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Brain morphometric changes in fibromyalgia and the impact of psychometric and clinical factors: a volumetric and diffusion-tensor imaging study

Brain morphometric changes in fibromyalgia and the impact of psychometric and clinical factors: a... Background Previous studies have repeatedly found distinct brain morphometric changes in patients with fibromy- algia (FM), mainly affecting gray and white matter abnormalities in areas related to sensory and affective pain process- ing. However, few studies have thus far linked different types of structural changes and not much is known about behavioral and clinical determinants that might influence the emergence and progression of such changes. Methods We used voxel-based morphometry ( VBM) and diffusion-tensor imaging (DTI) to detect regional patterns of (micro)structural gray (GM) and white matter ( WM) alterations in 23 patients with FM compared to 21 healthy controls (HC), while considering the influence of demographic, psychometric, and clinical variables (age, symptom severity, pain duration, heat pain threshold, depression scores). Results VBM and DTI revealed striking patterns of brain morphometric changes in FM patients. Bilateral middle temporal gyrus (MTG), parahippocampal gyrus, left dorsal anterior cingulate cortex (dACC), right putamen, right caudate nucleus, and left dorsolateral prefrontal cortex (DLPFC) showed significantly decreased GM volumes. In con- trast, increased GM volume was observed in bilateral cerebellum and left thalamus. Beyond that, patients displayed microstructural changes of WM connectivity within the medial lemniscus, corpus callosum, and tracts surrounding and connecting the thalamus. Sensory-discriminative aspects of pain (pain severity, pain thresholds) primarily showed negative correlations with GM within bilateral putamen, pallidum, right midcingulate cortex (MCC), and multiple thalamic substructures, whereas the chronicity of pain was negatively correlated with GM volumes within right insular cortex and left rolandic operculum. Aec ff tive-motivational aspects of pain (depressive mood, general activity) were related to GM and FA values within bilateral putamen and thalamus. Conclusions Our results suggest a variety of distinct structural brain changes in FM, particularly affecting areas involved in pain and emotion processing such as the thalamus, putamen, and insula. Keywords Fibromyalgia, Pain, MRI, Brain morphometry, Voxel-based morphometry, Diffusion tensor imaging *Correspondence: Martin Diers martin.diers@rub.de Full list of author information is available at the end of the article © The Author(s) 2023. 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. 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However, a variety of Introduction methodological differences should be considered when Fibromyalgia syndrome (hereinafter also referred to as comparing previous findings (e.g., data acquisition and “FM” for fibromyalgia) is a chronic pain disorder primar - analysis, heterogeneity of FM samples, different diag - ily characterized by widespread musculoskeletal pain that nostic criteria). Due to the diversity of symptoms expe- is oftentimes accompanied by a number of additional rienced in FM, it poses a special challenge to isolate the symptoms including cognitive, sleep and mood issues, specific effect that chronic pain has on patients’ brain fatigue, exhaustion, and an elevated risk for comorbidi- morphometry. ties [1, 2]. Patients with FM display an increased sensitiv- In this study, we explored morphometric GM and ity (lower pain thresholds/higher pain ratings) to various WM brain changes in FM compared to healthy controls pain modalities (thermal [3, 4], pressure [4, 5], electrical (HC) using magnetic resonance imaging (MRI) while [6, 7], chemical [8, 9]). This phenomenon usually involves considering the influence of various demographic, psy - allodynia (perceived pain due to a non-painful stimulus) chometric, behavioral, and clinical variables, involving and hyperalgesia (increased pain from a painful stimulus) age, symptom severity, pain duration, heat pain thresh- [10, 11]. old, and depression scores. We performed voxel-based The condition-specific combination of persistent physi - morphometry (VBM) on high-resolution T1-weighted ological, cognitive, and affective symptoms (listed above), MRI images in order to detect characteristic GM volu- along with continuous psychological distress, leads to a metric changes in FM. VBM is an analysis technique significant reported reduction of the perceived quality of that comprises a voxel-wise measurement of focal dif- life [12, 13] and is highly disabling. However, at the cur- ferences in local concentrations of brain tissue. FM- rent time, there is no universally recognized and effective specific WM changes were assessed using a diffusion treatment for FM and patients have a low probability of tensor imaging (DTI) sequence that utilizes anisotropic full recovery [14]. diffusion to estimate the WM (axonal) organization of The heterogeneity and quantity of FM symptoms have the brain. led to a candid debate about the etiology and pathophysi- We expected FM patients to display characteristic ological basis of the disorder, particularly concerning GM volumetric changes that have been reported in the neural background. Chronic pain disorders in gen- preceding investigation, primarily involving decreases eral have repeatedly been shown to be associated with in areas associated with pain and emotion processing, extensive structural, functional, and metabolic changes such as anterior cingulate cortex (ACC), amygdala, to the neural pain network of patients. In this context, parahippocampal gyrus, insula, and prefrontal corti- particularly pronounced structural gray (GM) and white ces, as well as increases within cerebellar structures matter (WM) alterations have also been demonstrated in [15, 19, 20, 22]. Additionally, we hypothesized that FM [15–20]. It is conceivable that the observed changes FM patients would exhibit distinct microstructural reflect cortical plasticity processes due to the chronically changes to their WM fibers, as continuous nociception increased nociceptive input. Previous studies on GM and related stress have been shown to affect specific volumetric outcomes have reported distinct alterations orientation-dependent aspects of WM connectiv- among FM patients, either in total volume [21, 22] or in ity [25, 26]. In view of our psychometric, behavioral, specific brain areas, such as the thalamus or cerebellum and clinical data, we expected pain severity, heat  pain [15, 17, 20]. On another note, several studies have found threshold, pain duration, depressive mood, and the the extent of GM decreases in chronic pain disorders to general activity level to be associated with morpholog- be depending on the previous pain duration as well as to ical brain changes in areas related to pain and emotion interact with the patients’ age [17, 22, 23]. processing. With regard to WM changes in FM, Lutz et  al. [19] demonstrated decreased fractional anisotropy (FA) Materials and methods in both thalami and insular regions, while reporting Participants increased FA, inter alia, in the amygdalae, hippocampi, Twenty-three female FM patients (aged 50.48 ± 9.89  years, and anterior cingulate gyri. Decreased FA of the right range 32 to 68 years) and twenty-one female HC subjects thalamus was also observed in a different study by Sund - (aged 46.62 ± 13.08  years, range 25 to 68  years) partici- gren et  al. [24]. More recent investigations by Kim et  al. pated in the study. A two-sample t-test showed no statisti- [25] and Ceko et al. [17] found reduced FA values inside cally significant age difference between groups (t (42) = 1.1, the corpus callosum, an area that is connected to bilateral p = 0.3). Left-handed persons, as assessed with the sensorimotor cortex [25]. Edinburgh Handedness Inventory [27], were excluded. As seen from the results listed above, structural brain FM diagnoses were obtained by medical professionals changes have been determined within a large number of M osch et al. Arthritis Research & Therapy (2023) 25:81 Page 3 of 12 Table 1 Demographic, psychometric, and clinical data for FM and HC FM HC M SD Range M SD Range Age (years) 50.5 9.9 32–68 46.6 13.1 28–68 Pain duration in years 14.9 11.8 2–44 CES-D 22.1 6.5 14–39 6.5 14–39 6–19 FIQ Physical functioning 1.4 0.6 0.2–2.4 Total 60.2 17.6 19–88.2 FSQ Symptom Severity Score 9.5 9.9 1–12 Widespread Pain Index 10.8 3.7 6–19 MPI Pain severity 4.0 15.8 6–19 Interference 4.1 1.3 0.7–5.7 Life control 3.4 1.3 0–6 Aec ff tive distress 3.4 1.5 0–5.7 Support 4.4 1.7 0–6 Punishing responses 1.3 1.3 0–5.3 Solicitous responses 3.8 1.8 0–6 Distracting responses 3.4 1.4 0–5.7 General activity level 7.2 2.4 2.6–11.5 FM fibromyalgia, HC healthy controls, M mean, SD standard deviation, CES-D Center for Epidemiologic Studies Depression Scale, FIQ Fibromyalgia Impact Questionnaire, FSQ Fibromyalgia Survey Questionnaire, MPI West Haven-Yale Multidimensional Pain Inventory and disorders fulfilled the criteria postulated by Wolfe Psychological questionnaire and physiological pain et  al. [2] (Fibromyalgia Survey Questionnaire (FSQ), threshold assessment see Table  1). FM patients were mainly recruited FM patients completed the West Haven-Yale Multidi- through social media support groups, whereas HC were mensional Pain Inventory (MPI) [29] (German version: recruited via newspaper announcements and face-to- Flor et  al. [30]), the Fibromyalgia Impact Questionnaire face acquisition at several blood donation events of the (FIQ-G) [31], and the Fibromyalgia Survey Question- German Red Cross. None of the tested participants naire (FSQ) [32]. In patients and controls, the presence had taken pain medication on the examination day. of depression symptoms was assessed using the CES-D Furthermore, opioid use had been suspended no later [33] (Center for Epidemiologic Studies Depression Scale; than 3  days prior to the MRI session (2 cases: 1 × fen- German version: ADS, Hautzinger and Bailer [34]). Addi- tanyl patches, 1 × tramadol). We also excluded users of tionally, the Edinburgh Handedness Inventory (EHI) [27] psychotropic medication, as well as psychotic patients was assessed. Table 1 presents the demographic, psycho- and patients with an acute major depression and bipolar metric, and clinical data for FM patients and HC. The disorder. Sixteen FM patients reported previous major structured clinical interview SKID-I [28] was conducted depressive episodes, four of whom also had a history of in all participants in order to rule out any acute mental generalized anxiety disorder and/or PTSD as assessed illness. with the structured clinical interview SKID-I [28]. None Individual heat pain thresholds were determined using of the HC reported current or past psychopathological a 3 × 3 cm contact thermode (PATHWAY Pain & Sensory symptoms. Evaluation System, Medoc Ltd. Advanced Medical Sys- The investigation took place at the Department of Neu - tem, Israel) and the software MEDOC Main Station 6.3. rology, Berufsgenossenschaftliches Universitätsklinikum Ascending thermal stimulation cycles were presented on Bergmannsheil, in Bochum between August 2019 and the participants’ left thenar and the mean value of the last December 2020 and was approved by the ethics review three out of five consecutive thresholds was calculated. board of the Medical Faculty Bochum, Ruhr University For heat  pain threshold, subjects were asked to stop the (15–5489). All participants gave written informed con- stimulation via a mouse button when they started per- sent prior to participating in the study. ceiving the stimulus as just painful. Mosch et al. Arthritis Research & Therapy (2023) 25:81 Page 4 of 12 Clinical and behavioral data analysis Voxel‑based morphometry: gray matter volume analysis Clinical data and behavioral measures were analyzed Group differences in local concentrations of brain tis - using SPSS Version 26 for Windows (IBM Corp., 2019). sue were assessed across the entire brain through voxel- Age in years, CES-D, and individual heat thresholds that based morphometry (VBM) which was implemented were determined prior to the experiment (see the “Psy- in SPM12 using CAT12. Segmented tissue class images chological questionnaire and physiological pain thresh- were created in spatial correspondence to the template old assessment” section) were compared between HC in MNI152NLin2009cAsym space. TIV was used as a and FM using two-sample t-tests. covariate during the analyses in order to correct for dif- ferent brain sizes. Age was also included as a covariate MRI data acquisition to take age-related gray matter changes into account. A MRI data were obtained on a Philips Achieva 3  T MRI two-sample t-test general linear model (GLM) was per- scanner using a 32-channel standard head coil, packed formed to assess brain volumetric differences between with foam pads for fixation purposes. A high-resolution HC and FM. We applied a cluster-level correction of Magnetization Prepared Rapid Gradient (MPRAGE), family-wise error (FWE) for multiple comparisons at a comprising 204 sagittal slices, was obtained for each threshold of p < 0.05. In consideration of previous VBM subject (TR = 6.98  ms, TE = 3.2  ms, flip angle 8°, 1 mm studies showing volumetric changes of specific brain voxel size, FOV 256 × 204 mm , acquisition time: 0.43 s). areas, we decided to perform further analyses using a less Diffusion-weighted images were acquired