Background & Aims
Fibromyalgia syndrome (FMS) is characterised by chronic pain, widespread sensitivity to somatic stimulation, fatigue and cognitive difficulties [1]. Previous research has demonstrated changes in central nervous system function in people with FMS. Studies of resting state functional MRI have demonstrated altered connectivity between cortical structures and to the brainstem, notably the periaqueductal grey matter (PAG) [2,3,4]. We previously studied whether people with FMS can generate an endogenous analgesic response [5]. That fMRI experiment utilised a 2×2 factorial design, with applied temperature (low, high) and cognitive task difficulty (easy, hard) adjusted for individual differences in pain sensitivity and task performance, respectively. When compared to controls, we found that attentional analgesia was preserved in FMS. Here we explore whether the amount of endogenous analgesia is correlated with brain activity, and if FMS and control subjects show the same relationship.
Methods
Twenty people with FMS (mean age 43, range 25-60; 18 females) and 20 healthy subjects (mean age 35, range 20-59; 18 females) were recruited (P=0.03). All subjects were right-handed. Subjects underwent clinical assessment (e.g. ACR Widespread Pain and Symptom Severity Indices) and quantitative sensory testing (reported elsewhere [5]). Subjects’ performance at the Rapid Serial Visual Presentation (RSVP) task was measured and adjusted. The temperature of CHEPS thermode (MEDOC) was adjusted to produce a pain rating of (6/10), and a warm thermal stimulus (0/10). Task and thermal stimulation were presented concurrently (Easy|Low; Hard|Low; Easy|High; Hard|High) and responses record with brainstem optimised whole-brain fMRI (3T Siemens Skyra). Analysis was performed in FSL software, with an inter-subject regression model performed at the whole brain level (cluster threshold Z>3.1, P(corrected)<0.05), and within PAG, locus coeruleus (LC) and rostral ventromedial medulla (RVM) masks.
Results
The average temperature eliciting a pain rating of 6/10 (used for fMRI) in people with FMS was 42±2°C, and in control subjects 43±2°C (P=0.047). The median interstimulus interval for the hard version of the RSVP task was 96ms for people with FMS and 64ms in controls (P=0.008). Individual analgesic ratings for FMS and controls (Easy|High minus Hard|High) were demeaned across the entire group and regressed against brain activity (Hard|High minus Easy|High), with separate regressors for mean and analgesic ratings for each sub-group (i.e. four regressors). At the whole brain level, two-group difference demonstrated that analgesic ratings were positively related to brain activity in the medial prefrontal cortex (mPFC), adjacent to the rostral anterior cingulate (rACC), in FMS but not control subjects. Within a priori defined regions of interest, the same relationship was observed in the PAG alone (assessed via permutation testing and threshold free cluster enhancement, P(corrected)<0.05).
Conclusions
By using a model that explored potentially distinct associations between analgesia and brain activity, it was possible to identify potentially different mechanisms by which the brain achieves the same goal: namely endogenous analgesia. The association between analgesic efficacy of distraction and mPFC/rACC and PAG activity in people with FMS, but not controls, may reflect engagement of a descending pain modulatory system, whose activity (in the presence of chronic pain) confers an analgesic advantage. Interestingly the “same” areas investigated in a pre-clinical pain model using optogenetic selection of a circuit involving PAG and pre-limbic regions, revealed that activation is analgesic in the presence of nociceptive stimulation [6]. Whilst some recent studies have opened the intriguing possibility that autoimmune responses may be causative in FMS [7], it is also apparent that the pain produced will also depend on top-down processes, and thus amenable to psychological intervention.
References
(1)Sarzi-Puttini, P., Giorgi, V., Marotto, D., & Atzeni, F. (2020). Fibromyalgia: an update on clinical characteristics, aetiopathogenesis and treatment. Nature Reviews Rheumatology, 16(11), 645–660. https://doi.org/10.1038/s41584-020-00506-w
(2)Kim, J., Loggia, M. L., Cahalan, C. M., Harris, R. E., Beissner, F., Garcia, R. G., Kim, H., Barbieri, R., Wasan, A. D., Edwards, R. R., & Napadow, V. (2015). The Somatosensory Link in Fibromyalgia: Functional Connectivity of the Primary Somatosensory Cortex Is Altered by Sustained Pain and Is Associated With Clinical/Autonomic Dysfunction. Arthritis & Rheumatology, 67(5), 1395–1405. https://doi.org/10.1002/art.39043
(3)Ichesco, E., Puiu, T., Hampson, J. P., Kairys, A. E., Clauw, D. J., Harte, S. E., Peltier, S. J., Harris, R. E., & Schmidt?Wilcke, T. (2016). Altered fMRI resting?state connectivity in individuals with fibromyalgia on acute pain stimulation. European Journal of Pain, 20(7), 1079–1089. https://doi.org/10.1002/ejp.832
(4)Truini, A., Tinelli, E., Gerardi, M. C., Calistri, V., Iannuccelli, C., Cesa, S. L., Tarsitani, L., Mainero, C., Sarzi-Puttini, P., Cruccu, G., Caramia, F., & Franco, M. D. (2016). Abnormal resting state functional connectivity of the periaqueductal grey in patients with fibromyalgia. Clinical and Experimental Rheumatology, 34(2 Suppl 96), S129-33.
(5)Oliva, V., Gregory, R., Brooks, J. C. W., & Pickering, A. E. (2022). Central pain modulatory mechanisms of attentional analgesia are preserved in fibromyalgia. PAIN, 163(1), 125–136. https://doi.org/10.1097/j.pain.0000000000002319
(6)Drake, R. A., Steel, K. A., Apps, R., Lumb, B. M., & Pickering, A. E. (2021). Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats. eLife, 10, e65156. https://doi.org/10.7554/elife.65156
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Presenting Author
Jonathan Brooks
Poster Authors
Jonathan Brooks
BSc MSc PhD
University of East Anglia
Lead Author
Valeria Oliva PhD
Center for Behavioral Sciences and Mental Health, Italian National Health Institute.
Lead Author
Robert Gregory
Bristol Medical Practice
Lead Author
Anthony Pickering MB ChB
PhD
University of Bristol
Lead Author
Topics
- Specific Pain Conditions/Pain in Specific Populations: Fibromyalgia