PROJECT SUMMARY Shoulder pain is extremely common after stroke and occurs in 30-70% of patients. Chronic post stroke shoulder pain (PSSP) contributes to depression, interferes with motor recovery, and decreases quality of life. Although PSSP is thought to be caused by damage to the myofascial tissues around the shoulder joint, the pathophysiology of myofascial dysfunction and pain in PSSP has not been elucidated, leading to missed opportunities for early diagnosis and variable success with pain management. The accumulation of hyaluronic acid (HA) in muscle and its fascia can cause myofascial dysfunction. HA is a glycosaminoglycan (GAG) and a chief constituent of the extracellular matrix of muscle. In physiologic quantities, it functions as a lubricant and a viscoelastic shock absorber, enabling force transmission during muscle contraction and stretch. Reduced joint mobility and spasticity can result in focal accumulation and alteration of HA in muscle, leading to the development of taut bands, dysfunctional gliding of deep fascia and muscle layers, reduced range of motion (ROM), and pain. Muscle HA concentrations can be imaged using T1rho (T1ρ) MRI, and myofascial dysfunction can be assessed using echo texture analysis and shear strain mapping on quantitative ultrasound (US), which may serve as useful biomarkers to elucidate the pathophysiology of myofascial dysfunction in PSSP. Hence, in the R61 phase we will: (1) Quantify the extent of GAG/HA accumulation using T1ρ MRI in the paretic versus non-paretic shoulder rotator muscles, and correlate the T1ρ MRI measurements with US echo texture measurements to develop a clinic-friendly tool to infer the extent of HA accumulation; and (2) Distinguish between latent versus active PSSP using US shear strain mapping of the same muscles on the paretic side compared with the non-paretic side during passive shoulder external rotation (ER), which is strongly associated with PSSP. To proceed to the R33 phase, we will demonstrate a statistically significant difference in (1) GAG/HA accumulation using T1ρ MRI, and (2) shear strain mapping for latent and active PSSP using quantitative US. In the R33 phase, we will use the imaging metrics identified in the R61 phase to monitor treatment response in a clinical trial of intramuscular (IM) hyaluronidase injections to increase pain-free passive shoulder ER-ROM. We will administer human recombinant hyaluronidase or normal saline injections in the dysfunctional shoulder girdle muscles, and measure pain-free shoulder ER-ROM (primary outcome) (1) pre-injection, (2) 1–2 weeks post-injection (primary endpoint) and (3) 6-8 weeks post-injection. We expect that local hyaluronidase injections will breakdown the accumulated HA leading to increased pain-free shoulder ER, and that the improvement will correlate with quantitative MRI and US imaging metrics. At its conclusion, this proposal will develop quantitative imaging biomarkers of myofascial dysfunction to monitor response to treatment and aligns with the NIH HEAL Initiative to bolster research to enhance pain management.

PROJECT NARRATIVE Shoulder pain occurs in 30-70% of patients after stroke, contributes to depression, interferes with motor recovery, and leads to decreased quality of life. However, the cause of the myofascial dysfunction has not been elucidated leading to missed opportunities for early diagnosis and variable success with treatment. This project is of significant public health importance, because it will develop quantitative imaging biomarkers of myofascial tissues and assess their ability to monitor responses and predict outcomes in post stroke shoulder pain, and aligns with the NIH HEAL Initiative to bolster research to improve treatment, prevention of opioid misuse and opioid use disorder, and enhance pain management.