Detangling spinal respiratory network responses to cervical epidural stimulation after spinal cord injury

Respiratory insufficiency is the leading cause of mortality after spinal cord injury, yet current pacing strategies override brainstem rhythm generators, limiting adaptability and rehabilitation. Electrical stimulation of the spinal cord in the locomotor system enables volitional patterned movements after injury by activating spinal central pattern generators. However, as the central pattern generators for breathing lie in the brainstem, it is unclear what neural populations are acted upon when rhythmic bursting is reanimated by electrical stimulation of the cervical spinal cord after injury. Here, in anesthetized rats with cervical injury, we show that inspiratory-triggered, expiratory-triggered, and tonic stimulation all elicit diaphragm motor output, but descending inputs and spinal inhibition are necessary to achieve appropriate endogenous respiratory patterning. Short-latency responses and increasing immediate early gene expression indicate recruitment of local spinal interneurons, including inhibitory populations. This furthers our understanding of the respiratory neural populations epidural stimulation interacts with and highlights the necessity of inspiratory-patterned stimulation.