using a diffu - conservative uncorrected threshold of p < 0.001. sion-weighted spin-echo (DwiSE) sequence (TR = 6.4  s, 2 3 TE = 74.6  ms, b-value = 800  s/mm , 2 mm voxel size, Analysis of diffusion MRI data FOV = 224 × 120 mm , acquisition time: 0.49  s) along Diffusion MRI was used to examine group differences 32 diffusion encoding directions. Additionally, one of certain orientation-dependent aspects of brain tissue T2-weighted image with no diffusion (b = 0) was col- microstructure by analyzing the diffusion of water mol - lected. All volumes were manually angulated in parallel ecules. Diffusion MRI connectometry is a novel approach to the AC–PC line and adjusted to include all frontal, that allows tracking possible differences of WM tracts central, parietal, and occipital cortical areas as well as between groups as well as examining correlations of upper parts of the temporal cortex and the cerebellum. WM fibers with a variable of interest within the frame - work of a correlational tractography. Connectometry Regions of interest adopts a “tracking the correlation” paradigm that differs Relevant brain areas such as the thalamus, amygdala, fundamentally from the conventional DTI analysis para- putamen, pallidum, caudate nucleus, supplementary digm of finding the correlation between test variables motor area (SMA), middle temporal gyrus (MTG), cer- and tract parameters. Within this framework, we used ebellum, and insular, parahippocampal, prefrontal, FA as the diffusion index of interest. FA is a scalar vec - orbitofrontal, cingulate, and primary and secondary tor representing the directional selectivity of the random somatosensory (SI, SII) cortices were defined based on diffusion of water molecules, with higher FA pointing the automated anatomical labeling (AAL) atlas 3 [35]. towards highly anisotropic water diffusion (e.g., heav - ily myelinated tracts) [37]. As reported by Yeh et al. [38], Whole‑brain volumetric analysis diffusion MRI connectometry can be more sensitive than High-resolution structural MPRAGE images were seg- conventional voxel-wise FA or APC mapping. However, mented in SPM using the Computational Anatomy Tool- it should be noted beforehand that FA changes cannot be box CAT12 (Structural Brain Mapping group [36], Jena interpreted in a linear fashion as changes of WM connec- University Hospital, Jena, Germany; http:// dbm. neuro. tivity in a specific direction [39]. uni- jena. de/ cat/) (GM, WM, and cerebrospinal fluid The connectometry was performed using DSI Studio (CSF)), normalized to Montreal Neurological Institute (November 2020 build, Yeh et  al. [40], http:// dsi- studio. (MNI) standard space and smoothed with an isotropic labso lver. org). The b-table was examined using an auto - Gaussian kernel of 8 mm FWHM. Total intracranial vol- mated quality control routine to ensure its accuracy. Raw ume (TIV) was estimated as the sum of the three main diffusion data were motion and eddy-current corrected brain tissue volumes (GM, WM, and CSF). Whole-brain using DSI Studio’s built-in preprocessing routine which group comparisons of cerebrospinal fluid (CSF), GM, is based on FMRIB Software Library’s (FSL) correspond- and WM volumes as well as the total intracranial volume ing “eddy” tool. Corrected data were then reconstructed (TIV) were calculated in SPSS using two-sample inde- in the MNI space using Q-Space Diffeomorphic Recon - pendent t-tests (p < 0.05). struction (QSDR) [41, 42]. The transformed distribution M osch et al. Arthritis Research & Therapy (2023) 25:81 Page 5 of 12 was used to obtain the spin distribution function (SDF) as well as high scores of pain severity (MPI: 4.0 ± 15.8), with a diffusion sampling length ratio of 1.25. FM impact (FIQ: 60.2 ± 17.6), and depression (CES-D: A correlational group tractography between FA and 22.1 ± 6.5). The individual heat  pain threshold deter - group (HC: 0; FM: 1) was carried out to compare regional mined prior to the experiment revealed no significant FA values of HC and FM, using the participants’ age as a group differences between FM and HC, with a clear ten - covariate. Correlational tractography has been shown to dency towards lower values in FM (mean = 46.1) com- offer greater sensitivity than conventional tract- or voxel- pared to HC (mean = 46.9) (t(41) = 1.6, p = 0.09). based methods [40]. To map the different levels of corre - lation between the tracks and the group factor, different Whole‑brain volumetric changes in FM patients t-score thresholds of 2, 2.5, and 3 were used to visually CSF as well as WM volumes did not differ significantly study the tract-wise correlations at different cut-offs. between FM and HC (CSF: t(43) = 0.9, p = 0.18; WM: In this regard, each threshold can be viewed as a differ - t(42) = 0.13, p = 0.449). In contrast, GM volumes were ent hypothesis. High t thresholds will map tracks with a shown to be significantly reduced in FM (mean = 797 ± 48 3 3 stronger correlation effect, whereas lower t thresholds cm ) compared to HC (mean = 831 ± 61 cm ), t(40) = 2.1, will map tracks with a weak correlation [40]. Models with p = 0.021 (see Fig.  1). Apart from this, FM patients a t-score threshold of 2 and a length threshold of 20 vox- (mean = 1793 ± 63 cm ) also displayed significantly els yielded the strongest correlation while providing con- decreased TIV compared to HC (mean = 1842 ± 63 cm ), sistent results. The same parameters have been reported t(43) = 2.7, p = 0.011. in a variety of previous connectometry studies using DSI Studio [38, 40, 43]. Topology-informed pruning with Regional GM volumetric changes in FM patients 4 iterations was implemented to filter the tracks and a Group comparisons revealed FM-specific structural total of 4000 randomized permutations were applied to changes in a number of brain areas. When correcting for obtain the null distribution of the track length. As sug- multiple comparisons (p < 0.05, FWE corrected), patients gested by the developer, a highly confirmative thresh - displayed decreased GM volumes in the left temporal old of FDR = 0.05, corrected for the false discovery rate pole (of the superior (STG) and middle temporal gyrus (FDR), was used to select tracts on a whole-brain level (MTG)) and right MTG. Significantly increased GM through a deterministic fiber tracking algorithm [44] to reveal all subcomponents of the fascicles that are signifi - cantly associated to our study variable group (FM vs HC). Yeh et  al. [40] provide a detailed and complete descrip- tion of diffusion MRI connectometry and the underlying methodology. Correlations of VBM and DTI data with clinical and behavioral measures Regional relative GM volumes (corrected for different brain sizes) and FA values were correlated with demo- graphic, psychometric, behavioral, and clinical vari- ables using Pearson’s correlation coefficient (r) and a significance level of p < 0.05 in SPSS. In this analysis, we focused on brain regions that have displayed morpho- metric changes in our preceding analyses. The analyzed variables comprised three categories: (1) sensory-dis- criminative aspects of pain perception: pain severity (MPI) and heat pain threshold; (2)] chronicity: pain dura- tion; (3) affective-motivational aspects of pain: depressive mood (CES-D) and the general activity level (MPI) (see Table 1). Fig. 1 Whole-brain group comparisons of brain tissues (CSF, GM, and WM). Bar charts of the mean CSF, GM, and WM whole-brain tissue Results volumes (cm. ) for HC and FM. Individual GM mean values for each participant are indicated by black dots. CSF, cerebrospinal fluid; GM, Clinical and behavioral characteristics of the participants gray matter; WM, white matter; HC, healthy controls; FM, patients with FM patients reported longstanding disease with a mean fibromyalgia; n.s., not significant; *p < .05 pain duration of 14.9 (± 11.8; range 2 to 44  years) years Mosch et al. Arthritis Research & Therapy (2023) 25:81 Page 6 of 12 Table 2 Brain regions showing significantly decreased or increased GM volume in FM compared to HC (p < 0.05, FWE corrected) MNI coordinates Comparison Laterality x y z Cluster size (voxel) Z score Brain region HC > FM Temporal pole (STG/ L − 36 14 − 27 193 4.8 MTG) MTG R 54 − 60 6 365 4.7 FM > HC Cerebellum R 27 − 80 − 38 2036 4.9 26 − 48 − 26 191 3.8 L − 23 − 78 − 35 1489 4.7 STG superior temporal gyrus, MTG middle temporal gyrus, L left, R right, voxel size: 2.3 × 2.3 × 2.3 mm Fig. 2 Brain regions with increased or decreased GM volumes in FM compared to HC. Structures that showed increased GM volume in FM are depicted in blue. Decreased GM volume is illustrated in red. A Axial and sagittal sectional images of the relevant clusters showing group differences. B 3D rendered illustration of the clusters. L, left; R, right; P, posterior; A, anterior; MTG, middle temporal gyrus. p(FWE) < .05 volume was found in major clusters within the bilateral in FM compared to HC involved left SMA, left thalamus, cerebellum (Table 2 and Fig. 2). and right putamen (see Table S1). Using a less conservative threshold (p < 0.001 uncor- rected), we found a number of additional regional volu- DTI connectometry results metric changes in FM. This involved decreased GM One FM patient was excluded due to insufficient DTI volumes in left MTG, right fusiform gyrus, parahip- data quality. Correlational group tractography for HC and pocampal gyrus, orbitofrontal cortex (OFC), right pre- FM revealed several tracts in which FA values were nega- central cortex, right SMA, left dorsal anterior cingulate tively correlated with the group parameter, indicating cortex (dACC), right putamen, right caudate nucleus, decreased FA and thus orientation-dependent changes and left dorsolateral prefrontal cortex. On the other to regional WM connectivity in FM (FDR < 0.05). These hand, further brain areas showing increased GM volumes tracts involved left corticospinal tract, bilateral fornix, right corticospinal tract, bilateral superior corticostriatal M osch et al. Arthritis Research & Therapy (2023) 25:81 Page 7 of 12 tract, left cerebellum, right superior thalamic radiation, chronicity showed negative correlations with FA values left arcuate fasciculus, left dentato-rubro-thalamic tract, within the left insular cortex (r = − 0.53, p = 0.036) and and bilateral medial lemniscus and middle cerebellar multiple cerebellar lobules (Crus I, Crus II, Cerebellum peduncle. 3 and 6; correlation coefficients r from − 0.51 to − 0.64, On the other hand, a number of tracks displayed posi- p-values from 0.045 to 0.007). tive correlations with the group parameter, indicating Regarding affective-motivational aspects, depressive increased FA in FM. Such correlations were found in mood was negatively correlated with GM volumes of left right parolfactory cingulum, bilateral cerebellum, tape- putamen (CES-D: r = − 0.31, p = 0.043), while the MPI tum corporis callosi, forceps major and minor of the scale of the general activity level was positively corre- corpus callosum, and right inferior fronto-occipital fas- lated with the structure (r = 0.39, p = 0.033). Furthermore, ciculus. WM tracts showing significant correlations with FA within the left MCC was positively correlated with the group factor are illustrated in Fig. 3. CES-D scores (r = 0.31, p = 0.048) and bilateral FA values in the amygdala were positively correlated with the MPI Correlations with clinical and behavioral measures scale of the general activity level (L: r = 0.45, p = 0.043; R: Regarding sensory-discriminative aspects of pain percep- r = 0.5, p = 0.021). tion, the MPI scale of pain severity was negatively corre- lated with FA values of multiple thalamic substructures, Discussion including ventral posterolateral as well as pulvinar ante- The primary aim of the present investigation was to rior, pulvinar medial, pulvinar lateral, and pulvinar infe- explore the precise form and extent of structural GM and rior thalamus (correlation coefficients r from 0.44 to 0.62, WM changes related to FM as well as to explore possible p-values from 0.048 to 0.003) (see Fig.  4). Additionally, correlations with clinical and behavioral measures. Group the individual pain thresholds were negatively correlated comparisons in fact demonstrated striking patterns of with GM volumes of the right middle cingulate cortex brain morphometric changes in FM patients compared (MCC) (r = − 0.31, p = 0.039), bilateral posterior cingu- to HC. In our initial analysis, we found whole-brain GM late cortex (PCC) (L: r = − 0.3, p = 0.046; R: r = − 0.38, volumes as well as TIV to be significantly decreased in p = 0.01), and cerebellar lobule Crus II (r = − 0.32, FM compared to HC. Similar findings have emerged in p = 0.037) as well as FA values of bilateral insula (L: previous studies (e.g., Kuchinad et  al. [22]) and support r = − 0.39, p = 0.01; R: r = − 0.34; p = 0.029), right MCC the notion of premature brain aging in patients with FM. (r = − 0.36, p = 0.02), left amygdala (r = − 0.37, p = 0.016), right putamen (r = − 0.35, p = 0.024) and multiple cer- Voxel‑based morphometry ebellar lobules (right Crus I, Crus II, Cerebellum 7b and In addition to these general changes, we were particularly 9; correlation coefficients r from − 0.31 to − 0.41, p-values interested in the specific brain areas affected by the mor - from 0.045 to 0.01). phometric changes. For this purpose, we performed a Concerning the chronicity, the duration of pain symp- VBM analysis that revealed distinct regional GM changes toms was negatively correlated with GM volumes of the in our FM group. The most profound GM alterations right insular cortex (r = − 0.43, p = 0.037) as well as left were detected in the bilateral cerebellum. Increased cer- rolandic operculum (r = − 0.5, p = 0.017) and positively ebellar GM volume related to FM has been demonstrated correlated with right MCC (r = 0.41, p = 0.046). Moreover, in previous studies [45, 46]. Although the cerebellum Fig. 3 Correlational group tractography results. Comparison between fractional anisotropy (FA) positively (red) and negatively (blue) associated with the group parameter. t threshold: 2; length threshold: 20 voxels; permutation count: 4000, pruning iterations: 4; FDR < .05 Mosch et al. Arthritis Research & Therapy (2023) 25:81 Page 8 of 12 Fig. 4 Brain regions that showed a significant correlation of GM or FA with behavioral/clinical data. Solid lines: correlations with GM volume; dashed lines: correlations with FA values; red lines: negative correlations; blue lines: positive correlations; AMG, amygdala; MCC, middle cingulate cortex; PCC, posterior cingulate cortex; SII, secondary somatosensory cortex; PU, putamen; PA, pallidum plays a rather subordinate role in pain research, the area functional connectivity of the area) was found to be asso- has repeatedly been shown to be an inherent part of the ciated with dysfunctional pain-related control processes pain processing network and is strongly interconnected and increased anticipatory anxiety [53, 57]. with the cerebral cortex [47, 48]. Beyond that, Kim et al. Most of the brain regions showing altered GM vol- [49] compared FM and HC using covariance network umes when adopting a less conservative threshold of analysis and found denser connections in the cerebellum p < 0.001 are significant components of the neu - uncorr. as well as weaker connections in the frontal lobe of FM ral pain network, some of which have previously been patients. The present study identified the most exten - demonstrated to be reduced in FM. More precisely, sive abnormalities in Cerebellar lobules VIIb and Crus decreased GM volume or density has been reported in II, which are known to be associated with higher-order parahippocampal gyrus [22, 58], prefrontal cortex, and processes (e.g., executive, emotional, and cognitive) and ACC [15, 17, 20]. As all of these structures are related lobule VIII, which is related to sensorimotor functions to stress (parahippocampal gyrus) and pain processing, [50, 51]. the observed changes might well be consequences of a Adopting a relatively conservative FWE correction for long-term exposure to these symptoms. It should also be multiple comparisons, we demonstrated significantly noted that prefrontal and cingulate cortices are generally decreased GM volumes of the left temporal pole (STG/ ascribed pain modulatory and analgesic functions. Thus, MTG) and right MTG in FM. Decreased GM volume of GM atrophy in such areas could contribute to the main- the left MTG has recently been found by Sundermann tenance of chronic pain symptoms in FM. et al. [52] in patients with FM and osteoarthritis. Accord- ingly, it may be argued that the group differences reported Diffusion MRI connectometry analysis above could be related to chronic pain in general, rather FA is a parameter reflecting the directionality of water than FM in particular. In this regard, decreased GM vol- diffusion, or rather the degree to which the diffusion var - ume of the MTG has also been observed in patients with ies in different directions. However, due to a number of migraine [53], chronic myofascial pain [54], and trigemi- possible confounders contributing to metrics like FA, nal neuralgia [55]. Intriguingly, the area has recently been differences in scalar diffusion measures such as FA can - hypothesized to play a key role in redirecting attention not be interpreted linearly as WM connectivity changes away from pain and keeping involuntary thoughts about into a specific direction [39] (e.g., lower FA = low con- pain out of awareness [56]. In view of this, it is hardly nectivity/tissue damage). Hereinafter, we therefore avoid surprising that decreased MTG volume (and altered making statements as to whether the observed changes M osch et al. Arthritis Research & Therapy (2023) 25:81 Page 9 of 12 amount, e.g., to possible decreases in WM integrity. FM between GM volume of the right insular cortex Nevertheless, the regional microstructural WM group and the chronicity/duration of pain symptoms. This differences we detected provide valuable information finding is in line with a number of previous investiga - about which areas and tracts show the most pronounced tions that reported a pronounced reduction of insular changes in FM. volume related to persisting chronic pain [68, 69]. GM To begin with, FM displayed decreased FA in bilateral volume of the left putamen was negatively associated medial lemniscus (also known as Reil’s band), a major with depressive symptoms, validating the previously ascending pathway consisting of heavily myelinated postulated importance of the putamen in depressive axons that is known to transmit tactile and propriocep- disorders. In this context, Sacchet et  al. [70] reported tive information from the skin and joints to the thalamus greater age-related volumetric decreases in the struc- and somatosensory cortex. In this way, the medial lem- ture in patients with major depressive disorder. Con- niscus plays a crucial role for processing of conscious sistently, we found GM volume of bilateral putamen to proprioception, fine touch, and 2-point discrimination. be positively correlated with the general activity level, Interestingly, FM patients have previously been found representing an opposite pole to decreased activity lev- to show disruptions in all of these fields. For instance, els that can typically be observed in depressive disor- FM has been linked to postural balance disorders and ders. Accordingly, affective-motivational components abnormalities of the proprioceptive system [59–61]. An of pain likewise play a decisive role in regard to the example for altered sensations of fine touch in FM is the observed structural changes. This is further validated phenomenon of allodynia, a heightened sensitivity to through the involvement of bilateral amygdala, which non-nociceptive stimuli [62, 63]. Only recently, soma- demonstrated FA positively correlated with the general tosensory temporal discrimination (STD), a measure activity level. Intriguingly, FA values of multiple pain- for two-point discrimination, has been shown to be sig- related ROIs were negatively correlated with the indi- nificantly prolonged in FM (in all extremities) [64]. The vidual heat  pain threshold, including bilateral insula, described findings clearly match the microstructural left amygdala, right MCC, right putamen, and multiple changes of WM connectivity (decreased FA) we found cerebellar lobules. Accordingly, increased pain sensitiv- within the medial lemniscus of FM patients. ity was found to be associated with greater FA within Interestingly, decreased FA was also found along tracts the examined ROIs of the pain network. surrounding and connecting the thalamus, such as tha- lamic radiation and dentato-rubro-thalamic tracts, indi- cating changes to the area’s WM connectivity. This is of Limitations particular interest, as the thalamus is widely known to be As noted earlier, some methodological characteristics of critically involved in distributing and processing nocicep- this study need to be considered when interpreting the tive information. results. In this regard, the informative value of diffusion Further, a number of white matter tracts showing sig- indices such as FA is a critical factor. Regional anisotropy nificantly increased FA in FM were located in and around can be influenced by a number of confounding variables the corpus callosum (tapetum corporis callosi, forceps (e.g., axon diameter, packing density, and number of major, and forceps minor of the corpus callosum), an axons) [71]. Due to these and other reasons, differences area that is known to be strongly connected to bilat- in FA indicate some form of change to microstructural eral sensorimotor cortex. Similar reductions of local FA WM connectivity, but cannot be linearly interpreted as values within the corpus callosum in FM have recently WM integrity changes into a certain direction [39]. How- been described by Tu et al. [65] and Aster et al. [66]. On ever, we have attempted to circumvent this issue through another note, the area is widely known to mediate inter- our cautious interpretation of the findings. hemispheric transfer [67]. u Th s, microstructural changes Another limitation that should be mentioned is associ- to the corpus callosum might consequently indicate a sig- ated to the ROI-wise approach we have picked to inves- nificant change to interhemispheric connectivity. tigate the relationship of regional brain morphometry and behavioral measures. Arguably, this procedure can Behavioral and clinical measures in some cases lead to partial volume effects. However, we Pain severity scores were negatively correlated with FA have decided to implement a ROI-wise approach, in addi- values in several thalamic substructures. These find - tion to our WM tractography, as similar approaches have ings underline the significance of the observed changes been used in numerous investigations on chronic pain on in close relation with sensory-discriminative aspects which we have based our study design thematically and of pain, such as the reported pain severity. On another methodically [17, 19, 24, 72]. Furthermore, we found a note, we observed a significant negative correlation in ROI-wise approach to be the most suitable way for us to Mosch et al. Arthritis Research & Therapy (2023) 25:81 Page 10 of 12 M.D. discussed the results and commented on the manuscript. The authors investigate the correlations described above, as our goal read and approved the final manuscript. was to explore possible associations of different regional microstructural characteristics with behavioral and clini- Funding Open Access funding enabled and organized by Projekt DEAL. We acknowl- cal data. The consistent ROI-wise approach entails com - edge support by the Open Access Publication Funds of the Ruhr University parability of regional GM volumetric and diffusion data. Bochum. This work was supported by the Deutsche Forschungsgemeinschaft In general, our investigation was designed as an initial (DFG) (DI1553/5). exploration of the topic described above, providing clues Availability of data and materials to plan possible follow-up studies. This context explains Further information and requests for resources and reagents should be our exploratory approach and should also be taken into directed to and will be fulfilled by the lead contact, Martin Diers (martin. diers@rub.de). account when interpreting the results. Declarations Conclusions The described findings delineate major structural brain Ethics approval and consent to participate changes in FM, affecting large parts of the neural pain The study was approved by the ethics review board of the Medical Faculty Bochum, Ruhr University (15–5489). All participants gave written informed network. Arguably, some of the most distinct FM-related consent prior to participating in the study. regional morphometric changes were found in the thala- mus, putamen, and insula, involving significantly reduced Consent for publication Not applicable. FA values that were related to the subjectively perceived pain severity as well as GM decreases. However, such Competing interests morphometric changes have repeatedly been shown to be The authors declare no competing interests. reversible after cessation of pain [73, 74] and might rep- Author details resent a temporary consequence of chronic nociceptive Clinical and Experimental Behavioral Medicine, Alexandrinenstraße 1–3, input, rather than permanent brain damage. This is also 44791 Bochum, Germany. Department of Psychosomatic Medicine and Psy- chotherapy, LWL University Hospital, Ruhr University Bochum, Alexandrinen- supported by the fact that we found positive correlations straße 1-3, 44791 Bochum, Germany. of GM in bilateral putamen with the general activity level, which could serve as an example for possible control Received: 8 December 2022 Accepted: 7 May 2023 strategies to reverse maladaptive neural changes. Abbreviations References AAL Automatic anatomical labeling atlas 1. Rehm SE, Koroschetz J, Gockel U, Brosz M, Freynhagen R, Tolle TR, et al. CSF Cerebrospinal fluid A cross-sectional survey of 3035 patients with fibromyalgia: subgroups DTI Diffusion-tensor imaging of patients with typical comorbidities and sensory symptom profiles. FA Fractional anisotropy Rheumatology. 2010;49:1146–52. FDR False discovery rate 2. Wolfe F, Clauw DJ, Fitzcharles M-A, Goldenberg DL, Häuser W, Katz RL, FM Fibromyalgia et al. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. FWE Family-wise error Semin Arthritis Rheum. 2016;46:319–29. GM Gray matter 3. Cook DB, Lange G, Ciccone DS, Wen-Ching L, Steffener J, Natelson BH. HC Healthy controls Functional imaging of pain in patients with primary fibromyalgia. J Rheu- MRI Magnetic resonance imaging matol. 2004;31:364–78. ROI Region of interest 4. Petzke F, Clauw DJ, Ambrose K, Khine A, Gracely RH. Increased pain sensi- TIV Total intracranial volume tivity in fibromyalgia: effects of stimulus type and mode of presentation. VBM Voxel-based morphometry Pain. 2003;105:403–13. WM White matter 5. Diers M, Yilmaz P, Rance M, Thieme K, Gracely RH, Rolko C, et al. Treat- ment-related changes in brain activation in patients with fibromyalgia syndrome. Exp Brain Res. 2012;218:619–28. Supplementary Information 6. Diers M, Koeppe C, Yilmaz P, Thieme K, Markela-Lerenc J, Schiltenwolf The online version contains supplementary material available at https:// doi. M, et al. Pain ratings and somatosensory evoked responses to repetitive org/ 10. 