Pujol et al. Arthritis Research & Therapy (2022) 24:252 https://doi.org/10.1186/s13075-022-02942-3 RESEARCH Open Access Distinctive alterations in the functional anatomy of the cerebral cortex in pain‑sensitized osteoarthritis and fibromyalgia patients Jesus Pujol1,2*, Laura Blanco‑Hinojo1,2, Andrea Doreste1, Fabiola Ojeda3, Gerard Martínez‑Vilavella1, Víctor Pérez‑Sola2,4, Joan Deus1,5 and Jordi Monfort3 Abstract Background: Pain-sensitized osteoarthritis and fibromyalgia patients characteristically show nociceptive system augmented responsiveness as a common feature. However, sensitization can be originally related to the peripheral injury in osteoarthritis patients, whereas pain and bodily discomfort spontaneously occur in fibromyalgia with no apparent origin. We investigated the distinct functional repercussion of pain sensitization in the cerebral cortex in both conditions. Methods: Thirty-one pain-sensitized knee osteoarthritis patients and 38 fibromyalgia patients were compared with matched control groups. And new samples of 34 sensitized knee osteoarthritis and 63 fibromyalgia patients were used to directly compare each condition. A combined measure of local functional connectivity was estimated to map functional alterations in the cerebral cortex at rest. Results: In osteoarthritis, weaker local connectivity was identified in the insula, which is a cortical area processing important aspects of the brain response to painful stimulation. In contrast, fibromyalgia patients showed weaker con‑ nectivity in the sensorimotor cortex extensively affecting the cortical representation of the body. Conclusions: In osteoarthritis, weaker insular cortex connectivity is compatible with reduced neural activity during metabolic recovery after repeated activation. In the fibromyalgia neurophysiological context, weaker connectivity may better express both reduced neural activity and increased excitability, particularly affecting the sensorimotor cortex in patients with spontaneous body pain. Such a combination is compatible with a central gain enhancement mechanism, where low sensory tolerance results from the over-amplification of central sensory reception to compen‑ sate a presumably weak sensory input. We propose that deficient proprioception could be a factor contributing to weak sensory input. Keywords: Functional MRI, Pain sensitization, Fibromyalgia, Knee osteoarthritis, Somatosensory cortex, Insular cortex Background Knee osteoarthritis is often associated with augmented pain responses due to the sensitization of the nocic- *Correspondence: 21404jpn@comb.cat eptive system [1, 2]. In this case, lower pain thresholds 1 MRI Research Unit, Department of Radiology, Hospital del Mar, Passeig and regional spreading of pain can be originally related Marítim 25‑29. , 08003 Barcelona, Spain to the peripheral damage. In contrast, augmented pain Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Pujol et al. Arthritis Research & Therapy (2022) 24:252 Page 2 of 13 sensitivity characteristically occurs in fibromyalgia with identification of distinctive alterations may contribute to no evident origin [3]. The International Association for a better understanding of the sensitization phenomena. the Study of Pain (IASP) has recently proposed the term nociplastic pain precisely to indicate the presence of pain Methods arising from altered nociception despite no clear evi- All studies were conducted in accordance with the prin- dence of tissue damage or lesion of the somatosensory ciples expressed in the Declaration of Helsinki, and each system [4, 5]. protocol was approved by the Ethical Committee of Clin- A number of changes in functional connectivity have ical Research of the Parc de Salut Mar of Barcelona (ref. been identified on the brain scale in knee osteoarthritis MP-TAP-2016–01) or the Ethics and Institutional Review [6–11]. The insula appears to be particularly affected with Board of the Autonomous University of Barcelona (ref. a loss of its central role as a hub in pain network organi- PID2021-127703OB-I00). All participants provided writ- zation [8] and altered functional relationships with other ten informed consent. networks [7, 8, 11]. In fibromyalgia, changes in connectiv- ity have been identified in the insula (e.g., [12]) and each Study design nociception-processing level (e.g., [2, 13–16]), including This was an observational case–control study that used the sensorimotor cortex [2, 14, 15] and affecting areas historical samples to compare each patient’s condition in processing other sensory modalities [2, 