Spreading Depolarizations and Perfusion in Non-traumatic Spinal Cord Injury

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Cervical spondylotic myelopathy (CSM) is the most common cause of spinal cord damage in older adults. It is characterized by physical compression of the spinal cord and often progresses gradually over months to years, manifesting as weakness, numbness, and pain. Because it is a disease that disproportionately affects an aging population and leads to decreased quality of life, it has a high relevance to Veterans. Many patients with CSM have favorable outcomes after surgical intervention, but opportunities to improve outcomes through mechanistic understanding of the disease process and improved diagnostic markers would be beneficial to improve diagnosis and patient management, potentially leading to improvements in therapies. This project aims to examine the role of spreading depolarization and perfusion deficits in the context of CSM in preclinical animal models. Spreading depolarization (SD) is an abnormal wave of ionic and electrical that propagates through central nervous system tissues after an insult. While SDs have been well-established and characterized after acute physical trauma, they have not been investigated with persistent or repetitive physical compression of the spinal cord that is the hallmark of CSM. Further, SDs and underlying perfusion deficits are tightly coupled. Neurons with sufficient oxygen and glucose can recover from SDs, but neurons that are lack sufficient metabolic substrates have a high likelihood of being irreparably damaged by SDs. This project will use an animal model and electrophysiological recordings to characterize SD events in the spinal cord in the context of continuous or dynamic physical compression (Aim 1). In parallel, it will examine the perfusion deficits in the spinal cord using MRI or intraspinal pressure sensors in the context of a clinically relevant animal model of CSM with progressive spinal cord compression (Aim 2). Collectively, these studies will elucidate the mechanisms of spinal cord damage in CSM and may provide new avenues for diagnostic markers. Detecting abnormal perfusion noninvasively with MRI has a clear translational path for subsequent clinical studies of CSM patients. The team of investigators on this project have individual expertise in all of the different subject areas, and their combined multi-disciplinary approach to these studies will collectively examine a new research area with potential high clinical relevance and translational opportunities.