Vsx2 neurons are vital and sufficient for spinal cord stimulation therapies to be effective to restore motor function in those with spinal cord injury


In a multi-year research program coordinated by the two directors of .NeuroRestore – Grégoire Courtine, a neuroscience professor at EPFL, and Jocelyne Bloch, a neurosurgeon at Lausanne University Hospital (CHUV) – patients who had been paralyzed by a spinal cord injury and who underwent targeted epidural electrical stimulation of the area that controls leg movement were able to regain some motor function.

In the new study by NeuroRestore scientists, appearing today in Nature, not only was the efficacy of this therapy demonstrated in nine patients, but the improved motor function was shown to last in patients after the neurorehabilitation process was completed and when the electrical stimulation was turned off.

This suggested that the nerve fibers used for walking had reorganized. The scientists believe it was crucial to understand exactly how this neuronal reorganization occurs in order to develop more effective treatments and improve the lives of as many patients as possible.

Vsx2 neurons reorganize to restore walking

To arrive at this understanding, the research team first studied the underlying mechanisms in mice. This revealed a surprising property in a family of neurons expressing the Vsx2 gene: while these neurons aren’t necessary for walking in healthy mice, they were essential for the recovery of motor function after spinal cord injury.

Credit: EPFL

This discovery was the culmination of several phases of fundamental research. For the first time, the scientists were able to visualize spinal cord activity of a patient while walking. This led to an unexpected finding: during the spinal-cord stimulation process, neuronal activity actually decreased during walking. The scientists hypothesized that this was because the neuronal activity was selectively directed towards recovering motor function.

To test their hypothesis, the research team developed advanced molecular technology. “We established the first 3D molecular cartography of the spinal cord,” says Courtine.

“Our model let us observe the recovery process with enhanced granularity—at the neuron level.”

Thanks to their highly precise model, the scientists found that spinal cord stimulation activates Vsx2 neurons and that these neurons become increasingly important as the reorganization process unfolds.

A versatile spinal implant

Stéphanie Lacour, a fellow EPFL professor, helped the research team validate their findings with the epidural implants developed in her lab.

Lacour adapted the implants by adding light-emitting diodes that enabled the system to not just stimulate the spinal cord, but also to deactivate the Vsx2 neurons alone through an optogenetic process.

When the system was used on mice with a spinal cord injury, the mice stopped walking immediately as a result of the deactivated neurons – but there was no effect on healthy mice. This implies that Vsx2 neurons are both necessary and sufficient for spinal cord stimulation therapies to be effective and lead to neural reorganization.

“It’s essential for neuroscientists to be able to understand the specific role that each neuronal subpopulation plays in a complex activity like walking,” says Bloch. “Our new study, in which nine clinical-trial patients were able to recover some degree of motor function thanks to our implants, is giving us valuable insight into the reorganization process for spinal cord neurons.”

Jordan Squair, who focuses on regenerative therapies within .Neurorestore, adds, “This paves the way to more targeted treatments for paralyzed patients. We can now aim to manipulate these neurons to regenerate the spinal cord.”

Spinal cord injury (SCI) is one of the most devastating diseases in the world. Effective treatment with restoration of sensory and motor function remains one of the greatest challenges in neuroscience. About 27 million people worldwide have been chronically disabled as a result of SCI (James et al., 2019). In addition, there could be 10,000–20,000 new SCI patients in the United States and 60,000 new SCI patients in China every year (Qiu, 2009; National Spinal Cord Injury Statistical Center, 2014).

China has the largest number of SCI patients in the world. It is estimated that the direct lifetime cost of care ranged from $1.1 million to $4.7 million per person for more than one million SCI people in North America. For SCI patients in North America alone, the total direct cost of acute treatment and chronic care in the United States exceeded $7 billion per year (Badhiwala et al., 2018). Therefore, it is extremely important to find an effective treatment for SCI.

