Project Summary/Abstract The proposed SPiRE builds on preliminary work in which we have observed a relationship between efficacy of the corticospinal tract serving the plantarflexors and walking function, specifically ankle plantarflexor power, in individuals with chronic post-stroke hemiparesis. We have observed robust associations between: i) PF corticospinal efficacy, and ii) modulation of corticospinal drive, and PF power, particularly in individuals post- stroke. Importantly, clinical and demographic factors including: age, stroke chronicity, and lesion location, neither explain, nor modify, these associations. In combination, these findings lead to our central premise, that improved efficacy of the corticospinal tract serving the plantarflexors will enable augmentation of ankle PF power and contribute to improved walking function in individuals post-stroke. Here we propose to investigate use of paired associative stimulation (PAS) to enhance corticospinal efficacy and to the plantarflexors through targeted neuroplasticity. We will explore three approaches to PAS to determine its efficacy for enhancing: i) neural responses, ii) biomechanical effects (A2), and iii) retention of neural and biomechanical effects. Objectives. The proposed SPiRE focused on methodological variables required to optimize efficacy of PAS on: a) corticospinal efficacy to the plantarflexors, and b) walking function (quantified as A2) in Veterans with post- stroke walking dysfunction. By achieving our aims, data generated from this SPiRE will contribute to development of more focused and relevant hypotheses to be tested in future studies supported through competitive Merit Review. However, before motivating a larger study, we first seek to determine the salience and magnitude of effects of PAS. In addition to exploring methodological issues related to PAS, data generated from the proposed SPiRE will enable us to determine the appropriate scope of a future project including sample size and dosing. Our objectives are consistent with the programmatic guidelines of the SPiRE (RX-20-009), particularly as they relate to senior investigators. Specifically: i) this work has not previously been funded; ii) the question to be addressed in this proposal represents a new area of research, and a new collaboration, for the PI, and iii) we seek to develop our methodology, determine feasibility, and generate preliminary/exploratory data for sake of determining effect sizes and computing statistical power for future large scale studies in human subjects. We will compare effects of PAS targeting ankle plantarflexion when delivered: at rest, during submaximal activity, and during walking.