Sensorimotor plasticity after spinal cord injury: a longitudinal and translational study

Abstract

Objective: The objective was to track and compare the progression of neuroplastic changes in a large animal model and humans with spinal cord injury.

Methods: A total of 37 individuals with acute traumatic spinal cord injury were followed over time (1, 3, 6, and 12 months post-injury) with repeated neurophysiological assessments. Somatosensory and motor evoked potentials were recorded in the upper extremities above the level of injury. In a reverse-translational approach, similar neurophysiological techniques were examined in a porcine model of thoracic spinal cord injury. Twelve Yucatan mini-pigs underwent a contusive spinal cord injury at T10 and tracked with somatosensory and motor evoked potentials assessments in the fore- and hind limbs pre- (baseline, post-laminectomy) and post-injury (10 min, 3 h, 12 weeks).

Results: In both humans and pigs, the sensory responses in the cranial coordinates of upper extremities/forelimbs progressively increased from immediately post-injury to later time points. Motor responses in the forelimbs increased immediately after experimental injury in pigs, remaining elevated at 12 weeks. In humans, motor evoked potentials were significantly higher at 1-month (and remained so at 1 year) compared to normative values.

Conclusions: Despite notable differences between experimental models and the human condition, the brain's response to spinal cord injury is remarkably similar between humans and pigs. Our findings further underscore the utility of this large animal model in translational spinal cord injury research.

Figure 1

Brachial plexus anatomy and assessments of sensorimotor evoked potentials. The ulnar nerve originates from the C8‐T1 nerve roots forming, in part, the medial cord of the brachial plexus. It also innervates the abductor digiti minimi. In response to electrical stimulation, evoked potentials are generated by the transmission of the afferent (somatosensory evoked potentials) or efferent (motor evoked potentials) volleys between the periphery and the cortex. Thus, somatosensory and motor evoked potentials provide unique indices of the integrity of the afferent and efferent volley in spinal, brain‐stem, and thalamocortical pathways, as well as primary sensorimotor cortical regions. By virtue of the anatomical arrangement of the ulnar nerve, damage to the spinal cord at or above C8 will result in impaired somatosensory and motor evoked potentials. However, damage below C8 facilitates the recording of normal ulnar somatosensory and motor evoked potentials (i.e., intact pathways).

Figure 2

Design of human and animal study. (A) A total of 37 patients with spinal cord injury were enrolled in the study and meticulously followed up for a year. Neurophysiological (somatosensory and motor evoked potentials) and behavioral assessments (sensory and motor score) were performed 1, 3, 6, and 12 months post‐injury. (B) Twelve female Yucatan miniature pigs underwent behavioral training for 5 days. Subsequently, the baseline measurement was conducted on the day before the surgery. Follow‐up measurements were conducted weekly for 12 weeks starting 7 days after the surgery allowing the animals to recover. On the day of surgery, animals were anaesthetized and intubated. Prior to the surgical procedures baseline somatosensory and motor evoked potentials were recorded. Following laminectomy, somatosensory and motor evoked potentials were recorded again in order to ensure that the spinal cord was not damaged. The spinal cord injury was then induced by contusing and compressing the spinal cord. Somatosensory and motor evoked potentials were recorded immediately after the compression. All animals underwent follow‐up assessments of somatosensory and motor evoked potentials at 3 h and 12 weeks post‐injury. (C) Experimental set‐up of the neurophysiological assessment in pigs. Four screws served as recording and stimulation electrodes (black = active, red = reference). To reduce the high impedance (i.e., due to the thickness of the pig's skull) the screws were drilled in to skull.

Figure 3

Neurophysiological assessments in human patients. (A) Human ulnar somatosensory evoked potential amplitudes increased over time independent of the injury severity. (B) Motor evoked potentials remained stable independent of the injury severity. In comparison to healthy controls, the motor evoked potential amplitudes in patients was elevated. (C) Temporal progression tibial somatosensory evoked potentials in patients with spinal cord injuries. In comparison to healthy controls, the tibial somatosensory evoked potentials remained impaired over time. Specifically, smaller amplitudes and prolonged latencies hallmarked the patient population. AIS Scale: A – no motor or sensory function preserved below the level of lesion, B – sensory but not motor function is preserved, C and D – Motor and sensory function is preserved, but impaired to variable degree.14

Figure 4

Neurophysiological assessments in yucatan miniature pigs. (A) The medial somatosensory evoked potentials were not affected by the laminectomy and spinal cord injury and remained stable up to 3 h post‐injury. An increase in amplitudes was evident 12 weeks post‐injury alluding to potential reorganization of the somatosensory cortex. (B) Motor evoked potentials were unaffected by the laminectomy. However, the spinal cord injury induced a massive increase in motor evoked potential amplitudes likely due to an increase in cortical excitability. The motor evoked potentials remained elevated over the follow‐up period (12 weeks). (C) Temporal progression of left and right tibial somatosensory evoked potentials. The somatosensory evoked potentials remained stable after laminectomy confirming that the surgical procedure did not harm the spinal cord. Following the contusion, the somatosensory evoked potentials were abolished and did not recover over a period of 12 weeks reflecting the severity of the injury.

Figure 5

Immunohistochemistry findings. (A) Representative Eriochrome cyanine R–stained images of axially sectioned spinal cords. Cross‐sectional sections of spinal cord tissue, at 12 weeks post‐injury, stained with Eriochrome cyanine R to detect tightly packed myelin in SHAM (top row) and spinal‐cord–injured pigs (bottom row). Scale bar = 1 mm. Spinal cord injury results in the loss of myelin, large cavitation, and tissue disorganization extending away from the lesion epicenter. Total spared gray matter (left panel) and spared white matter (right panel) determined by area measurements taken from axial sections of spinal cord tissue 800 μm apart in all spinal cord injured animals.