14]. Interestingly, terms of the IDAC measures with a corresponding con- the insula may reinforce its role as a connectivity hub trol group matched by age and sex. And new patient sam- [14] and the coupling to the posterior cingulate cortex ples were recruited to directly compare both disorders. [16] in fibromyalgia in the opposite direction to the effect observed in knee osteoarthritis [7, 8]. All in all, the avail- Study populations able data at the large cortical scale led us to hypothesize The study was conducted at the Hospital del Mar, Bar- that alterations in cerebral cortex local connectivity meas- celona, Spain. All the participants were recruited by ures would be distinct in primary and secondary sensiti- Rheumatology researchers from the Osteoarthritis and zation disorders. Fibromyalgia Referral Units. Historical samples included We investigated the functional repercussions of pain 31 pain-sensitized knee osteoarthritis patients (Osteo- sensitization on cerebral cortex local, short-distance con- arthritis Sample 1) matched to 23 control subjects [2] nectivity using iso-distance average correlation (IDAC) and 38 fibromyalgia patients (Fibromyalgia Sample 1) to measures [17]. IDAC expresses the functional coupling 35 control subjects [20]. The new samples included 34 of a brain unit (voxel) with their neighboring elements. sensitized knee osteoarthritis patients (Osteoarthritis Three IDAC measures were combined to inform on the Sample 2) recruited in 2019 and 2020 and 63 fibromyal- rich spatial structure of cortical connectivity. Local func- gia patients (Fibromyalgia Sample 2) recruited in 2021 tional connectivity maps may provide information about and 2022. Patients from the new samples participated cortical functioning insofar as variations in local connec- in two different intervention studies (EudraCT registra- tivity are related to neural activity variations. However, tion 2016–005,082-31 and ClinicalTrials.gov identifier for optimal interpretation, it is important to consider NCT03785535). Only baseline (prior to any intervention) that variations in local connectivity are related to varia- images were used in the present analysis. tions in the activity of both principal/pyramidal neurons Sample selection and inclusion criteria have been and inhibitory interneurons. That is, stronger connectiv- previously described [2, 20, 21]. In short, the included ity may express higher principal neuron activity (more osteoarthritis patients showed a radiological and clinical coactivated elements) [17], but also higher inhibitory diagnosis of knee osteoarthritis based upon the Ameri- interneuron activity (higher neural synchronization) [18], can Rheumatism Association criteria [22] and pain sensi- and vice versa [19]. tization affecting the knee defined by combining clinical In this study, we used combined IDAC measures to and experimental (pain thresholds) evidence (see below) identify changes in local functional connectivity of the [2, 21]. Fibromyalgia patients were all diagnosed by a cerebral cortex in pain-sensitized knee osteoarthritis and rheumatologist in accordance with the American Col- fibromyalgia patients. Each clinical condition was pri- lege of Rheumatology criteria for fibromyalgia [23] and marily compared with a matched control group and new were consecutively recruited during clinical follow-up to samples were used to directly compare both disorders. make up a homogeneous sample with durable and severe We suspected that the functional anatomy of the cerebral symptoms (minimum Fibromyalgia Impact Question- cortex may be affected differently in primary and second- naire (FIQ) score [24], 40 out of 100 points). As for the ary sensitization disorders to the extent that sensitiza- control groups, subjects with relevant medical or neu- tion could have different origins. In such a context, the rological disorder, any form of chronic or acute pain, Pujol et al. Arthritis Research & Therapy (2022) 24:252 Page 3 of 13 substance abuse, or psychiatric disease were not consid- USA) with acquisition parameters set as repetition time, ered for inclusion. 