1186/ s13075- 023- 03064-0. intramuscular and intracutaneous stimulation in fibromyalgia syndrome. J Clin Neurophysiol. 2008;25:153–60. Additional file 1: Table S1. Brain regions showing significantly greater 7. Sörensen J, Graven-Nielsen T, Henriksson KG, Bengtsson, Arendt-Nielsen GM volume in HC compared to FM and vice versa (p ≤ 0.001 uncorrected). L. Hyperexcitability in Fibromyalgia. J Rheumatol. 1998;25:152–5. 8. Diers M, Schley MT, Rance M, Yilmaz P, Lauer L, Rukwied R, et al. Differen- tial central pain processing following repetitive intramuscular proton/ Acknowledgements prostaglandin E2 injections in female fibromyalgia patients and healthy None. controls. Eur J Pain. 2011;15:716–23. 9. Morris V, Cruwys S, Kidd B. Increased capsaicin-induced secondary Authors’ contributions hyperalgesia as a marker of abnormal sensory activity in patients with M.D. designed the research; B.M. performed the research and analyzed the MRI fibromyalgia. Neurosci Lett. 1998;250:205–7. data; B.M. and M.D. conducted the statistical analysis; B.M., V.H., S.H., and M.D. 10. Clauw DJ, Arnold LM, McCarberg BH. The Science of Fibromyalgia. Mayo interpreted the results; B.M. and M.D. wrote the article; and B.M., V.H., S.H., and Clin Proc. 2011;86:907–11. M osch et al. Arthritis Research & Therapy (2023) 25:81 Page 11 of 12 11. Henriksson K. Fibromyalgia - from syndrome to disease. Overview of 35. Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, pathogenetic mechanisms. J Rehabil Med. 2003;35:89–94. Delcroix N, et al. Automated Anatomical Labeling of Activations in SPM 12. Gormsen L, Rosenberg R, Bach FW, Jensen TS. Depression, anxiety, health- Using a Macroscopic Anatomical Parcellation of the MNI MRI Single- related quality of life and pain in patients with chronic fibromyalgia and Subject Brain. Neuroimage. 2002;15:273–89. neuropathic pain. Eur J Pain. 2010;14:127.e1-127.e8. 36. Gaser C, Dahnke R. CAT - A Computational Anatomy Toolbox for the 13. Verbunt JA, Pernot DH, Smeets RJ. Disability and quality of life in patients Analysis of Structural MRI Data. 2020. Available from: http:// www. neuro. with fibromyalgia. Health Qual Life Outcomes. 2008;6:8.uni- jena. de/ cat/. 14. Bengtsson A, Bäckman E, Lindblom B, Skogh T. Long term follow-up of 37. Kochunov P, Williamson DE, Lancaster J, Fox P, Cornell J, Blangero J, et al. fibromyalgia patients: clinical symptoms, muscular function, laboratory Fractional anisotropy of water diffusion in cerebral white matter across tests-an eight year comparison study. J Musculoskelet Pain. 1994;2:67–80. the lifespan. Neurobiol Aging. 2012;33:9–20. 15. Burgmer M, Gaubitz M, Konrad C, Wrenger M, Hilgart S, Heuft G, et al. 38. Yeh F-C, Tang P-F, Tseng W-YI. Diffusion MRI connectometry automati- Decreased gray matter volumes in the cingulo-frontal cortex and the cally reveals affected fiber pathways in individuals with chronic stroke. amygdala in patients with fibromyalgia. Psychosom Med. 2009;71:566–73. NeuroImage Clin. 2013;2:912–21. 16. Cauda F, Palermo S, Costa T, Torta R, Duca S, Vercelli U, et al. Gray matter 39. Jones DK, Knösche TR, Turner R. White matter integrity, fiber count, alterations in chronic pain: a network-oriented meta-analytic approach. and other fallacies: The do’s and don’ts of diffusion MRI. Neuroimage. NeuroImage Clin. 2014;4:676–86. 2013;73:239–54. 17. Ceko M, Bushnell MC, Fitzcharles M-A, Schweinhardt P. Fibromyalgia 40. Yeh F-C, Badre D, Verstynen T. Connectometry: a statistical approach interacts with age to change the brain. NeuroImage Clin. 2013;3:249–60. harnessing the analytical potential of the local connectome. Neuroimage. 18. Diaz-Piedra C, Guzman MA, Buela-Casal G, Catena A. The impact of 2016;125:162–71. fibromyalgia symptoms on brain morphometry. Brain Imaging Behav. 41. Yeh F-C, Wedeen VJ, Tseng W-YI. Estimation of fiber orientation and spin den- 2016;10:1184–97. sity distribution by diffusion deconvolution. NeuroImage. 2011;55:1054–62. 19. Lutz J, Jäger L, de Quervain D, Krauseneck T, Padberg F, Wichnalek M, 42. Yeh F-C, Tseng W-YI. NTU-90: A high angular resolution brain atlas et al. White and gray matter abnormalities in the brain of patients with constructed by q-space diffeomorphic reconstruction. NeuroImage. fibromyalgia: a diffusion-tensor and volumetric imaging study. Arthritis 2011;58:91–9. Rheum. 2008;58:3960–9. 43. Hodgdon EA, Courtney KE, Yan M, Yang R, Alam T, Walker JC, et al. White 20. Robinson ME, Craggs JG, Price DD, Perlstein WM, Staud R. Gray matter matter integrity in adolescent irritability: a preliminary study. Psychiatry volumes of pain-related brain areas are decreased in fibromyalgia Res Neuroimaging. 2022;324:111491. syndrome. J Pain. 2011;12:436–43. 44. Yeh F-C, Verstynen TD, Wang Y, Fernández-Miranda JC, Tseng W-YI. Deter- 21. Jensen KB, Srinivasan P, Spaeth R, Tan Y, Kosek E, Petzke F, et al. ministic diffusion fiber tracking improved by quantitative anisotropy. Overlapping structural and functional brain changes in patients with PLoS ONE. 2013;8:e80713. long-term exposure to fibromyalgia pain: brain changes in long-term 45. Schmidt-Wilcke T, Luerding R, Weigand T, Jürgens T, Schuierer G, Leinisch fibromyalgia. Arthritis Rheum. 2013;65:3293–303. E, et al. Striatal grey matter increase in patients suffering from fibromyal- 22. Kuchinad A, Schweinhardt P, Seminowicz DA, Wood PB, Chizh BA, Bush- gia – a voxel-based morphometry study. Pain. 2007;132:S109–16. nell MC. Accelerated brain gray matter loss in fibromyalgia patients: 46. Shi H, Yuan C, Dai Z, Ma H, Sheng L. Gray matter abnormalities associated premature aging of the brain? J Neurosci. 2007;27:4004–7. with fibromyalgia: a meta-analysis of voxel-based morphometric studies. 23. Apkarian AV. Chronic back pain is associated with decreased prefrontal Semin Arthritis Rheum. 2016;46:330–7. and thalamic gray matter density. J Neurosci. 2004;24:10410–5. 47. Diano M, D’Agata F, Cauda F, Costa T, Geda E, Sacco K, et al. Cerebellar 24. Sundgren PC, Petrou M, Harris RE, Fan X, Foerster B, Mehrotra N, et al. clustering and functional connectivity during pain processing. Cerebel- Diffusion-weighted and diffusion tensor imaging in fibromyalgia lum. 2016;15:343–56. patients: a prospective study of whole brain diffusivity, apparent 48. Moulton EA, Schmahmann JD, Becerra L, Borsook D. The cerebellum and diffusion coefficient, and fraction anisotropy in different regions pain: passive integrator or active participator? Brain Res Rev. 2010;65:14–27. of the brain and correlation with symptom severity. Acad Radiol. 49. Kim H, Kim J, Loggia ML, Cahalan C, Garcia RG, Vangel MG, et al. Fibromy- 2007;14:839–46. algia is characterized by altered frontal and cerebellar structural covari- 25. Kim DJ, Lim M, Kim JS, Son KM, Kim HA, Chung CK. Altered white mat- ance brain networks. NeuroImage Clin. 2015;7:667–77. ter integrity in the corpus callosum in fibromyalgia patients identi- 50. Stoodley CJ, Valera EM, Schmahmann JD. Functional topography of the fied by tract-based spatial statistical analysis: abnormal white matter cerebellum for motor and cognitive tasks: An fMRI study. Neuroimage. integrity in fibromyalgia. Arthritis Rheumatol. 2014;66:3190–9. 2012;59:1560–70. 26. May A. Chronic pain may change the structure of the brain. Pain. 51. Stoodley C, Schmahmann J. Functional topography in the human 2008;137:7–15. cerebellum: a meta-analysis of neuroimaging studies. Neuroimage. 27. Oldfield RC. The assessment and analysis of handedness: The Edin- 2009;44:489–501. burgh Inventory. Neuropsychologia. 1971;9:97–113. 52. Sundermann B, Dehghan Nayyeri M, Pfleiderer B, Stahlberg K, Jünke L, 28. Wittchen HU, Wunderlich U, Gruschwitz S, Zaudig M. SKID I. Strukturi- Baie L, et al. Subtle changes of gray matter volume in fibromyalgia reflect ertes Klinisches Interview für DSM-IV. Achse I: Psychische Störungen. chronic musculoskeletal pain rather than disease-specific effects. Eur J Interviewheft und Beurteilungsheft. Eine deutschsprachige, erweiterte Neurosci. 2019;50:3958–67. Bearb. d. amerikanischen Originalversion des SKID I. Göttingen: 53. Coppola G, Petolicchio B, Di Renzo A, Tinelli E, Di Lorenzo C, Parisi V, et al. Hogrefe; 1997. Cerebral gray matter volume in patients with chronic migraine: correla- 29. Kerns RD, Turk DC, Rudy TE. The West Haven-Yale Multidimensional Pain tions with clinical features. J Headache Pain. 2017;18:115. Inventory ( WHYMPI). Pain. 1985;23:345–56. 54. Niddam DM, Lee S-H, Su Y-T, Chan R-C. Brain structural changes in 30. Flor H, Rudy TE, Birbaumer N, Streit B, Schugens MM. Zur Anwendbarkeit patients with chronic myofascial pain. Eur J Pain. 2017;21:148–58. des West Haven-Yale Multidimensional Pain Inventory im deutschen 55. Li M, Yan J, Li S, Wang T, Zhan W, Wen H, et al. Reduced volume of gray Sprachraum. Schmerz. 1990;4:82–7. matter in patients with trigeminal neuralgia. Brain Imaging Behav. 31. Oenbaecher M, ff Waltz M, Schoeps P. Validation of a German ver - 2017;11:486–92. sion of the Fibromyalgia Impact Questionnaire (FIQ-G). J Rheumatol. 56. Kucyi A, Salomons TV, Davis KD. Cognitive behavioral training 2000;27:1984–8. reverses the effect of pain exposure on brain network activity. Pain. 32. Häuser W, Jung E, Erbslöh-Möller B, Gesmann M, Kühn-Becker H, Peter- 2016;157:1895–904. mann F, et al. Validation of the Fibromyalgia Survey Questionnaire within 57. Yun J-Y, Kim J-C, Ku J, Shin J-E, Kim J-J, Choi S-H. The left middle temporal a cross-sectional survey. PLoS ONE. 2012;7:e37504. gyrus in the middle of an impaired social-affective communication 33. Radloff LS. The CES-D Scale: a self-report depression scale for research in network in social anxiety disorder. J Aec ff t Disord. 2017;214:53–9. the general population. Appl Psychol Meas. 1977;1:385–401. 58. Wood PB, Glabus MF, Simpson R, Patterson JC 2nd. Changes in gray mat- 34. Hautzinger M, Bailer M. Allgemeine Depressionsskala (ADS) [General ter density in fibromyalgia: correlation with dopamine metabolism. J Pain. Depression Scale]. Weinheim: Beltz Test GmbH; 1993. 2009;10:609–18. Mosch et al. Arthritis Research & Therapy (2023) 25:81 Page 12 of 12 59. Akkaya N, Akkaya S, Atalay NS, Acar M, Catalbas N, Sahin F. Assessment of the relationship between postural stability and sleep quality in patients with fibromyalgia. Clin Rheumatol. 2013;32:325-31. 60. Gucmen B, Kocyigit BF, Nacitarhan V, Berk E, Koca T, Akyol A. The relation- ship between cervical proprioception and balance in patients with fibromyalgia syndrome. Rheumatol Int. 2022;42:311-8. 61. Núñez-Fuentes D, Obrero-Gaitán E, Zagalaz-Anula N, Ibáñez-Vera AJ, Achalandabaso-Ochoa A, López-Ruiz M del C, et al. Alteration of postural balance in patients with fibromyalgia syndrome—a systematic review and meta-analysis. Diagnostics. 2021;11:127. 62. Arendt-Nielsen L, Graven-Nielsen T. Central sensitization in fibromy- algia and other musculoskeletal disorders. Curr Pain Headache Rep. 2003;7:355–61. 63. Staud R, Domingo M. Evidence for abnormal pain processing in fibromy- algia syndrome. Pain Med. 2001;2:208–15. 64. Tertemiz OF, Tepe N. Is two-point discrimination test a new diagnostic method for the diagnosis of fibromyalgia? Arch Neuropsychiatry [Inter - net]. 2020 [cited 2022 Jul 21]; Available from: http:// submi ssion. norop sikiy atria rsivi. com/ defau lt. aspx?s= publi c~kabul & mId= 27245. 65. Tu Y, Wang J, Xiong F, Gao F. Disrupted white matter microstructure in patients with fibromyalgia owing predominantly to psychological factors: a diffusion tensor imaging study. Pain Physician. 2022;25. 66. Aster H-C, Evdokimov D, Braun A, Üçeyler N, Kampf T, Pham M, et al. CNS imaging characteristics in fibromyalgia patients with and without periph- eral nerve involvement. Sci Rep. 2022;12:6707. 67. van der Knaap LJ, van der Ham IJM. How does the corpus callo- sum mediate interhemispheric transfer? A review. Behav Brain Res. 2011;223:211–21. 68. Baliki MN, Schnitzer TJ, Bauer WR, Apkarian AV. Brain morphological signa- tures for chronic pain. PLoS ONE. 2011;6:e26010. 69. Geha PY, Baliki MN, Harden RN, Bauer WR, Parrish TB, Apkarian AV. The brain in chronic CRPS pain: abnormal gray-white matter interactions in emotional and autonomic regions. Neuron. 2008;60:570–81. 70. Sacchet MD, Camacho MC, Livermore EE, Thomas EAC, Gotlib IH. Acceler- ated aging of the putamen in patients with major depressive disorder. J Psychiatry Neurosci. 2017;42:164–71. 71. Takahashi M, Hackney DB, Zhang G, Wehrli SL, Wright AC, O’Brien WT, et al. Magnetic resonance microimaging of intraaxonal water diffusion in live excised lamprey spinal cord. Proc Natl Acad Sci. 2002;99:16192–6. 72. Szabó N, Kincses ZT, Párdutz Á, Tajti J, Szok D, Tuka B, et al. White matter microstructural alterations in migraine: a diffusion-weighted MRI study. Pain. 2012;153:651–6. 73. Rodriguez-Raecke R, Niemeier A, Ihle K, Ruether W, May A. Brain gray matter decrease in chronic pain is the consequence and not the cause of pain. J Neurosci. 2009;29:13746–50. 74. Ruscheweyh R, Deppe M, Lohmann H, Stehling C, Flöel A, Ringelstein BE, et al. Pain is associated with regional grey matter reduction in the general population. Pain. 2011;152:904–11. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? 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Brain morphometric changes in fibromyalgia and the impact of psychometric and clinical factors: a volumetric and diffusion-tensor imaging study

