Silent progression in disease activity-free relapsing multiple sclerosis.

OBJECTIVE: Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, "no evidence of disease activity" at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation. METHODS: Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates. RESULTS: Relapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05). INTERPRETATION: Long-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666.

Assessing the Reconceptualization of Pain in Graduate-Entry Physiotherapy Students Using the Concept of Pain Inventory for Adults: The University of Technology Sydney Physiotherapy Student Surveys Project.

INTRODUCTION: Validly and reliably assessing conceptual change is essential for evaluating the effectiveness of pain science education for physiotherapy students. We aimed to 1) evaluate concept of pain before and after a 14-week pain science education university subject, 2) assess structural validity of the Concept of Pain Inventory for Adults (COPI-Adult) in postgraduate entry-level physiotherapy students, and 3) explore possible relationships between baseline variables and baseline COPI-Adult scores. REVIEW OF LITERATURE: As the COPI-Adult is a newly developed questionnaire, there is a lack of data regarding its psychometric properties. SUBJECTS: Of 129 enrolled students at an Australian university, 124 (96%) and 114 (88%) completed the baseline and follow-up questionnaires, respectively. METHODS: In this prospective cohort study, students who commenced the degree in 2020 or 2021 completed online questionnaires, including the COPI-Adult, at the start and end of their first semester. This semester included a 14-week pain science education subject and other physiotherapy-related subjects. Higher COPI-Adult scores (range = 0-52) indicate better alignment with contemporary pain science. We 1) compared differences in concept of pain before and after the semester, 2) performed a confirmatory factor analysis on the COPI-Adult, and 3) performed exploratory regression analyses. RESULTS: Concept of Pain Inventory for Adults scores increased from baseline (median [interquartile range]: 39 [36-44]) to follow-up (48 [44-51]). The COPI-Adult retained its 1-factor structure, with acceptable internal consistency (Cronbach's alpha = 0.80). Exploratory analysis showed that previously completing a subject on pain was related to higher COPI-Adult baseline scores. Age, gender, and mental health diagnosis did not relate to baseline COPI-Adult scores. DISCUSSION AND CONCLUSION: Following a 14-week pain science education subject embedded within a physiotherapy degree, students improved their concept of pain. The COPI-Adult maintains a 1-factor structure in this population. Completing a previous subject on pain was associated with higher COPI-Adult scores.

Amygdala functional connectivity mediates the association between catastrophizing and threat-safety learning in youth with chronic pain.

ABSTRACT: There is a need to identify brain connectivity alterations predictive of transdiagnostic processes that may confer vulnerability for affective symptomology. Here, we tested whether amygdala resting-state functional connectivity (rsFC) mediated the relationship between catastrophizing (negative threat appraisals and predicting poorer functioning) and altered threat-safety discrimination learning (critical to flexibly adapt to new and changing environments) in adolescents with persistent pain. We examined amygdala rsFC in 46 youth with chronic pain and 29 healthy peers (age M = 15.8, SD = 2.9; 64 females) and its relationship with catastrophizing and threat-safety learning. We used a developmentally appropriate threat-safety learning paradigm and performed amygdala seed-based rsFC and whole-brain mediation analyses. Patients exhibited enhanced connectivity between the left amygdala and right supramarginal gyrus (SMG) (cluster-level P-FDR < 0.05), whereas right amygdala rsFC showed no group differences. Only in patients, elevated catastrophizing was associated with facilitated threat-safety learning (CS+>CS-; rp = 0.49, P = 0.001). Furthermore, in patients, elevated catastrophizing was associated with reduced left amygdala connectivity with SMG / parietal operculum, and increased left amygdala connectivity with hippocampus, dorsal striatum, paracingulate, and motor regions (P < 0.001). In addition, blunted left amygdala rsFC with right SMG/parietal operculum mediated the association between catastrophizing and threat-safety learning (P < 0.001). To conclude, rsFC between the left amygdala (a core emotion hub) and inferior parietal lobe (involved in appraisal and integration of bodily signals and attentional reorienting) explains associations between daily-life relevant catastrophizing and threat-safety learning. Findings provide a putative model for understanding pathophysiology involved in core psychological processes that cut across diagnoses, including disabling pain, and are relevant for their etiology.