2000 ms; echo time, 50 ms; pulse angle, 90°; 24-cm field of view; 64 × 64-pixel matrix; and slice thickness 4 mm. Clinical assessments Functional MRI for the rest of the samples was acquired Osteoarthritis samples using a Philips Achieva 3.0-T magnet (Philips Healthcare, Screening included complete medical history, physi- Best, The Netherlands) with repetition time, 2000 ms; cal examination, ECG, and X-ray of the knee. The pres- echo time, 35 ms; pulse angle, 70°; 23-cm field of view; ence and severity of pain sensitization were evaluated 64 × 64-pixel matrix; and slice thickness, 3.59 mm. High- by expert clinical judgment, pain intensity scores in the resolution 3D anatomical images were also obtained in preceding 24 h based on items 3 to 6 of the Brief Pain each case based on a T1-weighted three-dimensional fast Inventory [25], number of tender points around the knee spoiled gradient inversion recovery-prepared sequence, on the 10-site extended Arendt-Nielsen peripatellar which served to assist image processing. map [1, 2], and pain temporal summation in an 11-point numerical rating scale (NRS) after 10 repeated pressure stimulations on the anterior/medial tibial surface [2]. Iso‑distant average correlation (IDAC) maps Additional clinical assessments included The Western Imaging data were processed using MATLAB version Ontario and McMaster Universities Osteoarthritis Index 2016a (The MathWorks Inc, Natick, Mass) and Statisti- (WOMAC) physical-function scale (Cronbach’s alpha cal Parametric Mapping software (SPM12; The Wellcome internal consistency ranging from 0.70 to 0.95) [26], the Department of Imaging Neuroscience, London). Image PainDETECT questionnaire (Cronbach’s alpha of 0.86 for processing steps adopted to generate the cerebral cor- the whole scale) [27], and an 11-point pain rating gener- tex IDAC maps have been previously reported [17], and ated with a pressure of 4 kg/cm2 during 2 s on the tibial a detailed description is provided in Additional file 1. surface. Below is a summary. Functional MRI images were slice-time corrected, Fibromyalgia samples realigned, co-registered to their corresponding ana- Clinical assessments included complete medical history tomical image, re-sliced to 3 × 3 × 3 mm resolution, and and physical examination, review of the American Col- smoothed by convolving the image with a 4 × 4 × 4 mm lege of Rheumatology criteria for fibromyalgia [23], num- full width at half maximum (FWHM) Gaussian kernel. ber of tender points out of 18 body sites (pain threshold Motion-affected image volumes were discarded using equal or under 4 kg/cm2), Fibromyalgia Impact Question- conventional scrubbing procedures [31]. naire (Cronbach’s alpha of 0.82 for the total items) [24], IDAC measures were then estimated in native space. General Perception of Health according to the 36-Item The computation was conducted in a gray matter mask Short-Form Health Survey (Cronbach’s alpha > 0.75) [28, split into left and right hemispheres. Whole-cortex IDAC 29], Hospital Anxiety and Depression Scale (HADS) maps were generated by estimating the average temporal ratings (Cronbach’s alpha of 0.86 for both Anxiety and correlation of each voxel with all its neighboring voxels Depression sub-scales) [30], and a 101-point numerical placed at increasingly separated Euclidean iso-distant rating of spontaneous (non-evoked) pain globally per- intervals (definition and mathematical formulation are ceived in the body before functional magnetic resonance provided in the Additional file 1). Three IDAC maps were imaging (MRI). obtained at distance intervals of 5–10 mm, 15–20 mm, and 25–30 mm. The analyses were adjusted by includ- MRI acquisition ing 6 rigid body realignment parameters, their first-order In all study samples, functional MRI was acquired in the derivatives, average white matter, CSF, and global brain resting state and as the first sequence in the session. Par- signal as regressors. All functional MRI time series were ticipants were instructed to relax, stay awake, and lie still, band-passed with a discrete cosine transform (DCT) while keeping their eyes closed throughout. Each scan filter letting through frequencies in the 0.01–0.1-Hz was obtained using eight-channel phased-array head interval. coils and single-shot echo-planar imaging (EPI) software. Finally, the resulting IDAC maps in native space were The functional sequences always consisted of gradient normalized to the Montreal Neurological Institute (MNI) recalled acquisition in the steady state, lasted 6 min, and space with a back-transformation process. That is, origi- generated 180 whole-brain image volumes (TR, 2 s). nal EPI images had previously been normalized using Functional MRI for the Osteoarthritis Sample 1 and the study-specific templates based on the 3D anatomical corresponding control group was acquired using a 1.5-T images and the estimated parameters were applied to the Signa Excite system (General Electric, Milwaukee, WI, inverse normalization of IDAC maps. Pujol et al. Arthritis Research & Therapy (2022) 24:252 Page 4 of 13 Multi-distance IDAC color maps were obtained All study analyses were based on statistical parametric from the overlay of the three IDAC maps using an RGB brain maps. In the first analysis, osteoarthritis and fibro- color codification (see Figs. 2 and 4). RGB color chan- myalgia patients were compared with their respective nels enabled the display of three values simultaneously. control groups to map brain areas with altered connec- Red corresponds to the results from 5–10-mm IDAC tivity (primary analysis) and to determine whether the map analyses, green from 15–20 mm, and blue from alterations involve the spatial structure (i.e., differential 25–30 mm. The overlapping of these primary colors pro- implication of distinct local distances). The ANOVA test- duces a full range of secondary colors. Composite RGB ing the main effect of the group across the three distances maps were generated from the between-group compari- showed significant differences between osteoarthritis son t-maps obtained for each distance. patients and control subjects involving the insula bilat- erally extending to the ventral-lateral frontal cortex and visual areas in the occipital cortex. Group-by-distance Statistical analysis interaction showed a significant effect in the left pos- Sample size terior insula and right anterior insula (Supplementary There is no consensus as to sample size estimation for Table 1 and Supplementary Fig. 1 in Additional file 1). functional MRI studies. Empirical experiments have In fibromyalgia patients, significant differences were demonstrated that a number above 24 subjects is optimal identified with their respective controls across the three to achieve 80% power for a corrected threshold of 0.05 in distances in the sensorimotor cortex involving most lev- conventional task activation experiments [32]. els of the cortical body representation and visual areas in We used a double approach to characterize cerebral the occipital cortex. Significant group-by-distance inter- cortex functional alterations in two patient conditions action was observed in the inferior (opercular) level of representing distinct age populations. Firstly, the com- the somatosensory cortex, angular gyrus, and visual cor- parison of each clinical disorder with a matched control tices (Supplementary Table 1 and Supplementary Fig. 1 in group allowed us to appreciate qualitative differences as Additional file 1). to the functional anatomy of the alterations. In a second Post hoc analysis comparing patients and control analysis, new samples of osteoarthritis and fibromyalgia groups showed that all the alterations were in the direc- patients were directly compared using age as a covariate tion of weaker connectivity in patients compared to which enabled us to confirm group differences in the cor- control subjects in both osteoarthritis and fibromyalgia tical distribution of changes. In addition, the age effect on (Figs. 1 and 2). The analysis also revealed that, as a gen- connectivity measures was directly assessed with a corre- eral effect, the alteration implicated the short distances lation analysis to further separate age from clinical condi- more than the long distance, indicating that the dysfunc- tion effects. tional effect primarily involves regional, short-distance IDAC connectivity maps were included in SPM group- cortical information transfer (Fig. 2). wise random-effects analyses adopting a 2 × 3 mixed In the second analysis, a new group of osteoarthritis design ANOVA (ANCOVA) model (e.g., group [patients, patients was directly compared with a new group of fibro- controls] by distance [5–10 mm, 15–20 mm, and myalgia patients adjusting for age. Results from group 25–30 mm]). A motion summary measure (mean inter- effects across the three distances showed significant dif- frame motion [31]) for each participant was included as a ferences in the sensorimotor cortex in the direction of covariate in all analyses and age when directly comparing weaker connectivity in fibromyalgia patients compared osteoarthritis with fibromyalgia patients. We specifically to knee osteoarthritis patients (Supplementary Table 2 tested for group effects to map brain areas with altered in Additional file 1 and Fig. 3). Significant group-by-dis- connectivity (primary study question) and for group-by- tance interaction was observed in the inferior (opercular) distance interactions to determine whether the altera- level of the somatosensory cortex, angular gyri, lateral tions concerned to the spatial structure (i.e., differential