Sixty-four individuals with stroke will be recruited. Efforts will be made to recruit the same participants for each protocol. A REDCap database for this study will be setup to manage every step involved in the protocol.

The experiment uses a two-arm, cross-over, double-blinded, pre-test-post-test, randomized controlled design. After confirming eligibility, all enrolled participants will be scheduled for one anatomic brain MRI data collection and 6 arm/ hand experiments: 2 for each aim, one with TIZ and the other with placebo. All experiments will take place on separate days at least one week apart. During each of the experimental sessions, the participant will complete the protocol both before and 1.5 hours after administration of either TIZ or a placebo. The order of using TIZ or a placebo will be double-blinded and randomized to balance the FMA of the participants who receive the TIZ or placebo during their first session. In Aim 1, individuals will perform various isometric tasks with their paretic upper limb while high-density surface electromyography is used to estimate the behavior of their motor units. In Aim 2, individuals will perform isometric shoulder abduction with their cortical activity estimated with electroencephalography and their muscle activity recorded with electromyography. In Aim 3, individuals will be placed in a novel robotic device and asked to produce various shoulder abduction torques while either being perturbed by the device to elicit stretch reflexes or asked to perform reaching and hand-opening tasks. For all aims, joint torque and surface electromyographic data will be obtained from each participant before and 1.5 hours after administration of placebo or Tizanidine. Additionally, electroencephalographic data will be obtained during the second aim and joint kinematics will be obtained in the third aim. In all aims, participants will be seated in a Biodex chair (System 3 ProTM; Shirley, New York, USA) with their paretic limb interfaced to a novel haptic device (NACT-3D, Plaisier et. al., 2023) to measure and manipulate the forces/torques experienced by the participant. Throughout each session, straps will be placed across the chest and waist to prevent unwanted movement. The total time from enrollment to completion of participants is expected to be 8-12 weeks, during which participants will be instructed to keep performing routine daily activities.

AE and SAE reporting Adverse event (AE) report form has been implemented in the RedCap database, which can be used at any time. The investigators will report all AEs to the Northwestern Institutional Review Board (IRB) per established policies and requirements. The investigators will create AE reports every six months to review for trends and troubleshoot any issues that arise and require study protocol revision. If any AEs are reported that require follow-up medical care, the investigators will immediately refer the participant back to his/her physician team.

Serious adverse events (SAEs) that are unanticipated, serious, and possibility related to the study intervention will be reported to the Independent Monitor(s), IRB, and National Institute of Child Health and Human Development (NICHD) in accordance with requirements. Unexpected fatal or life-threatening AEs related to the intervention will be reported to the Northwestern IRB in accordance with IRB requirements within 24 hours, and to the NICHD program Officer with 7 days. Other serious and unexpected AEs related to the intervention will also be reported to the Northwestern IRB in accordance with IRB requirements within 24 hours, and to the NICHD program Official within 15 days. Anticipated or unrelated SAEs will be handled in a less urgent manner but will be reported to the PIs, IRB, NICHD, and other oversight organizations in accordance with their requirements. In the annual AE summary, the PIs Report will state that they have reviewed all AE reports.