In recent years, we have proposed and been studying a new concept for SCI treatment called GEMINI spinal cord fusion (SCF) (Canavero, 2015; Canavero and Ren, 2016; Canavero et al., 2016). In this protocol, an extremely sharp surgical knife quickly and relatively atraumatically cuts the spinal cord, resulting in a complete spinal cord transection. Topical application of a fusogen (polyethylene glycol, PEG) can acutely fuse the membranes of the transected axons in the stumps of the transected spinal cord to restore spinal nerve anatomic and electrical continuity across the site of the spinal cord transection (Canavero and Ren, 2016; Canavero et al., 2016, 2017; Ren et al., 2019). To verify the efficacy of SCF, our team initially used rodents as small animal experimental models to carry out SCF research.

Studies have shown that mice and rats treated with PEG gradually recovered motor function in their hind limbs. Through the detection of somatosensory evoked potentials (SSEPs) and diffusion tensor imaging (DTI, a novel magnetic resonance imaging technique that assesses the microstructural integrity of nerve fiber tracts; D’Souza et al., 2017), we showed that animals treated with topical PEG had restoration of the conduction of action potentials and the neural continuity at the site of spinal cord transection (Ye et al., 2016; Ren et al., 2017).

Based on these findings, our team further validated the efficacy of SCF in large animals (beagles and monkeys) and successfully confirmed the above DTI and electrophysiological results seen in rodents. In addition, beagles and monkeys regained hind leg standing and crawling function at 2 and 3 months postoperatively, respectively. We also verified the role of PEG in restoring nerve continuity via histology examinations (Liu et al., 2018; Ren et al., 2019; Ren and Canavero, 2020).

Currently, most paraplegic patients have chronic SCI from the remote trauma. The majority of participants in clinical SCI trials are also patients with chronic SCI. For example, in 2005, a study reported an omental–collagen bridge procedure in a patient with chronic SCI for 3 and one half years (Goldsmith et al., 2005). In 2014, another study reported a technique of bridging the defect in the spinal cord at the site of injury using a peripheral nerve bathed with bulbar olfactory ensheathing cells in a patient with chronic SCI for 21 months (Tabakow et al., 2014).

A linearly ordered collagen scaffold reported in 2016 was used to treat five patients with chronic SCI for an average time of 13 months (Xiao et al., 2016). One thing that all three studies have in common with the treatment of SCI is the removal of glial scars in the area of SCI prior to bridging the spinal stumps using different substances. Participants in these three studies also had different degrees of neurological recovery after surgery. Because all the participants were patients with chronic SCI, the postoperative functional recovery time window was longer than our previous animal experiments.

Because our previous animal experiments were performed in an acute spinal cord transection model, in order to transform SCF into the clinic, we needed to transform SCF into the clinical practice; therefore, our team developed several new surgical models for SCF in clinical paraplegic patients and conducted a clinical trial (ChiCTR2000030788)1 of SCF. The first model for clinical translational (Model I) was the vascular pedicle hemisected spinal cord transplantation (vSCT).

This surgical model consists of removing the area of SCI scar area to produce two acutely transected spinal cord stumps. Half of the spinal cord tissue with the posterior spinal artery was cut from the distal or proximal spinal cord stump to serve as a neural bridge between the distal and proximal spinal cord stumps.

In addition, our team conducted preclinical experiments of vSCT in a beagle animal model to verify the feasibility and effectiveness of vSCT. Compared with the control group who showed no recovery of function, beagles treated with local PEG fusion during the vSCT showed recovery of spinal nerve continuity in the postoperative DTI study. In addition, PEG-treated beagles regained some ability to stand and crawl on their hind legs 2 months after the vSCT. The histological examination also demonstrated restored spinal cord continuity in the PEG-treated beagles (Ren et al., 2021).

During the subsequent clinical recruitment process, we found that some patients had a SCI in the lower thoracic area or had marked distal spinal cord atrophy (distal cord dysfunction). Cutting half of the spinal cord tissue from the proximal spinal cord tissue site would lead to ascent of the single neurologic level. Therefore, these patients were not suitable for the vSCT treatment. To treat these paraplegic patients, based on a clinical trial of peripheral nerves for SCI reported in 2014 (Tabakow et al., 2014), we developed a second clinical translational model of SCF (Model II), sural nerve transplantation (SNT). In this article, we present the preliminary results of 12 patients with the above-mentioned conditions after SNT treatment to demonstrate the safety, feasibility, and effectiveness of SNT.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8882688/

Original Research: Open access.
The neurons that restore walking after paralysis” by Claudia Kathe et al. Nature


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