occipito-temporal junction, and lateral (ventral and dor- implication of distinct local distances). In all analyses, sal) frontal cortex. A separate analysis by local connectiv- results were considered significant when clusters formed ity distances showed that weaker somatosensory cortex at a threshold of p < 0.005 survived whole-brain family- connectivity in fibromyalgia mainly involved the short wise error (FWE) correction (p < 0.05), calculated using distances (Fig. 4). In addition, osteoarthritis patients SPM. showed weaker connectivity than fibromyalgia patients in the left frontal operculum, inferior parietal lobe, and Results medial frontal pole. Therefore, patient group comparison The characteristics of the study samples are reported in overall identified areas overlapping with the patterns of Table 1. alterations observed when each condition was compared Pujol et al. Arthritis Research & Therapy (2022) 24:252 Page 5 of 13 Table 1 Clinical characteristics of the study samples Control subjects (N = 23) Osteoarthritis Sample 1 (N = 31) Osteoarthritis Sample 2 (N = 34) Age, years mean 63.3 (7.5) 65.6 (8.8) 63.7 (7.7) Sex, number F/M 13/10 27/4 26/8 Radiological severity ___ 2.0 (0.7) 2.3 (0.5) WOMAC index, total 3.7 (6.3) 33.0 (11.9) 40.7 (19.6) PainDetect 2.9 (3.7) 10.5 (5.7) 11.2 (6.2) Clinical pain intensity (BPI)a 4.6 (6.0) 17.4 (5.4) 19.8 (6.7) Tibial region ­painb 0.9 (1.3) 7.3 (1.6) 6.9 (2.2) Number of knee tender points 0.3 (0.7) 3.9 (1.7) 6.7 (2.2) Temporal summation 0.3 (0.7) 1.8 (1.5) 1.6 (2.6) Spontaneous body pain (max. 100) ___ ___ 4 (14) Control subjects (N = 35) Fibromyalgia Sample 1 (N = 38) Fibromyalgia Sample 2 (N = 63) Age, years mean 43.9 (6.0) 46.4 (7.5) 49.3 (8.0) Sex, number F/M 35/0 38/0 63/0 Illness duration, years ___ 7.0 (4.6) 6.6 (6.1) Fibromyalgia tender points, n° ___ 16.0 (1.9) 17.1 (1.5) FIQ, total score ___ 66.8 (13.9) 66.6 (13.9) FIQ, functional capacity ___ 4.9 (1.9) 6.0 (2.1) General Perception of Health-SF36 ___ 31.2 (18.3) 39.2 (15.2) HADS ratings for depression ___ 8.8 (4.9) 8.9 (3.9) HADS ratings for anxiety ___ 11.3 (4.0) 10.3 (4.9) Spontaneous body pain (max. 100) ___ 71.7 (15.4) 73.1 (16.7) Quantitative data are expressed as mean (SD) General Perception of Health according to the 36-Item Short-Form Health Survey (maximum score, 100) WOMAC Western Ontario and McMaster Universities Osteoarthritis Index, BPI Brief Pain Inventory, FIQ Fibromyalgia Impact Questionnaire (maximum score, 100), HADS Hospital Anxiety and Depression Scale a Severity score on items 3 to 6 of the Brief Pain Inventory b Pain generated with a pressure of 4 kg/cm2 during 2 s Fig. 1 Main effects of group across the three local connectivity distances. Osteoarthritis and fibromyalgia patients are compared with their respective control groups. All the identified alterations were in the direction of weaker connectivity in the patient condition Pujol et al. Arthritis Research & Therapy (2022) 24:252 Page 6 of 13 Fig. 2 Separate analysis by each local connectivity distance and the RGB composite display. As a general effect, the alteration implicated more the short distances and were all in the direction of weaker connectivity in the patient condition compared with the respective control group with its respective control group, which confirms that However, a negative correlation with age was observed the distribution of cortical dysfunction is distinct in both in the left auditory cortex at a lower threshold (Supple- clinical conditions. mentary Fig. 2 in Additional file 1). This analysis indicates A final analysis was conducted to assess the effect of that, although the effect was marginal in osteoarthritis, it age on study connectivity measures in patients. Across was also in the direction of age-related local connectivity groups and distances, including both osteoarthritis weakening in the auditory cortex. and fibromyalgia patients, the most relevant effect was observed in the auditory cortex showing a negative cor- Discussion relation between functional connectivity and age (Fig. 5, We used combined measures of local connectivity to Supplementary Table 3 in Additional file 1). There were map functional alterations in the cerebral cortex in two no significant results when comparing the age effect clinical conditions showing augmented sensitivity to between osteoarthritis and fibromyalgia. Separate analy- pain as a common feature, but with suspected differ- ses by group and distances revealed a negative corre- ent origins. The results revealed a distinctive pattern of lation (older age, weaker connectivity) in