Plasticity of the injured human spinal cord: insights revealed by spinal cord functional MRI

Abstract

Introduction: While numerous studies have documented evidence for plasticity of the human brain there is little evidence that the human spinal cord can change after injury. Here, we employ a novel spinal fMRI design where we stimulate normal and abnormal sensory dermatomes in persons with traumatic spinal cord injury and perform a connectivity analysis to understand how spinal networks process information.

Methods: Spinal fMRI data was collected at 3 Tesla at two institutions from 38 individuals using the standard SEEP functional MR imaging techniques. Thermal stimulation was applied to four dermatomes in an interleaved timing pattern during each fMRI acquisition. SCI patients were stimulated in dermatomes both above (normal sensation) and below the level of their injury. Sub-group analysis was performed on healthy controls (n = 20), complete SCI (n = 3), incomplete SCI (n = 9) and SCI patients who recovered full function (n = 6).

Results: Patients with chronic incomplete SCI, when stimulated in a dermatome of normal sensation, showed an increased number of active voxels relative to controls (p = 0.025). There was an inverse relationship between the degree of sensory impairment and the number of active voxels in the region of the spinal cord corresponding to that dermatome of abnormal sensation (R(2) = 0.93, p<0.001). Lastly, a connectivity analysis demonstrated a significantly increased number of intraspinal connections in incomplete SCI patients relative to controls suggesting altered processing of afferent sensory signals.

Conclusions: In this work we demonstrate the use of spinal fMRI to investigate changes in spinal processing of somatosensory information in the human spinal cord. We provide evidence for plasticity of the human spinal cord after traumatic injury based on an increase in the average number of active voxels in dermatomes of normal sensation in chronic SCI patients and an increased number of intraspinal connections in incomplete SCI patients relative to healthy controls.

Figure 1. Spinal Coordinates.

The above coordinate system was used to localize regions of the cervical spinal cord to the associated sensory dermatome. The pink arrow represents a rostral landmark – the ponto-medullary junction. The blue line represents the anterior border of the spinal cord. Shown on the right is an axial view with the white cerebrospinal fluid (CSF) along with the coordinates used to identify the ventral-dorsal and right-left divisions of the spinal cord. Zones of the spinal cord (C1 through C8) are labeled in white lettering and based on anatomic dissection of the cervical nerve rootlets as they emerge from the spinal cord (see text for further details and reference).

Figure 2. Single subject results.

Shown is the spinal fMRI region of interest analysis of an uninjured 24-year-old male who underwent thermal stimulation of the C5 and C8 dermatomes on both the right and left side. The blue bar graphs represent the absolute number of active voxels contained within the dorsal quadrant each spinal cord zone. Positive indicates a change in proton density above the resting baseline and negative indicates a change below the resting baseline. Below each bar graph is the activation pattern across the stimulated region in axial cross-section. A T2 anatomical image is provided to the right for reference.

Figure 3. Region of interest analysis.

Left panel: A region of interest (ROI) analysis conducted in a healthy individual (A and B) and a chronic SCI patient (C and D); axial images through the cervical zone of the spinal cord corresponding to the dermatome stimulated. A: Thermal stimulation of the right C5 dermatome of a 30 year old male. B: Thermal stimulation of the left C8 dermatome of the same individual. C: Thermal stimulation of the right C5 dermatome in a 19 year old male with a chronic C6 ASIA D SCI. D: Thermal stimulation of the left C8 dermatome in the same individual. Right: Quantification of the ROI analysis across all healthy controls (n = 20) and incomplete SCI patients (n = 9). Bar graph: uninjured controls stimulated at the C5 dermatome (blue) and C8 dermatome (red). Incomplete, chronic SCI patients stimulated above the level of injury (green) and below the level of injury (purple). A one way ANOVA was significant at p = 0.003. Post hoc tukey test revealed a significant difference between thermal stimulation above the level of injury in chronic SCI patients, *p = 0.025. There was no significant difference between thermal stimulation of the C5 and C8 regions of control participants. There was no significant difference between thermal stimulation below the level of injury in chronic SCI patients and thermal stimulation of either the C5 or C8 regions in healthy controls.

Figure 4. Spinal fMRI/sensory deficit relationship.

Pearson’s correlation analysis between the absolute number of active voxels in the spinal cord dorsal quadrant region of interest (corresponding to the dermatome stimulated) and the AIS clinical sensory score of that same dermatome. All data contained within this analysis was taken from incomplete SCI patients who were stimulated in dermatomes below the level of their SCI. R² = 0.93, p<0.001. AIS sensory score  = 8, normal sensation. AIS sensory score  = 0, no sensation. AIS sensory score encompasses both pin-prick and light touch clinical tests.

Figure 5. Spinal connectivity analysis.

From left to right: Interspinal connectivity analysis in healthy controls (projected image), statistical comparison of controls to incomplete SCI patients (bar graph), interspinal connectivity analysis in incomplete SCI patient (projected image) and statistical comparison of controls to recovered SCI patients. The projected images represent a single subject from three angles (oblique left, coronal, obliqe right). The blue lines represent interspinal connections, the orange-yellow lines represent spinal cord-caudal brainstem connections and the red spectrum represents spinal cord-rostral brainstem connections. The number of inter-spinal connections to the prime cluster is shown as a projected image for both uninjured controls (A) and incomplete, chronic SCI patients (B). A one-way ANOVA comparing the mean number of interspinal connections to the prime cluster across healthy control (blue and red bar graph), incomplete SCI (green and purple bar graph) and recovered SCI participants (yellow and orange bar graph) was significant (p<0.001). Significant post-hoc Tukey tests included the difference between control participants stimulated in the C5 dermatome and incomplete SCI patients stimulated above the level of injury (* p = 0.045, blue vs. green bar graph) and recovered SCI participants stimulated above the level of injury (# p = 0.03, blue vs. yellow bar graph).