PROJECT SUMMARY Approximately 60% of hemiparetic stroke-survivors experience significant chronic motor deficits in their paretic upper limb, typically caused by damage to the corticospinal tract (CST). Alternative neural pathways, such as the cortico-reticulospinal tract (CRST), can be recruited to achieve movement of the affected arm and hand, but may have undesirable consequences. For example, the diffuse, bilateral branching of reticulospinal neurons can produce abnormal muscle co-activations (synergies) in the paretic limb, and involuntary mirror movements (associated reactions) between limbs. Together, these effects create stereotypical movement patterns post- stroke, and there is growing interest in novel "anti-synergy" interventions to enhance usage of residual CST systems rather than strengthening the CRST. Imaging has the potential to become an invaluable tool for evaluating whether rehabilitative strategies can preferentially access CST versus CRST pathways. However, current functional imaging research has focused on cortical activity, and must theoretically infer what pathway is used. Structural MRI can directly assess changes in white matter pathways, but it is limited to detecting long- term plasticity. To guide new interventions, there is a critical need to directly evaluate what descending motor pathways are active during specific movements. Thus, the overall objective of this study is to generate a novel fMRI dataset in participants with post-stroke hemiparesis, capturing neural activity during unilateral hand- grasping throughout the CST and CRST, and to evaluate differences when grasping with the paretic versus non- paretic hand. Our lab has developed advanced strategies to improve fMRI signal quality, but we show that large datasets per person are still needed to accurately localize and interpret activation patterns; this is challenging in stroke-survivors, who may fatigue quickly. Our innovative MRI-compatible hand-grip device provides supported, adjustable arm positioning and real-time force feedback, allowing us to reproduce a motor task across multiple sessions and generate sufficient data. In Aim 1, we acquire multi-echo fMRI data in the brain and brainstem; we hypothesize that increased reliance on the CRST will cause increased ipsilateral cortical and brainstem activation when grasping with the paretic limb, and that this will correlate with functional impairment (Upper-Extremity Fugl- Meyer Assessment). In Aim 2, we acquire fMRI data in the spinal cord; we hypothesize that grasping with the paretic hand will be associated with increased activation in more superior cord segments (intra-limb synergies) and grasping with the non-paretic hand will correspond to increased activation in the contralateral hemi-cord (associated reactions). We will also explore how neural activity correlates with individual EMG measures of muscle co-activation. This work is significant because it will provide direct evidence of descending motor ...