This study is to create a test that can accurately find and measure the problem areas in muscle and fascia tissue, also known as myofascial pain. The hypothesis is that a combination of imaging findings will be able to detect when myofascial pain is present. The goal is to improve management of myofascial pain by making better tools to find changes in the muscle and fascia tissues for a more personalized treatment. This project was funded by the HEAL initiative (https://heal.nih.gov/).

The objective of the R61 phase is to use novel imaging techniques to develop a diagnostic biosignature to objectively and accurately determine the location and severity of abnormal myofascial tissue. A cross-sectional study design approach with 3 groups: plantar fasciitis (n=50), Achilles tendinopathy (n=25), and pain-free controls (n=25) to test Specific Aim: Develop a diagnostic imaging biosignature of myofascial tissue to differentiate individuals with plantar fasciitis from other foot pain without a myofascial component (Achilles tendinopathy) and from matched pain-free controls.

The goal is to develop a diagnostic imaging biosignature that will be able to distinguish between A-MTrP in individuals with plantar fasciitis compared to healthy tissue control (pain-free controls). The biosignature developed in this R61 phase will be screened for clinical utility and considered of interest for further study if it meets the following milestone criteria: area under the receiver operating characteristic curve (ROC AUC) >0.7, sensitivity >60%, and specificity >60%. The ROC analysis will estimate diagnostic performance by comparing differences in biosignatures between tissue where myofascial pain is present vs. tissue where pain is absent.

The proposed sample size of 50 individuals with plantar fasciitis, 25 individuals with Achilles tendinopathy, and 25 matched controls was chosen to provide a confidence interval halfwidth of 0.10 for an AUC of 0.70, assuming 5 muscle measurements for each participant and an overall A-MTrPs prevalence of 0.36 in individuals with plantar fasciitis. Further assuming the 20 biomarkers to be considered in the R61 phase have AUCs uniformly distributed from 0.5 to 0.8, will have at least 85% power to obtain a biosignature meeting the milestone criteria.

Inclusion criteria for plantar fasciitis group:

• Clinical diagnosis of plantar fasciitis
• Duration of plantar fasciitis pain greater than or equal to 3 months
• Severity of plantar fasciitis pain greater than or equal to 3/10

Inclusion criteria for Achilles tendinopathy group:

• Clinical diagnosis of insertional Achilles tendinopathy:
• Duration of Achilles tendinopathy pain greater than or equal to 3 months
• Severity of Achilles tendon pain greater than or equal to 3/10

Control group:

• Similar age, sex, and BMI as plantar fasciitis and Achilles tendinopathy groups

Exclusion criteria:

• Younger than 18 years of age
• History of an invasive procedures to the foot and ankle on the side of interest
• History of lower extremity injections, dry needling, or EPAT/ESWT within past 3 months on the side of interest
• Contraindications for MRI (e.g. non-MR compatible implanted devices, claustrophobia, inability to remain still comfortably for 1 hour in a supine position, body size too large for MR scanner)
• Clinically unstable medical or psychiatric issues
• Pregnant or possibly pregnant
• Co-morbidities associated with changes in musculoskeletal imaging, including: Diagnosed systemic conditions affecting the foot and ankle (e.g., rheumatoid arthritis, spondyloarthropathy, gout) endocrine disorder with complications (e.g., uncontrolled Type I or II diabetes, diabetic peripheral neuropathy) Neuromuscular diseases (e.g., Charcot-Marie-Tooth (CMT) disease) Connective tissue disorder (e.g. Marfan's syndrome, Ehlers-Danlos) Osteoarthritis of the foot or ankle History of foot or ankle fracture Infection of the foot or ankle (e.g., infectious fasciitis, calcaneal osteomyelitis) within the past year Familial hypercholesterolemia Neoplasms involving the foot, Plantar fibromatosis
• Control group only: Persistent or recurrent leg pain in the past 6 months
• Plantar fasciitis and Achilles tendinopathy groups only: Other source of heel or foot pain (e.g., tarsal tunnel syndrome, peripheral neuropathy, lumbar radiculopathy, calcaneal stress fracture, Morton's neuroma, fibromyalgia) or co-occurring plantar fasciitis and Achilles tendinopathy (for the Achilles tendinopathy group).

All data that is necessary to validate primary outcomes and publications will be preserved and shared to allow other researchers the ability to reproduce the data and obtain additional findings that can advance the results. To ensure that other users can efficiently and accurately use the dataset, as well as to prevent misinterpretation or misuse, we will provide metadata and associated documentation. Information needed to understand the meaning of variable names and information about coding for missing data will be recorded in data dictionaries and readme files that will subsequently be shared alongside final datasets. Protocols, methods, statistical analyses, and any other relevant documentation derived from notes during data collection will be incorporated into readme files that will accompany the data when shared.

IPD will be available within 1 year of completing the study or upon publication, whichever occurs first. The data will remain available for at least 10 years. The primary outcome data and accompanying metadata will be deposited into an NIH Helping End Addiction Long-term (HEAL) compliant data repository.

The primary outcome data and accompanying metadata will be deposited into an NIH Helping End Addiction Long-term (HEAL) compliant data repository. In accordance with International Committee of Medical Journal Editors (ICMJE), we will prepare the primary analysis datasets for review and reproducibility by peer-reviewed journals.

Publications will be made available to the public using open access publishing, so that they become immediately available to the public. All publications will be accessible through PubMed, Google Scholar, and through open access.