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Abstract

Background Previous studies have repeatedly found distinct brain morphometric changes in patients with fibromy- algia (FM), mainly affecting gray and white matter abnormalities in areas related to sensory and affective pain process- ing. However, few studies have thus far linked different types of structural changes and not much is known about behavioral and clinical determinants that might influence the emergence and progression of such changes. Methods We used voxel-based morphometry ( VBM) and diffusion-tensor imaging (DTI) to detect regional patterns of (micro)structural gray (GM) and white matter ( WM) alterations in 23 patients with FM compared to 21 healthy controls (HC), while considering the influence of demographic, psychometric, and clinical variables (age, symptom severity, pain duration, heat pain threshold, depression scores). Results VBM and DTI revealed striking patterns of brain morphometric changes in FM patients. Bilateral middle temporal gyrus (MTG), parahippocampal gyrus, left dorsal anterior cingulate cortex (dACC), right putamen, right caudate nucleus, and left dorsolateral prefrontal cortex (DLPFC) showed significantly decreased GM volumes. In con- trast, increased GM volume was observed in bilateral cerebellum and left thalamus. Beyond that, patients displayed microstructural changes of WM connectivity within the medial lemniscus, corpus callosum, and tracts surrounding and connecting the thalamus. Sensory-discriminative aspects of pain (pain severity, pain thresholds) primarily showed negative correlations with GM within bilateral putamen, pallidum, right midcingulate cortex (MCC), and multiple thalamic substructures, whereas the chronicity of pain was negatively correlated with GM volumes within right insular cortex and left rolandic operculum. Aec ff tive-motivational aspects of pain (depressive mood, general activity) were related to GM and FA values within bilateral putamen and thalamus. Conclusions Our results suggest a variety of distinct structural brain changes in FM, particularly affecting areas involved in pain and emotion processing such as the thalamus, putamen, and insula. Keywords Fibromyalgia, Pain, MRI, Brain morphometry, Voxel-based morphometry, Diffusion tensor imaging *Correspondence: Martin Diers martin.diers@rub.de Full list of author information is available at the end of the article © The Author(s) 2023. 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. Mosch et al. Arthritis Research & Therapy (2023) 25:81 Page 2 of 12 different pain-related structures. However, a variety of Introduction methodological differences should be considered when Fibromyalgia syndrome (hereinafter also referred to as comparing previous findings (e.g., data acquisition and “FM” for fibromyalgia) is a chronic pain disorder primar - analysis, heterogeneity of FM samples, different diag - ily characterized by widespread musculoskeletal pain that nostic criteria). Due to the diversity of symptoms expe- is oftentimes accompanied by a number of additional rienced in FM, it poses a special challenge to isolate the symptoms including cognitive, sleep and mood issues, specific effect that chronic pain has on patients’ brain fatigue, exhaustion, and an elevated risk for comorbidi- morphometry. ties [1, 2]. Patients with FM display an increased sensitiv- In this study, we explored morphometric GM and ity (lower pain thresholds/higher pain ratings) to various WM brain changes in FM compared to healthy controls pain modalities (thermal [3, 4], pressure [4, 5], electrical (HC) using magnetic resonance imaging (MRI) while [6, 7], chemical [8, 9]). This phenomenon usually involves considering the influence of various demographic, psy - allodynia (perceived pain due to a non-painful stimulus) chometric, behavioral, and clinical variables, involving and hyperalgesia (increased pain from a painful stimulus) age, symptom severity, pain duration, heat pain thresh- [10, 11]. old, and depression scores. We performed voxel-based The condition-specific combination of persistent physi - morphometry (VBM) on high-resolution T1-weighted ological, cognitive, and affective symptoms (listed above), MRI images in order to detect characteristic GM volu- along with continuous psychological distress, leads to a metric changes in FM. VBM is an analysis technique significant reported reduction of the perceived quality of that comprises a voxel-wise measurement of focal dif- life [12, 13] and is highly disabling. However, at the cur- ferences in local concentrations of brain tissue. FM- rent time, there is no universally recognized and effective specific WM changes were assessed using a diffusion treatment for FM and patients have a low probability of tensor imaging (DTI) sequence that utilizes anisotropic full recovery [14]. diffusion to estimate the WM (axonal) organization of The heterogeneity and quantity of FM symptoms have the brain. led to a candid debate about the etiology and pathophysi- We expected FM patients to display characteristic ological basis of the disorder, particularly concerning GM volumetric changes that have been reported in the neural background. Chronic pain disorders in gen- preceding investigation, primarily involving decreases eral have repeatedly been shown to be associated with in areas associated with pain and emotion processing, extensive structural, functional, and metabolic changes such as anterior cingulate cortex (ACC), amygdala, to the neural pain network of patients. In this context, parahippocampal gyrus, insula, and prefrontal corti- particularly pronounced structural gray (GM) and white ces, as well as increases within cerebellar structures matter (WM) alterations have also been demonstrated in [15, 19, 20, 22]. Additionally, we hypothesized that FM [15–20]. It is conceivable that the observed changes FM patients would exhibit distinct microstructural reflect cortical plasticity processes due to the chronically changes to their WM fibers, as continuous nociception increased nociceptive input. Previous studies on GM and related stress have been shown to affect specific volumetric outcomes have reported distinct alterations orientation-dependent aspects of WM connectiv- among FM patients, either in total volume [21, 22] or in ity [25, 26]. In view of our psychometric, behavioral, specific brain areas, such as the thalamus or cerebellum and clinical data, we expected pain severity, heat  pain [15, 17, 20]. On another note, several studies have found threshold, pain duration, depressive mood, and the the extent of GM decreases in chronic pain disorders to general activity level to be associated with morpholog- be depending on the previous pain duration as well as to ical brain changes in areas related to pain and emotion interact with the patients’ age [17, 22, 23]. processing. With regard to WM changes in FM, Lutz et  al. [19] demonstrated decreased fractional anisotropy (FA) Materials and methods in both thalami and insular regions, while reporting Participants increased FA, inter alia, in the amygdalae, hippocampi, Twenty-three female FM patients (aged 50.48 ± 9.89  years, and anterior cingulate gyri. Decreased FA of the right range 32 to 68 years) and twenty-one female HC subjects thalamus was also observed in a different study by Sund - (aged 46.62 ± 13.08  years, range 25 to 68  years) partici- gren et  al. [24]. More recent investigations by Kim et  al. pated in the study. A two-sample t-test showed no statisti- [25] and Ceko et al. [17] found reduced FA values inside cally significant age difference between groups (t (42) = 1.1, the corpus callosum, an area that is connected to bilateral p = 0.3). Left-handed persons, as assessed with the sensorimotor cortex [25]. Edinburgh Handedness Inventory [27], were excluded. As seen from the results listed above, structural brain FM diagnoses were obtained by medical professionals changes have been determined within a large number of M osch et al. Arthritis Research & Therapy (2023) 25:81 Page 3 of 12 Table 1 Demographic, psychometric, and clinical data for FM and HC FM HC M SD Range M SD Range Age (years) 50.5 9.9 32–68 46.6 13.1 28–68 Pain duration in years 14.9 11.8 2–44 CES-D 22.1 6.5 14–39 6.5 14–39 6–19 FIQ Physical functioning 1.4 0.6 0.2–2.4 Total 60.2 17.6 19–88.2 FSQ Symptom Severity Score 9.5 9.9 1–12 Widespread Pain Index 10.8 3.7 6–19 MPI Pain severity 4.0 15.8 6–19 Interference 4.1 1.3 0.7–5.7 Life control 3.4 1.3 0–6 Aec ff tive distress 3.4 1.5 0–5.7 Support 4.4 1.7 0–6 Punishing responses 1.3 1.3 0–5.3 Solicitous responses 3.8 1.8 0–6 Distracting responses 3.4 1.4 0–5.7 General activity level 7.2 2.4 2.6–11.5 FM fibromyalgia, HC healthy controls, M mean, SD standard deviation, CES-D Center for Epidemiologic Studies Depression Scale, FIQ Fibromyalgia Impact Questionnaire, FSQ Fibromyalgia Survey Questionnaire, MPI West Haven-Yale Multidimensional Pain Inventory and disorders fulfilled the criteria postulated by Wolfe Psychological questionnaire and physiological pain et  al. [2] (Fibromyalgia Survey Questionnaire (FSQ), threshold assessment see Table  1). FM patients were mainly recruited FM patients completed the West Haven-Yale Multidi- through social media support groups, whereas HC were mensional Pain Inventory (MPI) [29] (German version: recruited via newspaper announcements and face-to- Flor et  al. [30]), the Fibromyalgia Impact Questionnaire face acquisition at several blood donation events of the (FIQ-G) [31], and the Fibromyalgia Survey Question- German Red Cross. None of the tested participants naire (FSQ) [32]. In patients and controls, the presence had taken pain medication on the examination day. of depression symptoms was assessed using the CES-D Furthermore, opioid use had been suspended no later [33] (Center for Epidemiologic Studies Depression Scale; than 3  days prior to the MRI session (2 cases: 1 × fen- German version: ADS, Hautzinger and Bailer [34]). Addi- tanyl patches, 1 × tramadol). We also excluded users of tionally, the Edinburgh Handedness Inventory (EHI) [27] psychotropic medication, as well as psychotic patients was assessed. Table 1 presents the demographic, psycho- and patients with an acute major depression and bipolar metric, and clinical data for FM patients and HC. The disorder. Sixteen FM patients reported previous major structured clinical interview SKID-I [28] was conducted depressive episodes, four of whom also had a history of in all participants in order to rule out any acute mental generalized anxiety disorder and/or PTSD as assessed illness. with the structured clinical interview SKID-I [28]. None Individual heat pain thresholds were determined using of the HC reported current or past psychopathological a 3 × 3 cm contact thermode (PATHWAY Pain & Sensory symptoms. Evaluation System, Medoc Ltd. Advanced Medical Sys- The investigation took place at the Department of Neu - tem, Israel) and the software MEDOC Main Station 6.3. rology, Berufsgenossenschaftliches Universitätsklinikum Ascending thermal stimulation cycles were presented on Bergmannsheil, in Bochum between August 2019 and the participants’ left thenar and the mean value of the last December 2020 and was approved by the ethics review three out of five consecutive thresholds was calculated. board of the Medical Faculty Bochum, Ruhr University For heat  pain threshold, subjects were asked to stop the (15–5489). All participants gave written informed con- stimulation via a mouse button when they started per- sent prior to participating in the study. ceiving the stimulus as just painful. Mosch et al. Arthritis Research & Therapy (2023) 25:81 Page 4 of 12 Clinical and behavioral data analysis Voxel‑based morphometry: gray matter volume analysis Clinical data and behavioral measures were analyzed Group differences in local concentrations of brain tis - using SPSS Version 26 for Windows (IBM Corp., 2019). sue were assessed across the entire brain through voxel- Age in years, CES-D, and individual heat thresholds that based morphometry (VBM) which was implemented were determined prior to the experiment (see the “Psy- in SPM12 using CAT12. Segmented tissue class images chological questionnaire and physiological pain thresh- were created in spatial correspondence to the template old assessment” section) were compared between HC in MNI152NLin2009cAsym space. TIV was used as a and FM using two-sample t-tests. covariate during the analyses in order to correct for dif- ferent brain sizes. Age was also included as a covariate MRI data acquisition to take age-related gray matter changes into account. A MRI data were obtained on a Philips Achieva 3  T MRI two-sample t-test general linear model (GLM) was per- scanner using a 32-channel standard head coil, packed formed to assess brain volumetric differences between with foam pads for fixation purposes. A high-resolution HC and FM. We applied a cluster-level correction of Magnetization Prepared Rapid Gradient (MPRAGE), family-wise error (FWE) for multiple comparisons at a comprising 204 sagittal slices, was obtained for each threshold of p < 0.05. In consideration of previous VBM subject (TR = 6.98  ms, TE = 3.2  ms, flip angle 8°, 1 mm studies showing volumetric changes of specific brain voxel size, FOV 256 × 204 mm , acquisition time: 0.43 s). areas, we decided to perform further analyses using a less Diffusion-weighted images were acquired using a diffu - conservative uncorrected threshold of p < 0.001. sion-weighted spin-echo (DwiSE) sequence (TR = 6.4  s, 2 3 TE = 74.6  