pittsburgh, PA, USA; Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA, USA.
⁴ Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
⁵ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
⁸ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA.
⁹ Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁰ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA; Center for Neural Basis of Cognition, Pittsburgh, PA, USA; Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
¹¹ Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA; Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA, USA.
¹² Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA; Center for Neural Basis of Cognition, Pittsburgh, PA, USA; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA.
¹³ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA; Center for Neural Basis of Cognition, Pittsburgh, PA, USA; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: mcapo@pitt.edu.

PMID: 40975061
DOI: 10.1016/j.neuron.2025.08.023

Free article

Neural mechanisms underlying the recovery of voluntary control of motoneurons after paralysis with spinal cord stimulation

Josep-Maria Balaguer et al. Neuron. 2025.

Free article

. 2025 Sep 19:S0896-6273(25)00658-0.

doi: 10.1016/j.neuron.2025.08.023. Online ahead of print.

Authors

Affiliations

¹ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA; Center for Neural Basis of Cognition, Pittsburgh, PA, USA.
² Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
³ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Center for Neural Basis of Cognition, Pittsburgh, PA, USA; Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA, USA.
⁴ Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
⁵ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
⁸ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA.
⁹ Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁰ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA; Center for Neural Basis of Cognition, Pittsburgh, PA, USA; Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
¹¹ Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA; Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA, USA.
¹² Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA; Center for Neural Basis of Cognition, Pittsburgh, PA, USA; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA.
¹³ Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA; Center for Neural Basis of Cognition, Pittsburgh, PA, USA; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: mcapo@pitt.edu.

PMID: 40975061
DOI: 10.1016/j.neuron.2025.08.023

Abstract

Spinal cord stimulation (SCS) improves motor control after paralysis. This evidence led to the hypothesis that SCS facilitates residual supraspinal inputs to spinal motoneurons. Here, we demonstrate that this hypothesis is not supported by experimental evidence. Instead, we show that residual supraspinal inputs modulate motoneurons' membrane potential to transform subthreshold SCS pulses into suprathreshold action potentials, thereby entraining motoneuron activity to SCS. Despite this entrainment, residual supraspinal inputs can control motoneuron firing rates by modulating the number of subthreshold SCS pulses transformed into action potentials, resulting in volitional modulation of motor output for a restricted set of SCS parameters. Furthermore, we predict that residual supraspinal inhibitory drive can silence unwanted suprathreshold motoneuron activity, enlarging the functional set of SCS parameters. Finally, we demonstrate that this set of functional stimulation parameters is further restricted by lesion severity, highlighting an intrinsic limitation of SCS in cases of severe injury.

Keywords: computer models; motoneurons; motor neuron; motor units; non-human primates; spinal cord injury; spinal cord stimulation; stroke.

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Conflict of interest statement

Declaration of interests M.C. and D.J.W. hold patents in relation to spinal cord stimulation. M.C., D.J.W., and P.C.G. are founders and board members of Reach Neuro, a company developing spinal cord stimulation technologies for stroke. E.P. has interests in Reach Neuro because of marital status with M.C.

Update of

SUPRASPINAL CONTROL OF MOTONEURONS AFTER PARALYSIS ENABLED BY SPINAL CORD STIMULATION.
Balaguer JM, Prat-Ortega G, Verma N, Yadav P, Sorensen E, de Freitas R, Ensel S, Borda L, Donadio S, Liang L, Ho J, Damiani A, Grigsby E, Fields DP, Gonzalez-Martinez JA, Gerszten PC, Fisher LE, Weber DJ, Pirondini E, Capogrosso M. Balaguer JM, et al. medRxiv [Preprint]. 2023 Dec 1:2023.11.29.23298779. doi: 10.1101/2023.11.29.23298779. medRxiv. 2023. Update in: Neuron. 2025 Sep 19:S0896-6273(25)00658-0. doi: 10.1016/j.neuron.2025.08.023. PMID: 38076797 Free PMC article. Updated. Preprint.

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Neural mechanisms underlying the recovery of voluntary control of motoneurons after paralysis with spinal cord stimulation

Affiliations

Neural mechanisms underlying the recovery of voluntary control of motoneurons after paralysis with spinal cord stimulation

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

Grants and funding

LinkOut - more resources

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