PROJECT SUMMARY/ABSTRACT Respiratory failure after spinal cord injury (SCI) impairs the health of the injured patients, and respiratory failure is the leading cause of death in patients with SCI. Treatment of respiratory failure consists of mechanical ventilation, in which a mechanical pump is used to facilitate air exchange with the lungs. Mechanical ventilation is invasive, costly, limiting, and carries with it a high risk of complications and death. Mechanical ventilation provides an unvarying pattern of ventilation that is not responsive to physiological demands; it does not recapitulate normal breathing. Normal breathing is a complex behavior under both voluntary and involuntary neural control; it is responsive (in milliseconds or less) to the physiological state of the patient. Restoration of fully integrated, naturalistic breathing would represent a significant advance in the treatment of respiratory failure following SCI. The main hurdle to accessing the neural network for breathing for therapeutic purposes is that the neural mechanisms controlling respiration reside deep in the brainstem, which is dangerous to access surgically. Recently, we elucidated a novel breathing pathway in the spinal cord that can be modulated by electrical stimulation of the cervical spine, an area that is surgically accessible. We have compiled significant data that stimulating the cervical spine can restore or augment breathing. Clinically approved epidural spinal cord stimulators exist to treat pain, and these stimulators can also be used to stimulate the cervical spine to restore respiratory function. The main objective of this project is to provide proof of the concept that cervical epidural stimulation can improve respiratory function in ventilator-dependent patients with SCI and define the stimulation parameters that most effectively restore more normal breathing. The deliverables for this 5-year project include establishing the safety and feasibility of epidural stimulation for respiratory rehabilitation in SCI and providing an algorithm to select the optimum stimulation variables to augment respiratory activity in each patient (e.g., stimulation site, dose, and timing). If successful, we anticipate using epidural stimulation to partially or completely wean each patient with SCI off mechanical ventilation, which would have immediate benefits — increased independence, improved quality of life, and decreased costs and risks associated with mechanical ventilation. Conventional thinking is that once the spinal cord is injured, little or no functional recovery is possible. This dire sense of irrreversibility is at odds with our research in spinal cord neuromodulation, which has shown that substantial recovery of voluntary hand and upper extremity function can result from epidural spinal cord stimulation. A similar neurmodulatory strategy may be used to augment or restore respiratory function in patients with SCI. If successful, this neuromodulatory strategy t...