ms, b-value = 800  s/mm , 2 mm voxel size, Analysis of diffusion MRI data FOV = 224 × 120 mm , acquisition time: 0.49  s) along Diffusion MRI was used to examine group differences 32 diffusion encoding directions. Additionally, one of certain orientation-dependent aspects of brain tissue T2-weighted image with no diffusion (b = 0) was col- microstructure by analyzing the diffusion of water mol - lected. All volumes were manually angulated in parallel ecules. Diffusion MRI connectometry is a novel approach to the AC–PC line and adjusted to include all frontal, that allows tracking possible differences of WM tracts central, parietal, and occipital cortical areas as well as between groups as well as examining correlations of upper parts of the temporal cortex and the cerebellum. WM fibers with a variable of interest within the frame - work of a correlational tractography. Connectometry Regions of interest adopts a “tracking the correlation” paradigm that differs Relevant brain areas such as the thalamus, amygdala, fundamentally from the conventional DTI analysis para- putamen, pallidum, caudate nucleus, supplementary digm of finding the correlation between test variables motor area (SMA), middle temporal gyrus (MTG), cer- and tract parameters. Within this framework, we used ebellum, and insular, parahippocampal, prefrontal, FA as the diffusion index of interest. FA is a scalar vec - orbitofrontal, cingulate, and primary and secondary tor representing the directional selectivity of the random somatosensory (SI, SII) cortices were defined based on diffusion of water molecules, with higher FA pointing the automated anatomical labeling (AAL) atlas 3 [35]. towards highly anisotropic water diffusion (e.g., heav - ily myelinated tracts) [37]. As reported by Yeh et al. [38], Whole‑brain volumetric analysis diffusion MRI connectometry can be more sensitive than High-resolution structural MPRAGE images were seg- conventional voxel-wise FA or APC mapping. However, mented in SPM using the Computational Anatomy Tool- it should be noted beforehand that FA changes cannot be box CAT12 (Structural Brain Mapping group [36], Jena interpreted in a linear fashion as changes of WM connec- University Hospital, Jena, Germany; http:// dbm. neuro. tivity in a specific direction [39]. uni- jena. de/ cat/) (GM, WM, and cerebrospinal fluid The connectometry was performed using DSI Studio (CSF)), normalized to Montreal Neurological Institute (November 2020 build, Yeh et  al. [40], http:// dsi- studio. (MNI) standard space and smoothed with an isotropic labso lver. org). The b-table was examined using an auto - Gaussian kernel of 8 mm FWHM. Total intracranial vol- mated quality control routine to ensure its accuracy. Raw ume (TIV) was estimated as the sum of the three main diffusion data were motion and eddy-current corrected brain tissue volumes (GM, WM, and CSF). Whole-brain using DSI Studio’s built-in preprocessing routine which group comparisons of cerebrospinal fluid (CSF), GM, is based on FMRIB Software Library’s (FSL) correspond- and WM volumes as well as the total intracranial volume ing “eddy” tool. Corrected data were then reconstructed (TIV) were calculated in SPSS using two-sample inde- in the MNI space using Q-Space Diffeomorphic Recon - pendent t-tests (p < 0.05). struction (QSDR) [41, 42]. The transformed distribution M osch et al. Arthritis Research & Therapy (2023) 25:81 Page 5 of 12 was used to obtain the spin distribution function (SDF) as well as high scores of pain severity (MPI: 4.0 ± 15.8), with a diffusion sampling length ratio of 1.25. FM impact (FIQ: 60.2 ± 17.6), and depression (CES-D: A correlational group tractography between FA and 22.1 ± 6.5). The individual heat  pain threshold deter - group (HC: 0; FM: 1) was carried out to compare regional mined prior to the experiment revealed no significant FA values of HC and FM, using the participants’ age as a group differences between FM and HC, with a clear ten - covariate. Correlational tractography has been shown to dency towards lower values in FM (mean = 46.1) com- offer greater sensitivity than conventional tract- or voxel- pared to HC (mean = 46.9) (t(41) = 1.6, p = 0.09). based methods [40]. To map the different levels of corre - lation between the tracks and the group factor, different Whole‑brain volumetric changes in FM patients t-score thresholds of 2, 2.5, and 3 were used to visually CSF as well as WM volumes did not differ significantly study the tract-wise correlations at different cut-offs. between FM and HC (CSF: t(43) = 0.9, p = 0.18; WM: In this regard, each threshold can be viewed as a differ - t(42) = 0.13, p = 0.449). In contrast, GM volumes were ent hypothesis. High t thresholds will map tracks with a shown to be significantly reduced in FM (mean = 797 ± 48 3 3 stronger correlation effect, whereas lower t thresholds cm ) compared to HC (mean = 831 ± 61 cm ), t(40) = 2.1, will map tracks with a weak correlation [40]. Models with p = 0.021 (see Fig.  1). Apart from this, FM patients a t-score threshold of 2 and a length threshold of 20 vox- (mean = 1793 ± 63 cm ) also displayed significantly els yielded the strongest correlation while providing con- decreased TIV compared to HC (mean = 1842 ± 63 cm ), sistent results. The same parameters have been reported t(43) = 2.7, p = 0.011. in a variety of previous connectometry studies using DSI Studio [38, 40, 43]. Topology-informed pruning with Regional GM volumetric changes in FM patients 4 iterations was implemented to filter the tracks and a Group comparisons revealed FM-specific structural total of 4000 randomized permutations were applied to changes in a number of brain areas. When correcting for obtain the null distribution of the track length. As sug- multiple comparisons (p < 0.05, FWE corrected), patients gested by the developer, a highly confirmative thresh - displayed decreased GM volumes in the left temporal old of FDR = 0.05, corrected for the false discovery rate pole (of the superior (STG) and middle temporal gyrus (FDR), was used to select tracts on a whole-brain level (MTG)) and right MTG. Significantly increased GM through a deterministic fiber tracking algorithm [44] to reveal all subcomponents of the fascicles that are signifi - cantly associated to our study variable group (FM vs HC). Yeh et  al. [40] provide a detailed and complete descrip- tion of diffusion MRI connectometry and the underlying methodology. Correlations of VBM and DTI data with clinical and behavioral measures Regional relative GM volumes (corrected for different brain sizes) and FA values were correlated with demo- graphic, psychometric, behavioral, and clinical vari- ables using Pearson’s correlation coefficient (r) and a significance level of p < 0.05 in SPSS. In this analysis, we focused on brain regions that have displayed morpho- metric changes in our preceding analyses. The analyzed variables comprised three categories: (1) sensory-dis- criminative aspects of pain perception: pain severity (MPI) and heat pain threshold; (2)] chronicity: pain dura- tion; (3) affective-motivational aspects of pain: depressive mood (CES-D) and the general activity level (MPI) (see Table 1). Fig. 1 Whole-brain group comparisons of brain tissues (CSF, GM, and WM). Bar charts of the mean CSF, GM, and WM whole-brain tissue Results volumes (cm. ) for HC and FM. Individual GM mean values for each participant are indicated by black dots. CSF, cerebrospinal fluid; GM, Clinical and behavioral characteristics of the participants gray matter; WM, white matter; HC, healthy controls; FM, patients with FM patients reported longstanding disease with a mean fibromyalgia; n.s., not significant; *p < .05 pain duration of 14.9 (± 11.8; range 2 to 44  years) years Mosch et al. Arthritis Research & Therapy (2023) 25:81 Page 6 of 12 Table 2 Brain regions showing significantly decreased or increased GM volume in FM compared to HC (p < 0.05, FWE corrected) MNI coordinates Comparison Laterality x y z Cluster size (voxel) Z score Brain region HC > FM Temporal pole (STG/ L − 36 14 − 27 193 4.8 MTG) MTG R 54 − 60 6 365 4.7 FM > HC Cerebellum R 27 − 80 − 38 2036 4.9 26 − 48 − 26 191 3.8 L − 23 − 78 − 35 1489 4.7 STG superior temporal gyrus, MTG middle temporal gyrus, L left, R right, voxel size: 2.3 × 2.3 × 2.3 mm Fig. 2 Brain regions with increased or decreased GM volumes in FM compared to HC. Structures that showed increased GM volume in FM are depicted in blue. Decreased GM volume is illustrated in red. A Axial and sagittal sectional images of the relevant clusters showing group differences. B 3D rendered illustration of the clusters. L, left; R, right; P, posterior; A, anterior; MTG, middle temporal gyrus. p(FWE) < .05 volume was found in major clusters within the bilateral in FM compared to HC involved left SMA, left thalamus, cerebellum (Table 2 and Fig. 2). and right putamen (see Table S1). Using a less conservative threshold (p < 0.001 uncor- rected), we found a number of additional regional volu- DTI connectometry results metric changes in FM. This involved decreased GM One FM patient was excluded due to insufficient DTI volumes in left MTG, right fusiform gyrus, parahip- data quality. Correlational group tractography for HC and pocampal gyrus, orbitofrontal cortex (OFC), right pre- FM revealed several tracts in which FA values were nega- central cortex, right SMA, left dorsal anterior cingulate tively correlated with the group parameter, indicating cortex (dACC), right putamen, right caudate nucleus, decreased FA and thus orientation-dependent changes and left dorsolateral prefrontal cortex. On the other to regional WM connectivity in FM (FDR < 0.05). These hand, further brain areas showing increased GM volumes tracts involved left corticospinal tract, bilateral fornix, right corticospinal tract, bilateral superior corticostriatal M osch et al. Arthritis Research & Therapy (2023) 25:81 Page 7 of 12 tract, left cerebellum, right superior thalamic radiation, chronicity showed negative correlations with FA values left arcuate fasciculus, left dentato-rubro-thalamic tract, within the left insular cortex (r = − 0.53, p = 0.036) and and bilateral medial lemniscus and middle cerebellar multiple cerebellar lobules (Crus I, Crus II, Cerebellum peduncle. 3 and 6; correlation coefficients r from − 0.51 to − 0.64, On the other hand, a number of tracks displayed posi- p-values from 0.045 to 0.007). tive correlations with the group parameter, indicating Regarding affective-motivational aspects, depressive increased FA in FM. Such correlations were found in mood was negatively correlated with GM volumes of left right parolfactory cingulum, bilateral cerebellum, tape- putamen (CES-D: r = − 0.31, p = 0.043), while the MPI tum corporis callosi, forceps major and minor of the scale of the general activity level was positively corre- corpus callosum, and right inferior fronto-occipital fas- lated with the structure (r = 0.39, p = 0.033). Furthermore, ciculus. WM tracts showing significant correlations with FA within the left MCC was positively correlated with the group factor are illustrated in Fig. 3. CES-D scores (r = 0.31, p = 0.048) and bilateral FA values in the amygdala were positively correlated with the MPI Correlations with clinical and behavioral measures scale of the general activity level (L: r = 0.45, p = 0.043; R: Regarding sensory-discriminative aspects of pain percep- r = 0.5, p = 0.021). tion, the MPI scale of pain severity was negatively corre- lated with FA values of multiple thalamic substructures, Discussion including ventral posterolateral as well as pulvinar ante- The primary aim of the present investigation was to rior, pulvinar medial, pulvinar lateral, and pulvinar infe- explore the precise form and extent of structural GM and rior thalamus (correlation coefficients r from 0.44 to 0.62, WM changes related to FM as well as to explore possible p-values from 0.048 to 0.003) (see Fig.  4). Additionally, correlations with clinical and behavioral measures. Group the individual pain thresholds were negatively correlated comparisons in fact demonstrated striking patterns of with GM volumes of the right middle cingulate cortex brain morphometric changes in FM patients compared (MCC) (r = − 0.31, p = 0.039), bilateral posterior cingu- to HC. In our initial analysis, we found whole-brain GM late cortex (PCC) (L: r = − 0.3, p = 0.046; R: r = − 0.38, volumes as well as TIV to be significantly decreased in p = 0.01), and cerebellar lobule Crus II (r = − 0.32, FM compared to HC. Similar findings have emerged in p = 0.037) as well as FA values of bilateral insula (L: previous studies (e.g., Kuchinad et  al. [22]) and support r = − 0.39, p = 0.01; R: r = − 0.34; p = 0.029), right MCC the notion of premature brain aging in patients with FM. (r = − 0.36, p = 0.02), left amygdala (r = − 0.37, p = 0.016), right putamen (r = − 0.35, p = 0.024) and multiple cer- Voxel‑based morphometry ebellar lobules (right Crus I, Crus II, Cerebellum 7b and In addition to these general changes, we were particularly 9; correlation coefficients r from − 0.31 to − 0.41, p-values interested in the specific brain areas affected by the mor - from 0.045 to 0.01). phometric changes. For this purpose, we performed a Concerning the chronicity, the duration of pain symp- VBM analysis that revealed distinct regional GM changes toms was negatively correlated with GM volumes of the in our FM group. The most profound GM alterations right insular cortex (r = − 0.43, p = 0.037) as well as left were detected in the bilateral cerebellum. Increased cer- rolandic operculum (r = − 0.5, p = 0.017) and positively