Anatomical and Functional Neuroimaging Biomarkers for Spinal Cord Alterations in Degenerative Cervical Myelopathy

Abstract

Degenerative cervical myelopathy (DCM) is a common form of age-related, non-traumatic cervical cord compression that can lead to sensory or motor symptoms like loss of balance, loss of hand coordination, and pain. Previous investigations into DCM have found evidence of structural changes in both the white matter (WM) and gray matter (GM) that are associated with subjective clinical measurements and imply that they are the source of this impediment. However, whether the damage to these tissues can reflect clinical severity and impact spinal cord functionality is undetermined. Establishing these relationships and alterations can not only further our understanding of DCM’s pathophysiology but also help to create biomarkers that inform surgical decision making and reduce permanent neurological damage. Therefore, in my dissertation studies, I applied three different imaging methodologies to investigate changes in the structure and function of the DCM spinal cord. In my first study to indirectly measure the change in WM content between conservative and surgical treatment groups, I categorized DCM patients based on their modified Japanese Orthopaedic Association (mJOA) score (mild: 15-17; moderate/severe: 0-14). Comparisons between healthy controls (HCs) and the moderate/severe DCM groups revealed significant decreases in magnetization transfer ratio (MTR) in the ventral regional of the spinal cord, as well as several ventral cord tracts (e.g., ventral corticospinal and reticulospinal). Significant correlations were also found between the MTR values of the ventral reticulospinal tract and both upper and lower limb motor mJOA scores. To determine whether DCM impacts GM volume, I extracted overall and regional GM volumes from the level of maximum compression (MCL). When compared to HCs, the GM volume in DCM patients was significantly decreased in all GM regions. However, the GM of the spinal cord plays a key role in neuronal interconnectivity because it houses cell bodies that help form reflex arcs capable of responding to stimuli without input from the brain. To quantify any impairment to the GM spinal cord reflex arcs, an electrical stimulation paradigm aimed at activating these reflex arcs by inducing a minimal motor response was applied to the median nerve. This threshold was found to significantly increase in DCM subjects. Furthermore, the GM volume in the ventral region of DCM patients was also found to correlate to WM MTR in the ventral cord. Together, these first two structural MRI studies demonstrate a ventral region injury pattern that impacts motor performance and worsens as the myelopathy progresses. Not only can establishing this severity-sensitive injury pattern help to give insight into the progressive development of DCM, but it could also be applied as an objective indicator of structural damage by clinicians looking to prevent permanent neurological damage in patients. However, what this injury pattern cannot demonstrate is how these structural changes affect functional activity in the spinal cord. In my final study, subjects underwent two task-based fMRI sessions (sub-motor and motor) with electrical stimulation to the median nerve. The amount of blood oxygenation-level dependent (BOLD) activated voxels in HCs increased from the sub-motor stimulation condition to the motor stimulation condition and peaked at the C7 segment in both conditions. HC activations were bilaterally distributed and primarily located within the GM. Conversely in DCM patients, BOLD activations decreased from sub-motor and motor conditions, peaked at C6 during sub-motor activation, and were more distributed to the ipsilateral side of stimulation. The DCM sub-motor condition also had significant spikes in deactivation at C6, especially when compared to the HC sub-motor at C6. This task-based fMRI study represents the first effort to demonstrate a disruption to the overall, segmental, and lateralized functional activation and deactivation patterns in DCM spinal cords, which could indicate compensatory spinal cord mechanisms helping to retain partial motor and sensory functions in the wake of compressive structural damage. Combined, these studies establish a ventral cord injury pattern in DCM that could serve as structural biomarkers indicating severity-associated damage and alterations in functional patterns that could help to pave the way for the development of fMRI as a clinical biomarker.