Abstract
BackgroundPain is a highly prevalent symptom experienced by patients across numerous rare musculoskeletal conditions. Much remains unknown regarding the central, neurobiological processes associated with clinical pain in musculoskeletal disease states. Fibrodysplasia ossificans progressiva (FOP) is an inherited condition characterized by substantial physical disability and pain. FOP arises from mutations of the bone morphogenetic protein (BMP) receptor Activin A receptor type 1 (ACVR1) causing patients to undergo painful flare-ups as well as heterotopic ossification (HO) of skeletal muscles, tendons, ligaments, and fascia. To date, the neurobiological processes that underlie pain in FOP have rarely been investigated. We examined pain and central pain mechanism in FOP as a model primary musculoskeletal condition. Central nervous system (CNS) functional properties were investigated in FOP patients (N = 17) stratified into low (0–3; 0–10 Scale) and high (≥ 4) pain cohorts using functional near-infrared spectroscopy (fNIRS). Associations among clinical pain, mental health, and physical health were also quantified using responses derived from a battery of clinical questionnaires.ResultsResting-state fNIRS revealed suppressed power of hemodynamic activity within the slow-5 frequency sub-band (0.01–0.027 Hz) in the prefrontal cortex in high pain FOP patients, where reduced power of slow-5, prefrontal cortex oscillations exhibited robust negative correlations with pain levels. Higher clinical pain intensities were also associated with higher magnitudes of depressive symptoms.ConclusionsOur findings not only demonstrate a robust coupling among prefrontal cortex functionality and clinical pain in FOP but lays the groundwork for utilizing fNIRS to objectively monitor and central pain mechanisms in FOP and other musculoskeletal disorders.
Highlights
Pain is a highly common driver of reduced quality of life across rare, musculoskeletal diseases [4, 21, 32]
Mental health and physical health Of the 17 enrolled Fibrodysplasia ossificans progressiva (FOP) patients (Table 1), 11 individuals (6 males, 5 females) were categorized in the low pain (Pain Level: 0–3/10) cohort at the time of functional near-infrared spectroscopy (fNIRS) data acquisition, while 6 female patients were allotted to the high pain (Pain Level: ≥ 4) group
A comparison of pain levels between the first and second evaluation time points demonstrated that while pain intensity remained relatively stable for many FOP patients, others showed increases or decreases in pain (Fig. 2)
Summary
Pain is a highly common driver of reduced quality of life across rare, musculoskeletal diseases [4, 21, 32]. While there have been advances in understanding central abnormalities in musculoskeletal diseases [26, 50], Peng et al Orphanet J Rare Dis (2021) 16:54 neurological processes underlying pain in a chronic musculoskeletal state remain largely undefined. The mutant form of ACVR1 confers activin-A-dependent osteogenic signaling, which results in the heterotopic ossification (HO) of soft, connective tissue structures such as skeletal muscles, tendons, ligaments, and fascia [7, 13, 14], often leading to progressive immobilization and persistent pain. Much remains unknown regarding the central, neurobiological processes associated with clinical pain in musculoskeletal disease states. FOP arises from mutations of the bone morphogenetic protein (BMP) receptor Activin A receptor type 1 (ACVR1) causing patients to undergo painful flare-ups as well as heterotopic ossification (HO) of skeletal muscles, tendons, ligaments, and fascia. Associations among clinical pain, mental health, and physical health were quantified using responses derived from a battery of clinical questionnaires
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