the auditory functional alterations in the cerebral cortex. The most cortex, visual cortex, somatosensory cortex, and frontal relevant alterations in local connectivity for osteoarthri- operculum/anterior insula (gustatory cortex) in fibro- tis patients were identified in the insular cortex, which myalgia patients. In osteoarthritis patients, a significant processes important aspects of the brain response to negative correlation was restricted to the lateral aspect of pain [33], whereas fibromyalgia patients showed altera- the frontal pole at the whole-brain significance threshold. tions in the sensorimotor cortex extensively affecting the Pujol et al. Arthritis Research & Therapy (2022) 24:252 Page 7 of 13 Fig. 3 Comparison between osteoarthritis and fibromyalgia patients. Significant main group effect across the three distances (top) and group-by-distance interactions (bottom) are presented cortical representation of the body. In both groups, corti- the cortex. In fibromyalgia, however, the situation may cal dysfunction occurred in the form of lower connectiv- be interestingly more intricate. Indeed, neurophysiologi- ity, although this may express distinct pathophysiological cal studies consistently show a deficient inhibition of alterations in osteoarthritis and fibromyalgia. the cerebral cortex in fibromyalgia patients [43]. A defi- Sensitized osteoarthritis patients characteristically cient inhibition from gamma-aminobutyric acid (GABA) show increased pain and neural activity in response to interneurons may further contribute to local functional mechanical stimulation [1, 2]. However, in the absence of connectivity reduction, due to a loss in their synchroni- a stimulus (i.e., at rest), severe knee osteoarthritis is asso- zation effect [18]. Therefore, lower intra-regional senso- ciated with weakened functional connectivity [7, 8] and rimotor cortex connectivity may express both reduced reduced gray matter volume in the insular cortex [34–36]. activity of principal neurons (fewer active neurons) and Volume reductions in osteoarthritis may be reversible reduced activity of inhibitory interneurons (reduced after successful treatment, indicating that the anatomi- synchronization). cal alteration is not a predisposing factor but rather the In fibromyalgia, therefore, spontaneous pain and bod- consequence of biological stress from long-lasting pain ily discomfort occur without an obvious sensory input [37–40]. A valuable MR spectroscopy study demon- increase in individuals with low basal metabolism in a strated reversible reductions in N-acetylaspartate (NAA), hyperexcitable sensorimotor cortex. This combination of a marker of neural integrity, that led the authors to con- elements is phenomenologically compatible with a state clude that augmented neural activity in pain-processing of deafferentation hypersensitivity, where sensitization is areas would impair mitochondria-dependent energy sup- proposed to be the effect of gain enhancement of central ply and reduce resting neuronal activity [41]. In this con- sensory reception to compensate a “weak” sensory input text, lower local connectivity in the insular cortex in our [44–47]. “Central gain enhancement,” in the form of over- study is compatible with reduced neural activity during amplification of multi-level auditory signal reception, has metabolic recovery at rest following repeated activation been characterized in the case of hearing loss to account in osteoarthritis patients. for perceptual distortions in the quiet environment (tin- In fibromyalgia patients, imaging research has dem- nitus) and loudness intolerance (hyperacusis) [44, 48, 49]. onstrated baseline hypometabolism in the brain [42], The possibility of a relatively weak sensory input exists despite patients complaining of spontaneous, resting in more than one sensory domain in fibromyalgia [50, pain. Therefore, lower local connectivity in our study is 51], but let us focus on the proprioceptive system. The again consistent with reduced overall neural activity in female sex is an important risk factor for fibromyalgia Pujol et al. Arthritis Research & Therapy (2022) 24:252 Page 8 of 13 Fig. 4 Separate analysis by local connectivity distances comparing osteoarthritis and fibromyalgia patients. The bottom images show the RGB composite display [52]. Women characteristically show lower muscle (and nociceptive input [20]. In this context, sensory imbalance tendon) mass relative to the total body mass [53] and might also be accentuated from a net increase in body thus a less prominent proprioceptive (e.g., muscle spin- mass. Although obesity is not a necessary condition, a dles and Golgi tendon organs) structure. In addition, a high body mass index (without a parallel increase in mus- relevant portion (34%) of severe fibromyalgia patients cle mass) is a significant risk for developing fibromyalgia show low levels of insulin-like growth factors [54], [52, 56, 57]. Interestingly, increases in body mass index which mediate the growth hormone action of stimulat- were found to be coupled with the expansion of the cer- ing the collagen synthesis in tendon and skeletal muscle ebral cortex representation of the body in children [58], and ultimately optimizing their tensile properties [55]. which may well illustrate the somatosensory imbalance in It has been proposed that a primary imbalance between the cortical reception fields. nociceptive/non-nociceptive input, per se, could favor Beyond the body composition argument, however, pain perception without the need of a net increase in the most compelling evidence for a weak proprioceptive Pujol et al. Arthritis Research & Therapy (2022) 24:252 Page 9 of 13 Fig. 5 Age correlation analysis results. Top, negative correlation with age (older age, weaker connectivity) across groups and distances, including both osteoarthritis and fibromyalgia patients. The middle and bottom images show significant negative correlations with age in osteoarthritis (OA) and fibromyalgia (FM) patients for each local connectivity distance input in fibromyalgia is related to its low efficiency. For the phenomenon may be particularly detrimental due example, Ehlers-Danlos and related joint hypermobility to relevant pathway sharing and multi-level crosstalk syndromes are characterized by both high overlap with between mechanical non-nociceptive and nociceptive fibromyalgia symptoms and dysfunctional propriocep- somatosensory modalities [75, 76], which prevent the tion [59]. Also, joint hypermobility is three times more amplification of neural signals from being selective. Rel- frequent in fibromyalgia than in control groups [60]. evantly, such gain enhancement effects may contribute to And, importantly, upon specific proprioception test- low pain tolerance added to the aforementioned primary ing in fibromyalgia cohorts, significant alterations have pain propensity related to nociceptive/non-nociceptive been demonstrated in muscle contraction [61, 62], mus- input imbalance itself [20, 75]. cle relaxation [63], vibration perception [61], joint posi- Differences in the response to treatments further sup- tion sense [64–67], and the proprioceptive component port distinct pathophysiological mechanisms for pain of postural control [61, 65, 68–71] with frequent falls sensitization in both situations. For example, anti-inflam- [68, 72, 73]. Problems in postural control or balance are matory drugs are analgesic in osteoarthritis through the also related to altered vestibular and visual dysfunction inhibition of nociceptive sensitization [77, 78], whereas [68, 73, 74], which may indicate that sensory weakness opioids, powerful analgesic agents, may paradoxically is not limited to proprioception in fibromyalgia [50, 51]. favor pain sensitization [21], presumably by promoting the Therefore, the data support that proprioceptive (non- release of inflammatory mediators in the nervous system nociceptive) input may be relatively weak in fibromyalgia. [79]. In fibromyalgia, conventional analgesic/anti-inflam- This situation may promote compensatory mechanisms matory drugs are generally not effective [80]. In contrast, in the form of neural gain enhancement to optimize the significant effects on fibromyalgia symptom relief have signal, albeit at the expense of excessive noise (i.e., pain been obtained by stimulating proprioception with exer- and sensory discomfort). In the somatosensory system, cise or instrumental mechanical stimulation [80, 81]. In Pujol et al. Arthritis Research & Therapy (2022) 24:252 Page 10 of 13 a broader perspective, research on non-pharmacological extent that the results revealed different pathophysiological treatments for fibromyalgia is expanding with approaches mechanisms in both clinical conditions. Our observations seeking to modify the severity of symptoms through edu- may support the rational development of therapeutic strat- cation on the neurobiology of pain, used in combination egies in pain-sensitized patients, particularly in fibromyal- with exercise [82–84]. gia by further suggesting the targeting of the proprioceptive A limitation in our study is the comparison of clini- system. cal