Stimulation of the cuneiform nucleus enables training and boosts recovery after spinal cord injury

Abstract

Severe spinal cord injuries result in permanent paraparesis in spite of the frequent sparing of small portions of white matter. Spared fiber tracts are often incapable of maintaining and modulating the activity of lower spinal motor centers. Effects of rehabilitative training thus remain limited. Here, we activated spared descending brainstem fibers by electrical deep brain stimulation of the cuneiform nucleus of the mesencephalic locomotor region, the main control center for locomotion in the brainstem, in adult female Lewis rats. We show that deep brain stimulation of the cuneiform nucleus enhances the weak remaining motor drive in highly paraparetic rats with severe, incomplete spinal cord injuries and enables high-intensity locomotor training. Stimulation of the cuneiform nucleus during rehabilitative aquatraining after subchronic (n = 8 stimulated vs. n = 7 unstimulated vs. n = 7 untrained rats) and chronic (n = 14 stimulated vs. n = 9 unstimulated vs. n = 9 untrained rats) spinal cord injury re-established substantial locomotion and improved long-term recovery of motor function. We additionally identified a safety window of stimulation parameters ensuring context-specific locomotor control in intact rats (n = 18) and illustrate the importance of timing of treatment initiation after spinal cord injury (n = 14). This study highlights stimulation of the cuneiform nucleus as a highly promising therapeutic strategy to enhance motor recovery after subchronic and chronic incomplete spinal cord injury with direct clinical applicability.

Functional Contribution of Mesencephalic Locomotor Region Nuclei to Locomotor Recovery After Spinal Cord Injury

“…Not surprisingly, reticulospinal pathways appear to contribute to functional locomotor recovery following SCI (Filli et al, 2014; Zörner et al, 2014; Engmann et al, 2020; Asboth et al, 2018), presumably by relaying MLR and/or cortical inputs. Although anatomical reorganization has been reported between medullary-projecting midbrain neurons following cervical SCI (Zörner et al, 2014) and axonal midbrain sprouting in the medulla after thoracic SCI (Hofer et al, 2022), we found no anatomical changes in genetically identified glutamatergic medullary-projecting CnF or PPN nuclei after thoracic SCI, despite functional behavioral and motor improvements. Indeed, genetic deletion of glutamatergic neurons of the CnF or PPN impaired spontaneous locomotor recovery during walking and swimming, but deficits were stronger upon genetic ablation of CnF neurons than those of the PPN.…”

“…Although anatomical reorganization has been reported between medullary-projecting midbrain neurons following cervical SCI (Zörner et al, 2014) and axonal midbrain sprouting in the medulla after thoracic SCI (Hofer et al, 2022), we found no anatomical changes in genetically identified glutamatergic medullary-projecting CnF or PPN nuclei after thoracic SCI, despite functional behavioral and motor improvements. Indeed, genetic deletion of glutamatergic neurons of the CnF or PPN impaired spontaneous locomotor recovery during walking and swimming, but (which was not certified by peer review) is the author/funder.…”

“…Electrical stimulation of the CnF has also been recently shown to promote quadrupedal locomotion of chronic thoracic SCI rats (Hofer et al, 2022). Using a less severe thoracic SCI, we also found that optogenetic photo-stimulation of glutamatergic neurons of the CnF with long trains of 20 Hz for 1 s increased postural tone and initiated locomotion in chronic SCI mice, with functionally better stepping ability and smoothness in locomotion than during spontaneous episode of locomotion.…”

“…Furthermore, glutamatergic CnF neurons accelerate locomotor rhythm and speed during ongoing locomotion, whereas glutamatergic and cholinergic PPN neurons only prolong the stance phase, contributing to postural adjustments and slowing locomotor rhythm in normal conditions (Josset et al, 2018). With ongoing clinical trials aiming to assess deep brain stimulation in the vicinity of the PPN of patients with incomplete spinal cord injury (SCI) (Stieglitz LH, 2017) and DBS in the PPN (Bonizzato et al, 2021) or the CnF (Hofer et al, 2022) improving locomotor recovery in animal models of SCI, it is now urgent to gain a better understanding of how these distinct neuronal populations of the midbrain can contribute to and promote functional locomotor recovery after SCI.…”

Functional contribution of mesencephalic locomotor region nuclei to locomotor recovery after spinal cord injury

“… 1 , 2 , 3 , 4 , 5 , 6 , 7 Recently, deep brain stimulation of the mesencephalic locomotor region (MLR), a supraspinal locomotor center, has been shown to improve locomotor functions in rats with chronic but incomplete SCI with even a few spared axonal fibers. 6 , 7 , 8 Interestingly, these functional changes come with an extensive reorganization in the brainstem region after SCI, 9 thus supporting the important contribution of the MLR to locomotor recovery after incomplete SCI.…”