PROJECT SUMMARY / ABSTRACT Spinal cord injury (SCI) is a devastating event in terms of a person’s health, physical function, costs (direct and indirect), and life expectancy. It has been conventionally thought that individuals with severe SCIs, with no motor function below the level of injury, will not recover the ability to functionally move their lower extremities or voluntarily walk. However, spinal cord stimulation (SCS) has emerged as a promising intervention challenging this long-held assumption. While spinal cord stimulation allows for restored voluntary movement after severe SCI, there is a lack of mechanistic understanding regarding how it works and why some individuals respond better than others. Thus, the overall objective of this proposal is to apply neuroimaging biomarkers to generate fundamental knowledge regarding responsiveness to spinal cord stimulation (SCS). Aim 1: Use neuroimaging biomarkers to understand responsiveness to epidural SCS in participants with severe SCI, during volitional movement and standing tasks. Using high-resolution MRI in a prospective design, the applicant hypothesizes that the laterality of cord damage, detected prior to surgical implantation, will predict ipsilateral lower extremity muscle responsiveness to epidural SCS prior to any training. Aim 2: Use neuroimaging biomarkers to understand responsiveness to transcutaneous SCS in participants with severe SCI, during volitional movement tasks and sensory examination. Using high- resolution MRI in a prospective design, the applicant hypothesizes that total spinal cord spared tissue will predict bilateral lower extremity muscle responsiveness to transcutaneous SCS prior to any training, and that posterior cord spared tissue will predict light touch sensory recovery prior to any training. Significance: Successful completion of these Aims will advance the NIH/NICHD NCMRR aim: “to enhance the health, productivity, independence, and quality of life of people with physical disabilities.” One important problem in the field of SCS is a lack of foundational knowledge on why the intervention works. Neuroimaging holds pronounced potential to address this problem. Neuroimaging biomarkers will not only improve the understanding of responsiveness to this intervention after SCI, but will also help drive individualized approaches for using SCS, selection of epidural versus transcutaneous SCS, prognosis for improvement using SCS, and the identification of who is likely to optimally respond before activity-based recovery training. Completion of the proposed aims will lead to the high likelihood of sustained, powerful influence on the SCS field, laying a vital foundation for using MRI biomarkers to guide SCS intervention, ultimately improving the clinical management of persons with SCI.