ebellar GM volume related to FM has been demonstrated correlated with right MCC (r = 0.41, p = 0.046). Moreover, in previous studies [45, 46]. Although the cerebellum Fig. 3 Correlational group tractography results. Comparison between fractional anisotropy (FA) positively (red) and negatively (blue) associated with the group parameter. t threshold: 2; length threshold: 20 voxels; permutation count: 4000, pruning iterations: 4; FDR < .05 Mosch et al. Arthritis Research & Therapy (2023) 25:81 Page 8 of 12 Fig. 4 Brain regions that showed a significant correlation of GM or FA with behavioral/clinical data. Solid lines: correlations with GM volume; dashed lines: correlations with FA values; red lines: negative correlations; blue lines: positive correlations; AMG, amygdala; MCC, middle cingulate cortex; PCC, posterior cingulate cortex; SII, secondary somatosensory cortex; PU, putamen; PA, pallidum plays a rather subordinate role in pain research, the area functional connectivity of the area) was found to be asso- has repeatedly been shown to be an inherent part of the ciated with dysfunctional pain-related control processes pain processing network and is strongly interconnected and increased anticipatory anxiety [53, 57]. with the cerebral cortex [47, 48]. Beyond that, Kim et al. Most of the brain regions showing altered GM vol- [49] compared FM and HC using covariance network umes when adopting a less conservative threshold of analysis and found denser connections in the cerebellum p < 0.001 are significant components of the neu - uncorr. as well as weaker connections in the frontal lobe of FM ral pain network, some of which have previously been patients. The present study identified the most exten - demonstrated to be reduced in FM. More precisely, sive abnormalities in Cerebellar lobules VIIb and Crus decreased GM volume or density has been reported in II, which are known to be associated with higher-order parahippocampal gyrus [22, 58], prefrontal cortex, and processes (e.g., executive, emotional, and cognitive) and ACC [15, 17, 20]. As all of these structures are related lobule VIII, which is related to sensorimotor functions to stress (parahippocampal gyrus) and pain processing, [50, 51]. the observed changes might well be consequences of a Adopting a relatively conservative FWE correction for long-term exposure to these symptoms. It should also be multiple comparisons, we demonstrated significantly noted that prefrontal and cingulate cortices are generally decreased GM volumes of the left temporal pole (STG/ ascribed pain modulatory and analgesic functions. Thus, MTG) and right MTG in FM. Decreased GM volume of GM atrophy in such areas could contribute to the main- the left MTG has recently been found by Sundermann tenance of chronic pain symptoms in FM. et al. [52] in patients with FM and osteoarthritis. Accord- ingly, it may be argued that the group differences reported Diffusion MRI connectometry analysis above could be related to chronic pain in general, rather FA is a parameter reflecting the directionality of water than FM in particular. In this regard, decreased GM vol- diffusion, or rather the degree to which the diffusion var - ume of the MTG has also been observed in patients with ies in different directions. However, due to a number of migraine [53], chronic myofascial pain [54], and trigemi- possible confounders contributing to metrics like FA, nal neuralgia [55]. Intriguingly, the area has recently been differences in scalar diffusion measures such as FA can - hypothesized to play a key role in redirecting attention not be interpreted linearly as WM connectivity changes away from pain and keeping involuntary thoughts about into a specific direction [39] (e.g., lower FA = low con- pain out of awareness [56]. In view of this, it is hardly nectivity/tissue damage). Hereinafter, we therefore avoid surprising that decreased MTG volume (and altered making statements as to whether the observed changes M osch et al. Arthritis Research & Therapy (2023) 25:81 Page 9 of 12 amount, e.g., to possible decreases in WM integrity. FM between GM volume of the right insular cortex Nevertheless, the regional microstructural WM group and the chronicity/duration of pain symptoms. This differences we detected provide valuable information finding is in line with a number of previous investiga - about which areas and tracts show the most pronounced tions that reported a pronounced reduction of insular changes in FM. volume related to persisting chronic pain [68, 69]. GM To begin with, FM displayed decreased FA in bilateral volume of the left putamen was negatively associated medial lemniscus (also known as Reil’s band), a major with depressive symptoms, validating the previously ascending pathway consisting of heavily myelinated postulated importance of the putamen in depressive axons that is known to transmit tactile and propriocep- disorders. In this context, Sacchet et  al. [70] reported tive information from the skin and joints to the thalamus greater age-related volumetric decreases in the struc- and somatosensory cortex. In this way, the medial lem- ture in patients with major depressive disorder. Con- niscus plays a crucial role for processing of conscious sistently, we found GM volume of bilateral putamen to proprioception, fine touch, and 2-point discrimination. be positively correlated with the general activity level, Interestingly, FM patients have previously been found representing an opposite pole to decreased activity lev- to show disruptions in all of these fields. For instance, els that can typically be observed in depressive disor- FM has been linked to postural balance disorders and ders. Accordingly, affective-motivational components abnormalities of the proprioceptive system [59–61]. An of pain likewise play a decisive role in regard to the example for altered sensations of fine touch in FM is the observed structural changes. This is further validated phenomenon of allodynia, a heightened sensitivity to through the involvement of bilateral amygdala, which non-nociceptive stimuli [62, 63]. Only recently, soma- demonstrated FA positively correlated with the general tosensory temporal discrimination (STD), a measure activity level. Intriguingly, FA values of multiple pain- for two-point discrimination, has been shown to be sig- related ROIs were negatively correlated with the indi- nificantly prolonged in FM (in all extremities) [64]. The vidual heat  pain threshold, including bilateral insula, described findings clearly match the microstructural left amygdala, right MCC, right putamen, and multiple changes of WM connectivity (decreased FA) we found cerebellar lobules. Accordingly, increased pain sensitiv- within the medial lemniscus of FM patients. ity was found to be associated with greater FA within Interestingly, decreased FA was also found along tracts the examined ROIs of the pain network. surrounding and connecting the thalamus, such as tha- lamic radiation and dentato-rubro-thalamic tracts, indi- cating changes to the area’s WM connectivity. This is of Limitations particular interest, as the thalamus is widely known to be As noted earlier, some methodological characteristics of critically involved in distributing and processing nocicep- this study need to be considered when interpreting the tive information. results. In this regard, the informative value of diffusion Further, a number of white matter tracts showing sig- indices such as FA is a critical factor. Regional anisotropy nificantly increased FA in FM were located in and around can be influenced by a number of confounding variables the corpus callosum (tapetum corporis callosi, forceps (e.g., axon diameter, packing density, and number of major, and forceps minor of the corpus callosum), an axons) [71]. Due to these and other reasons, differences area that is known to be strongly connected to bilat- in FA indicate some form of change to microstructural eral sensorimotor cortex. Similar reductions of local FA WM connectivity, but cannot be linearly interpreted as values within the corpus callosum in FM have recently WM integrity changes into a certain direction [39]. How- been described by Tu et al. [65] and Aster et al. [66]. On ever, we have attempted to circumvent this issue through another note, the area is widely known to mediate inter- our cautious interpretation of the findings. hemispheric transfer [67]. u Th s, microstructural changes Another limitation that should be mentioned is associ- to the corpus callosum might consequently indicate a sig- ated to the ROI-wise approach we have picked to inves- nificant change to interhemispheric connectivity. tigate the relationship of regional brain morphometry and behavioral measures. Arguably, this procedure can Behavioral and clinical measures in some cases lead to partial volume effects. However, we Pain severity scores were negatively correlated with FA have decided to implement a ROI-wise approach, in addi- values in several thalamic substructures. These find - tion to our WM tractography, as similar approaches have ings underline the significance of the observed changes been used in numerous investigations on chronic pain on in close relation with sensory-discriminative aspects which we have based our study design thematically and of pain, such as the reported pain severity. On another methodically [17, 19, 24, 72]. Furthermore, we found a note, we observed a significant negative correlation in ROI-wise approach to be the most suitable way for us to Mosch et al. Arthritis Research & Therapy (2023) 25:81 Page 10 of 12 M.D. discussed the results and commented on the manuscript. The authors investigate the correlations described above, as our goal read and approved the final manuscript. was to explore possible associations of different regional microstructural characteristics with behavioral and clini- Funding Open Access funding enabled and organized by Projekt DEAL. We acknowl- cal data. The consistent ROI-wise approach entails com - edge support by the Open Access Publication Funds of the Ruhr University parability of regional GM volumetric and diffusion data. Bochum. This work was supported by the Deutsche Forschungsgemeinschaft In general, our investigation was designed as an initial (DFG) (DI1553/5). exploration of the topic described above, providing clues Availability of data and materials to plan possible follow-up studies. This context explains Further information and requests for resources and reagents should be our exploratory approach and should also be taken into directed to and will be fulfilled by the lead contact, Martin Diers (martin. diers@rub.de). account when interpreting the results. Declarations Conclusions The described findings delineate major structural brain Ethics approval and consent to participate changes in FM, affecting large parts of the neural pain The study was approved by the ethics review board of the Medical Faculty Bochum, Ruhr University (15–5489). All participants gave written informed network. Arguably, some of the most distinct FM-related consent prior to participating in the study. regional morphometric changes were found in the thala- mus, putamen, and insula, involving significantly reduced Consent for publication Not applicable. FA values that were related to the subjectively perceived pain severity as well as GM decreases. However, such Competing interests morphometric changes have repeatedly been shown to be The authors declare no competing interests. reversible after cessation of pain [73, 74] and might rep- Author details resent a temporary consequence of chronic nociceptive Clinical and Experimental Behavioral Medicine, Alexandrinenstraße 1–3, input, rather than permanent brain damage. This is also 44791 Bochum, Germany. Department of Psychosomatic Medicine and Psy- chotherapy, LWL University Hospital, Ruhr University Bochum, Alexandrinen- supported by the fact that we found positive correlations straße 1-3, 44791 Bochum, Germany. of GM in bilateral putamen with the general activity level, which could serve as an example for possible control Received: 8 December 2022 Accepted: 7 May 2023 strategies to reverse maladaptive neural changes. Abbreviations References AAL Automatic anatomical labeling atlas 1. Rehm SE, Koroschetz J, Gockel U, Brosz M, Freynhagen R, Tolle TR, et al. CSF Cerebrospinal fluid A cross-sectional survey of 3035 patients with fibromyalgia: subgroups DTI Diffusion-tensor imaging of patients with typical comorbidities and sensory symptom profiles. FA Fractional anisotropy Rheumatology. 2010;49:1146–52. FDR False discovery rate 2. Wolfe F, Clauw DJ, Fitzcharles M-A, Goldenberg DL, Häuser W, Katz RL, FM Fibromyalgia et al. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. FWE Family-wise error Semin Arthritis Rheum. 2016;46:319–29. GM Gray matter 3. Cook DB, Lange G, Ciccone DS, Wen-Ching L, Steffener J, Natelson BH. HC Healthy controls Functional imaging of pain in patients with primary fibromyalgia. J Rheu- MRI Magnetic resonance imaging matol. 2004;31:364–78. ROI Region of interest 4. Petzke F, Clauw DJ, Ambrose K, Khine A, Gracely RH. Increased pain sensi- TIV Total intracranial volume tivity in fibromyalgia: effects of stimulus type and mode of presentation. VBM Voxel-based morphometry Pain. 2003;105:403–13. WM White matter 5. Diers M, Yilmaz P, Rance M, Thieme K, Gracely RH, Rolko C, et al. Treat- ment-related changes in brain activation in patients with fibromyalgia syndrome. Exp Brain Res. 2012;218:619–28. Supplementary Information 6. Diers M, Koeppe C, Yilmaz P, Thieme K, Markela-Lerenc J, Schiltenwolf The online version contains supplementary material available at https:// doi. M, et al. Pain ratings and somatosensory evoked responses to repetitive org/ 10. 