populations typically showing significant age dif- ferences. We adopted what we considered to be the Abbreviations optimal strategy to circumvent such a limitation. Each IDAC: Iso-distance average correlation; NRS: Numerical rating scale; EPI: Echo- clinical condition was compared with a matched con- planar imaging; MRI: Magnetic resonance imaging; MNI: Montreal Neurologi‑ trol sample and new samples were used to compare cal Institute. groups adjusting for age. In addition, the effect of age was directly tested in the study samples. We found a Supplementary Information general effect of age with local connectivity weakening The online version contains supplementary material available at https://​doi.​ org/​10.​1186/​s13075-​022-​02942-3. in the sensory cortex. Importantly, the lowest values in connectivity in the sensory cortex were observed Additional file 1: Supplementary Material. Description of data: Supple‑ in the young group (i.e., fibromyalgia), which would mentary Methods. Supplementary Figures. Supplementary Tables. essentially rule out the effect of age in terms of the dif- ferences observed between fibromyalgia and osteoar- Authors’ contributions thritis patients. JP: study conception and design, acquisition and interpretation of the data, and writing up of the first draft of the paper. LBH: acquisition and analysis of We would also mention that the described imaging the data. AD: acquisition and analysis of the data. FO: acquisition and analysis findings in both pain sensitization conditions do not of the data. GMV: acquisition and analysis of the data. VPS: study conception comprehensively express all the functional repercussions and design. JD: study conception and design and interpretation of the data. JM: study conception and design and interpretation of the data. The authors on the brain. We used a specific measure that captured read and approved the final manuscript. changes in the local functional structure of the cerebral cortex. However, previous research has demonstrated Funding This work was supported in part by the Ministry of Economy, Industry and distinct brain alterations using, for instance, large-scale Competitiveness of Spain (Grant PSI2017-83777-P). The funder has no role in functional connectivity measures [6–16]. It is also rel- this study. evant to emphasize that fibromyalgia is a complex syn- Availability of data and materials drome showing a variety of comorbid expressions (e.g., The datasets used and/or analyzed during the current study are available from migraine, irritable bowel syndrome, chronic fatigue syn- the corresponding author on reasonable request. drome, depression, and catastrophizing) that were not considered in the present study, whose aim was limited to Declarations comparing two clinical disorders. Ethics approval and consent to participate Each protocol was approved by the Ethical Committee of Clinical Research of Conclusions the Parc de Salut Mar of Barcelona or the Ethics and Institutional Review Board of the Autonomous University of Barcelona. All participants provided written In osteoarthritis, we observed functional alterations within informed consent. the insula at rest, which is a cortical structure showing robust activation during painful stimulation. This finding Consent for publication Not applicable. may be interpreted as an eventual consequence of repeated nociceptive input in this condition. In fibromyalgia, func- Competing interests tional disturbances implicated the sensorimotor cortex The authors declare that they have no competing interests. extensively affecting the cortical representation of the body. Author details In the fibromyalgia neurophysiological context, the identi- 1 MRI Research Unit, Department of Radiology, Hospital del Mar, Passeig fied changes can be better understood in terms of a deaffer- Marítim 25‑29. , 08003 Barcelona, Spain. 2 CIBER de Salud Mental, Instituto de Salud Carlos III, Barcelona, Spain. 3 Rheumatology Department, Hospital del entation hypersensitivity phenomenon, where sensitization Mar, Barcelona, Spain. 4 Institute of Neuropsychiatry and Addictions, Hospital is proposed to be the effect of gain enhancement of central del Mar- IMIM, Pompeu i Fabra University, Barcelona, Spain. 5 Department sensory reception to compensate a weak sensory input. of Psychobiology and Methodology in Health Sciences, Autonomous University of Barcelona, Barcelona, Spain. We would propose that deficient proprioception could be a contributing factor to weak sensory input. 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