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Early phrenic motor neuron loss and transient respiratory abnormalities after unilateral cervical spinal cord contusion.

ABSTRACT: Contusion-type cervical spinal cord injury (SCI) is one of the most common forms of SCI observed in patients. In particular, injuries targeting the C3-C5 region affect the pool of phrenic motor neurons (PhMNs) that innervates the diaphragm, resulting in significant and often chronic respiratory dysfunction. Using a previously described rat model of unilateral midcervical C4 contusion with the Infinite Horizon Impactor, we have characterized the early time course of PhMN degeneration and consequent respiratory deficits following injury, as this knowledge is important for designing relevant treatment strategies targeting protection and plasticity of PhMN circuitry. PhMN loss (48% of the ipsilateral pool) occurred almost entirely during the first 24 h post-injury, resulting in persistent phrenic nerve axonal degeneration and denervation at the diaphragm neuromuscular junction (NMJ). Reduced diaphragm compound muscle action potential amplitudes following phrenic nerve stimulation were observed as early as the first day post-injury (30% of pre-injury maximum amplitude), with slow functional improvement over time that was associated with partial reinnervation at the diaphragm NMJ. Consistent with ipsilateral diaphragmatic compromise, the injury resulted in rapid, yet only transient, changes in overall ventilatory parameters measured via whole-body plethysmography, including increased respiratory rate, decreased tidal volume, and decreased peak inspiratory flow. Despite significant ipsilateral PhMN loss, the respiratory system has the capacity to quickly compensate for partially impaired hemidiaphragm function, suggesting that C4 hemicontusion in rats is a model of SCI that manifests subacute respiratory abnormalities. Collectively, these findings demonstrate significant and persistent diaphragm compromise in a clinically relevant model of midcervical contusion SCI; however, the therapeutic window for PhMN protection is restricted to early time points post-injury. On the contrary, preventing loss of innervation by PhMNs and/or inducing plasticity in spared PhMN axons at the diaphragm NMJ are relevant long-term targets.

SUBMITTER: Nicaise C

PROVIDER: S-EPMC3689927 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Fine motor skills are thought to rely on the integrity of ascending sensory pathways in the spinal dorsal column as well as descending motor pathways that have a neocortical origin. However, the neurophysiological processes underlying communication between the somatosensory and motor pathways that regulate fine motor skills during spontaneous recovery after spinal cord contusion injury remain unclear. Here, we established a rat model of cervical hemicontusive injury using C5 laminectomy followed by contusional displacement of 1.2 mm (mild injury) or 2.0 mm (severe injury) to the C5 spinal cord. Electrophysiological recordings were performed on the brachial muscles up to 12 weeks after injury to investigate the mechanisms by which spinal cord pathways participate in motor function. After spinal cord contusion injury, the amplitudes of somatosensory and motor-evoked potentials were reduced, and the latencies were increased. The forelimb open field locomotion test, grooming test, rearing test and Montoya staircase test revealed improvement in functions. With increasing time after injury, the amplitudes of somatosensory and motor-evoked potentials in rats with mild spinal cord injury increased gradually, and the latencies gradually shortened. In comparison, the recovery times of somatosensory and motor-evoked potential amplitudes and latencies were longer, and the recovery of motor function was delayed in rats with severe spinal cord injury. Correlation analysis revealed that somatosensory-evoked potential and motor-evoked potential parameters were correlated with gross and fine motor function in rats with mild spinal cord contusion injury. In contrast, only somatosensory-evoked potential amplitude was correlated with fine motor skills in rats with severe spinal cord injury. Our results show that changes in both somatosensory and motor-evoked potentials can reflect the changes in gross and fine motor functions after mild spinal cord contusion injury, and that the change in somatosensory-evoked potential amplitude can also reflect the change in fine motor function after severe spinal cord contusion injury. This study was approved by the Animal Ethics Committee of Nanfang Hospital, Southern Medical University, China (approval No. NFYY-2017-67) on June 11, 2017.

Project description:BackgroundAmyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease characterized by both upper and lower motor neuron degeneration. While neuroimaging studies of the brain can detect upper motor neuron degeneration, these brain MRI scans also include the upper part of the cervical spinal cord, which offers the possibility to expand the focus also towards lower motor neuron degeneration. Here, we set out to investigate cross-sectional and longitudinal disease effects in the upper cervical spinal cord in patients with ALS, progressive muscular atrophy (PMA: primarily lower motor neuron involvement) and primary lateral sclerosis (PLS: primarily upper motor neuron involvement), and their relation to disease severity and grey and white matter brain measurements.MethodsWe enrolled 108 ALS patients without C9orf72 repeat expansion (ALS C9-), 26 ALS patients with C9orf72 repeat expansion (ALS C9+), 28 PLS patients, 56 PMA patients and 114 controls. During up to five visits, longitudinal T1-weighted brain MRI data were acquired and used to segment the upper cervical spinal cord (UCSC, up to C3) and individual cervical segments (C1 to C4) to calculate cross-sectional areas (CSA). Using linear (mixed-effects) models, the CSA differences were assessed between groups and correlated with disease severity. Furthermore, a relationship between CSA and brain measurements was examined in terms of cortical thickness of the precentral gyrus and white matter integrity of the corticospinal tract.ResultsCompared to controls, CSAs at baseline showed significantly thinner UCSC in all groups in the MND spectrum. Over time, ALS C9- patients demonstrated significant thinning of the UCSC and, more specifically, of segment C3 compared to controls. Progressive thinning over time was also observed in C1 of PMA patients, while ALS C9+ and PLS patients did not show any longitudinal changes. Longitudinal spinal cord measurements showed a significant relationship with disease severity and we found a significant correlation between spinal cord and motor cortex thickness or corticospinal tract integrity for PLS and PMA, but not for ALS patients.DiscussionOur findings demonstrate atrophy of the upper cervical spinal cord in the motor neuron disease spectrum, which was progressive over time for all but PLS patients. Cervical spinal cord imaging in ALS seems to capture different disease effects than brain neuroimaging. Atrophy of the cervical spinal cord is therefore a promising additional biomarker for both diagnosis and disease progression and could help in the monitoring of treatment effects in future clinical trials.

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Early phrenic motor neuron loss and transient respiratory abnormalities after unilateral cervical spinal cord contusion.

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