Recruitment of upper-limb motoneurons with epidural electrical stimulation of the cervical spinal cord

Epidural electrical stimulation (EES) of lumbosacral sensorimotor circuits improves leg motor control in animals and humans with spinal cord injury (SCI). Upper-limb motor control involves similar circuits, located in the cervical spinal cord, suggesting that EES could also improve arm and hand movements after quadriplegia. However, the ability of cervical EES to selectively modulate specific upper-limb motor nuclei remains unclear. Here, we combined a computational model of the cervical spinal cord with experiments in macaque monkeys to explore the mechanisms of upper-limb motoneuron recruitment with EES and characterize the selectivity of cervical interfaces. We show that lateral electrodes produce a segmental recruitment of arm motoneurons mediated by the direct activation of sensory afferents, and that muscle responses to EES are modulated during movement. Intraoperative recordings suggested similar properties in humans at rest. These modelling and experimental results can be applied for the development of neurotechnologies designed for the improvement of arm and hand control in humans with quadriplegia.

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Marco Capogrosso, Nathan Greiner Feb 19, 2020 Data collection was performed with the following commercial and custom code: -Custom code developed in RPvdsEx to control an RZ2 BioAmp Processor (Tucker-Davis Technologies, Alachua, US), to record the electromyographic activity induced by epidural electrical stimulation (EES) in monkeys. -NIM Eclipse system software (Medtronic plc, Fridley, Minnesota, USA), to record the electromyographic activity induced by epidural electrical stimulation (EES) in humans. The computer code to build the computational model, the simulation results, and the corresponding figures of the manuscript can be found at https://bitbucket.org/ngreiner/greiner_et_al_2020/src/master/.
Data analysis was performed using custom Matlab (Matlab, The Mathworks, Inc.) code. Computer simulations were performed with COMSOL v5.2a (COMSOL, Burlington MA) and Matlab for the finite element modeling part, and with Python 3.7 and the NEURON simulation environment for the neurophysical simulations. The simulation results (and corresponding figures) presented in the article can be reproduced in full using the research material at https://bitbucket.org/ngreiner/ greiner_et_al_2020/src/master/.

October 2018
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All the routines and data necessary to reproduce the computational model and all figures related to simulations in this manuscript are accessible from the following public repository: https://bitbucket.org/ngreiner/greiner_et_al_2020/src/master/. This repository also includes all the experimental data used in comparisons with simulation results. All the other experimental data can be delivered upon specific requests to the corresponding authors No statistical methods were used to pre-determine sample sizes. All data was analyzed in all animals independently and no formal statistical comparison between populations was performed. Sample sizes are similar to those reported in previous publications using similar experimental procedures (Citation 39, Citation 55).
The EMG signals recorded in one muscle of one animal were discarded from analysis: their interpretation led to aberrant conclusions.
To document the muscular responses induced in any of the 5 macaque monkeys involved in our experiments by any given epidural electrode and for any stimulation amplitude, we repeated the stimulation 4 times. Replication of the experimental protocol was successful in all animals. Replication of the entire protocols in a given animal on different days was not possible due to the experimental constraints described in the Methods of our manuscript (terminal procedures, or single acute surgical session).
No randomization was introduced in our experiments. Since no formal statistical comparisons were required in our study and all animals were independently analyzed, no randomization was necessary and the same protocol was performed on all animals.
The investigators were not blinded to tested conditions. All animals underwent the same protocol, therefore blinding is not relevant for this study.
The study involved 5 Macaca Fascicularis monkeys. 4 of them were female, respectively aged of 11, 9, 9 and 7 years. 1 was male, aged of 12 years.

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October 2018

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Magnetic resonance imaging
The study did not involve samples collected from the field.
All procedures were carried out in accordance to the Guide for Care and Use of Laboratory Animals and the principle of the 3Rs. Protocols were approved by local veterinary authorities of the Canton of Fribourg (authorizations are reported in the Methods of our manuscript) including the ethical assessment by the local (cantonal) Survey Committee on Animal Experimentation and acceptance by the Federal Veterinary Office (BVET, Bern, Switzerland). Authorization numbers for the experiments and each animal involved in the study are provided in Supplementary Table 2 of our manuscript. Data were acquired during routine clinical procedures. Data were anonymised and we don't have access to population characteristics .
Anonymized clinical data were provided to us by Dr. Etienne PRALONG. Data were acquired during routine clinical practice.
After discussion with SwissEthics we confirmed that the use of anonymised clinical data is not subject to further ethical oversight Anatomical T1 and T2 weighted images of the cervical spine (not shown in the manuscript but available upon request) from animals sedated with ketamine.
GE 3T clinical research scanner.
No behavioral performance were measured. Structural.
Brain and spinal cord.
No pre-processing was performed. No functional data was acquired. Only structural anatomical measurements were performed using OsiriX DICOM reader, v 11.0