Mechanisms through which epidural electrical stimulation restores locomotion after spinal cord injury

Epidural electrical stimulation (EES) of the lumbar spinal cord restored
locomotion in rodents, nonhuman primates and humans with spinal cord injury
(SCI). However, the neural structures through which EES enables motor pattern
formation remain poorly understood. Using calcium imaging and chemogenetic
inactivation experiments, we demonstrate that the activation of proprioceptive
feedback circuits contributes to motor pattern formation during EES. However,
EES also recruits cutaneous low-threshold mechanoreceptor feedback circuits.
Modeling experiments showed that the activation of these pathways with EES is
detrimental to the production of locomotion. To augment the facilitation of
movements with EES, we thus reasoned that these two types of circuits should be
targeted with opposing neuromodulators. This understanding translated into a
circuit-specific electrochemical neuromodulation therapy based on noradrenergic
receptor modulation that enabled robust locomotion in paralyzed mice and rats.
These findings establish a mechanistic framework for the design of targeted
neuromodulation therapies in human patients.