Neural correlates of conditioned pain responses in fibromyalgia subjects indicate preferential formation of new pain associations rather than extinction of irrelevant ones

Abstract

Behavioral studies have demonstrated aberrant safety processing in fibromyalgia subjects (FMSs) and suggested that patients accumulate new potential pain-related threats more effectively than extinguishing no longer relevant ones. The aim of the current study was to investigate the neural correlates of conditioned pain responses and their relationship with emotional distress in FMS (n = 67) and healthy controls (HCs, n = 34). Using functional magnetic resonance imaging, we traced conditioned pain responses to an identical moderately painful pressure (P30) depending on whether it was following a green (P30green) or a red (P30red) cue. The cues were previously associated with individually calibrated painful pressure stimuli of low and high intensity, corresponding to visual analogue scale 10 and 50 mm, respectively. Fibromyalgia subjects displayed increased P30green ratings over time, while P30red ratings remained elevated. Healthy controls adapted all pain ratings to resemble moderate pain. Fibromyalgia subjects exhibited increased activation for [P30green>P30red] in M1/anterior insula, whereas HC showed increased S2/mid-insula response to [P30red>P30green]. High pain catastrophizing scale (PCS) ratings in fibromyalgia (FM) covaried with heightened brain activation for [P30green] × PCS in left dorsolateral prefrontal cortex and medial prefrontal cortex/orbitofrontal cortex; and [P30green>P30red] × PCS in dorsal anterior cingulate cortex/mid-cingulate cortex; superior temporal pole, extending to anterior insula; bilateral thalamus; and posterior insula. Psychophysiological interaction analysis for FM [P30green>P30red] × PCS revealed a dissociation in functional connectivity between thalamus and bilateral inferior parietal lobe. In alignment with behavioral data, FMS displayed a cerebral response suggesting preferential formation of new pain-related associations while simultaneously maintaining no longer relevant ones. The opposite was observed in HC. Increased responses to pain-related threats in FM may contribute to dysfunctional pain-protective behaviors and disability.

Polymorphisms of the μ‐opioid receptor gene influence cerebral pain processing in fibromyalgia

“…In addition, there was no correlation observed between PCC activation obtained from the ROI analysis and PCS scores. Note that using data from the same project we recently found that higher catastrophizing in FM is associated with increased BOLD response in prefrontal cortices and reduced functional connectivity between inferior parietal lobe and thalamus during pressure pain stimulation in a previously conditioned low‐pain condition (Sandström et al., 2020). Importantly, the previously reported correlation between the BOLD response and catastrophizing was located in other brain regions than the OPRM1 effect observed in the current data.…”

“…Note that this study is part of a larger project (see study plan https://osf.io/8zqak) including additional imaging methods and paradigms investigating pain processing in FM (Albrecht et al., 2019). One goal of the overall project was to investigate conditioned pain responses in FM subjects (Sandström et al., 2020), which have previously displayed deficits in conditioning and contingency learning (Jenewein et al., 2013; Meulders et al., 2018). Given the need to ensure successful pain conditioning in a sufficient number of participants, a larger number of FM subjects than HC was included in the project, resulting in different group sizes also in the current study.…”

“…Intensity of pressure stimulations were individually calibrated to represent approximately 10/100 VAS (P10) and 50/100 VAS (P50). Figure adapted from (Sandström et al., 2020)…”

“…Behavioural data analysis was performed with R (RStudio Team, 2016) and included 118 participants (FM patients n = 79, HC n = 39) ( Table 1). A chi-squared test and fisher's exact test were used to analyse genotype frequencies and to assess deviations from Hardy-Weinberg equilibrium.…”

Serotonergic gene-to-gene interaction is associated with mood and GABA concentrations but not with pain-related cerebral processing in fibromyalgia subjects and healthy controls

“…Stimulus intensity was individually calibrated to match 10 mm (P10) and 50 mm (P50) on a VAS ranging from 0 mm (no pain) to 100 mm (strongest imaginable pain). The procedure is described in Additional file 1 and in [ 45 , 46 ].…”