Abstract
Spinal cord injury (SCI) induces haemodynamic instability that threatens survival1-3, impairs neurological recovery4,5, increases the risk of cardiovascular disease6,7, and reduces quality of life8,9. Haemodynamic instability in this context is due to the interruption of supraspinal efferent commands to sympathetic circuits located in the spinal cord10, which prevents the natural baroreflex from controlling these circuits to adjust peripheral vascular resistance. Epidural electrical stimulation (EES) of the spinal cord has been shown to compensate for interrupted supraspinal commands to motor circuits below the injury11, and restored walking after paralysis12. Here, we leveraged these concepts to develop EES protocols that restored haemodynamic stability after SCI. We established a preclinical model that enabled us to dissect the topology and dynamics of the sympathetic circuits, and to understand how EES can engage these circuits. We incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic haemodynamic regulator that operates in a closed loop. This 'neuroprosthetic baroreflex' controlled haemodynamics for extended periods of time in rodents, non-human primates and humans, after both acute and chronic SCI. We will now conduct clinical trials to turn the neuroprosthetic baroreflex into a commonly available therapy for people with SCI.
Highlights
Institute, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, 5
The Spinal cord injury (SCI) instantly induced a transient spike in blood pressure and sympathetic nerve activity (Extended Data Fig. 2b-c), followed by a pronounced depression that persisted throughout the chronic phase (Fig. 1d). 24/7 monitoring of blood pressure and sympathetic nerve activity in home cage revealed that the SCI led to profound hemodynamic instability (Extended Data Fig. 2d-g)
After SCI, rats could no longer recover from the simulated orthostatic challenge (Fig. 1d). They exhibited sustained hypotension, the severity of which linearly correlated with the pressure in the chamber (Extended Data Fig. 2i). These results indicate that our preclinical model reproduced the hallmarks of hemodynamic instability observed in humans, and established heuristic conditions to dissect the mechanisms through which therapies could regulate hemodynamics after severe SCI
Summary
Spinal cord injury induces hemodynamic instability that threatens survival[1,2,3], impairs neurological recovery[4,5], increases cardiovascular disease risk[6,7], and reduces quality of life[8,9]. We established a novel preclinical model that enabled us to dissect the topology and dynamics of the sympathetic circuits, and understand how epidural electrical stimulation can engage these circuits We incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic hemodynamic regulator operating in closed-loop. The lumbosacral spinal cord contains a paucity of sympathetic efferent neurons, casting doubt that this approach harnesses the full potential of TESS to activate sympathetic circuits and achieve hemodynamic stability after SCI
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