Project Summary Post-stroke impairments, including muscle weakness, hyperactive muscle (hypertonia) and associated stretch reflexes (spasticity), and loss of independent joint control (flexion synergy), pose significant challenges to routine daily activities, making stroke a leading contributor to motor dysfunction in the United States. Our extensive research has identified abnormally increased motor neuron excitability post-stroke, hinting at elevated spinal norepinephrine (NE) levels. NE, a potent neuromodulator, not only intensifies and prolongs inputs to motoneurons but also increases reliance on indirect contralesional cortico-reticular tracts, as shown in the previous cycle of this R01 grant. Our central hypothesis suggests that reducing NE levels will diminish spinal motoneuron excitability, encourage the use of direct motor pathways from the lesional hemisphere, and improve motor performance in individuals post hemiparetic stroke. To validate this hypothesis, we will evaluate the impact of the drug Tizanidine (Zanaflex®, TIZ) on spinal motoneuron excitability, motor cortical activity, descending pathways utilization, and motor behavior of the paretic arm and hand in chronic hemiparetic stroke across various aims. More specifically, in Aim 1 we propose to evaluate Tizanidine's effect on spinal motoneuron excitability using high-density surface EMG during isometric tasks. Aim 2 will explore NE's role in amplifying the use of indirect motor pathways through EEG/EMG signals and kinetics during isometric shoulder abduction and hand-opening tasks. Aim 3 will examine NE's modulation of flexion synergy and spasticity, assessing spasticity expression before and during movement, as well as reaching distance and hand-opening ability as a function of shoulder abduction loading using a novel robotic paradigm. Anticipated results are expected to illustrate how NE-driven pathophysiological adaptations contribute to motor impairments in chronic stroke. This understanding will inform more effective rehabilitative strategies, integrating pharmacology with targeted physical interventions, aiming to enhance upper limb motor function and improve the quality of life for individuals post-hemiparetic stroke.