1186/ s13075- 023- 03064-0. intramuscular and intracutaneous stimulation in fibromyalgia syndrome. J Clin Neurophysiol. 2008;25:153–60. Additional file 1: Table S1. Brain regions showing significantly greater 7. Sörensen J, Graven-Nielsen T, Henriksson KG, Bengtsson, Arendt-Nielsen GM volume in HC compared to FM and vice versa (p ≤ 0.001 uncorrected). L. Hyperexcitability in Fibromyalgia. J Rheumatol. 1998;25:152–5. 8. Diers M, Schley MT, Rance M, Yilmaz P, Lauer L, Rukwied R, et al. Differen- tial central pain processing following repetitive intramuscular proton/ Acknowledgements prostaglandin E2 injections in female fibromyalgia patients and healthy None. controls. Eur J Pain. 2011;15:716–23. 9. Morris V, Cruwys S, Kidd B. Increased capsaicin-induced secondary Authors’ contributions hyperalgesia as a marker of abnormal sensory activity in patients with M.D. designed the research; B.M. performed the research and analyzed the MRI fibromyalgia. Neurosci Lett. 1998;250:205–7. data; B.M. and M.D. conducted the statistical analysis; B.M., V.H., S.H., and M.D. 10. Clauw DJ, Arnold LM, McCarberg BH. The Science of Fibromyalgia. Mayo interpreted the results; B.M. and M.D. wrote the article; and B.M., V.H., S.H., and Clin Proc. 2011;86:907–11. M osch et al. Arthritis Research & Therapy (2023) 25:81 Page 11 of 12 11. Henriksson K. Fibromyalgia - from syndrome to disease. Overview of 35. Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, pathogenetic mechanisms. J Rehabil Med. 2003;35:89–94. Delcroix N, et al. Automated Anatomical Labeling of Activations in SPM 12. Gormsen L, Rosenberg R, Bach FW, Jensen TS. Depression, anxiety, health- Using a Macroscopic Anatomical Parcellation of the MNI MRI Single- related quality of life and pain in patients with chronic fibromyalgia and Subject Brain. Neuroimage. 2002;15:273–89. neuropathic pain. Eur J Pain. 2010;14:127.e1-127.e8. 36. Gaser C, Dahnke R. CAT - A Computational Anatomy Toolbox for the 13. Verbunt JA, Pernot DH, Smeets RJ. Disability and quality of life in patients Analysis of Structural MRI Data. 2020. Available from: http:// www. neuro. with fibromyalgia. Health Qual Life Outcomes. 2008;6:8.uni- jena. de/ cat/. 14. Bengtsson A, Bäckman E, Lindblom B, Skogh T. Long term follow-up of 37. Kochunov P, Williamson DE, Lancaster J, Fox P, Cornell J, Blangero J, et al. fibromyalgia patients: clinical symptoms, muscular function, laboratory Fractional anisotropy of water diffusion in cerebral white matter across tests-an eight year comparison study. J Musculoskelet Pain. 1994;2:67–80. the lifespan. Neurobiol Aging. 2012;33:9–20. 15. Burgmer M, Gaubitz M, Konrad C, Wrenger M, Hilgart S, Heuft G, et al. 38. Yeh F-C, Tang P-F, Tseng W-YI. Diffusion MRI connectometry automati- Decreased gray matter volumes in the cingulo-frontal cortex and the cally reveals affected fiber pathways in individuals with chronic stroke. amygdala in patients with fibromyalgia. Psychosom Med. 2009;71:566–73. NeuroImage Clin. 2013;2:912–21. 16. Cauda F, Palermo S, Costa T, Torta R, Duca S, Vercelli U, et al. Gray matter 39. Jones DK, Knösche TR, Turner R. White matter integrity, fiber count, alterations in chronic pain: a network-oriented meta-analytic approach. and other fallacies: The do’s and don’ts of diffusion MRI. Neuroimage. NeuroImage Clin. 2014;4:676–86. 2013;73:239–54. 17. Ceko M, Bushnell MC, Fitzcharles M-A, Schweinhardt P. Fibromyalgia 40. Yeh F-C, Badre D, Verstynen T. Connectometry: a statistical approach interacts with age to change the brain. NeuroImage Clin. 2013;3:249–60. harnessing the analytical potential of the local connectome. Neuroimage. 18. Diaz-Piedra C, Guzman MA, Buela-Casal G, Catena A. The impact of 2016;125:162–71. fibromyalgia symptoms on brain morphometry. Brain Imaging Behav. 41. Yeh F-C, Wedeen VJ, Tseng W-YI. Estimation of fiber orientation and spin den- 2016;10:1184–97. sity distribution by diffusion deconvolution. NeuroImage. 2011;55:1054–62. 19. Lutz J, Jäger L, de Quervain D, Krauseneck T, Padberg F, Wichnalek M, 42. Yeh F-C, Tseng W-YI. NTU-90: A high angular resolution brain atlas et al. White and gray matter abnormalities in the brain of patients with constructed by q-space diffeomorphic reconstruction. NeuroImage. fibromyalgia: a diffusion-tensor and volumetric imaging study. Arthritis 2011;58:91–9. Rheum. 2008;58:3960–9. 43. Hodgdon EA, Courtney KE, Yan M, Yang R, Alam T, Walker JC, et al. White 20. Robinson ME, Craggs JG, Price DD, Perlstein WM, Staud R. Gray matter matter integrity in adolescent irritability: a preliminary study. Psychiatry volumes of pain-related brain areas are decreased in fibromyalgia Res Neuroimaging. 2022;324:111491. syndrome. J Pain. 2011;12:436–43. 44. Yeh F-C, Verstynen TD, Wang Y, Fernández-Miranda JC, Tseng W-YI. Deter- 21. Jensen KB, Srinivasan P, Spaeth R, Tan Y, Kosek E, Petzke F, et al. ministic diffusion fiber tracking improved by quantitative anisotropy. Overlapping structural and functional brain changes in patients with PLoS ONE. 2013;8:e80713. long-term exposure to fibromyalgia pain: brain changes in long-term 45. Schmidt-Wilcke T, Luerding R, Weigand T, Jürgens T, Schuierer G, Leinisch fibromyalgia. Arthritis Rheum. 2013;65:3293–303. E, et al. Striatal grey matter increase in patients suffering from fibromyal- 22. Kuchinad A, Schweinhardt P, Seminowicz DA, Wood PB, Chizh BA, Bush- gia – a voxel-based morphometry study. Pain. 2007;132:S109–16. nell MC. Accelerated brain gray matter loss in fibromyalgia patients: 46. Shi H, Yuan C, Dai Z, Ma H, Sheng L. Gray matter abnormalities associated premature aging of the brain? J Neurosci. 2007;27:4004–7. with fibromyalgia: a meta-analysis of voxel-based morphometric studies. 23. Apkarian AV. Chronic back pain is associated with decreased prefrontal Semin Arthritis Rheum. 2016;46:330–7. and thalamic gray matter density. J Neurosci. 2004;24:10410–5. 47. Diano M, D’Agata F, Cauda F, Costa T, Geda E, Sacco K, et al. Cerebellar 24. Sundgren PC, Petrou M, Harris RE, Fan X, Foerster B, Mehrotra N, et al. clustering and functional connectivity during pain processing. Cerebel- Diffusion-weighted and diffusion tensor imaging in fibromyalgia lum. 2016;15:343–56. patients: a prospective study of whole brain diffusivity, apparent 48. Moulton EA, Schmahmann JD, Becerra L, Borsook D. The cerebellum and diffusion coefficient, and fraction anisotropy in different regions pain: passive integrator or active participator? Brain Res Rev. 2010;65:14–27. of the brain and correlation with symptom severity. Acad Radiol. 49. Kim H, Kim J, Loggia ML, Cahalan C, Garcia RG, Vangel MG, et al. Fibromy- 2007;14:839–46. algia is characterized by altered frontal and cerebellar structural covari- 25. Kim DJ, Lim M, Kim JS, Son KM, Kim HA, Chung CK. Altered white mat- ance brain networks. NeuroImage Clin. 2015;7:667–77. ter integrity in the corpus callosum in fibromyalgia patients identi- 50. Stoodley CJ, Valera EM, Schmahmann JD. Functional topography of the fied by tract-based spatial statistical analysis: abnormal white matter cerebellum for motor and cognitive tasks: An fMRI study. Neuroimage. integrity in fibromyalgia. Arthritis Rheumatol. 2014;66:3190–9. 2012;59:1560–70. 26. May A. Chronic pain may change the structure of the brain. Pain. 51. Stoodley C, Schmahmann J. Functional topography in the human 2008;137:7–15. cerebellum: a meta-analysis of neuroimaging studies. Neuroimage. 27. Oldfield RC. The assessment and analysis of handedness: The Edin- 2009;44:489–501. burgh Inventory. Neuropsychologia. 1971;9:97–113. 52. Sundermann B, Dehghan Nayyeri M, Pfleiderer B, Stahlberg K, Jünke L, 28. Wittchen HU, Wunderlich U, Gruschwitz S, Zaudig M. SKID I. Strukturi- Baie L, et al. Subtle changes of gray matter volume in fibromyalgia reflect ertes Klinisches Interview für DSM-IV. Achse I: Psychische Störungen. chronic musculoskeletal pain rather than disease-specific effects. Eur J Interviewheft und Beurteilungsheft. Eine deutschsprachige, erweiterte Neurosci. 2019;50:3958–67. Bearb. d. amerikanischen Originalversion des SKID I. Göttingen: 53. Coppola G, Petolicchio B, Di Renzo A, Tinelli E, Di Lorenzo C, Parisi V, et al. Hogrefe; 1997. Cerebral gray matter volume in patients with chronic migraine: correla- 29. Kerns RD, Turk DC, Rudy TE. The West Haven-Yale Multidimensional Pain tions with clinical features. J Headache Pain. 2017;18:115. Inventory ( WHYMPI). Pain. 1985;23:345–56. 54. Niddam DM, Lee S-H, Su Y-T, Chan R-C. Brain structural changes in 30. Flor H, Rudy TE, Birbaumer N, Streit B, Schugens MM. Zur Anwendbarkeit patients with chronic myofascial pain. Eur J Pain. 2017;21:148–58. des West Haven-Yale Multidimensional Pain Inventory im deutschen 55. Li M, Yan J, Li S, Wang T, Zhan W, Wen H, et al. Reduced volume of gray Sprachraum. Schmerz. 1990;4:82–7. matter in patients with trigeminal neuralgia. Brain Imaging Behav. 31. Oenbaecher M, ff Waltz M, Schoeps P. Validation of a German ver - 2017;11:486–92. sion of the Fibromyalgia Impact Questionnaire (FIQ-G). J Rheumatol. 56. Kucyi A, Salomons TV, Davis KD. Cognitive behavioral training 2000;27:1984–8. reverses the effect of pain exposure on brain network activity. Pain. 32. Häuser W, Jung E, Erbslöh-Möller B, Gesmann M, Kühn-Becker H, Peter- 2016;157:1895–904. mann F, et al. Validation of the Fibromyalgia Survey Questionnaire within 57. Yun J-Y, Kim J-C, Ku J, Shin J-E, Kim J-J, Choi S-H. The left middle temporal a cross-sectional survey. PLoS ONE. 2012;7:e37504. gyrus in the middle of an impaired social-affective communication 33. Radloff LS. The CES-D Scale: a self-report depression scale for research in network in social anxiety disorder. J Aec ff t Disord. 2017;214:53–9. the general population. Appl Psychol Meas. 1977;1:385–401. 58. Wood PB, Glabus MF, Simpson R, Patterson JC 2nd. Changes in gray mat- 34. Hautzinger M, Bailer M. Allgemeine Depressionsskala (ADS) [General ter density in fibromyalgia: correlation with dopamine metabolism. J Pain. Depression Scale]. Weinheim: Beltz Test GmbH; 1993. 2009;10:609–18. Mosch et al. Arthritis Research & Therapy (2023) 25:81 Page 12 of 12 59. Akkaya N, Akkaya S, Atalay NS, Acar M, Catalbas N, Sahin F. Assessment of the relationship between postural stability and sleep quality in patients with fibromyalgia. Clin Rheumatol. 2013;32:325-31. 60. Gucmen B, Kocyigit BF, Nacitarhan V, Berk E, Koca T, Akyol A. The relation- ship between cervical proprioception and balance in patients with fibromyalgia syndrome. Rheumatol Int. 2022;42:311-8. 61. Núñez-Fuentes D, Obrero-Gaitán E, Zagalaz-Anula N, Ibáñez-Vera AJ, Achalandabaso-Ochoa A, López-Ruiz M del C, et al. Alteration of postural balance in patients with fibromyalgia syndrome—a systematic review and meta-analysis. Diagnostics. 2021;11:127. 62. Arendt-Nielsen L, Graven-Nielsen T. Central sensitization in fibromy- algia and other musculoskeletal disorders. Curr Pain Headache Rep. 2003;7:355–61. 63. Staud R, Domingo M. Evidence for abnormal pain processing in fibromy- algia syndrome. Pain Med. 2001;2:208–15. 64. Tertemiz OF, Tepe N. Is two-point discrimination test a new diagnostic method for the diagnosis of fibromyalgia? Arch Neuropsychiatry [Inter - net]. 2020 [cited 2022 Jul 21]; Available from: http:// submi ssion. norop sikiy atria rsivi. com/ defau lt. aspx?s= publi c~kabul & mId= 27245. 65. Tu Y, Wang J, Xiong F, Gao F. Disrupted white matter microstructure in patients with fibromyalgia owing predominantly to psychological factors: a diffusion tensor imaging study. Pain Physician. 2022;25. 66. Aster H-C, Evdokimov D, Braun A, Üçeyler N, Kampf T, Pham M, et al. CNS imaging characteristics in fibromyalgia patients with and without periph- eral nerve involvement. Sci Rep. 2022;12:6707. 67. van der Knaap LJ, van der Ham IJM. How does the corpus callo- sum mediate interhemispheric transfer? A review. Behav Brain Res. 2011;223:211–21. 68. Baliki MN, Schnitzer TJ, Bauer WR, Apkarian AV. Brain morphological signa- tures for chronic pain. PLoS ONE. 2011;6:e26010. 69. Geha PY, Baliki MN, Harden RN, Bauer WR, Parrish TB, Apkarian AV. The brain in chronic CRPS pain: abnormal gray-white matter interactions in emotional and autonomic regions. Neuron. 2008;60:570–81. 70. Sacchet MD, Camacho MC, Livermore EE, Thomas EAC, Gotlib IH. Acceler- ated aging of the putamen in patients with major depressive disorder. J Psychiatry Neurosci. 2017;42:164–71. 71. Takahashi M, Hackney DB, Zhang G, Wehrli SL, Wright AC, O’Brien WT, et al. Magnetic resonance microimaging of intraaxonal water diffusion in live excised lamprey spinal cord. Proc Natl Acad Sci. 2002;99:16192–6. 72. Szabó N, Kincses ZT, Párdutz Á, Tajti J, Szok D, Tuka B, et al. White matter microstructural alterations in migraine: a diffusion-weighted MRI study. Pain. 2012;153:651–6. 73. Rodriguez-Raecke R, Niemeier A, Ihle K, Ruether W, May A. Brain gray matter decrease in chronic pain is the consequence and not the cause of pain. J Neurosci. 2009;29:13746–50. 74. Ruscheweyh R, Deppe M, Lohmann H, Stehling C, Flöel A, Ringelstein BE, et al. Pain is associated with regional grey matter reduction in the general population. Pain. 2011;152:904–11. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? 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Journal

Arthritis Research & TherapySpringer Journals

Published: May 19, 2023

Keywords: Fibromyalgia; Pain; MRI; Brain morphometry; Voxel-based morphometry; Diffusion tensor imaging

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